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qtjf0226

qtjf0226_p3, qtjf0226_p4, qtjf0226_p5, qtjf0226_p6, qtjf0226_p7

august 1, 2002, August 1, 2002

Task Notes Lead Responsibility Due Date 4. PEDIATRIC STUDIES (CONTINUED) Evaluate data from Actos 507 Evaluate data to support Amy Hagaman August 5 justification to proceed with Actos 508 Develop additional monitoring Amy Hagaman plan for Actos 508 Evaluate feasibility/business T. Muldoon case of request to FDA to M Ramstack delay start of Actos 508 pending Actos 506 data; 1 Haskins assess impact on pediatric exclusivity/patent Draft justification for Actos 508 Justification should be Amy Hagaman/Alfonso August 12 based on rebuttal of FDA Perez hypothesis regarding mechanism of action for bladder cancer and addition of clinical monitoring plan to protocol Last Update: August 1, 2002 Page 3 of 7 Confidential-Subject to Protective Order - TAK-THOMCL 00032212 Produced in MDL on 02/21/13 Source: https://www.indup3d8-00004ts.ucsf.edu/docs/qtjf0226 Task Notes Lead Responsibility Due Date 5A. NONCI INICAL/REVIEW OF TOX DATA (DAVID BARON) Conduct meeting between Identify mechanistic studies David Baron August 1 - DONE nonclinical safety and efficacy, for evaluation Janet Haskins regulatory, and project Schedule teleconference Mary Ramstack management with FDA Identify expert in oncology and pathology Identify nonclinicat back-up Pat Frank - telecon David Baron August 1 - DONE (example: Pat Frank and Chris Chris Durack report review Durack?) Request saccharin literature Janet Haskins August 1 - DONE search from Rya Send David Baron nonclinical Janet Haskins August 2 carcinogenicity studies Review doses used in CA Aziz Karim August 6 studies, clarify relationship to clinical doses 5B, NONCLINICAL/JUSTIFICATION DOCUMENT(DAVID BARON) Contact Jerry Oleski regarding Wendell Cheatham discrediting FDA tumor promoter hypothesis (inbittery) but busst Mary Roushur Last Update: August 1, 2002 Page 4 of 7 Confidential - Subject to Protective Order TAK-THOMCL-00032213 Produced in MDL on 02/21/13 Task Notes Lead Responsibility Due Date SB. NONCLINICAL/JUSTIFICATION DOCUMENTO (DAVID BARON) Evaluate and compare TCI structural models of all known PPAR agonists, including pioglitazone and NN622 Evaluate PPAR agonist TCI mechanistic tumor production hypotheses Evaluate effects of PPAR TCI agonists in urinary tract Develop justification document Baron Draft - August 16 Comments - August 19 Final version - August 20 6: INTRODUCTORY/CONCLUSION STATEMENTS Develop outline of response Hancock Aug 2 (table of contents) Send document sections to Aziz Karim - doses August 19 medical writing for compilation Amy Hagaman-507/506 Alfonso Perez - monitoring plan Last Update: August 1, 2002 Page 5 of 7 Confidentiat-Subject - to Protective Order TAK-THOMCL-00032214 Produced in MDL on 02/21/13- Source: https://www.indup538-00006ts.ucsf.edu/docs/qtjf0226 Task Notes Lead Responsibility Due Date 6. INTRODUCTORY/CONCLUSION STATEMENTS (CONTINUED) Send nonclinical David Baron August 20 rationale/justification section to medical writing for compilation Compile FDA package Larry Hancock August 21 Send package to TCI/EU for Mary Ramstack August 21 review Conduct review meeting for Janet Haskins/Team August 22 FDA package FDA Document to August 26 Regulatory Affairs 7. PACKAGE INSERTS/INFORMED CONSENT VERBIAGE Request NN622 literate Janet Haskins August 1 - DONE searches Identify package inserts with Janet Haskins August 12 similar class-related issues (i.e., ACE-inhibitors) Last Update: August 1, 2002 Page 6 of 7 Confidential - Subject to Protective Order TAK-THOMCL-00032215 Produced in MDL on 02/21/13 Source: https://www.indup63d8000007ts.ucsf.edu/docs/qtjf0226 Task Notes Lead Responsibility Due Date 8, COMPETITIVE INTELLIGENCE Update team on competitive Wendell Cheatham Ongoing - update provided intelligence Bill Bloke at each meeting 9. Q&A SHEET Develop Q&A sheet to support Wendell Cheatham Draft - August 5 Scientific Communications San Comments due - August 7 Review meeting-August 7 10. PATIENT REGISTRY Evaluate feasiblity of Pharmetric Database Rich Wilson OT developing large patient GE Database Rukmimi Rajagopalan registry Fred Murray 11: COMMUNICATIONS TO TAKEDA (TCI, TEUR&D, TPNA) 12, EVALUATE IMPACT ON TAK-559 prevelege Marline / average Last Update: August 1, 2002 Page 7 of 7 Confidential - Subject to Protective Order TAK-THOMCL-00032216 Produced in MDL on 02/21/13 Source:

Who is the lead responsible person for draft justification for actos 508?

qtjf0226

qtjf0226_p3, qtjf0226_p4, qtjf0226_p5, qtjf0226_p6, qtjf0226_p7

Amy Hagaman/Alfonso Perez

Task Notes Lead Responsibility Due Date 4. PEDIATRIC STUDIES (CONTINUED) Evaluate data from Actos 507 Evaluate data to support Amy Hagaman August 5 justification to proceed with Actos 508 Develop additional monitoring Amy Hagaman plan for Actos 508 Evaluate feasibility/business T. Muldoon case of request to FDA to M Ramstack delay start of Actos 508 pending Actos 506 data; 1 Haskins assess impact on pediatric exclusivity/patent Draft justification for Actos 508 Justification should be Amy Hagaman/Alfonso August 12 based on rebuttal of FDA Perez hypothesis regarding mechanism of action for bladder cancer and addition of clinical monitoring plan to protocol Last Update: August 1, 2002 Page 3 of 7 Confidential-Subject to Protective Order - TAK-THOMCL 00032212 Produced in MDL on 02/21/13 Source: https://www.indup3d8-00004ts.ucsf.edu/docs/qtjf0226 Task Notes Lead Responsibility Due Date 5A. NONCI INICAL/REVIEW OF TOX DATA (DAVID BARON) Conduct meeting between Identify mechanistic studies David Baron August 1 - DONE nonclinical safety and efficacy, for evaluation Janet Haskins regulatory, and project Schedule teleconference Mary Ramstack management with FDA Identify expert in oncology and pathology Identify nonclinicat back-up Pat Frank - telecon David Baron August 1 - DONE (example: Pat Frank and Chris Chris Durack report review Durack?) Request saccharin literature Janet Haskins August 1 - DONE search from Rya Send David Baron nonclinical Janet Haskins August 2 carcinogenicity studies Review doses used in CA Aziz Karim August 6 studies, clarify relationship to clinical doses 5B, NONCLINICAL/JUSTIFICATION DOCUMENT(DAVID BARON) Contact Jerry Oleski regarding Wendell Cheatham discrediting FDA tumor promoter hypothesis (inbittery) but busst Mary Roushur Last Update: August 1, 2002 Page 4 of 7 Confidential - Subject to Protective Order TAK-THOMCL-00032213 Produced in MDL on 02/21/13 Task Notes Lead Responsibility Due Date SB. NONCLINICAL/JUSTIFICATION DOCUMENTO (DAVID BARON) Evaluate and compare TCI structural models of all known PPAR agonists, including pioglitazone and NN622 Evaluate PPAR agonist TCI mechanistic tumor production hypotheses Evaluate effects of PPAR TCI agonists in urinary tract Develop justification document Baron Draft - August 16 Comments - August 19 Final version - August 20 6: INTRODUCTORY/CONCLUSION STATEMENTS Develop outline of response Hancock Aug 2 (table of contents) Send document sections to Aziz Karim - doses August 19 medical writing for compilation Amy Hagaman-507/506 Alfonso Perez - monitoring plan Last Update: August 1, 2002 Page 5 of 7 Confidentiat-Subject - to Protective Order TAK-THOMCL-00032214 Produced in MDL on 02/21/13- Source: https://www.indup538-00006ts.ucsf.edu/docs/qtjf0226 Task Notes Lead Responsibility Due Date 6. INTRODUCTORY/CONCLUSION STATEMENTS (CONTINUED) Send nonclinical David Baron August 20 rationale/justification section to medical writing for compilation Compile FDA package Larry Hancock August 21 Send package to TCI/EU for Mary Ramstack August 21 review Conduct review meeting for Janet Haskins/Team August 22 FDA package FDA Document to August 26 Regulatory Affairs 7. PACKAGE INSERTS/INFORMED CONSENT VERBIAGE Request NN622 literate Janet Haskins August 1 - DONE searches Identify package inserts with Janet Haskins August 12 similar class-related issues (i.e., ACE-inhibitors) Last Update: August 1, 2002 Page 6 of 7 Confidential - Subject to Protective Order TAK-THOMCL-00032215 Produced in MDL on 02/21/13 Source: https://www.indup63d8000007ts.ucsf.edu/docs/qtjf0226 Task Notes Lead Responsibility Due Date 8, COMPETITIVE INTELLIGENCE Update team on competitive Wendell Cheatham Ongoing - update provided intelligence Bill Bloke at each meeting 9. Q&A SHEET Develop Q&A sheet to support Wendell Cheatham Draft - August 5 Scientific Communications San Comments due - August 7 Review meeting-August 7 10. PATIENT REGISTRY Evaluate feasiblity of Pharmetric Database Rich Wilson OT developing large patient GE Database Rukmimi Rajagopalan registry Fred Murray 11: COMMUNICATIONS TO TAKEDA (TCI, TEUR&D, TPNA) 12, EVALUATE IMPACT ON TAK-559 prevelege Marline / average Last Update: August 1, 2002 Page 7 of 7 Confidential - Subject to Protective Order TAK-THOMCL-00032216 Produced in MDL on 02/21/13 Source:

Which is the core organization of Takeda pharmaceutical Company?

lmjf0226

lmjf0226_p0, lmjf0226_p1, lmjf0226_p2, lmjf0226_p3, lmjf0226_p4, lmjf0226_p5, lmjf0226_p6, lmjf0226_p7, lmjf0226_p8, lmjf0226_p9, lmjf0226_p10, lmjf0226_p11, lmjf0226_p12, lmjf0226_p13, lmjf0226_p14, lmjf0226_p15, lmjf0226_p16

Pharmaceutical development Division, Pharmaceutical Development Division

CONFIDENTIAL Final Draft November 11, 2002 (DRAFT) MINUTES OF THE 5th GLOBAL DEVELOPMENT COMMITTEE Date: October 1, 2002 9:00 - 18:00 October 2, 2002 9:00 - 14:00 Place: Takeda Osaka Head Office, Room 11F2AB Attendees: Dr. Kitazawa, Managing Director, Pharmaceutical Development Division Mr. Saito, General Manager, Dept. Strategic Development Formatted: Right: 0" JP Development Division: Mr. Ikeya, General Manager, Japan Development Center Mr. Funatsu, Senior Manager, Japan Development Center Mr. Nakajima, Senior Manager, Japan Development Center Mr. Oomura, Senior Manager, Japan Development Center Formatted: Right: 0" Mr. Nakamura, Senior Manager, Japan Development Center Mr. Oka, Manager, Japan Development Center Takeda Europe R&D Centre: Dr, Eckland, Managing Director Formatted: Right: 0" Mr. Wada, Deputy Managing Director, Project Management Dr. George, Deputy Managing Director & Director, Euro Develop I Dr. Collett, Director, Euro Drug Regulatory Affairs Mr. Moules, Director, Euro Development Il Takeda Pharmaceuticals North America: Mr. Kashiyae, Vice President, Research & Development Dr. Thom, Vice President, Research & Development Mr. Daly, Senior Vice President, Marketing Ms. Hoos, Director, Regulatory Affairs Dr. Elisseou, Director, Project Management Pharmaceutical International Division: Mr. Kuroiwa, General Manager, Product Planning & Management Pharmaceutical Research Division: Dr. Miyamoto, Director, Pharmacology Research Labs. I Formatted: Right: 0" Dr. Imura, Research Manager, Pharmacology Research Labs. II Dr. Sato, Research Head, Drug Safety Research Labs. Dr. Yamamoto, Research Head, Drug Safety Research Labs., et al. Strategic Product Planning Department: Dr. Sugiyama, Leader, MPDRAP-I Formatted: Right: 0" Dr. Furuya, Leader, MPDRAP-II Mr. Ueda, Leader, MPDRAP-IV, et al. Special Project Unit I: Mr. Ban, Project Leader Formatted: Right: 0" Secretariat of Global Development Committee: Dr. Heya, Group Manager, Dept. Strategic Development Formatted: Right: 0" Mr. Tabata, Manager, Dept. Strategic Development Mr. Morimoto, Manager, Dept. Strategic Development Dr. Hayakawa, Manager, Dept. Strategic Development Mr. Miyazaki, Manager, Dept. Strategic Development Mr. Kikuchi, Manager, Dept. Strategic Development 1 Confidential - Subject to Protective Order TAK-THOMCL-00012573 Produced in MDL on 09/14/12 Ms. Wakamatsu, Assistant manager, Dept. Strategic Development, et al. Attachment: NDA schedule for each project approved on the 5th GDC 1. Openings Remarks Dr. Kitazawa made opening remarks. He mentioned that TAKEDA has been driving for to be a global pharmaceutical company in this decade, concentrating all resource into the pharmaceutical business, under the clear-cut leadership of the CEO. Pharmaceutical Development Division is a core organization of Takeda Pharmaceutical Company, enhancing the pipeline products, which is the decisive factor for TAKEDA business. However, in the present condition, since the launch of Actos in 1999 there are no new products launched. While this situation is critical, the Pharmaceutical Development Division is thought to be conservative and lack of challenging spirit. He stated that his mission is to improve this conservative atmosphere and grow challenging spirit to develop and launch the new products earlier than scheduled. Formatted: Not Hidden 3. MPDRAP-I (Diabetes) 1) AD-4833 Update of US status by TPNA - Bladder tumor observed in NN622 study As for the bladder issues, an expected response from FDA is in early October and pediatric study (Actos 508) is temporarily on hold, however, this is not an official hold. In the recent teleconference discussing non-clinical issues, the experts could not identify any rational hypothesis that dual PPAR agonists may be linked to bladder tumogenesis. A clinical expert meeting is scheduled for October 1 and 2 to discuss how to screen/monitor bladder tumors in long-term clinical trials, since FDA may force TPNA to do it. Label changes may be requested by FDA and it is very difficult to assess the marketing impact of such label change at this moment. It was suggested to prepare non-clinical "White paper" to address the bladder issue. - US commitment study of 30mg VS. 45mg An sNDA will be submitted in this autumn, where studies 341, 342, 343 and 513 are included. The objectives of the submission are for 1) a safety purpose, not for an efficacy or new indication of 45mg, and 2) an update of oral contraceptive interaction results in the label. - Timelines and issues on Actos combination projects were presented. Actos-Metformin Convenience Pack is expected to file sNDA in March 2003 and to be approved in September 2003. TPNA believes stability data of 3 months are sufficient 2 Confidential - Subject to Protective Order TAK-THOMCL-00012574 Produced in MDL on 09/14/12 Source: but TPNA is going to consult with FDA before submission, and vender selection is under negotiation and moving forward. It was noted that an application for convenience pack for 45mg has to be submitted after 45mg combination therapy indication is approved. Actos-Metformin fixed Combination Tablets is expected to file IND in February 2003, to file NDA in November 2003 with 6 months stability data and to be approved in November 2004. In order to ship clinical supplies in January 2003, TCI asked TPNA to file NDA in January NOT in February, preceded by pre-IND meeting in December 2001, although TPNA's original target of IND was February. Since CMC documents will be the rate-limiting factor to file NDA, TCI is going to check if a start of the stability study can be brought forward. GSK will reportedly obtain the approval of their combination product within this year. With regard to Actos-SU Combination Tablet, it should take 18 months from the selection of SU to finalization of the SU combination tablet, TPNA is going to make a proposal for the SU product shortly - which su to choose and its dose levels. - Revision to language in package insert in terms of liver monitoring requirement Liver monitoring issue will be discussed between TPNA and EuR&D so that sNDA/variation for a label change may be submitted in January 2003. - Timelines of other studies were discussed and agreed mutually. Key results (TLGs) from studies 504 and 520 will be made available as scheduled, which are required for the European applications. EuR&D will not be involved in review process of TLGs. The development plan in dysmetabolic syndrome will be approved around late October in-house at TCI. An s NDA of atherosclerosis indication in US is scheduled for October 2005. Update of EU status by EuR&D - Current schedule of submission for mono & unrestricted combo therapy indications Variations to posology (45mg) and indications (monotherapy and first line combination therapy) are scheduled to be submitted in January 2003. Clock starts on 30 January 2003. - Prescription status variation (type II) Variation was submitted on 6th September 2002 and opinion is expected on 19th November 2002. - PROactive The first DSMB meeting is planned for 3Q 2003 and any scientific advance/opinion are invited before the meeting. Publication on baseline data is scheduled for early next year, therefore any modifications on endpoints including FDA suggestions have to be made before the publication. FDA should raise no issue on the protocol according to TPNA. 3 Confidential - Subject to Protective Order TAK-THOMCL-00012575 Produced in MDL on 09/14/12 Source: https://www.indup0442-00003s.ucsf.edu/docs/Imjf0226 - Actos/generic metformin combination tablet Flash data from a pilot BE study to be conducted by EuR&D will be available in mid of November. EU submission based PK/PD argument alone has a low chance of success, around 40%. Although the guidelines expect clinical data to be provided, clinical studies should not be conducted because there is a possibility that Actos bid might show better results than once daily even if daily dose is the same. In Europe, it was agreed to submit the BE study results from US with PK/PD argument as a challenge. It was also agreed that no interaction with authorities is made to ask about the development strategy, because we have to conduct clinical studies once the authorities request us to do them. EuR&D reported that EMO had no interest in Actos-Metformin Combination Pack due to the difficulty to register combination packs in EMEA/CPMP and its poor marketability in EU. CONCLUSIONS; TPNA to prepare non-clinical "White paper" to address bladder issue TPNA & EuR&D to discuss liver monitoring requirement to revise the language in US package insert and EU SPC in January 2003 Generic metformin fixed combination tablet to be pursued in Europe using PD modeling (but, chance of success is low) No interest in convenience pack in Europe Other Takeda Drugs Confidential - Subject to Protective Order TAK-THOMCL-00012576 Produced in MDL on 09/14/12 Source: https://www.indupo.42°00004s.ucsf.edu/docs//mjf0226 Other Takeda Drugs Other Takeda Drugs Other Takeda Drugs Other Takeda Drugs Confidential - Subject to Protective Order TAK-THOMCL-00012577 Produced in MDL on 09/14/12 Source: Other Takeda Drugs Other Takeda Drugs Other Takeda Drugs 6 Confidential - Subject to Protective Order TAK-THOMCL-00012578 Produced in MDL on 09/14/12 Source: Other Takeda Drugs 2) TAK-070 7 Confidential - Subject to Protective Order TAK-THOMCL-00012579 Produced in MDL on 09/14/12 Source: https://www.indupo442°00007ts.ucsf.edu/docs/Imjf0226 Other Takeda Drugs 8 Confidential - Subject to Protective Order TAK-THOMCL-00012580 Produced in MDL on 09/14/12 Source: https://www.indupo:42-00008.ucsf.edu/docs//mjf0226 Other Takeda Drugs investigators. However this issue IS to be discussed with Mitsubishi since they are 9 Confidential - Subject to Protective Order TAK-THOMCL-00012581 Produced in MDL on 09/14/12 Source: Other Takeda Drugs Confidential - Subject to Protective Order TAK-THOMCL-00012582 Produced in MDL on 09/14/12 Source: https://www.indupo.420000.ucsf.edu/docs//mjf0226 Other Takeda Drugs 11 Confidential - Subject to Protective Order TAK-THOMCL-00012583 Produced in MDL on 09/14/12 Source: https://www.indupo:4200ts.ucsf.edu/docs/Imjf0226 Other Takeda Drugs Confidential - Subject to Protective Order TAK-THOMCL-00012584 Produced in MDL on 09/14/12 Source: https://www.indupo442-0002s.ucsf.edu/docs/Imjf0226 Other Takeda Drugs Confidential - Subject to Protective Order TAK-THOMCL-00012585 Produced in MDL on 09/14/12 Source: Other Takeda Drugs Confidential - Subject to Protective Order TAK-THOMCL-00012586 Produced in MDL on 09/14/12 Source: https://www.indupo442°0001'.ucsf.edu/docs/Imjf0226 Other Takeda Drugs Confidential - Subject to Protective Order TAK-THOMCL-00012587 Produced in MDL on 09/14/12 Source: Other Takeda Drugs Confidential - Subject to Protective Order TAK-THOMCL-00012588 Produced in MDL on 09/14/12 Source: END 17 Confidential - Subject to Protective Order TAK-THOMCL-00012589 Produced in MDL on 09/14/12 Source: https://www.indupo442-0007ts.ucsf.edu/docs/Imjf0226

Who made the opening remarks ?

lmjf0226

lmjf0226_p0, lmjf0226_p1, lmjf0226_p2, lmjf0226_p3, lmjf0226_p4, lmjf0226_p5, lmjf0226_p6, lmjf0226_p7, lmjf0226_p8, lmjf0226_p9, lmjf0226_p10, lmjf0226_p11, lmjf0226_p12, lmjf0226_p13, lmjf0226_p14, lmjf0226_p15, lmjf0226_p16

Dr. Kitazawa

CONFIDENTIAL Final Draft November 11, 2002 (DRAFT) MINUTES OF THE 5th GLOBAL DEVELOPMENT COMMITTEE Date: October 1, 2002 9:00 - 18:00 October 2, 2002 9:00 - 14:00 Place: Takeda Osaka Head Office, Room 11F2AB Attendees: Dr. Kitazawa, Managing Director, Pharmaceutical Development Division Mr. Saito, General Manager, Dept. Strategic Development Formatted: Right: 0" JP Development Division: Mr. Ikeya, General Manager, Japan Development Center Mr. Funatsu, Senior Manager, Japan Development Center Mr. Nakajima, Senior Manager, Japan Development Center Mr. Oomura, Senior Manager, Japan Development Center Formatted: Right: 0" Mr. Nakamura, Senior Manager, Japan Development Center Mr. Oka, Manager, Japan Development Center Takeda Europe R&D Centre: Dr, Eckland, Managing Director Formatted: Right: 0" Mr. Wada, Deputy Managing Director, Project Management Dr. George, Deputy Managing Director & Director, Euro Develop I Dr. Collett, Director, Euro Drug Regulatory Affairs Mr. Moules, Director, Euro Development Il Takeda Pharmaceuticals North America: Mr. Kashiyae, Vice President, Research & Development Dr. Thom, Vice President, Research & Development Mr. Daly, Senior Vice President, Marketing Ms. Hoos, Director, Regulatory Affairs Dr. Elisseou, Director, Project Management Pharmaceutical International Division: Mr. Kuroiwa, General Manager, Product Planning & Management Pharmaceutical Research Division: Dr. Miyamoto, Director, Pharmacology Research Labs. I Formatted: Right: 0" Dr. Imura, Research Manager, Pharmacology Research Labs. II Dr. Sato, Research Head, Drug Safety Research Labs. Dr. Yamamoto, Research Head, Drug Safety Research Labs., et al. Strategic Product Planning Department: Dr. Sugiyama, Leader, MPDRAP-I Formatted: Right: 0" Dr. Furuya, Leader, MPDRAP-II Mr. Ueda, Leader, MPDRAP-IV, et al. Special Project Unit I: Mr. Ban, Project Leader Formatted: Right: 0" Secretariat of Global Development Committee: Dr. Heya, Group Manager, Dept. Strategic Development Formatted: Right: 0" Mr. Tabata, Manager, Dept. Strategic Development Mr. Morimoto, Manager, Dept. Strategic Development Dr. Hayakawa, Manager, Dept. Strategic Development Mr. Miyazaki, Manager, Dept. Strategic Development Mr. Kikuchi, Manager, Dept. Strategic Development 1 Confidential - Subject to Protective Order TAK-THOMCL-00012573 Produced in MDL on 09/14/12 Ms. Wakamatsu, Assistant manager, Dept. Strategic Development, et al. Attachment: NDA schedule for each project approved on the 5th GDC 1. Openings Remarks Dr. Kitazawa made opening remarks. He mentioned that TAKEDA has been driving for to be a global pharmaceutical company in this decade, concentrating all resource into the pharmaceutical business, under the clear-cut leadership of the CEO. Pharmaceutical Development Division is a core organization of Takeda Pharmaceutical Company, enhancing the pipeline products, which is the decisive factor for TAKEDA business. However, in the present condition, since the launch of Actos in 1999 there are no new products launched. While this situation is critical, the Pharmaceutical Development Division is thought to be conservative and lack of challenging spirit. He stated that his mission is to improve this conservative atmosphere and grow challenging spirit to develop and launch the new products earlier than scheduled. Formatted: Not Hidden 3. MPDRAP-I (Diabetes) 1) AD-4833 Update of US status by TPNA - Bladder tumor observed in NN622 study As for the bladder issues, an expected response from FDA is in early October and pediatric study (Actos 508) is temporarily on hold, however, this is not an official hold. In the recent teleconference discussing non-clinical issues, the experts could not identify any rational hypothesis that dual PPAR agonists may be linked to bladder tumogenesis. A clinical expert meeting is scheduled for October 1 and 2 to discuss how to screen/monitor bladder tumors in long-term clinical trials, since FDA may force TPNA to do it. Label changes may be requested by FDA and it is very difficult to assess the marketing impact of such label change at this moment. It was suggested to prepare non-clinical "White paper" to address the bladder issue. - US commitment study of 30mg VS. 45mg An sNDA will be submitted in this autumn, where studies 341, 342, 343 and 513 are included. The objectives of the submission are for 1) a safety purpose, not for an efficacy or new indication of 45mg, and 2) an update of oral contraceptive interaction results in the label. - Timelines and issues on Actos combination projects were presented. Actos-Metformin Convenience Pack is expected to file sNDA in March 2003 and to be approved in September 2003. TPNA believes stability data of 3 months are sufficient 2 Confidential - Subject to Protective Order TAK-THOMCL-00012574 Produced in MDL on 09/14/12 Source: but TPNA is going to consult with FDA before submission, and vender selection is under negotiation and moving forward. It was noted that an application for convenience pack for 45mg has to be submitted after 45mg combination therapy indication is approved. Actos-Metformin fixed Combination Tablets is expected to file IND in February 2003, to file NDA in November 2003 with 6 months stability data and to be approved in November 2004. In order to ship clinical supplies in January 2003, TCI asked TPNA to file NDA in January NOT in February, preceded by pre-IND meeting in December 2001, although TPNA's original target of IND was February. Since CMC documents will be the rate-limiting factor to file NDA, TCI is going to check if a start of the stability study can be brought forward. GSK will reportedly obtain the approval of their combination product within this year. With regard to Actos-SU Combination Tablet, it should take 18 months from the selection of SU to finalization of the SU combination tablet, TPNA is going to make a proposal for the SU product shortly - which su to choose and its dose levels. - Revision to language in package insert in terms of liver monitoring requirement Liver monitoring issue will be discussed between TPNA and EuR&D so that sNDA/variation for a label change may be submitted in January 2003. - Timelines of other studies were discussed and agreed mutually. Key results (TLGs) from studies 504 and 520 will be made available as scheduled, which are required for the European applications. EuR&D will not be involved in review process of TLGs. The development plan in dysmetabolic syndrome will be approved around late October in-house at TCI. An s NDA of atherosclerosis indication in US is scheduled for October 2005. Update of EU status by EuR&D - Current schedule of submission for mono & unrestricted combo therapy indications Variations to posology (45mg) and indications (monotherapy and first line combination therapy) are scheduled to be submitted in January 2003. Clock starts on 30 January 2003. - Prescription status variation (type II) Variation was submitted on 6th September 2002 and opinion is expected on 19th November 2002. - PROactive The first DSMB meeting is planned for 3Q 2003 and any scientific advance/opinion are invited before the meeting. Publication on baseline data is scheduled for early next year, therefore any modifications on endpoints including FDA suggestions have to be made before the publication. FDA should raise no issue on the protocol according to TPNA. 3 Confidential - Subject to Protective Order TAK-THOMCL-00012575 Produced in MDL on 09/14/12 Source: https://www.indup0442-00003s.ucsf.edu/docs/Imjf0226 - Actos/generic metformin combination tablet Flash data from a pilot BE study to be conducted by EuR&D will be available in mid of November. EU submission based PK/PD argument alone has a low chance of success, around 40%. Although the guidelines expect clinical data to be provided, clinical studies should not be conducted because there is a possibility that Actos bid might show better results than once daily even if daily dose is the same. In Europe, it was agreed to submit the BE study results from US with PK/PD argument as a challenge. It was also agreed that no interaction with authorities is made to ask about the development strategy, because we have to conduct clinical studies once the authorities request us to do them. EuR&D reported that EMO had no interest in Actos-Metformin Combination Pack due to the difficulty to register combination packs in EMEA/CPMP and its poor marketability in EU. CONCLUSIONS; TPNA to prepare non-clinical "White paper" to address bladder issue TPNA & EuR&D to discuss liver monitoring requirement to revise the language in US package insert and EU SPC in January 2003 Generic metformin fixed combination tablet to be pursued in Europe using PD modeling (but, chance of success is low) No interest in convenience pack in Europe Other Takeda Drugs Confidential - Subject to Protective Order TAK-THOMCL-00012576 Produced in MDL on 09/14/12 Source: https://www.indupo.42°00004s.ucsf.edu/docs//mjf0226 Other Takeda Drugs Other Takeda Drugs Other Takeda Drugs Other Takeda Drugs Confidential - Subject to Protective Order TAK-THOMCL-00012577 Produced in MDL on 09/14/12 Source: Other Takeda Drugs Other Takeda Drugs Other Takeda Drugs 6 Confidential - Subject to Protective Order TAK-THOMCL-00012578 Produced in MDL on 09/14/12 Source: Other Takeda Drugs 2) TAK-070 7 Confidential - Subject to Protective Order TAK-THOMCL-00012579 Produced in MDL on 09/14/12 Source: https://www.indupo442°00007ts.ucsf.edu/docs/Imjf0226 Other Takeda Drugs 8 Confidential - Subject to Protective Order TAK-THOMCL-00012580 Produced in MDL on 09/14/12 Source: https://www.indupo:42-00008.ucsf.edu/docs//mjf0226 Other Takeda Drugs investigators. However this issue IS to be discussed with Mitsubishi since they are 9 Confidential - Subject to Protective Order TAK-THOMCL-00012581 Produced in MDL on 09/14/12 Source: Other Takeda Drugs Confidential - Subject to Protective Order TAK-THOMCL-00012582 Produced in MDL on 09/14/12 Source: https://www.indupo.420000.ucsf.edu/docs//mjf0226 Other Takeda Drugs 11 Confidential - Subject to Protective Order TAK-THOMCL-00012583 Produced in MDL on 09/14/12 Source: https://www.indupo:4200ts.ucsf.edu/docs/Imjf0226 Other Takeda Drugs Confidential - Subject to Protective Order TAK-THOMCL-00012584 Produced in MDL on 09/14/12 Source: https://www.indupo442-0002s.ucsf.edu/docs/Imjf0226 Other Takeda Drugs Confidential - Subject to Protective Order TAK-THOMCL-00012585 Produced in MDL on 09/14/12 Source: Other Takeda Drugs Confidential - Subject to Protective Order TAK-THOMCL-00012586 Produced in MDL on 09/14/12 Source: https://www.indupo442°0001'.ucsf.edu/docs/Imjf0226 Other Takeda Drugs Confidential - Subject to Protective Order TAK-THOMCL-00012587 Produced in MDL on 09/14/12 Source: Other Takeda Drugs Confidential - Subject to Protective Order TAK-THOMCL-00012588 Produced in MDL on 09/14/12 Source: END 17 Confidential - Subject to Protective Order TAK-THOMCL-00012589 Produced in MDL on 09/14/12 Source: https://www.indupo442-0007ts.ucsf.edu/docs/Imjf0226

When is the clinical expert meeting scheduled?

lmjf0226

lmjf0226_p0, lmjf0226_p1, lmjf0226_p2, lmjf0226_p3, lmjf0226_p4, lmjf0226_p5, lmjf0226_p6, lmjf0226_p7, lmjf0226_p8, lmjf0226_p9, lmjf0226_p10, lmjf0226_p11, lmjf0226_p12, lmjf0226_p13, lmjf0226_p14, lmjf0226_p15, lmjf0226_p16

October 1 and 2, for October 1 and 2.

CONFIDENTIAL Final Draft November 11, 2002 (DRAFT) MINUTES OF THE 5th GLOBAL DEVELOPMENT COMMITTEE Date: October 1, 2002 9:00 - 18:00 October 2, 2002 9:00 - 14:00 Place: Takeda Osaka Head Office, Room 11F2AB Attendees: Dr. Kitazawa, Managing Director, Pharmaceutical Development Division Mr. Saito, General Manager, Dept. Strategic Development Formatted: Right: 0" JP Development Division: Mr. Ikeya, General Manager, Japan Development Center Mr. Funatsu, Senior Manager, Japan Development Center Mr. Nakajima, Senior Manager, Japan Development Center Mr. Oomura, Senior Manager, Japan Development Center Formatted: Right: 0" Mr. Nakamura, Senior Manager, Japan Development Center Mr. Oka, Manager, Japan Development Center Takeda Europe R&D Centre: Dr, Eckland, Managing Director Formatted: Right: 0" Mr. Wada, Deputy Managing Director, Project Management Dr. George, Deputy Managing Director & Director, Euro Develop I Dr. Collett, Director, Euro Drug Regulatory Affairs Mr. Moules, Director, Euro Development Il Takeda Pharmaceuticals North America: Mr. Kashiyae, Vice President, Research & Development Dr. Thom, Vice President, Research & Development Mr. Daly, Senior Vice President, Marketing Ms. Hoos, Director, Regulatory Affairs Dr. Elisseou, Director, Project Management Pharmaceutical International Division: Mr. Kuroiwa, General Manager, Product Planning & Management Pharmaceutical Research Division: Dr. Miyamoto, Director, Pharmacology Research Labs. I Formatted: Right: 0" Dr. Imura, Research Manager, Pharmacology Research Labs. II Dr. Sato, Research Head, Drug Safety Research Labs. Dr. Yamamoto, Research Head, Drug Safety Research Labs., et al. Strategic Product Planning Department: Dr. Sugiyama, Leader, MPDRAP-I Formatted: Right: 0" Dr. Furuya, Leader, MPDRAP-II Mr. Ueda, Leader, MPDRAP-IV, et al. Special Project Unit I: Mr. Ban, Project Leader Formatted: Right: 0" Secretariat of Global Development Committee: Dr. Heya, Group Manager, Dept. Strategic Development Formatted: Right: 0" Mr. Tabata, Manager, Dept. Strategic Development Mr. Morimoto, Manager, Dept. Strategic Development Dr. Hayakawa, Manager, Dept. Strategic Development Mr. Miyazaki, Manager, Dept. Strategic Development Mr. Kikuchi, Manager, Dept. Strategic Development 1 Confidential - Subject to Protective Order TAK-THOMCL-00012573 Produced in MDL on 09/14/12 Ms. Wakamatsu, Assistant manager, Dept. Strategic Development, et al. Attachment: NDA schedule for each project approved on the 5th GDC 1. Openings Remarks Dr. Kitazawa made opening remarks. He mentioned that TAKEDA has been driving for to be a global pharmaceutical company in this decade, concentrating all resource into the pharmaceutical business, under the clear-cut leadership of the CEO. Pharmaceutical Development Division is a core organization of Takeda Pharmaceutical Company, enhancing the pipeline products, which is the decisive factor for TAKEDA business. However, in the present condition, since the launch of Actos in 1999 there are no new products launched. While this situation is critical, the Pharmaceutical Development Division is thought to be conservative and lack of challenging spirit. He stated that his mission is to improve this conservative atmosphere and grow challenging spirit to develop and launch the new products earlier than scheduled. Formatted: Not Hidden 3. MPDRAP-I (Diabetes) 1) AD-4833 Update of US status by TPNA - Bladder tumor observed in NN622 study As for the bladder issues, an expected response from FDA is in early October and pediatric study (Actos 508) is temporarily on hold, however, this is not an official hold. In the recent teleconference discussing non-clinical issues, the experts could not identify any rational hypothesis that dual PPAR agonists may be linked to bladder tumogenesis. A clinical expert meeting is scheduled for October 1 and 2 to discuss how to screen/monitor bladder tumors in long-term clinical trials, since FDA may force TPNA to do it. Label changes may be requested by FDA and it is very difficult to assess the marketing impact of such label change at this moment. It was suggested to prepare non-clinical "White paper" to address the bladder issue. - US commitment study of 30mg VS. 45mg An sNDA will be submitted in this autumn, where studies 341, 342, 343 and 513 are included. The objectives of the submission are for 1) a safety purpose, not for an efficacy or new indication of 45mg, and 2) an update of oral contraceptive interaction results in the label. - Timelines and issues on Actos combination projects were presented. Actos-Metformin Convenience Pack is expected to file sNDA in March 2003 and to be approved in September 2003. TPNA believes stability data of 3 months are sufficient 2 Confidential - Subject to Protective Order TAK-THOMCL-00012574 Produced in MDL on 09/14/12 Source: but TPNA is going to consult with FDA before submission, and vender selection is under negotiation and moving forward. It was noted that an application for convenience pack for 45mg has to be submitted after 45mg combination therapy indication is approved. Actos-Metformin fixed Combination Tablets is expected to file IND in February 2003, to file NDA in November 2003 with 6 months stability data and to be approved in November 2004. In order to ship clinical supplies in January 2003, TCI asked TPNA to file NDA in January NOT in February, preceded by pre-IND meeting in December 2001, although TPNA's original target of IND was February. Since CMC documents will be the rate-limiting factor to file NDA, TCI is going to check if a start of the stability study can be brought forward. GSK will reportedly obtain the approval of their combination product within this year. With regard to Actos-SU Combination Tablet, it should take 18 months from the selection of SU to finalization of the SU combination tablet, TPNA is going to make a proposal for the SU product shortly - which su to choose and its dose levels. - Revision to language in package insert in terms of liver monitoring requirement Liver monitoring issue will be discussed between TPNA and EuR&D so that sNDA/variation for a label change may be submitted in January 2003. - Timelines of other studies were discussed and agreed mutually. Key results (TLGs) from studies 504 and 520 will be made available as scheduled, which are required for the European applications. EuR&D will not be involved in review process of TLGs. The development plan in dysmetabolic syndrome will be approved around late October in-house at TCI. An s NDA of atherosclerosis indication in US is scheduled for October 2005. Update of EU status by EuR&D - Current schedule of submission for mono & unrestricted combo therapy indications Variations to posology (45mg) and indications (monotherapy and first line combination therapy) are scheduled to be submitted in January 2003. Clock starts on 30 January 2003. - Prescription status variation (type II) Variation was submitted on 6th September 2002 and opinion is expected on 19th November 2002. - PROactive The first DSMB meeting is planned for 3Q 2003 and any scientific advance/opinion are invited before the meeting. Publication on baseline data is scheduled for early next year, therefore any modifications on endpoints including FDA suggestions have to be made before the publication. FDA should raise no issue on the protocol according to TPNA. 3 Confidential - Subject to Protective Order TAK-THOMCL-00012575 Produced in MDL on 09/14/12 Source: https://www.indup0442-00003s.ucsf.edu/docs/Imjf0226 - Actos/generic metformin combination tablet Flash data from a pilot BE study to be conducted by EuR&D will be available in mid of November. EU submission based PK/PD argument alone has a low chance of success, around 40%. Although the guidelines expect clinical data to be provided, clinical studies should not be conducted because there is a possibility that Actos bid might show better results than once daily even if daily dose is the same. In Europe, it was agreed to submit the BE study results from US with PK/PD argument as a challenge. It was also agreed that no interaction with authorities is made to ask about the development strategy, because we have to conduct clinical studies once the authorities request us to do them. EuR&D reported that EMO had no interest in Actos-Metformin Combination Pack due to the difficulty to register combination packs in EMEA/CPMP and its poor marketability in EU. CONCLUSIONS; TPNA to prepare non-clinical "White paper" to address bladder issue TPNA & EuR&D to discuss liver monitoring requirement to revise the language in US package insert and EU SPC in January 2003 Generic metformin fixed combination tablet to be pursued in Europe using PD modeling (but, chance of success is low) No interest in convenience pack in Europe Other Takeda Drugs Confidential - Subject to Protective Order TAK-THOMCL-00012576 Produced in MDL on 09/14/12 Source: https://www.indupo.42°00004s.ucsf.edu/docs//mjf0226 Other Takeda Drugs Other Takeda Drugs Other Takeda Drugs Other Takeda Drugs Confidential - Subject to Protective Order TAK-THOMCL-00012577 Produced in MDL on 09/14/12 Source: Other Takeda Drugs Other Takeda Drugs Other Takeda Drugs 6 Confidential - Subject to Protective Order TAK-THOMCL-00012578 Produced in MDL on 09/14/12 Source: Other Takeda Drugs 2) TAK-070 7 Confidential - Subject to Protective Order TAK-THOMCL-00012579 Produced in MDL on 09/14/12 Source: https://www.indupo442°00007ts.ucsf.edu/docs/Imjf0226 Other Takeda Drugs 8 Confidential - Subject to Protective Order TAK-THOMCL-00012580 Produced in MDL on 09/14/12 Source: https://www.indupo:42-00008.ucsf.edu/docs//mjf0226 Other Takeda Drugs investigators. However this issue IS to be discussed with Mitsubishi since they are 9 Confidential - Subject to Protective Order TAK-THOMCL-00012581 Produced in MDL on 09/14/12 Source: Other Takeda Drugs Confidential - Subject to Protective Order TAK-THOMCL-00012582 Produced in MDL on 09/14/12 Source: https://www.indupo.420000.ucsf.edu/docs//mjf0226 Other Takeda Drugs 11 Confidential - Subject to Protective Order TAK-THOMCL-00012583 Produced in MDL on 09/14/12 Source: https://www.indupo:4200ts.ucsf.edu/docs/Imjf0226 Other Takeda Drugs Confidential - Subject to Protective Order TAK-THOMCL-00012584 Produced in MDL on 09/14/12 Source: https://www.indupo442-0002s.ucsf.edu/docs/Imjf0226 Other Takeda Drugs Confidential - Subject to Protective Order TAK-THOMCL-00012585 Produced in MDL on 09/14/12 Source: Other Takeda Drugs Confidential - Subject to Protective Order TAK-THOMCL-00012586 Produced in MDL on 09/14/12 Source: https://www.indupo442°0001'.ucsf.edu/docs/Imjf0226 Other Takeda Drugs Confidential - Subject to Protective Order TAK-THOMCL-00012587 Produced in MDL on 09/14/12 Source: Other Takeda Drugs Confidential - Subject to Protective Order TAK-THOMCL-00012588 Produced in MDL on 09/14/12 Source: END 17 Confidential - Subject to Protective Order TAK-THOMCL-00012589 Produced in MDL on 09/14/12 Source: https://www.indupo442-0007ts.ucsf.edu/docs/Imjf0226

what is the date mentioned in the given information ?

nqjf0226

nqjf0226_p0, nqjf0226_p1

20 April 2006, 20 april 2006

Actos Pediatric Working Group Date: 20 April 2006 Time: 4:00pm - 5:00pm Meeting Minutes Place: Meeting Room 403 Attendees Attendees Alfonso Perez - Clinical Karen Kaluzny - Project Management X Stuart Kupfer - Clinical X Mary Jo Pritza - Regulatory X Brigit Isaacson - Clinical X Shari Bodnoff - Medical Writing X Pat Schwartz - Clinical Andy Roberts - Medical Writing X Mondira Bhattacharya - Product Safety Agenda Items GDC Update A TPC stressed the importance of the ACTOS pediatric program, and requested that the preparation of the written request be expedited. Next Steps - Developing Partial Clinical Hold Removal Request Document A meeting will be scheduled in early May to develop the overall structure of the document. In addition to the elements already defined, the team agreed that the following should be added: Any new nonclinical data regarding PPAR agonists and bladder safety Bladder safety analysis from CHICAGO study (Projected database lock: 5 June 2006) Post-meeting note: Additional safety analysis from ACTOS 506 study Action Items: Mondira will forward article regarding rosiglitazone and nonclinical bladder data to Andy. Andy will request a literature search for any new articles regarding PPARs and nonclinical bladder data. Mary Jo will follow-up with David Baron to determine if he is aware of any new data regarding PPARs and bladder safety. Mary Jo will determine if the FDA has received information about the PROactive extension and the second KNPC study being done to fulfill EMEA's requirements. Post-meeting note: Completed. Both protocols were sent to the FDA. Andy will follow-up with Regulatory to obtain examples of other clinical hold removal request documents. (Deb Yarbrough - TAK-428, Mary Jo - TAK-654) Karen will schedule the document development meeting for the second week of May. N:/Product Development and Planning/ACTOS/Working Groups/Pediatrics/<AUTO> Page 1 of 2 Confidential - Subject to Protective Order TAK-KUPFES-00716752 Produced in MDL on 09/19/12 Agenda Items Outstanding Issues - Action Items Karen and Brigit will work offline to develop the protocol timelines. Work on the protocol synopsis is already ongoing. N:/Product Development and Planning/ACTOS/Working Groups/Pediatrics/<AUTO> Page 2 of 2 Confidential - Subject to Protective Order TAK-KUPFES-00716753 Produced in MDL on 09/19/12 Source: https://www.indup4885-00002s.ucsf.edu/docs/nqjf0226

What is the meeting time mentioned here?

nqjf0226

nqjf0226_p0, nqjf0226_p1

4:00pm - 5:00pm

Actos Pediatric Working Group Date: 20 April 2006 Time: 4:00pm - 5:00pm Meeting Minutes Place: Meeting Room 403 Attendees Attendees Alfonso Perez - Clinical Karen Kaluzny - Project Management X Stuart Kupfer - Clinical X Mary Jo Pritza - Regulatory X Brigit Isaacson - Clinical X Shari Bodnoff - Medical Writing X Pat Schwartz - Clinical Andy Roberts - Medical Writing X Mondira Bhattacharya - Product Safety Agenda Items GDC Update A TPC stressed the importance of the ACTOS pediatric program, and requested that the preparation of the written request be expedited. Next Steps - Developing Partial Clinical Hold Removal Request Document A meeting will be scheduled in early May to develop the overall structure of the document. In addition to the elements already defined, the team agreed that the following should be added: Any new nonclinical data regarding PPAR agonists and bladder safety Bladder safety analysis from CHICAGO study (Projected database lock: 5 June 2006) Post-meeting note: Additional safety analysis from ACTOS 506 study Action Items: Mondira will forward article regarding rosiglitazone and nonclinical bladder data to Andy. Andy will request a literature search for any new articles regarding PPARs and nonclinical bladder data. Mary Jo will follow-up with David Baron to determine if he is aware of any new data regarding PPARs and bladder safety. Mary Jo will determine if the FDA has received information about the PROactive extension and the second KNPC study being done to fulfill EMEA's requirements. Post-meeting note: Completed. Both protocols were sent to the FDA. Andy will follow-up with Regulatory to obtain examples of other clinical hold removal request documents. (Deb Yarbrough - TAK-428, Mary Jo - TAK-654) Karen will schedule the document development meeting for the second week of May. N:/Product Development and Planning/ACTOS/Working Groups/Pediatrics/<AUTO> Page 1 of 2 Confidential - Subject to Protective Order TAK-KUPFES-00716752 Produced in MDL on 09/19/12 Agenda Items Outstanding Issues - Action Items Karen and Brigit will work offline to develop the protocol timelines. Work on the protocol synopsis is already ongoing. N:/Product Development and Planning/ACTOS/Working Groups/Pediatrics/<AUTO> Page 2 of 2 Confidential - Subject to Protective Order TAK-KUPFES-00716753 Produced in MDL on 09/19/12 Source: https://www.indup4885-00002s.ucsf.edu/docs/nqjf0226

what is the place mentioned ?

nqjf0226

nqjf0226_p0, nqjf0226_p1

meeting room 403, Meeting Room 403

Actos Pediatric Working Group Date: 20 April 2006 Time: 4:00pm - 5:00pm Meeting Minutes Place: Meeting Room 403 Attendees Attendees Alfonso Perez - Clinical Karen Kaluzny - Project Management X Stuart Kupfer - Clinical X Mary Jo Pritza - Regulatory X Brigit Isaacson - Clinical X Shari Bodnoff - Medical Writing X Pat Schwartz - Clinical Andy Roberts - Medical Writing X Mondira Bhattacharya - Product Safety Agenda Items GDC Update A TPC stressed the importance of the ACTOS pediatric program, and requested that the preparation of the written request be expedited. Next Steps - Developing Partial Clinical Hold Removal Request Document A meeting will be scheduled in early May to develop the overall structure of the document. In addition to the elements already defined, the team agreed that the following should be added: Any new nonclinical data regarding PPAR agonists and bladder safety Bladder safety analysis from CHICAGO study (Projected database lock: 5 June 2006) Post-meeting note: Additional safety analysis from ACTOS 506 study Action Items: Mondira will forward article regarding rosiglitazone and nonclinical bladder data to Andy. Andy will request a literature search for any new articles regarding PPARs and nonclinical bladder data. Mary Jo will follow-up with David Baron to determine if he is aware of any new data regarding PPARs and bladder safety. Mary Jo will determine if the FDA has received information about the PROactive extension and the second KNPC study being done to fulfill EMEA's requirements. Post-meeting note: Completed. Both protocols were sent to the FDA. Andy will follow-up with Regulatory to obtain examples of other clinical hold removal request documents. (Deb Yarbrough - TAK-428, Mary Jo - TAK-654) Karen will schedule the document development meeting for the second week of May. N:/Product Development and Planning/ACTOS/Working Groups/Pediatrics/<AUTO> Page 1 of 2 Confidential - Subject to Protective Order TAK-KUPFES-00716752 Produced in MDL on 09/19/12 Agenda Items Outstanding Issues - Action Items Karen and Brigit will work offline to develop the protocol timelines. Work on the protocol synopsis is already ongoing. N:/Product Development and Planning/ACTOS/Working Groups/Pediatrics/<AUTO> Page 2 of 2 Confidential - Subject to Protective Order TAK-KUPFES-00716753 Produced in MDL on 09/19/12 Source: https://www.indup4885-00002s.ucsf.edu/docs/nqjf0226

Why was it suggested to prepare non-clinical "White paper"?

lmjf0226

lmjf0226_p0, lmjf0226_p1, lmjf0226_p2, lmjf0226_p3, lmjf0226_p4, lmjf0226_p5, lmjf0226_p6, lmjf0226_p7, lmjf0226_p8, lmjf0226_p9, lmjf0226_p10, lmjf0226_p11, lmjf0226_p12, lmjf0226_p13, lmjf0226_p14, lmjf0226_p15, lmjf0226_p16

to address the bladder issue, to address the bladder issue.

CONFIDENTIAL Final Draft November 11, 2002 (DRAFT) MINUTES OF THE 5th GLOBAL DEVELOPMENT COMMITTEE Date: October 1, 2002 9:00 - 18:00 October 2, 2002 9:00 - 14:00 Place: Takeda Osaka Head Office, Room 11F2AB Attendees: Dr. Kitazawa, Managing Director, Pharmaceutical Development Division Mr. Saito, General Manager, Dept. Strategic Development Formatted: Right: 0" JP Development Division: Mr. Ikeya, General Manager, Japan Development Center Mr. Funatsu, Senior Manager, Japan Development Center Mr. Nakajima, Senior Manager, Japan Development Center Mr. Oomura, Senior Manager, Japan Development Center Formatted: Right: 0" Mr. Nakamura, Senior Manager, Japan Development Center Mr. Oka, Manager, Japan Development Center Takeda Europe R&D Centre: Dr, Eckland, Managing Director Formatted: Right: 0" Mr. Wada, Deputy Managing Director, Project Management Dr. George, Deputy Managing Director & Director, Euro Develop I Dr. Collett, Director, Euro Drug Regulatory Affairs Mr. Moules, Director, Euro Development Il Takeda Pharmaceuticals North America: Mr. Kashiyae, Vice President, Research & Development Dr. Thom, Vice President, Research & Development Mr. Daly, Senior Vice President, Marketing Ms. Hoos, Director, Regulatory Affairs Dr. Elisseou, Director, Project Management Pharmaceutical International Division: Mr. Kuroiwa, General Manager, Product Planning & Management Pharmaceutical Research Division: Dr. Miyamoto, Director, Pharmacology Research Labs. I Formatted: Right: 0" Dr. Imura, Research Manager, Pharmacology Research Labs. II Dr. Sato, Research Head, Drug Safety Research Labs. Dr. Yamamoto, Research Head, Drug Safety Research Labs., et al. Strategic Product Planning Department: Dr. Sugiyama, Leader, MPDRAP-I Formatted: Right: 0" Dr. Furuya, Leader, MPDRAP-II Mr. Ueda, Leader, MPDRAP-IV, et al. Special Project Unit I: Mr. Ban, Project Leader Formatted: Right: 0" Secretariat of Global Development Committee: Dr. Heya, Group Manager, Dept. Strategic Development Formatted: Right: 0" Mr. Tabata, Manager, Dept. Strategic Development Mr. Morimoto, Manager, Dept. Strategic Development Dr. Hayakawa, Manager, Dept. Strategic Development Mr. Miyazaki, Manager, Dept. Strategic Development Mr. Kikuchi, Manager, Dept. Strategic Development 1 Confidential - Subject to Protective Order TAK-THOMCL-00012573 Produced in MDL on 09/14/12 Ms. Wakamatsu, Assistant manager, Dept. Strategic Development, et al. Attachment: NDA schedule for each project approved on the 5th GDC 1. Openings Remarks Dr. Kitazawa made opening remarks. He mentioned that TAKEDA has been driving for to be a global pharmaceutical company in this decade, concentrating all resource into the pharmaceutical business, under the clear-cut leadership of the CEO. Pharmaceutical Development Division is a core organization of Takeda Pharmaceutical Company, enhancing the pipeline products, which is the decisive factor for TAKEDA business. However, in the present condition, since the launch of Actos in 1999 there are no new products launched. While this situation is critical, the Pharmaceutical Development Division is thought to be conservative and lack of challenging spirit. He stated that his mission is to improve this conservative atmosphere and grow challenging spirit to develop and launch the new products earlier than scheduled. Formatted: Not Hidden 3. MPDRAP-I (Diabetes) 1) AD-4833 Update of US status by TPNA - Bladder tumor observed in NN622 study As for the bladder issues, an expected response from FDA is in early October and pediatric study (Actos 508) is temporarily on hold, however, this is not an official hold. In the recent teleconference discussing non-clinical issues, the experts could not identify any rational hypothesis that dual PPAR agonists may be linked to bladder tumogenesis. A clinical expert meeting is scheduled for October 1 and 2 to discuss how to screen/monitor bladder tumors in long-term clinical trials, since FDA may force TPNA to do it. Label changes may be requested by FDA and it is very difficult to assess the marketing impact of such label change at this moment. It was suggested to prepare non-clinical "White paper" to address the bladder issue. - US commitment study of 30mg VS. 45mg An sNDA will be submitted in this autumn, where studies 341, 342, 343 and 513 are included. The objectives of the submission are for 1) a safety purpose, not for an efficacy or new indication of 45mg, and 2) an update of oral contraceptive interaction results in the label. - Timelines and issues on Actos combination projects were presented. Actos-Metformin Convenience Pack is expected to file sNDA in March 2003 and to be approved in September 2003. TPNA believes stability data of 3 months are sufficient 2 Confidential - Subject to Protective Order TAK-THOMCL-00012574 Produced in MDL on 09/14/12 Source: but TPNA is going to consult with FDA before submission, and vender selection is under negotiation and moving forward. It was noted that an application for convenience pack for 45mg has to be submitted after 45mg combination therapy indication is approved. Actos-Metformin fixed Combination Tablets is expected to file IND in February 2003, to file NDA in November 2003 with 6 months stability data and to be approved in November 2004. In order to ship clinical supplies in January 2003, TCI asked TPNA to file NDA in January NOT in February, preceded by pre-IND meeting in December 2001, although TPNA's original target of IND was February. Since CMC documents will be the rate-limiting factor to file NDA, TCI is going to check if a start of the stability study can be brought forward. GSK will reportedly obtain the approval of their combination product within this year. With regard to Actos-SU Combination Tablet, it should take 18 months from the selection of SU to finalization of the SU combination tablet, TPNA is going to make a proposal for the SU product shortly - which su to choose and its dose levels. - Revision to language in package insert in terms of liver monitoring requirement Liver monitoring issue will be discussed between TPNA and EuR&D so that sNDA/variation for a label change may be submitted in January 2003. - Timelines of other studies were discussed and agreed mutually. Key results (TLGs) from studies 504 and 520 will be made available as scheduled, which are required for the European applications. EuR&D will not be involved in review process of TLGs. The development plan in dysmetabolic syndrome will be approved around late October in-house at TCI. An s NDA of atherosclerosis indication in US is scheduled for October 2005. Update of EU status by EuR&D - Current schedule of submission for mono & unrestricted combo therapy indications Variations to posology (45mg) and indications (monotherapy and first line combination therapy) are scheduled to be submitted in January 2003. Clock starts on 30 January 2003. - Prescription status variation (type II) Variation was submitted on 6th September 2002 and opinion is expected on 19th November 2002. - PROactive The first DSMB meeting is planned for 3Q 2003 and any scientific advance/opinion are invited before the meeting. Publication on baseline data is scheduled for early next year, therefore any modifications on endpoints including FDA suggestions have to be made before the publication. FDA should raise no issue on the protocol according to TPNA. 3 Confidential - Subject to Protective Order TAK-THOMCL-00012575 Produced in MDL on 09/14/12 Source: https://www.indup0442-00003s.ucsf.edu/docs/Imjf0226 - Actos/generic metformin combination tablet Flash data from a pilot BE study to be conducted by EuR&D will be available in mid of November. EU submission based PK/PD argument alone has a low chance of success, around 40%. Although the guidelines expect clinical data to be provided, clinical studies should not be conducted because there is a possibility that Actos bid might show better results than once daily even if daily dose is the same. In Europe, it was agreed to submit the BE study results from US with PK/PD argument as a challenge. It was also agreed that no interaction with authorities is made to ask about the development strategy, because we have to conduct clinical studies once the authorities request us to do them. EuR&D reported that EMO had no interest in Actos-Metformin Combination Pack due to the difficulty to register combination packs in EMEA/CPMP and its poor marketability in EU. CONCLUSIONS; TPNA to prepare non-clinical "White paper" to address bladder issue TPNA & EuR&D to discuss liver monitoring requirement to revise the language in US package insert and EU SPC in January 2003 Generic metformin fixed combination tablet to be pursued in Europe using PD modeling (but, chance of success is low) No interest in convenience pack in Europe Other Takeda Drugs Confidential - Subject to Protective Order TAK-THOMCL-00012576 Produced in MDL on 09/14/12 Source: https://www.indupo.42°00004s.ucsf.edu/docs//mjf0226 Other Takeda Drugs Other Takeda Drugs Other Takeda Drugs Other Takeda Drugs Confidential - Subject to Protective Order TAK-THOMCL-00012577 Produced in MDL on 09/14/12 Source: Other Takeda Drugs Other Takeda Drugs Other Takeda Drugs 6 Confidential - Subject to Protective Order TAK-THOMCL-00012578 Produced in MDL on 09/14/12 Source: Other Takeda Drugs 2) TAK-070 7 Confidential - Subject to Protective Order TAK-THOMCL-00012579 Produced in MDL on 09/14/12 Source: https://www.indupo442°00007ts.ucsf.edu/docs/Imjf0226 Other Takeda Drugs 8 Confidential - Subject to Protective Order TAK-THOMCL-00012580 Produced in MDL on 09/14/12 Source: https://www.indupo:42-00008.ucsf.edu/docs//mjf0226 Other Takeda Drugs investigators. However this issue IS to be discussed with Mitsubishi since they are 9 Confidential - Subject to Protective Order TAK-THOMCL-00012581 Produced in MDL on 09/14/12 Source: Other Takeda Drugs Confidential - Subject to Protective Order TAK-THOMCL-00012582 Produced in MDL on 09/14/12 Source: https://www.indupo.420000.ucsf.edu/docs//mjf0226 Other Takeda Drugs 11 Confidential - Subject to Protective Order TAK-THOMCL-00012583 Produced in MDL on 09/14/12 Source: https://www.indupo:4200ts.ucsf.edu/docs/Imjf0226 Other Takeda Drugs Confidential - Subject to Protective Order TAK-THOMCL-00012584 Produced in MDL on 09/14/12 Source: https://www.indupo442-0002s.ucsf.edu/docs/Imjf0226 Other Takeda Drugs Confidential - Subject to Protective Order TAK-THOMCL-00012585 Produced in MDL on 09/14/12 Source: Other Takeda Drugs Confidential - Subject to Protective Order TAK-THOMCL-00012586 Produced in MDL on 09/14/12 Source: https://www.indupo442°0001'.ucsf.edu/docs/Imjf0226 Other Takeda Drugs Confidential - Subject to Protective Order TAK-THOMCL-00012587 Produced in MDL on 09/14/12 Source: Other Takeda Drugs Confidential - Subject to Protective Order TAK-THOMCL-00012588 Produced in MDL on 09/14/12 Source: END 17 Confidential - Subject to Protective Order TAK-THOMCL-00012589 Produced in MDL on 09/14/12 Source: https://www.indupo442-0007ts.ucsf.edu/docs/Imjf0226

who will forward the article regarding rosiglitazone and non clinical bladder data to andy ?

nqjf0226

nqjf0226_p0, nqjf0226_p1

Mondira

Actos Pediatric Working Group Date: 20 April 2006 Time: 4:00pm - 5:00pm Meeting Minutes Place: Meeting Room 403 Attendees Attendees Alfonso Perez - Clinical Karen Kaluzny - Project Management X Stuart Kupfer - Clinical X Mary Jo Pritza - Regulatory X Brigit Isaacson - Clinical X Shari Bodnoff - Medical Writing X Pat Schwartz - Clinical Andy Roberts - Medical Writing X Mondira Bhattacharya - Product Safety Agenda Items GDC Update A TPC stressed the importance of the ACTOS pediatric program, and requested that the preparation of the written request be expedited. Next Steps - Developing Partial Clinical Hold Removal Request Document A meeting will be scheduled in early May to develop the overall structure of the document. In addition to the elements already defined, the team agreed that the following should be added: Any new nonclinical data regarding PPAR agonists and bladder safety Bladder safety analysis from CHICAGO study (Projected database lock: 5 June 2006) Post-meeting note: Additional safety analysis from ACTOS 506 study Action Items: Mondira will forward article regarding rosiglitazone and nonclinical bladder data to Andy. Andy will request a literature search for any new articles regarding PPARs and nonclinical bladder data. Mary Jo will follow-up with David Baron to determine if he is aware of any new data regarding PPARs and bladder safety. Mary Jo will determine if the FDA has received information about the PROactive extension and the second KNPC study being done to fulfill EMEA's requirements. Post-meeting note: Completed. Both protocols were sent to the FDA. Andy will follow-up with Regulatory to obtain examples of other clinical hold removal request documents. (Deb Yarbrough - TAK-428, Mary Jo - TAK-654) Karen will schedule the document development meeting for the second week of May. N:/Product Development and Planning/ACTOS/Working Groups/Pediatrics/<AUTO> Page 1 of 2 Confidential - Subject to Protective Order TAK-KUPFES-00716752 Produced in MDL on 09/19/12 Agenda Items Outstanding Issues - Action Items Karen and Brigit will work offline to develop the protocol timelines. Work on the protocol synopsis is already ongoing. N:/Product Development and Planning/ACTOS/Working Groups/Pediatrics/<AUTO> Page 2 of 2 Confidential - Subject to Protective Order TAK-KUPFES-00716753 Produced in MDL on 09/19/12 Source: https://www.indup4885-00002s.ucsf.edu/docs/nqjf0226

Who presented an outline of the Cohen hypothesis?

myjf0226

myjf0226_p0, myjf0226_p1, myjf0226_p2, myjf0226_p3

Philip Collett

ACTOS FDA RESPONSE MEETING TPNA/TEUR&D/TCI AUGUST 12-13, 2002 Attendees: TPNA TEUR&D Sam Hamanaka David Eckland Claire Thom Yasuhiko Wada Ingrid Hood Glyn Belcher Alfonso Perez Philip Collett David Recker John Page TCI Mary Ramstack Katsuhisa Saito Janet Haskins Masahiro Miyazaki Dan Orlando Takashi Kuroiwa David Baron Takashi Nonoyama Chris Durack Keiichiro Sato Larry Hancock Hiroyuki Odaka Bob Ahlbrandt Tom Muldoon Karen Kaluzny Summary of July 31 Teleconference with FDA (J. Haskins) The FDA informed TPNA that they had received data from a rat tumor promoter study using dual PPAR agonists. Pioglitazone was used in this experiment, and the group of rats treated with pioglitazone experienced the same frequency of transitional cell tumors as the group treated with the dual PPAR agonist under investigation. The FDA clarified that due to this data, they had concerns with the dual PPAR mechanism, and considered pioglitazone to have a dual PPAR mechanism. There were three key messages from the teleconference: The FDA asked TPNA to consider a label change, as they feel that the current package insert does not adequately inform patients of the risk associated with bladder tumors. The FDA asked TPNA to research and propose a monitoring plan, which would be incorporated into clinical trials. The FDA stated that they were considering rescinding their written request to TPNA to conduct pediatric studies with pioglitazone. Confidential - Subject to Protective Order TAK-RAMSTM-00487173 Produced in MDL on 03/06/13 Source: ACTOS FDA Response Meeting August 12-13, 2002 Page 2 of 4 Summary of July 31 Teleconference with FDA (J. Haskins) - Continued The group summarized the FDA's concerns as follows: The FDA is not stating that ACTOS specifically causes or contributes to bladder tumors. The FDA no longer supports Dr. Cohen's hypothesis, since the tumor promoter study data they received demonstrated the presence of tumors without calculi. The FDA no longer feels that they understand how these findings relate to humans. Update from TCI Meeting with CEO (Mr. Saito) Mr. Saito updated the CEO on this situation on August 6. The following strategy was decided on: Attempt to keep current carcinogenicity label wording; if not possible, request that same labeling be applied to Avandia Find rationale to support not establishing monitoring plan, but if necessary, would compromise on monitoring wording to avoid changing carcinogenicity wording Develop argument to proceed with Actos 508 (safety/efficacy in pediatrics) study under current timelines, but are willing to postpone The following timelines were established: TPNA to send outline of response to TCI by August 19 Mr. Saito will present outline to CEO on August 20 TPNA will send draft document to TCI, TEUR&D, and Lilly on August 21 Document will be finalized by August 26 Response will be sent to FDA on August 28 Mr Saito also presented the following communication structure and schematic Leadership: Claire Thom, David Eckland, Mr. Saito Primary contacts: Mary Ramstack, Janet Haskins, Philip Collett, Mr. Miyazaki The only exception to this schematic will be that on August 26, TPNA will communicate directly with Lilly to distribute the draft document CEO Mr Saito TPNA TCI labs Lilly EU Confidential - Subject to Protective Order TAK-RAMSTM-00487174 Produced in MDL on 03/06/13 Source: ACTOS FDA Response Meeting August 12-13, 2002 Page 3 of 4 Highlights/Discussion Points from Preclinical Data Presentation In the rat oncogenicity study, thickening of the bladder and hypertrophy of the urothelium was observed in male rats. These findings were not dose- dependent. Nearly all of the tumors were found at the end of the study. Some cases of hyperplasia were seen in female rats at the highest dose level only, but no malignancies were seen. There were no tumors seen in the shorter term (12 month) rat toxicity studies. Glyn Belcher suggested creating a summary able for all toxicology studies with durations between 6 months and less than 2 years. In the mouse oncogenicity study, hyperplasia was seen in male mice only. These findings were not dose-dependent, and results were not statistically significant. One case of hyperplasia was observed in the placebo group. Philip Collett stated that the European authorities did not question the mouse data for ACTOS, but rather only the rat data. A list of all mutagenicity studies conducted with pioglitazone was shown, and David Baron acknowledged that TCI had conducted a very robust program that went beyond regulatory requirements. A study observing the effects of pioglitazone on urinary parameters in rats was conducted, and highlights are as follows: Simple hyperplasia seen in one male Increase in urine pH, urine volume, microcrystal count Slight decrease in magnesium, calcium, phosphorous, sodium, potassium, and chloride Conclusion: Changes in urinary components are considered to be factors in the etiology of proliferative lesions of the bladder: Pioglitazone ingestion Altered urinary physiology Calculus formation Urothelial ulceration an regeneration (hyperplasia) Benin papilloma Carcinoma Confidential - Subject to Protective Order TAK-RAMSTM-00487175 Produced in MDL on 03/06/13 Source: ACTOS FDA Response Meeting August 12-13, 2002 Page 4 of 4 Highlights from Cohen Hypothesis Discussion Philip Collett presented an outline of the Cohen hypothesis Male rat urine has a very high protein content, which is a function of sex hormones Raising the pH of male rat urine above 6.5 is significant in the development of calculi Because rats are quadropeds, they do not eliminate calculi as humans do The correlation observed in Cohen's paper is 0.61. The European authorities initially determined this to be quite low; however, Dr. Cohen authored an expert report which stated that the 0.61 correlation was actually high, as calculi can dissolve over time. In summary, the tumors seen in rats were due to the presence of calculi. The male rat urine milieu contributes to the formation of calculi. Because rats are quadropeds, they do not eliminate calculi as bipeds do. Main Points from Takeda Europe Experience Takeda Europe successfully employed the following strategy: Defended Cohen hypothesis, despite numerous challenges Stressed the "one sex, one species" argument Challenged authorities regarding implementing monitoring plan Offered to conduct a case control study post-approval Highlights from PPAR Agonist Discussion The group extensively discussed many aspects of the PPAR mechanism and ultimately decided to not address mechanistic issues in the initial FDA response. However, it was decided that this argument should be developed, as it may be necessary to use it in the future, and action items were assigned accordingly. Confidential - Subject to Protective Order TAK-RAMSTM-00487176 Produced in MDL on 03/06/13 Source:

What is significant in the development of calculi?

myjf0226

myjf0226_p0, myjf0226_p1, myjf0226_p2, myjf0226_p3

Raising the pH of male rat urine above 6.5

ACTOS FDA RESPONSE MEETING TPNA/TEUR&D/TCI AUGUST 12-13, 2002 Attendees: TPNA TEUR&D Sam Hamanaka David Eckland Claire Thom Yasuhiko Wada Ingrid Hood Glyn Belcher Alfonso Perez Philip Collett David Recker John Page TCI Mary Ramstack Katsuhisa Saito Janet Haskins Masahiro Miyazaki Dan Orlando Takashi Kuroiwa David Baron Takashi Nonoyama Chris Durack Keiichiro Sato Larry Hancock Hiroyuki Odaka Bob Ahlbrandt Tom Muldoon Karen Kaluzny Summary of July 31 Teleconference with FDA (J. Haskins) The FDA informed TPNA that they had received data from a rat tumor promoter study using dual PPAR agonists. Pioglitazone was used in this experiment, and the group of rats treated with pioglitazone experienced the same frequency of transitional cell tumors as the group treated with the dual PPAR agonist under investigation. The FDA clarified that due to this data, they had concerns with the dual PPAR mechanism, and considered pioglitazone to have a dual PPAR mechanism. There were three key messages from the teleconference: The FDA asked TPNA to consider a label change, as they feel that the current package insert does not adequately inform patients of the risk associated with bladder tumors. The FDA asked TPNA to research and propose a monitoring plan, which would be incorporated into clinical trials. The FDA stated that they were considering rescinding their written request to TPNA to conduct pediatric studies with pioglitazone. Confidential - Subject to Protective Order TAK-RAMSTM-00487173 Produced in MDL on 03/06/13 Source: ACTOS FDA Response Meeting August 12-13, 2002 Page 2 of 4 Summary of July 31 Teleconference with FDA (J. Haskins) - Continued The group summarized the FDA's concerns as follows: The FDA is not stating that ACTOS specifically causes or contributes to bladder tumors. The FDA no longer supports Dr. Cohen's hypothesis, since the tumor promoter study data they received demonstrated the presence of tumors without calculi. The FDA no longer feels that they understand how these findings relate to humans. Update from TCI Meeting with CEO (Mr. Saito) Mr. Saito updated the CEO on this situation on August 6. The following strategy was decided on: Attempt to keep current carcinogenicity label wording; if not possible, request that same labeling be applied to Avandia Find rationale to support not establishing monitoring plan, but if necessary, would compromise on monitoring wording to avoid changing carcinogenicity wording Develop argument to proceed with Actos 508 (safety/efficacy in pediatrics) study under current timelines, but are willing to postpone The following timelines were established: TPNA to send outline of response to TCI by August 19 Mr. Saito will present outline to CEO on August 20 TPNA will send draft document to TCI, TEUR&D, and Lilly on August 21 Document will be finalized by August 26 Response will be sent to FDA on August 28 Mr Saito also presented the following communication structure and schematic Leadership: Claire Thom, David Eckland, Mr. Saito Primary contacts: Mary Ramstack, Janet Haskins, Philip Collett, Mr. Miyazaki The only exception to this schematic will be that on August 26, TPNA will communicate directly with Lilly to distribute the draft document CEO Mr Saito TPNA TCI labs Lilly EU Confidential - Subject to Protective Order TAK-RAMSTM-00487174 Produced in MDL on 03/06/13 Source: ACTOS FDA Response Meeting August 12-13, 2002 Page 3 of 4 Highlights/Discussion Points from Preclinical Data Presentation In the rat oncogenicity study, thickening of the bladder and hypertrophy of the urothelium was observed in male rats. These findings were not dose- dependent. Nearly all of the tumors were found at the end of the study. Some cases of hyperplasia were seen in female rats at the highest dose level only, but no malignancies were seen. There were no tumors seen in the shorter term (12 month) rat toxicity studies. Glyn Belcher suggested creating a summary able for all toxicology studies with durations between 6 months and less than 2 years. In the mouse oncogenicity study, hyperplasia was seen in male mice only. These findings were not dose-dependent, and results were not statistically significant. One case of hyperplasia was observed in the placebo group. Philip Collett stated that the European authorities did not question the mouse data for ACTOS, but rather only the rat data. A list of all mutagenicity studies conducted with pioglitazone was shown, and David Baron acknowledged that TCI had conducted a very robust program that went beyond regulatory requirements. A study observing the effects of pioglitazone on urinary parameters in rats was conducted, and highlights are as follows: Simple hyperplasia seen in one male Increase in urine pH, urine volume, microcrystal count Slight decrease in magnesium, calcium, phosphorous, sodium, potassium, and chloride Conclusion: Changes in urinary components are considered to be factors in the etiology of proliferative lesions of the bladder: Pioglitazone ingestion Altered urinary physiology Calculus formation Urothelial ulceration an regeneration (hyperplasia) Benin papilloma Carcinoma Confidential - Subject to Protective Order TAK-RAMSTM-00487175 Produced in MDL on 03/06/13 Source: ACTOS FDA Response Meeting August 12-13, 2002 Page 4 of 4 Highlights from Cohen Hypothesis Discussion Philip Collett presented an outline of the Cohen hypothesis Male rat urine has a very high protein content, which is a function of sex hormones Raising the pH of male rat urine above 6.5 is significant in the development of calculi Because rats are quadropeds, they do not eliminate calculi as humans do The correlation observed in Cohen's paper is 0.61. The European authorities initially determined this to be quite low; however, Dr. Cohen authored an expert report which stated that the 0.61 correlation was actually high, as calculi can dissolve over time. In summary, the tumors seen in rats were due to the presence of calculi. The male rat urine milieu contributes to the formation of calculi. Because rats are quadropeds, they do not eliminate calculi as bipeds do. Main Points from Takeda Europe Experience Takeda Europe successfully employed the following strategy: Defended Cohen hypothesis, despite numerous challenges Stressed the "one sex, one species" argument Challenged authorities regarding implementing monitoring plan Offered to conduct a case control study post-approval Highlights from PPAR Agonist Discussion The group extensively discussed many aspects of the PPAR mechanism and ultimately decided to not address mechanistic issues in the initial FDA response. However, it was decided that this argument should be developed, as it may be necessary to use it in the future, and action items were assigned accordingly. Confidential - Subject to Protective Order TAK-RAMSTM-00487176 Produced in MDL on 03/06/13 Source:

What is the correlation observed in cohen's paper?

myjf0226

myjf0226_p0, myjf0226_p1, myjf0226_p2, myjf0226_p3

0.61

ACTOS FDA RESPONSE MEETING TPNA/TEUR&D/TCI AUGUST 12-13, 2002 Attendees: TPNA TEUR&D Sam Hamanaka David Eckland Claire Thom Yasuhiko Wada Ingrid Hood Glyn Belcher Alfonso Perez Philip Collett David Recker John Page TCI Mary Ramstack Katsuhisa Saito Janet Haskins Masahiro Miyazaki Dan Orlando Takashi Kuroiwa David Baron Takashi Nonoyama Chris Durack Keiichiro Sato Larry Hancock Hiroyuki Odaka Bob Ahlbrandt Tom Muldoon Karen Kaluzny Summary of July 31 Teleconference with FDA (J. Haskins) The FDA informed TPNA that they had received data from a rat tumor promoter study using dual PPAR agonists. Pioglitazone was used in this experiment, and the group of rats treated with pioglitazone experienced the same frequency of transitional cell tumors as the group treated with the dual PPAR agonist under investigation. The FDA clarified that due to this data, they had concerns with the dual PPAR mechanism, and considered pioglitazone to have a dual PPAR mechanism. There were three key messages from the teleconference: The FDA asked TPNA to consider a label change, as they feel that the current package insert does not adequately inform patients of the risk associated with bladder tumors. The FDA asked TPNA to research and propose a monitoring plan, which would be incorporated into clinical trials. The FDA stated that they were considering rescinding their written request to TPNA to conduct pediatric studies with pioglitazone. Confidential - Subject to Protective Order TAK-RAMSTM-00487173 Produced in MDL on 03/06/13 Source: ACTOS FDA Response Meeting August 12-13, 2002 Page 2 of 4 Summary of July 31 Teleconference with FDA (J. Haskins) - Continued The group summarized the FDA's concerns as follows: The FDA is not stating that ACTOS specifically causes or contributes to bladder tumors. The FDA no longer supports Dr. Cohen's hypothesis, since the tumor promoter study data they received demonstrated the presence of tumors without calculi. The FDA no longer feels that they understand how these findings relate to humans. Update from TCI Meeting with CEO (Mr. Saito) Mr. Saito updated the CEO on this situation on August 6. The following strategy was decided on: Attempt to keep current carcinogenicity label wording; if not possible, request that same labeling be applied to Avandia Find rationale to support not establishing monitoring plan, but if necessary, would compromise on monitoring wording to avoid changing carcinogenicity wording Develop argument to proceed with Actos 508 (safety/efficacy in pediatrics) study under current timelines, but are willing to postpone The following timelines were established: TPNA to send outline of response to TCI by August 19 Mr. Saito will present outline to CEO on August 20 TPNA will send draft document to TCI, TEUR&D, and Lilly on August 21 Document will be finalized by August 26 Response will be sent to FDA on August 28 Mr Saito also presented the following communication structure and schematic Leadership: Claire Thom, David Eckland, Mr. Saito Primary contacts: Mary Ramstack, Janet Haskins, Philip Collett, Mr. Miyazaki The only exception to this schematic will be that on August 26, TPNA will communicate directly with Lilly to distribute the draft document CEO Mr Saito TPNA TCI labs Lilly EU Confidential - Subject to Protective Order TAK-RAMSTM-00487174 Produced in MDL on 03/06/13 Source: ACTOS FDA Response Meeting August 12-13, 2002 Page 3 of 4 Highlights/Discussion Points from Preclinical Data Presentation In the rat oncogenicity study, thickening of the bladder and hypertrophy of the urothelium was observed in male rats. These findings were not dose- dependent. Nearly all of the tumors were found at the end of the study. Some cases of hyperplasia were seen in female rats at the highest dose level only, but no malignancies were seen. There were no tumors seen in the shorter term (12 month) rat toxicity studies. Glyn Belcher suggested creating a summary able for all toxicology studies with durations between 6 months and less than 2 years. In the mouse oncogenicity study, hyperplasia was seen in male mice only. These findings were not dose-dependent, and results were not statistically significant. One case of hyperplasia was observed in the placebo group. Philip Collett stated that the European authorities did not question the mouse data for ACTOS, but rather only the rat data. A list of all mutagenicity studies conducted with pioglitazone was shown, and David Baron acknowledged that TCI had conducted a very robust program that went beyond regulatory requirements. A study observing the effects of pioglitazone on urinary parameters in rats was conducted, and highlights are as follows: Simple hyperplasia seen in one male Increase in urine pH, urine volume, microcrystal count Slight decrease in magnesium, calcium, phosphorous, sodium, potassium, and chloride Conclusion: Changes in urinary components are considered to be factors in the etiology of proliferative lesions of the bladder: Pioglitazone ingestion Altered urinary physiology Calculus formation Urothelial ulceration an regeneration (hyperplasia) Benin papilloma Carcinoma Confidential - Subject to Protective Order TAK-RAMSTM-00487175 Produced in MDL on 03/06/13 Source: ACTOS FDA Response Meeting August 12-13, 2002 Page 4 of 4 Highlights from Cohen Hypothesis Discussion Philip Collett presented an outline of the Cohen hypothesis Male rat urine has a very high protein content, which is a function of sex hormones Raising the pH of male rat urine above 6.5 is significant in the development of calculi Because rats are quadropeds, they do not eliminate calculi as humans do The correlation observed in Cohen's paper is 0.61. The European authorities initially determined this to be quite low; however, Dr. Cohen authored an expert report which stated that the 0.61 correlation was actually high, as calculi can dissolve over time. In summary, the tumors seen in rats were due to the presence of calculi. The male rat urine milieu contributes to the formation of calculi. Because rats are quadropeds, they do not eliminate calculi as bipeds do. Main Points from Takeda Europe Experience Takeda Europe successfully employed the following strategy: Defended Cohen hypothesis, despite numerous challenges Stressed the "one sex, one species" argument Challenged authorities regarding implementing monitoring plan Offered to conduct a case control study post-approval Highlights from PPAR Agonist Discussion The group extensively discussed many aspects of the PPAR mechanism and ultimately decided to not address mechanistic issues in the initial FDA response. However, it was decided that this argument should be developed, as it may be necessary to use it in the future, and action items were assigned accordingly. Confidential - Subject to Protective Order TAK-RAMSTM-00487176 Produced in MDL on 03/06/13 Source:

Why didn't rats eliminate calculi as humans do?

myjf0226

myjf0226_p0, myjf0226_p1, myjf0226_p2, myjf0226_p3

Because rats are quadropeds., Because rats are quadropeds

ACTOS FDA RESPONSE MEETING TPNA/TEUR&D/TCI AUGUST 12-13, 2002 Attendees: TPNA TEUR&D Sam Hamanaka David Eckland Claire Thom Yasuhiko Wada Ingrid Hood Glyn Belcher Alfonso Perez Philip Collett David Recker John Page TCI Mary Ramstack Katsuhisa Saito Janet Haskins Masahiro Miyazaki Dan Orlando Takashi Kuroiwa David Baron Takashi Nonoyama Chris Durack Keiichiro Sato Larry Hancock Hiroyuki Odaka Bob Ahlbrandt Tom Muldoon Karen Kaluzny Summary of July 31 Teleconference with FDA (J. Haskins) The FDA informed TPNA that they had received data from a rat tumor promoter study using dual PPAR agonists. Pioglitazone was used in this experiment, and the group of rats treated with pioglitazone experienced the same frequency of transitional cell tumors as the group treated with the dual PPAR agonist under investigation. The FDA clarified that due to this data, they had concerns with the dual PPAR mechanism, and considered pioglitazone to have a dual PPAR mechanism. There were three key messages from the teleconference: The FDA asked TPNA to consider a label change, as they feel that the current package insert does not adequately inform patients of the risk associated with bladder tumors. The FDA asked TPNA to research and propose a monitoring plan, which would be incorporated into clinical trials. The FDA stated that they were considering rescinding their written request to TPNA to conduct pediatric studies with pioglitazone. Confidential - Subject to Protective Order TAK-RAMSTM-00487173 Produced in MDL on 03/06/13 Source: ACTOS FDA Response Meeting August 12-13, 2002 Page 2 of 4 Summary of July 31 Teleconference with FDA (J. Haskins) - Continued The group summarized the FDA's concerns as follows: The FDA is not stating that ACTOS specifically causes or contributes to bladder tumors. The FDA no longer supports Dr. Cohen's hypothesis, since the tumor promoter study data they received demonstrated the presence of tumors without calculi. The FDA no longer feels that they understand how these findings relate to humans. Update from TCI Meeting with CEO (Mr. Saito) Mr. Saito updated the CEO on this situation on August 6. The following strategy was decided on: Attempt to keep current carcinogenicity label wording; if not possible, request that same labeling be applied to Avandia Find rationale to support not establishing monitoring plan, but if necessary, would compromise on monitoring wording to avoid changing carcinogenicity wording Develop argument to proceed with Actos 508 (safety/efficacy in pediatrics) study under current timelines, but are willing to postpone The following timelines were established: TPNA to send outline of response to TCI by August 19 Mr. Saito will present outline to CEO on August 20 TPNA will send draft document to TCI, TEUR&D, and Lilly on August 21 Document will be finalized by August 26 Response will be sent to FDA on August 28 Mr Saito also presented the following communication structure and schematic Leadership: Claire Thom, David Eckland, Mr. Saito Primary contacts: Mary Ramstack, Janet Haskins, Philip Collett, Mr. Miyazaki The only exception to this schematic will be that on August 26, TPNA will communicate directly with Lilly to distribute the draft document CEO Mr Saito TPNA TCI labs Lilly EU Confidential - Subject to Protective Order TAK-RAMSTM-00487174 Produced in MDL on 03/06/13 Source: ACTOS FDA Response Meeting August 12-13, 2002 Page 3 of 4 Highlights/Discussion Points from Preclinical Data Presentation In the rat oncogenicity study, thickening of the bladder and hypertrophy of the urothelium was observed in male rats. These findings were not dose- dependent. Nearly all of the tumors were found at the end of the study. Some cases of hyperplasia were seen in female rats at the highest dose level only, but no malignancies were seen. There were no tumors seen in the shorter term (12 month) rat toxicity studies. Glyn Belcher suggested creating a summary able for all toxicology studies with durations between 6 months and less than 2 years. In the mouse oncogenicity study, hyperplasia was seen in male mice only. These findings were not dose-dependent, and results were not statistically significant. One case of hyperplasia was observed in the placebo group. Philip Collett stated that the European authorities did not question the mouse data for ACTOS, but rather only the rat data. A list of all mutagenicity studies conducted with pioglitazone was shown, and David Baron acknowledged that TCI had conducted a very robust program that went beyond regulatory requirements. A study observing the effects of pioglitazone on urinary parameters in rats was conducted, and highlights are as follows: Simple hyperplasia seen in one male Increase in urine pH, urine volume, microcrystal count Slight decrease in magnesium, calcium, phosphorous, sodium, potassium, and chloride Conclusion: Changes in urinary components are considered to be factors in the etiology of proliferative lesions of the bladder: Pioglitazone ingestion Altered urinary physiology Calculus formation Urothelial ulceration an regeneration (hyperplasia) Benin papilloma Carcinoma Confidential - Subject to Protective Order TAK-RAMSTM-00487175 Produced in MDL on 03/06/13 Source: ACTOS FDA Response Meeting August 12-13, 2002 Page 4 of 4 Highlights from Cohen Hypothesis Discussion Philip Collett presented an outline of the Cohen hypothesis Male rat urine has a very high protein content, which is a function of sex hormones Raising the pH of male rat urine above 6.5 is significant in the development of calculi Because rats are quadropeds, they do not eliminate calculi as humans do The correlation observed in Cohen's paper is 0.61. The European authorities initially determined this to be quite low; however, Dr. Cohen authored an expert report which stated that the 0.61 correlation was actually high, as calculi can dissolve over time. In summary, the tumors seen in rats were due to the presence of calculi. The male rat urine milieu contributes to the formation of calculi. Because rats are quadropeds, they do not eliminate calculi as bipeds do. Main Points from Takeda Europe Experience Takeda Europe successfully employed the following strategy: Defended Cohen hypothesis, despite numerous challenges Stressed the "one sex, one species" argument Challenged authorities regarding implementing monitoring plan Offered to conduct a case control study post-approval Highlights from PPAR Agonist Discussion The group extensively discussed many aspects of the PPAR mechanism and ultimately decided to not address mechanistic issues in the initial FDA response. However, it was decided that this argument should be developed, as it may be necessary to use it in the future, and action items were assigned accordingly. Confidential - Subject to Protective Order TAK-RAMSTM-00487176 Produced in MDL on 03/06/13 Source:

What is the fullform of MAA?

gmjf0226

gmjf0226_p0, gmjf0226_p1

Marketing Authorization Application

Minutes from Takeda Global Risk Management Forum/March 22, 2004 Facilitators: Glyn Belcher, MA, PhD, MB, BCHIR, FFPM/TEuRD Cal McNeill, MD/ TGRD Attendees: Mondira Bhattacharya MD, David Baron MD, Al Dietz MD, Barbara Hendrickson MD, Doug Joseph PharmD, Ron Law MD, Constance Kasprzak PharmD, Anna Lee MD, Olga Minkov BS MPN, Alfonso Perez MD, Jeremy Repp BIE, Mick Roebel PhD, Stephen Sainati MD, Claire Thom PharmD, Bill Welder MD EU Perspective Glyn Belcher Risk Management Identification of potential risk Clarification of risk Measurement of risk More extensive than risk minimization Should be done by Pharmacovigilance in Company. Risk Management starts during preclinical- clinical development marketing Risk management by pharmacovigilance in company: 1) Pre-clinical Every EU country sends in an Investigational Medicinal Product (IMP) documentation much like the IND which reviews preclinical safety signals and includes a plan on how to measure these safety signals in a clinical trial Includes specific attempts during clinical trials to clarify signals 2) Clinical trial yearly IMP safety report (global) will be required from May '04 onwards and includes all safety data in a year including nonclinical safety data. Regulators expect company to tell them what the problem is. Requires unblinding of serious unexpected reactions. Includes Postmarketing commitments 3) MAA (Marketing Authorization Application) = equivalent to NDA. As part of dossier, submit a risk management plan within one year. Risk management plan includes what you can say about safety of the drug and what you have not managed to clarify: more proactive in delineating what problems you know VS what you don't know Includes plans on further trials/studies to be done EXHIBIT Takeda Forum Risk Management 1 Bhattacharya March 22, 2004 11 1-12-13- Confidential - Subject to Protective Order TAK-BAROND-00208931 Produced in MDL on 09/02/12 Source: 4) Marketing 6 monthly PSUR's In the future, risk management plan will be reviewed to see how much of the safety signals have been clarified. Will include not just listings of events but more figures. Risk has to be clearly stated. Specific examples: Pioglitazone: Need to commit to studies to investigate certain signals 1) Bladder Cancer in Rats further epidemiologie study and pre-clinical investigations as part of license application Preclinical investigations done within TCI (Osaka). Some preclinical investigations are contracted out ie, to U of Nebraska which submits protocols but doesn't do actual work. Epi study; case control study: use retrospective data from general practitioners database. Other epi studies: prospective case cohort study; epi studies tagging people who receive the drug and compare results with historical data 2) Fluid Retention/CHI /Cardiac hypertrophy mechanistic studies will be conducted. As part of license application, studies in CHF patients + outcome studies were requested Safety signals will be clarified using these studies, 3) Liver problem PEM (prescription event monitoring) study similar to Japanese post- event marketing study. Prescribing doctor's name and patient's name are recorded in a central database from beginning of marketing. This database is reviewed for signals US Perspective Cal McNeill Discussion: Regulators will have similar interest in USA as in Europe. FDA expects sponsors to become proactive around safety issues from pre-clinical data to marketing phase Incorporate RM strategies in NDA submissions which is not the case at the moment but will begin incorporating risk management strategies for/ with Ramelteon. minimize risk throughout product's life-cylce guidance from FDA expected in September 2004 Risk Management - component of comprehensive product stewardship - pre-market/ clinical development - post-marketing General Discussion ALL Question 1 - Japan's role in RM: Who will direct company's position? Suggestion from Glyn: TGRD would formulate direct Risk Management plan and obtain Japan's input. Takeda Forum Risk Management 2 March 22, 2004 Confidential - Subject to Protective Order TAK-BAROND-00208932 Produced in MDL on 09/02/12 Source: https://www.induso/r56-00002.ucsf.edu/docs/gmjf0226

Who is the Director of Nonclinical Safety and Efficacy?

jsjf0226

jsjf0226_p0, jsjf0226_p1

David Baron, David baron

EXHIBIT 107 FDA Conference Call: August 13, 2002 FDA Personnel: Jeri El-Hage, Ph.D., Toxicology Team Leader Jena Weber, Project Manager TPNA Personnel: David Baron, Ph.D., Director, Nonclinical Safety and Efficacy Janet Haskins, Manager, Regulatory Affairs Pat Frank, Ph.D., TPNA Consultant This teleconference was held as a follow-up to a discussion between TPNA and the Agency on July 31, 2002. The purpose of this call was so that Dr. El-Hage could expand upon the nonclinical data related to dual PPAR agonists that were discussed with TPNA on July 31, 2002. Dr. El-Hage informed TPNA that in standard 2-year rat and mouse bioassay studies, several other dual PPAR agonists were shown to cause transitional cell tumors in the bladder and kidneys of male and female rats and male mice. Therefore, the Division is considering the relevance of these findings to this pharmaceutical class of drugs. She also noted that in follow-up unspecified mechanistic studies of the other dual PPAR agonists, no evidence of irritation by crystalluria or calculi was noted. Dr. El-Hage then described a tumor promoter-model study that was conducted by another sponsor in which pioglitazone was administered. The study was designed as follows: BBN was given to male Fisher rats in their drinking water for four weeks. Four groups were designated: Pioglitazone 40 mg/kg/day after BBN The study compound plus BBN (No dosages were specified, but Dr. El-Hage noted that multiple dosages were studied and the high dose was designed to be "equivalent" to 40 mg/kg pioglitazone) The negative control group received BBN only. The positive control group received uracil. Duration of daily dosing was 32-weeks after BBN. Results: 85% of the animals in the pioglitazone and the other sponsor's compound groups had tumor formation. Calculi formation was not confirmed in either group, but was looked for using unspecified methodology. 15% of the animals in the negative control group had tumor formation, while approximately 50% of the positive control group presented tumors in the presence of calculi formation (uracil) Confidential - Subject to Protective Order TAK-NAUGHP-00080811 Source: https://www.indup372.0000nts.ucsf.edu/docs/jsjf0226 Based on these findings, and the fact that the development of the other dual PPAR agonists has been discontinued, the Division expressed a concern that a possible risk of dual PPARs has not been addressed. Dr. El-Hage stated that prior to other dual PPAR agonists discontinuing development, monitoring for bladder tumors was required in their phase III clinical studies. She noted that the Division's internal consultant suggested screening urine for NMP-22. Dr. El-Hage believes this assay is approved for screening of bladder tumors and is commercially available. Finally Dr. El-Hage noted that she will be consulting with the CAC board in mid- September. She will inquire if they feel that the pioglitazone package insert adequately addresses our data as well as the data that the Division now has concerning other dual PPAR agonists. She suggested that TPNA might consider adding the föllowing sentence to our package-inser "Increased bladder and-renal transitional cell tumors were seen in other compounds in the same class of drugs." Confidential - Subject to Protective Order TAK-NAUGHP-00080812 Source: https://www.indup537/2-00002 ts.ucsf.edu/docs/jsjf0226

Who described tumor promoter-model study?

jsjf0226

jsjf0226_p0, jsjf0226_p1

Dr. El-Hage, dr. el-hage

EXHIBIT 107 FDA Conference Call: August 13, 2002 FDA Personnel: Jeri El-Hage, Ph.D., Toxicology Team Leader Jena Weber, Project Manager TPNA Personnel: David Baron, Ph.D., Director, Nonclinical Safety and Efficacy Janet Haskins, Manager, Regulatory Affairs Pat Frank, Ph.D., TPNA Consultant This teleconference was held as a follow-up to a discussion between TPNA and the Agency on July 31, 2002. The purpose of this call was so that Dr. El-Hage could expand upon the nonclinical data related to dual PPAR agonists that were discussed with TPNA on July 31, 2002. Dr. El-Hage informed TPNA that in standard 2-year rat and mouse bioassay studies, several other dual PPAR agonists were shown to cause transitional cell tumors in the bladder and kidneys of male and female rats and male mice. Therefore, the Division is considering the relevance of these findings to this pharmaceutical class of drugs. She also noted that in follow-up unspecified mechanistic studies of the other dual PPAR agonists, no evidence of irritation by crystalluria or calculi was noted. Dr. El-Hage then described a tumor promoter-model study that was conducted by another sponsor in which pioglitazone was administered. The study was designed as follows: BBN was given to male Fisher rats in their drinking water for four weeks. Four groups were designated: Pioglitazone 40 mg/kg/day after BBN The study compound plus BBN (No dosages were specified, but Dr. El-Hage noted that multiple dosages were studied and the high dose was designed to be "equivalent" to 40 mg/kg pioglitazone) The negative control group received BBN only. The positive control group received uracil. Duration of daily dosing was 32-weeks after BBN. Results: 85% of the animals in the pioglitazone and the other sponsor's compound groups had tumor formation. Calculi formation was not confirmed in either group, but was looked for using unspecified methodology. 15% of the animals in the negative control group had tumor formation, while approximately 50% of the positive control group presented tumors in the presence of calculi formation (uracil) Confidential - Subject to Protective Order TAK-NAUGHP-00080811 Source: https://www.indup372.0000nts.ucsf.edu/docs/jsjf0226 Based on these findings, and the fact that the development of the other dual PPAR agonists has been discontinued, the Division expressed a concern that a possible risk of dual PPARs has not been addressed. Dr. El-Hage stated that prior to other dual PPAR agonists discontinuing development, monitoring for bladder tumors was required in their phase III clinical studies. She noted that the Division's internal consultant suggested screening urine for NMP-22. Dr. El-Hage believes this assay is approved for screening of bladder tumors and is commercially available. Finally Dr. El-Hage noted that she will be consulting with the CAC board in mid- September. She will inquire if they feel that the pioglitazone package insert adequately addresses our data as well as the data that the Division now has concerning other dual PPAR agonists. She suggested that TPNA might consider adding the föllowing sentence to our package-inser "Increased bladder and-renal transitional cell tumors were seen in other compounds in the same class of drugs." Confidential - Subject to Protective Order TAK-NAUGHP-00080812 Source: https://www.indup537/2-00002 ts.ucsf.edu/docs/jsjf0226

What is the duration of daily dosing?

jsjf0226

jsjf0226_p0, jsjf0226_p1

32-weeks, 32-weeks after BBN.

EXHIBIT 107 FDA Conference Call: August 13, 2002 FDA Personnel: Jeri El-Hage, Ph.D., Toxicology Team Leader Jena Weber, Project Manager TPNA Personnel: David Baron, Ph.D., Director, Nonclinical Safety and Efficacy Janet Haskins, Manager, Regulatory Affairs Pat Frank, Ph.D., TPNA Consultant This teleconference was held as a follow-up to a discussion between TPNA and the Agency on July 31, 2002. The purpose of this call was so that Dr. El-Hage could expand upon the nonclinical data related to dual PPAR agonists that were discussed with TPNA on July 31, 2002. Dr. El-Hage informed TPNA that in standard 2-year rat and mouse bioassay studies, several other dual PPAR agonists were shown to cause transitional cell tumors in the bladder and kidneys of male and female rats and male mice. Therefore, the Division is considering the relevance of these findings to this pharmaceutical class of drugs. She also noted that in follow-up unspecified mechanistic studies of the other dual PPAR agonists, no evidence of irritation by crystalluria or calculi was noted. Dr. El-Hage then described a tumor promoter-model study that was conducted by another sponsor in which pioglitazone was administered. The study was designed as follows: BBN was given to male Fisher rats in their drinking water for four weeks. Four groups were designated: Pioglitazone 40 mg/kg/day after BBN The study compound plus BBN (No dosages were specified, but Dr. El-Hage noted that multiple dosages were studied and the high dose was designed to be "equivalent" to 40 mg/kg pioglitazone) The negative control group received BBN only. The positive control group received uracil. Duration of daily dosing was 32-weeks after BBN. Results: 85% of the animals in the pioglitazone and the other sponsor's compound groups had tumor formation. Calculi formation was not confirmed in either group, but was looked for using unspecified methodology. 15% of the animals in the negative control group had tumor formation, while approximately 50% of the positive control group presented tumors in the presence of calculi formation (uracil) Confidential - Subject to Protective Order TAK-NAUGHP-00080811 Source: https://www.indup372.0000nts.ucsf.edu/docs/jsjf0226 Based on these findings, and the fact that the development of the other dual PPAR agonists has been discontinued, the Division expressed a concern that a possible risk of dual PPARs has not been addressed. Dr. El-Hage stated that prior to other dual PPAR agonists discontinuing development, monitoring for bladder tumors was required in their phase III clinical studies. She noted that the Division's internal consultant suggested screening urine for NMP-22. Dr. El-Hage believes this assay is approved for screening of bladder tumors and is commercially available. Finally Dr. El-Hage noted that she will be consulting with the CAC board in mid- September. She will inquire if they feel that the pioglitazone package insert adequately addresses our data as well as the data that the Division now has concerning other dual PPAR agonists. She suggested that TPNA might consider adding the föllowing sentence to our package-inser "Increased bladder and-renal transitional cell tumors were seen in other compounds in the same class of drugs." Confidential - Subject to Protective Order TAK-NAUGHP-00080812 Source: https://www.indup537/2-00002 ts.ucsf.edu/docs/jsjf0226

Who updated the CEO on August 6?

myjf0226

myjf0226_p0, myjf0226_p1, myjf0226_p2, myjf0226_p3

Mr. Saito

ACTOS FDA RESPONSE MEETING TPNA/TEUR&D/TCI AUGUST 12-13, 2002 Attendees: TPNA TEUR&D Sam Hamanaka David Eckland Claire Thom Yasuhiko Wada Ingrid Hood Glyn Belcher Alfonso Perez Philip Collett David Recker John Page TCI Mary Ramstack Katsuhisa Saito Janet Haskins Masahiro Miyazaki Dan Orlando Takashi Kuroiwa David Baron Takashi Nonoyama Chris Durack Keiichiro Sato Larry Hancock Hiroyuki Odaka Bob Ahlbrandt Tom Muldoon Karen Kaluzny Summary of July 31 Teleconference with FDA (J. Haskins) The FDA informed TPNA that they had received data from a rat tumor promoter study using dual PPAR agonists. Pioglitazone was used in this experiment, and the group of rats treated with pioglitazone experienced the same frequency of transitional cell tumors as the group treated with the dual PPAR agonist under investigation. The FDA clarified that due to this data, they had concerns with the dual PPAR mechanism, and considered pioglitazone to have a dual PPAR mechanism. There were three key messages from the teleconference: The FDA asked TPNA to consider a label change, as they feel that the current package insert does not adequately inform patients of the risk associated with bladder tumors. The FDA asked TPNA to research and propose a monitoring plan, which would be incorporated into clinical trials. The FDA stated that they were considering rescinding their written request to TPNA to conduct pediatric studies with pioglitazone. Confidential - Subject to Protective Order TAK-RAMSTM-00487173 Produced in MDL on 03/06/13 Source: ACTOS FDA Response Meeting August 12-13, 2002 Page 2 of 4 Summary of July 31 Teleconference with FDA (J. Haskins) - Continued The group summarized the FDA's concerns as follows: The FDA is not stating that ACTOS specifically causes or contributes to bladder tumors. The FDA no longer supports Dr. Cohen's hypothesis, since the tumor promoter study data they received demonstrated the presence of tumors without calculi. The FDA no longer feels that they understand how these findings relate to humans. Update from TCI Meeting with CEO (Mr. Saito) Mr. Saito updated the CEO on this situation on August 6. The following strategy was decided on: Attempt to keep current carcinogenicity label wording; if not possible, request that same labeling be applied to Avandia Find rationale to support not establishing monitoring plan, but if necessary, would compromise on monitoring wording to avoid changing carcinogenicity wording Develop argument to proceed with Actos 508 (safety/efficacy in pediatrics) study under current timelines, but are willing to postpone The following timelines were established: TPNA to send outline of response to TCI by August 19 Mr. Saito will present outline to CEO on August 20 TPNA will send draft document to TCI, TEUR&D, and Lilly on August 21 Document will be finalized by August 26 Response will be sent to FDA on August 28 Mr Saito also presented the following communication structure and schematic Leadership: Claire Thom, David Eckland, Mr. Saito Primary contacts: Mary Ramstack, Janet Haskins, Philip Collett, Mr. Miyazaki The only exception to this schematic will be that on August 26, TPNA will communicate directly with Lilly to distribute the draft document CEO Mr Saito TPNA TCI labs Lilly EU Confidential - Subject to Protective Order TAK-RAMSTM-00487174 Produced in MDL on 03/06/13 Source: ACTOS FDA Response Meeting August 12-13, 2002 Page 3 of 4 Highlights/Discussion Points from Preclinical Data Presentation In the rat oncogenicity study, thickening of the bladder and hypertrophy of the urothelium was observed in male rats. These findings were not dose- dependent. Nearly all of the tumors were found at the end of the study. Some cases of hyperplasia were seen in female rats at the highest dose level only, but no malignancies were seen. There were no tumors seen in the shorter term (12 month) rat toxicity studies. Glyn Belcher suggested creating a summary able for all toxicology studies with durations between 6 months and less than 2 years. In the mouse oncogenicity study, hyperplasia was seen in male mice only. These findings were not dose-dependent, and results were not statistically significant. One case of hyperplasia was observed in the placebo group. Philip Collett stated that the European authorities did not question the mouse data for ACTOS, but rather only the rat data. A list of all mutagenicity studies conducted with pioglitazone was shown, and David Baron acknowledged that TCI had conducted a very robust program that went beyond regulatory requirements. A study observing the effects of pioglitazone on urinary parameters in rats was conducted, and highlights are as follows: Simple hyperplasia seen in one male Increase in urine pH, urine volume, microcrystal count Slight decrease in magnesium, calcium, phosphorous, sodium, potassium, and chloride Conclusion: Changes in urinary components are considered to be factors in the etiology of proliferative lesions of the bladder: Pioglitazone ingestion Altered urinary physiology Calculus formation Urothelial ulceration an regeneration (hyperplasia) Benin papilloma Carcinoma Confidential - Subject to Protective Order TAK-RAMSTM-00487175 Produced in MDL on 03/06/13 Source: ACTOS FDA Response Meeting August 12-13, 2002 Page 4 of 4 Highlights from Cohen Hypothesis Discussion Philip Collett presented an outline of the Cohen hypothesis Male rat urine has a very high protein content, which is a function of sex hormones Raising the pH of male rat urine above 6.5 is significant in the development of calculi Because rats are quadropeds, they do not eliminate calculi as humans do The correlation observed in Cohen's paper is 0.61. The European authorities initially determined this to be quite low; however, Dr. Cohen authored an expert report which stated that the 0.61 correlation was actually high, as calculi can dissolve over time. In summary, the tumors seen in rats were due to the presence of calculi. The male rat urine milieu contributes to the formation of calculi. Because rats are quadropeds, they do not eliminate calculi as bipeds do. Main Points from Takeda Europe Experience Takeda Europe successfully employed the following strategy: Defended Cohen hypothesis, despite numerous challenges Stressed the "one sex, one species" argument Challenged authorities regarding implementing monitoring plan Offered to conduct a case control study post-approval Highlights from PPAR Agonist Discussion The group extensively discussed many aspects of the PPAR mechanism and ultimately decided to not address mechanistic issues in the initial FDA response. However, it was decided that this argument should be developed, as it may be necessary to use it in the future, and action items were assigned accordingly. Confidential - Subject to Protective Order TAK-RAMSTM-00487176 Produced in MDL on 03/06/13 Source:

By when should TPNA send outline of response to TCI ?

myjf0226

myjf0226_p0, myjf0226_p1, myjf0226_p2, myjf0226_p3

by August 19, August 19

ACTOS FDA RESPONSE MEETING TPNA/TEUR&D/TCI AUGUST 12-13, 2002 Attendees: TPNA TEUR&D Sam Hamanaka David Eckland Claire Thom Yasuhiko Wada Ingrid Hood Glyn Belcher Alfonso Perez Philip Collett David Recker John Page TCI Mary Ramstack Katsuhisa Saito Janet Haskins Masahiro Miyazaki Dan Orlando Takashi Kuroiwa David Baron Takashi Nonoyama Chris Durack Keiichiro Sato Larry Hancock Hiroyuki Odaka Bob Ahlbrandt Tom Muldoon Karen Kaluzny Summary of July 31 Teleconference with FDA (J. Haskins) The FDA informed TPNA that they had received data from a rat tumor promoter study using dual PPAR agonists. Pioglitazone was used in this experiment, and the group of rats treated with pioglitazone experienced the same frequency of transitional cell tumors as the group treated with the dual PPAR agonist under investigation. The FDA clarified that due to this data, they had concerns with the dual PPAR mechanism, and considered pioglitazone to have a dual PPAR mechanism. There were three key messages from the teleconference: The FDA asked TPNA to consider a label change, as they feel that the current package insert does not adequately inform patients of the risk associated with bladder tumors. The FDA asked TPNA to research and propose a monitoring plan, which would be incorporated into clinical trials. The FDA stated that they were considering rescinding their written request to TPNA to conduct pediatric studies with pioglitazone. Confidential - Subject to Protective Order TAK-RAMSTM-00487173 Produced in MDL on 03/06/13 Source: ACTOS FDA Response Meeting August 12-13, 2002 Page 2 of 4 Summary of July 31 Teleconference with FDA (J. Haskins) - Continued The group summarized the FDA's concerns as follows: The FDA is not stating that ACTOS specifically causes or contributes to bladder tumors. The FDA no longer supports Dr. Cohen's hypothesis, since the tumor promoter study data they received demonstrated the presence of tumors without calculi. The FDA no longer feels that they understand how these findings relate to humans. Update from TCI Meeting with CEO (Mr. Saito) Mr. Saito updated the CEO on this situation on August 6. The following strategy was decided on: Attempt to keep current carcinogenicity label wording; if not possible, request that same labeling be applied to Avandia Find rationale to support not establishing monitoring plan, but if necessary, would compromise on monitoring wording to avoid changing carcinogenicity wording Develop argument to proceed with Actos 508 (safety/efficacy in pediatrics) study under current timelines, but are willing to postpone The following timelines were established: TPNA to send outline of response to TCI by August 19 Mr. Saito will present outline to CEO on August 20 TPNA will send draft document to TCI, TEUR&D, and Lilly on August 21 Document will be finalized by August 26 Response will be sent to FDA on August 28 Mr Saito also presented the following communication structure and schematic Leadership: Claire Thom, David Eckland, Mr. Saito Primary contacts: Mary Ramstack, Janet Haskins, Philip Collett, Mr. Miyazaki The only exception to this schematic will be that on August 26, TPNA will communicate directly with Lilly to distribute the draft document CEO Mr Saito TPNA TCI labs Lilly EU Confidential - Subject to Protective Order TAK-RAMSTM-00487174 Produced in MDL on 03/06/13 Source: ACTOS FDA Response Meeting August 12-13, 2002 Page 3 of 4 Highlights/Discussion Points from Preclinical Data Presentation In the rat oncogenicity study, thickening of the bladder and hypertrophy of the urothelium was observed in male rats. These findings were not dose- dependent. Nearly all of the tumors were found at the end of the study. Some cases of hyperplasia were seen in female rats at the highest dose level only, but no malignancies were seen. There were no tumors seen in the shorter term (12 month) rat toxicity studies. Glyn Belcher suggested creating a summary able for all toxicology studies with durations between 6 months and less than 2 years. In the mouse oncogenicity study, hyperplasia was seen in male mice only. These findings were not dose-dependent, and results were not statistically significant. One case of hyperplasia was observed in the placebo group. Philip Collett stated that the European authorities did not question the mouse data for ACTOS, but rather only the rat data. A list of all mutagenicity studies conducted with pioglitazone was shown, and David Baron acknowledged that TCI had conducted a very robust program that went beyond regulatory requirements. A study observing the effects of pioglitazone on urinary parameters in rats was conducted, and highlights are as follows: Simple hyperplasia seen in one male Increase in urine pH, urine volume, microcrystal count Slight decrease in magnesium, calcium, phosphorous, sodium, potassium, and chloride Conclusion: Changes in urinary components are considered to be factors in the etiology of proliferative lesions of the bladder: Pioglitazone ingestion Altered urinary physiology Calculus formation Urothelial ulceration an regeneration (hyperplasia) Benin papilloma Carcinoma Confidential - Subject to Protective Order TAK-RAMSTM-00487175 Produced in MDL on 03/06/13 Source: ACTOS FDA Response Meeting August 12-13, 2002 Page 4 of 4 Highlights from Cohen Hypothesis Discussion Philip Collett presented an outline of the Cohen hypothesis Male rat urine has a very high protein content, which is a function of sex hormones Raising the pH of male rat urine above 6.5 is significant in the development of calculi Because rats are quadropeds, they do not eliminate calculi as humans do The correlation observed in Cohen's paper is 0.61. The European authorities initially determined this to be quite low; however, Dr. Cohen authored an expert report which stated that the 0.61 correlation was actually high, as calculi can dissolve over time. In summary, the tumors seen in rats were due to the presence of calculi. The male rat urine milieu contributes to the formation of calculi. Because rats are quadropeds, they do not eliminate calculi as bipeds do. Main Points from Takeda Europe Experience Takeda Europe successfully employed the following strategy: Defended Cohen hypothesis, despite numerous challenges Stressed the "one sex, one species" argument Challenged authorities regarding implementing monitoring plan Offered to conduct a case control study post-approval Highlights from PPAR Agonist Discussion The group extensively discussed many aspects of the PPAR mechanism and ultimately decided to not address mechanistic issues in the initial FDA response. However, it was decided that this argument should be developed, as it may be necessary to use it in the future, and action items were assigned accordingly. Confidential - Subject to Protective Order TAK-RAMSTM-00487176 Produced in MDL on 03/06/13 Source:

When will Mr. Saito present outline to CEO?

myjf0226

myjf0226_p0, myjf0226_p1, myjf0226_p2, myjf0226_p3

on August 20, August 20

ACTOS FDA RESPONSE MEETING TPNA/TEUR&D/TCI AUGUST 12-13, 2002 Attendees: TPNA TEUR&D Sam Hamanaka David Eckland Claire Thom Yasuhiko Wada Ingrid Hood Glyn Belcher Alfonso Perez Philip Collett David Recker John Page TCI Mary Ramstack Katsuhisa Saito Janet Haskins Masahiro Miyazaki Dan Orlando Takashi Kuroiwa David Baron Takashi Nonoyama Chris Durack Keiichiro Sato Larry Hancock Hiroyuki Odaka Bob Ahlbrandt Tom Muldoon Karen Kaluzny Summary of July 31 Teleconference with FDA (J. Haskins) The FDA informed TPNA that they had received data from a rat tumor promoter study using dual PPAR agonists. Pioglitazone was used in this experiment, and the group of rats treated with pioglitazone experienced the same frequency of transitional cell tumors as the group treated with the dual PPAR agonist under investigation. The FDA clarified that due to this data, they had concerns with the dual PPAR mechanism, and considered pioglitazone to have a dual PPAR mechanism. There were three key messages from the teleconference: The FDA asked TPNA to consider a label change, as they feel that the current package insert does not adequately inform patients of the risk associated with bladder tumors. The FDA asked TPNA to research and propose a monitoring plan, which would be incorporated into clinical trials. The FDA stated that they were considering rescinding their written request to TPNA to conduct pediatric studies with pioglitazone. Confidential - Subject to Protective Order TAK-RAMSTM-00487173 Produced in MDL on 03/06/13 Source: ACTOS FDA Response Meeting August 12-13, 2002 Page 2 of 4 Summary of July 31 Teleconference with FDA (J. Haskins) - Continued The group summarized the FDA's concerns as follows: The FDA is not stating that ACTOS specifically causes or contributes to bladder tumors. The FDA no longer supports Dr. Cohen's hypothesis, since the tumor promoter study data they received demonstrated the presence of tumors without calculi. The FDA no longer feels that they understand how these findings relate to humans. Update from TCI Meeting with CEO (Mr. Saito) Mr. Saito updated the CEO on this situation on August 6. The following strategy was decided on: Attempt to keep current carcinogenicity label wording; if not possible, request that same labeling be applied to Avandia Find rationale to support not establishing monitoring plan, but if necessary, would compromise on monitoring wording to avoid changing carcinogenicity wording Develop argument to proceed with Actos 508 (safety/efficacy in pediatrics) study under current timelines, but are willing to postpone The following timelines were established: TPNA to send outline of response to TCI by August 19 Mr. Saito will present outline to CEO on August 20 TPNA will send draft document to TCI, TEUR&D, and Lilly on August 21 Document will be finalized by August 26 Response will be sent to FDA on August 28 Mr Saito also presented the following communication structure and schematic Leadership: Claire Thom, David Eckland, Mr. Saito Primary contacts: Mary Ramstack, Janet Haskins, Philip Collett, Mr. Miyazaki The only exception to this schematic will be that on August 26, TPNA will communicate directly with Lilly to distribute the draft document CEO Mr Saito TPNA TCI labs Lilly EU Confidential - Subject to Protective Order TAK-RAMSTM-00487174 Produced in MDL on 03/06/13 Source: ACTOS FDA Response Meeting August 12-13, 2002 Page 3 of 4 Highlights/Discussion Points from Preclinical Data Presentation In the rat oncogenicity study, thickening of the bladder and hypertrophy of the urothelium was observed in male rats. These findings were not dose- dependent. Nearly all of the tumors were found at the end of the study. Some cases of hyperplasia were seen in female rats at the highest dose level only, but no malignancies were seen. There were no tumors seen in the shorter term (12 month) rat toxicity studies. Glyn Belcher suggested creating a summary able for all toxicology studies with durations between 6 months and less than 2 years. In the mouse oncogenicity study, hyperplasia was seen in male mice only. These findings were not dose-dependent, and results were not statistically significant. One case of hyperplasia was observed in the placebo group. Philip Collett stated that the European authorities did not question the mouse data for ACTOS, but rather only the rat data. A list of all mutagenicity studies conducted with pioglitazone was shown, and David Baron acknowledged that TCI had conducted a very robust program that went beyond regulatory requirements. A study observing the effects of pioglitazone on urinary parameters in rats was conducted, and highlights are as follows: Simple hyperplasia seen in one male Increase in urine pH, urine volume, microcrystal count Slight decrease in magnesium, calcium, phosphorous, sodium, potassium, and chloride Conclusion: Changes in urinary components are considered to be factors in the etiology of proliferative lesions of the bladder: Pioglitazone ingestion Altered urinary physiology Calculus formation Urothelial ulceration an regeneration (hyperplasia) Benin papilloma Carcinoma Confidential - Subject to Protective Order TAK-RAMSTM-00487175 Produced in MDL on 03/06/13 Source: ACTOS FDA Response Meeting August 12-13, 2002 Page 4 of 4 Highlights from Cohen Hypothesis Discussion Philip Collett presented an outline of the Cohen hypothesis Male rat urine has a very high protein content, which is a function of sex hormones Raising the pH of male rat urine above 6.5 is significant in the development of calculi Because rats are quadropeds, they do not eliminate calculi as humans do The correlation observed in Cohen's paper is 0.61. The European authorities initially determined this to be quite low; however, Dr. Cohen authored an expert report which stated that the 0.61 correlation was actually high, as calculi can dissolve over time. In summary, the tumors seen in rats were due to the presence of calculi. The male rat urine milieu contributes to the formation of calculi. Because rats are quadropeds, they do not eliminate calculi as bipeds do. Main Points from Takeda Europe Experience Takeda Europe successfully employed the following strategy: Defended Cohen hypothesis, despite numerous challenges Stressed the "one sex, one species" argument Challenged authorities regarding implementing monitoring plan Offered to conduct a case control study post-approval Highlights from PPAR Agonist Discussion The group extensively discussed many aspects of the PPAR mechanism and ultimately decided to not address mechanistic issues in the initial FDA response. However, it was decided that this argument should be developed, as it may be necessary to use it in the future, and action items were assigned accordingly. Confidential - Subject to Protective Order TAK-RAMSTM-00487176 Produced in MDL on 03/06/13 Source:

When will the FDA Conference Call be held?

fsjf0226

fsjf0226_p0, fsjf0226_p1

July 31, 2002

EXHIBIT 102 FDA Conference Call on July 31, 2002 TPNA Personnel: Wendell Cheatham, M.D. Vice President, of Medial and Scientific Affairs Michael Elisseou, Ph.D., Director, Product Development and Planning Janet Haskins, Manager, Regulatory Affairs Ingrid Hoos, Director, Regulatory Affairs John Page, M.D., Director Product Safety Alfonso Perez, M.D., Sr. Director of Clinical Development Mary Ramstack, Sr. Manager, Product Development and Planning Claire Thom, Pharm.D., Vice President, Research and Development FDA Personnel: David Orloff, M.D., Division Director Bob Misbin, M.D., Medical Review Jena Weber, Project Manager Jeri El-Hage, Toxicology Team Leader Dr. Orloff stated that the purpose of the teleconference was to discuss three topics related to additional nonclinical data recently received by the Divisica: 1. a proposal to monitor bladder toxicity in long term clinical trials 2. the Division's inclination to rescind the written request for pediatric exclusivity 3. a labeling change that would reflect possible relatedness of tumor formation to drug mechanism of action Dr. Orloff stated_that the Division is considering additional data that indicates that the bladder tumors seen in the rat carcinogenicity study maybe a mixed PPAR class effect. He further noted that when pioglitazone was approved by the Division, the significance of these findings was tempered by the data presented by Takeda relating the tumor formation to the presence of calculi. He further indicated thatHowever_,-as-the Division has recently reviewed data for similar compounds, the additional--Additional data suggests that those tumors may have beenbe- drug related. Dr. Perez inquired about the Division's definition of long term trials and stated that urine cytology was preformed in two trials that were over one year in duration. Dr. Misbin noted that the Division considers long-term as a trial longer than one-year and inquired about what type of testing was conducted in the titals mentioned by Dr. Perez. Dr. Perez noted that urine cytology was performed for any subject presenting hematuria at any time Confidential - Subject to Protective Order TAK-RAMSTM-00235775 Produced in MDL on 09/18/12 Source: https://www.indup5367.0000nts.ucsf.edu/docs/fsjf0226 during the study. If a subject had atypical urothelial cells, they were referred for kidney, ureter and/or bladder examinations. Dr. Misbin stated that the cytology performed in TPNA's phase III program, did not provide much information, and he suggested that we might possibly be able to screen for an antigen. Dr. El-Hage, then noted that the Division has received data from another company that implied that pioglitazone was a tumor promoter. When questioned about this data, Dr. El-Hage noted that renal and bladder transitional cell tumors were reported using a promoter-model. Dr. Cheatham then inquired if it would be possible to share this data with TPNA. The Division noted that it is not possible to disclose the study specifically and referred TPNA to published data. Dr. El-Hage noted that she would be willing to speak with TPNA's toxicologist once he returned to the office. Further, the Division is no longer convinced that the bladder tumor formation in the rats is a result of the presence of calculi, but timay be related to a dual PPAR agonist effect. Dr. Cheatham noted that pioglitazone is a PPAR gamma agonist. Dr. Misbin responded that the Division is starting to consider pioglitazone to be a PPAR gamma and alplia agonist. Dr.-Misbin then noted that with monitoring in a long-term trial, we would be able to lay the issue relating to bladder tumor formation to rest. He further requested that we consider a class effect labeling. He-further-Dr. Misbin requested thatrequested that we submit in 3-4 weeks the following information: Proposal for a monitoring or surveillance program for long-term clinical trials. Post-marketing data relating to urinary tract findings. Proposal for a label language change, Suggested changes to our consent forms. He also further stated that we should be prepared for the likelihood that the written request to conduct the pediatric study would be rescinded. Dr. Misbin finished the conversation by inquiring about the timing of the efficacy supplement for the three combination trials. He stated that there are safety issues regarding the 45 mg dose that he would like to consider for the next labeling change. TPNA committed to submitting that supplement as soon as possible and ended the conference call.: Confidential - Subject to Protective Order TAK-RAMSTM-00235776 Produced in MDL on 09/18/12 Source: https://www.indup'5367.00002 ts.ucsf.edu/docs/fsjf0226

What is the heading of the document?

qtjf0226

qtjf0226_p0

ACTOS FDA RESPONSE TASK FORCE-TPNA

Baron and t 12-4-13 pu ACTOS FDA RESPONSE TASK FORCE - -TPNA August 2, 2002 Wendall Cheatham Korn Kaluegry Alfonso Perez Janet Haskins* Mary Ramstack* Aga sonfthi Ingrid Hoos chuch suart Michael Elisseou John Page Tom Huldom Claire Thom Dan Orlando David Baron (Chris Durak) Larry Hancock *Task Force Coordinators TASK FORCE STRATEGY The FDA has 3 key issues with respect to the non-clinical data related to bladder tumors. 1. They requested us to propose a method by which to monitor bladder toxicity in patients in our long term phase 4 clinical trials (long term was defined as at least 1 year). a. TPNA will investigate the feasibility and scientific merit of a clinical monitoring plan. If deemed appropriate, TPNA will develop monitoring plan 2. They requested us to give some consideration to a label change that would reflect possible relatedness of tumor formation to mechanism (dual PPAR agonist) instead of the current language ("The relationship of these findings in male rats to humans is unclear.") a. TPNA would like to challenge FDA hypothesis around tumor formation relationship to dual PPAR mechanism. b. TPNA goal is to supply justification to support maintaining current labeling. 3. They indicated an inclination to rescind the written request for pediatric exclusivity based on their concern about bladder tumors. a. Based on current verbiage in PI TPNA requests to conduct pediatric trial as scheduled. OR b. Request to delay initiation of Pediatric Study 508 pending 506 data availability Confidential - Subject to Protective Order TAK-THOMCL-00032209 Produced in MDL on 02/21/13

How many key issues does the FDA have with respect to the non-clinical data related to bladder tumors?

qtjf0226

qtjf0226_p0

The FDA has 3 key issues with respect to the non-clinical data related to bladder tumors., 3

Baron and t 12-4-13 pu ACTOS FDA RESPONSE TASK FORCE - -TPNA August 2, 2002 Wendall Cheatham Korn Kaluegry Alfonso Perez Janet Haskins* Mary Ramstack* Aga sonfthi Ingrid Hoos chuch suart Michael Elisseou John Page Tom Huldom Claire Thom Dan Orlando David Baron (Chris Durak) Larry Hancock *Task Force Coordinators TASK FORCE STRATEGY The FDA has 3 key issues with respect to the non-clinical data related to bladder tumors. 1. They requested us to propose a method by which to monitor bladder toxicity in patients in our long term phase 4 clinical trials (long term was defined as at least 1 year). a. TPNA will investigate the feasibility and scientific merit of a clinical monitoring plan. If deemed appropriate, TPNA will develop monitoring plan 2. They requested us to give some consideration to a label change that would reflect possible relatedness of tumor formation to mechanism (dual PPAR agonist) instead of the current language ("The relationship of these findings in male rats to humans is unclear.") a. TPNA would like to challenge FDA hypothesis around tumor formation relationship to dual PPAR mechanism. b. TPNA goal is to supply justification to support maintaining current labeling. 3. They indicated an inclination to rescind the written request for pediatric exclusivity based on their concern about bladder tumors. a. Based on current verbiage in PI TPNA requests to conduct pediatric trial as scheduled. OR b. Request to delay initiation of Pediatric Study 508 pending 506 data availability Confidential - Subject to Protective Order TAK-THOMCL-00032209 Produced in MDL on 02/21/13

What plan is developed by TPNA?

qtjf0226

qtjf0226_p0

monitoring plan, TPNA will develop monitoring plan.

Baron and t 12-4-13 pu ACTOS FDA RESPONSE TASK FORCE - -TPNA August 2, 2002 Wendall Cheatham Korn Kaluegry Alfonso Perez Janet Haskins* Mary Ramstack* Aga sonfthi Ingrid Hoos chuch suart Michael Elisseou John Page Tom Huldom Claire Thom Dan Orlando David Baron (Chris Durak) Larry Hancock *Task Force Coordinators TASK FORCE STRATEGY The FDA has 3 key issues with respect to the non-clinical data related to bladder tumors. 1. They requested us to propose a method by which to monitor bladder toxicity in patients in our long term phase 4 clinical trials (long term was defined as at least 1 year). a. TPNA will investigate the feasibility and scientific merit of a clinical monitoring plan. If deemed appropriate, TPNA will develop monitoring plan 2. They requested us to give some consideration to a label change that would reflect possible relatedness of tumor formation to mechanism (dual PPAR agonist) instead of the current language ("The relationship of these findings in male rats to humans is unclear.") a. TPNA would like to challenge FDA hypothesis around tumor formation relationship to dual PPAR mechanism. b. TPNA goal is to supply justification to support maintaining current labeling. 3. They indicated an inclination to rescind the written request for pediatric exclusivity based on their concern about bladder tumors. a. Based on current verbiage in PI TPNA requests to conduct pediatric trial as scheduled. OR b. Request to delay initiation of Pediatric Study 508 pending 506 data availability Confidential - Subject to Protective Order TAK-THOMCL-00032209 Produced in MDL on 02/21/13

What is TPNA's goal?

qtjf0226

qtjf0226_p0

is to supply justification to support maintaining current labeling.

Baron and t 12-4-13 pu ACTOS FDA RESPONSE TASK FORCE - -TPNA August 2, 2002 Wendall Cheatham Korn Kaluegry Alfonso Perez Janet Haskins* Mary Ramstack* Aga sonfthi Ingrid Hoos chuch suart Michael Elisseou John Page Tom Huldom Claire Thom Dan Orlando David Baron (Chris Durak) Larry Hancock *Task Force Coordinators TASK FORCE STRATEGY The FDA has 3 key issues with respect to the non-clinical data related to bladder tumors. 1. They requested us to propose a method by which to monitor bladder toxicity in patients in our long term phase 4 clinical trials (long term was defined as at least 1 year). a. TPNA will investigate the feasibility and scientific merit of a clinical monitoring plan. If deemed appropriate, TPNA will develop monitoring plan 2. They requested us to give some consideration to a label change that would reflect possible relatedness of tumor formation to mechanism (dual PPAR agonist) instead of the current language ("The relationship of these findings in male rats to humans is unclear.") a. TPNA would like to challenge FDA hypothesis around tumor formation relationship to dual PPAR mechanism. b. TPNA goal is to supply justification to support maintaining current labeling. 3. They indicated an inclination to rescind the written request for pediatric exclusivity based on their concern about bladder tumors. a. Based on current verbiage in PI TPNA requests to conduct pediatric trial as scheduled. OR b. Request to delay initiation of Pediatric Study 508 pending 506 data availability Confidential - Subject to Protective Order TAK-THOMCL-00032209 Produced in MDL on 02/21/13

What is the last point in the table?

qtjf0226

qtjf0226_p3, qtjf0226_p4, qtjf0226_p5, qtjf0226_p6, qtjf0226_p7

EVALUATE IMPACT ON TAK-559, Evaluate Impact on Tak-559

Task Notes Lead Responsibility Due Date 4. PEDIATRIC STUDIES (CONTINUED) Evaluate data from Actos 507 Evaluate data to support Amy Hagaman August 5 justification to proceed with Actos 508 Develop additional monitoring Amy Hagaman plan for Actos 508 Evaluate feasibility/business T. Muldoon case of request to FDA to M Ramstack delay start of Actos 508 pending Actos 506 data; 1 Haskins assess impact on pediatric exclusivity/patent Draft justification for Actos 508 Justification should be Amy Hagaman/Alfonso August 12 based on rebuttal of FDA Perez hypothesis regarding mechanism of action for bladder cancer and addition of clinical monitoring plan to protocol Last Update: August 1, 2002 Page 3 of 7 Confidential-Subject to Protective Order - TAK-THOMCL 00032212 Produced in MDL on 02/21/13 Source: https://www.indup3d8-00004ts.ucsf.edu/docs/qtjf0226 Task Notes Lead Responsibility Due Date 5A. NONCI INICAL/REVIEW OF TOX DATA (DAVID BARON) Conduct meeting between Identify mechanistic studies David Baron August 1 - DONE nonclinical safety and efficacy, for evaluation Janet Haskins regulatory, and project Schedule teleconference Mary Ramstack management with FDA Identify expert in oncology and pathology Identify nonclinicat back-up Pat Frank - telecon David Baron August 1 - DONE (example: Pat Frank and Chris Chris Durack report review Durack?) Request saccharin literature Janet Haskins August 1 - DONE search from Rya Send David Baron nonclinical Janet Haskins August 2 carcinogenicity studies Review doses used in CA Aziz Karim August 6 studies, clarify relationship to clinical doses 5B, NONCLINICAL/JUSTIFICATION DOCUMENT(DAVID BARON) Contact Jerry Oleski regarding Wendell Cheatham discrediting FDA tumor promoter hypothesis (inbittery) but busst Mary Roushur Last Update: August 1, 2002 Page 4 of 7 Confidential - Subject to Protective Order TAK-THOMCL-00032213 Produced in MDL on 02/21/13 Task Notes Lead Responsibility Due Date SB. NONCLINICAL/JUSTIFICATION DOCUMENTO (DAVID BARON) Evaluate and compare TCI structural models of all known PPAR agonists, including pioglitazone and NN622 Evaluate PPAR agonist TCI mechanistic tumor production hypotheses Evaluate effects of PPAR TCI agonists in urinary tract Develop justification document Baron Draft - August 16 Comments - August 19 Final version - August 20 6: INTRODUCTORY/CONCLUSION STATEMENTS Develop outline of response Hancock Aug 2 (table of contents) Send document sections to Aziz Karim - doses August 19 medical writing for compilation Amy Hagaman-507/506 Alfonso Perez - monitoring plan Last Update: August 1, 2002 Page 5 of 7 Confidentiat-Subject - to Protective Order TAK-THOMCL-00032214 Produced in MDL on 02/21/13- Source: https://www.indup538-00006ts.ucsf.edu/docs/qtjf0226 Task Notes Lead Responsibility Due Date 6. INTRODUCTORY/CONCLUSION STATEMENTS (CONTINUED) Send nonclinical David Baron August 20 rationale/justification section to medical writing for compilation Compile FDA package Larry Hancock August 21 Send package to TCI/EU for Mary Ramstack August 21 review Conduct review meeting for Janet Haskins/Team August 22 FDA package FDA Document to August 26 Regulatory Affairs 7. PACKAGE INSERTS/INFORMED CONSENT VERBIAGE Request NN622 literate Janet Haskins August 1 - DONE searches Identify package inserts with Janet Haskins August 12 similar class-related issues (i.e., ACE-inhibitors) Last Update: August 1, 2002 Page 6 of 7 Confidential - Subject to Protective Order TAK-THOMCL-00032215 Produced in MDL on 02/21/13 Source: https://www.indup63d8000007ts.ucsf.edu/docs/qtjf0226 Task Notes Lead Responsibility Due Date 8, COMPETITIVE INTELLIGENCE Update team on competitive Wendell Cheatham Ongoing - update provided intelligence Bill Bloke at each meeting 9. Q&A SHEET Develop Q&A sheet to support Wendell Cheatham Draft - August 5 Scientific Communications San Comments due - August 7 Review meeting-August 7 10. PATIENT REGISTRY Evaluate feasiblity of Pharmetric Database Rich Wilson OT developing large patient GE Database Rukmimi Rajagopalan registry Fred Murray 11: COMMUNICATIONS TO TAKEDA (TCI, TEUR&D, TPNA) 12, EVALUATE IMPACT ON TAK-559 prevelege Marline / average Last Update: August 1, 2002 Page 7 of 7 Confidential - Subject to Protective Order TAK-THOMCL-00032216 Produced in MDL on 02/21/13 Source:

What is the Draft's Due Date?

qtjf0226

qtjf0226_p3, qtjf0226_p4, qtjf0226_p5, qtjf0226_p6, qtjf0226_p7

August 5

Task Notes Lead Responsibility Due Date 4. PEDIATRIC STUDIES (CONTINUED) Evaluate data from Actos 507 Evaluate data to support Amy Hagaman August 5 justification to proceed with Actos 508 Develop additional monitoring Amy Hagaman plan for Actos 508 Evaluate feasibility/business T. Muldoon case of request to FDA to M Ramstack delay start of Actos 508 pending Actos 506 data; 1 Haskins assess impact on pediatric exclusivity/patent Draft justification for Actos 508 Justification should be Amy Hagaman/Alfonso August 12 based on rebuttal of FDA Perez hypothesis regarding mechanism of action for bladder cancer and addition of clinical monitoring plan to protocol Last Update: August 1, 2002 Page 3 of 7 Confidential-Subject to Protective Order - TAK-THOMCL 00032212 Produced in MDL on 02/21/13 Source: https://www.indup3d8-00004ts.ucsf.edu/docs/qtjf0226 Task Notes Lead Responsibility Due Date 5A. NONCI INICAL/REVIEW OF TOX DATA (DAVID BARON) Conduct meeting between Identify mechanistic studies David Baron August 1 - DONE nonclinical safety and efficacy, for evaluation Janet Haskins regulatory, and project Schedule teleconference Mary Ramstack management with FDA Identify expert in oncology and pathology Identify nonclinicat back-up Pat Frank - telecon David Baron August 1 - DONE (example: Pat Frank and Chris Chris Durack report review Durack?) Request saccharin literature Janet Haskins August 1 - DONE search from Rya Send David Baron nonclinical Janet Haskins August 2 carcinogenicity studies Review doses used in CA Aziz Karim August 6 studies, clarify relationship to clinical doses 5B, NONCLINICAL/JUSTIFICATION DOCUMENT(DAVID BARON) Contact Jerry Oleski regarding Wendell Cheatham discrediting FDA tumor promoter hypothesis (inbittery) but busst Mary Roushur Last Update: August 1, 2002 Page 4 of 7 Confidential - Subject to Protective Order TAK-THOMCL-00032213 Produced in MDL on 02/21/13 Task Notes Lead Responsibility Due Date SB. NONCLINICAL/JUSTIFICATION DOCUMENTO (DAVID BARON) Evaluate and compare TCI structural models of all known PPAR agonists, including pioglitazone and NN622 Evaluate PPAR agonist TCI mechanistic tumor production hypotheses Evaluate effects of PPAR TCI agonists in urinary tract Develop justification document Baron Draft - August 16 Comments - August 19 Final version - August 20 6: INTRODUCTORY/CONCLUSION STATEMENTS Develop outline of response Hancock Aug 2 (table of contents) Send document sections to Aziz Karim - doses August 19 medical writing for compilation Amy Hagaman-507/506 Alfonso Perez - monitoring plan Last Update: August 1, 2002 Page 5 of 7 Confidentiat-Subject - to Protective Order TAK-THOMCL-00032214 Produced in MDL on 02/21/13- Source: https://www.indup538-00006ts.ucsf.edu/docs/qtjf0226 Task Notes Lead Responsibility Due Date 6. INTRODUCTORY/CONCLUSION STATEMENTS (CONTINUED) Send nonclinical David Baron August 20 rationale/justification section to medical writing for compilation Compile FDA package Larry Hancock August 21 Send package to TCI/EU for Mary Ramstack August 21 review Conduct review meeting for Janet Haskins/Team August 22 FDA package FDA Document to August 26 Regulatory Affairs 7. PACKAGE INSERTS/INFORMED CONSENT VERBIAGE Request NN622 literate Janet Haskins August 1 - DONE searches Identify package inserts with Janet Haskins August 12 similar class-related issues (i.e., ACE-inhibitors) Last Update: August 1, 2002 Page 6 of 7 Confidential - Subject to Protective Order TAK-THOMCL-00032215 Produced in MDL on 02/21/13 Source: https://www.indup63d8000007ts.ucsf.edu/docs/qtjf0226 Task Notes Lead Responsibility Due Date 8, COMPETITIVE INTELLIGENCE Update team on competitive Wendell Cheatham Ongoing - update provided intelligence Bill Bloke at each meeting 9. Q&A SHEET Develop Q&A sheet to support Wendell Cheatham Draft - August 5 Scientific Communications San Comments due - August 7 Review meeting-August 7 10. PATIENT REGISTRY Evaluate feasiblity of Pharmetric Database Rich Wilson OT developing large patient GE Database Rukmimi Rajagopalan registry Fred Murray 11: COMMUNICATIONS TO TAKEDA (TCI, TEUR&D, TPNA) 12, EVALUATE IMPACT ON TAK-559 prevelege Marline / average Last Update: August 1, 2002 Page 7 of 7 Confidential - Subject to Protective Order TAK-THOMCL-00032216 Produced in MDL on 02/21/13 Source:

Which benefit start after 1 year of service?

ttjf0226

ttjf0226_p4

Extended Disability, extended disability

Dr. Tan January 14, 1999 Page 5 ELI LILLY AND COMPANY COMPENSATION AND BENEFITS PROGRAM (CONTINUED) Additional Company Benefits Medical and Dental Insurance Prescription Drug Benefits Reimbursement Accounts Illness Pay Extended Disability (Eligibility begins after 1 year of service) Credit Union Moving Plan (see enclosed brochure) Retirement Plan Employee Health Services Employee Activities Educational Assistance Program Savings Plan Holiday and Vacation Plan Please refer to the "Employee Compensation" booklet for the details. Optional Employee-Paíd Benefits Supplemental Life Insurance Dependent Life Insurance Flexible CarePlus (life/long-term care insurance) Confidential - Subject to Protective Order LLY-TANM-PF-00000050 Source: https://www.indup63/30-00005 ts.ucsf.edu/docs/ttjf0226

What is Ms Wakamatsu's role in Dept. Strategic Development?

lmjf0226

lmjf0226_p0, lmjf0226_p1, lmjf0226_p2, lmjf0226_p3, lmjf0226_p4, lmjf0226_p5, lmjf0226_p6, lmjf0226_p7, lmjf0226_p8, lmjf0226_p9, lmjf0226_p10, lmjf0226_p11, lmjf0226_p12, lmjf0226_p13, lmjf0226_p14, lmjf0226_p15, lmjf0226_p16

Assistant Manager, Assistant manager

CONFIDENTIAL Final Draft November 11, 2002 (DRAFT) MINUTES OF THE 5th GLOBAL DEVELOPMENT COMMITTEE Date: October 1, 2002 9:00 - 18:00 October 2, 2002 9:00 - 14:00 Place: Takeda Osaka Head Office, Room 11F2AB Attendees: Dr. Kitazawa, Managing Director, Pharmaceutical Development Division Mr. Saito, General Manager, Dept. Strategic Development Formatted: Right: 0" JP Development Division: Mr. Ikeya, General Manager, Japan Development Center Mr. Funatsu, Senior Manager, Japan Development Center Mr. Nakajima, Senior Manager, Japan Development Center Mr. Oomura, Senior Manager, Japan Development Center Formatted: Right: 0" Mr. Nakamura, Senior Manager, Japan Development Center Mr. Oka, Manager, Japan Development Center Takeda Europe R&D Centre: Dr, Eckland, Managing Director Formatted: Right: 0" Mr. Wada, Deputy Managing Director, Project Management Dr. George, Deputy Managing Director & Director, Euro Develop I Dr. Collett, Director, Euro Drug Regulatory Affairs Mr. Moules, Director, Euro Development Il Takeda Pharmaceuticals North America: Mr. Kashiyae, Vice President, Research & Development Dr. Thom, Vice President, Research & Development Mr. Daly, Senior Vice President, Marketing Ms. Hoos, Director, Regulatory Affairs Dr. Elisseou, Director, Project Management Pharmaceutical International Division: Mr. Kuroiwa, General Manager, Product Planning & Management Pharmaceutical Research Division: Dr. Miyamoto, Director, Pharmacology Research Labs. I Formatted: Right: 0" Dr. Imura, Research Manager, Pharmacology Research Labs. II Dr. Sato, Research Head, Drug Safety Research Labs. Dr. Yamamoto, Research Head, Drug Safety Research Labs., et al. Strategic Product Planning Department: Dr. Sugiyama, Leader, MPDRAP-I Formatted: Right: 0" Dr. Furuya, Leader, MPDRAP-II Mr. Ueda, Leader, MPDRAP-IV, et al. Special Project Unit I: Mr. Ban, Project Leader Formatted: Right: 0" Secretariat of Global Development Committee: Dr. Heya, Group Manager, Dept. Strategic Development Formatted: Right: 0" Mr. Tabata, Manager, Dept. Strategic Development Mr. Morimoto, Manager, Dept. Strategic Development Dr. Hayakawa, Manager, Dept. Strategic Development Mr. Miyazaki, Manager, Dept. Strategic Development Mr. Kikuchi, Manager, Dept. Strategic Development 1 Confidential - Subject to Protective Order TAK-THOMCL-00012573 Produced in MDL on 09/14/12 Ms. Wakamatsu, Assistant manager, Dept. Strategic Development, et al. Attachment: NDA schedule for each project approved on the 5th GDC 1. Openings Remarks Dr. Kitazawa made opening remarks. He mentioned that TAKEDA has been driving for to be a global pharmaceutical company in this decade, concentrating all resource into the pharmaceutical business, under the clear-cut leadership of the CEO. Pharmaceutical Development Division is a core organization of Takeda Pharmaceutical Company, enhancing the pipeline products, which is the decisive factor for TAKEDA business. However, in the present condition, since the launch of Actos in 1999 there are no new products launched. While this situation is critical, the Pharmaceutical Development Division is thought to be conservative and lack of challenging spirit. He stated that his mission is to improve this conservative atmosphere and grow challenging spirit to develop and launch the new products earlier than scheduled. Formatted: Not Hidden 3. MPDRAP-I (Diabetes) 1) AD-4833 Update of US status by TPNA - Bladder tumor observed in NN622 study As for the bladder issues, an expected response from FDA is in early October and pediatric study (Actos 508) is temporarily on hold, however, this is not an official hold. In the recent teleconference discussing non-clinical issues, the experts could not identify any rational hypothesis that dual PPAR agonists may be linked to bladder tumogenesis. A clinical expert meeting is scheduled for October 1 and 2 to discuss how to screen/monitor bladder tumors in long-term clinical trials, since FDA may force TPNA to do it. Label changes may be requested by FDA and it is very difficult to assess the marketing impact of such label change at this moment. It was suggested to prepare non-clinical "White paper" to address the bladder issue. - US commitment study of 30mg VS. 45mg An sNDA will be submitted in this autumn, where studies 341, 342, 343 and 513 are included. The objectives of the submission are for 1) a safety purpose, not for an efficacy or new indication of 45mg, and 2) an update of oral contraceptive interaction results in the label. - Timelines and issues on Actos combination projects were presented. Actos-Metformin Convenience Pack is expected to file sNDA in March 2003 and to be approved in September 2003. TPNA believes stability data of 3 months are sufficient 2 Confidential - Subject to Protective Order TAK-THOMCL-00012574 Produced in MDL on 09/14/12 Source: but TPNA is going to consult with FDA before submission, and vender selection is under negotiation and moving forward. It was noted that an application for convenience pack for 45mg has to be submitted after 45mg combination therapy indication is approved. Actos-Metformin fixed Combination Tablets is expected to file IND in February 2003, to file NDA in November 2003 with 6 months stability data and to be approved in November 2004. In order to ship clinical supplies in January 2003, TCI asked TPNA to file NDA in January NOT in February, preceded by pre-IND meeting in December 2001, although TPNA's original target of IND was February. Since CMC documents will be the rate-limiting factor to file NDA, TCI is going to check if a start of the stability study can be brought forward. GSK will reportedly obtain the approval of their combination product within this year. With regard to Actos-SU Combination Tablet, it should take 18 months from the selection of SU to finalization of the SU combination tablet, TPNA is going to make a proposal for the SU product shortly - which su to choose and its dose levels. - Revision to language in package insert in terms of liver monitoring requirement Liver monitoring issue will be discussed between TPNA and EuR&D so that sNDA/variation for a label change may be submitted in January 2003. - Timelines of other studies were discussed and agreed mutually. Key results (TLGs) from studies 504 and 520 will be made available as scheduled, which are required for the European applications. EuR&D will not be involved in review process of TLGs. The development plan in dysmetabolic syndrome will be approved around late October in-house at TCI. An s NDA of atherosclerosis indication in US is scheduled for October 2005. Update of EU status by EuR&D - Current schedule of submission for mono & unrestricted combo therapy indications Variations to posology (45mg) and indications (monotherapy and first line combination therapy) are scheduled to be submitted in January 2003. Clock starts on 30 January 2003. - Prescription status variation (type II) Variation was submitted on 6th September 2002 and opinion is expected on 19th November 2002. - PROactive The first DSMB meeting is planned for 3Q 2003 and any scientific advance/opinion are invited before the meeting. Publication on baseline data is scheduled for early next year, therefore any modifications on endpoints including FDA suggestions have to be made before the publication. FDA should raise no issue on the protocol according to TPNA. 3 Confidential - Subject to Protective Order TAK-THOMCL-00012575 Produced in MDL on 09/14/12 Source: https://www.indup0442-00003s.ucsf.edu/docs/Imjf0226 - Actos/generic metformin combination tablet Flash data from a pilot BE study to be conducted by EuR&D will be available in mid of November. EU submission based PK/PD argument alone has a low chance of success, around 40%. Although the guidelines expect clinical data to be provided, clinical studies should not be conducted because there is a possibility that Actos bid might show better results than once daily even if daily dose is the same. In Europe, it was agreed to submit the BE study results from US with PK/PD argument as a challenge. It was also agreed that no interaction with authorities is made to ask about the development strategy, because we have to conduct clinical studies once the authorities request us to do them. EuR&D reported that EMO had no interest in Actos-Metformin Combination Pack due to the difficulty to register combination packs in EMEA/CPMP and its poor marketability in EU. CONCLUSIONS; TPNA to prepare non-clinical "White paper" to address bladder issue TPNA & EuR&D to discuss liver monitoring requirement to revise the language in US package insert and EU SPC in January 2003 Generic metformin fixed combination tablet to be pursued in Europe using PD modeling (but, chance of success is low) No interest in convenience pack in Europe Other Takeda Drugs Confidential - Subject to Protective Order TAK-THOMCL-00012576 Produced in MDL on 09/14/12 Source: https://www.indupo.42°00004s.ucsf.edu/docs//mjf0226 Other Takeda Drugs Other Takeda Drugs Other Takeda Drugs Other Takeda Drugs Confidential - Subject to Protective Order TAK-THOMCL-00012577 Produced in MDL on 09/14/12 Source: Other Takeda Drugs Other Takeda Drugs Other Takeda Drugs 6 Confidential - Subject to Protective Order TAK-THOMCL-00012578 Produced in MDL on 09/14/12 Source: Other Takeda Drugs 2) TAK-070 7 Confidential - Subject to Protective Order TAK-THOMCL-00012579 Produced in MDL on 09/14/12 Source: https://www.indupo442°00007ts.ucsf.edu/docs/Imjf0226 Other Takeda Drugs 8 Confidential - Subject to Protective Order TAK-THOMCL-00012580 Produced in MDL on 09/14/12 Source: https://www.indupo:42-00008.ucsf.edu/docs//mjf0226 Other Takeda Drugs investigators. However this issue IS to be discussed with Mitsubishi since they are 9 Confidential - Subject to Protective Order TAK-THOMCL-00012581 Produced in MDL on 09/14/12 Source: Other Takeda Drugs Confidential - Subject to Protective Order TAK-THOMCL-00012582 Produced in MDL on 09/14/12 Source: https://www.indupo.420000.ucsf.edu/docs//mjf0226 Other Takeda Drugs 11 Confidential - Subject to Protective Order TAK-THOMCL-00012583 Produced in MDL on 09/14/12 Source: https://www.indupo:4200ts.ucsf.edu/docs/Imjf0226 Other Takeda Drugs Confidential - Subject to Protective Order TAK-THOMCL-00012584 Produced in MDL on 09/14/12 Source: https://www.indupo442-0002s.ucsf.edu/docs/Imjf0226 Other Takeda Drugs Confidential - Subject to Protective Order TAK-THOMCL-00012585 Produced in MDL on 09/14/12 Source: Other Takeda Drugs Confidential - Subject to Protective Order TAK-THOMCL-00012586 Produced in MDL on 09/14/12 Source: https://www.indupo442°0001'.ucsf.edu/docs/Imjf0226 Other Takeda Drugs Confidential - Subject to Protective Order TAK-THOMCL-00012587 Produced in MDL on 09/14/12 Source: Other Takeda Drugs Confidential - Subject to Protective Order TAK-THOMCL-00012588 Produced in MDL on 09/14/12 Source: END 17 Confidential - Subject to Protective Order TAK-THOMCL-00012589 Produced in MDL on 09/14/12 Source: https://www.indupo442-0007ts.ucsf.edu/docs/Imjf0226

Which drug's toxicity study results will be discussed ?

pljf0226

pljf0226_p0, pljf0226_p1, pljf0226_p2, pljf0226_p3, pljf0226_p4, pljf0226_p5

pioglitazone

08/07/2002 18:46 06 6204 2244 c. 2002 .08/08 21:49 FAX 06 6204 2244 TAKEDA DEVELOP DIVISION 001/006 1 16 TAKEDA CHEMICAL INDUSTRIES, LTD. Pharmaceutical Development Division 1-1, Doshomachi 4-chome, Chuo-ku OSAKA 540-8645, Japan Phone +81-6-6204-2259 / Facsimile +81-6-6204-2244 Dr. Claire Thom August 8, 2002 Takeda Pharmaceuticals North America, Inc. Ref: TPNA-TS-020808 475 Half Day Road, Suite 500 Lincolnshire, IL 60069, USA CC Mr. S. Hamanaka Urgent Re: ACTOS Pages( Including Cover) : 6 Dear Dr. Thom, We faxed you three documents regarding Actos. 1. Comments about a contact with NN 2. Action plan for NN issue 3. Discussion points to address the three key issues raised by the FDA If you have any questions, please do not hesitate to contact us. Best wishes, K.Saito Katsuhisa Saito Dept. Strategic Development Pharmaceutical Development Division Takeda Chemical Industries, LTD. Confidential - Subject to Protective Order TAK-THOMCL-00019744 Produced in MDL on 09/14/12 Source: https://www.induptotoouoonts.ucsf.edu/docs/pljf0226 08/07/2002 18:46 06 6204 2244 2002 08/08 21:49 FAX 06 6204 2244 TAKEDA DEVELOP DIVISION 002/006 = 16 Comments about a contact with Novo Nordisk (NN) 2002/08/08 DSRL, Takeda [Benefit of having a contact with NN] (1) We (TPNA and/or TCI) may be able to have more detailed information about their background of this issue including information about 2-year carcinogenicity studies of NN-622 and "promotion study" of pioglitazone and to find out some weak points in their experiments. [Risk of having a contact with NN] (1) They do not have any duty to show us their data. It means that NN does not always disclose their data even if we have a contact with NN. (2) They will select their information that they show us according to their strategy. (3) Information obtained from NN may not be able to be utilised to convince the FDA. (4) Takeda has an obligation to report to the authorities if we would obtain the information from NN. (5) Their information about "promotion study" may not be indispensable or critical because of the following reasons: i) Number of models for "promotion studies" about urinary bladder tumors is very limited, and at least we can guess their protocol. Most widely known model is two-stage carcinogenicity model (two stage means initiation and promotion); otherwise TG/KO mouse models might be used. No other models have been developed or well-validated if any. In two-stage carcinogenicity modcls, test article is dosed after exposure of an initiator to study promoting potential of the test article. Although these models are classified by kind of initiators used (BBN, MNU, FANFT and so on), method of exposure (in water, in diet, oral gavage, injection to the urinary bladder), dosage levels of initiators, duration of exposure and strains of animals (usually rats); however basic concepts of these models are about the same. Therefore, it is difficult to overturn their positive results even if they let us know their protocols. ii) It is well known that compounds which can induce microcrystal or calculi show promotion effects in two-stage carcinogenicity models of urinary bladder tumors. Therefore, positive results in the "promotion studies" do not always mean that "Cohen hypothesis" is wrong and we can still insist on the justice of the hypothesis. (6) In their official comments on their home page, they seem to follow "Cohen hypothesis" whatever FDA said to TPNA. It is favorable situation for us so far and we may be able to use their phrase as a rooters' song for pioglitazone in our response to FDA. However, if they pretend to question "Cohen hypothesis" on purpose at a Confidential - Subject to Protective Order TAK-THOMCL-00019745 Produced in MDL on 09/14/12 Source: https://www.indupbodo-oooo2ts.ucsf.edu/docs/pljf0226 08/07/2002 18:46 06 6204 2244 2002 08/08 21:49 FAX 06 6204 2244 TAKEDA DEVELOP DIVISION 003/006 3/6 contact, what can we do? (7) As we point out in our action plan (see Action 1, (1), iv), we can claim that the two-stage carcinogenicity model is considered to be too sensitive and likely to result in false positive. (8) We can ask FDA directly to disclose the details of "promotion study" and 2-year carcinogenicity studies in our first response to FDA. It is not too late to think about a contact with NN after FDA's response to our first comments. [Conclusion] (1) Benefit<<Risk (2) This would not be the best moment to have a contact with NN. (3) We would better respond to FDA based on published papers, our data, NN's official comments on their homepage and the information that FDA gave TPNA about NN-622 and pioglitazone and not on the information obtained from a contact with NN. Confidential - Subject to Protective Order TAK-THOMCL-00019746 Produced in MDL on 09/14/12 Source: https://www.indupboto-ouoo3ts.ucsf.edu/docs/pljf0226 08/07/2002 18:47 06 6204 2244 2002 08/08 21:49 FAX 06 6204 2244 TAKEDA DEVELOP DIVISION 004/006 4/6 Action plan for "NN issue" 2002/08/08 DSRL, Takeda Action 1. Develop rationale to argue against FDA's "PPAR hypothesis" by reviewing literatures on PPAR and urinary bladder tumors (1) No urinary bladder tumors by PPARa agonists i) No urinary bladder tumors by fibrates have been proved in human. ii) No urinary bladder tumors in 2-year carcinogenicity studies of PPARa agonists such as fibrates, di(2-ethylhexyl)phthalate (DEHP) and WY-14,643 [SBA etc.] iii) No urinary bladder tumors in various models of alternative methods for carcinogenicity testing. These models include p53+/-mice (clofibrate, DEHP, Wy-14,643), neonatal mice (clofibrate), FVB mice (clofibrate), Tg-rasH2 mice (clofibrate, DEHP), XPA-/- mice (DEHP, Wy-14,643) and Tg.AC mice (clofibrate) [Many authors, Toxicol. Pathol. 29 (Suppl.) 2001 etc.]. iv) There is one literature on an early prediction model to assess promoting effects, in which N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) was used as an initiator and clofibrate was shown to have an promoting effect on urinary bladder tumorigenesis (but not DEHP) [Hagiwara et al., Jpn. J. Cancer Res. 81, 1239-1246, 1990]. As for liver tumor, clofibrate is considered to be a promoter, but the promoting ability is dependent on the initiator used. It is quite unlikely that clofibrate has carcinogenic potential on the urinary bladder taking the results of 2-year carcinogenicity studies and various models of alternative methods into consideration, and the above-mentioned study using BBN as an initiator seems to be too sensitive and apt to result in false positive. (2) No urinary bladder tumors by PPARY agonists i) No urinary bladder tumors in 2-year carcinogenicity studies of PPARY agonists such as troglitazone and rosiglitazone [SBA etc.] (3) Low possibilities of urinary bladder tumors by dual agonists of PPARa and Y i) No abnormalities were noted in the urinary bladder in 13- and 26-week studies of TAK-559 in rats, while simple hyperplasia of the epithelium of the urinary bladder was seen in a few animals in a 13-week study of pioglitazone in aged rats (supplemental study conducted after the carcinogenicity study in rats). Flash data of carcinogenicity studies of TAK-559 will be available by October 2003. (4) There are several reports from various authors showing that PPARs, especially PPARY, are expressed in the urinary tract and bladder in animals and human. However, pioglitazone¹,2 , as well as troglitazone 1,2,3) , suppressed the growth of human-derived nonneoplastic and neoplastic urothelial cells [ (1) Nakashiro et al., Am. J. Pathol., 159, 591-597, 2001; (2) Kawakami et al., J. Cell. Physiol. 191, 310-319, 2002; (3) Guan et al., Neoplasia 1, 330-339, 1999] Confidential - Subject to Protective Order TAK-THOMCL-00019747 Produced in MDL on 09/14/12 08/07/2002 18:47 06 6204 2244 2002 08/08 21:49 FAX 06 6204 2244 TAKEDA DEVELOP DIVISION 005/006 5/6 Action 2. Conduct additional nonclinical studies to support "Takeda theory" and/or to object to "PPAR hypothesis" (1) Carbonic anhydrase inhibition assay Pioglitazone (retest), rosiglitazone, NN-622 (a/y, Novo Nordisk) and AZ-242 (a/y, Astra Zeneca) are already sent to PanLabs for enzyme inhibition assay using human red blood cell. Data will be available within a few weeks. i) If NN-622 has an inhibitory activity, we can claim that bladder tumors by NN-622 may be caused by similar mechanism with pioglitazone. ii) If not, we may not be able to mention anything about possible involvement of this enzyme, but there is little disadvantage because Dr. Cohen described in his White Paper that carbonic anhydrase inhibition may not be a single or major cause of urinary bladder tumor by pioglitazone. (2) Rat urothelial cell growth assay (University or Takeda) Referring to an in vitro experiment showing the suppressive actions of pioglitazone in human urothelial cells [see 1. (4)], effects of pioglitazone on the growth of rat-derived nonneoplastic and neoplastic urothelial cells will be examined. Because it would be most reasonable to perform both of rat and human cell studies in the same facility (Northwestern Univ., Chicago), we will come in contact with Northwestern Univ. to propose collaboration. If they refuse our proposal, the experiments will be donc in Takeda; however in such a case not only rat cell lines but also human cell lines have to be used to confirm reproducibility of the results in the literature at the risk of getting contradictory results to the literature. i) If pioglitazone shows no or suppressive effects on rat bladder cell lines, we can exclude direct promoting effects via PPARs in both rat and human. Also, this will support "Takeda/Cohen theory" indirectly. ii) If pioglitazone shows accelerative effects on rat bladder tumor cell lines, we might accept "PPAR hypothesis" as far as in rats. But even so, we can claim that "PPAR hypothesis" might be true only in rats but not in human based on the suppressive effects on human bladder cell lines. Action 3. Consult experts of urinary bladder to justify our plans and concepts from academic viewpoints (1) If necessary, we will ask them to write "White Paper". Confidential - Subject to Protective Order TAK-THOMCL-00019748 Produced in MDL on 09/14/12 Source: https://www.indupbotorouoosts.ucsf.edu/docs/pljf0226 08/07/2002 18:47 06 6204 2244 2002* 08/08 21:50 FAX 06 6204 2244 TAKEDA DEVELOP DIVISION 006/006 6/6 Discussion points to address the three key issues raised by the FDA Date: Monday, 12 and Tuesday, 13 August 2002 Venue: TPNA, Chicago ISSUES 1. They requested us to propose a method by which to monitor bladder toxicity in patients in our long term phase 4 clinical trials (long term was defined as at least 1 year). 2. They indicated an inclination to rescind the written request for pediatric exclusivity based on their concern about bladder tumors. 3. They requested us to give some consideration to a label change that would reflect possible relatedness of tumor formation to mechanism (dual PPAR agonist) instead of the current language ("The relationship of these findings in male rats to humans is unclear.") DISCUSSION POINTS a. to briefly review the toxicity study results of pioglitazone, particularly carcinogenicity studies b. to summarise discussions with the CPMP c. to submit literature suggesting that pioglitazone suppresses the cell growth, particularly urinary bladder cell d. to perform an in-vitro study to evaluate the cell growth and cell growth inhibition with piogliatzone e. to investigate carbonic anhydrase inhibiting activity of NN622, pioglitazone and rosiglitazone f. to compare PPAR agonists in terms of alpha and gamma activities g. to differentiate between glitazones and glitazars h. to consult with non-clinical external experts for their expertise i. to find a rationale for not doing clinical monitoring j. a monotoring method k. a case control study 1. a pharmacoepidemiology study m. to submit a report from a Japanese follow up study for pioglitazone n. to assess cases from database search for pioglitazone Confidential - Subject to Protective Order TAK-THOMCL-00019749 Produced in MDL on 09/14/12 Source: https://www.induptoto-ouoosts.ucsf.edu/docs/pljf0226

Who challenged authorities regrading implementing monitoring plan?

myjf0226

myjf0226_p0, myjf0226_p1, myjf0226_p2, myjf0226_p3

Takeda Europe

ACTOS FDA RESPONSE MEETING TPNA/TEUR&D/TCI AUGUST 12-13, 2002 Attendees: TPNA TEUR&D Sam Hamanaka David Eckland Claire Thom Yasuhiko Wada Ingrid Hood Glyn Belcher Alfonso Perez Philip Collett David Recker John Page TCI Mary Ramstack Katsuhisa Saito Janet Haskins Masahiro Miyazaki Dan Orlando Takashi Kuroiwa David Baron Takashi Nonoyama Chris Durack Keiichiro Sato Larry Hancock Hiroyuki Odaka Bob Ahlbrandt Tom Muldoon Karen Kaluzny Summary of July 31 Teleconference with FDA (J. Haskins) The FDA informed TPNA that they had received data from a rat tumor promoter study using dual PPAR agonists. Pioglitazone was used in this experiment, and the group of rats treated with pioglitazone experienced the same frequency of transitional cell tumors as the group treated with the dual PPAR agonist under investigation. The FDA clarified that due to this data, they had concerns with the dual PPAR mechanism, and considered pioglitazone to have a dual PPAR mechanism. There were three key messages from the teleconference: The FDA asked TPNA to consider a label change, as they feel that the current package insert does not adequately inform patients of the risk associated with bladder tumors. The FDA asked TPNA to research and propose a monitoring plan, which would be incorporated into clinical trials. The FDA stated that they were considering rescinding their written request to TPNA to conduct pediatric studies with pioglitazone. Confidential - Subject to Protective Order TAK-RAMSTM-00487173 Produced in MDL on 03/06/13 Source: ACTOS FDA Response Meeting August 12-13, 2002 Page 2 of 4 Summary of July 31 Teleconference with FDA (J. Haskins) - Continued The group summarized the FDA's concerns as follows: The FDA is not stating that ACTOS specifically causes or contributes to bladder tumors. The FDA no longer supports Dr. Cohen's hypothesis, since the tumor promoter study data they received demonstrated the presence of tumors without calculi. The FDA no longer feels that they understand how these findings relate to humans. Update from TCI Meeting with CEO (Mr. Saito) Mr. Saito updated the CEO on this situation on August 6. The following strategy was decided on: Attempt to keep current carcinogenicity label wording; if not possible, request that same labeling be applied to Avandia Find rationale to support not establishing monitoring plan, but if necessary, would compromise on monitoring wording to avoid changing carcinogenicity wording Develop argument to proceed with Actos 508 (safety/efficacy in pediatrics) study under current timelines, but are willing to postpone The following timelines were established: TPNA to send outline of response to TCI by August 19 Mr. Saito will present outline to CEO on August 20 TPNA will send draft document to TCI, TEUR&D, and Lilly on August 21 Document will be finalized by August 26 Response will be sent to FDA on August 28 Mr Saito also presented the following communication structure and schematic Leadership: Claire Thom, David Eckland, Mr. Saito Primary contacts: Mary Ramstack, Janet Haskins, Philip Collett, Mr. Miyazaki The only exception to this schematic will be that on August 26, TPNA will communicate directly with Lilly to distribute the draft document CEO Mr Saito TPNA TCI labs Lilly EU Confidential - Subject to Protective Order TAK-RAMSTM-00487174 Produced in MDL on 03/06/13 Source: ACTOS FDA Response Meeting August 12-13, 2002 Page 3 of 4 Highlights/Discussion Points from Preclinical Data Presentation In the rat oncogenicity study, thickening of the bladder and hypertrophy of the urothelium was observed in male rats. These findings were not dose- dependent. Nearly all of the tumors were found at the end of the study. Some cases of hyperplasia were seen in female rats at the highest dose level only, but no malignancies were seen. There were no tumors seen in the shorter term (12 month) rat toxicity studies. Glyn Belcher suggested creating a summary able for all toxicology studies with durations between 6 months and less than 2 years. In the mouse oncogenicity study, hyperplasia was seen in male mice only. These findings were not dose-dependent, and results were not statistically significant. One case of hyperplasia was observed in the placebo group. Philip Collett stated that the European authorities did not question the mouse data for ACTOS, but rather only the rat data. A list of all mutagenicity studies conducted with pioglitazone was shown, and David Baron acknowledged that TCI had conducted a very robust program that went beyond regulatory requirements. A study observing the effects of pioglitazone on urinary parameters in rats was conducted, and highlights are as follows: Simple hyperplasia seen in one male Increase in urine pH, urine volume, microcrystal count Slight decrease in magnesium, calcium, phosphorous, sodium, potassium, and chloride Conclusion: Changes in urinary components are considered to be factors in the etiology of proliferative lesions of the bladder: Pioglitazone ingestion Altered urinary physiology Calculus formation Urothelial ulceration an regeneration (hyperplasia) Benin papilloma Carcinoma Confidential - Subject to Protective Order TAK-RAMSTM-00487175 Produced in MDL on 03/06/13 Source: ACTOS FDA Response Meeting August 12-13, 2002 Page 4 of 4 Highlights from Cohen Hypothesis Discussion Philip Collett presented an outline of the Cohen hypothesis Male rat urine has a very high protein content, which is a function of sex hormones Raising the pH of male rat urine above 6.5 is significant in the development of calculi Because rats are quadropeds, they do not eliminate calculi as humans do The correlation observed in Cohen's paper is 0.61. The European authorities initially determined this to be quite low; however, Dr. Cohen authored an expert report which stated that the 0.61 correlation was actually high, as calculi can dissolve over time. In summary, the tumors seen in rats were due to the presence of calculi. The male rat urine milieu contributes to the formation of calculi. Because rats are quadropeds, they do not eliminate calculi as bipeds do. Main Points from Takeda Europe Experience Takeda Europe successfully employed the following strategy: Defended Cohen hypothesis, despite numerous challenges Stressed the "one sex, one species" argument Challenged authorities regarding implementing monitoring plan Offered to conduct a case control study post-approval Highlights from PPAR Agonist Discussion The group extensively discussed many aspects of the PPAR mechanism and ultimately decided to not address mechanistic issues in the initial FDA response. However, it was decided that this argument should be developed, as it may be necessary to use it in the future, and action items were assigned accordingly. Confidential - Subject to Protective Order TAK-RAMSTM-00487176 Produced in MDL on 03/06/13 Source:

What content is high in male rat urine?

myjf0226

myjf0226_p0, myjf0226_p1, myjf0226_p2, myjf0226_p3

protein, protien content

ACTOS FDA RESPONSE MEETING TPNA/TEUR&D/TCI AUGUST 12-13, 2002 Attendees: TPNA TEUR&D Sam Hamanaka David Eckland Claire Thom Yasuhiko Wada Ingrid Hood Glyn Belcher Alfonso Perez Philip Collett David Recker John Page TCI Mary Ramstack Katsuhisa Saito Janet Haskins Masahiro Miyazaki Dan Orlando Takashi Kuroiwa David Baron Takashi Nonoyama Chris Durack Keiichiro Sato Larry Hancock Hiroyuki Odaka Bob Ahlbrandt Tom Muldoon Karen Kaluzny Summary of July 31 Teleconference with FDA (J. Haskins) The FDA informed TPNA that they had received data from a rat tumor promoter study using dual PPAR agonists. Pioglitazone was used in this experiment, and the group of rats treated with pioglitazone experienced the same frequency of transitional cell tumors as the group treated with the dual PPAR agonist under investigation. The FDA clarified that due to this data, they had concerns with the dual PPAR mechanism, and considered pioglitazone to have a dual PPAR mechanism. There were three key messages from the teleconference: The FDA asked TPNA to consider a label change, as they feel that the current package insert does not adequately inform patients of the risk associated with bladder tumors. The FDA asked TPNA to research and propose a monitoring plan, which would be incorporated into clinical trials. The FDA stated that they were considering rescinding their written request to TPNA to conduct pediatric studies with pioglitazone. Confidential - Subject to Protective Order TAK-RAMSTM-00487173 Produced in MDL on 03/06/13 Source: ACTOS FDA Response Meeting August 12-13, 2002 Page 2 of 4 Summary of July 31 Teleconference with FDA (J. Haskins) - Continued The group summarized the FDA's concerns as follows: The FDA is not stating that ACTOS specifically causes or contributes to bladder tumors. The FDA no longer supports Dr. Cohen's hypothesis, since the tumor promoter study data they received demonstrated the presence of tumors without calculi. The FDA no longer feels that they understand how these findings relate to humans. Update from TCI Meeting with CEO (Mr. Saito) Mr. Saito updated the CEO on this situation on August 6. The following strategy was decided on: Attempt to keep current carcinogenicity label wording; if not possible, request that same labeling be applied to Avandia Find rationale to support not establishing monitoring plan, but if necessary, would compromise on monitoring wording to avoid changing carcinogenicity wording Develop argument to proceed with Actos 508 (safety/efficacy in pediatrics) study under current timelines, but are willing to postpone The following timelines were established: TPNA to send outline of response to TCI by August 19 Mr. Saito will present outline to CEO on August 20 TPNA will send draft document to TCI, TEUR&D, and Lilly on August 21 Document will be finalized by August 26 Response will be sent to FDA on August 28 Mr Saito also presented the following communication structure and schematic Leadership: Claire Thom, David Eckland, Mr. Saito Primary contacts: Mary Ramstack, Janet Haskins, Philip Collett, Mr. Miyazaki The only exception to this schematic will be that on August 26, TPNA will communicate directly with Lilly to distribute the draft document CEO Mr Saito TPNA TCI labs Lilly EU Confidential - Subject to Protective Order TAK-RAMSTM-00487174 Produced in MDL on 03/06/13 Source: ACTOS FDA Response Meeting August 12-13, 2002 Page 3 of 4 Highlights/Discussion Points from Preclinical Data Presentation In the rat oncogenicity study, thickening of the bladder and hypertrophy of the urothelium was observed in male rats. These findings were not dose- dependent. Nearly all of the tumors were found at the end of the study. Some cases of hyperplasia were seen in female rats at the highest dose level only, but no malignancies were seen. There were no tumors seen in the shorter term (12 month) rat toxicity studies. Glyn Belcher suggested creating a summary able for all toxicology studies with durations between 6 months and less than 2 years. In the mouse oncogenicity study, hyperplasia was seen in male mice only. These findings were not dose-dependent, and results were not statistically significant. One case of hyperplasia was observed in the placebo group. Philip Collett stated that the European authorities did not question the mouse data for ACTOS, but rather only the rat data. A list of all mutagenicity studies conducted with pioglitazone was shown, and David Baron acknowledged that TCI had conducted a very robust program that went beyond regulatory requirements. A study observing the effects of pioglitazone on urinary parameters in rats was conducted, and highlights are as follows: Simple hyperplasia seen in one male Increase in urine pH, urine volume, microcrystal count Slight decrease in magnesium, calcium, phosphorous, sodium, potassium, and chloride Conclusion: Changes in urinary components are considered to be factors in the etiology of proliferative lesions of the bladder: Pioglitazone ingestion Altered urinary physiology Calculus formation Urothelial ulceration an regeneration (hyperplasia) Benin papilloma Carcinoma Confidential - Subject to Protective Order TAK-RAMSTM-00487175 Produced in MDL on 03/06/13 Source: ACTOS FDA Response Meeting August 12-13, 2002 Page 4 of 4 Highlights from Cohen Hypothesis Discussion Philip Collett presented an outline of the Cohen hypothesis Male rat urine has a very high protein content, which is a function of sex hormones Raising the pH of male rat urine above 6.5 is significant in the development of calculi Because rats are quadropeds, they do not eliminate calculi as humans do The correlation observed in Cohen's paper is 0.61. The European authorities initially determined this to be quite low; however, Dr. Cohen authored an expert report which stated that the 0.61 correlation was actually high, as calculi can dissolve over time. In summary, the tumors seen in rats were due to the presence of calculi. The male rat urine milieu contributes to the formation of calculi. Because rats are quadropeds, they do not eliminate calculi as bipeds do. Main Points from Takeda Europe Experience Takeda Europe successfully employed the following strategy: Defended Cohen hypothesis, despite numerous challenges Stressed the "one sex, one species" argument Challenged authorities regarding implementing monitoring plan Offered to conduct a case control study post-approval Highlights from PPAR Agonist Discussion The group extensively discussed many aspects of the PPAR mechanism and ultimately decided to not address mechanistic issues in the initial FDA response. However, it was decided that this argument should be developed, as it may be necessary to use it in the future, and action items were assigned accordingly. Confidential - Subject to Protective Order TAK-RAMSTM-00487176 Produced in MDL on 03/06/13 Source:

What kind of meeting is mentioned in this letter?

myjf0226

myjf0226_p0, myjf0226_p1, myjf0226_p2, myjf0226_p3

ACTOS FDA RESPONSE MEETING

ACTOS FDA RESPONSE MEETING TPNA/TEUR&D/TCI AUGUST 12-13, 2002 Attendees: TPNA TEUR&D Sam Hamanaka David Eckland Claire Thom Yasuhiko Wada Ingrid Hood Glyn Belcher Alfonso Perez Philip Collett David Recker John Page TCI Mary Ramstack Katsuhisa Saito Janet Haskins Masahiro Miyazaki Dan Orlando Takashi Kuroiwa David Baron Takashi Nonoyama Chris Durack Keiichiro Sato Larry Hancock Hiroyuki Odaka Bob Ahlbrandt Tom Muldoon Karen Kaluzny Summary of July 31 Teleconference with FDA (J. Haskins) The FDA informed TPNA that they had received data from a rat tumor promoter study using dual PPAR agonists. Pioglitazone was used in this experiment, and the group of rats treated with pioglitazone experienced the same frequency of transitional cell tumors as the group treated with the dual PPAR agonist under investigation. The FDA clarified that due to this data, they had concerns with the dual PPAR mechanism, and considered pioglitazone to have a dual PPAR mechanism. There were three key messages from the teleconference: The FDA asked TPNA to consider a label change, as they feel that the current package insert does not adequately inform patients of the risk associated with bladder tumors. The FDA asked TPNA to research and propose a monitoring plan, which would be incorporated into clinical trials. The FDA stated that they were considering rescinding their written request to TPNA to conduct pediatric studies with pioglitazone. Confidential - Subject to Protective Order TAK-RAMSTM-00487173 Produced in MDL on 03/06/13 Source: ACTOS FDA Response Meeting August 12-13, 2002 Page 2 of 4 Summary of July 31 Teleconference with FDA (J. Haskins) - Continued The group summarized the FDA's concerns as follows: The FDA is not stating that ACTOS specifically causes or contributes to bladder tumors. The FDA no longer supports Dr. Cohen's hypothesis, since the tumor promoter study data they received demonstrated the presence of tumors without calculi. The FDA no longer feels that they understand how these findings relate to humans. Update from TCI Meeting with CEO (Mr. Saito) Mr. Saito updated the CEO on this situation on August 6. The following strategy was decided on: Attempt to keep current carcinogenicity label wording; if not possible, request that same labeling be applied to Avandia Find rationale to support not establishing monitoring plan, but if necessary, would compromise on monitoring wording to avoid changing carcinogenicity wording Develop argument to proceed with Actos 508 (safety/efficacy in pediatrics) study under current timelines, but are willing to postpone The following timelines were established: TPNA to send outline of response to TCI by August 19 Mr. Saito will present outline to CEO on August 20 TPNA will send draft document to TCI, TEUR&D, and Lilly on August 21 Document will be finalized by August 26 Response will be sent to FDA on August 28 Mr Saito also presented the following communication structure and schematic Leadership: Claire Thom, David Eckland, Mr. Saito Primary contacts: Mary Ramstack, Janet Haskins, Philip Collett, Mr. Miyazaki The only exception to this schematic will be that on August 26, TPNA will communicate directly with Lilly to distribute the draft document CEO Mr Saito TPNA TCI labs Lilly EU Confidential - Subject to Protective Order TAK-RAMSTM-00487174 Produced in MDL on 03/06/13 Source: ACTOS FDA Response Meeting August 12-13, 2002 Page 3 of 4 Highlights/Discussion Points from Preclinical Data Presentation In the rat oncogenicity study, thickening of the bladder and hypertrophy of the urothelium was observed in male rats. These findings were not dose- dependent. Nearly all of the tumors were found at the end of the study. Some cases of hyperplasia were seen in female rats at the highest dose level only, but no malignancies were seen. There were no tumors seen in the shorter term (12 month) rat toxicity studies. Glyn Belcher suggested creating a summary able for all toxicology studies with durations between 6 months and less than 2 years. In the mouse oncogenicity study, hyperplasia was seen in male mice only. These findings were not dose-dependent, and results were not statistically significant. One case of hyperplasia was observed in the placebo group. Philip Collett stated that the European authorities did not question the mouse data for ACTOS, but rather only the rat data. A list of all mutagenicity studies conducted with pioglitazone was shown, and David Baron acknowledged that TCI had conducted a very robust program that went beyond regulatory requirements. A study observing the effects of pioglitazone on urinary parameters in rats was conducted, and highlights are as follows: Simple hyperplasia seen in one male Increase in urine pH, urine volume, microcrystal count Slight decrease in magnesium, calcium, phosphorous, sodium, potassium, and chloride Conclusion: Changes in urinary components are considered to be factors in the etiology of proliferative lesions of the bladder: Pioglitazone ingestion Altered urinary physiology Calculus formation Urothelial ulceration an regeneration (hyperplasia) Benin papilloma Carcinoma Confidential - Subject to Protective Order TAK-RAMSTM-00487175 Produced in MDL on 03/06/13 Source: ACTOS FDA Response Meeting August 12-13, 2002 Page 4 of 4 Highlights from Cohen Hypothesis Discussion Philip Collett presented an outline of the Cohen hypothesis Male rat urine has a very high protein content, which is a function of sex hormones Raising the pH of male rat urine above 6.5 is significant in the development of calculi Because rats are quadropeds, they do not eliminate calculi as humans do The correlation observed in Cohen's paper is 0.61. The European authorities initially determined this to be quite low; however, Dr. Cohen authored an expert report which stated that the 0.61 correlation was actually high, as calculi can dissolve over time. In summary, the tumors seen in rats were due to the presence of calculi. The male rat urine milieu contributes to the formation of calculi. Because rats are quadropeds, they do not eliminate calculi as bipeds do. Main Points from Takeda Europe Experience Takeda Europe successfully employed the following strategy: Defended Cohen hypothesis, despite numerous challenges Stressed the "one sex, one species" argument Challenged authorities regarding implementing monitoring plan Offered to conduct a case control study post-approval Highlights from PPAR Agonist Discussion The group extensively discussed many aspects of the PPAR mechanism and ultimately decided to not address mechanistic issues in the initial FDA response. However, it was decided that this argument should be developed, as it may be necessary to use it in the future, and action items were assigned accordingly. Confidential - Subject to Protective Order TAK-RAMSTM-00487176 Produced in MDL on 03/06/13 Source:

what kind of drug is used to treat the group of rats?

myjf0226

myjf0226_p0, myjf0226_p1, myjf0226_p2, myjf0226_p3

pioglitazone, Pioglitazone

ACTOS FDA RESPONSE MEETING TPNA/TEUR&D/TCI AUGUST 12-13, 2002 Attendees: TPNA TEUR&D Sam Hamanaka David Eckland Claire Thom Yasuhiko Wada Ingrid Hood Glyn Belcher Alfonso Perez Philip Collett David Recker John Page TCI Mary Ramstack Katsuhisa Saito Janet Haskins Masahiro Miyazaki Dan Orlando Takashi Kuroiwa David Baron Takashi Nonoyama Chris Durack Keiichiro Sato Larry Hancock Hiroyuki Odaka Bob Ahlbrandt Tom Muldoon Karen Kaluzny Summary of July 31 Teleconference with FDA (J. Haskins) The FDA informed TPNA that they had received data from a rat tumor promoter study using dual PPAR agonists. Pioglitazone was used in this experiment, and the group of rats treated with pioglitazone experienced the same frequency of transitional cell tumors as the group treated with the dual PPAR agonist under investigation. The FDA clarified that due to this data, they had concerns with the dual PPAR mechanism, and considered pioglitazone to have a dual PPAR mechanism. There were three key messages from the teleconference: The FDA asked TPNA to consider a label change, as they feel that the current package insert does not adequately inform patients of the risk associated with bladder tumors. The FDA asked TPNA to research and propose a monitoring plan, which would be incorporated into clinical trials. The FDA stated that they were considering rescinding their written request to TPNA to conduct pediatric studies with pioglitazone. Confidential - Subject to Protective Order TAK-RAMSTM-00487173 Produced in MDL on 03/06/13 Source: ACTOS FDA Response Meeting August 12-13, 2002 Page 2 of 4 Summary of July 31 Teleconference with FDA (J. Haskins) - Continued The group summarized the FDA's concerns as follows: The FDA is not stating that ACTOS specifically causes or contributes to bladder tumors. The FDA no longer supports Dr. Cohen's hypothesis, since the tumor promoter study data they received demonstrated the presence of tumors without calculi. The FDA no longer feels that they understand how these findings relate to humans. Update from TCI Meeting with CEO (Mr. Saito) Mr. Saito updated the CEO on this situation on August 6. The following strategy was decided on: Attempt to keep current carcinogenicity label wording; if not possible, request that same labeling be applied to Avandia Find rationale to support not establishing monitoring plan, but if necessary, would compromise on monitoring wording to avoid changing carcinogenicity wording Develop argument to proceed with Actos 508 (safety/efficacy in pediatrics) study under current timelines, but are willing to postpone The following timelines were established: TPNA to send outline of response to TCI by August 19 Mr. Saito will present outline to CEO on August 20 TPNA will send draft document to TCI, TEUR&D, and Lilly on August 21 Document will be finalized by August 26 Response will be sent to FDA on August 28 Mr Saito also presented the following communication structure and schematic Leadership: Claire Thom, David Eckland, Mr. Saito Primary contacts: Mary Ramstack, Janet Haskins, Philip Collett, Mr. Miyazaki The only exception to this schematic will be that on August 26, TPNA will communicate directly with Lilly to distribute the draft document CEO Mr Saito TPNA TCI labs Lilly EU Confidential - Subject to Protective Order TAK-RAMSTM-00487174 Produced in MDL on 03/06/13 Source: ACTOS FDA Response Meeting August 12-13, 2002 Page 3 of 4 Highlights/Discussion Points from Preclinical Data Presentation In the rat oncogenicity study, thickening of the bladder and hypertrophy of the urothelium was observed in male rats. These findings were not dose- dependent. Nearly all of the tumors were found at the end of the study. Some cases of hyperplasia were seen in female rats at the highest dose level only, but no malignancies were seen. There were no tumors seen in the shorter term (12 month) rat toxicity studies. Glyn Belcher suggested creating a summary able for all toxicology studies with durations between 6 months and less than 2 years. In the mouse oncogenicity study, hyperplasia was seen in male mice only. These findings were not dose-dependent, and results were not statistically significant. One case of hyperplasia was observed in the placebo group. Philip Collett stated that the European authorities did not question the mouse data for ACTOS, but rather only the rat data. A list of all mutagenicity studies conducted with pioglitazone was shown, and David Baron acknowledged that TCI had conducted a very robust program that went beyond regulatory requirements. A study observing the effects of pioglitazone on urinary parameters in rats was conducted, and highlights are as follows: Simple hyperplasia seen in one male Increase in urine pH, urine volume, microcrystal count Slight decrease in magnesium, calcium, phosphorous, sodium, potassium, and chloride Conclusion: Changes in urinary components are considered to be factors in the etiology of proliferative lesions of the bladder: Pioglitazone ingestion Altered urinary physiology Calculus formation Urothelial ulceration an regeneration (hyperplasia) Benin papilloma Carcinoma Confidential - Subject to Protective Order TAK-RAMSTM-00487175 Produced in MDL on 03/06/13 Source: ACTOS FDA Response Meeting August 12-13, 2002 Page 4 of 4 Highlights from Cohen Hypothesis Discussion Philip Collett presented an outline of the Cohen hypothesis Male rat urine has a very high protein content, which is a function of sex hormones Raising the pH of male rat urine above 6.5 is significant in the development of calculi Because rats are quadropeds, they do not eliminate calculi as humans do The correlation observed in Cohen's paper is 0.61. The European authorities initially determined this to be quite low; however, Dr. Cohen authored an expert report which stated that the 0.61 correlation was actually high, as calculi can dissolve over time. In summary, the tumors seen in rats were due to the presence of calculi. The male rat urine milieu contributes to the formation of calculi. Because rats are quadropeds, they do not eliminate calculi as bipeds do. Main Points from Takeda Europe Experience Takeda Europe successfully employed the following strategy: Defended Cohen hypothesis, despite numerous challenges Stressed the "one sex, one species" argument Challenged authorities regarding implementing monitoring plan Offered to conduct a case control study post-approval Highlights from PPAR Agonist Discussion The group extensively discussed many aspects of the PPAR mechanism and ultimately decided to not address mechanistic issues in the initial FDA response. However, it was decided that this argument should be developed, as it may be necessary to use it in the future, and action items were assigned accordingly. Confidential - Subject to Protective Order TAK-RAMSTM-00487176 Produced in MDL on 03/06/13 Source:

In the rat oncogenicity study, what was observed in male rats?

myjf0226

myjf0226_p0, myjf0226_p1, myjf0226_p2, myjf0226_p3

thickening of the bladder and hypertrophy of the urothelium

ACTOS FDA RESPONSE MEETING TPNA/TEUR&D/TCI AUGUST 12-13, 2002 Attendees: TPNA TEUR&D Sam Hamanaka David Eckland Claire Thom Yasuhiko Wada Ingrid Hood Glyn Belcher Alfonso Perez Philip Collett David Recker John Page TCI Mary Ramstack Katsuhisa Saito Janet Haskins Masahiro Miyazaki Dan Orlando Takashi Kuroiwa David Baron Takashi Nonoyama Chris Durack Keiichiro Sato Larry Hancock Hiroyuki Odaka Bob Ahlbrandt Tom Muldoon Karen Kaluzny Summary of July 31 Teleconference with FDA (J. Haskins) The FDA informed TPNA that they had received data from a rat tumor promoter study using dual PPAR agonists. Pioglitazone was used in this experiment, and the group of rats treated with pioglitazone experienced the same frequency of transitional cell tumors as the group treated with the dual PPAR agonist under investigation. The FDA clarified that due to this data, they had concerns with the dual PPAR mechanism, and considered pioglitazone to have a dual PPAR mechanism. There were three key messages from the teleconference: The FDA asked TPNA to consider a label change, as they feel that the current package insert does not adequately inform patients of the risk associated with bladder tumors. The FDA asked TPNA to research and propose a monitoring plan, which would be incorporated into clinical trials. The FDA stated that they were considering rescinding their written request to TPNA to conduct pediatric studies with pioglitazone. Confidential - Subject to Protective Order TAK-RAMSTM-00487173 Produced in MDL on 03/06/13 Source: ACTOS FDA Response Meeting August 12-13, 2002 Page 2 of 4 Summary of July 31 Teleconference with FDA (J. Haskins) - Continued The group summarized the FDA's concerns as follows: The FDA is not stating that ACTOS specifically causes or contributes to bladder tumors. The FDA no longer supports Dr. Cohen's hypothesis, since the tumor promoter study data they received demonstrated the presence of tumors without calculi. The FDA no longer feels that they understand how these findings relate to humans. Update from TCI Meeting with CEO (Mr. Saito) Mr. Saito updated the CEO on this situation on August 6. The following strategy was decided on: Attempt to keep current carcinogenicity label wording; if not possible, request that same labeling be applied to Avandia Find rationale to support not establishing monitoring plan, but if necessary, would compromise on monitoring wording to avoid changing carcinogenicity wording Develop argument to proceed with Actos 508 (safety/efficacy in pediatrics) study under current timelines, but are willing to postpone The following timelines were established: TPNA to send outline of response to TCI by August 19 Mr. Saito will present outline to CEO on August 20 TPNA will send draft document to TCI, TEUR&D, and Lilly on August 21 Document will be finalized by August 26 Response will be sent to FDA on August 28 Mr Saito also presented the following communication structure and schematic Leadership: Claire Thom, David Eckland, Mr. Saito Primary contacts: Mary Ramstack, Janet Haskins, Philip Collett, Mr. Miyazaki The only exception to this schematic will be that on August 26, TPNA will communicate directly with Lilly to distribute the draft document CEO Mr Saito TPNA TCI labs Lilly EU Confidential - Subject to Protective Order TAK-RAMSTM-00487174 Produced in MDL on 03/06/13 Source: ACTOS FDA Response Meeting August 12-13, 2002 Page 3 of 4 Highlights/Discussion Points from Preclinical Data Presentation In the rat oncogenicity study, thickening of the bladder and hypertrophy of the urothelium was observed in male rats. These findings were not dose- dependent. Nearly all of the tumors were found at the end of the study. Some cases of hyperplasia were seen in female rats at the highest dose level only, but no malignancies were seen. There were no tumors seen in the shorter term (12 month) rat toxicity studies. Glyn Belcher suggested creating a summary able for all toxicology studies with durations between 6 months and less than 2 years. In the mouse oncogenicity study, hyperplasia was seen in male mice only. These findings were not dose-dependent, and results were not statistically significant. One case of hyperplasia was observed in the placebo group. Philip Collett stated that the European authorities did not question the mouse data for ACTOS, but rather only the rat data. A list of all mutagenicity studies conducted with pioglitazone was shown, and David Baron acknowledged that TCI had conducted a very robust program that went beyond regulatory requirements. A study observing the effects of pioglitazone on urinary parameters in rats was conducted, and highlights are as follows: Simple hyperplasia seen in one male Increase in urine pH, urine volume, microcrystal count Slight decrease in magnesium, calcium, phosphorous, sodium, potassium, and chloride Conclusion: Changes in urinary components are considered to be factors in the etiology of proliferative lesions of the bladder: Pioglitazone ingestion Altered urinary physiology Calculus formation Urothelial ulceration an regeneration (hyperplasia) Benin papilloma Carcinoma Confidential - Subject to Protective Order TAK-RAMSTM-00487175 Produced in MDL on 03/06/13 Source: ACTOS FDA Response Meeting August 12-13, 2002 Page 4 of 4 Highlights from Cohen Hypothesis Discussion Philip Collett presented an outline of the Cohen hypothesis Male rat urine has a very high protein content, which is a function of sex hormones Raising the pH of male rat urine above 6.5 is significant in the development of calculi Because rats are quadropeds, they do not eliminate calculi as humans do The correlation observed in Cohen's paper is 0.61. The European authorities initially determined this to be quite low; however, Dr. Cohen authored an expert report which stated that the 0.61 correlation was actually high, as calculi can dissolve over time. In summary, the tumors seen in rats were due to the presence of calculi. The male rat urine milieu contributes to the formation of calculi. Because rats are quadropeds, they do not eliminate calculi as bipeds do. Main Points from Takeda Europe Experience Takeda Europe successfully employed the following strategy: Defended Cohen hypothesis, despite numerous challenges Stressed the "one sex, one species" argument Challenged authorities regarding implementing monitoring plan Offered to conduct a case control study post-approval Highlights from PPAR Agonist Discussion The group extensively discussed many aspects of the PPAR mechanism and ultimately decided to not address mechanistic issues in the initial FDA response. However, it was decided that this argument should be developed, as it may be necessary to use it in the future, and action items were assigned accordingly. Confidential - Subject to Protective Order TAK-RAMSTM-00487176 Produced in MDL on 03/06/13 Source:

What is the due date to conduct review meeting for FDA package?

qtjf0226

qtjf0226_p3, qtjf0226_p4, qtjf0226_p5, qtjf0226_p6, qtjf0226_p7

August 22

Task Notes Lead Responsibility Due Date 4. PEDIATRIC STUDIES (CONTINUED) Evaluate data from Actos 507 Evaluate data to support Amy Hagaman August 5 justification to proceed with Actos 508 Develop additional monitoring Amy Hagaman plan for Actos 508 Evaluate feasibility/business T. Muldoon case of request to FDA to M Ramstack delay start of Actos 508 pending Actos 506 data; 1 Haskins assess impact on pediatric exclusivity/patent Draft justification for Actos 508 Justification should be Amy Hagaman/Alfonso August 12 based on rebuttal of FDA Perez hypothesis regarding mechanism of action for bladder cancer and addition of clinical monitoring plan to protocol Last Update: August 1, 2002 Page 3 of 7 Confidential-Subject to Protective Order - TAK-THOMCL 00032212 Produced in MDL on 02/21/13 Source: https://www.indup3d8-00004ts.ucsf.edu/docs/qtjf0226 Task Notes Lead Responsibility Due Date 5A. NONCI INICAL/REVIEW OF TOX DATA (DAVID BARON) Conduct meeting between Identify mechanistic studies David Baron August 1 - DONE nonclinical safety and efficacy, for evaluation Janet Haskins regulatory, and project Schedule teleconference Mary Ramstack management with FDA Identify expert in oncology and pathology Identify nonclinicat back-up Pat Frank - telecon David Baron August 1 - DONE (example: Pat Frank and Chris Chris Durack report review Durack?) Request saccharin literature Janet Haskins August 1 - DONE search from Rya Send David Baron nonclinical Janet Haskins August 2 carcinogenicity studies Review doses used in CA Aziz Karim August 6 studies, clarify relationship to clinical doses 5B, NONCLINICAL/JUSTIFICATION DOCUMENT(DAVID BARON) Contact Jerry Oleski regarding Wendell Cheatham discrediting FDA tumor promoter hypothesis (inbittery) but busst Mary Roushur Last Update: August 1, 2002 Page 4 of 7 Confidential - Subject to Protective Order TAK-THOMCL-00032213 Produced in MDL on 02/21/13 Task Notes Lead Responsibility Due Date SB. NONCLINICAL/JUSTIFICATION DOCUMENTO (DAVID BARON) Evaluate and compare TCI structural models of all known PPAR agonists, including pioglitazone and NN622 Evaluate PPAR agonist TCI mechanistic tumor production hypotheses Evaluate effects of PPAR TCI agonists in urinary tract Develop justification document Baron Draft - August 16 Comments - August 19 Final version - August 20 6: INTRODUCTORY/CONCLUSION STATEMENTS Develop outline of response Hancock Aug 2 (table of contents) Send document sections to Aziz Karim - doses August 19 medical writing for compilation Amy Hagaman-507/506 Alfonso Perez - monitoring plan Last Update: August 1, 2002 Page 5 of 7 Confidentiat-Subject - to Protective Order TAK-THOMCL-00032214 Produced in MDL on 02/21/13- Source: https://www.indup538-00006ts.ucsf.edu/docs/qtjf0226 Task Notes Lead Responsibility Due Date 6. INTRODUCTORY/CONCLUSION STATEMENTS (CONTINUED) Send nonclinical David Baron August 20 rationale/justification section to medical writing for compilation Compile FDA package Larry Hancock August 21 Send package to TCI/EU for Mary Ramstack August 21 review Conduct review meeting for Janet Haskins/Team August 22 FDA package FDA Document to August 26 Regulatory Affairs 7. PACKAGE INSERTS/INFORMED CONSENT VERBIAGE Request NN622 literate Janet Haskins August 1 - DONE searches Identify package inserts with Janet Haskins August 12 similar class-related issues (i.e., ACE-inhibitors) Last Update: August 1, 2002 Page 6 of 7 Confidential - Subject to Protective Order TAK-THOMCL-00032215 Produced in MDL on 02/21/13 Source: https://www.indup63d8000007ts.ucsf.edu/docs/qtjf0226 Task Notes Lead Responsibility Due Date 8, COMPETITIVE INTELLIGENCE Update team on competitive Wendell Cheatham Ongoing - update provided intelligence Bill Bloke at each meeting 9. Q&A SHEET Develop Q&A sheet to support Wendell Cheatham Draft - August 5 Scientific Communications San Comments due - August 7 Review meeting-August 7 10. PATIENT REGISTRY Evaluate feasiblity of Pharmetric Database Rich Wilson OT developing large patient GE Database Rukmimi Rajagopalan registry Fred Murray 11: COMMUNICATIONS TO TAKEDA (TCI, TEUR&D, TPNA) 12, EVALUATE IMPACT ON TAK-559 prevelege Marline / average Last Update: August 1, 2002 Page 7 of 7 Confidential - Subject to Protective Order TAK-THOMCL-00032216 Produced in MDL on 02/21/13 Source:

What is the time span where no tumors are seen?

myjf0226

myjf0226_p0, myjf0226_p1, myjf0226_p2, myjf0226_p3

shorter term (12 month)

ACTOS FDA RESPONSE MEETING TPNA/TEUR&D/TCI AUGUST 12-13, 2002 Attendees: TPNA TEUR&D Sam Hamanaka David Eckland Claire Thom Yasuhiko Wada Ingrid Hood Glyn Belcher Alfonso Perez Philip Collett David Recker John Page TCI Mary Ramstack Katsuhisa Saito Janet Haskins Masahiro Miyazaki Dan Orlando Takashi Kuroiwa David Baron Takashi Nonoyama Chris Durack Keiichiro Sato Larry Hancock Hiroyuki Odaka Bob Ahlbrandt Tom Muldoon Karen Kaluzny Summary of July 31 Teleconference with FDA (J. Haskins) The FDA informed TPNA that they had received data from a rat tumor promoter study using dual PPAR agonists. Pioglitazone was used in this experiment, and the group of rats treated with pioglitazone experienced the same frequency of transitional cell tumors as the group treated with the dual PPAR agonist under investigation. The FDA clarified that due to this data, they had concerns with the dual PPAR mechanism, and considered pioglitazone to have a dual PPAR mechanism. There were three key messages from the teleconference: The FDA asked TPNA to consider a label change, as they feel that the current package insert does not adequately inform patients of the risk associated with bladder tumors. The FDA asked TPNA to research and propose a monitoring plan, which would be incorporated into clinical trials. The FDA stated that they were considering rescinding their written request to TPNA to conduct pediatric studies with pioglitazone. Confidential - Subject to Protective Order TAK-RAMSTM-00487173 Produced in MDL on 03/06/13 Source: ACTOS FDA Response Meeting August 12-13, 2002 Page 2 of 4 Summary of July 31 Teleconference with FDA (J. Haskins) - Continued The group summarized the FDA's concerns as follows: The FDA is not stating that ACTOS specifically causes or contributes to bladder tumors. The FDA no longer supports Dr. Cohen's hypothesis, since the tumor promoter study data they received demonstrated the presence of tumors without calculi. The FDA no longer feels that they understand how these findings relate to humans. Update from TCI Meeting with CEO (Mr. Saito) Mr. Saito updated the CEO on this situation on August 6. The following strategy was decided on: Attempt to keep current carcinogenicity label wording; if not possible, request that same labeling be applied to Avandia Find rationale to support not establishing monitoring plan, but if necessary, would compromise on monitoring wording to avoid changing carcinogenicity wording Develop argument to proceed with Actos 508 (safety/efficacy in pediatrics) study under current timelines, but are willing to postpone The following timelines were established: TPNA to send outline of response to TCI by August 19 Mr. Saito will present outline to CEO on August 20 TPNA will send draft document to TCI, TEUR&D, and Lilly on August 21 Document will be finalized by August 26 Response will be sent to FDA on August 28 Mr Saito also presented the following communication structure and schematic Leadership: Claire Thom, David Eckland, Mr. Saito Primary contacts: Mary Ramstack, Janet Haskins, Philip Collett, Mr. Miyazaki The only exception to this schematic will be that on August 26, TPNA will communicate directly with Lilly to distribute the draft document CEO Mr Saito TPNA TCI labs Lilly EU Confidential - Subject to Protective Order TAK-RAMSTM-00487174 Produced in MDL on 03/06/13 Source: ACTOS FDA Response Meeting August 12-13, 2002 Page 3 of 4 Highlights/Discussion Points from Preclinical Data Presentation In the rat oncogenicity study, thickening of the bladder and hypertrophy of the urothelium was observed in male rats. These findings were not dose- dependent. Nearly all of the tumors were found at the end of the study. Some cases of hyperplasia were seen in female rats at the highest dose level only, but no malignancies were seen. There were no tumors seen in the shorter term (12 month) rat toxicity studies. Glyn Belcher suggested creating a summary able for all toxicology studies with durations between 6 months and less than 2 years. In the mouse oncogenicity study, hyperplasia was seen in male mice only. These findings were not dose-dependent, and results were not statistically significant. One case of hyperplasia was observed in the placebo group. Philip Collett stated that the European authorities did not question the mouse data for ACTOS, but rather only the rat data. A list of all mutagenicity studies conducted with pioglitazone was shown, and David Baron acknowledged that TCI had conducted a very robust program that went beyond regulatory requirements. A study observing the effects of pioglitazone on urinary parameters in rats was conducted, and highlights are as follows: Simple hyperplasia seen in one male Increase in urine pH, urine volume, microcrystal count Slight decrease in magnesium, calcium, phosphorous, sodium, potassium, and chloride Conclusion: Changes in urinary components are considered to be factors in the etiology of proliferative lesions of the bladder: Pioglitazone ingestion Altered urinary physiology Calculus formation Urothelial ulceration an regeneration (hyperplasia) Benin papilloma Carcinoma Confidential - Subject to Protective Order TAK-RAMSTM-00487175 Produced in MDL on 03/06/13 Source: ACTOS FDA Response Meeting August 12-13, 2002 Page 4 of 4 Highlights from Cohen Hypothesis Discussion Philip Collett presented an outline of the Cohen hypothesis Male rat urine has a very high protein content, which is a function of sex hormones Raising the pH of male rat urine above 6.5 is significant in the development of calculi Because rats are quadropeds, they do not eliminate calculi as humans do The correlation observed in Cohen's paper is 0.61. The European authorities initially determined this to be quite low; however, Dr. Cohen authored an expert report which stated that the 0.61 correlation was actually high, as calculi can dissolve over time. In summary, the tumors seen in rats were due to the presence of calculi. The male rat urine milieu contributes to the formation of calculi. Because rats are quadropeds, they do not eliminate calculi as bipeds do. Main Points from Takeda Europe Experience Takeda Europe successfully employed the following strategy: Defended Cohen hypothesis, despite numerous challenges Stressed the "one sex, one species" argument Challenged authorities regarding implementing monitoring plan Offered to conduct a case control study post-approval Highlights from PPAR Agonist Discussion The group extensively discussed many aspects of the PPAR mechanism and ultimately decided to not address mechanistic issues in the initial FDA response. However, it was decided that this argument should be developed, as it may be necessary to use it in the future, and action items were assigned accordingly. Confidential - Subject to Protective Order TAK-RAMSTM-00487176 Produced in MDL on 03/06/13 Source:

Who is the lead responsible person for the compilation of FDA package?

qtjf0226

qtjf0226_p3, qtjf0226_p4, qtjf0226_p5, qtjf0226_p6, qtjf0226_p7

Larry Hancock

Task Notes Lead Responsibility Due Date 4. PEDIATRIC STUDIES (CONTINUED) Evaluate data from Actos 507 Evaluate data to support Amy Hagaman August 5 justification to proceed with Actos 508 Develop additional monitoring Amy Hagaman plan for Actos 508 Evaluate feasibility/business T. Muldoon case of request to FDA to M Ramstack delay start of Actos 508 pending Actos 506 data; 1 Haskins assess impact on pediatric exclusivity/patent Draft justification for Actos 508 Justification should be Amy Hagaman/Alfonso August 12 based on rebuttal of FDA Perez hypothesis regarding mechanism of action for bladder cancer and addition of clinical monitoring plan to protocol Last Update: August 1, 2002 Page 3 of 7 Confidential-Subject to Protective Order - TAK-THOMCL 00032212 Produced in MDL on 02/21/13 Source: https://www.indup3d8-00004ts.ucsf.edu/docs/qtjf0226 Task Notes Lead Responsibility Due Date 5A. NONCI INICAL/REVIEW OF TOX DATA (DAVID BARON) Conduct meeting between Identify mechanistic studies David Baron August 1 - DONE nonclinical safety and efficacy, for evaluation Janet Haskins regulatory, and project Schedule teleconference Mary Ramstack management with FDA Identify expert in oncology and pathology Identify nonclinicat back-up Pat Frank - telecon David Baron August 1 - DONE (example: Pat Frank and Chris Chris Durack report review Durack?) Request saccharin literature Janet Haskins August 1 - DONE search from Rya Send David Baron nonclinical Janet Haskins August 2 carcinogenicity studies Review doses used in CA Aziz Karim August 6 studies, clarify relationship to clinical doses 5B, NONCLINICAL/JUSTIFICATION DOCUMENT(DAVID BARON) Contact Jerry Oleski regarding Wendell Cheatham discrediting FDA tumor promoter hypothesis (inbittery) but busst Mary Roushur Last Update: August 1, 2002 Page 4 of 7 Confidential - Subject to Protective Order TAK-THOMCL-00032213 Produced in MDL on 02/21/13 Task Notes Lead Responsibility Due Date SB. NONCLINICAL/JUSTIFICATION DOCUMENTO (DAVID BARON) Evaluate and compare TCI structural models of all known PPAR agonists, including pioglitazone and NN622 Evaluate PPAR agonist TCI mechanistic tumor production hypotheses Evaluate effects of PPAR TCI agonists in urinary tract Develop justification document Baron Draft - August 16 Comments - August 19 Final version - August 20 6: INTRODUCTORY/CONCLUSION STATEMENTS Develop outline of response Hancock Aug 2 (table of contents) Send document sections to Aziz Karim - doses August 19 medical writing for compilation Amy Hagaman-507/506 Alfonso Perez - monitoring plan Last Update: August 1, 2002 Page 5 of 7 Confidentiat-Subject - to Protective Order TAK-THOMCL-00032214 Produced in MDL on 02/21/13- Source: https://www.indup538-00006ts.ucsf.edu/docs/qtjf0226 Task Notes Lead Responsibility Due Date 6. INTRODUCTORY/CONCLUSION STATEMENTS (CONTINUED) Send nonclinical David Baron August 20 rationale/justification section to medical writing for compilation Compile FDA package Larry Hancock August 21 Send package to TCI/EU for Mary Ramstack August 21 review Conduct review meeting for Janet Haskins/Team August 22 FDA package FDA Document to August 26 Regulatory Affairs 7. PACKAGE INSERTS/INFORMED CONSENT VERBIAGE Request NN622 literate Janet Haskins August 1 - DONE searches Identify package inserts with Janet Haskins August 12 similar class-related issues (i.e., ACE-inhibitors) Last Update: August 1, 2002 Page 6 of 7 Confidential - Subject to Protective Order TAK-THOMCL-00032215 Produced in MDL on 02/21/13 Source: https://www.indup63d8000007ts.ucsf.edu/docs/qtjf0226 Task Notes Lead Responsibility Due Date 8, COMPETITIVE INTELLIGENCE Update team on competitive Wendell Cheatham Ongoing - update provided intelligence Bill Bloke at each meeting 9. Q&A SHEET Develop Q&A sheet to support Wendell Cheatham Draft - August 5 Scientific Communications San Comments due - August 7 Review meeting-August 7 10. PATIENT REGISTRY Evaluate feasiblity of Pharmetric Database Rich Wilson OT developing large patient GE Database Rukmimi Rajagopalan registry Fred Murray 11: COMMUNICATIONS TO TAKEDA (TCI, TEUR&D, TPNA) 12, EVALUATE IMPACT ON TAK-559 prevelege Marline / average Last Update: August 1, 2002 Page 7 of 7 Confidential - Subject to Protective Order TAK-THOMCL-00032216 Produced in MDL on 02/21/13 Source:

According to mouse oncogenicity study, what was seen male mice only?

myjf0226

myjf0226_p0, myjf0226_p1, myjf0226_p2, myjf0226_p3

hyperplasia

ACTOS FDA RESPONSE MEETING TPNA/TEUR&D/TCI AUGUST 12-13, 2002 Attendees: TPNA TEUR&D Sam Hamanaka David Eckland Claire Thom Yasuhiko Wada Ingrid Hood Glyn Belcher Alfonso Perez Philip Collett David Recker John Page TCI Mary Ramstack Katsuhisa Saito Janet Haskins Masahiro Miyazaki Dan Orlando Takashi Kuroiwa David Baron Takashi Nonoyama Chris Durack Keiichiro Sato Larry Hancock Hiroyuki Odaka Bob Ahlbrandt Tom Muldoon Karen Kaluzny Summary of July 31 Teleconference with FDA (J. Haskins) The FDA informed TPNA that they had received data from a rat tumor promoter study using dual PPAR agonists. Pioglitazone was used in this experiment, and the group of rats treated with pioglitazone experienced the same frequency of transitional cell tumors as the group treated with the dual PPAR agonist under investigation. The FDA clarified that due to this data, they had concerns with the dual PPAR mechanism, and considered pioglitazone to have a dual PPAR mechanism. There were three key messages from the teleconference: The FDA asked TPNA to consider a label change, as they feel that the current package insert does not adequately inform patients of the risk associated with bladder tumors. The FDA asked TPNA to research and propose a monitoring plan, which would be incorporated into clinical trials. The FDA stated that they were considering rescinding their written request to TPNA to conduct pediatric studies with pioglitazone. Confidential - Subject to Protective Order TAK-RAMSTM-00487173 Produced in MDL on 03/06/13 Source: ACTOS FDA Response Meeting August 12-13, 2002 Page 2 of 4 Summary of July 31 Teleconference with FDA (J. Haskins) - Continued The group summarized the FDA's concerns as follows: The FDA is not stating that ACTOS specifically causes or contributes to bladder tumors. The FDA no longer supports Dr. Cohen's hypothesis, since the tumor promoter study data they received demonstrated the presence of tumors without calculi. The FDA no longer feels that they understand how these findings relate to humans. Update from TCI Meeting with CEO (Mr. Saito) Mr. Saito updated the CEO on this situation on August 6. The following strategy was decided on: Attempt to keep current carcinogenicity label wording; if not possible, request that same labeling be applied to Avandia Find rationale to support not establishing monitoring plan, but if necessary, would compromise on monitoring wording to avoid changing carcinogenicity wording Develop argument to proceed with Actos 508 (safety/efficacy in pediatrics) study under current timelines, but are willing to postpone The following timelines were established: TPNA to send outline of response to TCI by August 19 Mr. Saito will present outline to CEO on August 20 TPNA will send draft document to TCI, TEUR&D, and Lilly on August 21 Document will be finalized by August 26 Response will be sent to FDA on August 28 Mr Saito also presented the following communication structure and schematic Leadership: Claire Thom, David Eckland, Mr. Saito Primary contacts: Mary Ramstack, Janet Haskins, Philip Collett, Mr. Miyazaki The only exception to this schematic will be that on August 26, TPNA will communicate directly with Lilly to distribute the draft document CEO Mr Saito TPNA TCI labs Lilly EU Confidential - Subject to Protective Order TAK-RAMSTM-00487174 Produced in MDL on 03/06/13 Source: ACTOS FDA Response Meeting August 12-13, 2002 Page 3 of 4 Highlights/Discussion Points from Preclinical Data Presentation In the rat oncogenicity study, thickening of the bladder and hypertrophy of the urothelium was observed in male rats. These findings were not dose- dependent. Nearly all of the tumors were found at the end of the study. Some cases of hyperplasia were seen in female rats at the highest dose level only, but no malignancies were seen. There were no tumors seen in the shorter term (12 month) rat toxicity studies. Glyn Belcher suggested creating a summary able for all toxicology studies with durations between 6 months and less than 2 years. In the mouse oncogenicity study, hyperplasia was seen in male mice only. These findings were not dose-dependent, and results were not statistically significant. One case of hyperplasia was observed in the placebo group. Philip Collett stated that the European authorities did not question the mouse data for ACTOS, but rather only the rat data. A list of all mutagenicity studies conducted with pioglitazone was shown, and David Baron acknowledged that TCI had conducted a very robust program that went beyond regulatory requirements. A study observing the effects of pioglitazone on urinary parameters in rats was conducted, and highlights are as follows: Simple hyperplasia seen in one male Increase in urine pH, urine volume, microcrystal count Slight decrease in magnesium, calcium, phosphorous, sodium, potassium, and chloride Conclusion: Changes in urinary components are considered to be factors in the etiology of proliferative lesions of the bladder: Pioglitazone ingestion Altered urinary physiology Calculus formation Urothelial ulceration an regeneration (hyperplasia) Benin papilloma Carcinoma Confidential - Subject to Protective Order TAK-RAMSTM-00487175 Produced in MDL on 03/06/13 Source: ACTOS FDA Response Meeting August 12-13, 2002 Page 4 of 4 Highlights from Cohen Hypothesis Discussion Philip Collett presented an outline of the Cohen hypothesis Male rat urine has a very high protein content, which is a function of sex hormones Raising the pH of male rat urine above 6.5 is significant in the development of calculi Because rats are quadropeds, they do not eliminate calculi as humans do The correlation observed in Cohen's paper is 0.61. The European authorities initially determined this to be quite low; however, Dr. Cohen authored an expert report which stated that the 0.61 correlation was actually high, as calculi can dissolve over time. In summary, the tumors seen in rats were due to the presence of calculi. The male rat urine milieu contributes to the formation of calculi. Because rats are quadropeds, they do not eliminate calculi as bipeds do. Main Points from Takeda Europe Experience Takeda Europe successfully employed the following strategy: Defended Cohen hypothesis, despite numerous challenges Stressed the "one sex, one species" argument Challenged authorities regarding implementing monitoring plan Offered to conduct a case control study post-approval Highlights from PPAR Agonist Discussion The group extensively discussed many aspects of the PPAR mechanism and ultimately decided to not address mechanistic issues in the initial FDA response. However, it was decided that this argument should be developed, as it may be necessary to use it in the future, and action items were assigned accordingly. Confidential - Subject to Protective Order TAK-RAMSTM-00487176 Produced in MDL on 03/06/13 Source:

what kind of cell tumours experienced the same frequency when group of rats treated with pioglitazone?

myjf0226

myjf0226_p0, myjf0226_p1, myjf0226_p2, myjf0226_p3

transitional, transitional cell tumors

ACTOS FDA RESPONSE MEETING TPNA/TEUR&D/TCI AUGUST 12-13, 2002 Attendees: TPNA TEUR&D Sam Hamanaka David Eckland Claire Thom Yasuhiko Wada Ingrid Hood Glyn Belcher Alfonso Perez Philip Collett David Recker John Page TCI Mary Ramstack Katsuhisa Saito Janet Haskins Masahiro Miyazaki Dan Orlando Takashi Kuroiwa David Baron Takashi Nonoyama Chris Durack Keiichiro Sato Larry Hancock Hiroyuki Odaka Bob Ahlbrandt Tom Muldoon Karen Kaluzny Summary of July 31 Teleconference with FDA (J. Haskins) The FDA informed TPNA that they had received data from a rat tumor promoter study using dual PPAR agonists. Pioglitazone was used in this experiment, and the group of rats treated with pioglitazone experienced the same frequency of transitional cell tumors as the group treated with the dual PPAR agonist under investigation. The FDA clarified that due to this data, they had concerns with the dual PPAR mechanism, and considered pioglitazone to have a dual PPAR mechanism. There were three key messages from the teleconference: The FDA asked TPNA to consider a label change, as they feel that the current package insert does not adequately inform patients of the risk associated with bladder tumors. The FDA asked TPNA to research and propose a monitoring plan, which would be incorporated into clinical trials. The FDA stated that they were considering rescinding their written request to TPNA to conduct pediatric studies with pioglitazone. Confidential - Subject to Protective Order TAK-RAMSTM-00487173 Produced in MDL on 03/06/13 Source: ACTOS FDA Response Meeting August 12-13, 2002 Page 2 of 4 Summary of July 31 Teleconference with FDA (J. Haskins) - Continued The group summarized the FDA's concerns as follows: The FDA is not stating that ACTOS specifically causes or contributes to bladder tumors. The FDA no longer supports Dr. Cohen's hypothesis, since the tumor promoter study data they received demonstrated the presence of tumors without calculi. The FDA no longer feels that they understand how these findings relate to humans. Update from TCI Meeting with CEO (Mr. Saito) Mr. Saito updated the CEO on this situation on August 6. The following strategy was decided on: Attempt to keep current carcinogenicity label wording; if not possible, request that same labeling be applied to Avandia Find rationale to support not establishing monitoring plan, but if necessary, would compromise on monitoring wording to avoid changing carcinogenicity wording Develop argument to proceed with Actos 508 (safety/efficacy in pediatrics) study under current timelines, but are willing to postpone The following timelines were established: TPNA to send outline of response to TCI by August 19 Mr. Saito will present outline to CEO on August 20 TPNA will send draft document to TCI, TEUR&D, and Lilly on August 21 Document will be finalized by August 26 Response will be sent to FDA on August 28 Mr Saito also presented the following communication structure and schematic Leadership: Claire Thom, David Eckland, Mr. Saito Primary contacts: Mary Ramstack, Janet Haskins, Philip Collett, Mr. Miyazaki The only exception to this schematic will be that on August 26, TPNA will communicate directly with Lilly to distribute the draft document CEO Mr Saito TPNA TCI labs Lilly EU Confidential - Subject to Protective Order TAK-RAMSTM-00487174 Produced in MDL on 03/06/13 Source: ACTOS FDA Response Meeting August 12-13, 2002 Page 3 of 4 Highlights/Discussion Points from Preclinical Data Presentation In the rat oncogenicity study, thickening of the bladder and hypertrophy of the urothelium was observed in male rats. These findings were not dose- dependent. Nearly all of the tumors were found at the end of the study. Some cases of hyperplasia were seen in female rats at the highest dose level only, but no malignancies were seen. There were no tumors seen in the shorter term (12 month) rat toxicity studies. Glyn Belcher suggested creating a summary able for all toxicology studies with durations between 6 months and less than 2 years. In the mouse oncogenicity study, hyperplasia was seen in male mice only. These findings were not dose-dependent, and results were not statistically significant. One case of hyperplasia was observed in the placebo group. Philip Collett stated that the European authorities did not question the mouse data for ACTOS, but rather only the rat data. A list of all mutagenicity studies conducted with pioglitazone was shown, and David Baron acknowledged that TCI had conducted a very robust program that went beyond regulatory requirements. A study observing the effects of pioglitazone on urinary parameters in rats was conducted, and highlights are as follows: Simple hyperplasia seen in one male Increase in urine pH, urine volume, microcrystal count Slight decrease in magnesium, calcium, phosphorous, sodium, potassium, and chloride Conclusion: Changes in urinary components are considered to be factors in the etiology of proliferative lesions of the bladder: Pioglitazone ingestion Altered urinary physiology Calculus formation Urothelial ulceration an regeneration (hyperplasia) Benin papilloma Carcinoma Confidential - Subject to Protective Order TAK-RAMSTM-00487175 Produced in MDL on 03/06/13 Source: ACTOS FDA Response Meeting August 12-13, 2002 Page 4 of 4 Highlights from Cohen Hypothesis Discussion Philip Collett presented an outline of the Cohen hypothesis Male rat urine has a very high protein content, which is a function of sex hormones Raising the pH of male rat urine above 6.5 is significant in the development of calculi Because rats are quadropeds, they do not eliminate calculi as humans do The correlation observed in Cohen's paper is 0.61. The European authorities initially determined this to be quite low; however, Dr. Cohen authored an expert report which stated that the 0.61 correlation was actually high, as calculi can dissolve over time. In summary, the tumors seen in rats were due to the presence of calculi. The male rat urine milieu contributes to the formation of calculi. Because rats are quadropeds, they do not eliminate calculi as bipeds do. Main Points from Takeda Europe Experience Takeda Europe successfully employed the following strategy: Defended Cohen hypothesis, despite numerous challenges Stressed the "one sex, one species" argument Challenged authorities regarding implementing monitoring plan Offered to conduct a case control study post-approval Highlights from PPAR Agonist Discussion The group extensively discussed many aspects of the PPAR mechanism and ultimately decided to not address mechanistic issues in the initial FDA response. However, it was decided that this argument should be developed, as it may be necessary to use it in the future, and action items were assigned accordingly. Confidential - Subject to Protective Order TAK-RAMSTM-00487176 Produced in MDL on 03/06/13 Source:

who conducted robust program?

myjf0226

myjf0226_p0, myjf0226_p1, myjf0226_p2, myjf0226_p3

TCI

ACTOS FDA RESPONSE MEETING TPNA/TEUR&D/TCI AUGUST 12-13, 2002 Attendees: TPNA TEUR&D Sam Hamanaka David Eckland Claire Thom Yasuhiko Wada Ingrid Hood Glyn Belcher Alfonso Perez Philip Collett David Recker John Page TCI Mary Ramstack Katsuhisa Saito Janet Haskins Masahiro Miyazaki Dan Orlando Takashi Kuroiwa David Baron Takashi Nonoyama Chris Durack Keiichiro Sato Larry Hancock Hiroyuki Odaka Bob Ahlbrandt Tom Muldoon Karen Kaluzny Summary of July 31 Teleconference with FDA (J. Haskins) The FDA informed TPNA that they had received data from a rat tumor promoter study using dual PPAR agonists. Pioglitazone was used in this experiment, and the group of rats treated with pioglitazone experienced the same frequency of transitional cell tumors as the group treated with the dual PPAR agonist under investigation. The FDA clarified that due to this data, they had concerns with the dual PPAR mechanism, and considered pioglitazone to have a dual PPAR mechanism. There were three key messages from the teleconference: The FDA asked TPNA to consider a label change, as they feel that the current package insert does not adequately inform patients of the risk associated with bladder tumors. The FDA asked TPNA to research and propose a monitoring plan, which would be incorporated into clinical trials. The FDA stated that they were considering rescinding their written request to TPNA to conduct pediatric studies with pioglitazone. Confidential - Subject to Protective Order TAK-RAMSTM-00487173 Produced in MDL on 03/06/13 Source: ACTOS FDA Response Meeting August 12-13, 2002 Page 2 of 4 Summary of July 31 Teleconference with FDA (J. Haskins) - Continued The group summarized the FDA's concerns as follows: The FDA is not stating that ACTOS specifically causes or contributes to bladder tumors. The FDA no longer supports Dr. Cohen's hypothesis, since the tumor promoter study data they received demonstrated the presence of tumors without calculi. The FDA no longer feels that they understand how these findings relate to humans. Update from TCI Meeting with CEO (Mr. Saito) Mr. Saito updated the CEO on this situation on August 6. The following strategy was decided on: Attempt to keep current carcinogenicity label wording; if not possible, request that same labeling be applied to Avandia Find rationale to support not establishing monitoring plan, but if necessary, would compromise on monitoring wording to avoid changing carcinogenicity wording Develop argument to proceed with Actos 508 (safety/efficacy in pediatrics) study under current timelines, but are willing to postpone The following timelines were established: TPNA to send outline of response to TCI by August 19 Mr. Saito will present outline to CEO on August 20 TPNA will send draft document to TCI, TEUR&D, and Lilly on August 21 Document will be finalized by August 26 Response will be sent to FDA on August 28 Mr Saito also presented the following communication structure and schematic Leadership: Claire Thom, David Eckland, Mr. Saito Primary contacts: Mary Ramstack, Janet Haskins, Philip Collett, Mr. Miyazaki The only exception to this schematic will be that on August 26, TPNA will communicate directly with Lilly to distribute the draft document CEO Mr Saito TPNA TCI labs Lilly EU Confidential - Subject to Protective Order TAK-RAMSTM-00487174 Produced in MDL on 03/06/13 Source: ACTOS FDA Response Meeting August 12-13, 2002 Page 3 of 4 Highlights/Discussion Points from Preclinical Data Presentation In the rat oncogenicity study, thickening of the bladder and hypertrophy of the urothelium was observed in male rats. These findings were not dose- dependent. Nearly all of the tumors were found at the end of the study. Some cases of hyperplasia were seen in female rats at the highest dose level only, but no malignancies were seen. There were no tumors seen in the shorter term (12 month) rat toxicity studies. Glyn Belcher suggested creating a summary able for all toxicology studies with durations between 6 months and less than 2 years. In the mouse oncogenicity study, hyperplasia was seen in male mice only. These findings were not dose-dependent, and results were not statistically significant. One case of hyperplasia was observed in the placebo group. Philip Collett stated that the European authorities did not question the mouse data for ACTOS, but rather only the rat data. A list of all mutagenicity studies conducted with pioglitazone was shown, and David Baron acknowledged that TCI had conducted a very robust program that went beyond regulatory requirements. A study observing the effects of pioglitazone on urinary parameters in rats was conducted, and highlights are as follows: Simple hyperplasia seen in one male Increase in urine pH, urine volume, microcrystal count Slight decrease in magnesium, calcium, phosphorous, sodium, potassium, and chloride Conclusion: Changes in urinary components are considered to be factors in the etiology of proliferative lesions of the bladder: Pioglitazone ingestion Altered urinary physiology Calculus formation Urothelial ulceration an regeneration (hyperplasia) Benin papilloma Carcinoma Confidential - Subject to Protective Order TAK-RAMSTM-00487175 Produced in MDL on 03/06/13 Source: ACTOS FDA Response Meeting August 12-13, 2002 Page 4 of 4 Highlights from Cohen Hypothesis Discussion Philip Collett presented an outline of the Cohen hypothesis Male rat urine has a very high protein content, which is a function of sex hormones Raising the pH of male rat urine above 6.5 is significant in the development of calculi Because rats are quadropeds, they do not eliminate calculi as humans do The correlation observed in Cohen's paper is 0.61. The European authorities initially determined this to be quite low; however, Dr. Cohen authored an expert report which stated that the 0.61 correlation was actually high, as calculi can dissolve over time. In summary, the tumors seen in rats were due to the presence of calculi. The male rat urine milieu contributes to the formation of calculi. Because rats are quadropeds, they do not eliminate calculi as bipeds do. Main Points from Takeda Europe Experience Takeda Europe successfully employed the following strategy: Defended Cohen hypothesis, despite numerous challenges Stressed the "one sex, one species" argument Challenged authorities regarding implementing monitoring plan Offered to conduct a case control study post-approval Highlights from PPAR Agonist Discussion The group extensively discussed many aspects of the PPAR mechanism and ultimately decided to not address mechanistic issues in the initial FDA response. However, it was decided that this argument should be developed, as it may be necessary to use it in the future, and action items were assigned accordingly. Confidential - Subject to Protective Order TAK-RAMSTM-00487176 Produced in MDL on 03/06/13 Source:

What is the task assigned to David Baron?

qtjf0226

qtjf0226_p3, qtjf0226_p4, qtjf0226_p5, qtjf0226_p6, qtjf0226_p7

Send nonclinical rationale/justification section to medical writing for compilation, Send nonclinical rationale/justification section to medical writing for compilation.

Task Notes Lead Responsibility Due Date 4. PEDIATRIC STUDIES (CONTINUED) Evaluate data from Actos 507 Evaluate data to support Amy Hagaman August 5 justification to proceed with Actos 508 Develop additional monitoring Amy Hagaman plan for Actos 508 Evaluate feasibility/business T. Muldoon case of request to FDA to M Ramstack delay start of Actos 508 pending Actos 506 data; 1 Haskins assess impact on pediatric exclusivity/patent Draft justification for Actos 508 Justification should be Amy Hagaman/Alfonso August 12 based on rebuttal of FDA Perez hypothesis regarding mechanism of action for bladder cancer and addition of clinical monitoring plan to protocol Last Update: August 1, 2002 Page 3 of 7 Confidential-Subject to Protective Order - TAK-THOMCL 00032212 Produced in MDL on 02/21/13 Source: https://www.indup3d8-00004ts.ucsf.edu/docs/qtjf0226 Task Notes Lead Responsibility Due Date 5A. NONCI INICAL/REVIEW OF TOX DATA (DAVID BARON) Conduct meeting between Identify mechanistic studies David Baron August 1 - DONE nonclinical safety and efficacy, for evaluation Janet Haskins regulatory, and project Schedule teleconference Mary Ramstack management with FDA Identify expert in oncology and pathology Identify nonclinicat back-up Pat Frank - telecon David Baron August 1 - DONE (example: Pat Frank and Chris Chris Durack report review Durack?) Request saccharin literature Janet Haskins August 1 - DONE search from Rya Send David Baron nonclinical Janet Haskins August 2 carcinogenicity studies Review doses used in CA Aziz Karim August 6 studies, clarify relationship to clinical doses 5B, NONCLINICAL/JUSTIFICATION DOCUMENT(DAVID BARON) Contact Jerry Oleski regarding Wendell Cheatham discrediting FDA tumor promoter hypothesis (inbittery) but busst Mary Roushur Last Update: August 1, 2002 Page 4 of 7 Confidential - Subject to Protective Order TAK-THOMCL-00032213 Produced in MDL on 02/21/13 Task Notes Lead Responsibility Due Date SB. NONCLINICAL/JUSTIFICATION DOCUMENTO (DAVID BARON) Evaluate and compare TCI structural models of all known PPAR agonists, including pioglitazone and NN622 Evaluate PPAR agonist TCI mechanistic tumor production hypotheses Evaluate effects of PPAR TCI agonists in urinary tract Develop justification document Baron Draft - August 16 Comments - August 19 Final version - August 20 6: INTRODUCTORY/CONCLUSION STATEMENTS Develop outline of response Hancock Aug 2 (table of contents) Send document sections to Aziz Karim - doses August 19 medical writing for compilation Amy Hagaman-507/506 Alfonso Perez - monitoring plan Last Update: August 1, 2002 Page 5 of 7 Confidentiat-Subject - to Protective Order TAK-THOMCL-00032214 Produced in MDL on 02/21/13- Source: https://www.indup538-00006ts.ucsf.edu/docs/qtjf0226 Task Notes Lead Responsibility Due Date 6. INTRODUCTORY/CONCLUSION STATEMENTS (CONTINUED) Send nonclinical David Baron August 20 rationale/justification section to medical writing for compilation Compile FDA package Larry Hancock August 21 Send package to TCI/EU for Mary Ramstack August 21 review Conduct review meeting for Janet Haskins/Team August 22 FDA package FDA Document to August 26 Regulatory Affairs 7. PACKAGE INSERTS/INFORMED CONSENT VERBIAGE Request NN622 literate Janet Haskins August 1 - DONE searches Identify package inserts with Janet Haskins August 12 similar class-related issues (i.e., ACE-inhibitors) Last Update: August 1, 2002 Page 6 of 7 Confidential - Subject to Protective Order TAK-THOMCL-00032215 Produced in MDL on 02/21/13 Source: https://www.indup63d8000007ts.ucsf.edu/docs/qtjf0226 Task Notes Lead Responsibility Due Date 8, COMPETITIVE INTELLIGENCE Update team on competitive Wendell Cheatham Ongoing - update provided intelligence Bill Bloke at each meeting 9. Q&A SHEET Develop Q&A sheet to support Wendell Cheatham Draft - August 5 Scientific Communications San Comments due - August 7 Review meeting-August 7 10. PATIENT REGISTRY Evaluate feasiblity of Pharmetric Database Rich Wilson OT developing large patient GE Database Rukmimi Rajagopalan registry Fred Murray 11: COMMUNICATIONS TO TAKEDA (TCI, TEUR&D, TPNA) 12, EVALUATE IMPACT ON TAK-559 prevelege Marline / average Last Update: August 1, 2002 Page 7 of 7 Confidential - Subject to Protective Order TAK-THOMCL-00032216 Produced in MDL on 02/21/13 Source:

Who is responsible for sending package to TCI/EU for review?

qtjf0226

qtjf0226_p3, qtjf0226_p4, qtjf0226_p5, qtjf0226_p6, qtjf0226_p7

Mary Ramstack

Task Notes Lead Responsibility Due Date 4. PEDIATRIC STUDIES (CONTINUED) Evaluate data from Actos 507 Evaluate data to support Amy Hagaman August 5 justification to proceed with Actos 508 Develop additional monitoring Amy Hagaman plan for Actos 508 Evaluate feasibility/business T. Muldoon case of request to FDA to M Ramstack delay start of Actos 508 pending Actos 506 data; 1 Haskins assess impact on pediatric exclusivity/patent Draft justification for Actos 508 Justification should be Amy Hagaman/Alfonso August 12 based on rebuttal of FDA Perez hypothesis regarding mechanism of action for bladder cancer and addition of clinical monitoring plan to protocol Last Update: August 1, 2002 Page 3 of 7 Confidential-Subject to Protective Order - TAK-THOMCL 00032212 Produced in MDL on 02/21/13 Source: https://www.indup3d8-00004ts.ucsf.edu/docs/qtjf0226 Task Notes Lead Responsibility Due Date 5A. NONCI INICAL/REVIEW OF TOX DATA (DAVID BARON) Conduct meeting between Identify mechanistic studies David Baron August 1 - DONE nonclinical safety and efficacy, for evaluation Janet Haskins regulatory, and project Schedule teleconference Mary Ramstack management with FDA Identify expert in oncology and pathology Identify nonclinicat back-up Pat Frank - telecon David Baron August 1 - DONE (example: Pat Frank and Chris Chris Durack report review Durack?) Request saccharin literature Janet Haskins August 1 - DONE search from Rya Send David Baron nonclinical Janet Haskins August 2 carcinogenicity studies Review doses used in CA Aziz Karim August 6 studies, clarify relationship to clinical doses 5B, NONCLINICAL/JUSTIFICATION DOCUMENT(DAVID BARON) Contact Jerry Oleski regarding Wendell Cheatham discrediting FDA tumor promoter hypothesis (inbittery) but busst Mary Roushur Last Update: August 1, 2002 Page 4 of 7 Confidential - Subject to Protective Order TAK-THOMCL-00032213 Produced in MDL on 02/21/13 Task Notes Lead Responsibility Due Date SB. NONCLINICAL/JUSTIFICATION DOCUMENTO (DAVID BARON) Evaluate and compare TCI structural models of all known PPAR agonists, including pioglitazone and NN622 Evaluate PPAR agonist TCI mechanistic tumor production hypotheses Evaluate effects of PPAR TCI agonists in urinary tract Develop justification document Baron Draft - August 16 Comments - August 19 Final version - August 20 6: INTRODUCTORY/CONCLUSION STATEMENTS Develop outline of response Hancock Aug 2 (table of contents) Send document sections to Aziz Karim - doses August 19 medical writing for compilation Amy Hagaman-507/506 Alfonso Perez - monitoring plan Last Update: August 1, 2002 Page 5 of 7 Confidentiat-Subject - to Protective Order TAK-THOMCL-00032214 Produced in MDL on 02/21/13- Source: https://www.indup538-00006ts.ucsf.edu/docs/qtjf0226 Task Notes Lead Responsibility Due Date 6. INTRODUCTORY/CONCLUSION STATEMENTS (CONTINUED) Send nonclinical David Baron August 20 rationale/justification section to medical writing for compilation Compile FDA package Larry Hancock August 21 Send package to TCI/EU for Mary Ramstack August 21 review Conduct review meeting for Janet Haskins/Team August 22 FDA package FDA Document to August 26 Regulatory Affairs 7. PACKAGE INSERTS/INFORMED CONSENT VERBIAGE Request NN622 literate Janet Haskins August 1 - DONE searches Identify package inserts with Janet Haskins August 12 similar class-related issues (i.e., ACE-inhibitors) Last Update: August 1, 2002 Page 6 of 7 Confidential - Subject to Protective Order TAK-THOMCL-00032215 Produced in MDL on 02/21/13 Source: https://www.indup63d8000007ts.ucsf.edu/docs/qtjf0226 Task Notes Lead Responsibility Due Date 8, COMPETITIVE INTELLIGENCE Update team on competitive Wendell Cheatham Ongoing - update provided intelligence Bill Bloke at each meeting 9. Q&A SHEET Develop Q&A sheet to support Wendell Cheatham Draft - August 5 Scientific Communications San Comments due - August 7 Review meeting-August 7 10. PATIENT REGISTRY Evaluate feasiblity of Pharmetric Database Rich Wilson OT developing large patient GE Database Rukmimi Rajagopalan registry Fred Murray 11: COMMUNICATIONS TO TAKEDA (TCI, TEUR&D, TPNA) 12, EVALUATE IMPACT ON TAK-559 prevelege Marline / average Last Update: August 1, 2002 Page 7 of 7 Confidential - Subject to Protective Order TAK-THOMCL-00032216 Produced in MDL on 02/21/13 Source:

Which product's liability claims are described here?

hrjf0226

hrjf0226_p0, hrjf0226_p1, hrjf0226_p2

ACTOS PRODUCTS LIABILITY CLAIMS, ACTOS PRODUCTS

Horizon - ACTOS PRODUCTS LIABILITY CLAIMS Page ) of 2 >: Home News & Events People Workplace & Services & Values Tools & Resources Tean Honcon EXHIBIT ACTOS PRODUCTS LIABILITY HORIZON CLAIMS 52 CURRENT LOCATION LEGAL HOLD RELATED TO ACTOS PRODUCTS LIABILITY CLAIMS: PLEASE READ Home THIS MESSAGE CAREFULLY Culture & Values Office of Ethics & Takeda continues to be involved in a small number of claims or lawsuits Compliance ("claims") relating to ACTOS® (pioglitazone HCI). As a result of these Litigation claims, all documents, materials, Information and things that exist or Resources continue to be developed pertaining to ACTOS® have been and continue ACTOS to be subject to a Legal Hold. PRODUCTS LIABILITY Additionally, all documents and materials that exist or continue to be CLAIMS developed pertaining to Combination medicines Involving ACTOS®, ACTIONS whether a marketed or development medicine, also continue to be subject I to a Legal Hold. Add to My Links Alert Me Each Takeda Employee or Contractor shall create an Outlook Folder entitled "ACTOS" beneath the "Legal Hold" folder provided as part of the implementation of CORP-B-019 "E-mail Management and Retention." Contact the Help Desk if your Outlook file folder structure does not - contain a "Legal Hold" folder. This means that all documents, materiais, and computer files (Including e- malls, word processing documents, slides, etc.) falling into this category must continue to be maintained until you are Informed otherwise, regardless of the specified record retention period that would apply to such materials under Takeda's current Records Retention Schedules and program. You are reminded that you must follow the requirements of both BOP, CORP-B-019 "E-mail Management and Retention" for the retention of electronic materials, and "Best Practices For The Physical And Electronic Storage Of Materials That Must Be Retained For Legal Reasons. " IN ALL CASES, THE FOLLOWING INSTRUCTIONS APPLY TO DOCUMENTS, MATERIALS, INFORMATION, AND THINGS, IN HARD COPY OR ELECTRONIC FORMAT, THAT ARE REQUIRED TO BE RETAINED PURSUANT TO THIS LEGAL HOLD. FOR MATERIALS THAT ARE RECORDS: For paper materials, documents, information, and other tangible things, that are records as defined by Takeda's Records Retention Schedules, you are required to retain such materials in your department. For documents, materials, and information recorded on disposable electronic storage media, such as floppy discs, CDs, video or any other portable medium, that are records as defined by Takeda's Records Retention Schedules, you are also reminded to retain such material In your department, http://horizon/C3/ACTOS%2OProduct%2OLiability%20Litiga/default.aspx 1/11/2007 Confidential - Subject to Protective Order TAK-RIM30b6-00000678 Source: Horizon - ACTOS PRODUCTS LIABILITY CLAIMS Page 2 of 2 For electronic information, documents, and materials in Takeda's electronic information management systems, including electronic materials saved in your desktop computer, you are reminded that this material may NOT be deleted under any circumstances. You are also instructed that e-mails and their attachments should be reviewed and organized Into the appropriate "Record" or "Legal Hold" folder as appropriate. FOR MATERIALS THAT ARE NOT RECORDS: For paper materials, documents, information, and other tangible things, and documents, materials, and information recorded on disposable electronic storage media, such as floppy discs, CDs, video or any other portable medium, that are NOT RECORDS as defined by Takeda's Records Retention Schedules, you must ensure that such materials are retained by placing such materials into boxes that are available for the retention of Legal Hold materials, to the extent that you do not retain such materials in your business files for business reference purposes. With respect to materials that are exact duplicates, as, for example, multiple photocopies that have not been annotated, only one such copy need be retained. Contact Records Management to obtain the necessary supplies. For electronic information, documents, and materials in Takeda's electronic information management systems, including electronic materials saved In your desktop computer, you are reminded that this material may NOT be deleted under any circumstances. You are also instructed that e-mails and their attachments should be reviewed and organized into the appropriate "Record" or "Legal Hold" folder as appropriate. GENERAL: To the extent that material exists both electronically and in paper format, the electronic material must be retained, and the paper copy must also be retained to the extent that it is not an exact printout of an electronic document. Any records fitting the classifications set forth above that have been placed into off-site storage are also not to be destroyed at any time. If you have any questions or need any assistance with respect to the retention of ACTOS®-related materials, please contact Arnold D'Angelo in the Law Department at 847-383-3450. Thank you for your continuing cooperation in this important matter. tp://horizon/C3/ACTOS%2OProduct%20Liability%20Litiga/default.aspx 1/11/2007 Confidential - Subject to Protective Order TAK-RIM30b6-00000679 Source: ittps://www.indup329c00002t.ucsf.edu/docs/hrjf0226 Confidential - Subject to Protective Order TAK-RIM30b6-00000680 Source: https://www.indup5320000003ts.ucsf.edu/docs/hrjf0226

Mention the first name listed in the "apologies"?

ltjf0226

ltjf0226_p0, ltjf0226_p1, ltjf0226_p2, ltjf0226_p3, ltjf0226_p4, ltjf0226_p5

Professor Ele Ferrannini

PROACTIVE Executive Committee Conference Call Minutes of Conference Call Date: Monday 28* November 2005 EXHIBIT NO. Time: 1900 hours In attendance: Professor Erland Erdmann (EE) Professor John Dormandy (JD) Professor Bernard Charbonnel (BC) Professor Massimo Massi-Benedetti (MMB) Mr Ian Moules (IM) Dr Alfonso Perez (AP) Mrs Lucy Bennett (LB) Dr Susan Crawford (SC) Apologles: Professor Ele Ferrannini Dr Allan Skene Dr Meng Tan Professor Robert Wilcox 1. Minutes of last meeting/conference call (15 October 2005) Minutes of the last meeting/conference call held on 15th October 2005 were accepted. The EC stressed that it has been recorded in minutes of previous meetings and teleconferences that its members wish to review the manuscript for all abstracts for future conferences The EC discussed the stage at which each manuscript would be ready for EC review. It was confirmed that the EC require a draft of the manuscript that demonstrates the aims of the paper, how to interpret the data and how the manuscript will be discussed in the context of other data. This is more than simply an outline of what would be included in the manuscript together with supporting data. Figures and tables are required at this stage of review. The EC Lead will take responsibility for determining the stage at which the manuscript is ready for review. The EC is not interested in refining the wording of manuscripts, but all authors would need to agree on the solidity of the data and would need to agree to presentation of an abstract, in order for the EC to carry out a review. JD advised the EC that previous indications to the Committee that the EAC reviewed all cases of heart failure resulting in death, as discussed during the last meeting/call, is incorrect The Enppoint Adjudication Committee reviewed all fatal events, however, there was no classification regarding death due to heart failure by the Committee/Panellists. This determination was made by the Investigator. Professor Rydén (Karolinska Institute, Stockholm) will lead an independent commission into heart failure and the results of these findings are awaited 1.1 Revised membership of the Executive Committee Following EE's initial discussions with Professor Ferrannini and Professor Wilcox, IM reported that he had written to them, outlining details of the contract held with EC members, together with the proposed honorarium The actual contracts are currently held up within Takeda but will be sent out within one week Action: IM to forward EC contracts to EC members. Takeda PROspective PioglitAzone Clinical Trial In MacroVascular Events Lilly Page of 6 Confidential - Subject to Protective Order TAK-MOULEI-00026121 Source: https://www.indup6osb-0000nts.ucsf.edu/docs/ltjf0226 PROACTIVE Executive Committee Conference Call Alfonso Perez, representing Takeda US, has joined the EC and was welcomed. Christian Schneider has been invited to assist with the work assigned to the Chair of the EC (EE). IM proposed that as Dr Schneider is not a full member of the EC, Takeda prepare a standard contract for him, which specifies that Dr Schneider would be paid on an hourly basis. EE expressed thanks for this support for his work and agreed that this type of contract would be appropriate. It was agreed that the next teleconference and meeting should be held at times to suit Professor Ferrannini and Professor Wilcox. There has been no recent communication from David Eckland. It was agreed that IM would contact DE to request formal notification of his resignation from the EC. Action: IM to contact David Eckland to request formal notification of his resignation from the EC 1.2 Statistical commentary: response to the BMJ article by Freemantle At the last meeting of the EC it was agreed that AMS would contact Gordon Murray (GM) and together they would write a response to the article in the BMJ by Nick Freemantle. This has not yet been done. BC commented that our response to The Lancet (regarding Professor Yudkin's letter) included reference to Freemantle's point, however, it was agreed that an official response should still be submitted to the BMJ. The response should be reviewed by the EC prior to submission. Action: AMS to finalise the response as soon as possible and forward to the EC for review. The response should include details of the date on which the Statistical Analysis Plan was finalised and the date of submission to the FDA vs. date of unblinding LB to follow-up with AMS 1.3 Response to The Lancet (correspondence / review by Professor Yki-Jarvinen) A copy of the response to articles in The Lancet has previously been distributed to members of the Writing Committee. This has now been submitted to The Lancet for publication. Action: LB to forward letters sent to The Lancet and the response from the Writing Committee, to the full list of authors [to be included in the Report to the ISC from its EC]. 1.4 AHA presentation and discussions on the issue of principal secondary endpoint EE reported on his presentation at the AHA in Dallas on 16th November Although there were positive comments received following the presentation, there were also accusations that the secondary endpoints had not been prespecified. EE requested a copy of the Statistical Analysis Plan (SAP) and has discussed with AP and Stuart Kupter (Takeda US) that the SAP be published. The EC are currently able to confirm the date on which the SAP was finalised (13 May 2005), the date of submission to the FDA (16 May 2005) and the date on which the study was unblinded (25 May 2005). However, AP reported that the FDA does not usually respond to requests confirming date of receipt. It was agreed that the ideal would be for the FDA to write to confirm the date of receipt. NCRL are able to provide a copy of the certificate of unblinding as documentary evidence to support our claim regarding this date. Action: AP to check with Takeda's regulatory department whether there was acknowledgement made by the FDA upon receipt of the SAP, or any document the FDA can provide to the EC to confirm the date of receipt. Takeda PROspective PioglitAzone Clinical Trial In MacroVascular Events Lilly Page 2 of 6 Confidential - Subject to Protective Order TAK-MOULEI-00026122 Source: :ttps://www.indup6osc-o0002ts.ucsf.edu/docs/ltjf0226 PROACTIVE Executive Committee Conference Call MMB noted that currently there are verbal rumours and nothing is in writing to suggest that the study has been managed inappropriately. The EC discussed that it would be helpful for journals to have evidence to support our dates, in order to support our claim that we submitted the SAP to the FDA prior to unblinding. It was agreed that the BMJ response by AMS should clearly set out the dates and that documentary evidence of these dates be submitted with the written response. The date of unblinding must be made explicitly clear. AMS and GM signatures would lend weight to the text; AMS as statistician and Director of the Study Coordinating Centre providing statistical expertise, and GM as independent statistician and member of the DSMC. Action: AMS to gather documentation and forward to the BMJ with response to the Freemantle article. 1.5 proactive-results.com EE reported that additional finance has been provided to On Screen Productions to add information to the website. The EC is pleased to see that the website is continuing to receive financial support. It was noted that all additions to the website should be seen by the EC prior to inclusion It was agreed that a formal cost proposal should be requested from On Screen Productions prior to any requests being submitted, in order to keep control of the website's budget. However, the EC expressed the view that they do not wish to be involved with the financial aspects of the website as this is Takeda's responsibility. It was agreed that Takeda should suggest additions to the site and the EC review and confirm whether they approve inclusion. IM stressed that the website is the Study and the EC's website, and not the Sponsor's. This was acknowledged. SC has completed the EASD notes to accompany the slides on the website; these will be discussed fully during the next EC meeting. Action: LB to invite Richard Cobourne to join the EC during the next EC meeting. 1.6 Chairman's letter to members of the ISC The EC wish that the ISC remain responsible for PROactive and we should continue to involve them by communicating with them every three months, by way of a Report to the ISC from its EC, as has occurred in the past. This should include a summary of what has been done, what is planned and to ask for suggestions. Action: LB to compose a Report to the ISC from its EC and forward to EE then the full EC for review. 1.7 EC Contracts The EC had been informed that contracts would be changed or extended, but this has not yet happened. IM reported that the contracts had been reviewed within Takeda; there is currently no specified time on existing contracts, however, IM proposed that Takeda send a letter confirming continuation. EC members require documentation to update their records as the study is taking place over such a long duration. JD currently has no contract, as he is no longer Chair. It was confirmed that EC contracts would be identical, with the exception of the contract for EE as Chair. It was finally agreed that new contracts would be required as certain sections of the original contracts (e.g. conduct of the study) are no longer applicable. Action: IM to circulate a copy of the EC contract to all members of the EC. Takeda PROspective PioglitAzone Clinical Trial In MacroVascular Events Lilly Page 3 of 6 Confidential - Subject to Protective Order TAK-MOULEI-00026123 Source: https://www.indup60sc-00003ts.ucsf.edu/docs/ltjf0226 PROACTIVE Executive Committee Conference Call 2. Publications, general update 2.1 Submission of the recurrent MI paper (03, Erdmann) to The Lancet EE has reviewed the recurrent MI paper, amending some tables and updating the text, and SC has now returned to EE the corrected and updated manuscript. EE will review this and forward to the EC within 3-4 days. Authorship: EE, JD, IM, AMS. EE also wishes to invite MMB and BC to become authors EE requested that the EC review the manuscript and as soon as it is returned he prefers to submit the paper to The Lancet. If The Lancet does not wish to publish, the manuscript will be submitted to Circulation in preference to Diabetes Care. It is hoped that The Lancet would consider publishing all PROactive papers. The Lancet asks for disclosure of correspondence with other journals regarding each submission and it was agreed to disclose all correspondence, in this instance with Circulation. IM requested the EC consider adding Stuart Kupfer to the list of authors. This request was denied. Action: EE to circulate revised recurrent MI paper to all members of the EC. 2.2 Rescheduling of meeting to discuss impact of pio on use of other agents paper (04, Scheen) / Mechanism of action paper (07, Laakso) BC reported that Professor Scheen is awaiting data that Takeda agreed to produce, to supplement preliminary data already received from NCRL. Professor Scheen has not yet commenced writing the manuscript. IM reported that he has not received any requests from either Professor Scheen or Professor Laakso for data but now that the clinical trial report is almost complete, there would be data available. Action: IM to provide data to BC within 15 days. Action: BC to forward data to Professor Scheen and Professor Laakso, ask to review and request further data as required. Action: SC to monitor requests for data and timelines for each manuscript. To avoid delays, authors should be instructed that SC could produce the first draft of each manuscript in order for the author to then correct/update the text. This would usually follow the initial teleconference with the authors. IM agreed that ghostwriters are required in order to ensure timely progress. IM reported that Takeda is also able to assign medical writers to the project. Takeda is keen to ensure that abstracts are prepared in time for the deadline for the AHA and as the outline manuscript procedure must also be followed, there is much work to be done. The steps for producing manuscripts/abstracts was reiterated 1. Upon receipt of request, NCRL/Takeda send data to the authors. 2. A teleconference will be held with all authors and the medical writer (SC) in order to outline ideas. 3. SC will compose the first draft of the manuscript and forward to all authors for review. 4. Further teleconferences may be required. 5. EC Lead to determine when draft manuscript is ready for full EC review. Takeda PROspective PioglitAzone Clinical Trial In MacroVascular Events Lilly Page 4 of 6 Confidential - Subject to Protective Order TAK-MOULEI-00026124 Source: ittps://www.indupt05c-00004ts.ucsf.edu/docs/ltjf022 PROACTIVE Executive Committee Conference Call Mechanism of Action paper (07 Laakso): Professor Laakso is required to specify the data that is needed. SC reported that she has contacted him several times but he has still not specified his data requirements. Action: BC send a letter to Professor Laakso on behalf of the EC to specify that the first draft of the manuscript must be produced by the end of 2005. Advise Professor Laakso that SC will be involved in writing the manuscript. 2.3 Progress of stroke paper (08) EE has forwarded the stroke abstract to the EC for review. JD had previously asked Professor Bousser if she would be interested in writing a paper on stroke (those who had entered with stroke / those who had experienced a stroke during the trial), Professor Bousser has agreed to assist but not to be first author. Professor Wilcox has also expressed interest in becoming an author (to be discussed during next EC teleconference). Takeda propose submission to the ACC as an abstract, AP confirmed that Takeda has the appropriate data to support the abstract and tables. Data has been prepared for the clinical trial report for the FDA, and it is this data that has been used to generate the abstract. AP explained that he had been unaware of the EC rules on submission of abstracts, when this was put forward. Takeda wish to submit an abstract for the late breaking clinical trial committee of the ACC to review for presentation in March 2006. The manuscript will be prepared as soon as possible. JD opposed submission of the abstract on the grounds that the clinical trial report includes data that the EC has not yet seen, on many subjects, including stroke. The minutes of the 15-10-05 EC meeting clearly state that the EC must see all new data generated. It is fundamentally wrong that Takeda determine what should be in the abstract, without full EC review. It will not be possible to complete the stroke abstract in time for an ACC submission deadline of 5th December. It was also reiterated that an abstract could not be prepared by somebody other than an author of the final manuscript. JD reinforced that the process must be the same for all abstracts and manuscripts. The EC must see the data. The list of authors must be finalised and the authors should discuss the data via teleconference. It will not be possible to complete this process within one week in order to submit to the ACC on 5th December. SC added that there was a second deadline of 5th January. It was agreed that if the data could be reviewed by the EC and the manuscript drafted by SC and the authors, then it might be possible to meet this second deadline. JD (EC Lead) would, in the meantime, finalise the list of authors (Professor Wilcox and Professor Bousser have agreed, Professor Betteridge and Professor Schernthaner were also on the original list of authors). 2.4 Economic Analysis Plan update MMB will attend a meeting to work on the economic analysis plan on 6th December 2005, The first analysis is based on UK costings, the second on costings in Germany. Some data is awaited; publication anticipated during the second quarter of 2006. 3. Abstracts and Presentations: ACC (stroke cohort) / ADA Abstracts for the ACC have already been discussed, in section 2.3 above. Abstracts for the ADA must follow the same rules as for all manuscripts/abstracts. 4. Clinical Trial Report IM reported that Takeda are in the final stages of completing the clinical trial report. The report has been sent to JD as EC Chair and Principal Investigator of the study, for review and signature. The EC discussed the most appropriate format for other EC members to be aware of the content of the report, which is -200 Takeda PROspective PioglitAzone Clinical Trial In MacroVascular Events Lilly Page 5 of 6 Confidential - Subject to Protective Order TAK-MOULEI-00026125 Source: https://www.indup6usc-00005ts.ucsf.edu/docs/ltjf0226 PROACTIVE Executive Committee Conference Call pages of text plus tables. JD expressed the view that the EC ought to see the report as it contains new data. JD offered to write accompanying notes so that EC members do not need to read the full report, much of which is routine. It was agreed that Takeda would forward to JD the final version of the report that they wish JD to review and sign. Members of the EC will receive the final version and notes for their information within 2 weeks. Action: Takeda to forward the final version of the Clinical Trial Report to JD for review/signature. Action: JD to forward notes on the final report to the EC within 2 weeks. 5. Heart Failure Review JD, LB and Dr Anne-Ruth van Troostenburg de Bruyn (Takeda Drug Safety) will visit Professor Rydén on 2nd December 2005 to discuss the commission. Professor Rydén has received 50 CIOMS forms for review prior to the meeting. A draft Terms of Reference exists and will be discussed further during the meeting and circulated for EC review/information. Action: JD/LB to forward the Heart Failure Terms of Reference to the EC. 6. PROactive Slides in circulation It was agreed to discuss slides in circulation with Richard Cobourne during the next EC meeting in February. 6.1 Error in EASD triglyceride slides To be discussed at the next EC meeting 7. Any Other Business 7.1 Questions and Answer document in preparation for responses to journals It was agreed that there is no longer a requirement to have the Q&A document for this purpose. 8. Dates of future meetings and conference calls Next EC teleconference: afternoon of Wednesday 28th December Next EC meeting: Thursday, 9th February for all EC members. [Post meeting note: the meeting will be held at the Kempinski Hotel, Münich Airport and not in Frankfurt.] Proposal: EC members should plan to arrive on the first flight into Münich and depart on the last flight out. EC members to notify LB of their flight times, aiming to arrive in time for the meeting to commence at 0900 hours and to finish on the same day. If flight times do not allow for this schedule, accommodation requests should be forwarded to LB. It was noted that the EC should plan meeting/call dates one year in advance in order to avoid non- attendance due to prior commitments. If the planned meeting is no longer required, it will be cancelled. There being no further business, the call finished at 2030 hours. Takeda PROspective PioglitAzone Clinical Trial In MacroVascular Events Lilly Page 6 of 6 Confidential - Subject to Protective Order TAK-MOULEI-00026126 Source:

What is the exhibit number?

hrjf0226

hrjf0226_p0, hrjf0226_p1, hrjf0226_p2

52

Horizon - ACTOS PRODUCTS LIABILITY CLAIMS Page ) of 2 >: Home News & Events People Workplace & Services & Values Tools & Resources Tean Honcon EXHIBIT ACTOS PRODUCTS LIABILITY HORIZON CLAIMS 52 CURRENT LOCATION LEGAL HOLD RELATED TO ACTOS PRODUCTS LIABILITY CLAIMS: PLEASE READ Home THIS MESSAGE CAREFULLY Culture & Values Office of Ethics & Takeda continues to be involved in a small number of claims or lawsuits Compliance ("claims") relating to ACTOS® (pioglitazone HCI). As a result of these Litigation claims, all documents, materials, Information and things that exist or Resources continue to be developed pertaining to ACTOS® have been and continue ACTOS to be subject to a Legal Hold. PRODUCTS LIABILITY Additionally, all documents and materials that exist or continue to be CLAIMS developed pertaining to Combination medicines Involving ACTOS®, ACTIONS whether a marketed or development medicine, also continue to be subject I to a Legal Hold. Add to My Links Alert Me Each Takeda Employee or Contractor shall create an Outlook Folder entitled "ACTOS" beneath the "Legal Hold" folder provided as part of the implementation of CORP-B-019 "E-mail Management and Retention." Contact the Help Desk if your Outlook file folder structure does not - contain a "Legal Hold" folder. This means that all documents, materiais, and computer files (Including e- malls, word processing documents, slides, etc.) falling into this category must continue to be maintained until you are Informed otherwise, regardless of the specified record retention period that would apply to such materials under Takeda's current Records Retention Schedules and program. You are reminded that you must follow the requirements of both BOP, CORP-B-019 "E-mail Management and Retention" for the retention of electronic materials, and "Best Practices For The Physical And Electronic Storage Of Materials That Must Be Retained For Legal Reasons. " IN ALL CASES, THE FOLLOWING INSTRUCTIONS APPLY TO DOCUMENTS, MATERIALS, INFORMATION, AND THINGS, IN HARD COPY OR ELECTRONIC FORMAT, THAT ARE REQUIRED TO BE RETAINED PURSUANT TO THIS LEGAL HOLD. FOR MATERIALS THAT ARE RECORDS: For paper materials, documents, information, and other tangible things, that are records as defined by Takeda's Records Retention Schedules, you are required to retain such materials in your department. For documents, materials, and information recorded on disposable electronic storage media, such as floppy discs, CDs, video or any other portable medium, that are records as defined by Takeda's Records Retention Schedules, you are also reminded to retain such material In your department, http://horizon/C3/ACTOS%2OProduct%2OLiability%20Litiga/default.aspx 1/11/2007 Confidential - Subject to Protective Order TAK-RIM30b6-00000678 Source: Horizon - ACTOS PRODUCTS LIABILITY CLAIMS Page 2 of 2 For electronic information, documents, and materials in Takeda's electronic information management systems, including electronic materials saved in your desktop computer, you are reminded that this material may NOT be deleted under any circumstances. You are also instructed that e-mails and their attachments should be reviewed and organized Into the appropriate "Record" or "Legal Hold" folder as appropriate. FOR MATERIALS THAT ARE NOT RECORDS: For paper materials, documents, information, and other tangible things, and documents, materials, and information recorded on disposable electronic storage media, such as floppy discs, CDs, video or any other portable medium, that are NOT RECORDS as defined by Takeda's Records Retention Schedules, you must ensure that such materials are retained by placing such materials into boxes that are available for the retention of Legal Hold materials, to the extent that you do not retain such materials in your business files for business reference purposes. With respect to materials that are exact duplicates, as, for example, multiple photocopies that have not been annotated, only one such copy need be retained. Contact Records Management to obtain the necessary supplies. For electronic information, documents, and materials in Takeda's electronic information management systems, including electronic materials saved In your desktop computer, you are reminded that this material may NOT be deleted under any circumstances. You are also instructed that e-mails and their attachments should be reviewed and organized into the appropriate "Record" or "Legal Hold" folder as appropriate. GENERAL: To the extent that material exists both electronically and in paper format, the electronic material must be retained, and the paper copy must also be retained to the extent that it is not an exact printout of an electronic document. Any records fitting the classifications set forth above that have been placed into off-site storage are also not to be destroyed at any time. If you have any questions or need any assistance with respect to the retention of ACTOS®-related materials, please contact Arnold D'Angelo in the Law Department at 847-383-3450. Thank you for your continuing cooperation in this important matter. tp://horizon/C3/ACTOS%2OProduct%20Liability%20Litiga/default.aspx 1/11/2007 Confidential - Subject to Protective Order TAK-RIM30b6-00000679 Source: ittps://www.indup329c00002t.ucsf.edu/docs/hrjf0226 Confidential - Subject to Protective Order TAK-RIM30b6-00000680 Source: https://www.indup5320000003ts.ucsf.edu/docs/hrjf0226

when was the last meeting/conference call held on ?

ltjf0226

ltjf0226_p0, ltjf0226_p1, ltjf0226_p2, ltjf0226_p3, ltjf0226_p4, ltjf0226_p5

15th October 2005, 15 October 2005

PROACTIVE Executive Committee Conference Call Minutes of Conference Call Date: Monday 28* November 2005 EXHIBIT NO. Time: 1900 hours In attendance: Professor Erland Erdmann (EE) Professor John Dormandy (JD) Professor Bernard Charbonnel (BC) Professor Massimo Massi-Benedetti (MMB) Mr Ian Moules (IM) Dr Alfonso Perez (AP) Mrs Lucy Bennett (LB) Dr Susan Crawford (SC) Apologles: Professor Ele Ferrannini Dr Allan Skene Dr Meng Tan Professor Robert Wilcox 1. Minutes of last meeting/conference call (15 October 2005) Minutes of the last meeting/conference call held on 15th October 2005 were accepted. The EC stressed that it has been recorded in minutes of previous meetings and teleconferences that its members wish to review the manuscript for all abstracts for future conferences The EC discussed the stage at which each manuscript would be ready for EC review. It was confirmed that the EC require a draft of the manuscript that demonstrates the aims of the paper, how to interpret the data and how the manuscript will be discussed in the context of other data. This is more than simply an outline of what would be included in the manuscript together with supporting data. Figures and tables are required at this stage of review. The EC Lead will take responsibility for determining the stage at which the manuscript is ready for review. The EC is not interested in refining the wording of manuscripts, but all authors would need to agree on the solidity of the data and would need to agree to presentation of an abstract, in order for the EC to carry out a review. JD advised the EC that previous indications to the Committee that the EAC reviewed all cases of heart failure resulting in death, as discussed during the last meeting/call, is incorrect The Enppoint Adjudication Committee reviewed all fatal events, however, there was no classification regarding death due to heart failure by the Committee/Panellists. This determination was made by the Investigator. Professor Rydén (Karolinska Institute, Stockholm) will lead an independent commission into heart failure and the results of these findings are awaited 1.1 Revised membership of the Executive Committee Following EE's initial discussions with Professor Ferrannini and Professor Wilcox, IM reported that he had written to them, outlining details of the contract held with EC members, together with the proposed honorarium The actual contracts are currently held up within Takeda but will be sent out within one week Action: IM to forward EC contracts to EC members. Takeda PROspective PioglitAzone Clinical Trial In MacroVascular Events Lilly Page of 6 Confidential - Subject to Protective Order TAK-MOULEI-00026121 Source: https://www.indup6osb-0000nts.ucsf.edu/docs/ltjf0226 PROACTIVE Executive Committee Conference Call Alfonso Perez, representing Takeda US, has joined the EC and was welcomed. Christian Schneider has been invited to assist with the work assigned to the Chair of the EC (EE). IM proposed that as Dr Schneider is not a full member of the EC, Takeda prepare a standard contract for him, which specifies that Dr Schneider would be paid on an hourly basis. EE expressed thanks for this support for his work and agreed that this type of contract would be appropriate. It was agreed that the next teleconference and meeting should be held at times to suit Professor Ferrannini and Professor Wilcox. There has been no recent communication from David Eckland. It was agreed that IM would contact DE to request formal notification of his resignation from the EC. Action: IM to contact David Eckland to request formal notification of his resignation from the EC 1.2 Statistical commentary: response to the BMJ article by Freemantle At the last meeting of the EC it was agreed that AMS would contact Gordon Murray (GM) and together they would write a response to the article in the BMJ by Nick Freemantle. This has not yet been done. BC commented that our response to The Lancet (regarding Professor Yudkin's letter) included reference to Freemantle's point, however, it was agreed that an official response should still be submitted to the BMJ. The response should be reviewed by the EC prior to submission. Action: AMS to finalise the response as soon as possible and forward to the EC for review. The response should include details of the date on which the Statistical Analysis Plan was finalised and the date of submission to the FDA vs. date of unblinding LB to follow-up with AMS 1.3 Response to The Lancet (correspondence / review by Professor Yki-Jarvinen) A copy of the response to articles in The Lancet has previously been distributed to members of the Writing Committee. This has now been submitted to The Lancet for publication. Action: LB to forward letters sent to The Lancet and the response from the Writing Committee, to the full list of authors [to be included in the Report to the ISC from its EC]. 1.4 AHA presentation and discussions on the issue of principal secondary endpoint EE reported on his presentation at the AHA in Dallas on 16th November Although there were positive comments received following the presentation, there were also accusations that the secondary endpoints had not been prespecified. EE requested a copy of the Statistical Analysis Plan (SAP) and has discussed with AP and Stuart Kupter (Takeda US) that the SAP be published. The EC are currently able to confirm the date on which the SAP was finalised (13 May 2005), the date of submission to the FDA (16 May 2005) and the date on which the study was unblinded (25 May 2005). However, AP reported that the FDA does not usually respond to requests confirming date of receipt. It was agreed that the ideal would be for the FDA to write to confirm the date of receipt. NCRL are able to provide a copy of the certificate of unblinding as documentary evidence to support our claim regarding this date. Action: AP to check with Takeda's regulatory department whether there was acknowledgement made by the FDA upon receipt of the SAP, or any document the FDA can provide to the EC to confirm the date of receipt. Takeda PROspective PioglitAzone Clinical Trial In MacroVascular Events Lilly Page 2 of 6 Confidential - Subject to Protective Order TAK-MOULEI-00026122 Source: :ttps://www.indup6osc-o0002ts.ucsf.edu/docs/ltjf0226 PROACTIVE Executive Committee Conference Call MMB noted that currently there are verbal rumours and nothing is in writing to suggest that the study has been managed inappropriately. The EC discussed that it would be helpful for journals to have evidence to support our dates, in order to support our claim that we submitted the SAP to the FDA prior to unblinding. It was agreed that the BMJ response by AMS should clearly set out the dates and that documentary evidence of these dates be submitted with the written response. The date of unblinding must be made explicitly clear. AMS and GM signatures would lend weight to the text; AMS as statistician and Director of the Study Coordinating Centre providing statistical expertise, and GM as independent statistician and member of the DSMC. Action: AMS to gather documentation and forward to the BMJ with response to the Freemantle article. 1.5 proactive-results.com EE reported that additional finance has been provided to On Screen Productions to add information to the website. The EC is pleased to see that the website is continuing to receive financial support. It was noted that all additions to the website should be seen by the EC prior to inclusion It was agreed that a formal cost proposal should be requested from On Screen Productions prior to any requests being submitted, in order to keep control of the website's budget. However, the EC expressed the view that they do not wish to be involved with the financial aspects of the website as this is Takeda's responsibility. It was agreed that Takeda should suggest additions to the site and the EC review and confirm whether they approve inclusion. IM stressed that the website is the Study and the EC's website, and not the Sponsor's. This was acknowledged. SC has completed the EASD notes to accompany the slides on the website; these will be discussed fully during the next EC meeting. Action: LB to invite Richard Cobourne to join the EC during the next EC meeting. 1.6 Chairman's letter to members of the ISC The EC wish that the ISC remain responsible for PROactive and we should continue to involve them by communicating with them every three months, by way of a Report to the ISC from its EC, as has occurred in the past. This should include a summary of what has been done, what is planned and to ask for suggestions. Action: LB to compose a Report to the ISC from its EC and forward to EE then the full EC for review. 1.7 EC Contracts The EC had been informed that contracts would be changed or extended, but this has not yet happened. IM reported that the contracts had been reviewed within Takeda; there is currently no specified time on existing contracts, however, IM proposed that Takeda send a letter confirming continuation. EC members require documentation to update their records as the study is taking place over such a long duration. JD currently has no contract, as he is no longer Chair. It was confirmed that EC contracts would be identical, with the exception of the contract for EE as Chair. It was finally agreed that new contracts would be required as certain sections of the original contracts (e.g. conduct of the study) are no longer applicable. Action: IM to circulate a copy of the EC contract to all members of the EC. Takeda PROspective PioglitAzone Clinical Trial In MacroVascular Events Lilly Page 3 of 6 Confidential - Subject to Protective Order TAK-MOULEI-00026123 Source: https://www.indup60sc-00003ts.ucsf.edu/docs/ltjf0226 PROACTIVE Executive Committee Conference Call 2. Publications, general update 2.1 Submission of the recurrent MI paper (03, Erdmann) to The Lancet EE has reviewed the recurrent MI paper, amending some tables and updating the text, and SC has now returned to EE the corrected and updated manuscript. EE will review this and forward to the EC within 3-4 days. Authorship: EE, JD, IM, AMS. EE also wishes to invite MMB and BC to become authors EE requested that the EC review the manuscript and as soon as it is returned he prefers to submit the paper to The Lancet. If The Lancet does not wish to publish, the manuscript will be submitted to Circulation in preference to Diabetes Care. It is hoped that The Lancet would consider publishing all PROactive papers. The Lancet asks for disclosure of correspondence with other journals regarding each submission and it was agreed to disclose all correspondence, in this instance with Circulation. IM requested the EC consider adding Stuart Kupfer to the list of authors. This request was denied. Action: EE to circulate revised recurrent MI paper to all members of the EC. 2.2 Rescheduling of meeting to discuss impact of pio on use of other agents paper (04, Scheen) / Mechanism of action paper (07, Laakso) BC reported that Professor Scheen is awaiting data that Takeda agreed to produce, to supplement preliminary data already received from NCRL. Professor Scheen has not yet commenced writing the manuscript. IM reported that he has not received any requests from either Professor Scheen or Professor Laakso for data but now that the clinical trial report is almost complete, there would be data available. Action: IM to provide data to BC within 15 days. Action: BC to forward data to Professor Scheen and Professor Laakso, ask to review and request further data as required. Action: SC to monitor requests for data and timelines for each manuscript. To avoid delays, authors should be instructed that SC could produce the first draft of each manuscript in order for the author to then correct/update the text. This would usually follow the initial teleconference with the authors. IM agreed that ghostwriters are required in order to ensure timely progress. IM reported that Takeda is also able to assign medical writers to the project. Takeda is keen to ensure that abstracts are prepared in time for the deadline for the AHA and as the outline manuscript procedure must also be followed, there is much work to be done. The steps for producing manuscripts/abstracts was reiterated 1. Upon receipt of request, NCRL/Takeda send data to the authors. 2. A teleconference will be held with all authors and the medical writer (SC) in order to outline ideas. 3. SC will compose the first draft of the manuscript and forward to all authors for review. 4. Further teleconferences may be required. 5. EC Lead to determine when draft manuscript is ready for full EC review. Takeda PROspective PioglitAzone Clinical Trial In MacroVascular Events Lilly Page 4 of 6 Confidential - Subject to Protective Order TAK-MOULEI-00026124 Source: ittps://www.indupt05c-00004ts.ucsf.edu/docs/ltjf022 PROACTIVE Executive Committee Conference Call Mechanism of Action paper (07 Laakso): Professor Laakso is required to specify the data that is needed. SC reported that she has contacted him several times but he has still not specified his data requirements. Action: BC send a letter to Professor Laakso on behalf of the EC to specify that the first draft of the manuscript must be produced by the end of 2005. Advise Professor Laakso that SC will be involved in writing the manuscript. 2.3 Progress of stroke paper (08) EE has forwarded the stroke abstract to the EC for review. JD had previously asked Professor Bousser if she would be interested in writing a paper on stroke (those who had entered with stroke / those who had experienced a stroke during the trial), Professor Bousser has agreed to assist but not to be first author. Professor Wilcox has also expressed interest in becoming an author (to be discussed during next EC teleconference). Takeda propose submission to the ACC as an abstract, AP confirmed that Takeda has the appropriate data to support the abstract and tables. Data has been prepared for the clinical trial report for the FDA, and it is this data that has been used to generate the abstract. AP explained that he had been unaware of the EC rules on submission of abstracts, when this was put forward. Takeda wish to submit an abstract for the late breaking clinical trial committee of the ACC to review for presentation in March 2006. The manuscript will be prepared as soon as possible. JD opposed submission of the abstract on the grounds that the clinical trial report includes data that the EC has not yet seen, on many subjects, including stroke. The minutes of the 15-10-05 EC meeting clearly state that the EC must see all new data generated. It is fundamentally wrong that Takeda determine what should be in the abstract, without full EC review. It will not be possible to complete the stroke abstract in time for an ACC submission deadline of 5th December. It was also reiterated that an abstract could not be prepared by somebody other than an author of the final manuscript. JD reinforced that the process must be the same for all abstracts and manuscripts. The EC must see the data. The list of authors must be finalised and the authors should discuss the data via teleconference. It will not be possible to complete this process within one week in order to submit to the ACC on 5th December. SC added that there was a second deadline of 5th January. It was agreed that if the data could be reviewed by the EC and the manuscript drafted by SC and the authors, then it might be possible to meet this second deadline. JD (EC Lead) would, in the meantime, finalise the list of authors (Professor Wilcox and Professor Bousser have agreed, Professor Betteridge and Professor Schernthaner were also on the original list of authors). 2.4 Economic Analysis Plan update MMB will attend a meeting to work on the economic analysis plan on 6th December 2005, The first analysis is based on UK costings, the second on costings in Germany. Some data is awaited; publication anticipated during the second quarter of 2006. 3. Abstracts and Presentations: ACC (stroke cohort) / ADA Abstracts for the ACC have already been discussed, in section 2.3 above. Abstracts for the ADA must follow the same rules as for all manuscripts/abstracts. 4. Clinical Trial Report IM reported that Takeda are in the final stages of completing the clinical trial report. The report has been sent to JD as EC Chair and Principal Investigator of the study, for review and signature. The EC discussed the most appropriate format for other EC members to be aware of the content of the report, which is -200 Takeda PROspective PioglitAzone Clinical Trial In MacroVascular Events Lilly Page 5 of 6 Confidential - Subject to Protective Order TAK-MOULEI-00026125 Source: https://www.indup6usc-00005ts.ucsf.edu/docs/ltjf0226 PROACTIVE Executive Committee Conference Call pages of text plus tables. JD expressed the view that the EC ought to see the report as it contains new data. JD offered to write accompanying notes so that EC members do not need to read the full report, much of which is routine. It was agreed that Takeda would forward to JD the final version of the report that they wish JD to review and sign. Members of the EC will receive the final version and notes for their information within 2 weeks. Action: Takeda to forward the final version of the Clinical Trial Report to JD for review/signature. Action: JD to forward notes on the final report to the EC within 2 weeks. 5. Heart Failure Review JD, LB and Dr Anne-Ruth van Troostenburg de Bruyn (Takeda Drug Safety) will visit Professor Rydén on 2nd December 2005 to discuss the commission. Professor Rydén has received 50 CIOMS forms for review prior to the meeting. A draft Terms of Reference exists and will be discussed further during the meeting and circulated for EC review/information. Action: JD/LB to forward the Heart Failure Terms of Reference to the EC. 6. PROactive Slides in circulation It was agreed to discuss slides in circulation with Richard Cobourne during the next EC meeting in February. 6.1 Error in EASD triglyceride slides To be discussed at the next EC meeting 7. Any Other Business 7.1 Questions and Answer document in preparation for responses to journals It was agreed that there is no longer a requirement to have the Q&A document for this purpose. 8. Dates of future meetings and conference calls Next EC teleconference: afternoon of Wednesday 28th December Next EC meeting: Thursday, 9th February for all EC members. [Post meeting note: the meeting will be held at the Kempinski Hotel, Münich Airport and not in Frankfurt.] Proposal: EC members should plan to arrive on the first flight into Münich and depart on the last flight out. EC members to notify LB of their flight times, aiming to arrive in time for the meeting to commence at 0900 hours and to finish on the same day. If flight times do not allow for this schedule, accommodation requests should be forwarded to LB. It was noted that the EC should plan meeting/call dates one year in advance in order to avoid non- attendance due to prior commitments. If the planned meeting is no longer required, it will be cancelled. There being no further business, the call finished at 2030 hours. Takeda PROspective PioglitAzone Clinical Trial In MacroVascular Events Lilly Page 6 of 6 Confidential - Subject to Protective Order TAK-MOULEI-00026126 Source:

What is the exhibit number?

jsjf0226

jsjf0226_p0, jsjf0226_p1

107

EXHIBIT 107 FDA Conference Call: August 13, 2002 FDA Personnel: Jeri El-Hage, Ph.D., Toxicology Team Leader Jena Weber, Project Manager TPNA Personnel: David Baron, Ph.D., Director, Nonclinical Safety and Efficacy Janet Haskins, Manager, Regulatory Affairs Pat Frank, Ph.D., TPNA Consultant This teleconference was held as a follow-up to a discussion between TPNA and the Agency on July 31, 2002. The purpose of this call was so that Dr. El-Hage could expand upon the nonclinical data related to dual PPAR agonists that were discussed with TPNA on July 31, 2002. Dr. El-Hage informed TPNA that in standard 2-year rat and mouse bioassay studies, several other dual PPAR agonists were shown to cause transitional cell tumors in the bladder and kidneys of male and female rats and male mice. Therefore, the Division is considering the relevance of these findings to this pharmaceutical class of drugs. She also noted that in follow-up unspecified mechanistic studies of the other dual PPAR agonists, no evidence of irritation by crystalluria or calculi was noted. Dr. El-Hage then described a tumor promoter-model study that was conducted by another sponsor in which pioglitazone was administered. The study was designed as follows: BBN was given to male Fisher rats in their drinking water for four weeks. Four groups were designated: Pioglitazone 40 mg/kg/day after BBN The study compound plus BBN (No dosages were specified, but Dr. El-Hage noted that multiple dosages were studied and the high dose was designed to be "equivalent" to 40 mg/kg pioglitazone) The negative control group received BBN only. The positive control group received uracil. Duration of daily dosing was 32-weeks after BBN. Results: 85% of the animals in the pioglitazone and the other sponsor's compound groups had tumor formation. Calculi formation was not confirmed in either group, but was looked for using unspecified methodology. 15% of the animals in the negative control group had tumor formation, while approximately 50% of the positive control group presented tumors in the presence of calculi formation (uracil) Confidential - Subject to Protective Order TAK-NAUGHP-00080811 Source: https://www.indup372.0000nts.ucsf.edu/docs/jsjf0226 Based on these findings, and the fact that the development of the other dual PPAR agonists has been discontinued, the Division expressed a concern that a possible risk of dual PPARs has not been addressed. Dr. El-Hage stated that prior to other dual PPAR agonists discontinuing development, monitoring for bladder tumors was required in their phase III clinical studies. She noted that the Division's internal consultant suggested screening urine for NMP-22. Dr. El-Hage believes this assay is approved for screening of bladder tumors and is commercially available. Finally Dr. El-Hage noted that she will be consulting with the CAC board in mid- September. She will inquire if they feel that the pioglitazone package insert adequately addresses our data as well as the data that the Division now has concerning other dual PPAR agonists. She suggested that TPNA might consider adding the föllowing sentence to our package-inser "Increased bladder and-renal transitional cell tumors were seen in other compounds in the same class of drugs." Confidential - Subject to Protective Order TAK-NAUGHP-00080812 Source: https://www.indup537/2-00002 ts.ucsf.edu/docs/jsjf0226

what is the date mentioned under the title - " minutes of conference call"?

ltjf0226

ltjf0226_p0, ltjf0226_p1, ltjf0226_p2, ltjf0226_p3, ltjf0226_p4, ltjf0226_p5

28th November 2005, Monday 28th November 2005, monday 28th november 2005

PROACTIVE Executive Committee Conference Call Minutes of Conference Call Date: Monday 28* November 2005 EXHIBIT NO. Time: 1900 hours In attendance: Professor Erland Erdmann (EE) Professor John Dormandy (JD) Professor Bernard Charbonnel (BC) Professor Massimo Massi-Benedetti (MMB) Mr Ian Moules (IM) Dr Alfonso Perez (AP) Mrs Lucy Bennett (LB) Dr Susan Crawford (SC) Apologles: Professor Ele Ferrannini Dr Allan Skene Dr Meng Tan Professor Robert Wilcox 1. Minutes of last meeting/conference call (15 October 2005) Minutes of the last meeting/conference call held on 15th October 2005 were accepted. The EC stressed that it has been recorded in minutes of previous meetings and teleconferences that its members wish to review the manuscript for all abstracts for future conferences The EC discussed the stage at which each manuscript would be ready for EC review. It was confirmed that the EC require a draft of the manuscript that demonstrates the aims of the paper, how to interpret the data and how the manuscript will be discussed in the context of other data. This is more than simply an outline of what would be included in the manuscript together with supporting data. Figures and tables are required at this stage of review. The EC Lead will take responsibility for determining the stage at which the manuscript is ready for review. The EC is not interested in refining the wording of manuscripts, but all authors would need to agree on the solidity of the data and would need to agree to presentation of an abstract, in order for the EC to carry out a review. JD advised the EC that previous indications to the Committee that the EAC reviewed all cases of heart failure resulting in death, as discussed during the last meeting/call, is incorrect The Enppoint Adjudication Committee reviewed all fatal events, however, there was no classification regarding death due to heart failure by the Committee/Panellists. This determination was made by the Investigator. Professor Rydén (Karolinska Institute, Stockholm) will lead an independent commission into heart failure and the results of these findings are awaited 1.1 Revised membership of the Executive Committee Following EE's initial discussions with Professor Ferrannini and Professor Wilcox, IM reported that he had written to them, outlining details of the contract held with EC members, together with the proposed honorarium The actual contracts are currently held up within Takeda but will be sent out within one week Action: IM to forward EC contracts to EC members. Takeda PROspective PioglitAzone Clinical Trial In MacroVascular Events Lilly Page of 6 Confidential - Subject to Protective Order TAK-MOULEI-00026121 Source: https://www.indup6osb-0000nts.ucsf.edu/docs/ltjf0226 PROACTIVE Executive Committee Conference Call Alfonso Perez, representing Takeda US, has joined the EC and was welcomed. Christian Schneider has been invited to assist with the work assigned to the Chair of the EC (EE). IM proposed that as Dr Schneider is not a full member of the EC, Takeda prepare a standard contract for him, which specifies that Dr Schneider would be paid on an hourly basis. EE expressed thanks for this support for his work and agreed that this type of contract would be appropriate. It was agreed that the next teleconference and meeting should be held at times to suit Professor Ferrannini and Professor Wilcox. There has been no recent communication from David Eckland. It was agreed that IM would contact DE to request formal notification of his resignation from the EC. Action: IM to contact David Eckland to request formal notification of his resignation from the EC 1.2 Statistical commentary: response to the BMJ article by Freemantle At the last meeting of the EC it was agreed that AMS would contact Gordon Murray (GM) and together they would write a response to the article in the BMJ by Nick Freemantle. This has not yet been done. BC commented that our response to The Lancet (regarding Professor Yudkin's letter) included reference to Freemantle's point, however, it was agreed that an official response should still be submitted to the BMJ. The response should be reviewed by the EC prior to submission. Action: AMS to finalise the response as soon as possible and forward to the EC for review. The response should include details of the date on which the Statistical Analysis Plan was finalised and the date of submission to the FDA vs. date of unblinding LB to follow-up with AMS 1.3 Response to The Lancet (correspondence / review by Professor Yki-Jarvinen) A copy of the response to articles in The Lancet has previously been distributed to members of the Writing Committee. This has now been submitted to The Lancet for publication. Action: LB to forward letters sent to The Lancet and the response from the Writing Committee, to the full list of authors [to be included in the Report to the ISC from its EC]. 1.4 AHA presentation and discussions on the issue of principal secondary endpoint EE reported on his presentation at the AHA in Dallas on 16th November Although there were positive comments received following the presentation, there were also accusations that the secondary endpoints had not been prespecified. EE requested a copy of the Statistical Analysis Plan (SAP) and has discussed with AP and Stuart Kupter (Takeda US) that the SAP be published. The EC are currently able to confirm the date on which the SAP was finalised (13 May 2005), the date of submission to the FDA (16 May 2005) and the date on which the study was unblinded (25 May 2005). However, AP reported that the FDA does not usually respond to requests confirming date of receipt. It was agreed that the ideal would be for the FDA to write to confirm the date of receipt. NCRL are able to provide a copy of the certificate of unblinding as documentary evidence to support our claim regarding this date. Action: AP to check with Takeda's regulatory department whether there was acknowledgement made by the FDA upon receipt of the SAP, or any document the FDA can provide to the EC to confirm the date of receipt. Takeda PROspective PioglitAzone Clinical Trial In MacroVascular Events Lilly Page 2 of 6 Confidential - Subject to Protective Order TAK-MOULEI-00026122 Source: :ttps://www.indup6osc-o0002ts.ucsf.edu/docs/ltjf0226 PROACTIVE Executive Committee Conference Call MMB noted that currently there are verbal rumours and nothing is in writing to suggest that the study has been managed inappropriately. The EC discussed that it would be helpful for journals to have evidence to support our dates, in order to support our claim that we submitted the SAP to the FDA prior to unblinding. It was agreed that the BMJ response by AMS should clearly set out the dates and that documentary evidence of these dates be submitted with the written response. The date of unblinding must be made explicitly clear. AMS and GM signatures would lend weight to the text; AMS as statistician and Director of the Study Coordinating Centre providing statistical expertise, and GM as independent statistician and member of the DSMC. Action: AMS to gather documentation and forward to the BMJ with response to the Freemantle article. 1.5 proactive-results.com EE reported that additional finance has been provided to On Screen Productions to add information to the website. The EC is pleased to see that the website is continuing to receive financial support. It was noted that all additions to the website should be seen by the EC prior to inclusion It was agreed that a formal cost proposal should be requested from On Screen Productions prior to any requests being submitted, in order to keep control of the website's budget. However, the EC expressed the view that they do not wish to be involved with the financial aspects of the website as this is Takeda's responsibility. It was agreed that Takeda should suggest additions to the site and the EC review and confirm whether they approve inclusion. IM stressed that the website is the Study and the EC's website, and not the Sponsor's. This was acknowledged. SC has completed the EASD notes to accompany the slides on the website; these will be discussed fully during the next EC meeting. Action: LB to invite Richard Cobourne to join the EC during the next EC meeting. 1.6 Chairman's letter to members of the ISC The EC wish that the ISC remain responsible for PROactive and we should continue to involve them by communicating with them every three months, by way of a Report to the ISC from its EC, as has occurred in the past. This should include a summary of what has been done, what is planned and to ask for suggestions. Action: LB to compose a Report to the ISC from its EC and forward to EE then the full EC for review. 1.7 EC Contracts The EC had been informed that contracts would be changed or extended, but this has not yet happened. IM reported that the contracts had been reviewed within Takeda; there is currently no specified time on existing contracts, however, IM proposed that Takeda send a letter confirming continuation. EC members require documentation to update their records as the study is taking place over such a long duration. JD currently has no contract, as he is no longer Chair. It was confirmed that EC contracts would be identical, with the exception of the contract for EE as Chair. It was finally agreed that new contracts would be required as certain sections of the original contracts (e.g. conduct of the study) are no longer applicable. Action: IM to circulate a copy of the EC contract to all members of the EC. Takeda PROspective PioglitAzone Clinical Trial In MacroVascular Events Lilly Page 3 of 6 Confidential - Subject to Protective Order TAK-MOULEI-00026123 Source: https://www.indup60sc-00003ts.ucsf.edu/docs/ltjf0226 PROACTIVE Executive Committee Conference Call 2. Publications, general update 2.1 Submission of the recurrent MI paper (03, Erdmann) to The Lancet EE has reviewed the recurrent MI paper, amending some tables and updating the text, and SC has now returned to EE the corrected and updated manuscript. EE will review this and forward to the EC within 3-4 days. Authorship: EE, JD, IM, AMS. EE also wishes to invite MMB and BC to become authors EE requested that the EC review the manuscript and as soon as it is returned he prefers to submit the paper to The Lancet. If The Lancet does not wish to publish, the manuscript will be submitted to Circulation in preference to Diabetes Care. It is hoped that The Lancet would consider publishing all PROactive papers. The Lancet asks for disclosure of correspondence with other journals regarding each submission and it was agreed to disclose all correspondence, in this instance with Circulation. IM requested the EC consider adding Stuart Kupfer to the list of authors. This request was denied. Action: EE to circulate revised recurrent MI paper to all members of the EC. 2.2 Rescheduling of meeting to discuss impact of pio on use of other agents paper (04, Scheen) / Mechanism of action paper (07, Laakso) BC reported that Professor Scheen is awaiting data that Takeda agreed to produce, to supplement preliminary data already received from NCRL. Professor Scheen has not yet commenced writing the manuscript. IM reported that he has not received any requests from either Professor Scheen or Professor Laakso for data but now that the clinical trial report is almost complete, there would be data available. Action: IM to provide data to BC within 15 days. Action: BC to forward data to Professor Scheen and Professor Laakso, ask to review and request further data as required. Action: SC to monitor requests for data and timelines for each manuscript. To avoid delays, authors should be instructed that SC could produce the first draft of each manuscript in order for the author to then correct/update the text. This would usually follow the initial teleconference with the authors. IM agreed that ghostwriters are required in order to ensure timely progress. IM reported that Takeda is also able to assign medical writers to the project. Takeda is keen to ensure that abstracts are prepared in time for the deadline for the AHA and as the outline manuscript procedure must also be followed, there is much work to be done. The steps for producing manuscripts/abstracts was reiterated 1. Upon receipt of request, NCRL/Takeda send data to the authors. 2. A teleconference will be held with all authors and the medical writer (SC) in order to outline ideas. 3. SC will compose the first draft of the manuscript and forward to all authors for review. 4. Further teleconferences may be required. 5. EC Lead to determine when draft manuscript is ready for full EC review. Takeda PROspective PioglitAzone Clinical Trial In MacroVascular Events Lilly Page 4 of 6 Confidential - Subject to Protective Order TAK-MOULEI-00026124 Source: ittps://www.indupt05c-00004ts.ucsf.edu/docs/ltjf022 PROACTIVE Executive Committee Conference Call Mechanism of Action paper (07 Laakso): Professor Laakso is required to specify the data that is needed. SC reported that she has contacted him several times but he has still not specified his data requirements. Action: BC send a letter to Professor Laakso on behalf of the EC to specify that the first draft of the manuscript must be produced by the end of 2005. Advise Professor Laakso that SC will be involved in writing the manuscript. 2.3 Progress of stroke paper (08) EE has forwarded the stroke abstract to the EC for review. JD had previously asked Professor Bousser if she would be interested in writing a paper on stroke (those who had entered with stroke / those who had experienced a stroke during the trial), Professor Bousser has agreed to assist but not to be first author. Professor Wilcox has also expressed interest in becoming an author (to be discussed during next EC teleconference). Takeda propose submission to the ACC as an abstract, AP confirmed that Takeda has the appropriate data to support the abstract and tables. Data has been prepared for the clinical trial report for the FDA, and it is this data that has been used to generate the abstract. AP explained that he had been unaware of the EC rules on submission of abstracts, when this was put forward. Takeda wish to submit an abstract for the late breaking clinical trial committee of the ACC to review for presentation in March 2006. The manuscript will be prepared as soon as possible. JD opposed submission of the abstract on the grounds that the clinical trial report includes data that the EC has not yet seen, on many subjects, including stroke. The minutes of the 15-10-05 EC meeting clearly state that the EC must see all new data generated. It is fundamentally wrong that Takeda determine what should be in the abstract, without full EC review. It will not be possible to complete the stroke abstract in time for an ACC submission deadline of 5th December. It was also reiterated that an abstract could not be prepared by somebody other than an author of the final manuscript. JD reinforced that the process must be the same for all abstracts and manuscripts. The EC must see the data. The list of authors must be finalised and the authors should discuss the data via teleconference. It will not be possible to complete this process within one week in order to submit to the ACC on 5th December. SC added that there was a second deadline of 5th January. It was agreed that if the data could be reviewed by the EC and the manuscript drafted by SC and the authors, then it might be possible to meet this second deadline. JD (EC Lead) would, in the meantime, finalise the list of authors (Professor Wilcox and Professor Bousser have agreed, Professor Betteridge and Professor Schernthaner were also on the original list of authors). 2.4 Economic Analysis Plan update MMB will attend a meeting to work on the economic analysis plan on 6th December 2005, The first analysis is based on UK costings, the second on costings in Germany. Some data is awaited; publication anticipated during the second quarter of 2006. 3. Abstracts and Presentations: ACC (stroke cohort) / ADA Abstracts for the ACC have already been discussed, in section 2.3 above. Abstracts for the ADA must follow the same rules as for all manuscripts/abstracts. 4. Clinical Trial Report IM reported that Takeda are in the final stages of completing the clinical trial report. The report has been sent to JD as EC Chair and Principal Investigator of the study, for review and signature. The EC discussed the most appropriate format for other EC members to be aware of the content of the report, which is -200 Takeda PROspective PioglitAzone Clinical Trial In MacroVascular Events Lilly Page 5 of 6 Confidential - Subject to Protective Order TAK-MOULEI-00026125 Source: https://www.indup6usc-00005ts.ucsf.edu/docs/ltjf0226 PROACTIVE Executive Committee Conference Call pages of text plus tables. JD expressed the view that the EC ought to see the report as it contains new data. JD offered to write accompanying notes so that EC members do not need to read the full report, much of which is routine. It was agreed that Takeda would forward to JD the final version of the report that they wish JD to review and sign. Members of the EC will receive the final version and notes for their information within 2 weeks. Action: Takeda to forward the final version of the Clinical Trial Report to JD for review/signature. Action: JD to forward notes on the final report to the EC within 2 weeks. 5. Heart Failure Review JD, LB and Dr Anne-Ruth van Troostenburg de Bruyn (Takeda Drug Safety) will visit Professor Rydén on 2nd December 2005 to discuss the commission. Professor Rydén has received 50 CIOMS forms for review prior to the meeting. A draft Terms of Reference exists and will be discussed further during the meeting and circulated for EC review/information. Action: JD/LB to forward the Heart Failure Terms of Reference to the EC. 6. PROactive Slides in circulation It was agreed to discuss slides in circulation with Richard Cobourne during the next EC meeting in February. 6.1 Error in EASD triglyceride slides To be discussed at the next EC meeting 7. Any Other Business 7.1 Questions and Answer document in preparation for responses to journals It was agreed that there is no longer a requirement to have the Q&A document for this purpose. 8. Dates of future meetings and conference calls Next EC teleconference: afternoon of Wednesday 28th December Next EC meeting: Thursday, 9th February for all EC members. [Post meeting note: the meeting will be held at the Kempinski Hotel, Münich Airport and not in Frankfurt.] Proposal: EC members should plan to arrive on the first flight into Münich and depart on the last flight out. EC members to notify LB of their flight times, aiming to arrive in time for the meeting to commence at 0900 hours and to finish on the same day. If flight times do not allow for this schedule, accommodation requests should be forwarded to LB. It was noted that the EC should plan meeting/call dates one year in advance in order to avoid non- attendance due to prior commitments. If the planned meeting is no longer required, it will be cancelled. There being no further business, the call finished at 2030 hours. Takeda PROspective PioglitAzone Clinical Trial In MacroVascular Events Lilly Page 6 of 6 Confidential - Subject to Protective Order TAK-MOULEI-00026126 Source:

what is the title of chapter 3?

jpjf0226

jpjf0226_p1, jpjf0226_p2, jpjf0226_p3, jpjf0226_p4, jpjf0226_p5, jpjf0226_p6, jpjf0226_p7

document storage period, Document Storage Period

3) Other places designated by the relevant core organizations 4. "Responsible person in charge of storage" shall mean the responsible person in charge of a core organization. 5. "Person in charge of storage" shall mean a person in the "Line Position" or the "Quasi-Line Position", as stipulated from Article 411 through Article 422 of the Business Organization Rule, appointed by the responsible person in charge of storage. Article 4 (Principles of Creating Documents) Clerical operations shall be performed, in principle, based on documents. However, efforts shall be made to minimize the amount of documents to be created. Chapter 2 Document Storage Functions Article 5 (Principles concerning Document Storage Functions ) In principle, for documents created internally, the document storage functions shall be the core organizations in charge of the creation; and for those created externally, the core organizations that have received the documents shall be the document storage functions, However, in the case of documents created internally, if the receiving core organizations are designated to store the documents, as stipulated by laws, regulations or Company Regulations, the receiving core organizations shall be the document storage function. (2) Notwithstanding the preceding paragraph, materials for the agenda of the Board of Directors and Management and Operations Committee, and other conferences, shall be stored at the core organizations functioning as the secretariats for the conferences. (3) Documents shall be, in principle, centrally stored at the document storage functions. In other words, functions other than the document storage functions shall not store the relevant documents, and shall thus dispose of any documents promptly after they are no longer necessary (delete any electromagnetic records; the same shall apply to the rest of this Policy). Article 6 (Duties of Responsible Person in Charge of Storage and Person in Charge of Storage) The responsible person in charge of storage shall have the person in charge of storage properly store, and dispose of, any stored documents in the relevant core organization, and ensure that any relevant subordinates observe this Policy and the Function Standards. Confidential - Subject to Protective Order TAKJ-TPC-00000253 Source: https://www.indup2378-00002ts.ucsf.edu/docs/jpjf0226 (2) The person in charge of storage shall properly store, and dispose of, any stored documents assigned, and properly store any records relevant to those storage and disposal. (3) In case the document storage functions are reorganized or abolished due to organizational changes, etc., the core organizations taking over the document-related operations shall continue to store the documents and retain the disposal records. Chapter 3 Document Storage Period Article 7 (Document Storage Period) The responsible person in charge of storage shall establish storage periods for different types of assigned documents, by checking opinions of the relevant internal functions, if necessary, and distinguish and designate the periods, in principle, as indicated below. However, if the storage periods are specified by laws, regulations or Company Regulations, they shall be established in compliance with those laws, regulations and Company Regulations. The starting point for determining a storage period shall be, in principle, the date on which the document is created. 1. To be stored permanently 2. To be stored for ten years 3. To be stored for seyen years 4. To be stored for five years 5. To be stored for three years 6. To be stored for one year 7. To be stored for less than one year (to be disposed of promptly after use) (2) If a document turns out not to be categorized into any document types designated for specified storage periods, the responsible person in charge of storage shall establish a storage period for the new document type, as stipulated in the preceding paragraph. (3) Concerning the provisions set forth in Paragraph 1 above, the following documents shall be stored permanently. 1. Articles of Incorporation and Company Regulations 2. Important documents concerning the General Meetings of Shareholders, the Board of Directors, the Management and Operations Committee, and other important conferences. 3. Important documents concerning mid/long-range management policies and plans 4. Important documents concerning the Company's rights and duties, including important contracts, lawsuits, registrations, etc. 5. Important documents concerning budgets, account settlements, and other Confidential $ Subject to Protective Order TAKJ-TPC-00000254 Source: https://www.indup2378-00003ts.ucsf.edu/docs/jpjf0226 accounting affairs 6. Important documents concerning personnel affairs, salaries, and labor management, etc. 7, Important documents concerning research/development and manufacturing 8. Other documents deemed to require permanent storage Chapter 4 Document Storage Methods, etc. Article 8 (Starting Document Storage) A member of the document storage function shall start storage of each document for the storage period established for the specified document type in the function. Article 9 (Document Storage Methods) Unless otherwise stipulated by laws and regulations, etc., document storage functions shall store, in principle, originals of the documents. However, if counterparts or copies need to be stored because the originals have already been delivered or because of the other reasons, the counterparts or copies shall be stored. (2) Unless otherwise stipulated by laws and regulations, etc., document storage functions shall store documents, in principle, in paper-based formats (printouts for electromagnetic records). However, if necessary for operational purposes, electromagnetic records may be stored as they are. Article 10 (Document Storage Place) Documents to be retained shall be stored properly at places specified in Item 3, Article 3. Except for those not supposed to be shared to protect confidentiality, and those still under development, the documents should not be stored in individual workers' desks or PCs. Article 11 (Handling of Documents the Storage Periods of Which Have Expired) When document storage periods expire, the document storage functions shall promptly dispose of the documents after obtaining approvals from the person in charge of storage. However, this provision shall not apply to cases in which the storage periods are extended by the responsible person in charge of storage in the function, who considers that the storage needs to be continued and establishes the extended storage periods. (2) After disposing of any stored documents or having them properly disposed of, the person in charge of storage stipulated in the preceding paragraph shall compile the Confidential - Subject to Protective Order TAKJ-TPC-00000255 Source: https://www.indup378-00004ts.ucsf.edu/docs/jpjf0226 disposal records (specifying the titles of the documents, disposal date/time, disposal methods, and names of persons who have disposed of the documents). The disposal records themselves shall be stored permanently. Chapter 5 Exceptions, etc. for Responding to disputes, etc. Article 12 (Requesting Document Storage) If disputes, etc. involving the Company have taken place, or may take place, and if the responsible person in charge of a core organization supervising or supposed to supervise the disputes, etc., or his/her appointee, requests the responsible person in charge of storage or the person in charge of storage within the core organization involved in the disputes, etc., to take necessary actions for storage, etc. of the documents relating to the disputes, etc., in order to respond properly to such disputes, etc., the contents of the requests shall prevail over the provisions of the preceding articles or any provisions of the function standards. (2) The responsible person in charge of storage or the person in charge of storage in a core organization, requested as in the preceding paragraph, shall ensure that the requests are thoroughly communicated to, and understood by, the relevant members of the organization, so that they can properly respond to the requests. (3) Irrespective of existence of any requests stipulated in Paragraph 1 above and notwithstanding the provisions of Paragraph 1 of the preceding article, documents relating to any disputes, etc. pending or in progress, involving the Company, shall not be disposed of. Article 13 (Cooperation from Other Functions) The responsible person in charge of storage or the person in charge of storage in a core organization that has received requests stipulated in Paragraph 1 of the preceding article, or the responsible person in charge of storage or the person in charge of storage in a core organization storing documents stipulated in Paragraph 3 of the preceding article shall have the relevant members of the function provide necessary cooperation to a core organization supervising or supposed to supervise the disputes, etc., so that adequate responses can be made to such disputes, etc. Chapter 6 Centralized Management of Function Standards and Self-Inspection Article 14 (Centralized Management of Function Standards) When Function Standards are enacted or revised by a core organization, the copies Confidential - Subject to Protective Order TAKJ-TPC-00000256 Source: https://www.indup237/8-00005ts.ucsf.edu/docs/jpjf0226 shall be sent to Administrative Legal Affairs, Legal Department. (2) Upon receiving the Function Standards, as stipulated in the preceding paragraph, Administrative Legal Affairs, Legal Department shall confirm the maintenance status, and check the appropriateness of the contents, as required. In the confirmation efforts, it may seek necessary assistance from Corporate Strategy & Planning Department or Intellectual Property Department. (3) Senior Vice President, Legal Department may provide each core organization with necessary advice on the Function Standards, based on the results of confirmation, etc. mentioned in the preceding paragraph. Such advice shall be duly respected by each core organization. Article 15 (Self-Inspection) The responsible person in charge of storage shall have the person in charge of storage conduct regular self-inspection to confirm that documents are properly managed in accordance with this Policy and Function Standards. Supplementary Provisions Article 1 The Function Standards, as stipulated in Paragraph 2, Article 2 of this Policy shall be properly prepared and finalized by September 30, 2010. Article 2 Article 1 and this article of the Supplementary Provisions shall be deleted as of October 1, 2010. Approval by Enacted : April 1, 1955 President Implemented : June 1, 1955 Confidential - Subject to Protective Order TAKJ-TPC-00000257 Source: https://www.indup2378-00006ts.ucsf.edu/docs/jpjf0226 Name of Company Regulation Policy on Document Control Revision Date Implementation Date Revision Date Implementation Date April 1, 2004 April 1, 2004 May 19, 2006 April 1, 2006 February 1, 2010 February 1, 2010 Confidential - Subject to Protective Order TAKJ-TPC-00000258 Confidential - Subject to Protective Order TAKJ-TPC-00000259 Source:

What is the graphical representation about?

xqjf0226

xqjf0226_p0, xqjf0226_p1, xqjf0226_p2, xqjf0226_p3

Summary of Segment Attractiveness

DOCUMENT PRODUCED IN NATIVE FORMAT Confidential - Subject to Protective Order LLY-HOVENR-00021523 Produced in MDL on 02/27/13 Source: https://www.indup4soscooo7ts.ucsf.edu/docs/xqjf0226 Always QD actos Rationale for 3 Segments pioglitazone HCI For performance that benefits the body. Summ ary of Segment Attractiveness (based on C urrent situation & future trends) Tre atment M achines, Life Ne gotiators, Struggle for Control 60 50 40 All 3 Segments Have Consistent Needs 30 20 10 0 7/1101 Com pany Con) dent al 11 Copy ght CPOO de LI yand Com pany 7/24/01 Company Confidential 1 File name/location Copyright C 2000 Eli Lilly and Company Source: https://www.indup4sos-oooozts.ucsf.edu/docs/xqjf0226 Always qo Pouver actos e Consistent Patient Needs pioglitazone HCI For performance that benefits the body. Treatment Life Struggle for Machines Negotiators Control Patient Aggressively arrest Aggressively arrest Aggressively arrest the progression of the progression of the progression of Needs diabetes diabetes diabetes Manage / treat Manage/treat Manage/treat existing complications complications complications Self reliance / Better control than Better control than management current therapy gives current therapy Maintain a high level Return to life before Avoid injectable of physical activity diabetes therapy Not limit success Flexibility in dosing Specific & explicit Avoid feeling sick To live for today instructions Not complicate health Not limit success provides status Maintain a high level Avoid feeling sick of physical activity Not complicate health Easy to use status Family support Easy to use Self Simple to understand reliance/management 7/24/01 Company Confidential 22 File name/location Copyright © 2000 Eli Lilly and Company Source: https://www.indup4608-00003s.ucsf.edu/docs/xqjf0226 Development of CSF #1: Condition the Market on IR and its Link to CV Risk Including Lipid Abnormalities Strength / Key Market Observations Opportunities/Threats Required Capability Weakness CSF Current:(HCTM) Communicate cutting edge information to opinion leaders on treating IR with TZDs and subsequent benefits (beta- MD- Poor understanding of diabetic cell preservation, reduced CV risk, dyslipidemia and role of OAD Threat durable glycemic efficacy Strength Physician ignorance in treating dyslipidemia, CV risk and IR together Threat Continue to generate and communicate ACTOS data on Physician don't see that TZDs treat more than treatment benefits, especially glycemic control Opportunity preventing complications Weakness Patients understand the disease(type 2), therefore interested in preventing long term complications Opportunity Physicians desire to limit long term Condition the complications Threat Market on IR and Future:(Scenario Planning) its Link to CV Promote to targeted MDs: (1) Need to Risk Including shift treatment paradigm from glucose Lipid Awareness among Endos and PCPs of control to treating IR (2) IR leads to CV Abnormalities importance of insulin resistance increases risk (3) Importance of treating diabetic (Holistic view of patient) Opportunity dyslipidemia with an OAD Strength Understanding of the importance of reducing CV risk improves Opportunity Leverage strict guidelines as need to Tighter NCEP guidelines along with greater pay more attention to diabetic lipid awareness Opportunity dyslipidemia Weakness Interim data showing reduced CV mortality is released (Avandia) Threat Failure to create perception that beta-cell Promote as class effect: beta-cell preservation is a class effect Threat function, reduction of CV risk Strength Durability data available for TZDs Opportunity IGT recognized as a disease (treatable with Avandia) Threat Promote TZDs as a class treat IGT Strength Source: https://www.indup460800004 s.ucsf.edu/docs/xqjf0226

On what basis, the Summary of Segment Attractiveness is carried out?

xqjf0226

xqjf0226_p0, xqjf0226_p1, xqjf0226_p2, xqjf0226_p3

based on current situation & future trends, Based on current situation & future trends., current situation & future trends

DOCUMENT PRODUCED IN NATIVE FORMAT Confidential - Subject to Protective Order LLY-HOVENR-00021523 Produced in MDL on 02/27/13 Source: https://www.indup4soscooo7ts.ucsf.edu/docs/xqjf0226 Always QD actos Rationale for 3 Segments pioglitazone HCI For performance that benefits the body. Summ ary of Segment Attractiveness (based on C urrent situation & future trends) Tre atment M achines, Life Ne gotiators, Struggle for Control 60 50 40 All 3 Segments Have Consistent Needs 30 20 10 0 7/1101 Com pany Con) dent al 11 Copy ght CPOO de LI yand Com pany 7/24/01 Company Confidential 1 File name/location Copyright C 2000 Eli Lilly and Company Source: https://www.indup4sos-oooozts.ucsf.edu/docs/xqjf0226 Always qo Pouver actos e Consistent Patient Needs pioglitazone HCI For performance that benefits the body. Treatment Life Struggle for Machines Negotiators Control Patient Aggressively arrest Aggressively arrest Aggressively arrest the progression of the progression of the progression of Needs diabetes diabetes diabetes Manage / treat Manage/treat Manage/treat existing complications complications complications Self reliance / Better control than Better control than management current therapy gives current therapy Maintain a high level Return to life before Avoid injectable of physical activity diabetes therapy Not limit success Flexibility in dosing Specific & explicit Avoid feeling sick To live for today instructions Not complicate health Not limit success provides status Maintain a high level Avoid feeling sick of physical activity Not complicate health Easy to use status Family support Easy to use Self Simple to understand reliance/management 7/24/01 Company Confidential 22 File name/location Copyright © 2000 Eli Lilly and Company Source: https://www.indup4608-00003s.ucsf.edu/docs/xqjf0226 Development of CSF #1: Condition the Market on IR and its Link to CV Risk Including Lipid Abnormalities Strength / Key Market Observations Opportunities/Threats Required Capability Weakness CSF Current:(HCTM) Communicate cutting edge information to opinion leaders on treating IR with TZDs and subsequent benefits (beta- MD- Poor understanding of diabetic cell preservation, reduced CV risk, dyslipidemia and role of OAD Threat durable glycemic efficacy Strength Physician ignorance in treating dyslipidemia, CV risk and IR together Threat Continue to generate and communicate ACTOS data on Physician don't see that TZDs treat more than treatment benefits, especially glycemic control Opportunity preventing complications Weakness Patients understand the disease(type 2), therefore interested in preventing long term complications Opportunity Physicians desire to limit long term Condition the complications Threat Market on IR and Future:(Scenario Planning) its Link to CV Promote to targeted MDs: (1) Need to Risk Including shift treatment paradigm from glucose Lipid Awareness among Endos and PCPs of control to treating IR (2) IR leads to CV Abnormalities importance of insulin resistance increases risk (3) Importance of treating diabetic (Holistic view of patient) Opportunity dyslipidemia with an OAD Strength Understanding of the importance of reducing CV risk improves Opportunity Leverage strict guidelines as need to Tighter NCEP guidelines along with greater pay more attention to diabetic lipid awareness Opportunity dyslipidemia Weakness Interim data showing reduced CV mortality is released (Avandia) Threat Failure to create perception that beta-cell Promote as class effect: beta-cell preservation is a class effect Threat function, reduction of CV risk Strength Durability data available for TZDs Opportunity IGT recognized as a disease (treatable with Avandia) Threat Promote TZDs as a class treat IGT Strength Source: https://www.indup460800004 s.ucsf.edu/docs/xqjf0226

What are the three segments indicated in the graph?

xqjf0226

xqjf0226_p0, xqjf0226_p1, xqjf0226_p2, xqjf0226_p3

Treatment Machines, Life Negotiators, Struggle for Control

DOCUMENT PRODUCED IN NATIVE FORMAT Confidential - Subject to Protective Order LLY-HOVENR-00021523 Produced in MDL on 02/27/13 Source: https://www.indup4soscooo7ts.ucsf.edu/docs/xqjf0226 Always QD actos Rationale for 3 Segments pioglitazone HCI For performance that benefits the body. Summ ary of Segment Attractiveness (based on C urrent situation & future trends) Tre atment M achines, Life Ne gotiators, Struggle for Control 60 50 40 All 3 Segments Have Consistent Needs 30 20 10 0 7/1101 Com pany Con) dent al 11 Copy ght CPOO de LI yand Com pany 7/24/01 Company Confidential 1 File name/location Copyright C 2000 Eli Lilly and Company Source: https://www.indup4sos-oooozts.ucsf.edu/docs/xqjf0226 Always qo Pouver actos e Consistent Patient Needs pioglitazone HCI For performance that benefits the body. Treatment Life Struggle for Machines Negotiators Control Patient Aggressively arrest Aggressively arrest Aggressively arrest the progression of the progression of the progression of Needs diabetes diabetes diabetes Manage / treat Manage/treat Manage/treat existing complications complications complications Self reliance / Better control than Better control than management current therapy gives current therapy Maintain a high level Return to life before Avoid injectable of physical activity diabetes therapy Not limit success Flexibility in dosing Specific & explicit Avoid feeling sick To live for today instructions Not complicate health Not limit success provides status Maintain a high level Avoid feeling sick of physical activity Not complicate health Easy to use status Family support Easy to use Self Simple to understand reliance/management 7/24/01 Company Confidential 22 File name/location Copyright © 2000 Eli Lilly and Company Source: https://www.indup4608-00003s.ucsf.edu/docs/xqjf0226 Development of CSF #1: Condition the Market on IR and its Link to CV Risk Including Lipid Abnormalities Strength / Key Market Observations Opportunities/Threats Required Capability Weakness CSF Current:(HCTM) Communicate cutting edge information to opinion leaders on treating IR with TZDs and subsequent benefits (beta- MD- Poor understanding of diabetic cell preservation, reduced CV risk, dyslipidemia and role of OAD Threat durable glycemic efficacy Strength Physician ignorance in treating dyslipidemia, CV risk and IR together Threat Continue to generate and communicate ACTOS data on Physician don't see that TZDs treat more than treatment benefits, especially glycemic control Opportunity preventing complications Weakness Patients understand the disease(type 2), therefore interested in preventing long term complications Opportunity Physicians desire to limit long term Condition the complications Threat Market on IR and Future:(Scenario Planning) its Link to CV Promote to targeted MDs: (1) Need to Risk Including shift treatment paradigm from glucose Lipid Awareness among Endos and PCPs of control to treating IR (2) IR leads to CV Abnormalities importance of insulin resistance increases risk (3) Importance of treating diabetic (Holistic view of patient) Opportunity dyslipidemia with an OAD Strength Understanding of the importance of reducing CV risk improves Opportunity Leverage strict guidelines as need to Tighter NCEP guidelines along with greater pay more attention to diabetic lipid awareness Opportunity dyslipidemia Weakness Interim data showing reduced CV mortality is released (Avandia) Threat Failure to create perception that beta-cell Promote as class effect: beta-cell preservation is a class effect Threat function, reduction of CV risk Strength Durability data available for TZDs Opportunity IGT recognized as a disease (treatable with Avandia) Threat Promote TZDs as a class treat IGT Strength Source: https://www.indup460800004 s.ucsf.edu/docs/xqjf0226

What is the conclusion obtained from the graph?

xqjf0226

xqjf0226_p0, xqjf0226_p1, xqjf0226_p2, xqjf0226_p3

All 3 Segments Have Consistent Needs., All 3 segments have consistent needs

DOCUMENT PRODUCED IN NATIVE FORMAT Confidential - Subject to Protective Order LLY-HOVENR-00021523 Produced in MDL on 02/27/13 Source: https://www.indup4soscooo7ts.ucsf.edu/docs/xqjf0226 Always QD actos Rationale for 3 Segments pioglitazone HCI For performance that benefits the body. Summ ary of Segment Attractiveness (based on C urrent situation & future trends) Tre atment M achines, Life Ne gotiators, Struggle for Control 60 50 40 All 3 Segments Have Consistent Needs 30 20 10 0 7/1101 Com pany Con) dent al 11 Copy ght CPOO de LI yand Com pany 7/24/01 Company Confidential 1 File name/location Copyright C 2000 Eli Lilly and Company Source: https://www.indup4sos-oooozts.ucsf.edu/docs/xqjf0226 Always qo Pouver actos e Consistent Patient Needs pioglitazone HCI For performance that benefits the body. Treatment Life Struggle for Machines Negotiators Control Patient Aggressively arrest Aggressively arrest Aggressively arrest the progression of the progression of the progression of Needs diabetes diabetes diabetes Manage / treat Manage/treat Manage/treat existing complications complications complications Self reliance / Better control than Better control than management current therapy gives current therapy Maintain a high level Return to life before Avoid injectable of physical activity diabetes therapy Not limit success Flexibility in dosing Specific & explicit Avoid feeling sick To live for today instructions Not complicate health Not limit success provides status Maintain a high level Avoid feeling sick of physical activity Not complicate health Easy to use status Family support Easy to use Self Simple to understand reliance/management 7/24/01 Company Confidential 22 File name/location Copyright © 2000 Eli Lilly and Company Source: https://www.indup4608-00003s.ucsf.edu/docs/xqjf0226 Development of CSF #1: Condition the Market on IR and its Link to CV Risk Including Lipid Abnormalities Strength / Key Market Observations Opportunities/Threats Required Capability Weakness CSF Current:(HCTM) Communicate cutting edge information to opinion leaders on treating IR with TZDs and subsequent benefits (beta- MD- Poor understanding of diabetic cell preservation, reduced CV risk, dyslipidemia and role of OAD Threat durable glycemic efficacy Strength Physician ignorance in treating dyslipidemia, CV risk and IR together Threat Continue to generate and communicate ACTOS data on Physician don't see that TZDs treat more than treatment benefits, especially glycemic control Opportunity preventing complications Weakness Patients understand the disease(type 2), therefore interested in preventing long term complications Opportunity Physicians desire to limit long term Condition the complications Threat Market on IR and Future:(Scenario Planning) its Link to CV Promote to targeted MDs: (1) Need to Risk Including shift treatment paradigm from glucose Lipid Awareness among Endos and PCPs of control to treating IR (2) IR leads to CV Abnormalities importance of insulin resistance increases risk (3) Importance of treating diabetic (Holistic view of patient) Opportunity dyslipidemia with an OAD Strength Understanding of the importance of reducing CV risk improves Opportunity Leverage strict guidelines as need to Tighter NCEP guidelines along with greater pay more attention to diabetic lipid awareness Opportunity dyslipidemia Weakness Interim data showing reduced CV mortality is released (Avandia) Threat Failure to create perception that beta-cell Promote as class effect: beta-cell preservation is a class effect Threat function, reduction of CV risk Strength Durability data available for TZDs Opportunity IGT recognized as a disease (treatable with Avandia) Threat Promote TZDs as a class treat IGT Strength Source: https://www.indup460800004 s.ucsf.edu/docs/xqjf0226

what is article 4?

jpjf0226

jpjf0226_p1, jpjf0226_p2, jpjf0226_p3, jpjf0226_p4, jpjf0226_p5, jpjf0226_p6, jpjf0226_p7

PRINCIPLES OF CREATING DOCUMENTS, principles of creating documents, (PRINCIPLES OF CREATING DOCUMENTS)

3) Other places designated by the relevant core organizations 4. "Responsible person in charge of storage" shall mean the responsible person in charge of a core organization. 5. "Person in charge of storage" shall mean a person in the "Line Position" or the "Quasi-Line Position", as stipulated from Article 411 through Article 422 of the Business Organization Rule, appointed by the responsible person in charge of storage. Article 4 (Principles of Creating Documents) Clerical operations shall be performed, in principle, based on documents. However, efforts shall be made to minimize the amount of documents to be created. Chapter 2 Document Storage Functions Article 5 (Principles concerning Document Storage Functions ) In principle, for documents created internally, the document storage functions shall be the core organizations in charge of the creation; and for those created externally, the core organizations that have received the documents shall be the document storage functions, However, in the case of documents created internally, if the receiving core organizations are designated to store the documents, as stipulated by laws, regulations or Company Regulations, the receiving core organizations shall be the document storage function. (2) Notwithstanding the preceding paragraph, materials for the agenda of the Board of Directors and Management and Operations Committee, and other conferences, shall be stored at the core organizations functioning as the secretariats for the conferences. (3) Documents shall be, in principle, centrally stored at the document storage functions. In other words, functions other than the document storage functions shall not store the relevant documents, and shall thus dispose of any documents promptly after they are no longer necessary (delete any electromagnetic records; the same shall apply to the rest of this Policy). Article 6 (Duties of Responsible Person in Charge of Storage and Person in Charge of Storage) The responsible person in charge of storage shall have the person in charge of storage properly store, and dispose of, any stored documents in the relevant core organization, and ensure that any relevant subordinates observe this Policy and the Function Standards. Confidential - Subject to Protective Order TAKJ-TPC-00000253 Source: https://www.indup2378-00002ts.ucsf.edu/docs/jpjf0226 (2) The person in charge of storage shall properly store, and dispose of, any stored documents assigned, and properly store any records relevant to those storage and disposal. (3) In case the document storage functions are reorganized or abolished due to organizational changes, etc., the core organizations taking over the document-related operations shall continue to store the documents and retain the disposal records. Chapter 3 Document Storage Period Article 7 (Document Storage Period) The responsible person in charge of storage shall establish storage periods for different types of assigned documents, by checking opinions of the relevant internal functions, if necessary, and distinguish and designate the periods, in principle, as indicated below. However, if the storage periods are specified by laws, regulations or Company Regulations, they shall be established in compliance with those laws, regulations and Company Regulations. The starting point for determining a storage period shall be, in principle, the date on which the document is created. 1. To be stored permanently 2. To be stored for ten years 3. To be stored for seyen years 4. To be stored for five years 5. To be stored for three years 6. To be stored for one year 7. To be stored for less than one year (to be disposed of promptly after use) (2) If a document turns out not to be categorized into any document types designated for specified storage periods, the responsible person in charge of storage shall establish a storage period for the new document type, as stipulated in the preceding paragraph. (3) Concerning the provisions set forth in Paragraph 1 above, the following documents shall be stored permanently. 1. Articles of Incorporation and Company Regulations 2. Important documents concerning the General Meetings of Shareholders, the Board of Directors, the Management and Operations Committee, and other important conferences. 3. Important documents concerning mid/long-range management policies and plans 4. Important documents concerning the Company's rights and duties, including important contracts, lawsuits, registrations, etc. 5. Important documents concerning budgets, account settlements, and other Confidential $ Subject to Protective Order TAKJ-TPC-00000254 Source: https://www.indup2378-00003ts.ucsf.edu/docs/jpjf0226 accounting affairs 6. Important documents concerning personnel affairs, salaries, and labor management, etc. 7, Important documents concerning research/development and manufacturing 8. Other documents deemed to require permanent storage Chapter 4 Document Storage Methods, etc. Article 8 (Starting Document Storage) A member of the document storage function shall start storage of each document for the storage period established for the specified document type in the function. Article 9 (Document Storage Methods) Unless otherwise stipulated by laws and regulations, etc., document storage functions shall store, in principle, originals of the documents. However, if counterparts or copies need to be stored because the originals have already been delivered or because of the other reasons, the counterparts or copies shall be stored. (2) Unless otherwise stipulated by laws and regulations, etc., document storage functions shall store documents, in principle, in paper-based formats (printouts for electromagnetic records). However, if necessary for operational purposes, electromagnetic records may be stored as they are. Article 10 (Document Storage Place) Documents to be retained shall be stored properly at places specified in Item 3, Article 3. Except for those not supposed to be shared to protect confidentiality, and those still under development, the documents should not be stored in individual workers' desks or PCs. Article 11 (Handling of Documents the Storage Periods of Which Have Expired) When document storage periods expire, the document storage functions shall promptly dispose of the documents after obtaining approvals from the person in charge of storage. However, this provision shall not apply to cases in which the storage periods are extended by the responsible person in charge of storage in the function, who considers that the storage needs to be continued and establishes the extended storage periods. (2) After disposing of any stored documents or having them properly disposed of, the person in charge of storage stipulated in the preceding paragraph shall compile the Confidential - Subject to Protective Order TAKJ-TPC-00000255 Source: https://www.indup378-00004ts.ucsf.edu/docs/jpjf0226 disposal records (specifying the titles of the documents, disposal date/time, disposal methods, and names of persons who have disposed of the documents). The disposal records themselves shall be stored permanently. Chapter 5 Exceptions, etc. for Responding to disputes, etc. Article 12 (Requesting Document Storage) If disputes, etc. involving the Company have taken place, or may take place, and if the responsible person in charge of a core organization supervising or supposed to supervise the disputes, etc., or his/her appointee, requests the responsible person in charge of storage or the person in charge of storage within the core organization involved in the disputes, etc., to take necessary actions for storage, etc. of the documents relating to the disputes, etc., in order to respond properly to such disputes, etc., the contents of the requests shall prevail over the provisions of the preceding articles or any provisions of the function standards. (2) The responsible person in charge of storage or the person in charge of storage in a core organization, requested as in the preceding paragraph, shall ensure that the requests are thoroughly communicated to, and understood by, the relevant members of the organization, so that they can properly respond to the requests. (3) Irrespective of existence of any requests stipulated in Paragraph 1 above and notwithstanding the provisions of Paragraph 1 of the preceding article, documents relating to any disputes, etc. pending or in progress, involving the Company, shall not be disposed of. Article 13 (Cooperation from Other Functions) The responsible person in charge of storage or the person in charge of storage in a core organization that has received requests stipulated in Paragraph 1 of the preceding article, or the responsible person in charge of storage or the person in charge of storage in a core organization storing documents stipulated in Paragraph 3 of the preceding article shall have the relevant members of the function provide necessary cooperation to a core organization supervising or supposed to supervise the disputes, etc., so that adequate responses can be made to such disputes, etc. Chapter 6 Centralized Management of Function Standards and Self-Inspection Article 14 (Centralized Management of Function Standards) When Function Standards are enacted or revised by a core organization, the copies Confidential - Subject to Protective Order TAKJ-TPC-00000256 Source: https://www.indup237/8-00005ts.ucsf.edu/docs/jpjf0226 shall be sent to Administrative Legal Affairs, Legal Department. (2) Upon receiving the Function Standards, as stipulated in the preceding paragraph, Administrative Legal Affairs, Legal Department shall confirm the maintenance status, and check the appropriateness of the contents, as required. In the confirmation efforts, it may seek necessary assistance from Corporate Strategy & Planning Department or Intellectual Property Department. (3) Senior Vice President, Legal Department may provide each core organization with necessary advice on the Function Standards, based on the results of confirmation, etc. mentioned in the preceding paragraph. Such advice shall be duly respected by each core organization. Article 15 (Self-Inspection) The responsible person in charge of storage shall have the person in charge of storage conduct regular self-inspection to confirm that documents are properly managed in accordance with this Policy and Function Standards. Supplementary Provisions Article 1 The Function Standards, as stipulated in Paragraph 2, Article 2 of this Policy shall be properly prepared and finalized by September 30, 2010. Article 2 Article 1 and this article of the Supplementary Provisions shall be deleted as of October 1, 2010. Approval by Enacted : April 1, 1955 President Implemented : June 1, 1955 Confidential - Subject to Protective Order TAKJ-TPC-00000257 Source: https://www.indup2378-00006ts.ucsf.edu/docs/jpjf0226 Name of Company Regulation Policy on Document Control Revision Date Implementation Date Revision Date Implementation Date April 1, 2004 April 1, 2004 May 19, 2006 April 1, 2006 February 1, 2010 February 1, 2010 Confidential - Subject to Protective Order TAKJ-TPC-00000258 Confidential - Subject to Protective Order TAKJ-TPC-00000259 Source:

Semi exclusive rights in how many countries?

trjf0226

trjf0226_p0, trjf0226_p1, trjf0226_p2, trjf0226_p3, trjf0226_p4, trjf0226_p5

20, 20 countries

EXHIBIT ROW - Contract (Not 7/19/99) 81 Project Cat Update Discussion with Jim Harper July 19, 1999 Agenda Il Status of negotiations with Takeda Il Review of major contract terms Overview of Outstanding Issues Product Liability Affiliate Definition 1 Summary of Project Valuation Discussion of Next Steps 1 Confidential - Subject to Protective Order LLY-RANSOM-00002623 Source: Summary of Terms for OUS Agreement License Exclusive rights in approximately 60 countries Semi exclusive rights in approximately 20 countries Upfront Fee $20 million signing fee with $5 million credible to Major Europe (Germany, $2.0m; UK, $1.25; France, $1.0m; Italy, $0.75m) Supply Price / Royalty Rate 30% supply price Royalty schedule (based on half year sales) Royalty Rate Year 1-3 Tiers Year 4 onward Tiers 5% $0 $85m $0 $170m 8% $85m $110m $170m - $220m 14% >$110m >220m Free Goods Year Commercial Free Goods Year 1 100% 30% Year 2 100% 20% Year 3 100% 10% Overview of Major Contract Terms Product Liability 80(Lilly)/20 sharing of Serious Adverse Events Takeda Cap at $20Million Minimum Sales 20% of Lowest Teir ($68 Million) or 55% of rolling one year forecast Ability to lower obligation for significant event Affiliate Definition Attempting to agree on a proposal which prevents Takeda from creating local JV around ACTOS in EU Competing Product TZD or ISE which is a substitute for Pioglitazone License reverts to non-exclusive 2 Confidential - Subject to Protective Order LLY-RANSOM-00002624 Source: https://www.indup5350.000021 ts.ucsf.edu/docs/trjf0226 Product Liability Overview Background Takeda's 30-year-old policy is not to share any product liability risk with its licensees. They consider that it is the licensee's business risk. Their policy resulted from significant product liability losses in the past. Takeda Concessions: Full responsibility for claims resulting from manufacturing defects. Full responsibility for claims that Lilly could have prevented if given appropriate data and information (failure to provide or errors). Full responsibility for claims relating to product sold by Takeda, its affiliates or licensees in semi-exclusive or markets entered by Takeda Shared responsibility for claims relating to serious adverse events. Sharing Proposal For serious adverse events not attributable to acts of either party, costs to be shared on an 80/20 basis (Lilly/Takeda) up to a maximum of $20MM for Takeda. Factors which Limit Pioglitazone's Product Liability Risk OUS Clean Safety Profile Nearly one year of US experience prior to first OUS launch Lilly's OUS Markets are historically not litigious Takeda sharing risk Product liability risk is significantly minimized 3 Confidential - Subject to Protective Order LLY-RANSOM-00002625 Source: https://www.indup5350.00003 ts.ucsf.edu/docs/trjf0226 Most Significant Adverse Events Risks for Pioglitazone Risk Onset Reversibility Clinical Findings Occurrence of ALT Elevation Within Only through Drug Placebo Liver Failure 12 months Transplant Rezulin 1,7% 0.7% ACTOS 0.26% 0.25% Avandia 0.20% 0.20% Cardiac Hypertrophy Unknown Unknown Observed during Preclinical Studies in Rats No cases in Humans Unknown Observed during Bladder Cancer Unknown Preclinical Studies in Rats No cases in Humans Within Yes Occurrence of Edema Edema 12 months Drug Placebo ACTOS 15.3% 7.0% Summary of Litigation Risk in the OUS Territories Out of 10,359 claims on the Litigation Support System database, only 10 claims have arose from the Territory in this Agreement: Country All Claims Drug Claims Australia 5 3 Saudi Arabia 1 1 South Africa 2 0 Spain 1 0 Sweden 1 1 Total 10 5 4 Confidential - Subject to Protective Order LLY-RANSOM-00002626 Source: https://www.indup5350-00004ts.ucsf.edu/docs/trjf0226 ******** Overview of Major Contract Terms Promotional Samples At Cost New Indications/Line Extension Takeda must offer to Lilly If Lilly agrees, then cost sharing based on expected benefit If Lilly disagrees, Takeda / Lilly agree on any damages due Lilly Promotional Trials Data Usage Both parties can gain access to each others trial data Split of 70/30 (Lilly in Exclusive) 50/50 in Semi-exclusive Sub-license Right to sub-license with Takeda's consent Floor Supply Price $0.17 / 30mg or Takeda's Cost from site of lowest cost Overview of Major Contract Terms Termination Right to terminate in specific markets if significant events occur Generic Entry Adjustment 50% royalty adjustment if generic enters the market and causes sales decline of 25% Intellectual Property Takeda owns all 5 Confidential - Subject to Protective Order LLY-RANSOM-00002627 Source: https://www.indup5350-00005ts.ucsf.edu/docs/trjf0226 ACTOS Sales Forecast versus Minimum Sales Comparison European Agreement $300,000,000 Pioglitazone $250,000,000 Sales Forecast $200,000,000 $150,000,000 $100,000,000 Minimum Sales Level $50,000,000 $0 2000 2001 2002 2003 2004 2005 2006 2007 Minimum Sales N/A N/A 41% 52% 37% 30% 26% 25% to Sales Forecast Ratio Potential Value of Actos™ to Lilly OUS, NPV US$ Millions the OEU Spain E. Europe Asia 1) Can./Mex. Total Peak Sales $85 $60 $85 $50 $70 $350 (2007) 12 Assomes that Takeda will enter Spanish market in 2003 and that they wit not enter any other exclusive market 1) Assumes terms to exclusive markets in EU and intercontimental 6 Confidential - Subject to Protective Order LLY-RANSOM-00002628 Source: https://www.indup5350-00006 ts.ucsf.edu/docs/trjf0226

what is the title of chapter 2?

jpjf0226

jpjf0226_p1, jpjf0226_p2, jpjf0226_p3, jpjf0226_p4, jpjf0226_p5, jpjf0226_p6, jpjf0226_p7

document storage functions, DOCUMENT STORAGE FUNCTIONS

3) Other places designated by the relevant core organizations 4. "Responsible person in charge of storage" shall mean the responsible person in charge of a core organization. 5. "Person in charge of storage" shall mean a person in the "Line Position" or the "Quasi-Line Position", as stipulated from Article 411 through Article 422 of the Business Organization Rule, appointed by the responsible person in charge of storage. Article 4 (Principles of Creating Documents) Clerical operations shall be performed, in principle, based on documents. However, efforts shall be made to minimize the amount of documents to be created. Chapter 2 Document Storage Functions Article 5 (Principles concerning Document Storage Functions ) In principle, for documents created internally, the document storage functions shall be the core organizations in charge of the creation; and for those created externally, the core organizations that have received the documents shall be the document storage functions, However, in the case of documents created internally, if the receiving core organizations are designated to store the documents, as stipulated by laws, regulations or Company Regulations, the receiving core organizations shall be the document storage function. (2) Notwithstanding the preceding paragraph, materials for the agenda of the Board of Directors and Management and Operations Committee, and other conferences, shall be stored at the core organizations functioning as the secretariats for the conferences. (3) Documents shall be, in principle, centrally stored at the document storage functions. In other words, functions other than the document storage functions shall not store the relevant documents, and shall thus dispose of any documents promptly after they are no longer necessary (delete any electromagnetic records; the same shall apply to the rest of this Policy). Article 6 (Duties of Responsible Person in Charge of Storage and Person in Charge of Storage) The responsible person in charge of storage shall have the person in charge of storage properly store, and dispose of, any stored documents in the relevant core organization, and ensure that any relevant subordinates observe this Policy and the Function Standards. Confidential - Subject to Protective Order TAKJ-TPC-00000253 Source: https://www.indup2378-00002ts.ucsf.edu/docs/jpjf0226 (2) The person in charge of storage shall properly store, and dispose of, any stored documents assigned, and properly store any records relevant to those storage and disposal. (3) In case the document storage functions are reorganized or abolished due to organizational changes, etc., the core organizations taking over the document-related operations shall continue to store the documents and retain the disposal records. Chapter 3 Document Storage Period Article 7 (Document Storage Period) The responsible person in charge of storage shall establish storage periods for different types of assigned documents, by checking opinions of the relevant internal functions, if necessary, and distinguish and designate the periods, in principle, as indicated below. However, if the storage periods are specified by laws, regulations or Company Regulations, they shall be established in compliance with those laws, regulations and Company Regulations. The starting point for determining a storage period shall be, in principle, the date on which the document is created. 1. To be stored permanently 2. To be stored for ten years 3. To be stored for seyen years 4. To be stored for five years 5. To be stored for three years 6. To be stored for one year 7. To be stored for less than one year (to be disposed of promptly after use) (2) If a document turns out not to be categorized into any document types designated for specified storage periods, the responsible person in charge of storage shall establish a storage period for the new document type, as stipulated in the preceding paragraph. (3) Concerning the provisions set forth in Paragraph 1 above, the following documents shall be stored permanently. 1. Articles of Incorporation and Company Regulations 2. Important documents concerning the General Meetings of Shareholders, the Board of Directors, the Management and Operations Committee, and other important conferences. 3. Important documents concerning mid/long-range management policies and plans 4. Important documents concerning the Company's rights and duties, including important contracts, lawsuits, registrations, etc. 5. Important documents concerning budgets, account settlements, and other Confidential $ Subject to Protective Order TAKJ-TPC-00000254 Source: https://www.indup2378-00003ts.ucsf.edu/docs/jpjf0226 accounting affairs 6. Important documents concerning personnel affairs, salaries, and labor management, etc. 7, Important documents concerning research/development and manufacturing 8. Other documents deemed to require permanent storage Chapter 4 Document Storage Methods, etc. Article 8 (Starting Document Storage) A member of the document storage function shall start storage of each document for the storage period established for the specified document type in the function. Article 9 (Document Storage Methods) Unless otherwise stipulated by laws and regulations, etc., document storage functions shall store, in principle, originals of the documents. However, if counterparts or copies need to be stored because the originals have already been delivered or because of the other reasons, the counterparts or copies shall be stored. (2) Unless otherwise stipulated by laws and regulations, etc., document storage functions shall store documents, in principle, in paper-based formats (printouts for electromagnetic records). However, if necessary for operational purposes, electromagnetic records may be stored as they are. Article 10 (Document Storage Place) Documents to be retained shall be stored properly at places specified in Item 3, Article 3. Except for those not supposed to be shared to protect confidentiality, and those still under development, the documents should not be stored in individual workers' desks or PCs. Article 11 (Handling of Documents the Storage Periods of Which Have Expired) When document storage periods expire, the document storage functions shall promptly dispose of the documents after obtaining approvals from the person in charge of storage. However, this provision shall not apply to cases in which the storage periods are extended by the responsible person in charge of storage in the function, who considers that the storage needs to be continued and establishes the extended storage periods. (2) After disposing of any stored documents or having them properly disposed of, the person in charge of storage stipulated in the preceding paragraph shall compile the Confidential - Subject to Protective Order TAKJ-TPC-00000255 Source: https://www.indup378-00004ts.ucsf.edu/docs/jpjf0226 disposal records (specifying the titles of the documents, disposal date/time, disposal methods, and names of persons who have disposed of the documents). The disposal records themselves shall be stored permanently. Chapter 5 Exceptions, etc. for Responding to disputes, etc. Article 12 (Requesting Document Storage) If disputes, etc. involving the Company have taken place, or may take place, and if the responsible person in charge of a core organization supervising or supposed to supervise the disputes, etc., or his/her appointee, requests the responsible person in charge of storage or the person in charge of storage within the core organization involved in the disputes, etc., to take necessary actions for storage, etc. of the documents relating to the disputes, etc., in order to respond properly to such disputes, etc., the contents of the requests shall prevail over the provisions of the preceding articles or any provisions of the function standards. (2) The responsible person in charge of storage or the person in charge of storage in a core organization, requested as in the preceding paragraph, shall ensure that the requests are thoroughly communicated to, and understood by, the relevant members of the organization, so that they can properly respond to the requests. (3) Irrespective of existence of any requests stipulated in Paragraph 1 above and notwithstanding the provisions of Paragraph 1 of the preceding article, documents relating to any disputes, etc. pending or in progress, involving the Company, shall not be disposed of. Article 13 (Cooperation from Other Functions) The responsible person in charge of storage or the person in charge of storage in a core organization that has received requests stipulated in Paragraph 1 of the preceding article, or the responsible person in charge of storage or the person in charge of storage in a core organization storing documents stipulated in Paragraph 3 of the preceding article shall have the relevant members of the function provide necessary cooperation to a core organization supervising or supposed to supervise the disputes, etc., so that adequate responses can be made to such disputes, etc. Chapter 6 Centralized Management of Function Standards and Self-Inspection Article 14 (Centralized Management of Function Standards) When Function Standards are enacted or revised by a core organization, the copies Confidential - Subject to Protective Order TAKJ-TPC-00000256 Source: https://www.indup237/8-00005ts.ucsf.edu/docs/jpjf0226 shall be sent to Administrative Legal Affairs, Legal Department. (2) Upon receiving the Function Standards, as stipulated in the preceding paragraph, Administrative Legal Affairs, Legal Department shall confirm the maintenance status, and check the appropriateness of the contents, as required. In the confirmation efforts, it may seek necessary assistance from Corporate Strategy & Planning Department or Intellectual Property Department. (3) Senior Vice President, Legal Department may provide each core organization with necessary advice on the Function Standards, based on the results of confirmation, etc. mentioned in the preceding paragraph. Such advice shall be duly respected by each core organization. Article 15 (Self-Inspection) The responsible person in charge of storage shall have the person in charge of storage conduct regular self-inspection to confirm that documents are properly managed in accordance with this Policy and Function Standards. Supplementary Provisions Article 1 The Function Standards, as stipulated in Paragraph 2, Article 2 of this Policy shall be properly prepared and finalized by September 30, 2010. Article 2 Article 1 and this article of the Supplementary Provisions shall be deleted as of October 1, 2010. Approval by Enacted : April 1, 1955 President Implemented : June 1, 1955 Confidential - Subject to Protective Order TAKJ-TPC-00000257 Source: https://www.indup2378-00006ts.ucsf.edu/docs/jpjf0226 Name of Company Regulation Policy on Document Control Revision Date Implementation Date Revision Date Implementation Date April 1, 2004 April 1, 2004 May 19, 2006 April 1, 2006 February 1, 2010 February 1, 2010 Confidential - Subject to Protective Order TAKJ-TPC-00000258 Confidential - Subject to Protective Order TAKJ-TPC-00000259 Source:

What percent is the Supply Price / Royalty Rate?

trjf0226

trjf0226_p0, trjf0226_p1, trjf0226_p2, trjf0226_p3, trjf0226_p4, trjf0226_p5

30% supply price, 30% SUPPLY PRICE

EXHIBIT ROW - Contract (Not 7/19/99) 81 Project Cat Update Discussion with Jim Harper July 19, 1999 Agenda Il Status of negotiations with Takeda Il Review of major contract terms Overview of Outstanding Issues Product Liability Affiliate Definition 1 Summary of Project Valuation Discussion of Next Steps 1 Confidential - Subject to Protective Order LLY-RANSOM-00002623 Source: Summary of Terms for OUS Agreement License Exclusive rights in approximately 60 countries Semi exclusive rights in approximately 20 countries Upfront Fee $20 million signing fee with $5 million credible to Major Europe (Germany, $2.0m; UK, $1.25; France, $1.0m; Italy, $0.75m) Supply Price / Royalty Rate 30% supply price Royalty schedule (based on half year sales) Royalty Rate Year 1-3 Tiers Year 4 onward Tiers 5% $0 $85m $0 $170m 8% $85m $110m $170m - $220m 14% >$110m >220m Free Goods Year Commercial Free Goods Year 1 100% 30% Year 2 100% 20% Year 3 100% 10% Overview of Major Contract Terms Product Liability 80(Lilly)/20 sharing of Serious Adverse Events Takeda Cap at $20Million Minimum Sales 20% of Lowest Teir ($68 Million) or 55% of rolling one year forecast Ability to lower obligation for significant event Affiliate Definition Attempting to agree on a proposal which prevents Takeda from creating local JV around ACTOS in EU Competing Product TZD or ISE which is a substitute for Pioglitazone License reverts to non-exclusive 2 Confidential - Subject to Protective Order LLY-RANSOM-00002624 Source: https://www.indup5350.000021 ts.ucsf.edu/docs/trjf0226 Product Liability Overview Background Takeda's 30-year-old policy is not to share any product liability risk with its licensees. They consider that it is the licensee's business risk. Their policy resulted from significant product liability losses in the past. Takeda Concessions: Full responsibility for claims resulting from manufacturing defects. Full responsibility for claims that Lilly could have prevented if given appropriate data and information (failure to provide or errors). Full responsibility for claims relating to product sold by Takeda, its affiliates or licensees in semi-exclusive or markets entered by Takeda Shared responsibility for claims relating to serious adverse events. Sharing Proposal For serious adverse events not attributable to acts of either party, costs to be shared on an 80/20 basis (Lilly/Takeda) up to a maximum of $20MM for Takeda. Factors which Limit Pioglitazone's Product Liability Risk OUS Clean Safety Profile Nearly one year of US experience prior to first OUS launch Lilly's OUS Markets are historically not litigious Takeda sharing risk Product liability risk is significantly minimized 3 Confidential - Subject to Protective Order LLY-RANSOM-00002625 Source: https://www.indup5350.00003 ts.ucsf.edu/docs/trjf0226 Most Significant Adverse Events Risks for Pioglitazone Risk Onset Reversibility Clinical Findings Occurrence of ALT Elevation Within Only through Drug Placebo Liver Failure 12 months Transplant Rezulin 1,7% 0.7% ACTOS 0.26% 0.25% Avandia 0.20% 0.20% Cardiac Hypertrophy Unknown Unknown Observed during Preclinical Studies in Rats No cases in Humans Unknown Observed during Bladder Cancer Unknown Preclinical Studies in Rats No cases in Humans Within Yes Occurrence of Edema Edema 12 months Drug Placebo ACTOS 15.3% 7.0% Summary of Litigation Risk in the OUS Territories Out of 10,359 claims on the Litigation Support System database, only 10 claims have arose from the Territory in this Agreement: Country All Claims Drug Claims Australia 5 3 Saudi Arabia 1 1 South Africa 2 0 Spain 1 0 Sweden 1 1 Total 10 5 4 Confidential - Subject to Protective Order LLY-RANSOM-00002626 Source: https://www.indup5350-00004ts.ucsf.edu/docs/trjf0226 ******** Overview of Major Contract Terms Promotional Samples At Cost New Indications/Line Extension Takeda must offer to Lilly If Lilly agrees, then cost sharing based on expected benefit If Lilly disagrees, Takeda / Lilly agree on any damages due Lilly Promotional Trials Data Usage Both parties can gain access to each others trial data Split of 70/30 (Lilly in Exclusive) 50/50 in Semi-exclusive Sub-license Right to sub-license with Takeda's consent Floor Supply Price $0.17 / 30mg or Takeda's Cost from site of lowest cost Overview of Major Contract Terms Termination Right to terminate in specific markets if significant events occur Generic Entry Adjustment 50% royalty adjustment if generic enters the market and causes sales decline of 25% Intellectual Property Takeda owns all 5 Confidential - Subject to Protective Order LLY-RANSOM-00002627 Source: https://www.indup5350-00005ts.ucsf.edu/docs/trjf0226 ACTOS Sales Forecast versus Minimum Sales Comparison European Agreement $300,000,000 Pioglitazone $250,000,000 Sales Forecast $200,000,000 $150,000,000 $100,000,000 Minimum Sales Level $50,000,000 $0 2000 2001 2002 2003 2004 2005 2006 2007 Minimum Sales N/A N/A 41% 52% 37% 30% 26% 25% to Sales Forecast Ratio Potential Value of Actos™ to Lilly OUS, NPV US$ Millions the OEU Spain E. Europe Asia 1) Can./Mex. Total Peak Sales $85 $60 $85 $50 $70 $350 (2007) 12 Assomes that Takeda will enter Spanish market in 2003 and that they wit not enter any other exclusive market 1) Assumes terms to exclusive markets in EU and intercontimental 6 Confidential - Subject to Protective Order LLY-RANSOM-00002628 Source: https://www.indup5350-00006 ts.ucsf.edu/docs/trjf0226

what is article 6?

jpjf0226

jpjf0226_p1, jpjf0226_p2, jpjf0226_p3, jpjf0226_p4, jpjf0226_p5, jpjf0226_p6, jpjf0226_p7

duties of responsible person in charge of storage and person in charge of storage, DUTIES OF RESPONSIBLE PERSON IN CHARGE OF STORAGE AND PERSON IN CHARGE OF STORAGE, (DUTIES OF RESPONSIBLE PERSON IN CHARGE OF STORAGE AND PERSON IN CHARGE OF STORAGE)

3) Other places designated by the relevant core organizations 4. "Responsible person in charge of storage" shall mean the responsible person in charge of a core organization. 5. "Person in charge of storage" shall mean a person in the "Line Position" or the "Quasi-Line Position", as stipulated from Article 411 through Article 422 of the Business Organization Rule, appointed by the responsible person in charge of storage. Article 4 (Principles of Creating Documents) Clerical operations shall be performed, in principle, based on documents. However, efforts shall be made to minimize the amount of documents to be created. Chapter 2 Document Storage Functions Article 5 (Principles concerning Document Storage Functions ) In principle, for documents created internally, the document storage functions shall be the core organizations in charge of the creation; and for those created externally, the core organizations that have received the documents shall be the document storage functions, However, in the case of documents created internally, if the receiving core organizations are designated to store the documents, as stipulated by laws, regulations or Company Regulations, the receiving core organizations shall be the document storage function. (2) Notwithstanding the preceding paragraph, materials for the agenda of the Board of Directors and Management and Operations Committee, and other conferences, shall be stored at the core organizations functioning as the secretariats for the conferences. (3) Documents shall be, in principle, centrally stored at the document storage functions. In other words, functions other than the document storage functions shall not store the relevant documents, and shall thus dispose of any documents promptly after they are no longer necessary (delete any electromagnetic records; the same shall apply to the rest of this Policy). Article 6 (Duties of Responsible Person in Charge of Storage and Person in Charge of Storage) The responsible person in charge of storage shall have the person in charge of storage properly store, and dispose of, any stored documents in the relevant core organization, and ensure that any relevant subordinates observe this Policy and the Function Standards. Confidential - Subject to Protective Order TAKJ-TPC-00000253 Source: https://www.indup2378-00002ts.ucsf.edu/docs/jpjf0226 (2) The person in charge of storage shall properly store, and dispose of, any stored documents assigned, and properly store any records relevant to those storage and disposal. (3) In case the document storage functions are reorganized or abolished due to organizational changes, etc., the core organizations taking over the document-related operations shall continue to store the documents and retain the disposal records. Chapter 3 Document Storage Period Article 7 (Document Storage Period) The responsible person in charge of storage shall establish storage periods for different types of assigned documents, by checking opinions of the relevant internal functions, if necessary, and distinguish and designate the periods, in principle, as indicated below. However, if the storage periods are specified by laws, regulations or Company Regulations, they shall be established in compliance with those laws, regulations and Company Regulations. The starting point for determining a storage period shall be, in principle, the date on which the document is created. 1. To be stored permanently 2. To be stored for ten years 3. To be stored for seyen years 4. To be stored for five years 5. To be stored for three years 6. To be stored for one year 7. To be stored for less than one year (to be disposed of promptly after use) (2) If a document turns out not to be categorized into any document types designated for specified storage periods, the responsible person in charge of storage shall establish a storage period for the new document type, as stipulated in the preceding paragraph. (3) Concerning the provisions set forth in Paragraph 1 above, the following documents shall be stored permanently. 1. Articles of Incorporation and Company Regulations 2. Important documents concerning the General Meetings of Shareholders, the Board of Directors, the Management and Operations Committee, and other important conferences. 3. Important documents concerning mid/long-range management policies and plans 4. Important documents concerning the Company's rights and duties, including important contracts, lawsuits, registrations, etc. 5. Important documents concerning budgets, account settlements, and other Confidential $ Subject to Protective Order TAKJ-TPC-00000254 Source: https://www.indup2378-00003ts.ucsf.edu/docs/jpjf0226 accounting affairs 6. Important documents concerning personnel affairs, salaries, and labor management, etc. 7, Important documents concerning research/development and manufacturing 8. Other documents deemed to require permanent storage Chapter 4 Document Storage Methods, etc. Article 8 (Starting Document Storage) A member of the document storage function shall start storage of each document for the storage period established for the specified document type in the function. Article 9 (Document Storage Methods) Unless otherwise stipulated by laws and regulations, etc., document storage functions shall store, in principle, originals of the documents. However, if counterparts or copies need to be stored because the originals have already been delivered or because of the other reasons, the counterparts or copies shall be stored. (2) Unless otherwise stipulated by laws and regulations, etc., document storage functions shall store documents, in principle, in paper-based formats (printouts for electromagnetic records). However, if necessary for operational purposes, electromagnetic records may be stored as they are. Article 10 (Document Storage Place) Documents to be retained shall be stored properly at places specified in Item 3, Article 3. Except for those not supposed to be shared to protect confidentiality, and those still under development, the documents should not be stored in individual workers' desks or PCs. Article 11 (Handling of Documents the Storage Periods of Which Have Expired) When document storage periods expire, the document storage functions shall promptly dispose of the documents after obtaining approvals from the person in charge of storage. However, this provision shall not apply to cases in which the storage periods are extended by the responsible person in charge of storage in the function, who considers that the storage needs to be continued and establishes the extended storage periods. (2) After disposing of any stored documents or having them properly disposed of, the person in charge of storage stipulated in the preceding paragraph shall compile the Confidential - Subject to Protective Order TAKJ-TPC-00000255 Source: https://www.indup378-00004ts.ucsf.edu/docs/jpjf0226 disposal records (specifying the titles of the documents, disposal date/time, disposal methods, and names of persons who have disposed of the documents). The disposal records themselves shall be stored permanently. Chapter 5 Exceptions, etc. for Responding to disputes, etc. Article 12 (Requesting Document Storage) If disputes, etc. involving the Company have taken place, or may take place, and if the responsible person in charge of a core organization supervising or supposed to supervise the disputes, etc., or his/her appointee, requests the responsible person in charge of storage or the person in charge of storage within the core organization involved in the disputes, etc., to take necessary actions for storage, etc. of the documents relating to the disputes, etc., in order to respond properly to such disputes, etc., the contents of the requests shall prevail over the provisions of the preceding articles or any provisions of the function standards. (2) The responsible person in charge of storage or the person in charge of storage in a core organization, requested as in the preceding paragraph, shall ensure that the requests are thoroughly communicated to, and understood by, the relevant members of the organization, so that they can properly respond to the requests. (3) Irrespective of existence of any requests stipulated in Paragraph 1 above and notwithstanding the provisions of Paragraph 1 of the preceding article, documents relating to any disputes, etc. pending or in progress, involving the Company, shall not be disposed of. Article 13 (Cooperation from Other Functions) The responsible person in charge of storage or the person in charge of storage in a core organization that has received requests stipulated in Paragraph 1 of the preceding article, or the responsible person in charge of storage or the person in charge of storage in a core organization storing documents stipulated in Paragraph 3 of the preceding article shall have the relevant members of the function provide necessary cooperation to a core organization supervising or supposed to supervise the disputes, etc., so that adequate responses can be made to such disputes, etc. Chapter 6 Centralized Management of Function Standards and Self-Inspection Article 14 (Centralized Management of Function Standards) When Function Standards are enacted or revised by a core organization, the copies Confidential - Subject to Protective Order TAKJ-TPC-00000256 Source: https://www.indup237/8-00005ts.ucsf.edu/docs/jpjf0226 shall be sent to Administrative Legal Affairs, Legal Department. (2) Upon receiving the Function Standards, as stipulated in the preceding paragraph, Administrative Legal Affairs, Legal Department shall confirm the maintenance status, and check the appropriateness of the contents, as required. In the confirmation efforts, it may seek necessary assistance from Corporate Strategy & Planning Department or Intellectual Property Department. (3) Senior Vice President, Legal Department may provide each core organization with necessary advice on the Function Standards, based on the results of confirmation, etc. mentioned in the preceding paragraph. Such advice shall be duly respected by each core organization. Article 15 (Self-Inspection) The responsible person in charge of storage shall have the person in charge of storage conduct regular self-inspection to confirm that documents are properly managed in accordance with this Policy and Function Standards. Supplementary Provisions Article 1 The Function Standards, as stipulated in Paragraph 2, Article 2 of this Policy shall be properly prepared and finalized by September 30, 2010. Article 2 Article 1 and this article of the Supplementary Provisions shall be deleted as of October 1, 2010. Approval by Enacted : April 1, 1955 President Implemented : June 1, 1955 Confidential - Subject to Protective Order TAKJ-TPC-00000257 Source: https://www.indup2378-00006ts.ucsf.edu/docs/jpjf0226 Name of Company Regulation Policy on Document Control Revision Date Implementation Date Revision Date Implementation Date April 1, 2004 April 1, 2004 May 19, 2006 April 1, 2006 February 1, 2010 February 1, 2010 Confidential - Subject to Protective Order TAKJ-TPC-00000258 Confidential - Subject to Protective Order TAKJ-TPC-00000259 Source:

In how many countires, license to Exclusive rights are provided?

trjf0226

trjf0226_p0, trjf0226_p1, trjf0226_p2, trjf0226_p3, trjf0226_p4, trjf0226_p5

60 COUNTRIES, in approximately 60 countries, 60

EXHIBIT ROW - Contract (Not 7/19/99) 81 Project Cat Update Discussion with Jim Harper July 19, 1999 Agenda Il Status of negotiations with Takeda Il Review of major contract terms Overview of Outstanding Issues Product Liability Affiliate Definition 1 Summary of Project Valuation Discussion of Next Steps 1 Confidential - Subject to Protective Order LLY-RANSOM-00002623 Source: Summary of Terms for OUS Agreement License Exclusive rights in approximately 60 countries Semi exclusive rights in approximately 20 countries Upfront Fee $20 million signing fee with $5 million credible to Major Europe (Germany, $2.0m; UK, $1.25; France, $1.0m; Italy, $0.75m) Supply Price / Royalty Rate 30% supply price Royalty schedule (based on half year sales) Royalty Rate Year 1-3 Tiers Year 4 onward Tiers 5% $0 $85m $0 $170m 8% $85m $110m $170m - $220m 14% >$110m >220m Free Goods Year Commercial Free Goods Year 1 100% 30% Year 2 100% 20% Year 3 100% 10% Overview of Major Contract Terms Product Liability 80(Lilly)/20 sharing of Serious Adverse Events Takeda Cap at $20Million Minimum Sales 20% of Lowest Teir ($68 Million) or 55% of rolling one year forecast Ability to lower obligation for significant event Affiliate Definition Attempting to agree on a proposal which prevents Takeda from creating local JV around ACTOS in EU Competing Product TZD or ISE which is a substitute for Pioglitazone License reverts to non-exclusive 2 Confidential - Subject to Protective Order LLY-RANSOM-00002624 Source: https://www.indup5350.000021 ts.ucsf.edu/docs/trjf0226 Product Liability Overview Background Takeda's 30-year-old policy is not to share any product liability risk with its licensees. They consider that it is the licensee's business risk. Their policy resulted from significant product liability losses in the past. Takeda Concessions: Full responsibility for claims resulting from manufacturing defects. Full responsibility for claims that Lilly could have prevented if given appropriate data and information (failure to provide or errors). Full responsibility for claims relating to product sold by Takeda, its affiliates or licensees in semi-exclusive or markets entered by Takeda Shared responsibility for claims relating to serious adverse events. Sharing Proposal For serious adverse events not attributable to acts of either party, costs to be shared on an 80/20 basis (Lilly/Takeda) up to a maximum of $20MM for Takeda. Factors which Limit Pioglitazone's Product Liability Risk OUS Clean Safety Profile Nearly one year of US experience prior to first OUS launch Lilly's OUS Markets are historically not litigious Takeda sharing risk Product liability risk is significantly minimized 3 Confidential - Subject to Protective Order LLY-RANSOM-00002625 Source: https://www.indup5350.00003 ts.ucsf.edu/docs/trjf0226 Most Significant Adverse Events Risks for Pioglitazone Risk Onset Reversibility Clinical Findings Occurrence of ALT Elevation Within Only through Drug Placebo Liver Failure 12 months Transplant Rezulin 1,7% 0.7% ACTOS 0.26% 0.25% Avandia 0.20% 0.20% Cardiac Hypertrophy Unknown Unknown Observed during Preclinical Studies in Rats No cases in Humans Unknown Observed during Bladder Cancer Unknown Preclinical Studies in Rats No cases in Humans Within Yes Occurrence of Edema Edema 12 months Drug Placebo ACTOS 15.3% 7.0% Summary of Litigation Risk in the OUS Territories Out of 10,359 claims on the Litigation Support System database, only 10 claims have arose from the Territory in this Agreement: Country All Claims Drug Claims Australia 5 3 Saudi Arabia 1 1 South Africa 2 0 Spain 1 0 Sweden 1 1 Total 10 5 4 Confidential - Subject to Protective Order LLY-RANSOM-00002626 Source: https://www.indup5350-00004ts.ucsf.edu/docs/trjf0226 ******** Overview of Major Contract Terms Promotional Samples At Cost New Indications/Line Extension Takeda must offer to Lilly If Lilly agrees, then cost sharing based on expected benefit If Lilly disagrees, Takeda / Lilly agree on any damages due Lilly Promotional Trials Data Usage Both parties can gain access to each others trial data Split of 70/30 (Lilly in Exclusive) 50/50 in Semi-exclusive Sub-license Right to sub-license with Takeda's consent Floor Supply Price $0.17 / 30mg or Takeda's Cost from site of lowest cost Overview of Major Contract Terms Termination Right to terminate in specific markets if significant events occur Generic Entry Adjustment 50% royalty adjustment if generic enters the market and causes sales decline of 25% Intellectual Property Takeda owns all 5 Confidential - Subject to Protective Order LLY-RANSOM-00002627 Source: https://www.indup5350-00005ts.ucsf.edu/docs/trjf0226 ACTOS Sales Forecast versus Minimum Sales Comparison European Agreement $300,000,000 Pioglitazone $250,000,000 Sales Forecast $200,000,000 $150,000,000 $100,000,000 Minimum Sales Level $50,000,000 $0 2000 2001 2002 2003 2004 2005 2006 2007 Minimum Sales N/A N/A 41% 52% 37% 30% 26% 25% to Sales Forecast Ratio Potential Value of Actos™ to Lilly OUS, NPV US$ Millions the OEU Spain E. Europe Asia 1) Can./Mex. Total Peak Sales $85 $60 $85 $50 $70 $350 (2007) 12 Assomes that Takeda will enter Spanish market in 2003 and that they wit not enter any other exclusive market 1) Assumes terms to exclusive markets in EU and intercontimental 6 Confidential - Subject to Protective Order LLY-RANSOM-00002628 Source: https://www.indup5350-00006 ts.ucsf.edu/docs/trjf0226

what is the name of pediatric program?

jfkf0226

jfkf0226_p0, jfkf0226_p1, jfkf0226_p2, jfkf0226_p3

ACTOS, ACTOS PEDIATRIC PROGRAM

ACTOS Pediatric Program 5 October 2006 P7327-00001 Source: https://www.industrydocuments.ucsf.edu/docs/jfkf0226 Overview of November 2006 Submission 0 Partial clinical hold removal request document: Summary document (Includes benefit- risk assessment) Meta-analysis report Kaiser first cohort report New epidemiology report(s) Executive summary of bladder cancer cases - CONFIRM P7327-00002 Source: https://wwww.industrydocuments.ucsf.edu/docs/jfkf0226 Overview of November 2006 Submission 0 PPSR (Proposed Pediatric Study Request) NEED TO CONFIRM FORMAT Clinical study synopsis P7327-00003 Source: https://www.industrydocuments.ucsf.edu/docs/jfkf0226 Clinical Study Synopsis 01-06-TL-OPI-527 Expert advisory meeting 4 October 2006 Draft synopsis available for team review on Monday, 9 October 2006 Team proposing to review synopsis in TARC instead of SRC Need detailed timelines of full study by 20 October 2006 Need budget, delineating what may be spent in FY06, by 20 October 2006 P7327-00004 Source: https://www.industrydocuments.ucsf.edu/docs/jfkf0226

What is the date mentioned in this page?

jfkf0226

jfkf0226_p0, jfkf0226_p1, jfkf0226_p2, jfkf0226_p3

5 October 2006

ACTOS Pediatric Program 5 October 2006 P7327-00001 Source: https://www.industrydocuments.ucsf.edu/docs/jfkf0226 Overview of November 2006 Submission 0 Partial clinical hold removal request document: Summary document (Includes benefit- risk assessment) Meta-analysis report Kaiser first cohort report New epidemiology report(s) Executive summary of bladder cancer cases - CONFIRM P7327-00002 Source: https://wwww.industrydocuments.ucsf.edu/docs/jfkf0226 Overview of November 2006 Submission 0 PPSR (Proposed Pediatric Study Request) NEED TO CONFIRM FORMAT Clinical study synopsis P7327-00003 Source: https://www.industrydocuments.ucsf.edu/docs/jfkf0226 Clinical Study Synopsis 01-06-TL-OPI-527 Expert advisory meeting 4 October 2006 Draft synopsis available for team review on Monday, 9 October 2006 Team proposing to review synopsis in TARC instead of SRC Need detailed timelines of full study by 20 October 2006 Need budget, delineating what may be spent in FY06, by 20 October 2006 P7327-00004 Source: https://www.industrydocuments.ucsf.edu/docs/jfkf0226

What is the title of this page?

ynjf0226

ynjf0226_p15, ynjf0226_p16

Actos plan overview, ACTOS PLAN OVERVIEW

Evolving Data Safety Congestive Heart Failure Actos in patients with NYHA class I Label change? Actos in patients with NYHA class II/III Label change? ADA/AHA position paper on TZDs and CHF Liver Long term liver safety study Label change? Weight Gain and Edema IITs: Body composition, visceral VS. subcutaneous fat, mechanism of edema formation <AUTO> Confidential - Subject to Protective Order LLY-HOVENR-00001910 Produced in MDL on 02/27/13 Source: Actos Plan Overview Issues/Uncertainties Strategic Intent: Competitive Threats Establish Actos as the "best oral" anti-diabetic Avandamet 4/1000 medication in treating Insulin Resistance through New Merk PPAR (05) sustained glycemic control and reduced cardiovascular risk. Other Lilly Drugs Critical Success Factors TZD's are prescribed earlier in the treatment of Type 2 Diabetes Contract negotiations in progress Actos is the first TZD prescribed (vs. Avandia) for patients with Type 2 Diabetes. Strengths/Opportunities Key Priorities TL's believe TZDs will provide improved durability & Drive a thoughtful, robust, and coherent set of medical b-cell preservation and reduced CV risk studies to document the full benefits of ACTOS Supporting studies on TZDs are underway Keep opinion leaders at the cutting edge ACTOS has a superior lipid profile (v. Avandia and Fund CME and other initiatives that allow the opinion others) leaders to "spread the word" ahead of our evolving label New lipid standards place more importance on lipid claims management in diabetes Drive behavior change with physicians via our sales force. Pre-diabetes and DPP Results Keep managed care from being a barrier. Window of opportunity exists - no new TZD entrants to market until 2005. <AUTO> Confidential - Subject to Protective Order LLY-HOVENR-00001911 Produced in MDL on 02/27/13 Source:

which are prescibed eariler in the treatment of type 2 diabetes under the title of "critical success factors"?

ynjf0226

ynjf0226_p15, ynjf0226_p16

"TZDs", "TZDS"

Evolving Data Safety Congestive Heart Failure Actos in patients with NYHA class I Label change? Actos in patients with NYHA class II/III Label change? ADA/AHA position paper on TZDs and CHF Liver Long term liver safety study Label change? Weight Gain and Edema IITs: Body composition, visceral VS. subcutaneous fat, mechanism of edema formation <AUTO> Confidential - Subject to Protective Order LLY-HOVENR-00001910 Produced in MDL on 02/27/13 Source: Actos Plan Overview Issues/Uncertainties Strategic Intent: Competitive Threats Establish Actos as the "best oral" anti-diabetic Avandamet 4/1000 medication in treating Insulin Resistance through New Merk PPAR (05) sustained glycemic control and reduced cardiovascular risk. Other Lilly Drugs Critical Success Factors TZD's are prescribed earlier in the treatment of Type 2 Diabetes Contract negotiations in progress Actos is the first TZD prescribed (vs. Avandia) for patients with Type 2 Diabetes. Strengths/Opportunities Key Priorities TL's believe TZDs will provide improved durability & Drive a thoughtful, robust, and coherent set of medical b-cell preservation and reduced CV risk studies to document the full benefits of ACTOS Supporting studies on TZDs are underway Keep opinion leaders at the cutting edge ACTOS has a superior lipid profile (v. Avandia and Fund CME and other initiatives that allow the opinion others) leaders to "spread the word" ahead of our evolving label New lipid standards place more importance on lipid claims management in diabetes Drive behavior change with physicians via our sales force. Pre-diabetes and DPP Results Keep managed care from being a barrier. Window of opportunity exists - no new TZD entrants to market until 2005. <AUTO> Confidential - Subject to Protective Order LLY-HOVENR-00001911 Produced in MDL on 02/27/13 Source:

What is the Plan TZD Share for the year 2003?

ynjf0226

ynjf0226_p0, ynjf0226_p1, ynjf0226_p2, ynjf0226_p3, ynjf0226_p4, ynjf0226_p5, ynjf0226_p6, ynjf0226_p7, ynjf0226_p8, ynjf0226_p9, ynjf0226_p10, ynjf0226_p11, ynjf0226_p12

19.7%

Actos 2004 0 Marketing Plan Review DALY 12 Lilly Answers That Matter. Confidential - Subject to Protective Order LLY-HOVENR-00001895 Produced in MDL on 02/27/13 Source: Agenda OAD Market / IR Review Evolving Medical Data Overview Q&A Discussion <AUTO> Confidential - Subject to Protective Order LLY-HOVENR-00001896 Produced in MDL on 02/27/13 Source: TZD Share of Oral Market % Retail TRx Share 25% Forecast Actual 20% 15% 10% 5% 0% 2000 2001 2002 2003 2004 2005 TZDs TRx (000s) 10,577 14,681 17,101 19,466 21,480 22,191 Orals TRx (000s) 79,521 87,291 93,471 98,004 102,218 105,807 Oral Share (TZDs) 13.3% 16.8% 18.3% 19.9% 21.0% 21.0% Plan TZD Share 13.3% 16.8% 18.3% 19.7% 20.6% 20.6% Forecast as % of Plan n/a n/a n/a 100.8% 102.0% 101.8% <AUTO> Confidential -- Subject to Protective Order LLY-HOVENR-00001897 Produced in MDL on 02/27/13 Source: Actos Share of TZDs Retail TRx SOM, IMS Health 60.00% Actual Foreçast 50.00% 40.00% Launch of Launch of Merck's BMS' PPAR's 30.00% PPAR's Q3 2005 Feb 2005 20.00% 10.00% 0.00% 2000 2001 2002 2003 2004 2005 TZDs TRx (000s) 10,577 14,681 17,101 19,407 21,479 22,902 Actos TRx (000s) 4,261 6,872 8,582 9,497 10,149 10,472 TZD Share 40.3% 46.8% 50.2% 49.0% 47.3% 45.7% Plan TZD Share n/a n/a n/a 46.1% 42.9% Forecast as a % of Plan n/a n/a n/a 106.3% 110.1% <AUTO> Confidential - Subject to Protective Order LLY-HOVENR-00001898 Produced in MDL on 02/27/13 Avandamet Uptake Retail TRx (000s), IMS Health TRx (000s) Assumes 36% of Avandamet scripts from Actos 500 Glucovance 450 400 350 Avandamet 300 Forecast 250 200 150 Avandamet at 31% of original 100 forecast. 50 Avandamet 0 1 2 3 4 5 6 7 8 9 10 11 12 13 15 Full Months Post Launch <AUTO> Confidential - Subject to Protective Order LLY-HOVENR-00001899 Produced in MDL on 02/27/13 Source: Consequences of IR Damage to Eyes Damage to Kidneys TG HDL-C LDL-C Damage to Nerves Increased CV Risk Increased CV Risk Hyperglycemia Dyslipidemia Insulin Resistance Central Hypertension Obesity Increased CV Risk Increased CV Risk <AUTO> Confidential - Subject to Protective Order LLY-HOVENR-00001900 Produced in MDL on 02/27/13 Source: Link between IR and CVD THE ROUTE TO CARDIOVASCULAR DISEASE 2.11.15-19 Hyperglycemia Insulin Hyper a path that leads to increased risk for MI Resistance Dys TYPE 2 DIABETES EQUALS PRIOR MI AS A CHD RISK FACTOR Pr S 7-year incidence of myocardial infarction (MI) (%) 25% 20% 15% 18.8% 20.2% 10% 5% 0% Nondiabetic patients Type 2 diabetics with prior MI without prior MI <AUTO> Confidential - Subject to Protective Order LLY-HOVENR-00001901 Produced in MDL on 02/27/13 Source: It is important to engage your customer in dialogue around IR, symptoms, and complications. This Map is a critical tool to help you explain the link of insulin resistance and Cardiovascular risk. Confidential - Subject to Protective Order LLY-HOVENR-00001902 Produced in MDL on 02/27/13 Source: https://www.indu 90818-00008 s.ucsf.edu/docs/ynjf0226 Drug/Class of Drug Most Appropriate for the Treatment of Insulin Resistance (Unaided) Total PCPs ENDOs (n=338) (n=302) (n=79) TZD/Glitazone (Net) 81% 81% 80% TZD/Glitazone/ ACTOS/ 77% 77% 77% Avandia ACTOS 3% I 4% I 3% Avandia 1% 1% 0% Biguanides 15% 15% 15% Sulfonylureas 4% I 4% 3% TZD association with treating IR is solidly in the minds of most MDs. However 1 in 5 think metformin or a sulfonylurea is most appropriate to treat IR as well What or class of drugs do you consider to be the most appropriate to treat insulin resistance? * indicates significant difference between subgroups @95% confidence level Q20b Confidential - Subject to Protective Order LLY-HOVENR-00001903 Produced in MDL on 02/27/13 Source: https://www.induposeis-oooogts.ucsf.edu/docs/ynjf0226 Q21. For the next series of statements, please tell me which of the two TZDs/Glitazones you believe is better in the following areas. Is Actos better, Avandia better, or are they both the same with regard to their. Confidential - Subject to Protective Order LLY-HOVENR-00001904 Produced in MDL on 02/27/13 Source: https://www.indu P0818-00010 s.ucsf.edu/docs/ynjf0226 Belief in IR = More Scripts! TZD Share of OAD Market 25.0% 20.0% 15.0% 10.0% 5.0% 0.0% 2 3 4 5 Doctors who rated the Importance (scale of 1-5) that an Oral Agent treat insulin resistance N=3 N=25 N=265 N=160 <AUTO> SOURCE: Message Effectiveness Wave 6, IMS Health Confidential - Subject to Protective Order LLY-HOVENR-00001905 Produced in MDL on 02/27/13 Source: https://www.induposts-oooanits.ucsf.edu/docs/ynjf0226 Frame: Why should reps focus on IR (What's In It For Me-WIIFM)? Key Point: When docs rate IR as more important, their TZD share is higher. Confidential - Subject to Protective Order LLY-HOVENR-00001906 Produced in MDL on 02/27/13 Source: https://www.indu P0818-00012 s.ucsf.edu/docs/ynjf0226 Strategic Intent & CSFs Strategic Intent: Establish Actos as the best OAD medication by treating insulin resistance, through sustained glycemic control and reduced cardiovascular risk. Critical Success Factors 1. TZD's prescribed earlier in treatment of Type 2 diabetes 2. Actos is the the first TZD used for Type 2 patients. <AUTO> Confidential - Subject to Protective Order LLY-HOVENR-00001907 Produced in MDL on 02/27/13 Source:

Which year has 13.3% Oral share (TZD)?

ynjf0226

ynjf0226_p0, ynjf0226_p1, ynjf0226_p2, ynjf0226_p3, ynjf0226_p4, ynjf0226_p5, ynjf0226_p6, ynjf0226_p7, ynjf0226_p8, ynjf0226_p9, ynjf0226_p10, ynjf0226_p11, ynjf0226_p12

2000

Actos 2004 0 Marketing Plan Review DALY 12 Lilly Answers That Matter. Confidential - Subject to Protective Order LLY-HOVENR-00001895 Produced in MDL on 02/27/13 Source: Agenda OAD Market / IR Review Evolving Medical Data Overview Q&A Discussion <AUTO> Confidential - Subject to Protective Order LLY-HOVENR-00001896 Produced in MDL on 02/27/13 Source: TZD Share of Oral Market % Retail TRx Share 25% Forecast Actual 20% 15% 10% 5% 0% 2000 2001 2002 2003 2004 2005 TZDs TRx (000s) 10,577 14,681 17,101 19,466 21,480 22,191 Orals TRx (000s) 79,521 87,291 93,471 98,004 102,218 105,807 Oral Share (TZDs) 13.3% 16.8% 18.3% 19.9% 21.0% 21.0% Plan TZD Share 13.3% 16.8% 18.3% 19.7% 20.6% 20.6% Forecast as % of Plan n/a n/a n/a 100.8% 102.0% 101.8% <AUTO> Confidential -- Subject to Protective Order LLY-HOVENR-00001897 Produced in MDL on 02/27/13 Source: Actos Share of TZDs Retail TRx SOM, IMS Health 60.00% Actual Foreçast 50.00% 40.00% Launch of Launch of Merck's BMS' PPAR's 30.00% PPAR's Q3 2005 Feb 2005 20.00% 10.00% 0.00% 2000 2001 2002 2003 2004 2005 TZDs TRx (000s) 10,577 14,681 17,101 19,407 21,479 22,902 Actos TRx (000s) 4,261 6,872 8,582 9,497 10,149 10,472 TZD Share 40.3% 46.8% 50.2% 49.0% 47.3% 45.7% Plan TZD Share n/a n/a n/a 46.1% 42.9% Forecast as a % of Plan n/a n/a n/a 106.3% 110.1% <AUTO> Confidential - Subject to Protective Order LLY-HOVENR-00001898 Produced in MDL on 02/27/13 Avandamet Uptake Retail TRx (000s), IMS Health TRx (000s) Assumes 36% of Avandamet scripts from Actos 500 Glucovance 450 400 350 Avandamet 300 Forecast 250 200 150 Avandamet at 31% of original 100 forecast. 50 Avandamet 0 1 2 3 4 5 6 7 8 9 10 11 12 13 15 Full Months Post Launch <AUTO> Confidential - Subject to Protective Order LLY-HOVENR-00001899 Produced in MDL on 02/27/13 Source: Consequences of IR Damage to Eyes Damage to Kidneys TG HDL-C LDL-C Damage to Nerves Increased CV Risk Increased CV Risk Hyperglycemia Dyslipidemia Insulin Resistance Central Hypertension Obesity Increased CV Risk Increased CV Risk <AUTO> Confidential - Subject to Protective Order LLY-HOVENR-00001900 Produced in MDL on 02/27/13 Source: Link between IR and CVD THE ROUTE TO CARDIOVASCULAR DISEASE 2.11.15-19 Hyperglycemia Insulin Hyper a path that leads to increased risk for MI Resistance Dys TYPE 2 DIABETES EQUALS PRIOR MI AS A CHD RISK FACTOR Pr S 7-year incidence of myocardial infarction (MI) (%) 25% 20% 15% 18.8% 20.2% 10% 5% 0% Nondiabetic patients Type 2 diabetics with prior MI without prior MI <AUTO> Confidential - Subject to Protective Order LLY-HOVENR-00001901 Produced in MDL on 02/27/13 Source: It is important to engage your customer in dialogue around IR, symptoms, and complications. This Map is a critical tool to help you explain the link of insulin resistance and Cardiovascular risk. Confidential - Subject to Protective Order LLY-HOVENR-00001902 Produced in MDL on 02/27/13 Source: https://www.indu 90818-00008 s.ucsf.edu/docs/ynjf0226 Drug/Class of Drug Most Appropriate for the Treatment of Insulin Resistance (Unaided) Total PCPs ENDOs (n=338) (n=302) (n=79) TZD/Glitazone (Net) 81% 81% 80% TZD/Glitazone/ ACTOS/ 77% 77% 77% Avandia ACTOS 3% I 4% I 3% Avandia 1% 1% 0% Biguanides 15% 15% 15% Sulfonylureas 4% I 4% 3% TZD association with treating IR is solidly in the minds of most MDs. However 1 in 5 think metformin or a sulfonylurea is most appropriate to treat IR as well What or class of drugs do you consider to be the most appropriate to treat insulin resistance? * indicates significant difference between subgroups @95% confidence level Q20b Confidential - Subject to Protective Order LLY-HOVENR-00001903 Produced in MDL on 02/27/13 Source: https://www.induposeis-oooogts.ucsf.edu/docs/ynjf0226 Q21. For the next series of statements, please tell me which of the two TZDs/Glitazones you believe is better in the following areas. Is Actos better, Avandia better, or are they both the same with regard to their. Confidential - Subject to Protective Order LLY-HOVENR-00001904 Produced in MDL on 02/27/13 Source: https://www.indu P0818-00010 s.ucsf.edu/docs/ynjf0226 Belief in IR = More Scripts! TZD Share of OAD Market 25.0% 20.0% 15.0% 10.0% 5.0% 0.0% 2 3 4 5 Doctors who rated the Importance (scale of 1-5) that an Oral Agent treat insulin resistance N=3 N=25 N=265 N=160 <AUTO> SOURCE: Message Effectiveness Wave 6, IMS Health Confidential - Subject to Protective Order LLY-HOVENR-00001905 Produced in MDL on 02/27/13 Source: https://www.induposts-oooanits.ucsf.edu/docs/ynjf0226 Frame: Why should reps focus on IR (What's In It For Me-WIIFM)? Key Point: When docs rate IR as more important, their TZD share is higher. Confidential - Subject to Protective Order LLY-HOVENR-00001906 Produced in MDL on 02/27/13 Source: https://www.indu P0818-00012 s.ucsf.edu/docs/ynjf0226 Strategic Intent & CSFs Strategic Intent: Establish Actos as the best OAD medication by treating insulin resistance, through sustained glycemic control and reduced cardiovascular risk. Critical Success Factors 1. TZD's prescribed earlier in treatment of Type 2 diabetes 2. Actos is the the first TZD used for Type 2 patients. <AUTO> Confidential - Subject to Protective Order LLY-HOVENR-00001907 Produced in MDL on 02/27/13 Source:

which has a superior lipid profile(v. avandia and others) under the title of "strength/opportunities?

ynjf0226

ynjf0226_p15, ynjf0226_p16

ACTOS

Evolving Data Safety Congestive Heart Failure Actos in patients with NYHA class I Label change? Actos in patients with NYHA class II/III Label change? ADA/AHA position paper on TZDs and CHF Liver Long term liver safety study Label change? Weight Gain and Edema IITs: Body composition, visceral VS. subcutaneous fat, mechanism of edema formation <AUTO> Confidential - Subject to Protective Order LLY-HOVENR-00001910 Produced in MDL on 02/27/13 Source: Actos Plan Overview Issues/Uncertainties Strategic Intent: Competitive Threats Establish Actos as the "best oral" anti-diabetic Avandamet 4/1000 medication in treating Insulin Resistance through New Merk PPAR (05) sustained glycemic control and reduced cardiovascular risk. Other Lilly Drugs Critical Success Factors TZD's are prescribed earlier in the treatment of Type 2 Diabetes Contract negotiations in progress Actos is the first TZD prescribed (vs. Avandia) for patients with Type 2 Diabetes. Strengths/Opportunities Key Priorities TL's believe TZDs will provide improved durability & Drive a thoughtful, robust, and coherent set of medical b-cell preservation and reduced CV risk studies to document the full benefits of ACTOS Supporting studies on TZDs are underway Keep opinion leaders at the cutting edge ACTOS has a superior lipid profile (v. Avandia and Fund CME and other initiatives that allow the opinion others) leaders to "spread the word" ahead of our evolving label New lipid standards place more importance on lipid claims management in diabetes Drive behavior change with physicians via our sales force. Pre-diabetes and DPP Results Keep managed care from being a barrier. Window of opportunity exists - no new TZD entrants to market until 2005. <AUTO> Confidential - Subject to Protective Order LLY-HOVENR-00001911 Produced in MDL on 02/27/13 Source:

Which study's synopsis is this?

jfkf0226

jfkf0226_p0, jfkf0226_p1, jfkf0226_p2, jfkf0226_p3

clinical, Clinical Study

ACTOS Pediatric Program 5 October 2006 P7327-00001 Source: https://www.industrydocuments.ucsf.edu/docs/jfkf0226 Overview of November 2006 Submission 0 Partial clinical hold removal request document: Summary document (Includes benefit- risk assessment) Meta-analysis report Kaiser first cohort report New epidemiology report(s) Executive summary of bladder cancer cases - CONFIRM P7327-00002 Source: https://wwww.industrydocuments.ucsf.edu/docs/jfkf0226 Overview of November 2006 Submission 0 PPSR (Proposed Pediatric Study Request) NEED TO CONFIRM FORMAT Clinical study synopsis P7327-00003 Source: https://www.industrydocuments.ucsf.edu/docs/jfkf0226 Clinical Study Synopsis 01-06-TL-OPI-527 Expert advisory meeting 4 October 2006 Draft synopsis available for team review on Monday, 9 October 2006 Team proposing to review synopsis in TARC instead of SRC Need detailed timelines of full study by 20 October 2006 Need budget, delineating what may be spent in FY06, by 20 October 2006 P7327-00004 Source: https://www.industrydocuments.ucsf.edu/docs/jfkf0226

what is the code mentioned under the title of clinical study synopsis?

jfkf0226

jfkf0226_p0, jfkf0226_p1, jfkf0226_p2, jfkf0226_p3

01-06-TL-OPI-527

ACTOS Pediatric Program 5 October 2006 P7327-00001 Source: https://www.industrydocuments.ucsf.edu/docs/jfkf0226 Overview of November 2006 Submission 0 Partial clinical hold removal request document: Summary document (Includes benefit- risk assessment) Meta-analysis report Kaiser first cohort report New epidemiology report(s) Executive summary of bladder cancer cases - CONFIRM P7327-00002 Source: https://wwww.industrydocuments.ucsf.edu/docs/jfkf0226 Overview of November 2006 Submission 0 PPSR (Proposed Pediatric Study Request) NEED TO CONFIRM FORMAT Clinical study synopsis P7327-00003 Source: https://www.industrydocuments.ucsf.edu/docs/jfkf0226 Clinical Study Synopsis 01-06-TL-OPI-527 Expert advisory meeting 4 October 2006 Draft synopsis available for team review on Monday, 9 October 2006 Team proposing to review synopsis in TARC instead of SRC Need detailed timelines of full study by 20 October 2006 Need budget, delineating what may be spent in FY06, by 20 October 2006 P7327-00004 Source: https://www.industrydocuments.ucsf.edu/docs/jfkf0226

When was expert advisory meeting ?

jfkf0226

jfkf0226_p0, jfkf0226_p1, jfkf0226_p2, jfkf0226_p3

4 october 2006, 4 OCTOBER 2006

ACTOS Pediatric Program 5 October 2006 P7327-00001 Source: https://www.industrydocuments.ucsf.edu/docs/jfkf0226 Overview of November 2006 Submission 0 Partial clinical hold removal request document: Summary document (Includes benefit- risk assessment) Meta-analysis report Kaiser first cohort report New epidemiology report(s) Executive summary of bladder cancer cases - CONFIRM P7327-00002 Source: https://wwww.industrydocuments.ucsf.edu/docs/jfkf0226 Overview of November 2006 Submission 0 PPSR (Proposed Pediatric Study Request) NEED TO CONFIRM FORMAT Clinical study synopsis P7327-00003 Source: https://www.industrydocuments.ucsf.edu/docs/jfkf0226 Clinical Study Synopsis 01-06-TL-OPI-527 Expert advisory meeting 4 October 2006 Draft synopsis available for team review on Monday, 9 October 2006 Team proposing to review synopsis in TARC instead of SRC Need detailed timelines of full study by 20 October 2006 Need budget, delineating what may be spent in FY06, by 20 October 2006 P7327-00004 Source: https://www.industrydocuments.ucsf.edu/docs/jfkf0226

What is the full form of PPSR?

jfkf0226

jfkf0226_p0, jfkf0226_p1, jfkf0226_p2, jfkf0226_p3

Proposed Pediatric Study Request, PROPOSED PEDIATRIC STUDY REQUEST

ACTOS Pediatric Program 5 October 2006 P7327-00001 Source: https://www.industrydocuments.ucsf.edu/docs/jfkf0226 Overview of November 2006 Submission 0 Partial clinical hold removal request document: Summary document (Includes benefit- risk assessment) Meta-analysis report Kaiser first cohort report New epidemiology report(s) Executive summary of bladder cancer cases - CONFIRM P7327-00002 Source: https://wwww.industrydocuments.ucsf.edu/docs/jfkf0226 Overview of November 2006 Submission 0 PPSR (Proposed Pediatric Study Request) NEED TO CONFIRM FORMAT Clinical study synopsis P7327-00003 Source: https://www.industrydocuments.ucsf.edu/docs/jfkf0226 Clinical Study Synopsis 01-06-TL-OPI-527 Expert advisory meeting 4 October 2006 Draft synopsis available for team review on Monday, 9 October 2006 Team proposing to review synopsis in TARC instead of SRC Need detailed timelines of full study by 20 October 2006 Need budget, delineating what may be spent in FY06, by 20 October 2006 P7327-00004 Source: https://www.industrydocuments.ucsf.edu/docs/jfkf0226

What study is described in the table given?

hfkf0226

hfkf0226_p0, hfkf0226_p1, hfkf0226_p2, hfkf0226_p3, hfkf0226_p4, hfkf0226_p5, hfkf0226_p6, hfkf0226_p7, hfkf0226_p8, hfkf0226_p9, hfkf0226_p10, hfkf0226_p11, hfkf0226_p12, hfkf0226_p13, hfkf0226_p14, hfkf0226_p15, hfkf0226_p16, hfkf0226_p17, hfkf0226_p18, hfkf0226_p19

PLACEBO- CONTROLLED DOSE RANGING STUDY, Glycemic Parameters in a 26-Week Placebo-Controlled Dose-Ranging Study.

NDA 21-073/S-023 Page 3 EXHIBIT 8 ACTOS Rully (pioglitazone hydrochloride) Tablets DESCRIPTION ACTOS (pioglitazone hydrochloride) is an oral antidiabetic agent that acts primarily by decreasing insulin resistance. ACTOS is used in the management of type 2 diabetes mellitus (also known as non-insulin-dependent diabetes mellitus [NIDDM] or adult-onset diabetes). Pharmacological studies indicate that ACTOS improves sensitivity to insulin in muscle and adipose tissue and inhibits hepatic giuconeogenesis. ACTOS improves glycemic control while reducing circulating insulin levels. Pioglitazone [()-5-[[4-[2-(5-ethyl-2-pyridinyl)ethoxy]phenyl]methyl}-2,4-]thiazolidine-dione monohydrochloride belongs to a different chemical class and has a different pharmacological action than the sulfonylureas, metformin, or the c--glucosidase inhibi-tors. The molecule contains one asymmetric carbon, and the compound is synthesized and used as the racemic mixture. The two enantiomers of pioglitazone interconvert in vivo. No differences were found in the pharmacologic activity between the two enan-tiomers. The structural formula is as shown: S o CH 3 N HC1 NH o o Pioglitazone hydrochloride is an odorless white crystalline powder that has a molecular formula of and a molecular weight of 392.90 daltons. It is soluble in N,N- dimethylformamide, slightly soluble in anhydrous ethanol, very slightly soluble in acetone and acetonitrile, practically insoluble in water, and insoluble in ether. ACTOS is available as a tablet for oral administration containing 15 mg, 30 mg, or 45 mg of pioglitazone (as the base) formulated with the following excipients: lactose monohydrate NF, hydroxypropylcellulose NF, carboxymethylcellulose calcium NF, and magnesium stearate NF. CLINICAL PHARMACOLOGY Mechanism of Action ACTOS is a thiazolidinedione antidiabetic agent that depends on the presence of insulin for its mechanism of action. ACTOS decreases insulin resistance in the periphery and in the liver resulting in increased insulin-dependent glucose disposal and decreased he-patic glucose output. Unlike sulfonylureas, pioglitazone is not an insulin secretagogue. Pioglitazone is a potent and highly selective agonist for peroxisome proliferator-activated receptor-gamma (PPARy). PPAR receptors are found in tissues important for insulin action such as adipose tissue, skeletal muscle, and liver. Activation of PPARY nuclear receptors modulates the transcription of a number of insulin responsive genes involved in the control of glucose and lipid metabolism. In animal models of diabetes, pioglitazone reduces the hyperglycemia, hyperinsulin-emia, and hypertriglyceridemia characteristic of insulin-resistant states such as type 2 diabetes. The metabolic changes produced by pioglitazone result in increased respon-siveness of insulin-dependent tissues and are observed in numerous animal models of insulin resistance. PLA-TAK-00062908 Source: NDA 21-073/S-023 Page 4 Since pioglitazone enhances the effects of circulating insulin (by decreasing insulin resistance), it does not lower blood glucose in animal models that lack endogenous insulin. Pharmacokinetics and Drug Metabolism Serum concentrations of total pioglitazone (pioglitazone plus active metabolites) remain elevated 24 hours after once daily dosing. Steady-state serum concentrations of both pioglitazone and total pioglitazone are achieved within 7 days. At steady-state, two of the pharmacologically active metabolites of pioglitazone, Metabolites III (M-III) and IV (M-IV), reach serum concentrations equal to or greater than pioglitazone. In both healthy volunteers and in patients with type 2 diabetes, pioglitazone comprises approx-imately 30% to 50% of the peak total pioglitazone serum concentrations and 20% to 25% of the total area under the serum concentration-time curve (AUC). Maximum serum concentration (Cmax), AUC, and trough serum concentrations (Cmin) for both pioglitazone and total pioglitazone increase proportionally at doses of 15 mg and 30 mg per day. There is a slightly less than proportional increase for pioglitazone and total pioglitazone at a dose of 60 mg per day. Absorption: Following oral administration, in the fasting state, pioglitazone is first measurable in serum within 30 minutes, with peak concentrations observed within 2 hours. Food slightly delays the time to peak serum concentration to 3 to 4 hours, but does not alter the extent of absorption. Distribution: The mean apparent volume of distribution (Vd/F) of pioglitazone following single-dose administration is 0.63 0.41 (mean SD) L/kg of body weight. Pioglita-zone is extensively protein bound (A 99%) in human serum, principally to serum albu-min. Pioglitazone also binds to other serum proteins, but with lower affinity. Metabolites M-III and M-IV also are extensively bound P 98%) to serum albumin. Metabolism: Pioglitazone is extensively metabolized by hydroxylation and oxidation; the metabolites also partly convert to glucuronide or sulfate conjugates. Metabolites M-II and M-IV (hydroxy derivatives of pioglitazone) and M-III (keto derivative of pioglita-zone) are pharmacologically active in animal models of type 2 diabetes. In addition to pioglitazone, M- III and M-IV are the principal drug-related species found in human serum following multiple dosing. At steady-state, in both healthy volunteers and in patients with type 2 diabetes, pioglitazone comprises approximately 30% to 50% of the total peak serum concentrations and 20% to 25% of the total AUC. In vitro data demonstrate that multiple CYP isoforms are involved in the metabolism of pioglitazone. The cytochrome P450 isoforms involved are CYP2C8 and, to a lesser degree, CYP3A4 with additional contributions from a variety of other isoforms including the mainly extrahepatic CYP1A1. In vivo studies of pioglitazone in combination with P450 inhibitors and substrates have been performed (see Drug Interactions). Urinary 6ß-hydroxycortisol/cortisol ratios measured in patients treated with ACTOS showed that pioglitazone is not a strong CYP3A4 enzyme inducer. PLA-TAK-00062909 Source: NDA 21-073/S-023 Page 5 Excretion and Elimination: Following oral administration, approximately 15% to 30% of the pioglitazone dose is recovered in the urine. Renal elimination of pioglitazone is negligible, and the drug is excreted primarily as metabolites and their conjugates. It is presumed that most of the oral dose is excreted into the bile either unchanged or as metabolites and eliminated in the feces, The mean serum half-life of pioglitazone and total pioglitazone ranges from 3 to 7 hours and 16 to 24 hours, respectively. Pioglitazone has an apparent clearance, CL/F, calculated to be 5 to 7 L/hr. Special Populations Renal Insufficiency The serum elimination half-life of pioglitazone, M-III, and M-IV remains unchanged in patients with moderate (creatinine clearance 30 to 60 mL/min) to severe (creatinine clearance < 30 mL/min) renal impairment when compared to normal subjects. No dose adjustment in patients with renal dysfunction is recommended (see DOSAGE AND ADMINISTRATION). Hepatic Insufficiency: Compared with normal controls, subjects with impaired hepatic function (Child-Pugh Grade B/C) have an approximate 45% reduction in pioglitazone and total pioglitazone mean peak concentrations but no change in the mean AUC values. ACTOS therapy should not be initiated if the patient exhibits clinical evidence of active liver disease or serum transaminase levels (ALT) exceed 2,5 times the upper limit of normal (see PRECAUTIONS, Hepatic Effects). Elderly: In healthy elderly subjects, peak serum concentrations of pioglitazone and total pioglitazone are not significantly different, but AUC values are slightly higher and the terminal half-life values slightly longer than for younger subjects. These changes were not of a magnitude that would be considered clinically relevant. Pediatrics: Pharmacokinetic data in the pediatric population are not available. Gender: The mean Cmex and AUC values were increased 20% to 60% in females. As monotherapy and in combination with sulfonylurea, metformin, or insulin, ACTOS im-proved glycemic control in both males and females. In controlled clinical trials, hemo-globin Ate (HbA1d) decreases from baseline were generally greater for females than for males (average mean difference in HbA1c 0,5%). Since therapy should be individual-ized for each patient to achieve glycemic control, no dose adjustment is recommended based on gender alone. Ethnicity: Pharmacokinetic data among various ethnic groups are not available. Drug-Drug Interactions The following drugs were studied in healthy volunteers with a co-administration of ACTOS 45 mg once daily. Listed below are the results: PLA-TAK-00062910 Source: NDA 21-073/S-023 Page 6 Oral Contraceptives: Co-administration of ACTOS (45 mg once daily) and an oral contraceptive (1 mg norethindrone plus 0.035 mg ethinyl estradiol once daily) for 21 days, resulted in 11% and 11-14% decrease in ethinyl estradiol AUC (0-24h) and Cmax respectively. There were no significant changes in norethindrone AUC (0-24h) and Gmax. In view of the high variability of ethinyl estradiol pharmacokinetics, the clinical significance of this finding is unknown. Fexofenadine HCI: Co-administration of ACTOS for 7 days with 60 mg fexofenadine administered orally fwice daily resulted in no significant effect on pioglitazone pharma- cokinetics. ACTOS had no significant effect on fexofenadine pharmacokinetics. Glipizide: Co-administration of ACTOS and 5 mg glipizide administered orally once daily for 7 days did not alter the steady-state pharmacokinetics of glipizide. Digoxin: Co-administration of ACTOS with 0.25 mg digoxin administered orally once daily for 7 days did not alter the steady-state pharmacokinetics of digoxin. Warfarin: Co-administration of ACTOS for 7 days with warfarin did not alter the steady-state pharmacokinetics of warfarin. ACTOS has no clinically significant effect on prothrombin time when administered to patients receiving chronic warfarin therapy Metformin: Co-administration of a single dose of metformin (1000 mg) and ACTOS after 7 days of ACTOS did not alter the pharmacokinetics of the single dose of metformin. Midazolam: Administration of ACTOS for 15 days followed by a single 7.5 mg dose of midazolam syrup resulted in a 26% reduction in midazolam Cmax and AUC. Ranitidine HCI: Co-administration of ACTOS for 7 days with ranitidine administered orally twice daily for either 4 or 7 days resulted in no significant effect on pioglitazone pharmacokinetics. ACTOS showed no significant effect on ranitidine pharmacokinetics. Nifedipine ER: Co-administration of ACTOS for 7 days with 30 mg nifedipine ER ad- ministered orally once daily for 4 days to male and female volunteers resulted in least square mean (90% CI) values for unchanged nifedipine of 0.83 (0.73 - 0.95) for Cmax and 0.88 (0.80 + 0.96) for AUC. In view of the high variability of nifedipine pharmaco-kinetics, the clinical significance of this finding is unknown. Ketoconazole: Co-administration of ACTOS for 7 days with ketoconazole 200 mg administered twice daily resulted in least square mean (90% CI) values for unchanged pioglitazone of 1.14 (1.06 - 1.23) for Cmaxt 1.34 (1.26 - 1.41) for AUC and 1.87 (1.71 - 2.04) for Cmin- Atorvastatin Calcium: Co-administration of ACTOS for 7 days with atorvastatin calcium (LIPITOR 80 mg once daily resulted in least square mean (90% CI) values for un-changed pioglitazone of 0.69 (0.57 n 0.85) for Cmax, 0,76 (0.65 - 0.88) for AUC and 0.96 (0,87 - 1.05) for Cmin- For unchanged atorvastatin the least square mean (90% CI) values were 0.77 (0.66 - 0.90) for Cmax, 0.86 (0.78 - 0.94) for AUC and 0,92 (0.82 - 1.02) for Cmin- PLA-TAK-00062911 Source: NDA 21-073/S-023 Page 7 Theophylline: Co-administration of ACTOS for 7 days with theophylline 400 mg admin-istered twice daily resulted in no change in the pharmacokinetics of either drug. Cytochrome P450: See PRECAUTIONS Pharmacodynamics and Clinical Effects Clinical studies demonstrate that ACTOS improves insulin sensitivity in insulin-resistant patients. ACTOS enhances cellular responsiveness to insulin, increases insulin-dependent glucose disposal, improves hepatic sensitivity to insulin, and improves dysfunctional glucose homeostasis. In patients with type 2 diabetes, the decreased insulin resistance produced by ACTOS results in lower plasma glucose concentrations, lower plasma insulin levels, and lower HbAte values. Based on results from an open-label extension study, the glucose lowering effects of ACTOS appear to persist for at least one year. In controlled clinical triais, ACTOS in combination with sulfonylurea, metformin, or insulin had an additive effect on glycemic control. Patients with lipid abnormalities were included in clinical trials with ACTOS. Overall, patients treated with ACTOS had mean decreases in triglycerides, mean increases in HDL cholesterol, and no consistent mean changes in LDL and total cholesterol. In a 26-week, placebo-controlled, dose-ranging study, mean triglyceride levels de-creased in the 15 mg, 30 mg, and 45 mg ACTOS dose groups compared to a mean in-crease in the placebo group. Mean HDL levels increased to a greater extent in patients treated with ACTOS than in the placebo-treated patients. There were no consistent differences for LDL and total cholesterol in patients treated with ACTOS compared to placebo (Table 1). Table 1 Lipids in a 26-Week Placeba-Controlled Monotherapy Dose-Ranging Study ACTOS ACTOS ACTOS 15 mg 30 mg 45 mg Placebo Once Once Once Daily Daily Daily Triglycerides (mg/dL) N=79 N=79 N=84 N=77 Baseline (mean) 262,8 283.8 261.1 259.7 Percent change from baseline (mean) 4.8% -9.0% -9.6% -9,3% HDL Cholesterol (mg/dL) N=79 N=79 N=83 N=77 Baseline (mean) 41.7 40.4 40.8 40.7 Percent change from baseline (mean) 8.1% 14.1% 12.2% 19.1% LDL Cholesterol (mg/dL) N=65 N=63 N=74 N=62 Baseline (mean) 138.8 131.9 135.6 126.8 Percent change from baseline (mean) 4.8% 7.2% 5.2% 6.0% Total Cholesterol (mg/dL) N=79 N=79 N=84 N=77 Baseline (mean) 224,6 220.0 222.7 213.7 Percent change from baseline (mean) 4.4% 4.6% 3,3% 6.4% In the two other monotherapy studies (24 weeks: and 16 weeks) and in combination therapy studies with sulfonylurea (24 weeks and 16 weeks) and metformin (24 weeks and 16 weeks), the results were generally consistent with the data above. in placebo-controlled trials, the placebo-corrected mean changes from baseline decreased 5% to 26% for triglycerides and increased 6% to 13% for HDL in patients treated with ACTOS. A similar pattern of results was seen in 24-week combination therapy studies of ACTOS with sulfonylurea or metformin. PLA-TAK-00062912 NDA 21-073/S-023 Page 8 In a combination therapy study with insulin (16 weeks), the placebo-corrected mean percent change from baseline in triglyceride values for patients treated with ACTOS was also decreased. A placebo-corrected mean change from baseline in LDL cholesterol of 7% was observed for the 15 mg dose group. Similar results to those noted above for HDL and total cholesterol were observed. A similar pattern of results was seen in a 24-week combination therapy study with ACTOS with insulin. Clinical Studies Monotherapy In the U.S., three randomized, double-blind, placebo-controlled trials with durations from 16 to 26 weeks were conducted to evaluate the use of ACTOS as monotherapy in patients with type 2 diabetes. These studies examined ACTOS at doses up to 45 mg or placebo once daily in 865 patients. In a 26-week dose-ranging study, 408 patients with type 2 diabetes were random-ized to receive 7.5 mg, 15 mg, 30 mg, or 45 mg of ACTOS, or placebo once daily. Therapy with any previous antidiabetic agent was discontinued 8 weeks prior to the double-blind period. Treatment with 15 mg, 30 mg, and 45 mg of ACTOS produced statistically significant improvements in HbA1c and fasting plasma glucose (FPG) at endpoint compared to placebo (see Figure 1, Table 2). Figure 1 shows the time course for changes in FPG and HbA1c for the entire study population in this 26-week study. FIGURE 1 MEAN CHANGE FROM BASELINE FOR FPG AND HBA1C IN A 26-WEEK PLACEBO-CONTROLLED DOSE-RANGING STUDY FPG HbA1e 20 1 10 0.8 0.6 -10 0.4 20 n.2 30 o 40 -a. -50 -0,4 -80 -0.8 -70 -0.8 -80 of o 2 4 e 10 14 18 22 25 0 2 of e 10 14 18 22 26 Weeks Weeks Placebo 15mg 30 mg 45 mg Placebo 15mg 30 my 45 mg PLA-TAK-00062913 NDA 21-073/S-023 Page 9 Table 2 shows HbA1c and FPG values for the entire study population. Table 2 Glycemic Parameters in a 26-Week Placebo-Controlled Dose-Ranging Study ACTOS ACTOS ACTOS Placeb 15 mg 30 mg 45 mg o Once Once Once Daily Daily Daily Total Population HbA16 (%) N=79 N=79 N=85 N=76 Baseline (mean) 10.4 10.2 10.2 10.3 Change from baseline (adjusted mean*) 0.7 -0.3 -0.3 -0.9 Difference from placebo (adjusted mean*) -1.0* -1.0* -1,6* FPG (mg/dL) N=79 N=79 N=84 N=77 Baseline (mean) 268 267 269 276 Change from baseline (adjusted mean*) 9 -30 -32 -56 Difference from placebo (adjusted mean*) -39* -41* -65* Adjusted for baseline, pooled center, and pooled center by treatment interaction * p 0.050 vs. placebo The study population included patients not previously treated with antidiabetic medication (naïve; 31%) and patients who were receiving antidiabetic medication at the time of study enrollment (previously treated; 69%). The data for the naïve and previously treated patient subsets are shown in Table 3. All patients entered an 8 week washout/run-in period prior to double-blind treatment. This run-in period was associated with little change in HbA1c and FPG values from screening to baseline for the naïve patients; however, for the previously- treated group, washout from previous antidiabetic medication resulted in deterioration of glycemic control and increases in HbA1c and FPG. Although most patients in the previously- treated group had a decrease from baseline in HbA1c and FPG with ACTOS, in many cases the values did not return to screening levels by the end of the study. The study design did not permit the evaluation of patients who switched directly to ACTOS from another antidiabetic agent. PLA-TAK-00062914 Source: NDA 21-073/S-023 Page 10 Table 3 Glycemic Parameters in a 26-Week Placebo-Controlled Dose-Ranging Study ACTOS ACTOS ACTOS Placebo 15 mg 30 mg 45 mg Once Once Once Daily Daily Daily Naïve to Therapy HbA1e (%) N=25 N=26 N=26 N=21 Screening (mean) 9.3 10.0 9.5 9.8 Baseline (mean) 9.0 9.9 9.3 10.0 Change from baseline (adjusted mean*) 0,6 -0.8 -0.6 -1.9 Difference from placebo (adjusted mean*) -1.4 -1.3 -2.6 FPG (mg/dL) N=25 N=26 N=26 N=21 Screening (mean) 223 245 239 239 Baseline (mean) 229 251 225 235 Change from baseline (adjusted mean*) 16 -37 -41 -64 Difference from placebo (adjusted mean*) -52 -56 -80 Previously Treated HbA1c (%) N=54 N=53 N=59 N=55 Screening (mean) 9.3 9.0 9.1 9.0 Baseline (mean) 10.9 10.4 10.4 10.6 Change from baseline (adjusted mean*) 0.8 -0,1 -0.0 -0.6 Difference from placebo (adjusted mean*) -1.0 -0,9 -1.4 FPG (mg/dL) N=54 N=53 N=58 N=56 Screening (mean) 222 209 230 215 Baseline (mean) 285 275 286 292 Change from baseline (adjusted mean*) 4 -32 -27 -55 Difference from placebo (adjusted mean*) -36 -31 -59 * Adjusted for baseline and pooled center In a 24-week placebo-controlled study, 260 patients with type 2 diabetes were randomized to one of two forced-titration ACTOS treatment groups or a mock titration placebo group. Therapy with any previous antidiabetic agent was discontinued 6 weeks prior to the double- blind period. in one ACTOS treatment group, patients received an initial dose of 7.5 mg once daily. After four weeks, the dose was increased to 15 mg once daily and after another four weeks, the dose was increased to 30 mg once daily for the remainder of the study (16 weeks). In the second ACTOS treatment group, patients received an initial dose of 15 mg once daily and were titrated to 30 mg once daily and 45 mg once daily in a similar manner. Treatment with ACTOS, as described, produced statistically significant improvements in HbA1c and FPG at endpoint compared to placebo (see Table 4). PLA-TAK-00062915 Source: NDA 21-073/S-023 Page 11 Table 4 Glycemic Parameters in a 24-Week Placebo-Controlled Forced-Titration Study ACTOS ACTOS Placebo 30 mg* 45 mg* Once Daily Once Daily Total Population HbAre (%) N=83 N=85 N=85 Baseline (mean) 10.8 10.3 10,8 Change from baseline (adjusted mean**) 0.9 -0.6 -0,6 Difference from placebo (adjusted mean** -1,5* -1.5" FPG (mg/dL) N=78 N=82 N=85 Basaline (mean) 279 268 281 Change from baseline (adjusted mean"*) 18 -44 -50 Difference from placebo (adjusted mean" ~62* ~68* Final dose in forced litration ++ Adjusted for baseline, pooled center, and paoled center by treatment interaction * p S. 0.050 vs. placebo For patients who had not been previously treated with anfidiabetic medication (24%), mean values at screening were 10,1% for HbA1g and 238 mg/dL for FPG. At baseline, mean HbA1c was 10.2% and mean FPG was 243 mg/dL. Compared with placebo, treat-ment with ACTOS titrated to a final dose of 30 mg and 45 mg resulted in reductions from baseline in mean HbArc of 2.3% and 2.6% and mean FPG of 63 mg/dL and 95 mg/dL, respectively. For patients who had been previously treated with antidiabetic medication (76%), this medication was discontinued at screening. Mean values at screening were 9.4% for HbArc and 216 mg/dL for FPG. At baseline, mean HbA1o was 10.7% and mean FPG was 290 mg/dL. Compared with placebo, treatment with ACTOS titrated to a final dose of 30 mg and 45 mg resulted in reductions from baseline in mean HbA1a of 1.3% and 1.4% and mean FPG of 55 mg/dL and 60 mg/dL, respectively. For many previously-treated patients, HbA1e and FPG had not returned to screening levels by the end of the study. In a 16-week study, 197 patients with type 2 diabetes were randomized to treatment with 30 mg of ACTOS or placebo once daily. Therapy with any previous antidiabetic agent was discontinued 6 weeks prior to the double-blind period. Treatment with 30 mg of ACTOS produced statistically significant improvements in HbA1 and FPG at endpoint compared to placebo (see Table 5). Table 5 Glycemic Parameters in a 16-Week Placebo-Controlled Study Placebo ACTOS 30 mg Once Daily Total Population HbAte (%) N=93 N=100 Baseline (mean) 10.3 10.5 Change from baseline (adjusted mean*) 0,8 -0,6 Difference from placebo (adjusted mean*) -1.4* FPG (mg/dL) N=91 N=99 Baseline (mean) 270 273 Change from baseline (adjusted mean") 8 -50 Difference from placebo (adjusted mean") -58* 7 Adjusted for baseline, pooted center, and pooled center by treatment interaction * P 5 0.050 vs. placabo PLA-TAK-00062916 Source: NDA 21-073/S-023 Page 12 For patients who had not been previously treated with antidiabetic medication (40%), mean values at screening were 10.3% for HbA1e and 240 mg/dL for FPG. At baseline, mean HbA1e was 10.4% and mean FPG was 254 mg/dL. Compared with placebo, treatment with ACTOS 30 mg resulted in reductions from baseline in mean HbA1e of 1.0% and mean FPG of 62 mg/dL. For patients who had been previously treated with antidiabetic medication (60%), this medication was discontinued at screening. Mean values at screening were 9.4% for HbA1e and 216 mg/dL for FPG. At baseline, mean HbA1c was 10,6% and mean FPG was 287 mg/dL. Compared with placebo, treatment with ACTOS 30 mg resulted in reductions from baseline in mean HbA1e of 1,3% and mean FPG of 46 mg/dL. For many previously- treated patients, HbA1e and FPG had not returned to screening levels by the end of the study. Combination Therapy Three 16-week, randomized, double-blind, placebo-controlled clinical studies and three 24- week randomized, double-blind, dose-controlled clinical studies were conducted to evaluate the effects of ACTOS on glycemic control in patients with type 2 diabetes who were inadequately controlled (HbA1c N 8%) despite current therapy with a sulfonylurea, metformin, or insulin. Previous diabetes treatment may have been monotherapy or combination therapy. ACTOS Plus Sulfonylurea Studies Two clinical studies were conducted with ACTOS in combination with a sulfonylurea. Both studies included patients with type 2 diabetes on a sulfonylurea, either alone or in combination with another antidiabetic agent. All other antidiabetic agents were withdrawn prior to starting study treatment. In the first study, 560 patients were randomized to receive 15 mg or 30 mg of ACTOS or placebo ance daily for 16 weeks in addition to their current sulfonylurea regimen. When compared to placebo at Week 16, the addition of ACTOS to the sulfonylurea significantly reduced the mean HbATo by 0,9% and 1.3% and mean FPG by 39 mg/dL and 58 mg/dL for the 15 mg and 30 mg doses, respectively. In the second study, 702 patients were randomized to receive 30 mg or 45 mg of ACTOS once daily for 24 weeks in addition to their current sulfonylurea regimen. The mean reductions from baseline at Week 24 in HbA1d were 1,55% and 1,67% for the 30 mg and 45 mg doses, respectively. Mean reductions from baseline in FPG were 51,5 mg/dL and 56.1 mg/dL. The therapeutic effect of ACTOS in combination with sulfonylurea was observed in patients regardless of whether the patients were receiving low, medium, or high doses of sulfonylurea. ACTOS Plus Metformin Studies Two clinical studies were conducted with ACTOS in combination with metformin. Both studies included patients with type 2 diabetes on metformin, either alone or in combination with another diabetic agent. All other antidiabetic agents were withdrawn prior to starting study treatment. In the first study, 328 patients were randomized to receive either 30 mg of ACTOS or placebo once daily for 16 weeks in addition to their current metformin regimen. When compared to placebo at Week 16, the addition of ACTOS to metformin significantly reduced the mean HbA1o by 0.8% and decreased the mean FPG by 38 mg/dL. In the secand study, 827 patients were randomized to receive either 30 mg or 45 mg of ACTOS once daily for 24 weeks in addition to their current metformin regimen. Source: https://www.industyeReeatents.ucsf.edu/docs/hfkf0226 PLA-TAK-00062917 NDA 21-073/S-023 Page 13 The mean reductions from baseline at Week 24 in HbAse were 0.80% and 1,01% for the 30 mg and 45 mg doses, respectively. Mean reductions from baseline in FPG were 38,2 mg/dL and 50.7 mg/dL. The therapeutic effect of ACTOS in combination with metformin was observed in patients regardless of whether the patients were receiving lower or higher doses of metformin. ACTOS Plus Insulin Studies Two clinical studies were conducted with ACTOS in combination with insulin. Both studies included patients with type 2 diabetes on insulin, either alone or in combination with another antidiabetic agent. All other antidiabetic agents were withdrawn prior to starting study treatment. In the first study, 566 patients receiving a median of 60.5 units per day of insulin were randomized to receive either 15 mg or 30 mg of ACTOS or placebo once daily for 16 weeks in addition to their insulin regimen. When compared to placebo at Week 16, the addition of ACTOS to insulin significantly reduced both HbA1c by 0.7% and 1.0% and FPG by 35 mg/dL and 49 mg/dL for the 15 mg and 30 mg dose, respectively, In the second study, 690 patients receiving a median of 60.0 units per day of insulin received either 30 mg or 45 mg of ACTOS once daily for 24 weeks in addition to their current insulin regimen. The mean reductions from baseline at Week 24 in HbA1c were 1.17% and 1.46% for the 30 mg and 45 mg doses, respectively. Mean reductions from baseline in FPG were 31,9 mg/dL and 45.8 mg/dL. Improved glycemic control was accompanied by mean decreases from baseline in insulin dose requirements of 6,0% and 9.4% per day for the 30 mg and 45 mg dose, respectively. The therapeutic effect of ACTOS in combination with insulin was observed in patients regardless of whether the patients were receiving lower or higher doses of insulin. INDICATIONS AND USAGE ACTOS is indicated as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes (non-insulin-dependent diabetes mellitus, NIDDM). ACTOS is indicated for monotherapy. ACTOS is also indicated for use in combination with a sulfonylurea, metformin, or insulin when diet and exercise plus the single agent does not result in adequate glycemic control. Management of type 2 diabetes should also include nutritional counseling, weight reduction as needed, and exercise. These efforts are important not only in the primary treatment of type 2 diabetes, but also to maintain the efficacy of drug therapy. CONTRAINDICATIONS ACTOS is contraindicated in patients with known hypersensitivity to this product or any of its components. WARNINGS Cardiac Failure and Other Cardiac Effects ACTOS, like other thiazolidinediones, can cause fluid retention when used alone or in combination with other antidiabetic agents, including insulin. Fluid retention may lead to or exacerbate heart failure. Patients should be observed for signs and symptoms of heart failure (see Information for Patients). ACTOS should be discontinued if any deterioration in cardiac status occurs. Patients with New York Heart Association (NYHA) Class III and IV cardiac status were not studied during pre-approval clinical trials; ACTOS is not recommended in these patients (see PRECAUTIONS, Cardiovascular). PLA-TAK-00062918 Source: NDA 21-073/S-023 Page 16 Hepatic Effects: In pre-approval clinical studies worldwide, over 4500 subjects were treated with ACTOS. In U.S. clinical studies, over 4700 patients with type 2 diabetes received ACTOS. There was no evidence of drug-induced hepatotoxicity or elevation of ALT levels in the clinical studies. During pre-approval placebo-controlled clinical trials in the U.S., a total of 4 of 1526 (0.26%) patients treated with ACTOS and 2 of 793 (0.25%) placebo-treated patients had ALT values 3 times the upper limit of normal. The ALT elevations in patients treated with ACTOS were reversible and were not clearly related to therapy with ACTOS. In postmarketing experience with ACTOS, reports of hepatitis and of hepatic enzyme elevations to 3 or more times the upper limit of normal have been received. Very rarely, these reports have involved hepatic failure with and without fatal outcome, although causality has not been established. Pioglitazone is structurally related to troglitazone, a thiazolidinedione no longer marketed in the United States, which was associated with idiosyncratic hepatotoxicity and cases of liver failure, liver transplants and death during postmarketing clinical use. In pre-approval controlled clinical trials in patients with type 2 diabetes, troglitazone was more frequently associated with clinically significant elevations of hepatic enzymes (ALT > 3 times the upper limit of normal) compared to placebo, and cases of reversible jaundice were reported. Pending the availability of the results of additional large, long-term controlled clinical triais and additional postmarketing safety data, it is recommended that patients treated with ACTOS undergo periodic monitoring of liver enzymes. Serum ALT (alanine aminotransferase) levels should be evaluated prior to the initiation of therapy with ACTOS in all patients and periodically therealter per the clinical judgment of the health care professional. Liver function tests should also be obtained for patients if symptoms suggestive of hepatic dysfunction occur, e.g., nausea, vomiting, abdominal pain, fatigue, anorexia, or dark urine. The decision whether to continue the patient on therapy with ACTOS should be guided by clinical judgment pending laboratory evaluations, If jaundice is observed, drug therapy should be discontinued. Therapy with ACTOS should not be initiated if the patient exhibits clinical evidence of active liver disease or the ALT levels exceed 2.5 times the upper limit of normal. Patients with mildly elevated liver enzymes (ALT levels at 1 to 2,5 times the upper limit of normal) at baseline or any time during therapy with ACTOS should be evaluated to determine the cause of the liver enzyme elevation. Initiation or continuation of therapy with ACTOS in patients with mildly elevated liver enzymes should proceed with caution and include appropriate clinical follow-up which may include more frequent liver enzyme monitoring. If serum transaminase levels are increased (ALT > 2.5 times the rupper limit of normal), liver function tests should be evaluated more frequently until the levels return to normal or pretreatment values. If ALT levels exceed 3 times the upper limit of normal, the test should be repeated as soon as possible. If ALT levels remain > 3 times the upper limit of normal or if the patient is jaundiced, ACTOS therapy should be discontinued. There are no data available to evaluate the safety of ACTOS in patients who experienced liver abnormalities, hepatic dysfunction, or jaundice while on troglitazone. ACTOS should not be used in patients who experienced jaundice while taking troglitazone. https://wwww.industryeneeatents.ucsf.edu/docs/hfkf0226 PLA-TAK-00062919 Source: NDA 21-073/S-023 Page 15 In insulin combination studies, a small number of patients with a history of previously existing cardiac disease developed congestive heart failure when treated with ACTOS in combination with insulin (see WARNINGS). Patients with NYHA Class III and IV cardiac status were not studied in these ACTOS clinical trials. ACTOS is not indicated in patients with NYHA Class III or IV cardiac status. In postmarketing experience with ACTOS, cases of congestive heart failure have been reported in patients both with and without previously known heart disease. Edema: ACTOS should be used with caution in patients with edema. In all U.S. clinical trials, edema was reported more frequently in patients treated with ACTOS than in placebo-treated patients and appears to be dose related (see ADVERSE REACTIONS). In postmarketing experience, reports of initiation or worsening of edema have been received. Weight Gain: Dose related weight gain was seen with ACTOS alone and in combination with other hypoglycemic agents (Table 6). The mechanism of weight gain is unclear but probably involves a combination of fluid retention and fat accumulation. Table 6 Weight Changes (kg) from Baseline during Double-Blind Clinical Trials with ACTOS Control Group ACTOS ACTOS ACTOS (Placebo) 15 mg 30 mg 45 mg Median Median Median Median (25°/75" percentile) percentile) percentile) percentile) 114 (-2.7/0.0) 0.9(-0.5/3.4) 1.0(-0.9/3.4) 2.6 (0.2/5.4) Monotherapy n=256 n = 79 n=188 n=79 -0,5 (-1.8/0.7) 2.0 (0.2/3.2) 3.1 (1.1/5.4) 4.1 (1.8/7.3) Combination Sulfonylurea n=187 n=183 n=528 N=333 Therapy Melformin -1.4 (-3.2/0.3) N/A 0.9(-0.3/3.2) 1.8(-0.9/5.0) n=160 n=567 N=407 0.2 (-1.4/1.4) 2.3 (0.5/4.3) 3.3 (0.9/6.3) 4.1 (1.4/6.8) insulin n=182 n=190 n=522 N=338 Note: Trial durations of 16 la 26 weeks Ovulation: Therapy with ACTOS, like other thiazolidinediones, may result in ovulation in some premenopausal anovulatory women. As a result, these patients may be at an increased risk for pregnancy while taking ACTOS. Thus, adequate contraception in premenopausal women should be recommended. This possible effect has not been investigated in clinical studies so the frequency of this occurrence is not known. Hematologic: ACTOS may cause decreases in hemoglobin and hematocrit. Across all clinical studies, mean hemoglobin values declined by 2% to 4% in patients treated with ACTOS. These changes primarily occurred within the first 4 to 12 weeks of therapy and remained relatively constant thereafter. These changes may be related to increased plasma volume and have rarely been associated with any significant hematologic clinical effects (see ADVERSE REACTIONS, Laboratory Abnormalities). PLA-TAK-00062920 Source: NDA 21-073/S-023 Page 14 In one 16-week U.S. double-blind, placebo-controlled clinical trial involving 566 patients with type 2 diabetes, ACTOS at doses of 15 mg and 30 mg in combination with insulin was compared to insulin therapy alone. This trial included patients with long-standing diabetes and a high prevalence of pre-existing medical conditions as follows: arterial hypertension (57.2%), peripheral neuropathy (22.6%), coronary heart disease (19.6%), retinopathy (13.1%), myocardial infarction (8.8%), vascular disease (6.4%), angina pectoris (4.4%), stroke and/or transient ischemic attack (4.1%), and congestive heart failure (2.3%). In this study two of the 191 patients receiving 15 mg ACTOS plus insulin (1.1%) and two of the 188 patients receiving 30 mg ACTOS plus insulin (1.1%) developed congestive heart failure compared with none of the 187 patients on insulin therapy alone. All four of these patients had previous histories of cardiovascular conditions including coronary artery disease, previous CABG procedures, and myocardial infarction. In a 24-week dose- controlled study in which ACTOS was coadministered with insulin, 0.3% of patients (1/345) on 30 mg and 0,9% (3/345) of patients on 45 mg reported CHF as a serious adverse event. Analysis of data from these studies did not identify specific factors that predict increased risk of congestive heart failure on combination therapy with insulin. In type 2 diabetest and congestive heart failure (systolic dysfunction) A 24-week post-marketing safety study was performed to compare ACTOS (n=262) to glyburide (n=256) in uncontrolled diabetic patients (mean HbA1c 8.8% at baseline) with NYHA Class Il and III heart failure and ejection fraction less than 40% (mean EF 30% at baseline). Over the course of the study, overnight hospitalization for congestive heart failure was reported in 9.9% of patients on ACTOS compared to 4.7% of patients on glyburide with a treatment difference observed from 6 weeks. This adverse event associated with ACTOS was more marked in patients using insulin at baseline and in patients over 64 years of age. No difference in cardiovascular mortality between the treatment groups was observed. ACTOS should be initiated at the lowest approved dose if it is prescribed for patients with type 2 diabetes and systolic heart failure (NYHA Class II). If subsequent dose escalation is necessary, the dose should be increased gradually only after several months of treatment with careful monitoring for weight gain, edema, or signs and symptoms of CHF exacerbation. PRECAUTIONS General ACTOS exerts its antihyperglycemic effect only in the presence of insulin. Therefore, ACTOS should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis. Hypoglycemia: Patients receiving ACTOS in combination with insulin or oral hypogly-cemic agents may be at risk for hypoglycemia, and a reduction in the dose of the con-comitant agent may be necessary. Cardiovascular: In U.S. placebo-controlled clinical trials that excluded patients with New York Heart Association (NYHA) Class III and IV cardiac status, the incidence of serious cardiac adverse events related to volume expansion was not increased in patients treated with ACTOS as monotherapy or in combination with sulfonylureas or metformin vs. placebo- treated patients. PLA-TAK-00062921 NDA 21-073/S-023 Page 17 Laboratory Tests FPG and HbAre measurements should be performed periodically to monitor glycemic control and the therapeutic response to ACTOS. Liver enzyme monitoring is recommended prior to inifiation of therapy with ACTOS in all patients and periodically thereafter per the clinical judgment of the health care professional (see PRECAUTIONS, General, Hepatic Effects and ADVERSE REACTIONS, Serum Transaminase Levels). Information for Patients It is important to instruct patients to adhere to dietary instructions and to have blood glucose and glycosylated hemoglobin tested regularly. During periods of stress such as fever, trauma, infection, or surgery, medication requirements may change and patients should be reminded to seek medical advice promptly. Patients who experience an unusually rapid increase in weight or edema or who develop shortness of breath or other symptoms of heart failure while on ACTOS should immediately report these symptoms to their physician. Patients should be told that blood tests for liver function will be performed prior to the start of therapy and periodically thereafter per the clinical judgment of the health care professional. Patients should be told to seek immediate medical advice for unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or dark urine. Patients should be fold to take ACTOS once daily. ACTOS can be taken with or without meals. If a dose is missed on one day, the dose should not be doubled the following day. When using combination therapy with insulin or oral hypoglycemic agents, the risks of hypoglycemia, its symptoms and treatment, and conditions that predispose to its development should be explained to patients and their family members, Therapy with ACTOS, like other thiazolidinediones, may result in ovulation in some premenopausal anovulatory women. As a result, these patients may be at an increased risk for pregnancy while taking ACTOS. Thus, adequate contraception in premeno-pausal women should be recommended. This possible effect has not been investigated in clinical studies so the frequency of this occurrence is not known. Drug Interactions In vivo drug-drug interaction studies have suggested that pioglitazone may be a weak inducer of CYP 450 isoform 3A4 substrate (see CLINICAL PHARMACOLOGY, Metabolism and Drug-Drug Interactions). Carcinogenesis, Mutagenesis, Impairment of Fertility A two-year carcinogenicity study was conducted in male and female rats at oral doses up to 63 mg/kg (approximately 14 times the maximum recommended human oral dose of 45 mg based on mg/m²). Drug-induced tumors were not observed in any organ ex-cept for the urinary bladder. Benign and/or malignant transitional cell neoplasms were observed in male rats at 4 mg/kg/day and above (approximately equal to the maximum recommended human oral dose based on mg/m²). A two-year carcinogenicity study was conducted in male and female mice at oral doses up to 100 mg/kg/day (approximately 11 times the maximum recommended human oral dose based on mg/m²). No drug-induced tumors were observed in any organ. Urinary tract tumors have been reported in rodents taking experimental drugs with dual PPAR aly activity; however ACTOS is a selective agonist for PPAR During prospective evaluation of urinary cytology involving more than 1800 patients receiving ACTOS in clinical trials up to one year in duration, no new cases of bladder tumors PLA-TAK-00062922 INDA 21-073/S-023 Page 18 were identified. Occasionally, abnormal urinary cytology results indicating possible malignancy were observed in both patients treated with ACTOS (0.72%) and patients treated with placebo (0.88%). Pioglitazone HCI was not mutagenic in a battery of genetic toxicology studies, including the Ames bacterial assay, a mammalian cell forward gene mutation assay (CHO/HPRT and AS52/XPRT), an in vitro cytogenetics assay using CHL cells, an unscheduled DNA synthesis assay, and an in vivo micronucleus assay. No adverse effects upon fertility were observed in male and female rats at oral doses up to 40 mg/kg pioglitazone HCI daily prior to and throughout mating and gestation (approximately 9 times the maximum recommended human oral dose based on mg/m²). Animal Toxicology Heart enlargement has been observed in mice (100 mg/kg), rats (4 mg/kg and above) and dogs (3 mg/kg) treated orally with pioglitazone HCI (approximately 11, 1, and 2 times the maximum recommended human oral dose for mice, rats, and dogs, respec-tively, based on mg/m². In a one-year rat study, drug-related early death due to apparent heart dysfunction occurred at an oral dose of 160 mg/kg/day (approximately 35 times the maximum recommended human oral dose based on mg/m²). Heart enlargement was seen in a 13- week study in monkeys at oral doses of 8.9 mg/kg and above (approximately 4 times the maximum recommended human oral dose based on mg/m²), but not in a 52-week study at oral doses up to 32 mg/kg (approximately 13 times the maximum recommended human oral dose based on mg/m²). Pregnancy Pregnancy Category C. Pioglitazone was not teratogenic in rats at oral doses up to 80 mg/kg or in rabbits given up to 160 mg/kg during organogenesis (approximately 17 and 40 times the maximum recommended human oral dose based on mg/m², respectively). Delayed parturition and embryotoxicity (as evidenced by increased postimplantation losses, delayed development and reduced fetal weights) were observed in rats at oral doses of 40 mg/kg/day and above (approximately 10 times the maximum recommended human oral dose based on mg/m²). No functional or behavioral toxicity was observed in offspring of rats. In rabbits, embryotoxicity was observed at an oral dose of 160 mg/kg (approximately 40 times the maximum recommended human oral dose based on mg/m²). Delayed postnatal development, attributed to decreased body weight, was observed in offspring of rats at oral doses of 10 mg/kg and above during late gestation and lactation periods (approximately 2 times the maximum recommended human oral dose based on mg/m²). There are no adequate and well-controlled studies in pregnant women. ACTOS should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Because current information strongly suggests that abnormal blood glucose levels during pregnancy are associated with a higher incidence of congenital anomalies, as well as increased neonatal morbidity and mortality, most experts recommend that insu-lin be used during pregnancy to maintain blood glucose levels as close to normal as possible. Nursing Mothers Pioglitazone is secreted in the milk of lactating rats. It is not known whether ACTOS is secreted in human milk. Because many drugs are excreted in human milk, ACTOS should not be administered to a breastfeeding woman, PLA-TAK-00062923 Source: NDA 21-073/S-023 Page 19 Pediatric Use Safety and effectiveness of ACTOS in pediatric patients have not been established. Elderly Use Approximately 500 patients in placebo-controlled clinical trials of ACTOS were 65 and over. No significant differences in effectiveness and safety were observed between these patients and younger patients. ADVERSE REACTIONS In worldwide clinical trials, over 5900 patients with type 2 diabetes have been treated with ACTOS. In U.S. clinical trials, over 4700 patients have received ACTOS, over 3300 patients have been treated for 6 months or longer, and over 450 patients for one year or longer. The overall incidence and types of adverse events reported in placebo-controlled clinical trials of ACTOS monotherapy at doses of 7.5 mg, 15 mg, 30 mg, or 45 mg once daily are shown in Table 7. Table 7 Placebo-Controlled Clinical Studies of ACTOS Monotherapy: Adverse Events Reported at a Frequency 5% of Patients Treated with ACTOS (% of Patients) Placebo ACTOS N=259 N=606 Upper Respiratory Tract Infection 8.5 13.2 Headache 6.9 9.1 Sinusitis 4.6 6.3 Myalgia 2.7 5.4 Tooth Disorder 2.3 5.3 Diabetes Mellitus Aggravated 8.1 5.1 Pharyngitis 0.8 5.1 For most clinical adverse events the incidence was similar for groups treated with ACTOS monotherapy and those treated in combination with sulfonylureas, metformin, and insulin. There was an increase in the occurrence of edema in the patients treated with ACTOS and insulin compared to insulin alone. In a 16-week, placebo-controlled ACTOS plus insulin trial (n=379), 10 patients treated with ACTOS plus insulin developed dyspnea and also, at some point during their therapy, developed either weight change or edema. Seven of these 10 patients received diuretics to treat these symptoms. This was not reported in the insulin plus placebo group. The incidence of withdrawals from placebo-controlled clinical trials due to an adverse event other than hyperglycemia was similar for patients treated with placebo (2.8%) or ACTOS (3.3%). In controlled combination therapy studies with either a sulfonylurea or insulin, mild to moderate hypoglycemia, which appears to be dose related, was reported (see PRECAUTIONS, General, Hypoglycemia and DOSAGE and ADMINISTRATION, Combination Therapy). In U.S. double-blind studies, anemia was reported in S 2% of patients treated with ACTOS plus sulfonylurea, metformin or insulin (see PRECAUTIONS, General, Hematologic). PLA-TAK-00062924 NDA 21-073/S-023 Page 20 In monotherapy studies, edema was reported for 4.8% of patients treated with ACTOS versus 1.2% of placebo-treated patients. In combination therapy studies, edema was reported for 7.2% of patients treated with ACTOS and sulfonylureas com-pared to 2.1% of patients on sulfonylureas alone. In combination therapy studies with metformin, edema was reported in 6,0% of patients on combination therapy compared to 2.5% of patients on metformin alone. In combination therapy studies with insulin, edema was reported in 15.3% of patients on combination therapy compared to 7,0% of patients on insulin alone, Most of these events were considered mild or moderate in intensity (see PRECAUTIONS, General, Edema). In one 16-week clinical trial of insulin plus ACTOS combination therapy, more patients developed congestive heart failure on combination therapy (1.1%) compared to none on insulin alone (see WARNINGS, Cardiac Failure and Other Cardiac Effects). Laboratory Abnormalities Hematologic: ACTOS may cause decreases in hemoglobin and hematocrit. The fall in hemoglobin and hematocrit with ACTOS appears to be dose related. Across all clinical studies, mean hemoglobin values declined by 2% to 4% in patients treated with ACTOS, These changes generally occurred within the first 4 to 12 weeks of therapy and remained relatively stable thereafter. These changes may be related to increased plasma volume associated with ACTOS therapy and have rarely been associated with any significant hematologic clinical effects. Serum Transaminase Levels: During all clinical studies in the U.S., 14 of 4780 (0.30%) patients treated with ACTOS had ALT values 3 times the upper limit of normal during treatment. All patients with follow-up values had reversible elevations in ALT. In the population of patients treated with ACTOS, mean values for bilirubin, AST, ALT, alkaline phosphatase, and GGT were decreased at the final visit compared with baseline. Fewer than 0.9% of patients treated with ACTOS were withdrawn from clinical trials in the U.S. due to abnormal liver function tests. In pre-approval clinical trials, there were no cases of idiosyncratic drug reactions leading to hepatic failure (see PRECAUTIONS, Hepatic Effects). CPK Levels: During required laboratory testing in clinical trials, sporadic, transient elevations in creatine phosphokinase levels (CPK) were observed. An isolated elevation to greater than 10 times the upper limit of normal was noted in 9 patients (values of 2150 to 11400 IU/L). Six of these patients continued to receive ACTOS, two patients had completed receiving study medication at the time of the elevated value and one patient discontinued study medication due to the elevation. These elevations resolved without any apparent clinical sequelae. The relationship of these events to ACTOS therapy is unknown. OVERDOSAGE During controlled clinical trials, one case of overdose with ACTOS was reported. A male patient took 120 mg per day for four days, then 180 mg per day for seven days, The patient denied any clinical symptoms during this period. In the event of overdosage, appropriate supportive treatment should be initiated according to patient's clinical signs and symptoms. Source: PLA-TAK-00062925 NDA 21-073/S-023 Page 21 DOSAGE AND ADMINISTRATION ACTOS should be taken once daily without regard to meals. The management of antidiabetic therapy should be individualized. Ideally, the response to therapy should be evaluated using HbA1c which is a better indicator of long-term glycemic control than FPG alone. HbA1e reflects glycemia over the past two to three months. In clinical use, it is recommended that patients be treated with ACTOS for a period of time adequate to evaluate change in HbA1d (three months) unless glycemic control deteriorates, Monotherapy ACTOS monotherapy in patients not adequately controlled with diet and exercise may be initiated at 15 mg or 30 mg once daily. For patients who respond inadequately to the initial dose of ACTOS, the dose can be increased in increments up to 45 mg once daily. For patients not responding adequately to monotherapy, combination therapy should be considered. Combination Therapy Sulfonylureas: ACTOS in combination with a sulfonylurea may be initiated at 15 mg or 30 mg once daily. The current sulfonylurea dose can be continued upon initiation of ACTOS therapy. If patients report hypoglycemia, the dose of the sulfonylurea should be decreased. Metformin: ACTOS in combination with metformín may be initiated at 15 mg or 30 mg once daily. The current metformin dose can be continued upon initiation of ACTOS therapy. It is unlikely that the dose of metformin will require adjustment due to hypo-glycemia during combination therapy with ACTOS. Insulin: ACTOS in combination with insulin may be initiated at 15 mg or 30 mg once daily. The current insulin dose can be continued upon initiation of ACTOS therapy. In patients receiving ACTOS and insulin, the insulin dose can be decreased by 10% to 25% if the patient reports hypoglycemia or if plasma glucose concentrations decrease to less than 100 mg/dL. Further adjustments should be individualized based on glucose-lowering response. Maximum Recommended Dose The dose of ACTOS should not exceed 45 mg once daily in monotherapy or in combination with sulfonylurea, metformin, or insulin. Dose adjustment in patients with renal insufficiency is not recommended (see CLINICAL PHARMACOLOGY, Pharmacokinetics and Drug Metabolism). Therapy with ACTOS should not be initiated if the patient exhibits clinical levidence of active liver disease or increased serum transaminase levels (ALT greater than 2.5 times the upper limit of normal) at start of therapy (see PRECAUTIONS, General, Hepatic Effects and CLINICAL PHARMACOLOGY, Special Populations, Hepatic Insufficiency). Liver enzyme monitoring is recommended in all patients prior to initiation of therapy with ACTOS and periodically thereafter (see PRECAUTIONS, General, Hepatic Effects). There are no data on the use of ACTOS in patients under 18 years of age; therefore, use of ACTOS in pediatric patients is not recommended. No data are available on the use of ACTOS in combination with another thiazolidinedione. Source: https://www.industryeeeateents.ucsf.edu/docs/hfkf0226 PLA-TAK-00062926 NDA 21-073/S-023 Page 22 HOW SUPPLIED ACTOS is available in 15 mg, 30 mg, and 45 mg tablets as follows: 15 mg Tablet: white to off-white, round, convex, non-scored tablet with "ACTOS" on one side, and "15" on the other, available in: NDC 64764-151-04 Bottle of 30 NDC 64764-151-05 Bottle of 90 NDC 64764-151-06 Bottle of 500 30 mg Tablet: white to off-white, round, flat, non-scored tablet with "ACTOS" on one side, and "30" on the other, available in: NDC 64764-301-14 Bottle of 30 NDC 64764-301-15 Bottle of 90 NDC 64764-301-16 Bottle of 500 45 mg Tablet: white to off-white, round, flat, non-scored tablet with "ACTOS" on one side, and "45" on the other, available in: NDC 64764-451-24 Bottle of 30 NDC 64764-451-25 Bottle of 90 NDC 64764-451-26 Bottle of 500 STORAGE Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Keep container tightly closed, and protect from moisture and humidity. Rx only Manufactured by: Takeda Chemical Industries, Ltd. Osaka, Japan Marketed by: Takeda Pharmaceuticals America, Inc. 475 Half Day Road Lincolnshire, IL 60069 and Ell Lilly and Company Lilly Corporate Center Indianapolis, IN 46285 ACTOS® is a registered trademark of Takeda Chemical Industries, Ltd. and used under license by Takeda Pharmaceuticals America, Inc. and Eli Lilly and Co. All other trademark names are the property of their respective owners. 5012100-07 Revised: July 2004 PLA-TAK-00062927 Source:

Which parameters are considered for the study(see heading of table 2)?

hfkf0226

hfkf0226_p0, hfkf0226_p1, hfkf0226_p2, hfkf0226_p3, hfkf0226_p4, hfkf0226_p5, hfkf0226_p6, hfkf0226_p7, hfkf0226_p8, hfkf0226_p9, hfkf0226_p10, hfkf0226_p11, hfkf0226_p12, hfkf0226_p13, hfkf0226_p14, hfkf0226_p15, hfkf0226_p16, hfkf0226_p17, hfkf0226_p18, hfkf0226_p19

GLYCEMIC, Glycemic Parameters

NDA 21-073/S-023 Page 3 EXHIBIT 8 ACTOS Rully (pioglitazone hydrochloride) Tablets DESCRIPTION ACTOS (pioglitazone hydrochloride) is an oral antidiabetic agent that acts primarily by decreasing insulin resistance. ACTOS is used in the management of type 2 diabetes mellitus (also known as non-insulin-dependent diabetes mellitus [NIDDM] or adult-onset diabetes). Pharmacological studies indicate that ACTOS improves sensitivity to insulin in muscle and adipose tissue and inhibits hepatic giuconeogenesis. ACTOS improves glycemic control while reducing circulating insulin levels. Pioglitazone [()-5-[[4-[2-(5-ethyl-2-pyridinyl)ethoxy]phenyl]methyl}-2,4-]thiazolidine-dione monohydrochloride belongs to a different chemical class and has a different pharmacological action than the sulfonylureas, metformin, or the c--glucosidase inhibi-tors. The molecule contains one asymmetric carbon, and the compound is synthesized and used as the racemic mixture. The two enantiomers of pioglitazone interconvert in vivo. No differences were found in the pharmacologic activity between the two enan-tiomers. The structural formula is as shown: S o CH 3 N HC1 NH o o Pioglitazone hydrochloride is an odorless white crystalline powder that has a molecular formula of and a molecular weight of 392.90 daltons. It is soluble in N,N- dimethylformamide, slightly soluble in anhydrous ethanol, very slightly soluble in acetone and acetonitrile, practically insoluble in water, and insoluble in ether. ACTOS is available as a tablet for oral administration containing 15 mg, 30 mg, or 45 mg of pioglitazone (as the base) formulated with the following excipients: lactose monohydrate NF, hydroxypropylcellulose NF, carboxymethylcellulose calcium NF, and magnesium stearate NF. CLINICAL PHARMACOLOGY Mechanism of Action ACTOS is a thiazolidinedione antidiabetic agent that depends on the presence of insulin for its mechanism of action. ACTOS decreases insulin resistance in the periphery and in the liver resulting in increased insulin-dependent glucose disposal and decreased he-patic glucose output. Unlike sulfonylureas, pioglitazone is not an insulin secretagogue. Pioglitazone is a potent and highly selective agonist for peroxisome proliferator-activated receptor-gamma (PPARy). PPAR receptors are found in tissues important for insulin action such as adipose tissue, skeletal muscle, and liver. Activation of PPARY nuclear receptors modulates the transcription of a number of insulin responsive genes involved in the control of glucose and lipid metabolism. In animal models of diabetes, pioglitazone reduces the hyperglycemia, hyperinsulin-emia, and hypertriglyceridemia characteristic of insulin-resistant states such as type 2 diabetes. The metabolic changes produced by pioglitazone result in increased respon-siveness of insulin-dependent tissues and are observed in numerous animal models of insulin resistance. PLA-TAK-00062908 Source: NDA 21-073/S-023 Page 4 Since pioglitazone enhances the effects of circulating insulin (by decreasing insulin resistance), it does not lower blood glucose in animal models that lack endogenous insulin. Pharmacokinetics and Drug Metabolism Serum concentrations of total pioglitazone (pioglitazone plus active metabolites) remain elevated 24 hours after once daily dosing. Steady-state serum concentrations of both pioglitazone and total pioglitazone are achieved within 7 days. At steady-state, two of the pharmacologically active metabolites of pioglitazone, Metabolites III (M-III) and IV (M-IV), reach serum concentrations equal to or greater than pioglitazone. In both healthy volunteers and in patients with type 2 diabetes, pioglitazone comprises approx-imately 30% to 50% of the peak total pioglitazone serum concentrations and 20% to 25% of the total area under the serum concentration-time curve (AUC). Maximum serum concentration (Cmax), AUC, and trough serum concentrations (Cmin) for both pioglitazone and total pioglitazone increase proportionally at doses of 15 mg and 30 mg per day. There is a slightly less than proportional increase for pioglitazone and total pioglitazone at a dose of 60 mg per day. Absorption: Following oral administration, in the fasting state, pioglitazone is first measurable in serum within 30 minutes, with peak concentrations observed within 2 hours. Food slightly delays the time to peak serum concentration to 3 to 4 hours, but does not alter the extent of absorption. Distribution: The mean apparent volume of distribution (Vd/F) of pioglitazone following single-dose administration is 0.63 0.41 (mean SD) L/kg of body weight. Pioglita-zone is extensively protein bound (A 99%) in human serum, principally to serum albu-min. Pioglitazone also binds to other serum proteins, but with lower affinity. Metabolites M-III and M-IV also are extensively bound P 98%) to serum albumin. Metabolism: Pioglitazone is extensively metabolized by hydroxylation and oxidation; the metabolites also partly convert to glucuronide or sulfate conjugates. Metabolites M-II and M-IV (hydroxy derivatives of pioglitazone) and M-III (keto derivative of pioglita-zone) are pharmacologically active in animal models of type 2 diabetes. In addition to pioglitazone, M- III and M-IV are the principal drug-related species found in human serum following multiple dosing. At steady-state, in both healthy volunteers and in patients with type 2 diabetes, pioglitazone comprises approximately 30% to 50% of the total peak serum concentrations and 20% to 25% of the total AUC. In vitro data demonstrate that multiple CYP isoforms are involved in the metabolism of pioglitazone. The cytochrome P450 isoforms involved are CYP2C8 and, to a lesser degree, CYP3A4 with additional contributions from a variety of other isoforms including the mainly extrahepatic CYP1A1. In vivo studies of pioglitazone in combination with P450 inhibitors and substrates have been performed (see Drug Interactions). Urinary 6ß-hydroxycortisol/cortisol ratios measured in patients treated with ACTOS showed that pioglitazone is not a strong CYP3A4 enzyme inducer. PLA-TAK-00062909 Source: NDA 21-073/S-023 Page 5 Excretion and Elimination: Following oral administration, approximately 15% to 30% of the pioglitazone dose is recovered in the urine. Renal elimination of pioglitazone is negligible, and the drug is excreted primarily as metabolites and their conjugates. It is presumed that most of the oral dose is excreted into the bile either unchanged or as metabolites and eliminated in the feces, The mean serum half-life of pioglitazone and total pioglitazone ranges from 3 to 7 hours and 16 to 24 hours, respectively. Pioglitazone has an apparent clearance, CL/F, calculated to be 5 to 7 L/hr. Special Populations Renal Insufficiency The serum elimination half-life of pioglitazone, M-III, and M-IV remains unchanged in patients with moderate (creatinine clearance 30 to 60 mL/min) to severe (creatinine clearance < 30 mL/min) renal impairment when compared to normal subjects. No dose adjustment in patients with renal dysfunction is recommended (see DOSAGE AND ADMINISTRATION). Hepatic Insufficiency: Compared with normal controls, subjects with impaired hepatic function (Child-Pugh Grade B/C) have an approximate 45% reduction in pioglitazone and total pioglitazone mean peak concentrations but no change in the mean AUC values. ACTOS therapy should not be initiated if the patient exhibits clinical evidence of active liver disease or serum transaminase levels (ALT) exceed 2,5 times the upper limit of normal (see PRECAUTIONS, Hepatic Effects). Elderly: In healthy elderly subjects, peak serum concentrations of pioglitazone and total pioglitazone are not significantly different, but AUC values are slightly higher and the terminal half-life values slightly longer than for younger subjects. These changes were not of a magnitude that would be considered clinically relevant. Pediatrics: Pharmacokinetic data in the pediatric population are not available. Gender: The mean Cmex and AUC values were increased 20% to 60% in females. As monotherapy and in combination with sulfonylurea, metformin, or insulin, ACTOS im-proved glycemic control in both males and females. In controlled clinical trials, hemo-globin Ate (HbA1d) decreases from baseline were generally greater for females than for males (average mean difference in HbA1c 0,5%). Since therapy should be individual-ized for each patient to achieve glycemic control, no dose adjustment is recommended based on gender alone. Ethnicity: Pharmacokinetic data among various ethnic groups are not available. Drug-Drug Interactions The following drugs were studied in healthy volunteers with a co-administration of ACTOS 45 mg once daily. Listed below are the results: PLA-TAK-00062910 Source: NDA 21-073/S-023 Page 6 Oral Contraceptives: Co-administration of ACTOS (45 mg once daily) and an oral contraceptive (1 mg norethindrone plus 0.035 mg ethinyl estradiol once daily) for 21 days, resulted in 11% and 11-14% decrease in ethinyl estradiol AUC (0-24h) and Cmax respectively. There were no significant changes in norethindrone AUC (0-24h) and Gmax. In view of the high variability of ethinyl estradiol pharmacokinetics, the clinical significance of this finding is unknown. Fexofenadine HCI: Co-administration of ACTOS for 7 days with 60 mg fexofenadine administered orally fwice daily resulted in no significant effect on pioglitazone pharma- cokinetics. ACTOS had no significant effect on fexofenadine pharmacokinetics. Glipizide: Co-administration of ACTOS and 5 mg glipizide administered orally once daily for 7 days did not alter the steady-state pharmacokinetics of glipizide. Digoxin: Co-administration of ACTOS with 0.25 mg digoxin administered orally once daily for 7 days did not alter the steady-state pharmacokinetics of digoxin. Warfarin: Co-administration of ACTOS for 7 days with warfarin did not alter the steady-state pharmacokinetics of warfarin. ACTOS has no clinically significant effect on prothrombin time when administered to patients receiving chronic warfarin therapy Metformin: Co-administration of a single dose of metformin (1000 mg) and ACTOS after 7 days of ACTOS did not alter the pharmacokinetics of the single dose of metformin. Midazolam: Administration of ACTOS for 15 days followed by a single 7.5 mg dose of midazolam syrup resulted in a 26% reduction in midazolam Cmax and AUC. Ranitidine HCI: Co-administration of ACTOS for 7 days with ranitidine administered orally twice daily for either 4 or 7 days resulted in no significant effect on pioglitazone pharmacokinetics. ACTOS showed no significant effect on ranitidine pharmacokinetics. Nifedipine ER: Co-administration of ACTOS for 7 days with 30 mg nifedipine ER ad- ministered orally once daily for 4 days to male and female volunteers resulted in least square mean (90% CI) values for unchanged nifedipine of 0.83 (0.73 - 0.95) for Cmax and 0.88 (0.80 + 0.96) for AUC. In view of the high variability of nifedipine pharmaco-kinetics, the clinical significance of this finding is unknown. Ketoconazole: Co-administration of ACTOS for 7 days with ketoconazole 200 mg administered twice daily resulted in least square mean (90% CI) values for unchanged pioglitazone of 1.14 (1.06 - 1.23) for Cmaxt 1.34 (1.26 - 1.41) for AUC and 1.87 (1.71 - 2.04) for Cmin- Atorvastatin Calcium: Co-administration of ACTOS for 7 days with atorvastatin calcium (LIPITOR 80 mg once daily resulted in least square mean (90% CI) values for un-changed pioglitazone of 0.69 (0.57 n 0.85) for Cmax, 0,76 (0.65 - 0.88) for AUC and 0.96 (0,87 - 1.05) for Cmin- For unchanged atorvastatin the least square mean (90% CI) values were 0.77 (0.66 - 0.90) for Cmax, 0.86 (0.78 - 0.94) for AUC and 0,92 (0.82 - 1.02) for Cmin- PLA-TAK-00062911 Source: NDA 21-073/S-023 Page 7 Theophylline: Co-administration of ACTOS for 7 days with theophylline 400 mg admin-istered twice daily resulted in no change in the pharmacokinetics of either drug. Cytochrome P450: See PRECAUTIONS Pharmacodynamics and Clinical Effects Clinical studies demonstrate that ACTOS improves insulin sensitivity in insulin-resistant patients. ACTOS enhances cellular responsiveness to insulin, increases insulin-dependent glucose disposal, improves hepatic sensitivity to insulin, and improves dysfunctional glucose homeostasis. In patients with type 2 diabetes, the decreased insulin resistance produced by ACTOS results in lower plasma glucose concentrations, lower plasma insulin levels, and lower HbAte values. Based on results from an open-label extension study, the glucose lowering effects of ACTOS appear to persist for at least one year. In controlled clinical triais, ACTOS in combination with sulfonylurea, metformin, or insulin had an additive effect on glycemic control. Patients with lipid abnormalities were included in clinical trials with ACTOS. Overall, patients treated with ACTOS had mean decreases in triglycerides, mean increases in HDL cholesterol, and no consistent mean changes in LDL and total cholesterol. In a 26-week, placebo-controlled, dose-ranging study, mean triglyceride levels de-creased in the 15 mg, 30 mg, and 45 mg ACTOS dose groups compared to a mean in-crease in the placebo group. Mean HDL levels increased to a greater extent in patients treated with ACTOS than in the placebo-treated patients. There were no consistent differences for LDL and total cholesterol in patients treated with ACTOS compared to placebo (Table 1). Table 1 Lipids in a 26-Week Placeba-Controlled Monotherapy Dose-Ranging Study ACTOS ACTOS ACTOS 15 mg 30 mg 45 mg Placebo Once Once Once Daily Daily Daily Triglycerides (mg/dL) N=79 N=79 N=84 N=77 Baseline (mean) 262,8 283.8 261.1 259.7 Percent change from baseline (mean) 4.8% -9.0% -9.6% -9,3% HDL Cholesterol (mg/dL) N=79 N=79 N=83 N=77 Baseline (mean) 41.7 40.4 40.8 40.7 Percent change from baseline (mean) 8.1% 14.1% 12.2% 19.1% LDL Cholesterol (mg/dL) N=65 N=63 N=74 N=62 Baseline (mean) 138.8 131.9 135.6 126.8 Percent change from baseline (mean) 4.8% 7.2% 5.2% 6.0% Total Cholesterol (mg/dL) N=79 N=79 N=84 N=77 Baseline (mean) 224,6 220.0 222.7 213.7 Percent change from baseline (mean) 4.4% 4.6% 3,3% 6.4% In the two other monotherapy studies (24 weeks: and 16 weeks) and in combination therapy studies with sulfonylurea (24 weeks and 16 weeks) and metformin (24 weeks and 16 weeks), the results were generally consistent with the data above. in placebo-controlled trials, the placebo-corrected mean changes from baseline decreased 5% to 26% for triglycerides and increased 6% to 13% for HDL in patients treated with ACTOS. A similar pattern of results was seen in 24-week combination therapy studies of ACTOS with sulfonylurea or metformin. PLA-TAK-00062912 NDA 21-073/S-023 Page 8 In a combination therapy study with insulin (16 weeks), the placebo-corrected mean percent change from baseline in triglyceride values for patients treated with ACTOS was also decreased. A placebo-corrected mean change from baseline in LDL cholesterol of 7% was observed for the 15 mg dose group. Similar results to those noted above for HDL and total cholesterol were observed. A similar pattern of results was seen in a 24-week combination therapy study with ACTOS with insulin. Clinical Studies Monotherapy In the U.S., three randomized, double-blind, placebo-controlled trials with durations from 16 to 26 weeks were conducted to evaluate the use of ACTOS as monotherapy in patients with type 2 diabetes. These studies examined ACTOS at doses up to 45 mg or placebo once daily in 865 patients. In a 26-week dose-ranging study, 408 patients with type 2 diabetes were random-ized to receive 7.5 mg, 15 mg, 30 mg, or 45 mg of ACTOS, or placebo once daily. Therapy with any previous antidiabetic agent was discontinued 8 weeks prior to the double-blind period. Treatment with 15 mg, 30 mg, and 45 mg of ACTOS produced statistically significant improvements in HbA1c and fasting plasma glucose (FPG) at endpoint compared to placebo (see Figure 1, Table 2). Figure 1 shows the time course for changes in FPG and HbA1c for the entire study population in this 26-week study. FIGURE 1 MEAN CHANGE FROM BASELINE FOR FPG AND HBA1C IN A 26-WEEK PLACEBO-CONTROLLED DOSE-RANGING STUDY FPG HbA1e 20 1 10 0.8 0.6 -10 0.4 20 n.2 30 o 40 -a. -50 -0,4 -80 -0.8 -70 -0.8 -80 of o 2 4 e 10 14 18 22 25 0 2 of e 10 14 18 22 26 Weeks Weeks Placebo 15mg 30 mg 45 mg Placebo 15mg 30 my 45 mg PLA-TAK-00062913 NDA 21-073/S-023 Page 9 Table 2 shows HbA1c and FPG values for the entire study population. Table 2 Glycemic Parameters in a 26-Week Placebo-Controlled Dose-Ranging Study ACTOS ACTOS ACTOS Placeb 15 mg 30 mg 45 mg o Once Once Once Daily Daily Daily Total Population HbA16 (%) N=79 N=79 N=85 N=76 Baseline (mean) 10.4 10.2 10.2 10.3 Change from baseline (adjusted mean*) 0.7 -0.3 -0.3 -0.9 Difference from placebo (adjusted mean*) -1.0* -1.0* -1,6* FPG (mg/dL) N=79 N=79 N=84 N=77 Baseline (mean) 268 267 269 276 Change from baseline (adjusted mean*) 9 -30 -32 -56 Difference from placebo (adjusted mean*) -39* -41* -65* Adjusted for baseline, pooled center, and pooled center by treatment interaction * p 0.050 vs. placebo The study population included patients not previously treated with antidiabetic medication (naïve; 31%) and patients who were receiving antidiabetic medication at the time of study enrollment (previously treated; 69%). The data for the naïve and previously treated patient subsets are shown in Table 3. All patients entered an 8 week washout/run-in period prior to double-blind treatment. This run-in period was associated with little change in HbA1c and FPG values from screening to baseline for the naïve patients; however, for the previously- treated group, washout from previous antidiabetic medication resulted in deterioration of glycemic control and increases in HbA1c and FPG. Although most patients in the previously- treated group had a decrease from baseline in HbA1c and FPG with ACTOS, in many cases the values did not return to screening levels by the end of the study. The study design did not permit the evaluation of patients who switched directly to ACTOS from another antidiabetic agent. PLA-TAK-00062914 Source: NDA 21-073/S-023 Page 10 Table 3 Glycemic Parameters in a 26-Week Placebo-Controlled Dose-Ranging Study ACTOS ACTOS ACTOS Placebo 15 mg 30 mg 45 mg Once Once Once Daily Daily Daily Naïve to Therapy HbA1e (%) N=25 N=26 N=26 N=21 Screening (mean) 9.3 10.0 9.5 9.8 Baseline (mean) 9.0 9.9 9.3 10.0 Change from baseline (adjusted mean*) 0,6 -0.8 -0.6 -1.9 Difference from placebo (adjusted mean*) -1.4 -1.3 -2.6 FPG (mg/dL) N=25 N=26 N=26 N=21 Screening (mean) 223 245 239 239 Baseline (mean) 229 251 225 235 Change from baseline (adjusted mean*) 16 -37 -41 -64 Difference from placebo (adjusted mean*) -52 -56 -80 Previously Treated HbA1c (%) N=54 N=53 N=59 N=55 Screening (mean) 9.3 9.0 9.1 9.0 Baseline (mean) 10.9 10.4 10.4 10.6 Change from baseline (adjusted mean*) 0.8 -0,1 -0.0 -0.6 Difference from placebo (adjusted mean*) -1.0 -0,9 -1.4 FPG (mg/dL) N=54 N=53 N=58 N=56 Screening (mean) 222 209 230 215 Baseline (mean) 285 275 286 292 Change from baseline (adjusted mean*) 4 -32 -27 -55 Difference from placebo (adjusted mean*) -36 -31 -59 * Adjusted for baseline and pooled center In a 24-week placebo-controlled study, 260 patients with type 2 diabetes were randomized to one of two forced-titration ACTOS treatment groups or a mock titration placebo group. Therapy with any previous antidiabetic agent was discontinued 6 weeks prior to the double- blind period. in one ACTOS treatment group, patients received an initial dose of 7.5 mg once daily. After four weeks, the dose was increased to 15 mg once daily and after another four weeks, the dose was increased to 30 mg once daily for the remainder of the study (16 weeks). In the second ACTOS treatment group, patients received an initial dose of 15 mg once daily and were titrated to 30 mg once daily and 45 mg once daily in a similar manner. Treatment with ACTOS, as described, produced statistically significant improvements in HbA1c and FPG at endpoint compared to placebo (see Table 4). PLA-TAK-00062915 Source: NDA 21-073/S-023 Page 11 Table 4 Glycemic Parameters in a 24-Week Placebo-Controlled Forced-Titration Study ACTOS ACTOS Placebo 30 mg* 45 mg* Once Daily Once Daily Total Population HbAre (%) N=83 N=85 N=85 Baseline (mean) 10.8 10.3 10,8 Change from baseline (adjusted mean**) 0.9 -0.6 -0,6 Difference from placebo (adjusted mean** -1,5* -1.5" FPG (mg/dL) N=78 N=82 N=85 Basaline (mean) 279 268 281 Change from baseline (adjusted mean"*) 18 -44 -50 Difference from placebo (adjusted mean" ~62* ~68* Final dose in forced litration ++ Adjusted for baseline, pooled center, and paoled center by treatment interaction * p S. 0.050 vs. placebo For patients who had not been previously treated with anfidiabetic medication (24%), mean values at screening were 10,1% for HbA1g and 238 mg/dL for FPG. At baseline, mean HbA1c was 10.2% and mean FPG was 243 mg/dL. Compared with placebo, treat-ment with ACTOS titrated to a final dose of 30 mg and 45 mg resulted in reductions from baseline in mean HbArc of 2.3% and 2.6% and mean FPG of 63 mg/dL and 95 mg/dL, respectively. For patients who had been previously treated with antidiabetic medication (76%), this medication was discontinued at screening. Mean values at screening were 9.4% for HbArc and 216 mg/dL for FPG. At baseline, mean HbA1o was 10.7% and mean FPG was 290 mg/dL. Compared with placebo, treatment with ACTOS titrated to a final dose of 30 mg and 45 mg resulted in reductions from baseline in mean HbA1a of 1.3% and 1.4% and mean FPG of 55 mg/dL and 60 mg/dL, respectively. For many previously-treated patients, HbA1e and FPG had not returned to screening levels by the end of the study. In a 16-week study, 197 patients with type 2 diabetes were randomized to treatment with 30 mg of ACTOS or placebo once daily. Therapy with any previous antidiabetic agent was discontinued 6 weeks prior to the double-blind period. Treatment with 30 mg of ACTOS produced statistically significant improvements in HbA1 and FPG at endpoint compared to placebo (see Table 5). Table 5 Glycemic Parameters in a 16-Week Placebo-Controlled Study Placebo ACTOS 30 mg Once Daily Total Population HbAte (%) N=93 N=100 Baseline (mean) 10.3 10.5 Change from baseline (adjusted mean*) 0,8 -0,6 Difference from placebo (adjusted mean*) -1.4* FPG (mg/dL) N=91 N=99 Baseline (mean) 270 273 Change from baseline (adjusted mean") 8 -50 Difference from placebo (adjusted mean") -58* 7 Adjusted for baseline, pooted center, and pooled center by treatment interaction * P 5 0.050 vs. placabo PLA-TAK-00062916 Source: NDA 21-073/S-023 Page 12 For patients who had not been previously treated with antidiabetic medication (40%), mean values at screening were 10.3% for HbA1e and 240 mg/dL for FPG. At baseline, mean HbA1e was 10.4% and mean FPG was 254 mg/dL. Compared with placebo, treatment with ACTOS 30 mg resulted in reductions from baseline in mean HbA1e of 1.0% and mean FPG of 62 mg/dL. For patients who had been previously treated with antidiabetic medication (60%), this medication was discontinued at screening. Mean values at screening were 9.4% for HbA1e and 216 mg/dL for FPG. At baseline, mean HbA1c was 10,6% and mean FPG was 287 mg/dL. Compared with placebo, treatment with ACTOS 30 mg resulted in reductions from baseline in mean HbA1e of 1,3% and mean FPG of 46 mg/dL. For many previously- treated patients, HbA1e and FPG had not returned to screening levels by the end of the study. Combination Therapy Three 16-week, randomized, double-blind, placebo-controlled clinical studies and three 24- week randomized, double-blind, dose-controlled clinical studies were conducted to evaluate the effects of ACTOS on glycemic control in patients with type 2 diabetes who were inadequately controlled (HbA1c N 8%) despite current therapy with a sulfonylurea, metformin, or insulin. Previous diabetes treatment may have been monotherapy or combination therapy. ACTOS Plus Sulfonylurea Studies Two clinical studies were conducted with ACTOS in combination with a sulfonylurea. Both studies included patients with type 2 diabetes on a sulfonylurea, either alone or in combination with another antidiabetic agent. All other antidiabetic agents were withdrawn prior to starting study treatment. In the first study, 560 patients were randomized to receive 15 mg or 30 mg of ACTOS or placebo ance daily for 16 weeks in addition to their current sulfonylurea regimen. When compared to placebo at Week 16, the addition of ACTOS to the sulfonylurea significantly reduced the mean HbATo by 0,9% and 1.3% and mean FPG by 39 mg/dL and 58 mg/dL for the 15 mg and 30 mg doses, respectively. In the second study, 702 patients were randomized to receive 30 mg or 45 mg of ACTOS once daily for 24 weeks in addition to their current sulfonylurea regimen. The mean reductions from baseline at Week 24 in HbA1d were 1,55% and 1,67% for the 30 mg and 45 mg doses, respectively. Mean reductions from baseline in FPG were 51,5 mg/dL and 56.1 mg/dL. The therapeutic effect of ACTOS in combination with sulfonylurea was observed in patients regardless of whether the patients were receiving low, medium, or high doses of sulfonylurea. ACTOS Plus Metformin Studies Two clinical studies were conducted with ACTOS in combination with metformin. Both studies included patients with type 2 diabetes on metformin, either alone or in combination with another diabetic agent. All other antidiabetic agents were withdrawn prior to starting study treatment. In the first study, 328 patients were randomized to receive either 30 mg of ACTOS or placebo once daily for 16 weeks in addition to their current metformin regimen. When compared to placebo at Week 16, the addition of ACTOS to metformin significantly reduced the mean HbA1o by 0.8% and decreased the mean FPG by 38 mg/dL. In the secand study, 827 patients were randomized to receive either 30 mg or 45 mg of ACTOS once daily for 24 weeks in addition to their current metformin regimen. Source: https://www.industyeReeatents.ucsf.edu/docs/hfkf0226 PLA-TAK-00062917 NDA 21-073/S-023 Page 13 The mean reductions from baseline at Week 24 in HbAse were 0.80% and 1,01% for the 30 mg and 45 mg doses, respectively. Mean reductions from baseline in FPG were 38,2 mg/dL and 50.7 mg/dL. The therapeutic effect of ACTOS in combination with metformin was observed in patients regardless of whether the patients were receiving lower or higher doses of metformin. ACTOS Plus Insulin Studies Two clinical studies were conducted with ACTOS in combination with insulin. Both studies included patients with type 2 diabetes on insulin, either alone or in combination with another antidiabetic agent. All other antidiabetic agents were withdrawn prior to starting study treatment. In the first study, 566 patients receiving a median of 60.5 units per day of insulin were randomized to receive either 15 mg or 30 mg of ACTOS or placebo once daily for 16 weeks in addition to their insulin regimen. When compared to placebo at Week 16, the addition of ACTOS to insulin significantly reduced both HbA1c by 0.7% and 1.0% and FPG by 35 mg/dL and 49 mg/dL for the 15 mg and 30 mg dose, respectively, In the second study, 690 patients receiving a median of 60.0 units per day of insulin received either 30 mg or 45 mg of ACTOS once daily for 24 weeks in addition to their current insulin regimen. The mean reductions from baseline at Week 24 in HbA1c were 1.17% and 1.46% for the 30 mg and 45 mg doses, respectively. Mean reductions from baseline in FPG were 31,9 mg/dL and 45.8 mg/dL. Improved glycemic control was accompanied by mean decreases from baseline in insulin dose requirements of 6,0% and 9.4% per day for the 30 mg and 45 mg dose, respectively. The therapeutic effect of ACTOS in combination with insulin was observed in patients regardless of whether the patients were receiving lower or higher doses of insulin. INDICATIONS AND USAGE ACTOS is indicated as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes (non-insulin-dependent diabetes mellitus, NIDDM). ACTOS is indicated for monotherapy. ACTOS is also indicated for use in combination with a sulfonylurea, metformin, or insulin when diet and exercise plus the single agent does not result in adequate glycemic control. Management of type 2 diabetes should also include nutritional counseling, weight reduction as needed, and exercise. These efforts are important not only in the primary treatment of type 2 diabetes, but also to maintain the efficacy of drug therapy. CONTRAINDICATIONS ACTOS is contraindicated in patients with known hypersensitivity to this product or any of its components. WARNINGS Cardiac Failure and Other Cardiac Effects ACTOS, like other thiazolidinediones, can cause fluid retention when used alone or in combination with other antidiabetic agents, including insulin. Fluid retention may lead to or exacerbate heart failure. Patients should be observed for signs and symptoms of heart failure (see Information for Patients). ACTOS should be discontinued if any deterioration in cardiac status occurs. Patients with New York Heart Association (NYHA) Class III and IV cardiac status were not studied during pre-approval clinical trials; ACTOS is not recommended in these patients (see PRECAUTIONS, Cardiovascular). PLA-TAK-00062918 Source: NDA 21-073/S-023 Page 16 Hepatic Effects: In pre-approval clinical studies worldwide, over 4500 subjects were treated with ACTOS. In U.S. clinical studies, over 4700 patients with type 2 diabetes received ACTOS. There was no evidence of drug-induced hepatotoxicity or elevation of ALT levels in the clinical studies. During pre-approval placebo-controlled clinical trials in the U.S., a total of 4 of 1526 (0.26%) patients treated with ACTOS and 2 of 793 (0.25%) placebo-treated patients had ALT values 3 times the upper limit of normal. The ALT elevations in patients treated with ACTOS were reversible and were not clearly related to therapy with ACTOS. In postmarketing experience with ACTOS, reports of hepatitis and of hepatic enzyme elevations to 3 or more times the upper limit of normal have been received. Very rarely, these reports have involved hepatic failure with and without fatal outcome, although causality has not been established. Pioglitazone is structurally related to troglitazone, a thiazolidinedione no longer marketed in the United States, which was associated with idiosyncratic hepatotoxicity and cases of liver failure, liver transplants and death during postmarketing clinical use. In pre-approval controlled clinical trials in patients with type 2 diabetes, troglitazone was more frequently associated with clinically significant elevations of hepatic enzymes (ALT > 3 times the upper limit of normal) compared to placebo, and cases of reversible jaundice were reported. Pending the availability of the results of additional large, long-term controlled clinical triais and additional postmarketing safety data, it is recommended that patients treated with ACTOS undergo periodic monitoring of liver enzymes. Serum ALT (alanine aminotransferase) levels should be evaluated prior to the initiation of therapy with ACTOS in all patients and periodically therealter per the clinical judgment of the health care professional. Liver function tests should also be obtained for patients if symptoms suggestive of hepatic dysfunction occur, e.g., nausea, vomiting, abdominal pain, fatigue, anorexia, or dark urine. The decision whether to continue the patient on therapy with ACTOS should be guided by clinical judgment pending laboratory evaluations, If jaundice is observed, drug therapy should be discontinued. Therapy with ACTOS should not be initiated if the patient exhibits clinical evidence of active liver disease or the ALT levels exceed 2.5 times the upper limit of normal. Patients with mildly elevated liver enzymes (ALT levels at 1 to 2,5 times the upper limit of normal) at baseline or any time during therapy with ACTOS should be evaluated to determine the cause of the liver enzyme elevation. Initiation or continuation of therapy with ACTOS in patients with mildly elevated liver enzymes should proceed with caution and include appropriate clinical follow-up which may include more frequent liver enzyme monitoring. If serum transaminase levels are increased (ALT > 2.5 times the rupper limit of normal), liver function tests should be evaluated more frequently until the levels return to normal or pretreatment values. If ALT levels exceed 3 times the upper limit of normal, the test should be repeated as soon as possible. If ALT levels remain > 3 times the upper limit of normal or if the patient is jaundiced, ACTOS therapy should be discontinued. There are no data available to evaluate the safety of ACTOS in patients who experienced liver abnormalities, hepatic dysfunction, or jaundice while on troglitazone. ACTOS should not be used in patients who experienced jaundice while taking troglitazone. https://wwww.industryeneeatents.ucsf.edu/docs/hfkf0226 PLA-TAK-00062919 Source: NDA 21-073/S-023 Page 15 In insulin combination studies, a small number of patients with a history of previously existing cardiac disease developed congestive heart failure when treated with ACTOS in combination with insulin (see WARNINGS). Patients with NYHA Class III and IV cardiac status were not studied in these ACTOS clinical trials. ACTOS is not indicated in patients with NYHA Class III or IV cardiac status. In postmarketing experience with ACTOS, cases of congestive heart failure have been reported in patients both with and without previously known heart disease. Edema: ACTOS should be used with caution in patients with edema. In all U.S. clinical trials, edema was reported more frequently in patients treated with ACTOS than in placebo-treated patients and appears to be dose related (see ADVERSE REACTIONS). In postmarketing experience, reports of initiation or worsening of edema have been received. Weight Gain: Dose related weight gain was seen with ACTOS alone and in combination with other hypoglycemic agents (Table 6). The mechanism of weight gain is unclear but probably involves a combination of fluid retention and fat accumulation. Table 6 Weight Changes (kg) from Baseline during Double-Blind Clinical Trials with ACTOS Control Group ACTOS ACTOS ACTOS (Placebo) 15 mg 30 mg 45 mg Median Median Median Median (25°/75" percentile) percentile) percentile) percentile) 114 (-2.7/0.0) 0.9(-0.5/3.4) 1.0(-0.9/3.4) 2.6 (0.2/5.4) Monotherapy n=256 n = 79 n=188 n=79 -0,5 (-1.8/0.7) 2.0 (0.2/3.2) 3.1 (1.1/5.4) 4.1 (1.8/7.3) Combination Sulfonylurea n=187 n=183 n=528 N=333 Therapy Melformin -1.4 (-3.2/0.3) N/A 0.9(-0.3/3.2) 1.8(-0.9/5.0) n=160 n=567 N=407 0.2 (-1.4/1.4) 2.3 (0.5/4.3) 3.3 (0.9/6.3) 4.1 (1.4/6.8) insulin n=182 n=190 n=522 N=338 Note: Trial durations of 16 la 26 weeks Ovulation: Therapy with ACTOS, like other thiazolidinediones, may result in ovulation in some premenopausal anovulatory women. As a result, these patients may be at an increased risk for pregnancy while taking ACTOS. Thus, adequate contraception in premenopausal women should be recommended. This possible effect has not been investigated in clinical studies so the frequency of this occurrence is not known. Hematologic: ACTOS may cause decreases in hemoglobin and hematocrit. Across all clinical studies, mean hemoglobin values declined by 2% to 4% in patients treated with ACTOS. These changes primarily occurred within the first 4 to 12 weeks of therapy and remained relatively constant thereafter. These changes may be related to increased plasma volume and have rarely been associated with any significant hematologic clinical effects (see ADVERSE REACTIONS, Laboratory Abnormalities). PLA-TAK-00062920 Source: NDA 21-073/S-023 Page 14 In one 16-week U.S. double-blind, placebo-controlled clinical trial involving 566 patients with type 2 diabetes, ACTOS at doses of 15 mg and 30 mg in combination with insulin was compared to insulin therapy alone. This trial included patients with long-standing diabetes and a high prevalence of pre-existing medical conditions as follows: arterial hypertension (57.2%), peripheral neuropathy (22.6%), coronary heart disease (19.6%), retinopathy (13.1%), myocardial infarction (8.8%), vascular disease (6.4%), angina pectoris (4.4%), stroke and/or transient ischemic attack (4.1%), and congestive heart failure (2.3%). In this study two of the 191 patients receiving 15 mg ACTOS plus insulin (1.1%) and two of the 188 patients receiving 30 mg ACTOS plus insulin (1.1%) developed congestive heart failure compared with none of the 187 patients on insulin therapy alone. All four of these patients had previous histories of cardiovascular conditions including coronary artery disease, previous CABG procedures, and myocardial infarction. In a 24-week dose- controlled study in which ACTOS was coadministered with insulin, 0.3% of patients (1/345) on 30 mg and 0,9% (3/345) of patients on 45 mg reported CHF as a serious adverse event. Analysis of data from these studies did not identify specific factors that predict increased risk of congestive heart failure on combination therapy with insulin. In type 2 diabetest and congestive heart failure (systolic dysfunction) A 24-week post-marketing safety study was performed to compare ACTOS (n=262) to glyburide (n=256) in uncontrolled diabetic patients (mean HbA1c 8.8% at baseline) with NYHA Class Il and III heart failure and ejection fraction less than 40% (mean EF 30% at baseline). Over the course of the study, overnight hospitalization for congestive heart failure was reported in 9.9% of patients on ACTOS compared to 4.7% of patients on glyburide with a treatment difference observed from 6 weeks. This adverse event associated with ACTOS was more marked in patients using insulin at baseline and in patients over 64 years of age. No difference in cardiovascular mortality between the treatment groups was observed. ACTOS should be initiated at the lowest approved dose if it is prescribed for patients with type 2 diabetes and systolic heart failure (NYHA Class II). If subsequent dose escalation is necessary, the dose should be increased gradually only after several months of treatment with careful monitoring for weight gain, edema, or signs and symptoms of CHF exacerbation. PRECAUTIONS General ACTOS exerts its antihyperglycemic effect only in the presence of insulin. Therefore, ACTOS should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis. Hypoglycemia: Patients receiving ACTOS in combination with insulin or oral hypogly-cemic agents may be at risk for hypoglycemia, and a reduction in the dose of the con-comitant agent may be necessary. Cardiovascular: In U.S. placebo-controlled clinical trials that excluded patients with New York Heart Association (NYHA) Class III and IV cardiac status, the incidence of serious cardiac adverse events related to volume expansion was not increased in patients treated with ACTOS as monotherapy or in combination with sulfonylureas or metformin vs. placebo- treated patients. PLA-TAK-00062921 NDA 21-073/S-023 Page 17 Laboratory Tests FPG and HbAre measurements should be performed periodically to monitor glycemic control and the therapeutic response to ACTOS. Liver enzyme monitoring is recommended prior to inifiation of therapy with ACTOS in all patients and periodically thereafter per the clinical judgment of the health care professional (see PRECAUTIONS, General, Hepatic Effects and ADVERSE REACTIONS, Serum Transaminase Levels). Information for Patients It is important to instruct patients to adhere to dietary instructions and to have blood glucose and glycosylated hemoglobin tested regularly. During periods of stress such as fever, trauma, infection, or surgery, medication requirements may change and patients should be reminded to seek medical advice promptly. Patients who experience an unusually rapid increase in weight or edema or who develop shortness of breath or other symptoms of heart failure while on ACTOS should immediately report these symptoms to their physician. Patients should be told that blood tests for liver function will be performed prior to the start of therapy and periodically thereafter per the clinical judgment of the health care professional. Patients should be told to seek immediate medical advice for unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or dark urine. Patients should be fold to take ACTOS once daily. ACTOS can be taken with or without meals. If a dose is missed on one day, the dose should not be doubled the following day. When using combination therapy with insulin or oral hypoglycemic agents, the risks of hypoglycemia, its symptoms and treatment, and conditions that predispose to its development should be explained to patients and their family members, Therapy with ACTOS, like other thiazolidinediones, may result in ovulation in some premenopausal anovulatory women. As a result, these patients may be at an increased risk for pregnancy while taking ACTOS. Thus, adequate contraception in premeno-pausal women should be recommended. This possible effect has not been investigated in clinical studies so the frequency of this occurrence is not known. Drug Interactions In vivo drug-drug interaction studies have suggested that pioglitazone may be a weak inducer of CYP 450 isoform 3A4 substrate (see CLINICAL PHARMACOLOGY, Metabolism and Drug-Drug Interactions). Carcinogenesis, Mutagenesis, Impairment of Fertility A two-year carcinogenicity study was conducted in male and female rats at oral doses up to 63 mg/kg (approximately 14 times the maximum recommended human oral dose of 45 mg based on mg/m²). Drug-induced tumors were not observed in any organ ex-cept for the urinary bladder. Benign and/or malignant transitional cell neoplasms were observed in male rats at 4 mg/kg/day and above (approximately equal to the maximum recommended human oral dose based on mg/m²). A two-year carcinogenicity study was conducted in male and female mice at oral doses up to 100 mg/kg/day (approximately 11 times the maximum recommended human oral dose based on mg/m²). No drug-induced tumors were observed in any organ. Urinary tract tumors have been reported in rodents taking experimental drugs with dual PPAR aly activity; however ACTOS is a selective agonist for PPAR During prospective evaluation of urinary cytology involving more than 1800 patients receiving ACTOS in clinical trials up to one year in duration, no new cases of bladder tumors PLA-TAK-00062922 INDA 21-073/S-023 Page 18 were identified. Occasionally, abnormal urinary cytology results indicating possible malignancy were observed in both patients treated with ACTOS (0.72%) and patients treated with placebo (0.88%). Pioglitazone HCI was not mutagenic in a battery of genetic toxicology studies, including the Ames bacterial assay, a mammalian cell forward gene mutation assay (CHO/HPRT and AS52/XPRT), an in vitro cytogenetics assay using CHL cells, an unscheduled DNA synthesis assay, and an in vivo micronucleus assay. No adverse effects upon fertility were observed in male and female rats at oral doses up to 40 mg/kg pioglitazone HCI daily prior to and throughout mating and gestation (approximately 9 times the maximum recommended human oral dose based on mg/m²). Animal Toxicology Heart enlargement has been observed in mice (100 mg/kg), rats (4 mg/kg and above) and dogs (3 mg/kg) treated orally with pioglitazone HCI (approximately 11, 1, and 2 times the maximum recommended human oral dose for mice, rats, and dogs, respec-tively, based on mg/m². In a one-year rat study, drug-related early death due to apparent heart dysfunction occurred at an oral dose of 160 mg/kg/day (approximately 35 times the maximum recommended human oral dose based on mg/m²). Heart enlargement was seen in a 13- week study in monkeys at oral doses of 8.9 mg/kg and above (approximately 4 times the maximum recommended human oral dose based on mg/m²), but not in a 52-week study at oral doses up to 32 mg/kg (approximately 13 times the maximum recommended human oral dose based on mg/m²). Pregnancy Pregnancy Category C. Pioglitazone was not teratogenic in rats at oral doses up to 80 mg/kg or in rabbits given up to 160 mg/kg during organogenesis (approximately 17 and 40 times the maximum recommended human oral dose based on mg/m², respectively). Delayed parturition and embryotoxicity (as evidenced by increased postimplantation losses, delayed development and reduced fetal weights) were observed in rats at oral doses of 40 mg/kg/day and above (approximately 10 times the maximum recommended human oral dose based on mg/m²). No functional or behavioral toxicity was observed in offspring of rats. In rabbits, embryotoxicity was observed at an oral dose of 160 mg/kg (approximately 40 times the maximum recommended human oral dose based on mg/m²). Delayed postnatal development, attributed to decreased body weight, was observed in offspring of rats at oral doses of 10 mg/kg and above during late gestation and lactation periods (approximately 2 times the maximum recommended human oral dose based on mg/m²). There are no adequate and well-controlled studies in pregnant women. ACTOS should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Because current information strongly suggests that abnormal blood glucose levels during pregnancy are associated with a higher incidence of congenital anomalies, as well as increased neonatal morbidity and mortality, most experts recommend that insu-lin be used during pregnancy to maintain blood glucose levels as close to normal as possible. Nursing Mothers Pioglitazone is secreted in the milk of lactating rats. It is not known whether ACTOS is secreted in human milk. Because many drugs are excreted in human milk, ACTOS should not be administered to a breastfeeding woman, PLA-TAK-00062923 Source: NDA 21-073/S-023 Page 19 Pediatric Use Safety and effectiveness of ACTOS in pediatric patients have not been established. Elderly Use Approximately 500 patients in placebo-controlled clinical trials of ACTOS were 65 and over. No significant differences in effectiveness and safety were observed between these patients and younger patients. ADVERSE REACTIONS In worldwide clinical trials, over 5900 patients with type 2 diabetes have been treated with ACTOS. In U.S. clinical trials, over 4700 patients have received ACTOS, over 3300 patients have been treated for 6 months or longer, and over 450 patients for one year or longer. The overall incidence and types of adverse events reported in placebo-controlled clinical trials of ACTOS monotherapy at doses of 7.5 mg, 15 mg, 30 mg, or 45 mg once daily are shown in Table 7. Table 7 Placebo-Controlled Clinical Studies of ACTOS Monotherapy: Adverse Events Reported at a Frequency 5% of Patients Treated with ACTOS (% of Patients) Placebo ACTOS N=259 N=606 Upper Respiratory Tract Infection 8.5 13.2 Headache 6.9 9.1 Sinusitis 4.6 6.3 Myalgia 2.7 5.4 Tooth Disorder 2.3 5.3 Diabetes Mellitus Aggravated 8.1 5.1 Pharyngitis 0.8 5.1 For most clinical adverse events the incidence was similar for groups treated with ACTOS monotherapy and those treated in combination with sulfonylureas, metformin, and insulin. There was an increase in the occurrence of edema in the patients treated with ACTOS and insulin compared to insulin alone. In a 16-week, placebo-controlled ACTOS plus insulin trial (n=379), 10 patients treated with ACTOS plus insulin developed dyspnea and also, at some point during their therapy, developed either weight change or edema. Seven of these 10 patients received diuretics to treat these symptoms. This was not reported in the insulin plus placebo group. The incidence of withdrawals from placebo-controlled clinical trials due to an adverse event other than hyperglycemia was similar for patients treated with placebo (2.8%) or ACTOS (3.3%). In controlled combination therapy studies with either a sulfonylurea or insulin, mild to moderate hypoglycemia, which appears to be dose related, was reported (see PRECAUTIONS, General, Hypoglycemia and DOSAGE and ADMINISTRATION, Combination Therapy). In U.S. double-blind studies, anemia was reported in S 2% of patients treated with ACTOS plus sulfonylurea, metformin or insulin (see PRECAUTIONS, General, Hematologic). PLA-TAK-00062924 NDA 21-073/S-023 Page 20 In monotherapy studies, edema was reported for 4.8% of patients treated with ACTOS versus 1.2% of placebo-treated patients. In combination therapy studies, edema was reported for 7.2% of patients treated with ACTOS and sulfonylureas com-pared to 2.1% of patients on sulfonylureas alone. In combination therapy studies with metformin, edema was reported in 6,0% of patients on combination therapy compared to 2.5% of patients on metformin alone. In combination therapy studies with insulin, edema was reported in 15.3% of patients on combination therapy compared to 7,0% of patients on insulin alone, Most of these events were considered mild or moderate in intensity (see PRECAUTIONS, General, Edema). In one 16-week clinical trial of insulin plus ACTOS combination therapy, more patients developed congestive heart failure on combination therapy (1.1%) compared to none on insulin alone (see WARNINGS, Cardiac Failure and Other Cardiac Effects). Laboratory Abnormalities Hematologic: ACTOS may cause decreases in hemoglobin and hematocrit. The fall in hemoglobin and hematocrit with ACTOS appears to be dose related. Across all clinical studies, mean hemoglobin values declined by 2% to 4% in patients treated with ACTOS, These changes generally occurred within the first 4 to 12 weeks of therapy and remained relatively stable thereafter. These changes may be related to increased plasma volume associated with ACTOS therapy and have rarely been associated with any significant hematologic clinical effects. Serum Transaminase Levels: During all clinical studies in the U.S., 14 of 4780 (0.30%) patients treated with ACTOS had ALT values 3 times the upper limit of normal during treatment. All patients with follow-up values had reversible elevations in ALT. In the population of patients treated with ACTOS, mean values for bilirubin, AST, ALT, alkaline phosphatase, and GGT were decreased at the final visit compared with baseline. Fewer than 0.9% of patients treated with ACTOS were withdrawn from clinical trials in the U.S. due to abnormal liver function tests. In pre-approval clinical trials, there were no cases of idiosyncratic drug reactions leading to hepatic failure (see PRECAUTIONS, Hepatic Effects). CPK Levels: During required laboratory testing in clinical trials, sporadic, transient elevations in creatine phosphokinase levels (CPK) were observed. An isolated elevation to greater than 10 times the upper limit of normal was noted in 9 patients (values of 2150 to 11400 IU/L). Six of these patients continued to receive ACTOS, two patients had completed receiving study medication at the time of the elevated value and one patient discontinued study medication due to the elevation. These elevations resolved without any apparent clinical sequelae. The relationship of these events to ACTOS therapy is unknown. OVERDOSAGE During controlled clinical trials, one case of overdose with ACTOS was reported. A male patient took 120 mg per day for four days, then 180 mg per day for seven days, The patient denied any clinical symptoms during this period. In the event of overdosage, appropriate supportive treatment should be initiated according to patient's clinical signs and symptoms. Source: PLA-TAK-00062925 NDA 21-073/S-023 Page 21 DOSAGE AND ADMINISTRATION ACTOS should be taken once daily without regard to meals. The management of antidiabetic therapy should be individualized. Ideally, the response to therapy should be evaluated using HbA1c which is a better indicator of long-term glycemic control than FPG alone. HbA1e reflects glycemia over the past two to three months. In clinical use, it is recommended that patients be treated with ACTOS for a period of time adequate to evaluate change in HbA1d (three months) unless glycemic control deteriorates, Monotherapy ACTOS monotherapy in patients not adequately controlled with diet and exercise may be initiated at 15 mg or 30 mg once daily. For patients who respond inadequately to the initial dose of ACTOS, the dose can be increased in increments up to 45 mg once daily. For patients not responding adequately to monotherapy, combination therapy should be considered. Combination Therapy Sulfonylureas: ACTOS in combination with a sulfonylurea may be initiated at 15 mg or 30 mg once daily. The current sulfonylurea dose can be continued upon initiation of ACTOS therapy. If patients report hypoglycemia, the dose of the sulfonylurea should be decreased. Metformin: ACTOS in combination with metformín may be initiated at 15 mg or 30 mg once daily. The current metformin dose can be continued upon initiation of ACTOS therapy. It is unlikely that the dose of metformin will require adjustment due to hypo-glycemia during combination therapy with ACTOS. Insulin: ACTOS in combination with insulin may be initiated at 15 mg or 30 mg once daily. The current insulin dose can be continued upon initiation of ACTOS therapy. In patients receiving ACTOS and insulin, the insulin dose can be decreased by 10% to 25% if the patient reports hypoglycemia or if plasma glucose concentrations decrease to less than 100 mg/dL. Further adjustments should be individualized based on glucose-lowering response. Maximum Recommended Dose The dose of ACTOS should not exceed 45 mg once daily in monotherapy or in combination with sulfonylurea, metformin, or insulin. Dose adjustment in patients with renal insufficiency is not recommended (see CLINICAL PHARMACOLOGY, Pharmacokinetics and Drug Metabolism). Therapy with ACTOS should not be initiated if the patient exhibits clinical levidence of active liver disease or increased serum transaminase levels (ALT greater than 2.5 times the upper limit of normal) at start of therapy (see PRECAUTIONS, General, Hepatic Effects and CLINICAL PHARMACOLOGY, Special Populations, Hepatic Insufficiency). Liver enzyme monitoring is recommended in all patients prior to initiation of therapy with ACTOS and periodically thereafter (see PRECAUTIONS, General, Hepatic Effects). There are no data on the use of ACTOS in patients under 18 years of age; therefore, use of ACTOS in pediatric patients is not recommended. No data are available on the use of ACTOS in combination with another thiazolidinedione. Source: https://www.industryeeeateents.ucsf.edu/docs/hfkf0226 PLA-TAK-00062926 NDA 21-073/S-023 Page 22 HOW SUPPLIED ACTOS is available in 15 mg, 30 mg, and 45 mg tablets as follows: 15 mg Tablet: white to off-white, round, convex, non-scored tablet with "ACTOS" on one side, and "15" on the other, available in: NDC 64764-151-04 Bottle of 30 NDC 64764-151-05 Bottle of 90 NDC 64764-151-06 Bottle of 500 30 mg Tablet: white to off-white, round, flat, non-scored tablet with "ACTOS" on one side, and "30" on the other, available in: NDC 64764-301-14 Bottle of 30 NDC 64764-301-15 Bottle of 90 NDC 64764-301-16 Bottle of 500 45 mg Tablet: white to off-white, round, flat, non-scored tablet with "ACTOS" on one side, and "45" on the other, available in: NDC 64764-451-24 Bottle of 30 NDC 64764-451-25 Bottle of 90 NDC 64764-451-26 Bottle of 500 STORAGE Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Keep container tightly closed, and protect from moisture and humidity. Rx only Manufactured by: Takeda Chemical Industries, Ltd. Osaka, Japan Marketed by: Takeda Pharmaceuticals America, Inc. 475 Half Day Road Lincolnshire, IL 60069 and Ell Lilly and Company Lilly Corporate Center Indianapolis, IN 46285 ACTOS® is a registered trademark of Takeda Chemical Industries, Ltd. and used under license by Takeda Pharmaceuticals America, Inc. and Eli Lilly and Co. All other trademark names are the property of their respective owners. 5012100-07 Revised: July 2004 PLA-TAK-00062927 Source:

Prior to what, the patients entered an 8 week washout/run-in-period?

hfkf0226

hfkf0226_p0, hfkf0226_p1, hfkf0226_p2, hfkf0226_p3, hfkf0226_p4, hfkf0226_p5, hfkf0226_p6, hfkf0226_p7, hfkf0226_p8, hfkf0226_p9, hfkf0226_p10, hfkf0226_p11, hfkf0226_p12, hfkf0226_p13, hfkf0226_p14, hfkf0226_p15, hfkf0226_p16, hfkf0226_p17, hfkf0226_p18, hfkf0226_p19

double-blind treatment

NDA 21-073/S-023 Page 3 EXHIBIT 8 ACTOS Rully (pioglitazone hydrochloride) Tablets DESCRIPTION ACTOS (pioglitazone hydrochloride) is an oral antidiabetic agent that acts primarily by decreasing insulin resistance. ACTOS is used in the management of type 2 diabetes mellitus (also known as non-insulin-dependent diabetes mellitus [NIDDM] or adult-onset diabetes). Pharmacological studies indicate that ACTOS improves sensitivity to insulin in muscle and adipose tissue and inhibits hepatic giuconeogenesis. ACTOS improves glycemic control while reducing circulating insulin levels. Pioglitazone [()-5-[[4-[2-(5-ethyl-2-pyridinyl)ethoxy]phenyl]methyl}-2,4-]thiazolidine-dione monohydrochloride belongs to a different chemical class and has a different pharmacological action than the sulfonylureas, metformin, or the c--glucosidase inhibi-tors. The molecule contains one asymmetric carbon, and the compound is synthesized and used as the racemic mixture. The two enantiomers of pioglitazone interconvert in vivo. No differences were found in the pharmacologic activity between the two enan-tiomers. The structural formula is as shown: S o CH 3 N HC1 NH o o Pioglitazone hydrochloride is an odorless white crystalline powder that has a molecular formula of and a molecular weight of 392.90 daltons. It is soluble in N,N- dimethylformamide, slightly soluble in anhydrous ethanol, very slightly soluble in acetone and acetonitrile, practically insoluble in water, and insoluble in ether. ACTOS is available as a tablet for oral administration containing 15 mg, 30 mg, or 45 mg of pioglitazone (as the base) formulated with the following excipients: lactose monohydrate NF, hydroxypropylcellulose NF, carboxymethylcellulose calcium NF, and magnesium stearate NF. CLINICAL PHARMACOLOGY Mechanism of Action ACTOS is a thiazolidinedione antidiabetic agent that depends on the presence of insulin for its mechanism of action. ACTOS decreases insulin resistance in the periphery and in the liver resulting in increased insulin-dependent glucose disposal and decreased he-patic glucose output. Unlike sulfonylureas, pioglitazone is not an insulin secretagogue. Pioglitazone is a potent and highly selective agonist for peroxisome proliferator-activated receptor-gamma (PPARy). PPAR receptors are found in tissues important for insulin action such as adipose tissue, skeletal muscle, and liver. Activation of PPARY nuclear receptors modulates the transcription of a number of insulin responsive genes involved in the control of glucose and lipid metabolism. In animal models of diabetes, pioglitazone reduces the hyperglycemia, hyperinsulin-emia, and hypertriglyceridemia characteristic of insulin-resistant states such as type 2 diabetes. The metabolic changes produced by pioglitazone result in increased respon-siveness of insulin-dependent tissues and are observed in numerous animal models of insulin resistance. PLA-TAK-00062908 Source: NDA 21-073/S-023 Page 4 Since pioglitazone enhances the effects of circulating insulin (by decreasing insulin resistance), it does not lower blood glucose in animal models that lack endogenous insulin. Pharmacokinetics and Drug Metabolism Serum concentrations of total pioglitazone (pioglitazone plus active metabolites) remain elevated 24 hours after once daily dosing. Steady-state serum concentrations of both pioglitazone and total pioglitazone are achieved within 7 days. At steady-state, two of the pharmacologically active metabolites of pioglitazone, Metabolites III (M-III) and IV (M-IV), reach serum concentrations equal to or greater than pioglitazone. In both healthy volunteers and in patients with type 2 diabetes, pioglitazone comprises approx-imately 30% to 50% of the peak total pioglitazone serum concentrations and 20% to 25% of the total area under the serum concentration-time curve (AUC). Maximum serum concentration (Cmax), AUC, and trough serum concentrations (Cmin) for both pioglitazone and total pioglitazone increase proportionally at doses of 15 mg and 30 mg per day. There is a slightly less than proportional increase for pioglitazone and total pioglitazone at a dose of 60 mg per day. Absorption: Following oral administration, in the fasting state, pioglitazone is first measurable in serum within 30 minutes, with peak concentrations observed within 2 hours. Food slightly delays the time to peak serum concentration to 3 to 4 hours, but does not alter the extent of absorption. Distribution: The mean apparent volume of distribution (Vd/F) of pioglitazone following single-dose administration is 0.63 0.41 (mean SD) L/kg of body weight. Pioglita-zone is extensively protein bound (A 99%) in human serum, principally to serum albu-min. Pioglitazone also binds to other serum proteins, but with lower affinity. Metabolites M-III and M-IV also are extensively bound P 98%) to serum albumin. Metabolism: Pioglitazone is extensively metabolized by hydroxylation and oxidation; the metabolites also partly convert to glucuronide or sulfate conjugates. Metabolites M-II and M-IV (hydroxy derivatives of pioglitazone) and M-III (keto derivative of pioglita-zone) are pharmacologically active in animal models of type 2 diabetes. In addition to pioglitazone, M- III and M-IV are the principal drug-related species found in human serum following multiple dosing. At steady-state, in both healthy volunteers and in patients with type 2 diabetes, pioglitazone comprises approximately 30% to 50% of the total peak serum concentrations and 20% to 25% of the total AUC. In vitro data demonstrate that multiple CYP isoforms are involved in the metabolism of pioglitazone. The cytochrome P450 isoforms involved are CYP2C8 and, to a lesser degree, CYP3A4 with additional contributions from a variety of other isoforms including the mainly extrahepatic CYP1A1. In vivo studies of pioglitazone in combination with P450 inhibitors and substrates have been performed (see Drug Interactions). Urinary 6ß-hydroxycortisol/cortisol ratios measured in patients treated with ACTOS showed that pioglitazone is not a strong CYP3A4 enzyme inducer. PLA-TAK-00062909 Source: NDA 21-073/S-023 Page 5 Excretion and Elimination: Following oral administration, approximately 15% to 30% of the pioglitazone dose is recovered in the urine. Renal elimination of pioglitazone is negligible, and the drug is excreted primarily as metabolites and their conjugates. It is presumed that most of the oral dose is excreted into the bile either unchanged or as metabolites and eliminated in the feces, The mean serum half-life of pioglitazone and total pioglitazone ranges from 3 to 7 hours and 16 to 24 hours, respectively. Pioglitazone has an apparent clearance, CL/F, calculated to be 5 to 7 L/hr. Special Populations Renal Insufficiency The serum elimination half-life of pioglitazone, M-III, and M-IV remains unchanged in patients with moderate (creatinine clearance 30 to 60 mL/min) to severe (creatinine clearance < 30 mL/min) renal impairment when compared to normal subjects. No dose adjustment in patients with renal dysfunction is recommended (see DOSAGE AND ADMINISTRATION). Hepatic Insufficiency: Compared with normal controls, subjects with impaired hepatic function (Child-Pugh Grade B/C) have an approximate 45% reduction in pioglitazone and total pioglitazone mean peak concentrations but no change in the mean AUC values. ACTOS therapy should not be initiated if the patient exhibits clinical evidence of active liver disease or serum transaminase levels (ALT) exceed 2,5 times the upper limit of normal (see PRECAUTIONS, Hepatic Effects). Elderly: In healthy elderly subjects, peak serum concentrations of pioglitazone and total pioglitazone are not significantly different, but AUC values are slightly higher and the terminal half-life values slightly longer than for younger subjects. These changes were not of a magnitude that would be considered clinically relevant. Pediatrics: Pharmacokinetic data in the pediatric population are not available. Gender: The mean Cmex and AUC values were increased 20% to 60% in females. As monotherapy and in combination with sulfonylurea, metformin, or insulin, ACTOS im-proved glycemic control in both males and females. In controlled clinical trials, hemo-globin Ate (HbA1d) decreases from baseline were generally greater for females than for males (average mean difference in HbA1c 0,5%). Since therapy should be individual-ized for each patient to achieve glycemic control, no dose adjustment is recommended based on gender alone. Ethnicity: Pharmacokinetic data among various ethnic groups are not available. Drug-Drug Interactions The following drugs were studied in healthy volunteers with a co-administration of ACTOS 45 mg once daily. Listed below are the results: PLA-TAK-00062910 Source: NDA 21-073/S-023 Page 6 Oral Contraceptives: Co-administration of ACTOS (45 mg once daily) and an oral contraceptive (1 mg norethindrone plus 0.035 mg ethinyl estradiol once daily) for 21 days, resulted in 11% and 11-14% decrease in ethinyl estradiol AUC (0-24h) and Cmax respectively. There were no significant changes in norethindrone AUC (0-24h) and Gmax. In view of the high variability of ethinyl estradiol pharmacokinetics, the clinical significance of this finding is unknown. Fexofenadine HCI: Co-administration of ACTOS for 7 days with 60 mg fexofenadine administered orally fwice daily resulted in no significant effect on pioglitazone pharma- cokinetics. ACTOS had no significant effect on fexofenadine pharmacokinetics. Glipizide: Co-administration of ACTOS and 5 mg glipizide administered orally once daily for 7 days did not alter the steady-state pharmacokinetics of glipizide. Digoxin: Co-administration of ACTOS with 0.25 mg digoxin administered orally once daily for 7 days did not alter the steady-state pharmacokinetics of digoxin. Warfarin: Co-administration of ACTOS for 7 days with warfarin did not alter the steady-state pharmacokinetics of warfarin. ACTOS has no clinically significant effect on prothrombin time when administered to patients receiving chronic warfarin therapy Metformin: Co-administration of a single dose of metformin (1000 mg) and ACTOS after 7 days of ACTOS did not alter the pharmacokinetics of the single dose of metformin. Midazolam: Administration of ACTOS for 15 days followed by a single 7.5 mg dose of midazolam syrup resulted in a 26% reduction in midazolam Cmax and AUC. Ranitidine HCI: Co-administration of ACTOS for 7 days with ranitidine administered orally twice daily for either 4 or 7 days resulted in no significant effect on pioglitazone pharmacokinetics. ACTOS showed no significant effect on ranitidine pharmacokinetics. Nifedipine ER: Co-administration of ACTOS for 7 days with 30 mg nifedipine ER ad- ministered orally once daily for 4 days to male and female volunteers resulted in least square mean (90% CI) values for unchanged nifedipine of 0.83 (0.73 - 0.95) for Cmax and 0.88 (0.80 + 0.96) for AUC. In view of the high variability of nifedipine pharmaco-kinetics, the clinical significance of this finding is unknown. Ketoconazole: Co-administration of ACTOS for 7 days with ketoconazole 200 mg administered twice daily resulted in least square mean (90% CI) values for unchanged pioglitazone of 1.14 (1.06 - 1.23) for Cmaxt 1.34 (1.26 - 1.41) for AUC and 1.87 (1.71 - 2.04) for Cmin- Atorvastatin Calcium: Co-administration of ACTOS for 7 days with atorvastatin calcium (LIPITOR 80 mg once daily resulted in least square mean (90% CI) values for un-changed pioglitazone of 0.69 (0.57 n 0.85) for Cmax, 0,76 (0.65 - 0.88) for AUC and 0.96 (0,87 - 1.05) for Cmin- For unchanged atorvastatin the least square mean (90% CI) values were 0.77 (0.66 - 0.90) for Cmax, 0.86 (0.78 - 0.94) for AUC and 0,92 (0.82 - 1.02) for Cmin- PLA-TAK-00062911 Source: NDA 21-073/S-023 Page 7 Theophylline: Co-administration of ACTOS for 7 days with theophylline 400 mg admin-istered twice daily resulted in no change in the pharmacokinetics of either drug. Cytochrome P450: See PRECAUTIONS Pharmacodynamics and Clinical Effects Clinical studies demonstrate that ACTOS improves insulin sensitivity in insulin-resistant patients. ACTOS enhances cellular responsiveness to insulin, increases insulin-dependent glucose disposal, improves hepatic sensitivity to insulin, and improves dysfunctional glucose homeostasis. In patients with type 2 diabetes, the decreased insulin resistance produced by ACTOS results in lower plasma glucose concentrations, lower plasma insulin levels, and lower HbAte values. Based on results from an open-label extension study, the glucose lowering effects of ACTOS appear to persist for at least one year. In controlled clinical triais, ACTOS in combination with sulfonylurea, metformin, or insulin had an additive effect on glycemic control. Patients with lipid abnormalities were included in clinical trials with ACTOS. Overall, patients treated with ACTOS had mean decreases in triglycerides, mean increases in HDL cholesterol, and no consistent mean changes in LDL and total cholesterol. In a 26-week, placebo-controlled, dose-ranging study, mean triglyceride levels de-creased in the 15 mg, 30 mg, and 45 mg ACTOS dose groups compared to a mean in-crease in the placebo group. Mean HDL levels increased to a greater extent in patients treated with ACTOS than in the placebo-treated patients. There were no consistent differences for LDL and total cholesterol in patients treated with ACTOS compared to placebo (Table 1). Table 1 Lipids in a 26-Week Placeba-Controlled Monotherapy Dose-Ranging Study ACTOS ACTOS ACTOS 15 mg 30 mg 45 mg Placebo Once Once Once Daily Daily Daily Triglycerides (mg/dL) N=79 N=79 N=84 N=77 Baseline (mean) 262,8 283.8 261.1 259.7 Percent change from baseline (mean) 4.8% -9.0% -9.6% -9,3% HDL Cholesterol (mg/dL) N=79 N=79 N=83 N=77 Baseline (mean) 41.7 40.4 40.8 40.7 Percent change from baseline (mean) 8.1% 14.1% 12.2% 19.1% LDL Cholesterol (mg/dL) N=65 N=63 N=74 N=62 Baseline (mean) 138.8 131.9 135.6 126.8 Percent change from baseline (mean) 4.8% 7.2% 5.2% 6.0% Total Cholesterol (mg/dL) N=79 N=79 N=84 N=77 Baseline (mean) 224,6 220.0 222.7 213.7 Percent change from baseline (mean) 4.4% 4.6% 3,3% 6.4% In the two other monotherapy studies (24 weeks: and 16 weeks) and in combination therapy studies with sulfonylurea (24 weeks and 16 weeks) and metformin (24 weeks and 16 weeks), the results were generally consistent with the data above. in placebo-controlled trials, the placebo-corrected mean changes from baseline decreased 5% to 26% for triglycerides and increased 6% to 13% for HDL in patients treated with ACTOS. A similar pattern of results was seen in 24-week combination therapy studies of ACTOS with sulfonylurea or metformin. PLA-TAK-00062912 NDA 21-073/S-023 Page 8 In a combination therapy study with insulin (16 weeks), the placebo-corrected mean percent change from baseline in triglyceride values for patients treated with ACTOS was also decreased. A placebo-corrected mean change from baseline in LDL cholesterol of 7% was observed for the 15 mg dose group. Similar results to those noted above for HDL and total cholesterol were observed. A similar pattern of results was seen in a 24-week combination therapy study with ACTOS with insulin. Clinical Studies Monotherapy In the U.S., three randomized, double-blind, placebo-controlled trials with durations from 16 to 26 weeks were conducted to evaluate the use of ACTOS as monotherapy in patients with type 2 diabetes. These studies examined ACTOS at doses up to 45 mg or placebo once daily in 865 patients. In a 26-week dose-ranging study, 408 patients with type 2 diabetes were random-ized to receive 7.5 mg, 15 mg, 30 mg, or 45 mg of ACTOS, or placebo once daily. Therapy with any previous antidiabetic agent was discontinued 8 weeks prior to the double-blind period. Treatment with 15 mg, 30 mg, and 45 mg of ACTOS produced statistically significant improvements in HbA1c and fasting plasma glucose (FPG) at endpoint compared to placebo (see Figure 1, Table 2). Figure 1 shows the time course for changes in FPG and HbA1c for the entire study population in this 26-week study. FIGURE 1 MEAN CHANGE FROM BASELINE FOR FPG AND HBA1C IN A 26-WEEK PLACEBO-CONTROLLED DOSE-RANGING STUDY FPG HbA1e 20 1 10 0.8 0.6 -10 0.4 20 n.2 30 o 40 -a. -50 -0,4 -80 -0.8 -70 -0.8 -80 of o 2 4 e 10 14 18 22 25 0 2 of e 10 14 18 22 26 Weeks Weeks Placebo 15mg 30 mg 45 mg Placebo 15mg 30 my 45 mg PLA-TAK-00062913 NDA 21-073/S-023 Page 9 Table 2 shows HbA1c and FPG values for the entire study population. Table 2 Glycemic Parameters in a 26-Week Placebo-Controlled Dose-Ranging Study ACTOS ACTOS ACTOS Placeb 15 mg 30 mg 45 mg o Once Once Once Daily Daily Daily Total Population HbA16 (%) N=79 N=79 N=85 N=76 Baseline (mean) 10.4 10.2 10.2 10.3 Change from baseline (adjusted mean*) 0.7 -0.3 -0.3 -0.9 Difference from placebo (adjusted mean*) -1.0* -1.0* -1,6* FPG (mg/dL) N=79 N=79 N=84 N=77 Baseline (mean) 268 267 269 276 Change from baseline (adjusted mean*) 9 -30 -32 -56 Difference from placebo (adjusted mean*) -39* -41* -65* Adjusted for baseline, pooled center, and pooled center by treatment interaction * p 0.050 vs. placebo The study population included patients not previously treated with antidiabetic medication (naïve; 31%) and patients who were receiving antidiabetic medication at the time of study enrollment (previously treated; 69%). The data for the naïve and previously treated patient subsets are shown in Table 3. All patients entered an 8 week washout/run-in period prior to double-blind treatment. This run-in period was associated with little change in HbA1c and FPG values from screening to baseline for the naïve patients; however, for the previously- treated group, washout from previous antidiabetic medication resulted in deterioration of glycemic control and increases in HbA1c and FPG. Although most patients in the previously- treated group had a decrease from baseline in HbA1c and FPG with ACTOS, in many cases the values did not return to screening levels by the end of the study. The study design did not permit the evaluation of patients who switched directly to ACTOS from another antidiabetic agent. PLA-TAK-00062914 Source: NDA 21-073/S-023 Page 10 Table 3 Glycemic Parameters in a 26-Week Placebo-Controlled Dose-Ranging Study ACTOS ACTOS ACTOS Placebo 15 mg 30 mg 45 mg Once Once Once Daily Daily Daily Naïve to Therapy HbA1e (%) N=25 N=26 N=26 N=21 Screening (mean) 9.3 10.0 9.5 9.8 Baseline (mean) 9.0 9.9 9.3 10.0 Change from baseline (adjusted mean*) 0,6 -0.8 -0.6 -1.9 Difference from placebo (adjusted mean*) -1.4 -1.3 -2.6 FPG (mg/dL) N=25 N=26 N=26 N=21 Screening (mean) 223 245 239 239 Baseline (mean) 229 251 225 235 Change from baseline (adjusted mean*) 16 -37 -41 -64 Difference from placebo (adjusted mean*) -52 -56 -80 Previously Treated HbA1c (%) N=54 N=53 N=59 N=55 Screening (mean) 9.3 9.0 9.1 9.0 Baseline (mean) 10.9 10.4 10.4 10.6 Change from baseline (adjusted mean*) 0.8 -0,1 -0.0 -0.6 Difference from placebo (adjusted mean*) -1.0 -0,9 -1.4 FPG (mg/dL) N=54 N=53 N=58 N=56 Screening (mean) 222 209 230 215 Baseline (mean) 285 275 286 292 Change from baseline (adjusted mean*) 4 -32 -27 -55 Difference from placebo (adjusted mean*) -36 -31 -59 * Adjusted for baseline and pooled center In a 24-week placebo-controlled study, 260 patients with type 2 diabetes were randomized to one of two forced-titration ACTOS treatment groups or a mock titration placebo group. Therapy with any previous antidiabetic agent was discontinued 6 weeks prior to the double- blind period. in one ACTOS treatment group, patients received an initial dose of 7.5 mg once daily. After four weeks, the dose was increased to 15 mg once daily and after another four weeks, the dose was increased to 30 mg once daily for the remainder of the study (16 weeks). In the second ACTOS treatment group, patients received an initial dose of 15 mg once daily and were titrated to 30 mg once daily and 45 mg once daily in a similar manner. Treatment with ACTOS, as described, produced statistically significant improvements in HbA1c and FPG at endpoint compared to placebo (see Table 4). PLA-TAK-00062915 Source: NDA 21-073/S-023 Page 11 Table 4 Glycemic Parameters in a 24-Week Placebo-Controlled Forced-Titration Study ACTOS ACTOS Placebo 30 mg* 45 mg* Once Daily Once Daily Total Population HbAre (%) N=83 N=85 N=85 Baseline (mean) 10.8 10.3 10,8 Change from baseline (adjusted mean**) 0.9 -0.6 -0,6 Difference from placebo (adjusted mean** -1,5* -1.5" FPG (mg/dL) N=78 N=82 N=85 Basaline (mean) 279 268 281 Change from baseline (adjusted mean"*) 18 -44 -50 Difference from placebo (adjusted mean" ~62* ~68* Final dose in forced litration ++ Adjusted for baseline, pooled center, and paoled center by treatment interaction * p S. 0.050 vs. placebo For patients who had not been previously treated with anfidiabetic medication (24%), mean values at screening were 10,1% for HbA1g and 238 mg/dL for FPG. At baseline, mean HbA1c was 10.2% and mean FPG was 243 mg/dL. Compared with placebo, treat-ment with ACTOS titrated to a final dose of 30 mg and 45 mg resulted in reductions from baseline in mean HbArc of 2.3% and 2.6% and mean FPG of 63 mg/dL and 95 mg/dL, respectively. For patients who had been previously treated with antidiabetic medication (76%), this medication was discontinued at screening. Mean values at screening were 9.4% for HbArc and 216 mg/dL for FPG. At baseline, mean HbA1o was 10.7% and mean FPG was 290 mg/dL. Compared with placebo, treatment with ACTOS titrated to a final dose of 30 mg and 45 mg resulted in reductions from baseline in mean HbA1a of 1.3% and 1.4% and mean FPG of 55 mg/dL and 60 mg/dL, respectively. For many previously-treated patients, HbA1e and FPG had not returned to screening levels by the end of the study. In a 16-week study, 197 patients with type 2 diabetes were randomized to treatment with 30 mg of ACTOS or placebo once daily. Therapy with any previous antidiabetic agent was discontinued 6 weeks prior to the double-blind period. Treatment with 30 mg of ACTOS produced statistically significant improvements in HbA1 and FPG at endpoint compared to placebo (see Table 5). Table 5 Glycemic Parameters in a 16-Week Placebo-Controlled Study Placebo ACTOS 30 mg Once Daily Total Population HbAte (%) N=93 N=100 Baseline (mean) 10.3 10.5 Change from baseline (adjusted mean*) 0,8 -0,6 Difference from placebo (adjusted mean*) -1.4* FPG (mg/dL) N=91 N=99 Baseline (mean) 270 273 Change from baseline (adjusted mean") 8 -50 Difference from placebo (adjusted mean") -58* 7 Adjusted for baseline, pooted center, and pooled center by treatment interaction * P 5 0.050 vs. placabo PLA-TAK-00062916 Source: NDA 21-073/S-023 Page 12 For patients who had not been previously treated with antidiabetic medication (40%), mean values at screening were 10.3% for HbA1e and 240 mg/dL for FPG. At baseline, mean HbA1e was 10.4% and mean FPG was 254 mg/dL. Compared with placebo, treatment with ACTOS 30 mg resulted in reductions from baseline in mean HbA1e of 1.0% and mean FPG of 62 mg/dL. For patients who had been previously treated with antidiabetic medication (60%), this medication was discontinued at screening. Mean values at screening were 9.4% for HbA1e and 216 mg/dL for FPG. At baseline, mean HbA1c was 10,6% and mean FPG was 287 mg/dL. Compared with placebo, treatment with ACTOS 30 mg resulted in reductions from baseline in mean HbA1e of 1,3% and mean FPG of 46 mg/dL. For many previously- treated patients, HbA1e and FPG had not returned to screening levels by the end of the study. Combination Therapy Three 16-week, randomized, double-blind, placebo-controlled clinical studies and three 24- week randomized, double-blind, dose-controlled clinical studies were conducted to evaluate the effects of ACTOS on glycemic control in patients with type 2 diabetes who were inadequately controlled (HbA1c N 8%) despite current therapy with a sulfonylurea, metformin, or insulin. Previous diabetes treatment may have been monotherapy or combination therapy. ACTOS Plus Sulfonylurea Studies Two clinical studies were conducted with ACTOS in combination with a sulfonylurea. Both studies included patients with type 2 diabetes on a sulfonylurea, either alone or in combination with another antidiabetic agent. All other antidiabetic agents were withdrawn prior to starting study treatment. In the first study, 560 patients were randomized to receive 15 mg or 30 mg of ACTOS or placebo ance daily for 16 weeks in addition to their current sulfonylurea regimen. When compared to placebo at Week 16, the addition of ACTOS to the sulfonylurea significantly reduced the mean HbATo by 0,9% and 1.3% and mean FPG by 39 mg/dL and 58 mg/dL for the 15 mg and 30 mg doses, respectively. In the second study, 702 patients were randomized to receive 30 mg or 45 mg of ACTOS once daily for 24 weeks in addition to their current sulfonylurea regimen. The mean reductions from baseline at Week 24 in HbA1d were 1,55% and 1,67% for the 30 mg and 45 mg doses, respectively. Mean reductions from baseline in FPG were 51,5 mg/dL and 56.1 mg/dL. The therapeutic effect of ACTOS in combination with sulfonylurea was observed in patients regardless of whether the patients were receiving low, medium, or high doses of sulfonylurea. ACTOS Plus Metformin Studies Two clinical studies were conducted with ACTOS in combination with metformin. Both studies included patients with type 2 diabetes on metformin, either alone or in combination with another diabetic agent. All other antidiabetic agents were withdrawn prior to starting study treatment. In the first study, 328 patients were randomized to receive either 30 mg of ACTOS or placebo once daily for 16 weeks in addition to their current metformin regimen. When compared to placebo at Week 16, the addition of ACTOS to metformin significantly reduced the mean HbA1o by 0.8% and decreased the mean FPG by 38 mg/dL. In the secand study, 827 patients were randomized to receive either 30 mg or 45 mg of ACTOS once daily for 24 weeks in addition to their current metformin regimen. Source: https://www.industyeReeatents.ucsf.edu/docs/hfkf0226 PLA-TAK-00062917 NDA 21-073/S-023 Page 13 The mean reductions from baseline at Week 24 in HbAse were 0.80% and 1,01% for the 30 mg and 45 mg doses, respectively. Mean reductions from baseline in FPG were 38,2 mg/dL and 50.7 mg/dL. The therapeutic effect of ACTOS in combination with metformin was observed in patients regardless of whether the patients were receiving lower or higher doses of metformin. ACTOS Plus Insulin Studies Two clinical studies were conducted with ACTOS in combination with insulin. Both studies included patients with type 2 diabetes on insulin, either alone or in combination with another antidiabetic agent. All other antidiabetic agents were withdrawn prior to starting study treatment. In the first study, 566 patients receiving a median of 60.5 units per day of insulin were randomized to receive either 15 mg or 30 mg of ACTOS or placebo once daily for 16 weeks in addition to their insulin regimen. When compared to placebo at Week 16, the addition of ACTOS to insulin significantly reduced both HbA1c by 0.7% and 1.0% and FPG by 35 mg/dL and 49 mg/dL for the 15 mg and 30 mg dose, respectively, In the second study, 690 patients receiving a median of 60.0 units per day of insulin received either 30 mg or 45 mg of ACTOS once daily for 24 weeks in addition to their current insulin regimen. The mean reductions from baseline at Week 24 in HbA1c were 1.17% and 1.46% for the 30 mg and 45 mg doses, respectively. Mean reductions from baseline in FPG were 31,9 mg/dL and 45.8 mg/dL. Improved glycemic control was accompanied by mean decreases from baseline in insulin dose requirements of 6,0% and 9.4% per day for the 30 mg and 45 mg dose, respectively. The therapeutic effect of ACTOS in combination with insulin was observed in patients regardless of whether the patients were receiving lower or higher doses of insulin. INDICATIONS AND USAGE ACTOS is indicated as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes (non-insulin-dependent diabetes mellitus, NIDDM). ACTOS is indicated for monotherapy. ACTOS is also indicated for use in combination with a sulfonylurea, metformin, or insulin when diet and exercise plus the single agent does not result in adequate glycemic control. Management of type 2 diabetes should also include nutritional counseling, weight reduction as needed, and exercise. These efforts are important not only in the primary treatment of type 2 diabetes, but also to maintain the efficacy of drug therapy. CONTRAINDICATIONS ACTOS is contraindicated in patients with known hypersensitivity to this product or any of its components. WARNINGS Cardiac Failure and Other Cardiac Effects ACTOS, like other thiazolidinediones, can cause fluid retention when used alone or in combination with other antidiabetic agents, including insulin. Fluid retention may lead to or exacerbate heart failure. Patients should be observed for signs and symptoms of heart failure (see Information for Patients). ACTOS should be discontinued if any deterioration in cardiac status occurs. Patients with New York Heart Association (NYHA) Class III and IV cardiac status were not studied during pre-approval clinical trials; ACTOS is not recommended in these patients (see PRECAUTIONS, Cardiovascular). PLA-TAK-00062918 Source: NDA 21-073/S-023 Page 16 Hepatic Effects: In pre-approval clinical studies worldwide, over 4500 subjects were treated with ACTOS. In U.S. clinical studies, over 4700 patients with type 2 diabetes received ACTOS. There was no evidence of drug-induced hepatotoxicity or elevation of ALT levels in the clinical studies. During pre-approval placebo-controlled clinical trials in the U.S., a total of 4 of 1526 (0.26%) patients treated with ACTOS and 2 of 793 (0.25%) placebo-treated patients had ALT values 3 times the upper limit of normal. The ALT elevations in patients treated with ACTOS were reversible and were not clearly related to therapy with ACTOS. In postmarketing experience with ACTOS, reports of hepatitis and of hepatic enzyme elevations to 3 or more times the upper limit of normal have been received. Very rarely, these reports have involved hepatic failure with and without fatal outcome, although causality has not been established. Pioglitazone is structurally related to troglitazone, a thiazolidinedione no longer marketed in the United States, which was associated with idiosyncratic hepatotoxicity and cases of liver failure, liver transplants and death during postmarketing clinical use. In pre-approval controlled clinical trials in patients with type 2 diabetes, troglitazone was more frequently associated with clinically significant elevations of hepatic enzymes (ALT > 3 times the upper limit of normal) compared to placebo, and cases of reversible jaundice were reported. Pending the availability of the results of additional large, long-term controlled clinical triais and additional postmarketing safety data, it is recommended that patients treated with ACTOS undergo periodic monitoring of liver enzymes. Serum ALT (alanine aminotransferase) levels should be evaluated prior to the initiation of therapy with ACTOS in all patients and periodically therealter per the clinical judgment of the health care professional. Liver function tests should also be obtained for patients if symptoms suggestive of hepatic dysfunction occur, e.g., nausea, vomiting, abdominal pain, fatigue, anorexia, or dark urine. The decision whether to continue the patient on therapy with ACTOS should be guided by clinical judgment pending laboratory evaluations, If jaundice is observed, drug therapy should be discontinued. Therapy with ACTOS should not be initiated if the patient exhibits clinical evidence of active liver disease or the ALT levels exceed 2.5 times the upper limit of normal. Patients with mildly elevated liver enzymes (ALT levels at 1 to 2,5 times the upper limit of normal) at baseline or any time during therapy with ACTOS should be evaluated to determine the cause of the liver enzyme elevation. Initiation or continuation of therapy with ACTOS in patients with mildly elevated liver enzymes should proceed with caution and include appropriate clinical follow-up which may include more frequent liver enzyme monitoring. If serum transaminase levels are increased (ALT > 2.5 times the rupper limit of normal), liver function tests should be evaluated more frequently until the levels return to normal or pretreatment values. If ALT levels exceed 3 times the upper limit of normal, the test should be repeated as soon as possible. If ALT levels remain > 3 times the upper limit of normal or if the patient is jaundiced, ACTOS therapy should be discontinued. There are no data available to evaluate the safety of ACTOS in patients who experienced liver abnormalities, hepatic dysfunction, or jaundice while on troglitazone. ACTOS should not be used in patients who experienced jaundice while taking troglitazone. https://wwww.industryeneeatents.ucsf.edu/docs/hfkf0226 PLA-TAK-00062919 Source: NDA 21-073/S-023 Page 15 In insulin combination studies, a small number of patients with a history of previously existing cardiac disease developed congestive heart failure when treated with ACTOS in combination with insulin (see WARNINGS). Patients with NYHA Class III and IV cardiac status were not studied in these ACTOS clinical trials. ACTOS is not indicated in patients with NYHA Class III or IV cardiac status. In postmarketing experience with ACTOS, cases of congestive heart failure have been reported in patients both with and without previously known heart disease. Edema: ACTOS should be used with caution in patients with edema. In all U.S. clinical trials, edema was reported more frequently in patients treated with ACTOS than in placebo-treated patients and appears to be dose related (see ADVERSE REACTIONS). In postmarketing experience, reports of initiation or worsening of edema have been received. Weight Gain: Dose related weight gain was seen with ACTOS alone and in combination with other hypoglycemic agents (Table 6). The mechanism of weight gain is unclear but probably involves a combination of fluid retention and fat accumulation. Table 6 Weight Changes (kg) from Baseline during Double-Blind Clinical Trials with ACTOS Control Group ACTOS ACTOS ACTOS (Placebo) 15 mg 30 mg 45 mg Median Median Median Median (25°/75" percentile) percentile) percentile) percentile) 114 (-2.7/0.0) 0.9(-0.5/3.4) 1.0(-0.9/3.4) 2.6 (0.2/5.4) Monotherapy n=256 n = 79 n=188 n=79 -0,5 (-1.8/0.7) 2.0 (0.2/3.2) 3.1 (1.1/5.4) 4.1 (1.8/7.3) Combination Sulfonylurea n=187 n=183 n=528 N=333 Therapy Melformin -1.4 (-3.2/0.3) N/A 0.9(-0.3/3.2) 1.8(-0.9/5.0) n=160 n=567 N=407 0.2 (-1.4/1.4) 2.3 (0.5/4.3) 3.3 (0.9/6.3) 4.1 (1.4/6.8) insulin n=182 n=190 n=522 N=338 Note: Trial durations of 16 la 26 weeks Ovulation: Therapy with ACTOS, like other thiazolidinediones, may result in ovulation in some premenopausal anovulatory women. As a result, these patients may be at an increased risk for pregnancy while taking ACTOS. Thus, adequate contraception in premenopausal women should be recommended. This possible effect has not been investigated in clinical studies so the frequency of this occurrence is not known. Hematologic: ACTOS may cause decreases in hemoglobin and hematocrit. Across all clinical studies, mean hemoglobin values declined by 2% to 4% in patients treated with ACTOS. These changes primarily occurred within the first 4 to 12 weeks of therapy and remained relatively constant thereafter. These changes may be related to increased plasma volume and have rarely been associated with any significant hematologic clinical effects (see ADVERSE REACTIONS, Laboratory Abnormalities). PLA-TAK-00062920 Source: NDA 21-073/S-023 Page 14 In one 16-week U.S. double-blind, placebo-controlled clinical trial involving 566 patients with type 2 diabetes, ACTOS at doses of 15 mg and 30 mg in combination with insulin was compared to insulin therapy alone. This trial included patients with long-standing diabetes and a high prevalence of pre-existing medical conditions as follows: arterial hypertension (57.2%), peripheral neuropathy (22.6%), coronary heart disease (19.6%), retinopathy (13.1%), myocardial infarction (8.8%), vascular disease (6.4%), angina pectoris (4.4%), stroke and/or transient ischemic attack (4.1%), and congestive heart failure (2.3%). In this study two of the 191 patients receiving 15 mg ACTOS plus insulin (1.1%) and two of the 188 patients receiving 30 mg ACTOS plus insulin (1.1%) developed congestive heart failure compared with none of the 187 patients on insulin therapy alone. All four of these patients had previous histories of cardiovascular conditions including coronary artery disease, previous CABG procedures, and myocardial infarction. In a 24-week dose- controlled study in which ACTOS was coadministered with insulin, 0.3% of patients (1/345) on 30 mg and 0,9% (3/345) of patients on 45 mg reported CHF as a serious adverse event. Analysis of data from these studies did not identify specific factors that predict increased risk of congestive heart failure on combination therapy with insulin. In type 2 diabetest and congestive heart failure (systolic dysfunction) A 24-week post-marketing safety study was performed to compare ACTOS (n=262) to glyburide (n=256) in uncontrolled diabetic patients (mean HbA1c 8.8% at baseline) with NYHA Class Il and III heart failure and ejection fraction less than 40% (mean EF 30% at baseline). Over the course of the study, overnight hospitalization for congestive heart failure was reported in 9.9% of patients on ACTOS compared to 4.7% of patients on glyburide with a treatment difference observed from 6 weeks. This adverse event associated with ACTOS was more marked in patients using insulin at baseline and in patients over 64 years of age. No difference in cardiovascular mortality between the treatment groups was observed. ACTOS should be initiated at the lowest approved dose if it is prescribed for patients with type 2 diabetes and systolic heart failure (NYHA Class II). If subsequent dose escalation is necessary, the dose should be increased gradually only after several months of treatment with careful monitoring for weight gain, edema, or signs and symptoms of CHF exacerbation. PRECAUTIONS General ACTOS exerts its antihyperglycemic effect only in the presence of insulin. Therefore, ACTOS should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis. Hypoglycemia: Patients receiving ACTOS in combination with insulin or oral hypogly-cemic agents may be at risk for hypoglycemia, and a reduction in the dose of the con-comitant agent may be necessary. Cardiovascular: In U.S. placebo-controlled clinical trials that excluded patients with New York Heart Association (NYHA) Class III and IV cardiac status, the incidence of serious cardiac adverse events related to volume expansion was not increased in patients treated with ACTOS as monotherapy or in combination with sulfonylureas or metformin vs. placebo- treated patients. PLA-TAK-00062921 NDA 21-073/S-023 Page 17 Laboratory Tests FPG and HbAre measurements should be performed periodically to monitor glycemic control and the therapeutic response to ACTOS. Liver enzyme monitoring is recommended prior to inifiation of therapy with ACTOS in all patients and periodically thereafter per the clinical judgment of the health care professional (see PRECAUTIONS, General, Hepatic Effects and ADVERSE REACTIONS, Serum Transaminase Levels). Information for Patients It is important to instruct patients to adhere to dietary instructions and to have blood glucose and glycosylated hemoglobin tested regularly. During periods of stress such as fever, trauma, infection, or surgery, medication requirements may change and patients should be reminded to seek medical advice promptly. Patients who experience an unusually rapid increase in weight or edema or who develop shortness of breath or other symptoms of heart failure while on ACTOS should immediately report these symptoms to their physician. Patients should be told that blood tests for liver function will be performed prior to the start of therapy and periodically thereafter per the clinical judgment of the health care professional. Patients should be told to seek immediate medical advice for unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or dark urine. Patients should be fold to take ACTOS once daily. ACTOS can be taken with or without meals. If a dose is missed on one day, the dose should not be doubled the following day. When using combination therapy with insulin or oral hypoglycemic agents, the risks of hypoglycemia, its symptoms and treatment, and conditions that predispose to its development should be explained to patients and their family members, Therapy with ACTOS, like other thiazolidinediones, may result in ovulation in some premenopausal anovulatory women. As a result, these patients may be at an increased risk for pregnancy while taking ACTOS. Thus, adequate contraception in premeno-pausal women should be recommended. This possible effect has not been investigated in clinical studies so the frequency of this occurrence is not known. Drug Interactions In vivo drug-drug interaction studies have suggested that pioglitazone may be a weak inducer of CYP 450 isoform 3A4 substrate (see CLINICAL PHARMACOLOGY, Metabolism and Drug-Drug Interactions). Carcinogenesis, Mutagenesis, Impairment of Fertility A two-year carcinogenicity study was conducted in male and female rats at oral doses up to 63 mg/kg (approximately 14 times the maximum recommended human oral dose of 45 mg based on mg/m²). Drug-induced tumors were not observed in any organ ex-cept for the urinary bladder. Benign and/or malignant transitional cell neoplasms were observed in male rats at 4 mg/kg/day and above (approximately equal to the maximum recommended human oral dose based on mg/m²). A two-year carcinogenicity study was conducted in male and female mice at oral doses up to 100 mg/kg/day (approximately 11 times the maximum recommended human oral dose based on mg/m²). No drug-induced tumors were observed in any organ. Urinary tract tumors have been reported in rodents taking experimental drugs with dual PPAR aly activity; however ACTOS is a selective agonist for PPAR During prospective evaluation of urinary cytology involving more than 1800 patients receiving ACTOS in clinical trials up to one year in duration, no new cases of bladder tumors PLA-TAK-00062922 INDA 21-073/S-023 Page 18 were identified. Occasionally, abnormal urinary cytology results indicating possible malignancy were observed in both patients treated with ACTOS (0.72%) and patients treated with placebo (0.88%). Pioglitazone HCI was not mutagenic in a battery of genetic toxicology studies, including the Ames bacterial assay, a mammalian cell forward gene mutation assay (CHO/HPRT and AS52/XPRT), an in vitro cytogenetics assay using CHL cells, an unscheduled DNA synthesis assay, and an in vivo micronucleus assay. No adverse effects upon fertility were observed in male and female rats at oral doses up to 40 mg/kg pioglitazone HCI daily prior to and throughout mating and gestation (approximately 9 times the maximum recommended human oral dose based on mg/m²). Animal Toxicology Heart enlargement has been observed in mice (100 mg/kg), rats (4 mg/kg and above) and dogs (3 mg/kg) treated orally with pioglitazone HCI (approximately 11, 1, and 2 times the maximum recommended human oral dose for mice, rats, and dogs, respec-tively, based on mg/m². In a one-year rat study, drug-related early death due to apparent heart dysfunction occurred at an oral dose of 160 mg/kg/day (approximately 35 times the maximum recommended human oral dose based on mg/m²). Heart enlargement was seen in a 13- week study in monkeys at oral doses of 8.9 mg/kg and above (approximately 4 times the maximum recommended human oral dose based on mg/m²), but not in a 52-week study at oral doses up to 32 mg/kg (approximately 13 times the maximum recommended human oral dose based on mg/m²). Pregnancy Pregnancy Category C. Pioglitazone was not teratogenic in rats at oral doses up to 80 mg/kg or in rabbits given up to 160 mg/kg during organogenesis (approximately 17 and 40 times the maximum recommended human oral dose based on mg/m², respectively). Delayed parturition and embryotoxicity (as evidenced by increased postimplantation losses, delayed development and reduced fetal weights) were observed in rats at oral doses of 40 mg/kg/day and above (approximately 10 times the maximum recommended human oral dose based on mg/m²). No functional or behavioral toxicity was observed in offspring of rats. In rabbits, embryotoxicity was observed at an oral dose of 160 mg/kg (approximately 40 times the maximum recommended human oral dose based on mg/m²). Delayed postnatal development, attributed to decreased body weight, was observed in offspring of rats at oral doses of 10 mg/kg and above during late gestation and lactation periods (approximately 2 times the maximum recommended human oral dose based on mg/m²). There are no adequate and well-controlled studies in pregnant women. ACTOS should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Because current information strongly suggests that abnormal blood glucose levels during pregnancy are associated with a higher incidence of congenital anomalies, as well as increased neonatal morbidity and mortality, most experts recommend that insu-lin be used during pregnancy to maintain blood glucose levels as close to normal as possible. Nursing Mothers Pioglitazone is secreted in the milk of lactating rats. It is not known whether ACTOS is secreted in human milk. Because many drugs are excreted in human milk, ACTOS should not be administered to a breastfeeding woman, PLA-TAK-00062923 Source: NDA 21-073/S-023 Page 19 Pediatric Use Safety and effectiveness of ACTOS in pediatric patients have not been established. Elderly Use Approximately 500 patients in placebo-controlled clinical trials of ACTOS were 65 and over. No significant differences in effectiveness and safety were observed between these patients and younger patients. ADVERSE REACTIONS In worldwide clinical trials, over 5900 patients with type 2 diabetes have been treated with ACTOS. In U.S. clinical trials, over 4700 patients have received ACTOS, over 3300 patients have been treated for 6 months or longer, and over 450 patients for one year or longer. The overall incidence and types of adverse events reported in placebo-controlled clinical trials of ACTOS monotherapy at doses of 7.5 mg, 15 mg, 30 mg, or 45 mg once daily are shown in Table 7. Table 7 Placebo-Controlled Clinical Studies of ACTOS Monotherapy: Adverse Events Reported at a Frequency 5% of Patients Treated with ACTOS (% of Patients) Placebo ACTOS N=259 N=606 Upper Respiratory Tract Infection 8.5 13.2 Headache 6.9 9.1 Sinusitis 4.6 6.3 Myalgia 2.7 5.4 Tooth Disorder 2.3 5.3 Diabetes Mellitus Aggravated 8.1 5.1 Pharyngitis 0.8 5.1 For most clinical adverse events the incidence was similar for groups treated with ACTOS monotherapy and those treated in combination with sulfonylureas, metformin, and insulin. There was an increase in the occurrence of edema in the patients treated with ACTOS and insulin compared to insulin alone. In a 16-week, placebo-controlled ACTOS plus insulin trial (n=379), 10 patients treated with ACTOS plus insulin developed dyspnea and also, at some point during their therapy, developed either weight change or edema. Seven of these 10 patients received diuretics to treat these symptoms. This was not reported in the insulin plus placebo group. The incidence of withdrawals from placebo-controlled clinical trials due to an adverse event other than hyperglycemia was similar for patients treated with placebo (2.8%) or ACTOS (3.3%). In controlled combination therapy studies with either a sulfonylurea or insulin, mild to moderate hypoglycemia, which appears to be dose related, was reported (see PRECAUTIONS, General, Hypoglycemia and DOSAGE and ADMINISTRATION, Combination Therapy). In U.S. double-blind studies, anemia was reported in S 2% of patients treated with ACTOS plus sulfonylurea, metformin or insulin (see PRECAUTIONS, General, Hematologic). PLA-TAK-00062924 NDA 21-073/S-023 Page 20 In monotherapy studies, edema was reported for 4.8% of patients treated with ACTOS versus 1.2% of placebo-treated patients. In combination therapy studies, edema was reported for 7.2% of patients treated with ACTOS and sulfonylureas com-pared to 2.1% of patients on sulfonylureas alone. In combination therapy studies with metformin, edema was reported in 6,0% of patients on combination therapy compared to 2.5% of patients on metformin alone. In combination therapy studies with insulin, edema was reported in 15.3% of patients on combination therapy compared to 7,0% of patients on insulin alone, Most of these events were considered mild or moderate in intensity (see PRECAUTIONS, General, Edema). In one 16-week clinical trial of insulin plus ACTOS combination therapy, more patients developed congestive heart failure on combination therapy (1.1%) compared to none on insulin alone (see WARNINGS, Cardiac Failure and Other Cardiac Effects). Laboratory Abnormalities Hematologic: ACTOS may cause decreases in hemoglobin and hematocrit. The fall in hemoglobin and hematocrit with ACTOS appears to be dose related. Across all clinical studies, mean hemoglobin values declined by 2% to 4% in patients treated with ACTOS, These changes generally occurred within the first 4 to 12 weeks of therapy and remained relatively stable thereafter. These changes may be related to increased plasma volume associated with ACTOS therapy and have rarely been associated with any significant hematologic clinical effects. Serum Transaminase Levels: During all clinical studies in the U.S., 14 of 4780 (0.30%) patients treated with ACTOS had ALT values 3 times the upper limit of normal during treatment. All patients with follow-up values had reversible elevations in ALT. In the population of patients treated with ACTOS, mean values for bilirubin, AST, ALT, alkaline phosphatase, and GGT were decreased at the final visit compared with baseline. Fewer than 0.9% of patients treated with ACTOS were withdrawn from clinical trials in the U.S. due to abnormal liver function tests. In pre-approval clinical trials, there were no cases of idiosyncratic drug reactions leading to hepatic failure (see PRECAUTIONS, Hepatic Effects). CPK Levels: During required laboratory testing in clinical trials, sporadic, transient elevations in creatine phosphokinase levels (CPK) were observed. An isolated elevation to greater than 10 times the upper limit of normal was noted in 9 patients (values of 2150 to 11400 IU/L). Six of these patients continued to receive ACTOS, two patients had completed receiving study medication at the time of the elevated value and one patient discontinued study medication due to the elevation. These elevations resolved without any apparent clinical sequelae. The relationship of these events to ACTOS therapy is unknown. OVERDOSAGE During controlled clinical trials, one case of overdose with ACTOS was reported. A male patient took 120 mg per day for four days, then 180 mg per day for seven days, The patient denied any clinical symptoms during this period. In the event of overdosage, appropriate supportive treatment should be initiated according to patient's clinical signs and symptoms. Source: PLA-TAK-00062925 NDA 21-073/S-023 Page 21 DOSAGE AND ADMINISTRATION ACTOS should be taken once daily without regard to meals. The management of antidiabetic therapy should be individualized. Ideally, the response to therapy should be evaluated using HbA1c which is a better indicator of long-term glycemic control than FPG alone. HbA1e reflects glycemia over the past two to three months. In clinical use, it is recommended that patients be treated with ACTOS for a period of time adequate to evaluate change in HbA1d (three months) unless glycemic control deteriorates, Monotherapy ACTOS monotherapy in patients not adequately controlled with diet and exercise may be initiated at 15 mg or 30 mg once daily. For patients who respond inadequately to the initial dose of ACTOS, the dose can be increased in increments up to 45 mg once daily. For patients not responding adequately to monotherapy, combination therapy should be considered. Combination Therapy Sulfonylureas: ACTOS in combination with a sulfonylurea may be initiated at 15 mg or 30 mg once daily. The current sulfonylurea dose can be continued upon initiation of ACTOS therapy. If patients report hypoglycemia, the dose of the sulfonylurea should be decreased. Metformin: ACTOS in combination with metformín may be initiated at 15 mg or 30 mg once daily. The current metformin dose can be continued upon initiation of ACTOS therapy. It is unlikely that the dose of metformin will require adjustment due to hypo-glycemia during combination therapy with ACTOS. Insulin: ACTOS in combination with insulin may be initiated at 15 mg or 30 mg once daily. The current insulin dose can be continued upon initiation of ACTOS therapy. In patients receiving ACTOS and insulin, the insulin dose can be decreased by 10% to 25% if the patient reports hypoglycemia or if plasma glucose concentrations decrease to less than 100 mg/dL. Further adjustments should be individualized based on glucose-lowering response. Maximum Recommended Dose The dose of ACTOS should not exceed 45 mg once daily in monotherapy or in combination with sulfonylurea, metformin, or insulin. Dose adjustment in patients with renal insufficiency is not recommended (see CLINICAL PHARMACOLOGY, Pharmacokinetics and Drug Metabolism). Therapy with ACTOS should not be initiated if the patient exhibits clinical levidence of active liver disease or increased serum transaminase levels (ALT greater than 2.5 times the upper limit of normal) at start of therapy (see PRECAUTIONS, General, Hepatic Effects and CLINICAL PHARMACOLOGY, Special Populations, Hepatic Insufficiency). Liver enzyme monitoring is recommended in all patients prior to initiation of therapy with ACTOS and periodically thereafter (see PRECAUTIONS, General, Hepatic Effects). There are no data on the use of ACTOS in patients under 18 years of age; therefore, use of ACTOS in pediatric patients is not recommended. No data are available on the use of ACTOS in combination with another thiazolidinedione. Source: https://www.industryeeeateents.ucsf.edu/docs/hfkf0226 PLA-TAK-00062926 NDA 21-073/S-023 Page 22 HOW SUPPLIED ACTOS is available in 15 mg, 30 mg, and 45 mg tablets as follows: 15 mg Tablet: white to off-white, round, convex, non-scored tablet with "ACTOS" on one side, and "15" on the other, available in: NDC 64764-151-04 Bottle of 30 NDC 64764-151-05 Bottle of 90 NDC 64764-151-06 Bottle of 500 30 mg Tablet: white to off-white, round, flat, non-scored tablet with "ACTOS" on one side, and "30" on the other, available in: NDC 64764-301-14 Bottle of 30 NDC 64764-301-15 Bottle of 90 NDC 64764-301-16 Bottle of 500 45 mg Tablet: white to off-white, round, flat, non-scored tablet with "ACTOS" on one side, and "45" on the other, available in: NDC 64764-451-24 Bottle of 30 NDC 64764-451-25 Bottle of 90 NDC 64764-451-26 Bottle of 500 STORAGE Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Keep container tightly closed, and protect from moisture and humidity. Rx only Manufactured by: Takeda Chemical Industries, Ltd. Osaka, Japan Marketed by: Takeda Pharmaceuticals America, Inc. 475 Half Day Road Lincolnshire, IL 60069 and Ell Lilly and Company Lilly Corporate Center Indianapolis, IN 46285 ACTOS® is a registered trademark of Takeda Chemical Industries, Ltd. and used under license by Takeda Pharmaceuticals America, Inc. and Eli Lilly and Co. All other trademark names are the property of their respective owners. 5012100-07 Revised: July 2004 PLA-TAK-00062927 Source:

What is the floor supply price?

trjf0226

trjf0226_p0, trjf0226_p1, trjf0226_p2, trjf0226_p3, trjf0226_p4, trjf0226_p5

"$0.17 / 30 mg or Takedas cost from site of lowest cost"

EXHIBIT ROW - Contract (Not 7/19/99) 81 Project Cat Update Discussion with Jim Harper July 19, 1999 Agenda Il Status of negotiations with Takeda Il Review of major contract terms Overview of Outstanding Issues Product Liability Affiliate Definition 1 Summary of Project Valuation Discussion of Next Steps 1 Confidential - Subject to Protective Order LLY-RANSOM-00002623 Source: Summary of Terms for OUS Agreement License Exclusive rights in approximately 60 countries Semi exclusive rights in approximately 20 countries Upfront Fee $20 million signing fee with $5 million credible to Major Europe (Germany, $2.0m; UK, $1.25; France, $1.0m; Italy, $0.75m) Supply Price / Royalty Rate 30% supply price Royalty schedule (based on half year sales) Royalty Rate Year 1-3 Tiers Year 4 onward Tiers 5% $0 $85m $0 $170m 8% $85m $110m $170m - $220m 14% >$110m >220m Free Goods Year Commercial Free Goods Year 1 100% 30% Year 2 100% 20% Year 3 100% 10% Overview of Major Contract Terms Product Liability 80(Lilly)/20 sharing of Serious Adverse Events Takeda Cap at $20Million Minimum Sales 20% of Lowest Teir ($68 Million) or 55% of rolling one year forecast Ability to lower obligation for significant event Affiliate Definition Attempting to agree on a proposal which prevents Takeda from creating local JV around ACTOS in EU Competing Product TZD or ISE which is a substitute for Pioglitazone License reverts to non-exclusive 2 Confidential - Subject to Protective Order LLY-RANSOM-00002624 Source: https://www.indup5350.000021 ts.ucsf.edu/docs/trjf0226 Product Liability Overview Background Takeda's 30-year-old policy is not to share any product liability risk with its licensees. They consider that it is the licensee's business risk. Their policy resulted from significant product liability losses in the past. Takeda Concessions: Full responsibility for claims resulting from manufacturing defects. Full responsibility for claims that Lilly could have prevented if given appropriate data and information (failure to provide or errors). Full responsibility for claims relating to product sold by Takeda, its affiliates or licensees in semi-exclusive or markets entered by Takeda Shared responsibility for claims relating to serious adverse events. Sharing Proposal For serious adverse events not attributable to acts of either party, costs to be shared on an 80/20 basis (Lilly/Takeda) up to a maximum of $20MM for Takeda. Factors which Limit Pioglitazone's Product Liability Risk OUS Clean Safety Profile Nearly one year of US experience prior to first OUS launch Lilly's OUS Markets are historically not litigious Takeda sharing risk Product liability risk is significantly minimized 3 Confidential - Subject to Protective Order LLY-RANSOM-00002625 Source: https://www.indup5350.00003 ts.ucsf.edu/docs/trjf0226 Most Significant Adverse Events Risks for Pioglitazone Risk Onset Reversibility Clinical Findings Occurrence of ALT Elevation Within Only through Drug Placebo Liver Failure 12 months Transplant Rezulin 1,7% 0.7% ACTOS 0.26% 0.25% Avandia 0.20% 0.20% Cardiac Hypertrophy Unknown Unknown Observed during Preclinical Studies in Rats No cases in Humans Unknown Observed during Bladder Cancer Unknown Preclinical Studies in Rats No cases in Humans Within Yes Occurrence of Edema Edema 12 months Drug Placebo ACTOS 15.3% 7.0% Summary of Litigation Risk in the OUS Territories Out of 10,359 claims on the Litigation Support System database, only 10 claims have arose from the Territory in this Agreement: Country All Claims Drug Claims Australia 5 3 Saudi Arabia 1 1 South Africa 2 0 Spain 1 0 Sweden 1 1 Total 10 5 4 Confidential - Subject to Protective Order LLY-RANSOM-00002626 Source: https://www.indup5350-00004ts.ucsf.edu/docs/trjf0226 ******** Overview of Major Contract Terms Promotional Samples At Cost New Indications/Line Extension Takeda must offer to Lilly If Lilly agrees, then cost sharing based on expected benefit If Lilly disagrees, Takeda / Lilly agree on any damages due Lilly Promotional Trials Data Usage Both parties can gain access to each others trial data Split of 70/30 (Lilly in Exclusive) 50/50 in Semi-exclusive Sub-license Right to sub-license with Takeda's consent Floor Supply Price $0.17 / 30mg or Takeda's Cost from site of lowest cost Overview of Major Contract Terms Termination Right to terminate in specific markets if significant events occur Generic Entry Adjustment 50% royalty adjustment if generic enters the market and causes sales decline of 25% Intellectual Property Takeda owns all 5 Confidential - Subject to Protective Order LLY-RANSOM-00002627 Source: https://www.indup5350-00005ts.ucsf.edu/docs/trjf0226 ACTOS Sales Forecast versus Minimum Sales Comparison European Agreement $300,000,000 Pioglitazone $250,000,000 Sales Forecast $200,000,000 $150,000,000 $100,000,000 Minimum Sales Level $50,000,000 $0 2000 2001 2002 2003 2004 2005 2006 2007 Minimum Sales N/A N/A 41% 52% 37% 30% 26% 25% to Sales Forecast Ratio Potential Value of Actos™ to Lilly OUS, NPV US$ Millions the OEU Spain E. Europe Asia 1) Can./Mex. Total Peak Sales $85 $60 $85 $50 $70 $350 (2007) 12 Assomes that Takeda will enter Spanish market in 2003 and that they wit not enter any other exclusive market 1) Assumes terms to exclusive markets in EU and intercontimental 6 Confidential - Subject to Protective Order LLY-RANSOM-00002628 Source: https://www.indup5350-00006 ts.ucsf.edu/docs/trjf0226

What is the royalty adjustment if generic enters the market ?

trjf0226

trjf0226_p0, trjf0226_p1, trjf0226_p2, trjf0226_p3, trjf0226_p4, trjf0226_p5

50% royalty adjustment, 50%

EXHIBIT ROW - Contract (Not 7/19/99) 81 Project Cat Update Discussion with Jim Harper July 19, 1999 Agenda Il Status of negotiations with Takeda Il Review of major contract terms Overview of Outstanding Issues Product Liability Affiliate Definition 1 Summary of Project Valuation Discussion of Next Steps 1 Confidential - Subject to Protective Order LLY-RANSOM-00002623 Source: Summary of Terms for OUS Agreement License Exclusive rights in approximately 60 countries Semi exclusive rights in approximately 20 countries Upfront Fee $20 million signing fee with $5 million credible to Major Europe (Germany, $2.0m; UK, $1.25; France, $1.0m; Italy, $0.75m) Supply Price / Royalty Rate 30% supply price Royalty schedule (based on half year sales) Royalty Rate Year 1-3 Tiers Year 4 onward Tiers 5% $0 $85m $0 $170m 8% $85m $110m $170m - $220m 14% >$110m >220m Free Goods Year Commercial Free Goods Year 1 100% 30% Year 2 100% 20% Year 3 100% 10% Overview of Major Contract Terms Product Liability 80(Lilly)/20 sharing of Serious Adverse Events Takeda Cap at $20Million Minimum Sales 20% of Lowest Teir ($68 Million) or 55% of rolling one year forecast Ability to lower obligation for significant event Affiliate Definition Attempting to agree on a proposal which prevents Takeda from creating local JV around ACTOS in EU Competing Product TZD or ISE which is a substitute for Pioglitazone License reverts to non-exclusive 2 Confidential - Subject to Protective Order LLY-RANSOM-00002624 Source: https://www.indup5350.000021 ts.ucsf.edu/docs/trjf0226 Product Liability Overview Background Takeda's 30-year-old policy is not to share any product liability risk with its licensees. They consider that it is the licensee's business risk. Their policy resulted from significant product liability losses in the past. Takeda Concessions: Full responsibility for claims resulting from manufacturing defects. Full responsibility for claims that Lilly could have prevented if given appropriate data and information (failure to provide or errors). Full responsibility for claims relating to product sold by Takeda, its affiliates or licensees in semi-exclusive or markets entered by Takeda Shared responsibility for claims relating to serious adverse events. Sharing Proposal For serious adverse events not attributable to acts of either party, costs to be shared on an 80/20 basis (Lilly/Takeda) up to a maximum of $20MM for Takeda. Factors which Limit Pioglitazone's Product Liability Risk OUS Clean Safety Profile Nearly one year of US experience prior to first OUS launch Lilly's OUS Markets are historically not litigious Takeda sharing risk Product liability risk is significantly minimized 3 Confidential - Subject to Protective Order LLY-RANSOM-00002625 Source: https://www.indup5350.00003 ts.ucsf.edu/docs/trjf0226 Most Significant Adverse Events Risks for Pioglitazone Risk Onset Reversibility Clinical Findings Occurrence of ALT Elevation Within Only through Drug Placebo Liver Failure 12 months Transplant Rezulin 1,7% 0.7% ACTOS 0.26% 0.25% Avandia 0.20% 0.20% Cardiac Hypertrophy Unknown Unknown Observed during Preclinical Studies in Rats No cases in Humans Unknown Observed during Bladder Cancer Unknown Preclinical Studies in Rats No cases in Humans Within Yes Occurrence of Edema Edema 12 months Drug Placebo ACTOS 15.3% 7.0% Summary of Litigation Risk in the OUS Territories Out of 10,359 claims on the Litigation Support System database, only 10 claims have arose from the Territory in this Agreement: Country All Claims Drug Claims Australia 5 3 Saudi Arabia 1 1 South Africa 2 0 Spain 1 0 Sweden 1 1 Total 10 5 4 Confidential - Subject to Protective Order LLY-RANSOM-00002626 Source: https://www.indup5350-00004ts.ucsf.edu/docs/trjf0226 ******** Overview of Major Contract Terms Promotional Samples At Cost New Indications/Line Extension Takeda must offer to Lilly If Lilly agrees, then cost sharing based on expected benefit If Lilly disagrees, Takeda / Lilly agree on any damages due Lilly Promotional Trials Data Usage Both parties can gain access to each others trial data Split of 70/30 (Lilly in Exclusive) 50/50 in Semi-exclusive Sub-license Right to sub-license with Takeda's consent Floor Supply Price $0.17 / 30mg or Takeda's Cost from site of lowest cost Overview of Major Contract Terms Termination Right to terminate in specific markets if significant events occur Generic Entry Adjustment 50% royalty adjustment if generic enters the market and causes sales decline of 25% Intellectual Property Takeda owns all 5 Confidential - Subject to Protective Order LLY-RANSOM-00002627 Source: https://www.indup5350-00005ts.ucsf.edu/docs/trjf0226 ACTOS Sales Forecast versus Minimum Sales Comparison European Agreement $300,000,000 Pioglitazone $250,000,000 Sales Forecast $200,000,000 $150,000,000 $100,000,000 Minimum Sales Level $50,000,000 $0 2000 2001 2002 2003 2004 2005 2006 2007 Minimum Sales N/A N/A 41% 52% 37% 30% 26% 25% to Sales Forecast Ratio Potential Value of Actos™ to Lilly OUS, NPV US$ Millions the OEU Spain E. Europe Asia 1) Can./Mex. Total Peak Sales $85 $60 $85 $50 $70 $350 (2007) 12 Assomes that Takeda will enter Spanish market in 2003 and that they wit not enter any other exclusive market 1) Assumes terms to exclusive markets in EU and intercontimental 6 Confidential - Subject to Protective Order LLY-RANSOM-00002628 Source: https://www.indup5350-00006 ts.ucsf.edu/docs/trjf0226

what is the promotional trails data usage for( Lilly in exclusive) ?

trjf0226

trjf0226_p0, trjf0226_p1, trjf0226_p2, trjf0226_p3, trjf0226_p4, trjf0226_p5

Split of 70/30, split of 70/30 (Lilly in exclusive), Split of 70/30 (Lilly in Exclusive)

EXHIBIT ROW - Contract (Not 7/19/99) 81 Project Cat Update Discussion with Jim Harper July 19, 1999 Agenda Il Status of negotiations with Takeda Il Review of major contract terms Overview of Outstanding Issues Product Liability Affiliate Definition 1 Summary of Project Valuation Discussion of Next Steps 1 Confidential - Subject to Protective Order LLY-RANSOM-00002623 Source: Summary of Terms for OUS Agreement License Exclusive rights in approximately 60 countries Semi exclusive rights in approximately 20 countries Upfront Fee $20 million signing fee with $5 million credible to Major Europe (Germany, $2.0m; UK, $1.25; France, $1.0m; Italy, $0.75m) Supply Price / Royalty Rate 30% supply price Royalty schedule (based on half year sales) Royalty Rate Year 1-3 Tiers Year 4 onward Tiers 5% $0 $85m $0 $170m 8% $85m $110m $170m - $220m 14% >$110m >220m Free Goods Year Commercial Free Goods Year 1 100% 30% Year 2 100% 20% Year 3 100% 10% Overview of Major Contract Terms Product Liability 80(Lilly)/20 sharing of Serious Adverse Events Takeda Cap at $20Million Minimum Sales 20% of Lowest Teir ($68 Million) or 55% of rolling one year forecast Ability to lower obligation for significant event Affiliate Definition Attempting to agree on a proposal which prevents Takeda from creating local JV around ACTOS in EU Competing Product TZD or ISE which is a substitute for Pioglitazone License reverts to non-exclusive 2 Confidential - Subject to Protective Order LLY-RANSOM-00002624 Source: https://www.indup5350.000021 ts.ucsf.edu/docs/trjf0226 Product Liability Overview Background Takeda's 30-year-old policy is not to share any product liability risk with its licensees. They consider that it is the licensee's business risk. Their policy resulted from significant product liability losses in the past. Takeda Concessions: Full responsibility for claims resulting from manufacturing defects. Full responsibility for claims that Lilly could have prevented if given appropriate data and information (failure to provide or errors). Full responsibility for claims relating to product sold by Takeda, its affiliates or licensees in semi-exclusive or markets entered by Takeda Shared responsibility for claims relating to serious adverse events. Sharing Proposal For serious adverse events not attributable to acts of either party, costs to be shared on an 80/20 basis (Lilly/Takeda) up to a maximum of $20MM for Takeda. Factors which Limit Pioglitazone's Product Liability Risk OUS Clean Safety Profile Nearly one year of US experience prior to first OUS launch Lilly's OUS Markets are historically not litigious Takeda sharing risk Product liability risk is significantly minimized 3 Confidential - Subject to Protective Order LLY-RANSOM-00002625 Source: https://www.indup5350.00003 ts.ucsf.edu/docs/trjf0226 Most Significant Adverse Events Risks for Pioglitazone Risk Onset Reversibility Clinical Findings Occurrence of ALT Elevation Within Only through Drug Placebo Liver Failure 12 months Transplant Rezulin 1,7% 0.7% ACTOS 0.26% 0.25% Avandia 0.20% 0.20% Cardiac Hypertrophy Unknown Unknown Observed during Preclinical Studies in Rats No cases in Humans Unknown Observed during Bladder Cancer Unknown Preclinical Studies in Rats No cases in Humans Within Yes Occurrence of Edema Edema 12 months Drug Placebo ACTOS 15.3% 7.0% Summary of Litigation Risk in the OUS Territories Out of 10,359 claims on the Litigation Support System database, only 10 claims have arose from the Territory in this Agreement: Country All Claims Drug Claims Australia 5 3 Saudi Arabia 1 1 South Africa 2 0 Spain 1 0 Sweden 1 1 Total 10 5 4 Confidential - Subject to Protective Order LLY-RANSOM-00002626 Source: https://www.indup5350-00004ts.ucsf.edu/docs/trjf0226 ******** Overview of Major Contract Terms Promotional Samples At Cost New Indications/Line Extension Takeda must offer to Lilly If Lilly agrees, then cost sharing based on expected benefit If Lilly disagrees, Takeda / Lilly agree on any damages due Lilly Promotional Trials Data Usage Both parties can gain access to each others trial data Split of 70/30 (Lilly in Exclusive) 50/50 in Semi-exclusive Sub-license Right to sub-license with Takeda's consent Floor Supply Price $0.17 / 30mg or Takeda's Cost from site of lowest cost Overview of Major Contract Terms Termination Right to terminate in specific markets if significant events occur Generic Entry Adjustment 50% royalty adjustment if generic enters the market and causes sales decline of 25% Intellectual Property Takeda owns all 5 Confidential - Subject to Protective Order LLY-RANSOM-00002627 Source: https://www.indup5350-00005ts.ucsf.edu/docs/trjf0226 ACTOS Sales Forecast versus Minimum Sales Comparison European Agreement $300,000,000 Pioglitazone $250,000,000 Sales Forecast $200,000,000 $150,000,000 $100,000,000 Minimum Sales Level $50,000,000 $0 2000 2001 2002 2003 2004 2005 2006 2007 Minimum Sales N/A N/A 41% 52% 37% 30% 26% 25% to Sales Forecast Ratio Potential Value of Actos™ to Lilly OUS, NPV US$ Millions the OEU Spain E. Europe Asia 1) Can./Mex. Total Peak Sales $85 $60 $85 $50 $70 $350 (2007) 12 Assomes that Takeda will enter Spanish market in 2003 and that they wit not enter any other exclusive market 1) Assumes terms to exclusive markets in EU and intercontimental 6 Confidential - Subject to Protective Order LLY-RANSOM-00002628 Source: https://www.indup5350-00006 ts.ucsf.edu/docs/trjf0226

What is the promotional trials data usage for (semi exclusive)?

trjf0226

trjf0226_p0, trjf0226_p1, trjf0226_p2, trjf0226_p3, trjf0226_p4, trjf0226_p5

50/50 in Semi-exclusive

EXHIBIT ROW - Contract (Not 7/19/99) 81 Project Cat Update Discussion with Jim Harper July 19, 1999 Agenda Il Status of negotiations with Takeda Il Review of major contract terms Overview of Outstanding Issues Product Liability Affiliate Definition 1 Summary of Project Valuation Discussion of Next Steps 1 Confidential - Subject to Protective Order LLY-RANSOM-00002623 Source: Summary of Terms for OUS Agreement License Exclusive rights in approximately 60 countries Semi exclusive rights in approximately 20 countries Upfront Fee $20 million signing fee with $5 million credible to Major Europe (Germany, $2.0m; UK, $1.25; France, $1.0m; Italy, $0.75m) Supply Price / Royalty Rate 30% supply price Royalty schedule (based on half year sales) Royalty Rate Year 1-3 Tiers Year 4 onward Tiers 5% $0 $85m $0 $170m 8% $85m $110m $170m - $220m 14% >$110m >220m Free Goods Year Commercial Free Goods Year 1 100% 30% Year 2 100% 20% Year 3 100% 10% Overview of Major Contract Terms Product Liability 80(Lilly)/20 sharing of Serious Adverse Events Takeda Cap at $20Million Minimum Sales 20% of Lowest Teir ($68 Million) or 55% of rolling one year forecast Ability to lower obligation for significant event Affiliate Definition Attempting to agree on a proposal which prevents Takeda from creating local JV around ACTOS in EU Competing Product TZD or ISE which is a substitute for Pioglitazone License reverts to non-exclusive 2 Confidential - Subject to Protective Order LLY-RANSOM-00002624 Source: https://www.indup5350.000021 ts.ucsf.edu/docs/trjf0226 Product Liability Overview Background Takeda's 30-year-old policy is not to share any product liability risk with its licensees. They consider that it is the licensee's business risk. Their policy resulted from significant product liability losses in the past. Takeda Concessions: Full responsibility for claims resulting from manufacturing defects. Full responsibility for claims that Lilly could have prevented if given appropriate data and information (failure to provide or errors). Full responsibility for claims relating to product sold by Takeda, its affiliates or licensees in semi-exclusive or markets entered by Takeda Shared responsibility for claims relating to serious adverse events. Sharing Proposal For serious adverse events not attributable to acts of either party, costs to be shared on an 80/20 basis (Lilly/Takeda) up to a maximum of $20MM for Takeda. Factors which Limit Pioglitazone's Product Liability Risk OUS Clean Safety Profile Nearly one year of US experience prior to first OUS launch Lilly's OUS Markets are historically not litigious Takeda sharing risk Product liability risk is significantly minimized 3 Confidential - Subject to Protective Order LLY-RANSOM-00002625 Source: https://www.indup5350.00003 ts.ucsf.edu/docs/trjf0226 Most Significant Adverse Events Risks for Pioglitazone Risk Onset Reversibility Clinical Findings Occurrence of ALT Elevation Within Only through Drug Placebo Liver Failure 12 months Transplant Rezulin 1,7% 0.7% ACTOS 0.26% 0.25% Avandia 0.20% 0.20% Cardiac Hypertrophy Unknown Unknown Observed during Preclinical Studies in Rats No cases in Humans Unknown Observed during Bladder Cancer Unknown Preclinical Studies in Rats No cases in Humans Within Yes Occurrence of Edema Edema 12 months Drug Placebo ACTOS 15.3% 7.0% Summary of Litigation Risk in the OUS Territories Out of 10,359 claims on the Litigation Support System database, only 10 claims have arose from the Territory in this Agreement: Country All Claims Drug Claims Australia 5 3 Saudi Arabia 1 1 South Africa 2 0 Spain 1 0 Sweden 1 1 Total 10 5 4 Confidential - Subject to Protective Order LLY-RANSOM-00002626 Source: https://www.indup5350-00004ts.ucsf.edu/docs/trjf0226 ******** Overview of Major Contract Terms Promotional Samples At Cost New Indications/Line Extension Takeda must offer to Lilly If Lilly agrees, then cost sharing based on expected benefit If Lilly disagrees, Takeda / Lilly agree on any damages due Lilly Promotional Trials Data Usage Both parties can gain access to each others trial data Split of 70/30 (Lilly in Exclusive) 50/50 in Semi-exclusive Sub-license Right to sub-license with Takeda's consent Floor Supply Price $0.17 / 30mg or Takeda's Cost from site of lowest cost Overview of Major Contract Terms Termination Right to terminate in specific markets if significant events occur Generic Entry Adjustment 50% royalty adjustment if generic enters the market and causes sales decline of 25% Intellectual Property Takeda owns all 5 Confidential - Subject to Protective Order LLY-RANSOM-00002627 Source: https://www.indup5350-00005ts.ucsf.edu/docs/trjf0226 ACTOS Sales Forecast versus Minimum Sales Comparison European Agreement $300,000,000 Pioglitazone $250,000,000 Sales Forecast $200,000,000 $150,000,000 $100,000,000 Minimum Sales Level $50,000,000 $0 2000 2001 2002 2003 2004 2005 2006 2007 Minimum Sales N/A N/A 41% 52% 37% 30% 26% 25% to Sales Forecast Ratio Potential Value of Actos™ to Lilly OUS, NPV US$ Millions the OEU Spain E. Europe Asia 1) Can./Mex. Total Peak Sales $85 $60 $85 $50 $70 $350 (2007) 12 Assomes that Takeda will enter Spanish market in 2003 and that they wit not enter any other exclusive market 1) Assumes terms to exclusive markets in EU and intercontimental 6 Confidential - Subject to Protective Order LLY-RANSOM-00002628 Source: https://www.indup5350-00006 ts.ucsf.edu/docs/trjf0226

what is the name of the plan review ?

ynjf0226

ynjf0226_p0, ynjf0226_p1, ynjf0226_p2, ynjf0226_p3, ynjf0226_p4, ynjf0226_p5, ynjf0226_p6, ynjf0226_p7, ynjf0226_p8, ynjf0226_p9, ynjf0226_p10, ynjf0226_p11, ynjf0226_p12

Marketing plan review., MARKETING PLAN REVIEW, MARKETING PLAN

Actos 2004 0 Marketing Plan Review DALY 12 Lilly Answers That Matter. Confidential - Subject to Protective Order LLY-HOVENR-00001895 Produced in MDL on 02/27/13 Source: Agenda OAD Market / IR Review Evolving Medical Data Overview Q&A Discussion <AUTO> Confidential - Subject to Protective Order LLY-HOVENR-00001896 Produced in MDL on 02/27/13 Source: TZD Share of Oral Market % Retail TRx Share 25% Forecast Actual 20% 15% 10% 5% 0% 2000 2001 2002 2003 2004 2005 TZDs TRx (000s) 10,577 14,681 17,101 19,466 21,480 22,191 Orals TRx (000s) 79,521 87,291 93,471 98,004 102,218 105,807 Oral Share (TZDs) 13.3% 16.8% 18.3% 19.9% 21.0% 21.0% Plan TZD Share 13.3% 16.8% 18.3% 19.7% 20.6% 20.6% Forecast as % of Plan n/a n/a n/a 100.8% 102.0% 101.8% <AUTO> Confidential -- Subject to Protective Order LLY-HOVENR-00001897 Produced in MDL on 02/27/13 Source: Actos Share of TZDs Retail TRx SOM, IMS Health 60.00% Actual Foreçast 50.00% 40.00% Launch of Launch of Merck's BMS' PPAR's 30.00% PPAR's Q3 2005 Feb 2005 20.00% 10.00% 0.00% 2000 2001 2002 2003 2004 2005 TZDs TRx (000s) 10,577 14,681 17,101 19,407 21,479 22,902 Actos TRx (000s) 4,261 6,872 8,582 9,497 10,149 10,472 TZD Share 40.3% 46.8% 50.2% 49.0% 47.3% 45.7% Plan TZD Share n/a n/a n/a 46.1% 42.9% Forecast as a % of Plan n/a n/a n/a 106.3% 110.1% <AUTO> Confidential - Subject to Protective Order LLY-HOVENR-00001898 Produced in MDL on 02/27/13 Avandamet Uptake Retail TRx (000s), IMS Health TRx (000s) Assumes 36% of Avandamet scripts from Actos 500 Glucovance 450 400 350 Avandamet 300 Forecast 250 200 150 Avandamet at 31% of original 100 forecast. 50 Avandamet 0 1 2 3 4 5 6 7 8 9 10 11 12 13 15 Full Months Post Launch <AUTO> Confidential - Subject to Protective Order LLY-HOVENR-00001899 Produced in MDL on 02/27/13 Source: Consequences of IR Damage to Eyes Damage to Kidneys TG HDL-C LDL-C Damage to Nerves Increased CV Risk Increased CV Risk Hyperglycemia Dyslipidemia Insulin Resistance Central Hypertension Obesity Increased CV Risk Increased CV Risk <AUTO> Confidential - Subject to Protective Order LLY-HOVENR-00001900 Produced in MDL on 02/27/13 Source: Link between IR and CVD THE ROUTE TO CARDIOVASCULAR DISEASE 2.11.15-19 Hyperglycemia Insulin Hyper a path that leads to increased risk for MI Resistance Dys TYPE 2 DIABETES EQUALS PRIOR MI AS A CHD RISK FACTOR Pr S 7-year incidence of myocardial infarction (MI) (%) 25% 20% 15% 18.8% 20.2% 10% 5% 0% Nondiabetic patients Type 2 diabetics with prior MI without prior MI <AUTO> Confidential - Subject to Protective Order LLY-HOVENR-00001901 Produced in MDL on 02/27/13 Source: It is important to engage your customer in dialogue around IR, symptoms, and complications. This Map is a critical tool to help you explain the link of insulin resistance and Cardiovascular risk. Confidential - Subject to Protective Order LLY-HOVENR-00001902 Produced in MDL on 02/27/13 Source: https://www.indu 90818-00008 s.ucsf.edu/docs/ynjf0226 Drug/Class of Drug Most Appropriate for the Treatment of Insulin Resistance (Unaided) Total PCPs ENDOs (n=338) (n=302) (n=79) TZD/Glitazone (Net) 81% 81% 80% TZD/Glitazone/ ACTOS/ 77% 77% 77% Avandia ACTOS 3% I 4% I 3% Avandia 1% 1% 0% Biguanides 15% 15% 15% Sulfonylureas 4% I 4% 3% TZD association with treating IR is solidly in the minds of most MDs. However 1 in 5 think metformin or a sulfonylurea is most appropriate to treat IR as well What or class of drugs do you consider to be the most appropriate to treat insulin resistance? * indicates significant difference between subgroups @95% confidence level Q20b Confidential - Subject to Protective Order LLY-HOVENR-00001903 Produced in MDL on 02/27/13 Source: https://www.induposeis-oooogts.ucsf.edu/docs/ynjf0226 Q21. For the next series of statements, please tell me which of the two TZDs/Glitazones you believe is better in the following areas. Is Actos better, Avandia better, or are they both the same with regard to their. Confidential - Subject to Protective Order LLY-HOVENR-00001904 Produced in MDL on 02/27/13 Source: https://www.indu P0818-00010 s.ucsf.edu/docs/ynjf0226 Belief in IR = More Scripts! TZD Share of OAD Market 25.0% 20.0% 15.0% 10.0% 5.0% 0.0% 2 3 4 5 Doctors who rated the Importance (scale of 1-5) that an Oral Agent treat insulin resistance N=3 N=25 N=265 N=160 <AUTO> SOURCE: Message Effectiveness Wave 6, IMS Health Confidential - Subject to Protective Order LLY-HOVENR-00001905 Produced in MDL on 02/27/13 Source: https://www.induposts-oooanits.ucsf.edu/docs/ynjf0226 Frame: Why should reps focus on IR (What's In It For Me-WIIFM)? Key Point: When docs rate IR as more important, their TZD share is higher. Confidential - Subject to Protective Order LLY-HOVENR-00001906 Produced in MDL on 02/27/13 Source: https://www.indu P0818-00012 s.ucsf.edu/docs/ynjf0226 Strategic Intent & CSFs Strategic Intent: Establish Actos as the best OAD medication by treating insulin resistance, through sustained glycemic control and reduced cardiovascular risk. Critical Success Factors 1. TZD's prescribed earlier in treatment of Type 2 diabetes 2. Actos is the the first TZD used for Type 2 patients. <AUTO> Confidential - Subject to Protective Order LLY-HOVENR-00001907 Produced in MDL on 02/27/13 Source:

What is the goal of TPNA?

yljf0226

yljf0226_p0, yljf0226_p1

to supply justification to support maintaining current labeling.

ACTOS FDA Response Strategy TASK FORCE -TPNA Alfonso Perez Janet Haskins* Mary Ramstack* Ingrid Hoos Michael Elisseou John Page (Rich Wilson) Claire Thom Dan Orlando David Baron (Chris Durack) Larry Hancock Karen Kaluzny Masatake Kashiyae Chuck Burant *Task Force Coordinators TASK FORCE STRATEGIES: The FDA has 3 key issues with respect to the non-clinical data related to bladder tumors, 1. They requested us to propose a method by which to monitor bladder toxicity in patients in our long term phase 4 clinical trials (long term was defined as at least 1 year). a, TPNA will challenge the FDA request to conduct clinical monitoring in long-term studies. 2. They requested us to give some consideration to a label change that would reflect possible relatedness of tumor formation to mechanism (dual PP AR agonist) instead of the current language ("The relationship of these findings in male rats to humans is unclear.") a. TPNA would like to challenge FDA hypothesis around tumor formation relationship to dual PPAR mechanism. b. TPNA goal is to supply justification to support maintaining current labeling. 3. They indicated an inclination to rescind the written request for pediatric exclusivity based on their concern about bladder tumors. a. Based on current verbiage in PI TPNA requests to conduct pediatric trial as scheduled. Last revision; August 7, 2002 EXHIBIT 2) WIT: Ramslude DATE: 10-1-13 Confidential - Subject to Protective Order Juliana Zajicek CSR TAK-RAMSTM-00236225 Produced in MDL on 09/18/12 Source: ACTOS FDA Response Strategy 1.0: INTRODUCTION Restate questions from FDA Raise feasibility issues - theoretical versus clinical questions Summarize assessment and action plan around each question Frame response as risk/benefit assessment of Actos clinical program (Frame broadly). 2.0: NONCLINICAL Key Messages: Pivotal studies conducted by Takeda followed GLPs versus anecdotally reported promoter model studies, which did not. Rat findings not duplicated in mouse, monkey, or dog. Therefore, the findings appear to be species specific and not relevant to humans (Rat studies - females had benign tumors only) Clinical and post-marketing data to date shows a very low incidence of bladder cancer and strengthens argument that rat findings are species specific. Supporting arguments Question source of pioglitazone used by Novo Nordisk Examine bladder concentrations in rodent studies 3.0: PPAR MECHANISM Key Points: Revalidate Sam Cohen's original hypothesis 1996, using 1999 EMEA argument for support Background on PPARs. Dual versus gamma versus alpha Structure Mechanism of action, in particular urinary tract tumorígenesis Promoter models Application of model to standard acceptable GLP models NN622 Compare/contrast structure of pioglitazone to NN622 Determine correlation between fibrates and bladder cancer (Section 6.0?) Determine correlation between PPAR-alpha agonists and bladder cancer (Section 6.0?) Argument will answer FDA's theoretical hypotheses with facts 4.0: CLINICAL Key Message: Epidemiological evaluations strongly indicate that there is no increased risk of bladder cancer associated with pioglitazone. Frequency of bladder cancer incidents in ACTOS trials is in line with the frequency observed in the general population. Monitoring is not possible because it in unreliable (not sensitive enough, many false positives). There may also be ethical and logistic issues. Supporting arguments Forms of monitoring done [US (011,031), EU, JP (OCT020)], investigate what worked/what didn't without invalidating what was done Additional assessments of data - Searching current clinical and post-marketing databases Last revision: August 7, 2002 Confidential - Subject to Protective Order TAK-RAMSTM-00236226 Produced in MDL on 09/18/12 Source: ts.ucsf.edu/docs/yljf0226

what is the first point given in table for bladder cancer alongside of clinical findings ?

trjf0226

trjf0226_p0, trjf0226_p1, trjf0226_p2, trjf0226_p3, trjf0226_p4, trjf0226_p5

observed during preclinical studies in rats, OBSERVED DURING PRECLINICAL STUDIES IN RATS

EXHIBIT ROW - Contract (Not 7/19/99) 81 Project Cat Update Discussion with Jim Harper July 19, 1999 Agenda Il Status of negotiations with Takeda Il Review of major contract terms Overview of Outstanding Issues Product Liability Affiliate Definition 1 Summary of Project Valuation Discussion of Next Steps 1 Confidential - Subject to Protective Order LLY-RANSOM-00002623 Source: Summary of Terms for OUS Agreement License Exclusive rights in approximately 60 countries Semi exclusive rights in approximately 20 countries Upfront Fee $20 million signing fee with $5 million credible to Major Europe (Germany, $2.0m; UK, $1.25; France, $1.0m; Italy, $0.75m) Supply Price / Royalty Rate 30% supply price Royalty schedule (based on half year sales) Royalty Rate Year 1-3 Tiers Year 4 onward Tiers 5% $0 $85m $0 $170m 8% $85m $110m $170m - $220m 14% >$110m >220m Free Goods Year Commercial Free Goods Year 1 100% 30% Year 2 100% 20% Year 3 100% 10% Overview of Major Contract Terms Product Liability 80(Lilly)/20 sharing of Serious Adverse Events Takeda Cap at $20Million Minimum Sales 20% of Lowest Teir ($68 Million) or 55% of rolling one year forecast Ability to lower obligation for significant event Affiliate Definition Attempting to agree on a proposal which prevents Takeda from creating local JV around ACTOS in EU Competing Product TZD or ISE which is a substitute for Pioglitazone License reverts to non-exclusive 2 Confidential - Subject to Protective Order LLY-RANSOM-00002624 Source: https://www.indup5350.000021 ts.ucsf.edu/docs/trjf0226 Product Liability Overview Background Takeda's 30-year-old policy is not to share any product liability risk with its licensees. They consider that it is the licensee's business risk. Their policy resulted from significant product liability losses in the past. Takeda Concessions: Full responsibility for claims resulting from manufacturing defects. Full responsibility for claims that Lilly could have prevented if given appropriate data and information (failure to provide or errors). Full responsibility for claims relating to product sold by Takeda, its affiliates or licensees in semi-exclusive or markets entered by Takeda Shared responsibility for claims relating to serious adverse events. Sharing Proposal For serious adverse events not attributable to acts of either party, costs to be shared on an 80/20 basis (Lilly/Takeda) up to a maximum of $20MM for Takeda. Factors which Limit Pioglitazone's Product Liability Risk OUS Clean Safety Profile Nearly one year of US experience prior to first OUS launch Lilly's OUS Markets are historically not litigious Takeda sharing risk Product liability risk is significantly minimized 3 Confidential - Subject to Protective Order LLY-RANSOM-00002625 Source: https://www.indup5350.00003 ts.ucsf.edu/docs/trjf0226 Most Significant Adverse Events Risks for Pioglitazone Risk Onset Reversibility Clinical Findings Occurrence of ALT Elevation Within Only through Drug Placebo Liver Failure 12 months Transplant Rezulin 1,7% 0.7% ACTOS 0.26% 0.25% Avandia 0.20% 0.20% Cardiac Hypertrophy Unknown Unknown Observed during Preclinical Studies in Rats No cases in Humans Unknown Observed during Bladder Cancer Unknown Preclinical Studies in Rats No cases in Humans Within Yes Occurrence of Edema Edema 12 months Drug Placebo ACTOS 15.3% 7.0% Summary of Litigation Risk in the OUS Territories Out of 10,359 claims on the Litigation Support System database, only 10 claims have arose from the Territory in this Agreement: Country All Claims Drug Claims Australia 5 3 Saudi Arabia 1 1 South Africa 2 0 Spain 1 0 Sweden 1 1 Total 10 5 4 Confidential - Subject to Protective Order LLY-RANSOM-00002626 Source: https://www.indup5350-00004ts.ucsf.edu/docs/trjf0226 ******** Overview of Major Contract Terms Promotional Samples At Cost New Indications/Line Extension Takeda must offer to Lilly If Lilly agrees, then cost sharing based on expected benefit If Lilly disagrees, Takeda / Lilly agree on any damages due Lilly Promotional Trials Data Usage Both parties can gain access to each others trial data Split of 70/30 (Lilly in Exclusive) 50/50 in Semi-exclusive Sub-license Right to sub-license with Takeda's consent Floor Supply Price $0.17 / 30mg or Takeda's Cost from site of lowest cost Overview of Major Contract Terms Termination Right to terminate in specific markets if significant events occur Generic Entry Adjustment 50% royalty adjustment if generic enters the market and causes sales decline of 25% Intellectual Property Takeda owns all 5 Confidential - Subject to Protective Order LLY-RANSOM-00002627 Source: https://www.indup5350-00005ts.ucsf.edu/docs/trjf0226 ACTOS Sales Forecast versus Minimum Sales Comparison European Agreement $300,000,000 Pioglitazone $250,000,000 Sales Forecast $200,000,000 $150,000,000 $100,000,000 Minimum Sales Level $50,000,000 $0 2000 2001 2002 2003 2004 2005 2006 2007 Minimum Sales N/A N/A 41% 52% 37% 30% 26% 25% to Sales Forecast Ratio Potential Value of Actos™ to Lilly OUS, NPV US$ Millions the OEU Spain E. Europe Asia 1) Can./Mex. Total Peak Sales $85 $60 $85 $50 $70 $350 (2007) 12 Assomes that Takeda will enter Spanish market in 2003 and that they wit not enter any other exclusive market 1) Assumes terms to exclusive markets in EU and intercontimental 6 Confidential - Subject to Protective Order LLY-RANSOM-00002628 Source: https://www.indup5350-00006 ts.ucsf.edu/docs/trjf0226

Mention the year given for Actos?

ynjf0226

ynjf0226_p0, ynjf0226_p1, ynjf0226_p2, ynjf0226_p3, ynjf0226_p4, ynjf0226_p5, ynjf0226_p6, ynjf0226_p7, ynjf0226_p8, ynjf0226_p9, ynjf0226_p10, ynjf0226_p11, ynjf0226_p12

Actos 2004, 2004

Actos 2004 0 Marketing Plan Review DALY 12 Lilly Answers That Matter. Confidential - Subject to Protective Order LLY-HOVENR-00001895 Produced in MDL on 02/27/13 Source: Agenda OAD Market / IR Review Evolving Medical Data Overview Q&A Discussion <AUTO> Confidential - Subject to Protective Order LLY-HOVENR-00001896 Produced in MDL on 02/27/13 Source: TZD Share of Oral Market % Retail TRx Share 25% Forecast Actual 20% 15% 10% 5% 0% 2000 2001 2002 2003 2004 2005 TZDs TRx (000s) 10,577 14,681 17,101 19,466 21,480 22,191 Orals TRx (000s) 79,521 87,291 93,471 98,004 102,218 105,807 Oral Share (TZDs) 13.3% 16.8% 18.3% 19.9% 21.0% 21.0% Plan TZD Share 13.3% 16.8% 18.3% 19.7% 20.6% 20.6% Forecast as % of Plan n/a n/a n/a 100.8% 102.0% 101.8% <AUTO> Confidential -- Subject to Protective Order LLY-HOVENR-00001897 Produced in MDL on 02/27/13 Source: Actos Share of TZDs Retail TRx SOM, IMS Health 60.00% Actual Foreçast 50.00% 40.00% Launch of Launch of Merck's BMS' PPAR's 30.00% PPAR's Q3 2005 Feb 2005 20.00% 10.00% 0.00% 2000 2001 2002 2003 2004 2005 TZDs TRx (000s) 10,577 14,681 17,101 19,407 21,479 22,902 Actos TRx (000s) 4,261 6,872 8,582 9,497 10,149 10,472 TZD Share 40.3% 46.8% 50.2% 49.0% 47.3% 45.7% Plan TZD Share n/a n/a n/a 46.1% 42.9% Forecast as a % of Plan n/a n/a n/a 106.3% 110.1% <AUTO> Confidential - Subject to Protective Order LLY-HOVENR-00001898 Produced in MDL on 02/27/13 Avandamet Uptake Retail TRx (000s), IMS Health TRx (000s) Assumes 36% of Avandamet scripts from Actos 500 Glucovance 450 400 350 Avandamet 300 Forecast 250 200 150 Avandamet at 31% of original 100 forecast. 50 Avandamet 0 1 2 3 4 5 6 7 8 9 10 11 12 13 15 Full Months Post Launch <AUTO> Confidential - Subject to Protective Order LLY-HOVENR-00001899 Produced in MDL on 02/27/13 Source: Consequences of IR Damage to Eyes Damage to Kidneys TG HDL-C LDL-C Damage to Nerves Increased CV Risk Increased CV Risk Hyperglycemia Dyslipidemia Insulin Resistance Central Hypertension Obesity Increased CV Risk Increased CV Risk <AUTO> Confidential - Subject to Protective Order LLY-HOVENR-00001900 Produced in MDL on 02/27/13 Source: Link between IR and CVD THE ROUTE TO CARDIOVASCULAR DISEASE 2.11.15-19 Hyperglycemia Insulin Hyper a path that leads to increased risk for MI Resistance Dys TYPE 2 DIABETES EQUALS PRIOR MI AS A CHD RISK FACTOR Pr S 7-year incidence of myocardial infarction (MI) (%) 25% 20% 15% 18.8% 20.2% 10% 5% 0% Nondiabetic patients Type 2 diabetics with prior MI without prior MI <AUTO> Confidential - Subject to Protective Order LLY-HOVENR-00001901 Produced in MDL on 02/27/13 Source: It is important to engage your customer in dialogue around IR, symptoms, and complications. This Map is a critical tool to help you explain the link of insulin resistance and Cardiovascular risk. Confidential - Subject to Protective Order LLY-HOVENR-00001902 Produced in MDL on 02/27/13 Source: https://www.indu 90818-00008 s.ucsf.edu/docs/ynjf0226 Drug/Class of Drug Most Appropriate for the Treatment of Insulin Resistance (Unaided) Total PCPs ENDOs (n=338) (n=302) (n=79) TZD/Glitazone (Net) 81% 81% 80% TZD/Glitazone/ ACTOS/ 77% 77% 77% Avandia ACTOS 3% I 4% I 3% Avandia 1% 1% 0% Biguanides 15% 15% 15% Sulfonylureas 4% I 4% 3% TZD association with treating IR is solidly in the minds of most MDs. However 1 in 5 think metformin or a sulfonylurea is most appropriate to treat IR as well What or class of drugs do you consider to be the most appropriate to treat insulin resistance? * indicates significant difference between subgroups @95% confidence level Q20b Confidential - Subject to Protective Order LLY-HOVENR-00001903 Produced in MDL on 02/27/13 Source: https://www.induposeis-oooogts.ucsf.edu/docs/ynjf0226 Q21. For the next series of statements, please tell me which of the two TZDs/Glitazones you believe is better in the following areas. Is Actos better, Avandia better, or are they both the same with regard to their. Confidential - Subject to Protective Order LLY-HOVENR-00001904 Produced in MDL on 02/27/13 Source: https://www.indu P0818-00010 s.ucsf.edu/docs/ynjf0226 Belief in IR = More Scripts! TZD Share of OAD Market 25.0% 20.0% 15.0% 10.0% 5.0% 0.0% 2 3 4 5 Doctors who rated the Importance (scale of 1-5) that an Oral Agent treat insulin resistance N=3 N=25 N=265 N=160 <AUTO> SOURCE: Message Effectiveness Wave 6, IMS Health Confidential - Subject to Protective Order LLY-HOVENR-00001905 Produced in MDL on 02/27/13 Source: https://www.induposts-oooanits.ucsf.edu/docs/ynjf0226 Frame: Why should reps focus on IR (What's In It For Me-WIIFM)? Key Point: When docs rate IR as more important, their TZD share is higher. Confidential - Subject to Protective Order LLY-HOVENR-00001906 Produced in MDL on 02/27/13 Source: https://www.indu P0818-00012 s.ucsf.edu/docs/ynjf0226 Strategic Intent & CSFs Strategic Intent: Establish Actos as the best OAD medication by treating insulin resistance, through sustained glycemic control and reduced cardiovascular risk. Critical Success Factors 1. TZD's prescribed earlier in treatment of Type 2 diabetes 2. Actos is the the first TZD used for Type 2 patients. <AUTO> Confidential - Subject to Protective Order LLY-HOVENR-00001907 Produced in MDL on 02/27/13 Source:

what is the percentage of TZD share in the year 2000 ?

ynjf0226

ynjf0226_p0, ynjf0226_p1, ynjf0226_p2, ynjf0226_p3, ynjf0226_p4, ynjf0226_p5, ynjf0226_p6, ynjf0226_p7, ynjf0226_p8, ynjf0226_p9, ynjf0226_p10, ynjf0226_p11, ynjf0226_p12

40.3%

Actos 2004 0 Marketing Plan Review DALY 12 Lilly Answers That Matter. Confidential - Subject to Protective Order LLY-HOVENR-00001895 Produced in MDL on 02/27/13 Source: Agenda OAD Market / IR Review Evolving Medical Data Overview Q&A Discussion <AUTO> Confidential - Subject to Protective Order LLY-HOVENR-00001896 Produced in MDL on 02/27/13 Source: TZD Share of Oral Market % Retail TRx Share 25% Forecast Actual 20% 15% 10% 5% 0% 2000 2001 2002 2003 2004 2005 TZDs TRx (000s) 10,577 14,681 17,101 19,466 21,480 22,191 Orals TRx (000s) 79,521 87,291 93,471 98,004 102,218 105,807 Oral Share (TZDs) 13.3% 16.8% 18.3% 19.9% 21.0% 21.0% Plan TZD Share 13.3% 16.8% 18.3% 19.7% 20.6% 20.6% Forecast as % of Plan n/a n/a n/a 100.8% 102.0% 101.8% <AUTO> Confidential -- Subject to Protective Order LLY-HOVENR-00001897 Produced in MDL on 02/27/13 Source: Actos Share of TZDs Retail TRx SOM, IMS Health 60.00% Actual Foreçast 50.00% 40.00% Launch of Launch of Merck's BMS' PPAR's 30.00% PPAR's Q3 2005 Feb 2005 20.00% 10.00% 0.00% 2000 2001 2002 2003 2004 2005 TZDs TRx (000s) 10,577 14,681 17,101 19,407 21,479 22,902 Actos TRx (000s) 4,261 6,872 8,582 9,497 10,149 10,472 TZD Share 40.3% 46.8% 50.2% 49.0% 47.3% 45.7% Plan TZD Share n/a n/a n/a 46.1% 42.9% Forecast as a % of Plan n/a n/a n/a 106.3% 110.1% <AUTO> Confidential - Subject to Protective Order LLY-HOVENR-00001898 Produced in MDL on 02/27/13 Avandamet Uptake Retail TRx (000s), IMS Health TRx (000s) Assumes 36% of Avandamet scripts from Actos 500 Glucovance 450 400 350 Avandamet 300 Forecast 250 200 150 Avandamet at 31% of original 100 forecast. 50 Avandamet 0 1 2 3 4 5 6 7 8 9 10 11 12 13 15 Full Months Post Launch <AUTO> Confidential - Subject to Protective Order LLY-HOVENR-00001899 Produced in MDL on 02/27/13 Source: Consequences of IR Damage to Eyes Damage to Kidneys TG HDL-C LDL-C Damage to Nerves Increased CV Risk Increased CV Risk Hyperglycemia Dyslipidemia Insulin Resistance Central Hypertension Obesity Increased CV Risk Increased CV Risk <AUTO> Confidential - Subject to Protective Order LLY-HOVENR-00001900 Produced in MDL on 02/27/13 Source: Link between IR and CVD THE ROUTE TO CARDIOVASCULAR DISEASE 2.11.15-19 Hyperglycemia Insulin Hyper a path that leads to increased risk for MI Resistance Dys TYPE 2 DIABETES EQUALS PRIOR MI AS A CHD RISK FACTOR Pr S 7-year incidence of myocardial infarction (MI) (%) 25% 20% 15% 18.8% 20.2% 10% 5% 0% Nondiabetic patients Type 2 diabetics with prior MI without prior MI <AUTO> Confidential - Subject to Protective Order LLY-HOVENR-00001901 Produced in MDL on 02/27/13 Source: It is important to engage your customer in dialogue around IR, symptoms, and complications. This Map is a critical tool to help you explain the link of insulin resistance and Cardiovascular risk. Confidential - Subject to Protective Order LLY-HOVENR-00001902 Produced in MDL on 02/27/13 Source: https://www.indu 90818-00008 s.ucsf.edu/docs/ynjf0226 Drug/Class of Drug Most Appropriate for the Treatment of Insulin Resistance (Unaided) Total PCPs ENDOs (n=338) (n=302) (n=79) TZD/Glitazone (Net) 81% 81% 80% TZD/Glitazone/ ACTOS/ 77% 77% 77% Avandia ACTOS 3% I 4% I 3% Avandia 1% 1% 0% Biguanides 15% 15% 15% Sulfonylureas 4% I 4% 3% TZD association with treating IR is solidly in the minds of most MDs. However 1 in 5 think metformin or a sulfonylurea is most appropriate to treat IR as well What or class of drugs do you consider to be the most appropriate to treat insulin resistance? * indicates significant difference between subgroups @95% confidence level Q20b Confidential - Subject to Protective Order LLY-HOVENR-00001903 Produced in MDL on 02/27/13 Source: https://www.induposeis-oooogts.ucsf.edu/docs/ynjf0226 Q21. For the next series of statements, please tell me which of the two TZDs/Glitazones you believe is better in the following areas. Is Actos better, Avandia better, or are they both the same with regard to their. Confidential - Subject to Protective Order LLY-HOVENR-00001904 Produced in MDL on 02/27/13 Source: https://www.indu P0818-00010 s.ucsf.edu/docs/ynjf0226 Belief in IR = More Scripts! TZD Share of OAD Market 25.0% 20.0% 15.0% 10.0% 5.0% 0.0% 2 3 4 5 Doctors who rated the Importance (scale of 1-5) that an Oral Agent treat insulin resistance N=3 N=25 N=265 N=160 <AUTO> SOURCE: Message Effectiveness Wave 6, IMS Health Confidential - Subject to Protective Order LLY-HOVENR-00001905 Produced in MDL on 02/27/13 Source: https://www.induposts-oooanits.ucsf.edu/docs/ynjf0226 Frame: Why should reps focus on IR (What's In It For Me-WIIFM)? Key Point: When docs rate IR as more important, their TZD share is higher. Confidential - Subject to Protective Order LLY-HOVENR-00001906 Produced in MDL on 02/27/13 Source: https://www.indu P0818-00012 s.ucsf.edu/docs/ynjf0226 Strategic Intent & CSFs Strategic Intent: Establish Actos as the best OAD medication by treating insulin resistance, through sustained glycemic control and reduced cardiovascular risk. Critical Success Factors 1. TZD's prescribed earlier in treatment of Type 2 diabetes 2. Actos is the the first TZD used for Type 2 patients. <AUTO> Confidential - Subject to Protective Order LLY-HOVENR-00001907 Produced in MDL on 02/27/13 Source:

what is Actos TRx (000s) in the year 2003 ?

ynjf0226

ynjf0226_p0, ynjf0226_p1, ynjf0226_p2, ynjf0226_p3, ynjf0226_p4, ynjf0226_p5, ynjf0226_p6, ynjf0226_p7, ynjf0226_p8, ynjf0226_p9, ynjf0226_p10, ynjf0226_p11, ynjf0226_p12

9,497

Actos 2004 0 Marketing Plan Review DALY 12 Lilly Answers That Matter. Confidential - Subject to Protective Order LLY-HOVENR-00001895 Produced in MDL on 02/27/13 Source: Agenda OAD Market / IR Review Evolving Medical Data Overview Q&A Discussion <AUTO> Confidential - Subject to Protective Order LLY-HOVENR-00001896 Produced in MDL on 02/27/13 Source: TZD Share of Oral Market % Retail TRx Share 25% Forecast Actual 20% 15% 10% 5% 0% 2000 2001 2002 2003 2004 2005 TZDs TRx (000s) 10,577 14,681 17,101 19,466 21,480 22,191 Orals TRx (000s) 79,521 87,291 93,471 98,004 102,218 105,807 Oral Share (TZDs) 13.3% 16.8% 18.3% 19.9% 21.0% 21.0% Plan TZD Share 13.3% 16.8% 18.3% 19.7% 20.6% 20.6% Forecast as % of Plan n/a n/a n/a 100.8% 102.0% 101.8% <AUTO> Confidential -- Subject to Protective Order LLY-HOVENR-00001897 Produced in MDL on 02/27/13 Source: Actos Share of TZDs Retail TRx SOM, IMS Health 60.00% Actual Foreçast 50.00% 40.00% Launch of Launch of Merck's BMS' PPAR's 30.00% PPAR's Q3 2005 Feb 2005 20.00% 10.00% 0.00% 2000 2001 2002 2003 2004 2005 TZDs TRx (000s) 10,577 14,681 17,101 19,407 21,479 22,902 Actos TRx (000s) 4,261 6,872 8,582 9,497 10,149 10,472 TZD Share 40.3% 46.8% 50.2% 49.0% 47.3% 45.7% Plan TZD Share n/a n/a n/a 46.1% 42.9% Forecast as a % of Plan n/a n/a n/a 106.3% 110.1% <AUTO> Confidential - Subject to Protective Order LLY-HOVENR-00001898 Produced in MDL on 02/27/13 Avandamet Uptake Retail TRx (000s), IMS Health TRx (000s) Assumes 36% of Avandamet scripts from Actos 500 Glucovance 450 400 350 Avandamet 300 Forecast 250 200 150 Avandamet at 31% of original 100 forecast. 50 Avandamet 0 1 2 3 4 5 6 7 8 9 10 11 12 13 15 Full Months Post Launch <AUTO> Confidential - Subject to Protective Order LLY-HOVENR-00001899 Produced in MDL on 02/27/13 Source: Consequences of IR Damage to Eyes Damage to Kidneys TG HDL-C LDL-C Damage to Nerves Increased CV Risk Increased CV Risk Hyperglycemia Dyslipidemia Insulin Resistance Central Hypertension Obesity Increased CV Risk Increased CV Risk <AUTO> Confidential - Subject to Protective Order LLY-HOVENR-00001900 Produced in MDL on 02/27/13 Source: Link between IR and CVD THE ROUTE TO CARDIOVASCULAR DISEASE 2.11.15-19 Hyperglycemia Insulin Hyper a path that leads to increased risk for MI Resistance Dys TYPE 2 DIABETES EQUALS PRIOR MI AS A CHD RISK FACTOR Pr S 7-year incidence of myocardial infarction (MI) (%) 25% 20% 15% 18.8% 20.2% 10% 5% 0% Nondiabetic patients Type 2 diabetics with prior MI without prior MI <AUTO> Confidential - Subject to Protective Order LLY-HOVENR-00001901 Produced in MDL on 02/27/13 Source: It is important to engage your customer in dialogue around IR, symptoms, and complications. This Map is a critical tool to help you explain the link of insulin resistance and Cardiovascular risk. Confidential - Subject to Protective Order LLY-HOVENR-00001902 Produced in MDL on 02/27/13 Source: https://www.indu 90818-00008 s.ucsf.edu/docs/ynjf0226 Drug/Class of Drug Most Appropriate for the Treatment of Insulin Resistance (Unaided) Total PCPs ENDOs (n=338) (n=302) (n=79) TZD/Glitazone (Net) 81% 81% 80% TZD/Glitazone/ ACTOS/ 77% 77% 77% Avandia ACTOS 3% I 4% I 3% Avandia 1% 1% 0% Biguanides 15% 15% 15% Sulfonylureas 4% I 4% 3% TZD association with treating IR is solidly in the minds of most MDs. However 1 in 5 think metformin or a sulfonylurea is most appropriate to treat IR as well What or class of drugs do you consider to be the most appropriate to treat insulin resistance? * indicates significant difference between subgroups @95% confidence level Q20b Confidential - Subject to Protective Order LLY-HOVENR-00001903 Produced in MDL on 02/27/13 Source: https://www.induposeis-oooogts.ucsf.edu/docs/ynjf0226 Q21. For the next series of statements, please tell me which of the two TZDs/Glitazones you believe is better in the following areas. Is Actos better, Avandia better, or are they both the same with regard to their. Confidential - Subject to Protective Order LLY-HOVENR-00001904 Produced in MDL on 02/27/13 Source: https://www.indu P0818-00010 s.ucsf.edu/docs/ynjf0226 Belief in IR = More Scripts! TZD Share of OAD Market 25.0% 20.0% 15.0% 10.0% 5.0% 0.0% 2 3 4 5 Doctors who rated the Importance (scale of 1-5) that an Oral Agent treat insulin resistance N=3 N=25 N=265 N=160 <AUTO> SOURCE: Message Effectiveness Wave 6, IMS Health Confidential - Subject to Protective Order LLY-HOVENR-00001905 Produced in MDL on 02/27/13 Source: https://www.induposts-oooanits.ucsf.edu/docs/ynjf0226 Frame: Why should reps focus on IR (What's In It For Me-WIIFM)? Key Point: When docs rate IR as more important, their TZD share is higher. Confidential - Subject to Protective Order LLY-HOVENR-00001906 Produced in MDL on 02/27/13 Source: https://www.indu P0818-00012 s.ucsf.edu/docs/ynjf0226 Strategic Intent & CSFs Strategic Intent: Establish Actos as the best OAD medication by treating insulin resistance, through sustained glycemic control and reduced cardiovascular risk. Critical Success Factors 1. TZD's prescribed earlier in treatment of Type 2 diabetes 2. Actos is the the first TZD used for Type 2 patients. <AUTO> Confidential - Subject to Protective Order LLY-HOVENR-00001907 Produced in MDL on 02/27/13 Source:

how much percent of drug quantity present in rezulin under the title of 'clinical findings'?

trjf0226

trjf0226_p0, trjf0226_p1, trjf0226_p2, trjf0226_p3, trjf0226_p4, trjf0226_p5

1.7%, 1.7

EXHIBIT ROW - Contract (Not 7/19/99) 81 Project Cat Update Discussion with Jim Harper July 19, 1999 Agenda Il Status of negotiations with Takeda Il Review of major contract terms Overview of Outstanding Issues Product Liability Affiliate Definition 1 Summary of Project Valuation Discussion of Next Steps 1 Confidential - Subject to Protective Order LLY-RANSOM-00002623 Source: Summary of Terms for OUS Agreement License Exclusive rights in approximately 60 countries Semi exclusive rights in approximately 20 countries Upfront Fee $20 million signing fee with $5 million credible to Major Europe (Germany, $2.0m; UK, $1.25; France, $1.0m; Italy, $0.75m) Supply Price / Royalty Rate 30% supply price Royalty schedule (based on half year sales) Royalty Rate Year 1-3 Tiers Year 4 onward Tiers 5% $0 $85m $0 $170m 8% $85m $110m $170m - $220m 14% >$110m >220m Free Goods Year Commercial Free Goods Year 1 100% 30% Year 2 100% 20% Year 3 100% 10% Overview of Major Contract Terms Product Liability 80(Lilly)/20 sharing of Serious Adverse Events Takeda Cap at $20Million Minimum Sales 20% of Lowest Teir ($68 Million) or 55% of rolling one year forecast Ability to lower obligation for significant event Affiliate Definition Attempting to agree on a proposal which prevents Takeda from creating local JV around ACTOS in EU Competing Product TZD or ISE which is a substitute for Pioglitazone License reverts to non-exclusive 2 Confidential - Subject to Protective Order LLY-RANSOM-00002624 Source: https://www.indup5350.000021 ts.ucsf.edu/docs/trjf0226 Product Liability Overview Background Takeda's 30-year-old policy is not to share any product liability risk with its licensees. They consider that it is the licensee's business risk. Their policy resulted from significant product liability losses in the past. Takeda Concessions: Full responsibility for claims resulting from manufacturing defects. Full responsibility for claims that Lilly could have prevented if given appropriate data and information (failure to provide or errors). Full responsibility for claims relating to product sold by Takeda, its affiliates or licensees in semi-exclusive or markets entered by Takeda Shared responsibility for claims relating to serious adverse events. Sharing Proposal For serious adverse events not attributable to acts of either party, costs to be shared on an 80/20 basis (Lilly/Takeda) up to a maximum of $20MM for Takeda. Factors which Limit Pioglitazone's Product Liability Risk OUS Clean Safety Profile Nearly one year of US experience prior to first OUS launch Lilly's OUS Markets are historically not litigious Takeda sharing risk Product liability risk is significantly minimized 3 Confidential - Subject to Protective Order LLY-RANSOM-00002625 Source: https://www.indup5350.00003 ts.ucsf.edu/docs/trjf0226 Most Significant Adverse Events Risks for Pioglitazone Risk Onset Reversibility Clinical Findings Occurrence of ALT Elevation Within Only through Drug Placebo Liver Failure 12 months Transplant Rezulin 1,7% 0.7% ACTOS 0.26% 0.25% Avandia 0.20% 0.20% Cardiac Hypertrophy Unknown Unknown Observed during Preclinical Studies in Rats No cases in Humans Unknown Observed during Bladder Cancer Unknown Preclinical Studies in Rats No cases in Humans Within Yes Occurrence of Edema Edema 12 months Drug Placebo ACTOS 15.3% 7.0% Summary of Litigation Risk in the OUS Territories Out of 10,359 claims on the Litigation Support System database, only 10 claims have arose from the Territory in this Agreement: Country All Claims Drug Claims Australia 5 3 Saudi Arabia 1 1 South Africa 2 0 Spain 1 0 Sweden 1 1 Total 10 5 4 Confidential - Subject to Protective Order LLY-RANSOM-00002626 Source: https://www.indup5350-00004ts.ucsf.edu/docs/trjf0226 ******** Overview of Major Contract Terms Promotional Samples At Cost New Indications/Line Extension Takeda must offer to Lilly If Lilly agrees, then cost sharing based on expected benefit If Lilly disagrees, Takeda / Lilly agree on any damages due Lilly Promotional Trials Data Usage Both parties can gain access to each others trial data Split of 70/30 (Lilly in Exclusive) 50/50 in Semi-exclusive Sub-license Right to sub-license with Takeda's consent Floor Supply Price $0.17 / 30mg or Takeda's Cost from site of lowest cost Overview of Major Contract Terms Termination Right to terminate in specific markets if significant events occur Generic Entry Adjustment 50% royalty adjustment if generic enters the market and causes sales decline of 25% Intellectual Property Takeda owns all 5 Confidential - Subject to Protective Order LLY-RANSOM-00002627 Source: https://www.indup5350-00005ts.ucsf.edu/docs/trjf0226 ACTOS Sales Forecast versus Minimum Sales Comparison European Agreement $300,000,000 Pioglitazone $250,000,000 Sales Forecast $200,000,000 $150,000,000 $100,000,000 Minimum Sales Level $50,000,000 $0 2000 2001 2002 2003 2004 2005 2006 2007 Minimum Sales N/A N/A 41% 52% 37% 30% 26% 25% to Sales Forecast Ratio Potential Value of Actos™ to Lilly OUS, NPV US$ Millions the OEU Spain E. Europe Asia 1) Can./Mex. Total Peak Sales $85 $60 $85 $50 $70 $350 (2007) 12 Assomes that Takeda will enter Spanish market in 2003 and that they wit not enter any other exclusive market 1) Assumes terms to exclusive markets in EU and intercontimental 6 Confidential - Subject to Protective Order LLY-RANSOM-00002628 Source: https://www.indup5350-00006 ts.ucsf.edu/docs/trjf0226

what is the percentage of plan TZD share in the year 2004 ?

ynjf0226

ynjf0226_p0, ynjf0226_p1, ynjf0226_p2, ynjf0226_p3, ynjf0226_p4, ynjf0226_p5, ynjf0226_p6, ynjf0226_p7, ynjf0226_p8, ynjf0226_p9, ynjf0226_p10, ynjf0226_p11, ynjf0226_p12

42.9%

Actos 2004 0 Marketing Plan Review DALY 12 Lilly Answers That Matter. Confidential - Subject to Protective Order LLY-HOVENR-00001895 Produced in MDL on 02/27/13 Source: Agenda OAD Market / IR Review Evolving Medical Data Overview Q&A Discussion <AUTO> Confidential - Subject to Protective Order LLY-HOVENR-00001896 Produced in MDL on 02/27/13 Source: TZD Share of Oral Market % Retail TRx Share 25% Forecast Actual 20% 15% 10% 5% 0% 2000 2001 2002 2003 2004 2005 TZDs TRx (000s) 10,577 14,681 17,101 19,466 21,480 22,191 Orals TRx (000s) 79,521 87,291 93,471 98,004 102,218 105,807 Oral Share (TZDs) 13.3% 16.8% 18.3% 19.9% 21.0% 21.0% Plan TZD Share 13.3% 16.8% 18.3% 19.7% 20.6% 20.6% Forecast as % of Plan n/a n/a n/a 100.8% 102.0% 101.8% <AUTO> Confidential -- Subject to Protective Order LLY-HOVENR-00001897 Produced in MDL on 02/27/13 Source: Actos Share of TZDs Retail TRx SOM, IMS Health 60.00% Actual Foreçast 50.00% 40.00% Launch of Launch of Merck's BMS' PPAR's 30.00% PPAR's Q3 2005 Feb 2005 20.00% 10.00% 0.00% 2000 2001 2002 2003 2004 2005 TZDs TRx (000s) 10,577 14,681 17,101 19,407 21,479 22,902 Actos TRx (000s) 4,261 6,872 8,582 9,497 10,149 10,472 TZD Share 40.3% 46.8% 50.2% 49.0% 47.3% 45.7% Plan TZD Share n/a n/a n/a 46.1% 42.9% Forecast as a % of Plan n/a n/a n/a 106.3% 110.1% <AUTO> Confidential - Subject to Protective Order LLY-HOVENR-00001898 Produced in MDL on 02/27/13 Avandamet Uptake Retail TRx (000s), IMS Health TRx (000s) Assumes 36% of Avandamet scripts from Actos 500 Glucovance 450 400 350 Avandamet 300 Forecast 250 200 150 Avandamet at 31% of original 100 forecast. 50 Avandamet 0 1 2 3 4 5 6 7 8 9 10 11 12 13 15 Full Months Post Launch <AUTO> Confidential - Subject to Protective Order LLY-HOVENR-00001899 Produced in MDL on 02/27/13 Source: Consequences of IR Damage to Eyes Damage to Kidneys TG HDL-C LDL-C Damage to Nerves Increased CV Risk Increased CV Risk Hyperglycemia Dyslipidemia Insulin Resistance Central Hypertension Obesity Increased CV Risk Increased CV Risk <AUTO> Confidential - Subject to Protective Order LLY-HOVENR-00001900 Produced in MDL on 02/27/13 Source: Link between IR and CVD THE ROUTE TO CARDIOVASCULAR DISEASE 2.11.15-19 Hyperglycemia Insulin Hyper a path that leads to increased risk for MI Resistance Dys TYPE 2 DIABETES EQUALS PRIOR MI AS A CHD RISK FACTOR Pr S 7-year incidence of myocardial infarction (MI) (%) 25% 20% 15% 18.8% 20.2% 10% 5% 0% Nondiabetic patients Type 2 diabetics with prior MI without prior MI <AUTO> Confidential - Subject to Protective Order LLY-HOVENR-00001901 Produced in MDL on 02/27/13 Source: It is important to engage your customer in dialogue around IR, symptoms, and complications. This Map is a critical tool to help you explain the link of insulin resistance and Cardiovascular risk. Confidential - Subject to Protective Order LLY-HOVENR-00001902 Produced in MDL on 02/27/13 Source: https://www.indu 90818-00008 s.ucsf.edu/docs/ynjf0226 Drug/Class of Drug Most Appropriate for the Treatment of Insulin Resistance (Unaided) Total PCPs ENDOs (n=338) (n=302) (n=79) TZD/Glitazone (Net) 81% 81% 80% TZD/Glitazone/ ACTOS/ 77% 77% 77% Avandia ACTOS 3% I 4% I 3% Avandia 1% 1% 0% Biguanides 15% 15% 15% Sulfonylureas 4% I 4% 3% TZD association with treating IR is solidly in the minds of most MDs. However 1 in 5 think metformin or a sulfonylurea is most appropriate to treat IR as well What or class of drugs do you consider to be the most appropriate to treat insulin resistance? * indicates significant difference between subgroups @95% confidence level Q20b Confidential - Subject to Protective Order LLY-HOVENR-00001903 Produced in MDL on 02/27/13 Source: https://www.induposeis-oooogts.ucsf.edu/docs/ynjf0226 Q21. For the next series of statements, please tell me which of the two TZDs/Glitazones you believe is better in the following areas. Is Actos better, Avandia better, or are they both the same with regard to their. Confidential - Subject to Protective Order LLY-HOVENR-00001904 Produced in MDL on 02/27/13 Source: https://www.indu P0818-00010 s.ucsf.edu/docs/ynjf0226 Belief in IR = More Scripts! TZD Share of OAD Market 25.0% 20.0% 15.0% 10.0% 5.0% 0.0% 2 3 4 5 Doctors who rated the Importance (scale of 1-5) that an Oral Agent treat insulin resistance N=3 N=25 N=265 N=160 <AUTO> SOURCE: Message Effectiveness Wave 6, IMS Health Confidential - Subject to Protective Order LLY-HOVENR-00001905 Produced in MDL on 02/27/13 Source: https://www.induposts-oooanits.ucsf.edu/docs/ynjf0226 Frame: Why should reps focus on IR (What's In It For Me-WIIFM)? Key Point: When docs rate IR as more important, their TZD share is higher. Confidential - Subject to Protective Order LLY-HOVENR-00001906 Produced in MDL on 02/27/13 Source: https://www.indu P0818-00012 s.ucsf.edu/docs/ynjf0226 Strategic Intent & CSFs Strategic Intent: Establish Actos as the best OAD medication by treating insulin resistance, through sustained glycemic control and reduced cardiovascular risk. Critical Success Factors 1. TZD's prescribed earlier in treatment of Type 2 diabetes 2. Actos is the the first TZD used for Type 2 patients. <AUTO> Confidential - Subject to Protective Order LLY-HOVENR-00001907 Produced in MDL on 02/27/13 Source:

how much percent of placebo present in avandia alongside of the clinical findings?

trjf0226

trjf0226_p0, trjf0226_p1, trjf0226_p2, trjf0226_p3, trjf0226_p4, trjf0226_p5

0.20, 0.20%

EXHIBIT ROW - Contract (Not 7/19/99) 81 Project Cat Update Discussion with Jim Harper July 19, 1999 Agenda Il Status of negotiations with Takeda Il Review of major contract terms Overview of Outstanding Issues Product Liability Affiliate Definition 1 Summary of Project Valuation Discussion of Next Steps 1 Confidential - Subject to Protective Order LLY-RANSOM-00002623 Source: Summary of Terms for OUS Agreement License Exclusive rights in approximately 60 countries Semi exclusive rights in approximately 20 countries Upfront Fee $20 million signing fee with $5 million credible to Major Europe (Germany, $2.0m; UK, $1.25; France, $1.0m; Italy, $0.75m) Supply Price / Royalty Rate 30% supply price Royalty schedule (based on half year sales) Royalty Rate Year 1-3 Tiers Year 4 onward Tiers 5% $0 $85m $0 $170m 8% $85m $110m $170m - $220m 14% >$110m >220m Free Goods Year Commercial Free Goods Year 1 100% 30% Year 2 100% 20% Year 3 100% 10% Overview of Major Contract Terms Product Liability 80(Lilly)/20 sharing of Serious Adverse Events Takeda Cap at $20Million Minimum Sales 20% of Lowest Teir ($68 Million) or 55% of rolling one year forecast Ability to lower obligation for significant event Affiliate Definition Attempting to agree on a proposal which prevents Takeda from creating local JV around ACTOS in EU Competing Product TZD or ISE which is a substitute for Pioglitazone License reverts to non-exclusive 2 Confidential - Subject to Protective Order LLY-RANSOM-00002624 Source: https://www.indup5350.000021 ts.ucsf.edu/docs/trjf0226 Product Liability Overview Background Takeda's 30-year-old policy is not to share any product liability risk with its licensees. They consider that it is the licensee's business risk. Their policy resulted from significant product liability losses in the past. Takeda Concessions: Full responsibility for claims resulting from manufacturing defects. Full responsibility for claims that Lilly could have prevented if given appropriate data and information (failure to provide or errors). Full responsibility for claims relating to product sold by Takeda, its affiliates or licensees in semi-exclusive or markets entered by Takeda Shared responsibility for claims relating to serious adverse events. Sharing Proposal For serious adverse events not attributable to acts of either party, costs to be shared on an 80/20 basis (Lilly/Takeda) up to a maximum of $20MM for Takeda. Factors which Limit Pioglitazone's Product Liability Risk OUS Clean Safety Profile Nearly one year of US experience prior to first OUS launch Lilly's OUS Markets are historically not litigious Takeda sharing risk Product liability risk is significantly minimized 3 Confidential - Subject to Protective Order LLY-RANSOM-00002625 Source: https://www.indup5350.00003 ts.ucsf.edu/docs/trjf0226 Most Significant Adverse Events Risks for Pioglitazone Risk Onset Reversibility Clinical Findings Occurrence of ALT Elevation Within Only through Drug Placebo Liver Failure 12 months Transplant Rezulin 1,7% 0.7% ACTOS 0.26% 0.25% Avandia 0.20% 0.20% Cardiac Hypertrophy Unknown Unknown Observed during Preclinical Studies in Rats No cases in Humans Unknown Observed during Bladder Cancer Unknown Preclinical Studies in Rats No cases in Humans Within Yes Occurrence of Edema Edema 12 months Drug Placebo ACTOS 15.3% 7.0% Summary of Litigation Risk in the OUS Territories Out of 10,359 claims on the Litigation Support System database, only 10 claims have arose from the Territory in this Agreement: Country All Claims Drug Claims Australia 5 3 Saudi Arabia 1 1 South Africa 2 0 Spain 1 0 Sweden 1 1 Total 10 5 4 Confidential - Subject to Protective Order LLY-RANSOM-00002626 Source: https://www.indup5350-00004ts.ucsf.edu/docs/trjf0226 ******** Overview of Major Contract Terms Promotional Samples At Cost New Indications/Line Extension Takeda must offer to Lilly If Lilly agrees, then cost sharing based on expected benefit If Lilly disagrees, Takeda / Lilly agree on any damages due Lilly Promotional Trials Data Usage Both parties can gain access to each others trial data Split of 70/30 (Lilly in Exclusive) 50/50 in Semi-exclusive Sub-license Right to sub-license with Takeda's consent Floor Supply Price $0.17 / 30mg or Takeda's Cost from site of lowest cost Overview of Major Contract Terms Termination Right to terminate in specific markets if significant events occur Generic Entry Adjustment 50% royalty adjustment if generic enters the market and causes sales decline of 25% Intellectual Property Takeda owns all 5 Confidential - Subject to Protective Order LLY-RANSOM-00002627 Source: https://www.indup5350-00005ts.ucsf.edu/docs/trjf0226 ACTOS Sales Forecast versus Minimum Sales Comparison European Agreement $300,000,000 Pioglitazone $250,000,000 Sales Forecast $200,000,000 $150,000,000 $100,000,000 Minimum Sales Level $50,000,000 $0 2000 2001 2002 2003 2004 2005 2006 2007 Minimum Sales N/A N/A 41% 52% 37% 30% 26% 25% to Sales Forecast Ratio Potential Value of Actos™ to Lilly OUS, NPV US$ Millions the OEU Spain E. Europe Asia 1) Can./Mex. Total Peak Sales $85 $60 $85 $50 $70 $350 (2007) 12 Assomes that Takeda will enter Spanish market in 2003 and that they wit not enter any other exclusive market 1) Assumes terms to exclusive markets in EU and intercontimental 6 Confidential - Subject to Protective Order LLY-RANSOM-00002628 Source: https://www.indup5350-00006 ts.ucsf.edu/docs/trjf0226

in which month and the year the launch of Merck's PPAR's took place?

ynjf0226

ynjf0226_p0, ynjf0226_p1, ynjf0226_p2, ynjf0226_p3, ynjf0226_p4, ynjf0226_p5, ynjf0226_p6, ynjf0226_p7, ynjf0226_p8, ynjf0226_p9, ynjf0226_p10, ynjf0226_p11, ynjf0226_p12

FEB 2005, feb 2005

Actos 2004 0 Marketing Plan Review DALY 12 Lilly Answers That Matter. Confidential - Subject to Protective Order LLY-HOVENR-00001895 Produced in MDL on 02/27/13 Source: Agenda OAD Market / IR Review Evolving Medical Data Overview Q&A Discussion <AUTO> Confidential - Subject to Protective Order LLY-HOVENR-00001896 Produced in MDL on 02/27/13 Source: TZD Share of Oral Market % Retail TRx Share 25% Forecast Actual 20% 15% 10% 5% 0% 2000 2001 2002 2003 2004 2005 TZDs TRx (000s) 10,577 14,681 17,101 19,466 21,480 22,191 Orals TRx (000s) 79,521 87,291 93,471 98,004 102,218 105,807 Oral Share (TZDs) 13.3% 16.8% 18.3% 19.9% 21.0% 21.0% Plan TZD Share 13.3% 16.8% 18.3% 19.7% 20.6% 20.6% Forecast as % of Plan n/a n/a n/a 100.8% 102.0% 101.8% <AUTO> Confidential -- Subject to Protective Order LLY-HOVENR-00001897 Produced in MDL on 02/27/13 Source: Actos Share of TZDs Retail TRx SOM, IMS Health 60.00% Actual Foreçast 50.00% 40.00% Launch of Launch of Merck's BMS' PPAR's 30.00% PPAR's Q3 2005 Feb 2005 20.00% 10.00% 0.00% 2000 2001 2002 2003 2004 2005 TZDs TRx (000s) 10,577 14,681 17,101 19,407 21,479 22,902 Actos TRx (000s) 4,261 6,872 8,582 9,497 10,149 10,472 TZD Share 40.3% 46.8% 50.2% 49.0% 47.3% 45.7% Plan TZD Share n/a n/a n/a 46.1% 42.9% Forecast as a % of Plan n/a n/a n/a 106.3% 110.1% <AUTO> Confidential - Subject to Protective Order LLY-HOVENR-00001898 Produced in MDL on 02/27/13 Avandamet Uptake Retail TRx (000s), IMS Health TRx (000s) Assumes 36% of Avandamet scripts from Actos 500 Glucovance 450 400 350 Avandamet 300 Forecast 250 200 150 Avandamet at 31% of original 100 forecast. 50 Avandamet 0 1 2 3 4 5 6 7 8 9 10 11 12 13 15 Full Months Post Launch <AUTO> Confidential - Subject to Protective Order LLY-HOVENR-00001899 Produced in MDL on 02/27/13 Source: Consequences of IR Damage to Eyes Damage to Kidneys TG HDL-C LDL-C Damage to Nerves Increased CV Risk Increased CV Risk Hyperglycemia Dyslipidemia Insulin Resistance Central Hypertension Obesity Increased CV Risk Increased CV Risk <AUTO> Confidential - Subject to Protective Order LLY-HOVENR-00001900 Produced in MDL on 02/27/13 Source: Link between IR and CVD THE ROUTE TO CARDIOVASCULAR DISEASE 2.11.15-19 Hyperglycemia Insulin Hyper a path that leads to increased risk for MI Resistance Dys TYPE 2 DIABETES EQUALS PRIOR MI AS A CHD RISK FACTOR Pr S 7-year incidence of myocardial infarction (MI) (%) 25% 20% 15% 18.8% 20.2% 10% 5% 0% Nondiabetic patients Type 2 diabetics with prior MI without prior MI <AUTO> Confidential - Subject to Protective Order LLY-HOVENR-00001901 Produced in MDL on 02/27/13 Source: It is important to engage your customer in dialogue around IR, symptoms, and complications. This Map is a critical tool to help you explain the link of insulin resistance and Cardiovascular risk. Confidential - Subject to Protective Order LLY-HOVENR-00001902 Produced in MDL on 02/27/13 Source: https://www.indu 90818-00008 s.ucsf.edu/docs/ynjf0226 Drug/Class of Drug Most Appropriate for the Treatment of Insulin Resistance (Unaided) Total PCPs ENDOs (n=338) (n=302) (n=79) TZD/Glitazone (Net) 81% 81% 80% TZD/Glitazone/ ACTOS/ 77% 77% 77% Avandia ACTOS 3% I 4% I 3% Avandia 1% 1% 0% Biguanides 15% 15% 15% Sulfonylureas 4% I 4% 3% TZD association with treating IR is solidly in the minds of most MDs. However 1 in 5 think metformin or a sulfonylurea is most appropriate to treat IR as well What or class of drugs do you consider to be the most appropriate to treat insulin resistance? * indicates significant difference between subgroups @95% confidence level Q20b Confidential - Subject to Protective Order LLY-HOVENR-00001903 Produced in MDL on 02/27/13 Source: https://www.induposeis-oooogts.ucsf.edu/docs/ynjf0226 Q21. For the next series of statements, please tell me which of the two TZDs/Glitazones you believe is better in the following areas. Is Actos better, Avandia better, or are they both the same with regard to their. Confidential - Subject to Protective Order LLY-HOVENR-00001904 Produced in MDL on 02/27/13 Source: https://www.indu P0818-00010 s.ucsf.edu/docs/ynjf0226 Belief in IR = More Scripts! TZD Share of OAD Market 25.0% 20.0% 15.0% 10.0% 5.0% 0.0% 2 3 4 5 Doctors who rated the Importance (scale of 1-5) that an Oral Agent treat insulin resistance N=3 N=25 N=265 N=160 <AUTO> SOURCE: Message Effectiveness Wave 6, IMS Health Confidential - Subject to Protective Order LLY-HOVENR-00001905 Produced in MDL on 02/27/13 Source: https://www.induposts-oooanits.ucsf.edu/docs/ynjf0226 Frame: Why should reps focus on IR (What's In It For Me-WIIFM)? Key Point: When docs rate IR as more important, their TZD share is higher. Confidential - Subject to Protective Order LLY-HOVENR-00001906 Produced in MDL on 02/27/13 Source: https://www.indu P0818-00012 s.ucsf.edu/docs/ynjf0226 Strategic Intent & CSFs Strategic Intent: Establish Actos as the best OAD medication by treating insulin resistance, through sustained glycemic control and reduced cardiovascular risk. Critical Success Factors 1. TZD's prescribed earlier in treatment of Type 2 diabetes 2. Actos is the the first TZD used for Type 2 patients. <AUTO> Confidential - Subject to Protective Order LLY-HOVENR-00001907 Produced in MDL on 02/27/13 Source:

what is the TZD's TRx (000s) in the year 2005 ?

ynjf0226

ynjf0226_p0, ynjf0226_p1, ynjf0226_p2, ynjf0226_p3, ynjf0226_p4, ynjf0226_p5, ynjf0226_p6, ynjf0226_p7, ynjf0226_p8, ynjf0226_p9, ynjf0226_p10, ynjf0226_p11, ynjf0226_p12

22,902

Actos 2004 0 Marketing Plan Review DALY 12 Lilly Answers That Matter. Confidential - Subject to Protective Order LLY-HOVENR-00001895 Produced in MDL on 02/27/13 Source: Agenda OAD Market / IR Review Evolving Medical Data Overview Q&A Discussion <AUTO> Confidential - Subject to Protective Order LLY-HOVENR-00001896 Produced in MDL on 02/27/13 Source: TZD Share of Oral Market % Retail TRx Share 25% Forecast Actual 20% 15% 10% 5% 0% 2000 2001 2002 2003 2004 2005 TZDs TRx (000s) 10,577 14,681 17,101 19,466 21,480 22,191 Orals TRx (000s) 79,521 87,291 93,471 98,004 102,218 105,807 Oral Share (TZDs) 13.3% 16.8% 18.3% 19.9% 21.0% 21.0% Plan TZD Share 13.3% 16.8% 18.3% 19.7% 20.6% 20.6% Forecast as % of Plan n/a n/a n/a 100.8% 102.0% 101.8% <AUTO> Confidential -- Subject to Protective Order LLY-HOVENR-00001897 Produced in MDL on 02/27/13 Source: Actos Share of TZDs Retail TRx SOM, IMS Health 60.00% Actual Foreçast 50.00% 40.00% Launch of Launch of Merck's BMS' PPAR's 30.00% PPAR's Q3 2005 Feb 2005 20.00% 10.00% 0.00% 2000 2001 2002 2003 2004 2005 TZDs TRx (000s) 10,577 14,681 17,101 19,407 21,479 22,902 Actos TRx (000s) 4,261 6,872 8,582 9,497 10,149 10,472 TZD Share 40.3% 46.8% 50.2% 49.0% 47.3% 45.7% Plan TZD Share n/a n/a n/a 46.1% 42.9% Forecast as a % of Plan n/a n/a n/a 106.3% 110.1% <AUTO> Confidential - Subject to Protective Order LLY-HOVENR-00001898 Produced in MDL on 02/27/13 Avandamet Uptake Retail TRx (000s), IMS Health TRx (000s) Assumes 36% of Avandamet scripts from Actos 500 Glucovance 450 400 350 Avandamet 300 Forecast 250 200 150 Avandamet at 31% of original 100 forecast. 50 Avandamet 0 1 2 3 4 5 6 7 8 9 10 11 12 13 15 Full Months Post Launch <AUTO> Confidential - Subject to Protective Order LLY-HOVENR-00001899 Produced in MDL on 02/27/13 Source: Consequences of IR Damage to Eyes Damage to Kidneys TG HDL-C LDL-C Damage to Nerves Increased CV Risk Increased CV Risk Hyperglycemia Dyslipidemia Insulin Resistance Central Hypertension Obesity Increased CV Risk Increased CV Risk <AUTO> Confidential - Subject to Protective Order LLY-HOVENR-00001900 Produced in MDL on 02/27/13 Source: Link between IR and CVD THE ROUTE TO CARDIOVASCULAR DISEASE 2.11.15-19 Hyperglycemia Insulin Hyper a path that leads to increased risk for MI Resistance Dys TYPE 2 DIABETES EQUALS PRIOR MI AS A CHD RISK FACTOR Pr S 7-year incidence of myocardial infarction (MI) (%) 25% 20% 15% 18.8% 20.2% 10% 5% 0% Nondiabetic patients Type 2 diabetics with prior MI without prior MI <AUTO> Confidential - Subject to Protective Order LLY-HOVENR-00001901 Produced in MDL on 02/27/13 Source: It is important to engage your customer in dialogue around IR, symptoms, and complications. This Map is a critical tool to help you explain the link of insulin resistance and Cardiovascular risk. Confidential - Subject to Protective Order LLY-HOVENR-00001902 Produced in MDL on 02/27/13 Source: https://www.indu 90818-00008 s.ucsf.edu/docs/ynjf0226 Drug/Class of Drug Most Appropriate for the Treatment of Insulin Resistance (Unaided) Total PCPs ENDOs (n=338) (n=302) (n=79) TZD/Glitazone (Net) 81% 81% 80% TZD/Glitazone/ ACTOS/ 77% 77% 77% Avandia ACTOS 3% I 4% I 3% Avandia 1% 1% 0% Biguanides 15% 15% 15% Sulfonylureas 4% I 4% 3% TZD association with treating IR is solidly in the minds of most MDs. However 1 in 5 think metformin or a sulfonylurea is most appropriate to treat IR as well What or class of drugs do you consider to be the most appropriate to treat insulin resistance? * indicates significant difference between subgroups @95% confidence level Q20b Confidential - Subject to Protective Order LLY-HOVENR-00001903 Produced in MDL on 02/27/13 Source: https://www.induposeis-oooogts.ucsf.edu/docs/ynjf0226 Q21. For the next series of statements, please tell me which of the two TZDs/Glitazones you believe is better in the following areas. Is Actos better, Avandia better, or are they both the same with regard to their. Confidential - Subject to Protective Order LLY-HOVENR-00001904 Produced in MDL on 02/27/13 Source: https://www.indu P0818-00010 s.ucsf.edu/docs/ynjf0226 Belief in IR = More Scripts! TZD Share of OAD Market 25.0% 20.0% 15.0% 10.0% 5.0% 0.0% 2 3 4 5 Doctors who rated the Importance (scale of 1-5) that an Oral Agent treat insulin resistance N=3 N=25 N=265 N=160 <AUTO> SOURCE: Message Effectiveness Wave 6, IMS Health Confidential - Subject to Protective Order LLY-HOVENR-00001905 Produced in MDL on 02/27/13 Source: https://www.induposts-oooanits.ucsf.edu/docs/ynjf0226 Frame: Why should reps focus on IR (What's In It For Me-WIIFM)? Key Point: When docs rate IR as more important, their TZD share is higher. Confidential - Subject to Protective Order LLY-HOVENR-00001906 Produced in MDL on 02/27/13 Source: https://www.indu P0818-00012 s.ucsf.edu/docs/ynjf0226 Strategic Intent & CSFs Strategic Intent: Establish Actos as the best OAD medication by treating insulin resistance, through sustained glycemic control and reduced cardiovascular risk. Critical Success Factors 1. TZD's prescribed earlier in treatment of Type 2 diabetes 2. Actos is the the first TZD used for Type 2 patients. <AUTO> Confidential - Subject to Protective Order LLY-HOVENR-00001907 Produced in MDL on 02/27/13 Source:

what is the total number of all claims under the title of "summary of litigation risk in the ous territories"?

trjf0226

trjf0226_p0, trjf0226_p1, trjf0226_p2, trjf0226_p3, trjf0226_p4, trjf0226_p5

10

EXHIBIT ROW - Contract (Not 7/19/99) 81 Project Cat Update Discussion with Jim Harper July 19, 1999 Agenda Il Status of negotiations with Takeda Il Review of major contract terms Overview of Outstanding Issues Product Liability Affiliate Definition 1 Summary of Project Valuation Discussion of Next Steps 1 Confidential - Subject to Protective Order LLY-RANSOM-00002623 Source: Summary of Terms for OUS Agreement License Exclusive rights in approximately 60 countries Semi exclusive rights in approximately 20 countries Upfront Fee $20 million signing fee with $5 million credible to Major Europe (Germany, $2.0m; UK, $1.25; France, $1.0m; Italy, $0.75m) Supply Price / Royalty Rate 30% supply price Royalty schedule (based on half year sales) Royalty Rate Year 1-3 Tiers Year 4 onward Tiers 5% $0 $85m $0 $170m 8% $85m $110m $170m - $220m 14% >$110m >220m Free Goods Year Commercial Free Goods Year 1 100% 30% Year 2 100% 20% Year 3 100% 10% Overview of Major Contract Terms Product Liability 80(Lilly)/20 sharing of Serious Adverse Events Takeda Cap at $20Million Minimum Sales 20% of Lowest Teir ($68 Million) or 55% of rolling one year forecast Ability to lower obligation for significant event Affiliate Definition Attempting to agree on a proposal which prevents Takeda from creating local JV around ACTOS in EU Competing Product TZD or ISE which is a substitute for Pioglitazone License reverts to non-exclusive 2 Confidential - Subject to Protective Order LLY-RANSOM-00002624 Source: https://www.indup5350.000021 ts.ucsf.edu/docs/trjf0226 Product Liability Overview Background Takeda's 30-year-old policy is not to share any product liability risk with its licensees. They consider that it is the licensee's business risk. Their policy resulted from significant product liability losses in the past. Takeda Concessions: Full responsibility for claims resulting from manufacturing defects. Full responsibility for claims that Lilly could have prevented if given appropriate data and information (failure to provide or errors). Full responsibility for claims relating to product sold by Takeda, its affiliates or licensees in semi-exclusive or markets entered by Takeda Shared responsibility for claims relating to serious adverse events. Sharing Proposal For serious adverse events not attributable to acts of either party, costs to be shared on an 80/20 basis (Lilly/Takeda) up to a maximum of $20MM for Takeda. Factors which Limit Pioglitazone's Product Liability Risk OUS Clean Safety Profile Nearly one year of US experience prior to first OUS launch Lilly's OUS Markets are historically not litigious Takeda sharing risk Product liability risk is significantly minimized 3 Confidential - Subject to Protective Order LLY-RANSOM-00002625 Source: https://www.indup5350.00003 ts.ucsf.edu/docs/trjf0226 Most Significant Adverse Events Risks for Pioglitazone Risk Onset Reversibility Clinical Findings Occurrence of ALT Elevation Within Only through Drug Placebo Liver Failure 12 months Transplant Rezulin 1,7% 0.7% ACTOS 0.26% 0.25% Avandia 0.20% 0.20% Cardiac Hypertrophy Unknown Unknown Observed during Preclinical Studies in Rats No cases in Humans Unknown Observed during Bladder Cancer Unknown Preclinical Studies in Rats No cases in Humans Within Yes Occurrence of Edema Edema 12 months Drug Placebo ACTOS 15.3% 7.0% Summary of Litigation Risk in the OUS Territories Out of 10,359 claims on the Litigation Support System database, only 10 claims have arose from the Territory in this Agreement: Country All Claims Drug Claims Australia 5 3 Saudi Arabia 1 1 South Africa 2 0 Spain 1 0 Sweden 1 1 Total 10 5 4 Confidential - Subject to Protective Order LLY-RANSOM-00002626 Source: https://www.indup5350-00004ts.ucsf.edu/docs/trjf0226 ******** Overview of Major Contract Terms Promotional Samples At Cost New Indications/Line Extension Takeda must offer to Lilly If Lilly agrees, then cost sharing based on expected benefit If Lilly disagrees, Takeda / Lilly agree on any damages due Lilly Promotional Trials Data Usage Both parties can gain access to each others trial data Split of 70/30 (Lilly in Exclusive) 50/50 in Semi-exclusive Sub-license Right to sub-license with Takeda's consent Floor Supply Price $0.17 / 30mg or Takeda's Cost from site of lowest cost Overview of Major Contract Terms Termination Right to terminate in specific markets if significant events occur Generic Entry Adjustment 50% royalty adjustment if generic enters the market and causes sales decline of 25% Intellectual Property Takeda owns all 5 Confidential - Subject to Protective Order LLY-RANSOM-00002627 Source: https://www.indup5350-00005ts.ucsf.edu/docs/trjf0226 ACTOS Sales Forecast versus Minimum Sales Comparison European Agreement $300,000,000 Pioglitazone $250,000,000 Sales Forecast $200,000,000 $150,000,000 $100,000,000 Minimum Sales Level $50,000,000 $0 2000 2001 2002 2003 2004 2005 2006 2007 Minimum Sales N/A N/A 41% 52% 37% 30% 26% 25% to Sales Forecast Ratio Potential Value of Actos™ to Lilly OUS, NPV US$ Millions the OEU Spain E. Europe Asia 1) Can./Mex. Total Peak Sales $85 $60 $85 $50 $70 $350 (2007) 12 Assomes that Takeda will enter Spanish market in 2003 and that they wit not enter any other exclusive market 1) Assumes terms to exclusive markets in EU and intercontimental 6 Confidential - Subject to Protective Order LLY-RANSOM-00002628 Source: https://www.indup5350-00006 ts.ucsf.edu/docs/trjf0226

what is the first TZD used for type 2 patients ?

ynjf0226

ynjf0226_p0, ynjf0226_p1, ynjf0226_p2, ynjf0226_p3, ynjf0226_p4, ynjf0226_p5, ynjf0226_p6, ynjf0226_p7, ynjf0226_p8, ynjf0226_p9, ynjf0226_p10, ynjf0226_p11, ynjf0226_p12

ACTOS, Actos

Actos 2004 0 Marketing Plan Review DALY 12 Lilly Answers That Matter. Confidential - Subject to Protective Order LLY-HOVENR-00001895 Produced in MDL on 02/27/13 Source: Agenda OAD Market / IR Review Evolving Medical Data Overview Q&A Discussion <AUTO> Confidential - Subject to Protective Order LLY-HOVENR-00001896 Produced in MDL on 02/27/13 Source: TZD Share of Oral Market % Retail TRx Share 25% Forecast Actual 20% 15% 10% 5% 0% 2000 2001 2002 2003 2004 2005 TZDs TRx (000s) 10,577 14,681 17,101 19,466 21,480 22,191 Orals TRx (000s) 79,521 87,291 93,471 98,004 102,218 105,807 Oral Share (TZDs) 13.3% 16.8% 18.3% 19.9% 21.0% 21.0% Plan TZD Share 13.3% 16.8% 18.3% 19.7% 20.6% 20.6% Forecast as % of Plan n/a n/a n/a 100.8% 102.0% 101.8% <AUTO> Confidential -- Subject to Protective Order LLY-HOVENR-00001897 Produced in MDL on 02/27/13 Source: Actos Share of TZDs Retail TRx SOM, IMS Health 60.00% Actual Foreçast 50.00% 40.00% Launch of Launch of Merck's BMS' PPAR's 30.00% PPAR's Q3 2005 Feb 2005 20.00% 10.00% 0.00% 2000 2001 2002 2003 2004 2005 TZDs TRx (000s) 10,577 14,681 17,101 19,407 21,479 22,902 Actos TRx (000s) 4,261 6,872 8,582 9,497 10,149 10,472 TZD Share 40.3% 46.8% 50.2% 49.0% 47.3% 45.7% Plan TZD Share n/a n/a n/a 46.1% 42.9% Forecast as a % of Plan n/a n/a n/a 106.3% 110.1% <AUTO> Confidential - Subject to Protective Order LLY-HOVENR-00001898 Produced in MDL on 02/27/13 Avandamet Uptake Retail TRx (000s), IMS Health TRx (000s) Assumes 36% of Avandamet scripts from Actos 500 Glucovance 450 400 350 Avandamet 300 Forecast 250 200 150 Avandamet at 31% of original 100 forecast. 50 Avandamet 0 1 2 3 4 5 6 7 8 9 10 11 12 13 15 Full Months Post Launch <AUTO> Confidential - Subject to Protective Order LLY-HOVENR-00001899 Produced in MDL on 02/27/13 Source: Consequences of IR Damage to Eyes Damage to Kidneys TG HDL-C LDL-C Damage to Nerves Increased CV Risk Increased CV Risk Hyperglycemia Dyslipidemia Insulin Resistance Central Hypertension Obesity Increased CV Risk Increased CV Risk <AUTO> Confidential - Subject to Protective Order LLY-HOVENR-00001900 Produced in MDL on 02/27/13 Source: Link between IR and CVD THE ROUTE TO CARDIOVASCULAR DISEASE 2.11.15-19 Hyperglycemia Insulin Hyper a path that leads to increased risk for MI Resistance Dys TYPE 2 DIABETES EQUALS PRIOR MI AS A CHD RISK FACTOR Pr S 7-year incidence of myocardial infarction (MI) (%) 25% 20% 15% 18.8% 20.2% 10% 5% 0% Nondiabetic patients Type 2 diabetics with prior MI without prior MI <AUTO> Confidential - Subject to Protective Order LLY-HOVENR-00001901 Produced in MDL on 02/27/13 Source: It is important to engage your customer in dialogue around IR, symptoms, and complications. This Map is a critical tool to help you explain the link of insulin resistance and Cardiovascular risk. Confidential - Subject to Protective Order LLY-HOVENR-00001902 Produced in MDL on 02/27/13 Source: https://www.indu 90818-00008 s.ucsf.edu/docs/ynjf0226 Drug/Class of Drug Most Appropriate for the Treatment of Insulin Resistance (Unaided) Total PCPs ENDOs (n=338) (n=302) (n=79) TZD/Glitazone (Net) 81% 81% 80% TZD/Glitazone/ ACTOS/ 77% 77% 77% Avandia ACTOS 3% I 4% I 3% Avandia 1% 1% 0% Biguanides 15% 15% 15% Sulfonylureas 4% I 4% 3% TZD association with treating IR is solidly in the minds of most MDs. However 1 in 5 think metformin or a sulfonylurea is most appropriate to treat IR as well What or class of drugs do you consider to be the most appropriate to treat insulin resistance? * indicates significant difference between subgroups @95% confidence level Q20b Confidential - Subject to Protective Order LLY-HOVENR-00001903 Produced in MDL on 02/27/13 Source: https://www.induposeis-oooogts.ucsf.edu/docs/ynjf0226 Q21. For the next series of statements, please tell me which of the two TZDs/Glitazones you believe is better in the following areas. Is Actos better, Avandia better, or are they both the same with regard to their. Confidential - Subject to Protective Order LLY-HOVENR-00001904 Produced in MDL on 02/27/13 Source: https://www.indu P0818-00010 s.ucsf.edu/docs/ynjf0226 Belief in IR = More Scripts! TZD Share of OAD Market 25.0% 20.0% 15.0% 10.0% 5.0% 0.0% 2 3 4 5 Doctors who rated the Importance (scale of 1-5) that an Oral Agent treat insulin resistance N=3 N=25 N=265 N=160 <AUTO> SOURCE: Message Effectiveness Wave 6, IMS Health Confidential - Subject to Protective Order LLY-HOVENR-00001905 Produced in MDL on 02/27/13 Source: https://www.induposts-oooanits.ucsf.edu/docs/ynjf0226 Frame: Why should reps focus on IR (What's In It For Me-WIIFM)? Key Point: When docs rate IR as more important, their TZD share is higher. Confidential - Subject to Protective Order LLY-HOVENR-00001906 Produced in MDL on 02/27/13 Source: https://www.indu P0818-00012 s.ucsf.edu/docs/ynjf0226 Strategic Intent & CSFs Strategic Intent: Establish Actos as the best OAD medication by treating insulin resistance, through sustained glycemic control and reduced cardiovascular risk. Critical Success Factors 1. TZD's prescribed earlier in treatment of Type 2 diabetes 2. Actos is the the first TZD used for Type 2 patients. <AUTO> Confidential - Subject to Protective Order LLY-HOVENR-00001907 Produced in MDL on 02/27/13 Source:

For which type of diabetes the TZD's prescribed earlier in treatment?

ynjf0226

ynjf0226_p0, ynjf0226_p1, ynjf0226_p2, ynjf0226_p3, ynjf0226_p4, ynjf0226_p5, ynjf0226_p6, ynjf0226_p7, ynjf0226_p8, ynjf0226_p9, ynjf0226_p10, ynjf0226_p11, ynjf0226_p12

Type 2 diabetes

Actos 2004 0 Marketing Plan Review DALY 12 Lilly Answers That Matter. Confidential - Subject to Protective Order LLY-HOVENR-00001895 Produced in MDL on 02/27/13 Source: Agenda OAD Market / IR Review Evolving Medical Data Overview Q&A Discussion <AUTO> Confidential - Subject to Protective Order LLY-HOVENR-00001896 Produced in MDL on 02/27/13 Source: TZD Share of Oral Market % Retail TRx Share 25% Forecast Actual 20% 15% 10% 5% 0% 2000 2001 2002 2003 2004 2005 TZDs TRx (000s) 10,577 14,681 17,101 19,466 21,480 22,191 Orals TRx (000s) 79,521 87,291 93,471 98,004 102,218 105,807 Oral Share (TZDs) 13.3% 16.8% 18.3% 19.9% 21.0% 21.0% Plan TZD Share 13.3% 16.8% 18.3% 19.7% 20.6% 20.6% Forecast as % of Plan n/a n/a n/a 100.8% 102.0% 101.8% <AUTO> Confidential -- Subject to Protective Order LLY-HOVENR-00001897 Produced in MDL on 02/27/13 Source: Actos Share of TZDs Retail TRx SOM, IMS Health 60.00% Actual Foreçast 50.00% 40.00% Launch of Launch of Merck's BMS' PPAR's 30.00% PPAR's Q3 2005 Feb 2005 20.00% 10.00% 0.00% 2000 2001 2002 2003 2004 2005 TZDs TRx (000s) 10,577 14,681 17,101 19,407 21,479 22,902 Actos TRx (000s) 4,261 6,872 8,582 9,497 10,149 10,472 TZD Share 40.3% 46.8% 50.2% 49.0% 47.3% 45.7% Plan TZD Share n/a n/a n/a 46.1% 42.9% Forecast as a % of Plan n/a n/a n/a 106.3% 110.1% <AUTO> Confidential - Subject to Protective Order LLY-HOVENR-00001898 Produced in MDL on 02/27/13 Avandamet Uptake Retail TRx (000s), IMS Health TRx (000s) Assumes 36% of Avandamet scripts from Actos 500 Glucovance 450 400 350 Avandamet 300 Forecast 250 200 150 Avandamet at 31% of original 100 forecast. 50 Avandamet 0 1 2 3 4 5 6 7 8 9 10 11 12 13 15 Full Months Post Launch <AUTO> Confidential - Subject to Protective Order LLY-HOVENR-00001899 Produced in MDL on 02/27/13 Source: Consequences of IR Damage to Eyes Damage to Kidneys TG HDL-C LDL-C Damage to Nerves Increased CV Risk Increased CV Risk Hyperglycemia Dyslipidemia Insulin Resistance Central Hypertension Obesity Increased CV Risk Increased CV Risk <AUTO> Confidential - Subject to Protective Order LLY-HOVENR-00001900 Produced in MDL on 02/27/13 Source: Link between IR and CVD THE ROUTE TO CARDIOVASCULAR DISEASE 2.11.15-19 Hyperglycemia Insulin Hyper a path that leads to increased risk for MI Resistance Dys TYPE 2 DIABETES EQUALS PRIOR MI AS A CHD RISK FACTOR Pr S 7-year incidence of myocardial infarction (MI) (%) 25% 20% 15% 18.8% 20.2% 10% 5% 0% Nondiabetic patients Type 2 diabetics with prior MI without prior MI <AUTO> Confidential - Subject to Protective Order LLY-HOVENR-00001901 Produced in MDL on 02/27/13 Source: It is important to engage your customer in dialogue around IR, symptoms, and complications. This Map is a critical tool to help you explain the link of insulin resistance and Cardiovascular risk. Confidential - Subject to Protective Order LLY-HOVENR-00001902 Produced in MDL on 02/27/13 Source: https://www.indu 90818-00008 s.ucsf.edu/docs/ynjf0226 Drug/Class of Drug Most Appropriate for the Treatment of Insulin Resistance (Unaided) Total PCPs ENDOs (n=338) (n=302) (n=79) TZD/Glitazone (Net) 81% 81% 80% TZD/Glitazone/ ACTOS/ 77% 77% 77% Avandia ACTOS 3% I 4% I 3% Avandia 1% 1% 0% Biguanides 15% 15% 15% Sulfonylureas 4% I 4% 3% TZD association with treating IR is solidly in the minds of most MDs. However 1 in 5 think metformin or a sulfonylurea is most appropriate to treat IR as well What or class of drugs do you consider to be the most appropriate to treat insulin resistance? * indicates significant difference between subgroups @95% confidence level Q20b Confidential - Subject to Protective Order LLY-HOVENR-00001903 Produced in MDL on 02/27/13 Source: https://www.induposeis-oooogts.ucsf.edu/docs/ynjf0226 Q21. For the next series of statements, please tell me which of the two TZDs/Glitazones you believe is better in the following areas. Is Actos better, Avandia better, or are they both the same with regard to their. Confidential - Subject to Protective Order LLY-HOVENR-00001904 Produced in MDL on 02/27/13 Source: https://www.indu P0818-00010 s.ucsf.edu/docs/ynjf0226 Belief in IR = More Scripts! TZD Share of OAD Market 25.0% 20.0% 15.0% 10.0% 5.0% 0.0% 2 3 4 5 Doctors who rated the Importance (scale of 1-5) that an Oral Agent treat insulin resistance N=3 N=25 N=265 N=160 <AUTO> SOURCE: Message Effectiveness Wave 6, IMS Health Confidential - Subject to Protective Order LLY-HOVENR-00001905 Produced in MDL on 02/27/13 Source: https://www.induposts-oooanits.ucsf.edu/docs/ynjf0226 Frame: Why should reps focus on IR (What's In It For Me-WIIFM)? Key Point: When docs rate IR as more important, their TZD share is higher. Confidential - Subject to Protective Order LLY-HOVENR-00001906 Produced in MDL on 02/27/13 Source: https://www.indu P0818-00012 s.ucsf.edu/docs/ynjf0226 Strategic Intent & CSFs Strategic Intent: Establish Actos as the best OAD medication by treating insulin resistance, through sustained glycemic control and reduced cardiovascular risk. Critical Success Factors 1. TZD's prescribed earlier in treatment of Type 2 diabetes 2. Actos is the the first TZD used for Type 2 patients. <AUTO> Confidential - Subject to Protective Order LLY-HOVENR-00001907 Produced in MDL on 02/27/13 Source:

what has to be establish as the the best OAD medication by treating insulin resistance ?

ynjf0226

ynjf0226_p0, ynjf0226_p1, ynjf0226_p2, ynjf0226_p3, ynjf0226_p4, ynjf0226_p5, ynjf0226_p6, ynjf0226_p7, ynjf0226_p8, ynjf0226_p9, ynjf0226_p10, ynjf0226_p11, ynjf0226_p12

ACTOS, Actos

Actos 2004 0 Marketing Plan Review DALY 12 Lilly Answers That Matter. Confidential - Subject to Protective Order LLY-HOVENR-00001895 Produced in MDL on 02/27/13 Source: Agenda OAD Market / IR Review Evolving Medical Data Overview Q&A Discussion <AUTO> Confidential - Subject to Protective Order LLY-HOVENR-00001896 Produced in MDL on 02/27/13 Source: TZD Share of Oral Market % Retail TRx Share 25% Forecast Actual 20% 15% 10% 5% 0% 2000 2001 2002 2003 2004 2005 TZDs TRx (000s) 10,577 14,681 17,101 19,466 21,480 22,191 Orals TRx (000s) 79,521 87,291 93,471 98,004 102,218 105,807 Oral Share (TZDs) 13.3% 16.8% 18.3% 19.9% 21.0% 21.0% Plan TZD Share 13.3% 16.8% 18.3% 19.7% 20.6% 20.6% Forecast as % of Plan n/a n/a n/a 100.8% 102.0% 101.8% <AUTO> Confidential -- Subject to Protective Order LLY-HOVENR-00001897 Produced in MDL on 02/27/13 Source: Actos Share of TZDs Retail TRx SOM, IMS Health 60.00% Actual Foreçast 50.00% 40.00% Launch of Launch of Merck's BMS' PPAR's 30.00% PPAR's Q3 2005 Feb 2005 20.00% 10.00% 0.00% 2000 2001 2002 2003 2004 2005 TZDs TRx (000s) 10,577 14,681 17,101 19,407 21,479 22,902 Actos TRx (000s) 4,261 6,872 8,582 9,497 10,149 10,472 TZD Share 40.3% 46.8% 50.2% 49.0% 47.3% 45.7% Plan TZD Share n/a n/a n/a 46.1% 42.9% Forecast as a % of Plan n/a n/a n/a 106.3% 110.1% <AUTO> Confidential - Subject to Protective Order LLY-HOVENR-00001898 Produced in MDL on 02/27/13 Avandamet Uptake Retail TRx (000s), IMS Health TRx (000s) Assumes 36% of Avandamet scripts from Actos 500 Glucovance 450 400 350 Avandamet 300 Forecast 250 200 150 Avandamet at 31% of original 100 forecast. 50 Avandamet 0 1 2 3 4 5 6 7 8 9 10 11 12 13 15 Full Months Post Launch <AUTO> Confidential - Subject to Protective Order LLY-HOVENR-00001899 Produced in MDL on 02/27/13 Source: Consequences of IR Damage to Eyes Damage to Kidneys TG HDL-C LDL-C Damage to Nerves Increased CV Risk Increased CV Risk Hyperglycemia Dyslipidemia Insulin Resistance Central Hypertension Obesity Increased CV Risk Increased CV Risk <AUTO> Confidential - Subject to Protective Order LLY-HOVENR-00001900 Produced in MDL on 02/27/13 Source: Link between IR and CVD THE ROUTE TO CARDIOVASCULAR DISEASE 2.11.15-19 Hyperglycemia Insulin Hyper a path that leads to increased risk for MI Resistance Dys TYPE 2 DIABETES EQUALS PRIOR MI AS A CHD RISK FACTOR Pr S 7-year incidence of myocardial infarction (MI) (%) 25% 20% 15% 18.8% 20.2% 10% 5% 0% Nondiabetic patients Type 2 diabetics with prior MI without prior MI <AUTO> Confidential - Subject to Protective Order LLY-HOVENR-00001901 Produced in MDL on 02/27/13 Source: It is important to engage your customer in dialogue around IR, symptoms, and complications. This Map is a critical tool to help you explain the link of insulin resistance and Cardiovascular risk. Confidential - Subject to Protective Order LLY-HOVENR-00001902 Produced in MDL on 02/27/13 Source: https://www.indu 90818-00008 s.ucsf.edu/docs/ynjf0226 Drug/Class of Drug Most Appropriate for the Treatment of Insulin Resistance (Unaided) Total PCPs ENDOs (n=338) (n=302) (n=79) TZD/Glitazone (Net) 81% 81% 80% TZD/Glitazone/ ACTOS/ 77% 77% 77% Avandia ACTOS 3% I 4% I 3% Avandia 1% 1% 0% Biguanides 15% 15% 15% Sulfonylureas 4% I 4% 3% TZD association with treating IR is solidly in the minds of most MDs. However 1 in 5 think metformin or a sulfonylurea is most appropriate to treat IR as well What or class of drugs do you consider to be the most appropriate to treat insulin resistance? * indicates significant difference between subgroups @95% confidence level Q20b Confidential - Subject to Protective Order LLY-HOVENR-00001903 Produced in MDL on 02/27/13 Source: https://www.induposeis-oooogts.ucsf.edu/docs/ynjf0226 Q21. For the next series of statements, please tell me which of the two TZDs/Glitazones you believe is better in the following areas. Is Actos better, Avandia better, or are they both the same with regard to their. Confidential - Subject to Protective Order LLY-HOVENR-00001904 Produced in MDL on 02/27/13 Source: https://www.indu P0818-00010 s.ucsf.edu/docs/ynjf0226 Belief in IR = More Scripts! TZD Share of OAD Market 25.0% 20.0% 15.0% 10.0% 5.0% 0.0% 2 3 4 5 Doctors who rated the Importance (scale of 1-5) that an Oral Agent treat insulin resistance N=3 N=25 N=265 N=160 <AUTO> SOURCE: Message Effectiveness Wave 6, IMS Health Confidential - Subject to Protective Order LLY-HOVENR-00001905 Produced in MDL on 02/27/13 Source: https://www.induposts-oooanits.ucsf.edu/docs/ynjf0226 Frame: Why should reps focus on IR (What's In It For Me-WIIFM)? Key Point: When docs rate IR as more important, their TZD share is higher. Confidential - Subject to Protective Order LLY-HOVENR-00001906 Produced in MDL on 02/27/13 Source: https://www.indu P0818-00012 s.ucsf.edu/docs/ynjf0226 Strategic Intent & CSFs Strategic Intent: Establish Actos as the best OAD medication by treating insulin resistance, through sustained glycemic control and reduced cardiovascular risk. Critical Success Factors 1. TZD's prescribed earlier in treatment of Type 2 diabetes 2. Actos is the the first TZD used for Type 2 patients. <AUTO> Confidential - Subject to Protective Order LLY-HOVENR-00001907 Produced in MDL on 02/27/13 Source:

What is the Specific example given?

gmjf0226

gmjf0226_p0, gmjf0226_p1

Pioglitazone: Need to commit to studies to investigate certain signals, pioglitazone: need to commit to studies to investigate certain signals

Minutes from Takeda Global Risk Management Forum/March 22, 2004 Facilitators: Glyn Belcher, MA, PhD, MB, BCHIR, FFPM/TEuRD Cal McNeill, MD/ TGRD Attendees: Mondira Bhattacharya MD, David Baron MD, Al Dietz MD, Barbara Hendrickson MD, Doug Joseph PharmD, Ron Law MD, Constance Kasprzak PharmD, Anna Lee MD, Olga Minkov BS MPN, Alfonso Perez MD, Jeremy Repp BIE, Mick Roebel PhD, Stephen Sainati MD, Claire Thom PharmD, Bill Welder MD EU Perspective Glyn Belcher Risk Management Identification of potential risk Clarification of risk Measurement of risk More extensive than risk minimization Should be done by Pharmacovigilance in Company. Risk Management starts during preclinical- clinical development marketing Risk management by pharmacovigilance in company: 1) Pre-clinical Every EU country sends in an Investigational Medicinal Product (IMP) documentation much like the IND which reviews preclinical safety signals and includes a plan on how to measure these safety signals in a clinical trial Includes specific attempts during clinical trials to clarify signals 2) Clinical trial yearly IMP safety report (global) will be required from May '04 onwards and includes all safety data in a year including nonclinical safety data. Regulators expect company to tell them what the problem is. Requires unblinding of serious unexpected reactions. Includes Postmarketing commitments 3) MAA (Marketing Authorization Application) = equivalent to NDA. As part of dossier, submit a risk management plan within one year. Risk management plan includes what you can say about safety of the drug and what you have not managed to clarify: more proactive in delineating what problems you know VS what you don't know Includes plans on further trials/studies to be done EXHIBIT Takeda Forum Risk Management 1 Bhattacharya March 22, 2004 11 1-12-13- Confidential - Subject to Protective Order TAK-BAROND-00208931 Produced in MDL on 09/02/12 Source: 4) Marketing 6 monthly PSUR's In the future, risk management plan will be reviewed to see how much of the safety signals have been clarified. Will include not just listings of events but more figures. Risk has to be clearly stated. Specific examples: Pioglitazone: Need to commit to studies to investigate certain signals 1) Bladder Cancer in Rats further epidemiologie study and pre-clinical investigations as part of license application Preclinical investigations done within TCI (Osaka). Some preclinical investigations are contracted out ie, to U of Nebraska which submits protocols but doesn't do actual work. Epi study; case control study: use retrospective data from general practitioners database. Other epi studies: prospective case cohort study; epi studies tagging people who receive the drug and compare results with historical data 2) Fluid Retention/CHI /Cardiac hypertrophy mechanistic studies will be conducted. As part of license application, studies in CHF patients + outcome studies were requested Safety signals will be clarified using these studies, 3) Liver problem PEM (prescription event monitoring) study similar to Japanese post- event marketing study. Prescribing doctor's name and patient's name are recorded in a central database from beginning of marketing. This database is reviewed for signals US Perspective Cal McNeill Discussion: Regulators will have similar interest in USA as in Europe. FDA expects sponsors to become proactive around safety issues from pre-clinical data to marketing phase Incorporate RM strategies in NDA submissions which is not the case at the moment but will begin incorporating risk management strategies for/ with Ramelteon. minimize risk throughout product's life-cylce guidance from FDA expected in September 2004 Risk Management - component of comprehensive product stewardship - pre-market/ clinical development - post-marketing General Discussion ALL Question 1 - Japan's role in RM: Who will direct company's position? Suggestion from Glyn: TGRD would formulate direct Risk Management plan and obtain Japan's input. Takeda Forum Risk Management 2 March 22, 2004 Confidential - Subject to Protective Order TAK-BAROND-00208932 Produced in MDL on 09/02/12 Source: https://www.induso/r56-00002.ucsf.edu/docs/gmjf0226

what is the month and year of overview of submission ?

jfkf0226

jfkf0226_p0, jfkf0226_p1, jfkf0226_p2, jfkf0226_p3

NOVEMBER 2006, November 2006

ACTOS Pediatric Program 5 October 2006 P7327-00001 Source: https://www.industrydocuments.ucsf.edu/docs/jfkf0226 Overview of November 2006 Submission 0 Partial clinical hold removal request document: Summary document (Includes benefit- risk assessment) Meta-analysis report Kaiser first cohort report New epidemiology report(s) Executive summary of bladder cancer cases - CONFIRM P7327-00002 Source: https://wwww.industrydocuments.ucsf.edu/docs/jfkf0226 Overview of November 2006 Submission 0 PPSR (Proposed Pediatric Study Request) NEED TO CONFIRM FORMAT Clinical study synopsis P7327-00003 Source: https://www.industrydocuments.ucsf.edu/docs/jfkf0226 Clinical Study Synopsis 01-06-TL-OPI-527 Expert advisory meeting 4 October 2006 Draft synopsis available for team review on Monday, 9 October 2006 Team proposing to review synopsis in TARC instead of SRC Need detailed timelines of full study by 20 October 2006 Need budget, delineating what may be spent in FY06, by 20 October 2006 P7327-00004 Source: https://www.industrydocuments.ucsf.edu/docs/jfkf0226

Which country would have similar interest as in Europe?

gmjf0226

gmjf0226_p0, gmjf0226_p1

USA, usa

Minutes from Takeda Global Risk Management Forum/March 22, 2004 Facilitators: Glyn Belcher, MA, PhD, MB, BCHIR, FFPM/TEuRD Cal McNeill, MD/ TGRD Attendees: Mondira Bhattacharya MD, David Baron MD, Al Dietz MD, Barbara Hendrickson MD, Doug Joseph PharmD, Ron Law MD, Constance Kasprzak PharmD, Anna Lee MD, Olga Minkov BS MPN, Alfonso Perez MD, Jeremy Repp BIE, Mick Roebel PhD, Stephen Sainati MD, Claire Thom PharmD, Bill Welder MD EU Perspective Glyn Belcher Risk Management Identification of potential risk Clarification of risk Measurement of risk More extensive than risk minimization Should be done by Pharmacovigilance in Company. Risk Management starts during preclinical- clinical development marketing Risk management by pharmacovigilance in company: 1) Pre-clinical Every EU country sends in an Investigational Medicinal Product (IMP) documentation much like the IND which reviews preclinical safety signals and includes a plan on how to measure these safety signals in a clinical trial Includes specific attempts during clinical trials to clarify signals 2) Clinical trial yearly IMP safety report (global) will be required from May '04 onwards and includes all safety data in a year including nonclinical safety data. Regulators expect company to tell them what the problem is. Requires unblinding of serious unexpected reactions. Includes Postmarketing commitments 3) MAA (Marketing Authorization Application) = equivalent to NDA. As part of dossier, submit a risk management plan within one year. Risk management plan includes what you can say about safety of the drug and what you have not managed to clarify: more proactive in delineating what problems you know VS what you don't know Includes plans on further trials/studies to be done EXHIBIT Takeda Forum Risk Management 1 Bhattacharya March 22, 2004 11 1-12-13- Confidential - Subject to Protective Order TAK-BAROND-00208931 Produced in MDL on 09/02/12 Source: 4) Marketing 6 monthly PSUR's In the future, risk management plan will be reviewed to see how much of the safety signals have been clarified. Will include not just listings of events but more figures. Risk has to be clearly stated. Specific examples: Pioglitazone: Need to commit to studies to investigate certain signals 1) Bladder Cancer in Rats further epidemiologie study and pre-clinical investigations as part of license application Preclinical investigations done within TCI (Osaka). Some preclinical investigations are contracted out ie, to U of Nebraska which submits protocols but doesn't do actual work. Epi study; case control study: use retrospective data from general practitioners database. Other epi studies: prospective case cohort study; epi studies tagging people who receive the drug and compare results with historical data 2) Fluid Retention/CHI /Cardiac hypertrophy mechanistic studies will be conducted. As part of license application, studies in CHF patients + outcome studies were requested Safety signals will be clarified using these studies, 3) Liver problem PEM (prescription event monitoring) study similar to Japanese post- event marketing study. Prescribing doctor's name and patient's name are recorded in a central database from beginning of marketing. This database is reviewed for signals US Perspective Cal McNeill Discussion: Regulators will have similar interest in USA as in Europe. FDA expects sponsors to become proactive around safety issues from pre-clinical data to marketing phase Incorporate RM strategies in NDA submissions which is not the case at the moment but will begin incorporating risk management strategies for/ with Ramelteon. minimize risk throughout product's life-cylce guidance from FDA expected in September 2004 Risk Management - component of comprehensive product stewardship - pre-market/ clinical development - post-marketing General Discussion ALL Question 1 - Japan's role in RM: Who will direct company's position? Suggestion from Glyn: TGRD would formulate direct Risk Management plan and obtain Japan's input. Takeda Forum Risk Management 2 March 22, 2004 Confidential - Subject to Protective Order TAK-BAROND-00208932 Produced in MDL on 09/02/12 Source: https://www.induso/r56-00002.ucsf.edu/docs/gmjf0226

What is the Suggestion from Glyn?

gmjf0226

gmjf0226_p0, gmjf0226_p1

"TGRD would formulate direct Risk Management plan and obtain Japans input", "tgrd would formulate direct risk management plan and obtain japans input"

Minutes from Takeda Global Risk Management Forum/March 22, 2004 Facilitators: Glyn Belcher, MA, PhD, MB, BCHIR, FFPM/TEuRD Cal McNeill, MD/ TGRD Attendees: Mondira Bhattacharya MD, David Baron MD, Al Dietz MD, Barbara Hendrickson MD, Doug Joseph PharmD, Ron Law MD, Constance Kasprzak PharmD, Anna Lee MD, Olga Minkov BS MPN, Alfonso Perez MD, Jeremy Repp BIE, Mick Roebel PhD, Stephen Sainati MD, Claire Thom PharmD, Bill Welder MD EU Perspective Glyn Belcher Risk Management Identification of potential risk Clarification of risk Measurement of risk More extensive than risk minimization Should be done by Pharmacovigilance in Company. Risk Management starts during preclinical- clinical development marketing Risk management by pharmacovigilance in company: 1) Pre-clinical Every EU country sends in an Investigational Medicinal Product (IMP) documentation much like the IND which reviews preclinical safety signals and includes a plan on how to measure these safety signals in a clinical trial Includes specific attempts during clinical trials to clarify signals 2) Clinical trial yearly IMP safety report (global) will be required from May '04 onwards and includes all safety data in a year including nonclinical safety data. Regulators expect company to tell them what the problem is. Requires unblinding of serious unexpected reactions. Includes Postmarketing commitments 3) MAA (Marketing Authorization Application) = equivalent to NDA. As part of dossier, submit a risk management plan within one year. Risk management plan includes what you can say about safety of the drug and what you have not managed to clarify: more proactive in delineating what problems you know VS what you don't know Includes plans on further trials/studies to be done EXHIBIT Takeda Forum Risk Management 1 Bhattacharya March 22, 2004 11 1-12-13- Confidential - Subject to Protective Order TAK-BAROND-00208931 Produced in MDL on 09/02/12 Source: 4) Marketing 6 monthly PSUR's In the future, risk management plan will be reviewed to see how much of the safety signals have been clarified. Will include not just listings of events but more figures. Risk has to be clearly stated. Specific examples: Pioglitazone: Need to commit to studies to investigate certain signals 1) Bladder Cancer in Rats further epidemiologie study and pre-clinical investigations as part of license application Preclinical investigations done within TCI (Osaka). Some preclinical investigations are contracted out ie, to U of Nebraska which submits protocols but doesn't do actual work. Epi study; case control study: use retrospective data from general practitioners database. Other epi studies: prospective case cohort study; epi studies tagging people who receive the drug and compare results with historical data 2) Fluid Retention/CHI /Cardiac hypertrophy mechanistic studies will be conducted. As part of license application, studies in CHF patients + outcome studies were requested Safety signals will be clarified using these studies, 3) Liver problem PEM (prescription event monitoring) study similar to Japanese post- event marketing study. Prescribing doctor's name and patient's name are recorded in a central database from beginning of marketing. This database is reviewed for signals US Perspective Cal McNeill Discussion: Regulators will have similar interest in USA as in Europe. FDA expects sponsors to become proactive around safety issues from pre-clinical data to marketing phase Incorporate RM strategies in NDA submissions which is not the case at the moment but will begin incorporating risk management strategies for/ with Ramelteon. minimize risk throughout product's life-cylce guidance from FDA expected in September 2004 Risk Management - component of comprehensive product stewardship - pre-market/ clinical development - post-marketing General Discussion ALL Question 1 - Japan's role in RM: Who will direct company's position? Suggestion from Glyn: TGRD would formulate direct Risk Management plan and obtain Japan's input. Takeda Forum Risk Management 2 March 22, 2004 Confidential - Subject to Protective Order TAK-BAROND-00208932 Produced in MDL on 09/02/12 Source: https://www.induso/r56-00002.ucsf.edu/docs/gmjf0226

what is the executive summary of bladder cancer cases ?

jfkf0226

jfkf0226_p0, jfkf0226_p1, jfkf0226_p2, jfkf0226_p3

CONFIRM

ACTOS Pediatric Program 5 October 2006 P7327-00001 Source: https://www.industrydocuments.ucsf.edu/docs/jfkf0226 Overview of November 2006 Submission 0 Partial clinical hold removal request document: Summary document (Includes benefit- risk assessment) Meta-analysis report Kaiser first cohort report New epidemiology report(s) Executive summary of bladder cancer cases - CONFIRM P7327-00002 Source: https://wwww.industrydocuments.ucsf.edu/docs/jfkf0226 Overview of November 2006 Submission 0 PPSR (Proposed Pediatric Study Request) NEED TO CONFIRM FORMAT Clinical study synopsis P7327-00003 Source: https://www.industrydocuments.ucsf.edu/docs/jfkf0226 Clinical Study Synopsis 01-06-TL-OPI-527 Expert advisory meeting 4 October 2006 Draft synopsis available for team review on Monday, 9 October 2006 Team proposing to review synopsis in TARC instead of SRC Need detailed timelines of full study by 20 October 2006 Need budget, delineating what may be spent in FY06, by 20 October 2006 P7327-00004 Source: https://www.industrydocuments.ucsf.edu/docs/jfkf0226

Full form of PEM?

gmjf0226

gmjf0226_p0, gmjf0226_p1

prescription event monitoring

Minutes from Takeda Global Risk Management Forum/March 22, 2004 Facilitators: Glyn Belcher, MA, PhD, MB, BCHIR, FFPM/TEuRD Cal McNeill, MD/ TGRD Attendees: Mondira Bhattacharya MD, David Baron MD, Al Dietz MD, Barbara Hendrickson MD, Doug Joseph PharmD, Ron Law MD, Constance Kasprzak PharmD, Anna Lee MD, Olga Minkov BS MPN, Alfonso Perez MD, Jeremy Repp BIE, Mick Roebel PhD, Stephen Sainati MD, Claire Thom PharmD, Bill Welder MD EU Perspective Glyn Belcher Risk Management Identification of potential risk Clarification of risk Measurement of risk More extensive than risk minimization Should be done by Pharmacovigilance in Company. Risk Management starts during preclinical- clinical development marketing Risk management by pharmacovigilance in company: 1) Pre-clinical Every EU country sends in an Investigational Medicinal Product (IMP) documentation much like the IND which reviews preclinical safety signals and includes a plan on how to measure these safety signals in a clinical trial Includes specific attempts during clinical trials to clarify signals 2) Clinical trial yearly IMP safety report (global) will be required from May '04 onwards and includes all safety data in a year including nonclinical safety data. Regulators expect company to tell them what the problem is. Requires unblinding of serious unexpected reactions. Includes Postmarketing commitments 3) MAA (Marketing Authorization Application) = equivalent to NDA. As part of dossier, submit a risk management plan within one year. Risk management plan includes what you can say about safety of the drug and what you have not managed to clarify: more proactive in delineating what problems you know VS what you don't know Includes plans on further trials/studies to be done EXHIBIT Takeda Forum Risk Management 1 Bhattacharya March 22, 2004 11 1-12-13- Confidential - Subject to Protective Order TAK-BAROND-00208931 Produced in MDL on 09/02/12 Source: 4) Marketing 6 monthly PSUR's In the future, risk management plan will be reviewed to see how much of the safety signals have been clarified. Will include not just listings of events but more figures. Risk has to be clearly stated. Specific examples: Pioglitazone: Need to commit to studies to investigate certain signals 1) Bladder Cancer in Rats further epidemiologie study and pre-clinical investigations as part of license application Preclinical investigations done within TCI (Osaka). Some preclinical investigations are contracted out ie, to U of Nebraska which submits protocols but doesn't do actual work. Epi study; case control study: use retrospective data from general practitioners database. Other epi studies: prospective case cohort study; epi studies tagging people who receive the drug and compare results with historical data 2) Fluid Retention/CHI /Cardiac hypertrophy mechanistic studies will be conducted. As part of license application, studies in CHF patients + outcome studies were requested Safety signals will be clarified using these studies, 3) Liver problem PEM (prescription event monitoring) study similar to Japanese post- event marketing study. Prescribing doctor's name and patient's name are recorded in a central database from beginning of marketing. This database is reviewed for signals US Perspective Cal McNeill Discussion: Regulators will have similar interest in USA as in Europe. FDA expects sponsors to become proactive around safety issues from pre-clinical data to marketing phase Incorporate RM strategies in NDA submissions which is not the case at the moment but will begin incorporating risk management strategies for/ with Ramelteon. minimize risk throughout product's life-cylce guidance from FDA expected in September 2004 Risk Management - component of comprehensive product stewardship - pre-market/ clinical development - post-marketing General Discussion ALL Question 1 - Japan's role in RM: Who will direct company's position? Suggestion from Glyn: TGRD would formulate direct Risk Management plan and obtain Japan's input. Takeda Forum Risk Management 2 March 22, 2004 Confidential - Subject to Protective Order TAK-BAROND-00208932 Produced in MDL on 09/02/12 Source: https://www.induso/r56-00002.ucsf.edu/docs/gmjf0226