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what is 'RE' in the letter?

sqjf0226

sqjf0226_p0, sqjf0226_p1

preservation of documents and electronic data relating to actos, Preservation of Documents and Electronic Data relating to Actos

EXHIBIT Takeda 40 TO: Sam Hamanaka DATE: July 19, 2002 Mark Booth Wendell Cheatham Rich Daly Terry Fukumoto Dean Hart Masatake Kashiyae Curtis Rhine Lori Smith Claire Thom Lee Voight Chuck Whitmer FROM: Marlene Dubas CC: Tom Muldoon RE: Preservation of Documents And Electronic Data relating to Actos MEMO: A motion has been filed to add Takeda Pharmaceuticals North America, Inc. and Takeda Pharmaceuticals America, Inc. as defendants in a lawsuit. The plaintiff in this lawsuit seeks damages for personal injury and wrongful death allegedly resulting from the use of certain prescription drugs, including Actos. To be able to respond to discovery requests from the plaintiff, if that becomes necessary, we must take steps to preserve any documents that may be called for in this lawsuit. Until further notice, you are instructed to preserve any and all documents and electronic data which discuss, mention, or relate to Actos. This means do not destroy, delete, throw away or otherwise discard any such documents or electronic data. This includes correspondence, records, and data, contained in your paper and electronic files, regardless of form and including email correspondence and attachments and electronic data. Continued Confidential - Subject to Protective Order TAK-RIM30b6-00000653 Source: https://www.indup53090007ts.ucsf.edu/docs/sqjf0226 Memo to: Distribution July 19, 2002 Page 2 Action Steps: Please interpret this directive in its broadest sense to prevent the deletion or destruction of any recorded information and data relating in any way to Actos. Please take steps immediately to preserve such documents and data within your department. Please distribute this memo to members of your group and advise them of the importance of following these instructions. If you have any questions regarding the implementation of this directive, please contact me. Marlene Charra Marlene C. Dubas Confidential - Subject to Protective Order TAK-RIM30b6-00000654 Source: https://www.indup5309-00002s.ucsf.edu/docs/sqjf0226

Heading of the first paragraph?

lzjf0226

lzjf0226_p2, lzjf0226_p3, lzjf0226_p4, lzjf0226_p5, lzjf0226_p6

SIXTH OBJECTION

GENERAL OBJECTIONS FIRST OBJECTION The Interrogatory arguably seeks information that is either privileged or protected from discovery under the attorney-client privilege, work product doctrine, joint defense or common interest privilege, or the self-critical analysis doctrine. Takeda objects to producing this type of privileged or otherwise protected information. SECOND OBJECTION Takeda objects that the Interrogatory exceeds the permissible scope of discovery under the applicable Rules of Civil Procedure. THIRD OBJECTION Takeda objects to the extent that the Interrogatory seeks information that would violate the privacy rights of individuals, confidentiality agreements between it and any of its customers, other arrangements between it and any person, or court orders restricting the disclosure of information. FOURTH OBJECTION Takeda objects to the extent that the Interrogatory seeks production of patient or medical provider identifying information not related to the plaintiff in this case on the grounds of HIPPA, patient privacy, doctor-patient privilege, and FDA regulations prohibiting dissemination of such information. FIFTH OBJECTION Takeda objects to the extent that the Interrogatory seeks production of information that is not within Takeda's possession, custody, or control. 2 PLA-TAK-00061863 P7071-00003 Source: https://www.industrydocuments.ucsf.edu/docs//zjf0226 SIXTH OBJECTION Takeda objects to the extent that the Interrogatory seeks information or material pertaining to alleged side effects or adverse reactions to Actos other than those of the character allegedly experienced by plaintiffs on the ground that such information is not relevant to any claim or defense involved in this action. RESPONSE Supplemental Interrogatory No. 2: During a July 25, 2013 hearing before Judge Patrick Hanna counsel of Defendants advised the court that "claims, settlements and litigation" had been made during a timeframe as early as 2002 concerning personal injuries relating to Actos. For these claims, please provide: a. Date(s) of the personal injury claims made relating to Actos; b. Identity of party or parties bringing or making the personal injury claims; c. Location of where these personal injury claims were brought or made and which Takeda entities they were brought or made against; d. Court or other authority or agency charged with adjudicating these personal injury claims; e. Identity of the lawyers and law firms representing Takeda in these personal injury claims from inception to the present day; f. Date(s) of any litigation hold(s) put in place for these personal injury claims; g. Current status of these personal injury claims; h. If these claims have been resolved, how they were resolved; and i. If they were resolved, when were they resolved? Response: In addition to the General Objections, Takeda objects to Supplemental Interrogatory No. 2, including all of its subparts, on the following grounds: (1) is overly broad and unduly burdensome; (2) it seeks information that is not relevant and not reasonably calculated to lead to the discovery of admissible evidence; (3) it is vague and/or ambiguous; and (4) it calls for the production of information protected from discovery by the work product doctrine, the attorney- 3 PLA-TAK-00061864 P7071-00004 Source: https://www.industrydocuments.ucsf.edu/docs//zjf0226 client privilege, and other applicable privileges. Takeda further objects on the ground that this interrogatory, particularly subpart b, seeks the production of patient identifying information that Takeda is prohibited from disseminating pursuant to FDA regulations, HIPPA, and other applicable laws protecting patient privacy. Subject to and without waiving these or any other objection, Takeda directs Plaintiffs to Attachment A. Responding further, Takeda states that a general Actos "product liability" litigation hold was implemented at Takeda Pharmaceuticals U.S.A., Inc. (f/k/a Takeda Pharmaceuticals North America, Inc.) and Takeda Pharmaceuticals America, Inc. in July 2002 when Takeda Pharmaceuticals U.S.A., Inc. (f/k/a Takeda Pharmaceuticals North America, Inc.) and Takeda Pharmaceuticals America, Inc. received notice of the first Actos personal injury lawsuit, which was filed by Plaintiff Elizabeth McMillan in the Circuit Court of Jackson County, Missouri. The general Actos "product liability" litigation hold became applicable to Takeda Development Center Americas, Inc. (f/k/a Takeda Global Research & Development Center, Inc.) at the time of its incorporation in 2004 and has been refreshed periodically since that time. Dated: August 7, 2013 By, Sara J. Gourley (IL Bar No. 3127154) Sherry A. Khutson (IL Bar No. 6276306) SIDLEY AUSTIN LLP 1 South Dearborn Street Chicago, IL 60603 (313)853-7000 (Telephone) (312)853-7036 (Facsimile) [email protected] [email protected] Scott W. Sayler (MO Bar No. 36088) Rebecca J. Schwartz (MO Bar No. 46341) SHOOK, HARDY & BACON, LLP 2555 Grand Boulevard Kansas City, MO 64106 (816) 474-6550 (Telephone) 4 PLA-TAK-00061865 P7071-00005 Source: https://www.industrydocuments.ucsf.edu/docs//zjf0226 (816)421-5547 (Facsimile) [email protected] [email protected] Counsel for Defendants 5 PLA-TAK-00061866 P7071-00006 Source: https://www.industrydocuments.ucsf.edu/docs//zjf0226 CERTIFICATE OF SERVICE I hereby certify that on August 7, 2013, a copy of the above Defendant's Response to Plaintiffs' Supplemental Interrogatory Regarding 2010 Actos Bladder Cancer Claim was served on the PSC via e-mail. Sherry A. Kenutson (IL Bar No. 6276306) SIDLEY AUSTIN LLP 1 South Dearborn Street Chicago, IL 60603 (313) 853-7000 (Telephone) (312) 853-7036 (Facsimile) [email protected] [email protected] 6 PLA-TAK-00061867 P7071-00007 Source: https://www.industrydocuments.ucsf.edu/docs//zjf0226

Name of the judge?

lzjf0226

lzjf0226_p2, lzjf0226_p3, lzjf0226_p4, lzjf0226_p5, lzjf0226_p6

Patrick Hanna

GENERAL OBJECTIONS FIRST OBJECTION The Interrogatory arguably seeks information that is either privileged or protected from discovery under the attorney-client privilege, work product doctrine, joint defense or common interest privilege, or the self-critical analysis doctrine. Takeda objects to producing this type of privileged or otherwise protected information. SECOND OBJECTION Takeda objects that the Interrogatory exceeds the permissible scope of discovery under the applicable Rules of Civil Procedure. THIRD OBJECTION Takeda objects to the extent that the Interrogatory seeks information that would violate the privacy rights of individuals, confidentiality agreements between it and any of its customers, other arrangements between it and any person, or court orders restricting the disclosure of information. FOURTH OBJECTION Takeda objects to the extent that the Interrogatory seeks production of patient or medical provider identifying information not related to the plaintiff in this case on the grounds of HIPPA, patient privacy, doctor-patient privilege, and FDA regulations prohibiting dissemination of such information. FIFTH OBJECTION Takeda objects to the extent that the Interrogatory seeks production of information that is not within Takeda's possession, custody, or control. 2 PLA-TAK-00061863 P7071-00003 Source: https://www.industrydocuments.ucsf.edu/docs//zjf0226 SIXTH OBJECTION Takeda objects to the extent that the Interrogatory seeks information or material pertaining to alleged side effects or adverse reactions to Actos other than those of the character allegedly experienced by plaintiffs on the ground that such information is not relevant to any claim or defense involved in this action. RESPONSE Supplemental Interrogatory No. 2: During a July 25, 2013 hearing before Judge Patrick Hanna counsel of Defendants advised the court that "claims, settlements and litigation" had been made during a timeframe as early as 2002 concerning personal injuries relating to Actos. For these claims, please provide: a. Date(s) of the personal injury claims made relating to Actos; b. Identity of party or parties bringing or making the personal injury claims; c. Location of where these personal injury claims were brought or made and which Takeda entities they were brought or made against; d. Court or other authority or agency charged with adjudicating these personal injury claims; e. Identity of the lawyers and law firms representing Takeda in these personal injury claims from inception to the present day; f. Date(s) of any litigation hold(s) put in place for these personal injury claims; g. Current status of these personal injury claims; h. If these claims have been resolved, how they were resolved; and i. If they were resolved, when were they resolved? Response: In addition to the General Objections, Takeda objects to Supplemental Interrogatory No. 2, including all of its subparts, on the following grounds: (1) is overly broad and unduly burdensome; (2) it seeks information that is not relevant and not reasonably calculated to lead to the discovery of admissible evidence; (3) it is vague and/or ambiguous; and (4) it calls for the production of information protected from discovery by the work product doctrine, the attorney- 3 PLA-TAK-00061864 P7071-00004 Source: https://www.industrydocuments.ucsf.edu/docs//zjf0226 client privilege, and other applicable privileges. Takeda further objects on the ground that this interrogatory, particularly subpart b, seeks the production of patient identifying information that Takeda is prohibited from disseminating pursuant to FDA regulations, HIPPA, and other applicable laws protecting patient privacy. Subject to and without waiving these or any other objection, Takeda directs Plaintiffs to Attachment A. Responding further, Takeda states that a general Actos "product liability" litigation hold was implemented at Takeda Pharmaceuticals U.S.A., Inc. (f/k/a Takeda Pharmaceuticals North America, Inc.) and Takeda Pharmaceuticals America, Inc. in July 2002 when Takeda Pharmaceuticals U.S.A., Inc. (f/k/a Takeda Pharmaceuticals North America, Inc.) and Takeda Pharmaceuticals America, Inc. received notice of the first Actos personal injury lawsuit, which was filed by Plaintiff Elizabeth McMillan in the Circuit Court of Jackson County, Missouri. The general Actos "product liability" litigation hold became applicable to Takeda Development Center Americas, Inc. (f/k/a Takeda Global Research & Development Center, Inc.) at the time of its incorporation in 2004 and has been refreshed periodically since that time. Dated: August 7, 2013 By, Sara J. Gourley (IL Bar No. 3127154) Sherry A. Khutson (IL Bar No. 6276306) SIDLEY AUSTIN LLP 1 South Dearborn Street Chicago, IL 60603 (313)853-7000 (Telephone) (312)853-7036 (Facsimile) [email protected] [email protected] Scott W. Sayler (MO Bar No. 36088) Rebecca J. Schwartz (MO Bar No. 46341) SHOOK, HARDY & BACON, LLP 2555 Grand Boulevard Kansas City, MO 64106 (816) 474-6550 (Telephone) 4 PLA-TAK-00061865 P7071-00005 Source: https://www.industrydocuments.ucsf.edu/docs//zjf0226 (816)421-5547 (Facsimile) [email protected] [email protected] Counsel for Defendants 5 PLA-TAK-00061866 P7071-00006 Source: https://www.industrydocuments.ucsf.edu/docs//zjf0226 CERTIFICATE OF SERVICE I hereby certify that on August 7, 2013, a copy of the above Defendant's Response to Plaintiffs' Supplemental Interrogatory Regarding 2010 Actos Bladder Cancer Claim was served on the PSC via e-mail. Sherry A. Kenutson (IL Bar No. 6276306) SIDLEY AUSTIN LLP 1 South Dearborn Street Chicago, IL 60603 (313) 853-7000 (Telephone) (312) 853-7036 (Facsimile) [email protected] [email protected] 6 PLA-TAK-00061867 P7071-00007 Source: https://www.industrydocuments.ucsf.edu/docs//zjf0226

When was the hearing before Judge?

lzjf0226

lzjf0226_p2, lzjf0226_p3, lzjf0226_p4, lzjf0226_p5, lzjf0226_p6

July 25, 2013

GENERAL OBJECTIONS FIRST OBJECTION The Interrogatory arguably seeks information that is either privileged or protected from discovery under the attorney-client privilege, work product doctrine, joint defense or common interest privilege, or the self-critical analysis doctrine. Takeda objects to producing this type of privileged or otherwise protected information. SECOND OBJECTION Takeda objects that the Interrogatory exceeds the permissible scope of discovery under the applicable Rules of Civil Procedure. THIRD OBJECTION Takeda objects to the extent that the Interrogatory seeks information that would violate the privacy rights of individuals, confidentiality agreements between it and any of its customers, other arrangements between it and any person, or court orders restricting the disclosure of information. FOURTH OBJECTION Takeda objects to the extent that the Interrogatory seeks production of patient or medical provider identifying information not related to the plaintiff in this case on the grounds of HIPPA, patient privacy, doctor-patient privilege, and FDA regulations prohibiting dissemination of such information. FIFTH OBJECTION Takeda objects to the extent that the Interrogatory seeks production of information that is not within Takeda's possession, custody, or control. 2 PLA-TAK-00061863 P7071-00003 Source: https://www.industrydocuments.ucsf.edu/docs//zjf0226 SIXTH OBJECTION Takeda objects to the extent that the Interrogatory seeks information or material pertaining to alleged side effects or adverse reactions to Actos other than those of the character allegedly experienced by plaintiffs on the ground that such information is not relevant to any claim or defense involved in this action. RESPONSE Supplemental Interrogatory No. 2: During a July 25, 2013 hearing before Judge Patrick Hanna counsel of Defendants advised the court that "claims, settlements and litigation" had been made during a timeframe as early as 2002 concerning personal injuries relating to Actos. For these claims, please provide: a. Date(s) of the personal injury claims made relating to Actos; b. Identity of party or parties bringing or making the personal injury claims; c. Location of where these personal injury claims were brought or made and which Takeda entities they were brought or made against; d. Court or other authority or agency charged with adjudicating these personal injury claims; e. Identity of the lawyers and law firms representing Takeda in these personal injury claims from inception to the present day; f. Date(s) of any litigation hold(s) put in place for these personal injury claims; g. Current status of these personal injury claims; h. If these claims have been resolved, how they were resolved; and i. If they were resolved, when were they resolved? Response: In addition to the General Objections, Takeda objects to Supplemental Interrogatory No. 2, including all of its subparts, on the following grounds: (1) is overly broad and unduly burdensome; (2) it seeks information that is not relevant and not reasonably calculated to lead to the discovery of admissible evidence; (3) it is vague and/or ambiguous; and (4) it calls for the production of information protected from discovery by the work product doctrine, the attorney- 3 PLA-TAK-00061864 P7071-00004 Source: https://www.industrydocuments.ucsf.edu/docs//zjf0226 client privilege, and other applicable privileges. Takeda further objects on the ground that this interrogatory, particularly subpart b, seeks the production of patient identifying information that Takeda is prohibited from disseminating pursuant to FDA regulations, HIPPA, and other applicable laws protecting patient privacy. Subject to and without waiving these or any other objection, Takeda directs Plaintiffs to Attachment A. Responding further, Takeda states that a general Actos "product liability" litigation hold was implemented at Takeda Pharmaceuticals U.S.A., Inc. (f/k/a Takeda Pharmaceuticals North America, Inc.) and Takeda Pharmaceuticals America, Inc. in July 2002 when Takeda Pharmaceuticals U.S.A., Inc. (f/k/a Takeda Pharmaceuticals North America, Inc.) and Takeda Pharmaceuticals America, Inc. received notice of the first Actos personal injury lawsuit, which was filed by Plaintiff Elizabeth McMillan in the Circuit Court of Jackson County, Missouri. The general Actos "product liability" litigation hold became applicable to Takeda Development Center Americas, Inc. (f/k/a Takeda Global Research & Development Center, Inc.) at the time of its incorporation in 2004 and has been refreshed periodically since that time. Dated: August 7, 2013 By, Sara J. Gourley (IL Bar No. 3127154) Sherry A. Khutson (IL Bar No. 6276306) SIDLEY AUSTIN LLP 1 South Dearborn Street Chicago, IL 60603 (313)853-7000 (Telephone) (312)853-7036 (Facsimile) [email protected] [email protected] Scott W. Sayler (MO Bar No. 36088) Rebecca J. Schwartz (MO Bar No. 46341) SHOOK, HARDY & BACON, LLP 2555 Grand Boulevard Kansas City, MO 64106 (816) 474-6550 (Telephone) 4 PLA-TAK-00061865 P7071-00005 Source: https://www.industrydocuments.ucsf.edu/docs//zjf0226 (816)421-5547 (Facsimile) [email protected] [email protected] Counsel for Defendants 5 PLA-TAK-00061866 P7071-00006 Source: https://www.industrydocuments.ucsf.edu/docs//zjf0226 CERTIFICATE OF SERVICE I hereby certify that on August 7, 2013, a copy of the above Defendant's Response to Plaintiffs' Supplemental Interrogatory Regarding 2010 Actos Bladder Cancer Claim was served on the PSC via e-mail. Sherry A. Kenutson (IL Bar No. 6276306) SIDLEY AUSTIN LLP 1 South Dearborn Street Chicago, IL 60603 (313) 853-7000 (Telephone) (312) 853-7036 (Facsimile) [email protected] [email protected] 6 PLA-TAK-00061867 P7071-00007 Source: https://www.industrydocuments.ucsf.edu/docs//zjf0226

What is the date mentioned?

ttjf0226

ttjf0226_p4

January 14, 1999

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 the name of the company mentioned in the letterhead?

kmjf0226

kmjf0226_p0, kmjf0226_p1, kmjf0226_p2, kmjf0226_p3

DEPARTMENT OF HEALTH & HUMAN SERVICES

Public Health Service DEPARTMENT OF HEALTH & HUMAN SERVICES Food and Drug Administration Rockville, MD 20857 NDA 21-073/S-026 DISCIPLINE REVIEW LETTER Takeda Global Research & Development Center, Inc. RECEIVED Attention: Mary Jo Pritza, MPH, PharmD REGULATORY AFFAIRS DEPARTMENT Manager, Regulatory Affairs One Takeda Parkway FEB 1 9 2007 Deerfield, IL 60015 Dear Ms. Pritza: TAKEDA GLOBAL RESEARCH & DEVELOPMENT CENTER, ING Please refer to your January 24, 2006, supplemental new drug application (NDA) submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act for Actos (pioglitazone HCI) tablets, 15 mg, 30 mg, and 45 mg. We also refer to your submissions dated June 1, August 22 and 31, October 10, November 14, and December 15, 2006, and to our proposed labeling revisions sent to you (via e-mail) on February 7, 2007. Our review of the clinical section of your response to our labeling revisions is complete, and our summary of the rationale for our changes to your proposed label appear below. 1. Movement of proposed information regarding outcome of the PROactive trial from the Clinical Studies section to the ADVERSE REACTIONS section, and inclusion of information only from the primary endpoint: This was a failed trial; statistical significance for the primary endpoint was not met, and the statistical evaluation does not support consideration of secondary endpoints in the event of failure to demonstrate significance for the primary endpoint. Even if you could demonstrate that it is statistically legitimate to consider secondary endpoints, the proposed "main" secondary endpoint was not placed in the statistical analysis plan until well after the trial had ended. Although technically it is possible to add new endpoints prior to breaking the blind, the long period of time (months) between study cessation and insertion of the new endpoint into the plan, the short period of time (days) between this addition and breaking of the blind, and the proposal to use this late- coming endpoint in the setting of a failed primary endpoint, give this endpoint the appearance of a post hoc analysis rather than a prospectively defined endpoint. Confidential - Subject to Protective Order TAK-PRITZM-00247931 Produced in MDL on 9/25/12 Source: https://www.induspo334-00001s.ucsf.edu/docs/kmjf0226 NDA 21-073/S-026 When one considers events of heart failure as well as the components of the primary endpoint (which did not include heart failure), there is even less of a numerical difference in the risk of adverse cardiovascular events for pioglitazone as compared to placebo. Under the Physician Labeling Rule (PLR), information from studies which do not directly support an approved indication will be removed from the Clinical Studies section. Although this label is not under the PLR, the next time you submit a supplement, it will be, and therefore, even if these data were to appear into the Clinical Studies section at this time, they would be removed with the first PLR label. Although we consider PROactive to be a failed trial from an efficacy standpoint, the trial does provide some reassuring safety information. Namely, it appears that pioglitazone is likely not associated with a significantly increased risk of macrovascular events compared to placebo. Given the drug's association with heart failure risk, the question of risk for other cardiovascular events has been of great concern. As such, the Division feels that addition of information to the ADVERSE REACTIONS section of the label could provide some reassurance to prescribers regarding this safety issue and would like to proceed with labeling negotiations to ensure that this relevant information is made available to the public. 2. Removal of proposed information regarding CHICAGO from the Clinical Studies section: At this time, neither the Division of Metabolism and Endocrinology Products, nor the Division of Cardiovascular and Renal Products, considers carotid intima media thickness to be a validated surrogate for risk of cardiovascular events. Although results of imaging studies have been included in labels for lipid-altering drugs, the clinical benefits of those drugs have been established in clinical outcomes studies, hence, implied claims of benefit with CIMT are less of a concern in those labels. For those drugs, CIMT results are essentially superseded by clinical outcomes data. In this label, the implied claim of benefit on the atherosclerotic process is not supported by the PROactive results. Although, when you attempted to apply the endpoint analyses from PROactive to CHICAGO, numerically slightly fewer serious cardiovascular endpoint events occurred among the pioglitazone group patients than among the placebo group patients, the difference was not significant, and was accounted for entirely by one type of event (percutaneous coronary intervention). Additionally, there was no difference between treatment groups for the incidence of events within the overall Cardiac and Vascular Disorders MedDRA System Organ Classes. Thus, this trial is not broadly supportive of decreased risk of macrovascular events. Additionally, edema and weight gain occurred more commonly among the pioglitazone group patients than among the placebo group patients. Confidential - Subject to Protective Order AK-PRITZM-00247932 Produced in MDL on 9/25/12 Source: NDA 21-073/S-026 As with the data from PROactive, the CHICAGO data do not directly support an approved indication, and thus, even if they were included in the Clinical Studies section at this time, the data would be removed with the first PLR label. We are providing these comments to you before we complete our review of the entire application to give you preliminary notice of issues that we have identified. In conformance with the prescription drug user fee reauthorization agreements, these comments do not reflect a final decision on the information reviewed and should not be construed to do so. These comments are preliminary and subject to change as we finalize our review of your application. In addition, we may identify other information that must be provided before we can approve this application. If you respond to these issues during this review cycle, depending on the timing of your response, and in conformance with the user fee reauthorization agreements, we may not be able to consider your response before we take an action on your application during this review cycle. If you have any questions, please call Ms. Jena Weber, Regulatory Project Manager, at 301-796-1306. Sincerely, (See appended electronic signature page) Mary H. Parks, M.D. Director Division of Metabolism and Endocrinology Products Office of Drug Evaluation II Center for Drug Evaluation and Research Confidential - Subject to Protective Order TAK-PRITZM-00247933 Produced in MDL on 9/25/12 Source: https://[email protected] ucsf.edu/docs/kmjf0226 This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. /s/ Mary Parks 2/13/2007 09:19:28 AM Confidential - Subject to Protective Order AK-PRITZM-00247934 Produced in MDL on 9/25/12 Source: https://www.indupo34-00004s.ucsf.edu/docs/kmjf0226

What is the company name ?

ttjf0226

ttjf0226_p4

ELI LILLY AND COMPANY

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 the fullform of NDA?

kmjf0226

kmjf0226_p0, kmjf0226_p1, kmjf0226_p2, kmjf0226_p3

New drug application., new drug application

Public Health Service DEPARTMENT OF HEALTH & HUMAN SERVICES Food and Drug Administration Rockville, MD 20857 NDA 21-073/S-026 DISCIPLINE REVIEW LETTER Takeda Global Research & Development Center, Inc. RECEIVED Attention: Mary Jo Pritza, MPH, PharmD REGULATORY AFFAIRS DEPARTMENT Manager, Regulatory Affairs One Takeda Parkway FEB 1 9 2007 Deerfield, IL 60015 Dear Ms. Pritza: TAKEDA GLOBAL RESEARCH & DEVELOPMENT CENTER, ING Please refer to your January 24, 2006, supplemental new drug application (NDA) submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act for Actos (pioglitazone HCI) tablets, 15 mg, 30 mg, and 45 mg. We also refer to your submissions dated June 1, August 22 and 31, October 10, November 14, and December 15, 2006, and to our proposed labeling revisions sent to you (via e-mail) on February 7, 2007. Our review of the clinical section of your response to our labeling revisions is complete, and our summary of the rationale for our changes to your proposed label appear below. 1. Movement of proposed information regarding outcome of the PROactive trial from the Clinical Studies section to the ADVERSE REACTIONS section, and inclusion of information only from the primary endpoint: This was a failed trial; statistical significance for the primary endpoint was not met, and the statistical evaluation does not support consideration of secondary endpoints in the event of failure to demonstrate significance for the primary endpoint. Even if you could demonstrate that it is statistically legitimate to consider secondary endpoints, the proposed "main" secondary endpoint was not placed in the statistical analysis plan until well after the trial had ended. Although technically it is possible to add new endpoints prior to breaking the blind, the long period of time (months) between study cessation and insertion of the new endpoint into the plan, the short period of time (days) between this addition and breaking of the blind, and the proposal to use this late- coming endpoint in the setting of a failed primary endpoint, give this endpoint the appearance of a post hoc analysis rather than a prospectively defined endpoint. Confidential - Subject to Protective Order TAK-PRITZM-00247931 Produced in MDL on 9/25/12 Source: https://www.induspo334-00001s.ucsf.edu/docs/kmjf0226 NDA 21-073/S-026 When one considers events of heart failure as well as the components of the primary endpoint (which did not include heart failure), there is even less of a numerical difference in the risk of adverse cardiovascular events for pioglitazone as compared to placebo. Under the Physician Labeling Rule (PLR), information from studies which do not directly support an approved indication will be removed from the Clinical Studies section. Although this label is not under the PLR, the next time you submit a supplement, it will be, and therefore, even if these data were to appear into the Clinical Studies section at this time, they would be removed with the first PLR label. Although we consider PROactive to be a failed trial from an efficacy standpoint, the trial does provide some reassuring safety information. Namely, it appears that pioglitazone is likely not associated with a significantly increased risk of macrovascular events compared to placebo. Given the drug's association with heart failure risk, the question of risk for other cardiovascular events has been of great concern. As such, the Division feels that addition of information to the ADVERSE REACTIONS section of the label could provide some reassurance to prescribers regarding this safety issue and would like to proceed with labeling negotiations to ensure that this relevant information is made available to the public. 2. Removal of proposed information regarding CHICAGO from the Clinical Studies section: At this time, neither the Division of Metabolism and Endocrinology Products, nor the Division of Cardiovascular and Renal Products, considers carotid intima media thickness to be a validated surrogate for risk of cardiovascular events. Although results of imaging studies have been included in labels for lipid-altering drugs, the clinical benefits of those drugs have been established in clinical outcomes studies, hence, implied claims of benefit with CIMT are less of a concern in those labels. For those drugs, CIMT results are essentially superseded by clinical outcomes data. In this label, the implied claim of benefit on the atherosclerotic process is not supported by the PROactive results. Although, when you attempted to apply the endpoint analyses from PROactive to CHICAGO, numerically slightly fewer serious cardiovascular endpoint events occurred among the pioglitazone group patients than among the placebo group patients, the difference was not significant, and was accounted for entirely by one type of event (percutaneous coronary intervention). Additionally, there was no difference between treatment groups for the incidence of events within the overall Cardiac and Vascular Disorders MedDRA System Organ Classes. Thus, this trial is not broadly supportive of decreased risk of macrovascular events. Additionally, edema and weight gain occurred more commonly among the pioglitazone group patients than among the placebo group patients. Confidential - Subject to Protective Order AK-PRITZM-00247932 Produced in MDL on 9/25/12 Source: NDA 21-073/S-026 As with the data from PROactive, the CHICAGO data do not directly support an approved indication, and thus, even if they were included in the Clinical Studies section at this time, the data would be removed with the first PLR label. We are providing these comments to you before we complete our review of the entire application to give you preliminary notice of issues that we have identified. In conformance with the prescription drug user fee reauthorization agreements, these comments do not reflect a final decision on the information reviewed and should not be construed to do so. These comments are preliminary and subject to change as we finalize our review of your application. In addition, we may identify other information that must be provided before we can approve this application. If you respond to these issues during this review cycle, depending on the timing of your response, and in conformance with the user fee reauthorization agreements, we may not be able to consider your response before we take an action on your application during this review cycle. If you have any questions, please call Ms. Jena Weber, Regulatory Project Manager, at 301-796-1306. Sincerely, (See appended electronic signature page) Mary H. Parks, M.D. Director Division of Metabolism and Endocrinology Products Office of Drug Evaluation II Center for Drug Evaluation and Research Confidential - Subject to Protective Order TAK-PRITZM-00247933 Produced in MDL on 9/25/12 Source: https://[email protected] ucsf.edu/docs/kmjf0226 This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. /s/ Mary Parks 2/13/2007 09:19:28 AM Confidential - Subject to Protective Order AK-PRITZM-00247934 Produced in MDL on 9/25/12 Source: https://www.indupo34-00004s.ucsf.edu/docs/kmjf0226

What is the date mentioned?

gnjf0226

gnjf0226_p0

August 16, 1999

Lilly Eli Lilly and Company Pharmaceutical Division Lilly Corporate Center Indianapolis, Indiana 46285 317.276.2000 August 16, 1999 Alan D. Mackenzie Senior Vice President, Sales and Marketing Takeda Pharmaceuticals America, Inc. 475 Half Day Road Suite 500 Lincolnshire, IL 60069 RE: Amendment #1 to Co-Promotion Agreement Dear Alan: This letter will set forth the terms under which Takeda Pharmaceuticals America, Inc. ("TPA") and Eli Lilly and Company ("Lilly") have agreed to amend the Co-Promotion Agreement between TPA and Lilly dated December 14, 1998 (the "Agreement"). As we have agreed, in addition to the 500 sales representatives required under Section 2.04(A) of the Agreement, Lilly will retain an additional 255 Lilly sales representatives for the period October 1, 1999 through September 30, 2000, with a preference for utilizing full time Lilly employees rather than a contracted sales force. The additional sales force will promote ACTOSTM in first detail position and PROZAC® or another Lilly product in second detail position, and will target mid-decile primary care physicians. In consideration of the above facts, the parties agree to amend the Agreement as follows: 1. The reimbursement cap for the details above the Lilly Actos Target Detail Level, as currently reflected in Sections 2.04(A) and (C), shall be raised to 1.1 million (rather than 800,000 plus 25%, i.e., 1 million) for the term October 1, 1999 through September 30, 2000 only. Takeda will reimburse Lilly $75 for each Primary Detail made by the Lilly Diabetes Care sales force and each Actos detail made by the additional Lilly primary care sales force (said sales force described above), provided the number of total details (sum of Diabetes Care sales force Primary Details and additional primary care sales force Actos details) from October 1, 1999 through September 30, 2000 is at least equal to seventy-two percent (72%) of the 1.1 million cap. The remainder of the terms shall remain the same. 2. This amendment shall change the terms of the Agreement only for the period October 1, 1999 through September 30, 2000. On October 1, 2000, the original terms of the Agreement, including but not limited to the reimbursement cap as reflected in Sections 2.04(A) and (C), shall be automatically reinstated and operational with no further action required by either party. The parties hereby ratify the Agreement, which shall continue in full force and effect as modified by this Amendment. EXHIBIT Hoven #9 5/1/13 RRD Confirtential --- Subricant to Order

What is the name of the addressee?

kmjf0226

kmjf0226_p0, kmjf0226_p1, kmjf0226_p2, kmjf0226_p3

Mary Jo Pritza, MPH, PharmD, Ms. Pritza

Public Health Service DEPARTMENT OF HEALTH & HUMAN SERVICES Food and Drug Administration Rockville, MD 20857 NDA 21-073/S-026 DISCIPLINE REVIEW LETTER Takeda Global Research & Development Center, Inc. RECEIVED Attention: Mary Jo Pritza, MPH, PharmD REGULATORY AFFAIRS DEPARTMENT Manager, Regulatory Affairs One Takeda Parkway FEB 1 9 2007 Deerfield, IL 60015 Dear Ms. Pritza: TAKEDA GLOBAL RESEARCH & DEVELOPMENT CENTER, ING Please refer to your January 24, 2006, supplemental new drug application (NDA) submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act for Actos (pioglitazone HCI) tablets, 15 mg, 30 mg, and 45 mg. We also refer to your submissions dated June 1, August 22 and 31, October 10, November 14, and December 15, 2006, and to our proposed labeling revisions sent to you (via e-mail) on February 7, 2007. Our review of the clinical section of your response to our labeling revisions is complete, and our summary of the rationale for our changes to your proposed label appear below. 1. Movement of proposed information regarding outcome of the PROactive trial from the Clinical Studies section to the ADVERSE REACTIONS section, and inclusion of information only from the primary endpoint: This was a failed trial; statistical significance for the primary endpoint was not met, and the statistical evaluation does not support consideration of secondary endpoints in the event of failure to demonstrate significance for the primary endpoint. Even if you could demonstrate that it is statistically legitimate to consider secondary endpoints, the proposed "main" secondary endpoint was not placed in the statistical analysis plan until well after the trial had ended. Although technically it is possible to add new endpoints prior to breaking the blind, the long period of time (months) between study cessation and insertion of the new endpoint into the plan, the short period of time (days) between this addition and breaking of the blind, and the proposal to use this late- coming endpoint in the setting of a failed primary endpoint, give this endpoint the appearance of a post hoc analysis rather than a prospectively defined endpoint. Confidential - Subject to Protective Order TAK-PRITZM-00247931 Produced in MDL on 9/25/12 Source: https://www.induspo334-00001s.ucsf.edu/docs/kmjf0226 NDA 21-073/S-026 When one considers events of heart failure as well as the components of the primary endpoint (which did not include heart failure), there is even less of a numerical difference in the risk of adverse cardiovascular events for pioglitazone as compared to placebo. Under the Physician Labeling Rule (PLR), information from studies which do not directly support an approved indication will be removed from the Clinical Studies section. Although this label is not under the PLR, the next time you submit a supplement, it will be, and therefore, even if these data were to appear into the Clinical Studies section at this time, they would be removed with the first PLR label. Although we consider PROactive to be a failed trial from an efficacy standpoint, the trial does provide some reassuring safety information. Namely, it appears that pioglitazone is likely not associated with a significantly increased risk of macrovascular events compared to placebo. Given the drug's association with heart failure risk, the question of risk for other cardiovascular events has been of great concern. As such, the Division feels that addition of information to the ADVERSE REACTIONS section of the label could provide some reassurance to prescribers regarding this safety issue and would like to proceed with labeling negotiations to ensure that this relevant information is made available to the public. 2. Removal of proposed information regarding CHICAGO from the Clinical Studies section: At this time, neither the Division of Metabolism and Endocrinology Products, nor the Division of Cardiovascular and Renal Products, considers carotid intima media thickness to be a validated surrogate for risk of cardiovascular events. Although results of imaging studies have been included in labels for lipid-altering drugs, the clinical benefits of those drugs have been established in clinical outcomes studies, hence, implied claims of benefit with CIMT are less of a concern in those labels. For those drugs, CIMT results are essentially superseded by clinical outcomes data. In this label, the implied claim of benefit on the atherosclerotic process is not supported by the PROactive results. Although, when you attempted to apply the endpoint analyses from PROactive to CHICAGO, numerically slightly fewer serious cardiovascular endpoint events occurred among the pioglitazone group patients than among the placebo group patients, the difference was not significant, and was accounted for entirely by one type of event (percutaneous coronary intervention). Additionally, there was no difference between treatment groups for the incidence of events within the overall Cardiac and Vascular Disorders MedDRA System Organ Classes. Thus, this trial is not broadly supportive of decreased risk of macrovascular events. Additionally, edema and weight gain occurred more commonly among the pioglitazone group patients than among the placebo group patients. Confidential - Subject to Protective Order AK-PRITZM-00247932 Produced in MDL on 9/25/12 Source: NDA 21-073/S-026 As with the data from PROactive, the CHICAGO data do not directly support an approved indication, and thus, even if they were included in the Clinical Studies section at this time, the data would be removed with the first PLR label. We are providing these comments to you before we complete our review of the entire application to give you preliminary notice of issues that we have identified. In conformance with the prescription drug user fee reauthorization agreements, these comments do not reflect a final decision on the information reviewed and should not be construed to do so. These comments are preliminary and subject to change as we finalize our review of your application. In addition, we may identify other information that must be provided before we can approve this application. If you respond to these issues during this review cycle, depending on the timing of your response, and in conformance with the user fee reauthorization agreements, we may not be able to consider your response before we take an action on your application during this review cycle. If you have any questions, please call Ms. Jena Weber, Regulatory Project Manager, at 301-796-1306. Sincerely, (See appended electronic signature page) Mary H. Parks, M.D. Director Division of Metabolism and Endocrinology Products Office of Drug Evaluation II Center for Drug Evaluation and Research Confidential - Subject to Protective Order TAK-PRITZM-00247933 Produced in MDL on 9/25/12 Source: https://[email protected] ucsf.edu/docs/kmjf0226 This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. /s/ Mary Parks 2/13/2007 09:19:28 AM Confidential - Subject to Protective Order AK-PRITZM-00247934 Produced in MDL on 9/25/12 Source: https://www.indupo34-00004s.ucsf.edu/docs/kmjf0226

To whom is this letter addressed?

gnjf0226

gnjf0226_p0

Alan D. Mackenzie, Alan

Lilly Eli Lilly and Company Pharmaceutical Division Lilly Corporate Center Indianapolis, Indiana 46285 317.276.2000 August 16, 1999 Alan D. Mackenzie Senior Vice President, Sales and Marketing Takeda Pharmaceuticals America, Inc. 475 Half Day Road Suite 500 Lincolnshire, IL 60069 RE: Amendment #1 to Co-Promotion Agreement Dear Alan: This letter will set forth the terms under which Takeda Pharmaceuticals America, Inc. ("TPA") and Eli Lilly and Company ("Lilly") have agreed to amend the Co-Promotion Agreement between TPA and Lilly dated December 14, 1998 (the "Agreement"). As we have agreed, in addition to the 500 sales representatives required under Section 2.04(A) of the Agreement, Lilly will retain an additional 255 Lilly sales representatives for the period October 1, 1999 through September 30, 2000, with a preference for utilizing full time Lilly employees rather than a contracted sales force. The additional sales force will promote ACTOSTM in first detail position and PROZAC® or another Lilly product in second detail position, and will target mid-decile primary care physicians. In consideration of the above facts, the parties agree to amend the Agreement as follows: 1. The reimbursement cap for the details above the Lilly Actos Target Detail Level, as currently reflected in Sections 2.04(A) and (C), shall be raised to 1.1 million (rather than 800,000 plus 25%, i.e., 1 million) for the term October 1, 1999 through September 30, 2000 only. Takeda will reimburse Lilly $75 for each Primary Detail made by the Lilly Diabetes Care sales force and each Actos detail made by the additional Lilly primary care sales force (said sales force described above), provided the number of total details (sum of Diabetes Care sales force Primary Details and additional primary care sales force Actos details) from October 1, 1999 through September 30, 2000 is at least equal to seventy-two percent (72%) of the 1.1 million cap. The remainder of the terms shall remain the same. 2. This amendment shall change the terms of the Agreement only for the period October 1, 1999 through September 30, 2000. On October 1, 2000, the original terms of the Agreement, including but not limited to the reimbursement cap as reflected in Sections 2.04(A) and (C), shall be automatically reinstated and operational with no further action required by either party. The parties hereby ratify the Agreement, which shall continue in full force and effect as modified by this Amendment. EXHIBIT Hoven #9 5/1/13 RRD Confirtential --- Subricant to Order

What is the full form of TPA?

gnjf0226

gnjf0226_p0

Takeda Pharmaceuticals America Inc., Takeda Pharmaceuticals America, Inc., Takeda Pharmaceuticals America

Lilly Eli Lilly and Company Pharmaceutical Division Lilly Corporate Center Indianapolis, Indiana 46285 317.276.2000 August 16, 1999 Alan D. Mackenzie Senior Vice President, Sales and Marketing Takeda Pharmaceuticals America, Inc. 475 Half Day Road Suite 500 Lincolnshire, IL 60069 RE: Amendment #1 to Co-Promotion Agreement Dear Alan: This letter will set forth the terms under which Takeda Pharmaceuticals America, Inc. ("TPA") and Eli Lilly and Company ("Lilly") have agreed to amend the Co-Promotion Agreement between TPA and Lilly dated December 14, 1998 (the "Agreement"). As we have agreed, in addition to the 500 sales representatives required under Section 2.04(A) of the Agreement, Lilly will retain an additional 255 Lilly sales representatives for the period October 1, 1999 through September 30, 2000, with a preference for utilizing full time Lilly employees rather than a contracted sales force. The additional sales force will promote ACTOSTM in first detail position and PROZAC® or another Lilly product in second detail position, and will target mid-decile primary care physicians. In consideration of the above facts, the parties agree to amend the Agreement as follows: 1. The reimbursement cap for the details above the Lilly Actos Target Detail Level, as currently reflected in Sections 2.04(A) and (C), shall be raised to 1.1 million (rather than 800,000 plus 25%, i.e., 1 million) for the term October 1, 1999 through September 30, 2000 only. Takeda will reimburse Lilly $75 for each Primary Detail made by the Lilly Diabetes Care sales force and each Actos detail made by the additional Lilly primary care sales force (said sales force described above), provided the number of total details (sum of Diabetes Care sales force Primary Details and additional primary care sales force Actos details) from October 1, 1999 through September 30, 2000 is at least equal to seventy-two percent (72%) of the 1.1 million cap. The remainder of the terms shall remain the same. 2. This amendment shall change the terms of the Agreement only for the period October 1, 1999 through September 30, 2000. On October 1, 2000, the original terms of the Agreement, including but not limited to the reimbursement cap as reflected in Sections 2.04(A) and (C), shall be automatically reinstated and operational with no further action required by either party. The parties hereby ratify the Agreement, which shall continue in full force and effect as modified by this Amendment. EXHIBIT Hoven #9 5/1/13 RRD Confirtential --- Subricant to Order

What kind of a letter is this ?

kmjf0226

kmjf0226_p0, kmjf0226_p1, kmjf0226_p2, kmjf0226_p3

DISCIPLINE REVIEW LETTER

Public Health Service DEPARTMENT OF HEALTH & HUMAN SERVICES Food and Drug Administration Rockville, MD 20857 NDA 21-073/S-026 DISCIPLINE REVIEW LETTER Takeda Global Research & Development Center, Inc. RECEIVED Attention: Mary Jo Pritza, MPH, PharmD REGULATORY AFFAIRS DEPARTMENT Manager, Regulatory Affairs One Takeda Parkway FEB 1 9 2007 Deerfield, IL 60015 Dear Ms. Pritza: TAKEDA GLOBAL RESEARCH & DEVELOPMENT CENTER, ING Please refer to your January 24, 2006, supplemental new drug application (NDA) submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act for Actos (pioglitazone HCI) tablets, 15 mg, 30 mg, and 45 mg. We also refer to your submissions dated June 1, August 22 and 31, October 10, November 14, and December 15, 2006, and to our proposed labeling revisions sent to you (via e-mail) on February 7, 2007. Our review of the clinical section of your response to our labeling revisions is complete, and our summary of the rationale for our changes to your proposed label appear below. 1. Movement of proposed information regarding outcome of the PROactive trial from the Clinical Studies section to the ADVERSE REACTIONS section, and inclusion of information only from the primary endpoint: This was a failed trial; statistical significance for the primary endpoint was not met, and the statistical evaluation does not support consideration of secondary endpoints in the event of failure to demonstrate significance for the primary endpoint. Even if you could demonstrate that it is statistically legitimate to consider secondary endpoints, the proposed "main" secondary endpoint was not placed in the statistical analysis plan until well after the trial had ended. Although technically it is possible to add new endpoints prior to breaking the blind, the long period of time (months) between study cessation and insertion of the new endpoint into the plan, the short period of time (days) between this addition and breaking of the blind, and the proposal to use this late- coming endpoint in the setting of a failed primary endpoint, give this endpoint the appearance of a post hoc analysis rather than a prospectively defined endpoint. Confidential - Subject to Protective Order TAK-PRITZM-00247931 Produced in MDL on 9/25/12 Source: https://www.induspo334-00001s.ucsf.edu/docs/kmjf0226 NDA 21-073/S-026 When one considers events of heart failure as well as the components of the primary endpoint (which did not include heart failure), there is even less of a numerical difference in the risk of adverse cardiovascular events for pioglitazone as compared to placebo. Under the Physician Labeling Rule (PLR), information from studies which do not directly support an approved indication will be removed from the Clinical Studies section. Although this label is not under the PLR, the next time you submit a supplement, it will be, and therefore, even if these data were to appear into the Clinical Studies section at this time, they would be removed with the first PLR label. Although we consider PROactive to be a failed trial from an efficacy standpoint, the trial does provide some reassuring safety information. Namely, it appears that pioglitazone is likely not associated with a significantly increased risk of macrovascular events compared to placebo. Given the drug's association with heart failure risk, the question of risk for other cardiovascular events has been of great concern. As such, the Division feels that addition of information to the ADVERSE REACTIONS section of the label could provide some reassurance to prescribers regarding this safety issue and would like to proceed with labeling negotiations to ensure that this relevant information is made available to the public. 2. Removal of proposed information regarding CHICAGO from the Clinical Studies section: At this time, neither the Division of Metabolism and Endocrinology Products, nor the Division of Cardiovascular and Renal Products, considers carotid intima media thickness to be a validated surrogate for risk of cardiovascular events. Although results of imaging studies have been included in labels for lipid-altering drugs, the clinical benefits of those drugs have been established in clinical outcomes studies, hence, implied claims of benefit with CIMT are less of a concern in those labels. For those drugs, CIMT results are essentially superseded by clinical outcomes data. In this label, the implied claim of benefit on the atherosclerotic process is not supported by the PROactive results. Although, when you attempted to apply the endpoint analyses from PROactive to CHICAGO, numerically slightly fewer serious cardiovascular endpoint events occurred among the pioglitazone group patients than among the placebo group patients, the difference was not significant, and was accounted for entirely by one type of event (percutaneous coronary intervention). Additionally, there was no difference between treatment groups for the incidence of events within the overall Cardiac and Vascular Disorders MedDRA System Organ Classes. Thus, this trial is not broadly supportive of decreased risk of macrovascular events. Additionally, edema and weight gain occurred more commonly among the pioglitazone group patients than among the placebo group patients. Confidential - Subject to Protective Order AK-PRITZM-00247932 Produced in MDL on 9/25/12 Source: NDA 21-073/S-026 As with the data from PROactive, the CHICAGO data do not directly support an approved indication, and thus, even if they were included in the Clinical Studies section at this time, the data would be removed with the first PLR label. We are providing these comments to you before we complete our review of the entire application to give you preliminary notice of issues that we have identified. In conformance with the prescription drug user fee reauthorization agreements, these comments do not reflect a final decision on the information reviewed and should not be construed to do so. These comments are preliminary and subject to change as we finalize our review of your application. In addition, we may identify other information that must be provided before we can approve this application. If you respond to these issues during this review cycle, depending on the timing of your response, and in conformance with the user fee reauthorization agreements, we may not be able to consider your response before we take an action on your application during this review cycle. If you have any questions, please call Ms. Jena Weber, Regulatory Project Manager, at 301-796-1306. Sincerely, (See appended electronic signature page) Mary H. Parks, M.D. Director Division of Metabolism and Endocrinology Products Office of Drug Evaluation II Center for Drug Evaluation and Research Confidential - Subject to Protective Order TAK-PRITZM-00247933 Produced in MDL on 9/25/12 Source: https://[email protected] ucsf.edu/docs/kmjf0226 This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. /s/ Mary Parks 2/13/2007 09:19:28 AM Confidential - Subject to Protective Order AK-PRITZM-00247934 Produced in MDL on 9/25/12 Source: https://www.indupo34-00004s.ucsf.edu/docs/kmjf0226

Which two companies have agreed to amend the Co-Promotion Agreement?

gnjf0226

gnjf0226_p0

Takeda Pharmaceuticals America, Inc. ("TPA") and Eli Lilly and Company ("Lilly")

Lilly Eli Lilly and Company Pharmaceutical Division Lilly Corporate Center Indianapolis, Indiana 46285 317.276.2000 August 16, 1999 Alan D. Mackenzie Senior Vice President, Sales and Marketing Takeda Pharmaceuticals America, Inc. 475 Half Day Road Suite 500 Lincolnshire, IL 60069 RE: Amendment #1 to Co-Promotion Agreement Dear Alan: This letter will set forth the terms under which Takeda Pharmaceuticals America, Inc. ("TPA") and Eli Lilly and Company ("Lilly") have agreed to amend the Co-Promotion Agreement between TPA and Lilly dated December 14, 1998 (the "Agreement"). As we have agreed, in addition to the 500 sales representatives required under Section 2.04(A) of the Agreement, Lilly will retain an additional 255 Lilly sales representatives for the period October 1, 1999 through September 30, 2000, with a preference for utilizing full time Lilly employees rather than a contracted sales force. The additional sales force will promote ACTOSTM in first detail position and PROZAC® or another Lilly product in second detail position, and will target mid-decile primary care physicians. In consideration of the above facts, the parties agree to amend the Agreement as follows: 1. The reimbursement cap for the details above the Lilly Actos Target Detail Level, as currently reflected in Sections 2.04(A) and (C), shall be raised to 1.1 million (rather than 800,000 plus 25%, i.e., 1 million) for the term October 1, 1999 through September 30, 2000 only. Takeda will reimburse Lilly $75 for each Primary Detail made by the Lilly Diabetes Care sales force and each Actos detail made by the additional Lilly primary care sales force (said sales force described above), provided the number of total details (sum of Diabetes Care sales force Primary Details and additional primary care sales force Actos details) from October 1, 1999 through September 30, 2000 is at least equal to seventy-two percent (72%) of the 1.1 million cap. The remainder of the terms shall remain the same. 2. This amendment shall change the terms of the Agreement only for the period October 1, 1999 through September 30, 2000. On October 1, 2000, the original terms of the Agreement, including but not limited to the reimbursement cap as reflected in Sections 2.04(A) and (C), shall be automatically reinstated and operational with no further action required by either party. The parties hereby ratify the Agreement, which shall continue in full force and effect as modified by this Amendment. EXHIBIT Hoven #9 5/1/13 RRD Confirtential --- Subricant to Order

What is the name of the company?

lljf0226

lljf0226_p0

THE UPJOHN COMPANY

EXHIBIT Billie AKEDA Aat THE UPJOHN COMPANY KALAMAZOO, MICHIGAN 49001 0199.U SA. J. a MITCHELL M.D., PoD. TELEPHONE: (616)323-4000 Vica Chairmas of the Boand TELEZHONS: (§/6) PAX: (aid) 383-3277 September 21, 1993 Tai Matsuzawa, Ph.D. Managing Director Vice President, Pharmaceutical Group Takeda Chemical Industries, Ltd. 1-1, Doshomachi 4-Chome Chuo-Ku, Osaka 541 Japan Dear Doctor Matsuzawa: As you know, Upjohn has committed to notify Takeda by October 1, 1993, of our intentions regarding further clinical development of pioglitazone. On September 20 our Pharmaceutical Executive Council, Upjohn's highest scientific decision-making body, carefully reviewed the results of the toxicology and clinical studies. The decision of the Council was that Upjohn will not go forward with pioglitazone in the clinic. The Council decided that further clinical development of pioglitazone could not be justified based on their concern regarding pioglitazone's margin of safety. As a consequence of this decision, Upjohn also must decline participation with Takeda on the proposed pioglitazone study in Canada. It is with deep regret that I convey this message. As you know Upjohn and Takeda enjoy a strong and beneficial relationship based on mutual respect. It is a great disappointment to us that we will not have the opportunity of further interactions and collaboration with Takeda on this project. Hopefully, we will find other opportunities for collaboration in the future. I have instructed my staff to work closely with Takeda personnel in regards to the release of any information, data, FDA notifications, and other issues to ensure Takeda's interests and wishes are followed. With best personal regards, Sincerely, President, Upjohn Laboratories Worldwide Research, Development, & Medical Affairs CONFIDENTIAL - SUBJECT TO PROTECTIVE ORDER UPJ-0065603 Source:

What is the date mentioned?

lljf0226

lljf0226_p0

September 21, 1993

EXHIBIT Billie AKEDA Aat THE UPJOHN COMPANY KALAMAZOO, MICHIGAN 49001 0199.U SA. J. a MITCHELL M.D., PoD. TELEPHONE: (616)323-4000 Vica Chairmas of the Boand TELEZHONS: (§/6) PAX: (aid) 383-3277 September 21, 1993 Tai Matsuzawa, Ph.D. Managing Director Vice President, Pharmaceutical Group Takeda Chemical Industries, Ltd. 1-1, Doshomachi 4-Chome Chuo-Ku, Osaka 541 Japan Dear Doctor Matsuzawa: As you know, Upjohn has committed to notify Takeda by October 1, 1993, of our intentions regarding further clinical development of pioglitazone. On September 20 our Pharmaceutical Executive Council, Upjohn's highest scientific decision-making body, carefully reviewed the results of the toxicology and clinical studies. The decision of the Council was that Upjohn will not go forward with pioglitazone in the clinic. The Council decided that further clinical development of pioglitazone could not be justified based on their concern regarding pioglitazone's margin of safety. As a consequence of this decision, Upjohn also must decline participation with Takeda on the proposed pioglitazone study in Canada. It is with deep regret that I convey this message. As you know Upjohn and Takeda enjoy a strong and beneficial relationship based on mutual respect. It is a great disappointment to us that we will not have the opportunity of further interactions and collaboration with Takeda on this project. Hopefully, we will find other opportunities for collaboration in the future. I have instructed my staff to work closely with Takeda personnel in regards to the release of any information, data, FDA notifications, and other issues to ensure Takeda's interests and wishes are followed. With best personal regards, Sincerely, President, Upjohn Laboratories Worldwide Research, Development, & Medical Affairs CONFIDENTIAL - SUBJECT TO PROTECTIVE ORDER UPJ-0065603 Source:

To whom is this letter addressed?

lljf0226

lljf0226_p0

Doctor Matsuzawa, Matsuzawa, Tai Matsuzawa, Ph.D., Tai Matsuzawa, Ph.D

EXHIBIT Billie AKEDA Aat THE UPJOHN COMPANY KALAMAZOO, MICHIGAN 49001 0199.U SA. J. a MITCHELL M.D., PoD. TELEPHONE: (616)323-4000 Vica Chairmas of the Boand TELEZHONS: (§/6) PAX: (aid) 383-3277 September 21, 1993 Tai Matsuzawa, Ph.D. Managing Director Vice President, Pharmaceutical Group Takeda Chemical Industries, Ltd. 1-1, Doshomachi 4-Chome Chuo-Ku, Osaka 541 Japan Dear Doctor Matsuzawa: As you know, Upjohn has committed to notify Takeda by October 1, 1993, of our intentions regarding further clinical development of pioglitazone. On September 20 our Pharmaceutical Executive Council, Upjohn's highest scientific decision-making body, carefully reviewed the results of the toxicology and clinical studies. The decision of the Council was that Upjohn will not go forward with pioglitazone in the clinic. The Council decided that further clinical development of pioglitazone could not be justified based on their concern regarding pioglitazone's margin of safety. As a consequence of this decision, Upjohn also must decline participation with Takeda on the proposed pioglitazone study in Canada. It is with deep regret that I convey this message. As you know Upjohn and Takeda enjoy a strong and beneficial relationship based on mutual respect. It is a great disappointment to us that we will not have the opportunity of further interactions and collaboration with Takeda on this project. Hopefully, we will find other opportunities for collaboration in the future. I have instructed my staff to work closely with Takeda personnel in regards to the release of any information, data, FDA notifications, and other issues to ensure Takeda's interests and wishes are followed. With best personal regards, Sincerely, President, Upjohn Laboratories Worldwide Research, Development, & Medical Affairs CONFIDENTIAL - SUBJECT TO PROTECTIVE ORDER UPJ-0065603 Source:

As a consequence of the decision Upjohn must decline participation with which company?

lljf0226

lljf0226_p0

Takeda

EXHIBIT Billie AKEDA Aat THE UPJOHN COMPANY KALAMAZOO, MICHIGAN 49001 0199.U SA. J. a MITCHELL M.D., PoD. TELEPHONE: (616)323-4000 Vica Chairmas of the Boand TELEZHONS: (§/6) PAX: (aid) 383-3277 September 21, 1993 Tai Matsuzawa, Ph.D. Managing Director Vice President, Pharmaceutical Group Takeda Chemical Industries, Ltd. 1-1, Doshomachi 4-Chome Chuo-Ku, Osaka 541 Japan Dear Doctor Matsuzawa: As you know, Upjohn has committed to notify Takeda by October 1, 1993, of our intentions regarding further clinical development of pioglitazone. On September 20 our Pharmaceutical Executive Council, Upjohn's highest scientific decision-making body, carefully reviewed the results of the toxicology and clinical studies. The decision of the Council was that Upjohn will not go forward with pioglitazone in the clinic. The Council decided that further clinical development of pioglitazone could not be justified based on their concern regarding pioglitazone's margin of safety. As a consequence of this decision, Upjohn also must decline participation with Takeda on the proposed pioglitazone study in Canada. It is with deep regret that I convey this message. As you know Upjohn and Takeda enjoy a strong and beneficial relationship based on mutual respect. It is a great disappointment to us that we will not have the opportunity of further interactions and collaboration with Takeda on this project. Hopefully, we will find other opportunities for collaboration in the future. I have instructed my staff to work closely with Takeda personnel in regards to the release of any information, data, FDA notifications, and other issues to ensure Takeda's interests and wishes are followed. With best personal regards, Sincerely, President, Upjohn Laboratories Worldwide Research, Development, & Medical Affairs CONFIDENTIAL - SUBJECT TO PROTECTIVE ORDER UPJ-0065603 Source:

A 79-year-old female was enrolled in the study for how many days?

gyjf0226

gyjf0226_p1, gyjf0226_p2

200 days

aked TAXEDA MARMACEUTICALS NORTH AMERICA, INC. Case Number Two: A 79-year-old female, enrolled in the study for 200 days, was hospitalized for a bladder biopsy for possible recurrence of her bladder cancer. Cystoscopy revealed cancer in situ versus a recurrence of transitional cell bladder cancer. This patient has been discontinued from the trial. She has had a history of bladder cancer since 1996 and has a positive history of tobacco use. Drug Treatment: Pioglitazone HCI As noted in the November 6th, conference call, TPNA will continue to investigate all cases of bladder cancer and as directed by the Division. Patients diagnosed with bladder cancer during the course of the study will be withdrawn from the trial and the study medication blind for those patients will be broken and reported to you. Also included in this submission are TPNA's minutes from the November 1st and 6th conference calls with the Division. If you have any questions regarding this submission, please feel free to contact mc. Sincerely Clinton Janet L. Haskins Manager, Regulatory Affairs Takeda Pharmaceuticals North America. Inc. 847-383-3243 (Telephone) 847-383-3427 (Fax) Confidential - Subject to Protective Order TAK-INDNDA-01273548 Produced in MDL on 09/11/2012 DEPARTMENT OF HEALTH AND HUMAN SERVICES Form Approved: OMB No. 0910-0014. PUBLIC HEALTH SERVICE Expiration Date: November 30, 2002 See OMB Statement on Reverse. FOOD AND DRUG ADMINISTRATION INVESTIGATIONAL NEW DRUG APPLICATION (IND) NOTE: No drug may be shipped or cinical (TITLE 21, CODE OF FEDERAL REGULATIONS (CFR) PART 312) investigation begun until an IND for that investigation is in effect (21 CFR 312.40). 1. NAME OF SPONSER 2. DATE OF SUBMISSION Takeda Pharmaceuticals North America. Inc. 11/18/2002 3. ADDRESS (Number, Streel, City, State and Zip Code) 4. TELEPHONE NUMBER (Include Area Code) 475 Half Day Road, Suite 500 847-383-3739 Lincolnshire, IL 60069 5. NAME(S) OF DRUG (include all available names: Trade, Generic, Chemical. Code) 6. IND NUMBER (II previously assigned) ACTOS® (pioglitazone HCI) 33.729 7. INDICATION(S) (Covered by this submission) N/A 3. PHASE(S) OF CLINICAL INVESTIGATION TO BE CONDUCTED: PHASE 1 PHASE 2 PHASE 3 OTHER N/A (Specify) 9. LIST NUMBERS OF ALL INVESTIGATIONAL NEW DRUG APPLICATIONS (21 CFR Part 312), NEW DRUG OR ANTIBIOTIC APPLICATIONS (21 CFR Part 314), DRUG MASTER FILES (21 CFR Part 314.420), AND PRODUCT LICENSE APPLICATIONS (21 CFR Part 601) REFERRED TO IN THIS APPLICATION. N/A 10. IND submission should be consecutively numbered. The Initial IND should be numbered "Serial number: 000." The next submission (e.g., amendment, report, or correspondence) SERIAL NUMBER should be numbered "Serial Number: 001." Subsequent submissions should be numbered 5 consecutively In the order In which they are submitted. 0 1 11. THIS SUBMISSION CONTAINS THE FOLLOWING: (Check ell that apply) INITIAL INVESTIGATIONAL NEW DRUG APPLICATION (IND) RESPONSE TO CLINICAL KOLD PROTOCOL AMENDMENT(S): INFORMATION AMENDMENT(S) IND SAFETY REPORT(S): NEW PROTOCOL CHEMISTRY/MICROBIOLOGY INITIAL WRITTEN REPORT CHANGE IN PROTOCOL PHARMACOLOGYITOXICOLOGY FOLLOW-UP TO A WRITTEN REPORT NEW INVESTIGATOR CLINICAL RESPONSE TO FDA REQUEST FOR INFORMATION ANNUAL REPORT GENERAL CORRESPONDENCE REQUEST FOR REINSTATEMENT OF IND THAT IS WITHDRAWN, OTHER INACTIVATED, TERMINATED OR DISCONTINUED (Specify) CHECK ONLY IF APPLICABLE JUSTIFICATION STATEMENT MUST BE SUBMITTED WITH APPLICATION FOR ANY CHECKED BELOW. REFER TO THE CITED CFR SECTION FOR FURTHER INFORMATION. TREATMENT IND 21 CFR 312.36(b) TREATMENT PROTOCOL 21 CFR 312.35(a) CHARGE REQUEST/NOTIFICATION 21 CFR312.7(d) FOR FDA USE ONLY CDR/DBIND/DGD RECEIPT STAMP DDR RECEIPT STAMP DIVISION ASSIGNMENT: IND NUMBER ASSIGNED: FORM FDA 1571 (9/02) PREVIOUS EDITION IS OBSOLETE. PAGE 1 OF 2 PX FF Confidential - Subject to Protective Order TAK-INDNDA-01273549 Produced in MDL on 09/11/2012 Source: https://www.indus79c00003s.ucsf.edu/docs/gyjf0226

The patient had a history of bladder cancer since when?

gyjf0226

gyjf0226_p1, gyjf0226_p2

1996, since 1996

aked TAXEDA MARMACEUTICALS NORTH AMERICA, INC. Case Number Two: A 79-year-old female, enrolled in the study for 200 days, was hospitalized for a bladder biopsy for possible recurrence of her bladder cancer. Cystoscopy revealed cancer in situ versus a recurrence of transitional cell bladder cancer. This patient has been discontinued from the trial. She has had a history of bladder cancer since 1996 and has a positive history of tobacco use. Drug Treatment: Pioglitazone HCI As noted in the November 6th, conference call, TPNA will continue to investigate all cases of bladder cancer and as directed by the Division. Patients diagnosed with bladder cancer during the course of the study will be withdrawn from the trial and the study medication blind for those patients will be broken and reported to you. Also included in this submission are TPNA's minutes from the November 1st and 6th conference calls with the Division. If you have any questions regarding this submission, please feel free to contact mc. Sincerely Clinton Janet L. Haskins Manager, Regulatory Affairs Takeda Pharmaceuticals North America. Inc. 847-383-3243 (Telephone) 847-383-3427 (Fax) Confidential - Subject to Protective Order TAK-INDNDA-01273548 Produced in MDL on 09/11/2012 DEPARTMENT OF HEALTH AND HUMAN SERVICES Form Approved: OMB No. 0910-0014. PUBLIC HEALTH SERVICE Expiration Date: November 30, 2002 See OMB Statement on Reverse. FOOD AND DRUG ADMINISTRATION INVESTIGATIONAL NEW DRUG APPLICATION (IND) NOTE: No drug may be shipped or cinical (TITLE 21, CODE OF FEDERAL REGULATIONS (CFR) PART 312) investigation begun until an IND for that investigation is in effect (21 CFR 312.40). 1. NAME OF SPONSER 2. DATE OF SUBMISSION Takeda Pharmaceuticals North America. Inc. 11/18/2002 3. ADDRESS (Number, Streel, City, State and Zip Code) 4. TELEPHONE NUMBER (Include Area Code) 475 Half Day Road, Suite 500 847-383-3739 Lincolnshire, IL 60069 5. NAME(S) OF DRUG (include all available names: Trade, Generic, Chemical. Code) 6. IND NUMBER (II previously assigned) ACTOS® (pioglitazone HCI) 33.729 7. INDICATION(S) (Covered by this submission) N/A 3. PHASE(S) OF CLINICAL INVESTIGATION TO BE CONDUCTED: PHASE 1 PHASE 2 PHASE 3 OTHER N/A (Specify) 9. LIST NUMBERS OF ALL INVESTIGATIONAL NEW DRUG APPLICATIONS (21 CFR Part 312), NEW DRUG OR ANTIBIOTIC APPLICATIONS (21 CFR Part 314), DRUG MASTER FILES (21 CFR Part 314.420), AND PRODUCT LICENSE APPLICATIONS (21 CFR Part 601) REFERRED TO IN THIS APPLICATION. N/A 10. IND submission should be consecutively numbered. The Initial IND should be numbered "Serial number: 000." The next submission (e.g., amendment, report, or correspondence) SERIAL NUMBER should be numbered "Serial Number: 001." Subsequent submissions should be numbered 5 consecutively In the order In which they are submitted. 0 1 11. THIS SUBMISSION CONTAINS THE FOLLOWING: (Check ell that apply) INITIAL INVESTIGATIONAL NEW DRUG APPLICATION (IND) RESPONSE TO CLINICAL KOLD PROTOCOL AMENDMENT(S): INFORMATION AMENDMENT(S) IND SAFETY REPORT(S): NEW PROTOCOL CHEMISTRY/MICROBIOLOGY INITIAL WRITTEN REPORT CHANGE IN PROTOCOL PHARMACOLOGYITOXICOLOGY FOLLOW-UP TO A WRITTEN REPORT NEW INVESTIGATOR CLINICAL RESPONSE TO FDA REQUEST FOR INFORMATION ANNUAL REPORT GENERAL CORRESPONDENCE REQUEST FOR REINSTATEMENT OF IND THAT IS WITHDRAWN, OTHER INACTIVATED, TERMINATED OR DISCONTINUED (Specify) CHECK ONLY IF APPLICABLE JUSTIFICATION STATEMENT MUST BE SUBMITTED WITH APPLICATION FOR ANY CHECKED BELOW. REFER TO THE CITED CFR SECTION FOR FURTHER INFORMATION. TREATMENT IND 21 CFR 312.36(b) TREATMENT PROTOCOL 21 CFR 312.35(a) CHARGE REQUEST/NOTIFICATION 21 CFR312.7(d) FOR FDA USE ONLY CDR/DBIND/DGD RECEIPT STAMP DDR RECEIPT STAMP DIVISION ASSIGNMENT: IND NUMBER ASSIGNED: FORM FDA 1571 (9/02) PREVIOUS EDITION IS OBSOLETE. PAGE 1 OF 2 PX FF Confidential - Subject to Protective Order TAK-INDNDA-01273549 Produced in MDL on 09/11/2012 Source: https://www.indus79c00003s.ucsf.edu/docs/gyjf0226

Who is the general manager of International development Dept. of Takeda Chemical Industires, Ltd.?

mljf0226

mljf0226_p1

K. Kitazawa, Ph. D.

Dr. Ruppel October 25 Page 2 of 2 We are sorry for having had a delay in responding to your request because of my absence on business abroad. Sincerely yours, TAKEDA CHEMICAL INDUSTRIES, LTD. K. Ritazawa, Ph.D. General Manager International Development Dept. Pharmaceutical Development Div. CONFIDENTIAL - SUBJECT TO PROTECTIVE ORDER UPJ-0065653 Source: https://wwww.indupoo3-00002s.ucsf.edu/docs/mljf0226

The woman had a positive history of what?

gyjf0226

gyjf0226_p1, gyjf0226_p2

tobacco use

aked TAXEDA MARMACEUTICALS NORTH AMERICA, INC. Case Number Two: A 79-year-old female, enrolled in the study for 200 days, was hospitalized for a bladder biopsy for possible recurrence of her bladder cancer. Cystoscopy revealed cancer in situ versus a recurrence of transitional cell bladder cancer. This patient has been discontinued from the trial. She has had a history of bladder cancer since 1996 and has a positive history of tobacco use. Drug Treatment: Pioglitazone HCI As noted in the November 6th, conference call, TPNA will continue to investigate all cases of bladder cancer and as directed by the Division. Patients diagnosed with bladder cancer during the course of the study will be withdrawn from the trial and the study medication blind for those patients will be broken and reported to you. Also included in this submission are TPNA's minutes from the November 1st and 6th conference calls with the Division. If you have any questions regarding this submission, please feel free to contact mc. Sincerely Clinton Janet L. Haskins Manager, Regulatory Affairs Takeda Pharmaceuticals North America. Inc. 847-383-3243 (Telephone) 847-383-3427 (Fax) Confidential - Subject to Protective Order TAK-INDNDA-01273548 Produced in MDL on 09/11/2012 DEPARTMENT OF HEALTH AND HUMAN SERVICES Form Approved: OMB No. 0910-0014. PUBLIC HEALTH SERVICE Expiration Date: November 30, 2002 See OMB Statement on Reverse. FOOD AND DRUG ADMINISTRATION INVESTIGATIONAL NEW DRUG APPLICATION (IND) NOTE: No drug may be shipped or cinical (TITLE 21, CODE OF FEDERAL REGULATIONS (CFR) PART 312) investigation begun until an IND for that investigation is in effect (21 CFR 312.40). 1. NAME OF SPONSER 2. DATE OF SUBMISSION Takeda Pharmaceuticals North America. Inc. 11/18/2002 3. ADDRESS (Number, Streel, City, State and Zip Code) 4. TELEPHONE NUMBER (Include Area Code) 475 Half Day Road, Suite 500 847-383-3739 Lincolnshire, IL 60069 5. NAME(S) OF DRUG (include all available names: Trade, Generic, Chemical. Code) 6. IND NUMBER (II previously assigned) ACTOS® (pioglitazone HCI) 33.729 7. INDICATION(S) (Covered by this submission) N/A 3. PHASE(S) OF CLINICAL INVESTIGATION TO BE CONDUCTED: PHASE 1 PHASE 2 PHASE 3 OTHER N/A (Specify) 9. LIST NUMBERS OF ALL INVESTIGATIONAL NEW DRUG APPLICATIONS (21 CFR Part 312), NEW DRUG OR ANTIBIOTIC APPLICATIONS (21 CFR Part 314), DRUG MASTER FILES (21 CFR Part 314.420), AND PRODUCT LICENSE APPLICATIONS (21 CFR Part 601) REFERRED TO IN THIS APPLICATION. N/A 10. IND submission should be consecutively numbered. The Initial IND should be numbered "Serial number: 000." The next submission (e.g., amendment, report, or correspondence) SERIAL NUMBER should be numbered "Serial Number: 001." Subsequent submissions should be numbered 5 consecutively In the order In which they are submitted. 0 1 11. THIS SUBMISSION CONTAINS THE FOLLOWING: (Check ell that apply) INITIAL INVESTIGATIONAL NEW DRUG APPLICATION (IND) RESPONSE TO CLINICAL KOLD PROTOCOL AMENDMENT(S): INFORMATION AMENDMENT(S) IND SAFETY REPORT(S): NEW PROTOCOL CHEMISTRY/MICROBIOLOGY INITIAL WRITTEN REPORT CHANGE IN PROTOCOL PHARMACOLOGYITOXICOLOGY FOLLOW-UP TO A WRITTEN REPORT NEW INVESTIGATOR CLINICAL RESPONSE TO FDA REQUEST FOR INFORMATION ANNUAL REPORT GENERAL CORRESPONDENCE REQUEST FOR REINSTATEMENT OF IND THAT IS WITHDRAWN, OTHER INACTIVATED, TERMINATED OR DISCONTINUED (Specify) CHECK ONLY IF APPLICABLE JUSTIFICATION STATEMENT MUST BE SUBMITTED WITH APPLICATION FOR ANY CHECKED BELOW. REFER TO THE CITED CFR SECTION FOR FURTHER INFORMATION. TREATMENT IND 21 CFR 312.36(b) TREATMENT PROTOCOL 21 CFR 312.35(a) CHARGE REQUEST/NOTIFICATION 21 CFR312.7(d) FOR FDA USE ONLY CDR/DBIND/DGD RECEIPT STAMP DDR RECEIPT STAMP DIVISION ASSIGNMENT: IND NUMBER ASSIGNED: FORM FDA 1571 (9/02) PREVIOUS EDITION IS OBSOLETE. PAGE 1 OF 2 PX FF Confidential - Subject to Protective Order TAK-INDNDA-01273549 Produced in MDL on 09/11/2012 Source: https://www.indus79c00003s.ucsf.edu/docs/gyjf0226

what is the name of the industry ?

mljf0226

mljf0226_p1

TAKEDA CHEMICAL INDUSTRIES , LTD ., TAKEDA CHEMICAL INDUSTRIES, LTD.

Dr. Ruppel October 25 Page 2 of 2 We are sorry for having had a delay in responding to your request because of my absence on business abroad. Sincerely yours, TAKEDA CHEMICAL INDUSTRIES, LTD. K. Ritazawa, Ph.D. General Manager International Development Dept. Pharmaceutical Development Div. CONFIDENTIAL - SUBJECT TO PROTECTIVE ORDER UPJ-0065653 Source: https://wwww.indupoo3-00002s.ucsf.edu/docs/mljf0226

How many pages are there in total?

mljf0226

mljf0226_p1

2, Page 2 of 2

Dr. Ruppel October 25 Page 2 of 2 We are sorry for having had a delay in responding to your request because of my absence on business abroad. Sincerely yours, TAKEDA CHEMICAL INDUSTRIES, LTD. K. Ritazawa, Ph.D. General Manager International Development Dept. Pharmaceutical Development Div. CONFIDENTIAL - SUBJECT TO PROTECTIVE ORDER UPJ-0065653 Source: https://wwww.indupoo3-00002s.ucsf.edu/docs/mljf0226

what is the month and date mentioned in this letter, at the top ?

mljf0226

mljf0226_p1

october 25, October 25

Dr. Ruppel October 25 Page 2 of 2 We are sorry for having had a delay in responding to your request because of my absence on business abroad. Sincerely yours, TAKEDA CHEMICAL INDUSTRIES, LTD. K. Ritazawa, Ph.D. General Manager International Development Dept. Pharmaceutical Development Div. CONFIDENTIAL - SUBJECT TO PROTECTIVE ORDER UPJ-0065653 Source: https://wwww.indupoo3-00002s.ucsf.edu/docs/mljf0226

What is the date mentioned?

nljf0226

nljf0226_p0, nljf0226_p1

January 21, 1999

FROM FAX05-6204-2943 1999m 18218(*)21 28./95624801941295 P 1 1/3 Takeda Chemical Industries, Ltd. Takeda Product Planning & Management Dept., International Division 1-1 Doshomachi 4-chome, Chuo-Ku, Osaka 541, JAPAN Tel: +81 6 (204) 2852 Fax: +81 6 (204) 2943 TELEFAX M E S SA G E To: E. Lilly & Company Date: January 21, 1999 Att: Mr. Larry Ellingson From: Kunio Iwatani Executive Director Actos Product Team CC: Mr. Hamanaka, TPA Subject: Upjohn Matter Dear Mr. Ellingson, Enclosed please find a copy of Upjohn's letter to US FDA dated January 7, 1994. In the letter Upjohn said that in preliminary clinical evaluation in the United States, pioglitazone did not satisfy Upjohn's internal requirement for reduction blood glucose; therefore, the considerable programs required for development of pioglitazone are not in line with Upjohn's business needs. ... They did not mention about safety of pioglitazone. After Upjohn's decision, Takeda approached FDA and consulted whether Takeda might go further the clinical development works on pioglitazone. Since the FDA's response was positive to go ahead, Takeda took over Upjohn's works and finally filed NDA on January 15, 1999. This is the story of the fact. Although there may be rumors about the reasons of Upjohn's abandonment of pioglitazone development, specially from the viewpoints of safety issues, it might be advisable for us to keep saying that Upjohn's decision is based on DALY 19 JAN 21 '99 07:43 06 6204 2943 PAGE.01 Confidential - Subject to Protective Order LLY-CRCARCH-00003000 Source: https://www.indupoodsouoonts.ucsf.edu/docs/nljf0226 FROM FAX06-6204-2943 19994 1821E (*) 21 : P. 2 2 2/3 the results of their internal business evaluation, and efficacy and safety of pioglitazone have been demonstrated clearly by Takeda. With our best regards, Kunio Iwatani JAN 21 '99 07:43 06 6204 2943 PAGE.02 Confidential - Subject to Protective Order LLY-CRCARCH-00003001 Source: https://www.induptods.00002t ts. ucsf.edu/docs/nljf0226

to which department it belongs to ?

gyjf0226

gyjf0226_p1, gyjf0226_p2

department of health and human services., DEPARTMENT OF HEALTH AND HUMAN SERVICES

aked TAXEDA MARMACEUTICALS NORTH AMERICA, INC. Case Number Two: A 79-year-old female, enrolled in the study for 200 days, was hospitalized for a bladder biopsy for possible recurrence of her bladder cancer. Cystoscopy revealed cancer in situ versus a recurrence of transitional cell bladder cancer. This patient has been discontinued from the trial. She has had a history of bladder cancer since 1996 and has a positive history of tobacco use. Drug Treatment: Pioglitazone HCI As noted in the November 6th, conference call, TPNA will continue to investigate all cases of bladder cancer and as directed by the Division. Patients diagnosed with bladder cancer during the course of the study will be withdrawn from the trial and the study medication blind for those patients will be broken and reported to you. Also included in this submission are TPNA's minutes from the November 1st and 6th conference calls with the Division. If you have any questions regarding this submission, please feel free to contact mc. Sincerely Clinton Janet L. Haskins Manager, Regulatory Affairs Takeda Pharmaceuticals North America. Inc. 847-383-3243 (Telephone) 847-383-3427 (Fax) Confidential - Subject to Protective Order TAK-INDNDA-01273548 Produced in MDL on 09/11/2012 DEPARTMENT OF HEALTH AND HUMAN SERVICES Form Approved: OMB No. 0910-0014. PUBLIC HEALTH SERVICE Expiration Date: November 30, 2002 See OMB Statement on Reverse. FOOD AND DRUG ADMINISTRATION INVESTIGATIONAL NEW DRUG APPLICATION (IND) NOTE: No drug may be shipped or cinical (TITLE 21, CODE OF FEDERAL REGULATIONS (CFR) PART 312) investigation begun until an IND for that investigation is in effect (21 CFR 312.40). 1. NAME OF SPONSER 2. DATE OF SUBMISSION Takeda Pharmaceuticals North America. Inc. 11/18/2002 3. ADDRESS (Number, Streel, City, State and Zip Code) 4. TELEPHONE NUMBER (Include Area Code) 475 Half Day Road, Suite 500 847-383-3739 Lincolnshire, IL 60069 5. NAME(S) OF DRUG (include all available names: Trade, Generic, Chemical. Code) 6. IND NUMBER (II previously assigned) ACTOS® (pioglitazone HCI) 33.729 7. INDICATION(S) (Covered by this submission) N/A 3. PHASE(S) OF CLINICAL INVESTIGATION TO BE CONDUCTED: PHASE 1 PHASE 2 PHASE 3 OTHER N/A (Specify) 9. LIST NUMBERS OF ALL INVESTIGATIONAL NEW DRUG APPLICATIONS (21 CFR Part 312), NEW DRUG OR ANTIBIOTIC APPLICATIONS (21 CFR Part 314), DRUG MASTER FILES (21 CFR Part 314.420), AND PRODUCT LICENSE APPLICATIONS (21 CFR Part 601) REFERRED TO IN THIS APPLICATION. N/A 10. IND submission should be consecutively numbered. The Initial IND should be numbered "Serial number: 000." The next submission (e.g., amendment, report, or correspondence) SERIAL NUMBER should be numbered "Serial Number: 001." Subsequent submissions should be numbered 5 consecutively In the order In which they are submitted. 0 1 11. THIS SUBMISSION CONTAINS THE FOLLOWING: (Check ell that apply) INITIAL INVESTIGATIONAL NEW DRUG APPLICATION (IND) RESPONSE TO CLINICAL KOLD PROTOCOL AMENDMENT(S): INFORMATION AMENDMENT(S) IND SAFETY REPORT(S): NEW PROTOCOL CHEMISTRY/MICROBIOLOGY INITIAL WRITTEN REPORT CHANGE IN PROTOCOL PHARMACOLOGYITOXICOLOGY FOLLOW-UP TO A WRITTEN REPORT NEW INVESTIGATOR CLINICAL RESPONSE TO FDA REQUEST FOR INFORMATION ANNUAL REPORT GENERAL CORRESPONDENCE REQUEST FOR REINSTATEMENT OF IND THAT IS WITHDRAWN, OTHER INACTIVATED, TERMINATED OR DISCONTINUED (Specify) CHECK ONLY IF APPLICABLE JUSTIFICATION STATEMENT MUST BE SUBMITTED WITH APPLICATION FOR ANY CHECKED BELOW. REFER TO THE CITED CFR SECTION FOR FURTHER INFORMATION. TREATMENT IND 21 CFR 312.36(b) TREATMENT PROTOCOL 21 CFR 312.35(a) CHARGE REQUEST/NOTIFICATION 21 CFR312.7(d) FOR FDA USE ONLY CDR/DBIND/DGD RECEIPT STAMP DDR RECEIPT STAMP DIVISION ASSIGNMENT: IND NUMBER ASSIGNED: FORM FDA 1571 (9/02) PREVIOUS EDITION IS OBSOLETE. PAGE 1 OF 2 PX FF Confidential - Subject to Protective Order TAK-INDNDA-01273549 Produced in MDL on 09/11/2012 Source: https://www.indus79c00003s.ucsf.edu/docs/gyjf0226

what is the date of submission?

gyjf0226

gyjf0226_p1, gyjf0226_p2

11/18/2002

aked TAXEDA MARMACEUTICALS NORTH AMERICA, INC. Case Number Two: A 79-year-old female, enrolled in the study for 200 days, was hospitalized for a bladder biopsy for possible recurrence of her bladder cancer. Cystoscopy revealed cancer in situ versus a recurrence of transitional cell bladder cancer. This patient has been discontinued from the trial. She has had a history of bladder cancer since 1996 and has a positive history of tobacco use. Drug Treatment: Pioglitazone HCI As noted in the November 6th, conference call, TPNA will continue to investigate all cases of bladder cancer and as directed by the Division. Patients diagnosed with bladder cancer during the course of the study will be withdrawn from the trial and the study medication blind for those patients will be broken and reported to you. Also included in this submission are TPNA's minutes from the November 1st and 6th conference calls with the Division. If you have any questions regarding this submission, please feel free to contact mc. Sincerely Clinton Janet L. Haskins Manager, Regulatory Affairs Takeda Pharmaceuticals North America. Inc. 847-383-3243 (Telephone) 847-383-3427 (Fax) Confidential - Subject to Protective Order TAK-INDNDA-01273548 Produced in MDL on 09/11/2012 DEPARTMENT OF HEALTH AND HUMAN SERVICES Form Approved: OMB No. 0910-0014. PUBLIC HEALTH SERVICE Expiration Date: November 30, 2002 See OMB Statement on Reverse. FOOD AND DRUG ADMINISTRATION INVESTIGATIONAL NEW DRUG APPLICATION (IND) NOTE: No drug may be shipped or cinical (TITLE 21, CODE OF FEDERAL REGULATIONS (CFR) PART 312) investigation begun until an IND for that investigation is in effect (21 CFR 312.40). 1. NAME OF SPONSER 2. DATE OF SUBMISSION Takeda Pharmaceuticals North America. Inc. 11/18/2002 3. ADDRESS (Number, Streel, City, State and Zip Code) 4. TELEPHONE NUMBER (Include Area Code) 475 Half Day Road, Suite 500 847-383-3739 Lincolnshire, IL 60069 5. NAME(S) OF DRUG (include all available names: Trade, Generic, Chemical. Code) 6. IND NUMBER (II previously assigned) ACTOS® (pioglitazone HCI) 33.729 7. INDICATION(S) (Covered by this submission) N/A 3. PHASE(S) OF CLINICAL INVESTIGATION TO BE CONDUCTED: PHASE 1 PHASE 2 PHASE 3 OTHER N/A (Specify) 9. LIST NUMBERS OF ALL INVESTIGATIONAL NEW DRUG APPLICATIONS (21 CFR Part 312), NEW DRUG OR ANTIBIOTIC APPLICATIONS (21 CFR Part 314), DRUG MASTER FILES (21 CFR Part 314.420), AND PRODUCT LICENSE APPLICATIONS (21 CFR Part 601) REFERRED TO IN THIS APPLICATION. N/A 10. IND submission should be consecutively numbered. The Initial IND should be numbered "Serial number: 000." The next submission (e.g., amendment, report, or correspondence) SERIAL NUMBER should be numbered "Serial Number: 001." Subsequent submissions should be numbered 5 consecutively In the order In which they are submitted. 0 1 11. THIS SUBMISSION CONTAINS THE FOLLOWING: (Check ell that apply) INITIAL INVESTIGATIONAL NEW DRUG APPLICATION (IND) RESPONSE TO CLINICAL KOLD PROTOCOL AMENDMENT(S): INFORMATION AMENDMENT(S) IND SAFETY REPORT(S): NEW PROTOCOL CHEMISTRY/MICROBIOLOGY INITIAL WRITTEN REPORT CHANGE IN PROTOCOL PHARMACOLOGYITOXICOLOGY FOLLOW-UP TO A WRITTEN REPORT NEW INVESTIGATOR CLINICAL RESPONSE TO FDA REQUEST FOR INFORMATION ANNUAL REPORT GENERAL CORRESPONDENCE REQUEST FOR REINSTATEMENT OF IND THAT IS WITHDRAWN, OTHER INACTIVATED, TERMINATED OR DISCONTINUED (Specify) CHECK ONLY IF APPLICABLE JUSTIFICATION STATEMENT MUST BE SUBMITTED WITH APPLICATION FOR ANY CHECKED BELOW. REFER TO THE CITED CFR SECTION FOR FURTHER INFORMATION. TREATMENT IND 21 CFR 312.36(b) TREATMENT PROTOCOL 21 CFR 312.35(a) CHARGE REQUEST/NOTIFICATION 21 CFR312.7(d) FOR FDA USE ONLY CDR/DBIND/DGD RECEIPT STAMP DDR RECEIPT STAMP DIVISION ASSIGNMENT: IND NUMBER ASSIGNED: FORM FDA 1571 (9/02) PREVIOUS EDITION IS OBSOLETE. PAGE 1 OF 2 PX FF Confidential - Subject to Protective Order TAK-INDNDA-01273549 Produced in MDL on 09/11/2012 Source: https://www.indus79c00003s.ucsf.edu/docs/gyjf0226

what is the telephone number (include area code)?

gyjf0226

gyjf0226_p1, gyjf0226_p2

847-383-3739

aked TAXEDA MARMACEUTICALS NORTH AMERICA, INC. Case Number Two: A 79-year-old female, enrolled in the study for 200 days, was hospitalized for a bladder biopsy for possible recurrence of her bladder cancer. Cystoscopy revealed cancer in situ versus a recurrence of transitional cell bladder cancer. This patient has been discontinued from the trial. She has had a history of bladder cancer since 1996 and has a positive history of tobacco use. Drug Treatment: Pioglitazone HCI As noted in the November 6th, conference call, TPNA will continue to investigate all cases of bladder cancer and as directed by the Division. Patients diagnosed with bladder cancer during the course of the study will be withdrawn from the trial and the study medication blind for those patients will be broken and reported to you. Also included in this submission are TPNA's minutes from the November 1st and 6th conference calls with the Division. If you have any questions regarding this submission, please feel free to contact mc. Sincerely Clinton Janet L. Haskins Manager, Regulatory Affairs Takeda Pharmaceuticals North America. Inc. 847-383-3243 (Telephone) 847-383-3427 (Fax) Confidential - Subject to Protective Order TAK-INDNDA-01273548 Produced in MDL on 09/11/2012 DEPARTMENT OF HEALTH AND HUMAN SERVICES Form Approved: OMB No. 0910-0014. PUBLIC HEALTH SERVICE Expiration Date: November 30, 2002 See OMB Statement on Reverse. FOOD AND DRUG ADMINISTRATION INVESTIGATIONAL NEW DRUG APPLICATION (IND) NOTE: No drug may be shipped or cinical (TITLE 21, CODE OF FEDERAL REGULATIONS (CFR) PART 312) investigation begun until an IND for that investigation is in effect (21 CFR 312.40). 1. NAME OF SPONSER 2. DATE OF SUBMISSION Takeda Pharmaceuticals North America. Inc. 11/18/2002 3. ADDRESS (Number, Streel, City, State and Zip Code) 4. TELEPHONE NUMBER (Include Area Code) 475 Half Day Road, Suite 500 847-383-3739 Lincolnshire, IL 60069 5. NAME(S) OF DRUG (include all available names: Trade, Generic, Chemical. Code) 6. IND NUMBER (II previously assigned) ACTOS® (pioglitazone HCI) 33.729 7. INDICATION(S) (Covered by this submission) N/A 3. PHASE(S) OF CLINICAL INVESTIGATION TO BE CONDUCTED: PHASE 1 PHASE 2 PHASE 3 OTHER N/A (Specify) 9. LIST NUMBERS OF ALL INVESTIGATIONAL NEW DRUG APPLICATIONS (21 CFR Part 312), NEW DRUG OR ANTIBIOTIC APPLICATIONS (21 CFR Part 314), DRUG MASTER FILES (21 CFR Part 314.420), AND PRODUCT LICENSE APPLICATIONS (21 CFR Part 601) REFERRED TO IN THIS APPLICATION. N/A 10. IND submission should be consecutively numbered. The Initial IND should be numbered "Serial number: 000." The next submission (e.g., amendment, report, or correspondence) SERIAL NUMBER should be numbered "Serial Number: 001." Subsequent submissions should be numbered 5 consecutively In the order In which they are submitted. 0 1 11. THIS SUBMISSION CONTAINS THE FOLLOWING: (Check ell that apply) INITIAL INVESTIGATIONAL NEW DRUG APPLICATION (IND) RESPONSE TO CLINICAL KOLD PROTOCOL AMENDMENT(S): INFORMATION AMENDMENT(S) IND SAFETY REPORT(S): NEW PROTOCOL CHEMISTRY/MICROBIOLOGY INITIAL WRITTEN REPORT CHANGE IN PROTOCOL PHARMACOLOGYITOXICOLOGY FOLLOW-UP TO A WRITTEN REPORT NEW INVESTIGATOR CLINICAL RESPONSE TO FDA REQUEST FOR INFORMATION ANNUAL REPORT GENERAL CORRESPONDENCE REQUEST FOR REINSTATEMENT OF IND THAT IS WITHDRAWN, OTHER INACTIVATED, TERMINATED OR DISCONTINUED (Specify) CHECK ONLY IF APPLICABLE JUSTIFICATION STATEMENT MUST BE SUBMITTED WITH APPLICATION FOR ANY CHECKED BELOW. REFER TO THE CITED CFR SECTION FOR FURTHER INFORMATION. TREATMENT IND 21 CFR 312.36(b) TREATMENT PROTOCOL 21 CFR 312.35(a) CHARGE REQUEST/NOTIFICATION 21 CFR312.7(d) FOR FDA USE ONLY CDR/DBIND/DGD RECEIPT STAMP DDR RECEIPT STAMP DIVISION ASSIGNMENT: IND NUMBER ASSIGNED: FORM FDA 1571 (9/02) PREVIOUS EDITION IS OBSOLETE. PAGE 1 OF 2 PX FF Confidential - Subject to Protective Order TAK-INDNDA-01273549 Produced in MDL on 09/11/2012 Source: https://www.indus79c00003s.ucsf.edu/docs/gyjf0226

What is the serial number mentioned in the form?

gyjf0226

gyjf0226_p1, gyjf0226_p2

5 0 1

aked TAXEDA MARMACEUTICALS NORTH AMERICA, INC. Case Number Two: A 79-year-old female, enrolled in the study for 200 days, was hospitalized for a bladder biopsy for possible recurrence of her bladder cancer. Cystoscopy revealed cancer in situ versus a recurrence of transitional cell bladder cancer. This patient has been discontinued from the trial. She has had a history of bladder cancer since 1996 and has a positive history of tobacco use. Drug Treatment: Pioglitazone HCI As noted in the November 6th, conference call, TPNA will continue to investigate all cases of bladder cancer and as directed by the Division. Patients diagnosed with bladder cancer during the course of the study will be withdrawn from the trial and the study medication blind for those patients will be broken and reported to you. Also included in this submission are TPNA's minutes from the November 1st and 6th conference calls with the Division. If you have any questions regarding this submission, please feel free to contact mc. Sincerely Clinton Janet L. Haskins Manager, Regulatory Affairs Takeda Pharmaceuticals North America. Inc. 847-383-3243 (Telephone) 847-383-3427 (Fax) Confidential - Subject to Protective Order TAK-INDNDA-01273548 Produced in MDL on 09/11/2012 DEPARTMENT OF HEALTH AND HUMAN SERVICES Form Approved: OMB No. 0910-0014. PUBLIC HEALTH SERVICE Expiration Date: November 30, 2002 See OMB Statement on Reverse. FOOD AND DRUG ADMINISTRATION INVESTIGATIONAL NEW DRUG APPLICATION (IND) NOTE: No drug may be shipped or cinical (TITLE 21, CODE OF FEDERAL REGULATIONS (CFR) PART 312) investigation begun until an IND for that investigation is in effect (21 CFR 312.40). 1. NAME OF SPONSER 2. DATE OF SUBMISSION Takeda Pharmaceuticals North America. Inc. 11/18/2002 3. ADDRESS (Number, Streel, City, State and Zip Code) 4. TELEPHONE NUMBER (Include Area Code) 475 Half Day Road, Suite 500 847-383-3739 Lincolnshire, IL 60069 5. NAME(S) OF DRUG (include all available names: Trade, Generic, Chemical. Code) 6. IND NUMBER (II previously assigned) ACTOS® (pioglitazone HCI) 33.729 7. INDICATION(S) (Covered by this submission) N/A 3. PHASE(S) OF CLINICAL INVESTIGATION TO BE CONDUCTED: PHASE 1 PHASE 2 PHASE 3 OTHER N/A (Specify) 9. LIST NUMBERS OF ALL INVESTIGATIONAL NEW DRUG APPLICATIONS (21 CFR Part 312), NEW DRUG OR ANTIBIOTIC APPLICATIONS (21 CFR Part 314), DRUG MASTER FILES (21 CFR Part 314.420), AND PRODUCT LICENSE APPLICATIONS (21 CFR Part 601) REFERRED TO IN THIS APPLICATION. N/A 10. IND submission should be consecutively numbered. The Initial IND should be numbered "Serial number: 000." The next submission (e.g., amendment, report, or correspondence) SERIAL NUMBER should be numbered "Serial Number: 001." Subsequent submissions should be numbered 5 consecutively In the order In which they are submitted. 0 1 11. THIS SUBMISSION CONTAINS THE FOLLOWING: (Check ell that apply) INITIAL INVESTIGATIONAL NEW DRUG APPLICATION (IND) RESPONSE TO CLINICAL KOLD PROTOCOL AMENDMENT(S): INFORMATION AMENDMENT(S) IND SAFETY REPORT(S): NEW PROTOCOL CHEMISTRY/MICROBIOLOGY INITIAL WRITTEN REPORT CHANGE IN PROTOCOL PHARMACOLOGYITOXICOLOGY FOLLOW-UP TO A WRITTEN REPORT NEW INVESTIGATOR CLINICAL RESPONSE TO FDA REQUEST FOR INFORMATION ANNUAL REPORT GENERAL CORRESPONDENCE REQUEST FOR REINSTATEMENT OF IND THAT IS WITHDRAWN, OTHER INACTIVATED, TERMINATED OR DISCONTINUED (Specify) CHECK ONLY IF APPLICABLE JUSTIFICATION STATEMENT MUST BE SUBMITTED WITH APPLICATION FOR ANY CHECKED BELOW. REFER TO THE CITED CFR SECTION FOR FURTHER INFORMATION. TREATMENT IND 21 CFR 312.36(b) TREATMENT PROTOCOL 21 CFR 312.35(a) CHARGE REQUEST/NOTIFICATION 21 CFR312.7(d) FOR FDA USE ONLY CDR/DBIND/DGD RECEIPT STAMP DDR RECEIPT STAMP DIVISION ASSIGNMENT: IND NUMBER ASSIGNED: FORM FDA 1571 (9/02) PREVIOUS EDITION IS OBSOLETE. PAGE 1 OF 2 PX FF Confidential - Subject to Protective Order TAK-INDNDA-01273549 Produced in MDL on 09/11/2012 Source: https://www.indus79c00003s.ucsf.edu/docs/gyjf0226

what is the expiration date ?

gyjf0226

gyjf0226_p1, gyjf0226_p2

november 30, 2002, November 30, 2002

aked TAXEDA MARMACEUTICALS NORTH AMERICA, INC. Case Number Two: A 79-year-old female, enrolled in the study for 200 days, was hospitalized for a bladder biopsy for possible recurrence of her bladder cancer. Cystoscopy revealed cancer in situ versus a recurrence of transitional cell bladder cancer. This patient has been discontinued from the trial. She has had a history of bladder cancer since 1996 and has a positive history of tobacco use. Drug Treatment: Pioglitazone HCI As noted in the November 6th, conference call, TPNA will continue to investigate all cases of bladder cancer and as directed by the Division. Patients diagnosed with bladder cancer during the course of the study will be withdrawn from the trial and the study medication blind for those patients will be broken and reported to you. Also included in this submission are TPNA's minutes from the November 1st and 6th conference calls with the Division. If you have any questions regarding this submission, please feel free to contact mc. Sincerely Clinton Janet L. Haskins Manager, Regulatory Affairs Takeda Pharmaceuticals North America. Inc. 847-383-3243 (Telephone) 847-383-3427 (Fax) Confidential - Subject to Protective Order TAK-INDNDA-01273548 Produced in MDL on 09/11/2012 DEPARTMENT OF HEALTH AND HUMAN SERVICES Form Approved: OMB No. 0910-0014. PUBLIC HEALTH SERVICE Expiration Date: November 30, 2002 See OMB Statement on Reverse. FOOD AND DRUG ADMINISTRATION INVESTIGATIONAL NEW DRUG APPLICATION (IND) NOTE: No drug may be shipped or cinical (TITLE 21, CODE OF FEDERAL REGULATIONS (CFR) PART 312) investigation begun until an IND for that investigation is in effect (21 CFR 312.40). 1. NAME OF SPONSER 2. DATE OF SUBMISSION Takeda Pharmaceuticals North America. Inc. 11/18/2002 3. ADDRESS (Number, Streel, City, State and Zip Code) 4. TELEPHONE NUMBER (Include Area Code) 475 Half Day Road, Suite 500 847-383-3739 Lincolnshire, IL 60069 5. NAME(S) OF DRUG (include all available names: Trade, Generic, Chemical. Code) 6. IND NUMBER (II previously assigned) ACTOS® (pioglitazone HCI) 33.729 7. INDICATION(S) (Covered by this submission) N/A 3. PHASE(S) OF CLINICAL INVESTIGATION TO BE CONDUCTED: PHASE 1 PHASE 2 PHASE 3 OTHER N/A (Specify) 9. LIST NUMBERS OF ALL INVESTIGATIONAL NEW DRUG APPLICATIONS (21 CFR Part 312), NEW DRUG OR ANTIBIOTIC APPLICATIONS (21 CFR Part 314), DRUG MASTER FILES (21 CFR Part 314.420), AND PRODUCT LICENSE APPLICATIONS (21 CFR Part 601) REFERRED TO IN THIS APPLICATION. N/A 10. IND submission should be consecutively numbered. The Initial IND should be numbered "Serial number: 000." The next submission (e.g., amendment, report, or correspondence) SERIAL NUMBER should be numbered "Serial Number: 001." Subsequent submissions should be numbered 5 consecutively In the order In which they are submitted. 0 1 11. THIS SUBMISSION CONTAINS THE FOLLOWING: (Check ell that apply) INITIAL INVESTIGATIONAL NEW DRUG APPLICATION (IND) RESPONSE TO CLINICAL KOLD PROTOCOL AMENDMENT(S): INFORMATION AMENDMENT(S) IND SAFETY REPORT(S): NEW PROTOCOL CHEMISTRY/MICROBIOLOGY INITIAL WRITTEN REPORT CHANGE IN PROTOCOL PHARMACOLOGYITOXICOLOGY FOLLOW-UP TO A WRITTEN REPORT NEW INVESTIGATOR CLINICAL RESPONSE TO FDA REQUEST FOR INFORMATION ANNUAL REPORT GENERAL CORRESPONDENCE REQUEST FOR REINSTATEMENT OF IND THAT IS WITHDRAWN, OTHER INACTIVATED, TERMINATED OR DISCONTINUED (Specify) CHECK ONLY IF APPLICABLE JUSTIFICATION STATEMENT MUST BE SUBMITTED WITH APPLICATION FOR ANY CHECKED BELOW. REFER TO THE CITED CFR SECTION FOR FURTHER INFORMATION. TREATMENT IND 21 CFR 312.36(b) TREATMENT PROTOCOL 21 CFR 312.35(a) CHARGE REQUEST/NOTIFICATION 21 CFR312.7(d) FOR FDA USE ONLY CDR/DBIND/DGD RECEIPT STAMP DDR RECEIPT STAMP DIVISION ASSIGNMENT: IND NUMBER ASSIGNED: FORM FDA 1571 (9/02) PREVIOUS EDITION IS OBSOLETE. PAGE 1 OF 2 PX FF Confidential - Subject to Protective Order TAK-INDNDA-01273549 Produced in MDL on 09/11/2012 Source: https://www.indus79c00003s.ucsf.edu/docs/gyjf0226

what is the name of the sponsor ?

gyjf0226

gyjf0226_p1, gyjf0226_p2

Takeda Pharmaceuticals North america , Inc., Takeda Pharmaceuticals North America, Inc.

aked TAXEDA MARMACEUTICALS NORTH AMERICA, INC. Case Number Two: A 79-year-old female, enrolled in the study for 200 days, was hospitalized for a bladder biopsy for possible recurrence of her bladder cancer. Cystoscopy revealed cancer in situ versus a recurrence of transitional cell bladder cancer. This patient has been discontinued from the trial. She has had a history of bladder cancer since 1996 and has a positive history of tobacco use. Drug Treatment: Pioglitazone HCI As noted in the November 6th, conference call, TPNA will continue to investigate all cases of bladder cancer and as directed by the Division. Patients diagnosed with bladder cancer during the course of the study will be withdrawn from the trial and the study medication blind for those patients will be broken and reported to you. Also included in this submission are TPNA's minutes from the November 1st and 6th conference calls with the Division. If you have any questions regarding this submission, please feel free to contact mc. Sincerely Clinton Janet L. Haskins Manager, Regulatory Affairs Takeda Pharmaceuticals North America. Inc. 847-383-3243 (Telephone) 847-383-3427 (Fax) Confidential - Subject to Protective Order TAK-INDNDA-01273548 Produced in MDL on 09/11/2012 DEPARTMENT OF HEALTH AND HUMAN SERVICES Form Approved: OMB No. 0910-0014. PUBLIC HEALTH SERVICE Expiration Date: November 30, 2002 See OMB Statement on Reverse. FOOD AND DRUG ADMINISTRATION INVESTIGATIONAL NEW DRUG APPLICATION (IND) NOTE: No drug may be shipped or cinical (TITLE 21, CODE OF FEDERAL REGULATIONS (CFR) PART 312) investigation begun until an IND for that investigation is in effect (21 CFR 312.40). 1. NAME OF SPONSER 2. DATE OF SUBMISSION Takeda Pharmaceuticals North America. Inc. 11/18/2002 3. ADDRESS (Number, Streel, City, State and Zip Code) 4. TELEPHONE NUMBER (Include Area Code) 475 Half Day Road, Suite 500 847-383-3739 Lincolnshire, IL 60069 5. NAME(S) OF DRUG (include all available names: Trade, Generic, Chemical. Code) 6. IND NUMBER (II previously assigned) ACTOS® (pioglitazone HCI) 33.729 7. INDICATION(S) (Covered by this submission) N/A 3. PHASE(S) OF CLINICAL INVESTIGATION TO BE CONDUCTED: PHASE 1 PHASE 2 PHASE 3 OTHER N/A (Specify) 9. LIST NUMBERS OF ALL INVESTIGATIONAL NEW DRUG APPLICATIONS (21 CFR Part 312), NEW DRUG OR ANTIBIOTIC APPLICATIONS (21 CFR Part 314), DRUG MASTER FILES (21 CFR Part 314.420), AND PRODUCT LICENSE APPLICATIONS (21 CFR Part 601) REFERRED TO IN THIS APPLICATION. N/A 10. IND submission should be consecutively numbered. The Initial IND should be numbered "Serial number: 000." The next submission (e.g., amendment, report, or correspondence) SERIAL NUMBER should be numbered "Serial Number: 001." Subsequent submissions should be numbered 5 consecutively In the order In which they are submitted. 0 1 11. THIS SUBMISSION CONTAINS THE FOLLOWING: (Check ell that apply) INITIAL INVESTIGATIONAL NEW DRUG APPLICATION (IND) RESPONSE TO CLINICAL KOLD PROTOCOL AMENDMENT(S): INFORMATION AMENDMENT(S) IND SAFETY REPORT(S): NEW PROTOCOL CHEMISTRY/MICROBIOLOGY INITIAL WRITTEN REPORT CHANGE IN PROTOCOL PHARMACOLOGYITOXICOLOGY FOLLOW-UP TO A WRITTEN REPORT NEW INVESTIGATOR CLINICAL RESPONSE TO FDA REQUEST FOR INFORMATION ANNUAL REPORT GENERAL CORRESPONDENCE REQUEST FOR REINSTATEMENT OF IND THAT IS WITHDRAWN, OTHER INACTIVATED, TERMINATED OR DISCONTINUED (Specify) CHECK ONLY IF APPLICABLE JUSTIFICATION STATEMENT MUST BE SUBMITTED WITH APPLICATION FOR ANY CHECKED BELOW. REFER TO THE CITED CFR SECTION FOR FURTHER INFORMATION. TREATMENT IND 21 CFR 312.36(b) TREATMENT PROTOCOL 21 CFR 312.35(a) CHARGE REQUEST/NOTIFICATION 21 CFR312.7(d) FOR FDA USE ONLY CDR/DBIND/DGD RECEIPT STAMP DDR RECEIPT STAMP DIVISION ASSIGNMENT: IND NUMBER ASSIGNED: FORM FDA 1571 (9/02) PREVIOUS EDITION IS OBSOLETE. PAGE 1 OF 2 PX FF Confidential - Subject to Protective Order TAK-INDNDA-01273549 Produced in MDL on 09/11/2012 Source: https://www.indus79c00003s.ucsf.edu/docs/gyjf0226

what has to be investigated before starting pioglitazone therapy?

psjf0226

psjf0226_p4, psjf0226_p5

any macroscopic haematuria

Takeda In light of age-related risks (especially. bladder cancer, fractures and heart failure), the balance of benefits and risks should be considered carefully I both before and during treatment in the elderly Bladder Cancer Cases of bladder cancer were reported more frequently in a meta-analysis of controlled clinical trials with pioglitazone (19 cases from 12506 patients, 0.15%) than in control groups (7 cases from 10212 patients, 0.07%) HR=2.64 (95% CI 1.11-6.31, P=0.029). After excluding patients in whom exposure to study drug was less than one year at the time of diagnosis of bladder cancer, there were 7 cases (0.06%) on pioglitazone and 2 cases (0.02%) in control groups: Available epidemiological data also suggest a small increased risk of bladder cancer in diabetic patients treated with pioglitazone, in particular in patients treated for the longest durations and with the highest cumulative doses. A possible risk after short term treatment cannot be excluded. Risk factors for bladder cancer should be assessed before initiating pioglitazone treatment (risks include age, smoking history, exposure to-some occupational or chemotherapy-agents e.g. cyclophosphamide or prior radiation treatment in the pelvic region) Any macroscopic haematuria should be investigated before starting pioglitazone therapy, Patients should be advised to promptly seek the attention of their physician if macroscopic haematuria or other symptoms such as dysuria or urinary urgency develop during treatment. Section 4.8 - Undesirable effects Inclusion of bladder cancer as an uncommon adverse reaction. List of revisions to the Patient Information Leaflet Section 1 - What Actos/Competact is and what it is used for It is an anti-diabetic medicine used to treat type 2 (non-insulin dependent) diabetes mellitus, when metformin is not suitable or has failed to work adequately. Your doctor will check whether Actos/Competact is working 3 to 6 months after you start taking it. Actos may be used on its own in patients who are unable to take metformin, and where treatment with diet and exercise has failed to control blood sugar or may be added to other therapies (such as metformin, sulphonylurea or insulin) which have failed to provide sufficient control of blood sugar. Section 2 - Before you take Actos/Competact Do not take Actos/Competact if you have or have ever had bladder cancer. if you have blood in your urine that-your docter has not checked. Section 4 - Possible side effects Heart failure has been experienced commonly (1 to 10 users in 100) in patients taking Actos in combination with insulin. Symptoms are unusual shortness of breath or rapid increase in weight or localised swelling (oedema). If you experience any of these, especially if you are over the age of 65, seek medical advice straight away. Bladder cancer has been experienced uncommonly (1-to-10 users in 1000) in patients taking Actos/Competact: Signs and symptoms include blood in your urine, pain when urinating or a sudden need to urinate. If you experience-any of these, talk to your doctor as soon as possible. Confidential - Subject to Protective Order TAK-TYNANJ-00213202 Source: https://wwww.indup.49000005 s.ucsf.edu/docs/psjf0226 Takeda Localised swelling (oedema) has also been experienced very commonly in patients taking Actos in combination with insulin If you experience this side effect, talk to your doctor as soon as possible Broken bones have been reported commonly (1 to 10 users in 100) in women patients taking Actos. If you experience this side effect, talk to your doctor as soon as possible. Blurred vision due to swelling (or fluid) at the back of the eye (frequency not known) has also been reported in patients taking Actos. If you experience this symptom for the first time, talk to your docter as soon-as-possible Also, if you already have-blurred vision and the symptom-gets-warse, talk to your doctor as. soon as possible. Confidential - Subject to Protective Order TAK-TYNANJ-00213203 Source: https://www.indup5449000006 s.ucsf.edu/docs/psjf0226

what has been experienced commonly in patients taking actos in combination with insulin?

psjf0226

psjf0226_p4, psjf0226_p5

heart failure, Heart failure

Takeda In light of age-related risks (especially. bladder cancer, fractures and heart failure), the balance of benefits and risks should be considered carefully I both before and during treatment in the elderly Bladder Cancer Cases of bladder cancer were reported more frequently in a meta-analysis of controlled clinical trials with pioglitazone (19 cases from 12506 patients, 0.15%) than in control groups (7 cases from 10212 patients, 0.07%) HR=2.64 (95% CI 1.11-6.31, P=0.029). After excluding patients in whom exposure to study drug was less than one year at the time of diagnosis of bladder cancer, there were 7 cases (0.06%) on pioglitazone and 2 cases (0.02%) in control groups: Available epidemiological data also suggest a small increased risk of bladder cancer in diabetic patients treated with pioglitazone, in particular in patients treated for the longest durations and with the highest cumulative doses. A possible risk after short term treatment cannot be excluded. Risk factors for bladder cancer should be assessed before initiating pioglitazone treatment (risks include age, smoking history, exposure to-some occupational or chemotherapy-agents e.g. cyclophosphamide or prior radiation treatment in the pelvic region) Any macroscopic haematuria should be investigated before starting pioglitazone therapy, Patients should be advised to promptly seek the attention of their physician if macroscopic haematuria or other symptoms such as dysuria or urinary urgency develop during treatment. Section 4.8 - Undesirable effects Inclusion of bladder cancer as an uncommon adverse reaction. List of revisions to the Patient Information Leaflet Section 1 - What Actos/Competact is and what it is used for It is an anti-diabetic medicine used to treat type 2 (non-insulin dependent) diabetes mellitus, when metformin is not suitable or has failed to work adequately. Your doctor will check whether Actos/Competact is working 3 to 6 months after you start taking it. Actos may be used on its own in patients who are unable to take metformin, and where treatment with diet and exercise has failed to control blood sugar or may be added to other therapies (such as metformin, sulphonylurea or insulin) which have failed to provide sufficient control of blood sugar. Section 2 - Before you take Actos/Competact Do not take Actos/Competact if you have or have ever had bladder cancer. if you have blood in your urine that-your docter has not checked. Section 4 - Possible side effects Heart failure has been experienced commonly (1 to 10 users in 100) in patients taking Actos in combination with insulin. Symptoms are unusual shortness of breath or rapid increase in weight or localised swelling (oedema). If you experience any of these, especially if you are over the age of 65, seek medical advice straight away. Bladder cancer has been experienced uncommonly (1-to-10 users in 1000) in patients taking Actos/Competact: Signs and symptoms include blood in your urine, pain when urinating or a sudden need to urinate. If you experience-any of these, talk to your doctor as soon as possible. Confidential - Subject to Protective Order TAK-TYNANJ-00213202 Source: https://wwww.indup.49000005 s.ucsf.edu/docs/psjf0226 Takeda Localised swelling (oedema) has also been experienced very commonly in patients taking Actos in combination with insulin If you experience this side effect, talk to your doctor as soon as possible Broken bones have been reported commonly (1 to 10 users in 100) in women patients taking Actos. If you experience this side effect, talk to your doctor as soon as possible. Blurred vision due to swelling (or fluid) at the back of the eye (frequency not known) has also been reported in patients taking Actos. If you experience this symptom for the first time, talk to your docter as soon-as-possible Also, if you already have-blurred vision and the symptom-gets-warse, talk to your doctor as. soon as possible. Confidential - Subject to Protective Order TAK-TYNANJ-00213203 Source: https://www.indup5449000006 s.ucsf.edu/docs/psjf0226

Under which department , The Cleveland Clinic Foundation operates?

zfkf0226

zfkf0226_p0, zfkf0226_p1

Department of Cardiovascular Medicine., Department of Cardiovascular Medicine

CONFIDENTIAL February 1, 2007 The Cleveland Clinic Foundation Department of Cardiovascular Research and Education 9500 Euclid Avenue F25 Cleveland, OH 44195 Re: Consulting Services Agreement/Steven Nissen, MD and the Cleveland Clinic Cardiovascular Coordinating Center (C5) To Whom It May Concern: This letter sets forth the terms of our agreement under which The Cleveland Clinic Foundation ("Institution") will provide certain consulting services to Takeda Global Research & Development Center, Inc. ("TGRD") during the term hereof. Steven Nissen, MD, an employee of Institution, is appointed by Institution to conduct the Services (as defined below) hereunder. 1. Description of Services. Institution is hereby retained by TGRD to perform the meta-analysis services requested by TGRD (collectively, the "Services"). The Services are more definitively described in Attachment A, the Project Work Order or ("PWO"). Institution shall ensure that: (a) Steven Nissen, MD and the Cleveland Clinic Cardiovascular Coordinating Center (C5) will perform all of the Services personally without resort to any delegate or assignee; (b) the Services will be performed in conformity with generally accepted professional standards; (c) it will use its best efforts and all due diligence in performing the Services: (d) it at all times acts in a fiduciary capacity with respect to TGRD; and (e) it complies with all applicable laws and regulations, as well as any TGRD policies and procedures diselosed to Institution. Institution hereby agrees that the Services do not involve the counseling or promotion of any activity that violates any state or federal law. 2. Reports. Any reports required of Institution are described on the PWO. 3. TGRD's Representative. TGRD hereby designates the person identified on the PWO to serve as TGRD's representative ("TGRD Representative") in all interactions with Institution with respect to the Services. TGRD may change the TGRD Representative at any time upon written notice to Institution. 4. Compensation and Payment. In consideration for Institution's performance of the Services, TGRD shall pay Institution the amounts specified on, or calculated in accordance with, the PWO. Institution hereby acknowledges that such compensation (i) constitutes fair market value for the Services, (ii) is not being given in exchange for any explicit or implicit agreement by Institution to recommend or provide favorable status for any of TGRD's products or to influence such Institution's formulary, prescribing or dispensing decisions, and (iii) has not been determined in a manner that takes into account the volume or value of any referrals generated by Institution. Institution shall submit a detailed invoice to TGRD at the end of the Services. Travel time is not Confidential - Subject to TAK-TYNANJ-00043878 compensable. Payment will be made within thirty (30) days of TGRD's receipt from Institution of invoices meeting the foregoing requirements. Payment shall be made payable as follows: The Cleveland Clinic Foundation Department of Cardiovascular Medicine Attn: Terri Zito PO Box 931535 Cleveland, Ohio 44193-5005Tax ID#: 34-0714585 5. Reimbursement for Expenses. TGRD shall also pay Institution for all reasonable out-of-pocket expenses incurred in performing the Services; provided that: (a)if Institution or its employees performing Services reside in the Chicago metropolitan area, then local travel within the Chicago metropolitan area to or from TGRD's offices in Lincolnshire, Illinois will not be reimbursed; (b) automobile travel will be reimbursed at the then-current IRS mileage rates; (c) travel outside the Chicago metropolitan area will require TGRD's prior written consent; (d) approved domestic travel shall be by coach fare; and (e) out-of-pocket expenses in excess of $10.00 each must be documented with original receipts or copies of third party invoices. TGRD shall reimburse Institution for authorized out-of-pocket expenses within thirty (30) days of receipt of Institution's invoice plus all required receipts. 6. Confidentiality. (a) In the course of performing Services, Institution may be given or have access to confidential and proprietary information of TGRD or its affiliates, including but not limited to pricing information, marketing strategies and tactics, research and development information, and/or data relating to the approval, administration, use or experience relating to any or all of TGRD's products (whether marketed or in development), all of which information is considered confidential by TGRD and of irreplaceable value (collectively, "Confidential Information"). (b) For a period of ten (10) years from the date hereof, Institution shall not, without TGRD's prior written consent, use (except to render Services hereunder) or disclose to any third party, any Confidential Information. Institution shall employ the same standard of care in protecting the Confidential Information as it would employ to protect its own confidential information. (c) At any time upon request by TGRD or immediately on the expiration or earlier termination of this Agreement, whichever event occurs first, Institution shall return to TGRD all Confidential Information, including all notes, memoranda, and analyses of the Confidential Information and any and all excerpts or copies of said Information, whether in written, electronic or other format. Institution shall have the right to use the results arising from its participation for its own internal research and education purposes without the payment of royalties or other fees. (d) The foregoing restrictions on use and disclosure shall not apply to Confidential Information which Institution can prove: (i) was in its possession as evidenced by written records, pre-dating disclosure hereunder; (ii) was or became public knowledge through no fault of Institution: (iii) was disclosed to Institution by a third party who was not bound by any confidentiality restriction and did not so bind Institution; or (iv) was required to be disclosed by law, court order or other governmental order on demand; provided Institution shall immediately notify TGRD in writing and allow TGRD to attempt to limit disclosure by appropriate legal means. Failing such efforts Institution shall use its best efforts to maintain the confidentiality of the Confidential Information being disclosed to the greatest extent possible. Confidential - Subject to TAK-TYNANJ-00043879

What is written in big bold letters at the bottom?

nljf0226

nljf0226_p0, nljf0226_p1

DALY 19

FROM FAX05-6204-2943 1999m 18218(*)21 28./95624801941295 P 1 1/3 Takeda Chemical Industries, Ltd. Takeda Product Planning & Management Dept., International Division 1-1 Doshomachi 4-chome, Chuo-Ku, Osaka 541, JAPAN Tel: +81 6 (204) 2852 Fax: +81 6 (204) 2943 TELEFAX M E S SA G E To: E. Lilly & Company Date: January 21, 1999 Att: Mr. Larry Ellingson From: Kunio Iwatani Executive Director Actos Product Team CC: Mr. Hamanaka, TPA Subject: Upjohn Matter Dear Mr. Ellingson, Enclosed please find a copy of Upjohn's letter to US FDA dated January 7, 1994. In the letter Upjohn said that in preliminary clinical evaluation in the United States, pioglitazone did not satisfy Upjohn's internal requirement for reduction blood glucose; therefore, the considerable programs required for development of pioglitazone are not in line with Upjohn's business needs. ... They did not mention about safety of pioglitazone. After Upjohn's decision, Takeda approached FDA and consulted whether Takeda might go further the clinical development works on pioglitazone. Since the FDA's response was positive to go ahead, Takeda took over Upjohn's works and finally filed NDA on January 15, 1999. This is the story of the fact. Although there may be rumors about the reasons of Upjohn's abandonment of pioglitazone development, specially from the viewpoints of safety issues, it might be advisable for us to keep saying that Upjohn's decision is based on DALY 19 JAN 21 '99 07:43 06 6204 2943 PAGE.01 Confidential - Subject to Protective Order LLY-CRCARCH-00003000 Source: https://www.indupoodsouoonts.ucsf.edu/docs/nljf0226 FROM FAX06-6204-2943 19994 1821E (*) 21 : P. 2 2 2/3 the results of their internal business evaluation, and efficacy and safety of pioglitazone have been demonstrated clearly by Takeda. With our best regards, Kunio Iwatani JAN 21 '99 07:43 06 6204 2943 PAGE.02 Confidential - Subject to Protective Order LLY-CRCARCH-00003001 Source: https://www.induptods.00002t ts. ucsf.edu/docs/nljf0226

Which medicine is used to treat type 2 diabetes mellitus?

psjf0226

psjf0226_p4, psjf0226_p5

Actos/Competact

Takeda In light of age-related risks (especially. bladder cancer, fractures and heart failure), the balance of benefits and risks should be considered carefully I both before and during treatment in the elderly Bladder Cancer Cases of bladder cancer were reported more frequently in a meta-analysis of controlled clinical trials with pioglitazone (19 cases from 12506 patients, 0.15%) than in control groups (7 cases from 10212 patients, 0.07%) HR=2.64 (95% CI 1.11-6.31, P=0.029). After excluding patients in whom exposure to study drug was less than one year at the time of diagnosis of bladder cancer, there were 7 cases (0.06%) on pioglitazone and 2 cases (0.02%) in control groups: Available epidemiological data also suggest a small increased risk of bladder cancer in diabetic patients treated with pioglitazone, in particular in patients treated for the longest durations and with the highest cumulative doses. A possible risk after short term treatment cannot be excluded. Risk factors for bladder cancer should be assessed before initiating pioglitazone treatment (risks include age, smoking history, exposure to-some occupational or chemotherapy-agents e.g. cyclophosphamide or prior radiation treatment in the pelvic region) Any macroscopic haematuria should be investigated before starting pioglitazone therapy, Patients should be advised to promptly seek the attention of their physician if macroscopic haematuria or other symptoms such as dysuria or urinary urgency develop during treatment. Section 4.8 - Undesirable effects Inclusion of bladder cancer as an uncommon adverse reaction. List of revisions to the Patient Information Leaflet Section 1 - What Actos/Competact is and what it is used for It is an anti-diabetic medicine used to treat type 2 (non-insulin dependent) diabetes mellitus, when metformin is not suitable or has failed to work adequately. Your doctor will check whether Actos/Competact is working 3 to 6 months after you start taking it. Actos may be used on its own in patients who are unable to take metformin, and where treatment with diet and exercise has failed to control blood sugar or may be added to other therapies (such as metformin, sulphonylurea or insulin) which have failed to provide sufficient control of blood sugar. Section 2 - Before you take Actos/Competact Do not take Actos/Competact if you have or have ever had bladder cancer. if you have blood in your urine that-your docter has not checked. Section 4 - Possible side effects Heart failure has been experienced commonly (1 to 10 users in 100) in patients taking Actos in combination with insulin. Symptoms are unusual shortness of breath or rapid increase in weight or localised swelling (oedema). If you experience any of these, especially if you are over the age of 65, seek medical advice straight away. Bladder cancer has been experienced uncommonly (1-to-10 users in 1000) in patients taking Actos/Competact: Signs and symptoms include blood in your urine, pain when urinating or a sudden need to urinate. If you experience-any of these, talk to your doctor as soon as possible. Confidential - Subject to Protective Order TAK-TYNANJ-00213202 Source: https://wwww.indup.49000005 s.ucsf.edu/docs/psjf0226 Takeda Localised swelling (oedema) has also been experienced very commonly in patients taking Actos in combination with insulin If you experience this side effect, talk to your doctor as soon as possible Broken bones have been reported commonly (1 to 10 users in 100) in women patients taking Actos. If you experience this side effect, talk to your doctor as soon as possible. Blurred vision due to swelling (or fluid) at the back of the eye (frequency not known) has also been reported in patients taking Actos. If you experience this symptom for the first time, talk to your docter as soon-as-possible Also, if you already have-blurred vision and the symptom-gets-warse, talk to your doctor as. soon as possible. Confidential - Subject to Protective Order TAK-TYNANJ-00213203 Source: https://www.indup5449000006 s.ucsf.edu/docs/psjf0226

How many cases of bladder cancer from 12506 patients were reported?

psjf0226

psjf0226_p4, psjf0226_p5

19 cases

Takeda In light of age-related risks (especially. bladder cancer, fractures and heart failure), the balance of benefits and risks should be considered carefully I both before and during treatment in the elderly Bladder Cancer Cases of bladder cancer were reported more frequently in a meta-analysis of controlled clinical trials with pioglitazone (19 cases from 12506 patients, 0.15%) than in control groups (7 cases from 10212 patients, 0.07%) HR=2.64 (95% CI 1.11-6.31, P=0.029). After excluding patients in whom exposure to study drug was less than one year at the time of diagnosis of bladder cancer, there were 7 cases (0.06%) on pioglitazone and 2 cases (0.02%) in control groups: Available epidemiological data also suggest a small increased risk of bladder cancer in diabetic patients treated with pioglitazone, in particular in patients treated for the longest durations and with the highest cumulative doses. A possible risk after short term treatment cannot be excluded. Risk factors for bladder cancer should be assessed before initiating pioglitazone treatment (risks include age, smoking history, exposure to-some occupational or chemotherapy-agents e.g. cyclophosphamide or prior radiation treatment in the pelvic region) Any macroscopic haematuria should be investigated before starting pioglitazone therapy, Patients should be advised to promptly seek the attention of their physician if macroscopic haematuria or other symptoms such as dysuria or urinary urgency develop during treatment. Section 4.8 - Undesirable effects Inclusion of bladder cancer as an uncommon adverse reaction. List of revisions to the Patient Information Leaflet Section 1 - What Actos/Competact is and what it is used for It is an anti-diabetic medicine used to treat type 2 (non-insulin dependent) diabetes mellitus, when metformin is not suitable or has failed to work adequately. Your doctor will check whether Actos/Competact is working 3 to 6 months after you start taking it. Actos may be used on its own in patients who are unable to take metformin, and where treatment with diet and exercise has failed to control blood sugar or may be added to other therapies (such as metformin, sulphonylurea or insulin) which have failed to provide sufficient control of blood sugar. Section 2 - Before you take Actos/Competact Do not take Actos/Competact if you have or have ever had bladder cancer. if you have blood in your urine that-your docter has not checked. Section 4 - Possible side effects Heart failure has been experienced commonly (1 to 10 users in 100) in patients taking Actos in combination with insulin. Symptoms are unusual shortness of breath or rapid increase in weight or localised swelling (oedema). If you experience any of these, especially if you are over the age of 65, seek medical advice straight away. Bladder cancer has been experienced uncommonly (1-to-10 users in 1000) in patients taking Actos/Competact: Signs and symptoms include blood in your urine, pain when urinating or a sudden need to urinate. If you experience-any of these, talk to your doctor as soon as possible. Confidential - Subject to Protective Order TAK-TYNANJ-00213202 Source: https://wwww.indup.49000005 s.ucsf.edu/docs/psjf0226 Takeda Localised swelling (oedema) has also been experienced very commonly in patients taking Actos in combination with insulin If you experience this side effect, talk to your doctor as soon as possible Broken bones have been reported commonly (1 to 10 users in 100) in women patients taking Actos. If you experience this side effect, talk to your doctor as soon as possible. Blurred vision due to swelling (or fluid) at the back of the eye (frequency not known) has also been reported in patients taking Actos. If you experience this symptom for the first time, talk to your docter as soon-as-possible Also, if you already have-blurred vision and the symptom-gets-warse, talk to your doctor as. soon as possible. Confidential - Subject to Protective Order TAK-TYNANJ-00213203 Source: https://www.indup5449000006 s.ucsf.edu/docs/psjf0226

What is the PO Box number?

zfkf0226

zfkf0226_p0, zfkf0226_p1

931535

CONFIDENTIAL February 1, 2007 The Cleveland Clinic Foundation Department of Cardiovascular Research and Education 9500 Euclid Avenue F25 Cleveland, OH 44195 Re: Consulting Services Agreement/Steven Nissen, MD and the Cleveland Clinic Cardiovascular Coordinating Center (C5) To Whom It May Concern: This letter sets forth the terms of our agreement under which The Cleveland Clinic Foundation ("Institution") will provide certain consulting services to Takeda Global Research & Development Center, Inc. ("TGRD") during the term hereof. Steven Nissen, MD, an employee of Institution, is appointed by Institution to conduct the Services (as defined below) hereunder. 1. Description of Services. Institution is hereby retained by TGRD to perform the meta-analysis services requested by TGRD (collectively, the "Services"). The Services are more definitively described in Attachment A, the Project Work Order or ("PWO"). Institution shall ensure that: (a) Steven Nissen, MD and the Cleveland Clinic Cardiovascular Coordinating Center (C5) will perform all of the Services personally without resort to any delegate or assignee; (b) the Services will be performed in conformity with generally accepted professional standards; (c) it will use its best efforts and all due diligence in performing the Services: (d) it at all times acts in a fiduciary capacity with respect to TGRD; and (e) it complies with all applicable laws and regulations, as well as any TGRD policies and procedures diselosed to Institution. Institution hereby agrees that the Services do not involve the counseling or promotion of any activity that violates any state or federal law. 2. Reports. Any reports required of Institution are described on the PWO. 3. TGRD's Representative. TGRD hereby designates the person identified on the PWO to serve as TGRD's representative ("TGRD Representative") in all interactions with Institution with respect to the Services. TGRD may change the TGRD Representative at any time upon written notice to Institution. 4. Compensation and Payment. In consideration for Institution's performance of the Services, TGRD shall pay Institution the amounts specified on, or calculated in accordance with, the PWO. Institution hereby acknowledges that such compensation (i) constitutes fair market value for the Services, (ii) is not being given in exchange for any explicit or implicit agreement by Institution to recommend or provide favorable status for any of TGRD's products or to influence such Institution's formulary, prescribing or dispensing decisions, and (iii) has not been determined in a manner that takes into account the volume or value of any referrals generated by Institution. Institution shall submit a detailed invoice to TGRD at the end of the Services. Travel time is not Confidential - Subject to TAK-TYNANJ-00043878 compensable. Payment will be made within thirty (30) days of TGRD's receipt from Institution of invoices meeting the foregoing requirements. Payment shall be made payable as follows: The Cleveland Clinic Foundation Department of Cardiovascular Medicine Attn: Terri Zito PO Box 931535 Cleveland, Ohio 44193-5005Tax ID#: 34-0714585 5. Reimbursement for Expenses. TGRD shall also pay Institution for all reasonable out-of-pocket expenses incurred in performing the Services; provided that: (a)if Institution or its employees performing Services reside in the Chicago metropolitan area, then local travel within the Chicago metropolitan area to or from TGRD's offices in Lincolnshire, Illinois will not be reimbursed; (b) automobile travel will be reimbursed at the then-current IRS mileage rates; (c) travel outside the Chicago metropolitan area will require TGRD's prior written consent; (d) approved domestic travel shall be by coach fare; and (e) out-of-pocket expenses in excess of $10.00 each must be documented with original receipts or copies of third party invoices. TGRD shall reimburse Institution for authorized out-of-pocket expenses within thirty (30) days of receipt of Institution's invoice plus all required receipts. 6. Confidentiality. (a) In the course of performing Services, Institution may be given or have access to confidential and proprietary information of TGRD or its affiliates, including but not limited to pricing information, marketing strategies and tactics, research and development information, and/or data relating to the approval, administration, use or experience relating to any or all of TGRD's products (whether marketed or in development), all of which information is considered confidential by TGRD and of irreplaceable value (collectively, "Confidential Information"). (b) For a period of ten (10) years from the date hereof, Institution shall not, without TGRD's prior written consent, use (except to render Services hereunder) or disclose to any third party, any Confidential Information. Institution shall employ the same standard of care in protecting the Confidential Information as it would employ to protect its own confidential information. (c) At any time upon request by TGRD or immediately on the expiration or earlier termination of this Agreement, whichever event occurs first, Institution shall return to TGRD all Confidential Information, including all notes, memoranda, and analyses of the Confidential Information and any and all excerpts or copies of said Information, whether in written, electronic or other format. Institution shall have the right to use the results arising from its participation for its own internal research and education purposes without the payment of royalties or other fees. (d) The foregoing restrictions on use and disclosure shall not apply to Confidential Information which Institution can prove: (i) was in its possession as evidenced by written records, pre-dating disclosure hereunder; (ii) was or became public knowledge through no fault of Institution: (iii) was disclosed to Institution by a third party who was not bound by any confidentiality restriction and did not so bind Institution; or (iv) was required to be disclosed by law, court order or other governmental order on demand; provided Institution shall immediately notify TGRD in writing and allow TGRD to attempt to limit disclosure by appropriate legal means. Failing such efforts Institution shall use its best efforts to maintain the confidentiality of the Confidential Information being disclosed to the greatest extent possible. Confidential - Subject to TAK-TYNANJ-00043879

what is the IND mumber (if previously assigned ) ?

tyjf0226

tyjf0226_p0, tyjf0226_p1, tyjf0226_p2, tyjf0226_p3

33,729

Takeda TAKEDA PHARMACEUTICALS NORTH AMERICA, INC. 5 November 1, 2002 David Orloff, M.D. Division of Metabolic & Endocrine Drug Product (HFD-510) Office of Drug Evaluation II Center for Drug Evaluation & Research Document Control Room 14B-19 Food and Drug Administration 5600 Fishers Lane Rockville, MD 20857 ACTOS® (pioglitazone HCI) Tablets, 15, 30 and 45 mg Serial No. 497 Response to FDA Request for Information Dear Dr. Orloff: Reference is made to teleconferences held between the Division and Takeda Pharmaceuticals North America, Inc. (TPNA) on July 31, 2002 and August 13, 2002 and the submission dated August 28, 2002 (Serial No. 485) to the above noted IND. The purpose of this submission is to provide the Division with additional information that may have some bearing on the manner in which the pediatric written request for ACTOS is being considered. The initial response to the matters discussed at the July 31st teleconference, submitted to the Division on August 28th, was intended to initiate dialog between TPNA and the Division. In the interim, TPNA has been in numerous consultations with nonclinical and clinical experts to gather the most comprehensive and up-to-date viewpoints in order to address this complex issue. We recognize that TPNA's initial response has not addressed the Division's concerns. Since there has been no opportunity for further discussion with the Division subsequent to the August 28th response, we propose that formal action on the written request not be taken at this time. In the August 28" response, TPNA committed not to proceed with the pediatric study governed by the written request. Additionally, as we discussed this morning, the Pediatric home page carries a comprehensive list of products that have received a pediatric written request. ACTOS is currently on this list. Since this list is updated regularly, TPNA assumes that products are removed from the list to reflect any change in status to the written request. It is also our understanding that persons interested in the pharmaceutical industry review-this list on a regular basis. Questions will obviously arise if ACTOS is deleted. This very public disclosure will generate speculation on the nature of the removal, which could unfavorably reflect on the safety profile of ACTOS. 475 Half Day Road, Suite 500 Lincolnshire, Illinois 60069 Phone: 847-383-3000 Confidential - Subject to Protective Order TAK-THOMCL-00015503 Produced in MDL on 09/14/12 Source: Takeda TAKEDA PHARMACEUTICALS NORTHAMERICA,INC We understand that until we reach resolution of our ongoing discussion regarding the rat bladder findings, the Division is concerned about the use of ACTOS in pediatric patients. Therefore, we reconfirm our commitment to suspend pediatric studies. Should these discussions not assuage the Agency's concerns, the written request can be rescinded at a later date. We also reconfirm our commitment to resolving our differences with respect to the interpretation of the rat bladder findings. We look forward to discussing these issues, preferably in a face-to-face meeting, at your earliest convenience. Sincerely, Josech Janet L. Haskins Manager, Regulatory Affairs Takeda Pharmaceuticals North America, Inc. 847-383-3243 (Telephone) 847-383-3427 (Fax) 475 Half Day Road, Suite 500 Lincolnshire, Illinols 60069 Phone: 847-383-3000 Confidential - Subject to Protective Order TAK-THOMCL-00015504 Produced in MDL on 09/14/12 Source: https://www.indup292-00002 ts.ucsf.edu/docs/tyjf0226 :. DEPARTMENT OF HEALTH AND HUMAN SERVICES Form Approved: OMB No. 0910-0014. PUBLIC HEALTH SERVICE Expiration Date: November 30, 2002 See OMB Statement on Reverse, FOOD AND DRUG ADMINISTRATION INVESTIGATIONAL NEW DRUG APPLICATION (IND) NOTE: No drug may be shipped or clinical investigation begun until an IND for that (TITLE 21, CODE OF FEDERAL REGULATIONS (CFR) PART 312) investigation is in effect (21 CFR 312.40). 1. NAME OF SPONSER 2. DATE OF SUBMISSION Takeda Pharmaceuticals North America, Inc. 11/1/02 3. ADDRESS (Number, Street, City, State and Zip Code) 4. TELEPHONE NUMBER (Include Area Code) 475 Half Day Road, Suite 500 847-383-3243 Lincolnshire, IL 60069 5. NAME(S) OF DRUG (Include all available names: Trade, Generic, Chemical, Code) 6. IND NUMBER (If previously assigned) ACTOS® (pioglitazone HCI) 33,729 7. INDICATION(S) (Covered by this submission) N/A 8. PHASE(S) OF CLINICAL INVESTIGATION TO BE CONDUCTED: PHASE 1 PHASE 2 PHASE 3 OTHER N/A (Specify) 9. LIST NUMBERS OF ALL INVESTIGATIONAL NEW DRUG APPLICATIONS (21 CFR Part 312), NEW DRUG OR ANTIBIOTIC APPLICATIONS (21 CFR Part 314), DRUG MASTER FILES (21 CFR Part 314.420), AND PRODUCT LICENSE APPLICATIONS (21 CFR Part 601) REFERRED TO IN THIS APPLICATION. N/A 10. IND submission should be consecutively numbered. The Initial IND should be numbered "Serial number: 000." The next submission (e.g., amendment, report, or correspondence) SERIAL NUMBER should be numbered "Serial Number: 001." Subsequent submissions should be numbered 4 9 7 consecutively in the order in which they are submitted. 11. THIS SUBMISSION CONTAINS THE FOLLOWING: (Check all that apply) INITIAL INVESTIGATIONAL NEW DRUG APPLICATION (IND) RESPONSE TO CLINICAL HOLD PROTOCOL AMENDMENT(S): INFORMATION AMENDMENT(S): IND SAFETY REPORT(S): NEW PROTOCOL CHEMISTRY/MICROBIOLOGY INITIAL WRITTEN REPORT CHANGE IN PROTOCOL PHARMACOLOGYITOXICOLOGY FOLLOW-UP TO A WRITTEN REPORT NEW INVESTIGATOR CLINICAL RESPONSE TO FDA REQUEST FOR INFORMATION ANNUAL REPORT GENERAL CORRESPONDENCE REQUEST FOR REINSTATEMENT OF IND THAT IS WITHDRAWN, OTHER INACTIVATED, TERMINATED OR DISCONTINUED (Spacify) CHECK ONLY IF APPLICABLE JUSTIFICATION STATEMENT MUST BE SUBMITTED WITH APPLICATION FOR ANY CHECKED BELOW. REFER TO THE CITED CFR SECTION FOR FURTHER INFORMATION. TREATMENT IND 21 CFR 312.35(b) TREATMENT PROTOCOL 21 CFR 312.35(a) CHARGE REQUEST/NOTIFICATION: 21 CFR312.7(d) FOR FDA USE ONLY CDR/DBIND/DGD RECEIPT STAMP DDR RECEIPT STAMP DIVISION ASSIGNMENT: IND NUMBER ASSIGNED: FORM FDA 1571 (9/02) PREVIOUS EDITION IS OBSOLETE. PAGE 1 OF 2 PSC Media Arts Braneh (301)443.1090 EF Confidential - Subject to Protective Order TAK-THOMCL-00015505 Produced in MDL on 09/14/12 Source: https://www.indu2292-00003s.ucsf.edu/docs/tyjf0226 12. CONTENTS OF APPLICATION ) This application contains the following items: (Check all that apply) 1. Form FDA 1571 [21 CFR 312.23(a)(1)] 2. Table of Contents [21 CFR 312.23(a)(2) 3. Introductory statement [21 CFR 312.23(a)(3)] 4. General Investigational plan [21 CFR 312.23(a)(3)] 5. Investigator's brochure [21 CFR 312.23(a)(5)] 6. Protocol(s) [21 CFR 312.23(a)(6)] a. Study protocol(s) [21 CFR 312.23(a)(6)] b. Investigator data [21 CFR 312.23(a)(6)(iii)(b)] or completed Form(s) FDA 1572 c. Facilities data [21 CFR 312.23(a)(6)(iii)(b)] or completed Form(s) FDA 1572 d. Institutional Review Board data [21 CFR 312.23(a)(6)(iii)(b)] or completed Form(s) FDA 1572 7. Chemistry, manufacturing, and control data [21 CFR 312.23(a)(7)] Environmental assessment or claim for exclusion [21 CFR 312.23(a)(7)(iv)(e)] 8. Pharmacology and toxicology data [21 CFR 312.23(a)(8)] 9. Previous human experience [21 CFR 312.23(a)(9)] 10. Additional information [21 CFR 312.23(a)(10)] 13. IS ANY PART OF THE CLINICAL STUDY TO BE CONDUCTED BY A CONTRACT RESEARCH ORGANIZATION? YES NO IF YES, WILL ANY SPONSOR OBLIGATIONS BE TRANSFERRED TO THE CONTRACT RESEARCH ORGANIZATION? YES NO IF YES, ATTACH A STATEMENT CONTAINING THE NAME AND ADDRESS OF THE CONTRACT RESEARCH ORGANIZATION, IDENTIFICATION OF THE CLINICAL STUDY, AND A LISTING OF THE OBLIGATIONS TRANSFERRED. 14. NAME AND TITLE OF THE PERSON RESPONSIBLE FOR MONITORING THE CONDUCT AND PROGRESS OF THE CLINICAL INVESTIGATIONS N/A 15. NAME(S) AND TITLE(S) OF THE PERSON(S) RESPONSIBLE FOR REVIEW AND EVALUATION OF INFORMATION RELEVANT TO THE SAFETY OF THE DRUG N/A I agree not to begin clinical Investigations until 30 days after FDA's receipt of the IND unless I receive earlier notification by FDA that the studies may begin. I also agree not to begin or continue clinical Investigations covered by the IND if those studies are placed on clinical hold. I agree that an Institutional Review Board (IRB) that complies with the requirements set fourth in 21 CFR Part 56 will be responsible for Initial and continuing review and approval of each of the studies in the proposed clinical Investigation. I agree to conduct the Investigation in accordance with all other applicable regulatory requirements. 16. NAME OF SPONSOR OR SPONSOR'S AUTHORIZED 17. SIGNATURE OF SPONSOR OR SPONSOR'S AUTHORIZED REPRESENTATIVE REPRESENTATIVE Janet L. Haskins 18, ADDRESS (Number, Street, City, State and Zip Code) 19. TELEPHONE NUMBER (Include Area Code) 20. DATE 475 Half Day Road, Suite 500 847-383-3243 11/1/02 Lincolnshire, IL 60069 (WARNING: A willfully false statement is a criminal offense, U.S.C. Title 18, Sec. 1001.) Public reporting burden for this collection of information is estimated to average 100 hours per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data neaded, and completing reviewing the collection of Information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to: Food and Drug. Administration Food and Drug Administration "An agency may not conduct or sponsor, and a CBER (HFM-99) CDER (HFD-94) person is not required to respond to, a 1401 Rockville Pike 12229 Wilkins Avenue collection of information unless It displays a Rockville, MD 20852-1448 Rockville, MD 20852 currently valid OMB control number.' Please DO NOT RETURN this application to this address. FORM FDA 1571 (9/02) PREVIOUS EDITION IS OBSOLETE. PAGE 2 OF 2 PSC Modia Arts Branch (301) 443-1090 EF Confidential - Subject to Protective Order TAK-THOMCL-00015506 Produced in MDL on 09/14/12 Source: https://www.indup229/2-00004ts.ucsf.edu/docs/tyjf0226

What is the serial number mentioned in the form?

tyjf0226

tyjf0226_p0, tyjf0226_p1, tyjf0226_p2, tyjf0226_p3

4 9 7

Takeda TAKEDA PHARMACEUTICALS NORTH AMERICA, INC. 5 November 1, 2002 David Orloff, M.D. Division of Metabolic & Endocrine Drug Product (HFD-510) Office of Drug Evaluation II Center for Drug Evaluation & Research Document Control Room 14B-19 Food and Drug Administration 5600 Fishers Lane Rockville, MD 20857 ACTOS® (pioglitazone HCI) Tablets, 15, 30 and 45 mg Serial No. 497 Response to FDA Request for Information Dear Dr. Orloff: Reference is made to teleconferences held between the Division and Takeda Pharmaceuticals North America, Inc. (TPNA) on July 31, 2002 and August 13, 2002 and the submission dated August 28, 2002 (Serial No. 485) to the above noted IND. The purpose of this submission is to provide the Division with additional information that may have some bearing on the manner in which the pediatric written request for ACTOS is being considered. The initial response to the matters discussed at the July 31st teleconference, submitted to the Division on August 28th, was intended to initiate dialog between TPNA and the Division. In the interim, TPNA has been in numerous consultations with nonclinical and clinical experts to gather the most comprehensive and up-to-date viewpoints in order to address this complex issue. We recognize that TPNA's initial response has not addressed the Division's concerns. Since there has been no opportunity for further discussion with the Division subsequent to the August 28th response, we propose that formal action on the written request not be taken at this time. In the August 28" response, TPNA committed not to proceed with the pediatric study governed by the written request. Additionally, as we discussed this morning, the Pediatric home page carries a comprehensive list of products that have received a pediatric written request. ACTOS is currently on this list. Since this list is updated regularly, TPNA assumes that products are removed from the list to reflect any change in status to the written request. It is also our understanding that persons interested in the pharmaceutical industry review-this list on a regular basis. Questions will obviously arise if ACTOS is deleted. This very public disclosure will generate speculation on the nature of the removal, which could unfavorably reflect on the safety profile of ACTOS. 475 Half Day Road, Suite 500 Lincolnshire, Illinois 60069 Phone: 847-383-3000 Confidential - Subject to Protective Order TAK-THOMCL-00015503 Produced in MDL on 09/14/12 Source: Takeda TAKEDA PHARMACEUTICALS NORTHAMERICA,INC We understand that until we reach resolution of our ongoing discussion regarding the rat bladder findings, the Division is concerned about the use of ACTOS in pediatric patients. Therefore, we reconfirm our commitment to suspend pediatric studies. Should these discussions not assuage the Agency's concerns, the written request can be rescinded at a later date. We also reconfirm our commitment to resolving our differences with respect to the interpretation of the rat bladder findings. We look forward to discussing these issues, preferably in a face-to-face meeting, at your earliest convenience. Sincerely, Josech Janet L. Haskins Manager, Regulatory Affairs Takeda Pharmaceuticals North America, Inc. 847-383-3243 (Telephone) 847-383-3427 (Fax) 475 Half Day Road, Suite 500 Lincolnshire, Illinols 60069 Phone: 847-383-3000 Confidential - Subject to Protective Order TAK-THOMCL-00015504 Produced in MDL on 09/14/12 Source: https://www.indup292-00002 ts.ucsf.edu/docs/tyjf0226 :. DEPARTMENT OF HEALTH AND HUMAN SERVICES Form Approved: OMB No. 0910-0014. PUBLIC HEALTH SERVICE Expiration Date: November 30, 2002 See OMB Statement on Reverse, FOOD AND DRUG ADMINISTRATION INVESTIGATIONAL NEW DRUG APPLICATION (IND) NOTE: No drug may be shipped or clinical investigation begun until an IND for that (TITLE 21, CODE OF FEDERAL REGULATIONS (CFR) PART 312) investigation is in effect (21 CFR 312.40). 1. NAME OF SPONSER 2. DATE OF SUBMISSION Takeda Pharmaceuticals North America, Inc. 11/1/02 3. ADDRESS (Number, Street, City, State and Zip Code) 4. TELEPHONE NUMBER (Include Area Code) 475 Half Day Road, Suite 500 847-383-3243 Lincolnshire, IL 60069 5. NAME(S) OF DRUG (Include all available names: Trade, Generic, Chemical, Code) 6. IND NUMBER (If previously assigned) ACTOS® (pioglitazone HCI) 33,729 7. INDICATION(S) (Covered by this submission) N/A 8. PHASE(S) OF CLINICAL INVESTIGATION TO BE CONDUCTED: PHASE 1 PHASE 2 PHASE 3 OTHER N/A (Specify) 9. LIST NUMBERS OF ALL INVESTIGATIONAL NEW DRUG APPLICATIONS (21 CFR Part 312), NEW DRUG OR ANTIBIOTIC APPLICATIONS (21 CFR Part 314), DRUG MASTER FILES (21 CFR Part 314.420), AND PRODUCT LICENSE APPLICATIONS (21 CFR Part 601) REFERRED TO IN THIS APPLICATION. N/A 10. IND submission should be consecutively numbered. The Initial IND should be numbered "Serial number: 000." The next submission (e.g., amendment, report, or correspondence) SERIAL NUMBER should be numbered "Serial Number: 001." Subsequent submissions should be numbered 4 9 7 consecutively in the order in which they are submitted. 11. THIS SUBMISSION CONTAINS THE FOLLOWING: (Check all that apply) INITIAL INVESTIGATIONAL NEW DRUG APPLICATION (IND) RESPONSE TO CLINICAL HOLD PROTOCOL AMENDMENT(S): INFORMATION AMENDMENT(S): IND SAFETY REPORT(S): NEW PROTOCOL CHEMISTRY/MICROBIOLOGY INITIAL WRITTEN REPORT CHANGE IN PROTOCOL PHARMACOLOGYITOXICOLOGY FOLLOW-UP TO A WRITTEN REPORT NEW INVESTIGATOR CLINICAL RESPONSE TO FDA REQUEST FOR INFORMATION ANNUAL REPORT GENERAL CORRESPONDENCE REQUEST FOR REINSTATEMENT OF IND THAT IS WITHDRAWN, OTHER INACTIVATED, TERMINATED OR DISCONTINUED (Spacify) CHECK ONLY IF APPLICABLE JUSTIFICATION STATEMENT MUST BE SUBMITTED WITH APPLICATION FOR ANY CHECKED BELOW. REFER TO THE CITED CFR SECTION FOR FURTHER INFORMATION. TREATMENT IND 21 CFR 312.35(b) TREATMENT PROTOCOL 21 CFR 312.35(a) CHARGE REQUEST/NOTIFICATION: 21 CFR312.7(d) FOR FDA USE ONLY CDR/DBIND/DGD RECEIPT STAMP DDR RECEIPT STAMP DIVISION ASSIGNMENT: IND NUMBER ASSIGNED: FORM FDA 1571 (9/02) PREVIOUS EDITION IS OBSOLETE. PAGE 1 OF 2 PSC Media Arts Braneh (301)443.1090 EF Confidential - Subject to Protective Order TAK-THOMCL-00015505 Produced in MDL on 09/14/12 Source: https://www.indu2292-00003s.ucsf.edu/docs/tyjf0226 12. CONTENTS OF APPLICATION ) This application contains the following items: (Check all that apply) 1. Form FDA 1571 [21 CFR 312.23(a)(1)] 2. Table of Contents [21 CFR 312.23(a)(2) 3. Introductory statement [21 CFR 312.23(a)(3)] 4. General Investigational plan [21 CFR 312.23(a)(3)] 5. Investigator's brochure [21 CFR 312.23(a)(5)] 6. Protocol(s) [21 CFR 312.23(a)(6)] a. Study protocol(s) [21 CFR 312.23(a)(6)] b. Investigator data [21 CFR 312.23(a)(6)(iii)(b)] or completed Form(s) FDA 1572 c. Facilities data [21 CFR 312.23(a)(6)(iii)(b)] or completed Form(s) FDA 1572 d. Institutional Review Board data [21 CFR 312.23(a)(6)(iii)(b)] or completed Form(s) FDA 1572 7. Chemistry, manufacturing, and control data [21 CFR 312.23(a)(7)] Environmental assessment or claim for exclusion [21 CFR 312.23(a)(7)(iv)(e)] 8. Pharmacology and toxicology data [21 CFR 312.23(a)(8)] 9. Previous human experience [21 CFR 312.23(a)(9)] 10. Additional information [21 CFR 312.23(a)(10)] 13. IS ANY PART OF THE CLINICAL STUDY TO BE CONDUCTED BY A CONTRACT RESEARCH ORGANIZATION? YES NO IF YES, WILL ANY SPONSOR OBLIGATIONS BE TRANSFERRED TO THE CONTRACT RESEARCH ORGANIZATION? YES NO IF YES, ATTACH A STATEMENT CONTAINING THE NAME AND ADDRESS OF THE CONTRACT RESEARCH ORGANIZATION, IDENTIFICATION OF THE CLINICAL STUDY, AND A LISTING OF THE OBLIGATIONS TRANSFERRED. 14. NAME AND TITLE OF THE PERSON RESPONSIBLE FOR MONITORING THE CONDUCT AND PROGRESS OF THE CLINICAL INVESTIGATIONS N/A 15. NAME(S) AND TITLE(S) OF THE PERSON(S) RESPONSIBLE FOR REVIEW AND EVALUATION OF INFORMATION RELEVANT TO THE SAFETY OF THE DRUG N/A I agree not to begin clinical Investigations until 30 days after FDA's receipt of the IND unless I receive earlier notification by FDA that the studies may begin. I also agree not to begin or continue clinical Investigations covered by the IND if those studies are placed on clinical hold. I agree that an Institutional Review Board (IRB) that complies with the requirements set fourth in 21 CFR Part 56 will be responsible for Initial and continuing review and approval of each of the studies in the proposed clinical Investigation. I agree to conduct the Investigation in accordance with all other applicable regulatory requirements. 16. NAME OF SPONSOR OR SPONSOR'S AUTHORIZED 17. SIGNATURE OF SPONSOR OR SPONSOR'S AUTHORIZED REPRESENTATIVE REPRESENTATIVE Janet L. Haskins 18, ADDRESS (Number, Street, City, State and Zip Code) 19. TELEPHONE NUMBER (Include Area Code) 20. DATE 475 Half Day Road, Suite 500 847-383-3243 11/1/02 Lincolnshire, IL 60069 (WARNING: A willfully false statement is a criminal offense, U.S.C. Title 18, Sec. 1001.) Public reporting burden for this collection of information is estimated to average 100 hours per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data neaded, and completing reviewing the collection of Information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to: Food and Drug. Administration Food and Drug Administration "An agency may not conduct or sponsor, and a CBER (HFM-99) CDER (HFD-94) person is not required to respond to, a 1401 Rockville Pike 12229 Wilkins Avenue collection of information unless It displays a Rockville, MD 20852-1448 Rockville, MD 20852 currently valid OMB control number.' Please DO NOT RETURN this application to this address. FORM FDA 1571 (9/02) PREVIOUS EDITION IS OBSOLETE. PAGE 2 OF 2 PSC Modia Arts Branch (301) 443-1090 EF Confidential - Subject to Protective Order TAK-THOMCL-00015506 Produced in MDL on 09/14/12 Source: https://www.indup229/2-00004ts.ucsf.edu/docs/tyjf0226

what is the date of submission ?

tyjf0226

tyjf0226_p0, tyjf0226_p1, tyjf0226_p2, tyjf0226_p3

11/1/02

Takeda TAKEDA PHARMACEUTICALS NORTH AMERICA, INC. 5 November 1, 2002 David Orloff, M.D. Division of Metabolic & Endocrine Drug Product (HFD-510) Office of Drug Evaluation II Center for Drug Evaluation & Research Document Control Room 14B-19 Food and Drug Administration 5600 Fishers Lane Rockville, MD 20857 ACTOS® (pioglitazone HCI) Tablets, 15, 30 and 45 mg Serial No. 497 Response to FDA Request for Information Dear Dr. Orloff: Reference is made to teleconferences held between the Division and Takeda Pharmaceuticals North America, Inc. (TPNA) on July 31, 2002 and August 13, 2002 and the submission dated August 28, 2002 (Serial No. 485) to the above noted IND. The purpose of this submission is to provide the Division with additional information that may have some bearing on the manner in which the pediatric written request for ACTOS is being considered. The initial response to the matters discussed at the July 31st teleconference, submitted to the Division on August 28th, was intended to initiate dialog between TPNA and the Division. In the interim, TPNA has been in numerous consultations with nonclinical and clinical experts to gather the most comprehensive and up-to-date viewpoints in order to address this complex issue. We recognize that TPNA's initial response has not addressed the Division's concerns. Since there has been no opportunity for further discussion with the Division subsequent to the August 28th response, we propose that formal action on the written request not be taken at this time. In the August 28" response, TPNA committed not to proceed with the pediatric study governed by the written request. Additionally, as we discussed this morning, the Pediatric home page carries a comprehensive list of products that have received a pediatric written request. ACTOS is currently on this list. Since this list is updated regularly, TPNA assumes that products are removed from the list to reflect any change in status to the written request. It is also our understanding that persons interested in the pharmaceutical industry review-this list on a regular basis. Questions will obviously arise if ACTOS is deleted. This very public disclosure will generate speculation on the nature of the removal, which could unfavorably reflect on the safety profile of ACTOS. 475 Half Day Road, Suite 500 Lincolnshire, Illinois 60069 Phone: 847-383-3000 Confidential - Subject to Protective Order TAK-THOMCL-00015503 Produced in MDL on 09/14/12 Source: Takeda TAKEDA PHARMACEUTICALS NORTHAMERICA,INC We understand that until we reach resolution of our ongoing discussion regarding the rat bladder findings, the Division is concerned about the use of ACTOS in pediatric patients. Therefore, we reconfirm our commitment to suspend pediatric studies. Should these discussions not assuage the Agency's concerns, the written request can be rescinded at a later date. We also reconfirm our commitment to resolving our differences with respect to the interpretation of the rat bladder findings. We look forward to discussing these issues, preferably in a face-to-face meeting, at your earliest convenience. Sincerely, Josech Janet L. Haskins Manager, Regulatory Affairs Takeda Pharmaceuticals North America, Inc. 847-383-3243 (Telephone) 847-383-3427 (Fax) 475 Half Day Road, Suite 500 Lincolnshire, Illinols 60069 Phone: 847-383-3000 Confidential - Subject to Protective Order TAK-THOMCL-00015504 Produced in MDL on 09/14/12 Source: https://www.indup292-00002 ts.ucsf.edu/docs/tyjf0226 :. DEPARTMENT OF HEALTH AND HUMAN SERVICES Form Approved: OMB No. 0910-0014. PUBLIC HEALTH SERVICE Expiration Date: November 30, 2002 See OMB Statement on Reverse, FOOD AND DRUG ADMINISTRATION INVESTIGATIONAL NEW DRUG APPLICATION (IND) NOTE: No drug may be shipped or clinical investigation begun until an IND for that (TITLE 21, CODE OF FEDERAL REGULATIONS (CFR) PART 312) investigation is in effect (21 CFR 312.40). 1. NAME OF SPONSER 2. DATE OF SUBMISSION Takeda Pharmaceuticals North America, Inc. 11/1/02 3. ADDRESS (Number, Street, City, State and Zip Code) 4. TELEPHONE NUMBER (Include Area Code) 475 Half Day Road, Suite 500 847-383-3243 Lincolnshire, IL 60069 5. NAME(S) OF DRUG (Include all available names: Trade, Generic, Chemical, Code) 6. IND NUMBER (If previously assigned) ACTOS® (pioglitazone HCI) 33,729 7. INDICATION(S) (Covered by this submission) N/A 8. PHASE(S) OF CLINICAL INVESTIGATION TO BE CONDUCTED: PHASE 1 PHASE 2 PHASE 3 OTHER N/A (Specify) 9. LIST NUMBERS OF ALL INVESTIGATIONAL NEW DRUG APPLICATIONS (21 CFR Part 312), NEW DRUG OR ANTIBIOTIC APPLICATIONS (21 CFR Part 314), DRUG MASTER FILES (21 CFR Part 314.420), AND PRODUCT LICENSE APPLICATIONS (21 CFR Part 601) REFERRED TO IN THIS APPLICATION. N/A 10. IND submission should be consecutively numbered. The Initial IND should be numbered "Serial number: 000." The next submission (e.g., amendment, report, or correspondence) SERIAL NUMBER should be numbered "Serial Number: 001." Subsequent submissions should be numbered 4 9 7 consecutively in the order in which they are submitted. 11. THIS SUBMISSION CONTAINS THE FOLLOWING: (Check all that apply) INITIAL INVESTIGATIONAL NEW DRUG APPLICATION (IND) RESPONSE TO CLINICAL HOLD PROTOCOL AMENDMENT(S): INFORMATION AMENDMENT(S): IND SAFETY REPORT(S): NEW PROTOCOL CHEMISTRY/MICROBIOLOGY INITIAL WRITTEN REPORT CHANGE IN PROTOCOL PHARMACOLOGYITOXICOLOGY FOLLOW-UP TO A WRITTEN REPORT NEW INVESTIGATOR CLINICAL RESPONSE TO FDA REQUEST FOR INFORMATION ANNUAL REPORT GENERAL CORRESPONDENCE REQUEST FOR REINSTATEMENT OF IND THAT IS WITHDRAWN, OTHER INACTIVATED, TERMINATED OR DISCONTINUED (Spacify) CHECK ONLY IF APPLICABLE JUSTIFICATION STATEMENT MUST BE SUBMITTED WITH APPLICATION FOR ANY CHECKED BELOW. REFER TO THE CITED CFR SECTION FOR FURTHER INFORMATION. TREATMENT IND 21 CFR 312.35(b) TREATMENT PROTOCOL 21 CFR 312.35(a) CHARGE REQUEST/NOTIFICATION: 21 CFR312.7(d) FOR FDA USE ONLY CDR/DBIND/DGD RECEIPT STAMP DDR RECEIPT STAMP DIVISION ASSIGNMENT: IND NUMBER ASSIGNED: FORM FDA 1571 (9/02) PREVIOUS EDITION IS OBSOLETE. PAGE 1 OF 2 PSC Media Arts Braneh (301)443.1090 EF Confidential - Subject to Protective Order TAK-THOMCL-00015505 Produced in MDL on 09/14/12 Source: https://www.indu2292-00003s.ucsf.edu/docs/tyjf0226 12. CONTENTS OF APPLICATION ) This application contains the following items: (Check all that apply) 1. Form FDA 1571 [21 CFR 312.23(a)(1)] 2. Table of Contents [21 CFR 312.23(a)(2) 3. Introductory statement [21 CFR 312.23(a)(3)] 4. General Investigational plan [21 CFR 312.23(a)(3)] 5. Investigator's brochure [21 CFR 312.23(a)(5)] 6. Protocol(s) [21 CFR 312.23(a)(6)] a. Study protocol(s) [21 CFR 312.23(a)(6)] b. Investigator data [21 CFR 312.23(a)(6)(iii)(b)] or completed Form(s) FDA 1572 c. Facilities data [21 CFR 312.23(a)(6)(iii)(b)] or completed Form(s) FDA 1572 d. Institutional Review Board data [21 CFR 312.23(a)(6)(iii)(b)] or completed Form(s) FDA 1572 7. Chemistry, manufacturing, and control data [21 CFR 312.23(a)(7)] Environmental assessment or claim for exclusion [21 CFR 312.23(a)(7)(iv)(e)] 8. Pharmacology and toxicology data [21 CFR 312.23(a)(8)] 9. Previous human experience [21 CFR 312.23(a)(9)] 10. Additional information [21 CFR 312.23(a)(10)] 13. IS ANY PART OF THE CLINICAL STUDY TO BE CONDUCTED BY A CONTRACT RESEARCH ORGANIZATION? YES NO IF YES, WILL ANY SPONSOR OBLIGATIONS BE TRANSFERRED TO THE CONTRACT RESEARCH ORGANIZATION? YES NO IF YES, ATTACH A STATEMENT CONTAINING THE NAME AND ADDRESS OF THE CONTRACT RESEARCH ORGANIZATION, IDENTIFICATION OF THE CLINICAL STUDY, AND A LISTING OF THE OBLIGATIONS TRANSFERRED. 14. NAME AND TITLE OF THE PERSON RESPONSIBLE FOR MONITORING THE CONDUCT AND PROGRESS OF THE CLINICAL INVESTIGATIONS N/A 15. NAME(S) AND TITLE(S) OF THE PERSON(S) RESPONSIBLE FOR REVIEW AND EVALUATION OF INFORMATION RELEVANT TO THE SAFETY OF THE DRUG N/A I agree not to begin clinical Investigations until 30 days after FDA's receipt of the IND unless I receive earlier notification by FDA that the studies may begin. I also agree not to begin or continue clinical Investigations covered by the IND if those studies are placed on clinical hold. I agree that an Institutional Review Board (IRB) that complies with the requirements set fourth in 21 CFR Part 56 will be responsible for Initial and continuing review and approval of each of the studies in the proposed clinical Investigation. I agree to conduct the Investigation in accordance with all other applicable regulatory requirements. 16. NAME OF SPONSOR OR SPONSOR'S AUTHORIZED 17. SIGNATURE OF SPONSOR OR SPONSOR'S AUTHORIZED REPRESENTATIVE REPRESENTATIVE Janet L. Haskins 18, ADDRESS (Number, Street, City, State and Zip Code) 19. TELEPHONE NUMBER (Include Area Code) 20. DATE 475 Half Day Road, Suite 500 847-383-3243 11/1/02 Lincolnshire, IL 60069 (WARNING: A willfully false statement is a criminal offense, U.S.C. Title 18, Sec. 1001.) Public reporting burden for this collection of information is estimated to average 100 hours per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data neaded, and completing reviewing the collection of Information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to: Food and Drug. Administration Food and Drug Administration "An agency may not conduct or sponsor, and a CBER (HFM-99) CDER (HFD-94) person is not required to respond to, a 1401 Rockville Pike 12229 Wilkins Avenue collection of information unless It displays a Rockville, MD 20852-1448 Rockville, MD 20852 currently valid OMB control number.' Please DO NOT RETURN this application to this address. FORM FDA 1571 (9/02) PREVIOUS EDITION IS OBSOLETE. PAGE 2 OF 2 PSC Modia Arts Branch (301) 443-1090 EF Confidential - Subject to Protective Order TAK-THOMCL-00015506 Produced in MDL on 09/14/12 Source: https://www.indup229/2-00004ts.ucsf.edu/docs/tyjf0226

what is the Name(s) of drug (include all available names: Trade , Generic, Chemical, Code)?

tyjf0226

tyjf0226_p0, tyjf0226_p1, tyjf0226_p2, tyjf0226_p3

ACTOS (Pioglitazone HCI), ACTOS (pioglitazone HCI)

Takeda TAKEDA PHARMACEUTICALS NORTH AMERICA, INC. 5 November 1, 2002 David Orloff, M.D. Division of Metabolic & Endocrine Drug Product (HFD-510) Office of Drug Evaluation II Center for Drug Evaluation & Research Document Control Room 14B-19 Food and Drug Administration 5600 Fishers Lane Rockville, MD 20857 ACTOS® (pioglitazone HCI) Tablets, 15, 30 and 45 mg Serial No. 497 Response to FDA Request for Information Dear Dr. Orloff: Reference is made to teleconferences held between the Division and Takeda Pharmaceuticals North America, Inc. (TPNA) on July 31, 2002 and August 13, 2002 and the submission dated August 28, 2002 (Serial No. 485) to the above noted IND. The purpose of this submission is to provide the Division with additional information that may have some bearing on the manner in which the pediatric written request for ACTOS is being considered. The initial response to the matters discussed at the July 31st teleconference, submitted to the Division on August 28th, was intended to initiate dialog between TPNA and the Division. In the interim, TPNA has been in numerous consultations with nonclinical and clinical experts to gather the most comprehensive and up-to-date viewpoints in order to address this complex issue. We recognize that TPNA's initial response has not addressed the Division's concerns. Since there has been no opportunity for further discussion with the Division subsequent to the August 28th response, we propose that formal action on the written request not be taken at this time. In the August 28" response, TPNA committed not to proceed with the pediatric study governed by the written request. Additionally, as we discussed this morning, the Pediatric home page carries a comprehensive list of products that have received a pediatric written request. ACTOS is currently on this list. Since this list is updated regularly, TPNA assumes that products are removed from the list to reflect any change in status to the written request. It is also our understanding that persons interested in the pharmaceutical industry review-this list on a regular basis. Questions will obviously arise if ACTOS is deleted. This very public disclosure will generate speculation on the nature of the removal, which could unfavorably reflect on the safety profile of ACTOS. 475 Half Day Road, Suite 500 Lincolnshire, Illinois 60069 Phone: 847-383-3000 Confidential - Subject to Protective Order TAK-THOMCL-00015503 Produced in MDL on 09/14/12 Source: Takeda TAKEDA PHARMACEUTICALS NORTHAMERICA,INC We understand that until we reach resolution of our ongoing discussion regarding the rat bladder findings, the Division is concerned about the use of ACTOS in pediatric patients. Therefore, we reconfirm our commitment to suspend pediatric studies. Should these discussions not assuage the Agency's concerns, the written request can be rescinded at a later date. We also reconfirm our commitment to resolving our differences with respect to the interpretation of the rat bladder findings. We look forward to discussing these issues, preferably in a face-to-face meeting, at your earliest convenience. Sincerely, Josech Janet L. Haskins Manager, Regulatory Affairs Takeda Pharmaceuticals North America, Inc. 847-383-3243 (Telephone) 847-383-3427 (Fax) 475 Half Day Road, Suite 500 Lincolnshire, Illinols 60069 Phone: 847-383-3000 Confidential - Subject to Protective Order TAK-THOMCL-00015504 Produced in MDL on 09/14/12 Source: https://www.indup292-00002 ts.ucsf.edu/docs/tyjf0226 :. DEPARTMENT OF HEALTH AND HUMAN SERVICES Form Approved: OMB No. 0910-0014. PUBLIC HEALTH SERVICE Expiration Date: November 30, 2002 See OMB Statement on Reverse, FOOD AND DRUG ADMINISTRATION INVESTIGATIONAL NEW DRUG APPLICATION (IND) NOTE: No drug may be shipped or clinical investigation begun until an IND for that (TITLE 21, CODE OF FEDERAL REGULATIONS (CFR) PART 312) investigation is in effect (21 CFR 312.40). 1. NAME OF SPONSER 2. DATE OF SUBMISSION Takeda Pharmaceuticals North America, Inc. 11/1/02 3. ADDRESS (Number, Street, City, State and Zip Code) 4. TELEPHONE NUMBER (Include Area Code) 475 Half Day Road, Suite 500 847-383-3243 Lincolnshire, IL 60069 5. NAME(S) OF DRUG (Include all available names: Trade, Generic, Chemical, Code) 6. IND NUMBER (If previously assigned) ACTOS® (pioglitazone HCI) 33,729 7. INDICATION(S) (Covered by this submission) N/A 8. PHASE(S) OF CLINICAL INVESTIGATION TO BE CONDUCTED: PHASE 1 PHASE 2 PHASE 3 OTHER N/A (Specify) 9. LIST NUMBERS OF ALL INVESTIGATIONAL NEW DRUG APPLICATIONS (21 CFR Part 312), NEW DRUG OR ANTIBIOTIC APPLICATIONS (21 CFR Part 314), DRUG MASTER FILES (21 CFR Part 314.420), AND PRODUCT LICENSE APPLICATIONS (21 CFR Part 601) REFERRED TO IN THIS APPLICATION. N/A 10. IND submission should be consecutively numbered. The Initial IND should be numbered "Serial number: 000." The next submission (e.g., amendment, report, or correspondence) SERIAL NUMBER should be numbered "Serial Number: 001." Subsequent submissions should be numbered 4 9 7 consecutively in the order in which they are submitted. 11. THIS SUBMISSION CONTAINS THE FOLLOWING: (Check all that apply) INITIAL INVESTIGATIONAL NEW DRUG APPLICATION (IND) RESPONSE TO CLINICAL HOLD PROTOCOL AMENDMENT(S): INFORMATION AMENDMENT(S): IND SAFETY REPORT(S): NEW PROTOCOL CHEMISTRY/MICROBIOLOGY INITIAL WRITTEN REPORT CHANGE IN PROTOCOL PHARMACOLOGYITOXICOLOGY FOLLOW-UP TO A WRITTEN REPORT NEW INVESTIGATOR CLINICAL RESPONSE TO FDA REQUEST FOR INFORMATION ANNUAL REPORT GENERAL CORRESPONDENCE REQUEST FOR REINSTATEMENT OF IND THAT IS WITHDRAWN, OTHER INACTIVATED, TERMINATED OR DISCONTINUED (Spacify) CHECK ONLY IF APPLICABLE JUSTIFICATION STATEMENT MUST BE SUBMITTED WITH APPLICATION FOR ANY CHECKED BELOW. REFER TO THE CITED CFR SECTION FOR FURTHER INFORMATION. TREATMENT IND 21 CFR 312.35(b) TREATMENT PROTOCOL 21 CFR 312.35(a) CHARGE REQUEST/NOTIFICATION: 21 CFR312.7(d) FOR FDA USE ONLY CDR/DBIND/DGD RECEIPT STAMP DDR RECEIPT STAMP DIVISION ASSIGNMENT: IND NUMBER ASSIGNED: FORM FDA 1571 (9/02) PREVIOUS EDITION IS OBSOLETE. PAGE 1 OF 2 PSC Media Arts Braneh (301)443.1090 EF Confidential - Subject to Protective Order TAK-THOMCL-00015505 Produced in MDL on 09/14/12 Source: https://www.indu2292-00003s.ucsf.edu/docs/tyjf0226 12. CONTENTS OF APPLICATION ) This application contains the following items: (Check all that apply) 1. Form FDA 1571 [21 CFR 312.23(a)(1)] 2. Table of Contents [21 CFR 312.23(a)(2) 3. Introductory statement [21 CFR 312.23(a)(3)] 4. General Investigational plan [21 CFR 312.23(a)(3)] 5. Investigator's brochure [21 CFR 312.23(a)(5)] 6. Protocol(s) [21 CFR 312.23(a)(6)] a. Study protocol(s) [21 CFR 312.23(a)(6)] b. Investigator data [21 CFR 312.23(a)(6)(iii)(b)] or completed Form(s) FDA 1572 c. Facilities data [21 CFR 312.23(a)(6)(iii)(b)] or completed Form(s) FDA 1572 d. Institutional Review Board data [21 CFR 312.23(a)(6)(iii)(b)] or completed Form(s) FDA 1572 7. Chemistry, manufacturing, and control data [21 CFR 312.23(a)(7)] Environmental assessment or claim for exclusion [21 CFR 312.23(a)(7)(iv)(e)] 8. Pharmacology and toxicology data [21 CFR 312.23(a)(8)] 9. Previous human experience [21 CFR 312.23(a)(9)] 10. Additional information [21 CFR 312.23(a)(10)] 13. IS ANY PART OF THE CLINICAL STUDY TO BE CONDUCTED BY A CONTRACT RESEARCH ORGANIZATION? YES NO IF YES, WILL ANY SPONSOR OBLIGATIONS BE TRANSFERRED TO THE CONTRACT RESEARCH ORGANIZATION? YES NO IF YES, ATTACH A STATEMENT CONTAINING THE NAME AND ADDRESS OF THE CONTRACT RESEARCH ORGANIZATION, IDENTIFICATION OF THE CLINICAL STUDY, AND A LISTING OF THE OBLIGATIONS TRANSFERRED. 14. NAME AND TITLE OF THE PERSON RESPONSIBLE FOR MONITORING THE CONDUCT AND PROGRESS OF THE CLINICAL INVESTIGATIONS N/A 15. NAME(S) AND TITLE(S) OF THE PERSON(S) RESPONSIBLE FOR REVIEW AND EVALUATION OF INFORMATION RELEVANT TO THE SAFETY OF THE DRUG N/A I agree not to begin clinical Investigations until 30 days after FDA's receipt of the IND unless I receive earlier notification by FDA that the studies may begin. I also agree not to begin or continue clinical Investigations covered by the IND if those studies are placed on clinical hold. I agree that an Institutional Review Board (IRB) that complies with the requirements set fourth in 21 CFR Part 56 will be responsible for Initial and continuing review and approval of each of the studies in the proposed clinical Investigation. I agree to conduct the Investigation in accordance with all other applicable regulatory requirements. 16. NAME OF SPONSOR OR SPONSOR'S AUTHORIZED 17. SIGNATURE OF SPONSOR OR SPONSOR'S AUTHORIZED REPRESENTATIVE REPRESENTATIVE Janet L. Haskins 18, ADDRESS (Number, Street, City, State and Zip Code) 19. TELEPHONE NUMBER (Include Area Code) 20. DATE 475 Half Day Road, Suite 500 847-383-3243 11/1/02 Lincolnshire, IL 60069 (WARNING: A willfully false statement is a criminal offense, U.S.C. Title 18, Sec. 1001.) Public reporting burden for this collection of information is estimated to average 100 hours per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data neaded, and completing reviewing the collection of Information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to: Food and Drug. Administration Food and Drug Administration "An agency may not conduct or sponsor, and a CBER (HFM-99) CDER (HFD-94) person is not required to respond to, a 1401 Rockville Pike 12229 Wilkins Avenue collection of information unless It displays a Rockville, MD 20852-1448 Rockville, MD 20852 currently valid OMB control number.' Please DO NOT RETURN this application to this address. FORM FDA 1571 (9/02) PREVIOUS EDITION IS OBSOLETE. PAGE 2 OF 2 PSC Modia Arts Branch (301) 443-1090 EF Confidential - Subject to Protective Order TAK-THOMCL-00015506 Produced in MDL on 09/14/12 Source: https://www.indup229/2-00004ts.ucsf.edu/docs/tyjf0226

what is the form approved : OMB No

tyjf0226

tyjf0226_p0, tyjf0226_p1, tyjf0226_p2, tyjf0226_p3

0910-0014, 0910-0014.

Takeda TAKEDA PHARMACEUTICALS NORTH AMERICA, INC. 5 November 1, 2002 David Orloff, M.D. Division of Metabolic & Endocrine Drug Product (HFD-510) Office of Drug Evaluation II Center for Drug Evaluation & Research Document Control Room 14B-19 Food and Drug Administration 5600 Fishers Lane Rockville, MD 20857 ACTOS® (pioglitazone HCI) Tablets, 15, 30 and 45 mg Serial No. 497 Response to FDA Request for Information Dear Dr. Orloff: Reference is made to teleconferences held between the Division and Takeda Pharmaceuticals North America, Inc. (TPNA) on July 31, 2002 and August 13, 2002 and the submission dated August 28, 2002 (Serial No. 485) to the above noted IND. The purpose of this submission is to provide the Division with additional information that may have some bearing on the manner in which the pediatric written request for ACTOS is being considered. The initial response to the matters discussed at the July 31st teleconference, submitted to the Division on August 28th, was intended to initiate dialog between TPNA and the Division. In the interim, TPNA has been in numerous consultations with nonclinical and clinical experts to gather the most comprehensive and up-to-date viewpoints in order to address this complex issue. We recognize that TPNA's initial response has not addressed the Division's concerns. Since there has been no opportunity for further discussion with the Division subsequent to the August 28th response, we propose that formal action on the written request not be taken at this time. In the August 28" response, TPNA committed not to proceed with the pediatric study governed by the written request. Additionally, as we discussed this morning, the Pediatric home page carries a comprehensive list of products that have received a pediatric written request. ACTOS is currently on this list. Since this list is updated regularly, TPNA assumes that products are removed from the list to reflect any change in status to the written request. It is also our understanding that persons interested in the pharmaceutical industry review-this list on a regular basis. Questions will obviously arise if ACTOS is deleted. This very public disclosure will generate speculation on the nature of the removal, which could unfavorably reflect on the safety profile of ACTOS. 475 Half Day Road, Suite 500 Lincolnshire, Illinois 60069 Phone: 847-383-3000 Confidential - Subject to Protective Order TAK-THOMCL-00015503 Produced in MDL on 09/14/12 Source: Takeda TAKEDA PHARMACEUTICALS NORTHAMERICA,INC We understand that until we reach resolution of our ongoing discussion regarding the rat bladder findings, the Division is concerned about the use of ACTOS in pediatric patients. Therefore, we reconfirm our commitment to suspend pediatric studies. Should these discussions not assuage the Agency's concerns, the written request can be rescinded at a later date. We also reconfirm our commitment to resolving our differences with respect to the interpretation of the rat bladder findings. We look forward to discussing these issues, preferably in a face-to-face meeting, at your earliest convenience. Sincerely, Josech Janet L. Haskins Manager, Regulatory Affairs Takeda Pharmaceuticals North America, Inc. 847-383-3243 (Telephone) 847-383-3427 (Fax) 475 Half Day Road, Suite 500 Lincolnshire, Illinols 60069 Phone: 847-383-3000 Confidential - Subject to Protective Order TAK-THOMCL-00015504 Produced in MDL on 09/14/12 Source: https://www.indup292-00002 ts.ucsf.edu/docs/tyjf0226 :. DEPARTMENT OF HEALTH AND HUMAN SERVICES Form Approved: OMB No. 0910-0014. PUBLIC HEALTH SERVICE Expiration Date: November 30, 2002 See OMB Statement on Reverse, FOOD AND DRUG ADMINISTRATION INVESTIGATIONAL NEW DRUG APPLICATION (IND) NOTE: No drug may be shipped or clinical investigation begun until an IND for that (TITLE 21, CODE OF FEDERAL REGULATIONS (CFR) PART 312) investigation is in effect (21 CFR 312.40). 1. NAME OF SPONSER 2. DATE OF SUBMISSION Takeda Pharmaceuticals North America, Inc. 11/1/02 3. ADDRESS (Number, Street, City, State and Zip Code) 4. TELEPHONE NUMBER (Include Area Code) 475 Half Day Road, Suite 500 847-383-3243 Lincolnshire, IL 60069 5. NAME(S) OF DRUG (Include all available names: Trade, Generic, Chemical, Code) 6. IND NUMBER (If previously assigned) ACTOS® (pioglitazone HCI) 33,729 7. INDICATION(S) (Covered by this submission) N/A 8. PHASE(S) OF CLINICAL INVESTIGATION TO BE CONDUCTED: PHASE 1 PHASE 2 PHASE 3 OTHER N/A (Specify) 9. LIST NUMBERS OF ALL INVESTIGATIONAL NEW DRUG APPLICATIONS (21 CFR Part 312), NEW DRUG OR ANTIBIOTIC APPLICATIONS (21 CFR Part 314), DRUG MASTER FILES (21 CFR Part 314.420), AND PRODUCT LICENSE APPLICATIONS (21 CFR Part 601) REFERRED TO IN THIS APPLICATION. N/A 10. IND submission should be consecutively numbered. The Initial IND should be numbered "Serial number: 000." The next submission (e.g., amendment, report, or correspondence) SERIAL NUMBER should be numbered "Serial Number: 001." Subsequent submissions should be numbered 4 9 7 consecutively in the order in which they are submitted. 11. THIS SUBMISSION CONTAINS THE FOLLOWING: (Check all that apply) INITIAL INVESTIGATIONAL NEW DRUG APPLICATION (IND) RESPONSE TO CLINICAL HOLD PROTOCOL AMENDMENT(S): INFORMATION AMENDMENT(S): IND SAFETY REPORT(S): NEW PROTOCOL CHEMISTRY/MICROBIOLOGY INITIAL WRITTEN REPORT CHANGE IN PROTOCOL PHARMACOLOGYITOXICOLOGY FOLLOW-UP TO A WRITTEN REPORT NEW INVESTIGATOR CLINICAL RESPONSE TO FDA REQUEST FOR INFORMATION ANNUAL REPORT GENERAL CORRESPONDENCE REQUEST FOR REINSTATEMENT OF IND THAT IS WITHDRAWN, OTHER INACTIVATED, TERMINATED OR DISCONTINUED (Spacify) CHECK ONLY IF APPLICABLE JUSTIFICATION STATEMENT MUST BE SUBMITTED WITH APPLICATION FOR ANY CHECKED BELOW. REFER TO THE CITED CFR SECTION FOR FURTHER INFORMATION. TREATMENT IND 21 CFR 312.35(b) TREATMENT PROTOCOL 21 CFR 312.35(a) CHARGE REQUEST/NOTIFICATION: 21 CFR312.7(d) FOR FDA USE ONLY CDR/DBIND/DGD RECEIPT STAMP DDR RECEIPT STAMP DIVISION ASSIGNMENT: IND NUMBER ASSIGNED: FORM FDA 1571 (9/02) PREVIOUS EDITION IS OBSOLETE. PAGE 1 OF 2 PSC Media Arts Braneh (301)443.1090 EF Confidential - Subject to Protective Order TAK-THOMCL-00015505 Produced in MDL on 09/14/12 Source: https://www.indu2292-00003s.ucsf.edu/docs/tyjf0226 12. CONTENTS OF APPLICATION ) This application contains the following items: (Check all that apply) 1. Form FDA 1571 [21 CFR 312.23(a)(1)] 2. Table of Contents [21 CFR 312.23(a)(2) 3. Introductory statement [21 CFR 312.23(a)(3)] 4. General Investigational plan [21 CFR 312.23(a)(3)] 5. Investigator's brochure [21 CFR 312.23(a)(5)] 6. Protocol(s) [21 CFR 312.23(a)(6)] a. Study protocol(s) [21 CFR 312.23(a)(6)] b. Investigator data [21 CFR 312.23(a)(6)(iii)(b)] or completed Form(s) FDA 1572 c. Facilities data [21 CFR 312.23(a)(6)(iii)(b)] or completed Form(s) FDA 1572 d. Institutional Review Board data [21 CFR 312.23(a)(6)(iii)(b)] or completed Form(s) FDA 1572 7. Chemistry, manufacturing, and control data [21 CFR 312.23(a)(7)] Environmental assessment or claim for exclusion [21 CFR 312.23(a)(7)(iv)(e)] 8. Pharmacology and toxicology data [21 CFR 312.23(a)(8)] 9. Previous human experience [21 CFR 312.23(a)(9)] 10. Additional information [21 CFR 312.23(a)(10)] 13. IS ANY PART OF THE CLINICAL STUDY TO BE CONDUCTED BY A CONTRACT RESEARCH ORGANIZATION? YES NO IF YES, WILL ANY SPONSOR OBLIGATIONS BE TRANSFERRED TO THE CONTRACT RESEARCH ORGANIZATION? YES NO IF YES, ATTACH A STATEMENT CONTAINING THE NAME AND ADDRESS OF THE CONTRACT RESEARCH ORGANIZATION, IDENTIFICATION OF THE CLINICAL STUDY, AND A LISTING OF THE OBLIGATIONS TRANSFERRED. 14. NAME AND TITLE OF THE PERSON RESPONSIBLE FOR MONITORING THE CONDUCT AND PROGRESS OF THE CLINICAL INVESTIGATIONS N/A 15. NAME(S) AND TITLE(S) OF THE PERSON(S) RESPONSIBLE FOR REVIEW AND EVALUATION OF INFORMATION RELEVANT TO THE SAFETY OF THE DRUG N/A I agree not to begin clinical Investigations until 30 days after FDA's receipt of the IND unless I receive earlier notification by FDA that the studies may begin. I also agree not to begin or continue clinical Investigations covered by the IND if those studies are placed on clinical hold. I agree that an Institutional Review Board (IRB) that complies with the requirements set fourth in 21 CFR Part 56 will be responsible for Initial and continuing review and approval of each of the studies in the proposed clinical Investigation. I agree to conduct the Investigation in accordance with all other applicable regulatory requirements. 16. NAME OF SPONSOR OR SPONSOR'S AUTHORIZED 17. SIGNATURE OF SPONSOR OR SPONSOR'S AUTHORIZED REPRESENTATIVE REPRESENTATIVE Janet L. Haskins 18, ADDRESS (Number, Street, City, State and Zip Code) 19. TELEPHONE NUMBER (Include Area Code) 20. DATE 475 Half Day Road, Suite 500 847-383-3243 11/1/02 Lincolnshire, IL 60069 (WARNING: A willfully false statement is a criminal offense, U.S.C. Title 18, Sec. 1001.) Public reporting burden for this collection of information is estimated to average 100 hours per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data neaded, and completing reviewing the collection of Information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to: Food and Drug. Administration Food and Drug Administration "An agency may not conduct or sponsor, and a CBER (HFM-99) CDER (HFD-94) person is not required to respond to, a 1401 Rockville Pike 12229 Wilkins Avenue collection of information unless It displays a Rockville, MD 20852-1448 Rockville, MD 20852 currently valid OMB control number.' Please DO NOT RETURN this application to this address. FORM FDA 1571 (9/02) PREVIOUS EDITION IS OBSOLETE. PAGE 2 OF 2 PSC Modia Arts Branch (301) 443-1090 EF Confidential - Subject to Protective Order TAK-THOMCL-00015506 Produced in MDL on 09/14/12 Source: https://www.indup229/2-00004ts.ucsf.edu/docs/tyjf0226

What is the word written in bold on the top of the document?

psjf0226

psjf0226_p0

Takeda

a Takeda 19th January 2012 Direct Healthcare Professional Communication on pioglitazone and a small increased risk of Urinary Bladder Cancer. Dear Healthcare Professional, Summary Following the letter that vas-sent to you in July 2011, this communication is to inform you of the confirmed updated Summary of Product Characteristics (SmPC) wording for pioglitazone containing products* as well as the provision of a Prescriber's Guide. Since the letter sent in July 2011, the European Medicines Agency has amended the wording of Section 4.1 of the SmPC to emphasize that pioglitazone should not be used first line In addition, Section 1 of the Patient Information Leaflet has been updated to state pioglitazone should be used when metformin is not suitable or has failed to work adequately and additional heart failure, oedema, bone fracture and blurred vision wording has been added to Section 4 of the Patient Information Leaflet. Takeda Pharmaceuticals Europe Ltd. informed you of safety data concerning pioglitazone containing products* New epidemiological data and a meta-analysis of randomized clinical trials became available which indicated a small increased risk of urinary bladder cancer with pioglitazone-containing products* Other known risk factors for bladder cancer are: age, smoking history, exposure to some occupational or chemotherapy agents e.g. cyclophosphamide or prior radiation treatment in the pelvic region. Annex A lists the revisions to the product information; full product information is available at https://www.takeda.coauk/healtheare-professionals/CHMPaspx and will be available on the electronic Medicines Compendium (eMC) website www.medicines.org uk from 21st January 2012. Use of pioglitazone is now contraindicated in patients with: - current active bladder cancer or - a history of bladder cancer or uninvestigated macroscopic haematuria, Risk factors for bladder cancer should be assessed before initiating pioglitazone treatment Any unexplained macroscopic haematuria should be investigated before starting pioglitazone therapy Patients should be advised to promptly seek the attention of their physician if macroscopic haematuria or other symptoms such as dysuria or urinary urgency develop during treatment. In light of age-related risks (especially bladder cancer, fractures and heart failure), the balance of benefits and risks should be considered carefully before initiating treatment in the elderly. Takeda UK Lid. EXHIBIT Takeda House, Mereury Park, Wecombelane, Woobuta Green, 53 High Wycombe HP10 OHH teats thes, Pit No. Confidential - Subject to Protective Order TAK-TYNANJ-00213198 Source: https://www.indup5.449000007 ts. .ucsf.edu/docs/psjf0226

What is the date mentioned?

psjf0226

psjf0226_p0

19th January 2012

a Takeda 19th January 2012 Direct Healthcare Professional Communication on pioglitazone and a small increased risk of Urinary Bladder Cancer. Dear Healthcare Professional, Summary Following the letter that vas-sent to you in July 2011, this communication is to inform you of the confirmed updated Summary of Product Characteristics (SmPC) wording for pioglitazone containing products* as well as the provision of a Prescriber's Guide. Since the letter sent in July 2011, the European Medicines Agency has amended the wording of Section 4.1 of the SmPC to emphasize that pioglitazone should not be used first line In addition, Section 1 of the Patient Information Leaflet has been updated to state pioglitazone should be used when metformin is not suitable or has failed to work adequately and additional heart failure, oedema, bone fracture and blurred vision wording has been added to Section 4 of the Patient Information Leaflet. Takeda Pharmaceuticals Europe Ltd. informed you of safety data concerning pioglitazone containing products* New epidemiological data and a meta-analysis of randomized clinical trials became available which indicated a small increased risk of urinary bladder cancer with pioglitazone-containing products* Other known risk factors for bladder cancer are: age, smoking history, exposure to some occupational or chemotherapy agents e.g. cyclophosphamide or prior radiation treatment in the pelvic region. Annex A lists the revisions to the product information; full product information is available at https://www.takeda.coauk/healtheare-professionals/CHMPaspx and will be available on the electronic Medicines Compendium (eMC) website www.medicines.org uk from 21st January 2012. Use of pioglitazone is now contraindicated in patients with: - current active bladder cancer or - a history of bladder cancer or uninvestigated macroscopic haematuria, Risk factors for bladder cancer should be assessed before initiating pioglitazone treatment Any unexplained macroscopic haematuria should be investigated before starting pioglitazone therapy Patients should be advised to promptly seek the attention of their physician if macroscopic haematuria or other symptoms such as dysuria or urinary urgency develop during treatment. In light of age-related risks (especially bladder cancer, fractures and heart failure), the balance of benefits and risks should be considered carefully before initiating treatment in the elderly. Takeda UK Lid. EXHIBIT Takeda House, Mereury Park, Wecombelane, Woobuta Green, 53 High Wycombe HP10 OHH teats thes, Pit No. Confidential - Subject to Protective Order TAK-TYNANJ-00213198 Source: https://www.indup5.449000007 ts. .ucsf.edu/docs/psjf0226

what is the name of pharmaceuticals ?

xyjf0226

xyjf0226_p0, xyjf0226_p1, xyjf0226_p2

Takeda Pharmaceuticals North America, Inc., TAkeda pharmaceuticals North America ,INc.

DEPARTMENT OF HEALTH & HUMAN SERVICES Public Hesith Service Food and Drug Administration Rockville, MD 20857 IND 33,729 RECEIVED REGULATORY AFFAIRS DEPARTMENT Takeda Pharmaceuticals North America, Inc. JUN 1 6 2003 Attention: Janet L. Haskins Manager, Regulatory Affairs Takeda Pharmaceuticals Norto America, lac 475 Half Day Road, Suite 500 Lincolnsbire, IL 60069 Dear Ms. Haskins: Please refer to your Investigational New Drug Application (IND) submitted January 15, 1999, under section 505(i) of the Federal Food, Drug, and Cosmetic Act for Actos (pioglitazone HCI) Tablets, 15 mg, 30 mg and 45 mg. We also refer to your amendment dated May 8, 2003 (serial # 525), received on May 9, 2003, that provided a response to our November 13, 2002, letter which cited the reasons this protocol was placed on clinical hold and the information needed to resolve the clinical hold issues. We have completed the review of your submission and have concluded that removal of the clinical hold is not warranted. We acknowledge your agreement to monitor for bladder tumors in your clinical studies, and to amend the label and consent documents. However, until further information on bladder effects from ongoing studies is available, we do not believe studies in pediatric patients are warranted. Until you have submitted the required information and we notify you that you may initiate trials, this IND remains on clinical hold and you may not legally conduct clinical studies under it. Please identify your response to the clinical hold issues as a "CLINICAL HOLD COMPLETE RESPONSE." To facilitate a response to your submission, submit this information in triplicate to the IND. In addition, send a copy of the cover letter to Ms. Jena Weber. Following receipt of your complete response to these issues, we will notify you of our decision within 30 days. 424 Confidential - Subject to Protective Order TAK-INDNDA-01577085 Produced in MDL on 01/31/13 Source: https://www.indup739c0000ts.ucsf.edu/docs/xyjf0226 IND 33,729 Page 2 Correspondence to this IND can be sent to the following address: U.S. Postal Service/ Courier/Overnight Mail: Food and Drug Administration Center for Drug Evaluation and Research Division of Metabolic and Endocrine Drug Products, HFD-510 Attention: Division Document Room, 8B-45 5600 Fishers Lane Rockville, Maryland 20857 You may, at any time, appeal the clinical hold decision to the Director, Office of Drug Evaluation ODE II. However, note that our procedures specify that review by the Office Director is automatic for continuance of a clinical hold. If you have any questions, please call Ms. Jena Weber, Regulatory Project Manager, at 301-827-6422. Sincerely, (See appended electronic signature page) David G. Orloff, M.D. Director Division of Metabolic and Endocrine Drug Products Office of Drug Evaluation II Center for Drug Evaluation and Research 425 Confidential - Subject to Protective Order TAK-INDNDA-01577086 Produced in MDL on 01/31/13 Source: https://www.indup,739.00002.ucsf.edu/docs/xyjf0226 This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. 1s/ David Orloff 6/13/03 11:53:49 AM 426 Confidential - Subject to Protective Order TAK-INDNDA-01577087 Produced in MDL on 01/31/13 Source: https://www.indup739-00003ts.ucsf.edu/docs/xyjf0226

to whom this letter is written ?

xyjf0226

xyjf0226_p0, xyjf0226_p1, xyjf0226_p2

Ms. Haskins, janet L. haskins, Janet L. Haskins

DEPARTMENT OF HEALTH & HUMAN SERVICES Public Hesith Service Food and Drug Administration Rockville, MD 20857 IND 33,729 RECEIVED REGULATORY AFFAIRS DEPARTMENT Takeda Pharmaceuticals North America, Inc. JUN 1 6 2003 Attention: Janet L. Haskins Manager, Regulatory Affairs Takeda Pharmaceuticals Norto America, lac 475 Half Day Road, Suite 500 Lincolnsbire, IL 60069 Dear Ms. Haskins: Please refer to your Investigational New Drug Application (IND) submitted January 15, 1999, under section 505(i) of the Federal Food, Drug, and Cosmetic Act for Actos (pioglitazone HCI) Tablets, 15 mg, 30 mg and 45 mg. We also refer to your amendment dated May 8, 2003 (serial # 525), received on May 9, 2003, that provided a response to our November 13, 2002, letter which cited the reasons this protocol was placed on clinical hold and the information needed to resolve the clinical hold issues. We have completed the review of your submission and have concluded that removal of the clinical hold is not warranted. We acknowledge your agreement to monitor for bladder tumors in your clinical studies, and to amend the label and consent documents. However, until further information on bladder effects from ongoing studies is available, we do not believe studies in pediatric patients are warranted. Until you have submitted the required information and we notify you that you may initiate trials, this IND remains on clinical hold and you may not legally conduct clinical studies under it. Please identify your response to the clinical hold issues as a "CLINICAL HOLD COMPLETE RESPONSE." To facilitate a response to your submission, submit this information in triplicate to the IND. In addition, send a copy of the cover letter to Ms. Jena Weber. Following receipt of your complete response to these issues, we will notify you of our decision within 30 days. 424 Confidential - Subject to Protective Order TAK-INDNDA-01577085 Produced in MDL on 01/31/13 Source: https://www.indup739c0000ts.ucsf.edu/docs/xyjf0226 IND 33,729 Page 2 Correspondence to this IND can be sent to the following address: U.S. Postal Service/ Courier/Overnight Mail: Food and Drug Administration Center for Drug Evaluation and Research Division of Metabolic and Endocrine Drug Products, HFD-510 Attention: Division Document Room, 8B-45 5600 Fishers Lane Rockville, Maryland 20857 You may, at any time, appeal the clinical hold decision to the Director, Office of Drug Evaluation ODE II. However, note that our procedures specify that review by the Office Director is automatic for continuance of a clinical hold. If you have any questions, please call Ms. Jena Weber, Regulatory Project Manager, at 301-827-6422. Sincerely, (See appended electronic signature page) David G. Orloff, M.D. Director Division of Metabolic and Endocrine Drug Products Office of Drug Evaluation II Center for Drug Evaluation and Research 425 Confidential - Subject to Protective Order TAK-INDNDA-01577086 Produced in MDL on 01/31/13 Source: https://www.indup,739.00002.ucsf.edu/docs/xyjf0226 This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. 1s/ David Orloff 6/13/03 11:53:49 AM 426 Confidential - Subject to Protective Order TAK-INDNDA-01577087 Produced in MDL on 01/31/13 Source: https://www.indup739-00003ts.ucsf.edu/docs/xyjf0226

When did Regulatory affairs department receive this letter?

xyjf0226

xyjf0226_p0, xyjf0226_p1, xyjf0226_p2

JUN 16 2003

DEPARTMENT OF HEALTH & HUMAN SERVICES Public Hesith Service Food and Drug Administration Rockville, MD 20857 IND 33,729 RECEIVED REGULATORY AFFAIRS DEPARTMENT Takeda Pharmaceuticals North America, Inc. JUN 1 6 2003 Attention: Janet L. Haskins Manager, Regulatory Affairs Takeda Pharmaceuticals Norto America, lac 475 Half Day Road, Suite 500 Lincolnsbire, IL 60069 Dear Ms. Haskins: Please refer to your Investigational New Drug Application (IND) submitted January 15, 1999, under section 505(i) of the Federal Food, Drug, and Cosmetic Act for Actos (pioglitazone HCI) Tablets, 15 mg, 30 mg and 45 mg. We also refer to your amendment dated May 8, 2003 (serial # 525), received on May 9, 2003, that provided a response to our November 13, 2002, letter which cited the reasons this protocol was placed on clinical hold and the information needed to resolve the clinical hold issues. We have completed the review of your submission and have concluded that removal of the clinical hold is not warranted. We acknowledge your agreement to monitor for bladder tumors in your clinical studies, and to amend the label and consent documents. However, until further information on bladder effects from ongoing studies is available, we do not believe studies in pediatric patients are warranted. Until you have submitted the required information and we notify you that you may initiate trials, this IND remains on clinical hold and you may not legally conduct clinical studies under it. Please identify your response to the clinical hold issues as a "CLINICAL HOLD COMPLETE RESPONSE." To facilitate a response to your submission, submit this information in triplicate to the IND. In addition, send a copy of the cover letter to Ms. Jena Weber. Following receipt of your complete response to these issues, we will notify you of our decision within 30 days. 424 Confidential - Subject to Protective Order TAK-INDNDA-01577085 Produced in MDL on 01/31/13 Source: https://www.indup739c0000ts.ucsf.edu/docs/xyjf0226 IND 33,729 Page 2 Correspondence to this IND can be sent to the following address: U.S. Postal Service/ Courier/Overnight Mail: Food and Drug Administration Center for Drug Evaluation and Research Division of Metabolic and Endocrine Drug Products, HFD-510 Attention: Division Document Room, 8B-45 5600 Fishers Lane Rockville, Maryland 20857 You may, at any time, appeal the clinical hold decision to the Director, Office of Drug Evaluation ODE II. However, note that our procedures specify that review by the Office Director is automatic for continuance of a clinical hold. If you have any questions, please call Ms. Jena Weber, Regulatory Project Manager, at 301-827-6422. Sincerely, (See appended electronic signature page) David G. Orloff, M.D. Director Division of Metabolic and Endocrine Drug Products Office of Drug Evaluation II Center for Drug Evaluation and Research 425 Confidential - Subject to Protective Order TAK-INDNDA-01577086 Produced in MDL on 01/31/13 Source: https://www.indup,739.00002.ucsf.edu/docs/xyjf0226 This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. 1s/ David Orloff 6/13/03 11:53:49 AM 426 Confidential - Subject to Protective Order TAK-INDNDA-01577087 Produced in MDL on 01/31/13 Source: https://www.indup739-00003ts.ucsf.edu/docs/xyjf0226

To whom was this letter written?

psjf0226

psjf0226_p0

Healthcare Professional

a Takeda 19th January 2012 Direct Healthcare Professional Communication on pioglitazone and a small increased risk of Urinary Bladder Cancer. Dear Healthcare Professional, Summary Following the letter that vas-sent to you in July 2011, this communication is to inform you of the confirmed updated Summary of Product Characteristics (SmPC) wording for pioglitazone containing products* as well as the provision of a Prescriber's Guide. Since the letter sent in July 2011, the European Medicines Agency has amended the wording of Section 4.1 of the SmPC to emphasize that pioglitazone should not be used first line In addition, Section 1 of the Patient Information Leaflet has been updated to state pioglitazone should be used when metformin is not suitable or has failed to work adequately and additional heart failure, oedema, bone fracture and blurred vision wording has been added to Section 4 of the Patient Information Leaflet. Takeda Pharmaceuticals Europe Ltd. informed you of safety data concerning pioglitazone containing products* New epidemiological data and a meta-analysis of randomized clinical trials became available which indicated a small increased risk of urinary bladder cancer with pioglitazone-containing products* Other known risk factors for bladder cancer are: age, smoking history, exposure to some occupational or chemotherapy agents e.g. cyclophosphamide or prior radiation treatment in the pelvic region. Annex A lists the revisions to the product information; full product information is available at https://www.takeda.coauk/healtheare-professionals/CHMPaspx and will be available on the electronic Medicines Compendium (eMC) website www.medicines.org uk from 21st January 2012. Use of pioglitazone is now contraindicated in patients with: - current active bladder cancer or - a history of bladder cancer or uninvestigated macroscopic haematuria, Risk factors for bladder cancer should be assessed before initiating pioglitazone treatment Any unexplained macroscopic haematuria should be investigated before starting pioglitazone therapy Patients should be advised to promptly seek the attention of their physician if macroscopic haematuria or other symptoms such as dysuria or urinary urgency develop during treatment. In light of age-related risks (especially bladder cancer, fractures and heart failure), the balance of benefits and risks should be considered carefully before initiating treatment in the elderly. Takeda UK Lid. EXHIBIT Takeda House, Mereury Park, Wecombelane, Woobuta Green, 53 High Wycombe HP10 OHH teats thes, Pit No. Confidential - Subject to Protective Order TAK-TYNANJ-00213198 Source: https://www.indup5.449000007 ts. .ucsf.edu/docs/psjf0226

What is the fifth point?

frjf0226

frjf0226_p0, frjf0226_p1, frjf0226_p2, frjf0226_p3, frjf0226_p4, frjf0226_p5

WAC AND AWP generally;, WAC and AWP generally;

EXHIBIT 47 (1) LEGAL HOLD RELATED TO ACTOS PRODUCTS LIABILITY CLAIMS: PLEASE READ THIS MESSAGE CAREFULLY Takeda continues to be involved in a small number of claims or lawsuits ("claims") relating to ACTOS (pioglitazone HCI). As a result of these claims, all documents, materials, information and things that exist or continue to be developed pertaining to ACTOS® have been and continue to be subject to a Legal Hold. Additionally, all documents and materials that exist or continue to be developed pertaining to Combination medicines involving ACTOS®, whether a marketed or development medicine, also continue to be subject to a Legal Hold. 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, materials, and computer files (including e-mails, 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. 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 sheuld 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, Last printed 11/30/2012 4:28:00 AM 20122830-042845 doc Confidential - Subject to Protective Order TAK-RIM30b6-00000663 Source: 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. (2) LEGAL HOLD RELATED TO PHARMACEUTICAL AVERAGE WHOLESALE PRICING LITIGATION: PLEASE READ THIS MESSAGE CAREFULLY Takeda Pharmaceuticals North America, Inc. ("TPNA"), along with numerous other pharmaceutical companies, continues to be named as a defendant in AWP lawsuits filed by state and local governmental entities. These lawsuits involve issues related to product pricing, price reporting and marketing. Although several of these lawsuits have been filed around the country, TPNA currently is involved only in small number of these cases. In these cases, plaintiffs generally have alleged that pharmaceutical companies failed to report accurate prices for their products, including Average Wholesale Price ("AWP") and Wholesale Acquisition Cost ("WAC"). These alleged failures purportedly caused state or local governmental agencies to overpay pharmacies and other providers when reimbursing them for prescription drugs dispensed to Medicaid patients. Plaintiffs seek recovery under various legal theories. All documents and data that relate to the saie, marketing, or distribution of TPNA pharmaceutical products may be relevant in these cases and must continue to be maintained until you are informed otherwise. By way of example, documents and data that relate to the following subjects may be relevant in these cases; 1. Transactional data regarding sales and distribution of TPNA products to individual customers, including transactional data regarding discounts, chargebacks, and rebates; 2. Contracts with third parties that purchase, distribute, receive or provide reimbursement for TPNA pharmaceutical products, including wholesalers, HMOs, GPOs, and PBMs; Last printed 11/30/2012 4:28:00 AM 20122830-042845 doc Confidential - Subject to Protective Order TAK-RIM30b6-00000664 Source: https://www.indup5316-.00002ts.ucsf.edu/docs/frjf0226 3. Reports to any third party, including, but not limited to, RedBook, First Data Bank, Blue Book, Medi-Span, or other price reporting service, regarding prices for TPNA products; 4. Communications with RedBook, First Data Bank, Blue Book, Medi-Span, or other pricing reporting services, regarding prices for TPNA products; 5. WAC and AWP generally; 6. Medicare and Medicaid reimbursement for TPNA pharmaceutical products generally; 7. Calculation and reporting of Average Manufacturer Price and Best Price for TPNA products, as may be required by federal and state laws and regulations; 8. Communications with any state or federal governmental agency regarding TPNA's participation in the Medicaid program; 9. Invoices, internal sales projections, and profit statements that indicate the price TPNA paid for its products and the profits TPNA made based upon sales of these products; 10. Meetings at which sales, marketing, and pricing decisions were discussed; 11. Communications with providers, if any, relating to the use of the terms "spread" or "profit" in the context of the sale or marketing of TPNA products; 12. Marketing materials (including proposed materials), if any, relating to the cost and "spread" for TPNA products; 13. Provision of free samples or nominally priced TPNA products to any providers; and 14. Educational grants regarding TPNA products; These requirements are related to all TPNA marketed products. Each Takeda Employee or Contractor shall create an Outlook Folder entitled "AWP" 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, materials, and computer files (including e-mails, 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 BOP, CORP-B-019 "E-mail Management and Retention" for the retention of electronic materials, and the "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. Last printed 11/30/2012 4:28:00 AM 20122830-042845 doc Confidential - Subject to Protective Order TAK-RIM30b6-00000665 Source: https://www.indup53/16-00001 ts.ucsf.edu/docs/frjf0226 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. 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 these materials, please contact Rick Jett in the Law Department at 847-383-2788. Thank you for your continuing cooperation in this important matter. Last printed 11/30/2012 4:28:00 AM 20122830-042845.doc Confidential - Subject to Protective Order TAK-RIM30b6-00000666 Source: https://www.indup3c.00004ts.ucsf.edu/docs/frjf0226 (3) LEGAL HOLD RELATED TO STATE OF FLORIDA PHARMACEUTICAL INDUSTRY MARKETING INVESTIGATION: PLEASE READ THIS MESSAGE CAREFULLY As you know, Takeda received a subpoena from the State of Florida on June 11, 2002 that requested documents relating to patient education and compliance and persistency agreements for ACTOS®, as well as scripts and training manuals regarding those types of agreements. As a result of the Florida subpoena, all documents and materials regarding these types of agreements for ACTOS that existed as of June 11, 2002 have been and continue to be subject to a Legal Hold. Each Takeda Employee or Contractor shall create an Outlook Folder entitled "Florida Investigation" 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, materials, and computer files (including e-mails, 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. 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, Last printed 11/30/2012 4:28:00 AM 20122830-042845.doc Confidential - Subject to Protective Order TAK-RIM30b6-00000667 Source: https://www.indup534c-00005ts.ucsf.edu/docs/frjf0226 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. Last printed 11/30/2012 4:28:00 AM 20122830-042845.doc Confidential - Subject to Protective Order TAK-RIM30b6-00000668 Source: Ittps://www.indup531c-00006ts.ucsf.edu/docs/frjf0226

Education grants regarding which products?

frjf0226

frjf0226_p0, frjf0226_p1, frjf0226_p2, frjf0226_p3, frjf0226_p4, frjf0226_p5

TPNA, TPNA products

EXHIBIT 47 (1) LEGAL HOLD RELATED TO ACTOS PRODUCTS LIABILITY CLAIMS: PLEASE READ THIS MESSAGE CAREFULLY Takeda continues to be involved in a small number of claims or lawsuits ("claims") relating to ACTOS (pioglitazone HCI). As a result of these claims, all documents, materials, information and things that exist or continue to be developed pertaining to ACTOS® have been and continue to be subject to a Legal Hold. Additionally, all documents and materials that exist or continue to be developed pertaining to Combination medicines involving ACTOS®, whether a marketed or development medicine, also continue to be subject to a Legal Hold. 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, materials, and computer files (including e-mails, 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. 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 sheuld 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, Last printed 11/30/2012 4:28:00 AM 20122830-042845 doc Confidential - Subject to Protective Order TAK-RIM30b6-00000663 Source: 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. (2) LEGAL HOLD RELATED TO PHARMACEUTICAL AVERAGE WHOLESALE PRICING LITIGATION: PLEASE READ THIS MESSAGE CAREFULLY Takeda Pharmaceuticals North America, Inc. ("TPNA"), along with numerous other pharmaceutical companies, continues to be named as a defendant in AWP lawsuits filed by state and local governmental entities. These lawsuits involve issues related to product pricing, price reporting and marketing. Although several of these lawsuits have been filed around the country, TPNA currently is involved only in small number of these cases. In these cases, plaintiffs generally have alleged that pharmaceutical companies failed to report accurate prices for their products, including Average Wholesale Price ("AWP") and Wholesale Acquisition Cost ("WAC"). These alleged failures purportedly caused state or local governmental agencies to overpay pharmacies and other providers when reimbursing them for prescription drugs dispensed to Medicaid patients. Plaintiffs seek recovery under various legal theories. All documents and data that relate to the saie, marketing, or distribution of TPNA pharmaceutical products may be relevant in these cases and must continue to be maintained until you are informed otherwise. By way of example, documents and data that relate to the following subjects may be relevant in these cases; 1. Transactional data regarding sales and distribution of TPNA products to individual customers, including transactional data regarding discounts, chargebacks, and rebates; 2. Contracts with third parties that purchase, distribute, receive or provide reimbursement for TPNA pharmaceutical products, including wholesalers, HMOs, GPOs, and PBMs; Last printed 11/30/2012 4:28:00 AM 20122830-042845 doc Confidential - Subject to Protective Order TAK-RIM30b6-00000664 Source: https://www.indup5316-.00002ts.ucsf.edu/docs/frjf0226 3. Reports to any third party, including, but not limited to, RedBook, First Data Bank, Blue Book, Medi-Span, or other price reporting service, regarding prices for TPNA products; 4. Communications with RedBook, First Data Bank, Blue Book, Medi-Span, or other pricing reporting services, regarding prices for TPNA products; 5. WAC and AWP generally; 6. Medicare and Medicaid reimbursement for TPNA pharmaceutical products generally; 7. Calculation and reporting of Average Manufacturer Price and Best Price for TPNA products, as may be required by federal and state laws and regulations; 8. Communications with any state or federal governmental agency regarding TPNA's participation in the Medicaid program; 9. Invoices, internal sales projections, and profit statements that indicate the price TPNA paid for its products and the profits TPNA made based upon sales of these products; 10. Meetings at which sales, marketing, and pricing decisions were discussed; 11. Communications with providers, if any, relating to the use of the terms "spread" or "profit" in the context of the sale or marketing of TPNA products; 12. Marketing materials (including proposed materials), if any, relating to the cost and "spread" for TPNA products; 13. Provision of free samples or nominally priced TPNA products to any providers; and 14. Educational grants regarding TPNA products; These requirements are related to all TPNA marketed products. Each Takeda Employee or Contractor shall create an Outlook Folder entitled "AWP" 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, materials, and computer files (including e-mails, 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 BOP, CORP-B-019 "E-mail Management and Retention" for the retention of electronic materials, and the "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. Last printed 11/30/2012 4:28:00 AM 20122830-042845 doc Confidential - Subject to Protective Order TAK-RIM30b6-00000665 Source: https://www.indup53/16-00001 ts.ucsf.edu/docs/frjf0226 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. 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 these materials, please contact Rick Jett in the Law Department at 847-383-2788. Thank you for your continuing cooperation in this important matter. Last printed 11/30/2012 4:28:00 AM 20122830-042845.doc Confidential - Subject to Protective Order TAK-RIM30b6-00000666 Source: https://www.indup3c.00004ts.ucsf.edu/docs/frjf0226 (3) LEGAL HOLD RELATED TO STATE OF FLORIDA PHARMACEUTICAL INDUSTRY MARKETING INVESTIGATION: PLEASE READ THIS MESSAGE CAREFULLY As you know, Takeda received a subpoena from the State of Florida on June 11, 2002 that requested documents relating to patient education and compliance and persistency agreements for ACTOS®, as well as scripts and training manuals regarding those types of agreements. As a result of the Florida subpoena, all documents and materials regarding these types of agreements for ACTOS that existed as of June 11, 2002 have been and continue to be subject to a Legal Hold. Each Takeda Employee or Contractor shall create an Outlook Folder entitled "Florida Investigation" 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, materials, and computer files (including e-mails, 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. 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, Last printed 11/30/2012 4:28:00 AM 20122830-042845.doc Confidential - Subject to Protective Order TAK-RIM30b6-00000667 Source: https://www.indup534c-00005ts.ucsf.edu/docs/frjf0226 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. Last printed 11/30/2012 4:28:00 AM 20122830-042845.doc Confidential - Subject to Protective Order TAK-RIM30b6-00000668 Source: Ittps://www.indup531c-00006ts.ucsf.edu/docs/frjf0226

To whom a copy of cover letter has to be sent ?

xyjf0226

xyjf0226_p0, xyjf0226_p1, xyjf0226_p2

Ms. Jens Weber

DEPARTMENT OF HEALTH & HUMAN SERVICES Public Hesith Service Food and Drug Administration Rockville, MD 20857 IND 33,729 RECEIVED REGULATORY AFFAIRS DEPARTMENT Takeda Pharmaceuticals North America, Inc. JUN 1 6 2003 Attention: Janet L. Haskins Manager, Regulatory Affairs Takeda Pharmaceuticals Norto America, lac 475 Half Day Road, Suite 500 Lincolnsbire, IL 60069 Dear Ms. Haskins: Please refer to your Investigational New Drug Application (IND) submitted January 15, 1999, under section 505(i) of the Federal Food, Drug, and Cosmetic Act for Actos (pioglitazone HCI) Tablets, 15 mg, 30 mg and 45 mg. We also refer to your amendment dated May 8, 2003 (serial # 525), received on May 9, 2003, that provided a response to our November 13, 2002, letter which cited the reasons this protocol was placed on clinical hold and the information needed to resolve the clinical hold issues. We have completed the review of your submission and have concluded that removal of the clinical hold is not warranted. We acknowledge your agreement to monitor for bladder tumors in your clinical studies, and to amend the label and consent documents. However, until further information on bladder effects from ongoing studies is available, we do not believe studies in pediatric patients are warranted. Until you have submitted the required information and we notify you that you may initiate trials, this IND remains on clinical hold and you may not legally conduct clinical studies under it. Please identify your response to the clinical hold issues as a "CLINICAL HOLD COMPLETE RESPONSE." To facilitate a response to your submission, submit this information in triplicate to the IND. In addition, send a copy of the cover letter to Ms. Jena Weber. Following receipt of your complete response to these issues, we will notify you of our decision within 30 days. 424 Confidential - Subject to Protective Order TAK-INDNDA-01577085 Produced in MDL on 01/31/13 Source: https://www.indup739c0000ts.ucsf.edu/docs/xyjf0226 IND 33,729 Page 2 Correspondence to this IND can be sent to the following address: U.S. Postal Service/ Courier/Overnight Mail: Food and Drug Administration Center for Drug Evaluation and Research Division of Metabolic and Endocrine Drug Products, HFD-510 Attention: Division Document Room, 8B-45 5600 Fishers Lane Rockville, Maryland 20857 You may, at any time, appeal the clinical hold decision to the Director, Office of Drug Evaluation ODE II. However, note that our procedures specify that review by the Office Director is automatic for continuance of a clinical hold. If you have any questions, please call Ms. Jena Weber, Regulatory Project Manager, at 301-827-6422. Sincerely, (See appended electronic signature page) David G. Orloff, M.D. Director Division of Metabolic and Endocrine Drug Products Office of Drug Evaluation II Center for Drug Evaluation and Research 425 Confidential - Subject to Protective Order TAK-INDNDA-01577086 Produced in MDL on 01/31/13 Source: https://www.indup,739.00002.ucsf.edu/docs/xyjf0226 This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. 1s/ David Orloff 6/13/03 11:53:49 AM 426 Confidential - Subject to Protective Order TAK-INDNDA-01577087 Produced in MDL on 01/31/13 Source: https://www.indup739-00003ts.ucsf.edu/docs/xyjf0226

Which reimbursement for TPNA pharmaceutical products is generally given?

frjf0226

frjf0226_p0, frjf0226_p1, frjf0226_p2, frjf0226_p3, frjf0226_p4, frjf0226_p5

Medicare and Medicaid

EXHIBIT 47 (1) LEGAL HOLD RELATED TO ACTOS PRODUCTS LIABILITY CLAIMS: PLEASE READ THIS MESSAGE CAREFULLY Takeda continues to be involved in a small number of claims or lawsuits ("claims") relating to ACTOS (pioglitazone HCI). As a result of these claims, all documents, materials, information and things that exist or continue to be developed pertaining to ACTOS® have been and continue to be subject to a Legal Hold. Additionally, all documents and materials that exist or continue to be developed pertaining to Combination medicines involving ACTOS®, whether a marketed or development medicine, also continue to be subject to a Legal Hold. 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, materials, and computer files (including e-mails, 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. 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 sheuld 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, Last printed 11/30/2012 4:28:00 AM 20122830-042845 doc Confidential - Subject to Protective Order TAK-RIM30b6-00000663 Source: 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. (2) LEGAL HOLD RELATED TO PHARMACEUTICAL AVERAGE WHOLESALE PRICING LITIGATION: PLEASE READ THIS MESSAGE CAREFULLY Takeda Pharmaceuticals North America, Inc. ("TPNA"), along with numerous other pharmaceutical companies, continues to be named as a defendant in AWP lawsuits filed by state and local governmental entities. These lawsuits involve issues related to product pricing, price reporting and marketing. Although several of these lawsuits have been filed around the country, TPNA currently is involved only in small number of these cases. In these cases, plaintiffs generally have alleged that pharmaceutical companies failed to report accurate prices for their products, including Average Wholesale Price ("AWP") and Wholesale Acquisition Cost ("WAC"). These alleged failures purportedly caused state or local governmental agencies to overpay pharmacies and other providers when reimbursing them for prescription drugs dispensed to Medicaid patients. Plaintiffs seek recovery under various legal theories. All documents and data that relate to the saie, marketing, or distribution of TPNA pharmaceutical products may be relevant in these cases and must continue to be maintained until you are informed otherwise. By way of example, documents and data that relate to the following subjects may be relevant in these cases; 1. Transactional data regarding sales and distribution of TPNA products to individual customers, including transactional data regarding discounts, chargebacks, and rebates; 2. Contracts with third parties that purchase, distribute, receive or provide reimbursement for TPNA pharmaceutical products, including wholesalers, HMOs, GPOs, and PBMs; Last printed 11/30/2012 4:28:00 AM 20122830-042845 doc Confidential - Subject to Protective Order TAK-RIM30b6-00000664 Source: https://www.indup5316-.00002ts.ucsf.edu/docs/frjf0226 3. Reports to any third party, including, but not limited to, RedBook, First Data Bank, Blue Book, Medi-Span, or other price reporting service, regarding prices for TPNA products; 4. Communications with RedBook, First Data Bank, Blue Book, Medi-Span, or other pricing reporting services, regarding prices for TPNA products; 5. WAC and AWP generally; 6. Medicare and Medicaid reimbursement for TPNA pharmaceutical products generally; 7. Calculation and reporting of Average Manufacturer Price and Best Price for TPNA products, as may be required by federal and state laws and regulations; 8. Communications with any state or federal governmental agency regarding TPNA's participation in the Medicaid program; 9. Invoices, internal sales projections, and profit statements that indicate the price TPNA paid for its products and the profits TPNA made based upon sales of these products; 10. Meetings at which sales, marketing, and pricing decisions were discussed; 11. Communications with providers, if any, relating to the use of the terms "spread" or "profit" in the context of the sale or marketing of TPNA products; 12. Marketing materials (including proposed materials), if any, relating to the cost and "spread" for TPNA products; 13. Provision of free samples or nominally priced TPNA products to any providers; and 14. Educational grants regarding TPNA products; These requirements are related to all TPNA marketed products. Each Takeda Employee or Contractor shall create an Outlook Folder entitled "AWP" 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, materials, and computer files (including e-mails, 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 BOP, CORP-B-019 "E-mail Management and Retention" for the retention of electronic materials, and the "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. Last printed 11/30/2012 4:28:00 AM 20122830-042845 doc Confidential - Subject to Protective Order TAK-RIM30b6-00000665 Source: https://www.indup53/16-00001 ts.ucsf.edu/docs/frjf0226 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. 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 these materials, please contact Rick Jett in the Law Department at 847-383-2788. Thank you for your continuing cooperation in this important matter. Last printed 11/30/2012 4:28:00 AM 20122830-042845.doc Confidential - Subject to Protective Order TAK-RIM30b6-00000666 Source: https://www.indup3c.00004ts.ucsf.edu/docs/frjf0226 (3) LEGAL HOLD RELATED TO STATE OF FLORIDA PHARMACEUTICAL INDUSTRY MARKETING INVESTIGATION: PLEASE READ THIS MESSAGE CAREFULLY As you know, Takeda received a subpoena from the State of Florida on June 11, 2002 that requested documents relating to patient education and compliance and persistency agreements for ACTOS®, as well as scripts and training manuals regarding those types of agreements. As a result of the Florida subpoena, all documents and materials regarding these types of agreements for ACTOS that existed as of June 11, 2002 have been and continue to be subject to a Legal Hold. Each Takeda Employee or Contractor shall create an Outlook Folder entitled "Florida Investigation" 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, materials, and computer files (including e-mails, 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. 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, Last printed 11/30/2012 4:28:00 AM 20122830-042845.doc Confidential - Subject to Protective Order TAK-RIM30b6-00000667 Source: https://www.indup534c-00005ts.ucsf.edu/docs/frjf0226 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. Last printed 11/30/2012 4:28:00 AM 20122830-042845.doc Confidential - Subject to Protective Order TAK-RIM30b6-00000668 Source: Ittps://www.indup531c-00006ts.ucsf.edu/docs/frjf0226

What is the designation of Alfonso T. Perez, M.D.?

zfkf0226

zfkf0226_p4

Vice President, Clinical Research

prior to such event or in connection therewith. Sections 6. 7 8, 9. 12. 13, 14. 15 and 16 of this Agreement shall survive the expiration or earlier termination of this Agreement. 16. Miscellaneous. (a) Neither party may assign all or any part of this Agreement without the prior written consent of the other party; provided, however, that TGRD may assign this Agreement to a corporate affiliate or to a successor to all or substantially all of its business. (b) This Agreement, together with any attachments and PWOs, constitutes the entire agreement of the parties with respect to the subject matter described herein and supersedes any prior agreements (whether written or oral) relating to said subject matter. (c) This Agreement may not be amended except in writing signed by duly authorized representatives of both parties. (d) Pursuant to the Federal Acquisitions Regulation (FAR), Title 48, Code of Federal Regulations, Chapter 1, TGRD is required to notify its vendors that certain federal contract clauses may be applicable to such vendors, including Institution. These clauses set forth requirements including, but not limited to affirmative action programs and subcontracting with small businesses, small disadvantaged businesses, women-owned businesses. veteran- owned small businesses, service-disabled veteran-owned small businesses, and HUB Zone small businesses. To the extent applicable, all such clauses that are in effect during the term of this Agreement are hereby incorporated into this Agreement with the same force and effect as though they had been set forth herein. BY ACCEPTANCE OF THIS AGREEMENT, INSTITUTION HEREBY CERTIFIES THAT NEITHER INSTITUTION NOR ANY OF INSTITUTION'S PRINCIPALS IS PRESENTLY DEBARRED, SUSPENDED, PROPOSED FOR DEBARMENT, OR DECLARED INELIGIBLE FOR THE AWARD OF CONTRACTS BY ANY FEDERAL AGENCY. (e) If applicable to Institution's Services hereunder, Institution warrants that in providing the goods and/or Services specified herein, Institution will comply with the following laws, executive order, and the regulations promulgated thereunder, as the same may be amended, when applicable: (i) the Vietnam Era Veterans Readjustment Assistance Act of 1974, (ii) Executive Order 11246, and (iii) the Rehabilitation Act of 1973. Any clause required to be set forth in a document of this type by such laws, administrative regulations or executive orders shall be deemed to be incorporated herein by this reference. Institution shall not discriminate against any employee or applicant for employment because of race, color, religion, sex. national origin, disability, or covered veteran status. Please signify your acceptance of this letter Agreement by dating and signing both originals and returning one to the TGRD Representative noted below. TGRD appreciates your agreement to assist us. Sincerely, Agreed and A ,ccepted: Takeda Global Research & Development Center, Inc. By: Strawberry The By Cleveland Clinic Foundation a Alfonse T. Perez. M.D. Richard A. Rudick, M.D. Vice President, Clinical Research Chairman, Division of Clinical Research 5/8/07 APPROVED AS TO FORM CCF - OFFICE OF GENERAI GOUNSEL technical TEK. 15463 the 19 Confidential - Subject to TAK-TYNANJ-00043882

By whom was this agreement Agreed and Accepted?

zfkf0226

zfkf0226_p4

Richard A. Rudick, Richard A. Rudick, M.D., Richard A. Rudick, M.D. Chairman, Division of Clinical Research

prior to such event or in connection therewith. Sections 6. 7 8, 9. 12. 13, 14. 15 and 16 of this Agreement shall survive the expiration or earlier termination of this Agreement. 16. Miscellaneous. (a) Neither party may assign all or any part of this Agreement without the prior written consent of the other party; provided, however, that TGRD may assign this Agreement to a corporate affiliate or to a successor to all or substantially all of its business. (b) This Agreement, together with any attachments and PWOs, constitutes the entire agreement of the parties with respect to the subject matter described herein and supersedes any prior agreements (whether written or oral) relating to said subject matter. (c) This Agreement may not be amended except in writing signed by duly authorized representatives of both parties. (d) Pursuant to the Federal Acquisitions Regulation (FAR), Title 48, Code of Federal Regulations, Chapter 1, TGRD is required to notify its vendors that certain federal contract clauses may be applicable to such vendors, including Institution. These clauses set forth requirements including, but not limited to affirmative action programs and subcontracting with small businesses, small disadvantaged businesses, women-owned businesses. veteran- owned small businesses, service-disabled veteran-owned small businesses, and HUB Zone small businesses. To the extent applicable, all such clauses that are in effect during the term of this Agreement are hereby incorporated into this Agreement with the same force and effect as though they had been set forth herein. BY ACCEPTANCE OF THIS AGREEMENT, INSTITUTION HEREBY CERTIFIES THAT NEITHER INSTITUTION NOR ANY OF INSTITUTION'S PRINCIPALS IS PRESENTLY DEBARRED, SUSPENDED, PROPOSED FOR DEBARMENT, OR DECLARED INELIGIBLE FOR THE AWARD OF CONTRACTS BY ANY FEDERAL AGENCY. (e) If applicable to Institution's Services hereunder, Institution warrants that in providing the goods and/or Services specified herein, Institution will comply with the following laws, executive order, and the regulations promulgated thereunder, as the same may be amended, when applicable: (i) the Vietnam Era Veterans Readjustment Assistance Act of 1974, (ii) Executive Order 11246, and (iii) the Rehabilitation Act of 1973. Any clause required to be set forth in a document of this type by such laws, administrative regulations or executive orders shall be deemed to be incorporated herein by this reference. Institution shall not discriminate against any employee or applicant for employment because of race, color, religion, sex. national origin, disability, or covered veteran status. Please signify your acceptance of this letter Agreement by dating and signing both originals and returning one to the TGRD Representative noted below. TGRD appreciates your agreement to assist us. Sincerely, Agreed and A ,ccepted: Takeda Global Research & Development Center, Inc. By: Strawberry The By Cleveland Clinic Foundation a Alfonse T. Perez. M.D. Richard A. Rudick, M.D. Vice President, Clinical Research Chairman, Division of Clinical Research 5/8/07 APPROVED AS TO FORM CCF - OFFICE OF GENERAI GOUNSEL technical TEK. 15463 the 19 Confidential - Subject to TAK-TYNANJ-00043882

What is the full form of FAR?

zfkf0226

zfkf0226_p4

Federal Acquisitions Regulation

prior to such event or in connection therewith. Sections 6. 7 8, 9. 12. 13, 14. 15 and 16 of this Agreement shall survive the expiration or earlier termination of this Agreement. 16. Miscellaneous. (a) Neither party may assign all or any part of this Agreement without the prior written consent of the other party; provided, however, that TGRD may assign this Agreement to a corporate affiliate or to a successor to all or substantially all of its business. (b) This Agreement, together with any attachments and PWOs, constitutes the entire agreement of the parties with respect to the subject matter described herein and supersedes any prior agreements (whether written or oral) relating to said subject matter. (c) This Agreement may not be amended except in writing signed by duly authorized representatives of both parties. (d) Pursuant to the Federal Acquisitions Regulation (FAR), Title 48, Code of Federal Regulations, Chapter 1, TGRD is required to notify its vendors that certain federal contract clauses may be applicable to such vendors, including Institution. These clauses set forth requirements including, but not limited to affirmative action programs and subcontracting with small businesses, small disadvantaged businesses, women-owned businesses. veteran- owned small businesses, service-disabled veteran-owned small businesses, and HUB Zone small businesses. To the extent applicable, all such clauses that are in effect during the term of this Agreement are hereby incorporated into this Agreement with the same force and effect as though they had been set forth herein. BY ACCEPTANCE OF THIS AGREEMENT, INSTITUTION HEREBY CERTIFIES THAT NEITHER INSTITUTION NOR ANY OF INSTITUTION'S PRINCIPALS IS PRESENTLY DEBARRED, SUSPENDED, PROPOSED FOR DEBARMENT, OR DECLARED INELIGIBLE FOR THE AWARD OF CONTRACTS BY ANY FEDERAL AGENCY. (e) If applicable to Institution's Services hereunder, Institution warrants that in providing the goods and/or Services specified herein, Institution will comply with the following laws, executive order, and the regulations promulgated thereunder, as the same may be amended, when applicable: (i) the Vietnam Era Veterans Readjustment Assistance Act of 1974, (ii) Executive Order 11246, and (iii) the Rehabilitation Act of 1973. Any clause required to be set forth in a document of this type by such laws, administrative regulations or executive orders shall be deemed to be incorporated herein by this reference. Institution shall not discriminate against any employee or applicant for employment because of race, color, religion, sex. national origin, disability, or covered veteran status. Please signify your acceptance of this letter Agreement by dating and signing both originals and returning one to the TGRD Representative noted below. TGRD appreciates your agreement to assist us. Sincerely, Agreed and A ,ccepted: Takeda Global Research & Development Center, Inc. By: Strawberry The By Cleveland Clinic Foundation a Alfonse T. Perez. M.D. Richard A. Rudick, M.D. Vice President, Clinical Research Chairman, Division of Clinical Research 5/8/07 APPROVED AS TO FORM CCF - OFFICE OF GENERAI GOUNSEL technical TEK. 15463 the 19 Confidential - Subject to TAK-TYNANJ-00043882

What is the number written above TAK-INDNDA-01577086?

xyjf0226

xyjf0226_p0, xyjf0226_p1, xyjf0226_p2

425

DEPARTMENT OF HEALTH & HUMAN SERVICES Public Hesith Service Food and Drug Administration Rockville, MD 20857 IND 33,729 RECEIVED REGULATORY AFFAIRS DEPARTMENT Takeda Pharmaceuticals North America, Inc. JUN 1 6 2003 Attention: Janet L. Haskins Manager, Regulatory Affairs Takeda Pharmaceuticals Norto America, lac 475 Half Day Road, Suite 500 Lincolnsbire, IL 60069 Dear Ms. Haskins: Please refer to your Investigational New Drug Application (IND) submitted January 15, 1999, under section 505(i) of the Federal Food, Drug, and Cosmetic Act for Actos (pioglitazone HCI) Tablets, 15 mg, 30 mg and 45 mg. We also refer to your amendment dated May 8, 2003 (serial # 525), received on May 9, 2003, that provided a response to our November 13, 2002, letter which cited the reasons this protocol was placed on clinical hold and the information needed to resolve the clinical hold issues. We have completed the review of your submission and have concluded that removal of the clinical hold is not warranted. We acknowledge your agreement to monitor for bladder tumors in your clinical studies, and to amend the label and consent documents. However, until further information on bladder effects from ongoing studies is available, we do not believe studies in pediatric patients are warranted. Until you have submitted the required information and we notify you that you may initiate trials, this IND remains on clinical hold and you may not legally conduct clinical studies under it. Please identify your response to the clinical hold issues as a "CLINICAL HOLD COMPLETE RESPONSE." To facilitate a response to your submission, submit this information in triplicate to the IND. In addition, send a copy of the cover letter to Ms. Jena Weber. Following receipt of your complete response to these issues, we will notify you of our decision within 30 days. 424 Confidential - Subject to Protective Order TAK-INDNDA-01577085 Produced in MDL on 01/31/13 Source: https://www.indup739c0000ts.ucsf.edu/docs/xyjf0226 IND 33,729 Page 2 Correspondence to this IND can be sent to the following address: U.S. Postal Service/ Courier/Overnight Mail: Food and Drug Administration Center for Drug Evaluation and Research Division of Metabolic and Endocrine Drug Products, HFD-510 Attention: Division Document Room, 8B-45 5600 Fishers Lane Rockville, Maryland 20857 You may, at any time, appeal the clinical hold decision to the Director, Office of Drug Evaluation ODE II. However, note that our procedures specify that review by the Office Director is automatic for continuance of a clinical hold. If you have any questions, please call Ms. Jena Weber, Regulatory Project Manager, at 301-827-6422. Sincerely, (See appended electronic signature page) David G. Orloff, M.D. Director Division of Metabolic and Endocrine Drug Products Office of Drug Evaluation II Center for Drug Evaluation and Research 425 Confidential - Subject to Protective Order TAK-INDNDA-01577086 Produced in MDL on 01/31/13 Source: https://www.indup,739.00002.ucsf.edu/docs/xyjf0226 This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. 1s/ David Orloff 6/13/03 11:53:49 AM 426 Confidential - Subject to Protective Order TAK-INDNDA-01577087 Produced in MDL on 01/31/13 Source: https://www.indup739-00003ts.ucsf.edu/docs/xyjf0226

What is the contact number of Ms. Jena Weber, Regulatory Project Manager?

xyjf0226

xyjf0226_p0, xyjf0226_p1, xyjf0226_p2

301-827-6422

DEPARTMENT OF HEALTH & HUMAN SERVICES Public Hesith Service Food and Drug Administration Rockville, MD 20857 IND 33,729 RECEIVED REGULATORY AFFAIRS DEPARTMENT Takeda Pharmaceuticals North America, Inc. JUN 1 6 2003 Attention: Janet L. Haskins Manager, Regulatory Affairs Takeda Pharmaceuticals Norto America, lac 475 Half Day Road, Suite 500 Lincolnsbire, IL 60069 Dear Ms. Haskins: Please refer to your Investigational New Drug Application (IND) submitted January 15, 1999, under section 505(i) of the Federal Food, Drug, and Cosmetic Act for Actos (pioglitazone HCI) Tablets, 15 mg, 30 mg and 45 mg. We also refer to your amendment dated May 8, 2003 (serial # 525), received on May 9, 2003, that provided a response to our November 13, 2002, letter which cited the reasons this protocol was placed on clinical hold and the information needed to resolve the clinical hold issues. We have completed the review of your submission and have concluded that removal of the clinical hold is not warranted. We acknowledge your agreement to monitor for bladder tumors in your clinical studies, and to amend the label and consent documents. However, until further information on bladder effects from ongoing studies is available, we do not believe studies in pediatric patients are warranted. Until you have submitted the required information and we notify you that you may initiate trials, this IND remains on clinical hold and you may not legally conduct clinical studies under it. Please identify your response to the clinical hold issues as a "CLINICAL HOLD COMPLETE RESPONSE." To facilitate a response to your submission, submit this information in triplicate to the IND. In addition, send a copy of the cover letter to Ms. Jena Weber. Following receipt of your complete response to these issues, we will notify you of our decision within 30 days. 424 Confidential - Subject to Protective Order TAK-INDNDA-01577085 Produced in MDL on 01/31/13 Source: https://www.indup739c0000ts.ucsf.edu/docs/xyjf0226 IND 33,729 Page 2 Correspondence to this IND can be sent to the following address: U.S. Postal Service/ Courier/Overnight Mail: Food and Drug Administration Center for Drug Evaluation and Research Division of Metabolic and Endocrine Drug Products, HFD-510 Attention: Division Document Room, 8B-45 5600 Fishers Lane Rockville, Maryland 20857 You may, at any time, appeal the clinical hold decision to the Director, Office of Drug Evaluation ODE II. However, note that our procedures specify that review by the Office Director is automatic for continuance of a clinical hold. If you have any questions, please call Ms. Jena Weber, Regulatory Project Manager, at 301-827-6422. Sincerely, (See appended electronic signature page) David G. Orloff, M.D. Director Division of Metabolic and Endocrine Drug Products Office of Drug Evaluation II Center for Drug Evaluation and Research 425 Confidential - Subject to Protective Order TAK-INDNDA-01577086 Produced in MDL on 01/31/13 Source: https://www.indup,739.00002.ucsf.edu/docs/xyjf0226 This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. 1s/ David Orloff 6/13/03 11:53:49 AM 426 Confidential - Subject to Protective Order TAK-INDNDA-01577087 Produced in MDL on 01/31/13 Source: https://www.indup739-00003ts.ucsf.edu/docs/xyjf0226

What is the full form of ODE?

xyjf0226

xyjf0226_p0, xyjf0226_p1, xyjf0226_p2

Office of Drug Evaluation

DEPARTMENT OF HEALTH & HUMAN SERVICES Public Hesith Service Food and Drug Administration Rockville, MD 20857 IND 33,729 RECEIVED REGULATORY AFFAIRS DEPARTMENT Takeda Pharmaceuticals North America, Inc. JUN 1 6 2003 Attention: Janet L. Haskins Manager, Regulatory Affairs Takeda Pharmaceuticals Norto America, lac 475 Half Day Road, Suite 500 Lincolnsbire, IL 60069 Dear Ms. Haskins: Please refer to your Investigational New Drug Application (IND) submitted January 15, 1999, under section 505(i) of the Federal Food, Drug, and Cosmetic Act for Actos (pioglitazone HCI) Tablets, 15 mg, 30 mg and 45 mg. We also refer to your amendment dated May 8, 2003 (serial # 525), received on May 9, 2003, that provided a response to our November 13, 2002, letter which cited the reasons this protocol was placed on clinical hold and the information needed to resolve the clinical hold issues. We have completed the review of your submission and have concluded that removal of the clinical hold is not warranted. We acknowledge your agreement to monitor for bladder tumors in your clinical studies, and to amend the label and consent documents. However, until further information on bladder effects from ongoing studies is available, we do not believe studies in pediatric patients are warranted. Until you have submitted the required information and we notify you that you may initiate trials, this IND remains on clinical hold and you may not legally conduct clinical studies under it. Please identify your response to the clinical hold issues as a "CLINICAL HOLD COMPLETE RESPONSE." To facilitate a response to your submission, submit this information in triplicate to the IND. In addition, send a copy of the cover letter to Ms. Jena Weber. Following receipt of your complete response to these issues, we will notify you of our decision within 30 days. 424 Confidential - Subject to Protective Order TAK-INDNDA-01577085 Produced in MDL on 01/31/13 Source: https://www.indup739c0000ts.ucsf.edu/docs/xyjf0226 IND 33,729 Page 2 Correspondence to this IND can be sent to the following address: U.S. Postal Service/ Courier/Overnight Mail: Food and Drug Administration Center for Drug Evaluation and Research Division of Metabolic and Endocrine Drug Products, HFD-510 Attention: Division Document Room, 8B-45 5600 Fishers Lane Rockville, Maryland 20857 You may, at any time, appeal the clinical hold decision to the Director, Office of Drug Evaluation ODE II. However, note that our procedures specify that review by the Office Director is automatic for continuance of a clinical hold. If you have any questions, please call Ms. Jena Weber, Regulatory Project Manager, at 301-827-6422. Sincerely, (See appended electronic signature page) David G. Orloff, M.D. Director Division of Metabolic and Endocrine Drug Products Office of Drug Evaluation II Center for Drug Evaluation and Research 425 Confidential - Subject to Protective Order TAK-INDNDA-01577086 Produced in MDL on 01/31/13 Source: https://www.indup,739.00002.ucsf.edu/docs/xyjf0226 This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. 1s/ David Orloff 6/13/03 11:53:49 AM 426 Confidential - Subject to Protective Order TAK-INDNDA-01577087 Produced in MDL on 01/31/13 Source: https://www.indup739-00003ts.ucsf.edu/docs/xyjf0226

What is written above Page 2 on the top?

xyjf0226

xyjf0226_p0, xyjf0226_p1, xyjf0226_p2

IND 33, 729

DEPARTMENT OF HEALTH & HUMAN SERVICES Public Hesith Service Food and Drug Administration Rockville, MD 20857 IND 33,729 RECEIVED REGULATORY AFFAIRS DEPARTMENT Takeda Pharmaceuticals North America, Inc. JUN 1 6 2003 Attention: Janet L. Haskins Manager, Regulatory Affairs Takeda Pharmaceuticals Norto America, lac 475 Half Day Road, Suite 500 Lincolnsbire, IL 60069 Dear Ms. Haskins: Please refer to your Investigational New Drug Application (IND) submitted January 15, 1999, under section 505(i) of the Federal Food, Drug, and Cosmetic Act for Actos (pioglitazone HCI) Tablets, 15 mg, 30 mg and 45 mg. We also refer to your amendment dated May 8, 2003 (serial # 525), received on May 9, 2003, that provided a response to our November 13, 2002, letter which cited the reasons this protocol was placed on clinical hold and the information needed to resolve the clinical hold issues. We have completed the review of your submission and have concluded that removal of the clinical hold is not warranted. We acknowledge your agreement to monitor for bladder tumors in your clinical studies, and to amend the label and consent documents. However, until further information on bladder effects from ongoing studies is available, we do not believe studies in pediatric patients are warranted. Until you have submitted the required information and we notify you that you may initiate trials, this IND remains on clinical hold and you may not legally conduct clinical studies under it. Please identify your response to the clinical hold issues as a "CLINICAL HOLD COMPLETE RESPONSE." To facilitate a response to your submission, submit this information in triplicate to the IND. In addition, send a copy of the cover letter to Ms. Jena Weber. Following receipt of your complete response to these issues, we will notify you of our decision within 30 days. 424 Confidential - Subject to Protective Order TAK-INDNDA-01577085 Produced in MDL on 01/31/13 Source: https://www.indup739c0000ts.ucsf.edu/docs/xyjf0226 IND 33,729 Page 2 Correspondence to this IND can be sent to the following address: U.S. Postal Service/ Courier/Overnight Mail: Food and Drug Administration Center for Drug Evaluation and Research Division of Metabolic and Endocrine Drug Products, HFD-510 Attention: Division Document Room, 8B-45 5600 Fishers Lane Rockville, Maryland 20857 You may, at any time, appeal the clinical hold decision to the Director, Office of Drug Evaluation ODE II. However, note that our procedures specify that review by the Office Director is automatic for continuance of a clinical hold. If you have any questions, please call Ms. Jena Weber, Regulatory Project Manager, at 301-827-6422. Sincerely, (See appended electronic signature page) David G. Orloff, M.D. Director Division of Metabolic and Endocrine Drug Products Office of Drug Evaluation II Center for Drug Evaluation and Research 425 Confidential - Subject to Protective Order TAK-INDNDA-01577086 Produced in MDL on 01/31/13 Source: https://www.indup,739.00002.ucsf.edu/docs/xyjf0226 This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. 1s/ David Orloff 6/13/03 11:53:49 AM 426 Confidential - Subject to Protective Order TAK-INDNDA-01577087 Produced in MDL on 01/31/13 Source: https://www.indup739-00003ts.ucsf.edu/docs/xyjf0226

what is the unit mentioned in the letter ?

zsjf0226

zsjf0226_p0, zsjf0226_p1

7200

FROM THE DESK OF: Timothy J. Gumbleton UNIT: 7200 BLOG: 24-1 EXT: 5-7054 TO: PJDaniels DATE: 9/23/93 csolanoff PLRuppel - Twelch from Dr. mitchell to Dr. Matsuzana Attached is a copy of the letter It was faxed today. Dr. Mitchell added one sentence at the bottom of like Paragraph 3. He said that me further contact with Takeda should be made until we receive a reply from them. Please call if you have any questions. Upjehn ) DALY 18 CONFIDENTIAL - SUBJECT UPJ-0065602DE1 - TAKENA Aot THE UPJOHN COMPANY KALAMAZOO, MICHIGAN U.S.A. J.R. MITCHELL. MD. P.D. TELEPHONE: (616) 323.4000 Vice Chairmas of the Boand TELEPHONE: (614) FAX: (616) 185-5791 September 21, 1993 Tai Matsuzawa, Ph.D. Managing Director Vice President, Pharmaceutical Group Takeda Chemical Industries, Ltd. 1-1, Doshomachi 4-Chome Chuo-Ku, Osaka 541 Japan Dear Doctor Matsuzawa: As you know, Upjohn has committed to notify Takeda by October 1, 1993, of our intentions regarding further clinical development of pioglitazone. On September 20 our Pharmaceutical Executive Council, Upjohn's highest scientific decision-making body, carefully reviewed the results of the toxicology and clinical studies. The decision of the Council was that Upjohn will not go forward with pioglitazone in the clinic. The Council decided that further clinical development of pioglitazone could not be justified based on their concern regarding pioglitazone's margin of safety. As a consequence of this decision, Upjohn also must decline participation with Takeda on the proposed pioglitazone study in Canada. It is with deep regret that I convey this message. As you know Upjohn and Takeda enjoy a strong and beneficial relationship based on mutual respect. It is a great disappointment to us that we will not have the opportunity of further interactions and collaboration with Takeda on this project. Hopefully, we will find other opportunities for collaboration in the future. I have instructed my staff to work closely with Takeda personnel in regards to the release of any information, data, FDA notifications, and other issues to ensure Takeda's interests and wishes are followed. With best personal regards, Sincerely, President, Upjohn Laboratories Worldwide Research, Development, & Medical Affairs CONEIDENTIAL - SUBJECT TO PROTECTIVE ORDER UPJ-0065603 Source:

what is the date mentioned

zsjf0226

zsjf0226_p0, zsjf0226_p1

9/23/93

FROM THE DESK OF: Timothy J. Gumbleton UNIT: 7200 BLOG: 24-1 EXT: 5-7054 TO: PJDaniels DATE: 9/23/93 csolanoff PLRuppel - Twelch from Dr. mitchell to Dr. Matsuzana Attached is a copy of the letter It was faxed today. Dr. Mitchell added one sentence at the bottom of like Paragraph 3. He said that me further contact with Takeda should be made until we receive a reply from them. Please call if you have any questions. Upjehn ) DALY 18 CONFIDENTIAL - SUBJECT UPJ-0065602DE1 - TAKENA Aot THE UPJOHN COMPANY KALAMAZOO, MICHIGAN U.S.A. J.R. MITCHELL. MD. P.D. TELEPHONE: (616) 323.4000 Vice Chairmas of the Boand TELEPHONE: (614) FAX: (616) 185-5791 September 21, 1993 Tai Matsuzawa, Ph.D. Managing Director Vice President, Pharmaceutical Group Takeda Chemical Industries, Ltd. 1-1, Doshomachi 4-Chome Chuo-Ku, Osaka 541 Japan Dear Doctor Matsuzawa: As you know, Upjohn has committed to notify Takeda by October 1, 1993, of our intentions regarding further clinical development of pioglitazone. On September 20 our Pharmaceutical Executive Council, Upjohn's highest scientific decision-making body, carefully reviewed the results of the toxicology and clinical studies. The decision of the Council was that Upjohn will not go forward with pioglitazone in the clinic. The Council decided that further clinical development of pioglitazone could not be justified based on their concern regarding pioglitazone's margin of safety. As a consequence of this decision, Upjohn also must decline participation with Takeda on the proposed pioglitazone study in Canada. It is with deep regret that I convey this message. As you know Upjohn and Takeda enjoy a strong and beneficial relationship based on mutual respect. It is a great disappointment to us that we will not have the opportunity of further interactions and collaboration with Takeda on this project. Hopefully, we will find other opportunities for collaboration in the future. I have instructed my staff to work closely with Takeda personnel in regards to the release of any information, data, FDA notifications, and other issues to ensure Takeda's interests and wishes are followed. With best personal regards, Sincerely, President, Upjohn Laboratories Worldwide Research, Development, & Medical Affairs CONEIDENTIAL - SUBJECT TO PROTECTIVE ORDER UPJ-0065603 Source:

What is the date of the signature of the chairman of the Division of clinical research?

zfkf0226

zfkf0226_p4

5/8/07

prior to such event or in connection therewith. Sections 6. 7 8, 9. 12. 13, 14. 15 and 16 of this Agreement shall survive the expiration or earlier termination of this Agreement. 16. Miscellaneous. (a) Neither party may assign all or any part of this Agreement without the prior written consent of the other party; provided, however, that TGRD may assign this Agreement to a corporate affiliate or to a successor to all or substantially all of its business. (b) This Agreement, together with any attachments and PWOs, constitutes the entire agreement of the parties with respect to the subject matter described herein and supersedes any prior agreements (whether written or oral) relating to said subject matter. (c) This Agreement may not be amended except in writing signed by duly authorized representatives of both parties. (d) Pursuant to the Federal Acquisitions Regulation (FAR), Title 48, Code of Federal Regulations, Chapter 1, TGRD is required to notify its vendors that certain federal contract clauses may be applicable to such vendors, including Institution. These clauses set forth requirements including, but not limited to affirmative action programs and subcontracting with small businesses, small disadvantaged businesses, women-owned businesses. veteran- owned small businesses, service-disabled veteran-owned small businesses, and HUB Zone small businesses. To the extent applicable, all such clauses that are in effect during the term of this Agreement are hereby incorporated into this Agreement with the same force and effect as though they had been set forth herein. BY ACCEPTANCE OF THIS AGREEMENT, INSTITUTION HEREBY CERTIFIES THAT NEITHER INSTITUTION NOR ANY OF INSTITUTION'S PRINCIPALS IS PRESENTLY DEBARRED, SUSPENDED, PROPOSED FOR DEBARMENT, OR DECLARED INELIGIBLE FOR THE AWARD OF CONTRACTS BY ANY FEDERAL AGENCY. (e) If applicable to Institution's Services hereunder, Institution warrants that in providing the goods and/or Services specified herein, Institution will comply with the following laws, executive order, and the regulations promulgated thereunder, as the same may be amended, when applicable: (i) the Vietnam Era Veterans Readjustment Assistance Act of 1974, (ii) Executive Order 11246, and (iii) the Rehabilitation Act of 1973. Any clause required to be set forth in a document of this type by such laws, administrative regulations or executive orders shall be deemed to be incorporated herein by this reference. Institution shall not discriminate against any employee or applicant for employment because of race, color, religion, sex. national origin, disability, or covered veteran status. Please signify your acceptance of this letter Agreement by dating and signing both originals and returning one to the TGRD Representative noted below. TGRD appreciates your agreement to assist us. Sincerely, Agreed and A ,ccepted: Takeda Global Research & Development Center, Inc. By: Strawberry The By Cleveland Clinic Foundation a Alfonse T. Perez. M.D. Richard A. Rudick, M.D. Vice President, Clinical Research Chairman, Division of Clinical Research 5/8/07 APPROVED AS TO FORM CCF - OFFICE OF GENERAI GOUNSEL technical TEK. 15463 the 19 Confidential - Subject to TAK-TYNANJ-00043882

Name of the first person in the To list?

zsjf0226

zsjf0226_p0, zsjf0226_p1

PJ Daniels, pj Daniels

FROM THE DESK OF: Timothy J. Gumbleton UNIT: 7200 BLOG: 24-1 EXT: 5-7054 TO: PJDaniels DATE: 9/23/93 csolanoff PLRuppel - Twelch from Dr. mitchell to Dr. Matsuzana Attached is a copy of the letter It was faxed today. Dr. Mitchell added one sentence at the bottom of like Paragraph 3. He said that me further contact with Takeda should be made until we receive a reply from them. Please call if you have any questions. Upjehn ) DALY 18 CONFIDENTIAL - SUBJECT UPJ-0065602DE1 - TAKENA Aot THE UPJOHN COMPANY KALAMAZOO, MICHIGAN U.S.A. J.R. MITCHELL. MD. P.D. TELEPHONE: (616) 323.4000 Vice Chairmas of the Boand TELEPHONE: (614) FAX: (616) 185-5791 September 21, 1993 Tai Matsuzawa, Ph.D. Managing Director Vice President, Pharmaceutical Group Takeda Chemical Industries, Ltd. 1-1, Doshomachi 4-Chome Chuo-Ku, Osaka 541 Japan Dear Doctor Matsuzawa: As you know, Upjohn has committed to notify Takeda by October 1, 1993, of our intentions regarding further clinical development of pioglitazone. On September 20 our Pharmaceutical Executive Council, Upjohn's highest scientific decision-making body, carefully reviewed the results of the toxicology and clinical studies. The decision of the Council was that Upjohn will not go forward with pioglitazone in the clinic. The Council decided that further clinical development of pioglitazone could not be justified based on their concern regarding pioglitazone's margin of safety. As a consequence of this decision, Upjohn also must decline participation with Takeda on the proposed pioglitazone study in Canada. It is with deep regret that I convey this message. As you know Upjohn and Takeda enjoy a strong and beneficial relationship based on mutual respect. It is a great disappointment to us that we will not have the opportunity of further interactions and collaboration with Takeda on this project. Hopefully, we will find other opportunities for collaboration in the future. I have instructed my staff to work closely with Takeda personnel in regards to the release of any information, data, FDA notifications, and other issues to ensure Takeda's interests and wishes are followed. With best personal regards, Sincerely, President, Upjohn Laboratories Worldwide Research, Development, & Medical Affairs CONEIDENTIAL - SUBJECT TO PROTECTIVE ORDER UPJ-0065603 Source:

When did Regulatory affairs department receive this letter?

kmjf0226

kmjf0226_p0, kmjf0226_p1, kmjf0226_p2, kmjf0226_p3

FEB 19 2007, Feb 19 2007

Public Health Service DEPARTMENT OF HEALTH & HUMAN SERVICES Food and Drug Administration Rockville, MD 20857 NDA 21-073/S-026 DISCIPLINE REVIEW LETTER Takeda Global Research & Development Center, Inc. RECEIVED Attention: Mary Jo Pritza, MPH, PharmD REGULATORY AFFAIRS DEPARTMENT Manager, Regulatory Affairs One Takeda Parkway FEB 1 9 2007 Deerfield, IL 60015 Dear Ms. Pritza: TAKEDA GLOBAL RESEARCH & DEVELOPMENT CENTER, ING Please refer to your January 24, 2006, supplemental new drug application (NDA) submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act for Actos (pioglitazone HCI) tablets, 15 mg, 30 mg, and 45 mg. We also refer to your submissions dated June 1, August 22 and 31, October 10, November 14, and December 15, 2006, and to our proposed labeling revisions sent to you (via e-mail) on February 7, 2007. Our review of the clinical section of your response to our labeling revisions is complete, and our summary of the rationale for our changes to your proposed label appear below. 1. Movement of proposed information regarding outcome of the PROactive trial from the Clinical Studies section to the ADVERSE REACTIONS section, and inclusion of information only from the primary endpoint: This was a failed trial; statistical significance for the primary endpoint was not met, and the statistical evaluation does not support consideration of secondary endpoints in the event of failure to demonstrate significance for the primary endpoint. Even if you could demonstrate that it is statistically legitimate to consider secondary endpoints, the proposed "main" secondary endpoint was not placed in the statistical analysis plan until well after the trial had ended. Although technically it is possible to add new endpoints prior to breaking the blind, the long period of time (months) between study cessation and insertion of the new endpoint into the plan, the short period of time (days) between this addition and breaking of the blind, and the proposal to use this late- coming endpoint in the setting of a failed primary endpoint, give this endpoint the appearance of a post hoc analysis rather than a prospectively defined endpoint. Confidential - Subject to Protective Order TAK-PRITZM-00247931 Produced in MDL on 9/25/12 Source: https://www.induspo334-00001s.ucsf.edu/docs/kmjf0226 NDA 21-073/S-026 When one considers events of heart failure as well as the components of the primary endpoint (which did not include heart failure), there is even less of a numerical difference in the risk of adverse cardiovascular events for pioglitazone as compared to placebo. Under the Physician Labeling Rule (PLR), information from studies which do not directly support an approved indication will be removed from the Clinical Studies section. Although this label is not under the PLR, the next time you submit a supplement, it will be, and therefore, even if these data were to appear into the Clinical Studies section at this time, they would be removed with the first PLR label. Although we consider PROactive to be a failed trial from an efficacy standpoint, the trial does provide some reassuring safety information. Namely, it appears that pioglitazone is likely not associated with a significantly increased risk of macrovascular events compared to placebo. Given the drug's association with heart failure risk, the question of risk for other cardiovascular events has been of great concern. As such, the Division feels that addition of information to the ADVERSE REACTIONS section of the label could provide some reassurance to prescribers regarding this safety issue and would like to proceed with labeling negotiations to ensure that this relevant information is made available to the public. 2. Removal of proposed information regarding CHICAGO from the Clinical Studies section: At this time, neither the Division of Metabolism and Endocrinology Products, nor the Division of Cardiovascular and Renal Products, considers carotid intima media thickness to be a validated surrogate for risk of cardiovascular events. Although results of imaging studies have been included in labels for lipid-altering drugs, the clinical benefits of those drugs have been established in clinical outcomes studies, hence, implied claims of benefit with CIMT are less of a concern in those labels. For those drugs, CIMT results are essentially superseded by clinical outcomes data. In this label, the implied claim of benefit on the atherosclerotic process is not supported by the PROactive results. Although, when you attempted to apply the endpoint analyses from PROactive to CHICAGO, numerically slightly fewer serious cardiovascular endpoint events occurred among the pioglitazone group patients than among the placebo group patients, the difference was not significant, and was accounted for entirely by one type of event (percutaneous coronary intervention). Additionally, there was no difference between treatment groups for the incidence of events within the overall Cardiac and Vascular Disorders MedDRA System Organ Classes. Thus, this trial is not broadly supportive of decreased risk of macrovascular events. Additionally, edema and weight gain occurred more commonly among the pioglitazone group patients than among the placebo group patients. Confidential - Subject to Protective Order AK-PRITZM-00247932 Produced in MDL on 9/25/12 Source: NDA 21-073/S-026 As with the data from PROactive, the CHICAGO data do not directly support an approved indication, and thus, even if they were included in the Clinical Studies section at this time, the data would be removed with the first PLR label. We are providing these comments to you before we complete our review of the entire application to give you preliminary notice of issues that we have identified. In conformance with the prescription drug user fee reauthorization agreements, these comments do not reflect a final decision on the information reviewed and should not be construed to do so. These comments are preliminary and subject to change as we finalize our review of your application. In addition, we may identify other information that must be provided before we can approve this application. If you respond to these issues during this review cycle, depending on the timing of your response, and in conformance with the user fee reauthorization agreements, we may not be able to consider your response before we take an action on your application during this review cycle. If you have any questions, please call Ms. Jena Weber, Regulatory Project Manager, at 301-796-1306. Sincerely, (See appended electronic signature page) Mary H. Parks, M.D. Director Division of Metabolism and Endocrinology Products Office of Drug Evaluation II Center for Drug Evaluation and Research Confidential - Subject to Protective Order TAK-PRITZM-00247933 Produced in MDL on 9/25/12 Source: https://[email protected] ucsf.edu/docs/kmjf0226 This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. /s/ Mary Parks 2/13/2007 09:19:28 AM Confidential - Subject to Protective Order AK-PRITZM-00247934 Produced in MDL on 9/25/12 Source: https://www.indupo34-00004s.ucsf.edu/docs/kmjf0226

from whose desk this letter is written ?

zsjf0226

zsjf0226_p0, zsjf0226_p1

timothy J Gumbleton, Timothy J. Gumbleton

FROM THE DESK OF: Timothy J. Gumbleton UNIT: 7200 BLOG: 24-1 EXT: 5-7054 TO: PJDaniels DATE: 9/23/93 csolanoff PLRuppel - Twelch from Dr. mitchell to Dr. Matsuzana Attached is a copy of the letter It was faxed today. Dr. Mitchell added one sentence at the bottom of like Paragraph 3. He said that me further contact with Takeda should be made until we receive a reply from them. Please call if you have any questions. Upjehn ) DALY 18 CONFIDENTIAL - SUBJECT UPJ-0065602DE1 - TAKENA Aot THE UPJOHN COMPANY KALAMAZOO, MICHIGAN U.S.A. J.R. MITCHELL. MD. P.D. TELEPHONE: (616) 323.4000 Vice Chairmas of the Boand TELEPHONE: (614) FAX: (616) 185-5791 September 21, 1993 Tai Matsuzawa, Ph.D. Managing Director Vice President, Pharmaceutical Group Takeda Chemical Industries, Ltd. 1-1, Doshomachi 4-Chome Chuo-Ku, Osaka 541 Japan Dear Doctor Matsuzawa: As you know, Upjohn has committed to notify Takeda by October 1, 1993, of our intentions regarding further clinical development of pioglitazone. On September 20 our Pharmaceutical Executive Council, Upjohn's highest scientific decision-making body, carefully reviewed the results of the toxicology and clinical studies. The decision of the Council was that Upjohn will not go forward with pioglitazone in the clinic. The Council decided that further clinical development of pioglitazone could not be justified based on their concern regarding pioglitazone's margin of safety. As a consequence of this decision, Upjohn also must decline participation with Takeda on the proposed pioglitazone study in Canada. It is with deep regret that I convey this message. As you know Upjohn and Takeda enjoy a strong and beneficial relationship based on mutual respect. It is a great disappointment to us that we will not have the opportunity of further interactions and collaboration with Takeda on this project. Hopefully, we will find other opportunities for collaboration in the future. I have instructed my staff to work closely with Takeda personnel in regards to the release of any information, data, FDA notifications, and other issues to ensure Takeda's interests and wishes are followed. With best personal regards, Sincerely, President, Upjohn Laboratories Worldwide Research, Development, & Medical Affairs CONEIDENTIAL - SUBJECT TO PROTECTIVE ORDER UPJ-0065603 Source:

Whose letter's copy is attached?

zsjf0226

zsjf0226_p0, zsjf0226_p1

Dr. Mitchell, DR. Mitchell

FROM THE DESK OF: Timothy J. Gumbleton UNIT: 7200 BLOG: 24-1 EXT: 5-7054 TO: PJDaniels DATE: 9/23/93 csolanoff PLRuppel - Twelch from Dr. mitchell to Dr. Matsuzana Attached is a copy of the letter It was faxed today. Dr. Mitchell added one sentence at the bottom of like Paragraph 3. He said that me further contact with Takeda should be made until we receive a reply from them. Please call if you have any questions. Upjehn ) DALY 18 CONFIDENTIAL - SUBJECT UPJ-0065602DE1 - TAKENA Aot THE UPJOHN COMPANY KALAMAZOO, MICHIGAN U.S.A. J.R. MITCHELL. MD. P.D. TELEPHONE: (616) 323.4000 Vice Chairmas of the Boand TELEPHONE: (614) FAX: (616) 185-5791 September 21, 1993 Tai Matsuzawa, Ph.D. Managing Director Vice President, Pharmaceutical Group Takeda Chemical Industries, Ltd. 1-1, Doshomachi 4-Chome Chuo-Ku, Osaka 541 Japan Dear Doctor Matsuzawa: As you know, Upjohn has committed to notify Takeda by October 1, 1993, of our intentions regarding further clinical development of pioglitazone. On September 20 our Pharmaceutical Executive Council, Upjohn's highest scientific decision-making body, carefully reviewed the results of the toxicology and clinical studies. The decision of the Council was that Upjohn will not go forward with pioglitazone in the clinic. The Council decided that further clinical development of pioglitazone could not be justified based on their concern regarding pioglitazone's margin of safety. As a consequence of this decision, Upjohn also must decline participation with Takeda on the proposed pioglitazone study in Canada. It is with deep regret that I convey this message. As you know Upjohn and Takeda enjoy a strong and beneficial relationship based on mutual respect. It is a great disappointment to us that we will not have the opportunity of further interactions and collaboration with Takeda on this project. Hopefully, we will find other opportunities for collaboration in the future. I have instructed my staff to work closely with Takeda personnel in regards to the release of any information, data, FDA notifications, and other issues to ensure Takeda's interests and wishes are followed. With best personal regards, Sincerely, President, Upjohn Laboratories Worldwide Research, Development, & Medical Affairs CONEIDENTIAL - SUBJECT TO PROTECTIVE ORDER UPJ-0065603 Source:

what is the date mentioned ?

hmjf0226

hmjf0226_p0

February 6, 1996, february 6 , 1996

Encl. 2 Draft 2/11 TAKEDA INTERNATIONAL COMMUNICATION Date February 6, 1996 To Dr. K Kitazawa General Manager International Development From T. Suzuki Senior Research Head Drug Safety Research Laboratories Subject A Prompt Report for Interim Results of AD-4833 2Y Rat & Mouse Studies We are performing two-yoar carcinogenicity studics in rats and mice at MPI (formerly: IRDC) Rescarch Labs. Pathological examinations of these studies have almost finished recently. : In the rat study, a treatment-related increase in incidence of transitional coll tumors in the urinary bladder was seen. 1) Rat study Sixty Sprague-Dawley BR rats/sex</group were administered AD-4833 (HCI) at doses of 1, 4, 8, 16 and 63mg/kg/day for males and 1, 4, 16 and 63mg/kg/day for females. The incidence of transitional cell bonign tumor and/or transitional cell carcinoma in the urinary bladder was increased in males receiving 4mg/kg/day or more. In females, transitional cell benign tumor in the same organ was seen in each one animal receiving 1, 4 and 16mig/kg/day. There is no treatment- xclated increase in incidence of tumors in any other organs. 2) Mouse study Sixty Cri:CD (ICR) BR mice/sex/group were administered AD-4833 (HCI) at doses of 3, 10. 30 and 100mg/kg/day. There is no treatment-related increase in incidence of tumors in any organs. Thero is no treatment-rclated increase in incidence of tumors in any organs in 2-year mouse and one year dog and monkey study. Thus, it is supposed that increased tumors in urinary bladder might be species specific. Tompodine Sugar Tsuyoshi Suzuki, M. S. Confidential - Subject to Protective Order TAK-COHENS-00006201 Produced in MDL on 09/14/12 Source:

to whom this letter is written ?

hmjf0226

hmjf0226_p0

Dr . k. Kitazawa, Dr. K. KItazawa

Encl. 2 Draft 2/11 TAKEDA INTERNATIONAL COMMUNICATION Date February 6, 1996 To Dr. K Kitazawa General Manager International Development From T. Suzuki Senior Research Head Drug Safety Research Laboratories Subject A Prompt Report for Interim Results of AD-4833 2Y Rat & Mouse Studies We are performing two-yoar carcinogenicity studics in rats and mice at MPI (formerly: IRDC) Rescarch Labs. Pathological examinations of these studies have almost finished recently. : In the rat study, a treatment-related increase in incidence of transitional coll tumors in the urinary bladder was seen. 1) Rat study Sixty Sprague-Dawley BR rats/sex</group were administered AD-4833 (HCI) at doses of 1, 4, 8, 16 and 63mg/kg/day for males and 1, 4, 16 and 63mg/kg/day for females. The incidence of transitional cell bonign tumor and/or transitional cell carcinoma in the urinary bladder was increased in males receiving 4mg/kg/day or more. In females, transitional cell benign tumor in the same organ was seen in each one animal receiving 1, 4 and 16mig/kg/day. There is no treatment- xclated increase in incidence of tumors in any other organs. 2) Mouse study Sixty Cri:CD (ICR) BR mice/sex/group were administered AD-4833 (HCI) at doses of 3, 10. 30 and 100mg/kg/day. There is no treatment-related increase in incidence of tumors in any organs. Thero is no treatment-rclated increase in incidence of tumors in any organs in 2-year mouse and one year dog and monkey study. Thus, it is supposed that increased tumors in urinary bladder might be species specific. Tompodine Sugar Tsuyoshi Suzuki, M. S. Confidential - Subject to Protective Order TAK-COHENS-00006201 Produced in MDL on 09/14/12 Source:

this letter is written by whom ?

hmjf0226

hmjf0226_p0

Tsuyoshi Suzuki , M S ., T. Suzuki

Encl. 2 Draft 2/11 TAKEDA INTERNATIONAL COMMUNICATION Date February 6, 1996 To Dr. K Kitazawa General Manager International Development From T. Suzuki Senior Research Head Drug Safety Research Laboratories Subject A Prompt Report for Interim Results of AD-4833 2Y Rat & Mouse Studies We are performing two-yoar carcinogenicity studics in rats and mice at MPI (formerly: IRDC) Rescarch Labs. Pathological examinations of these studies have almost finished recently. : In the rat study, a treatment-related increase in incidence of transitional coll tumors in the urinary bladder was seen. 1) Rat study Sixty Sprague-Dawley BR rats/sex</group were administered AD-4833 (HCI) at doses of 1, 4, 8, 16 and 63mg/kg/day for males and 1, 4, 16 and 63mg/kg/day for females. The incidence of transitional cell bonign tumor and/or transitional cell carcinoma in the urinary bladder was increased in males receiving 4mg/kg/day or more. In females, transitional cell benign tumor in the same organ was seen in each one animal receiving 1, 4 and 16mig/kg/day. There is no treatment- xclated increase in incidence of tumors in any other organs. 2) Mouse study Sixty Cri:CD (ICR) BR mice/sex/group were administered AD-4833 (HCI) at doses of 3, 10. 30 and 100mg/kg/day. There is no treatment-related increase in incidence of tumors in any organs. Thero is no treatment-rclated increase in incidence of tumors in any organs in 2-year mouse and one year dog and monkey study. Thus, it is supposed that increased tumors in urinary bladder might be species specific. Tompodine Sugar Tsuyoshi Suzuki, M. S. Confidential - Subject to Protective Order TAK-COHENS-00006201 Produced in MDL on 09/14/12 Source:

Which laboratory is T. Suzuki associated with ?

hmjf0226

hmjf0226_p0

Drug Safety Research Laboratories, drug safety research laboratories .

Encl. 2 Draft 2/11 TAKEDA INTERNATIONAL COMMUNICATION Date February 6, 1996 To Dr. K Kitazawa General Manager International Development From T. Suzuki Senior Research Head Drug Safety Research Laboratories Subject A Prompt Report for Interim Results of AD-4833 2Y Rat & Mouse Studies We are performing two-yoar carcinogenicity studics in rats and mice at MPI (formerly: IRDC) Rescarch Labs. Pathological examinations of these studies have almost finished recently. : In the rat study, a treatment-related increase in incidence of transitional coll tumors in the urinary bladder was seen. 1) Rat study Sixty Sprague-Dawley BR rats/sex</group were administered AD-4833 (HCI) at doses of 1, 4, 8, 16 and 63mg/kg/day for males and 1, 4, 16 and 63mg/kg/day for females. The incidence of transitional cell bonign tumor and/or transitional cell carcinoma in the urinary bladder was increased in males receiving 4mg/kg/day or more. In females, transitional cell benign tumor in the same organ was seen in each one animal receiving 1, 4 and 16mig/kg/day. There is no treatment- xclated increase in incidence of tumors in any other organs. 2) Mouse study Sixty Cri:CD (ICR) BR mice/sex/group were administered AD-4833 (HCI) at doses of 3, 10. 30 and 100mg/kg/day. There is no treatment-related increase in incidence of tumors in any organs. Thero is no treatment-rclated increase in incidence of tumors in any organs in 2-year mouse and one year dog and monkey study. Thus, it is supposed that increased tumors in urinary bladder might be species specific. Tompodine Sugar Tsuyoshi Suzuki, M. S. Confidential - Subject to Protective Order TAK-COHENS-00006201 Produced in MDL on 09/14/12 Source:

what is the date mentioned in the letter

pljf0226

pljf0226_p0, pljf0226_p1, pljf0226_p2, pljf0226_p3, pljf0226_p4, pljf0226_p5

august 8 , 2002, August 8, 2002

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

What is the name of the industry given here?

pljf0226

pljf0226_p0, pljf0226_p1, pljf0226_p2, pljf0226_p3, pljf0226_p4, pljf0226_p5

Takeda chemical industries, LTD ., TAKEDA CHEMICAL INDUSTRIES, LTD.

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

to whom this letter is written ?

pljf0226

pljf0226_p0, pljf0226_p1, pljf0226_p2, pljf0226_p3, pljf0226_p4, pljf0226_p5

Dr. Thom, Dr. Claire Thom

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

what is the name mentioned in CC

pljf0226

pljf0226_p0, pljf0226_p1, pljf0226_p2, pljf0226_p3, pljf0226_p4, pljf0226_p5

Mr . S . Hamanaka, Mr. S. Hamanaka

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 sent this letter?

pljf0226

pljf0226_p0, pljf0226_p1, pljf0226_p2, pljf0226_p3, pljf0226_p4, pljf0226_p5

Katsuhisa Saito, katsuhisa saito

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

what is Ref: code mentioned ?

pljf0226

pljf0226_p0, pljf0226_p1, pljf0226_p2, pljf0226_p3, pljf0226_p4, pljf0226_p5

TPNA-TS-020808

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

what is the fax number mentioned in the letter at the top?

pljf0226

pljf0226_p0, pljf0226_p1, pljf0226_p2, pljf0226_p3, pljf0226_p4, pljf0226_p5

06 6204 2244

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

what is the date and time mentioned ?

sljf0226

sljf0226_p0

10/27/93 09:36:07

From: PLK --RCC1 Date and time 10/27/93 09:36:07 To: PJDANIEL--PW17PO PETER J. DANIELS CC: RJWELTER--PW17PO RICHARD J. WELTER LTWELCH --RCC1 LAWRENCE T WELCH From: plruppel Subject: Pioglitazone statement Actually, this statement reflects pretty accurately the stand that Jim Moe and Larry Olanoff presented to Takeda in Osaka. There are preclinical issues and the amount of preclinical work that would be needed to address these issues and the modest clinical efficacy that has been seen do not justify development in accordance with Upjohn's business needs. Larry does not feel that there is a need for an "Upjohn statement" Please let me know if you want to discuss this further. Patty Forwarding note from PJDANIEL--PW17 10/26/93 15:44 *** From: PJDANIEL To: PLRUPPEL--RCC1 RUPPEL, PATRICIA CC: PJDANIEL -- RJWELTER LTWELCH - -RCC1 WELCH, LAWRENCE Subject: Pioglitazone statement Patty, thanks for the Takeda letter. Some of my colleagues are concerned about the lack of frankness (and honesty?) of the Takeda statement. We realise we are hemmed in by a confidentiality clause, but does this have the endorsement of our senior management. Regards, Peter. tile - Takeda Boull fizone liceuse agt CONFIDENTIAL - SUBJECT TO PROTECTIVE ORDER JPJ-0065604 Source: https://www.induporde-oooonts.ucsf.edu/docs/sljf0226

what is mentioned in the subject ?

sljf0226

sljf0226_p0

pioglitazone statement, Pioglitazone statement

From: PLK --RCC1 Date and time 10/27/93 09:36:07 To: PJDANIEL--PW17PO PETER J. DANIELS CC: RJWELTER--PW17PO RICHARD J. WELTER LTWELCH --RCC1 LAWRENCE T WELCH From: plruppel Subject: Pioglitazone statement Actually, this statement reflects pretty accurately the stand that Jim Moe and Larry Olanoff presented to Takeda in Osaka. There are preclinical issues and the amount of preclinical work that would be needed to address these issues and the modest clinical efficacy that has been seen do not justify development in accordance with Upjohn's business needs. Larry does not feel that there is a need for an "Upjohn statement" Please let me know if you want to discuss this further. Patty Forwarding note from PJDANIEL--PW17 10/26/93 15:44 *** From: PJDANIEL To: PLRUPPEL--RCC1 RUPPEL, PATRICIA CC: PJDANIEL -- RJWELTER LTWELCH - -RCC1 WELCH, LAWRENCE Subject: Pioglitazone statement Patty, thanks for the Takeda letter. Some of my colleagues are concerned about the lack of frankness (and honesty?) of the Takeda statement. We realise we are hemmed in by a confidentiality clause, but does this have the endorsement of our senior management. Regards, Peter. tile - Takeda Boull fizone liceuse agt CONFIDENTIAL - SUBJECT TO PROTECTIVE ORDER JPJ-0065604 Source: https://www.induporde-oooonts.ucsf.edu/docs/sljf0226

To whom this email was send?

sljf0226

sljf0226_p0

PETER J. DANIELS, PJ DANIEL--PW17PO PETER J. DANIELS

From: PLK --RCC1 Date and time 10/27/93 09:36:07 To: PJDANIEL--PW17PO PETER J. DANIELS CC: RJWELTER--PW17PO RICHARD J. WELTER LTWELCH --RCC1 LAWRENCE T WELCH From: plruppel Subject: Pioglitazone statement Actually, this statement reflects pretty accurately the stand that Jim Moe and Larry Olanoff presented to Takeda in Osaka. There are preclinical issues and the amount of preclinical work that would be needed to address these issues and the modest clinical efficacy that has been seen do not justify development in accordance with Upjohn's business needs. Larry does not feel that there is a need for an "Upjohn statement" Please let me know if you want to discuss this further. Patty Forwarding note from PJDANIEL--PW17 10/26/93 15:44 *** From: PJDANIEL To: PLRUPPEL--RCC1 RUPPEL, PATRICIA CC: PJDANIEL -- RJWELTER LTWELCH - -RCC1 WELCH, LAWRENCE Subject: Pioglitazone statement Patty, thanks for the Takeda letter. Some of my colleagues are concerned about the lack of frankness (and honesty?) of the Takeda statement. We realise we are hemmed in by a confidentiality clause, but does this have the endorsement of our senior management. Regards, Peter. tile - Takeda Boull fizone liceuse agt CONFIDENTIAL - SUBJECT TO PROTECTIVE ORDER JPJ-0065604 Source: https://www.induporde-oooonts.ucsf.edu/docs/sljf0226

what is the date mentioned in the forwarding note ?

sljf0226

sljf0226_p0

10/26/93, 10/26/93 15:44

From: PLK --RCC1 Date and time 10/27/93 09:36:07 To: PJDANIEL--PW17PO PETER J. DANIELS CC: RJWELTER--PW17PO RICHARD J. WELTER LTWELCH --RCC1 LAWRENCE T WELCH From: plruppel Subject: Pioglitazone statement Actually, this statement reflects pretty accurately the stand that Jim Moe and Larry Olanoff presented to Takeda in Osaka. There are preclinical issues and the amount of preclinical work that would be needed to address these issues and the modest clinical efficacy that has been seen do not justify development in accordance with Upjohn's business needs. Larry does not feel that there is a need for an "Upjohn statement" Please let me know if you want to discuss this further. Patty Forwarding note from PJDANIEL--PW17 10/26/93 15:44 *** From: PJDANIEL To: PLRUPPEL--RCC1 RUPPEL, PATRICIA CC: PJDANIEL -- RJWELTER LTWELCH - -RCC1 WELCH, LAWRENCE Subject: Pioglitazone statement Patty, thanks for the Takeda letter. Some of my colleagues are concerned about the lack of frankness (and honesty?) of the Takeda statement. We realise we are hemmed in by a confidentiality clause, but does this have the endorsement of our senior management. Regards, Peter. tile - Takeda Boull fizone liceuse agt CONFIDENTIAL - SUBJECT TO PROTECTIVE ORDER JPJ-0065604 Source: https://www.induporde-oooonts.ucsf.edu/docs/sljf0226

what is the time mentioned in the forwarding note ?

sljf0226

sljf0226_p0

15:44

From: PLK --RCC1 Date and time 10/27/93 09:36:07 To: PJDANIEL--PW17PO PETER J. DANIELS CC: RJWELTER--PW17PO RICHARD J. WELTER LTWELCH --RCC1 LAWRENCE T WELCH From: plruppel Subject: Pioglitazone statement Actually, this statement reflects pretty accurately the stand that Jim Moe and Larry Olanoff presented to Takeda in Osaka. There are preclinical issues and the amount of preclinical work that would be needed to address these issues and the modest clinical efficacy that has been seen do not justify development in accordance with Upjohn's business needs. Larry does not feel that there is a need for an "Upjohn statement" Please let me know if you want to discuss this further. Patty Forwarding note from PJDANIEL--PW17 10/26/93 15:44 *** From: PJDANIEL To: PLRUPPEL--RCC1 RUPPEL, PATRICIA CC: PJDANIEL -- RJWELTER LTWELCH - -RCC1 WELCH, LAWRENCE Subject: Pioglitazone statement Patty, thanks for the Takeda letter. Some of my colleagues are concerned about the lack of frankness (and honesty?) of the Takeda statement. We realise we are hemmed in by a confidentiality clause, but does this have the endorsement of our senior management. Regards, Peter. tile - Takeda Boull fizone liceuse agt CONFIDENTIAL - SUBJECT TO PROTECTIVE ORDER JPJ-0065604 Source: https://www.induporde-oooonts.ucsf.edu/docs/sljf0226

To whom this email was forwaded?

sljf0226

sljf0226_p0

PLRUPPEL--RCC1 RUPPEL, PATRICIA, RUPPEL, PATRICIA

From: PLK --RCC1 Date and time 10/27/93 09:36:07 To: PJDANIEL--PW17PO PETER J. DANIELS CC: RJWELTER--PW17PO RICHARD J. WELTER LTWELCH --RCC1 LAWRENCE T WELCH From: plruppel Subject: Pioglitazone statement Actually, this statement reflects pretty accurately the stand that Jim Moe and Larry Olanoff presented to Takeda in Osaka. There are preclinical issues and the amount of preclinical work that would be needed to address these issues and the modest clinical efficacy that has been seen do not justify development in accordance with Upjohn's business needs. Larry does not feel that there is a need for an "Upjohn statement" Please let me know if you want to discuss this further. Patty Forwarding note from PJDANIEL--PW17 10/26/93 15:44 *** From: PJDANIEL To: PLRUPPEL--RCC1 RUPPEL, PATRICIA CC: PJDANIEL -- RJWELTER LTWELCH - -RCC1 WELCH, LAWRENCE Subject: Pioglitazone statement Patty, thanks for the Takeda letter. Some of my colleagues are concerned about the lack of frankness (and honesty?) of the Takeda statement. We realise we are hemmed in by a confidentiality clause, but does this have the endorsement of our senior management. Regards, Peter. tile - Takeda Boull fizone liceuse agt CONFIDENTIAL - SUBJECT TO PROTECTIVE ORDER JPJ-0065604 Source: https://www.induporde-oooonts.ucsf.edu/docs/sljf0226

what is the name of the company

zsjf0226

zsjf0226_p0, zsjf0226_p1

THE UPJOHN COMPANY

FROM THE DESK OF: Timothy J. Gumbleton UNIT: 7200 BLOG: 24-1 EXT: 5-7054 TO: PJDaniels DATE: 9/23/93 csolanoff PLRuppel - Twelch from Dr. mitchell to Dr. Matsuzana Attached is a copy of the letter It was faxed today. Dr. Mitchell added one sentence at the bottom of like Paragraph 3. He said that me further contact with Takeda should be made until we receive a reply from them. Please call if you have any questions. Upjehn ) DALY 18 CONFIDENTIAL - SUBJECT UPJ-0065602DE1 - TAKENA Aot THE UPJOHN COMPANY KALAMAZOO, MICHIGAN U.S.A. J.R. MITCHELL. MD. P.D. TELEPHONE: (616) 323.4000 Vice Chairmas of the Boand TELEPHONE: (614) FAX: (616) 185-5791 September 21, 1993 Tai Matsuzawa, Ph.D. Managing Director Vice President, Pharmaceutical Group Takeda Chemical Industries, Ltd. 1-1, Doshomachi 4-Chome Chuo-Ku, Osaka 541 Japan Dear Doctor Matsuzawa: As you know, Upjohn has committed to notify Takeda by October 1, 1993, of our intentions regarding further clinical development of pioglitazone. On September 20 our Pharmaceutical Executive Council, Upjohn's highest scientific decision-making body, carefully reviewed the results of the toxicology and clinical studies. The decision of the Council was that Upjohn will not go forward with pioglitazone in the clinic. The Council decided that further clinical development of pioglitazone could not be justified based on their concern regarding pioglitazone's margin of safety. As a consequence of this decision, Upjohn also must decline participation with Takeda on the proposed pioglitazone study in Canada. It is with deep regret that I convey this message. As you know Upjohn and Takeda enjoy a strong and beneficial relationship based on mutual respect. It is a great disappointment to us that we will not have the opportunity of further interactions and collaboration with Takeda on this project. Hopefully, we will find other opportunities for collaboration in the future. I have instructed my staff to work closely with Takeda personnel in regards to the release of any information, data, FDA notifications, and other issues to ensure Takeda's interests and wishes are followed. With best personal regards, Sincerely, President, Upjohn Laboratories Worldwide Research, Development, & Medical Affairs CONEIDENTIAL - SUBJECT TO PROTECTIVE ORDER UPJ-0065603 Source:

what is the date and year mentioned ?

zsjf0226

zsjf0226_p0, zsjf0226_p1

september 21 , 1993, September 21, 1993

FROM THE DESK OF: Timothy J. Gumbleton UNIT: 7200 BLOG: 24-1 EXT: 5-7054 TO: PJDaniels DATE: 9/23/93 csolanoff PLRuppel - Twelch from Dr. mitchell to Dr. Matsuzana Attached is a copy of the letter It was faxed today. Dr. Mitchell added one sentence at the bottom of like Paragraph 3. He said that me further contact with Takeda should be made until we receive a reply from them. Please call if you have any questions. Upjehn ) DALY 18 CONFIDENTIAL - SUBJECT UPJ-0065602DE1 - TAKENA Aot THE UPJOHN COMPANY KALAMAZOO, MICHIGAN U.S.A. J.R. MITCHELL. MD. P.D. TELEPHONE: (616) 323.4000 Vice Chairmas of the Boand TELEPHONE: (614) FAX: (616) 185-5791 September 21, 1993 Tai Matsuzawa, Ph.D. Managing Director Vice President, Pharmaceutical Group Takeda Chemical Industries, Ltd. 1-1, Doshomachi 4-Chome Chuo-Ku, Osaka 541 Japan Dear Doctor Matsuzawa: As you know, Upjohn has committed to notify Takeda by October 1, 1993, of our intentions regarding further clinical development of pioglitazone. On September 20 our Pharmaceutical Executive Council, Upjohn's highest scientific decision-making body, carefully reviewed the results of the toxicology and clinical studies. The decision of the Council was that Upjohn will not go forward with pioglitazone in the clinic. The Council decided that further clinical development of pioglitazone could not be justified based on their concern regarding pioglitazone's margin of safety. As a consequence of this decision, Upjohn also must decline participation with Takeda on the proposed pioglitazone study in Canada. It is with deep regret that I convey this message. As you know Upjohn and Takeda enjoy a strong and beneficial relationship based on mutual respect. It is a great disappointment to us that we will not have the opportunity of further interactions and collaboration with Takeda on this project. Hopefully, we will find other opportunities for collaboration in the future. I have instructed my staff to work closely with Takeda personnel in regards to the release of any information, data, FDA notifications, and other issues to ensure Takeda's interests and wishes are followed. With best personal regards, Sincerely, President, Upjohn Laboratories Worldwide Research, Development, & Medical Affairs CONEIDENTIAL - SUBJECT TO PROTECTIVE ORDER UPJ-0065603 Source:

Which company is mentioned in the letterhead?

zsjf0226

zsjf0226_p0, zsjf0226_p1

THE UPJOHN COMPANY

FROM THE DESK OF: Timothy J. Gumbleton UNIT: 7200 BLOG: 24-1 EXT: 5-7054 TO: PJDaniels DATE: 9/23/93 csolanoff PLRuppel - Twelch from Dr. mitchell to Dr. Matsuzana Attached is a copy of the letter It was faxed today. Dr. Mitchell added one sentence at the bottom of like Paragraph 3. He said that me further contact with Takeda should be made until we receive a reply from them. Please call if you have any questions. Upjehn ) DALY 18 CONFIDENTIAL - SUBJECT UPJ-0065602DE1 - TAKENA Aot THE UPJOHN COMPANY KALAMAZOO, MICHIGAN U.S.A. J.R. MITCHELL. MD. P.D. TELEPHONE: (616) 323.4000 Vice Chairmas of the Boand TELEPHONE: (614) FAX: (616) 185-5791 September 21, 1993 Tai Matsuzawa, Ph.D. Managing Director Vice President, Pharmaceutical Group Takeda Chemical Industries, Ltd. 1-1, Doshomachi 4-Chome Chuo-Ku, Osaka 541 Japan Dear Doctor Matsuzawa: As you know, Upjohn has committed to notify Takeda by October 1, 1993, of our intentions regarding further clinical development of pioglitazone. On September 20 our Pharmaceutical Executive Council, Upjohn's highest scientific decision-making body, carefully reviewed the results of the toxicology and clinical studies. The decision of the Council was that Upjohn will not go forward with pioglitazone in the clinic. The Council decided that further clinical development of pioglitazone could not be justified based on their concern regarding pioglitazone's margin of safety. As a consequence of this decision, Upjohn also must decline participation with Takeda on the proposed pioglitazone study in Canada. It is with deep regret that I convey this message. As you know Upjohn and Takeda enjoy a strong and beneficial relationship based on mutual respect. It is a great disappointment to us that we will not have the opportunity of further interactions and collaboration with Takeda on this project. Hopefully, we will find other opportunities for collaboration in the future. I have instructed my staff to work closely with Takeda personnel in regards to the release of any information, data, FDA notifications, and other issues to ensure Takeda's interests and wishes are followed. With best personal regards, Sincerely, President, Upjohn Laboratories Worldwide Research, Development, & Medical Affairs CONEIDENTIAL - SUBJECT TO PROTECTIVE ORDER UPJ-0065603 Source:

in which country the upjohn company is located ?

zsjf0226

zsjf0226_p0, zsjf0226_p1

U.S.A, USA

FROM THE DESK OF: Timothy J. Gumbleton UNIT: 7200 BLOG: 24-1 EXT: 5-7054 TO: PJDaniels DATE: 9/23/93 csolanoff PLRuppel - Twelch from Dr. mitchell to Dr. Matsuzana Attached is a copy of the letter It was faxed today. Dr. Mitchell added one sentence at the bottom of like Paragraph 3. He said that me further contact with Takeda should be made until we receive a reply from them. Please call if you have any questions. Upjehn ) DALY 18 CONFIDENTIAL - SUBJECT UPJ-0065602DE1 - TAKENA Aot THE UPJOHN COMPANY KALAMAZOO, MICHIGAN U.S.A. J.R. MITCHELL. MD. P.D. TELEPHONE: (616) 323.4000 Vice Chairmas of the Boand TELEPHONE: (614) FAX: (616) 185-5791 September 21, 1993 Tai Matsuzawa, Ph.D. Managing Director Vice President, Pharmaceutical Group Takeda Chemical Industries, Ltd. 1-1, Doshomachi 4-Chome Chuo-Ku, Osaka 541 Japan Dear Doctor Matsuzawa: As you know, Upjohn has committed to notify Takeda by October 1, 1993, of our intentions regarding further clinical development of pioglitazone. On September 20 our Pharmaceutical Executive Council, Upjohn's highest scientific decision-making body, carefully reviewed the results of the toxicology and clinical studies. The decision of the Council was that Upjohn will not go forward with pioglitazone in the clinic. The Council decided that further clinical development of pioglitazone could not be justified based on their concern regarding pioglitazone's margin of safety. As a consequence of this decision, Upjohn also must decline participation with Takeda on the proposed pioglitazone study in Canada. It is with deep regret that I convey this message. As you know Upjohn and Takeda enjoy a strong and beneficial relationship based on mutual respect. It is a great disappointment to us that we will not have the opportunity of further interactions and collaboration with Takeda on this project. Hopefully, we will find other opportunities for collaboration in the future. I have instructed my staff to work closely with Takeda personnel in regards to the release of any information, data, FDA notifications, and other issues to ensure Takeda's interests and wishes are followed. With best personal regards, Sincerely, President, Upjohn Laboratories Worldwide Research, Development, & Medical Affairs CONEIDENTIAL - SUBJECT TO PROTECTIVE ORDER UPJ-0065603 Source:

what is the fax mentioned ?

pljf0226

pljf0226_p0, pljf0226_p1, pljf0226_p2, pljf0226_p3, pljf0226_p4, pljf0226_p5

06 6204 2244

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

what is year date and time mentioned?

pljf0226

pljf0226_p0, pljf0226_p1, pljf0226_p2, pljf0226_p3, pljf0226_p4, pljf0226_p5

2002 08/08 21:49

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

what is the name of the division ?

pljf0226

pljf0226_p0, pljf0226_p1, pljf0226_p2, pljf0226_p3, pljf0226_p4, pljf0226_p5

Takeda Develop division, TAKEDA DEVELOP DIVISION

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

to whom they can ask directly to disclose the details of "promotion study"?

pljf0226

pljf0226_p0, pljf0226_p1, pljf0226_p2, pljf0226_p3, pljf0226_p4, pljf0226_p5

FDA

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

what is the date mentioned in the letter

syjf0226

syjf0226_p0, syjf0226_p1, syjf0226_p2

8 January 2003, 8 january 2003

8 January 2003 To: MPDRAP I Leader cc: CEOs and General Managers of Pharmaceutical Units My Concerns about sNDA for Actos 45mg in the USA (Reconfirmation) Pharmaceutical International Division Y. Narai I express my opinion about the conclusion drawn at MPDRAP Committee Meeting where it was agreed that sNDA to obtain the approval of the 45mg combination indications would be submitted, as well as the safety update based on the commitment studies. As you know, Actos is the essential product for TPNA and is vital to the survival of TPNA. If unfavorable revisions in the Actos labeling are made, it invites the serious risk to Actos in the US. TPNA is now under attack from GSK, especially by Avandamet and is eager to maintain their market share. In addition to this attack, if the indications of Actos are reduced, TPNA is pushed into critical situation. This issue seriously damages not only US market but also Takeda's global strategy. Therefore, HQ should be extremely cautious about the issues related to Actos. If this sNDA raises the argument for the indications of Actos, for example, reductions in the indications, the issues will come to a critical path like as I mentioned. So we should go into action on condition that there is no such risk. Combination therapy in the US market accounts for 64% of total Actos sales. (29% in combination with SU, 27% Metformin and 8% Insulin) Regarding the possibility of the risk of labeling revision, International Division entrusts Development Division with final decision. However, just to be sure, I would like to reconfirm that this sNDA dose not lead to a serious situation. I heard that TPNA R&D suggested to HQ and is getting ready for sNDA for the 45mg combination indications. However, HQ should carefully judge whether this sNDA should be submitted to the FDA or not. I think that sNDA for efficacy should be submitted only when there is no risk that this sNDA damages the current labeling. According to the results of PNFP-343, combination with insulin, edema was observed more often than Avandia, which dose not have the indication for combination with insulin and CHF in this study seems to be dose related. Confidential - Subject to Protective Order TAK-THOMCL-00005583 Produced in MDL on 09/14/12 Source: https://www.indupt2290c0000ts.ucsf.edu/docs/syjf0226 Combination with Insulin (%) 2 5 Edema Actos Avandia 20 1 5 00 5 0 Placcbo 15-30mg 30mg 45mg Placebo Avandia PNFP-014 PNFP-343 Data from PI (%) 3.5 CHF Actos Avandia 3 2.5 3 1.5 1 0.5 0 Placebo 15+30mg 30mg 45mg Placcbo 4mg 8mg Total of PNFP-010, PNFP-343 Data from PI 014, 027 And based upon the results of PNFP 341, combination with SU, the incidences of edema and CHF in Actos groups were similar to those for Avandia in combination with insulin. Combination with SU (%) Avandia in combination 3 5 Edema Actos with Insulin 20 05 1 0 5 0 Placebo 15:30mg 30mg 45mg Placebo Avandia PNFP-010 PNFP-341 Data from PI Confidential - Subject to Protective Order TAK-THOMCL-00005584 Produced in MDL on 09/14/12 Source: https://www.indup2290000002ts.ucsf.edu/docs/syjf0226 (%) Avandia in combination 3.0 CHF Actos 3 with Insulin 2.5 2 1.5 1 0.5 c Placebo 15+30mg 30mg 45mg Placebo 4mg 8mg Total of PNFP-010, PNFP-341 Data from PI 014,027 Clinical development is not in my line. However, I am compelled to be concerned about the results of these studies. Can you undoubtedly assure that the MPDRAP conclusion dose not have an adverse affect on the current labeling? This issue was already discussed at MPDRAP Committee Meeting, but I would like you to reconfirm the conclusion at the meeting. END (Reference] Combination with Metformin L 6 (%) Edema L 4 - L 2 - Actos Avandia 10 - 8 - 8 - 4 2 - 0 Placebo 30mg 30mg 45mg 7° 5t* 4mg 8mg PNFP-027 PNFP-342 Data from PI (%) CHF 3.6 8 2.5 Actos 2 1.5 I 0.5 0 Placebo 15+30mg 30mg 45mg Total of PNFP-010, 014,027 PNFP-342 Confidential - Subject to Protective Order TAK-THOMCL-00005585 Produced in MDL on 09/14/12 Source: https://www.indupt2290000003t.ucsf.edu/docs/syjf0226

To whom this letter is addressed?

syjf0226

syjf0226_p0, syjf0226_p1, syjf0226_p2

MPDRAP I Leader

8 January 2003 To: MPDRAP I Leader cc: CEOs and General Managers of Pharmaceutical Units My Concerns about sNDA for Actos 45mg in the USA (Reconfirmation) Pharmaceutical International Division Y. Narai I express my opinion about the conclusion drawn at MPDRAP Committee Meeting where it was agreed that sNDA to obtain the approval of the 45mg combination indications would be submitted, as well as the safety update based on the commitment studies. As you know, Actos is the essential product for TPNA and is vital to the survival of TPNA. If unfavorable revisions in the Actos labeling are made, it invites the serious risk to Actos in the US. TPNA is now under attack from GSK, especially by Avandamet and is eager to maintain their market share. In addition to this attack, if the indications of Actos are reduced, TPNA is pushed into critical situation. This issue seriously damages not only US market but also Takeda's global strategy. Therefore, HQ should be extremely cautious about the issues related to Actos. If this sNDA raises the argument for the indications of Actos, for example, reductions in the indications, the issues will come to a critical path like as I mentioned. So we should go into action on condition that there is no such risk. Combination therapy in the US market accounts for 64% of total Actos sales. (29% in combination with SU, 27% Metformin and 8% Insulin) Regarding the possibility of the risk of labeling revision, International Division entrusts Development Division with final decision. However, just to be sure, I would like to reconfirm that this sNDA dose not lead to a serious situation. I heard that TPNA R&D suggested to HQ and is getting ready for sNDA for the 45mg combination indications. However, HQ should carefully judge whether this sNDA should be submitted to the FDA or not. I think that sNDA for efficacy should be submitted only when there is no risk that this sNDA damages the current labeling. According to the results of PNFP-343, combination with insulin, edema was observed more often than Avandia, which dose not have the indication for combination with insulin and CHF in this study seems to be dose related. Confidential - Subject to Protective Order TAK-THOMCL-00005583 Produced in MDL on 09/14/12 Source: https://www.indupt2290c0000ts.ucsf.edu/docs/syjf0226 Combination with Insulin (%) 2 5 Edema Actos Avandia 20 1 5 00 5 0 Placcbo 15-30mg 30mg 45mg Placebo Avandia PNFP-014 PNFP-343 Data from PI (%) 3.5 CHF Actos Avandia 3 2.5 3 1.5 1 0.5 0 Placebo 15+30mg 30mg 45mg Placcbo 4mg 8mg Total of PNFP-010, PNFP-343 Data from PI 014, 027 And based upon the results of PNFP 341, combination with SU, the incidences of edema and CHF in Actos groups were similar to those for Avandia in combination with insulin. Combination with SU (%) Avandia in combination 3 5 Edema Actos with Insulin 20 05 1 0 5 0 Placebo 15:30mg 30mg 45mg Placebo Avandia PNFP-010 PNFP-341 Data from PI Confidential - Subject to Protective Order TAK-THOMCL-00005584 Produced in MDL on 09/14/12 Source: https://www.indup2290000002ts.ucsf.edu/docs/syjf0226 (%) Avandia in combination 3.0 CHF Actos 3 with Insulin 2.5 2 1.5 1 0.5 c Placebo 15+30mg 30mg 45mg Placebo 4mg 8mg Total of PNFP-010, PNFP-341 Data from PI 014,027 Clinical development is not in my line. However, I am compelled to be concerned about the results of these studies. Can you undoubtedly assure that the MPDRAP conclusion dose not have an adverse affect on the current labeling? This issue was already discussed at MPDRAP Committee Meeting, but I would like you to reconfirm the conclusion at the meeting. END (Reference] Combination with Metformin L 6 (%) Edema L 4 - L 2 - Actos Avandia 10 - 8 - 8 - 4 2 - 0 Placebo 30mg 30mg 45mg 7° 5t* 4mg 8mg PNFP-027 PNFP-342 Data from PI (%) CHF 3.6 8 2.5 Actos 2 1.5 I 0.5 0 Placebo 15+30mg 30mg 45mg Total of PNFP-010, 014,027 PNFP-342 Confidential - Subject to Protective Order TAK-THOMCL-00005585 Produced in MDL on 09/14/12 Source: https://www.indupt2290000003t.ucsf.edu/docs/syjf0226

what is mentioned in the CC?

syjf0226

syjf0226_p0, syjf0226_p1, syjf0226_p2

CEOs and general managers of pharmaceutical units, CEOs and General Managers of Pharmaceutical Units

8 January 2003 To: MPDRAP I Leader cc: CEOs and General Managers of Pharmaceutical Units My Concerns about sNDA for Actos 45mg in the USA (Reconfirmation) Pharmaceutical International Division Y. Narai I express my opinion about the conclusion drawn at MPDRAP Committee Meeting where it was agreed that sNDA to obtain the approval of the 45mg combination indications would be submitted, as well as the safety update based on the commitment studies. As you know, Actos is the essential product for TPNA and is vital to the survival of TPNA. If unfavorable revisions in the Actos labeling are made, it invites the serious risk to Actos in the US. TPNA is now under attack from GSK, especially by Avandamet and is eager to maintain their market share. In addition to this attack, if the indications of Actos are reduced, TPNA is pushed into critical situation. This issue seriously damages not only US market but also Takeda's global strategy. Therefore, HQ should be extremely cautious about the issues related to Actos. If this sNDA raises the argument for the indications of Actos, for example, reductions in the indications, the issues will come to a critical path like as I mentioned. So we should go into action on condition that there is no such risk. Combination therapy in the US market accounts for 64% of total Actos sales. (29% in combination with SU, 27% Metformin and 8% Insulin) Regarding the possibility of the risk of labeling revision, International Division entrusts Development Division with final decision. However, just to be sure, I would like to reconfirm that this sNDA dose not lead to a serious situation. I heard that TPNA R&D suggested to HQ and is getting ready for sNDA for the 45mg combination indications. However, HQ should carefully judge whether this sNDA should be submitted to the FDA or not. I think that sNDA for efficacy should be submitted only when there is no risk that this sNDA damages the current labeling. According to the results of PNFP-343, combination with insulin, edema was observed more often than Avandia, which dose not have the indication for combination with insulin and CHF in this study seems to be dose related. Confidential - Subject to Protective Order TAK-THOMCL-00005583 Produced in MDL on 09/14/12 Source: https://www.indupt2290c0000ts.ucsf.edu/docs/syjf0226 Combination with Insulin (%) 2 5 Edema Actos Avandia 20 1 5 00 5 0 Placcbo 15-30mg 30mg 45mg Placebo Avandia PNFP-014 PNFP-343 Data from PI (%) 3.5 CHF Actos Avandia 3 2.5 3 1.5 1 0.5 0 Placebo 15+30mg 30mg 45mg Placcbo 4mg 8mg Total of PNFP-010, PNFP-343 Data from PI 014, 027 And based upon the results of PNFP 341, combination with SU, the incidences of edema and CHF in Actos groups were similar to those for Avandia in combination with insulin. Combination with SU (%) Avandia in combination 3 5 Edema Actos with Insulin 20 05 1 0 5 0 Placebo 15:30mg 30mg 45mg Placebo Avandia PNFP-010 PNFP-341 Data from PI Confidential - Subject to Protective Order TAK-THOMCL-00005584 Produced in MDL on 09/14/12 Source: https://www.indup2290000002ts.ucsf.edu/docs/syjf0226 (%) Avandia in combination 3.0 CHF Actos 3 with Insulin 2.5 2 1.5 1 0.5 c Placebo 15+30mg 30mg 45mg Placebo 4mg 8mg Total of PNFP-010, PNFP-341 Data from PI 014,027 Clinical development is not in my line. However, I am compelled to be concerned about the results of these studies. Can you undoubtedly assure that the MPDRAP conclusion dose not have an adverse affect on the current labeling? This issue was already discussed at MPDRAP Committee Meeting, but I would like you to reconfirm the conclusion at the meeting. END (Reference] Combination with Metformin L 6 (%) Edema L 4 - L 2 - Actos Avandia 10 - 8 - 8 - 4 2 - 0 Placebo 30mg 30mg 45mg 7° 5t* 4mg 8mg PNFP-027 PNFP-342 Data from PI (%) CHF 3.6 8 2.5 Actos 2 1.5 I 0.5 0 Placebo 15+30mg 30mg 45mg Total of PNFP-010, 014,027 PNFP-342 Confidential - Subject to Protective Order TAK-THOMCL-00005585 Produced in MDL on 09/14/12 Source: https://www.indupt2290000003t.ucsf.edu/docs/syjf0226

combination therapy in the us market accounts for how much % of total actos sales .

syjf0226

syjf0226_p0, syjf0226_p1, syjf0226_p2

64%, 64

8 January 2003 To: MPDRAP I Leader cc: CEOs and General Managers of Pharmaceutical Units My Concerns about sNDA for Actos 45mg in the USA (Reconfirmation) Pharmaceutical International Division Y. Narai I express my opinion about the conclusion drawn at MPDRAP Committee Meeting where it was agreed that sNDA to obtain the approval of the 45mg combination indications would be submitted, as well as the safety update based on the commitment studies. As you know, Actos is the essential product for TPNA and is vital to the survival of TPNA. If unfavorable revisions in the Actos labeling are made, it invites the serious risk to Actos in the US. TPNA is now under attack from GSK, especially by Avandamet and is eager to maintain their market share. In addition to this attack, if the indications of Actos are reduced, TPNA is pushed into critical situation. This issue seriously damages not only US market but also Takeda's global strategy. Therefore, HQ should be extremely cautious about the issues related to Actos. If this sNDA raises the argument for the indications of Actos, for example, reductions in the indications, the issues will come to a critical path like as I mentioned. So we should go into action on condition that there is no such risk. Combination therapy in the US market accounts for 64% of total Actos sales. (29% in combination with SU, 27% Metformin and 8% Insulin) Regarding the possibility of the risk of labeling revision, International Division entrusts Development Division with final decision. However, just to be sure, I would like to reconfirm that this sNDA dose not lead to a serious situation. I heard that TPNA R&D suggested to HQ and is getting ready for sNDA for the 45mg combination indications. However, HQ should carefully judge whether this sNDA should be submitted to the FDA or not. I think that sNDA for efficacy should be submitted only when there is no risk that this sNDA damages the current labeling. According to the results of PNFP-343, combination with insulin, edema was observed more often than Avandia, which dose not have the indication for combination with insulin and CHF in this study seems to be dose related. Confidential - Subject to Protective Order TAK-THOMCL-00005583 Produced in MDL on 09/14/12 Source: https://www.indupt2290c0000ts.ucsf.edu/docs/syjf0226 Combination with Insulin (%) 2 5 Edema Actos Avandia 20 1 5 00 5 0 Placcbo 15-30mg 30mg 45mg Placebo Avandia PNFP-014 PNFP-343 Data from PI (%) 3.5 CHF Actos Avandia 3 2.5 3 1.5 1 0.5 0 Placebo 15+30mg 30mg 45mg Placcbo 4mg 8mg Total of PNFP-010, PNFP-343 Data from PI 014, 027 And based upon the results of PNFP 341, combination with SU, the incidences of edema and CHF in Actos groups were similar to those for Avandia in combination with insulin. Combination with SU (%) Avandia in combination 3 5 Edema Actos with Insulin 20 05 1 0 5 0 Placebo 15:30mg 30mg 45mg Placebo Avandia PNFP-010 PNFP-341 Data from PI Confidential - Subject to Protective Order TAK-THOMCL-00005584 Produced in MDL on 09/14/12 Source: https://www.indup2290000002ts.ucsf.edu/docs/syjf0226 (%) Avandia in combination 3.0 CHF Actos 3 with Insulin 2.5 2 1.5 1 0.5 c Placebo 15+30mg 30mg 45mg Placebo 4mg 8mg Total of PNFP-010, PNFP-341 Data from PI 014,027 Clinical development is not in my line. However, I am compelled to be concerned about the results of these studies. Can you undoubtedly assure that the MPDRAP conclusion dose not have an adverse affect on the current labeling? This issue was already discussed at MPDRAP Committee Meeting, but I would like you to reconfirm the conclusion at the meeting. END (Reference] Combination with Metformin L 6 (%) Edema L 4 - L 2 - Actos Avandia 10 - 8 - 8 - 4 2 - 0 Placebo 30mg 30mg 45mg 7° 5t* 4mg 8mg PNFP-027 PNFP-342 Data from PI (%) CHF 3.6 8 2.5 Actos 2 1.5 I 0.5 0 Placebo 15+30mg 30mg 45mg Total of PNFP-010, 014,027 PNFP-342 Confidential - Subject to Protective Order TAK-THOMCL-00005585 Produced in MDL on 09/14/12 Source: https://www.indupt2290000003t.ucsf.edu/docs/syjf0226

What is the due date to evaluate data from actos 507?

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:

who is the lead responsibility for developing additional monitoring plan for actos 508

qtjf0226

qtjf0226_p3, qtjf0226_p4, qtjf0226_p5, qtjf0226_p6, qtjf0226_p7

Amy hagaman, Amy Hagaman

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 due date for "draft justification for actos 508" ?

qtjf0226

qtjf0226_p3, qtjf0226_p4, qtjf0226_p5, qtjf0226_p6, qtjf0226_p7

august 12, August 12

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: