1. Clinical Trial Disclosure 20 November 2008

2. 11/20/20082 Goals of Clinical Trial Disclosure Communication!  Provide clinical trial information to patients  Provide access to results of clinical trials  Enhance accountability and transparency of clinical trial information Desired long term result of transparency: improvement of industry reputation

3. 11/20/20083 Terminology Disclosure = public disclosure of any study information. Includes registration of the study and posting of results  Registration = public display of study protocol information on ClinicalTrials.gov or any other required website (EudraCT, other country websites)  Posting of Results = public display of study results on a publicly accessible website (clinicaltrials.gov/results, clinicalstudyresults.org, company websites)

4. 11/20/20084 Public Disclosure of Study Information Part 1: Register Protocol Information Part 2: Post Trial Results ClinicalTrials.gov Publicly Accessible Website Before enrollment of first subject One year after trial completion: Marketed drugs Clinical Trial Life Cycle Consistency

5. 11/20/20085 Approved Protocol Statistical Analysis Plan Clinical Study Report Synopsis Documents Must be Consistent Registratio ns Results Postin gs Primary Publications

6. 11/20/20086 Clinical Trial Disclosure History 1980’s1990’s200020022004200520062007 1988 Hope Act AIDS Study Enrollment 1997 LAW FDAMA Section 113 Register Studies in Serious, Life threatening diseases Clinicaltrials.gov Implemented PhRMA Principles Register all hypothesis testing studies ICMJE Editorial Register to be published Paxil/GSK Lawsuit consent decree WHO ICTRP Initiated to develop registry standards FACT ACT Introduced in Senate Maine Law Enacted FDA-AA Enacted September 2007 Maine Regulations Enacted

7. 11/20/20087 Current Disclosure Governance Registration  Law FDAMA 113 (Serious, Life- threatening indications) Best Pharmaceuticals for Children Act (Expanded Access trials) State of Maine (Hypothesis- testing trials) FDA-Amendments Act 2007 International Law  Guidance ICMJE PhRMA IFPMA WHO Dec of Helsinki Results Disclosure  Law State of Maine FDA-Amendments Act  Guidance PhRMA IFPMA ICMJE Dec of Helsinki

8. 11/20/20088 Declaration of Helsinki Oct 2008 19. Every clinical trial must be registered in a publicly accessible database before recruitment of the first subject. 30. Authors, editors and publishers all have ethical obligations with regard to the publication of the results of research. Authors have a duty to make publicly available the results of their research on human subjects and are accountable for the completeness and accuracy of their reports. They should adhere to accepted guidelines for ethical reporting. Negative and inconclusive as well as positive results should be published or otherwise made publicly available. Sources of funding, institutional affiliations and conflicts of interest should be declared in the publication. Reports of research not in accordance with the principles of this Declaration should not be accepted for publication.

9. 11/20/20089 Penalties for Non-compliance Potential audits by State and Federal agencies Civil monetary penalties of up to $10,000 per single proceeding and $10,000 per day until corrected NIH will post notices of violations in clinicaltrials.gov for public view NIH may publish non-compliances  Zarin, Tse and Ide, N Engl J Med 353; 26; December 29, 2005

10. 11/20/200810 Mandatory Israel Italy South Africa Taiwan Brazil Czech Republic Proposed France EU Peds Argentina Croatia Switzerland Canada Voluntary Australia/NZ Germany Japan Netherlands Spain UK ISRCTN India China Latin America Sri Lanka Public Registry Requirements ROW (as of July 2008)

11. 11/20/200811 New EU Disclosures Coming in 2009 Pediatric Trials Article 41 of Regulation (EC) No 1901/2006  All peds trials conducted in EU and Outside if part of the PIP  Protocol information will be made public when received (1Q2009)  Results public within 6 months of study completion, regardless of marketing autorization (3-4Q2009)

12. 11/20/200812 New EU Disclosures Coming in 2009 Clinical Trials other than Phase I Article 57(2) of Regulation (EC) No 726/2004 and the guideline published by the EC  All Phase 2-4 trials contained in EudraCT  Protocol information will be made public when received (1Q2009)  Results public within 12 months of study completion, regardless of marketing authorization (3-4Q2009)

13. 11/20/200813 State of Maine Law

14. 11/20/200814 Purpose of the Maine Regulations Define obligations of manufacturers and labelers of prescription drugs, biologics and device combinations Publicly disclose on internet web sites information about clinical trials of …products…that are or have been FDA-approved for marketing and are or have been dispensed, administered, delivered or promoted in Maine Protect consumers

15. 11/20/200815 Maine Regulations Applicable Clinical Trial Initiated-on or after October 15, 2002 Hypothesis Testing as defined in 21 CFR 99.3(b)  Sec. 99.3 (b) For purposes of this part, a clinical investigation is an investigation in humans that tests a specific clinical hypothesis. Intended to test safety or efficacy… with one or more human subject Either  Part of an application for a research or marketing permit (IND, NDA, etc)  Post-marketing study of FDA approved product Off-label uses Studies to support marketing or educational efforts or materials to prescribers or consumers Bioequivalency of a generic

16. 11/20/200816 Hypothesis-Testing Trials Also known as confirmatory or clinically directive Intended to examine pre-stated questions using predetermined, statistically valid plans for data analysis Provide firm evidence of safety and/or effectiveness

17. 11/20/200817 Maine Public Registration What to RegisterWhen to Register Protocol information, trial dates, investigator locations, administrative information Product Information (NDA#, alias names, NCT#)  Trials completed before rules adoption: April 1, 2008  Trials completed after rules adoption (the latest date): First date administered, dispensed, delivered or promoted in Maine July 1, 2007 21 days after patient enrollment has begun Link/citation of articleOnce available Link to package insert, recalls/marketing/safety alerts Once available

18. 11/20/200818 Maine Results Disclosure What to PostWhen to Post ICH E3 Study Synopsis After 8 Dec 2008, Post results on ClinicalTrials.gov/results After Drug is FDA approved and available in Maine  Post results by the first date product is marketed in the state Trials completed before rules: by April 1, 2008 Trials discontinued for safety before rules: 30 days after cessation or July 1, 2007 Trials completed after rules: by 1 year after trial completion  Can delay twice for 6 months for additional data analysis  Max 24 Months Link/citation of article Once available Link to package insert, recalls/marketing/safety alerts Once available Web site sponsor relationship to product Initial posting

19. 11/20/200819 Maine: Where to Disclose Register trial information and identification information on a publicly funded Internet web site  www.clinicaltrials.gov Post results on a publicly funded Internet web site, or if not available, a publicly accessible Internet web site  www.clinicalstudyresults.org  Company web sites  After 8 Dec 2008, www.clinicaltrials.gov

20. 11/20/200820 Maine General Requirements Inform Maine in writing of where you will:  Register protocol information  Post product identification information  Post results Maintain accuracy of information  Update when necessary Investigator contact information and recruiting status Study completion date Publication citations Safety messages (recall/marketing or safety alerts)

21. 11/20/200821 Points to Consider: Results Results databases demonstrate the pharmaceutical industry’s commitment to transparency, disclosure of clinical development endeavors. Result summaries should be completed, reviewed with same care, scrutiny and authority as manuscripts. Result summaries should be neutral and non- promotional. Information must be accurate, scientifically sound, purely factual, fair, objective, up-to-date, neutral, and not misleading in any way.

22. 11/20/200822 FDA Amendments Act 2007 (FDAAA)

23. 11/20/200823 FDA Amendments Act 2007 Also Known as FDAAA or FDA 3 Passed and effective 9/27/2007 Title 8: Clinical Trial Databases Applies to Phase 2-4 Drug, Device and Biologic Trials Register trials on clinicaltrials.gov Post results of trials  FDA AA: Basic results: 9/27/2008 AE/SAE results: 9/27/2009 (start 8 Dec 2008 due to Maine) Update completion dates and recruiting status within 30 days  Maine law is NOT currently preempted: post ICH E3 synopsis by 4/1/2008 Submit FDA Certification Form 3674 with submissions

24. 11/20/200824 FDAAA Key Sections Definitions Registration Basic Results Expanded Results Certification of Compliance Additional Requirements

25. 11/20/200825 FDAAA Definition: Completion Date NEW, different definition No longer LSLV “The term ‘completion date’ means, with respect to an applicable clinical trial, the date that the final subject was examined or received an intervention for the purposes of final collection of data for the primary outcome, whether the clinical trial concluded according to the pre- specified protocol or was terminated.” May require early blind breaking and interim analyses with updates

26. 11/20/200826 FDAAA Definition: Applicable Clinical Trial Drug or biologic: Controlled clinical investigation, other than a phase 1 clinical investigation, of a drug subject to section 505 of the Federal Food, Drug, and Cosmetic Act Includes investigator initiated research and observational trials if it involves administering drug to human subjects during a clinical trial, outside of the course of medical practice. Device: A prospective clinical study of health outcomes comparing an intervention with a device subject to section 510(k), 515 or 520(m) of the Federal Food, Drug and Cosmetic Act against a control in human subjects (does not include a small feasibility trial)

27. 11/20/200827 FDAAA Definition: Clinical Investigation “Clinical investigation means any experiment in which a drug is administered or dispensed to, or used involving, one or more human subjects. For the purposes of this part, an experiment is any use of a drug except for the use of a marketed drug in the course of medical practice. “ Consistent with Title 21, 312.3

28. 11/20/200828 FDAAA Definition: Responsible Party Sponsor of a clinical trial as defined in 21 CFR 50.3 Sponsor may delegate responsibility to the principal investigator as long as the investigator is responsible for conducting the trial, has access to and control over the data and has the right to publish the results.

29. 11/20/200829 Registration

30. 11/20/200830 FDAAA Registration Timing Trials in serious, life-threatening indications: By Dec 26, 2007 (ongoing trials) or within 21 days of enrollment of the first subject (new trials) All other applicable trials: By September 27, 2008 (ongoing) or within 21 days of enrollment of the first subject (new trials) NOTE: Still need to register trials on or before first subject enrollment to ensure ability to publish in ICMJE Journal

31. 11/20/200831 FDAAA Required Data Elements Descriptive Information  brief title, intended for the lay public  brief summary, intended for the lay public  primary purpose  study design  study phase  study type  primary disease or condition being studied, or the focus of the study;  intervention name and intervention type  study start date  expected completion date  target number of subjects  primary and secondary outcome measures and timeframes

32. 11/20/200832 FDAAA Required Data Elements (2) Recruitment information  eligibility criteria  gender  age limits  whether the trial accepts healthy volunteers  overall recruitment status  individual site status  expanded access to the drug for those who do not qualify for enrollment in the clinical trial and how to obtain information about such access Location and contact information, including—  name of the sponsor;  responsible party, by official title  facility name and facility contact information (including the city, State, and zip code for each clinical trial location, or a toll-free number through which such location information may be accessed)

33. 11/20/200833 FDAAA Required Data Elements (3) Administrative data (which the Secretary may make publicly available as necessary), including —  the unique protocol identification number  other protocol identification numbers, if any EUDRA CT, UTRN, etc  Food and Drug Administration IND/IDE protocol number  record verification date

34. 11/20/200834 Basic Results

35. 11/20/200835 FDAAA Basic Results Applicable Trials: Ongoing or new trials of FDA approved drugs ClinicalTrials.gov ready to accept “Basic Results” of applicable trials by September 27, 2008  Demographic and baseline characteristics  Primary and secondary outcomes (match registration)  Point of contact for Scientific Information  Agreements with investigators restricting their ability to discuss results HHS/NIH will consult with experts on risk communication and they may post information with the results to ensure that information does not mislead the patients or public

36. 11/20/200836 FDAAA Basic Results: Requirements Demographic and Baseline Characteristics  Table of values for each arm  Include # patients dropped  Include # patients excluded from the analysis Primary and Secondary Outcomes  Table of values for each arm  Include information on statistical tests

37. 11/20/200837 FDAAA Results Posting Timeline Posting Results  Trials completed before drug is initially approved Post results no later than 30 days after approval  Trials completed after FDA approval Post results not later than one year after the earlier of the estimated or actual completion dates Continue to comply with Maine by posting ICH E3 synopses on clinicalstudyresults.org or company website  Trial Status Changes: Post actual completion date and change in recruitment status within 30 days of status change  Do not need to post results of trials of new indications for approved drugs until 30 days after approval of the new indication

38. 11/20/200838 FDAAA Adverse Event Disclosure Post safety results starting 8 Dec 2008 due to Maine SAEs  Tabular format grouped by organ system  List number and frequency for each event in each arm Frequent AEs  Same as SAEs, plus AEs that exceeds frequency of 5% within any arm  List number and frequency for each event in each arm

39. 11/20/200839 Expanded Results

40. 11/20/200840 FDAAA Expanded Results: FUTURE Expand results disclosure by rulemaking no later than September 27, 2010 for each applicable clinical trial for FDA approved drugs and devices Information on the following will be required to be disclosed:  Lay and technical summary of results if not misleading or promotional  Full protocol if needed to interpret results  Potential to post results from trials conducted with unapproved drugs (even if licensure is not sought)  Define accuracy and quality control procedures to ensure entries are not false or misleading and are non-promotional  Other categories as the Secretary determines appropriate

41. 11/20/200841 Certification of Compliance FDA Form 3674

42. 11/20/200842 FDAAA Certification of Compliance B) "CERTIFICATION TO ACCOMPANY DRUG, BIOLOGICAL PRODUCT, AND DEVICE SUBMISSIONS.—At the time of submission of an application under section 505 of the Federal Food, Drug, and Cosmetic Act, section 515 of such Act, section 520(m) of such Act, or section 351 of this Act, or submission of a report under section 510(k) of such Act, such application or submission shall be accompanied by a certification that all applicable requirements of this subsection have been met. Where available, such certification shall include the appropriate National Clinical Trial control numbers. “ Form 3674 should be attached to the cover letter of the submission Companies are submitting with IND and NDA Submissions www.fda.gov/cder/regulatory/FDAAA_certification.htm

43. 11/20/200843 FDA- 3674 Certification Form

44. 11/20/200844 FDA- 3674 Certification Form

45. 11/20/200845 FDAAA Additional Requirements

46. 11/20/200846 FDAAA Additional Requirements HHS can request posting results of previously conducted trials up to September 27, 1997 if this information is necessary to protect the public Informed Consent documents will need to include a statement that information has been or will be included in the registry data bank HHS will hold a public meeting by March 27, 2009 to provide an opportunity to receive input on regulation development

47. 11/20/200847 FDAAA Compliance Sponsor will review information and update if needed at least every 12 months NIH will provide publicly accessible audit trail of changes Trial information and certifications must be submitted and must not be false or misleading Sponsor will have 30 days to correct non- compliances

48. 11/20/200848 FDAAA Preemption “Upon the expansion of the registry and databank…no state of political subdivision of a state may establish or continue in effect any requirement for registration of clinical trials or for the inclusion of information relating to the results of clinical trials in a database.” NIH has until September 27, 2010 to expand the database Maine Clinical Trial Disclosure Law will still be in effect until expansion of registry databank (at least)

49. 11/20/200849 FDAAA Implementation Key Dates DateEvent September 27, 2007FDAAA Enactment Date December 27, 2007Companies update Registrations and begin to send in Certification form with submissions NIH add links to FDA Websites September 27, 2008Companies begin to post basic results March 27, 2009HHS holds a public meeting September 27, 2009Companies begin to post SAE/AE data September 27, 2010HHS enacts expanded results regulations

50. 11/20/200850 International Committee of Medical Journal Editors (ICMJE)

51. 11/20/200851 ICMJE Policy Initiated 2005; Updated 2007  Consider a trial for publication in ICMJE Journal only if it has been registered before the enrollment of the first patient Applies to all clinical trials  Register phase 1 trials after 1 July 2008 Sponsor must register WHO 20 item “minimum dataset” Results posting may affect ability to publish

52. 11/20/200852 Ingelfinger Rule The rule requires that author-researchers not release the details of their findings to the mass media before their work undergoes peer review and is published. See: Harnad, Stevan (2000) Ingelfinger Over-Ruled: The Role of the Web in the Future of Refereed Medical Journal Publishing. The Lancet 256:s16.

53. 11/20/200853 Ingelfinger Rule Challenges Federal and State Law require posting of results within 1 year of LSLV Posting may be considered pre-publication and violation of Ingelfinger Rule Publication in high tier journals may be affected Consider timing carefully when developing publication strategy

54. 11/20/200854 US Disclosure Law Summary ItemMaineFDAAAFDAMA 113 Applicable Clinical Trial Hypotheses- testing clinical trial Phase 2b-4 Initiated on or after 10/15/2002 Controlled Clinical investigation Phase 2-4 Ongoing or initiated after 9/27/2007 Trials in serious, life- threatening illnesses; Register trials starting March 2000 Registration Timing Within 21 days of initial enrollment; however, ICMJE requires registration before the enrollment of the first subject Maintain Accuracy Register reason for Discontinuation of trial within 30 days Update as needed to ensure data accuracy Register actual completion date and change in recruitment status within 30 days of status change. Update at least yearly Register study completion date within 10 days of completion. Results Posting Post results after drug is marketed starting 4/1/2008 Post-marketing studies: post results 1 year after LSLV Post on clinicaltrials.gov Post Basic Results after drug is approved starting 9/27/2008 Post-marketing studies: post results 1 year after Study Completion (LSLV for the primary outcome) No requirement

55. 11/20/200855 Summary Disclosure of results requirements rapidly changing worldwide Involve appropriate stakeholders in process development activities Carefully design partnership agreements to define disclosure responsibilities Appropriate trials must be registered on publicly accessible registry (i.e., clinicaltrials.gov) and results databases (i.e., clinicalstudyresults.org, and soon to include clinicaltrials.gov)

56. 11/20/200856 Zarin, D. and Keselman, A. Registering a Clinical Trial in ClinicalTrials.gov. Chest 131: 2007 1-00 Godlee, f. An international standard for disclosure of clinical trial information. Editorial. BMJ vol. 332, 13 May 2006 Parascandola, M. Comprehensive registration of clinical trials: Are we there yet? Research Practitioner vol. 6, no. 4, July-Aug 2005,131-138 Malek, L. and Anderson, J. Sponsors Beware: FDAAA Creates Compliance Challenges for Drugs and Medical Device Clinical Trials. Bloomberg Law Reports, vol. 1 no. 2, 2008,1-4 Zarin, D. and Tse T. Moving Toward Transparency of Clinical Trials. Science vol. 319; 7 March 2008, 1340-1342 Groves T. Editorial. Mandatory disclosure of trial results for drugs and devices: New US law will require public posting of all the main results and data on harms. BMJ 2008;336:170 Hirsch, L. Trial registration and results disclosure: impact of US legislation on sponsors, investigators, and medical journal editors. Current Medical Research and Opinion. vol. 24, no. 6, 2008, 1683-1689 Ghersi, D. et al. Reporting the Findings of Clinical Trials: A Discussion Paper. Bulletin of the World Health Organization 86 (6) June 2008, 492-493 Lee K, Bacchetti P, Sim I. Publication of Clinical Trials Supporting Successful New Drug Applications: A Literature Analysis. PLoS Medicine; 2008(5)9:e191-200. Clinical Trial Disclosure Articles

57. 11/20/200857 Important Web sites FDAMA 113 (serious, life-threatening indications) http://www.fda.gov/cder/guidance/4856fnl.htm Best Pharmaceuticals for Children Act (expanded access trials) http://www.fda.gov/opacom/laws/pharmkids/conten ts.html http://www.fda.gov/opacom/laws/pharmkids/conten ts.html State of Maine (hypothesis-testing trials) http://www.maine.gov/dhhs/boh/clinical_tri als.htm FDA Amendments Act of 2007 http://frwebgate.access.gpo.gov/cgi- bin/getdoc.cgi?dbname=110_cong_publ ic_laws&docid=f:publ085.110.pdf PhRMA (Pharmaceutical Research and Manufacturers of America) http://homepage.vghtpe.gov.tw/~mre/goo dexp/Fercap-Survey/PhRMA- Principles-on-Conduct-of-Clinical- Trials.pdf http://www.phrma.org/clinical_trials/ IFPMA (International Federation of Pharmaceutical Manufacturers & Associations) http://www.ifpma.org/ IFPMA Portal http://clinicaltrials.ifpma.org/no_cache/e n/myportal/index.htm ICMJE (International Committee of Medical Journal Editors) http://www.icmje.org/clin_trialup.html WHO (World Health Organization International Clinical Trial Registration platform) http://www.who.int/ictrp/en/

58. 11/20/200858 Contact Information Pamela Rose Associate Director Clinical Trial Registration & Results Disclosure Takeda Global Research and Development Center, Inc. Phone: 847-582-5758 E-mail: pamela.rose@tgrd.com

59. 11/20/200859 QUESTIONS?