Mark S. Brown Margaret K. Feltz November 7-9, 2005 Washington, D.C.

1. Clinical Trial Development: A Focus on Publication of Trial InformationatThe Sixth Annual Pharmaceutical Compliance Congress and Best Practices Forum Mark S. Brown Margaret K. Feltz November 7-9, 2005 Washington, D.C. *The comments and opinions expressed herein are the authors’ only and should not be attributed to King and Spaulding or Purdue Pharma L.P.

2. Agenda • Why is this such a hot topic now? • What is required? What is suggested? • Why is this harder than it seems? • Roadblocks and Challenges • Questions and Answers

3. Goals – Conducting Research vs. Reporting Research Results • The goal of research is: To generate scientific and clinical knowledge • The goal of reporting is: To ensure that scientific and clinical knowledge gained from research will be listed and shared from study initiation to conclusion to ensure that positive and negative findings can be evaluated in the broad context of outcome possibilities • Both positive and negative results have intrinsic value

4. Clinical Trial Registry vs. Clinical Trial Results Database • Clinical Trials Registry • “Provides patients and physicians with information about ongoing clinical trials that are open and recruiting patients.” • Clinical Study Results Database • “Designed to improve accessibility to, and transparency of, the results of clinical studies. This electronic database is a central standardized repository for published and unpublished clinical studies that have already been completed. This industry-sponsored registry will provide access to the results of all hypothesis-testing clinical studies of marketed drugs – regardless of outcomes.”

5. Pop Quiz! – Who Said It? • “Results! Why, man, I have gotten a lot of results. I know several thousand things that won't work.” • “Just because something doesn't do what you planned it to do doesn't mean it's useless.” • “I have not failed. I've just found 10,000 ways that won't work.” • Thomas A. Edison • (US inventor, 1847-1931)

6. NY AG Paxil Case - Background • June 2004 – NY Attorney General Eliot Spitzer sued GlaxoSmithKline alleging that the company failed to disclose certain clinical data that suggested that Paxil was no better than a placebo in treating depression in pediatric populations and could lead to suicidal ideation. • Suit based on NY consumer protection law making “any deception, misrepresentation, concealment or suppression” of a material fact illegal. • Paxil is not approved for use in pediatric populations.

7. NY AG Paxil Case - Settlement • GSK required to post summaries of clinical studies on all GSK drugs marketed in the United States • Must maintain a clinical trial registry on a website • Free and unrestricted access • For 10 years • “Clinical studies” are defined to include: • Any “research investigation on human subjects to answer specific questions about a GSK drug.” • Definition is not limited to randomized, controlled, or blinded studies.

8. NY AG Paxil Case - Settlement • By the end of 2005, GSK required to post summaries of studies that were completed after the merger of Glaxo Wellcome and SmithKline Beecham. • For ongoing studies of marketed products, GSK has 10 months from completion of trial to post data. • GSK may seek to delay posting of summaries of studies where required to protect intellectual property or to comply with policies of journals to which manuscripts have been submitted.

9. NY AG Paxil Case - Settlement • GSK shall make a “reasonable effort” to encourage the publication of studies in which GSK was a significant participant. • In future studies, GSK will make a “reasonable effort” to exclude contractual provisions that may limit the publication of clinical study reports.

10. NY AG Paxil Case - Settlement • GSK to ensure that all Medical Information letters and other communications to physicians concerning a GSK drug “shall fairly and accurately reflect the safety and efficacy data from clinical studies concerning the off-label use.” • GSK required to submit to the NY AG Medical Information Letters or other communications to physician regarding Paxil or depression in pediatrics. • $2.5 million fee for disgorgement and costs

11. NY AG Paxil Case - Ramifications • Spitzer contends failure to report negative clinical trial data a problem that “runs throughout the industry” and is “an area of continuing interest.” • Motivating states to investigate drug advertising and promotion based on consumer protection laws. • States intruding in FDA’s jurisdiction and comprehensive regulation of drug advertising and promotion. • Copycat actions brought in state courts. • Preemption anyone?

12. FDA Clinical Reporting Obligations • IND Annual Reports must include for each study: • Brief Summary of Study Status (e.g., completed, ongoing, number of subjects entered, dropouts, etc.) • If study completed or interim results known, brief summary shall also include a brief description of results.

13. FDA Clinical Reporting Obligations • NDA Annual Report must include clinical data: • Copies/abstracts of published clinical trials of the drug • Summaries of completed, unpublished clinical trials or pre-publication manuscripts, if available, conducted by or otherwise obtained by the company. • A study is considered completed one year after its conclusion. • No affirmative obligation to prepare or submit final report on study of an approved drug.

14. FDA Clinical Reporting Obligations • NDA Annual Report must also include: • Analysis of available pediatric safety and efficacy data, regardless of whether manufacturer is proposing revisions to the product labeling. • Status report of each post-marketing study of the drug undertaken by or on behalf of the sponsor, including pediatric studies required by FDA or that the sponsor has agreed to undertake.

15. Clinical Trial Registry:www.clinicaltrials.gov • Clinical trial registry launched in Feb. 2000, pursuant to FDAMA. • Administered by NIH and National Library of Medicine in conjunction with FDA. • Includes all Phase II-IV studies for products to treat serious or life-threatening diseases. • Does not require posting of results.

16. PhRMA Principles • Pharmaceutical Research & Manufacturers of America (PhRMA) Principles of Conduct of Clinical Trials and Communication of Clinical Trial Results (the “Principles”) • www.ClinicalStudyResults.org • Standardized format, including: • Results from all hypothesis testing clinical studies • Mainly Phase III and Phase IV studies • October 1, 2002 forward • For all drug products approved in the United States • Regardless of publication status • Companies urged to post unpublished study summaries within one year of study completion

17. Clinical Trial Registries – Publication Standards set by ICMJE • ICMJE member journals* require as a condition of consideration for publication, registration in a public clinical trials registry • Must register on or before onset of patient enrollment; • Applies to all trials enrolling after 7/1/05. • For trials enrolling before 7/1/05, registration required by 9/13/05 before journal will consider publishing trial data * JAMA, NEJM, New Zealand Medical Journal, Norwegian Med. J., CMAJ, The Lancet, National Library of Medicine, Annals of Internal Med, Croatian Med. J., Dutch Journal of Med., J. of the Danish Med. Assoc., Annals of Internal Med., The Med. J. of Australia

18. Clinical Trial Registries – Publication Standards set by ICMJE • ICMJE does not advocate a particular registry but requires that the registry be: • Accessible to the public • Free of charge • Open to all prospective registrants • Managed by a non-profit organization • Valid • Electronically searchable • Contain standardized entries • www.clinicaltrials.gov meets the ICMJE criteria

19. Joint Position* on the Disclosure of Clinical Trial Information • Desire to balance public health benefits associated with clinical trial publication with protections of individual privacy, intellectual property and contract rights • Committed to transparency via vehicles of clinical trials registry and clinical trials results databases • Implementation Dates: • Trials initiated on/after 7/1/05 should be included in registry • Ongoing trials should be included by 9/13/05 * Industry groups include European Federation of Pharmaceutical Industries & Associations, International Federation of Pharmaceutical Manufacturers and Associations, Japanese Pharmaceutical Manufacturers Association and Pharmaceutical Research & Manufacturers of America

20. Joint Position (cont.) – Clinical Trials Registry • Clinical Trials Registry – a repository of information on ongoing clinical trials • All non-exploratory clinical trials submitted for listing in a free publicly accessible registry within 21 days of initiation of patient enrollment, unless there are alternative national requirements • Registry contains basic information sufficient to inform interested subjects and practitioners about how to enroll in trial • Trials identified by unique identifier that permits users to track a trial through multiple databases, including results databases

21. Joint Position (cont.) – Clinical Trials Results Database • Clinical Trials Results Database – a repository for the summary results of completed clinical trials • Results of all non-exploratory clinical trials conducted on a drug that is approved for marketing and is commercially available in at least one country should be disclosed on a free, publicly accessible clinical trial results database, regardless of outcome • Exploratory study results should be publicly disclosed if they have significant medical importance and may impact labeling • If results are published in a peer-reviewed medical journal, the database should include a citation or link to article or summary of results, posted in standardized format • All results should include the trial’s unique identifier • Results should be posted within one year after drug is first approved and commercially available within a country or, for trials completed after this initial phase, within one year of trial completion unless such posting would compromise publication in a peer-reviewed medical journal.

22. Fair Access to Clinical Trials Act (“FACT Act”) • Introduced in both the House (HR 5252) and Senate (S 2933). • Would require sponsors of clinical trials to register and publish information about drugs, devices, and biologics. • Would expand www.clinicaltrials.gov to create a publicly accessible national data bank of clinical trial information – both a registry and results database.

23. FACT Act • The legislation would: • Foster transparency and accountability in health-related treatment research and development. • Maintain a registry for ongoing clinical trials for serious or life-threatening diseases. • Establish a clinical trials results database of all publicly and privately funded trials, regardless of outcome. • Be accessible to scientific community, health care professionals, and the public.

24. FACT Act • The legislation would: • Apply to clinical trials for drugs, biologics, and medical devices. • Require that foreign trials submitted to FDA or used in advertising to U.S. physicians be registered in the database at the time of submission. • Exempt Phase I trials conducted only to test safety of unapproved products. • Impose penalties and fines for non-compliance.

25. Maine Clinical Trial Disclosure LawLD 1618 (22 M.S.R.A. §2700-A) • Manufacturers or labelers that are required to report marketing costs under 22 M.R.S.A. §2698-A are also required to post clinical trial data on a publicly accessible internet website beginning on October 15, 2005 • Posting requirement applies to: • Any “clinical investigation” (as defined by the FDA)* conducted on or after October 15, 2002 that is intended to test the safety or efficacy of a drug or biologic in humans and intended to be submitted to the FDA in support of a marketing application • This includes Phase I, II, III and IV trials * FDA defines a clinical investigation as “any experiment in which a drug is administered or dispensed to, or used involving, one ore more human subjects. … [A]n experiment is any use of a drug except for the use of a marketed drug in the course of medical practice.” 21 C.F.R. § 312.3(b).

26. Maine Clinical Trial Disclosure Law • If the trial disclosure requirement applies, the following information must be posted: • Name of entity conducting trial • Summary of purpose of trial • Dates trial occurred • Results of trial – including potential adverse events

27. Transparency & Accountability • With regard to the industry decision to publish summaries of clinical trial results to a results database, PhRMA president Billy Tauzin said that: “[The industry is] doing this because [it] recognizes that sometimes what the law requires doesn’t give patients all they need. Patients – both those with manageable conditions and those who are gravely ill – need information about new drugs that are being tested.”

28. Why does this seem so difficult? • Roadblocks and Challenges: • Ambiguity • Intellectual Property Concerns • Off Label Promotion Restrictions • Ethical Considerations • Burdens on Companies

29. Roadblocks – Ambiguity • Registry vs. Results Database – where is there crossover? • What does “within one year of trial completion” mean? • What constitutes “publication”?

30. Roadblocks – IP Concerns • Inclusion of Phase II or earlier data? Inclusion of Phase III and IV trials of marketed products has more wide-spread support. • “Hypothesis-generating” vs. “Hypothesis-testing” trials • What is the impact of reporting clinical trial information on competitive advantage when bringing a new drug to market? • Would you expect that reporting clinical trial data in a database or on a website would hamper an investigator’s ability to publish findings in a medical journal?

31. Roadblocks – IP Concerns • “To put major information out about particularly early-phase trials, their design and how they are being done…would be tantamount to disclosure of the regulatory strategy, the timing and just enormous disclosure of critical information that…[would] prevent the ability of companies to gain an appropriate return on their investment.” Dr. Larry Hirsch Merck Executive Director, Medical Communications

32. Roadblocks – Off Label Promotion Restrictions • If a clinical trial focuses on an off-label use or is a head-to-head comparison with another product, how should results be reported to avoid being construed as promotion claims? • Clinical Trial data should be posted in a non-promotional manner. • DDMAC will look at both the content and the context of data posting. • Distinction between data and conclusions. • Conclusions could turn data posting into promotion.

33. Roadblocks – Ethical Considerations • What are the risks created by making available data that has not been published in a peer-reviewed journal or otherwise been validated? • By reporting both positive and negative clinical trial results, are we flooding the medical literature and websites with data that is not necessarily useful? • Could providing positive and negative clinical trial results on the internet negatively impact the doctor/patient relationship?

34. Roadblocks – Burdens on Companies • Will mandatory clinical trial reporting make pharmaceutical companies more risk averse? Will these requirements affect clinical trial design for your company? If so, how? • What kind of constraints do these reporting requirements place on your company? • Time constraints? • Financial constraints? • Staffing constraints?

35. Mark S. Brown Partner King & Spaulding LLP 1700 Pennsylvania Avenue, N.W. Washington, D.C. 20006 P: (202) 626-5443 F: (202) 626-3737 E: mbrown@kslaw.com Web: http://www.kslaw.com Margaret K. Feltz Senior Manager Purdue Pharma L. P. One Stamford Forum Stamford, CT 06901 P: (203) 588-8754 F: (203) 588-6269 E: margaret.feltz@pharma.com Web: www.pharma.com Our Contact Information