1. Clinical Trial Registries: Panacea or Pablum?? Presented by: Michael A. Swit, Esq. Vice President, The Weinberg Group Inc. michael.swit@weinberggroup.com 760.633.3343

2. 2 Clinical Trials Registries: Evolution of Legal Requirements Michael A. Swit, Esq. Vice President, The Weinberg Group Inc. Clinical Trials Registries: Critical Legal Issues Demetrios L. Kouzoukas, Esq. Of Counsel, Covington & Burling LLP Clinical Trials Disclosure: Are We Meeting the Target Audiences in The EU? Gesine Bejeuhr, Pharm.D., Ph.D. VFA, German Association of Research-Based Pharm. Co., Germany Overview of Session

3. Clinical Trial Registries: Evolution of Legal Requirements Presented by: Michael A. Swit, Esq. Vice President, The Weinberg Group Inc. michael.swit@weinberggroup.com 760.633.3343

4. 4 Disclaimer The views and opinions expressed in the following PowerPoint slides are those of the individual presenter and should not be attributed to Drug Information Association, Inc. (“DIA”), its directors, officers, employees, volunteers, members, chapters, councils, Special Interest Area Communities or affiliates, or any organization with which the presenter is employed or affiliated, or any of the organization’s clients. These PowerPoint slides are the intellectual property of the individual presenter and are protected under the copyright laws of the United States of America and other countries. Used by permission. All rights reserved. Drug Information Association, DIA and DIA logo are registered trademarks or trademarks of Drug Information Association Inc. All other trademarks are the property of their respective owners. These slides support an oral briefing and should not be solely relied upon for any conclusion of law or fact.

5. 5 MY OBJECTIVES TODAY The Evolution of Demand for Clinical Trial Registries, including the impact of the 2007 Food & Drug Administration Amendments Act (FDAAA) Review of Key National and International Registries

6. 6 DEFINITIONS – DISTINGUISH: Clinical Trials Registry – information on clinical trials that are active or completed, but not any substantive information on the results of the study vs. Clinical Trials Results Database – the results of the trials – in summary or other fashion -- are available for review

7. 7 GENERAL PURPOSES OF REGISTRIES & DATABASES List & track clinical trials Make available design of clinical studies – Principle 16 of Helsinki Declaration -- http://www.wma.net/e/policy/b3.htm Facilitate patient recruitment Create a record of results of evidence so that balanced and informed medical decisions may be made Eliminate duplicative research Eliminate “publication bias” – i.e., the tendency for only positive data to be published …. “transparency”

8. 8 THE EVOLVING DEMAND FOR REGISTRIES FDAMA §113 – –Since Feb. 2000 –All persons conducting clinical trials of experimental treatments for “serious or life-threatening” diseases and conditions –Where the trial is to test “effectiveness” – i.e., Phase 2, 3 or 4 studies with efficacy endpoints –Must register certain information with U.S. government, within 21 days of study enrollment opening –Done via ClinicalTrials.gov

9. 9 THE ROLE OF ELLIOTT SPITZER GSK Settlement -- 2004 –Allegation – GSK failed to disclose results of certain Paxil® studies in adolescent and pediatric patients –Required establishment of Clinical Trials Register and posting of Summaries of Clinical Study Reports for –all GSK studies from Dec. 27, 2000 on; and –Any earlier study “likely to be material to a physician’s medical judgment of the GSK drug” Future contracts – to avoid limitations on publication

10. 10 THE EDITORS STEP INTO THE FRAY International Committee of Medical Journal Editors (ICMJE) -- if you want to be published, study must be registered Requirements –Register at or before onset of patient enrollment –Applies to any study beginning enrollment after July 1, 2005 If begun before that, you had to register by Sept. 13, 2005 –Information to be included – consistent with WHO

11. 11 THE EDITORS – ICMJE … “Clinical trial” – “any research project that prospectively assigns human subjects to intervention or concurrent control or comparison groups to study the cause and effect relationship between a medical intervention and a health outcome” –Excludes studies for other purposes such as to study pharmacokinetics or major toxicity studies but studies of adverse events are covered –Thus, includes devices or even surgical procedures

12. 12 EDITORS – ICMJE … Acceptable registers – must be: –Electronically searchable and publicly accessible at no charge –Open to all registrants –Not-for-profit –Must have mechanism to ensure validity of registration data

13. 13 BIG PHARMA “CAVES” January 2005 – major associations announce plan to create a comprehensive clinical trial registry – of “hypothesis-testing clinical trials” (aka -- “confirmatory clinical trials” ) Associations: –European Federation of Pharmaceutical Industries and Assns. (EFPIA), –International Federation of Pharmaceutical Manufacturers and Associations (IFPMA), –Japanese Pharmaceutical Mfrs. Assn. (JPMA), and –PhRMA –

14. 14 PhRMA – ClinicalStudyResults.org 2002 – PhRMA publishes “Principles on the Conduct of Clinical Trials and Communication of Clinical Trials Results” Position today – –All “hypothesis-testing” studies – regardless of seriousness of condition – those that “serve to examine pre-stated questions using statistically valid plans for data analysis and provide firm evidence of safety and/or efficacy to support product claims” n/a to “exploratory studies” – unless result found to be of medical significance

15. 15 PhRMA … “Will contain” results from all hypothesis- testing clinical studies completed since Oct. 1, 2002 for approved drug products –Published articles –Unpublished study summaries Timing – one year after completion of studies (same as NDA annual report duty) –Could be delayed if submitted to peer-review journal

16. 16 PhRMA … Is a voluntary results registry Registry contains a complete summary of trial, regardless of the outcome Does not apply to drugs not yet marketed – allows protection of confidential information and intellectual property

17. 17 WHO – INTERNATIONAL CLINICAL TRIALS REGISTRY PLATFORM (ICTRP) ICTRP – not a registry itself, but to provide standards to existing registries -- http://www.who.int/ictrp/en/ All trials – including “earliest” stage and exploratory studies Trial Registration Data Set -- 20 key details to be disclosed when study begun – –http://www.who.int/ictrp/network/trds/en/index.htm Portal – to search among other registries Deduping – goal – avoid duplicative registrations (and conflicting information) Results – strongly encouraged to be reported – although first goal of WHO is registration

18. 18 WHO & ICTRP … “Interventional clinical trials” – all should be registered – “any research study that prospectively assigns people to one or more health-related interventions (e.g., preventive care, drugs, surgical procedures, behavioral treatments, etc.) to evaluate the effects.” Primary and Associate Registers – will be the network for registration Universal clinical trial number To search – go to Search Portal: –http://apps.who.int/trialsearch/

19. 19 WHO & ICTRP … The Data Providers of the ICTRP Search Portal currently are: –Australian New Zealand Clinical Trials Registry (ANZCTR) –Chinese Clinical Trial Register (ChiCTR) –ClinicalTrials.gov (U.S.) –Clinical Trials Registry - India (CTRI) –German Clinical Trials Register (DRKS) –Iranian Registry of Clinical Trials (IRCT) –ISRCTN.org –Sri Lanka Clinical Trials Registry (SLCTR) –The Netherlands National Trial Register (NTR)

20. 20 FDAAA & CLINICAL TRIAL REGISTRIES Prior U.S. Law on registries – FDAMA §113 – –Limitations: Only applies to –“serious or life-threatening” diseases –Drugs – not devices No mechanism to ensure compliance by all performing clinicals Inconsistent information in required data fields Only applies to studies under INDs No requirement for Clinical Trials Results Food & Drug Administration Amendments Act of 2007 (FDAAA) – Public Law 110-85 – Sept. 27, 2007

21. 21 FDAAA & TRIAL REGISTRIES … Section 801 -- Expands Trial Registry System Much more detailed information required on the clinical studies Applies to drugs and devices –Devices – under 510k’s, PMAs or PDPs and HDEs or Section 522 Postmarket Surveillance –Drugs – “controlled clinical investigation” other than a Phase I study Not pegged to serious or life threatening

22. 22 FDAAA & TRIAL REGISTRIES … Where “applicable clinical trial” is ongoing on date of enactment or initiated after enactment –90 days after enactment if ongoing –21 days after first patient in if initiated Posting of data – –Drug – within 30 days of submission –Device – If not previously cleared, not earlier than date of clearance or approval If previously cleared, not until 30 days after clinical trial results data is to be submitted

23. 23 FDAAA & CLINICAL TRIAL RESULTS Linking to FDA Data –For clinical trials that form “the primary basis for an efficacy claim” or are post-market trials –Data Advisory committee (if any) consideration – any summary by FDA Posted pediatric assessments or reports Public Health Advisories Drugs -- FDA Action Package required under 505(l)(2) Devices –Detailed Summary of Safety & Effectiveness info for PMAs –510k summary of safety & effectiveness data Medline citations NIH Database of structured product labels

24. 24 FDAAA & TRIAL RESULTS … Phase-In of Data Results –1-Year Demographic and baseline characteristics of patients Primary and secondary outcomes Point of contact Any agreements between sponsor and investigator that “squelches” the investigator –3-Year – Rulemaking required not later than 3 years post-enactment for greater expansion of results database

25. 25 FDAAA & TRIAL RESULTS … Expanded Registry and Results Database under Rulemaking –Would cover trials on both approved and unapproved products –Required Summary in lay language Summary in technical language Full study protocol Submission date – generally 1 year after completion date or estimated completion date of study Public Meeting – within 18 months of FDAAA – held in April 2009 Adverse Events – how to incorporate into databanks? –Within 18 months, rulemaking needed on how to do –If not, default provisions will go into effect

26. 26 FDAAA & TRIAL RESULTS … FDA Submission Certification – NDAs, PMAs, BLAs, 510k’s and HDEs will have to include certification that all applicable requirements on trials information have been submitted –Noncompliance or false information in a certification = “Prohibited Act” under FDCA –Form 3674 – vehicle for compliance

27. 27 FDA Submission Certification -- 3674

28. 28 FDAAA & TRIAL RESULTS … Civil Money Penalties – –up to $10,000 for all violations in a single adjudication –Failure to correct within 30 days, $10,000 per day Preemption – “upon the expansion,” no state may establish or continue in effect any requirement on registries or results

29. 29 STATE LEGISLATION State laws generally apply to drug/device manufacturers conducting business in that state Maine – the frontrunner –Applies to drug and biologics studies –Requires drug manufacturers to register study and disclose all results –Violators assessed fine of $10,000/day

30. 30 STATE LEGISLATION … Numerous states have had pending legislation –California Requires drug manufacturers to post all results of drug/biologics trials, including incomplete studies within ninety days Allows time extension for publication Contains federal preemption language Industry opposition

31. 31 STATE LEGISLATION … New York –Requires drug manufacturers who market drugs in NY to post all information/results within 90 days of trial completion – Allows 6-month time extension for publication – No preemption language

32. 32 STATE LEGISLATION … Implications for drug/device manufacturers –Compliance with potentially 50 different laws –Preemption of state requirements –Cost of registering –Time consuming

33. 33 Call, e-mail, fax or write: Michael A. Swit, Esq. Vice President The Weinberg Group Inc. 336 North Coast Hwy. 101 Suite C Encinitas, CA 92024 Phone 760.633.3343 Fax 760.454.2979 Cell 760.815.4762 michael.swit@weinberggroup.com www.weinberggroup.com Questions?

34. 34 About your speaker… Michael A. Swit, Esq., is a Vice President at THE WEINBERG GROUP, where he develops and ensures the execution of a broad array of regulatory and other services to drug and biologics clients seeking to market products in the United States. His expertise includes FDA development strategies, compliance and enforcement initiatives, recalls and crisis management, submissions and related traditional FDA regulatory activities, labeling and advertising, and clinical research efforts. Mr. Swit has been addressing critical FDA legal and regulatory issues since 1984. His multi-faceted experience includes serving for three and a half years as corporate vice president, general counsel and secretary of Par Pharmaceutical, a prominent, publicly-traded, generic drug company and, thus, he brings an industry and commercial perspective to his work with FDA-regulated companies. Mr. Swit then served for over four years as CEO of FDANews.com, a premier publisher of FDA regulatory newsletters and other specialty information products for the FDA-regulated community. His private FDA regulatory law practice has included service as Special Counsel in the FDA Law Practice Group in the San Diego office of Heller Ehrman White & McAuliffe and with the Food & Drug Law practice at McKenna & Cuneo, both in the firm’s Washington office and later in San Diego. He first practiced FDA regulatory law with the D.C. office of Burditt & Radzius. Mr. Swit has taught and written on a wide variety of subjects relating to FDA law, regulation and related commercial activities, including, since 1989, co-directing a three-day intensive course on the generic drug approval process and editing a guide to the generic drug approval process, Getting Your Generic Drug Approved. A former member of the Food & Drug Law Journal Editorial Board, he also has been a prominent speaker at numerous conferences sponsored by such organizations as RAPS, FDLI, and DIA. A magna cum laude graduate of Bowdoin College, he received his law degree from Emory University Law School and is a member of the California, D.C. and Virginia bars.