Expansion of Clinical Trial Registration and Results Reporting Requirements

1. Expansion of Clinical Trial Registration and Results Reporting Requirements Deborah A. Zarin, M.D. ClinicalTrials.gov National Library of Medicine May 2008

2. History of ClinicalTrials.gov • FDAMA 113: Mandates Registry (1997) • ClinicalTrials.gov Launched in Feb 2000 • Calls for Increased Transparency of Clinical Trials • Maine State Law; State Attorneys General • Journal Editors (2004); • ClinicalTrials.gov Accommodates Other Policies • PL 110-85, Sec. 801: Expands Registry (2007) May 2008

3. Steady Growth May 2008

4. ClinicalTrials.gov Statistics(from 4/3/2008) Number Percent Total 53,956 100% Type of Trial* Observational 8,171 15% Interventional 45,737 85% Drug & Biologic 34,903 Medical Procedure 11,200 Behavioral, Gene Transfer, Other 5,484 Device 2,839 International Sites In the US only 27,056 50% At least 1 site in the US 4,141 8% Outside the US 17,229 32% Missing 5,530 10% *48 Missing Study Type Information May 2008 4

5. ClinicalTrials.gov Statistics Cont.(from 4/3/2008) NumberPercent (N = 53,956) • Trials by Data Provider • University, other 21,480 40% • US Federal (including NIH) 16,808 31% • Industry 15,668 29% • User Statistics • Page Views per month 20 Million • Unique visitors per month 500,000 May 2008 5

6. Search Engine • 56,000 trials in Registry • Search Engine makes it useful • Features • Spelling correction/relaxation • Alzimers = Alzheimer’s • Synonymy from UMLS • Heart attach = myocardial infarction • Search within a field • Hierarchy from MeSH • Crohn’s is a type of IBD May 2008

7. Overview of New Requirements FDAAA PL 110-85 9/27/07 May 2008

8. Key Milestones • December 26, 2007 • New registration requirements effective • Linking to existing results • September 27, 2008 • BASIC Results reporting requirements effective • September 27, 2009 – Adverse Events • September 27, 2010 • ENHANCED results implemented May 2008

9. New Registration Requirements • Drug and device trials • Exclude “phase 1” • 12 Previously optional data elements now required • 4 new data elements are required • Registration due within 21 days of first enrollment • Penalties for non-compliance May 2008

10. Other Registration Issues • Trials for devices that are not approved/cleared are not posted publicly (“lock box”) • Updates • As necessary to keep information accurate • Within 30 days of recruitment status change • At least every 12 months for other changes • Changes are date stamped and tracked publicly May 2008

11. Who Must Register?“Responsible Party” • The sponsor of the clinical trial -- OR -- • The principal investigator (PI) of such clinical trial if so designated by a sponsor, grantee, contractor, or awardee, so long as the PI is responsible for conducting the trial and has sufficient data rights. May 2008

12. May 2008 12

13. Requirements for Results Reporting May 2008

14. Links to Existing Results • December 26, 2007 (90 days after enactment) • FDA Information, including • Advisory Committee summary document • Posted assessment of drug clinical trial results • Public health advisories regarding drug or device • Drug action package for approval document • Safety and effectiveness summary (devices) • NIH Information • MEDLINE - Citation of published results • DailyMed – FDA structured product labels May 2008

15. Basic Results Database • Which trials? • trials of approved drugs/devices • When? • 12 months after “completion date” if approved product • or later if submitting an sNDA • or 30 days after product approval May 2008

16. Basic Results: Statutory Requirements Demographic and baseline characteristics Primary and secondary outcomes Point of contact Certain agreements Restrictions on PI to discuss or publish results May 2008

17. Basic Results Tables • Participant flow • Demographic and baseline characteristics • Overall and by arm • Values for primary and secondary outcomes • By arm • Scientifically appropriate tests of statistical significance May 2008

18. Overall Approach to Collecting Results Information Results tables are similar to those found in journal articles Data entry systems will use terms familiar to investigators Technical items (e.g., statistical tests) would be necessary for any official study report Multiple modalities of user support services will be important (e.g., online, telephone) May 2008

19. Published Participant Flow May 2008 19 Source: Kimmick GG et al. Breast J. 2006 Mar-Apr;12(2):114-22.

20. Published Baseline Data May 2008 20 Source: Kimmick GG et al. Breast J. 2006 Mar-Apr;12(2):114-22.

21. Published Primary Outcome May 2008 21 Source: Kimmick GG et al. Breast J. 2006 Mar-Apr;12(2):114-22.

22. Challenges and Goals for Data Entry System Need to accommodate full range of study designs and data types Need for structure to optimize data quality and search capabilities, and to allow for control over data display Need to be usable by full range of international trial community Large data providers (e.g., drug companies, NIH ICs) Academic medical centers Individual investigators Desire to promote “good trial practices”, but must accommodate all practices May 2008

23. Data Entry Mechanisms • Electronic Data Interchange – upload data in XML format • Manual Data Entry – enter data using a Web-based Results Registration System (RRS) • analogous to the Protocol Registration System (PRS) for the registry May 2008

24. Basic Results Data Entry System • Prepopulates certain data elements from registry, if provided (e.g., Arm Description) • Lists some prespecified baseline demographics (e.g., gender, ethnicity) • Allows users to enter and edit tables • Column labels: e.g., Arms • Row labels: e.g., demographics, outcome measures • Cells: e.g., measurement values May 2008

25. Measurement Types Dichotomous Continuous (Years) Multiple Categories May 2008

26. Time To Event May 2008

27. Participant Flow Number entered study Number completed study Number not completed study Other details Phase specific information Study specific information Number achieved milestones, as specified by registrant May 2008 27

28. Demographic & Baseline Characteristics Commonly used measures Age (continuous and categorical) Gender Race/Ethnicity Region of enrollment Measures specific to each trial For each measure Name of measure Value, total and by arm Names and values of categories, if categorical Measure of dispersion, if continuous Other details, if time-to-event May 2008 28

29. Outcomes Pre-specified primary and secondary outcome measures from registry For each measure Description Units Value by arm or other comparison group Names and values for categories, if categorical Measure of dispersion, if continuous Other details if time to event Statistics (cont. next slide) May 2008 29

30. Outcomes Statistics (cont.) Test of non-inferiority? (y/n) If yes, other details For each p-value provided Name of test (e.g., Chi-squared, ANOVA) Other details/comments For each confidence interval provided % (e.g., 95% confidence interval) Name of estimate (e.g., OR, RR) Value of estimate Other details/comments May 2008 30

31. Issues to Consider in Developing Public Display Simple, tabular format (“just the facts”) Provide context Study design Background information Display links to other similar trials Consider linking to systematic reviews and other resources Link to published articles and FDA reviews, when available May 2008 31

32. Data Display Mechanisms • Summary result records displayed in a Results Database at ClinicalTrials.gov • Results records linked to registry records via NCT number • Similar search engine and “look and feel” • Details to be determined May 2008

33. How to Facilitate Rational Use of Data • Provide context • Study design • Background information • Consider linking to systematic reviews • Link to other resources May 2008

34. Seeking Public Input • Updated information on status of implementation • http://prsinfo.clinicaltrials.gov/fdaaa • Public comment on early versions is critical • Short timeline for development – May to September 2008 • Describes rulemaking process for expanded registry and results database • Public Meeting by March 2009 to inform rulemaking for “expanded” results database May 2008 34