1. May 20081 Expansion of Clinical Trial Registration and Results Reporting Requirements Deborah A. Zarin, M.D. ClinicalTrials.gov National Library of Medicine

2. May 20082 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)

3. May 20083 Steady Growth

4. May 200844 ClinicalTrials.gov Statistics (from 4/3/2008) NumberPercent Total53,956 100% Type of Trial* Observational 8,171 15% Interventional45,737 85% –Drug & Biologic34,903 –Medical Procedure11,200 –Behavioral, Gene Transfer, Other 5,484 –Device 2,839 International Sites In the US only27,056 50% At least 1 site in the US 4,141 8% Outside the US17,229 32% Missing 5,530 10% * 48 Missing Study Type Information

5. May 200855 ClinicalTrials.gov Statistics Cont. (from 4/3/2008) Trials by Data Provider University, other21,480 40% US Federal (including NIH)16,808 31% Industry15,668 29% User Statistics Page Views per month 20 Million Unique visitors per month 500,000 NumberPercent (N = 53,956)

6. May 20086 Search Engine 56,000 trials in Registry Search Engine makes it useful Features –Spelling correction/relaxation Alzimers = Alzheimers –Synonymy from UMLS Heart attach = myocardial infarction –Search within a field –Hierarchy from MeSH Crohns is a type of IBD

7. May 20087 Overview of New Requirements FDAAA PL 110-85 9/27/07

8. May 20088 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

9. May 20089 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

10. May 200810 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

11. May 200811 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.

12. May 200812

13. May 200813 Requirements for Results Reporting

14. May 200814 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

15. May 200815 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

16. May 200816 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

17. May 200817 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

18. May 200818 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)

19. May 200819 Published Participant Flow Source: Kimmick GG et al. Breast J. 2006 Mar-Apr;12(2):114-22.

20. May 200820 Published Baseline Data Source: Kimmick GG et al. Breast J. 2006 Mar-Apr;12(2):114-22.

21. May 200821 Published Primary Outcome Source: Kimmick GG et al. Breast J. 2006 Mar-Apr;12(2):114-22.

22. May 200822 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

23. May 200823 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

24. May 200824 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

25. May 200825 Measurement Types Dichotomous Continuous (Years) Multiple Categories

26. May 200826 Time To Event

27. May 200827 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

28. May 200828 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

29. May 200829 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)

30. May 200830 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

31. May 200831 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

32. May 200832 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

33. May 200833 How to Facilitate Rational Use of Data Provide context –Study design –Background information Consider linking to systematic reviews Link to other resources

34. May 200834 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 34