Session 1 Background and Legislative Requirements

1. Session 1Background and Legislative Requirements

2. ClinicalTrials.gov Background Dr. Deborah A. Zarin

3. ClinicalTrials.gov Team Jerry Sheehan Betsy Humphreys Director • Deborah Zarin Project Leads • Annice Bergeris • Nicholas Ide • Alison Robbins • Tony Tse • Rebecca Williams Quality Assurance • John Frye • Cherryl Macalintal • Alex Valentine • Systems Development • Jane Fun • John Gillen • Alex Kostyukovsky • Russell Loane • Allison Yu • Domain Expert • William Harlan • Administration • Tamia Whitfield

4. Ethical and Scientific Rationale for Increased Clinical Trial Transparency • Subjects put themselves at risk • Subject’s right to be informed • All available options, including ongoing trials • Previous research, including completed trials • Avoid redundant trials • Support Evidenced-Based Medicine (EBM) • Detect reporting problems • Lack of publication • Unexplained changes to protocol

5. Recent Events: Lack of Transparency in Clinical Research

6. Source: Figure 1A. Turner et al. (NEJM, 2008)

7. The investigation was launched following concerns… • …although the ENHANCE trial ended in April 2006, the data had not yet been released. • …[the sponsors] did not register the clinical trial in a timely manner. • …[the sponsors] attempted to change the study endpoints, and thus the study results, prior to the public release of the results.

8. Source: Silverstein FE et al. JAMA. 2000 Sep 13;284(10):1247-55.

9. Kaplan-Meier estimates for ulcer complications according to traditional definition. Results are truncated after 12 months, no ulcer complications occurred after this period. Adapted from Lu 2001. Source: Jüni P, Rutjes AW, Dieppe PA. BMJ. 2002 Jun 1;324(7349):1287-8.

10. ClinicalTrials.gov • Prospective registry • Interventional and observational “trials” • Approved by IRB (or equivalent) • Conform to regulations of national health authorities • All sponsor types • All intervention types • Summary of key protocol items • Consistent with ICMJE and WHO • Links to publications, other info • Does not include unpublished results

11. Policies and Users Ottawa Statement Sponsor Policy (e.g., NIH, VA) PL 110-85 ICMJE Maine FDAMA 113 BPCA WHO ClinicalTrials.gov Recruitment (e.g., patients, physicians) Health Policy Makers Systematic Reviewers Journal Editors Research Funders

12. International Registries and Number of Trials (as of 2/4/08)

13. Characteristics of ClinicalTrials.gov Web-based registration system (PRS) Register through organizational accounts Key part of validation XML data upload (<20% records) Data are dynamic—”data provider” can modify data at any time Changes are tracked

14. Homepage - ClinicalTrials.gov

17. http://ClinicalTrials.gov/archive

19. ClinicalTrials.gov General Statistics

21. ClinicalTrials.gov Statistics(as of 2/4/2008) Number Percent Total 50,564 100% Type of Trial* Observational 7,701 15% Interventional 42,836 85% • Drug & Biologic 32,835 • Surgical Procedure 10,856 • Behavioral, Gene Transfer, Other 4,809 • Device 2,628 International Sites US only 25,485 50% Non-US only 15,982 32% US & Non-US mixed 3,934 8% Missing 5,163 10% * 27 records missing Study Type information 21

22. ClinicalTrials.gov Statistics Cont.(as of 2/4/2008) NumberPercent • Trials by Data Provider • US Federal (including NIH) 16,430 33% • University, other 19,803 39% • Industry 14,331 28% • User Statistics • Page Views per month 20 Million • Unique visitors per month 500,000 22

23. Organizational Accounts Total            4,792   • Fed accounts   71 • NIH accounts   26 • Industry           1,783 • Other               2,912

24. Validation of Data for Registry • Issues • Quality Assurance: Are the entries as accurate and informative as possible? • Validation (w/o access to protocols): Is the fundamental information true? • QA Process at ClinicalTrials.gov • System of automated and manual checks • Staff works with data provider to correct/improve records • Links inserted

26. ENHANCE 2 1 3 Source: Kastelein JJ, Sager PT, de Groot E, Veltri E. Am Heart J. 2005 Feb;149(2):234-9.

27. Primary Outcome Measures: • Change in ultrasound-determined average carotid artery intima-media thickness (IMT) on a per subject basis between baseline and endpoint. [ Time Frame: 24 months ] • Primary Outcome Measures: • Change in ultrasound-determined average carotid artery intima-media thickness (IMT) on a per subject basis between baseline and endpoint. [ Time Frame: 24 months ]

28. Legislative RequirementsJerry Sheehan