1 Session 1 Background and Legislative Requirements

2 ClinicalTrials.gov Background Dr. Deborah A. Zarin

3 ClinicalTrials.gov Team 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 Jerry SheehanBetsy Humphreys

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 Sep 13;284(10):

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 Source: Jüni P, Rutjes AW, Dieppe PA. BMJ Jun 1;324(7349):

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types Summary of key protocol items –Consistent with ICMJE and WHO Links to publications, other info Does not include unpublished results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 ClinicalTrials.gov FDAMA 113 BPCA Maine PL Sponsor Policy (e.g., NIH, VA) ICMJE WHO Ottawa Statement Recruitment (e.g., patients, physicians) Journal Editors Research Funders Systematic Reviewers Health Policy Makers

12 International Registries and Number of Trials (as of 2/4/08) ClinicalTrials.gov50,564 ISRCTN (UK)6,514 Australian New Zealand Clinical Trial Registry (ANZCTR) 1,973 Netherlands Trial Registry1,111 UMIN Clinical Trials Registry (Japan)943 Chinese Clinical Trial Register (ChiCTR)34 Clinical Trials Registry – India (CTRI)16

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

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19 ClinicalTrials.gov General Statistics

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21 ClinicalTrials.gov Statistics (as of 2/4/2008) NumberPercent Total50, % Type of Trial* Observational 7,701 15% Interventional42,836 85% –Drug & Biologic32,835 –Surgical Procedure10,856 –Behavioral, Gene Transfer, Other 4,809 –Device 2,628 International Sites US only25,485 50% Non-US only15,982 32% US & Non-US mixed 3,934 8% Missing 5,163 10% * 27 records missing Study Type information

22 ClinicalTrials.gov Statistics Cont. (as of 2/4/2008) User Statistics Page Views per month 20 Million Unique visitors per month 500,000 NumberPercent Trials by Data Provider US Federal (including NIH)16,430 33% University, other19,803 39% Industry14,331 28%

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

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26 ENHANCE Source: Kastelein JJ, Sager PT, de Groot E, Veltri E. Am Heart J Feb;149(2):

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 Requirements Jerry Sheehan