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Everything You Need to Know About Clinical Trials Registration and Results Reporting Requirements

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  1. Everything You Need to Know About Clinical Trials Registration and Results Reporting Requirements Deborah A. Zarin, M.D. ClinicalTrials.gov October 2009 1 1

  2. Background

  3. February 27, 2009 Recent Events

  4. February 26, 2009

  5. 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.

  6. Zarin DA, Tse T. Medicine. Moving toward transparency of clinical trials. Science. 2008 Mar 7;319(5868):1340-2.

  7. Levels of “Transparency” 7 Zarin DA, Tse T.. Science. 2008 Mar 7;319(5868):1340-2.

  8. Reasons to Register Clinical Trials and Report Results • Human Subject Protections • Allows potential participants to find studies • Assists ethical review boards and others to determine appropriateness of studies being reviewed (e.g., harms, benefits, redundancy) • Promote fulfillment of ethical responsibility to human volunteers – research contributes to medical knowledge • Research Integrity • Facilitates tracking of protocol changes • Increases transparency of research enterprise • Evidence Based Medicine • Facilitates tracking of studies and outcome measures • Allows for more complete identification of relevant studies • Allocation of Resources • Promotes more efficient allocation of resources

  9. ClinicalTrials.gov—the basics

  10. History of ClinicalTrials.gov FDAMA 113 (1997): Mandates Registry IND trials for serious and life-threatening diseases or conditions ClinicalTrials.gov Launched in February 2000 Calls for Increased Transparency of Clinical Trials Maine State Law; State Attorneys General Journal Editors (2004) ClinicalTrials.gov Accommodates Other Policies FDAAA 801 (2007): Expands Registry and Adds Results Database 10 10 10

  11. New Registrations Continue to Increase 11

  12. ClinicalTrials.gov Statistics (as of 10/05/09) • Number Percent • Total 79,605 100% • Type of Trial • Observational 12,956 16% • Interventional* 66,649 83% • Drug & Biologic 54,208 • Surgical Procedure 8,470 • Behavioral, Gene • Transfer, Other 13,369 • Device 4,742 • International Sites (172 countries) • US only 37,271 47% • Non-US only 28,263 35% • US & Non-US mixed 5,686 7% • Missing 8,385 11% 12 12 *231 “delayed posting” device trials included in “total,” but excluded from other statistics

  13. ClinicalTrials.gov Statistics (cont.)(as of 10/05/09) NumberPercent • Trials by Sponsor • US Federal (including NIH) 10,777 14% • Industry 25,737 32% • University, Other 43,091 54% • Total 79,605 • User Statistics • Page Views per month 60 Million • Unique visitors per month 900,000 13 13

  14. Value-Added Links

  15. Search Interface

  16. Legal and other requirements

  17. ICMJE Policy • Editorial 2004 and updates • Registration required for manuscript consideration for following: • Interventional studies • Any phase • Any intervention • ClinicalTrials.gov or WHO Primary registry • Registration prior to enrollment first participant

  18. Public Law 110-85Sec.801 Expanded Clinical Trial Registry Enacted on September 27, 2007 Requires Trial Registration (Dec 2007) Phase II-IV drug and device trials for all diseases Data elements: ClinicalTrials.gov + ~ WHO/ICMJE Requires Results Reporting (Sept 2008) Trials of FDA-approved or cleared drugs and devices “Basic” Results: Baseline Characteristics, Primary & Secondary Outcomes, Statistical Analyses Adverse Events (Sept 2009) “Expansion” of results by rulemaking (Sept 2010) Added enforcement provisions 34 34 34 34

  19. Enforcement Provisions Notices of non-compliances Civil monetary penalties up to $10,000/day Withholding of NIH grant funds

  20. Key Terms Applicable Clinical Trials Interventional trials Phase 2-4 drug, biologic, device >= one site in U.S. Ongoing as of 9/27/07, or later Responsible Party Sponsor, grantee PI if designated Primary Completion Date

  21. Key Milestones: FDAAA - Sec.801 Expanded Clinical Trial Registry December 26, 2007 New registration requirements effective Linking to existing results September 27, 2008 “Basic Results” reporting requirements effective April 2009 - Public Meeting September 27, 2009 – Adverse Events September 27, 2010 – Rulemaking Due 38

  22. Key Points: Memo from Dr. Kington, Acting Director, to NIH Grant Awardess • “For grants, NIH is generally not the sponsor … and, as such, NIH would not be the responsible party.” • “Responsible parties who have not yet registered their clinical trials should do so immediately.” • “Thank you for your attention to this important matter and your commitment to helping enhance the transparency of NIH funded clinical trials.”

  23. Basic Results Database 40

  24. Basic Results Database: General Characteristics Results of “applicable clinical trials” of FDA-approved/cleared medical products Generally, submission within 12 months of the earlier of estimated or actual trial completion date (of primary outcome) Delayed Submission of Results Seeking initial approval Seeking approval of a new use Extensions for “good cause” 41 41 41 41 41

  25. Adverse Events If the Secretary fails to issue regulation by March 2009, default provisions take effect in September 2009 SERIOUS ADVERSE EVENTS Table of anticipated & unanticipated serious adverse events Grouped by organ system Number and frequency of event in each clinical trial arm FREQUENT (other) ADVERSE EVENTS Table of anticipated & unanticipated adverse events Exceed a frequency of 5 percent within any trial arm Grouped by organ system Number and frequency of event in each trial arm 42 42 42 42 42

  26. Basic Results Modules Participant Flow Baseline and Demographic Characteristics Outcome Measures Adverse Events (summary data) Other Information “Certain Agreements” Restricting Results Disclosure Overall Limitations and Caveats Results Point of Contact

  27. Current Status – “Basic Results”(as of 02/06/09) • Functional Web-based Data Entry System • Launched in September 2008 • 662 Results Records have been submitted • Industry: 449 records from > 100 data providers • NIH: 24 records • Rate of submission continues to increase • 40 records per week now • Anticipate about 150 per week 44 44

  28. Sample Posted Results 45 45 45

  29. Participant Flow “A table ..., including the number of patients who dropped out of the clinical trial and the number of patients excluded from the analysis, if any.” [Sec. 282(j)(3)(C)(i)]

  30. Reasons Not Completed An Investigational Drug on Clinical Outcomes in Patients With Aortic Stenosis NCT00092677 47

  31. Arms Milestone Reasons Not Completed 48

  32. Baseline Measures “A table of the demographic and baseline data collected overall and for each arm of the clinical trial…” [Sec. 282(j)(3)(C)(i)]

  33. “Default” Required Measures User-Specified Measure Categories