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ClinicalTrials Update on Clinical Trial Registration and Results Reporting Requirements

ClinicalTrials.gov Update on Clinical Trial Registration and Results Reporting Requirements. Rebecca J. Williams, Pharm.D., MPH ClinicalTrials.gov June 22, 2009. 1. 1. History of ClinicalTrials.gov. FDAMA 113 (1997): Mandates Registry

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ClinicalTrials Update on Clinical Trial Registration and Results Reporting Requirements

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  1. ClinicalTrials.gov Update on Clinical Trial Registration and Results Reporting Requirements Rebecca J. Williams, Pharm.D., MPH ClinicalTrials.gov June 22, 2009 1 1

  2. 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 2 2 2

  3. ClinicalTrials.gov Statistics(as of 06/17/09) • Number Percent • Total 74,623 100% • Type of Trial* • Observational 11,529 16% • Interventional 62,210 84% • Drug & Biologic 45,863 • Surgical Procedure 8,073 • Behavioral, Gene • Transfer, Other 11,903 • Device** 4,318 • International Sites (167 countries) • US only 35,376 47% • Non-US only 25,960 35% • US & Non-US mixed 5,366 7% • Missing 7,921 11% *213 records missing Study Type information **213 device trials – “delayed posting” 3 3

  4. ClinicalTrials.gov Statistics (cont.)(as of 06/17/09) NumberPercent • Trials by Data Provider • US Federal (including NIH) 18,859 25% • Industry 23,328 31% • University, Other 32,436 44% • Total 74,623 • User Statistics • Page Views per month 40 Million • Unique visitors per month 500,000 4 4

  5. Update on Clinical Trial Registration

  6. 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) Public Meeting (April 2009) 6 6 6 6

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

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

  9. Key Points: Memo to NIH Grant Awardees from IC Directors • “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.”

  10. Bottom Line • Register within 21 days of enrollment: • Phase 2-4 interventional trials that include a drug, device or biologic • Regardless of whether or not the trial is being used to support an FDA application • Report results: • Any trial described above once the drug, device or biologic has been approved; OR • Within one year of “primary completion date” • Keep all information up to date! 10

  11. New Registrations Continue to Increase 11

  12. Basic Results Database 12

  13. 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” 13 13 13 13 13

  14. Basic Results Information: Statutory Requirements • Demographic & baseline characteristics • Table of values, overall and for each arm • # of patients dropped out & excluded from analysis • Primary and secondary outcomes • Table of values for each primary & secondary outcome measure, by arm • Scientifically appropriate tests of statistical significance • Point of contact (for scientific information) • Certain agreements (restrictions on PI to discuss or publish results after trial completion date) 14 14 14 14 14

  15. 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 15 15 15 15 15

  16. 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

  17. Current Status – “Basic Results”(as of 06/17/09) • Functional Web-based Data Entry System • Launched in September 2008 • 973 Results Records have been submitted • Industry: 686 records from 125 data providers • Other: 287 records from 193 data providers • Rate of submission continues to increase • 40 records per week now • Anticipate about 150 per week 17 17 17

  18. Lessons Learned from Early Submissions of Basic Results • Many iterations with NLM staff were necessary to reach minimal quality standards and to correct serious flaws • Data Providers must be able to understand the study design and data analysis • Typically, the investigator and a statistician will need to be involved 18

  19. Quality Assurance Challenges Data tables will be the public representation of the study—must be clear and informative; NLM review of records focuses on: Apparent validity (when possible) Meaningful entries Internal consistency/logic Format Detailed Review of Results Submissionhttp://prsinfo.clinicaltrials.gov/DetailedReview.pdf

  20. Key Quality Assurance Criteria Common Errors

  21. Table Structure Must be Logical

  22. BEFORE Revision (Public View) Measured Values Inconsistency between columns and rows: Measure “at week 10” and Measure “after 18 weeks of treatment” 22 22

  23. Data Must Make Sense • Outcome Measure Name, Description, Units and Data are Compatible

  24. BEFORE Revision (Public View) Primary Outcome Measure: Time to Invasive Disease-Free Survival • Mismatch: • Title: Time to… • Unit: Number of participants • Mismatch: • Measure Name: Time to… • Unit: Number of participants Measured Values

  25. BEFORE Revision (Public View) Measured Values Inconsistency between Units of Measure, “average hours per day,” and Measure Data: value provided is greater than the total number of hours in a day 25 25

  26. Tables Must Be Informative • Scales should include: • Full name • Construct or domain (e.g., pain) • Direction of scores (Best/Worst Value) • Other information as necessary • Measures Have Useful Descriptions • Avoid Abbreviations

  27. BEFORE Revision (Public View) • Need information about this scale • Full Name • Construct/domain • Range and directionality Need information about these values (e.g., is “0” better or worse than “2”?) Baseline Measures Are these the only possible scores? Need to change to “participants” – data represent “number of participants” with a particular score 27 27

  28. Statistical Analyses • Must be Logical • Compatible with Data • Informative (report informative metrics)

  29. BEFORE Revision (Public View) Measured Values • Inconsistency between Measure Data and Method of Estimation • Reported Mean Difference: “9” • By Inspection: 9.3 – 7.8 = 1.5 Statistical Analysis 1 for Parental Stress 29 29

  30. Sample Posted Results 30 30 30

  31. Informative Entry

  32. Informative Entry

  33. Additional Information(at http://prsinfo.clinicaltrials.gov/fdaaa.html) "Basic Results" Data Element Definitions Helpful Hints - tips on entering results data, including examples of common study models (e.g., crossover design) Detailed Review Items - describes items evaluated by the staff at NLM Common Errors - overview of common types of errors identified in submitted records with "basic results" Pre-Submission Checklist 33 33 33 33 33

  34. Public Meeting and Comments • Public Meeting – April 20, 2009 • To provide an opportunity for input from interested parties with regard to the regulations for the expanded results database • Requested comments on items in Federal Register Notice by June 22, 2009 • Docket No. NIH-2009-0002 • http://www.regulations.gov

  35. Additional Information Email LISTSERV and other FDAAA information: http://prsinfo.clinicaltrials.gov/fdaaa.html Other general information: http://prsinfo.clinicaltrials.gov Questions? register@clinicaltrials.gov 35 35 35 35

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