ClinicalTrials and FDAAA for NIH Grantees

1. ClinicalTrials.gov and FDAAA for NIH Grantees NIH Regional Seminar - June 2013 Rebecca J. Williams, PharmD, MPH Assistant Director, ClinicalTrials.gov National Library of Medicine http://ClinicalTrials.gov

2. Overview • Introduction to the Food and Drug Administration Amendments Act of 2007 (FDAAA) • Why FDAAA Title VIII? • Requirements it establishes • Next Steps • FDAAA for NIH Extramural Grantees • Implementation for NIH grants • OER resources • ClinicalTrials.gov Practical Considerations • Protocol Registration System (PRS) • Resources

3. Introduction to FDAAA

4. Three Key Issues with Publications • Not all trials are published • Publications do not always include all prespecified outcome measures • Unacknowledged changes are made to the trial protocol that would affect the interpretation of the findings • e.g., changes to the prespecified outcome measures

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. The Controversies Continue…

8. Summary of Findings • Fewer than half of NIH funded trials registered at ClinicalTrials.gov after September 2005 and completed by December 2008 were published in a peer reviewed biomedical journal indexed by Medline within 30 months of trial completion • After a median of 51 months after study completion, a third of NIH-funded trials in the sample remained unpublished BMJ 2011;344:d7292 doi

9. Rationale for Registering and Reporting Clinical Trial Results • Responsibility to human subjects and the public • Research integrity • Evidence-based medicine • Allocation of resources

10. Levels of “Transparency” 10 Zarin DA, Tse T. Science. 2008

11. ClinicalTrials.gov – Milestones • 1997 - Food and Drug Administration Modernization Act (FDAMA) • 2000 - ClinicalTrials.gov launched • 2005 - International Committee of Medical Journal Editors (ICMJE) policy • 2007 - FDAAA (Title VIII of Public Law 110-85) • Expanded clinical trial registration requirement and imposed new results submission requirements • Added enforcement provisions including up to $10,000/day in civil monetary penalties and withholding remaining or future grant funds FDAAA = Food and Drug Administration Amendments Act of 2007

12. What does FDAAA require? The responsible party for an applicable clinical trial (ACT) subject to FDAAA must : • Register the ACT in ClinicalTrials.gov no later than 21 days after enrollment of the first participant; • Submit summary results (including adverse event information) for certain trials not later than 1 year after the trial’s (primary) completion date. • Delays allowed in some circumstances 12

13. FDAAA Key Terms • Applicable Clinical Trials (ACTs) • Responsible Party • (Primary) Completion Date 13

14. What is an ACT? • “Applicable Clinical Trials”* (ACTs) subject to FDAAA are: • Interventional studies of drugs, biologics, & devices • Not phase 1 drugs, not small feasibility devices • US FDA jurisdiction (e.g., IND/IDE orUS site) • ACTs initiated on or after 9/27/07 or ongoing as of 12/26/07 *http://prsinfo.clinicaltrials.gov/ElaborationsOnDefinitions.pdf

15. Who is the Responsible Party? • “Responsible Party”* is defined as: • Sponsor [only one per trial] • IND/IDE holder; if none, then • Person or entity who “initiated” the trial • Funding recipient if grant or sponsored research agreement • Funder if procurement funding agreement (contract) • Sponsor may designate the Principal Investigator (PI) as Responsible Party [only one per trial] • If PI meets certain requirements (e.g., has access to and control over data, right to publish) *http://prsinfo.clinicaltrials.gov/ElaborationsOnDefinitions.pdf

16. FDAAA Registration Requirements • Where do I register? • ClinicalTrials.gov web-based Protocol Registration System (PRS); interactive data entry or XML upload • Tool available for cancer centers also submitting protocol information to NCI Clinical Trials Reporting Program (CTRP) • When do I register? • May register before initiation*; must register no later than 21 days after enrolling the first participant • Updates (if any) required at least once every 12 months • Recruitment status and (primary) completion date must be updated within 30 days *International Committee of Medical Journal Editors (ICMJE) requires registration prior to enrollment of first participant as a condition of consideration for publication

17. FDAAA Registration Requirements • What do I register? • ClinicalTrials.gov/FDAAA data elements*, including: • Study Design and Locations • Responsible Party (updated format Aug 2011) • Sponsor • Sponsor Investigator • Principal Investigator (designated by Sponsor) • Complete NIH Grant Number in Secondary ID * ClinicalTrials.gov Protocol Data Element Definitions (DRAFT): http://prsinfo.clinicaltrials.gov/definitions.html

18. FDAAA Results Requirements • Which Trials Must Submit Results? • “Applicable clinical trials” of FDA approved or cleared drugs, biologics, devices • Interventional studies of drugs, biologics, or devices • Not phase 1 drug or not small feasibility device • US FDA jurisdiction (e.g., IND/IDE or US site) • Initiated on or after 9/27/07 or ongoing as of 12/26/07 18 18 http://www.clinicaltrials.gov/ct2/manage-recs/fdaaa

19. FDAAA Results Requirements • When Must Results be Submitted? • Within 12 months of (primary) completion date; • “The date that the final subject was examined or received an intervention for the purposes of final collection of data for the primary outcome, whether the clinical trial concluded according to the prespecified protocol or was terminated.” • OR within 30 days of product approval or clearance • Delays possible • Seeking approval of a new use • Extensions for “good cause” 19 19 http://www.clinicaltrials.gov/ct2/manage-recs/fdaaa

20. FDAAA Results Requirements • What Information Must be Submitted? • Scientific Information (per arm) • Participant Flow • Number of participants started • Number of participants completed • Baseline Characteristics • Number of Participants Analyzed • Age and Gender • Outcome Measures • Number of Participants Analyzed • Title and Description • Measure Type (e.g., mean) and Measure of Dispersion (e.g., SD) • Statistical analyses, as appropriate 20 20 http://www.clinicaltrials.gov/ct2/manage-recs/fdaaa

21. FDAAA Results Requirements • What information? (cont.) • Scientific Information (per arm) • Adverse Events – Serious and “Other” • Number of Participants Affected/At Risk • Adverse Event Term and Organ System • Limitations and Caveats (optional) • Administrative Information • Results Point of Contact • Certain Agreements (related to investigator’s right to publish, if not an employee of sponsor) 21 21 http://www.clinicaltrials.gov/ct2/manage-recs/fdaaa

22. FDAAA Results Requirements - Clarifications • Does NOT prescribe how study should be conducted • Summary results at the end of the trial • No interim or “real time” reporting • No participant level reporting • Information currently targeted at readers of the medical literature • “Tables” of information; “just the facts” • No narrative discussion or results/conclusions

23. Registration, Results Submission and Publication • International Committee of Medical Journal Editors (ICMJE) requires registration of all clinical trials as a condition of publication • Must register prior to enrollment of first participant • Deadlines for submitting results to ClinicalTrials.gov are independent of publication status • Submitting results to ClinicalTrials.gov will not interfere with publication* • But, failing to register the trial will! * Laine C, Horton R, DeAngelis C, et al. Ann Intern Med. 2007; http://www.icmje.org/faq_clinical.html

24. Results and non-ACTs • Non-ACTs registered in ClinicalTrials.gov are *not* required to submit results to ClinicalTrials.gov • Phase 1 trials • Observational studies • Exception: Pediatric postmarket surveillance of devices • Note: Other policies may apply

26. Participant Flow - ClinicalTrials.gov Format NCT00145249 NCT00145249

27. Baseline Measures - ClinicalTrials.gov Format “Default” Required Measures NCT00145249

28. Outcome Measures - ClinicalTrials.gov Format NCT00145249

29. Outcome Measures - ClinicalTrials.gov Format (cont’d) NCT00145249

31. Adverse Events - ClinicalTrials.gov Format 31 NCT00145249

32. Experience with Results Database • Entering results is similar to the process of preparing a journal article • Data provider must be familiar with the study design and data analysis • Typically, the investigator and/or a statistician will need to be involved 32

33. General Review Criteria • Protocol and results must be clear and informative • Review focuses on: • Logic and internal consistency • Apparent validity • Meaningful entries • Formatting 33

34. Who is the Audience? PI and Clinical Research Team Other Medical Researchers in same field Other Medical Researchers in other fields Other Readers of the medical literature Science Writers Lay Public (readers of consumer health literature) 34

35. FDAAA – Other Considerations • FDA Requirements • Certification of Compliance to FDA • Form 3674 must accompany human drug, biological, and device product submissions • FDA Compliance Program 7348.810: Sponsors, Contract Research Organizations, and Monitors • Instructs FDA staff to identify SOPs and determine if studies were registered on ClinicalTrials.gov appropriately • Informed Consent Regulations (21 CFR § 50.25(c)) • A statement must be included in informed consent documents of applicable clinical trials initiated on or after March 7, 2012 regarding the availability of information at ClinicalTrials.gov • http://www.fda.gov/RegulatoryInformation/Guidances/ucm125335.htm • http://www.fda.gov/ICECI/ComplianceManuals/ComplianceProgramManual/default.htm • http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=50.25

36. FDAAA - Next Steps • HHS plans to issue regulations that will prescribe procedures for registering and submitting results of clinical trials to ClinicalTrials.gov in accordance with FDAAA • Notice of Proposed Rulemaking (NPRM) • Fall 2012 HHS Unified Agenda estimated publication in the Federal Register in January 2013

37. Overview of Rulemaking Process Food and Drug Administration Amendments Act of 2007 Announcement in Department’s Unified Agenda of Regulatory Action Agency Develops Draft Notice of Proposed Rulemaking (NPRM) Department and OMB Review NPRM Published in Federal Register Public Comment Period (typically 60 – 90 days) Agency Responds to Comments/ Develops Final Rule Department and OMB Review Final Rule Published in Federal Register 37

38. Additional Issues in Rulemaking • Expand results reporting to trials of unapproved products? • Include narrative summaries? Can it be done without being promotional and misleading? • Technical; Lay language • Data quality verification • Process • External sources • Full protocol versus extract “necessary to help evaluate the results”

39. ClinicalTrials.gov Practical Considerations

40. Who is the Responsible Party? • “Responsible Party”* is defined as: • Sponsor [only one per trial] • IND/IDE holder; if none, then • Person or entity who “initiated” the trial • Funding recipient if grant or sponsored research agreement • Funder if procurement funding agreement (contract) • Sponsor may designate the Principal Investigator (PI) as Responsible Party [only one per trial] • If PI meets certain requirements (e.g., has access to and control over data, right to publish) *http://prsinfo.clinicaltrials.gov/ElaborationsOnDefinitions.pdf

41. PRS Responsible Party Format • Updated format August 2011 • Responsible Party (RP) must approve and release record • If RP = Sponsor; no change in process • Administrator “releases” record; fewer data elements • If RP ≠ Sponsor; new process • Record is in the Sponsor’s PRS Organization Account • Investigator must be specified as a User in the PRS and name must be properly formatted (for public display) • Investigator “releases” record • Administrator receives notification after release • See: “Responsible Party FAQ” on PRS Main Menu under Help http://register.clinicaltrials.gov/

42. PRS Responsible Party Format www.diahome.org

43. PRS Responsible Party Format

44. PRS Entry of Grant Number

45. Additional PRS Resources • Problems Report • Allows investigators and administrators of organizational accounts to identify potential problems with records • Record Owner issues • PRS Administrator issues • FDAAA issues (report is downloadable) • Trials missing FDAAA required data elements • Trials that reached (primary) completion date more than one year ago and results are not posted on ClinicalTrials.gov • Note: For informational purposes only. The Responsible Party must determine if the trial is an “applicable clinical trial” subject to FDAAA requirements.

46. PRS Information Resources • Protocol Registration • Data Element Definitions • Review Criteria • Results • Data Element Definitions • Review Criteria • Simplified, Printable Results Templates • Helpful Hints and Common Errors • User’s Guide [PRS Main Menu] 46 http://www.clinicaltrials.gov/ct2/manage-recs/resources

47. Recorded Presentations Available at: http://prsinfo.clinicaltrials.gov/index.html Eight presentations with audio and slides Results 5. Participant Flow Module 6. Baseline Characteristics Module 7. Outcome Measures and Statistical Analysis Module 8. Adverse Events Module • Overview of ClinicalTrials.gov • Key FDAAA Issues • PRS Information and Data Review Process • PRS Accounts and Registration

48. CTSA Training Opportunity • ClinicalTrials.gov Results Database Train-the-Trainer Workshop • Goal is to train key personnel at CTSA institutions on FDAAA and results database requirements so that they may serve as a knowledge source for investigators at their institution • Next workshops are June 10-11(registration is closed) and July 22-23, 2013

49. Select Publications Zarin DA, Tse T, Williams RJ, Califf RM, Ide NC. The ClinicalTrials.gov results database – update and key issues. N Engl J Med 2011;852-860. Tse T, Williams RJ, Zarin DA. Update on registration of clinical trials in ClinicalTrials.gov. Chest 2009;136:304-5. Tse T, Williams RJ, Zarin DA. Reporting basic results in ClinicalTrials.gov. Chest 2009;136:295-303. Zarin DA, Tse T. Moving toward transparency of clinical trials. Science 2008;319:1340-2.

50. Additional Information • General ClinicalTrials.gov information: • www.clinicaltrials.gov • Office of Extramural Research (OER) • http://grants.nih.gov/Clinicaltrials_fdaaa/ • Questions? • register@clinicaltrials.gov