Clinical Trials Registration and Results Reporting: Legislative Requirements

1. Clinical Trials Registration and Results Reporting: Legislative Requirements Jerry Sheehan Assistant Director for Policy Development National Library of Medicine – National Institutes of Health NLM Board of Regents Working Group on Clinical Trials 11 February 2008, Washington, DC NLM BOR WG on Clinical Trials

2. Why Register at ClinicalTrials.gov: Policies Mandating Registration • FDAMA Section 113 (1997) • Director of NIH to establish registry of drug trials related to serious and life-threatening conditions. • Sponsors required to submit information within 21 days of protocol approval. • ICMJE (2004) • Registration as precondition for publication • Applies to all types of clinical trials • State of Maine (2005) • Prescription drugs and biologics marketed in Maine • Register in ClinicalTrials.gov; Post results in publicly available Website (gov’t site when available) NLM BOR WG on Clinical Trials

3. New Reason to Register: P.L. 110-85 FDA Amendments Act • Title I — Prescription Drug User Fee Act of 2007 • Title II — Medical Device User Fee Amendments of 2007 • Title III — Pediatric Medical Device Safety and Improvement Act of 2007 • Title IV —Pediatric Research Equity Act of 2007 • Title V — Best Pharmaceuticals for Children Act of 2007 • Title VI — Reagan-Udall Foundation • Title VII — Conflicts of Interest • Title VIII—Clinical Trial Databases • Title IX — Enhanced Authorities Regarding Postmarket Safety of Drugs • Title X — Food Safety • Title XI — Other Provisions Enacted on September 27, 2007 NLM BOR WG on Clinical Trials

4. Overview of P.L.110-85 §801Expanded Clinical Trial Registry Data Bank • 90-Day Requirements (12/26/07) • Expand clinical trials registry to accept broader scope of trials, more required information • New registrations – submission of new information • Updating of existing records for ongoing trials (~13,000) • Establish links from registry to specified FDA & NIH (NLM) results information • 1 Year and beyond (9/27/2008+) • Basic results database and results reporting (1 year) • Public meeting to solicit stakeholder input (18 months) • Adverse event reporting (18-24 months) • Pilot Quality Control study with FDA to inform rulemaking • Expand Registry and Results Database by rulemaking (3 yrs) • Penalties for non-compliance

5. Who Must Register and Report Results -- Responsible Party Defined as: • The sponsor of the clinical trial -- OR -- • The principal investigator (PI) • if so designated by a sponsor, grantee, contractor, or awardee. • so long as the PI is responsible for conducting the trial and has sufficient data rights. NLM BOR WG on Clinical Trials

6. Which Trials to Register – Applicable Clinical Trials • Applicable Drug Clinical Trial • Controlled clinical investigations, other than Phase 1 investigations • Product subject to FDA regulation (drugs and biologics) • Applicable Device Clinical Trial • Controlled trials with health outcomes of devices subject to FDA regulation (other than small feasibility studies) • Pediatric postmarket surveillance • Voluntary submissions specifically authorized NLM BOR WG on Clinical Trials

7. Registration information • Registry “Content” includes 25 elements • Descriptive information (title, study design, primary/secondary outcome measures, etc.) • Recruitment information (eligibility, recruitment status, etc.) • Location and contact information (site-specific) • Administrative information (protocol ID, IND/IDE protocol no.) • Other elements to implement law, e.g., • Is outcome measure a safety issue (Yes/No)? (to allow searching) • FDA regulatory status (to determine if device registration can be posted) • Is this an applicable trial (Y/N)? (differentiate voluntary registration) • Information must be updated • At least once every 12 months if information has changed • Recruitment status to be updated within 30 days of any change NLM BOR WG on Clinical Trials

8. Timing of Registration and Posting of Information • Registration • In general within 21 days of first recruit • Posting of information • Drugs & Biologics: within 30 days of submission • Approved/Cleared Devices: within 30 days • Devices not previously approved/cleared • Not earlier than the date of approval/clearance • Not later than 30 days after such date NLM BOR WG on Clinical Trials

9. Linking to Results Information • Starting 90 days after enactment • NIH Information: • MEDLINE citation to published results • DailyMed structured product labels • FDA Information, including • Available summary document of trial discussed at FDA Advisory Committee meeting. • Posted FDA assessment of results of applicable drug trial conducted under section 505A or 505B. • FDA public health advisory regarding drug or device • FDA action package for approval document • Safety and effectiveness summary documents for devices NLM BOR WG on Clinical Trials

10. Basic Results Database: General Characteristics • Establish within 12 months of enactment • Results of applicable trials of approved/cleared medical products • Information to be provided • Demographic and Baseline Characteristics • Primary and Secondary Outcomes • Point of Contact (scientific queries) • Certain Agreements - restrictions on PI to discuss or publish results after trial completion • Deadline for submission • Within 12 months of the earlier of estimated or actual trial completion date • Delayed submission if certify seeking initial approval or new use. NLM BOR WG on Clinical Trials

11. Adverse Event Reporting • Rulemaking within 18 months • “Best method for including” AER info for serious and frequent adverse events • “Useful and not misleading” to patients, clinicians, scientists • Default provision if regulation not issued in 2 yrs • Table of SERIOUS Adverse Events (by arm) • Table of FREQUENT Adverse Events (by arm) • Exceed frequency of 5 percent within any arm • Grouped by organ system • Other information needed enhance patient understanding (consult with risk communication experts) NLM BOR WG on Clinical Trials

12. Expanded Results Database: By Rulemaking • Rulemaking within 3 years, to include/consider: • Results reporting for unapproved products? • Summary information (technical and non-technical) if can be done w/out being misleading, promotional • Timing of submissions (12 months or up to 18 months?) • Format of submitted information • Full protocols or information needed to evaluate results • Additional information for patients . . . • Sources of information to consider • Public meeting with stakeholders w/in 18 months • Pilot Quality control study by FDA and NIH • WHO data set NLM BOR WG on Clinical Trials

13. Penalties for Non-Compliance • Withholding of federal funding (e.g., from NIH, VA, others) • Monetary fines -- Up to $10,000 per violation and $10,000 per day • Notices of non-compliance posted in registry/results database • Processes needed to detect, determine, inform RP of non-compliance NLM BOR WG on Clinical Trials

14. Additional information • Available online: • NIH Fact Sheet • NIH Guide Notice (for grantees) • List of Registration Data Elements • Detailed Data Element Descriptions • ClinicalTrials.gov: • http://www.clinicaltrials.gov • Protocol Registration System: http://prsinfo.clinicaltrials.gov • Jerry Sheehan: SheehanJR@nlm.nih.gov NLM BOR WG on Clinical Trials