1. 11 February 2008NLM BOR WG on Clinical Trials1 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

2. 11 February 2008NLM BOR WG on Clinical Trials2 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)

3. 11 February 2008NLM BOR WG on Clinical Trials3 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

4. 4 Overview of P.L.110-85 §801 Expanded 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. 11 February 2008NLM BOR WG on Clinical Trials5 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.

6. 11 February 2008NLM BOR WG on Clinical Trials6 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

7. 11 February 2008NLM BOR WG on Clinical Trials7 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

8. 11 February 2008NLM BOR WG on Clinical Trials8 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

9. 11 February 2008NLM BOR WG on Clinical Trials9 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

10. 11 February 2008NLM BOR WG on Clinical Trials10 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.

11. 11 February 2008NLM BOR WG on Clinical Trials11 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)

12. 11 February 2008NLM BOR WG on Clinical Trials12 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

13. 11 February 2008NLM BOR WG on Clinical Trials13 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

14. 11 February 2008NLM BOR WG on Clinical Trials14 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 http://prsinfo.clinicaltrials.gov Jerry Sheehan: SheehanJR@nlm.nih.govSheehanJR@nlm.nih.gov