FDA AA - Title VIII Clinical Trial Databases Friday, 30 November 2007 MBC Sarah Doyle Larson Program Manager, Biomedical Regulatory Affairs Compliance

2 Agenda  Title VIII Overview  Timelines  Clinical Trial Registry  Clinical Trial Results Database  Other Provisions  Other Non-FDA Influences to Consider  State of Maine  WHO  ICMJE  Trade Associations  International Regulations and Standards

3 What is Title VIII?  Definitions  Registry = Protocol parameters for ongoing trials  Results Database = Results data from completed trials  Title VIII Mandates the expansion of to form a Clinical Trials Registry and Results Database  Broader scope of trials that must be registered  Increases the amount of data elements required in each posting  Requires submission of clinical trial results data  Penalties for noncompliance  Several “other” requirements  Implementation is a “phased” approach  Timelines for complying range from Dec. 26, 2007 to Sep. 27, 2010

4 FDA/NIH Implementation Timeline 1 Sept Congress Passes Law 90 Days (12/26/07) Linking to FDA and NIH information Expanded registry data elements Expanded registry scope Year (9/27/08) Basic results reporting Expanded registry scope 18 months (3/27/09) Public meeting to discuss expanded registry and results database Adverse events (if by rulemaking) 3 years (9/27/2010) Expansion of registry and results database by rulemaking 2 Years (9/27/09) Adverse events (if by default) 1 Timeline provided by Terry Toigo, Director, FDA Office of Special Health Issues, 27 Nov 2007

5 Clinical Trial Registry

6 Expanded Registry Data Bank – 26 Dec 2007  Scope of trials expanded beyond FDAMA §113  Drug/Biologics: All controlled clinical investigations, other than Ph. 1  Devices: All controlled trials with health outcomes; excludes small feasibility studies; includes pediatric postmarket surveillance  Additional Information Required:  Some previously optional fields are now mandatory  New data elements  Links to “results” information to be provided by FDA / NIH  Maintaining Postings:  Updates – at least once/every 12 months  Recruitment Status – w/in 30 days of change  Penalties for Noncompliance and Public Notices  NIH Implementation & Compliance: 90 Days (26 Dec 2007)

7  Newly initiated applicable trials:  register by later of: 26 Dec OR- 21 days > 1 st pt enrolled  “Ongoing” applicable trials as of 27 Sep 2007 that are not “completed” by 26 Dec 2007 …  if SLT = “yes”, update posting to include all req’d fields by: 26 Dec 2007  if SLT = “no”, update posting to include all req’d fields by: 27 Sep 2008  Notes regarding NIH “posting” dates:  Drugs OR approved/cleared Devices  w/in 30 days of receipt  Devices not previously approved/cleared  “held” for release until approved; then released w/in 30 days of approval Expanded Registry Data Bank – When to Register?

8 Clinical Trial Results Data Bank  Results Links  Basic Results  Expanded Results Data Bank

9  Scope:  Approved Drug, Biologics, Devices  CTs that form basis for efficacy claim or CTs conducted > approval  FDA Information to be posted (Links):  Advisory Committee Meetings  FDA assessment of results for pediatric trials (Sec 505A/B)  FDA public health advisories  FDA drug “action package” for approval documents  FDA device PMA or 510(k) summary of safety/efficacy  NIH Information to be posted (Links):  Medline citations  Label  Implementation Timeline: “Beginning” 26 Dec 2007  Responsibility of FDA/NIH  For applicable trials ongoing as of 27 Sep 2007, link 30 days > approval and w/in 30 days of results becoming public  For other trials posted prior to 27 Sep 2007: as available Results Data Bank “Links” – 26 Dec 2007

10  Scope:  Approved Drugs, Biologics, Devices  Includes applicable trials completed per protocol & terminated trials  Information to be posted:  Demographics & baseline characteristics of patient sample  Primary & Secondary Outcomes  Point of Contact  Certain Agreements  Implementation Timeline: 27 Sep 2008  In general, submit w/in 12 mos of completion date (estimated or actual)  Completion Date = LPLV  Delayed submission w/ certification:  Initial approval: Submit results w/in 30 days of initial approval/clearance  New use: Submit results w/in 30 days of  Approval/clearance of new use  Issuance of letter by FDA (e.g. complete response, not approving/clearing, not approvable)  Withdrawal w/out resubmission after 210 days  Limit if no action: 2 years Results Data Bank “Basic Results”– 27 Sep 2008

11  Public meeting to be held by 27 Mar 2009  Rulemaking for AE Reporting by 27 Mar 2009 (or default provision will apply on 27 Sep 2009)  Rulemaking for Expansion of Data Bank by 27 Sep 2010:  Scope:  Trials w/ completion date on or > Sept 1997 for approved products  May include unapproved products (whether approval was sought or not)  Information and format to be posted:  Non-technical & technical summaries of results (non promotional)  Protocol or other info needed to “evaluate” completeness of results  “Other categories as determined to be appropriate” by FDA  Results Submittal Timeline – extend from 12 mos to 18 mos?  How to address trials where results were posted < data bank “Expansion”?  Implement QC Procedures  Consider WHO Data Set Results Data Bank “Expanded Data Bank” 27 Sep 2010

12 Other Provisions

13  Certification w/ all submission - 27 Dec 2007  State Preemption – 27 Dec 2010  Modify ICF  Public Notice of Noncompliance; Penalties  Guidance to be issued re: how requirements apply to a pediatric postmarket surveillance  Voluntary submissions acceptable  QC Pilot Program  confirm completeness, accuracy, and ensure non-promotional  Consult w/ experts on risk communication  Waiver process for “extraordinary circumstances” when protecting public health or national security Other Provisions in Title VIII

14 Other non-FDA influences to consider

15  US States:  Maine - passed March 2007; FDAAA preemption effective 27 Sep 2010  Other State activity in 2007  WHO:  Policy: registration & results of ALL human subject trials  WHO Primary Registers  WHO data elements  ICMJE –  WHO data elements  Require prospective registration of “any research project that prospectively assigns human subjects to intervention or comparison groups to study the cause-and-effect relationship between a medical intervention and a health outcome”  As of July 2008, will no longer exclude Phase I  Ingelfinger Rule / Post results abstract <300 words if pub is pending  Trade Associations  PhRMA - joint position statement Jan 2005  BIO - Principles on Clinical Trials  Advamed Other Considerations

16 Varying International Standards  Mandatory  Israel (clinicaltrials.gov)  Italy (local language; country specific EUDRACT posting)  South Africa (country specific)  Taiwan  Proposed  France (local language; requirements similar to Italy)  Voluntary  Australia (country specific website)  China (country specific website)  Germany  India (country specific website)  Japan (country specific website)  Netherlands  Spain  UK (country specific website)  Local IRB/EC requirements

17 Summary  New FDAAA requirements begin 26 Dec 2007 and will continue through 27 Sep 2010  FDA / NIH is still in the process of implementing … Stay tuned!  In some cases, the NIH’s timeline for implementation allows little time to update internal SOPs and/or to complete tasks as required.  Rulemaking!  Lack of harmonization between FDAAA and other “influences”

18 Questions?