1 Session 2 Expanded Clinical Trials Registry Deborah A. Zarin, M.D. NLM Accomplishments Impact to Date Specific Data Element Issues

2 Enactment Expanded Clinical Trial Registry 1 yr2 yr3 yr18 m Linking to existing results information at FDA and NIH Launch Basic Results Database Expansion by Rulemaking: Final Rule Additional Adverse Events Data REGISTRY RESULTS 90 d Public Meeting 9/27/07 Pilot Quality Control Project Recommendation to Secretary – Narrative Summaries 12/26/079/27/083/27/099/27/10 New Administration Transition Phase

3 Accomplishments To Date ClinicalTrials.gov registration system (PRS) modified to enable compliance with expanded registration requirements (11/27/07) Links established from registry to NIH/NLM and FDA results information Information developed for affected communities –NLM Data Element Definitions and Fact Sheet –NIH Guide Notices (2) and FAQs – including instructions for initial NIH grantee/contractor compliance

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7 Enforceability of Data Elements Need to collect information not explicitly listed in the law More detail required than specified in law (e.g., “ study design ” ) Additional information necessary to comply with law (e.g, data required to implement search requirements) Competing concerns –Congressional intent to establish registry quickly –Difficulty of enforcing all necessary data elements without regulation HHS is considering rulemaking

8 Revisions to Registry “Data providers” are alerted to items that (may be) required by the FDAAA Omission of these items does not block acceptance of the record, and an NCT # is assigned Items in question include those with some complexity, those that are required to implement the law, and one that reflects NIH policy HHS is considering rulemaking

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13 New Records: 2007 vs New Accounts: 2007 vs ~45% SeptOctNovDec

14 Enhanced Registry Activity (12/1/07-1/20/08) New Study Submissions: 2,932 –419 records/week Updated Studies: 10,558 –1,508 records/week Overall Studies: 13,490 –1,927 records/week; 100% increase New PRS Accounts: 252 –36/week; 64% increase Current Backlog: ~600 records (~10 days)

15 Overall Characteristics: New Studies (12/1/07-1/20/08) Total 2,932 (100%) Type of Trial* Observational 628 (22%) Interventional 2,281 (78%) - Drug, Biologic 1,492 - Behavioral, Gene Transfer, Other Medical Procedure Device 227 (+27 delayed posting) * 23 records missing “Study Types” information

16 Overall Characteristics: New Studies (12/1/07-1/20/08) Total – Interventional Studies 2,281 (100%) Studies by Registrant Type University, Other1,397 (61%) Industry 645 (28%) US Federal (including NIH) 239 (11%) Studies by Facility Location US sites only 1,436 (63%) Non-US only 569 (25%) US & non-US mixed 73 ( 3%) Missing 203 ( 9%)

17 Overall Characteristics: Updated Studies (12/1/07-1/20/08) *4 records missing “Study Types” information Total10,558 (100%) Type of Trial* Observational 1,019 (10%) Interventional 9,535 (90%) - Drug, Biologic 8,080 - Behavioral, Gene Transfer, Other Medical Procedure 4,282 - Device 329

18 Overall Characteristics: Updated Studies (12/1/07-1/20/08) Total – Interventional Studies 9,535 (100%) Studies by Registrant Type University, Other1,947 (21%) Industry2,997 (31%) US Federal (including NIH)4,591 (48%) Studies by Facility Location US sites only 5,746 (60%) Non-US only 2,006 (21%) US & non-US mixed 1,158 (12%) Missing 625 ( 7%)

19 Delayed Posting of Device Trial Registrations Law appears to prohibit public posting of trials of devices that have not been approved/cleared by FDA – even when desired by registrant Would therefore: –Require removal from current database of some device trials voluntarily posted prior to passage of law –Preclude use of ClinicalTrials.gov for recruitment –Preclude use of ClinicalTrials.gov to comply with registration policy of journal editors (ICMJE) –Limit transparency of such trials funded by NIH or other gov ’ t agencies Complaints received from some companies; some registrants are omitting approval/clearance status of devices to circumvent HHS is studying possible options

20 Device Studies: Delayed Posting Must answer “yes” to following: Indicate whether this is an unapproved or uncleared device trial for which posting to ClinicalTrials.gov should be delayed in accordance with US Public Law , Title VIII, Section studies in “lock box” as of 2/7/08

21 Overall Interventional Device Studies (12/1/07-1/20/08) Delayed?Records Registrant TypeOverall Status Industry University, Other Federal (incl. NIH)Active Not Active Yes 27 ( 5%) 23 (10%) 4 ( 2%) 0 (0%) 26 1 No127 (24%) 75 (34%) 38 (15%)14 (22%) Missing377 (71%)123 (56%)204 (83%)50 (78%) Total531 (100%)221 (100%)246 (100%)64 (100%)

22 Delayed Posting General Characteristics Total: 32 studies (as of 2/7/08) Provider Type 27 Industry 5 Other Study Type 27 Interventional 4 Expanded Access 1 Observational

23 Analysis of Response: OVERALL Data Completion Statistics for Overall Active Phase II-IV Drug/Device Interventional Trials Submitted (12/1/07 - 1/20/08) Completed Data Registrant TypeTotal Primary Outcome Measure Number of Arms Responsible Party Industry 2,0291,947 (96%) 1,601 (90%) 1,576 (78%) Federal (incl. NIH) 2,5391,964 (77%) 227 ( 9%) 220 ( 9%) University, Other 1,2081,200 (99%) 1,199 (99%) 1,118 (93%)

24 * Source: Not so Lonely at the Top. Medical Product Outsourcing (MPO), July/August 2007 ** All device interventional and observational studies registered at ClinicalTrials.gov as of 2/4/08 *** Active, phase II-IV device interventional trials ****Includes: BiosenseWebster, ConorMedsystems, Cordis, Dupuy*, Ensure, Ethicon*, LifeScan, Visioncareinc Top Device Companies

25 Top Pharmaceutical Companies * Source: Top 10 Companies by U.S. Sales. IMS Health, IMS National Sales Perspective.3/2007 ** All interventional and observational studies registered at ClinicalTrials.gov as of 2/4/08 *** Active, phase II-IV drug/biologic interventional trials

26 Specific Data Element Issues Public Law , Section 801 PL Implementation NIH Policy

27 Evolution of Data Elements ClinicalTrials.gov has included data elements necessary to accommodate many policies –FDAMA –ICMJE Specific wording and structure of data elements has evolved with experience FDAAA has incorporated previously optional ICMJE data elements—usually identified by overall title (without details)

28 NIH Policy – “Board Approval” Submitted studies should have approval from a human subjects review board prior to the recruitment of the first patient Studies may be registered prior to board approval, if status is “Not yet recruiting” Data Elements –Board Approval Status (e.g., “Submitted, exempt”) –Board Name –Board Affiliation –Board Contact

29 Interventional “Study Design” Each of the following elements is required –Intervention Model – intervention assignments (e.g., parallel arms) –Number of Arms – number of comparative groups –Masking – knowledge of intervention assignments (e.g., double blind) –Allocation – participant assignment to intervention arm (e.g., randomized) Sources: ICH E3, 21 CFR

30 “Intervention Name” Provides sufficiently detailed description of the intervention(s) and to link intervention(s) to arm(s) Data Elements –Intervention Name: generic name for drugs; for others, sufficient detail to distinguish from similar interventions (e.g., devices) –Intervention Description: e.g., dosage –Arm Name or Label: way to identify arm –Arm Type: e.g., experimental, active comparator –Arm Description: if different from intervention description

31 ENHANCE Trial NCT

32 CATIE NCT

33 “Outcome Measure” Specific measurement that will be used to measure the effect of experimental variables in a study Requires the following –Outcome Measure: Description of the specific measure –Outcome Time Frame: Time point(s) at which outcome measure is assessed –[Safety Issue? (yes/no)]

34 PL Implementation Safety Issue? – “the safety issue, if any, being studied in the clinical trial as a primary or secondary outcome” Facility Contact – location information (e.g., city, state, country) to be able to search by “location of the clinical trial” Applicable Clinical Trial? –FDA Regulated Intervention? (Yes/No) –Section 801 Clinical Trial? (Yes/No) –Delayed Posting? (Yes/No)

35 Other Questions to Address Cut-off for modifying registry records? –Estimated completion date –Outcome measures –Target enrollment Good enough outcome measure? How should changes be displayed?