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Session 2Expanded Clinical Trials Registry

Deborah A. Zarin, M.D.

NLM AccomplishmentsImpact to Date

Specific Data Element Issues

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Enactment

Expanded Clinical Trial Registry

1 yr 2 yr 3 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

12/26/07 9/27/08 3/27/09 9/27/10

New AdministrationTransition Phase

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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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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

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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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Study Record

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18 Week Snapshot of New Accounts and Record September-December 2007 & 2006

New Records:2007 vs. 2006

New Accounts:2007 vs. 2006

~45%

Sept Oct Nov Dec

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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)

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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 479 - Medical Procedure 290 - Device 227

(+27 delayed posting)

* 23 records missing “Study Types” information

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Overall Characteristics: New Studies (12/1/07-1/20/08)

Total – Interventional Studies 2,281 (100%)

Studies by Registrant TypeUniversity, Other 1,397 (61%)Industry 645 (28%)US Federal (including NIH) 239 (11%)

Studies by Facility LocationUS sites only 1,436 (63%)Non-US only 569 (25%)US & non-US mixed 73 ( 3%)Missing 203 ( 9%)

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Overall Characteristics: Updated Studies (12/1/07-1/20/08)

*4 records missing “Study Types” information

Total 10,558 (100%)Type of Trial* Observational 1,019 (10%) Interventional 9,535 (90%) - Drug, Biologic 8,080 - Behavioral, Gene Transfer, Other 776 - Medical Procedure 4,282 - Device 329

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Overall Characteristics: Updated Studies (12/1/07-1/20/08)

Total – Interventional Studies 9,535 (100%)

Studies by Registrant TypeUniversity, Other 1,947 (21%)Industry 2,997 (31%)US Federal (including NIH) 4,591 (48%)

Studies by Facility LocationUS sites only 5,746 (60%)Non-US only 2,006 (21%)US & non-US mixed 1,158 (12%)Missing 625 ( 7%)

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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

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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 110-85, Title VIII, Section 801.

• 32 studies in “lock box” as of 2/7/08

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Overall Interventional Device Studies (12/1/07-1/20/08)

Delayed? Records

Registrant Type Overall Status

IndustryUniversity, Other

Federal (incl. NIH) Active

Not Active

Yes 27 ( 5%) 23 (10%) 4 ( 2%) 0 (0%) 26 1

No 127 (24%) 75 (34%) 38 (15%) 14 (22%) 110 17

Missing 377 (71%) 123 (56%) 204 (83%) 50 (78%) 272 105

Total 531 (100%) 221 (100%) 246 (100%) 64 (100%)

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Delayed Posting General Characteristics

Total: 32 studies (as of 2/7/08)Provider Type

27 Industry 5 Other

Study Type27 Interventional 4 Expanded Access 1 Observational

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Analysis of Response:OVERALL

Data Completion Statistics for OverallActive Phase II-IV Drug/Device Interventional Trials Submitted (12/1/07 - 1/20/08)

Completed Data

Registrant Type Total

Primary Outcome Measure

Number ofArms

Responsible Party

Industry 2,029 1,947 (96%) 1,601 (90%) 1,576 (78%)Federal (incl. NIH)

2,539 1,964 (77%) 227 ( 9%) 220 ( 9%)

University, Other

1,208 1,200 (99%) 1,199 (99%) 1,118 (93%)

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* 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

Rank* CompanyTotal **

Registered

No. FDAAA Trials***

Primary Outcome Measure # Arms

Responsible Party

FDA Regulated

1 Johnson and Johnson**** 125 76 100% 47% 5% 5%3 Medtronic 102 59 97% 53% 32% 32%

16 St. Jude Medical 50 26 96% 42% 19% 19%12 Abbott Laboratories 30 19 89% 68% 21% 21%9 Boston Scientific 23 19 100% 95% 95% 95%

26 Biomet 17 9 100% 89% 89% 89%11 Stryker Corp. 6 4 25% 25% 25% 25%26 C. R. Bard 5 3 100% 100% 33% 67%14 3M Healthcare 5 2 100% 100% 0% 0%22 Synthes 4 2 0% 0% 0% 0%7 Tyco Healthcare 4 2 100% 100% 0% 100%

13 B. Braun 3 1 100% 100% 0% 0%4 Baxter International 3 1 100% 0% 0% 0%2 GE Healthcare 2 1 100% 100% 100% 100%

17 Smith & Nephew 2 1 100% 100% 0% 0%24 Alcon 1 0 0% 0% 0% 0%

Top Device Companies

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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

Rank* CompanyTotal **

Registered

No. FDAAA Trials***

Primary Outcome Measure # Arms

Responsible Party

FDA Regulated

2 GlaxoSmithKline 1042 364 100% 1% 0% 0%7 Novartis 926 407 95% 30% 31% 3%1 Pfizer 667 250 100% 83% 84% 81%8 Sanofi-Aventis 532 245 71% 27% 77% 24%3 Merck & Co 471 193 98% 44% 44% 44%

10 Eli Lilly 468 174 98% 69% 60% 60%5 AstraZeneca 443 128 98% 56% 2% 58%4 Johnson & Johnson 291 81 99% 31% 31% 31%6 Amgen 254 104 90% 15% 98% 0%9 Hoffman-LaRoche 243 160 100% 99% 99% 99%

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Specific Data Element Issues

Public Law 110-85, Section 801PL 110-85 Implementation

NIH Policy

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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)

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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

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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 314.126

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“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

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ENHANCE TrialNCT00552097

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CATIENCT00014001

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“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)]

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PL 110-85 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)

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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?