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United States National Library of Medicine National Institutes of Health

NLM Accomplishments and Specific Data Element Issues

Session 2: Expanded Clinical Trials Registry

Deborah A. Zarin, M.D.

NLM Accomplishments

Impact to Date

Specific Data Element Issues

Timeline showing the statutory deadlines for completing certain elements of the clinical trial database provisions of Public Law 110-85. Expansion of the registry and linking to existing results information at FDA and NIH were to be completed no later than 90 days after enactment (i.e., by December 26, 2007).

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
Table listing ClinicalTrials.gov registration data elements. Labels indicate which elements are currently required in order to receive an NCT number from ClinicalTrials.gov, which elements are required to comply with P.L. 110-85, and which elements may ultimately be required to comply with PL 110-85. The data element table may be downloaded from the Website <http://prsinfo.clinicaltrials.gov/>
Listing of ClinicalTrials.gov registration data elements, continued.
Listing of ClinicalTrials.gov registration data elements, continued.

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

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

Study Record

Screenshot of a ClinicalTrials.gov study record for the CATIE-Alzheimer’s Disease Trial (NCT00015548), which resulted from a search of studies for “Alzheimers” and “Ohio”.
Screenshot illustrating hyperlinks from the study’s ClinicalTrials.gov registration record to relevant Medline citations, the full-text version of the cited article in NLM’s PubMedCentral archive, and the pdf version of the article on the publisher’s website. The article abstract contains the NCT number for the clinical trial, allowing a link back to the registration record in ClinicalTrials.gov.
Screenshot illustrating the link from the registration record to NLM’s DailyMed website, which contains structured product label information for approved drugs that may be used in a clinical trial.
Screenshot illustrating the link from the ClinicalTrials.gov registration record to a Web page containing links to other FDA information sources required by the law, such as drug action packages, device approval packages, and safety information.
Graph plotting the number of new trial registrations and new organizational accounts registered between September and December of 2006 and 2007. The graph shows a significant increase in new registrations in December 2007. The total number of records registered between September and December 2007 was approximately 45% higher than the number of records registered between September and December 2006. O

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)

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 497
– Medical Procedure 290
– Device 227

(+27 delayed posting)

* 23 records missing “Study Types” information

Overall Characteristics: New Studies

(12/1/07-1/20/08)

Total - Interventional Studies 2,281 (100%)
Studies by Registrant Type
University, Other 1,397 (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%)

Overall Characteristics: Updated Studies

(12/1/07-1/20/08)

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

*4 records missing “Study Types” information

Overall Characteristics: Updated Studies

(12/1/07-1/20/08)

Total - Interventional Studies 9,535 (100%)
Studies by Registrant Type
University, Other 1,947 (21%)
Industry 2,997 (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%)

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

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

Overall Interventional Device Studies

(12/1/07-1/20/08)

Delayed? Records Registrant Type Overall Status
Industry University, 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%)    

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

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 Type Total Primary Outcome Measure Number of Arms 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%)

Top Device Companies

Rank* Company Total** 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%

* 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 Pharmaceutical Companies

Rank* Company Total** 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 Sanodi-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%

* 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

Specific Data Element Issues

Public Law 110-85, Section 801

PL 110-85 Implementation

NIH Policy

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)

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

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

"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

ENHANCE Trial

NCT00552097

Arms Assigned interventions
EZ/Simva: Experimental Drug: ezetimibe (plus simvastatin) oral tablets; ezetimibe 10 mg (plus simvastatin 80 mg) once daily for 24 months
Placebo/Simva: Placebo Comparator Drug: placebo (plus simvastatin) tablets; placebo to match ezetimibe 10 mg (plus simvastatin 80 mg) once daily for 24 months

CATIE

NCT00014001

Condition Intervention Phase
Schizophrenia Drug: perphenazine Phase IV
Drug: olanzapine
Drug: quetiapine
Drug: risperidone
Drug: ziprasidone
Drug: clozapine
Drug: fluphenazine decanoate

"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)]

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)

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?

Last updated: 24 March 2008
First published: 24 March 2008
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