the registration of clinical trials deborah a. zarin, m.d. director, clinicaltrials.gov may 2007
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The Registration of Clinical Trials
Deborah A. Zarin, M.D.
Director, ClinicalTrials.gov
May 2007
2
Public Policy Challenges
• Use of Human Volunteers
• Concerns about the conduct of Trials
• Need to ensure access to (valid) Results
3
Proposed Role of Trial Registries and Results Databases
4
Definitions
• Prospective Registry– Captures summary protocol information before or
during the trial– Provides “denominator” data for monitoring “publication
bias”
• Results Database– Captures the results of a completed trial
• ClinicalTrials.gov – A prospective registry– Can link to publications
5
Trial Registration Policies
• US Federal legislation
• CMS policy
• US State legislation
• ICMJE
• WHO
• Other (Ottawa, AAMC, etc.)
6
The Rationale for Trial Registration
• Use of Human Volunteers– Participation is informed by prior research– Participation contributes to public knowledge
• Conduct of Clinical Trial– Provide public record of protocol items
• Ensuring Access to (Valid) Results– Provides “denominator” – Provides pre-specified outcome measures
8
Boldfaced Print: Items required by ClinicalTrials.gov (incorporates FDAMA 113)WHO: Items additionally required for ICMJE (WHO minimal registration data set)* Additional information required in some instancesItalicized print: Items not displayed at the public site
9
ClinicalTrials.gov Statistics
Number PercentTotal 40,343
Interventional Drug Trials 25,900 100%Non-IND 17,232 66.5%IND 8,688 33.5%– Phase I 1,759 6.8%– Phase II 3,190 12.3%– Phase III 2,892 11.1%– Phase IV 588 2.3%– Missing 239 1%
Source– NIH 9,196 35.5%– Industry 9,231 35.6%– University, other 7,473 28.9%
05/09/2007
10
ICMJE
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Compliance Update
• Intervention Name– Only two companies with any “missing” data– Total of 14 records (out of 39,000+)
• Primary Outcome Measures, since 1/1/06– Percentage with entries:
• NIH - 74%• Industry - 88%• Other - 89%
– Continued heterogeneity in quality
12
Necessary Features of a Trials Registry
• Provide non-duplicated list of all trials that meet users’ search criteria– Necessary to determine options for potential
subjects– Necessary to determine “denominator” for
scientific purposes
• This is difficult
13
Key Challenges: Drug Names
• Search engines depend on known names, lists of synonyms, and hierarchies
• “Code” names, without “de-coders”, lead to “hidden” trials
14
WHO Search Portal
15
WHO Search Portal - Example
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ClinicalTrials.gov - Search
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ClinicalTrials.gov - Example
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ClinicalTrials.gov - Synonymy
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Drug Serial Numbers: “Hidden” Trials
Gardasil® was approved on June 8, 2006
20
Pubmed Gardasil Search
• One month after approval (and promotion)
22
Use of Serial Numbers
• 11% of all drug studies in registry
• 20% of all industry drug studies in registry– 43% Phase 1– 35% Phase 2– 11% Phase 3– 1% Phase 4
23
Potential Impact of the Maine Law
24
Unmet Goals of Registration Policies: How can States Help?
• Produce a comprehensive list of clinical trials– Only some are required by law– Unknown numbers are not registered despite array of
policies
• States can broaden legal mandates re: scope– Use clear, objective language – Harmonize with Federal and other policies– Avoid subjective terms (eg, serious, exploratory)
25
Unmet Goals of Registration Policies: How can States Help?
• Ensure that entries are complete and informative– Federal law leaves room for vague entries– Some providers are reluctant to disclose all
information
• States can create clear mandates to provide complete information– Use WHO minimum data set– Harmonize requirements
26
Unmet Goals of Registration Policies: How can States Help?
• Ensure that users can find all trials that meet their search criteria– Multiple registries make searches incomplete– “Hidden” trials will result if search engines do
not use synonyms, hierarchies, etc
• States can mandate use of ClinicalTrials.gov
• States can require drug names and synonyms
27
Unmet Goals of Registration Policies: How can States Hurt?
• Creating multiple new registries without adequate search functions will lead to confusion
• Non-harmonized data requirements will pose large burden and make registration very complicated
• Use of vague terms in mandate will create confusion; e.g.:– Chemopreventative, exploratory, serious condition,
28
Reporting Trial Results
• Current– Link to PubMed/MEDLINE citation– Link to Drugs@FDA database– Link to unpublished results on clearly marked
sponsor site
29
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Sources of Independently Reviewed Trial Results
• Published literature
• FDA reports on website–Sparsely populated
–Difficult to navigate
–Trials not identified
31
Many Trials do not have Publicly Available Results
• Not all trials have a published article
• Not all articles include all key outcome measures
32
JAMA 2007:297;117:1917-1920.
FDA Site Not Complete
33
TrialDesign
Details of Methods
Statistical Plan
Participant Flow
Baseline Data
Outcomes in Each Arm, Absolute Numbers
Statistical Analyses
Discussion/Conclusions
GeneralPublic
Clinicians
Systematic Reviewers
Policymakers
Results Databases: Overview of Key Components and Intended Users
34
Validation of Data on Results
• Data are more complex, and stakes are higher
• No proposals provide access to protocol or source data
• Implications of an error
35
Possible Error in Registry that Would be Difficult to Detect
36
Possible Error in Results Database that Would be Difficult to Detect
37
How to “Validate” Results?
• Proposals call on FDA to “ensure accuracy and completeness” of structured data
• May be between 40 and 200+ trials per week
• What about “conclusions” or “risk-benefit” summary statements?
38
PAGE 3: M
ore re
sults
PAGE 2: R
esults
GSK Results Entry: COPERNICUS
• COREG (Carvedilol) in preventing death of patients with severe heart failure
• Primary outcome was all-cause mortality
• Stopped early by DMC for benefit at the 4th interim analysis
• Results are published on GSK website– 1 page of protocol and
analysis methods – 1.5 pages of results in tabular
formatPAGE 1
: Pro
toco
l sum
mar
y
39
FDA CDER Review of COPERNICUS
40
Results Databases—Key Questions
• Who are the intended users?
• What will they use it for?
• Are non-reviewed sponsor submissions adequate?
• Is independent review needed?
• If so, how can it be done?
41
Implications of Pending Legislation
• May facilitate linkages with improved FDA site
• May mandate registration with all 20 WHO data elements
• May mandate a results feasibility study
• May mandate a results database
• May pre-empt State laws?
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