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The Registration of Clinical Trials
Deborah A. Zarin, M.D.
Director, ClinicalTrials.gov
May 2007
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Public Policy Challenges
• Use of Human Volunteers
• Concerns about the conduct of Trials
• Need to ensure access to (valid) Results
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Proposed Role of Trial Registries and Results Databases
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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
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Trial Registration Policies
• US Federal legislation
• CMS policy
• US State legislation
• ICMJE
• WHO
• Other (Ottawa, AAMC, etc.)
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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
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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
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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
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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
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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
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Key Challenges: Drug Names
• Search engines depend on known names, lists of synonyms, and hierarchies
• “Code” names, without “de-coders”, lead to “hidden” trials
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WHO Search Portal
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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
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Pubmed Gardasil Search
• One month after approval (and promotion)
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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
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Potential Impact of the Maine Law
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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)
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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
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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
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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,
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Reporting Trial Results
• Current– Link to PubMed/MEDLINE citation– Link to Drugs@FDA database– Link to unpublished results on clearly marked
sponsor site
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Sources of Independently Reviewed Trial Results
• Published literature
• FDA reports on website–Sparsely populated
–Difficult to navigate
–Trials not identified
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Many Trials do not have Publicly Available Results
• Not all trials have a published article
• Not all articles include all key outcome measures
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JAMA 2007:297;117:1917-1920.
FDA Site Not Complete
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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
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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
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Possible Error in Registry that Would be Difficult to Detect
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Possible Error in Results Database that Would be Difficult to Detect
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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?
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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
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FDA CDER Review of COPERNICUS
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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?
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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?
