Transcript ClinicalTrials.gov - Columbia Law School

The Registration of
Clinical Trials
Deborah A. Zarin, M.D.
Director, ClinicalTrials.gov
May 2007
Public Policy Challenges
• Use of Human Volunteers
• Concerns about the conduct of Trials
• Need to ensure access to (valid) Results
2
Proposed Role of Trial Registries and
Results Databases
3
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
4
Trial Registration Policies
•
•
•
•
•
•
US Federal legislation
CMS policy
US State legislation
ICMJE
WHO
Other (Ottawa, AAMC, etc.)
5
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
6
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 instances
Italicized print: Items not displayed at the public site
8
ClinicalTrials.gov Statistics
Total
Interventional Drug Trials
Non-IND
IND
– Phase I
– Phase II
– Phase III
– Phase IV
– Missing
Source
– NIH
– Industry
– University, other
05/09/2007
Number
40,343
Percent
25,900
17,232
8,688
1,759
3,190
2,892
588
239
100%
66.5%
33.5%
6.8%
12.3%
11.1%
2.3%
1%
9,196
9,231
7,473
35.5%
35.6%
28.9%
9
ICMJE
10
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
11
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
12
Key Challenges: Drug Names
• Search engines depend on known names,
lists of synonyms, and hierarchies
• “Code” names, without “de-coders”, lead
to “hidden” trials
13
WHO Search Portal
14
WHO Search Portal - Example
15
ClinicalTrials.gov - Search
16
ClinicalTrials.gov - Example
17
ClinicalTrials.gov - Synonymy
18
Drug Serial Numbers: “Hidden” Trials
Gardasil® was approved on June 8, 2006
19
Pubmed Gardasil Search
• One month after approval (and promotion)
20
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
22
Potential Impact of the Maine Law
23
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)
24
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
25
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
26
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,
27
Reporting Trial Results
• Current
– Link to PubMed/MEDLINE citation
– Link to Drugs@FDA database
– Link to unpublished results on clearly marked
sponsor site
28
29
Sources of Independently Reviewed
Trial Results
• Published literature
• FDA reports on website
–Sparsely populated
–Difficult to navigate
–Trials not identified
30
Many Trials do not have Publicly
Available Results
• Not all trials have a published article
• Not all articles include all key outcome
measures
31
FDA Site Not Complete
32
JAMA 2007:297;117:1917-1920.
Results Databases: Overview of
Key Components and Intended Users
Trial
Design
Details of
Methods
Statistical
Plan
Participant
Flow
Baseline
Data
Outcomes in
Each Arm,
Absolute
Numbers
Statistical
Analyses
Discussion/
Conclusions
General
Public
Clinicians
Systematic
Reviewers
Policy
makers
33
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
34
Possible Error in Registry that
Would be Difficult to Detect
35
Possible Error in Results Database
that Would be Difficult to Detect
36
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?
37
GSK Results Entry: COPERNICUS
• COREG (Carvedilol) in
preventing death of patients
with severe heart failure
• Primary outcome was allcause 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
format
38
FDA CDER Review of COPERNICUS
39
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?
40
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?
41
Contact Us
[email protected]
www.ClinicalTrials.gov
42