Everything You Ever Wanted
to Know About
ClinicalTrials.gov
(Slides for presentation only.)
Deborah A. Zarin, M.D.
Director, ClinicalTrials.gov
May 2010
1
Background
2
What’s All The Fuss About?
• Suppression of research results impedes
the scientific process
• Suppression of clinical trial data is
particularly problematic:
– Trials depend on human volunteers;
– Trial results inform our medical decisions
3
Screen shot of Washington Post article.
A Silenced Drug Study Creates An Uproar.
By Shankar Vedantam
Wednesday, March 18, 2009
• “The results of Study 15 were never published or
shared with doctors, even as less rigorous studies that
came up with positive results for Seroquel were
published and used in marketing campaigns aimed at
physicians and in television ads aimed at consumers.”
• “The results of Study 15 were provided only to the Food
and Drug Administration -- and the agency has
strenuously maintained that it does not have the
authority to place such studies in the public domain.”
Screen shot of :
Lilly Sold Drug for Dementia Knowing It Didn’t Help,
Files Show
By Margaret Cronin Fisk, Elizabeth Lopatto and Jef Feeley
“Eli Lilly & Co. urged doctors to prescribe Zyprexa
for elderly patients with dementia, an unapproved
use for the antipsychotic... after [it] sent study
results to the U.S. Food and Drug Administration”
showing Zyprexa didn’t alleviate dementia
symptoms in older patients…”
Screen shot of :
The New England Journal of Medicine
Outcome Reporting in Industry-Sponsored Trials of Gabapentin for Off-Label Use
S. Swaroop Vedula, M.D., M.P.H., Lisa Bero, Ph.D., Roberta W. Scherer, Ph.D., and Kay Dickersin, Ph.D.
N Eng J Med. 2009 Nov 12;361:1963-71
Reasons to Register Clinical Trials
and Report Results
• Human Subject Protections
– Allows potential participants to find studies
– Assists ethical review boards and others to determine
appropriateness of studies being reviewed (e.g., harms, benefits,
redundancy)
– Promote fulfillment of ethical responsibility to human volunteers –
research contributes to medical knowledge
• Research Integrity
– Facilitates tracking of protocol changes
– Increases transparency of research enterprise
• Evidence Based Medicine
– Facilitates tracking of studies and outcome measures
– Allows for more complete identification of relevant studies
• Allocation of Resources
– Promotes more efficient allocation of resources
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Levels of “Transparency”
8
Zarin DA, Tse T.. Science. 2008 Mar 7;319(5868):1340-2.
10th Anniversary of
ClinicalTrials.gov
2000 - 2010
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History of ClinicalTrials.gov
• FDAMA 113 (1997): Mandates Registry
– IND trials for serious and life-threatening diseases
• ClinicalTrials.gov Launched in February 2000
• ClinicalTrials.gov Accommodates Other Policies
– Registration
• Int’l Committee of Medical Journal Editors (ICMJE)
• World Health Organization (WHO)
– Registration and Results Reporting
• Maine State Law; State Attorneys General
• European Medicines Agency (EMA)
• FDAAA 801 (2007): Expands Registry and Adds
Results Database
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FDAAA
Sec.801 Expanded Clinical Trial Registry
• Enacted on September 27, 2007
• Requires Trial Registration (Dec 2007)
– Phase II-IV drug and device trials for all diseases
– Data elements: ClinicalTrials.gov + ~ WHO/ICMJE
• Requires Results Reporting (Sept 2008)
– Trials of FDA-approved or cleared drugs and devices
– “Basic” Results: Baseline Characteristics, Primary &
Secondary Outcomes, Statistical Analyses
– Adverse Events (Sept 2009)
– “Expansion” of results by rulemaking (Sept 2010)
• Added enforcement provisions
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Trial Reporting:
The Bottom Line Based on All Policies
• Register all interventional studies prior to
enrollment of the first participant
• Keep entries up to date
• Report results for trials subject to FDAAA:
– Drugs, devices, biologics
– Not Phase 1
– One year after “primary completion date”
(unless special circumstances apply)
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ClinicalTrials.gov—the Basics
13
ClinicalTrials.gov Statistics
(as of 5/24/2010)
Number
Total
Type of Trial
Observational
Interventional
– Drug & Biologic
– Behavioral, Gene
Transfer, Other
– Surgical Procedure
– Device*
International Sites (172 countries)
US only
Non-US only
US & Non-US mixed
Missing
Percent
90,137
100%
15,252
74,107
53,628
17%
83%
15,373
9,227
5,538
41,513
33,414
5,823
9,387
46%
37%
6%
10%
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*287 applicable device clinical trials submitted, but qualify for “delayed posting” under FDAAA
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ClinicalTrials.gov Statistics (cont.)
(as of 5/24/10)
Number
Percent
10,828
29,233
50,076
90,137
12%
32%
55%
Trials by Sponsor
US Federal (including NIH)
Industry
University, Other
Total
User Statistics
Page Views per month
Unique visitors per month
70 Million
950,000
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ClinicalTrials.gov Visitors by “Role”
Screen shot of :
Map of the World indicating number of studies with locations in that region.
(N=13,097)
Patient - Volunteer
Researcher
Family/Friend
Patient - Learn
Provider
Other
Trial Team Personnel
Student/Educator
Healthy Volunteer
Investor
Journalist
Healthcare Admin
Advocate
23%
14%
13%
12%
10%
9%
7%
4%
3%
2%
1%
1%
1%
Source: American Customer Satisfaction Index (ASCI) Online Consumer Survey; Six-Month Period in 2007
Sample Registry Record
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Screen shot of ClinicalTrials.gov showing Full Text View
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Screen shot of ClinicalTrials.gov showing Tabular View
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Screen shot of ClinicalTrials.gov showing archive
21
Screen shot of MedlinePlus
22
Screen shot of ClinicalTrials.gov number in The New England Journal of Medicine
23
Screen shot of NLM Technical Bulletin article
24
Screen shot of journal citation in PubMed highlighting Secondary Source ID
25
Screen shot highlighting U.S. FDA Resources
26
Screen shot highlighting Clinical Trials in U.S. FDA 510 (k) Premarket Notification
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Basic Results Database
Basic Results Database
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Basic Results Reporting
Requirements
• Results of FDA-approved/cleared products
• Generally, submission within 12 months of
the earlier of estimated/actual primary
completion date
• Delayed Submission of Results
– Seeking initial approval
– Seeking approval of a new use
– Extensions for “good cause”
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Basic Results Modules
•
•
•
•
•
Participant Flow
Baseline and Demographic Characteristics
Outcome Measures
Adverse Events (summary data)
Other Information
– “Certain Agreements” Restricting Results
Disclosure
– Overall Limitations and Caveats
– Results Point of Contact
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Sample Posted Results
31
Screen shot of Clinical Trials Study Results
32
Arms
Screen shot of Participant Flow: Overall Study
Milestone
Reasons Not Completed
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Screen shot of Baseline Characteristics
“Default” Required
Measures
User-Specified
Measure
Categories
34
Screen shot of Outcome Measures
35
Screen shot of Primary Outcomes Measure
36
Screen shot of Measures Values and Statistical Analysis
Statistical Analysis
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Screen shot of Serious Adverse Effects
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ICJME
“…will not consider results posted in the
same primary clinical trials register in which
the initial registration resides as previous
publication if the results are presented in the
form of a brief, structured (<500 words)
abstract or table.”
[NOTE: Only about 23% of results records
have associated publications at this time.]
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Uses of ClinicalTrials.gov
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For those concerned with
human subjects protections…
• Complete list of ongoing and completed
trials of relevance
• Assurance that information about the trial
of interest
– is in the public domain
– for some trials, results will become public
41
For those with
medical conditions…
• Finding a trial in which to participate
• Finding an expanded access drug
• Finding a center of research for a given
condition/intervention
42
For those concerned with
human subjects protections…
• Complete list of ongoing and completed
trials of relevance
• Assurance that information about the trial
of interest
– is in the public domain
– for some trials, results will become public
43
Screen shot of ClinicalTrials.gov Advanced Search
44
Screen shot of ClinicalTrials.gov List Results
45
For those concerned with
research integrity…
•
•
•
•
•
Relatively complete list of trials
Description of protocol
Tracking of changes to protocols
Identifying all outcome measures
Providing results, regardless of journal
publication status
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Screen shot of ClinicalTrials.gov Advanced Search
47
Screen shot of ClinicalTrials.gov List Results
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For those
seeking study results…
• Linkages to PubMed
• Summary Results in database
• Results for all prespecified outcome
measures
• Standardized format facilitating
comparisons
49
Screen shot of ClinicalTrials.gov Advanced Search
Outcome Measures =
“Six Minute Walk”
Age Group =
“Child (birth-17)”
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Screen shot of ClinicalTrials.gov List Results
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Resources
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Help for Users
http://clinicaltrials.gov/ct2/info
53
Screen shot of ClinicalTrials.gov Online Training
http://www.nlm.nih.gov/bsd/viewlet/ct/index.html
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Screen shot of ClinicalTrials.gov Online Training
55
Help for Trial
Sponsors & Investigators
http://prsinfo.clinicaltrials.gov
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Screen shot of ClinicalTrials.gov Protocol Registration System
http://prsinfo.clinicaltrials.gov/icmje.html
57
Screen shot of ClinicalTrials.gov Protocol Registration System
http://prsinfo.clinicaltrials.gov/fdaaa.html
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Additional Background
• Tse T, Williams RJ, Zarin DA. Update on
registration of clinical trials in
ClinicalTrials.gov. Chest 2009;136:304-5.
• Tse T, Williams RJ, Zarin DA. Reporting
basic results in ClinicalTrials.gov. Chest
2009;136:295-303.
• Zarin DA, Tse T. Moving toward transparency
of clinical trials. Science 2008;319:1340-2.
• Wood AJ. Progress and deficiencies in the
registration of clinical trials. N Engl J Med
2009;360:824-30.
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Common “Myths” about
ClinicalTrials.gov
• “ClinicalTrials.gov matches
– patients who are interested in participating in research with
recruiting trials OR
– investigators who want to conduct trials with study sponsors.”
• FALSE. ClinicalTrials.gov does not provide any such
matching services. ClinicalTrials.gov does not endorse
the trials that it lists.
60
Common “Myths” about
ClinicalTrials.gov
• “Study data displayed in the ClinicalTrials.gov registry
and results database are provided by the NIH.”
• FALSE. Data about each study are provided by the study
sponsor or investigator.
61
Common “Myths” about
ClinicalTrials.gov
• “If I register my trial late and ClinicalTrials.gov accepts
the registration, then my trial satisfies the requirements
of FDAAA or the ICMJE policy.”
• FALSE. Although ClinicalTrials.gov will accept
registrations at anytime during the study life cycle
– FDAAA requires applicable clinical trials to be registered no later
than 21 days after enrollment of the first subject
– ICMJE requires trials to be registered prior to enrollment
62
Common “Myths” about
ClinicalTrials.gov
• “FDAAA only applies to clinical trials conducted under an
investigational new drug application (IND) or an
investigational device exemption (IDE).”
• FALSE. FDAAA applies to ALL non-phase 1
interventional studies (with one or more arms) of drugs,
biological products, or devices that:
– Have an IND/IDE, OR
– Have one or more sites in the U.S.
63
Common “Myths” about
ClinicalTrials.gov
• “Grantees do not need to register NIH-funded trials
because NIH automatically registers all studies that it
funds.”
• FALSE. NIH does not register grant-funded trials.
Grantees are responsible for registering trials in
accordance with relevant laws and policies (e.g.,
ICMJE).
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Additional Information
• Email LISTSERV and other FDAAA
information:
– http://prsinfo.clinicaltrials.gov/fdaaa.html
• Other general information:
– http://prsinfo.clinicaltrials.gov
• Questions?
– register@clinicaltrials.gov
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