Deborah Zarin

1. Opportunities and Challenges For
ClinicalTrials.gov
AAAS
Deborah A. Zarin, MD
Director, ClinicalTrials.gov

2. ClinicalTrials.gov and
Levels of “Transparency”
Zarin DA, Tse T. Science. 2008.
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3. 3
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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4. Three Key Scientific Problems
1. Not all trials are published
2. Publications do not always include all
prespecified outcome measures
3. Unacknowledged changes are made to the
trial protocol that would affect the
interpretation of the findings
– e.g., changes to the prespecified outcome
measures
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5. ClinicalTrials.gov
• Registry
– > 183,000 studies
– >500 new studies/week;
– > 10,000 submitting organizations from around
the world
• Results Database
– > 16,000 overall
– >110 new studies/week;
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6. Content of ClinicalTrials.gov Record
• One record per trial
• Registration section
– Submitted at trial
initiation
– Summarizes information
from trial protocol
– Condition
– Interventions
– Outcomes
– Design, etc
– Includes recruitment
information (e.g.,
eligibility, locations)
• Results section
– Submitted after trial
completion
– Summarizes trial results
• Participant flow
• Baseline characteristics
• Outcome measures
(including statistical
analyses)
• Adverse events
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7. Key Challenges
• Low rate of summary results reporting
• Poor quality reporting
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8. FDAAA “Basic” Results Reporting
(as of 9/5/2014)
Funder # Registered Trials (“pACTs”)
That May Need Results
% Reporting
Results
Total* Reporting
Results**
NIH 2,883 1,376 48%
Industry 11,730 7,348 63%
Other 4,470 1,355 30%
TOTAL 19,083 10,079 53%
*Total = [Non-phase 0/1 interventional studies AND (IND or IDE OR a drug, biologic, or device AND at least
one US site) AND completed after December 2007] AND [Primary Completion Date ≥ 1 Year]
**Reporting Results = Trials for which summary results are posted on ClinicalTrials.gov OR delayed
submission of results are acceptable (i.e. submission of a certification or an extension request)
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9. • Law in effect since September 2007
• Notice of Proposed Rulemaking (NPRM)
– Describes the procedures for registering and
submitting summary results of clinical trials to
ClinicalTrials.gov
– Clarifies definitions (e.g., “applicable clinical trial”;
“voluntary submissions”)
– Timelines for updates and corrections
– Effective date and compliance date
FDAAA Implementation
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10. 10

11. ClinicalTrials.gov Reporting Policies
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Reporting
Requirement
FDAAA NAPRM Draft NIH Policy ICMJE Policy
Scope Registration &
Results Reporting
Registration &
Results Reporting
Registration
Phase Not Phase 1 All All
Intervention Type Drugs, Biologics, &
Devices regulated by
the FDA
All All
Funding Any NIH Any
Enforcement Up to $10,000/day;
Loss of US Federal
funding
Loss of NIH funding Refusal to publish

12. Examples of Other Relevant Policies
• Veterans Affairs funded clinical trials
• PCORI funded studies
• Trials conducted under the CMS “coverage
with evidence development”
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13. Rulemaking Process – Next Steps
• Public comment period will be extended (March
23, 2015)
– Comments welcome on all aspects of proposed rule;
NPRM contains explicit requests for comment on
certain topics
– Submit written comments to Docket No. NIH-2011-
0003 at http://www.regulations.gov
• HHS will review and address all submitted
comments
• Publish Final Rule
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14. 14

15. N Engl J Med. 2014 Dec 24. Published online
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16. Draft NIH Policy
• NIH Draft Policy
– Submit comments by March 23, 2015
• clinicaltrials.disseminationpolicy@mail.nih.gov
• http://grants.nih.gov/grants/guide/notice-files/NOT-OD-15-019.html
• NIH Definition of Clinical Trial
• http://grants.nih.gov/grants/guide/notice-files/NOT-OD-15-015.html
• NIH Office of Extramural Research: What NIH
Grantees Need to Know About FDAAA
• http://grants.nih.gov/ClinicalTrials_fdaaa/
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17. Zarin DA. N Engl J Med. 2013 Aug 1;369(5):468-9.
“The traditional system of relying on investigators, sponsors, and
journal editors to decide whether, when, and how to report trial
results was based on trust.”
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18. Discrepant Reporting of Results
Becker & Ross. Unpublished manuscript; Hartung et al. Ann Intern Med. 2014:477-83; Becker et al. JAMA. 2014: 1063-5.
Hartung et al. (2014) Becker et al. (2014)
Sample Phase 3 & 4 trials with
results on Clinicaltrials.gov
& journal publication
Trials with results on
ClinicalTrials.gov & high-
impact journal publication
Key Discrepancies
POM Descriptions 15% 15%
POM Values 20% 16%
SAEs 35%
(Frequent underreporting or
omissions in publication)
39%
(Frequent underreporting or
omissions in publication)
Other AEs 37%
(Among ≥1 AE reported on
ClinicalTrials.gov)
48%
(Among all trials)
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19. Figure. Information loss as clinical trials data progress
from raw uncoded data to summary data
Uncoded
Data Type
Abstracted Coded Computerized Edited/
cleaned
Analyzable Analyzed/
Summary
Levelofinformation
Max
Min
Individual Participant-Level Data Aggregated Data
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20. Observations About
Trial Reporting
• The “journey” from initially collected participant-
level data to summary data is not completely
objective
• Documented bias towards reporting greater
benefits and fewer harms
• Greater transparency could help to inspire trust
• EMA: “the capacity for independent replication
of clinical trial data is a legitimate societal
objective…”
• Greater transparency could also help “the field”
engage in internal quality improvement
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21. IOM: Sharing Clinical Trial Data (2015)
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22. Basic IOM Recommendations
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When to Share What to Share
Trial Registration—Trial inception Data Sharing Plan, Registration
Data Elements
12 Months after Study
Completion
Summary-level Results,
Lay Summaries for participants
6 Months after Publication Post-Publication Data Package*
18 Months after Study
Completion
Full Data Package (i.e., full
analyzable data set, full protocol
(initial, final, all amendments), full
SAP, analytic code)
18 Mos. after Product
Abandonment OR 30 Days after
Regulatory Approval
Post-Regulatory Data Package**
* subset of the Full Data Package supporting the published findings, tables, and figures
**Full Data Package + CSR (redacted for CCI or PII)

23. Concept of Vertical Transparency
A B C D E F G H I J K L M N O P Q R S T U V W X Y
All Clinical Trials of Intervention X for Condition Y in Population X
Trial ID:
Type of Information:
Trial Registration Record
Summary Results Database
Journal Publication
Clinical Study Report (CSR)
Individual Participant-Level
Data (IPD)
• Uncoded
• Coded
• Analyzable
Trial A:
“Documented at all levels”
Trial Y:
“Invisible”
Trial K:
“Registration & Publication”
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24. Checklist for Journal Editors and
Peer Reviewers
 Ensure that trial registration…
 Is prior to Study Start Date
 Has meaningful entries
 Verify that registered outcome measures
 Are consistent with manuscript
 Are concordant with ClinicalTrials.gov results, if posted
 Check the “denominator” by searching
ClinicalTrials.gov
 For relevant registered trials
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25. Current: “Informational Chaos”
Diffuse, hard-to-access information about a single study
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Sponsor
Investigator
Other study documents
SAPs Full protocols
CSRs
Results database entries
Conference abstracts
Sample Routes of Dissemination of Information about a Single Study
ClinicalTrials.gov
Record
Journal publicationsIPD sets
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26. Potential Role for ClinicalTrials.gov
• Provide framework and access to key trial
information
– Registration
– Results
– Links
– Documents
• Provide context for available information
– List of all trials for given topic
– Documentation of what information is available for
each trial
– Help to avoid “disclosure biases” of all sorts
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27. ClinicalTrials.gov:
Informational Scaffold
Results database
entries
Journal publications
SAPs
IPD
Other Information
(e.g., press releases,
news articles, editorials)
CSRs
Full protocols
Other study
documentsConference abstracts
ClinicalTrials.gov
Record
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28. Select Publications
Available at: http://www.clinicaltrials.gov/ct2/resources/pubs
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Hartung DM, Zarin DA, Guise JM, et al. Reporting discrepancies between the
ClinicalTrials.gov results database and peer-reviewed publications. Ann Intern
Med. 2014 Apr 1;160(7):477-83.
Califf RM, Zarin DA, Kramer JM, Sherman RE, Aberle LH, Tasneem A.
Characteristics of clinical trials registered in ClinicalTrials.gov, 2007-2010. JAMA.
2012;307(17):1838-47.
Wong E, Williams R. ClinicalTrials.gov: Requirements and implementation
strategies. Regulatory Focus. 2012 May.
Ross JS, Tse T, Zarin DA, Xu H, Zhou L, Krumholz HM. Publication of NIH funded
trials registered in ClinicalTrials.gov: cross-sectional analysis. BMJ.
2012;344:d7292.
Zarin DA, Tse T, Williams RJ, Califf RM, Ide NC. The ClinicalTrials.gov results
database – update and key issues. N Engl J Med 2011;852-860.

29. Additional Information
General ClinicalTrials.gov information:
http://clinicaltrials.gov/ct2/about-site/
FDAAA related information:
http://clinicaltrials.gov/ct2/manage-recs/fdaaa
Office of Extramural Research (OER)
http://grants.nih.gov/Clinicaltrials_fdaaa/
Questions?
register@clinicaltrials.gov
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