Clinical Trials and FDAAA for NIH Grantees Part I

Report and
FDAAA for NIH Grantees
NIH Regional Seminar - June 2013
Rebecca J. Williams, PharmD, MPH
Assistant Director,
National Library of Medicine
• Introduction to the Food and Drug Administration
Amendments Act of 2007 (FDAAA)
– Why FDAAA Title VIII?
– Requirements it establishes
– Next Steps
• FDAAA for NIH Extramural Grantees
– Implementation for NIH grants
– OER resources
• Practical Considerations
– Protocol Registration System (PRS)
– Resources
Introduction to FDAAA
Three Key Issues with Publications
• Not all trials are published
• Publications do not always include all
prespecified outcome measures
• Unacknowledged changes are made to the
trial protocol that would affect the
interpretation of the findings
– e.g., changes to the prespecified outcome
Kaplan-Meier estimates for ulcer complications according to
traditional definition. Results are truncated after 12 months, no ulcer
complications occurred after this period. Adapted from Lu 2001.
Source: Jüni P, Rutjes AW, Dieppe PA. BMJ. 2002 Jun 1;324(7349):1287-8.
The Controversies Continue…
Summary of Findings
• Fewer than half of NIH funded trials registered at after September 2005 and
completed by December 2008 were published in a
peer reviewed biomedical journal indexed by
Medline within 30 months of trial completion
• After a median of 51 months after study
completion, a third of NIH-funded trials in the
sample remained unpublished
BMJ 2011;344:d7292 doi
Rationale for Registering and
Reporting Clinical Trial Results
• Responsibility to human subjects and
the public
• Research integrity
• Evidence-based medicine
• Allocation of resources
Levels of “Transparency”
Zarin DA, Tse T. Science. 2008
10 – Milestones
• 1997 - Food and Drug Administration
Modernization Act (FDAMA)
• 2000 - launched
• 2005 - International Committee of Medical Journal
Editors (ICMJE) policy
• 2007 - FDAAA (Title VIII of Public Law 110-85)
– Expanded clinical trial registration requirement and
imposed new results submission requirements
– Added enforcement provisions including up to
$10,000/day in civil monetary penalties and withholding
remaining or future grant funds
FDAAA = Food and Drug Administration Amendments Act of 2007
What does FDAAA require?
The responsible party for an applicable
clinical trial (ACT) subject to FDAAA must :
1. Register the ACT in no later
than 21 days after enrollment of the first
2. Submit summary results (including adverse
event information) for certain trials not later than
1 year after the trial’s (primary) completion date.
Delays allowed in some circumstances
FDAAA Key Terms
• Applicable Clinical Trials (ACTs)
• Responsible Party
• (Primary) Completion Date
What is an ACT?
• “Applicable Clinical Trials”* (ACTs)
subject to FDAAA are:
– Interventional studies of drugs, biologics, &
– Not phase 1 drugs, not small feasibility devices
– US FDA jurisdiction (e.g., IND/IDE or US site)
– ACTs initiated on or after 9/27/07 or ongoing as
of 12/26/07
Who is the Responsible Party?
• “Responsible Party”* is defined as:
– Sponsor [only one per trial]
• IND/IDE holder; if none, then
• Person or entity who “initiated” the trial
– Funding recipient if grant or sponsored research agreement
– Funder if procurement funding agreement (contract)
– Sponsor may designate the Principal
Investigator (PI) as Responsible Party [only one
per trial]
• If PI meets certain requirements (e.g., has access to
and control over data, right to publish)
FDAAA Registration Requirements
• Where do I register?
– web-based Protocol Registration
System (PRS); interactive data entry or XML upload
• Tool available for cancer centers also submitting protocol
information to NCI Clinical Trials Reporting Program (CTRP)
• When do I register?
– May register before initiation*; must register no later
than 21 days after enrolling the first participant
– Updates (if any) required at least once every 12 months
– Recruitment status and (primary) completion date must
be updated within 30 days
* International Committee of Medical Journal Editors (ICMJE) requires registration prior to enrollment of
first participant as a condition of consideration for publication
FDAAA Registration Requirements
• What do I register?
– data elements*,
• Study Design and Locations
• Responsible Party (updated format Aug 2011)
– Sponsor
– Sponsor Investigator
– Principal Investigator (designated by Sponsor)
• Complete NIH Grant Number in Secondary ID
* Protocol Data Element Definitions (DRAFT):
FDAAA Results Requirements
• Which Trials Must Submit Results?
– “Applicable clinical trials” of FDA approved or
cleared drugs, biologics, devices
• Interventional studies of drugs, biologics, or devices
• Not phase 1 drug or not small feasibility device
• US FDA jurisdiction (e.g., IND/IDE or US site)
– Initiated on or after 9/27/07 or ongoing as of
FDAAA Results Requirements
• When Must Results be Submitted?
– Within 12 months of (primary) completion date;
• “The date that the final subject was examined or received an
intervention for the purposes of final collection of data for the
primary outcome, whether the clinical trial concluded
according to the prespecified protocol or was terminated.”
– OR within 30 days of product approval or
– Delays possible
• Seeking approval of a new use
• Extensions for “good cause”
FDAAA Results Requirements
• What Information Must be Submitted?
– Scientific Information (per arm)
• Participant Flow
– Number of participants started
– Number of participants completed
• Baseline Characteristics
– Number of Participants Analyzed
– Age and Gender
• Outcome Measures
Number of Participants Analyzed
Title and Description
Measure Type (e.g., mean) and Measure of Dispersion (e.g., SD)
Statistical analyses, as appropriate
FDAAA Results Requirements
• What information? (cont.)
– Scientific Information (per arm)
• Adverse Events – Serious and “Other”
– Number of Participants Affected/At Risk
– Adverse Event Term and Organ System
• Limitations and Caveats (optional)
– Administrative Information
• Results Point of Contact
• Certain Agreements (related to investigator’s right to
publish, if not an employee of sponsor)
FDAAA Results Requirements Clarifications
• Does NOT prescribe how study should be
• Summary results at the end of the trial
– No interim or “real time” reporting
– No participant level reporting
• Information currently targeted at readers of
the medical literature
– “Tables” of information; “just the facts”
– No narrative discussion or results/conclusions
Registration, Results Submission
and Publication
• International Committee of Medical Journal
Editors (ICMJE) requires registration of all
clinical trials as a condition of publication
– Must register prior to enrollment of first participant
• Deadlines for submitting results to are independent of
publication status
• Submitting results to will
not interfere with publication*
– But, failing to register the trial will!
* Laine C, Horton R, DeAngelis C, et al. Ann Intern Med. 2007;
Results and non-ACTs
• Non-ACTs registered in
are *not* required to submit results to
– Phase 1 trials
– Observational studies
• Exception: Pediatric postmarket surveillance of
• NOTE: Other policies may apply
Participant Flow Format
Baseline Measures Format
“Default” Required Measures
Outcome Measures Format
Outcome Measures Format (cont’d)
Adverse Events Format
Experience with Results Database
• Entering results is similar to the
process of preparing a journal article
• Data provider must be familiar with the
study design and data analysis
– Typically, the investigator and/or a
statistician will need to be involved
General Review Criteria
• Protocol and results must be clear and
• Review focuses on:
– Logic and internal consistency
– Apparent validity
– Meaningful entries
– Formatting
Who is the Audience?
PI and Clinical Research Team
Other Medical Researchers in same field
Other Medical Researchers in other fields
Other Readers of the medical literature
Science Writers
Lay Public (readers of consumer health literature)
FDAAA – Other Considerations
• FDA Requirements
– Certification of Compliance to FDA
• Form 3674 must accompany human drug, biological, and
device product submissions
– FDA Compliance Program 7348.810: Sponsors,
Contract Research Organizations, and Monitors
• Instructs FDA staff to identify SOPs and determine if studies
were registered on appropriately
– Informed Consent Regulations (21 CFR § 50.25(c))
• A statement must be included in informed consent documents
of applicable clinical trials initiated on or after March 7, 2012
regarding the availability of information at
FDAAA - Next Steps
• HHS plans to issue regulations that will prescribe
procedures for registering and submitting results
of clinical trials to in accordance
with FDAAA
• Notice of Proposed Rulemaking (NPRM)
– Fall 2012 HHS Unified Agenda estimated publication in
the Federal Register in January 2013
Overview of Rulemaking Process
Food and Drug Administration Amendments Act of 2007
Announcement in Department’s Unified Agenda of Regulatory Action
Agency Develops Draft Notice of Proposed Rulemaking (NPRM)
Department and OMB Review
NPRM Published in Federal Register
Public Comment Period (typically 60 – 90 days)
Agency Responds to Comments/ Develops Final Rule
Department and OMB Review
Final Rule Published in Federal Register
Additional Issues in Rulemaking
• Expand results reporting to trials of unapproved
• Include narrative summaries? Can it be done
without being promotional and misleading?
• Technical; Lay language
• Data quality verification
• Process
• External sources
• Full protocol versus extract “necessary to help
evaluate the results”
38 Practical
Who is the Responsible Party?
• “Responsible Party”* is defined as:
– Sponsor [only one per trial]
• IND/IDE holder; if none, then
• Person or entity who “initiated” the trial
– Funding recipient if grant or sponsored research agreement
– Funder if procurement funding agreement (contract)
– Sponsor may designate the Principal
Investigator (PI) as Responsible Party [only one
per trial]
• If PI meets certain requirements (e.g., has access to
and control over data, right to publish)
PRS Responsible Party Format
• Updated format August 2011
• Responsible Party (RP) must approve and
release record
• If RP = Sponsor; no change in process
– Administrator “releases” record; fewer data elements
• If RP ≠ Sponsor; new process
– Record is in the Sponsor’s PRS Organization Account
– Investigator must be specified as a User in the PRS and name
must be properly formatted (for public display)
– Investigator “releases” record
» Administrator receives notification after release
• See: “Responsible Party FAQ” on PRS Main
Menu under Help
PRS Responsible Party Format
42 Information
PRS Responsible Party Format
PRS Entry of Grant Number
Additional PRS Resources
• Problems Report
– Allows investigators and administrators of
organizational accounts to identify potential problems
with records
• Record Owner issues
• PRS Administrator issues
• FDAAA issues (report is downloadable)
– Trials missing FDAAA required data elements
– Trials that reached (primary) completion date more than
one year ago and results are not posted on
– Note: For informational purposes only. The Responsible
Party must determine if the trial is an “applicable clinical
trial” subject to FDAAA requirements.
PRS Information Resources
• Protocol Registration
– Data Element Definitions
– Review Criteria
• Results
– Data Element Definitions
– Review Criteria
– Simplified, Printable Results Templates
– Helpful Hints and Common Errors
• User’s Guide [PRS Main Menu]
Recorded Presentations
• Available at:
• Eight presentations with audio and slides
1. Overview of
2. Key FDAAA Issues
3. PRS Information and
Data Review Process
4. PRS Accounts and
• Results
5. Participant Flow Module
6. Baseline Characteristics
7. Outcome Measures and
Statistical Analysis Module
8. Adverse Events Module
CTSA Training Opportunity
• Results Database Train-theTrainer Workshop
– Goal is to train key personnel at CTSA institutions on
FDAAA and results database requirements so that they
may serve as a knowledge source for investigators at
their institution
– Next workshops are June 10-11(registration is closed)
and July 22-23, 2013
Select Publications
Zarin DA, Tse T, Williams RJ, Califf RM, Ide NC. The results database – update and key issues.
N Engl J Med 2011;852-860.
Tse T, Williams RJ, Zarin DA. Update on registration of clinical
trials in Chest 2009;136:304-5.
Tse T, Williams RJ, Zarin DA. Reporting basic results in Chest 2009;136:295-303.
Zarin DA, Tse T. Moving toward transparency of clinical trials.
Science 2008;319:1340-2.
Additional Information
General information:
Office of Extramural Research (OER)
[email protected]

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