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  • Uploaded on and FDAAA for NIH Grantees. NIH Regional Seminar - June 2013 Rebecca J. Williams, PharmD , MPH Assistant Director, National Library of Medicine. Overview.

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clinicaltrials gov and fdaaa for nih grantees 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
three key issues with publications
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 measures

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.

summary of findings
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  • After a median of 51 months after study completion, a third of NIH-funded trials in the sample remained unpublished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
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
Levels of “Transparency”


Zarin DA, Tse T. Science. 2008

clinicaltrials gov milestones – 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
What does FDAAA require?

The responsible party for an applicable clinical trial (ACT) subject to FDAAA must :

  • Register the ACT in no later than 21 days after enrollment of the first participant;
  • 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
FDAAA Key Terms
  • Applicable Clinical Trials (ACTs)
  • Responsible Party
  • (Primary) Completion Date


what is an act
What is an ACT?
  • “Applicable Clinical Trials”* (ACTs) subject to FDAAA are:
    • Interventional studies of drugs, biologics, & devices
    • Not phase 1 drugs, not small feasibility devices
    • US FDA jurisdiction (e.g., IND/IDE orUS site)
    • ACTs initiated on or after 9/27/07 or ongoing as of 12/26/07


who is the responsible party
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
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 requirements1
FDAAA Registration Requirements
  • What do I register?
    • data elements*, including:
      • 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
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 12/26/07



fdaaa results requirements1
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 clearance
    • Delays possible
      • Seeking approval of a new use
      • Extensions for “good cause”



fdaaa results requirements2
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 requirements3
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
FDAAA Results Requirements - Clarifications
  • Does NOT prescribe how study should be conducted
  • 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
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
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 devices
  • Note: Other policies may apply
baseline measures clinicaltrials gov format
Baseline Measures - Format

“Default” Required Measures


experience with results database
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
General Review Criteria
  • Protocol and results must be clear and informative
  • Review focuses on:
    • Logic and internal consistency
    • Apparent validity
    • Meaningful entries
    • Formatting


who is the audience
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
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
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
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
Additional Issues in Rulemaking
  • Expand results reporting to trials of unapproved products?
  • 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”
who is the responsible party1
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
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

additional prs resources
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
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
Recorded Presentations

Available at:

Eight presentations with audio and slides


5. Participant Flow Module

6. Baseline Characteristics Module

7. Outcome Measures and Statistical Analysis Module

8. Adverse Events Module

  • Overview of
  • Key FDAAA Issues
  • PRS Information and Data Review Process
  • PRS Accounts and Registration
ctsa training opportunity
CTSA Training Opportunity
  • Results Database Train-the-Trainer 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
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
Additional Information
  • General information:
  • Office of Extramural Research (OER)
  • Questions?