1. ClinicalTrials.gov and FDAAA for NIH Grantees
NIH Regional Seminar - June 2012
Rebecca J. Williams, PharmD, MPH
Assistant Director, ClinicalTrials.gov
National Library of Medicine

2. Overview
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
ClinicalTrials.gov Practical Considerations
Protocol Registration System (PRS)
Resources
NEW SLIDE

3. Introduction to FDAAA

4. Three Key Issues 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

5. Zarin CTSA Webinar (10-21-09)
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 Jun 1;324(7349):
ClinicalTrials.gov / NLM 5

6. The Controversies Continue…

8. Summary of Findings
Fewer than half of NIH funded trials registered at ClinicalTrials.gov 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After a median of 51 months after study completion, a third of NIH-funded trials in the sample remained unpublished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

9. Rationale for Registering and Reporting Clinical Trial Results
Responsibility to human subjects and the public
Research integrity
Evidence-based medicine
Allocation of resources
I don’t understand the “allocation of resources” thing

10. Levels of “Transparency”
Zarin CTSA Webinar ( )
Levels of “Transparency” 10
Zarin DA, Tse T. Science. 2008
ClinicalTrials.gov / NLM

11. ClinicalTrials.gov – Milestones
Food and Drug Administration Modernization Act (FDAMA)
ClinicalTrials.gov launched
International Committee of Medical Journal Editors (ICMJE) policy
FDAAA (Title VIII of Public Law )
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
FDAMA* 113 (1997) mandates registry
Investigational New Drug application (IND) trials for serious and life-threatening diseases or conditions
ClinicalTrials.gov launched in February 2000
OTHERS:
Maine state law; state attorneys general
Investigators should be aware that since July 2005, the International Committee of Medical Journal Editors (ICMJE) have required, as a condition of consideration for publication in its member journals, prospective clinical trial registration in a public registry like ClinicalTrials.gov
FDAAA = Food and Drug Administration Amendments Act of 2007

12. What does FDAAA require?
The responsible party for an applicable clinical trial (ACT) subject to FDAAA must :
Register the ACT in ClinicalTrials.gov 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
the reporting of summary results information (including adverse events) no later than 1 year after the completion date for registered applicable clinical trials involving drugs that are approved under section 505 of the Food, Drug and Cosmetic Act (FDCA) or licensed under section 351 of the PHS Act, biologics, or of devices that are cleared under section 510k of FDCA 12

13. FDAAA Key Terms Applicable Clinical Trials (ACTs) Responsible Party
(Primary) Completion Date 13

14. 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 or US site)
ACTs initiated on or after 9/27/07 or ongoing as of 12/26/07 *

15. 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) *

16. FDAAA Registration Requirements
Where do I register?
ClinicalTrials.gov 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

17. FDAAA Registration Requirements
What do I register?
ClinicalTrials.gov/FDAAA 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
* ClinicalTrials.gov Protocol Data Element Definitions (DRAFT):

18. 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 18 18

19. 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” 19 19

20. 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
Title and Description
Measure Type (e.g., mean) and Measure of Dispersion (e.g., SD)
Statistical analyses, as appropriate 20 20

21. 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) 21 21

22. 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

23. 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 ClinicalTrials.gov are independent of publication status
Submitting results to ClinicalTrials.gov will not interfere with publication*
But, failing to register the trial will!
* Laine C, Horton R, DeAngelis C, et al. Ann Intern Med. 2007;

24. Results and non-ACTs
Non-ACTs registered in ClinicalTrials.gov are *not* required to submit results to ClinicalTrials.gov
Phase 1 trials
Observational studies
Exception: Pediatric postmarket surveillance of devices
Note: Other policies may apply

26. Participant Flow - ClinicalTrials.gov Format
NCT
NCT

27. Baseline Measures - ClinicalTrials.gov Format
“Default” Required Measures
NCT

28. Outcome Measures - ClinicalTrials.gov Format
NCT

29. Outcome Measures - ClinicalTrials.gov Format (cont’d)
NCT

30. Basic Information Needed for Outcome Measures

31. Adverse Events - ClinicalTrials.gov Format31
NCT

32. 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 32

33. General Review Criteria
Protocol and results must be clear and informative
Review focuses on:
Logic and internal consistency
Apparent validity
Meaningful entries
Formatting 33

34. 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) 34

35. FDAAA – Other Considerations
FDA Requirements
Certification of Compliance to FDA
Form 3674 must accompany human drug, biological, and device product submissions
FDA Compliance Program : Sponsors, Contract Research Organizations, and Monitors
Instructs FDA staff to identify SOPs and determine if studies were registered on ClinicalTrials.gov 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 ClinicalTrials.gov

36. FDAAA - Next Steps
HHS plans to issue regulations that will prescribe procedures for registering and submitting results of clinical trials to ClinicalTrials.gov in accordance with FDAAA
Notice of Proposed Rulemaking (NPRM)
Fall 2011 HHS Unified Agenda estimated publication in the Federal Register in April 2012

37. 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
Final Rule Published in Federal Register 37

38. 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”

39. ClinicalTrials.gov Practical Considerations

40. 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) *

41. 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

42. PRS Responsible Party Format
Drug Information Association

43. PRS Responsible Party Format

44. PRS Entry of Grant Number

45. 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 ClinicalTrials.gov
Note: For informational purposes only. The Responsible Party must determine if the trial is an “applicable clinical trial” subject to FDAAA requirements.

46. PRS Information Resources
Protocol Registration
Data Elements
Detailed Review Items
Results
Simplified, Printable Results Forms
Helpful Hints and Common Errors
User’s Guide [PRS Main Menu] 46

47. Recorded Presentations
Available at:
Eight presentations with audio and slides
Overview of ClinicalTrials.gov
Key FDAAA Issues
PRS Information and Data Review Process
PRS Accounts and Registration
Results
5. Participant Flow Module
6. Baseline Characteristics Module
7. Outcome Measures and Statistical Analysis Module
8. Adverse Events Module

48. CTSA Training Opportunity
ClinicalTrials.gov 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
Announcement soon of training date for Fall 2012

49. Select Publications
Zarin DA, Tse T, Williams RJ, Califf RM, Ide NC. The ClinicalTrials.gov results database – update and key issues. N Engl J Med 2011;
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:
Zarin DA, Tse T. Moving toward transparency of clinical trials. Science 2008;319:

50. Additional Information
General ClinicalTrials.gov information:
FDAAA related information:
Office of Extramural Research (OER)
Questions?