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1 and FDAAA for NIH Grantees
NIH Regional Seminar - June 2012 Rebecca J. Williams, PharmD, MPH Assistant Director, 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 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): / NLM 5

6 The Controversies Continue…


8 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completion After a median of 51 months after study completion, a third of NIH-funded trials in the sample remained unpublished BMJ 2011;344:d7292 doi

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 / NLM

11 – Milestones
Food and Drug Administration Modernization Act (FDAMA) 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 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 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 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? 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? 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):

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 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;

24 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


26 Participant Flow - Format

27 Baseline Measures - Format
“Default” Required Measures NCT

28 Outcome Measures - Format

29 Outcome Measures - Format (cont’d)

30 Basic Information Needed for Outcome Measures

31 Adverse Events - Format
31 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 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

36 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 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 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 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 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 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 results database – update and key issues. N Engl J Med 2011; 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: Zarin DA, Tse T. Moving toward transparency of clinical trials. Science 2008;319:

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

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