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Federal Law Expands Clinical Trial Registration Requirement

The information below provides an overview of the steps researchers must take to register their clinical trials on ClinicalTrials.gov.

The links below jump to detailed information.

• Introduction
• Which Laws?
• Which Journals?
• Which Studies?
• Which Registry?
• By When?
• By Whom?
• How?
• IRB Approval?
• What Happens to Unregistered Trials?
• Automation?
• What About Submitting Information About Trial Results?
• Additional Information

Introduction

Recent years and months have seen progressively expanded requirements to provide the public with information about clinical trials available and conducted, including the results of those trials. These requirements have come from federal laws and regulations, as well as editors of prominent medical journals. Clinical trial sponsors, and in some cases research investigators, must be aware of and comply with their obligations under these requirements.

Which Laws?

The Food and Drug Administration Modernization Act (FDAMA) of 1997 resulted in the establishment of ClinicalTrials.gov and mandated registration of FDA-regulated efficacy drug trials for serious or life-threatening diseases and conditions.

The Food and Drug Administration Amendments Act (FDAAA) of 2007 expands the scope of clinical trials that must be registered, requires registration information that was previously optional, adds a few additional registration data elements, requires eventual inclusion of trial results information, and provides penalties for noncompliance.

Which Journals?

Since 2005, many, if not most, medical journals began to require prospective public registration of certain clinical trials as a prerequisite for publication.

Included among them, for example are the International Committee of Medical Journal Editors (ICMJE) member journals:

• JAMA
• New England Journal of Medicine
• The New Zealand Medical Journal
• Norwegian Medical Journal
• CMAJ
• The Lancet
• Annals of Internal Medicine
• Croatian Medical Journal
• Nederlands Tijdschrift voor Geneeskunde (Dutch Journal of Medicine)
• Journal of the Danish Medical Association
• The Medical Journal of Australia

Which Studies?

Collectively, the FDAMA, FDAAA, and ICMJE requirements cover the following types of studies:

• Controlled clinical investigations of drugs and biologics subject to FDA regulation, other than Phase I trials.
• Controlled trials with health outcomes of devices subject to FDA regulation (other than small feasibility studies) and pediatric postmarket surveillance.
• Any research project that prospectively assigns human subjects to intervention and concurrent control or comparison groups in order to study the cause-and-effect relationship between a medical intervention and a health outcome.
• Clinically directive trials – those that test a clinical hypothesis about health outcomes, including all trials whose primary purpose is to affect clinical practice

Some journals have additional specifications for which studies must be registered. For example, JAMA requires registration of all randomized clinical trials (RCTs), except for Phase I trials, that “randomize” human research participants to an intervention.

For more information about which clinical trials must be registered, see:

• Paragraphs three, four, and five of " Is This Clinical Trial Fully Registered?: A Statement from the International Committee of Medical Journal Editors "
• Endnotes 1 and 2 of the Fact Sheet “Registration at ClinicalTrials.gov: As Required by Public Law 110-85, Title VIII at http://prsinfo.clinicaltrials.gov/s801-fact-sheet.pdf .
• Paragraph four of “JAMA Information for Authors: Publication of Clinical Trials in JAMA”

For assistance with determining whether FDA requires a specific trial to be registered, contact the Health System Legal Office at (734) 764-2178.

Which Registry?

ClinicalTrials.gov, sponsored by the United States National Library of Medicine, is the registry currently used to meet FDAMA and FDAAA mandates, and also meets all the ICMJE criteria.

By When?

For ICMJE publication:

• Before beginning subject enrollment*

* Note: The ICMJE requirement is more stringent than the FDAAA requirement (below) for timing of registration relative to patient/subject enrollment.

For FDAAA compliance:

• December 26, 2007 or 21 days after the first patient is enrolled* -- for trials initiated after 9/27/2007, or trials that are ongoing as of 12/26/2007
• September 27, 2008 – for trials that were ongoing as of 9/27/2007 and do not involve a “serious or life-threatening disease or condition”
• Exception – Trials that (1) were ongoing as of 9/27/2007, (2) do involve a “serious or life threatening disease or condition”, and (3) are completed by 12/26/2007, are not subject to the FDAAA requirements, but are likely to be subject to the pre-existing FDAMA registration requirements. For purposes of this exception, the “completion date” is the date the final subject was examined or received an intervention for the purposes of final collection of data for the primary outcome.

By Whom?

Sponsored clinical trials are likely to be registered on ClinicalTrials.gov by the lead sponsor (the clinical trial agreement negotiated through DRDA may specify who is responsible). Clinical trials conducted under an FDA IND or IDE are likely to be registered by the IND or IDE holder. Otherwise, trial registration falls to the study investigator. Before investigators register a sponsored trial, they should search the ClinicalTrials.gov website to be sure that the trial has not already been registered.

How?

To enter missing information on a previously registered trial:

• Go to www.ClinicalTrials.gov , log in to your account, and follow the navigational instructions to update/modify each protocol record.
• If a protocol record is already in compliance with ICMJE requirements (i.e., all optional ClinicalTrials.gov fields are already completed), the only additional information required will be yes/no answers to whether the trial outcome measure assesses a safety issue and whether the trial is an “applicable clinical trial” subject to FDAAA requirements (some trials register even if they are not required to); and designation of the party responsible for registration of the trial.

To register a trial for the first time:

Go to www.ClinicalTrials.gov and follow the navigational instructions to register a trial.

Step 1 - Open an organizational or individual account

If your research department or group already has an organization account, contact the account's "Protocol Registration System (PRS) Administrator" and skip to Step 2.

If your research department or group does not already have an organization account, identify the person(s) who will serve as the PRS Administrator(s) and have them set up an account. Be sure that the name of the organization account is specific to your research department or group (e.g., University of Michigan Dermatology, etc.). All future trial registrations for that organizational account will have to be entered by the account's PRS Administrator(s).

Alternatively, investigators who do not belong to a research department or group that has an organization account (or the potential for establishing one with a centralized PRS administrator) may open an individual account by following the instructions on the ClinicalTrials.gov web site.

Completion of the account application takes only minutes, but allow 1-2 days for ClinicalTrials.gov to respond with an account number for use in Step 2.

Step 2 - Register the trial

The required information will include variations on the following:

• Brief title
• Brief summary
• Primary purpose
• Interventional study design
• Study phase
• Study type
• Condition or focus of study
• Intervention type
• Intervention name
• Study start date
• Anticipated completion date
• Enrollment (target number of subjects)
• Primary and secondary outcome measures
• Safety issue – Yes/No (NEW)
• Eligibility criteria
• Gender
• Age limits
• Accepts healthy volunteers?
• Overall recruitment status
• Recruitment status (facility)
• Has expanded access?
• Expanded access status
• Sponsor
• Responsible party (NEW)
• Facility
• Facility contact
• Central contact
• Organization's unique protocol ID
• Secondary IDs
• IND/IDE?
• Record verification date (date the protocol information was last verified)
• Applicable clinical trial – Yes/No (NEW)
• FDA product status (NEW, but not required until September 2008)
• IRB approval status
• Oversight authority

With pertinent source information at hand (the protocol, informed consent document, and IRB application will be helpful), expect entry of each registration to take approximately an hour.

IRB Approval?

While the ClinicalTrials.gov registration form may prompt for entry of information regarding a trial's IRB approval, it is not necessary to obtain additional IRB approval of the content of the registration information itself. ClinicalTrials.gov has yet to determine if and how IRB validation of the registration information will be sought - stay tuned for more information.

What Happens to Unregistered Trials?

The FDAAA penalties for failure to register, or for providing false or misleading registration information, may include civil monetary penalties and, for federally-funded trials, the withholding or recovery of grant funds. Additionally, unregistered or improperly registered trials risk not being accepted for consideration by ICMJE member and other journals.

Automation?

The planning for future upgrades of the eResearch system includes features to automatically upload registration information from the eResearch application to the Engage bulletin-board and the ClinicalTrials.gov protocol registration system upon investigator request.

What About Submitting Information About Trial Results?

Submission of information about trial results will be required eventually, but is not at this time. Stay tuned for more information as details about that part of the requirement become available.

 

Additional Information

Additional information is available from:

• ClinicalTrials.gov at…

  ClinicalTrials.gov Protocol Registration System
  http://prsinfo.clinicaltrials.gov/fdaaa.html

  Fact Sheet
  http://prsinfo.clinicaltrials.gov/s801-fact-sheet.pdf

• The National Institutes of Health (NIH) at…

NIH Guide Notice NOT-OD-08-014
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-08-014.html

• The Food and Drug Administration (FDA) at…

Guidance on FDAMA
http://www.fda.gov/cder/guidance/4856FNL.PDF

• The International Committee of Medical Journal Editors (ICMJE) at…

http://www.icmje.org/#clin_trials
http://www.icmje.org/clin_trial.pdf
http://www.icmje.org/icmje_response.pdf
http://www.icmje.org/clin_trialup.htm

Ray Hutchinson, MD, Associate Dean
Pat Ward, MPA, Director
Research Regulatory Affairs
734-615-4199

Posted 12/17/07 Updated 1/3/08