Clinical Trial Registration Requirements
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.
- Which Laws?
- Which Journals?
- Which Studies?
- Which Registry?
- By When?
- By Whom?
- IRBMED Approval and Informed Consent Modifications?
- What Happens to Unregistered Trials?
- What About Submitting Information About Trial Results?
- What About Submitting Information About Adverse Events?
- Additional Information
Recent years and months have seen progressively expanded requirements to provide the public with information about clinical trials that are currently available or have been conducted, including the results of those trials and information about adverse events. 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.
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 expanded the scope of clinical trials that must be registered, requires registration information that was previously optional, adds additional registration data elements, requires inclusion of trial results and adverse event information, and provides penalties for noncompliance.
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, are the more than 700 International Committee of Medical Journal Editors (ICMJE) member journals such as:
- New England Journal of Medicine
- The New Zealand Medical Journal
- Norwegian Medical Journal
- 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
For a complete listing of journals that follow the ICMJE requirements, see http://www.icmje.org/journals.html
- Controlled clinical investigations of drugs and biologics subject to FDA regulation, other than Phase I trials. [NOTE: The European Medicines Agency (EMA) does include pediatric 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 study that prospectively assigns human participants or other groups of humans to one or more health-related interventions to evaluate the effects on health outcomes.
- 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. Please consult the instructions to authors for the journals in which you hope to publish the results of your trial.
Special Note: See the section on “Results” for guidance about which registered trials are and are not also required to post information about adverse events and trial results.
For more information about which clinical trials must be registered, see:
- ICMJE Frequently Asked Questions: Questions about Clinical Trials Registration at http://www.icmje.org/faq_clinical.html
- 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, or the Medical School Office of Regulatory Affairs at (734) 647-1576.
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.
- 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.
- December 26, 2007 or 21 days after the first patient is consented -- for trials initiated after 9/27/2007, or trials that are ongoing as of 12/26/2007 and that do involve a “serious or life threatening disease or condition”
- 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.
- the sponsor of the clinical trial, or
- the principal investigator of a clinical trial if designated by a sponsor, grantee, contractor, or awardee
In many cases, it is anticipated that 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. The principal investigator is expected to be the Responsible Party only when s/he is responsible for conducting the trial, has access to and control over the data from the clinical trial, and has the right to publish the results of the trial. Before a principal investigator registers a sponsored trial, they should search the ClinicalTrials.gov website to be sure that the trial has not already been registered.
Note: Some federal funding agencies have handled the trial registrations for their extramural studies. However, most are now transitioning this responsibility to the principal investigator at the lead study site. See the “How?” section below for information about what to do if your federal sponsor decides to transfer your trial’s registration responsibility to you.
- 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 individual account
There is no single, central University of Michigan organizational account. Rather, there are several different University of Michigan research departments or groups that have already established their own organizational accounts, and a large number of University of Michigan investigators who have established individual accounts (a single individual account can accommodate several individual trials). Under a special arrangement, these individual accounts are associated with the University of Michigan inside the Protocol Registration System (PRS) of ClinicalTrials.gov (more information about this is provided later in this section).
If your research department or group already has an organization account (examples of organization accounts already held by specific UM research groups include: UMichiganDerm, UMichiganArrhythmia, UMichiganCC, and UMichiganHS), 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, the investigator or other person who will serve as the PRS Administrator should set up an individual account by following the instructions on the ClinicalTrials.gov web site. Be sure that the name of the organization account includes “University of Michigan”, but is also specific to your research team, collaborative group, or department/unit (e.g., University of Michigan Dermatology, University of Michigan Jane Doe Research Team, etc.). All future trial registration information for that individual account will have to be entered by the individual account's PRS Administrator(s). Note that within the ClinicalTrials.gov Protocol Registration System (PRS), individual accounts originating from the University of Michigan will be associated with a “virtual” UM organization account (UMichigan).
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 depend on the type of study and why you are registering it.
- FDAAA Requirements: If you are registering an applicable clinical trial to comply with FDAAA requirements, you will have to enter more than just the required fields in ClinicalTrials.gov. Essentially, you will need to enter all fields in ClinicalTrials.gov (as applicable).
- Journal Publication Requirements: If you are only registering the study to comply with journal publication requirements, enter all of the “required” fields (indicated with asterisks) in ClinicalTrials.gov. If you have a specific journal in mind for anticipated publication, you will want to make sure that you enter the information required by that journal and confirm that no additional fields need to be completed per that journal’s requirements.
To get more information about the specific data fields, including which are required for ClinicalTrials.gov and/or FDAAA, see http://prsinfo.clinicaltrials.gov/definitions.html .
Please note that one of the fields solicits information about the trial’s Responsible Party. This field should be completed with information about the UM PI for the trial being registered. In other words, if the trial is being registered by UM, the UM PI for that trial serves as the Responsible Party for the purposes of the registration.
Please also note that some of the answers provided during the initial registration will have an impact on the basic results reporting requirements, which are discussed later in this document. Two fields meriting special attention will be the Primary Completion Date and Primary Outcome Measure.
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 1-2 hours.
NOTE: After initial registration of a clinical trial, it will be necessary to make updates to the record to reflect changes during the conduct of the trial. It is particularly important to keep the primary completion date (anticipated or actual) current because it will impact when the basic results information will need to be entered for applicable clinical trials under FDAAA.
To accept the transfer of trial registration responsibility from a federal funding agency for a trial previously registered by that agency:
- Unless the future Responsible Party (UM PI) is already associated with one of the few pre-existing UM organization accounts (UMichiganDerm, UMichiganArrhythmia, UMichiganCC, and UMichiganHS) or has already established an individual account, the future Responsible Party (UM PI) should establish an individual account (see Step 1 earlier in this section). Do this despite any direction from the federal funding agency to establish a new organizational account or add the registration to one of the pre-existing UM organizational accounts listed earlier in this paragraph (there is a special arrangement with ClinicalTrials.gov that accommodates this).
- Behind the scenes, the PRS system at ClinicalTrials.gov will associate the UM PI's individual account with the "virtual" UM organizational account (UMichigan - that's part of the special arrangement).
- The future Responsible Party (UM PI) should send the current Responsible Party (the federal funding agency) information about the PRS account used by the UM PI, including the following information as known and applicable: the pre-existing (UMichiganDerm, UMichiganArrhythmia, UMichiganCC, or UMichiganHS) or “virtual” (UMichigan) UM organization account, individual account user name, unique protocol number, agency grant number, NCT #, etc.).
- The current Responsible Party (federal funding agency) will use the information to transfer the trial's registration to the account used by the future Responsible Party (UM PI).
- The new Responsible Party (UM PI) should receive a notification or confirmation from ClinicalTrials.gov of the transfer.
- The new Responsible Party (UM PI) should periodically update the registration information as necessary to keep the information current and enter basic result and adverse event information at appropriate time points.
IRB Approval and Informed Consent Requirements
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 itself. ClinicalTrials.gov has not yet determined if and how IRB validation of the registration information will be sought.
New: Informed consent documents for clinical trials for which the FDA requires registration that are initiated on or after 3/7/2012, must include the following statement:
“A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. law. This Web site will not include information that can identify you. At most the Web site will include a summary of the results. You can search this Web site at any time. ”
The IRBMED informed consent document template will include guidance about when and how this statement should be incorporated into a study’s informed consent document.
What Happens to Unregistered or Incompletely Registered Trials?
The FDAAA penalties for failure to register, or for providing incomplete, false, or misleading registration information (including updates subsequent to initial registration), 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.
Submission of information about trial results is now required by the FDA for some trials. The Responsible Party must report results of certain “applicable clinical trials” that were initiated before or were ongoing as of September 27, 2007. The “applicable clinical trials” are:
- Trials of drugs and biologics: controlled, clinical investigations, other than Phase 1 investigations, of a product subject to FDA regulation [click here for expanded regulatory definition];
- Trials of devices: controlled trials, with health outcomes, of a product subject to FDA regulation (other than small feasibility studies), as well as pediatric post-market surveillance studies [click here for expanded regulatory definition].
Similarly, the results of pediatric Phase I trials registered in order to comply with the European Medicines Agency (EMA) must be reported.
Note: The requirement to enter trial results does not apply to “non-applicable” trials that are registered solely to comply with ICMJE requirements. In other words, the ICMJE requirements alone do not require results reporting for any trials. However, these journals will not consider results reporting to be “prior publication” which would bar publication with them. Therefore, they do not limit or restrict and FDA or EMA obligation to report results of “applicable clinical trials”.
For “applicable” clinical trials, a Responsible Party is required to submit basic results information no later than one (1) year after the primary completion date, or the date that the final subject was examined or received an intervention for the purposes of final collection of data for the primary outcome measure, regardless of whether the clinical trial concluded on schedule in accordance with the protocol or was terminated at a different time for another reason. Recall the “How?” section of this guidance, which emphasized the importance of entering and periodically adjusting the primary completion date and primary outcome measure to keep them consistent with actual trial conduct.
See the following website for information regarding the data elements associated with the basic results reporting: http://prsinfo.clinicaltrials.gov/results_definitions.html .
Delayed submission of basic results is allowed in certain circumstances with certification (request for extension). This would typically apply to industry sponsors. The certification (request for extension) must be submitted no later than one (1) year after the earlier of the estimated or actual primary completion date of the trial as entered in ClinicalTrials.gov.
A Responsible Party may submit a certification for delayed submission of results information for an applicable clinical trial that is:
- completed before the drug or device is initially approved, licensed, or cleared by the FDA, or
- studying a new use of an FDA-approved drug or device (i.e., a use not included in the labeling) for which the manufacturer of a drug or device is the sponsor of the trial and has filed or will file within a year an application to the FDA for approval or clearance of that use.
Certifications (requests for extensions) are submitted via the ClinicalTrials.gov Protocol Registration System.
What About Submitting Information About Adverse Events?
As of September 27, 2009, the Responsible Party is expected to submit summary adverse event information when providing basic results for applicable clinical trials. If the Responsible Party submits results information or updates a record that contains results information, s/he must submit adverse events information in order for the submission to be accepted by the system.
Serious adverse events and any adverse event that exceeds a frequency threshold of 5 percent within any arm of the clinical trial must be reported. Responsible Parties may voluntarily use a reporting threshold that is lower than 5 percent.
See the following website for information regarding the data elements associated with the adverse events reporting: http://prsinfo.clinicaltrials.gov/results_definitions.html#AdverseEvents
The planning for future upgrades of the eResearch system includes features to automatically upload registration information from the eResearch application to the ClinicalTrials.gov Protocol Registration System upon investigator request.
- ClinicalTrials.gov at…
ClinicalTrials.gov Protocol Registration System
- The National Institutes of Health (NIH) at…
NIH Guide Notice NOT-OD-08-014
NIH Guide Notice NOT-OD-10-007
- The Food and Drug Administration (FDA) at…
Food and Drug Administration Modernization Act (FDAMA) of 1997
Food and Drug Administration Amendments Act (FDAAA) of 2007
http://www.fda.gov/RegulatoryInformation/Legislation/FederalFoodDrugand CosmeticActFDCAct/SignificantAmendmentstotheFDCAct/FoodandDrug AdministrationAmendmentsActof2007/default.htm
- The International Committee of Medical Journal Editors (ICMJE) at…
- A recent article in NEJM (March 3, 2011) regarding ClinicalTrials.gov results database updates. http://www.nejm.org/doi/full/10.1056/NEJMsa1012065?query=featured_home#t=articleTop
- Applicable Drug Clinical Trial: a non-Phase I, clinical investigation designed to permit a comparison of a test intervention with a control, involving a drug which is the subject of a new drug application (NDA) or biologics license (BLA) or which would require an approved NDA or BLA in order for it to be legally marketed. A non-prescription drug that is or could be marketed under an existing over-the-counter drug monograph is not considered to be subject to this section. Note: clinical investigations designed to demonstrate that an investigational drug product is bioequivalent to a previously approved drug product or to demonstrate comparative bioavailability of two products are considered to be controlled clinical investigations.
- Applicable Device Clinical Trial: a prospective clinical investigation which compares an intervention with a device against a control in human subjects by assigning subjects to specific interventions in a clinical investigation according to a study protocol other than a small feasibility study.
Regulatory Definitions of Note
These definitions are extracted from Elaboration of Definitions of Responsible Party and Applicable Clinical Trial, whose full text pdf link appears in second paragraph of http://prsinfo.clinicaltrials.gov/ /fdaaa.html
Updated July 1, 2011