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What is the requirement?
For registration purposes, how is “clinical trial” defined and what are the registration deadlines?
What are the penalties for failing to register?
Who is responsible for registering a trial?
The terms "health-related interventions" and "health outcomes" suggest that this requirement applies only to biomedical clinical trials. Is that correct?
Are there any exceptions?
What if I am uncertain about whether to register my trial?
Where/what are the registries?
How is the UW involved?
Is existing UW practice affected by the new (fall, 2007) FDA/NIH registration requirement?
How do PIs register their trials?
Does the registration posting need to be reviewed by the Human Subjects Division?
Is more information available?
Over the past ten years, government agencies and the International Committee of Medical Journal Editors have issued laws and directives on the subject of trial registration. All parties have consistently agreed that the purpose of trial registration is to promote the public good by ensuring that the existence and design of clinically directive trials are publically available. The registration effort began with the development of a publically available Web site, ClinicalTrials.gov. ClinicalTrials.gov is a service of the NIH, developed by the National Library of Congress.
In 1997, the FDA/NIH began requiring registration for only a limited number of trials, Then, in September, 2007, the Food and Drug Amendments Act (Title VIII. Sec. 801) significantly expanded the scope of clinical trials that must be registered and set civil monetary penalties for failing to register “applicable trials.”
In 2004, the International Committee of Medical Journal Editors (ICMJE) defined trials that must be registered in order to be considered for publication in journals that adhere to ICMJE standards. In 2007 the ICMJE expanded the definition of trials that must be registered. Scores of journals (not limited to medical journals) have adopted the registration policy.
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According to the International Committee of Medical Journal Editors (ICMJE):
2005 definition statement: “Any research project that prospectively assigns human subjects to intervention and comparison groups to study the cause-and-effect relationship between a medical intervention and a health outcome. The trial must have at least one prospectively assigned concurrent control or comparison group in order to trigger the requirement for registration.” This definition specifically excluded Phase I trials.
2007 definition statement: “Any research study that prospectively assigns human participants or groups of humans to one or more health- related interventions to evaluate the effects on health outcomes.” This definition includes Phase I trials.
Deadlines for registration: Currently, the ICMJE follows its 2005 definition. The ICMJE will start to implement the expanded (2007) definition for all trials that begin enrollment on or after July 1, 2008. The ICMJE will not strictly impose this expanded definition until the stated date. However, trials that meet the expanded definition CAN be registered before the stated date, and the ICMJE encourages investigators to do so, noting that such action is consistent with their goal of “full transparency with respect to performance and reporting of clinical trials.
According to the FDA and the NIH:
2007 Definition: The Food and Drug Amendments Act (Title VIII. Sec. 801) requires registration for all “applicable clinical trials,” including Federal, industry-sponsored, and investigator-initiated that are:
1) Trials of drugs and biologics: Controlled, clinical investigations, other than Phase I investigations, of a product subject to FDA regulation, and
2) Trials of devices: Prospective clinical studies of health outcomes comparing an intervention with a device against a control in human subjects (other than small clinical trials to determine the feasibility of a device, or clinical trials to test prototype devices where the primary outcome measure relates to feasibility and not to health outcomes; and pediatric postmarket surveillance studies, as required under the Federal Food, Drug and Cosmetic Act.
Deadlines for registration: This Food and Drug Amendments Act of 2007 requires that all trials, regardless of sponsor, initiated after 9/27/07 or ongoing as of 12/26/07 must be registered in full by the later of 12/26/07 or 21 days after the first patient is enrolled. All trials that were ongoing as of 9/27/07 and do not involve serious or life-threatening conditions must be registered by 9/27/08.
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According to the ICMJE:
Unregistered trials will not be considered for publication in journals that adhere to ICMJE standards. This penalty has not changed over time.
According to the FDA/NIH (Food and Drug Amendments Act of 2007):
Penalties may include civil monetary penalties up to $10,000 fine for failing to submit or for submitting fraudulent information to ClinicalTrials.gov. After notification of noncompliance, the fine may go up to $10,000 per day until resolved. For federally funded grants, penalties may include the withholding or recovery of grant funds.
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Who is responsible for registering a trial?
Normally, the clinical trial will be registered by the sponsor.
•NIH-sponsored trials should normally be registered by the Institute that is funding the research
• Industry-sponsored trials (industry-written protocol) should normally be registered by the industry sponsor.
• Multi-site trials should be coordinated among the sites and registered by the “lead sponsor” so that ClinicalTrials.gov does not receive multiple registrations for the same trial.
However, some trials will need to be registered by the PI.
•Investigator-initiated trials (for which industry has supplied drug or grant funds) should normally be registered by the PI.
• Trials for which PIs hold their own INDs or IDEs should normally be registered by the PI. (PIs who hold their own INDs or IDEs are considered to be the trial sponsors.)
• Trials that the sponsor has declined to register.
The PI is ultimately responsible for determining that registration requirements are met. Although some sponsors will do the actual registration work, it is still the PI’s responsibility to ensure that the registration has been accomplished. Before enrolling subjects, every PI should ask the study’s sponsor, “Is this study fully registered?” If the sponsor responds affirmatively, PIs should personally check ClinicalTrials.gov to ensure that the trial has been registered.
For registration instructions at the UW, see below “How do PIs register their trials?”
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The terms “health-related interventions” and "health outcomes" suggest that this requirement applies only to biomedical clinical trials. Is that correct?
No. According to the ICMJE, “health-related” interventions include any intervention used to modify a biomedical or health-related outcome (for example, drugs, surgical procedures, devices, behavioral treatments, dietary interventions, and process-of-care changes). Health outcomes include any biomedical or health-related measures obtained in patients or participants, including pharmacokinetic measures and adverse events.
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Yes. Purely observational studies (those in which the assignment of the medical intervention is not at the discretion of the investigator) do not require registration.
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According to the ICMJE:
Those who are uncertain whether their trial meets the ICMJE definition should err on the side of registration if they wish to seek publication in an ICMJE journal.
According to the FDA and the NIH:
Both agencies encourage the registration of ALL trials, whether or not required under the FDA Amendments Act of 2007.
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Over time, ClinicalTrials.gov has become the registry of choice and is now the registry required by the FDA Amendments Act of 2007. ClinicalTrials.gov is a service of the NIH, developed by the National Library of Medicine.
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The UW is already registered as an institution at ClinicalTrials.gov, and hundreds of UW-based trials have already been registered at this site. In addition, ClinicalTrials.gov asks each institution to identify a PRS administrator. At the UW, the administrator is Gigi Streidl in the Office of Clinical Research, Office of Research and Graduate Education, Dean’s Office, School of Medicine.
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Is existing UW practice affected by the new FDA/NIH registration requirement?
From the beginning, the UW has promoted registration of trials/studies meeting the broad ICMJE definition. Therefore, the new FDA law does not expand the scope that the UW has applied for registering studies in the past, nor does the new FDA law change the UW existing practice for defining the “responsible party” for registering a trial.
What has been affected by the new FDA law is the penalty for noncompliance. As explained above at “What are the penalties for failing to register?” and in the information references below, failing to register applicable trials on ClinicalTrials.gov may now include civil monetary penalties and, for federally funded trials, the withhholding or the recovery of grant funds. The ICMJE penalty for failure to register continues to be the journals’ refusal to consider publication of trial results.
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If after reading this information, you determine that you need to register your clinical trial at ClinicalTrials.gov, call your trial's sponsor/program officer. Ask whether the trial has already been registered and/or whether the sponsor intends to register the trial.
• If the answer is "no" to both questions, proceed to step 1., below.
• If the sponsor states that the trial has already been registered,check the information about your trial on ClinicalTrials.gov., e.g., for multi-site studies, be sure that your site is listed and that the information is accurate.
• If the sponsor intends to register the trial, be sure that registration occurs before you enroll your first subject. Once the trial has been registered, check the record for accuracy.
To register your trial:
1.Send an email message to: gstreidl@u.washington.edu
2. Include in the message your name, telephone number, and email address.
3. Receive by return email a login name and a temporary password. Save your password - you will need it for periodic updates and verification (see below).
4. Go to the Clinicaltrials.gov Registration Web site.
5. Complete the login fields. In the “Organization” field, state “UWashington.”
6. Browse the Main Menu page. Under “User Account,” follow the instructions for changing your temporary password as soon as possible. Refer to the “User’s Guide” for additional information. As the PI, you are a “user,” and you are responsible for entering the information about your trial, ensuring that the information is correct, and updating the information in a timely manner.
7. On the Main Menu page, under Protocol Record, hit "Create" and complete the study description template. Note that the ClinicalTrials.gov-required fields are marked with a red asterisk (*) and the FDA-required fields are marked with a green FDAAA. Taken together, these data elements represent the requirements for an adequate registration. If you do not complete these fields, your trial may not be considered "fully registered." Note also that each field of the template is labeled and linked to a definition; however, several fields are potentially confusing and should be completed as follows:
• Organization’s Unique Protocol ID: Use the Human Subjects application number.
• Sponsor: The database will default to “University of Washington” (although the UW is not actually the trial’s sponsor).
• Collaborators: Sponsorship can be clarified by entering the actual sponsor’s name. For unsponsored research, either leave the field blank or enter "None".
• Record Verification Date: Enter the date on which you complete and submit the template.
• Conditions: Use the MeSH controlled vocabulary (provided). If you don’t, ClinicalTrials.gov staff is likely to delete your term and choose one of their own.
• Keywords: Use the MeSH controlled vocabulary (provided). If you don’t, ClinicalTrials.gov staff is likely to delete your term and choose one of their own.
8. If the PI did not personally complete the template, send the draft template to him/her for review and approval. Note: This is an important step.
9. Submit the completed , PI-approved, template. The completed template will go to the UW administrator. The administrator will check to be sure that the trial has been approved by the IRB and will release the template to ClinicalTrials.gov
NOTE: The PI is responsible for periodic updates to the study record, e.g., for study-specific changes such as recruitment status and protocol revisions. The PI is also responsible for verifying the study record once every six months while the study is open and annually after the study has closed.
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No. The UW Administrator will check with the Human Subjects Division to ensure that studies posted on ClinicalTrials.gov have been approved, but the UW Human Subjects Division will not review the postings.
Note: The HSD will continue to review postings for the UW Health Sciences “Studies Seeking Volunteers”
Web site. This Web site’s purpose is to recruit subjects.
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Is more information available?
Yes.
For more information about the ICMJE registration requirement, see:
The 2007 ICMJE editorial entitled “Clinical Trials Registration: Looking Back and Moving Ahead.”
For more information abut the FDA Amendments Act of 2007, see:
Guidance from the NIH Office of Extramural Research
NIH Fact Sheet
AAMC memorandum
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