Register Clinical Trials at ClinicalTrials.gov


What is the requirement?


Over the past ten years, government agencies and the International Committee of Medical Journal Editors (ICMJE) 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 publicly available. The registration effort began with the development of a publicly available website: 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 FDA 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 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.

The bottom line:
The FDA and the ICMJE each have their own requirements for registration, and while some of the requirements overlap, there are also significant differences. In order to comply with the law and preserve the ability to publish in many journals, both sets of requirements must be met.

For registration purposes, how is “clinical trial” defined and what are the registration deadlines?


According to the ICMJE:

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."

Registration Start Date: The ICMJE started to implement the expanded (2007) definition for all trials that began enrollment on or after July 1, 2008. Those who are uncertain whether their trial meets the expanded ICMJE definition should err on the side of registration if they wish to seek publication in an ICMJE journal. The ICMJE secretariat office is unable to review specific studies to determine whether registration is necessary. If researchers or others have questions about the need to register a specific study, they should err on the side of registration or consult the editorial office of the journal they wish to publish the study in. According to the FDA and the NIH:

2007 Definition: The FDA 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.

Registration Start Date: The FDA Amendments Act of 2007 required that all trials, regardless of sponsor, initiated after September 27, 2007 or ongoing as of December 26, 2007 must have been registered in full by the later of December 26, 2007 or 21 days after the first patient was enrolled. All trials that were ongoing as of September 27, 2007 and do not involve serious or life-threatening conditions must be registered by September 27, 2008.

Do I need to register a trial if the subjects were health care providers and not patients?


According to the ICMJE:

Some trials assign health care providers, rather than patients, to intervention and comparison/control groups. If the purpose of the trial is to examine the effect of the provider intervention on the health outcomes of the providers’ patients, then investigators should register the trial. If the purpose is to examine the effect only on the providers (for example, provider knowledge or attitudes), then registration is not necessary.

What are the penalties for failing to register?


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.

In addition, since 2005 many other medical journals have begun to require prospective public registration of certain clinical trials as a prerequisite for publication. Questions about policies of a specific journal should be addressed to that journal directly. An alpha list of journals whose editors or publishers have signed on to the ICMJE Uniform Requirements for Manuscripts Submitted to Biomedical Journals may be found at http://www.icmje.org/journals.html.

According to the FDA/NIH (FDA 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.

Who is responsible for registering a trial?


Normally, a 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 and is accurate. 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 UConn, see below "How do PIs register their trials?"

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.

Are there any exceptions?


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.

What if I am uncertain about whether to register my trial?


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.

Where / what are the registries?


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.

How is UConn involved?


UConn is registered as an institution with ClinicalTrials.gov. In addition, ClinicalTrials.gov asks each institution to identify a Protocol Registration System (PRS) Administrator to serve as the institution’s primary contact and be responsible for the process by which information is submitted. At UConn, the PRS Administrator is Doug Bradway, Office of Research Compliance.

How do PIs register their trials?


If after reading the above 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: doug.bradway@uconn.edu. The message should be sent by the person who will be creating the Protocol Record for a clinical trial, i.e., the PI or the PI's designee. A Protocol Record can have only one "User" (also known as "Owner").
  2. Include in the message your name, telephone number, and email address and state you would like to be registered as a User.
  3. Receive by return email a login name and a temporary password.
  4. Go to the Clinicaltrials.gov Registration web site.
  5. Complete the login fields. In the “Organization” field, state "UConn."
  6. Browse the Main Menu page. Under "User Account," follow the instructions for changing your temporary password as soon as possible. Save your password; you will need it for periodic updates and verification. Under "Help", refer to the "User’s Guide" for additional information. As the PI, or PI designee, you are a User and are responsible for entering the information about your trial, ensuring that the information is correct, and updating the information in a timely manner (for updating, see NOTE at the end of this section).
  7. On the Main Menu page, under "Protocol Record" click on “Create” and complete the study description template. Note that required fields are marked with:

    • * [a red asterisk] = required by ClinicalTrials.gov
    • FDAAA [in green] = required to comply with US Public Law 110-85, Section 801
    • (FDAAA) [in green] = may be required to comply with US Public Law 110-85, Section 801

    Work your way through the data fields to complete the Protocol Record. Data are saved as each screen is filled in, so that you can "Quit" at any time, saving the Record for later completion using "Modify".

    Complete the following (potentially confusing) fields as follows:

    • Organization’s Unique Protocol ID: Use the IRB number.
    • Secondary ID: now required; use grant number, or some other number unique to the trial; if necessary, make up your own
    • Board Name: use University of Connecticut IRB
    • Board Affiliation: use University of Connecticut
    • Board Contact E-Mail: doug.bradway@uconn.edu
    • Board Contact Phone: (860) 486-0986
    • Board Contact Address: Office of Research Compliance, 438 Whitney Rd., Ext., Unit 1246, Storrs, CT 06269.
    • Oversight Authorities: If this is not an FDA-regulated protocol, state "United States: IRB"
    • Collaborators: Other organizations (if any) providing support, including funding, design, implementation, data analysis and reporting.
    • Record Verification Date: Enter the month and year in which you complete and submit the Protocol Record to the PRS Administrator.
    • Primary Completion Date: final data collection date, specifically regarding the Primary Outcome Measure
    • Last Follow-Up Date: When creating the Protocol Record, specify the anticipated last follow-up date.
    • Specifying Study Arms: along with Data Definitions, help is available at https://register.clinicaltrials.gov/prs/html/arms.html
    • Conditions: Use the MeSH controlled vocabulary. 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. If you don’t, ClinicalTrials.gov staff is likely to delete your term and choose one of their own.
    • Investigators: list all investigators on the approved IRB protocol and Appendix A.

    Automatic messages from the electronic system:

    • WARNING: indicates a data element required by the FDA Amendments Act of 2007 has not been entered.
    • ERROR: indicates a serious problem that needs to be addressed
    • ALERT: indicates a problem that needs to be addressed; generally that problem is a missing data element required by ICMJE
    • NOTE: indicates a potential problem that should be reviewed and corrected, as needed
    • Protocol Records must be free of the first three messages in order to be approved and released to ClinicalTrials.gov for processing and publication

    ClinicalTrials.gov data element definitions are available to the User on the registration site, or at http://prsinfo.clinicaltrials.gov/definitions.html

  8. If the PI did not personally complete the Protocol Record, send the draft template to her/him for review and approval. Note: This is an important step. The PI will be required to sign-off on a paper copy of the completed template prior to release to ClinicalTrials.gov for publication on the site.
  9. Submit the completed, PI-approved, Protocol Record by clicking on "Complete". The completed template will go electronically to the UConn PRS Administrator. It is at this point that the Administrator will send a paper copy to the PI for sign-off, as described above in #8. The PRS Administrator will verify IRB Approval. After receipt of PI sign-off and confirmation of IRB approval, the Administrator will approve and release the template to ClinicalTrials.gov.

IMPORTANT NOTE: The PI, or PI designee, is responsible for updating the Protocol Record within 30 days of any changes made to the study, e.g., changes in recruitment status, protocol revisions, contact information, etc. The PI, or designee, is also responsible for verifying the Protocol Record at least once every six months while the study is active ( even if there have been no changes) and annually after the study has been completed. As a courtesy, for active studies at UConn, the UConn PRS Administrator will notify the User at 5 months that the Protocol Record is due to be updated in the next 30 days. For completed studies, the Administrator will notify the User at 11 months that the Protocol Record is due to be updated in the next 30 days.

Does the registration posting need review by the IRB?


No. The UConn PRS Administrator will verify IRB approval for each study in order to submit that documentation to ClinicalTrials.gov, but the UConn IRB will not review the postings.

Who do I contact if I have questions?


Contact Doug Bradway, PRS Administrator, at 860-486-0986 or doug.bradway@uconn.edu.

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 about the FDA Amendments Act of 2007, see:
Guidance from the NIH Office of Extramural Research (opens as a .pdf document)

NIH Fact Sheet
AAMC memorandum

For more information about the Results Registration System see:https://register.clinicaltrials.gov/prs/html/whats-new.html
To receive notification of future draft FDAAA 801 documents, join the NIH FDAAA Update LISTSERV at: https://list.nih.gov/cgi-bin/wa?SUBED1=fdaaa-update-l&A=1

The University of Connecticut gratefully acknowledges the education and support provided by Judie Fine at the UConn Health Center, Office of Clinical and Translational Research.