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ClinicalTrials.gov Requirements

iStock_000010875743XSmallFor registration purposes, how is “clinical trial” defined and what are the registration deadlines?

According to NIH policy:

A clinical trial is a research study in which one or more human subjects2 are prospectively assigned3 to one or more interventions4 (which may include placebo or other control) to evaluate the effects of those interventions on health-related biomedical or behavioral outcomes.5  All clinical trials must be registered within 21 days of enrollment of the first participant.

1See Common Rule definition of research at 45 CFR 46.102(d).

2See Common Rule definition of human subject at 45 CFR 46.102(f).

3The term “prospectively assigned” refers to a pre-defined process (e.g., randomization) specified in an approved protocol that stipulates the assignment of research subjects (individually or in clusters) to one or more arms (e.g., intervention, placebo, or other control) of a clinical trial.

4An intervention is defined as a manipulation of the subject or subject’s environment for the purpose of modifying one or more health-related biomedical or behavioral processes and/or endpoints.  Examples include:  drugs/small molecules/compounds; biologics; devices; procedures (e.g., surgical techniques); delivery systems (e.g., telemedicine, face-to-face interviews); strategies to change health-related behavior (e.g., diet, cognitive therapy, exercise, development of new habits); treatment strategies; prevention strategies; and, diagnostic strategies.

5Health-related biomedical or behavioral outcome is defined as the pre-specified goal(s) or condition(s) that reflect the effect of one or more interventions on human subjects’ biomedical or behavioral status or quality of life.  Examples include:  positive or negative changes to physiological or biological parameters (e.g., improvement of lung capacity, gene expression); positive or negative changes to psychological or neurodevelopmental parameters (e.g., mood management intervention for smokers; reading comprehension and /or information retention); positive or negative changes to disease processes; positive or negative changes to health-related behaviors; and, positive or negative changes to quality of life.

Registration Start Date: No later than 21 days after the first patient is enrolled.

According to the ICMJE:

A clinical trial is any research project that prospectively assigns people or a group of people to an intervention, with or without concurrent comparison or control groups, to study the cause-and-effect relationship between a health-related intervention and a health outcome. Health-related interventions are those used to modify a biomedical or health-related outcome; examples include drugs, surgical procedures, devices, behavioural treatments, educational programs, dietary interventions, quality improvement interventions, and process-of-care changes. Health outcomes are any biomedical or health-related measures obtained in patients or participants, including pharmacokinetic measures and adverse events.

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:

The U.S. Department of Health and Human Services in September 2016 issued a final rule that specifies requirements for registering certain clinical trials and submitting summary results information to ClinicalTrials.gov. The new rule expands the legal requirements for submitting registration and results information for clinical trials involving U.S. Food and Drug Administration-regulated drug, biological, and device products. 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 no later than 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:

Penalties may include civil monetary penalties up to $11,383 fine for failing to submit or for submitting fraudulent information to ClinicalTrials.gov. After notification of noncompliance, the fine may go up to $11,383 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.

  • 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.

  • NIH-sponsored trials should normally 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 Registration.

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.

How is UConn Health involved?

UConn Health 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 Health, the PRS Administrator is Ellen Ciesielski, Office of the Vice President for Research, Research Compliance Services at 860-679-6004.