ClinicalTrials.gov Standard Operating Procedures
UConn is committed to compliance with the regulations of the Food and Drug Administration, National Institutes of Health and International Committee of Medical Journal Editors in supporting Principal Investigators (PIs) with meeting the requirements concerning the public availability of clinical trial data in ClinicalTrials.gov.
For registration purposes, how is “clinical trial” defined and what are the registration deadlines?
According to NIH policy:
A clinical trial is a research study1 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: The NIH Policy on Dissemination of NIH-funded Clinical Trial Information applies to applications for funding submitted to NIH on or after 1/18/17. Registration is required no later than 21 days after the first patient is enrolled. The consent form for the trial is required to include the following language: “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.”
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:
- Trials of drugs and biologics: Controlled, clinical investigations, other than Phase I investigations, of a product subject to FDA regulation, and
- 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.
Who is responsible for registering a trial?
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.
The following types of trials will need to be registered by the PI:
- NIH-sponsored trials should 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.
Some clinical trials may 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.
For registration instructions at UConn, see Registration.
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. 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. A 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 can help with questions about meeting the requirements?
Please contact the local Protocol Registration and Results System (PRS) Administrator for UConn, Ellen Ciesielski, Office of the Vice President for Research, Research Compliance Services at 860-679-6004 for any questions related to ClinicalTrials.gov. The PRS Administrator serves as a point of contact for resolving requests by ClinicalTrials.gov and regularly monitors to promote compliance with the requirements.