Clinical trial requirements

Introduction

Biomedical or social/behavioral research is considered a "clinical trial" when it meets certain criteria, which typically involve:

• Prospective assignment of participants to one or more interventions (which may include placebo or other control);
• Evaluation of the effects of the interventions on biomedical or behavioral health-related outcomes.

The precise definition of clinical trial differs across federal regulations, policies, and other sources. Investigators should be aware that studies that meet the definition of clinical trial may be subject to additional regulatory and/or policy requirements, such as posting of consent forms on federal websites or registration of clinical trials on designated websites and reporting of study results. Clinical investigations may also meet the FDA definition of “applicable clinical trial,” in which case they must follow the agency’s trial registration and results reporting requirements.

There are multiple of factors (e.g., study design, purpose, funding source, intended publication outlet, etc.) that determine which requirements are applicable to a particular trial. Researchers are encouraged to familiarize themselves with the clinical trial requirements described below, and to seek assistance from Research Integrity staff for further guidance prior to commencing research activities.

Posting of consent forms for federally-funded clinical trials

All federally-funded studies approved by the IRB on or after January 21, 2019 must comply with the requirements at 45 CFR 46 (i.e., the Revised Common Rule). The Revised Common Rule includes a requirement specific to clinical trials to post an informed consent form used to enroll participants on a publicly available website.

What studies are subject to this requirement?

A study involves the recruitment of school children to evaluate two different tools for monitoring food intake. Food consumption behavior will be measured by asking children to activate a pocket camera during meals and to use a diary to record consumed food. Changes to eating behavior will be assessed.

Who is responsible for posting?

Adherence to the posting requirement is the responsibility of the awardee. For federally-funded projects where the University is the only awardee, the University Principal Investigator (PI) bears the responsibility of ensuring the requirement for posting of the consent form is met.

For multi-site research, generally the prime awardee is considered the responsible party and must ensure compliance with the posting requirement.

Where must the consent form be posted?

The consent form must be posted on a publicly available website approved for such posting. Currently there are two federal websites that will satisfy this requirement:

• ClinicalTrials.gov
• Regulations.gov (Docket ID: HHS-OPHS-2018-0021)

When must the posting occur?

The informed consent form must be posted on the federal website after the clinical trial is closed to recruitment, and no later than 60 days after the last study visit by any participant.

How do I know which consent version to post?

The Revised Common Rule requires that the version of the consent document that is posted must have been IRB-approved and used to enroll a participant in the clinical trial.

Registration and reporting of clinical trial results: Overview

ClinicalTrials.gov is a publicly available registry and results database administered by the National Library of Medicine. The site was created in 2000 as a result of the Food and Drug Administration Modernization Act of 1997 (FDAMA), and was meant to provide increased stewardship, transparency, and access to research and research results. Although posting requirements have been in place since that time for most FDA-regulated trials, they were significantly expanded on January 18, 2017. The revised requirements also apply to trials funded by NIH, whether or not they are FDA-regulated. The trials must be registered when they begin, the record must be updated throughout the study, and results must be provided when the study ends. Significant penalties can be applied by the agencies if these requirements are not met, including loss of an investigator’s ongoing or pending grant funding. In addition, many scientific journals have stated that they will not publish clinical trials that have not registered at ClinicalTrials.gov.

Registration and reporting of clinical trial results required by FDA regulations

Some studies are required to be registered at ClinicalTrials.gov in accordance with the federal regulations in Section 801 of the Food and Drug Administration Amendments Act (FDAAA 801) as implemented by 42 CFR Part 11 (i.e., the Final Rule for Clinical Trials Registration and Results Information Submission).

What studies are subject to this requirement?

Clinical trials that are subject to registration requirements are called applicable clinical trials. The following types of studies are considered to be applicable clinical trials:

• Applicable drug clinical trials (i.e., trials of drugs and biologics): controlled clinical investigations, other than Phase 1 investigations, of a product subject to FDA regulation.
• Applicable device clinical trials (i.e., trials of biomedical devices): controlled trials with health outcomes of devices subject to FDA regulation, other than small feasibility studies, and pediatric post-market surveillance.

Who is responsible for registering the applicable clinical trial?

A University or Affiliate investigator conducting an applicable clinical trial must comply with the registration requirements if:

• She or he is the Principal Investigator (PI), AND
• The clinical trial is not an industry trial whose protocol is developed, owned, and sponsored by a company. (Industry sponsors are responsible for registering their trials.)

Where must the applicable clinical trial be registered?

Clinical trial information for applicable clinical trials must be made publicly available via ClinicalTrials.gov, the Internet-accessible clinical trial registry and results data bank established by the National Library of Medicine at ClinicalTrials.gov.

When must the registration and results reporting occur?

• Initial registration: No later than 21 days after enrollment of the first participant.
• Interim updates: The record must be updated at least once a year (even if nothing has changed) until final results are reported. Certain types of changes must be reported within 30 days.
• Results reporting: No later than 12 months after the primary completion date (i.e., the last participant visit).

Consent form statement

For all applicable clinical trials registered on ClinicalTrials.gov, the regulations at 21 CFR 50 section 50.25 require the trial consent form(s) to include the following statement, without revision:

A description of this clinical trial will be available on https://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.

Potential consequences of noncompliance

• Identifying clinical trial record as non-compliant in ClinicalTrials.gov;
• For federally funded trials, grant funding can be withheld if required reporting cannot be verified;
• Civil monetary penalties of up to $10,000/day (amount to be adjusted going forward).

Registration and reporting of clinical trial results required by NIH policy

Investigators who plan to apply for NIH funding are advised to contact Research Integrity to determine whether their study could be considered a clinical trial. This is important because certain NIH Funding Opportunity Announcements (FOAs) are applicable only to clinical trials or non-clinical trials; applying for the wrong FOA will make the submission ineligible for funding. The NIH clinical trials website includes case studies, FAQs and a decision tool to help researchers understand the NIH definition of clinical trial.

What studies are subject to this requirement?

Clinical trials funded in whole or in part by the National Institutes of Health (NIH) in response to any type of application for funding (including competing renewals) submitted on or after January 18, 2017.

NIH Definition of a Clinical Trial: A research study in which one or more human subjects are prospectively assigned to one or more interventions (which may include placebo or other control) to evaluate the effects of those interventions on health-related biomedical or behavioral outcomes.

Criteria that define if a study is a clinical trial

1. Does the study involve human participants?
2. Are the participants prospectively assigned to an intervention*?
3. Is the study designed to evaluate the effect of the intervention on the participants?
4. Is the effect being evaluated a health-related biomedical or behavioral outcome?

*An 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. A manipulation or task is an intervention if it is used to modify a health-related biomedical or behavioral outcome. However, a manipulation or task used expressly for measurement, and not modification, would not be an intervention. 

An answer of "yes" to all questions means your study is a clinical trial, even if...

• You are studying healthy participants
• Your study does not have a comparison group (e.g., placebo or control)
• Your study is only designed to assess the pharmacokinetics, safety, and/or maximum tolerated dose of an investigational drug
• Your study is utilizing a behavioral intervention

Examples of studies that are clinical trials

A study involves the recruitment of healthy volunteers to test a new behavioral intervention. It is designed to evaluate the effect of a meditation intervention on adherence to exercise regimens and quality of life to inform the design of a subsequent, fully-powered trial.

• Does the study involve human participants? Yes, study participants are human participants.
• Are the participants prospectively assigned to an intervention? Yes, the participants are prospectively assigned to a behavioral intervention.
• Is the study designed to evaluate the effect of the intervention on the participants? Yes, the study is designed to evaluate the effect of the intervention on adherence, and quality of life.
• Is the effect being evaluated a health-related biomedical or behavioral outcome? Yes, adherence and quality of life are health-related outcomes.

A study involves the recruitment of school children to evaluate two different tools for monitoring food intake. Food consumption behavior will be measured by asking children to activate a pocket camera during meals and to use a diary to record consumed food. Changes to eating behavior will be assessed.

• Does the study involve human participants? Yes, children are human participants.
• Are the participants prospectively assigned to an intervention? Yes, the participants are prospectively assigned to two food monitoring methods.
• Is the study designed to evaluate the effect of the intervention on the participants? Yes, the study is designed to determine whether using the monitoring methods changes eating behavior.
• Is the effect being evaluated a health-related biomedical or behavioral outcome? Yes, eating behavior is a health-related outcome.

Who is responsible for registering the NIH-funded clinical trial?

A University or Affiliate investigator conducting an applicable clinical trial must comply with the registration requirements if:

• She or he is the Principal Investigator (PI), AND
• The clinical trial is not an industry trial whose protocol is developed, owned, and sponsored by a company. (Industry sponsors are responsible for registering their trials.)

Where must the NIH-funded clinical trial be registered?

Clinical trial information for applicable clinical trials must be made publicly available via ClinicalTrials.gov, the Internet-accessible clinical trial registry and results data bank established by the National Library of Medicine at ClinicalTrials.gov.

When must the registration and results reporting occur?

• Initial registration: No later than 21 days after enrollment of the first participant.
• Interim updates: The record must be updated at least once a year (even if nothing has changed) until final results are reported. Certain types of changes must be reported within 30 days.
• Results reporting: No later than 12 months after the primary completion date (i.e., the last participant visit).

Potential consequences of noncompliance

• May lead to suspension or termination of grant or contract funding;
• Can be considered in future funding decisions;
• Identifying clinical trial record as non-compliant in ClinicalTrials.gov.

Registration and reporting of clinical trial results required by ICMJE policy

Many journals have editorial policies regarding registration of clinical trials in online registries that include, but are not limited to, ClinicalTrials.gov. For example, over 1,000 journals follow the recommendations of the International Committee of Medical Journal Editors (ICMJE), which requires trial registration as a condition for the publication of research results generated by a clinical trial. Journals that do not adopt ICMJE recommendations may still have an editorial policy for clinical trial registration.

The purpose of clinical trial registration is to prevent selective publication and selective reporting of research outcomes, to prevent unnecessary duplication of research effort, to help patients and the public know what trials are planned or ongoing into which they might want to enroll, and to help give ethics review boards considering approval of new studies a view of similar work and data relevant to the research they are considering. Retrospective registration, for example at the time of manuscript submission, meets none of these purposes and therefore is not deemed acceptable.

What studies are subject to this requirement?

The ICMJE defines a clinical trial as 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 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, behavioral 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.

Who is responsible for registering the clinical trial?

A University or Affiliate investigator conducting an applicable clinical trial must comply with the registration requirements if:

• She or he is the Principal Investigator (PI), AND
• The clinical trial is not an industry trial whose protocol is developed, owned, and sponsored by a company. (Industry sponsors are responsible for registering their trials.)

Where must the clinical trial be registered?

The ICMJE accepts registration in the following registries:

• anzctr.org.au
• ClinicalTrials.gov
• ISRCTN.org
• umin.ac.jp/ctr/index/htm
• eudract.ema.europa.eu/

In addition to the above registries, ICMJE also accepts registration in any of the primary registries that participate in the WHO International Clinical Trials Portal.

When must the registration and results reporting occur?

• Initial registration: Prior to enrollment of first participant.
• Interim updates: The record must be updated at least once a year (even if nothing has changed) until final results are reported. Certain types of changes must be reported within 30 days.
• Results reporting: Not mandated in policy, but must meet the requirements of FDAAA 801.

Potential consequences of noncompliance

• Inability to publish in ICMJE or affiliated journal