Determine Whether NIH Considers Your Mechanistic Study a Clinical Trial

Funding News Edition: November 01, 2017
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Beyond trials of safety and efficacy, NIH supports mechanistic exploratory studies that qualify as clinical trials and seek to understand a biological or behavioral process, the pathophysiology of a disease, or the mechanism of action of an intervention.

Credit: NIAID

Beginning with applications due on or after January 25, 2018, NIH is implementing policy changes to the application and reporting requirements for awards that include clinical trials (CTs).

Because of these changes, some studies that were not considered CTs in the past will be going forward. Deciding whether a study is or isn’t a CT should not be the result of a scientific judgement call or even based on your prior experience. Rather, it should be determined using the Decision Tree for NIH Clinical Trial Definition, which we explain below.

For mechanistic studies specifically, you’ll need to pay close attention to the purpose of the research intervention.

Four Key Questions Determine CT Designation

A research study is a CT if all the following four questions are answered “yes.”

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

Answering “no” to any of these questions means, by the NIH definition, the study is not a CT.

These questions contain terminology—human participants, prospective assignment, intervention, health-related biomedical or behavioral outcome—that may mislead you if you aren’t mindful of how NIH defines them.

Human Participants

This aspect is fairly straightforward, but remember that the designation does not apply to secondary studies using existing unidentifiable biological specimens, data collected without identifiers, or data that are publicly available.

Prospective Assignment

NIH refers here to a predefined 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 CT.

Randomization is not a requirement for a study to be a CT as long as the assignment of the research subjects is predefined. Note: a single-arm trial qualifies as a predefined assignment.


NIH defines intervention 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.”

If the study is designed to evaluate the effect of the intervention on the participants, then the study is a CT. If the study generates data that are not used to measure an effect on the participants but only to assign the participants to a group or category (e.g., disease severity), then the study is likely not a CT. Similarly, if the study is solely intended to generate data about the operational characteristics of a medical or diagnostic device (e.g., signal-to-noise ratio, receiver operating characteristic curves), then the study is also not a CT.

See Cases 7a and 7b at NIH Definition of Clinical Trial Case Studies for examples of when the use of an investigational device is and is not a CT. Then see Cases 8a, 8b, and 8c for examples of when the use of an approved diagnostic device is or is not a CT.

Thus, purpose is paramount. Evaluate whether the prospectively-assigned intervention is intended to make and evaluate a change in a biomedical/biobehavioral outcome. Otherwise, the manipulation is not an intervention.

Health-Related Biomedical or Behavioral Outcome

This refers to the prespecified goals or conditions that reflect the effect of one or more interventions on human subjects’ biomedical or behavioral status or quality of life.

That definition is broad and goes beyond efficacy of an intervention; for example, it includes safety outcomes.

Mechanistic Studies

NIH describes mechanistic studies as designed to understand a biological or behavioral process, the pathophysiology of a disease, or the mechanism of action of an intervention. Not all mechanistic studies are CTs, but many are.

To determine whether your research qualifies as a CT, proceed through the Decision Tree for NIH Clinical Trial Definition:

  • Are human participants involved?
  • Are they prospectively assigned to an intervention?
  • Is the study designed to evaluate the effect of the intervention on the participants?

This third question is critical for mechanistic studies. The intervention must have the purpose of causing a health-related change that will be measured—absent that, the proposed research likely does not meet the NIH definition of a CT.

For instance, an inhaled methacholine challenge (a manipulation) is needed to assign a human subject into a predefined group or category such as mild asthma versus severe asthma. Because the manipulation is not used for the purpose of modifying a health-related outcome, the manipulation itself is not an intervention that would qualify the research as a CT.

Conversely, a project that recruits participants to receive an intervention for the purpose of subsequent in vitro analysis of cells would be considered a CT because the analysis evaluates the effect of the intervention on the participants—even though the measurement is being made in vitro.

  • Is the effect being evaluated a health-related biomedical or behavioral outcome?

For a study designed to understand a disease mechanism, relying on an intervention to modify a health-related outcome will likely be considered a CT. However, absent an intervention, studying a biomedical outcome alone does not qualify the study as a CT.

In the October 25, 2017 Guide notice, NIH gave the following examples of mechanistic studies that likely qualify as clinical trials:

  • Studies that use a manipulation (physiological or behavioral) to answer basic science questions about normal functions.
  • Studies that use an experimental manipulation in order to understand normal functioning or the pathophysiology of a disease or disorder, but do not aim to demonstrate clinical improvement.
  • Studies that involve the prospective use of efficacious interventions where the intent is to obtain and analyze biospecimens to identify genetic risk associations, novel biomarkers, examine the disease process, or characterize mechanisms of therapeutic response.
  • Studies in which an intervention with demonstrated efficacy for a population is being studied to understand mechanisms of response, non-response, or risk of adverse effects of the efficacious intervention.

Completing the Application Forms

If your mechanistic study qualifies as a CT, you need to apply to an appropriate funding opportunity announcement (that is, one that accepts CTs) and complete section G.500 - PHS Human Subjects and Clinical Trials Information as part of your application.

This section requires you to submit documents that you may not have prepared for mechanistic studies in the past—a recruitment and retention plan, study timeline, data and safety monitoring plan, protocol summary, statistical design and power section, and more. Complete the forms to the extent appropriate for your research. For simple mechanistic studies, don’t overcomplicate the paperwork.

Keep in mind, the peer reviewers who assess your application will reference NIH’s New Review Criteria for Research Project Applications Involving Clinical Trials. These questions include:

  • For trials focusing on mechanistic, behavioral, physiological, biochemical, or other biomedical endpoints, is this trial needed to advance scientific understanding?
  • Are the study populations (size, gender, age, demographic group), proposed intervention arms/dose, and duration of the trial, appropriate and well justified?

If you’ve not thought of your mechanistic studies as CTs in the past, but the research meets the four criteria above, you need to shift your approach to the Research Strategy and application forms such that you address the concerns and guidelines NIH has laid out for CT research.

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