Frequently Asked Questions - Mechanistic Clinical Trials

Q1. What is a “mechanistic clinical trial”?

A1. The NIH defines a clinical trial as:

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. (NOT-OD-15-015)

A mechanistic clinical trial is designed to understand, in humans, a biological or behavioral process, the pathophysiology of a disease, or the mechanism of action of an intervention*. (NOT-HL-19-690)

*For dissemination and implementation science, please consider NHLBI’s use of the term “intervention” to be synonymous with “implementation strategy,” or a systematic intervention process to adopt and integrate evidence-based health innovations into usual care.

Resources:

NIH Definition of a Clinical Trial and Decision Tool (tool for deciding whether a study meets the NIH definition of a clinical trial)

NIH Definition of Clinical Trial Case Studies

Q2. How does the NHLBI accept applications for mechanistic clinical trials?

A2. Investigator-initiated applications for mechanistic clinical trials may be submitted to the parent NIH R01 (Clinical Trial Required) Notice of Funding Opportunity (NOFO) (PA-20-183). Per a companion notice (NOT-HL-19-690) that NHLBI published in conjunction with this NOFO, NHLBI will only accept under this NOFO applications that meet the NHLBI definition of a mechanistic clinical trial. Applications for funding other types of clinical trials must be submitted in response to an NHLBI-published NOFO designed specifically for other types of trials (such as Early Phase, Single-site in Phase II and beyond, and Multi-site in Phase II and beyond – please reference our page on the Clinical Trial Development Continuum).

Q3. What is a “parent” notice of funding opportunity (such as the “parent” NIH R01) referenced above?

A3. Parent announcements are broad notices of funding opportunities issued centrally by NIH allowing applicants to submit investigator-initiated applications for specific activity codes. They are open for up to 3 years and use standard due dates. In contrast, individual ICs may issue their own NOFOs when they are soliciting applications for particular types of research or for research that has special requirements.

Q4. I am submitting an application for research that includes both a clinical trial and a number of basic research aims. Under what circumstances would this type of project with mixed clinical and basic science research aims be appropriate for one of the NHLBI NOFOs for clinical trials as opposed to the NIH Parent R01 (clinical trial required)?

A4. Only the NHLBI NOFO for multi-site clinical trials or the NOFO for single-site clinical trials are appropriate if the clinical trial that you are proposing is aimed at testing the safety and effectiveness of a clinical product, and is in Phase II or above. Associated research questions closely related to the aims of the clinical trial, such as understanding the intervention’s effects or the varied response of the participants to the intervention, are permitted as secondary aims under the NHLBI CT NOFOs.

However, if the study includes a mechanistic clinical trial, then it may be more appropriate to apply for funding under the NIH parent R01.

For dissemination and implementation studies that include a mix of clinical and methodological aims, consider the Dissemination and Implementation Research in Health NIH Parent R01 (Clinical Trial Optional).

You are strongly encouraged to discuss your application with your program officer for further guidance.

Q5. Does the review process differ for applications submitted in response to the NIH Parent R01 NOFO as compared to those submitted in response to an NHLBI clinical trial NOFO?

A5. Yes. Applications submitted to the NIH Parent R01 NOFO will be reviewed by a study section assembled by the NIH Center for Scientific Review. Applications submitted in response to an NHLBI NOFO will be reviewed by a primary (scientific) review group that NHLBI organizes. The focus of the review for mechanistic clinical trials is on the scientific question while for clinical trials the review focus is on the clinical trial itself (study design, outcomes, etc.).

Q6. Is there a limitation on the budget or project period when mechanistic trials are funded through the Parent R01?

A6. As is true of all R01 awards, application budgets are not limited but need to reflect the actual needs of the proposed project. The scope of the proposed project should determine the project period. Applications requesting $500,000 or more in direct cost in any year are required to obtain documented approval from the Institute stating that it will accept the application for initial peer review (https://www.nhlbi.nih.gov/grants-and-training/policies-and-guidelines/applications-with-direct-costs-of-500000-or-more-in-any-one-year). R01s are funded for 4 years unless they meet one of the exceptions mentioned in the NHLBI Funding and Operating Guidelines.

Q7. How can I tell if my study is a mechanistic clinical trial?

A7. This can be a difficult distinction, since some mechanistic clinical trials use general designs that are similar to those used for efficacy studies. In evaluating whether a particular study qualifies as a mechanistic clinical trial, NHLBI staff consider the study design in the context of the stated objective of the study and what may already be known about the mechanism of action and efficacy of the intervention. Examples of possible mechanistic studies include:

1. Studies to understand a biological or behavioral process that involves an intervention with a known mechanism of action; these studies could be performed in normal human subjects.
2. Studies to understand the pathophysiology of a disease typically involve outcome measures that are highly specific for particular biological pathways or processes.
3. Studies to understand health effects of products and behavioral interventions not being studied as clinical treatments.  Examples may include tobacco and cannabis interventions, sleep deprivation protocols, or high fat or sodium dietary interventions where the goal is to understand a biological process rather than to treat a condition.
4. Studies to understand the mechanism of action of an intervention may resemble a therapeutic clinical trial with regard to the population being studied, the intervention, outcome measures, and overall design. Nevertheless, these studies can be distinguished from efficacy trials by critical design details that should be evident in the grant application. These details include:
   1. A clearly stated hypothesis distinguishing between alternative mechanisms of action or testing the importance of a single, hypothesized mechanism of action,
   2. An argument for Significance that is based on a need to understand the intervention’s mechanism(s) of action prior to the next logical step as an efficacy or effectiveness study.
   3. Measurement of outcomes that can distinguish different mechanisms of action,
   4. A precisely defined plan for statistical analysis that tests the stated hypothesis, and
   5. A sample size that is justified and adequate to inform mechanism of action.

Q8. How do I proceed with dissemination and implementation research mechanistic clinical trials?

A8. Dissemination and implementation (D&I) research studies with the primary goal to understand how the implementation strategy, or intervention, works (i.e., its mechanism of action) are appropriate under the parent NIH R01 (Clinical Trial Required) Notice of Funding Opportunity (NOFO) (PA-20-183) as described above for mechanistic clinical trials. An example of this would be an experimental manipulation of audit and feedback (i.e., an implementation strategy) in a 2-arm trial to compare performance relative to target (arm 1) to performance relative to peers (arm 2) to isolate the mechanism of change. However, D&I research studies, including clinical trials and those that seek to study mechanisms of implementation strategies, are appropriate under the NIH R01 (Clinical Trial Optional) Notice of Funding Opportunity (NOFO) (PAR-22-105). Submitting to the D&I PAR increases the likelihood that your application is scrutinized by those with substantive expertise from the point of administrative review for adherence to NOFO requirements to possible scientific review by Science of Implementation in Health and Healthcare.

Case studies of mechanistic clinical trials may be found at https://grants.nih.gov/policy/clinical-trials/case-studies.htm#collapseS2_NIDDK_8

Grant applicants are strongly encouraged to review the synopsis of their proposals/specific aims and discuss the above issues with the appropriate NHLBI program staff/scientific contact prior to submitting an R01 application for support of a mechanistic clinical trial. Please also note that special procedures are required for mechanistic clinical trial applications with direct costs greater than $500,000 in any given year. For detailed information, prospective applicants should always refer to Section IV (Application and Submission Information) of the individual NOFO (notice of funding opportunity).