Career Development Programs (K-Series)

NIMH has published updated policies and guidance for investigators regarding human research protection and clinical research data and safety monitoring (NOT-MH-19-027 ). The application’s Protection of Human Subjects section and Data and Safety Monitoring Plan should reflect the policies and guidance in this notice. Plans for the protection of research subjects and data and safety monitoring will be reviewed by NIMH for consistency with NIMH and NIH policies and federal regulations. NIMH requires reporting of recruitment milestones for extramural-funded clinical research studies proposing to enroll 150 or more participants per study, and all clinical trials, regardless of the number of participants, as noted in NOT-MH-19-027 . This expectation will be stated in the NoA.

NIMH expects the registration and results reporting for all NIMH-supported clinical trials, regardless of whether they are subject to FDAAA (see Requirements for Registering & Reporting NIH-funded Clinical Trials in ClinicalTrials.gov ). This expectation will be stated in the NoA.

General NIH clinical trial information

The NIH definition of a clinical trial  was revised in 2014 in anticipation of stewardship reforms to ensure a clear and responsive definition of a clinical trial. 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 ). 

The NIH definition of a clinical trial applies to a wide range of clinical trials (mechanistic, exploratory/development, pilot/feasibility, interventional, behavioral). Many clinical studies that were not considered to be clinical trials under the pre-2014 classification scheme now fall under the revised NIH definition of a clinical trial. Resources (case studies , FAQs , and a decision tool ) are available to help applicants determine if their clinical study is considered to be a NIH-defined clinical trial.

NIH requires that all applications involving one or more independent clinical trials be submitted through a Notice of Funding Opportunity (NOFO) specifically designated as ‘Clinical Trial Required’, ‘Clinical Trial Optional’, or ‘Basic Experimental Studies with Humans’ (see Clinical Trial-Specific Funding Opportunities ).  

NIMH information on clinical trials

The following guidance is for individuals developing NIMH mentored research career development award (K99/R00, K01, K08, K23) applications in the area of intervention development and testing, as well as research focusing on the effectiveness of therapeutic, preventive, and services interventions. It is important that mentored career development applicants conducting intervention research develop their research plans to be consistent with the NIMH emphasis on an experimental therapeutics approach to intervention development and testing (see Support for Clinical Trials at NIMH). 

In this approach, throughout all phases of intervention development and testing (i.e., from the development of novel interventions through effectiveness testing) projects should be designed to assess the relationship between underlying disease processes and the mechanisms of action through which an intervention produces therapeutic change. 

As part of this approach, applications must include an examination of a hypothesized mechanism of action or proximal target based on evidence of disease processes and a clear hypothesis about how an intervention directed at changing that mechanism or proximal target could lead to improvement of a clinical endpoint or endpoints (e.g., symptom, symptom cluster), as well as address issues of safety and tolerability. For a more complete description of abovementioned approaches, applicants are strongly encouraged to review the associated NIMH funding opportunity announcements listed below.

The structure and budgetary constraints associated with a mentored career development award will limit the scope of the research that can be achieved. Applicants will need to thoughtfully balance the feasibility of developing their project within these constraints. Potential approaches may include:

1. Studies testing whether a novel intervention engages and alters the hypothesized mechanism of action or proximal target. Within this context, the term “target” refers to a factor that an intervention intends to modify, based on a hypothesis that modification of that factor will result in improvement of symptoms, behavior, or functional outcomes. The specific activities and milestones appropriate for the mentored career development award application focusing on target engagement and evaluation will depend on the type of intervention (behavioral, drug, and/or device) under study and its stage of development. Applicants should consider assessing target engagement and change using multiple units of analysis (e.g., genetic, neural circuits, physiology, behavior, self-report, etc.). Determining which units of analysis to use will depend on the scientific hypothesis proposed, and scientific feasibility.
2. Studies using a phased approach where phase 1 would support the testing and validating of the intervention’s mechanism of action (i.e., target identification and engagement), followed by additional studies relating the mechanism of action to functional or clinical effects (phase 2). Studies not using a phased approach must still include a mechanism of action (i.e., treatment target) as part of the study. Applicants that do not propose assessment of a mechanism of action and its engagement as part of the research protocol will be viewed as low program priority with the new NIMH intervention development requirements. For a more complete description of this phased intervention development approach for a mentored career development award please refer to the R61/R33 information on the Clinical Trials Funding Opportunity Announcements – Applicant Information page .
3. Pilot Studies of novel interventions, where there is already evidence of target engagement, for an evaluation of feasibility and acceptability of the intervention in a patient population, as well an evaluation of the relationship between change in the targeted mechanism and change in functional or clinical status. For a more complete description of this intervention approach for a mentored career development award please refer to the Development of Psychosocial Therapeutic and Preventive Interventions for Mental Disorders (R33 Clinical Trial Required) .
4. Research on the effectiveness of therapeutic, preventive, and services interventions (e.g., in broader target populations or community settings), including pilot studies that evaluate the feasibility and acceptability of approaches, as a pre-requisite to a larger-scale study, should be designed to explicitly address and re-confirm whether the intervention targets and associated change mechanisms identified under more controlled, efficacy conditions are operative in the effectiveness context. For a more complete description of this experimental approach please refer to Pilot Effectiveness Trials for Treatment, Preventive and Services Interventions (R34- Clinical Trial Required) .

For applications submitted after January 25, 2023, the NIH Data Management and Sharing (DMS) policy  applies to some career development awards (e.g., K01, K08, K23, K99, K22). Under the DMS policy, NIH expects investigators and institutions to plan and budget for the managing and sharing of data, submit a DMS plan for review when applying for funding, and comply with the approved DMS plan (see the 2023 Final NIH Policy for Data Management and Sharing  and Data Management and Sharing Resource page ).

The NIMH data sharing policy is detailed in NOT-MH-23-100 , and additional information for applicants and awardees can be found on the NIMH Data Management and Sharing for Applicants and Awardees website. Of note, K awardees are not required to deposit their data into the NIMH Data Archive.