Support for Clinical Trials at NIMH
In 2014, NIH revised its definition of a clinical trial (see NOT-OD-15-015) and in 2015, launched a multi-faceted effort to enhance its stewardship over clinical trials (see NIH webpage on Clinical Trial Requirements for Grants and Contracts). All applicants conducting research on human subjects are encouraged to visit this webpage to better understand the definition of a clinical trial, new requirements for clinical trial research, and NIH strategies for implementation. Given the current NIH definition of clinical trials, some investigators are discovering that their human subjects research is now considered to fall under the NIH definition of a clinical trial and is subject to the NIH clinical trial requirements. This includes ‘Basic Experimental Studies with Humans’ (abbreviated BESH) which are studies that are defined as both “basic science research” and “NIH-defined Clinical Trials” (see below for more information).
NIH requires that all applications involving one or more independent clinical trials be submitted through a Funding Opportunity Announcement (FOA) specifically designated as ‘Clinical Trial Required’, ‘Clinical Trial Optional’, or ‘Basic Experimental Studies with Humans’. The content below provides an overview of how the NIMH approaches its clinical trial portfolio and provides links to relevant NIMH FOAs that support clinical trial research. General inquiries regarding NIMH clinical trials and/or the clinical trial FOAs may be submitted to NIMHClinicalTrials@mail.nih.gov.
NIH 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). Go to NIH’s Definition of a Clinical Trial webpage to learn more and to find out if your study meets the NIH definition of a clinical trial.
NIMH FOAs to Address the Safety, Efficacy, and Effectiveness of Preventive, Therapeutic, and Services Interventions
NIMH solicits clinical trial applications through a series of FOAs that cover the intervention development pipeline, from first-in-human, early testing of new interventions, confirmatory efficacy trials, through to effectiveness trials. If the goal of the clinical trial application is to establish the safety, clinical efficacy, effectiveness, clinical management and/or implementation of preventive, therapeutic, or therapeutic interventions, the application must be submitted in response to one of the FOAs as outlined in the Clinical Trial Pipeline - Phase of Intervention Development below. Applications that involve clinical trials to establish safety, clinical efficacy, effectiveness, clinical management and/or implementation of interventions should NOT be submitted under the NIH Parent FOAs for clinical trials and, if done so, will be returned without review.
NIMH requires an experimental therapeutics approach (see Clinical Trials – Applicant FAQs, Q3) for the development and testing of therapeutic, preventive, and services interventions, in which the studies evaluate not only the clinical effect of the intervention, but also generate information about the mechanisms underlying a disorder or an intervention response. Studies proposed under these FOAs must clearly identify a target or mediator of the intervention being tested. A positive result will require that an intervention improves clinical outcomes and has a demonstrable effect on a target, such as a neural pathway, a key cognitive operation, interpersonal or contextual factor that is hypothesized to mediate the intervention’s effect, etc.
The NIMH FOAs for therapeutic, preventive, and services interventions support a wide range of intervention modalities: cognitive, behavioral, and other psychosocial approaches, psychopharmacological interventions, and interventions utilizing direct brain modulation/stimulation. The choice of targets, measures, and clinical endpoints will vary with the intervention modality. Applicants should carefully read the FOA to which they are responding and the Clinical Trials — Applicant FAQs for more detail on the expectations for specific intervention modalities. Applicants are strongly encouraged to contact a Scientific/Research Contact listed at the end of the relevant FOA to discuss the FOA and NIMH priorities.
|First in Human||Exploratory Experimental Therapeutics||Confirmatory Efficacy||Effectiveness (Prevention, Treatment, Services)|
First in Human and Early Stage Clinical Trials of Novel Investigational Drugs or Devices for Psychiatric Disorders (U01 - Clinical Trial Required)
Pilot Effectiveness Trials for Treatment, Preventive and Services Interventions (R34 - Clinical Trial Required)
Confirmatory Efficacy Clinical Trials of Non-Pharmacological Interventions for Mental Disorders (R01 Clinical Trial Required)
Limited NIMH Participation on Parent Research Grant FOAs are to Accommodate Mechanistic Clinical Trials
NIMH utilizes the NIH Parent R01 Clinical Trial Required, the NIH Parent R21 Clinical Trial Required, the NIH Parent R01 Basic Experimental Studies with Humans, and the NIH Parent R21 Basic Experimental Studies with Humans to accept only “mechanistic” clinical trial applications (see below for descriptors of “mechanistic” clinical trials).
The Basic Experimental Studies with Humans (BESH) FOAs are parent FOAs for studies that fall within the NIH definition of a clinical trial and also meet the definition of basic research, as described in NIH Guide Notice NOT-OD-19-024. Applicants proposing Basic Experimental Studies with Humans (BESH) are required to complete the full Human Subjects and Clinical Trial Information in the application form and to register and report results.
NIMH Support of Mechanistic Clinical Trials: NIH defines a mechanistic clinical trial as a study “designed to understand a biological or behavioral process, the pathophysiology of a disease, or the mechanism of action of an intervention.” NIMH supports mechanistic clinical trials that focus on biomarker studies that may provide information about physiological function, target engagement of therapeutics, and/or the impact of therapeutic responses. These types of studies do not have as a primary aim to establish the efficacy or effectiveness of the intervention.
NIMH considers two major categories of mechanistic trials (though there may be others):
- Mechanistic clinical trials using an intervention of known efficacy. These clinical trials utilize an efficacious intervention to investigate the pathophysiology, and/or psychopathology of mental disorders or the mechanisms of therapeutic responses; and to advance biomarkers of basic neurobiological processes. In such studies: (1) the primary aims do not involve establishing efficacy/effectiveness, and (2) the intervention chosen has already been demonstrated to have efficacy. These trials must be submitted under the NIH Parent R01 Clinical Trial Required or the NIH Parent R21 Clinical Trial Required
- Mechanistic clinical trials utilizing an experimental manipulation: These studies utilize experimental manipulation and are primarily focused on understanding brain function in healthy individuals or those with disorders by measuring responses to the experimental manipulation. Most of these mechanistic studies are expected to be responsive to the BESH FOAs (described above) since they are not intended to inform on the improvement of the health status of the individual or a group of individuals either by better understanding the mechanism of action of an intervention or a measurable improvement in health.
See the “Consolidated Notice on NIMH Clinical Trials Policies,” NOT-MH-20-105, for a summary of NIMH’s polices on support for mechanistic and other clinical trials.
Selected Other Clinical Trial FOAs
NIMH also participates on selected FOAs that seek or allow clinical trial applications, some of which include other grant mechanisms than noted above. Applications submitted to NIMH via these FOAs are expected to comport with NIMH’s experimental therapeutics approach.
These FOAs include:
- Announcements from other NIH Institutes or Centers (on which NIMH participates)
- Career (K) FOAs that accept independent clinical trials or Basic Experimental Studies with Humans (on which NIMH participates; see NIMH guidance for K applicants proposing Clinical Trials)
- Small Business Innovation Research (SBIR) and Small Business Technology Transfer (STTR) FOAs
A current listing of these FOAs can be found on the NIMH Funding Opportunities & Announcements webpage.
Additional Resources for Applicants
- Visit the National Database for Clinical Trials (NDCT).
- Visit the Clinical Research page for links to policies governing human subjects research safety and monitoring.
- View the Webinar: PHS Human Subjects and Clinical Trials Information Form Walk-through.
- Visit the NIH/NIMH Therapeutics Discovery Research page for links to NIMH programs and resources related to therapeutic discovery and development, as well as complementary programs available through broader NIH efforts.
- Gordon J. NIMH Director’s Messages: An Experimental Therapeutic Approach to Psychosocial Interventions. National Institute of Mental Health. March 20, 2017.
- Gogtay N and Insel T. NIMH Clinical Trials: Portfolio, Progress to Date, and the Road Forward. National Institute of Mental Health. 2015.
- Insel TR and Gogtay N. National Institute of Mental Health Clinical Trials: New Opportunities, New Expectations. JAMA Psychiatry . 2014 May 7.
- Insel TR. A New Approach to Clinical Trials. National Institute of Mental Health. February 27, 2014.
Published Guide Notices
- NOT-MH-19-006 (December 21, 2018) - NIMH Acceptance of Clinical Trial Applications under the Parent R01 and R21 Clinical Trial Required, or Basic Experimental Studies Involving Humans (BESH) Announcements is Limited to Mechanistic Clinical Trials
- NOT-MH-17-044 (August 17, 2017) - Notice of NIMH's Interest in Pediatric Pharmacologic Trials in Autism Spectrum Disorders, directed at testing selective GABAergic agents
- NOT-MH-17-039 (July 24, 2017) - Notice of NIMH's Interest to Highlight High-Priority Pediatric Pharmacologic Trial Research Areas
- NOT-MH-15-012 (March 17, 2015) - Data Sharing Expectations for Clinical Research Funded by NIMH
- NOT-MH-15-009 (January 16, 2015) - Notice Announcing Data Harmonization for NIMH Human Subjects Research via the PhenX Toolkit
- NOT-MH-14-015 (June 12, 2014) - Data Sharing Expectations for NIMH-funded Clinical Trials
- NOT-MH-14-004 (January 15, 2014) - Enhancing the Reliability of NIMH-Supported Research through Rigorous Study Design and Reporting
Clinical Trials — Applicant FAQs
- 1. I submitted an application to one of the Clinical Trials Requests for Applications Funding Opportunity Announcements, but it wasn’t funded. Can I submit a revised application to the new Clinical Trials Program Announcements? If so, would it be an A1 or an A0?
Yes, the NIMH clinical trials (CT) Program Announcements (PAR) Funding Opportunity Announcements allow for the resubmission of applications submitted to previous NIMH CT Requests for Applications FOAs. If you include a one-page Introduction summarizing your revisions and alter the text in the application, you can submit the application as an A1 application. If preferred, the previously reviewed application can be submitted without an Introduction page nor any documentation of revisions, then the application can be submitted as on A0 application. For additional information, consult the appropriate Program Official for consultation. See Section II: Award Information, “Application Types Allowed,” in the NIMH CT FOAs for specific details regarding Resubmissions, Revisions, and Renewals.
- 2. The Clinical Trial FOAs used to be RFAs, but now they are PARs. Does it make a difference?
The change from RFA to PAR was made for administrative purposes. The NIMH-issued Clinical Trial funding announcements remain a high priority, thus the NIMH continues to set-aside funds to support studies in the clinical trials pipeline.
- 3. What is the "experimental therapeutics approach" to designing a clinical study?
An empirically-grounded, mechanism-based approach begins with the selection of a theoretically grounded, potentially-mutable hypothesized target or mechanism through which the intervention is expected to have its effect. Investigators first rigorously evaluate the intervention’s effect on this target/mechanism. If the intervention adequately engages the target/mechanism, one can then test whether the changes produced in the target/mechanism affect clinical outcomes. Studies designed this way are more informative, resulting in important information about the relationship between the target/mechanism and clinical outcomes, even if the intervention does not lead to the expected clinical improvement.
Each FOA provides details that describe the experimental therapeutic approach as it relates to the particular research modality discussed. Please review the individual FOA most relevant to your planned research and contact the Scientific/Research Contact listed to discuss the proposed strategy and whether it fits within the experimental therapeutics approach.
If you are interested in designing a trial to test a drug/drug agent, additional descriptions of the experimental therapeutics approach to drug development can be found at:
Morgan P et al. Can the flow of medicines be improved? Fundamental pharmacokinetic and pharmacological principles toward improving Phase II survival. Drug Discov Today. 2012 May; 17(9-10):419-424. PMID: 22227532
- 4. What is a target?
The term “target” refers to a factor that an intervention is intended to modify, based on a hypothesis that modification of that factor will result in improvement of symptoms, behavior, or functional outcomes. A target may be a disease mechanism, a factor related to a disease mechanism, or a factor that confers significant risk. Targets can range from molecular processes, to synaptic- and circuit-level regions or networks, to neural systems and intrapersonal (e.g., cognitive, behavioral or emotional) interpersonal, family, and community processes, to provider behavior, decision-making or organizational policies or behaviors. Appropriate targets will depend on the intervention modality and the conceptual framework underlying hypotheses about its mechanism of action. Each FOA provides additional guidance, specific to the type of intervention, on defining a target and demonstrating target engagement.
- 5. How do I incorporate targets into my trial design?
Successful applications to NIMH Clinical Trials FOAs will describe a conceptual framework that clearly identifies the intervention’s target and provides solid evidence of the relevance of that target to the clinical symptom, behavior, or functional deficit that the intervention is intended to improve. The conceptual framework should also provide a scientifically-grounded hypothesis about the ability of the intervention to engage (or modify) the target, and the means by which target engagement will be assessed or measured. When multiple targets are proposed, it is incumbent upon the investigator to describe how elements of the intervention strategy uniquely engage said targets.
The ability to measure change in the target is key to the trial design. Clinical trials can then rigorously test whether effective target engagement changes symptom or functional outcomes in predicted directions. Verification of target engagement and associated symptom or functional improvement provides evidence in support of “validating” a target for further study. On the other hand, demonstration of adequate target engagement without symptom or functional change would mean that change in the target is insufficient for meaningful clinical change. Either outcome would be highly informative for determining if further study is warranted and if so, the design of the subsequent trial.
- 6. How is "target engagement" best measured?
Measures of target engagement must be objective, sensitive, valid, and reliable. The type of measures will depend on the intervention modality, the conceptual model, and the nature of the targeted construct. Target engagement measures should reflect the hypothesized mechanism of action of the intervention as directly as possible. NIMH discourages reliance on self-reports and other subjective measures, in favor of using more objective measures, where possible.
For pharmacological agents and devices, the measures used should be able to detect differences in the level of target engagement as the intervention is optimized (through changes in dose, intensity, frequency, etc.) and how it associates with side effects. These data are critical for demonstrating optimal target engagement of the treatment level or intensity to be evaluated in a future clinical trial. It is recognized that some cognitive, behavioral, and psychotherapeutic interventions without a direct biological impact may not be conducive to the same type of dose finding strategy. However, all interventions should be able to demonstrate adequate target engagement and make use of measures at multiple time points to evaluate the intervention parameters such as intensity, duration, and frequency (i.e., “dose”) needed to achieve target engagement.
- 7. How do I decide which NIMH-issued Clinical Trial FOA best fits my project?
NIMH strongly encourages potential applicants to talk with a Program Officer (Scientific/Research Contact) before preparing and applying for one of the Clinical Trial FOAs. Please email or call these contacts, but it is particularly helpful and efficient if you send a brief description of your project, including specific aims, in an email.
Scientific/Research Contacts are listed at the end of each FOA. Using the information in the “Clinical Trials Pipeline – Phase of Intervention Development” table, determine which FOA seems like the best fit for your project, and contact that Scientific/Research Contact for advice on the appropriateness of the FOA for the project’s goals, optimization of project's fit with NIMH priorities, and other Program staff to contact in the relevant research area for additional advice. Each FOA describes (in Part 2, Section I, “Funding Opportunity Description”) the purpose or objectives of the FOA, as well as NIMH priorities related to that announcement. Note that not all FOAs support all intervention modalities, so identify the FOA that supports both the phase of intervention development and the intervention modality.
- 8. What are some examples of mechanistic or biomarker studies that may be submitted to the NIH parent Clinical Trial R01 and R21 FOAs or the Basic Experimental Studies with Humans ( BESH) R01 and R21 FOAs?
Below are examples of the types of mechanistic/biomarker studies that can be submitted under the NIH parent Clinical Trial R01 and R21 announcements as well as the BESH FOAs (see Guide Notice NOT-MH-19-006). Studies in which a manipulation (physiological or behavioral) is used to answer basic science questions about normal brain function may be appropriate for BESH FOAs.
- Studies, including those to develop, validate, and/or apply novel measures of brain signaling and circuits contributing to cognition, emotional regulation and social behavior in healthy humans including, for example, PET, SPECT, and other neuroimaging approaches, as well as biomarkers of physiological processes may be appropriate for BESH FOAs.
- BESH FOAs may be appropriate for studies that use an experimental manipulation (e.g., CNS active drugs, direct neurostimulation or via a cognitive task activating of a specific neural circuit) in order to understand normal functioning or the pathophysiology of the disorder, but do not aim to understand how an intervention to improve health works and demonstrate clinical improvement. This includes circumscribed manipulations of a particular physiological or psychological process. Primary aims may include the short-term (acute) effects of the manipulation, including dose or parameters needed to attain that effect, but not the demonstration of change in clinical status or functional outcomes.
- Studies that involve the prospective use of efficacious interventions (e.g., biomedical, behavioral, cognitive, and other therapeutic approaches), where the intent is to obtain biospecimens (e.g., blood, patient-derived induced pluripotent stem cells) to identify genetic risk associations, novel biomarkers, examine the disease process, or characterize mechanisms of therapeutic response may be appropriate for the mechanistic trials accepted by NIMH under the NIH parent R21 or R01 clinical trial FOAs.
- Studies in which an intervention with demonstrated efficacy for that population (e.g., an SSRI, CBT, or ECT for depression) is being studied to understand mechanisms of response, non-response, or risk of adverse effects of the efficacious intervention. Regardless of FDA-approved indications, for all interventions – medications, devices, and non-pharmacological treatments - the application must convincingly document previous evidence of efficacy to be appropriate for the mechanistic trials accepted by NIMH under the NIH parent R21 or R01 clinical trial FOAs.
- Other exceptions to the requirement to submit under the NIMH Clinical Trial FOAs include, for example, continuations of NIMH-supported studies that have been added on to large clinical trials sponsored by other Institutes or organizations. These will be considered on a case by case basis.
NIMH strongly recommends that applicants contact the Scientific/Research Contact well before the receipt date to determine the which FOA is most appropriate for the proposed study.
- 9. I am an early career investigator who is eligible to apply for a mentored K from NIMH. I’m planning to propose a clinical trial in my mentored K application. Is NIMH still accepting mentored K applications that propose clinical trials?
The following types of clinical studies are not intended to be supported by NIMH under the NIH parent Clinical Trials R01 and R21 FOAs or parent BESH R01 and R21 FOAs (see Guide Notice NOT-MH-19-006):
- Clinical studies that that are not defined as clinical trials by the NIH definition of clinical trial. This includes observational studies that leverage a clinical trial cohort, but do not administer an intervention as part of the study (e.g., longitudinal follow-up and assessment of participants from completed clinical trials where there will be no additional recruitment or further treatment of participants). Such observational studies may be submitted to the NIH Parent R01 Clinical Trial Not Allowed or NIH Parent R21Clinical Trial Not Allowed.
- Early-stage trials of novel treatment approaches in humans that are prerequisite to clinical efficacy trials for pharmacological, device, or behavioral intervention development. These should be submitted to the appropriate Phase of Intervention Development trial FOA.
- Studies to develop or conduct tests of the clinical efficacy/effectiveness of preventive, therapeutic, or services interventions. These should be submitted to the appropriate Phase of Intervention Development trial FOA (NOT-MH-20-105).
- Studies that have safety, clinical efficacy, clinical management, and/or implementation as an aim. These should be submitted to the appropriate Phase of Intervention Development trial FOA.
- 10. I heard that some applications have been returned without review because they are not responsive to the NIMH-issued Clinical Trial FOAs. Is this true, and how can I be sure that my application is responsive?
Each FOA details the responsiveness criteria that will be applied and applications not responsive to those criteria will be administratively withdrawn prior to scientific review.
To avoid having an application returned due to non-compliance or non-responsiveness, ensure that all requirements of the FOA are met and that instructions are carefully followed. Please review these two important sections of the FOA:
- Within Part 2, Section I, “Funding Opportunity Description” of each FOA, there are series of statements that describe the areas of research interest of the FOA, followed by several bullets under the header “Examples of studies that are not responsive to this FOA and will not be reviewed” and “Non-responsive Areas of Research.” These examples should be carefully reviewed as research proposed in these areas will be returned as non-responsive.
- Within Part 2, Section IV, 2. “Content and Form of Application Submission” of the FOA, pay particular attention to the section on “PHS Human Subjects and Clinical Trials Form.” This section outlines the necessary components to be included in your application.
Common problems, by FOA type, that have resulted in applications to the NIMH-issued Clinical Trials FOAs being withdrawn prior to scientific review include, but are not limited to:
- Phased “Exploratory Clinical Trials” R61/R33 FOA ( and reissuances)
- Lack of quantifiable milestones and timeline.
- Lack of clear “go/no-go” criteria for continuing into the R33 phase of the award.
- Effectiveness FOAs (PAR-21-131, PAR-21-130, and PAR-21-129; and reissuances)
- Lack of a strong empirical justification of the need for an adaptation of a proposed intervention.
- General issues for the clinical trials FOAs
- Lack of study participant and recruitment descriptors.
- Lack of adequate evidence of an Investigational New Drug (IND) permission or Investigational Device Exemption (IDE) approval for FDA-regulated interventions.
- Lack of documentation regarding an FDA-submitted application for studies of pharmacologic compounds and devices.
- 11. I am an early career investigator who is eligible to apply for a mentored K from NIMH. I’m planning to propose a clinical trial in my mentored K application. Is NIMH still accepting mentored K applications that propose clinical trials?
Yes. For additional information and Program Contacts, see Guidance for NIMH Mentored K Applicants Proposing Clinical Trials webpage. Applicants proposing a study that meets the NIH definition of a clinical trial should apply using the appropriate clinical trials career development award program announcement.
Clinical trials proposed by mentored K award applicants should be aware that NIMH expects any clinical trial proposed to be consistent with the stated research goals and priorities as outlined in the clinical trials FOAs.
- 12. Are multi-site trials allowed?
Yes. If the purpose of the multi-site trial is to determine the effectiveness of interventions, and to test hypotheses regarding moderators, mediators, and mechanisms of action of these interventions, the applicant should use the Collaborative R01 for Effectiveness Research PAR-21-129.
- 13. Are multi-site trials expected to have a single Institutional Review Board (IRB)? Who will organize a single IRB?
Multi-site trials are required to propose use of a single IRB NOT-OD-18-004 (see in particular the Relevant Documents and Resources; Implementation of the sIRB Policy; and the FAQs on this policy for more information). It is the responsibility of the applicant to designate the IRB of record and secure appropriate agreements by IRBs from all institutions involved in the proposed multi-site trial. NIMH will expect all agreements to be in place prior to release of funding.
- 14. Is it necessary to register all clinical trials with ClinicalTrials.gov?
Per NIH Guide Notice NOT-OD-16-149, the expectation is that all investigators conducting clinical trials funded in whole or in part by the NIH will ensure that these trials are registered at, and information submitted to, ClinicalTrials.gov. However, per NOT-OD-19-126, studies that meet the NIH definition of a “clinical trial” and that also meet the Federal definition of basic science (also known as Basic Experimental Studies with Humans (BESH)) have flexibilities through September 2021. For these studies, NIH will continue to expect registration and reporting for prospective basic science studies involving human participants, with additional flexibility to allow reporting on existing basic science portals, with the expectation that data will eventually be transported to ClinicalTrials.gov.
In addition to the information above, NIMH also has its own expectations outlined in “Oversight and Monitoring of Clinical Research funded by the NIMH” (NOT-MH-19-027). All applicants should review this notice prior to submission.
- 15. Is data sharing encouraged? When are investigators expected to share the data?
Yes. NIMH expects investigators to share raw, de-identified, individual-level data via the NIMH Data Archive (NDA; see NOT-MH-19-033). Submission of descriptive/raw data is expected semi-annually (December 1 - January 15 deadline and December 1 - July 15 deadline); submission of all other data (processed, analyzed) is expected at the time of publication, or prior to the end of the grant, whichever occurs first. Established by the NIMH, NDA is a secure informatics platform for scientific collaboration and data-sharing that enables the effective communication of detailed research data, tools, and supporting documentation. The NDA links data across research projects through its Global Unique Identifier (GUID) and Data Dictionary technology. Investigators conducting NIMH-funded clinical trials are expected to use these technologies to submit data to NDA. Planning and budgeting for data sharing should be described in your application. A cost estimation tool for data sharing is available on the NDA website. Researchers should use the cost estimation tool when preparing budgets for applications submitted to NIMH. More details about the elements needed and budget guidelines can be found in Part 2, Section IV, 2. "Content and Form of Application Submission, Resource Sharing Plan" of the FOAs.
- 16. Is a recruitment plan required? Will NIMH monitor progress of the trial? What are the consequences for failing to meet the recruitment goals?
Yes. A detailed recruitment plan with target enrollment numbers is a required component of every application that enrolls participants. For each FOA, Part 2, Section IV, 2, "Content and Form of Application Submission," provides instructions to include detailed information about plans for study recruitment and enrollment. NIMH requires reporting of recruitment milestones for participants in all clinical trials, regardless of size as noted in NOT-MH-19-027 and the NIMH Policy for Recruitment of Participants in Clinical Research. Investigators are required to establish tri-annual recruitment milestones and report actual recruitment progress three times a year (April 1, August 1, and December 1) for the duration of recruitment. Failure to meet recruitment goals may result in withholding of funds or suspension of the trial.
- 17. What is a Data and Safety Monitoring Plan (DSMP)?
A DSMP is a plan that outlines oversight and monitoring necessary to ensure the safety of participants and the validity and integrity of the data in a clinical trial. This is required for all NIH-supported or conducted clinical trials. For more information, see:
- 18. How does an applicant decide whether a Data and Safety Monitoring Board (DSMB) is required?
- DSMBs are required for all multi-site clinical trials.
- DSMBs are generally required for Phase III clinical trials.
- A DSMB may be appropriate for Phase I or Phase II clinical trials if:
- the clinical trial is blinded, or
- the clinical trial involves high risk intervention(s), or
- the clinical trial includes vulnerable population(s).
The Program Official, in consultation with the NIMH Office of Clinical Research, will provide oversight to determine the level of monitoring required for funded studies. For more information, see:
- 19. Can applicants propose to use an Independent Safety Monitor (ISM) or a non-NIMH DSMB?
Yes. As part of the DSMP, applicants can propose an Independent Safety Monitor (ISM) or an independent non-NIMH DSMB (subject to review and approval by the Program Official). The application should identify the information to be monitored and the proposed frequency of monitoring. The monitoring responsibilities of the ISM and DSMB enhance, but do not replace, the monitoring responsibilities of the Principal Investigator (PI) and the IRB. The PI and study team retain responsibility for real-time clinical management of the study. The Program Official, in consultation with the NIMH Office of Clinical Research, will provide oversight to determine the level of monitoring required for funded studies.
For more information, see:
- 20. Does NIMH review the ISM and DSMB determinations?
Yes. Investigators are required to submit the summary of ISM and DSMB reviews, including recommendations and determinations, to the NIMH no later than the type 5 progress report. Failure to inform NIMH of the monitoring activities may result in withholding of funds or suspension of the trial. For more information, see:
- 21. How are adverse events reported?
The NIMH Reportable Events Policy outlines NIMH’s expectations regarding the submission of reportable events (i.e., Adverse Events (AEs); Serious Adverse Events (SAEs); Unanticipated Problems Involving Risks to Subjects or Others; protocol violations; non-compliance (serious or continuing); suspensions or terminations by monitoring entities (e.g., IRB, ISM); and suspensions or terminations by regulatory agencies) to NIMH. Also, see this Glossary of Terms for additional details.
This policy is specific to reporting to NIMH and does not replace regulations or policies requiring reporting of these events to other monitoring entities or regulatory agencies. Refer to the NIMH Clinical Research Toolbox for further guidance.
- 22. What materials may be included as “Other Clinical Trial-related Attachments” in Section 5.1 of the PHS Human Subjects and Clinical Trials Information section?
Each clinical trial FOA indicates that materials may be uploaded as attachments, labeled as “Intervention Manual/Materials.” Specifically, the FOAs indicate, “As appropriate, this may include screenshots of mobile interventions, technological specifications, training manuals or treatment algorithms.” In general, these attachments may include manuals/documents about the administration of the intervention, intervention training, and/or intervention content. Materials not allowed in this section include items that are part of the Research Strategy, such as presentations of preliminary data, descriptions of published research studies, etc.
- 23. What content should be presented in the Research Strategy section versus the Study Record: PHS Human Subjects and Clinical Trials Information sections?
For all FOAs, applicants are strongly encouraged to follow the PHS 398 Research Plan in Section IV.2. All content requested for the Research Strategy per these instructions should be included in the Research Strategy of the application. Please note that these FOA-specific instructions supersede the general instructions provided in the SF424 (R&R) Application Guide, as noted therein. Specifically, for each FOA, certain elements must be contained in the Research Strategy (e.g., measurement of target engagement, Go/No-Go criteria). Please refer to each FOA for the specific required elements. The FOAs do not request that these elements be presented in the PHS Human Subjects and Clinical Trials Information Form.
- 24. What materials can be included in an appendix of a NIMH clinical trial application?
NIH issued a new policy for allowable Appendix materials in applications, effective January 25, 2018 (please see NOT-OD-17-098; NOT-OD-18-126). For the NIMH Clinical Trials FOAs, the following materials may be included in an appendix:
- Blank data collection forms, blank survey forms and blank questionnaire forms or screenshots thereof.
- Simple lists of interview questions.
- Blank informed consent/assent forms.
- Other items only if they are specified in the FOA as allowable Appendix materials.
Most importantly, the appendices should not be used to circumvent the page limitations of the Research Strategy. Applications that simply relocate disallowed materials to other parts of the application will be withdrawn as noncompliant.