Support for Clinical Trials at NIMH

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, Q1) for the development and testing of therapeutic, preventive, and services interventions, in which the studies do not only evaluate 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 not only that an intervention improves clinical outcomes, but that it also 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.

* The intent of the U01 and R61/R33 for drug development is to support early phase clinical trials to de-risk drug and device therapeutic candidates for further development.

First in Human and Early Stage Clinical Trials of Novel Investigational Drugs or Devices for Psychiatric Disorders

• PAR-18-427 (U01 - Clinical Trial Required)

Scientific/Research Contact Information
General Inquiries: NIMHClinicalTrials@mail.nih.gov
Application Due Dates: Standard Dates Apply

Early Stage Testing of Pharmacologic or Device-based Interventions for the Treatment of Mental Disorders

• RFA-MH-18-702 (R61/R33 - Clinical Trial Required)
• RFA-MH-18-703 (R33 - Clinical Trial Required)

Scientific/Research Contact Information
General Inquiries: NIMHClinicalTrials@mail.nih.gov
Application Due Dates: February 15, 2019; June 15, 2019; October 15, 2019; February 14, 2020; June 15, 2020; October 15, 2020 for all application types (new, resubmission, and revision applications).

Development of Psychosocial Therapeutic and Preventive Interventions for Mental Disorders

• RFA-MH-18-704 (R61/R33 – Clinical Trial Required)
• RFA-MH-18-705 (R33 – Clinical Trial Required)

Scientific/Research Contact Information
General Inquiries: NIMHClinicalTrials@mail.nih.gov
Application Due Dates: February 15, 2019; June 15, 2019; October 15, 2019; February 14, 2020; June 15, 2020; October 15, 2020 for all application types (new, resubmission, and revision applications).

Confirmatory Efficacy Clinical Trials of Non-Pharmacological Interventions for Mental Disorders

• RFA-MH-18-707 (R01 – Clinical Trial Required)

Scientific/Research Contact Information
General Inquiries: NIMHClinicalTrials@mail.nih.gov
Application Due Dates: February 15, 2019; June 15, 2019; October 15, 2019; February 14, 2020; June 15, 2020; October 15, 2020 for all application types (new, resubmission, and revision applications).

Pilot Effectiveness Trials for Treatment, Preventive and Services Interventions

• RFA-MH-18-706 (R34 - Clinical Trial Required)

Scientific/Research Contact Information
General Inquiries: NIMHClinicalTrials@mail.nih.gov
Application Due Dates: February 15, 2019; June 15, 2019; October 15, 2019; February 14, 2020; June 15, 2020; October 15, 2020 for all application types (new, resubmission, and revision applications).

Clinical Trials to Test the Effectiveness of Treatment, Preventive, and Services Interventions

• RFA-MH-18-701 (R01 – Clinical Trial Required)
• RFA-MH-18-700 (Collaborative R01 – Clinical Trial Required)

Scientific/Research Contact Information
General Inquiries: NIMHClinicalTrials@mail.nih.gov
Application Due Dates: February 15, 2019; June 15, 2019; October 15, 2019; February 14, 2020; June 15, 2020; October 15, 2020 for all application types (new, resubmission, and revision applications).

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. The NIH definition of basic research is consistent with that in the federal code (32 CFR 272.3), “the systematic study directed toward greater knowledge or understanding of the fundamental aspects of phenomena or of observable facts without specific applications towards processes or products in mind”.  The phrase “without specific application towards processes or products” refers to the application of biomedical or behavioral products, procedures, or services intended to improve 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.

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. However, NIH is delaying enforcement of registration and reporting requirements for BESH studies until September 2019 (NOT-OD-18-212).

NIH defines a mechanistic clinical trial as: "A mechanistic study is designed to understand a biological or behavioral process, the pathophysiology of a disease, or the mechanism of action of an intervention.” Additionally, NIMH supports mechanistic clinical trials that focus on biomarker studies that may provide information about physiological function, target engagement of novel 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 consider two major categories of mechanistic trials (though there may be others):

1. 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 FOAs.
2. Mechanistic clinical trials utilizing an experimental manipulation: These studies utilize an 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.

NIH Guide Notice NOT-MH-19-006 describe the types of clinical trials that NIMH will support under the NIH Parent Clinical Trial and BESH FOAs.

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 model.

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.

Selected Publications

• 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

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1. What is an "experimental therapeutic approach" to designing a clinical study?

This approach begins with a 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 can affect clinical symptoms. 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 outcomes.

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 program officer 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:

• Soares HD. The use of mechanistic biomarkers for evaluating investigational CNS compounds in early drug development. Curr Opin Investig Drugs. 2010 Jul; 11(7):795-801.
• 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.

We encourage you to contact the Scientific/Research Contact listed at the end of the relevant FOA to discuss how the experimental therapeutics approach might be best applied to your particular study.

2. 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 cognitive or emotional 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.

3. 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.

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 a further study is warranted and if so, the design of the subsequent trial.

4. 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 treatment parameters such as intensity, duration, and frequency (i.e., “dose”) needed to achieve target engagement.

5. How do I decide which NIMH-issued Clinical Trial FOA from the Clinical Trial pipeline, to apply for?

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.

6. 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 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). Please contact the Program Officer (Scientific/Research Contact) well before the receipt dates, to ensure adequate time to determine which FOA might be most appropriate for the proposed study.

• 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. In the case of medications and devices, these would be for FDA-approved indications only. In the case of non-pharmacological interventions, 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 the applicants to contact the Program Officer (Scientific/Research Contact) to discuss their plans early in the development of their applications.

7. What type of clinical studies does NIMH not support under the NIH parent Clinical Trials R01 and R21 FOAs or parent BESH R01 and R21 FOAs?

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 R01Clinical 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.
• 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.

8. 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?

As described in each RFA FOAs issued by NIH, applications in response to RFA are administratively reviewed for responsiveness prior to scientific review. Applications determined to be non-responsive to the scientific focus of the RFA are withdrawn prior to scientific peer review. Applications are also returned if they are missing any of the key elements requested in the RFA, thus not compliant with the requirements of the RFA.
To avoid having an application being returned due to non-compliance or non-responsiveness, please ensure that all requirements of the RFA are met and that instructions are carefully followed. Please especially carefully 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.” 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.

Some applications propose study designs that are not in alignment with the experimental therapeutics goals of the FOAs. To avoid misalignment with the goals of the FOAs, we strongly recommend that applicants discuss their study plans with their Program Officer early in the development of their 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 (RFA-MH-18-702 and RFA-MH-18-704 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 (RFA-MH-18-706, RFA-MH-18-701, and RFA-MH-18-700; 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.

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?

Yes. For additional information and Program Contacts, please 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. Please consult with NIMH staff early in the process of developing an application. This early contact will provide an opportunity to ascertain NIMH policies and guidelines, as well as to discuss whether the proposed project includes a requisite target(s) and objective measure(s) of target engagement.

10. Are multi-site trials allowed?

Yes. However, NIMH strongly encourages a discussion with the Scientific/Research Contact for the relevant FOA before submitting applications for multi-site trials. 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 RFA-MH-18-700.

11. 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-17-076 (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.

12. 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 ClinicalTrials.gov, and that results information of these trials is submitted to ClinicalTrials.gov.  However, per NOT-OD-18-212, 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 some latitude with this requirement through September 2019. 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.gova>.

13. 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 National Database for Clinical Trials related to Mental Illness (NDCT; see NOT-MH-14-015 and NOT-MH-15-012). Submission of descriptive/raw data is expected semi-annually (every January 15 and July 15); 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, NDCT is a secure informatics platform for scientific collaboration and data-sharing that enables the effective communication of detailed research data, tools, and supporting documentation. NDCT 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 NDCT. Planning and budgeting for data sharing should be described in your application. A cost estimation tool for data sharing is available at https://ndct.nimh.nih.gov/preplanning/budget. Researchers should use that 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.

14. 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. As of October 1, 2017, NIMH requires reporting of recruitment milestones for participants in all clinical trials, regardless of size as noted in NOT-MH-16-013 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.

15. 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:

• NIMH Policy Governing the Monitoring of Clinical Trials
• NIMH Guidance for Developing a Data and Safety Monitoring Plan
• NIH Policy for Data and Safety Monitoring (NOT-98-084)
• Further Guidance on Data and Safety Monitoring for Phase I and Phase II Trials (NOT-OD-00-038)

16. 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 required for Phase I, Phase II, or Phase III 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:

• NIMH Guidance on Risk-Based Monitoring
• NIH FAQ on Human Subjects Research – Data and Safety Monitoring

17. 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 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.
For more information, see:

• NIMH Guidance on Risk-Based Monitoring
• Policy Governing Independent Safety Monitors and Independent Data and Safety Monitoring Boards

18. 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.

19. What materials can be included in an appendix of an 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). 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.

For clarification, these blank forms and lists are not and do not include items such as: data, data compilations, lists of variables or acronyms, data analyses, publications, manuals, instructions, descriptions or drawings/figures/diagrams of data collection methods or machines/devices.

• 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.