NIMH Clinical Trials Funding Opportunity Announcements - Applicant FAQs
- 1. What is different about the new NIMH-issued Funding Opportunity Announcements (FOAs) seeking Clinical Trials?
NIMH first issued a set of FOAs seeking clinical trials that conform to an experimental therapeutic approach in February 2014, and reissued those FOAs in May 2015. These FOAs solicited applications for the development and testing of therapeutic and preventive interventions, covering a wide range of intervention modalities: cognitive, behavioral and other psychosocial approaches, psychopharmacological interventions, and treatments utilizing direct brain stimulation. The current set of clinical trial FOAs attempts to better align the language in the FOAs with the concepts and language conventionally used with different research modalities. A major change in the current set of FOAs is that there are now two separate “early stage” FOAs for the development of 1) psychosocial interventions, and 2) drugs or direct brain stimulation devices. However, there have been changes to all of the FOAs in an effort to clarify NIMH’s interest in an experimental therapeutics approach to the development and testing of interventions across all modalities.
- 2. 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 therapeutic 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. See Q6 for advice about finding the most relevant FOA.
- 3. 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.
- 4. 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.
- 5. How is "target engagement" best measured?
Measures of target engagement must be objective, sensitive, 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, frequency, i.e., “dose”) needed to achieve target engagement.
- 6. How do I decide which FOA 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. Program Officers can assist with determining the appropriate FOA, as well as give advice to optimize the project's fit with NIMH priorities. Program Officers are listed as Scientific/Research Contacts at the end of each FOA; using the guidance below, determine which FOA seems like the best fit for your project, and email or call the Scientific/Research Contact for advice.
Your choice of FOA will depend on the stage of intervention development or testing you propose. The table at the top of the Clinical Trials Funding Opportunity Announcements web page, “Clinical Trials Pipeline – Phase of Intervention Development ” illustrates how each FOA supports different phases of the intervention development pipeline.
There are five FOAs that support very early stages of intervention development, including tests of target engagement and studies that associate target engagement with clinical outcomes in proof-of-concept and pilot studies. The FOA entitled “First in Human and Early Stage Clinical Trials of Novel Investigational Drugs or Devices for Psychiatric Disorders (U01) ” supports the rapid collection of data to “de-risk” novel investigational drugs or devices in order to attract private funding for further clinical development toward FDA-approved treatments. Additionally, this FOA is intended to support the testing of novel drugs or devices for use in pediatric populations (e.g., first in pediatric populations) to provide initial proof of concept for further development toward pediatric approval. A key expectation of this FOA is the formation of collaborative partnerships between biomedical researchers and biotechnology or industry researchers to facilitate psychiatric drug or device development.
Two versions of the FOA, “Development of Psychosocial Therapeutic and Preventive Interventions for Mental Disorders (R61/R33 and R33) ” support early stage investigations of target engagement and whether change in the target is associated with change in clinical measures. Intervention modalities of interest include behavioral, cognitive, interpersonal, or other psychosocial approaches. Eligible psychosocial interventions strategies might include in-person or technology-assisted delivery, provided the target and/or the intervention strategy is novel. This FOA supports the development and testing of novel psychosocial interventions, as defined above, as monotherapies or as augmentations to standard treatment.
Two versions of the FOA, “Early Stage Testing of Pharmacologic or Device-based Interventions for the Treatment of Mental Disorders (R61/R33 and R33) ” support early stage testing of pharmacologic or device-based interventions using a protocol design where the presumed mechanism of action of the intervention is adequately tested, to provide meaningful information where target modulation yields a dose-dependent neurophysiological/clinical/behavioral effect.
The FOA, “Confirmatory Efficacy Trials of Non-Pharmacological Interventions for Mental Disorders (R01) ” is available to support confirmatory efficacy trials of non-pharmacological therapeutic and preventive interventions, for adults or children with mental disorders, for which there is evidence of target engagement and a signal suggesting intervention efficacy. Interventions can include, but are not limited to, behavioral, cognitive, interpersonal, and device-based approaches, or combinations thereof. This FOA does not support confirmatory efficacy trials of pharmacological or device-based interventions, as it is expected that industry would support these types of trials.
There are also three FOAs that support studies to establish the effectiveness of interventions for use in community practice settings and to test hypotheses regarding moderators, mediators, and mechanisms of action of these interventions.
“Pilot Effectiveness Trials for Treatment, Preventive and Services Interventions (R34) ” encourages pilot research on the effectiveness of preventive and therapeutic interventions with previously demonstrated efficacy, as well as research on the development and preliminary testing of innovative services interventions that target patient-, provider-, organizational- or systems-level factors to improve access, engagement, quality, efficiency, and delivery of services.
Two versions of “Clinical Trials to Test Effectiveness of Treatment, Preventive, and Services Interventions (R01 and Collaborative R01 )” support larger clinical trials with adequate power to definitively address questions of effectiveness and services interventions. This set of FOAs is explicitly focused on research that addresses practice-relevant questions.
Each FOA describes (in Part 2, Section 1, “Funding Opportunity Description”) the purpose or objectives of the FOA, as well as NIMH priorities related to that announcement. Use the “Clinical Trials Pipeline – Phase of Intervention Development” Table to narrow down the FOA that is most likely to support the research you would like to propose, and then read the descriptions of each FOA. Scientific/Research Contacts are listed at the end of each FOA; they can advise you about the most appropriate FOA, and may direct you to other Program staff in the relevant research area for additional advice. You may call or email these contacts, but it is particularly helpful and efficient if you send a brief description of your project, including specific aims, in an email.
- 7. My trial does not fit any of these FOAs. Can I just submit an application to the parent NIH FOAs [ PA-16-160 (R01); PA-16-161 (R21); and PA-16-162 (R03)]?
No. NIMH is only allowing clinical trial applications to be submitted in response to these FOAs (see NOT-MH-14-007). The only exceptions to this submission policy are applications that are not developing or testing the efficacy of interventions, but utilize an intervention as a probe to identify biomarkers or otherwise interrogate the pathophysiology of a disorder or treatment response. These exemptions are detailed in Q8 . All other treatment development clinical trial applications submitted to NIMH must be in response to specific NIMH Clinical Trials FOAs and may not be submitted to any NIH parent FOA announcements.
- 8. Which types of clinical studies involving a clinical trial component may be submitted to the parent R01, R21, or R03 announcements, as outlined in NOT-MH-14-007 ? Can collaborative R01 clinical studies be submitted?
There are a few specific scenarios in which a study with an intervention component is exempt from the requirement to submit through the specific NIMH Clinical Trials FOAs, and could be submitted through the parent R01, R21, and R03 announcements. These exemptions primarily apply to projects that involve the use of efficacious interventions, including biomedical, behavioral, cognitive, and other psychotherapeutic approaches, where the aims do not involve establishing the efficacy/effectiveness of the intervention. Additionally, Collaborative R01 clinical studies meeting these exemption requirements can be submitted under PAR-14-165 , Clinical Studies of Mental Illness Not Involving Treatment Development, Efficacy, or Effectiveness Trials (Collaborative R01) or subsequent issuances of this FOA. Please contact your program officer well before the receipt dates, to ensure adequate time to determine whether an application is eligible to be submitted under the parent FOAs [PA-16-160 (R01); PA-16-161 (R21); and PA-16-162 (R03)] or PAR14-165. Applications submitted under the parent FOAs that involve clinical trials to develop or test efficacy of interventions will be returned and not reviewed.
- NOT-MH-14-007 states that "Applications…that utilize a clinical trial component…to examine potential novel biomarkers of treatment response for the intervention, rather than to test for efficacy," can be submitted under the parent R01 and R21 announcements. This notice exempts studies with aims that clearly indicate that the purpose of the study is to identify reliable and stable biomarkers that reflect a pathophysiological or disease process, that are correlated with individual treatment response, or identify subjects that would most benefit from the intervention, rather than having the primary goal of evaluating efficacy. This exception does not apply to early-stage novel treatment development studies in which biomarkers are collected during the intervention trial to establish CNS dosing for subsequent later stage trials. Trials that develop or conduct initial tests of the efficacy/effectiveness of treatments are not exempt and must be submitted to one of the NIMH Clinical Trials FOAs. PIs are encouraged to contact program staff prior to submitting their application, to make sure it fits the appropriate FOA.*
- Studies in which an intervention with demonstrated efficacy for that population (e.g., an SSRI 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 FDA-approved indications only. In the case of non-pharmacological interventions, previous evidence of efficacy must be convincingly documented in the application.*
- Studies that use an experimental manipulation (e.g., a neurotransmitter receptor agonist; or activation of a specific neurocircuit via direct neurostimulation or via a cognitive task) in order to understand the pathophysiology of the disorder, but do not aim to demonstrate clinical improvement. This exemption is for circumscribed manipulations of a particular physiological or psychological process. 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 in which a manipulation (physiological or behavioral) is used to answer basic science questions about normal brain function, and not to establish efficacy or advance treatment development.*
- A clinical research study that administers a standard, indicated intervention in order to control for confounds related to treatment heterogeneity, and the aims do not include evaluation of efficacy of the intervention. For example, a study of neural changes across a developmental time period in a population for which treatment is expected or indicated might administer an indicated intervention to standardize treatment across participants.*
- Longitudinal follow-up and assessment of participants from completed clinical trials where there will be no additional recruitment or further treatment of participants.**
- Continuations of NIMH-supported studies that have been added on to large clinical trials sponsored by other institutes or organizations, whether or not the NIMH-supported research involves examination of interventions outcomes, may be acceptable for submission to the parent FOAs.**
- 9. Where are applications submitted in response to these Clinical Trial FOAs reviewed?
Applications submitted in response to these FOAs will be reviewed by special emphasis panels at NIMH.
- 10. I heard that some applications have been returned without review because they are not responsive to the clinical trial FOAs. Is this true, and how can I be sure that my application is responsive?
It is standard procedure at NIH to return applications submitted to Requests for Applications (RFAs) that are not responsive to the RFA. (Language about this is found in the specific RFA issued by NIH.) Thus, applications submitted in response to the clinical trial RFAs are reviewed for responsiveness prior to scientific review, and returned to the submitting Institution if they are deemed not responsive to the scientific focus of the RFA. Applications are also returned if they are missing any of the key elements requested in the FOA.
To ensure that this does not happen to you, please carefully review 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, Number 2, “Content and Form of Application Submission” of the RFA, pay particular attention to the sections on “SF424(R&R) Other Project Information” and “PHS 398 Research Plan.” These sections outline the necessary components to be included in your application. If any these key components are missing, the application will be returned as non-responsive.
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. There are some additional common problems that have resulted in applications to the clinical trials FOAs being returned. For the phased “Exploratory Clinical Trials” R61/R33 FOA (previously, RFA-MH-16-406; and now RFA-MH-17-604 and RFA-MH-17-600), common problems include the lack of quantifiable milestones and timeline as well as a lack of clear “go/no-go” criteria for continuing into the R33 phase of the award. For the Effectiveness FOAs (RFA-MH-17-612; RFA-MH-17-608; and RFA-MH-17-610), a common problem is the lack of a strong empirical justification of the need for an adaptation of a proposed intervention. For all of the clinical trials FOAs, common problems could include: a lack of study participant and recruitment descriptors; failure to provide evidence of an Investigational New Drug (IND) permission or Investigational Device Exemption (IDE) approval; or, documented 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. However, as the notice (NOT-MH-14-007) indicates, mentored K award applicants should be aware that NIMH expects any clinical trial proposed to be consistent with the stated research goals and priorities relevant to clinical trials as outlined in the clinical trials FOAs and on the NIMH clinical trials website. Please be aware that applicants are strongly encouraged to review the NIMH clinical trials website and 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. For additional information and Program Contacts, please see: Guidance for NIMH Mentored K Applicants Proposing Clinical Trials.
- 12. 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.
- 13. Are multi-site trials expected to have a single Institutional Review Board (IRB)? Who will organize a single IRB?
Multi-site trials that propose a single IRB of record are preferred, and are required for most multi-site trial applications submitted on or after January 25, 2018, as noted in 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.
- 14. Is it necessary to register all clinical trials with clinicaltrials.gov?
Yes. All trials that are funded, regardless of the phase, will be expected to be registered with clinicaltrials.gov prior to funding.
- 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 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 NIH, 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 funded under this FOA are expected to use these technologies to submit data to NDCT. Planning and budgeting for data sharing should be described in your application. More details about the elements needed and budget guidelines can be found in Part 2, Section IV, Number 2, Resource Sharing Plan.
- 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, Number 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.
- 17. To assess long-term outcomes, I want to submit a grant application to conduct a systematic prospective follow-up of participants who took part in a now completed randomized trial. Should I use the Effectiveness Research FOA or the parent R01 FOA?
If you do not plan to enroll any new participants, and only previously randomized participants will be assessed, and you are not adding treatment as part of the proposed study, you should use the parent R01 FOA.
- 18. I want to apply for funding to further analyze an existing clinical trial database to address questions that are beyond those addressed in the planned primary analyses of the trial. Should I use the parent R01 FOA?
Because you do not plan to enroll new participants, and will not be re-contacting study participants, you should use the parent R01 FOA .
- 19. I want to apply for funding to test if a training intervention for care providers enhances their competence in identifying patients at high risk for suicide. I plan to randomize providers to receive the intervention or not. Should I use the parent R01 FOA?
The proposed study is a clinical trial evaluating the effect of an intervention for care providers, so you should use one of the NIMH Clinical Trials FOAs. The relevant FOAs for this type of study are RFA-MH-17-608 (R01) or RFA-MH-17-610 (Collaborative R01), Clinical Trials to Test the Effectiveness of Treatment, Preventive, and Services Interventions; and RFA-MH-17-612 (R34), Pilot Effectiveness Studies and Services Research Grants.
- 20. I want to apply for funding to conduct a prospective, naturalistic study of patients being treated in practice settings. Should I use the parent R01 FOA?
Because the participants are not assigned to treatment as part of the study, you should use the parent R01 FOA .
- 21. I want to apply for funding to test if a training intervention for care providers enhances their competence in identifying patients at high risk for suicide. I plan to randomize providers to receive the intervention or not. Should I use the parent R01 FOA?
The proposed study is a clinical trial, so you should use one of the Effectiveness Research FOAs (see Q6 , above, for more information).
- 22. What is a Data and Safety Monitoring Plan?
A data and safety monitoring plan (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:
- 23. 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:
- 24. Can applicants propose to use an Independent Safety Monitor (ISM) or a non-NIMH DSMB?
Yes. As part of a Data and Safety Monitoring Plan (DSMP), applicants can propose an ISM or an independent 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 Institutional Review Board (IRB). The PI and study team retain responsibility for real-time clinical management of the study.
For more information, see:
- 25. 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., Institutional Review Board (IRB), Independent Safety Monitor (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.
- 26. 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 2017 (please see NOT-OD-17-035). For the NIMH clinical trials RFAs, the following materials may be included in an appendix:
- Patent materials directly relevant to the project;
- Surveys, questionnaires, data collection instruments;
- Informed consent documents
In regard to intervention manuals, please note that the FOAs request that these protocols be included as an Other Attachment – not as appendix material.
Most importantly, the appendices should not be used to circumvent the page limitations of the Research Strategy.
*Please contact your program officer to ensure the proposed study is within NIMH priorities before preparing applications.
**Please contact your program officer before preparing an application, to ensure that the proposed longitudinal follow-up and/or assessment of participants from completed trials is within NIMH priorities.