NIMH Clinical Trials Funding Opportunity Announcements - Applicant FAQs
- 1. What is different about the new NIMH-issued Funding Opportunity Announcements (FOAs) seeking Clinical Trials? What is an "experimental therapeutic approach" to designing a clinical study?
NIMH is asking investigators to use an experimental therapeutic approach in the design of their clinical trial studies. The experimental therapeutic approach rigorously tests the intervention in a clinical trial design. The approach assesses the ability of the mechanism of action of the intervention to alter brain function or other targets that could lead to an improvement in symptoms or other desired outcomes. Rather than testing the intervention in a traditional efficacy outcome trial, the experimental medicine trial involves objective measures of target engagement and effects on brain function as initial evaluation points. Particularly in trials where the intervention is a medication, a dose finding study would be employed to identify a dose that adequately engages the target. The study results inform the first "go/no-go" decision point: only if the intervention adequately engages the target can an investigator ask whether the target can affect clinical symptoms.
In a subsequent study, using the experimentally defined dose, a positive impact on clinical symptoms constitutes proof of concept of a role for the target in the clinical or behavioral problem under study. The same principles are extended to devices, psychosocial/behavioral interventions, and organizational behaviors; for instance, a new behavioral intervention might target a psychological mechanism in which "dose" might correspond to length/number of sessions and target engagement would be assessed via quantitative measures of the mechanism. Note that in experimental therapeutic trials for drugs, devices, or psychosocial interventions, a negative result is also informative, suggesting attention and investment should be focused on other, more promising targets.
It is a common misconception that adding a biomarker or cognitive measure to a study designed primarily to examine clinical outcomes will make that study an "experimental therapeutic" trial. When a target engagement measure is used to simply monitor results of a clinical outcome study, without knowing how the dose impacts the target, both a lack of a target-engagement signal as well as a negative clinical outcome could be due to inadequate dosing. The more systematic experimental therapeutic strategy aims to accelerate treatment development by avoiding the inconclusive iterations that are typical of the current approach.
For additional discussion of the experimental therapeutics approach to drug development, see:
- a. 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.
- b. 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 Program Officer in the relevant portfolio area 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 hypothesized mechanism of action and its ability to modify disease, behavior, or functional outcomes. Targets can range from molecular- and circuit-level mechanisms proposed for pharmacologic agents, to neural systems, cognitive processes for psychosocial behaviors, or provider decision-making to organizational behaviors that are thought to underlie a psychosocial- or service-level intervention's benefits (see Table in FAQ3 below for a description of different examples of targets).
Clinical trials should rigorously test whether the intervention adequately engages the target in vivo and whether this target engagement changes disease or functional outcomes in predicted directions. Verification of target engagement and functional improvement provides evidence "validating" a target for further study. On the other hand demonstration of adequate target engagement without functional change would support "rejecting" the target. Both outcomes would be highly informative for the treatment development process.
- 3. How is "target engagement" best measured?
Measures of target engagement must be objective, sensitive, and reliable. Ideally these measures show variation in the clinical population that mirrors specific functional deficits. Brain based measures could include, for example, neurochemical assessment of receptor occupancy or enzyme activity via positron emission tomography (PET) or single-photon emission computed tomography (SPECT), measures of circuit activation via functional magnetic resonance imaging (fMRI) or fludeoxyglucose positron emission tomography (FDG PET), or measures of neuroplasticity via electroencephalography (EEG), as well as performance on behavioral tasks that reflect circuit activation. Other measures may be used for identifying engagement of clinician- or system-level targets. Note that target engagement measures need not correspond to the intervention target as in the table, but should reflect the mechanism of action of the intervention as directly as possible. For example, in the absence of a PET ligand, an fMRI measure may provide a sufficiently proximal surrogate of the intervention's action at a target that it can be used to determine an optimal dose.
Table: Examples of Targets, Descriptions, and Target Engagement Measures
Targets Target Engagement Molecular e.g., PET receptor occupancy Neural Circuit/Systems/Physiology e.g., FDG PET, fMRI, EEG, magnetoencephalography (MEG) activation patterns Psychological or Behavioral Processes e.g., performance in attention bias paradigms, expressed emotion, fear-potentiated startle Clinical Process e.g., referral or prescribing behavior, fidelity to effective intervention protocols, retention of patients in care Organizational/Systems level e.g., discharge planning, coordination/collaboration across systems, access to needed services, quality of care
- 4. What is the intent of the U01 announcement?
The purpose of the U01 announcement is to encourage cooperative agreement applications to support early stage therapeutic development for novel mechanisms of action, investigational drugs, drug candidates, or devices for the treatment of psychiatric disorders in areas of unmet medical need which will include first-in-human (FIH) studies, Phase Ib studies of novel agents, and Phase II proof-of-concept (POC) studies in psychiatric disorders. FIH and Phase Ib studies must assess target engagement (e.g., brain exposure), pharmacological effects, safety, and tolerability to assess feasibility and guide dose selection for Phase II/ POC studies in psychiatric disorders. POC studies must evaluate the drug's impact on clinically relevant physiological systems (functional measures) and clinical indicators of effect. The overall objective is to facilitate rapid collection of data to "de-risk" and help future funding of novel mechanism of action investigational drugs, novel drugs for use in adolescents with psychiatric disorders, or combination treatments.
- 5. What is the intent of the R21/R33 FOA?
The purpose of this FOA is to support the efficient pilot testing of novel interventions for mental disorders in adults and children through an experimental therapeutics approach. Under this FOA, trials must be designed so that results, whether positive or negative, will provide information of high scientific utility and will support "go/no-go" decisions about further development or testing of the intervention. Studies of novel interventions include, but are not limited to behavioral, pharmacological, biologics-based, cognitive, device-based, interpersonal, physiological, or combined approaches. Support will be provided for up to 2 years of milestone driven assessment of target engagement in the R21 phase, which, if successful, may be followed by up to 3 years of support for the R33 phase. The R33 phase supports studies relating the mechanism to functional or clinical effects. This R21/R33 mechanism is intended to speed the translation of emerging basic science findings into novel interventions in restoring function and reducing symptoms for those living with mental disorders.
- 6. What is the intent of the R01 FOA for Effectiveness Research?
This FOA is intended to support clinical trials that will determine the effectiveness of interventions, and to test hypotheses regarding moderators, mediators, and mechanisms of action of these interventions. The goal is to support clinical trials that test the therapeutic value of treatment and preventive interventions for which there is already evidence of efficacy, for use in community and practice settings, including research to evaluate the effectiveness or increase the clinical impact of pharmacologic, somatic, psychosocial (psychotherapeutic, behavioral), rehabilitative, and combination interventions to prevent or treat mental illness. This FOA can also support clinical trials to test patient-, provider-, organizational-, or systems-level services interventions to improve service access, engagement, quality, coordination, or delivery, with the goal of improved outcomes at the individual and population level.
Because the research covered under this announcement is focused on practice-relevant questions, applicants must justify the potential impact of the proposed intervention/services models on practice and public health in terms of the magnitude of likely improvements in key outcomes (e.g., effect size, safety/tolerability profile, value and efficiency, and dissemination potential), as compared to existing approaches. Effectiveness trials in response to this announcement should be designed not only to test the intervention effects on outcomes of interest, but also to explicitly address and re-confirm whether the intervention targets and associated change mechanisms identified under more controlled, efficacy conditions are operative in the effectiveness context.
- 7. What is the intent of the R34 FOA for Effectiveness and Services Research?
The purpose of this FOA is to encourage pilot research for: 1) effectiveness research on interventions with previously demonstrated efficacy, for use with broader target populations or for use in community practice settings, and 2) innovative services research directions that require preliminary testing or development. The approaches need to be justified in terms of their potential to substantially impact practice and public health and evidence regarding efficacy. This FOA does not support pilot treatment development trials. This FOA provides funding for evaluating the feasibility, tolerability, acceptability and safety of approaches to improving mental health or community functioning and modifying risk factors, and for obtaining the preliminary data needed as a pre-requisite to a larger-scale intervention trial (e.g., comparative effectiveness study, practical trial) or large-scale services study.
Applications should justify the potential impact of the proposed intervention/services models on practice and public health in terms of the magnitude of likely improvements in effect size, safety/tolerability profile, value and efficiency, or dissemination potential, as compared to existing approaches. Adaptations or augmentations of existing interventions should only be undertaken if there is an empirical rationale for the adaptation target and for the corresponding mechanism by which the adapted intervention or augmentation is expected to substantially enhance outcomes. For pilot tests of intervention effectiveness or service delivery approaches, the study should be designed to explicitly address whether the intervention engages the mechanism that is presumed to underlie the intervention effects.
- 8. How do I decide which FOA to apply for?
The NIMH strongly encourages potential applicants to talk with the Program Officers in the relevant portfolio area 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.
- 9. I want to apply for funding to test the efficacy of a novel intervention for which there is evidence of target engagement. Pilot studies provide evidence of feasibility, acceptability, and a signal for efficacy, but there is a need for a confirmatory, adequately powered clinical trial. Which FOA supports this type of trial?
The NIMH has issued RFA-MH-15-340 for non-pharmacological confirmatory efficacy trials. This FOA will support efficacy studies of behavioral, cognitive, interpersonal and device-based interventions. Currently, NIMH is not soliciting applications for Phase III efficacy trials of pharmacological interventions.
- 10. Where are applications submitted in response to these FOAs reviewed?
Applications submitted in response to these FOAs will be reviewed by special emphasis panels at the NIMH.
- 11. My trial does not fit any of these FOAs. Can I just submit an application to the parent NIH FOAs [PA-13-302 (R01) and PA-13-303 (R21)]?
No. The only trials currently allowed for submission under the parent FOAs are those for biomarker development. All other clinical trial applications submitted to the NIMH must be in response to specific FOAs and may not be submitted to any NIH parent FOA announcements.
- 12. Which types of clinical studies involving a clinical trial component may be submitted to the parent R01 or R21 announcements, as outlined in NOT-MH-14-007? Can collaborative R01 clinical studies be submitted?
a. Biomarker Studies: 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. To clarify, there are two scenarios in which a trial can be submitted under these mechanisms:
- i. Studies with aims that clearly indicate that the purpose of the study is biomarker development or refinement, including biomarkers of disorder and biomarkers of treatment response, and not an evaluation of efficacy. This exception does not apply to treatment development studies with biomarker measures as outcomes, regardless of whether efficacy is an outcome in the trial (e.g., a dose finding trial with an fMRI measure as a primary outcome). Clinical trials directed toward treatment development, including those that use only biomarkers as outcomes, must be submitted to one of the NIMH clinical trials FOAs.
- ii. Studies in which an intervention with known efficacy (e.g., an SSRI) is used as a manipulation to understand the pathophysiology of the disorder. The aims may include determination of mechanisms or biomarkers of disorder, but do not include efforts to demonstrate de novo efficacy.
- iii. Collaborative R01 clinical studies addressing the research areas described above can be submitted under PAR-14-165 , Clinical Studies of Mental Illness Not Involving Treatment Development, Efficacy, or Effectiveness Trials (Collaborative R01).
b. Follow-up analyses of previously completed clinical trials where no recruitment or interaction with participants will be conducted.
The exceptions noted above apply to biomedical treatments, as well as other efficacious interventions, including behavioral and cognitive approaches.
- 13. Are multi-site trials allowed?
Yes. NIMH strongly encourages prior discussion with Program Officers 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.
- 14. 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. 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. The NIMH will expect all agreements to be in place prior to release of funding.
- 15. 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.
- 16. Is data sharing encouraged? When are investigators expected to share the data?
Yes. NIMH will strongly encourage investigators to share raw, de-identified, individual-level data at the time of their regular progress reports. Program staff will work with the principal investigators to establish an appropriate data sharing plan and timeline for data to be available to the public prior to grant award. The NIMH is developing a process for managing these data when the data become available.
- 17. Is a recruitment plan required? Will the 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. Investigators with enrollment of 150 or more participants will be required to submit recruitment reports every 4 months. Failure to meet recruitment goals may result in withholding of funds or suspension of the trial.
- 18. 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.
- 19. 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.
- 20. 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 not use the parent R01 FOA.
- 21. 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.
- 22. I want to apply for funding to test whether a treatment intervention results in a more efficient and/or better-accepted care delivery strategy than usual care. I plan to randomize practices to using the intervention or not. Should I use the new Effectiveness Research FOA or the parent R01 FOA?
The proposed study is a clinical trial, so you should use the Effectiveness Research FOA.
- 23. What is a data and safety-monitoring plan?
A data and safety monitoring plan 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 intervention trials. For more information, see:NIH Policy for Data Sharing and Monitoring (NOT-98-084):
Further Guidance on Data and Safety Monitoring for Phase I and Phase II Trials (NOT-OD-00-038):
- 24. How does an applicant decide whether a Data Safety Monitoring Board (DSMB) is required?
- a. DSMBs are required for all multi-site clinical trials.
- b. DSMBs are generally required for Phase III clinical trials.
- c. A DSMB may be required for Phase I, Phase II, or Phase III clinical trials if:
- i. The clinical trial is blinded, or
- ii. The clinical trial involves high risk intervention(s), or
- iii. The clinical trial includes vulnerable population(s)
NIH FAQ: http://grants.nih.gov/grants/policy/hs/faqs_aps_dsm.htm#249
The NIMH Human Research Protection Unit (HRPU), in consultation with program staff, will provide oversight to determine the level of monitoring required for funded studies.
- 25. Can applicants propose to use a non NIMH (external) DSMB?
Yes. Applicants can propose an external DSMB. However, the funded external DSMB (i.e., constitution of membership, assessment of conflicts of interest, etc.) requires approval by the NIMH HRPU. Although the monitoring functions may be delegated to the grantee or an independent body (i.e., an external DSMB), NIH policies (cited above) require that the responsibility for oversight remains with the NIMH, and will be provided by the NIMH HRPU.
- 26. How are adverse events reported?
Investigators are required to report adverse events that are defined as routine to the Program Officer through the annual progress report. For adverse events that are defined as serious, the investigators must follow the reporting policy set by their respective Internal Review Board (IRB), and a copy of the report as well as the IRB deliberation should be sent to the NIMH and the external DSMB.
For more information, see: