- 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 factor that an intervention intends to modify, based on a hypothesis that modification of that factor will result in improvement of symptom, behavior, or functional outcomes. Targets can range from molecular, synaptic- and circuit-level sites proposed for pharmacologic agents, to neural systems and cognitive or emotional processes for psychotherapeutic interventions, to provider behavior, decision-making or organizational policies or behaviors for services interventions. An appropriate target is an intervening variable that has either been demonstrated to be associated with a clinical symptom or functional deficit, or is hypothesized (based on empirical evidence) to impact the biological pathway through which a clinical or functional benefit would be expected to occur, and thus is hypothesized to contribute to the intervention’s impact. In the case of services interventions, the intervention may target the patient (e.g., adherence), the provider (e.g., adherence to prescribing guidelines, fidelity in the delivery of research-supported psychosocial interventions), or the system/organization (e.g., organization climate, readiness to adopt evidence-based practices) in the service of improving access, engagement, or quality of mental health services. (See Table in FAQ3 below for a description of different examples of targets).
- 2.1. How do I incorporate targets into my trial design?
Successful applications to NIMH Clinical Trials FOAs will explicate a conceptual framework that clearly identifies the targeted mechanism and provides solid evidence of the relevance of that mechanism to the clinical symptom, behavior, or functional deficit that the intervention hopes 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.
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.). 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. However, all interventions should be able to demonstrate adequate target engagement, and make use of measures at multiple timepoints to inform questions of sequencing of intervention effects on proximal and distal measures (see chart in FAQ3), timing of improvement in the course of intervention, and other questions related to the optimal intensity of the intervention.
Clinical trials can then rigorously test whether this 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 support “rejecting” the target. Either outcome would be highly informative for the treatment development purpose.
- 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, MRS, EEG, MEG activation patterns Psychological or Behavioral Processes e.g., performance in attention bias paradigms, empathic accuracy, 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., organizational culture, climate, and/or structure, financing models, leadership, coordination/collaboration within and across systems
- 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. My trial does not fit any of these FOAs. Can I just submit an application to the parent NIH FOAs [PA-13-302 (R01), PA-13-303 (R21), and PA-13-304 (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 FAQ#10. All other treatment development clinical trial applications submitted to the NIMH must be in response to specific NIMH Clinical Trials FOAs and may not be submitted to any NIH parent FOA announcements.
- 10. 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). 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 or PAR14-165.
- 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 new treatments as part of their aims 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 for depression) is used as a manipulation to understand mechanisms of response, non-response, or risk of adverse effects of an 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 in which an intervention with known physiological effect (e.g., a neurotransmitter agonist, or activation of specific neurocircuitry via neurostimulation) is used as a manipulation to understand the pathophysiology of the disorder, but does not aim to establish efficacy or further treatment development. Evidence of adequate physiological effect at the intervention dose or intensity to be used must be clearly documented in the application.*
- 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.*
- 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.**
*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.
- 11. 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. I do not see a RFA that would support this type of trial. Should I use the parent R01 FOA?
Confirmatory Efficacy Clinical Trial applications are accepted under RFA-MH-15-340 , “Confirmatory Efficacy Clinical Trials of Non-Pharmacological Interventions for Mental Disorders (R01)”. The types of non-pharmacological interventions accepted under this RFA include but are not limited to: behavioral, cognitive, interpersonal approaches, or a combination thereof. Interventions using devices will also be accepted; however, given the varied nature of the regulatory path, investigators considering applications to evaluate devices are strongly encouraged to contact Scientific/Research Staff as early as possible to discuss these issues. For pharmacological studies, it is anticipated that industry will play a significant role in supporting such studies.
- 12. 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.
- 12.1: 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 every RFA issued by NIH.) Thus, applications submitted in response to the clinical trial RFAs are reviewed for responsiveness prior to 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. Of the applications received for the first receipt date (June/July 2014) for the clinical trial RFAs, approximately 27% of the applications were returned (across all the RFAs combined) as non-responsive.
To ensure that this does not happen to you, please carefully review two important sections of the FOA:
- Within Section I 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 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.
There are some common problems that have resulted in applications to the clinical trials RFAs being returned. For the R21/R33 RFA, one common problem was 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 RFAs (R34/R01/Collaborative R01), a common problem was the lack of a strong empirical justification on the need for an adaptation of a proposed intervention. Some applications lacked study participant and recruitment descriptors or a lack of evidence of an IND, IDE or documented FDA-submitted application for studies of pharmacologic compounds and devices. Very significantly, some applications proposed study designs that were not in alignment with the experimental therapeutics goals of the RFAs. As such, we strongly recommend that applicants discuss their study plans with their Program Officer early in the development their application.
- 13. I am an early career investigator who is eligible to apply for a mentored K from the 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 funding priority will be consistent with the stated research goals and priorities relevant to clinical trials as outlined in the clinical trials FOAs. 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. Please see Agency Contacts: (http://www.nimh.nih.gov/funding/training/contacts-for-research-training-and-career-development-programs.shtml). Such early contact will provide an opportunity to ascertain NIMH policies and guidelines as well as to discuss how to develop an appropriate project timeline. For additional information please see: Guidance for NIMH Mentored K Applicants Proposing Clinical Trials: http://www.nimh.nih.gov/funding/training/career-development-programs-k-series.shtml#12
- 14. 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.
- 15. 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.
- 16. 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.
- 17. 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 making data available to the public prior to grant award. The NIMH is developing a process for managing these data when the data become available. More information about NIMH expectations regarding the sharing of clinical trials data can be found in Guide Notice NOT-MH-14-105 .
- 18. 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.
- 19. 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.
- 20. 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.
- 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 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-15-320 (R01) or RFA-MH-15-325 (Collaborative R01), Clinical Trials to Test the Effectiveness of Treatment, Preventive, and Services Interventions; and RFA-MH-15-330 (R34), Pilot Effectiveness Studies and Services Research Grants.
- 22. 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.
- 23. 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.
- 24. 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):
- 25. 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.
- 26. 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.
- 27. 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:
- 28. What materials can be included an appendix of an NIMH clinical trial application?
The following materials may be included in an appendix:
- Published manuscripts and/or abstracts only when a free, online, publicly available journal link is not available;
- Manuscripts and/or abstracts accepted for publication but not yet published;
- Patents materials directly relevant to the project;
- Surveys, questionnaires, data collection instruments;
- Intervention protocols and manuals;
- Informed consent documents
No more than three manuscripts may be included per application. Most importantly, the appendices should not be used to circumvent the page limitations of the Research Strategy.