National Institutes of Health (NIH)
National Institute of Mental Health (NIMH)
Funding Opportunity Title
First in Human and Early Stage Clinical Trials of Novel Investigational Drugs or Devices for Psychiatric Disorders (U01)
U01 Research Project – Cooperative Agreements
Reissue of PAR-12-007
Funding Opportunity Announcement (FOA) Number
Companion Funding Opportunity
Catalog of Federal Domestic Assistance (CFDA) Number(s)
Funding Opportunity Purpose
The purpose of this Funding Opportunity Announcement (FOA) is to encourage cooperative agreement applications to support early stage clinical trials of novel mechanism of action, investigational drugs or drug candidates for the treatment of psychiatric disorders in areas of unmet medical need. The FOA will support milestone-driven early stage trials in pediatric and adult populations. First in human (FIH) and Phase Ib studies of novel Agents must assess target engagement (brain exposure), pharmacological effects, safety, and tolerability to assess feasibility for Phase II/proof of concept (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 FOA also supports feasibility and pilot studies of novel devices. The overall objective is to facilitate rapid collection of data to "de-risk" novel mechanism of action investigational drugs, novel drugs for use in pediatric populations with psychiatric disorders, devices or combination treatments in order to attract private funding for further clinical development as FDA-approved treatments. A key aspect of this FOA is the formation of collaborative partnerships between the biomedical researchers and biotechnology or industry researchers to facilitate psychiatric drug or device development.
February 24, 2014
Open Date (Earliest Submission Date)
May 5, 2014
Letter of Intent Due Date(s)
30 days before the application due date
Application Due Date(s)
Standard dates apply, by 5:00 PM local time of applicant organization.
Applicants are encouraged to apply early to allow adequate time to make any corrections to errors found in the application during the submission process by the due date.
AIDS Application Due Date(s)
Scientific Merit Review
Standard dates apply
Advisory Council Review
Standard dates apply
Earliest Start Date
Standard dates apply
May 8, 2017
Due Dates for E.O. 12372
Required Application Instructions
It is critical that applicants follow the instructions in the SF424 (R&R) Application Guide, except where instructed to do otherwise (in this FOA or in a Notice from the NIH Guide for Grants and Contracts). Conformance to all requirements (both in the Application Guide and the FOA) is required and strictly enforced. Applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions. Applications that do not comply with these instructions may be delayed or not accepted for review.
Part 1. Overview Information
Part 2. Full Text of the Announcement
Section I. Funding Opportunity Description
Section II. Award Information
Section III. Eligibility Information
Section IV. Application and Submission Information
Section V. Application Review Information
Section VI. Award Administration Information
Section VII. Agency Contacts
Section VIII. Other Information
Although many promising novel therapeutic targets for treating psychiatric disorders have been discovered in recent years, the translation into effective treatments has been unacceptably slow. For those Agents advancing to clinical testing, the success rate of new drug approvals for psychiatric disorders has been poor, with candidates often failing in late stage clinical trials after significant investment. In too many cases, the reasons for trial failures remain unclear but might include, for example, patient heterogeneity, unfavorable drug characteristics (toxicity, poor target engagement, sub-optimal pharmacokinetic (PK)/pharmacodynamics (PD) parameters), or inappropriate biological targets for the disorder. This situation has contributed to the decrease in pharmaceutical companies’ investment in psychiatric drug development and enlarged the “valley of death” for drug development.
The NIMH and NIH provide funding support and research resources to facilitate drug discovery/development of novel medications for psychiatric disorders through several avenues (see http://www.nimh.nih.gov/research-funding/therapeutics/index.shtml). A report of the National Advisory Mental Health Council’s Workgroup, entitled, From Discovery to Cure: Accelerating the Development of New and Personalized Interventions for Mental Illness evaluated NIMH’s portfolio, and funding opportunities/resources for drug discovery/development in light of the current trend of pharmaceutical companies and venture capital to decrease their investments in clinical trials for central nervous system (CNS) disorders. One of the recommendations of this workgroup was for NIMH to invest in early stage clinical trials of novel Agents that act on novel molecular pathways (receptors, enzymes, second messengers, etc.) that are not targeted with currently available psychiatric drugs, and that have a strong justification as a novel mechanism for the treatment of psychiatric disorders. In addition, a recommendation was made that such trials include biological measures to assess target engagement in brain and evaluate the Agent’s mechanism of action in humans. The incorporation of these additional measures into early stage trials is intended to provide very early signs of potential failure or success of the Agent and help inform whether further later stage trials should be considered.
While there have been far fewer examples of FDA-regulated devices being tested for the treatment of psychiatric indications, there are potential opportunities for these interventions as well. Therefore, this FOA also intends to support early stage clinical trials of devices, and expects that objective CNS measures of the device’s action on the brain be included in the trial design as a parallel to the drug development effort. Only FDA-regulated devices are included in this initiative, not computer-based devices.
The intent of this FOA is to test new mechanism of action Agents (defined as investigational drugs, drug candidates, rescued or repurposed drugs) in early stage trials (i.e., first in human (FIH), Phase Ib, and Phase II proof of concept (PoC) studies) using experimental medicine approaches to address unmet medical need for the treatment of psychiatric disorders. For this FOA, Phase Ib and Phase II/PoC trials are defined as follows: Phase Ib trials are defined as studies usually conducted in the target patient population to establish feasibility (e.g., target engagement, pharmacodynamics/pharmacokinetics (PD/PK), optimal dosing of the Agent) for a Phase II/PoC. Phase II/PoC trials are defined as studies designed to explore new hypotheses and to assess whether the Agent demonstrates an early signal of efficacy in the targeted patient population. In addition to clinical benefit, Phase II/PoC trials also include assessments of safety, tolerability, and PD/PK response of the Agent. Strategies to inform the selection of patients for PoC studies of the novel candidate Agent (e.g., approaches to segment or enrich subjects for inclusion in the trial) are strongly encouraged.
The overall objective of this FOA is to facilitate rapid collection of data to "de-risk" novel mechanism of action investigational drugs, rescued, or repurposed drugs for use in psychiatric disorders, in order to attract private funding for further clinical development of the Agent as an FDA-approved medication. In addition to the adult FIH and PoC studies, support is also provided for novel, first in children pharmacologic Agents in pediatric populations (i.e., first exposure in children or first in pediatric indication). A key aspect of this FOA is the formation of collaborative partnerships between the biomedical researchers and biotechnology or industry partners to facilitate psychiatric drug development. In cases where the PoC studies are successful, it is anticipated that the biotechnology or pharmaceutical company partner will pursue further clinical development of the Agent whenever feasible.
The FOA will support stand-alone FIH, Phase Ib or Phase II/PoC studies or a combination of these, with rigorous milestone-based go/no go decisions to progress from one study to the next if multiple trials are proposed. The duration of the project must be appropriate for the proposed project with a maximum of 1 year allowed for completion of a FIH or Phase Ib study and 3 years for a PoC study (4 year maximum for applications to complete both phases). FIH studies should assess Agent: 1) safety and tolerability, 2) target engagement, and 3) pharmacological effects on relevant circuits or systems ). Data resulting from FIH studies and Phase Ib trials in the target patient population are expected to determine optimal clinical dosing and to establish feasibility for further testing in PoC and efficacy trials. Agents must be sufficiently potent and selective for critical evaluation of target engagement and brain exposure. The Agent/indication (if successful) should have a major, not merely incremental, impact on unmet medical need in psychiatric disorders.
Phase II/PoC studies must assess the clinical efficacy signal of novel Agents using pharmacologically-based dosing, with validation of target engagement and exposure in brain, and must include biological measures of impact of the Agent on clinically relevant physiological systems to assess the link between hypothesized drug mechanism/target and clinical effect. PoC studies must be sufficiently powered to assess Agent impact (magnitude and duration of target modulation) on a physiological process that is associated with the clinical outcome measure (e.g., cognition, social function) and an outcome measure to assess clinical benefit must be included.
This FOA also supports feasibility and pivotal trials for novel FDA-regulated devices. For devices, the same experimental medicine strategy is expected, but under regulatory safety considerations for devices instead of drugs.
Overall, the goal is to "de-risk" novel mechanism of action investigational drugs or devices in order to attract private funding for further clinical development as FDA-approved treatments. These studies will: 1) accelerate the testing of new therapeutics for psychiatric disorders, 2) facilitate the validation of biological targets for therapeutic development, and 3) provide data assessing the relationship between clinical measures and biological indicators (mechanistic or PD biomarkers) of effect.
It is expected that successful applications will likely include multi-disciplinary teams of scientists with appropriate expertise for experimental evaluation and the clinical development of novel treatments. Scientists from both academia and biotechnology or pharmaceutical industry are encouraged to participate on the project. As an example, while an academic institution may be submitting the application, the company would be providing the Agent, input on trial design, and Agent know-how into the project. It is anticipated that the interaction of academic and non-profit research institutions with NIH and pharmaceutical industry will facilitate timely clinical evaluation and development of novel therapeutics. Applicants should outline proposed plans for further development of promising clinical candidates that are tested in the FIH, Phase Ib, and/or PoC studies through this program.
Prior to award, there must be an IND or IDE in place with the FDA for the proposed intervention. In addition, there should be documentation verifying the full participation of the pharmaceutical or biotechnology partner for rescue/repurpose studies and sufficient Agent supply to complete the study, and additional required documentation (e.g., confidential disclosure agreements (CDAs), collaborative research agreements (CRAs), licensing agreements, etc.). Timelines for submission of all documentation should be provided in the submitted application. It is expected that such documentation would be initiated early in the process of developing the application. Lack of appropriate documentation at the time of award could influence funding decisions.
For multi-site trials, use of centralized IRBs is encouraged. The number of trial sites should be limited to minimize variability of the data.
Strong subject recruitment is expected in these trials due to shortened timelines allowed for conducting the trials. Therefore a recruitment plan must be included and the notice of award will include the expectation that these recruitment goals will be met.
The testing of established or well-studied Agents for the treatment of psychiatric disorders is not the focus of this FOA. Such applications would be considered of very low priority.
Only FIH, Phase Ib, and Phase II/PoC studies of novel Agents on the regulatory path are appropriate for this announcement. Please refer to www.clinicaltrials.gov for a listing of Agents/mechanisms of action that are currently in trials in order to determine if the trial(s) is: 1) relevant to the proposed work, and could help inform the design of the U01 application; or 2) may be duplicative of the proposed application and therefore limit the innovation in the proposed application. Relevant trials should be acknowledged in the application.
Applicants are strongly encouraged to contact the relevant Scientific/Research Contact listed in Section VII of this FOA to determine: 1) if the proposed Agent/mechanism of action and clinical indication would be considered a priority for NIMH; and 2) if this, or other clinical trials FOAs, may be more appropriate for the proposed work. Applicants are also strongly encouraged to review the information on the NIMH website focused on clinical trials http://www.nimh.nih.gov/funding/clinical-trials-for-researchers/index.shtml.
Cooperative Agreement: A support mechanism used when there will be substantial Federal scientific or programmatic involvement. Substantial involvement means that, after award, NIH scientific or program staff will assist, guide, coordinate, or participate in project activities.
Application Types Allowed
The OER Glossary and the SF424 (R&R) Application Guide provide details on these application types.
Funds Available and Anticipated Number of Awards
The number of awards is contingent upon NIH appropriations and the submission of a sufficient number of meritorious applications.
Application budgets are not limited but need to reflect the actual needs of the proposed project.
Award Project Period
The total project period for an application submitted in response to this FOA may not exceed one year for FIH or Phase Ib and 3 years for PoC trials. Only applications that include both FIH and PoC trials may request 4 years. NIMH encourages shorter project periods.
NIH grants policies as described in the NIH Grants Policy Statement will apply to the applications submitted and awards made in response to this FOA.
Higher Education Institutions
The following types of Higher Education Institutions are always encouraged to apply for NIH support as Public or Private Institutions of Higher Education:
Nonprofits Other Than Institutions of Higher Education
Non-domestic (non-U.S.) Entities (Foreign Institutions) are
not eligible to apply.
Non-domestic (non-U.S.) components of U.S. Organizations are not eligible to apply.
Foreign components, as defined in the NIH Grants Policy Statement, are allowed.
Applicant organizations must complete and maintain the following registrations as described in the SF 424 (R&R) Application Guide to be eligible to apply for or receive an award. All registrations must be completed prior to the application being submitted. Registration can take 6 weeks or more, so applicants should begin the registration process as soon as possible. The NIH Policy on Late Submission of Grant Applications states that failure to complete registrations in advance of a due date is not a valid reason for a late submission.
Program Directors/Principal Investigators (PD(s)/PI(s))
All PD(s)/PI(s) must have an eRA Commons account and should work with their organizational officials to either create a new account or to affiliate an existing account with the applicant organization’s eRA Commons account. If the PD/PI is also the organizational Signing Official, they must have two distinct eRA Commons accounts, one for each role. Obtaining an eRA Commons account can take up to 2 weeks.
Any individual(s) with the skills, knowledge, and resources
necessary to carry out the proposed research as the Program Director(s)/Principal
Investigator(s) (PD(s)/PI(s)) is invited to work with his/her organization to
develop an application for support. Individuals from underrepresented racial
and ethnic groups as well as individuals with disabilities are always
encouraged to apply for NIH support.
For institutions/organizations proposing multiple PDs/PIs, visit the Multiple Program Director/Principal Investigator Policy and submission details in the Senior/Key Person Profile (Expanded) Component of the SF424 (R&R) Application Guide.
This FOA does not require cost sharing as defined in the NIH Grants Policy Statement.
Applicant organizations may submit more than one application, provided that each application is scientifically distinct.
NIH will not accept any application that is essentially the same as one already reviewed within the past thirty-seven months (as described in the NIH Grants Policy Statement), except for submission:
Applicants must download the SF424 (R&R) application package associated with this funding opportunity using the “Apply for Grant Electronically” button in this FOA or following the directions provided at Grants.gov.
It is critical that applicants follow the instructions in the SF424 (R&R) Application Guide, except where instructed in this funding opportunity announcement to do otherwise. Conformance to the requirements in the Application Guide is required and strictly enforced. Applications that are out of compliance with these instructions may be delayed or not accepted for review.
For information on Application Submission and Receipt, visit Frequently Asked Questions – Application Guide, Electronic Submission of Grant Applications.
Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows IC staff to estimate the potential review workload and plan the review.
By the date listed in Part 1. Overview Information, prospective applicants are asked to submit a letter of intent that includes the following information:
The letter of intent should be sent to:
Lois Winsky, Ph.D.
6001 Executive Boulevard. Room 7185, MSC 9641
Bethesda, MD 20892-9641
Rockville, MD 20852 (for express/courier service; non-USPS service)
All page limitations described in the SF424 Application Guide and the Table of Page Limits must be followed.
The forms package associated with this FOA includes all applicable components, required and optional. Please note that some components marked optional in the application package are required for submission of applications for this FOA. Follow all instructions in the SF424 (R&R) Application Guide to ensure you complete all appropriate “optional” components.
The following section supplements the instructions found in the SF424 (R&R) Application Guide and should be used for preparing an application to this FOA.
All instructions in the SF424 (R&R) Application Guide must be followed.
All instructions in the SF424 (R&R) Application Guide must be followed.
All instructions in the SF424 (R&R) Application Guide must be followed.
All instructions in the SF424 (R&R) Application Guide must be followed with the following additional instructions:
Biotechnology and pharmaceutical partners should include key personnel who have authority within the company to allocate resources to ensure successful completion of the proposed discovery and development efforts.
It is expected that successful applications will likely include multi-disciplinary teams of scientists with appropriate expertise for experimental evaluation and the clinical development of novel treatments. Scientists from both academia and biotechnology or pharmaceutical industry are encouraged to participate on the project. As an example, while an academic institution may be submitting the application, the company would be providing the Agent, input on trial design, and Agent know-how into the project. It is anticipated that the interaction of academic and non-profit research institutions with NIH and pharmaceutical industry will facilitate timely clinical evaluation and development of novel therapeutics.
All instructions in the SF424 (R&R) Application Guide must be followed.
All instructions in the SF424 (R&R) Application Guide must be followed.
All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions:
Research Strategy: For FIH, Phase Ib and Phase II/PoC studies, a clear description must be included of the approach for determining pharmacological dose/response relationships and target engagement of the drug candidate. Beyond these requirements, PoC studies also require a compelling scientific rationale for biological measures (mechanistic biomarkers) used to assess the link between hypothesized drug mechanism/target and clinical effect.
FIH studies should assess Agent: 1) safety and tolerability, 2) target engagement, and 3) pharmacological effects on relevant circuits or systems. Data resulting from FIH studies and Phase Ib trials in the target patient population are expected to determine optimal clinical dosing and to establish feasibility for further testing in PoC and efficacy trials. Agents must be sufficiently potent and selective for critical evaluation of target engagement and brain exposure. The Agent/indication (if successful) should have a major, not merely incremental, impact on unmet medical need in psychiatric disorders.
Subject selection must be well justified and would ideally ensure the individuals have the abnormality in the CNS pathway being studied; objective, biological measures should be used when feasible for subject selection. PoC studies should incorporate FDA-accepted clinical outcome measures to assess potential efficacy in addition to the biological measures. In selecting biological measures, applicants are encouraged to incorporate measures consistent with the goals of the NIMH RDoC framework (http://www.nimh.nih.gov/research-funding/nimh-research-domain-criteria-rdoc.shtml). Overall, the inclusion of biomarkers in the design of the study is encouraged, when appropriate: e.g., the inclusion of PK/PD biomarkers to assess target engagement, brain exposure and functional pharmacological activity of the Agent or the use of molecular markers of disease, pharmacogenomics, or other biomarkers as patient selection strategies. The goals of the Phase II/ PoC trials are to determine that the Agent modulates the target/mechanism and shows potential for efficacy in the proposed disease population, thereby building scientific data to "de-risk" the further clinical development of the Agent for a new therapeutic use that has not previously been explored.
The application must include a clear description of the outcome measures; subject eligibility criteria; recruitment and retention strategies; procedures to avoid bias in allocation of subjects to treatment and in assessment of outcomes; the treatment regimen; and subject follow-up procedures. Statistical methods must be proposed that are appropriately matched to the study design. Sample size, power calculations, and plans for analyses, data management, and quality control must be included.
A plan for robust subject recruitment must be included that addresses the shorter trial duration. Failure to maintain the planned recruitment rate could result in trial termination.
The application must include the status of all regulatory clearances necessary to conduct the proposed trial (e.g., status of the IND). IRB approval is not required at the time of application submission, but is required prior to funding, so NIMH encourages investigators to begin this process as early as possible. For multi-site trials, use of centralized IRBs is encouraged. The number of trial sites should be limited to minimize variability of the data.
Timeline and Milestones: The grant application should include a proposed timeline for reaching important study milestones such as: 1) obtaining IRP approval and regulatory clearance for the protocol, 2) establishing agreements with participating industry partners, 3) obtaining adequate supply of the investigational Agent or device, 4) finalizing the study procedures and training participating clinical site staff, and 5) enrolling 25%, 50%, 75% and 100% of the sample size.
A plan must be described for decision-making regarding identification and evaluation of promising drug candidates or devices for development. All applications must include clearly-specified, well-defined milestones, go/no go decision points, and timelines for assessing progress. In addition, if the proposed research includes both FIH or Phase Ib as well as PoC studies in patients, specific milestones and go/no-go criteria should be described for assessing the appropriateness of progressing to PoC studies.
Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans (Data Sharing Plan, Sharing Model Organisms, and Genome Wide Association Studies (GWAS)) as provided in the SF424 (R&R) Application Guide, with the following modification:
Appendix: Do not use the Appendix to circumvent page limits. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.
When conducting clinical research, follow all instructions for completing Planned Enrollment Reports as described in the SF424 (R&R) Application Guide.
When conducting clinical research, follow all instructions for completing Cumulative Inclusion Enrollment Report as described in the SF424 (R&R) Application Guide.
Part I. Overview Information contains information about Key Dates. Applicants are encouraged to submit applications before the due date to ensure they have time to make any application corrections that might be necessary for successful submission.
Organizations must submit applications to Grants.gov (the online portal to find and apply for grants across all Federal agencies). Applicants must then complete the submission process by tracking the status of the application in the eRA Commons, NIH’s electronic system for grants administration. NIH and Grants.gov systems check the application against many of the application instructions upon submission. Errors must be corrected and a changed/corrected application must be submitted to Grants.gov on or before the application due date. If a Changed/Corrected application is submitted after the deadline, the application will be considered late.
Applicants are responsible for viewing their application before the due date in the eRA Commons to ensure accurate and successful submission.
Information on the submission process and a definition of on-time submission are provided in the SF424 (R&R) Application Guide.
This initiative is not subject to intergovernmental review.
All NIH awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.
Pre-award costs are allowable only as described in the NIH Grants Policy Statement.
Applications must be submitted electronically following the instructions described in the SF424 (R&R) Application Guide. Paper applications will not be accepted.
Applicants must complete all required registrations before the application due date. Section III. Eligibility Information contains information about registration.
For assistance with your electronic application or for more information on the electronic submission process, visit Applying Electronically.
All PD(s)/PI(s) must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile Component of the SF424(R&R) Application Package. Failure to register in the Commons and to include a valid PD/PI Commons ID in the credential field will prevent the successful submission of an electronic application to NIH. See Section III of this FOA for information on registration requirements.
The applicant organization must ensure that the DUNS number it provides on the application is the same number used in the organization’s profile in the eRA Commons and for the System for Award Management. Additional information may be found in the SF424 (R&R) Application Guide.
See more tips for avoiding common errors.
Upon receipt, applications will be evaluated for completeness by the Center for Scientific Review, NIH. Applications that are incomplete will not be reviewed.
NIH encourages the use of common data elements (CDEs) in clinical and applied research, patient registries, and other human subject research to facilitate broader and more effective use of data and advance research across studies. CDEs are data elements that have been identified and defined for use in multiple data sets across different studies. Use of CDEs can facilitate data sharing and standardization to improve data quality and enable data integration from multiple studies and sources, including electronic health records. NIH has established a “Common Data Element (CDE) Resource Portal" (http://cde.nih.gov/) to assist investigators in identifying NIH-supported CDEs when developing protocols, case report forms, and other instruments for data collection. The Portal provides guidance about and access to NIH-supported CDE initiatives and other tools and resources for the appropriate use of CDEs and data standards in NIH-funded research. Investigators are encouraged to consult the Portal and describe in their applications any use they will make of NIH-supported CDEs in their projects.
Applicants requesting $500,000 or more in direct costs in any year (excluding consortium F&A) must contact NIH program staff at least 6 weeks before submitting the application and follow the Policy on the Acceptance for Review of Unsolicited Applications that Request $500,000 or More in Direct Costs as described in the SF424 (R&R) Application Guide.
Applicants are required to follow the instructions for post-submission materials, as described in NOT-OD-13-030.
Only the review criteria described below will be considered in the review process. As part of the NIH mission, all applications submitted to the NIH in support of biomedical and behavioral research are evaluated for scientific and technical merit through the NIH peer review system.
Reviewers will provide an overall impact score to reflect their assessment of the likelihood for the project to exert a sustained, powerful influence on the research field(s) involved, in consideration of the following review criteria and additional review criteria (as applicable for the project proposed).
Reviewers will consider each of the review criteria below in the determination of scientific merit, and give a separate score for each. An application does not need to be strong in all categories to be judged likely to have major scientific impact. For example, a project that by its nature is not innovative may be essential to advance a field.
Does the project address an important problem or a critical barrier to progress in the field? If the aims of the project are achieved, how will scientific knowledge, technical capability, and/or clinical practice be improved? How will successful completion of the aims change the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field?
Is there a strong biological rationale for clinical trials to advance the investigational drug or drug candidate or device for development as a potential treatment for psychiatric disorders? Does the study design evaluate the link between the presumed physiological target of the treatment and clinical effects? Will sufficient data be collected to "de-risk" the candidate therapeutic for further clinical development? Does the therapeutic drug candidate or device address an area of unmet medical need for interventions for psychiatric disorders? Does the experimental Agent or device represent a potentially significant advancement over existing treatments? Does the experimental Agent or device hold promise of being utilized in clinical practice?
Are the PD(s)/PI(s), collaborators, and other researchers well suited to the project? If Early Stage Investigators or New Investigators, or in the early stages of independent careers, do they have appropriate experience and training? If established, have they demonstrated an ongoing record of accomplishments that have advanced their field(s)? If the project is collaborative or multi-PD/PI, do the investigators have complementary and integrated expertise; are their leadership approach, governance and organizational structure appropriate for the project?
Is there evidence of proven expertise in recruiting subjects and conducting the FIH, Phase 1b and/or PoC trial and performing pharmacological and functional measures of target engagement? Is there a letter of support or other evidence of involvement of the private sector partner providing the investigational drug, drug candidate or device for the proposed studies, if a partner is proposed? Does the investigative team have sufficient methodological and statistical expertise (e.g., handling repeated measures designs, missing data, effect size) in the study and measurement of intervention change mechanisms? Is the staffing, governance, and organizational structure appropriate for conducting the study as proposed and within specified timelines? Is there a description of the expertise needed by any potential consultants?
Does the application challenge and seek to shift current research or clinical practice paradigms by utilizing novel theoretical concepts, approaches or methodologies, instrumentation, or interventions? Are the concepts, approaches or methodologies, instrumentation, or interventions novel to one field of research or novel in a broad sense? Is a refinement, improvement, or new application of theoretical concepts, approaches or methodologies, instrumentation, or interventions proposed?
Are the therapeutic targets, mechanisms, or measures to assess target biology considered to be novel?
Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Are potential problems, alternative strategies, and benchmarks for success presented? If the project is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed?
Is there a compelling scientific rationale for the clinical target? Is there a strong justification for the approach for determining pharmacological effects and target engagement of the drug candidate? Is the approach feasible? Is there a compelling scientific rationale for the biological measures (mechanistic biomarker) used to assess the link between hypothesized drug or device mechanism/target and clinical effect?
Are the clinical measures appropriate? Are proposed statistical methods appropriate for the study design? Is there a clear rationale for sample size based on power calculations? Are plans for analyses, data management, and quality control adequate?
Is the approach feasible in terms of realistically having in place everything necessary to carry out data acquisition and analysis in a timely manner?
If the application plans to progress from FIH studies in normal subjects to Phase Ib studies or to PoC studies in patients, are specific milestones and go/no-go criteria described for assessing the biological validity and feasibility of progressing to PoC studies?
If the project involves human subjects and/or NIH-defined clinical research, are the plans to address 1) the protection of human subjects from research risks, and 2) inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion or exclusion of children, justified in terms of the scientific goals and research strategy proposed?
Are subject inclusion criteria well justified and likely to show abnormality in the CNS pathway being studied? Are the recruitment strategy and plan well justified and feasible? Are clear, actionable study milestones proposed, including feasible subject accrual goals? Are likely problems anticipated?
Will the scientific environment in which the work will be done contribute to the probability of success? Are the institutional support, equipment and other physical resources available to the investigators adequate for the project proposed? Will the project benefit from unique features of the scientific environment, subject populations, or collaborative arrangements?
When pharmaceutical industry partners are involved, are key personnel included who have authority within the company to allocate resources to ensure successful completion of the proposed discovery and development efforts? Are the necessary agreements in place? Is there evidence that all necessary regulatory clearances and permissions (e.g., IND or IDE, permissions for rating scales) have been obtained or will be in place before funding?
As applicable for the project proposed, reviewers will evaluate the following additional items while determining scientific and technical merit, and in providing an overall impact score, but will not give separate scores for these items.
Milestones and Timeline
Are appropriate, evaluative milestones clearly defined for the aims associated with each stage of the early phase trials? Are milestones feasible, well developed, and quantifiable with regard to the specific aims of each stage? Is the timeline feasible? Are adequate criteria provided to assess milestone completion and operational feasibility of advancing from FIH to Phase Ib studies and/or PoC studies? Is strong subject recruitment described, especially given the shortened timelines expected for conducting the trials?
Protections for Human Subjects
For research that involves human subjects but does
not involve one of the six categories of research that are exempt under 45 CFR
Part 46, the committee will evaluate the justification for involvement of human
subjects and the proposed protections from research risk relating to their
participation according to the following five review criteria: 1) risk to
subjects, 2) adequacy of protection against risks, 3) potential benefits to the
subjects and others, 4) importance of the knowledge to be gained, and 5) data
and safety monitoring for clinical trials.
For research that involves human subjects and meets the criteria for one or more of the six categories of research that are exempt under 45 CFR Part 46, the committee will evaluate: 1) the justification for the exemption, 2) human subjects involvement and characteristics, and 3) sources of materials. For additional information on review of the Human Subjects section, please refer to the Guidelines for the Review of Human Subjects.
Inclusion of Women, Minorities, and Children
When the proposed project involves human subjects and/or NIH-defined clinical research, the committee will evaluate the proposed plans for the inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion (or exclusion) of children to determine if it is justified in terms of the scientific goals and research strategy proposed. For additional information on review of the Inclusion section, please refer to the Guidelines for the Review of Inclusion in Clinical Research.
The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following five points: 1) proposed use of the animals, and species, strains, ages, sex, and numbers to be used; 2) justifications for the use of animals and for the appropriateness of the species and numbers proposed; 3) adequacy of veterinary care; 4) procedures for limiting discomfort, distress, pain and injury to that which is unavoidable in the conduct of scientifically sound research including the use of analgesic, anesthetic, and tranquilizing drugs and/or comfortable restraining devices; and 5) methods of euthanasia and reason for selection if not consistent with the AVMA Guidelines on Euthanasia. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animal Section.
Reviewers will assess whether materials or procedures proposed are potentially hazardous to research personnel and/or the environment, and if needed, determine whether adequate protection is proposed.
For Resubmissions, the committee will evaluate the application as now presented, taking into consideration the responses to comments from the previous scientific review group and changes made to the project.
For Revisions, the committee will consider the appropriateness of the proposed expansion of the scope of the project. If the Revision application relates to a specific line of investigation presented in the original application that was not recommended for approval by the committee, then the committee will consider whether the responses to comments from the previous scientific review group are adequate and whether substantial changes are clearly evident.
As applicable for the project proposed, reviewers will consider each of the following items, but will not give scores for these items, and should not consider them in providing an overall impact score.
Applications from Foreign Organizations
Select Agent Research
Reviewers will assess the information provided in this section of the application, including 1) the Select Agent(s) to be used in the proposed research, 2) the registration status of all entities where Select Agent(s) will be used, 3) the procedures that will be used to monitor possession use and transfer of Select Agent(s), and 4) plans for appropriate biosafety, biocontainment, and security of the Select Agent(s).
Resource Sharing Plans
Reviewers will comment on whether the following Resource Sharing Plans, or the rationale for not sharing the following types of resources, are reasonable: 1) Data Sharing Plan; 2) Sharing Model Organisms; and 3) Genome Wide Association Studies (GWAS).
Budget and Period of Support
Reviewers will consider whether the budget and the requested period of support are fully justified and reasonable in relation to the proposed research.
Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s) convened by the NIMH, in accordance with NIH peer review policy and procedures, using the stated review criteria. Assignment to a Scientific Review Group will be shown in the eRA Commons.
As part of the scientific peer review, all applications:
Applications will be assigned on the basis of established PHS referral guidelines to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications. Following initial peer review, recommended applications will receive a second level of review by the National Advisory Mental Health Council. The following will be considered in making funding decisions:
After the peer review of the application is completed, the PD/PI will be able to access his or her Summary Statement (written critique) via the eRA Commons.
Information regarding the disposition of applications is available in the NIH Grants Policy Statement.
If the application is under consideration for funding, NIH will request "just-in-time" information from the applicant as described in the NIH Grants Policy Statement.
Prior to funding an application, the NIMH
Program Officer will contact the applicant to discuss the proposed milestones
and any changes suggested by the review panel as indicated in the Summary Statement.
The Program Officer and the applicant will negotiate and agree on a final set
of milestones. For funded applications proposing both the FIH and PoC
studies, the PD/PI will submit a progress report to the Program Officer upon
completion of the FIH studies in the first year. Receipt of this progress
report will trigger an administrative program review that will determine
whether or not the PoC should be awarded along with the additional years of
funding. The release of the additional years of funding funds will be
based on successful completion of negotiated FIH scientific milestones, on
program priorities, and on the availability of funds.
A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant organization for successful applications. The NoA signed by the grants management officer is the authorizing document and will be sent via email to the grantee’s business official.
Awardees must comply with any funding restrictions described in Section IV.5. Funding Restrictions. Selection of an application for award is not an authorization to begin performance. Any costs incurred before receipt of the NoA are at the recipient's risk. These costs may be reimbursed only to the extent considered allowable pre-award costs.
Any application awarded in response to this FOA will be subject to the DUNS, SAM Registration, and Transparency Act requirements as noted on the Award Conditions and Information for NIH Grants website.
All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the NoA. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General and Part II: Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Grantees, and Activities. More information is provided at Award Conditions and Information for NIH Grants.
Cooperative Agreement Terms and Conditions of Award
The following special terms of award are in addition to, and
not in lieu of, otherwise applicable U.S. Office of Management and Budget (OMB)
administrative guidelines, U.S. Department of Health and Human Services (DHHS)
grant administration regulations at 45 CFR Parts 74 and 92 (Part 92 is
applicable when State and local Governments are eligible to apply), and other
HHS, PHS, and NIH grant administration policies.
The administrative and funding instrument used for this program will be the cooperative agreement, an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH programmatic involvement with the awardees is anticipated during the performance of the activities. Under the cooperative agreement, the NIH purpose is to support and stimulate the recipients' activities by involvement in and otherwise working jointly with the award recipients in a partnership role; it is not to assume direction, prime responsibility, or a dominant role in the activities. Consistent with this concept, the dominant role and prime responsibility resides with the awardees for the project as a whole, although specific tasks and activities may be shared among the awardees and the NIH as defined below.
The PD(s)/PI(s) will have the primary responsibility for:
The PD(s)/PI(s) will have primary authority and responsibility to define objectives and approaches and to plan and conduct the proposed research. She/he will assume responsibility and accountability to the applicant organization and to the NIMH for performance and proper conduct of all research, including the NIH intramural component, if applicable, in accordance with the Terms and Conditions of Award.
The Principal Investigator will be a member of the Steering Committee and will be responsible for scheduling Steering Committee meetings and disseminating meeting notes to all participants within 2 weeks of each meeting (see below under Collaborative Responsibilities).
The Awardee Institution and/or Research Project Leader's Institution will retain primary custody of and have primary rights to data as specified under the NIMH approved Intellectual Property Patent Rights Agreements for New Chemical Entities or the data and research resource sharing plans (described below). The PD/PI will provide to the NIMH Program Official and Project Scientist(s) access to data generated under this cooperative agreement to allow them to periodically review the data consistent with current DHHS, PHS, and NIH policies.
Timely publication of major findings by the Steering Committee members is encouraged. Publication or oral presentation of work done under this agreement will require appropriate acknowledgment of NIMH support, including the assigned cooperative agreement award number.
NIH staff have substantial programmatic involvement that is above and beyond the normal stewardship role in awards, as described below:
The Project Scientist(s) interacts scientifically with the funded PIs and the collaborators on their cooperative agreement grants, and may provide appropriate assistance, including: 1) assisting in research planning, 2) suggesting studies within the scope of the cooperative agreement objectives and research activities, 3) presenting experimental findings from published sources or from relevant contract projects, 4) participating in the design of experiments, 5) participating in the analysis of results, and 6) advising in management and technical performance.
The Project Scientist(s) will be a member(s) of the Steering Committee.
FIH and PoC studies will be reviewed by an appropriate NIMH Data and Safety Monitoring Board (DSMB) to ensure the safety of participants and the validity and integrity of the data. The study protocol(s) and consent form(s) will be reviewed by the DSMB prior to initiation of the project. The DSMB will review study reports on a regular basis to monitor subject enrollment and retention, safety, quality of data collection, and integrity of the study. Applicants should refer to NIH’s policy on data and safety monitoring (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-038.html) as well as the NIMH Guidelines for Data and Safety Monitoring (http://www.nimh.nih.gov/funding/grant-writing-and-application-process/nimh-policy-on-data-and-safety-monitoring-in-extramural-investigator-initiated-clinical-trials.shtml.
Additionally, an NIMH Program Official will be responsible for the normal scientific and programmatic stewardship of the award, including monitoring implementation of the data and research resource sharing plans and will be named in the award notice.
As noted previously, both NIMH Project Scientist and Program Official will be given access to the data generated under this cooperative agreement, which will allow them to periodically review the data to ensure consistency with current DHHS, PHS, and NIH Policies.
Participation of NIH Intramural Scientists:
An NIH intramural scientist may not serve as the PD(s)/PI(s) but may participate as a collaborator, or consultant. However, an Intramural scientist may not receive salary, equipment, supplies, or other remuneration from awards resulting from this FOA. The Intramural scientist must obtain written approval of his/her NIH Institute Scientific Director for the amount of resources that may be allocated to the project. The approval must also specify that the conduct of the project will comply with the DHHS regulations for research involving human subjects (if applicable) and with the PHS policy on vertebrate animal research. The participation of an intramural scientist is independent of and unrelated to the role of the NIMH Project Scientist. For applications that include NIH intramural components, the intramural resource level will be included in the total cost of the overall application. The involvement of Intramural scientists needs to be consistent with NIH Policy. http://www1.od.nih.gov/oir/sourcebook/ethic-conduct/ethical-conduct-toc.htmÂ
Intramural research scientists participating as collaborators have the same rights and responsibilities as other researchers who are participating investigators in the funded cooperative agreement grants. Most often these investigators will be members of the Steering Committee, since they will likely be considered as key personnel.
Areas of Joint Responsibility include:
A governing Steering Committee composed of the PD(s)/PI(s), key personnel, NIMH Project Scientist(s), and NIMH Program Official will be established to assist in monitoring and developing the scientific content and direction of the program. The total membership by NIMH staff will not exceed one-third (1/3) of the membership of the Steering Committee. In all cases, the role of NIMH will be to assist, participate in deliberations, and facilitate discussion and not to direct activities.
The Steering Committee members will meet periodically to review progress, plan and design research activities, and establish priorities. The frequency of meetings, not fewer than two per year, will be determined by the PD(s)/PI(s) who will be responsible for scheduling the time and place (generally at one of the performance sites) and for preparing concise proceedings or minutes (action items and one-two page summary) which will be delivered to the members of the Committee within 2 weeks of the meeting.
Any disagreements that may arise in scientific or programmatic matters (within the scope of the award) between award recipients and the NIH may be brought to Dispute Resolution. A Dispute Resolution Panel composed of three members will be convened. It will have three members: a designee of the Steering Committee chosen without NIH staff voting, one NIH designee, and a third designee with expertise in the relevant area who is chosen by the other two; in the case of individual disagreement, the first member may be chosen by the individual awardee. This special dispute resolution procedure does not alter the awardee's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulation 42 CFR Part 50, Subpart D and DHHS regulation 45 CFR Part 16.
Intellectual Property and Patent Rights for New Chemical Entities or Devices
Since the development of new pharmacological treatments for psychiatric disorders is a major objective of this effort and active involvement by pharmaceutical laboratories is encouraged and would be facilitated by the existence of appropriate patent coverage, it is expected that applicants provide plans to address the handling of intellectual property for new chemical entities or devices under this FOA.
Under the earlier National Cooperative Drug Discovery/Development Groups (NCDDG) for the Treatment of Mental Disorders, Drug or Alcohol Addiction program, successful applicants were required to supply the following confidential materials to the NIMH Program Official listed under Section VII. Agency Contacts. Similar to the NCDDG, applicants are expected to address the three items noted below under this FOA, consistent with achieving the goals of this program:
1. Each applicant must provide a detailed description of the approach to be used for handling intellectual property and for licensing where appropriate, in particular where the invention may involve investigators from more than one institution. Procedures must be described for resolution of legal problems should they arise. Your attention is drawn to the NIH Extramural Technology Transfer Policies and Documents [http://grants.nih.gov/grants/intell-property.htm].
2. A formal statement of Intellectual Property among the PD(s)/PI(s) and their institutions as well as a detailed description of procedures to be followed for resolution of legal problems which may develop, must be signed and dated by the organizational official authorized to enter into intellectual property arrangements for each PD(s)/PI(s) and their institution(s). The signed agreement must be submitted prior to award to the appropriate NIMH staff at the addresses provided under Section VII. Agency Contacts.
3. Prior to the award, the PD(s)/PI(s) must provide a signed statement of acceptance of the participation of NIMH staff during performance of the award as outlined under "NIH Staff Responsibilities" in Section VI.2 - Cooperative Agreement Terms and Conditions of Award.
Note: Do NOT submit documents 1-3 above with the application. However, awards will not be made until these documents are received and approved by NIMH.
Progress of the project will be reviewed annually by the NIMH Project Officer at the time of each non-competing continuation application to assure that satisfactory progress is being made in achieving the project objectives, especially with respect to enrollment and quality of data collection, timely data sharing, and to ensure the site is following the procedures recommended and approved by the project Steering Committee.
By acceptance of these awards, the awardees agree to abide by decisions and policies of the project Steering Committee and the other terms and conditions listed above or referenced in the Notice of Grant Award.
When multiple years are involved, awardees will be required to submit the annual Non-Competing Progress Report (PHS 2590 or RPPR) and financial statements as required in the NIH Grants Policy Statement.
A final progress report, invention statement, and the expenditure data portion of the Federal Financial Report are required for closeout of an award, as described in the NIH Grants Policy Statement.
The Federal Funding Accountability and Transparency Act of 2006 (Transparency Act), includes a requirement for awardees of Federal grants to report information about first-tier subawards and executive compensation under Federal assistance awards issued in FY2011 or later. All awardees of applicable NIH grants and cooperative agreements are required to report to the Federal Subaward Reporting System (FSRS) available at www.fsrs.gov on all subawards over $25,000. See the NIH Grants Policy Statement for additional information on this reporting requirement.
NIMH requires reporting of recruitment milestones for participants in clinical trials as noted at http://grants.nih.gov/grants/guide/notice-files/NOT-MH-05-013.html. While trials in response to this FOA might not seek 150 subjects or more (the level at which this reporting has been required), all trials funded under this FOA must report recruitment milestones, including those with fewer than 150 subjects. This expectation will be stated in the notice of grant award.
The NIMH expects the registration and results reporting for all NIMH-supported clinical trials, regardless of whether or not they are subject to FDAAA (see http://grants.nih.gov/ClinicalTrials_fdaaa/at-a-glance.htm). This expectation will be stated in the notice of grant award.
We encourage inquiries concerning this funding opportunity
and welcome the opportunity to answer questions from potential applicants.
eRA Commons Help Desk (Questions regarding eRA Commons
registration, submitting and tracking an application, documenting system
problems that threaten submission by the due date, post submission issues)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)
Grants.gov Customer Support (Questions
regarding Grants.gov registration and submission, downloading forms and
Contact CenterTelephone: 800-518-4726
GrantsInfo (Questions regarding application instructions and
process, finding NIH grant resources)
Questions about first in human and Phase I studies of novel therapeutic drug candidates or devices should be directed to:
Lois Winsky, Ph.D.
National Institute of Mental Health (NIMH)
Questions about proof of concept studies for novel therapeutics drug candidates or devices for psychiatric disorders in adult populations should be directed to:
Mi Hillefors, M.D., Ph.D.
National Institute of Mental Health (NIMH)
Questions about proof of concept studies for novel therapeutic drug candidates or devices for psychiatric disorders in children and adolescents (first exposure in children or first in pediatric indication), or in adults with early developmental onset disorders including Tourette Syndrome, Attention Deficit Disorder, and Autism Spectrum Disorder should be directed to:
Margaret Grabb, Ph.D.
National Institute of Mental Health (NIMH)
David Armstrong, Ph.D.
National Institute of Mental Health (NIMH)
Rebecca Claycamp, M.S., CRA
National Institute of Mental Health (NIMH)
Recently issued trans-NIH policy notices may affect your application submission. A full list of policy notices published by NIH is provided in the NIH Guide for Grants and Contracts. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.
Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part 52 and 45 CFR Parts 74 and 92.
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