This Funding Opportunity Announcement (FOA) encourages applications for Countermeasures Against Chemical Threats (CounterACT) Cooperative Agreement (U01) Research Projects for research on the optimization of small molecule or biologic compounds that are excellent candidates for therapeutic development. The mission of the CounterACT Program is to foster and support research and development of new and improved therapeutics for chemical threats. Chemical threats are toxic chemicals that could be used in a terrorist attack or accidentally released from industrial production, storage or shipping. They include traditional chemical warfare agents, toxic industrial chemicals, pharmaceutical-based agents, and pesticides. A previously identified lead compound is required to be eligible for this funding opportunity. In this regard, lead compounds are defined as biologically active compounds or hits where affinity, potency, target selectivity, and preliminary safety have been established. The scope of research supported by this FOA includes development of appropriate human-relevant animal models and generation of in vivo efficacy data consistent with the intended use of the product in humans. It also includes bioanalytical assay development and validation, laboratory-scale and scaleable manufacturing of the product, and non-GLP toxicity and pharmacology studies. The scope of this FOA encompasses Technical Readiness Levels (TRLs) 4-5 - see TRLs. Each project must include annual milestones that create discrete go or no-go decision points in a progressive translational study plan.
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.
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.
There are several options available to submit your application through Grants.gov to NIH and Department of Health and Human Services partners. You must use one of these submission options to access the application forms for this opportunity.
This FOA invites applications for cooperative agreement translational research projects to optimize novel therapeutics (drug or biologic) that reduce mortality and morbidity resulting from acute exposures to chemical agents identified by the U.S. Government (USG) as threats to the population. These chemical threat agents are toxic compounds that could be released by a deliberate terrorist attack against civilians, or by accidental or natural disaster causing mass casualties. With the goal of treating or preventing injuries resulting from exposures to these toxic chemicals, NIH CounterACT lead optimization cooperative agreement projects will support studies for up to five years to generate the tools, efficacy in an appropriate animal model, and safety/toxicity and pharmacology data necessary to transition the proposed therapeutic(s) to advanced drug development, regulatory approval, and licensure.
Most of the advanced drug development activities required for regulatory approval and licensure are not covered under this FOA (to include GLP IND-enabling safety studies and pivotal efficacy studies in animals, cGMP production, and human safety clinical trials). However, the intention of the support described under this FOA is to optimize lead compounds so they are ready for such advanced activities that lead to regulatory approval and licensure. These activities could potentially be supported by other government, commercial, or non-profit sources after the completion of the NIH-supported project period.
One important federal agency that supports advanced research related to this FOA is the Biomedical Advanced Research and Development Authority (BARDA). Prior to transitioning the proposed lead product from CounterACT support to BARDA support, the project should have successfully addressed all of the following BARDA criteria in order to be eligible for consideration:
For purposes of the overall requirements for this FOA, the above BARDA criteria will be considered sufficient. Thus, the "Optimized Lead" developed by the end of the project period is a molecule that will be ready to enter IND-enabling GLP and GMP level studies in the next stage of the drug development process (not covered by this FOA).
For entry into the CounterACT lead optimization research program, the proposed project should have an already identified lead candidate(s) that has undergone preclinical evaluation. For the purpose of this FOA, lead candidates(s) are defined as biologically active and synthetically feasible compounds where specificity, affinity, potency, target selectivity, efficacy, and safety have been established. As such, sufficient bioactivity of the compound should be already demonstrated; this includes preliminary in vivo efficacy and/or validated target engagement for the indication with clinically relevant results. The ideal application to this announcement should also have either intellectual property ownership in place or no foreseeable restriction preventing the use and/or development of the lead candidate(s).
The CounterACT Program is part of the larger NIH Biodefense Program and the Chemical Countermeasures Research Program (CCRP) coordinated by the National Institute of Allergy and Infectious Diseases (NIAID). CounterACT and the CCRP are part of the HHS Public Health Emergency Medical Countermeasures Enterprise (PHEMCE), which coordinates medical countermeasures-related efforts across the Department of Health & Human Services (HHS) and other USG partners.
The overarching goal of the CounterACT program is to integrate cutting-edge research with the latest technological advances in science and medicine to enhance the nation's medical response capabilities during chemical emergencies. This is a trans-NIH effort, involving partnerships with the NEI, NIAID, NIAMS, NICHD, NIEHS, NIDA, and NINDS to execute the overall NIH Strategic Plan and Research Agenda for Medical Countermeasures Against Chemical Threats.
The NIH has developed a comprehensive research and product development program that includes Research Centers of Excellence (U54), individual research projects (U01), exploratory and developmental translational research projects (R21), SBIR projects, contracts, and Interagency Agreements with the Department of Defense (DoD) and HHS. The program supports basic, translational, and preclinical research aimed at the discovery and/or identification of better medical countermeasures against chemical threat agents, and guides their movement through the regulatory process in collaboration with other federal departments, agencies, and initiatives, such as the Biomedical Advanced Research and Development Authority (HHS BARDA), FDA Medical Countermeasures Initiative (MCMi), and the Defense Threat Reduction Agency (DoD DTRA).
CounterACT Optimization of Therapeutic Lead Compounds Program Directors/Principal Investigators (PDs/PIs) will become members of the CCRP, and will be able to utilize its resources, such as the CounterACT Preclinical Development Facility (CPDF). They will also be expected to participate in annual meetings of the CounterACT Network to share information and ideas.
D. Chemical Threats of Research Interest
The civilian chemical threat spectrum includes chemical warfare agents (e.g., sarin, chlorine, sulfur mustard), toxic industrial chemicals (e.g., cyanide, hydrogen sulfide), pesticides (e.g., parathion, brodifacoum), pharmaceutical-based agents (e.g., opioids), and other chemicals. These agents are included on the current Department of Homeland Security (DHS) Chemical Threat Risk Assessment (CTRA) list that NIH uses for the CounterACT program, which is for USG official use only and cannot be included in this FOA. Applicants are strongly urged to contact the Scientific/Research staff listed in this FOA to determine if their proposed threat agent(s) is of interest for this FOA. Applications that propose research on chemical threats that are not included on the CTRA list will not be selected for funding. Therefore, it is critical to contact NIH staff early, before time and effort are invested in developing an application to support research on a chemical or group of chemicals that is not a priority for this FOA. If research related to opioid threats is being proposed, see NOT-NS-18-019 for a description of research supported by this FOA.
Antidotes that are specific to a chemical will be considered; however, applicants should also consider research on acute effects and pathologies that are common to several chemical threat agents, so that the therapeutics being developed will have a broader spectrum of activity, i.e., efficacious against more than one chemical threat.
E. Special Biosafety Certification
Many of the chemical threat agents of interest are extremely hazardous to humans. This FOA will only consider supporting studies deemed safe for research personnel and the environment by appropriate official institutional biosafety review. Special biosafety certifications may be required to conduct research with some chemical threat agents, e.g., Schedule 1 chemical warfare agents regulated under the Chemical Weapons Convention (see Section 22.214.171.124 in the NIH Policy Statement). Therefore, applicants are encouraged to collaborate with laboratories that are already certified and legally authorized to work with restricted chemical agents, such as the U.S. Army Medical Research Institute of Chemical Defense (USAMRICD) and certain contract research organizations, when applicable. Applicants are strongly encouraged to contact the Scientific/Research Contact listed in this FOA for further information on working with restricted chemical agents.
F. Scientific Scope
This FOA will only support translational research. Translational research is the process of applying ideas, insights, and discoveries generated through basic scientific inquiry to the treatment or prevention of human disease. Projects supported by this translational research FOA are expected to generate sufficient preclinical data to deliver a single "Optimized Lead" candidate at the end of the funding period. More extensive advanced development support towards licensure could be available through other government, commercial, or non-profit sources. As described in the Early Drug Discovery and Development Guidelines: For Academic Researchers, Collaborators, and Start-up Companies, there are several kinds of studies and metrics that can lead to the selection of the "Optimized Lead" and these would depend on where in the optimization process you begin. The scope of research covered in this FOA can also be described by Technology Readiness Levels (TRLs). The TRLs covered in this FOA generally fall under TRLs 4 through 5.
Interested applicants without an already identified lead medical countermeasure should refer to the companion FOA "CounterACT Identification of Therapeutic Lead Compounds Cooperative Agreement (U01)" (PAR-18-NNN ). Conversely, applicants interested in more advanced GLP IND-enabling drug research and development, cGMP manufacturing, and/or human safety clinical efforts with their lead therapy product should directly explore funding opportunities available through HHS BARDA Broad Agency Announcements.
To achieve the desired BARDA criteria listed in Section I.A., research covered in this FOA includes, but is not necessarily limited to:
Important links to specific FDA Guidance and other regulatory information relevant to medical countermeasure research and development can be found under the FDA Guidance Documents section on the CounterACT website.
Examples of research covered in this FOA include, but are not necessarily limited to:
Although clinical trials are optional in this FOA, NIH-defined clinical trials will only be supported under limited circumstances. This FOA will not support IND-enabling safety studies conducted under Good Laboratory Practices (GLP), pivotal efficacy studies in animals, cGMP production, or Phase 1 and higher trials in humans. However, in some rare cases when sufficient preclinical studies have been completed, a small clinical trial may be included if the proposed research falls within the above stated scientific scope of this FOA and is clearly justified as essential for the purpose of optimizing a lead compound. If clinical trials are proposed, they must be feasible within the proposed budget and project period.
Milestone-driven research is used to ensure research is focused on a well-defined goal, thus achieving that goal with greatest efficiency. As translational research is inherently high-risk, the use of milestones provides clear indicators of a project's continued success or emergent difficulties.
Milestones toward therapeutic intervention are not a description of specific aims and experiments, but rather are discrete goals that create go or no-go decision points that include quantitative success criteria.
Annual milestones may be modified in negotiations with NIH program officials before an initial award is made, and during the review of annual non-competitive applications. Unmet milestones and an incomplete data package that prevents an adequate interpretation of the results will have a negative impact on the approval of these annual non-competing applications.
Partial budget reductions and/or restrictions in a given project year may also occur if aspects of the project are deemed futile, but others still show promise.
See Section IV.2 below for more specific instructions on developing appropriate milestones.
H. Special Considerations
This FOA will only support the development/optimization of lead compounds that can be used to reduce mortality or serious morbidity during a chemical emergency. The primary focus of research should be on optimizing pre-identified lead compounds that are effective when administered after a chemical exposure has occurred (post-exposure efficacy). Lead compounds that are only effective if administered prior to the chemical insult (prophylaxis efficacy) will be of lowest priority. The route and time(s) of administration of the therapeutic must be consistent with the intended use in humans, including the likely environment where the drug would be administered (pre-hospital or in-hospital settings). Animal model development, screening activity, and efficacy studies should be designed and well justified with these ultimate concept-of-use requirements in mind.
Therapeutics to prevent long-term or delayed chronic effects after an acute exposure would also be considered, and in this case, may be more appropriate for administration after evacuation from the exposure site and during in-hospital care.
Regulatory Approach : It is neither ethical nor feasible to perform human clinical trials to establish the efficacy of proposed therapeutic product(s) for injuries resulting from exposure to chemical threats. Therefore, a scientifically sound method in animals is usually required to demonstrate that a candidate medical countermeasure provides the intended protection. As such, some research supported by this FOA would typically follow the FDA Guidance for Industry - Product Development Under the Animal Rule. Additionally, research and development of combination therapies of two or more new drugs that have not been individually approved previously for the specified indication would need to abide by the FDA Guidance for Industry - Co-development of Two or More New Investigational Drugs for Use in Combination. Therefore, in most cases, it is usually advantageous that information in these and other FDA Guidance be reviewed in consultation with a partner possessing a history of regulatory experience especially with the FDA Animal Rule. FDA typically encourages drug sponsors/developers to communicate with the Agency early in development for issues related to data needed to support the rationale for candidate lead selection; the design of nonclinical pharmacology, toxicology, and drug activity studies, including design and potential uses of any proposed treatment studies in animal models; subsequent data requirements for the Pre-IND and IND applications; initial drug development plans, and regulatory requirements for demonstrating safety and efficacy. These interactions can be especially pertinent prior to potential efforts to develop higher order animal models that may be more relevant to the human condition to demonstrate therapeutic efficacy and safety.
Applicants are strongly urged to consider addressing effects of sex and age alone or in combination as biological variables in the proposed preclinical studies (see NOT-OD-15-102). Special consideration will be afforded to research particularly relevant to the pediatric population and others that are also considered to be especially vulnerable to the adverse health effects of chemical agents, including geriatric, pregnant, and/or individuals with pre-existing medical conditions. Animal models and studies that address vulnerabilities in these special subpopulations will be of high research priority.
Critical elements of a well-designed study include adequate scientific rigor, control of bias, reproducibility, dose-response, confirmation of mechanism, and transparency of reporting. As such, the NIH urges applicants to consider and directly address these elements in their application(s). Please see NOT-OD-15-103 for more information on enhancing reproducibility through rigor and transparency.
I. Intellectual Property (IP)
The NIH encourages the awardees and/or their collaborators to obtain and retain any Intellectual Property (IP) developed around the lead compound during the project period as appropriate. Recipients of awards are encouraged to work closely with their institutional Technology Transfer (or Industry Relations) Office to identify and foster relationships with potential licensing and commercialization partners early in the therapy development process. PDs/PIs are expected to work closely with their institutional technology transfer officials and in accordance with the NIH Grants Policy Statement to ensure that appropriate royalty agreements, patent filings, and all other necessary IP arrangements are managed in a timely manner and that commercialization plans are developed and updated over the course of the project, consistent with achieving the goals of the program. It is recognized that in the case of medical countermeasures, commercialization may be challenging. Therefore, applicants are encouraged to discuss alternative strategies with NIH Scientific/Research staff to get further guidance.
The OER Glossary and the SF424 (R&R) Application Guide provide details on these application types.
The number of awards is contingent upon NIH appropriations and the submission of a sufficient number of meritorious applications.
Application budgets may not exceed $500,000 in direct costs per year.
Many applications will not need to request the maximum budget and the requested budget will need to reflect the actual needs of the proposed project.
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
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. PD(s)/PI(s) should work with their organizational officials to either create a new account or to affiliate their existing account with the applicant organization in eRA Commons. 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.
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.
The NIH will not accept duplicate or highly overlapping applications under review at the same time. This means that the NIH will not accept:
Buttons to access the online ASSIST system or to download application forms are available in Part 1 of this FOA. See your administrative office for instructions if you plan to use an institutional system-to-system solution.
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:
David A. Jett, Ph.D.
Intellectual Property Strategy: Applications are expected to include an Intellectual Property (IP) strategy that is no more than one page. Applications that exceed this limit will be withdrawn. This attachment should be entitled "IP_Strategy.pdf" and reflected in the final image. Applicants are encouraged to prepare this section of the application in consultation with their institution's technology transfer officials, if applicable.
Applicants should describe the IP landscape surrounding their proposed therapeutic(s). This should include any known constraints that could impede the development of their medical countermeasure (e.g., certain restrictions under transfer or sharing agreements, applicants' previous or present IP filings and publications, similar approaches that are under patent and/or on the market, etc.) and how these issues could be addressed as appropriate and consistent with achieving the goals of the program. If the applicant proposes using a compound whose IP is not owned by the applicant's institution, either an investigational therapeutic, FDA-approved therapeutic, or other licensed product, the applicant should address any questions that may constrain or impede its ability to operate and move the compound forward consistent with achieving the goals of the program. Applicants should include a letter (see Letters of Support) from the entity that owns the IP indicating whether the entity will provide the compound, if there are any limits on the studies that can be performed with that compound, and agreement about public disclosure of results (including negative results), and whether there is an agreement already in place.
If patents pertinent to the therapeutic(s) being developed under this application have been filed, the applicants should indicate the details of filing dates, what types of patents are filed, application status, and associated United States Patent Office (USPTO) links, if applicable. Applicants should also discuss future IP filing plans. For a multiple-PD/PI, multiple-institution application, applicants should describe the infrastructure of each institution for bringing the compound(s) to practical application and for coordinating these efforts (e.g., how IP will be shared, licensing, managing IP) among the institutions.
Target Product Profile (TPP): A table based on a FDA Guidance for Industry and Review Staff (TPP — A Strategic Development Process Tool) that summarizes the minimal/ideal profile of the final marketed product and shows the ultimate goals of the proposed drug development effort, such as medical indication, patient population, delivery mode, shelf life, storage conditions, packaging, treatment duration, treatment regimen, and standards for clinical efficacy. It is essential that the TPP represents the ultimate utility of the candidate medical countermeasure within a post-exposure civilian-based mass casualty scenario, i.e., the described anticipated use of the product is consistent with the true intended use for which approval will be sought from FDA. Explain in no more than 1 page why the minimally acceptable and ideal parameters offer advantages over currently available treatments (where applicable). Applications containing a TPP section that exceeds one page will not be reviewed.
All instructions in the SF424 (R&R) Application Guide must be followed.
Due to the nature of translational research supported by this FOA, some studies and methodologies may not be considered innovative even though they are essential components of the overall project. Examples of this type of research include routine preclinical safety/toxicity evaluations and the use of previously established models of chemical-induced injuries to identify potential differences between specific subpopulations (e.g. adults versus children). Therefore, to address innovation, the application should clearly describe novel therapeutic approaches or interventions. This FOA also supports and encourages repurposing drugs approved for other indications, as long as the therapeutic approach using that drug is for a new indication.
All proposed projects should have a strong biological rationale for the intended approach and the proposed studies must exhibit methodological rigor. A well-structured application should, therefore, include clear rational experimental approaches that can yield significant data in support of the proposed indication. Applicants to the program are urged to consider the rationale for the chosen model(s) and endpoints, adequacy of controls, route and timing of therapeutic dosing, justification of sample size, statistical methods, blinding methods, strategies for randomization, and robustness and reproducibility of results. These criteria should also be addressed when describing all supporting data and in the design of the proposed studies within the Research Strategy section. This section should describe exactly how the research will enhance medical response capabilities during a chemical emergency and a detailed description of the current status of the proposed lead compound product (to include detailed chemical structure information for the proposed lead compound) and specific lead optimization plans. The lack of structural information for the lead compound may adversely affect the assessment of the potential for optimization. NIH has multiple safeguards to protect the integrity of and to maintain confidentiality in peer review. Optimization plans should include clear and quantitative goals for the desired outcomes to be achieved. These studies may include, but are not limited to, refining the compound's chemical, biological, and safety properties by addressing properties such as potency, selectivity, ADMET, hERG, Ames activity, etc., and its concept of use, i.e., how and when it will be administered to humans in the context of a civilian-based chemical emergency event. The proposed lead optimization project ideally must address the regulatory strategies necessary to advance the proposed medical countermeasure, e.g., addressing essential elements described in the relevant FDA Guidance for Industry - Product Development Under the Animal Rule (e.g., suitability of the proposed animal species, etc.), Co-development of Two or More New Investigational Drugs for Use in Combination, etc. The proposed overall research and regulatory strategies should aim to achieve the product specification set forth in the TPP by the end of the project period.
Milestones: Annual milestones must be proposed in response to this announcement. Milestones should describe the goal of the work and not just a statement that the work will be completed. The proposed milestones (with associated timelines) should be regarded as criteria for evaluating the progress and direction of the project. Milestones should not be just a restatement of the specific aims, but a quantitative description of what constitutes successful research progress and development. Applicant will, therefore, be expected to refer to these milestones in annual progress reports. The proposed milestones will be periodically revisited and may be revised when necessary as challenges are encountered or new information becomes available based on the trajectory of the research and the field at large. Given the high-risk and progressive nature of therapeutics discovery and development, results at any stage of a project might indicate a dead end, for example a toxicology study may reveal that a molecule is unsuitable for human use. Thus, the milestones should indicate the desired outcome of a study and not simply that the study was conducted. The milestones must provide objective and quantitative outcomes by which to justify advancing the project. The criteria for success of the studies conducted should be objective measures that can be used for evaluation by NIH. These should be measures that would be recognizable as appropriate endpoints in the specific scientific area. Examples of acceptable milestones are available on the NIH CounterACT website. A Gantt chart or table may be used to document the timelines associated with the proposed milestones over the course of the project period. The timeline and milestones information should be placed at the end of the Research Strategy.
The proposed series of translational research milestones should demonstrate a clear path towards the selection of an "Optimized Lead" by the end of the proposed project period. The "Optimized Lead" should unambiguously establish affinity, potency, and selectivity in an animal model predictive of the human response. Efficacy of the "Optimized Lead" should be demonstrated using a route of administration amenable to a post-exposure civilian-based mass casualty concept of use.
Letters of Support:
If collaborating with a private entity (e.g., regulatory support), include a letter of collaboration that addresses any agreement to provide service(s), any limits on the services that can be performed, any limitations on sharing of data (including negative results), and whether a licensing agreement(s) is in place, if applicable. This letter should come from an official within the private entity who has the appropriate authority.
The following modifications also apply:
If you answered “Yes” to the question “Are Human Subjects Involved?” on the R&R Other Project Information form, you must include at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials Information form or Delayed Onset Study record.
Study Record: PHS Human Subjects and Clinical Trials Information
All instructions in the SF424 (R&R) Application Guide must be followed.
All instructions in the SF424 (R&R) Application Guide must be followed.
See Part 1. Section III.1 for information regarding the requirement for obtaining a unique entity identifier and for completing and maintaining active registrations in System for Award Management (SAM), NATO Commercial and Government Entity (NCAGE) Code (if applicable), eRA Commons, and Grants.gov
Part I. Overview Information contains information about Key Dates and times. 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. When a submission date falls on a weekend or Federal holiday , the application deadline is automatically extended to the next business day.
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 and time. If a Changed/Corrected application is submitted after the deadline, the application will be considered late. Applications that miss the due date and time are subjected to the NIH Policy on Late Application Submission.
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.
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. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Guidelines for Applicants Experiencing System Issues. For assistance with application submission, contact the Application Submission Contacts in Section VII.
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.
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.
In addition, for applications involving clinical trials:
A proposed Clinical Trial application may include study design, methods, and intervention that are not by themselves innovative but address important questions or unmet needs. Additionally, the results of the clinical trial may indicate that further clinical development of the intervention is unwarranted or lead to new avenues of scientific investigation.
Does the project address an important problem or a critical barrier to progress in the field? Is the prior research that serves as the key support for the proposed research rigorous? 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?
Will the proposed study reduce mortality and morbidity during and after emergency events involving the release of chemical threat agents, i.e., clinical impact? Was the selection of the animal model and/or potential therapeutics based on sound and rigorous scientific rationales, e.g., target/pathway activity? How strong are the preliminary data supporting the choice of the proposed injury mechanism and/or therapeutics for the indication, i.e., biological relevance? Does the proposed TPP present a viable roadmap towards the development of a product that will be useful in a mass casualty chemical exposure scenario?
What is the likelihood that completion of all proposed research objectives achieves the specifications described in the TPP? Will the completion of the proposed objectives generate the data necessary to obtain additional support from an advanced drug developer described in Section A. Overview?
In addition, for applications involving clinical trials
Are the scientific rationale and need for a clinical trial to test the proposed hypothesis or intervention well supported by preliminary data, clinical and/or preclinical studies, or information in the literature or knowledge of biological mechanisms? For trials focusing on clinical or public health endpoints, is this clinical trial necessary for testing the safety, efficacy or effectiveness of an intervention that could lead to a change in clinical practice, community behaviors or health care policy? For trials focusing on mechanistic, behavioral, physiological, biochemical, or other biomedical endpoints, is this trial needed to advance scientific understanding?
Are the PD(s)/PI(s), collaborators, and other researchers well suited to the project? If Early Stage Investigators or those 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?
Are the scientific and/or administrative leadership qualifications and time commitment of the PD/PI adequate? Does the PD/PI have a strong background in the management of large and complex translational research projects? Is there adequate statistical and/or regulatory support for the experimental design, analysis, and interpretation of the generated preclinical data? Is there adequate personnel to manage existing and future intellectual property associated with this project?
In addition, for applications involving clinical trials
With regard to the proposed leadership for the project, do the PD/PI(s) and key personnel have the expertise, experience, and ability to organize, manage and implement the proposed clinical trial and meet milestones and timelines? Do they have appropriate expertise in study coordination, data management and statistics? For a multicenter trial, is the organizational structure appropriate and does the application identify a core of potential center investigators and staffing for a coordinating center?
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?
Even though this FOA supports and encourages repurposing drugs approved for other indications, is the therapeutic approach using that drug innovative for this new indication? Additionally, even though the routine tests used to characterize a therapeutic may not be innovative, are they essential for determining if a new innovative therapeutic approach is viable?
In addition, for applications involving clinical trials
Does the design/research plan include innovative elements, as appropriate, that enhance its sensitivity, potential for information or potential to advance scientific knowledge or clinical practice?
Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Have the investigators included plans to address weaknesses in the rigor of prior research that serves as the key support for the proposed project? Have the investigators presented strategies to ensure a robust and unbiased approach, as appropriate for the work proposed? 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? Have the investigators presented adequate plans to address relevant biological variables, such as sex, for studies in vertebrate animals or human subjects?
Is the overall timeline reasonable for the work proposed? Do the proposed studies and TPP sufficiently address key parameters necessary in drug development, such as compound toxicity/safety, pharmacology, pharmacokinetics/metabolism, and chemistry? Based on the provided structural information of the lead therapeutic, is the proposed optimization plan acceptable and achievable? Are there any insurmountable roadblocks that may prevent the ultimate development of a therapeutic medical product? Will the planned studies, activities, and expected result support the proposed indication, TPP, and regulatory strategy?
Are the proposed annual milestones robust and associated with clear and quantitative criteria for success that allow go/no-go decisions without unnecessary studies? For key experiments, does the application explain assumptions for power analysis, describe statistical analysis methods and criteria for data inclusion or exclusion, and detail the procedures of how blinding and randomization will be conducted? Would achieving all the proposed milestones in the application allow the project to achieve the ultimate goal of the project to potentially promote a single lead therapeutic compound for transition to an advanced developer for further support?
In addition, for applications involving clinical trials
Does the application adequately address the following, if applicable
Is the study design justified and appropriate to address primary and secondary outcome variable(s)/endpoints that will be clear, informative and relevant to the hypothesis being tested? Is the scientific rationale/premise of the study based on previously well-designed preclinical and/or clinical research? Given the methods used to assign participants and deliver interventions, is the study design adequately powered to answer the research question(s), test the proposed hypothesis/hypotheses, and provide interpretable results? Is the trial appropriately designed to conduct the research efficiently? Are the study populations (size, gender, age, demographic group), proposed intervention arms/dose, and duration of the trial, appropriate and well justified?
Are potential ethical issues adequately addressed? Is the process for obtaining informed consent or assent appropriate? Is the eligible population available? Are the plans for recruitment outreach, enrollment, retention, handling dropouts, missed visits, and losses to follow-up appropriate to ensure robust data collection? Are the planned recruitment timelines feasible and is the plan to monitor accrual adequate? Has the need for randomization (or not), masking (if appropriate), controls, and inclusion/exclusion criteria been addressed? Are differences addressed, if applicable, in the intervention effect due to sex/gender and race/ethnicity?
Are the plans to standardize, assure quality of, and monitor adherence to, the trial protocol and data collection or distribution guidelines appropriate? Is there a plan to obtain required study agent(s)? Does the application propose to use existing available resources, as applicable?
Data Management and Statistical Analysis
Are planned analyses and statistical approach appropriate for the proposed study design and methods used to assign participants and deliver interventions? Are the procedures for data management and quality control of data adequate at clinical site(s) or at center laboratories, as applicable? Have the methods for standardization of procedures for data management to assess the effect of the intervention and quality control been addressed? Is there a plan to complete data analysis within the proposed period of the award?
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 individuals of all ages (including children and older adults), justified in terms of the scientific goals and research strategy proposed?
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?
Are special biosafety precautions for working with highly toxic chemicals adequate? Have all proposed studies been deemed safe for research personnel and the environment by the appropriate institutional biosafety review official?
In addition, for applications involving clinical trials
If proposed, are the administrative, data coordinating, enrollment and laboratory/testing centers, appropriate for the trial proposed?
Does the application adequately address the capability and ability to conduct the trial at the proposed site(s) or centers? Are the plans to add or drop enrollment centers, as needed, appropriate?
If international site(s) is/are proposed, does the application adequately address the complexity of executing the clinical trial?
If multi-sites/centers, is there evidence of the ability of the individual site or center to: (1) enroll the proposed numbers; (2) adhere to the protocol; (3) collect and transmit data in an accurate and timely fashion; and, (4) operate within the proposed organizational structure?
Specific to applications involving clinical trials
Is the study timeline described in detail, taking into account start-up activities, the anticipated rate of enrollment, and planned follow-up assessment? Is the projected timeline feasible and well justified? Does the project incorporate efficiencies and utilize existing resources (e.g., CTSAs, practice-based research networks, electronic medical records, administrative database, or patient registries) to increase the efficiency of participant enrollment and data collection, as appropriate?
Are potential challenges and corresponding solutions discussed (e.g., strategies that can be implemented in the event of enrollment shortfalls)?
For research that involves human subjects but does not involve one of the 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 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.
Individuals Across the Lifespan
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 individuals of all ages (including children and older adults) 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 criteria: (1) description of proposed procedures involving animals, including species, strains, ages, sex, and total number to be used; (2) justifications for the use of animals versus alternative models and for the appropriateness of the species proposed; (3) interventions to minimize discomfort, distress, pain and injury; and (4) justification for euthanasia method if NOT consistent with the AVMA Guidelines for the Euthanasia of Animals. Reviewers will assess the use of chimpanzees as they would any other application proposing the use of vertebrate animals. 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.
Intellectual Property (IP) Strategy
If applicable, reviewers will comment on the following:
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).
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) Genomic Data Sharing Plan (GDS).
For projects involving key biological and/or chemical resources, reviewers will comment on the brief plans proposed for identifying and ensuring the validity of those resources.
Reviewers will consider whether the budget and the requested period of support are fully justified and reasonable in relation to the proposed research.
Information regarding the disposition of applications is available in the NIH Grants Policy Statement.
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 terms and conditions found on the Award Conditions and Information for NIH Grants website. This includes any recent legislation and policy applicable to awards that is highlighted on this website.
Individual awards are based on the application submitted to, and as approved by, the NIH and are subject to the IC-specific terms and conditions identified in the NoA.
ClinicalTrials.gov: If an award provides for one or more clinical trials. By law (Title VIII, Section 801 of Public Law 110-85), the "responsible party" must register and submit results information for certain “applicable clinical trials” on the ClinicalTrials.gov Protocol Registration and Results System Information Website (https://register.clinicaltrials.gov). NIH expects registration of all trials whether required under the law or not. For more information, see http://grants.nih.gov/ClinicalTrials_fdaaa/
Institutional Review Board or Independent Ethics Committee Approval: Grantee institutions must ensure that the application as well as all protocols are reviewed by their IRB or IEC. To help ensure the safety of participants enrolled in NIH-funded studies, the awardee must provide NIH copies of documents related to all major changes in the status of ongoing protocols. Data and Safety Monitoring Requirements: The NIH policy for data and safety monitoring requires oversight and monitoring of all NIH-conducted or -supported human biomedical and behavioral intervention studies (clinical trials) to ensure the safety of participants and the validity and integrity of the data. Further information concerning these requirements is found at http://grants.nih.gov/grants/policy/hs/data_safety.htm and in the application instructions (SF424 (R&R) and PHS 398).
Investigational New Drug or Investigational Device Exemption Requirements: Consistent with federal regulations, clinical research projects involving the use of investigational therapeutics, vaccines, or other medical interventions (including licensed products and devices for a purpose other than that for which they were licensed) in humans under a research protocol must be performed under a Food and Drug Administration (FDA) investigational new drug (IND) or investigational device exemption (IDE).
Recipients of federal financial assistance (FFA) from HHS must administer their programs in compliance with federal civil rights law. This means that recipients of HHS funds must ensure equal access to their programs without regard to a person’s race, color, national origin, disability, age and, in some circumstances, sex and religion. This includes ensuring your programs are accessible to persons with limited English proficiency. HHS recognizes that research projects are often limited in scope for many reasons that are nondiscriminatory, such as the principal investigator’s scientific interest, funding limitations, recruitment requirements, and other considerations. Thus, criteria in research protocols that target or exclude certain populations are warranted where nondiscriminatory justifications establish that such criteria are appropriate with respect to the health or safety of the subjects, the scientific study design, or the purpose of the research.
In accordance with the statutory provisions contained in Section 872 of the Duncan Hunter National Defense Authorization Act of Fiscal Year 2009 (Public Law 110-417), NIH awards will be subject to the Federal Awardee Performance and Integrity Information System (FAPIIS) requirements. FAPIIS requires Federal award making officials to review and consider information about an applicant in the designated integrity and performance system (currently FAPIIS) prior to making an award. An applicant, at its option, may review information in the designated integrity and performance systems accessible through FAPIIS and comment on any information about itself that a Federal agency previously entered and is currently in FAPIIS. The Federal awarding agency will consider any comments by the applicant, in addition to other information in FAPIIS, in making a judgement about the applicant’s integrity, business ethics, and record of performance under Federal awards when completing the review of risk posed by applicants as described in 45 CFR Part 75.205 “Federal awarding agency review of risk posed by applicants.” This provision will apply to all NIH grants and cooperative agreements except fellowships.
For additional guidance regarding how the provisions apply to NIH grant programs, please contact the Scientific/Research Contact that is identified in Section VII under Agency Contacts of this FOA. HHS provides general guidance to recipients of FFA on meeting their legal obligation to take reasonable steps to provide meaningful access to their programs by persons with limited English proficiency. Please see http://www.hhs.gov/ocr/civilrights/resources/laws/revisedlep.html. The HHS Office for Civil Rights also provides guidance on complying with civil rights laws enforced by HHS. Please see http://www.hhs.gov/ocr/civilrights/understanding/section1557/index.html; and http://www.hhs.gov/ocr/civilrights/understanding/index.html. Recipients of FFA also have specific legal obligations for serving qualified individuals with disabilities. Please see http://www.hhs.gov/ocr/civilrights/understanding/disability/index.html. Please contact the HHS Office for Civil Rights for more information about obligations and prohibitions under federal civil rights laws at http://www.hhs.gov/ocr/office/about/rgn-hqaddresses.html or call 1-800-368-1019 or TDD 1-800-537-7697. Also note it is an HHS Departmental goal to ensure access to quality, culturally competent care, including long-term services and supports, for vulnerable populations. For further guidance on providing culturally and linguistically appropriate services, recipients should review the National Standards for Culturally and Linguistically Appropriate Services in Health and Health Care at http://minorityhealth.hhs.gov/omh/browse.aspx?lvl=2&lvlid=53.
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 Part 75 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:
NIH Staff have substantial programmatic and scientific involvement that is above and beyond the normal program stewardship role in awards as described below:
Areas of Joint Responsibility include:
None; all responsibilities are divided between awardees and NIH staff as described above.
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 individual awardee 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.
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.
In accordance with the regulatory requirements provided at 45 CFR 75.113 and Appendix XII to 45 CFR Part 75, recipients that have currently active Federal grants, cooperative agreements, and procurement contracts from all Federal awarding agencies with a cumulative total value greater than $10,000,000 for any period of time during the period of performance of a Federal award, must report and maintain the currency of information reported in the System for Award Management (SAM) about civil, criminal, and administrative proceedings in connection with the award or performance of a Federal award that reached final disposition within the most recent five-year period. The recipient must also make semiannual disclosures regarding such proceedings. Proceedings information will be made publicly available in the designated integrity and performance system (currently FAPIIS). This is a statutory requirement under section 872 of Public Law 110-417, as amended (41 U.S.C. 2313). As required by section 3010 of Public Law 111-212, all information posted in the designated integrity and performance system on or after April 15, 2011, except past performance reviews required for Federal procurement contracts, will be publicly available. Full reporting requirements and procedures are found in Appendix XII to 45 CFR Part 75 – Award Term and Conditions for Recipient Integrity and Performance Matters.
Finding Help Online: http://grants.nih.gov/support/ (preferred method of contact)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)
General Grants Information (Questions regarding application processes and NIH grant resources)
Email: GrantsInfo@nih.gov (preferred method of contact)
Grants.gov Customer Support (Questions regarding Grants.gov registration and Workspace)
Contact Center Telephone: 800-518-4726
For programmatic questions related to this funding opportunity announcement or
?nervous system or cellular/metabolic toxicity research:
For questions related to ocular toxicity research:
Houmam Araj, Ph.D.
National Eye Institute (NEI)
For questions related to pulmonary toxicity research:
Srikanth S. Nadadur, Ph.D.
National Institute of Environmental Health Sciences (NIEHS)
For questions related to dermal/vesicant-induced toxicity research:
Hung Tseng, Ph.D.
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
For questions related to pharmaceutical-based toxicity (opioid overdose) research:
Tijuanna E. DeCoster, Ph.D., MPA
National Institute of Neurological Disorders and Stroke (NINDS)
Karen Robinson Smith
National Eye Institute (NEI)
Lisa A. Edwards, MBA
National Institute of Environmental Health Sciences (NIEHS)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
National Institute on Drug Abuse (NIDA)
Note: For help accessing PDF, RTF, MS Word, Excel, PowerPoint, Audio or Video files, see Help Downloading Files.