National Institutes of Health (NIH)
National Institute on Aging (NIA)
U01 Research Project Cooperative Agreements
See Notices of Special Interest associated with this funding opportunity
NOT-OD-23-012 Reminder: FORMS-H Grant Application Forms and Instructions Must be Used for Due Dates On or After January 25, 2023 - New Grant Application Instructions Now Available
NOT-OD-22-190 - Adjustments to NIH and AHRQ Grant Application Due Dates Between September 22 and September 30, 2022
The goal of this Funding Opportunity Announcement (FOA) is to provide funding support for the pre-clinical and early stage clinical (Phase I) development of novel small-molecule and biologic drug candidates that prevent Alzheimer's disease (AD), slow its progression, or treat its cognitive and behavioral symptoms. Participants in this program will receive funding for therapy development activities such as medicinal chemistry; pharmacokinetics (PK); Absorption, Distribution, Metabolism, Excretion, Toxicology (ADMET); efficacy in animal models; formulation development; chemical synthesis under Good Manufacturing Practices (GMP); Investigational New Drug (IND) enabling studies; and initial Phase I clinical testing. Applications not responsive to this FOA include: research on basic mechanisms of disease or mechanisms of drug action; development of biomarkers, devices, non-pharmacological interventions (e.g., exercise, diet, cognitive training), repurposed drugs and combinations therapies; discovery activities such as high-throughput screening and hit optimization; and stand-alone clinical trials.
30 days prior to the application due date
| Application Due Dates | Review and Award Cycles | ||||
|---|---|---|---|---|---|
| New | Renewal / Resubmission / Revision (as allowed) | AIDS | Scientific Merit Review | Advisory Council Review | Earliest Start Date |
| February 05, 2022 * | March 05, 2022 * | Not Applicable | July 2022 | October 2022 | December 2022 |
| June 05, 2022 * | July 05, 2022 * | Not Applicable | November 2022 | January 2023 | April 2023 |
| October 05, 2022 * | November 05, 2022 * | Not Applicable | March 2023 | May 2023 | July 2023 |
| February 05, 2023 * | March 05, 2023 * | Not Applicable | July 2023 | October 2023 | December 2023 |
| June 05, 2023 * | July 05, 2023 * | Not Applicable | November 2023 | January 2024 | April 2024 |
| October 05, 2023 * | November 05, 2023 * | Not Applicable | March 2024 | May 2024 | July 2024 |
| February 05, 2024 * | March 05, 2024 * | Not Applicable | July 2024 | October 2024 | December 2024 |
| June 05, 2024 * | July 05, 2024 * | Not Applicable | November 2024 | January 2025 | April 2025 |
| October 05, 2024 * | November 05, 2024 * | Not Applicable | March 2025 | May 2025 | July 2025 |
All applications are due by 5:00 PM local time of applicant organization. All types of non-AIDS applications allowed for this funding opportunity announcement are due on the listed date(s).
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.
Not Applicable
It is critical that applicants follow the instructions in the Research (R) Instructions in the SF424 (R&R) Application Guide,except where instructed to do otherwise (in this FOA or in a Notice from 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.
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.
- Use the NIH ASSIST system to prepare, submit and track your application online.
- Use an institutional system-to-system (S2S) solution to prepare and submit your application
to Grants.gov and eRA Commons to track your
application. Check with your institutional officials regarding availability.
- Use Grants.gov Workspace to prepare and submit your application and eRA Commons to track your application.
Overview
Alzheimer's disease (AD) is the most common cause of dementia in older persons and is among the greatest healthcare challenges of the 21st century. The disease currently affects an estimated 5.5 million in the United States; by 2050 this number could rise as high as 14 million. To avert this public health crisis, effective therapies that prevent AD, slow its progression, or treat its cognitive and behavioral symptoms are urgently needed. To catalyze drug development for AD, NIA is reissuing, with this Funding Opportunity Announcement (FOA), the Alzheimer's Drug Development Program (ADDP). The ADDP offers researchers funding for drug development activities that can be conducted in their own laboratories, in collaboration with contract research organizations (CROs) that specialize in various drug development activities including: medicinal chemistry; pharmacokinetics (PK); Absorption, Distribution, Metabolism, Excretion, Toxicology (ADMET); formulations development; efficacy in animal models; chemical synthesis under Good Manufacturing Practices (GMP); Investigational New Drug (IND) enabling safety-toxicology; and initial Phase I clinical testing.
Scope
The overarching goal of the ADDP is the development of a broad range of novel drug candidates for AD, including small molecules, natural products, and biologics against validated targets. The program is not designed to support research on basic mechanisms of disease or mechanisms of drug action; development of biomarkers, devices, non-pharmacological interventions (e.g., exercise, diet, cognitive training), repurposed drugs, and combination therapies; or activities such as high throughput screening.
To maintain portfolio diversity, this program does not support projects aimed at anti-amyloid therapies and tau immunotherapies.
Projects can enter the ADDP either at the Early Stage to optimize the agent's potency, drug-like properties, specificity, pharmacological properties, and/or ADMET properties and undergo Investigational New Drug (IND)-enabling safety toxicology, or at the Late Stage to advance development of candidates through IND-enabling toxicology studies and initial Phase I clinical testing.
Applicants are encouraged to contact NIA Scientific/Research Staff regarding the suitability of their projects for the ADDP and to clarify which entry stage is most appropriate for their project.
Stage Specific Entry Criteria
Early Stage Entry Criteria for Small Molecule Projects
Small molecule projects must meet the following requirements prior to entering the Early Stage:
- Rigorous data supporting the hypothesis that modulating the putative drug target/affected pathway will produce a desirable outcome for the intended AD indication (i.e., pre-clinical, prodromal/MCI, early, mid and late stage).
- A bioactive compound, in hand, that will serve as a starting point for optimization with proof of identity and purity (typically greater than 95%, as determined by, e.g., NMR, melting point, or LC/MS, with no single impurity greater than 0.5%).
- In vitro biological activity (typically less than 1 M in biochemical assays and less than 10 M in cell-based assays relevant to the drug target), confirmed by repeat dose-response testing, with more than one batch of compound.
- Selectivity for the intended target over closely related targets, if desired (and when the target is known).
- Availability of primary and secondary in vitro bioactivity assays that can be used or optimized for driving Structure-Activity Relationship (SAR) studies.
- Availability of preclinical animal model(s) that can be used to assess in vivo efficacy or target engagement (i.e., measurement of target binding or proximal downstream effects).
- Availability of selectivity and counter-screening assays to address potential activity at related targets and other undesirable activities or artifacts.
- Demonstration that the proposed secondary bioactivity assays and counter-screening and selectivity assays have sufficient reliability and throughput for their proposed use in the project.
- Demonstration of a clear correlation between activity in the primary assay and activity in confirmatory assays and models, sufficient enough to justify advancement criteria in a testing funnel.
- No obvious legal (e.g., intellectual property) constraints to pursuing the proposed chemical scaffold(s) and using the proposed assays and models for research purposes and/or commercial development.
Early Stage Entry Criteria for Biologics Projects
Biologics projects should meet the following qualifications prior to entering the Early Stage:
- Applicants should have one or more drug lead(s) from which a candidate can be derived.
- The drug lead(s) should be sufficiently characterized so that the parameters to be optimized can be quantitatively specified.
- Established preliminary in-vivo efficacy and target engagement data using agent(s) in relevant animal model(s). The agent(s) should show in-vivo efficacy using clinically relevant outcome measures (e.g., biochemical, neuropathological, behavioral, and/or functional, when possible) and in-vivo target engagement (e.g., measurement of target binding or proximal downstream effects) at the clinically intended site of action using sufficient experimental and statistical rigor in a relevant animal in-vivo proof-of-concept model.
- Applicants should have pre-existing data demonstrating that the key in vitro and in vivo assays proposed to optimize the leads are suitable for the proposed purpose and available in either the applicant's or collaborator's laboratories.
- Availability of animal and/or cell-based model(s) that can be used to assess in vivo efficacy or target engagement (i.e., measurement of target binding or proximal downstream effects).
- No obvious legal (e.g., intellectual property) constraints to pursuing the proposed biologic agent(s) using the proposed assays and models for research purposes and/or commercial development.
Late Stage Entry Criteria for Small Molecule Projects
Small molecule projects should meet the following qualifications prior to entering the Late Stage:
- A strong data package linking the putative drug target/affected pathway to the proposed disease indication and supporting the hypothesis that altering the target activity as proposed will produce desirable outcomes for the disease.
- Proposed compounds should have in vitro and in vivo biological activity and ADMET properties appropriate for the intended clinical use (i.e., the disease indication, patient population, delivery mode, treatment duration, and treatment regimen) and outcomes.
- A data package showing a clear and convincing demonstration of preclinical efficacy. The data package can include in vivo efficacy in an established AD animal model and/or in vivo target engagement at the clinically intended site of action. Studies using animal models presented to justify the choice of therapeutic target or drug candidate must be in compliance with NIH guidance on rigor and reproducibility . In particular, investigators proposing animal model studies are expected to follow the general Animals in Research: Reporting In Vivo Experiments (ARRIVE) guidelines for rigorous animal research. These studies should include a power analysis and associated assumptions for the determination of sample size, statistical handling of the data (such as criteria for data inclusion or exclusion), procedures used for blinding and randomization, and whether studies were balanced for sex and were replicated.
- A data package that includes Ames mutagenicity, hERG activity, microsome stability, CYP inhibition, plasma protein binding, and aqueous solubility.
- A data package that demonstrates the degree of selectivity for the intended target over closely related targets.
- A data package that includes counter-screening aimed at determining selectivity across a broad panel of unrelated pharmacological targets (e.g., G protein-coupled receptors, kinases, etc.) is also required.
- No obvious legal (e.g., intellectual property) constraints to pursuing the proposed small molecule(s) using the proposed assays and models for research purposes and/or commercial development.
Late Stage Entry Criteria for Biologics Projects
Biologics projects should meet the following qualifications prior to entering the Late Stage:
- A data package demonstrating completed optimization and final characterization of the candidate, such as structure/identity, selectivity, bioavailability stability, formulation, manufacturability, sufficient purity, clinically intended route of administration, minimal effective dose, optimal effective dose, time and duration of treatment as determined in relevant in vivo assays using clinically relevant functional and/or pathological outcome measures, and/or in vivo target engagement assays.
- In vivo study results that include assessments of pharmacokinetics, bioavailability at the relevant site of action, and the pharmacokinetics-pharmacodynamics relationship.
- Details concerning special formulations, if proposed (i.e., slow release, liposomes, nanoparticles, etc.).
- Rigorous evidence that the agent is a blood-brain-barrier penetrant (unless the agent is proposed to be delivered directly to the CNS).
- A data package showing a clear and convincing demonstration of efficacy. The data package can include in vivo efficacy in an established AD animal model and/or in vivo target engagement at the clinically intended site of action. Studies using animal models presented to justify the choice of therapeutic target or drug candidate must be in compliance with NIH guidance on rigor and reproducibility . In particular, investigators proposing animal model studies are expected to follow the general ARRIVE guidelines for rigorous animal research These studies should include a power analysis and associated assumptions for the determination of sample size, statistical handling of the data (such as criteria for data inclusion or exclusion), procedures used for blinding and randomization, and whether studies were balanced for sex and were replicated.
- No obvious legal (e.g., intellectual property) constraints to pursuing the proposed biologic agent(s) using the proposed assays and models for research purposes and/or commercial development.
Drug Development Activities Supported Through this Program
Supported Early Stage Activities for Small Molecule Projects
Examples of Early Stage activities for small molecule projects include, but are not limited to, the following:
- Establishment of the SAR
- Testing of analogs in bioactivity assays and animal models
- Testing of analogs in selectivity and counter-screening assays
- Assessment of efficacy and/or target engagement
- Identification of target engagement translational biomarkers
- Testing of analogs in ADMET assays (e.g., microsome stability, CYP induction and inhibition, solubility, permeability in MDCK or Caco-2 cells, plasma protein binding, brain/plasma ratio, PK in multiple species)
- Scale-up synthesis
- Compound stability studies
- Pre-formulation studies
- Multiple dose rodent PK testing with pharmacodynamic (PD) correlations, if possible
- Dose-range finding toxicology studies
- Initial IND-enabling toxicology
Supported Early Stage Activities for Biologics Projects
Examples of Early Stage activities for biologics projects include, but are not limited to, the following:
- Optimization of leads for improvement in potency, specificity, bioavailability, and suitability for human testing
- Selection of the best promoter or viral serotype for a gene therapy product
- Humanization of a mouse monoclonal antibody
- Characterization of identity and properties (e.g., cell phenotype, aggregation, epitope mapping, post-translational modifications, sequences, viscosity, stability)
- Assessment of in vitro activities (e.g., affinity, specificity, activity in cells, cellular uptake)
- Assessment of efficacy and/or target engagement
- Identification of target engagement translational biomarkers
- Assessment of in vivo pharmacology such as determination of dose range, dosing regimen, duration of treatment
- Assessment of PK/PD properties
- Evaluation of metabolism
- Minimizing a predicted or previously encountered toxicity
- Optimization of delivery systems and special formulations (i.e., slow release, liposomes, etc.)
- Optimization to have better suitability for the route of administration
- Developing a production plan
- Dose-range finding toxicology studies
- Initial IND-enabling toxicology
Supported Late Stage Activities for Small Molecule Projects
Examples of Late Stage activities for small molecule projects include, but are not limited to, the following:
- Scale-up synthesis
- Salt and polymorph screening
- Compound stability studies
- Pre-formulation studies
- Multiple dose rodent PK testing with PD correlations, if possible
- Dose-range finding toxicology studies
- Metabolite identification
- IND-enabling toxicology, with toxicokinetics, if applicable
- Pre-IND meeting
- IND document preparation (the PD/PI will be responsible for the submission of the IND application and scheduling meetings with the Food and Drug Administration (FDA))
- Good Manufacturing Practice (GMP) manufacturing of material for Phase I clinical testing
- First-in-human Phase I clinical trial (i.e., single dose or single ascending study. Clinical trial outcomes may include safety, tolerability, PK and PD, target engagement, and target modulation endpoints.)
Supported Late Stage Activities for Biologics Projects
Examples of Late Stage activities for biologics projects include but are not limited to the following:
- Chemistry, Manufacturing, and Control (CMC) activities (e.g., master and working cell banks development, purification development, CMC analytical development, formulation development, scale-up manufacturing, or cGMP manufacturing) for IND-enabling pharmacology/toxicology testing
- PK evaluations in species relevant for toxicology or human dose-prediction
- Preliminary safety such as safety pharmacology and/or dose-range finding toxicology
- IND-enabling toxicology, with toxicokinetics, if applicable
- Tumorigenicity evaluations particularly for gene therapies and cell therapies
- Immunogenicity evaluations
- Biodistribution studies
- Pre-IND meetings
- IND document preparation
- GMP manufacturing of material for Phase I clinical testing
- First in-human Phase I clinical trial (i.e., single dose or single ascending dose study. Clinical trial outcomes may include safety, tolerability, PK and PD, target engagement, and target modulation endpoints.)
Non-Responsiveness Criteria:
- Basic research and studies of disease mechanism
- Studies aimed at mechanisms of drug action
- Animal model development
- Stand alone preclinical efficacy studies in animal models
- Screening to identify hit compounds
- Projects aimed at anti-amyloid therapies
- Projects aimed at developing anti-tau immunotherapies
- Projects that propose to develop generic or off-patent compounds for AD
- Projects that propose to repurpose or develop new formulations or drug delivery systems for compounds that have previously been approved for another indication by FDA or any other worldwide regulatory agency
- Projects that propose to develop and/or test combination therapies
- Development of risk, detection, diagnostic, prognostic, predictive, and prevention biomarkers
- Development of diagnostics and diagnostic devices
- Stand-alone clinical trials
- Studies directed beyond Phase I clinical testing
Milestones
Milestone-driven research is used to ensure research is focused on a well-defined goal and achieving that goal with the greatest efficiency. As drug development research is inherently high risk, the use of milestones provides clear indicators of a project's continued success or emergent difficulties. The milestones must provide objective and quantitative success criteria which are recognizable as appropriate endpoints for a specific scientific goal and can be used to monitor the progress made by a research project. The milestones will serve as a basis for go/no-go decision making between NIA program staff and the project research team. Therefore, the application must include a table or list of go/no-go milestones with quantitative success criteria for each year of funding. Prior to funding of an application, NIA program staff will contact the applicant to discuss the proposed milestones and any modifications to the milestones recommended by the review committee or NIA Program staff. A final set of approved milestones will be specified in the Notice of Award. Progress towards achievement of the established milestones will be evaluated by a committee composed of NIA program staff. If warranted, the milestones for future years may be revised based on data and research progress during the preceding year.
Note: If a funded project does not make satisfactory progress toward the agreed upon milestones at any stage during the funding period, future year grant funding may be discontinued.
Quality and Compliance Requirements
Since one of the goals of this program is to generate drug candidates which will be eligible for FDA approval, adherence to compliance and quality criteria is required.
- It is expected that all IND enabling nonclinical studies will be performed in a manner consistent with Good Laboratory Practices (GLP) and current FDA guidance.
- All clinical trials must be performed following Good Clinical Practices (GCP) and in accord with the NIH Policy for Data and Safety Monitoring.
Intellectual Property
The ultimate goal of this program is to bring new therapies to the market. Therefore, the creation and protection of intellectual property (IP) that will make drug candidates attractive to potential licensing and commercialization partners is an important activity to be undertaken by the PD/PI in consultation with their institutions' technology transfer officials. This program is structured so that the awardee institution retains their assignment of IP and thereby controls the patent prosecution and licensing negotiations for drug candidates developed in this program. It is expected that the awardee institution will take responsibility for patent filings, maintenance, and licensing efforts toward eventual commercialization.
The National Institute on Aging (NIA) supports a central resource to NIA staff and extramural investigators to facilitate/support the conduct and management of clinical research. This resource, the Clinical Research Operations Management System (CROMS), is a comprehensive data management system to support the business functions, management, and oversight responsibilities of NIA grants that support the conduct of clinical research with human subjects. It is the expectation by NIA that all successful applicants will interface, integrate, or adapt their information system(s) and processes to interact with existing and future components of the CROMS as necessary, including the use of a CROMS data templates as specified.
See Section VIII. Other Information for award authorities and regulations.
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. See Section VI.2 for additional information about the substantial involvement for this FOA.
Resubmission
Revision
The OER Glossary and the SF424 (R&R) Application Guide provide details on these application types. Only those application types listed here are allowed for this FOA.
Optional: Accepting applications that either propose or do not propose clinical trial(s).
Need help determining whether you are doing a clinical trial?
The number of awards is contingent upon NIH appropriations and the submission of a sufficient number of meritorious applications.
Application budgets are limited to $1,500,000 in direct costs per year and need to reflect the actual needs of the proposed project
For Early Stage projects, the project period is limited to five years. For Late Stage projects, the project period is limited to four years.
NIH grants policies as described in the NIH Grants Policy Statement will apply to the applications submitted and awards made from this FOA.
1. Eligible Applicants
Higher Education Institutions
- Public/State Controlled Institutions of Higher Education
- Private Institutions of Higher Education
The following types of Higher Education Institutions are always encouraged to apply for NIH support as Public or Private Institutions of Higher Education:
- Hispanic-serving Institutions
- Historically Black Colleges and Universities (HBCUs)
- Tribally Controlled Colleges and Universities (TCCUs)
- Alaska Native and Native Hawaiian Serving Institutions
- Asian American Native American Pacific Islander Serving Institutions (AANAPISIs)
Nonprofits Other Than Institutions of Higher Education
- Nonprofits with 501(c)(3) IRS Status (Other than Institutions of Higher Education)
- Nonprofits without 501(c)(3) IRS Status (Other than Institutions of Higher Education)
For-Profit Organizations
- Small Businesses
- For-Profit Organizations (Other than Small Businesses)
Local Governments
- State Governments
- County Governments
- City or Township Governments
- Special District Governments
- Indian/Native American Tribal Governments (Federally Recognized)
- Indian/Native American Tribal Governments (Other than Federally Recognized)
Federal Governments
- Eligible Agencies of the Federal Government
- U.S. Territory or Possession
Other
- Independent School Districts
- Public Housing Authorities/Indian Housing Authorities
- Native American Tribal Organizations (other than Federally recognized tribal governments)
- Faith-based or Community-based Organizations
- Regional Organizations
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 not allowed.
Applicant organizations
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.
- Dun and Bradstreet Universal Numbering System (DUNS) - All registrations require that applicants be issued a DUNS number. After obtaining a DUNS number, applicants can begin both SAM and eRA Commons registrations. The same DUNS number must be used for all registrations, as well as on the grant application.
- System for Award Management (SAM) Applicants must complete and maintain an active registration, which requires renewal at least annually. The renewal process may require as much time as the initial registration. SAM registration includes the assignment of a Commercial and Government Entity (CAGE) Code for domestic organizations which have not already been assigned a CAGE Code.
- NATO Commercial and Government Entity (NCAGE) Code Foreign organizations must obtain an NCAGE code (in lieu of a CAGE code) in order to register in SAM.
- eRA Commons - Applicants must have an active DUNS number to register in eRA Commons. Organizations can register with the eRA Commons as they are working through their SAM or Grants.gov registration, but all registrations must be in place by time of submission. eRA Commons requires organizations to identify at least one Signing Official (SO) and at least one Program Director/Principal Investigator (PD/PI) account in order to submit an application.
- Grants.gov Applicants must have an active DUNS number and SAM registration in order to complete the Grants.gov registration.
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.
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.
2. Cost Sharing
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.
The NIH will not accept duplicate or highly overlapping applications under review at the same time. This means that the NIH will not accept:
- A new (A0) application that is submitted before issuance of the summary statement from the review of an overlapping new (A0) or resubmission (A1) application.
- A resubmission (A1) application that is submitted before issuance of the summary statement from the review of the previous new (A0) application.
- An application that has substantial overlap with another application pending appeal of initial peer review (see NOT-OD-11-101)
1. Requesting an Application Package
The application forms package specific to this opportunity must be accessed through ASSIST, Grants.gov Workspace or an institutional system-to-system solution. Links to apply using ASSIST or Grants.gov Workspace 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.
2. Content and Form of Application Submission
It is critical that applicants follow the instructions in the Research (R) 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.Letter of Intent
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:
- Descriptive title of proposed activity
- Name(s), address(es), and telephone number(s) of the PD(s)/PI(s)
- Names of other key personnel
- Participating institution(s)
- Number and title of this funding opportunity
The letter of intent should be sent to:
Lorenzo M. Refolo, Ph.D.
National Institute on Aging (NIA)
Telephone: 301-594-7576
Email: [email protected]
Page Limitations
All page limitations described in the SF424 Application Guide and the Table of Page Limits must be followed.
Note: Effective for due dates on or after January 25, 2023, the Data Management and Sharing (DMS) Plan will be attached in the Other Plan(s) attachment in FORMS-H and subsequent application forms packages. For due dates on or before January 24, 2023, the Data Sharing Plan and Genomic Data Sharing Plan GDS) will continue to be attached in the Resource Sharing Plan attachment in FORMS-G application forms packages.
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.
R&R or Modular Budget
PHS 398 Research Plan
Other Plan(s):
Note: Effective for due dates on or after January 25, 2023, the Data Management and Sharing Plan will be attached in the Other Plan(s) attachment in FORMS-H and subsequent application forms packages. For due dates on or before January 24, 2023, the Data Sharing Plan and Genomic Data Sharing Plan GDS) will continue to be attached in the Resource Sharing Plan attachment in FORMS-G application forms packages.
All applicants planning research (funded or conducted in whole or in part by NIH) that results in the generation of scientific data are required to comply with the instructions for the Data Management and Sharing Plan. All applications, regardless of the amount of direct costs requested for any one year, must address a Data Management and Sharing Plan.
All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions:
Specific Aims: The Specific Aims section should include aims delineated either for the Early or Late Stages of the project. For proposed Phase I clinical trials, define the aims of the study (e.g., safety, tolerability, pharmacokinetics and pharmacodynamics, target engagement and target modulation, dose-range).
Research Strategy:
Note: Applicants proposing human subjects and/or clinical trials must use the PHS Human Subjects and Clinical Trials Information Form to capture detailed study information. You may use the research strategy to discuss the overall approach but do not duplicate information collected in the PHS Human Subjects and Clinical Trials Information Form.
The Research Strategy section should include the following subsections:
- Clinical Impact (Significance)
- Biological Rationale and Profile of the Drug Candidate (Significance)
- Testing Strategy, Early or Late Stage (Approach)
- Milestones
- Innovation
- Intellectual Property
Clinical Impact (Significance):
- Applicants should include a brief statement of the therapeutic hypothesis that includes: the projected patient reduction of symptoms, slowing disease progression, side effects, dose administration and regimen, and sustainability of effect.
- Provide a Target Product Profile (TPP) in a table based on an FDA template that summarizes the minimal/ideal profile of the final marketed product and shows the ultimate goals of the proposed drug development effort, such as disease indication, patient population, delivery mode, treatment duration, treatment regimen, and standards for clinical efficacy.
- Applicants requesting funding for a clinical trial should include a clinical protocol and management plan.
- Indicate the target clinical population and specific stage of disease in which the treatment would be most efficacious.
- Describe possible clinical trial endpoints. Indicate if biomarkers are available in animal models and humans to detect if the drug engages the target.
- Describe the group clinical expertise used to determine the goals of the drug development program and the clinical trial.
- Discuss how the proposed project relates to therapeutic development efforts underway in academia and industry.
Biological Rationale and Profile of the Drug Candidate (Significance):
- Applicants should summarize the evidence that validates the drug target from cellular or animal models and clinical studies, provide a brief summary of the rationale for the selection of the target, the level of agreement in the field regarding the target's role in disease pathogenesis and clinical relevance of the target, including the optimal disease stage (e.g., asymptomatic, mild cognitive impairment (MCI), mild, moderate, or severe AD) to pharmacologically engage the target.
- Provide the evidence that altering target activity as proposed will give desirable outcomes for the proposed stage of AD.
- Applicants should discuss the disease-relevance of in vitro or in vivo models that are proposed or that have been used and whether the endpoints measured, and levels of activity observed are likely to be clinically relevant.
- Applicants should discuss plans to incorporate any translatable, clinically relevant biomarkers into their preclinical development program.
- Applicants should discuss how target engagement and/or pharmacodynamic markers will be used to detect activity at the putative target in preclinical models and in patients, if available or proposed for development
- Studies using animal models presented to justify the choice of therapeutic target or drug candidate must be in compliance with NIH guidance on rigor and reproducibility. In particular, investigators proposing animal model studies are expected to follow the general ARRIVE guidelines for rigorous animal research. These studies should include a power analysis and associated assumptions for the determination of sample size, statistical handling of the data (such as criteria for data inclusion or exclusion), procedures used for blinding and randomization, and whether studies were balanced for sex and were replicated.
- Provide a Drug Candidate Profile Table that summarizes the drug-like properties, pharmacological and ADMET activities of the drug candidate proposed for optimization or as the development candidate. Note any potential liabilities.
- For Early Stage projects, show that the drug candidate proposed as the starting point for optimization alters the activity of the putative target as intended and/or produces desired outcomes in disease models, with sufficient detail to allow reviewers to evaluate the rigor of the experimental design. Explain the choice of models, assays, and endpoints for these studies.
- For Late Stage projects, show that the proposed development candidate has clinically relevant in vivo activity, when delivered by the clinically intended route of administration, at exposure levels that can likely be achieved clinically with the proposed human dosing regimen.
- For Late Stage projects, show the data that demonstrate the relationship between drug candidate exposure and activity and explain how these data support the clinical dosing regimen proposed in the TPP.
Testing Strategy (Approach):
- Specify whether the project is proposed for entry at the Early or Late Stage.
- For small molecule projects, present evidence that the drug candidate(s) meet the entry requirements for the proposed project stage (Early or Late).
- For biologics projects, present evidence that the drug candidate(s) meet the entry requirements for the proposed project stage (Early or Late).
- Include a figure showing the Testing Funnel that shows how proposed assays will be ordered and grouped into testing tiers.
- Include a table of proposed activities that provides the following information: activity (e.g., medicinal chemistry, optimization of biologic candidate, assays, PK, etc.), throughput for testing chemical analogs or biologic derivatives, and advancement criteria through the testing funnel.
- Clearly indicate which activities will be conducted by the PD/PI and associated personnel and which activities will be conducted by contractors. Include experimental designs and justification for all studies that will be conducted by the PD/PI and associated personnel. Activities that will be conducted by Contract Research Organizations (CROs) should be specifically described in terms that will include expected deliverables.
- Explain the rationale for the choice of assays, assay design, and advancement criteria, and clarify how these relate to the desired drug properties presented in the Target Product Profile.
- Show assay validation data or present plans to optimize and validate assays.
- Include a Gantt chart that lays out each step in the critical path of the project (e.g., Optimization of drug-like properties, Optimization of bioactivity, Pharmacology profiling, Toxicology profiling, Efficacy in animal models, GMP synthesis, formulations development, and IND-enabling studies, Ph I clinical trial).
Additional Information Regarding Clinical Trials
- Applicants are strongly advised to discuss plans with NIH program staff prior to submitting their application to determine whether a clinical trial is feasible within the proposed funding timeframe.
- Applicants must submit supporting trial and regulatory documents to NIH for administrative review prior to the commencement of the trial.
Milestones:
- Because drug discovery and development are inherently high risk, it is expected that there may be significant attrition as projects progress. Therefore, the application must include a Table of go/no-go milestones with quantitative success criteria for each year of funding.
Innovation
- If the drug candidate targets the same molecule, pathway, or cellular process that has previously been tested in clinical trials for AD, explain why the proposed approach would be expected to provide a benefit over previously tested approaches.
- If similar drugs have been tested in clinical trials for AD, explain why the proposed drug candidate would be expected to give significantly better clinical outcomes.
- If the drug candidate is an improvement over an earlier generation of drug(s) that has not been marketed, discuss the advantages the proposed new drug candidate over those previously tested. Include results from previous clinical trials with related agents.
- Comment on the novelty of proposed approach, target, pathway, assays, or models.
Intellectual Property (IP)
Applicants are encouraged to prepare this section in consultation with their institutions' technology transfer officials.
- Applicants should describe any constraints of which they are aware that could impede their use of compounds, assays, or models for research purposes and/or commercial development (e.g., certain restrictions under transfer or sharing agreements, applicants' previous or present intellectual property filings and publications, compounds with similar structures that are under patent and/or on the market, etc.) and how these issues would be addressed. If the applicant's institution has filed pertinent patents, the applicant should indicate filing dates, the type of patent, and application status.
- For a multiple-PD/PI, multiple-institution application, applicants should describe the infrastructure of each institution for bringing the technologies to practical application and for coordinating these efforts (e.g., licensing, managing intellectual property) among the institutions consistent with achieving the goals of the program. Applicants should clarify how IP will be shared or otherwise managed if there are multiple PDs/PIs and institutions involved.
Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the SF424 (R&R) Application Guide.
The following modifications also apply:
- All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan.
- If patent protection is being sought, investigators should explain how data will be shared after filing for patent protection to allow for both further research and the development of commercial products to advance forward, consistent with achieving the goals of the program.
Appendix:
Only limited Appendix materials are allowed. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.
- No publications or other material, with the exception of blank questionnaires or blank surveys, may be included in the Appendix.
When involving human subjects research, clinical research, and/or NIH-defined clinical trials (and when applicable, clinical trials research experience) follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the SF424 (R&R) Application Guide, with the following additional instructions:
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.
Section 2 - Study Population Characteristics
2.5 Recruitment and Retention Plan
Applicants should provide a detailed recruitment and retention plan for the study. The recruitment plan should demonstrate how clinical sites will engage the community and ensure representation of a diverse study population.
Section 4 - Protocol Synopsis
4.1. Study Design
4.1a. Detailed Description
Include determination of dose levels.
4.1c. Interventions
For "Intervention Description", include route of administration.
4.2. Outcome Measures
At least one outcome measure should include PK assessments, with attention to demonstration of CNS penetration (if appropriate) and target engagement or modulation.
Note: Delayed onset does NOT apply to a study that can be described but will not start immediately (i.e., delayed start).All instructions in the SF424 (R&R) Application Guide must be followed.
All instructions in the SF424 (R&R) Application Guide must be followed.
3. Unique Entity Identifier and System for Award Management (SAM)
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.
5. Intergovernmental Review (E.O. 12372)
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 How to Apply Application Guide. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Dealing with System Issues guidance. For assistance with application submission, contact the Application Submission Contacts in Section VII.
Important reminders:
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 and compliance with application instructions by the Center for Scientific Review and responsiveness by components of participating organizations, NIH. Applications that are incomplete, non-compliant and/or nonresponsive will not be reviewed.
Applicants are required to follow the instructions for post-submission materials, as described in the policy. Any instructions provided here are in addition to the instructions in the policy.
1. Criteria
Note: Effective for due dates on or after January 25, 2023, the Data Sharing Plan and Genomic Data Sharing Plan (GDS) as part of the Resource Sharing Plan will not be evaluated at time of review.
Only the review criteria described below will be considered in the review process. Applications submitted to the NIH in support of the NIH mission are evaluated for scientific and technical merit through the NIH peer review system.
For this particular announcement, note the following:
- Projects should not be penalized if the mechanism of action of the compound is unknown. While this may add to the risk, the increased risk may be counterbalanced by increased novelty.
- Evaluation of the approach should focus on the biological rationale, the rigor and transparency of supporting preclinical data, the potential for identifying a compound/biologic with drug-like properties, potential patient benefit, competitive landscape (novelty), and strengths/weaknesses of studies to be conducted by the PD/PI.
- Work to be conducted by Contract Research Organizations (CROs), specifically expected deliverables for each type of CRO, is subject to review.
- Applications that propose entry at the Late Stage but that reviewers consider better suited for the Early Stage or vice versa should nevertheless be evaluated and scored based on the entry criteria and expectations for the proposed entry stage. Reviewers can note in their comments that the project may be more appropriate for entry at a different stage.
- Studies using animal models presented to justify the choice of therapeutic target or drug candidate must be in compliance with NIH guidance on rigor and reproducibility (https://grants.nih.gov/reproducibility/index.htm#guidance) as determined by NIH staff. In particular, investigators proposing animal model studies are expected to follow the general ARRIVE guidelines for rigorous animal research These studies should include a power analysis and associated assumptions for the determination of sample size, statistical handling of the data (such as criteria for data inclusion or exclusion), procedures used for blinding and randomization, and whether studies were balanced for sex and were replicated.
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.
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? Is the prior research that serves as the key support for the proposed project 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?
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?
Specific to this announcement:
- How significant an advantage does the proposed drug candidate offer over other treatments under development (in any drug class)?
- What is the likelihood that completion of the research objectives will lead to an AD therapy (i.e., is there a clear path into the clinic)?
- How strong are the data supporting the choice of therapeutic target and compound/biologic for the proposed stage of disease?
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?
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?
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?
Specific to this announcement:
- Would the proposed drug candidate be expected to give significantly better clinical outcomes than have been observed in previous efforts focused on the same therapeutic target?
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?
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?
In addition, for applications involving clinical trials
Does the application adequately address the following, if applicable
Study Design
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?
Specific to this announcement:
- Are the proposed studies appropriate, feasible and consistent with the proposed Target Product Profile (TPP), and likely to advance the project to the desired endpoint within the proposed timeframe?
- For key critical experiments (such as in vivo demonstration of efficacy and target engagement with a dose response):
- Are endpoints adequately described and is there a sound rationale for the choice of endpoints, assays, and models?
- Is there sufficient explanation for assumptions and reference to supporting data for the basis of power analyses?
- Is the description of planned data analyses and data handling rules such as criteria for data inclusion/exclusion, replication, blinding, and randomization, appropriate?
- Are appropriate minimal requirement(s) and assay(s) for the purity and activity of the reagents provided?
- If applicable, is the plan to validate the target engagement assays at the site of action relevant to the proposed therapy development?
- For small molecule projects are the proposed compounds suitable for SAR studies and optimization into a drug candidate?
- For biologics projects, is the proposed biologic agent(s) suitable for optimization into a drug candidate?
- Are the proposed in vivo studies and go/no-go criteria appropriate for declaring a development candidate?
- For Late Stage projects is it feasible to scale up the proposed development candidate to levels required for IND-enabling studies and clinical trials?
- Does the Late Stage plan include all the appropriate studies for obtaining an IND? Are the timelines realistic?
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?
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?
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.
Are the proposed project milestones and associated quantitative success criteria adequate and feasible?
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.
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.
Not Applicable
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.
Note: Effective for due dates on or after January 25, 2023, the Data Sharing Plan and Genomic Data Sharing Plan (GDS) as part of the Resource Sharing Plan will not be evaluated at time of review.
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.
- Has the applicant demonstrated that there are no constraints, of which they are aware, that could impede their use of drug candidates including small molecules or biologics, assays, or models for research purposes and/or commercial development?
- Has the applicant demonstrated that the proposed drug candidate is unlikely to be blocked or impeded by intellectual property constraints?
- Has the applicant described pertinent patent applications that have been filed, including the filing date(s), type of patent and application status?
- If multiple institutions are proposed, is it clear how intellectual property will be shared or otherwise managed to avoid encumbering the IP, consistent with achieving the goals of the program? Are these plans acceptable?
Reviewers will assess whether the project presents special opportunities for furthering research programs through the use of unusual talent, resources, populations, or environmental conditions that exist in other countries and either are not readily available in the United States or augment existing U.S. resources.
Not Applicable
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.
2. Review and Selection Process
Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s) convened by National Institute on Aging (NIA), 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 will receive a written critique.
Applications may undergo a selection process in which only those applications deemed to have the highest scientific and technical merit (generally the top half of applications under review) will be discussed and assigned an overall impact score.
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 appropriate national Advisory Council or Board. The following will be considered in making funding decisions:
- Scientific and technical merit of the proposed project as determined by scientific peer review.
- Availability of funds.
- Relevance of the proposed project to program priorities.
3. Anticipated Announcement and Award Dates
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. Refer to Part 1 for dates for peer review, advisory council review, and earliest start date.Information regarding the disposition of applications is available in the NIH Grants Policy Statement.
1. Award Notices
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.
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 recipient'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 and results reporting of all trials whether required under the law or not. For more information, see https://grants.nih.gov/policy/clinical-trials/reporting/index.htm
Institutional Review Board or Independent Ethics Committee Approval: Recipient institutions must ensure that 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).
2. Administrative and National Policy Requirements
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, Recipients, and Activities. More information is provided at Award Conditions and Information for NIH Grants.
Recipients of federal financial assistance (FFA) from HHS must administer their programs in compliance with federal civil rights laws that prohibit discrimination on the basis of race, color, national origin, disability, age and, in some circumstances, religion, conscience, and sex. This includes ensuring programs are accessible to persons with limited English proficiency. The HHS Office for Civil Rights provides guidance on complying with civil rights laws enforced by HHS. Please see https://www.hhs.gov/civil-rights/for-providers/provider-obligations/index.html and http://www.hhs.gov/ocr/civilrights/understanding/section1557/index.html.
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. 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.
- Recipients of FFA must ensure that their programs are accessible to persons with limited English proficiency. HHS provides 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 https://www.hhs.gov/civil-rights/for-individuals/special-topics/limited-english-proficiency/fact-sheet-guidance/index.html and https://www.lep.gov. 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 https://minorityhealth.hhs.gov/omh/browse.aspx?lvl=2&lvlid=53.
- 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.
- HHS funded health and education programs must be administered in an environment free of sexual harassment. Please see https://www.hhs.gov/civil-rights/for-individuals/sex-discrimination/index.html; https://www2.ed.gov/about/offices/list/ocr/docs/shguide.html; and https://www.eeoc.gov/eeoc/publications/upload/fs-sex.pdf. For information about NIH's commitment to supporting a safe and respectful work environment, who to contact with questions or concerns, and what NIH's expectations are for institutions and the individuals supported on NIH-funded awards, please see https://grants.nih.gov/grants/policy/harassment.htm.
- Recipients of FFA must also administer their programs in compliance with applicable federal religious nondiscrimination laws and applicable federal conscience protection and associated anti-discrimination laws. Collectively, these laws prohibit exclusion, adverse treatment, coercion, or other discrimination against persons or entities on the basis of their consciences, religious beliefs, or moral convictions. Please see https://www.hhs.gov/conscience/conscience-protections/index.html and https://www.hhs.gov/conscience/religious-freedom/index.html.
Please contact the HHS Office for Civil Rights for more information about obligations and prohibitions under federal civil rights laws at https://www.hhs.gov/ocr/about-us/contact-us/index.html or call 1-800-368-1019 or TDD 1-800-537-7697.
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.
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 2 CFR Part 200, 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 recipientsis 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 recipientsfor 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:
- Determining experimental approaches, designing protocols, conducting experiments, and analyzing and interpreting research data for studies funded through this U01. The PD/PI is ultimately responsible for the project and will make the final decisions regarding all project plans, provided that they can be executed within NIH-approved budgets and according to NIA/U01 grant and contract policies.
- Collaborating with NIA Program Staff in establishing a Go/No-Go milestone plan (typically a minimum of one milestone per funding year) at the start of the project and updated as needed.
- Submitting annual milestone progress reports in a standard format for evaluation by NIA Program Staff.
- Adhering to NIA/NIH policies, including those regarding data release, intellectual property, and publications.
- Implementing all scientific and policy decisions approved by the NIA/NIH.
- Working closely with his/her institution's technology transfer officials to ensure that royalty agreements, patent filings, and all other necessary intellectual property arrangements are completed in a timely manner.
- Submission of an IND with documentation for one of the following: 1) acceptance of clinical protocol by FDA; 2) elapse of the 30-day post filing waiting period without comment from the FDA; 3) completion of protocol changes or amendments requested by FDA.
- Submission of the data and safety monitoring plan (DSMP) in accordance with the NIA policies to NIA for review and notification of NIA approval.
- Registering Phase I trial on clinical trials.gov.
Awardees will retain custody of and have primary rights to the data and software developed under these awards, subject to Government rights of access consistent with current DHHS, PHS, and NIH policies.
NIH staff have substantial programmatic involvement that is above and beyond the normal stewardship role in awards, as described below:
- An NIA Program Officer will be assigned to the project and will be responsible for the normal scientific and programmatic stewardship of the award. The NIA Program Officer will be named in the award notice and will be the primary contact with the PI/PD. The Program Officer will be responsible for assessing the progress of the project towards accomplishment of milestones, and for recommending the level of continued funding.
- An NIA Project Scientist will be assigned to the project with substantial scientific and programmatic involvement during the conduct of this activity through technical assistance, advice and coordination that is above and beyond the normal stewardship role in awards. The Science Officer will provide additional expertise that is needed for proper scientific management of the award. This includes assisting the PI/PD in the development of a project milestone plan at the outset of the project, approving the final milestone language for incorporation into the award notice, enhancing the project's progress by providing access to various NIH resources, when appropriate, providing technical assistance, advice, and coordination to the project, although the dominant role and responsibilities for the activities funded by the U01 reside with the PI/PD.
- PLEASE NOTE: If a funded project does not make sufficient progress toward the agreed upon milestones at any stage, funding for the project may be discontinued.
Areas of Joint Responsibility include:
None; all responsibilities are divided between awardees and NIH staff as described above.
Data Management and Sharing
Note: The NIH Policy for Data Management and Sharing is effective for due dates on or after January 25, 2023.
Consistent with the NIH Policy for Data Management and Sharing, when data management and sharing is applicable to the award, recipients will be required to adhere to the Data Management and Sharing requirements as outlined in the NIH Grants Policy Statement. Upon the approval of a Data Management and Sharing Plan, it is required for recipients to implement the plan as described.
3. Reporting
When multiple years are involved, awardees will be required to submit the Research Performance Progress Report (RPPR) annually and financial statements as required in the NIH Grants Policy Statement.A final RPPR, 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.
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.
We encourage inquiries concerning this funding opportunity and welcome the opportunity to answer questions from potential applicants.
eRA Service Desk (Questions regarding ASSIST, eRA Commons, application errors and warnings, documenting system problems that threaten submission by the due date, and post-submission issues)
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 instructions, application processes, and NIH grant resources)
Email: [email protected] (preferred method of contact)
Telephone: 301-480-7075
Grants.gov Customer Support (Questions regarding Grants.gov registration and Workspace)
Contact Center Telephone: 800-518-4726
Email: [email protected]
Lorenzo M. Refolo, Ph.D.
National Institute on Aging (NIA)
Telephone: 301-594-7576
Email: [email protected]
Ramesh Vemuri, Ph.D.
National Institute on Aging (NIA)
Telephone: 301-402-7700
Email: [email protected]
Jeni Smits
National Institute on Aging (NIA)
Telephone: 301-496-1472
Email: [email protected]
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 Part 75.
and Human Services (HHS)
