Part 1. Overview Information

Key Dates

All applications are due by 5:00 PM local time of applicant organization. 

Applicants are encouraged to apply early to allow adequate time to make any corrections to errors found in the application during the submission process by the due date.

It is critical that applicants follow the instructions in the Research (R) Instructions in the How to Apply - Application Guide, except where instructed to do otherwise (in this NOFO or in a Notice from NIH Guide for Grants and Contracts).

Conformance to all requirements (both in the Application Guide and the NOFO) 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.

1. Use the NIH ASSIST system to prepare, submit and track your application online.
2. 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.
   
   
3. Use Grants.gov Workspace to prepare and submit your application and eRA Commons to track your application.



Table of Contents
Part 1. Overview Information
Key Dates
Part 2. Full Text of Announcement
Section I. Notice of Funding Opportunity Description
Section II. Award Information
Section III. Eligibility Information
Section IV. Application and Submission Information
Section V. Application Review Information
Section VI. Award Administration Information
Section VII. Agency Contacts
Section VIII. Other Information

Part 2. Full Text of Announcement

Section I. Notice of Funding Opportunity Description

 Purpose

Attaining effective therapies for rare diseases is challenging due to their low prevalence resulting in fewer patients, clinicians, researchers, and resources compared to common diseases. This leads to gaps in our understanding of a rare disease's natural history, and a dearth of suitable biomarkers or clinical outcome measures, or of other components needed to design, conduct, and interpret rigorous clinical trials.

This Notice of Funding Opportunity (NOFO) invites researchers to submit applications for support of clinical projects that address critical needs for clinical trial readiness in rare diseases. The Division of Rare Diseases Research Innovation (DRDRI) within the National Center for Advancing Translational Sciences (NCATS), along with the National Institutes of Health (NIH) Institutes and Centers (ICs) listed in Part 1, intend to facilitate rare diseases research by enabling efficient and effective movement of candidate therapeutics or diagnostics toward clinical trials and to increase their likelihood of success. This could be through the development and testing of rigorous biomarkers and clinical outcome assessment measures or by defining the presentation and course of a rare disease to enable the design of upcoming clinical trials.

Background

The NIH supports translational and clinical research on a broad range of diseases that are defined as rare; that is, diseases affecting fewer than 200,000 individuals in the United States (per the Rare Diseases Act of 2002). Progress in data science and an increased understanding of disease genetics lead experts to agree that more than an estimated 10,000 rare diseases are affecting millions of people in the United States. Most are serious or life-threatening, leading to significant morbidity and mortality, and the majority affect children. Despite advances in our understanding of the causes and mechanisms of many rare diseases, effective treatments are available for approximately 5%.

To address this significant public health concern, the NIH investment into discovery research has contributed to unprecedented opportunities to translate scientific advances into better treatments. Gene therapy and related approaches are an example of opportunities that have resulted from technological advances. However, to evaluate such potentially transformative treatments, researchers, biopharmaceutical companies, and regulators need high-quality natural history data, as well as biological and clinical outcome measures fit for the intended purpose. The absence of such information often represents a bottleneck in therapy development for many rare diseases.

This initiative aims to support studies that address these gaps in understanding of disease natural history and appropriate outcome measures, including biomarkers. Given the large number of rare diseases and the limited funding available, this initiative will focus on studies for which there are clinical development candidates for the indication(s), and for which there are unmet medical needs. The initiative will promote partnerships among academic investigators, industry, and patient groups, and will encourage interactions with the U.S. Food and Drug Administration (FDA). Use of existing data standards, tools, information technology platforms, and candidate clinical outcomes measures and biomarkers will also be encouraged, rather than the discovery or de novo development of such tools and resources.

Definitions

This NOFO describes a specialized type of clinical research that is intended to provide data necessary for the design of future clinical trials.

Clinical trial readiness is the state of having validated clinical research tools and knowledge of disease natural history necessary for the design of efficient clinical trials. Validated clinical research tools can include biomarkers or clinical outcome assessment measures that are fit-for-purpose within a defined context of use relevant to the clinical trials. Knowledge of disease natural history necessary for clinical trial design can include characteristics for stratification or determining inclusion and exclusion criteria; the stage of disease progression that may be responsive to treatment; and data needed for determining sample size through power calculations.

This NOFO uses terminology defined in the BEST (Biomarkers, EndpointS, and Other Tools) Resource, which was developed by the FDA-NIH Biomarker Working Group. Investigators are encouraged to use the terms below, where appropriate in their applications. Guidance to reviewers will include these definitions as a way to promote consistent evaluation of the applications. (See https://www.ncbi.nlm.nih.gov/books/NBK338448 for reference to the BEST Resource's glossary for the following definitions.)

Biomarker – A defined characteristic that is measured as an indicator of normal biological processes, pathogenic processes, or responses to an exposure or intervention, including therapeutic interventions. Molecular, histologic, radiographic, or physiologic characteristics are types of biomarkers. Categories of biomarkers include: Susceptibility/risk, diagnostic, monitoring, prognostic, predictive, pharmacodynamic/response, safety.

Clinical outcome assessment (COA) – An assessment of an outcome that reflects how an individual feels, functions or survives. The four types of COAs are clinician-reported, observer-reported, patient-reported, and performance outcomes.

Context of Use (COU) – A statement that fully and clearly describes the way the medical product development tool is to be used and the medical product development-related purpose of the use.

Concept – In a regulatory context, the concept is the aspect of an individual’s clinical, biological, physical, or functional state, or experience that the assessment is intended to capture (or reflect).

Validation – A process to establish that the performance of a test, tool, or instrument is acceptable for its intended purpose. For this NOFO, the intended purpose should be the collection of data in a clinical trial that will be used to determine whether to move forward with the intervention being tested to a later stage trial or for regulatory approval.

• Applications to this NOFO should focus on clinical validation. Clinical validation is defined as a process to establish that the test, tool, or instrument acceptably identifies, measures, or predicts the concept of interest.
• Biochemical and molecular biomarkers should have substantial data supporting analytical validation collected prior to submission of an application to this NOFO. Analytical validation is defined as a process to establish that the performance characteristics of a test, tool, or instrument are acceptable in terms of its sensitivity, specificity, accuracy, precision, and other relevant performance characteristics using a specified technical protocol (which may include specimen collection, handling and storage procedures). This is validation of the test’s, tool’s, or instrument’s technical performance, but is not validation of the item’s usefulness.

Scope

To optimize clinical trial readiness, there needs to be sufficient understanding of the rare disease to permit design, conduct, and interpretation of rigorous clinical trials. FDA published final guidance on considerations for the development of drugs and biological products for rare diseases. This NOFO is intended to support studies that address some of the issues presented in this guidance document, including the need for adequate understanding of the course of the disease and the need for sensitive and reliable biomarkers and outcome measures to be used during a clinical trial.

The proposed studies should have a research question able to be addressed within the defined timeline. The projects should not include clinical trials. If considering clinical trials, then please reference the NCATS website for other open funding opportunities.

Applicants are expected to have clinical expertise for the rare disease under study, including the capability for measuring COAs and analyzing appropriate biomarkers where applicable. Applicants should also have sufficient numbers of rare disease patients for inclusion in the study or have access to additional patients through collaboration.

Projects appropriate for this initiative need not be high-risk/high-reward studies; however, they should advance the field by facilitating clinical trial readiness through the development of missing components that are essential for rigorous clinical trials. Projects should be distinct from those supported through the traditional R01 mechanism.

Projects that are appropriate for this NOFO should focus on diseases that lack critical components of trial readiness and should have candidate therapeutics that will be ready for testing in upcoming clinical trials after the trial readiness study is completed. For the purpose of this initiative, clinical trial readiness can include two categories of projects:

1) Those that utilize sensitive, reliable, valid, and responsive tools to identify or select appropriate participants for clinical trials or to measure the effects of interventions. These tools include COA measures and biomarkers. Investigators are encouraged to use or modify existing resources, validate existing tools in specific rare disease populations, or add components to existing disease-specific tools (such as symptom scales).

2) Those that define the presentation and course of the rare disease in ways that are essential for the design of upcoming clinical trials (e.g., retrospective projects; longitudinal or cross-sectional approaches).

Leveraging Existing Research Resources

Applicants should leverage existing research resources for their clinical trial readiness studies. Such resources may include existing clinical research networks such as the Rare Diseases Clinical Research Network (RDCRN), NeuroNEXT, or other existing networks that have successfully conducted studies of rare diseases. Also, applicants should leverage existing research resources to streamline multi-center studies, such as the SMART IRB. Leveraging the resources and support from advocacy groups, private research foundations, academic institutions, other government agencies, and the NIH Intramural program are also encouraged. Researchers interested in conducting trial readiness studies through RDCRN should contact the NCATS Scientific/Research Contact listed in the Agency Contacts section below early in the process of designing the study.

Studies that leverage the resources of ongoing clinical trials or longitudinal studies supported through other Federal or private funds are also encouraged. Researchers may consider collecting data to validate new or improved COA measures or biomarkers as ancillary studies to ongoing clinical trials or longitudinal studies.

This NOFO will support applications for testing of biomarkers or outcome measures so that they are ready for use in multi-site studies. Biochemical or molecular biomarkers should include justification that describes accuracy, precision, analytical sensitivity, analytical specificity including interfering substances, dynamic range, and expected normal values. For imaging, radiological, or physiological biomarkers, the justification should provide preliminary data on the accuracy, reproducibility, sensitivity, and specificity as determined by study of a patient cohort (but not necessarily in the same rare disease). An appropriate study could start with a small, manageable set of well-justified candidate biomarkers, and based on data acquired during this study, be narrowed down to one or a few appropriate biomarkers to better characterize or validate for use in a clinical trial.

Examples of studies intended to be supported through this NOFO include, but are not limited to, the following:

• Studies aimed at the clinical validation of biomarkers or COAs with defined contexts of use in specific rare disease populations.
• Studies to develop or incorporate patient-reported or patient-centered outcomes.
• Studies to characterize rare disease patient cohorts regarding COA measures, biomarkers, genetic, epigenetic, or physiological factors that will be used to stratify patients or determine inclusion/exclusion criteria in upcoming clinical trials.
• Studies to characterize rare disease patient cohorts using candidate outcome measures to establish the variability of measures as needed for accurate power calculations or to determine the appropriate duration of upcoming clinical trials.
• Studies evaluating the responsiveness of biomarkers or COAs through the observation of patients who are receiving treatment as part of their clinical care.
• Studies to address knowledge gaps for clinical trial planning that also pilot innovative recruitment strategies for all populations who would be candidates for participation in upcoming rare disease trials.
• Studies that modify use of a tool in a specific rare disease population, such as the addition of disease-specific modules to an existing tool (e.g., disease-specific symptom scales).
• Ancillary studies that leverage ongoing clinical studies supported through other sources of funding.

Applications Not Responsive to this NOFO

The following types of studies are not responsive to this NOFO. Applications proposing such studies will be considered non-responsive and will not be reviewed or considered for funding.

• Studies which do not clearly address a rare disease, defined as diseases affecting fewer than 200,000 individuals in the U.S. Evidence supporting rare disease classification may include references confirming the prevalence and additional information if the disease has been granted orphan status by the FDA. Rationale should also be provided if focusing on a rare variant or subset of a more common condition, along with the scientific basis for separately studying the rare variant or subset.
• Natural history studies aimed at broadly exploring disease pathophysiology, genetic or epigenetic mechanisms with no direct connection to an upcoming clinical trial. Studies of patient genetics or pathophysiology will be responsive only if characterization is necessary for stratifying trial participants or determining inclusion/exclusion criteria in upcoming clinical trials.
• Studies of biomarker discovery or assay characterization.
• Applications that propose only to maintain patient registries. NCATS and the NIH ICs listed in Part 1 will not provide support to maintain or acquire additional data on study participants beyond the end of the clinical trial readiness grant.
• Applications that request support for infrastructure to establish new clinical trial networks. Applicants should leverage existing resources such as existing rare disease-focused networks (for example, the RDCRN.
• Studies aimed at determining the safety, pharmacokinetics, efficacy, or effectiveness of an intervention (drug, biologic, device, etc.) in humans.

Applications assigned to participating ICs that address the mission and priorities of ICs not participating in this NOFO will not be prioritized for funding.

See Section VIII. Other Information for award authorities and regulations.

Section II. Award Information

NIH grants policies as described in the NIH Grants Policy Statement will apply to the applications submitted and awards made from this NOFO.

Section III. Eligibility Information

1. Eligible Applicants

Higher Education Institutions - Includes all types

• Public/State Controlled Institutions of Higher Education
• Private Institutions of Higher Education

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 Organizations) 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 How to Apply- 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. Failure to complete registrations in advance of a due date is not a valid reason for a late submission, please reference the NIH Grants Policy Statement Section 2.3.9.2 Electronically Submitted Applications for additional information.

• 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.
  • Unique Entity Identifier (UEI) - A UEI is issued as part of the SAM.gov registration process. The same UEI must be used for all registrations, as well as on the grant application.
• eRA Commons - Once the unique organization identifier is established, organizations can register with eRA Commons in tandem with completing their Grants.gov registrations; 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 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 their organization to develop an application for 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 How to Apply-Application Guide.

2. Cost Sharing

This NOFO does not require cost sharing as defined in the NIH Grants Policy Statement Section 1.2 Definition of Terms.

3. Additional Information on Eligibility

Number of Applications

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, per NIH Grants Policy Statement Section 2.3.7.4 Submission of Resubmission Application. 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 NIH Grants Policy Statement 2.3.9.4 Similar, Essentially Identical, or Identical Applications).

Section IV. Application and Submission Information

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 NOFO. 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 How to Apply - Application Guide except where instructed in this notice of funding opportunity 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.

Page Limitations

All page limitations described in the How to Apply- Application Guide and the Table of Page Limits must be followed.

The following section supplements the instructions found in the How to Apply- Application Guide and should be used for preparing an application to this NOFO.

SF424(R&R) Cover

All instructions in the How to Apply - Application Guide must be followed.

SF424(R&R) Project/Performance Site Locations

All instructions in the How to Apply- Application Guide must be followed.

SF424(R&R) Other Project Information

All instructions in the How to Apply- Application Guide must be followed.

SF424(R&R) Senior/Key Person Profile

All instructions in the How to Apply- Application Guide must be followed.

R&R or Modular Budget

All instructions in the How to Apply- Application Guide must be followed.

R&R Subaward Budget

All instructions in the How to Apply-Application Guide must be followed.

PHS 398 Cover Page Supplement

All instructions in the How to Apply- Application Guide must be followed.

PHS 398 Research Plan

All instructions in the How to Apply- Application Guide must be followed, with the following additional instructions:

Research Strategy:

Evidence Supporting Rare Disease Classification – The Research Strategy should include a paragraph with the heading, "Evidence Supporting Rare Disease Classification". If the application does not include the following information, then it will be considered non-responsive and will not be reviewed. This section should provide the evidence that the disease/condition being studied is classified as a rare disease; i.e., there are 200,000 or fewer patients in the U.S. This section may include one or more references confirming the prevalence of the disease/condition that is the primary focus of the research application. If the disease/condition has been granted orphan status by the FDA, provide this information in this paragraph. If it is a rare variant or subset of a more common condition, provide the rationale for focusing a trial readiness study on this variant or subset. Describe the scientific basis for separating biomarker/clinical outcome assessment (COA) validation for this rare variant or subset from that of the common condition.

Need for Clinical Trial Readiness – The Research Strategy should include a subsection with the heading, "Urgent Need for Clinical Trial Readiness". This subsection should describe the need for conducting the trial readiness study at this time, or how the project addresses a critical barrier or bottleneck to progress toward clinical trials. Applicants should describe the clinical trial design issues (e.g., biomarker or COA validation, data for power calculations, defining inclusion/exclusion criteria, determining the duration of the trial, etc.) that will be addressed by this trial readiness study. Describe the potential impact of the proposed studies in addressing significant needs in the design and increasing the likelihood of success of upcoming clinical trials.

This section should also contain the following:

• A brief description of the state of development of candidate therapeutics or devices for this rare disease (even if the current applicants are not involved in the development of those therapeutics/devices).
• Timelines for the advance of therapeutics/devices to clinical trials.
• A brief description of the clinical trial(s) that would be enabled by the results of this trial readiness study. Provide letters of support (below) from the researchers who expect to conduct upcoming trials.
• Outline the next steps for moving into a clinical trial if the proposed study is successful—that is, provide the rationale that a clinical trial is feasible in the near future.
• Include a brief description of the currently available COA measures and/or biomarkers. If appropriate for the proposed study, describe how the study will result in advancements over the currently available measures/biomarkers. If the current measures/biomarkers are considered inadequate or insufficiently developed for use in upcoming trials, describe their limitations and how those limitations may compromise the success of upcoming trials. If the proposed trial readiness study is ancillary to an ongoing clinical trial or longitudinal study, describe that study and provide a letter of support (below) from the study's lead PD(s)/PI(s). Explain how the trial readiness study will lead to improvements in the design of future trials above that of the ongoing study.
• Describe any gaps in knowledge regarding the disease natural history that need to be addressed to achieve clinical trial readiness. Explain how the lack of this knowledge will compromise clinical trial design and how this study will overcome current obstacle(s).
• Briefly describe the role of companies or voluntary health organizations that are currently engaged or potentially available for clinical trial readiness studies or clinical trials for this disease, if applicable.

Biomarkers and Their Context of Use

If biomarker validation is proposed, the application should contain a subsection with the heading, "Biomarkers and Their Context of Use". This section should describe each biomarker that will be tested for validation and the context of use (COU). The COU should explain how, when, and why the biomarker is to be used in a clinical trial.

Biochemical/molecular biomarkers should have analytical validation before applying for a clinical trial readiness award through this program. Applications should include a table listing each biochemical/molecular biomarker to be tested for clinical validation, the intended use (e.g., diagnostic, predictive, treatment response, pharmacodynamic), the method of the assay (e.g., mass spectrometry, ELISA, surface plasmon resonance), the sensitivity, dynamic range, and expected normal values. Other characteristics of the assay such as accuracy, precision, specificity including interfering substances, etc. should also be described in the text of this subsection. Describe what a graph of each biomarker measurement over time is expected to show (e.g., linearly decreasing measurement, sigmoidal curve, etc.) and the expected relationship of the biomarker to COA measures (e.g., inversely proportional).

For imaging, radiological, or physiological biomarkers, the rationale should provide preliminary data on the accuracy, reproducibility, sensitivity, and specificity as determined by study of a patient cohort (but not necessarily in the same disease). Describe the equipment (i.e., instrument manufacturer and model) and expertise available at each clinical site for measuring the biomarker(s). Plans for the training of personnel at each site in the use of the standardized protocols, data quality control strategies, reference standards and approaches for verifying instrument calibration at the clinical sites should also be described as appropriate.

Clinical Outcome Assessment Measures

Clinical outcome assessment (COA) measures can be clinician-, observer-, or patient-reported, or performance outcomes. If COA measure validation is proposed, applications should provide a list of each COA measure that the study aims to clinically validate. Describe the construct validity (i.e., hypothesized relationship with other disease characteristics) and content validity (i.e., extent to which the COA measures the concept of interest) for each COA measure. Describe plans for analysis of test-retest and inter-rater reliability. Describe Rasch analysis for COA measure optimization if appropriate.

Natural History of Disease

Studies on the course of the disease may only be proposed for the purpose of developing readiness for upcoming clinical trials. If studies on aspects of the natural history of the disease are being proposed, describe any existing observational studies that may address these or other aspects and provide the rationale for how this study differs from what currently exists. Describe whether there are missed opportunities for coordinated efforts in the same rare disease. Also provide the rationale for how this study will support advancement of the development of rare disease medical products through characterization of an aspect of the disease natural history that must be addressed before a clinical trial can be planned or initiated (such as characterization of an external control group, identification of genotypic or phenotypic subpopulations necessary for defining inclusion/exclusion criteria, or other components of study design), and that this study can address this characterization within the study timeframe. 

Statistical Analysis Plans

A section describing the plans for statistical analysis of the data and tests for validation of biomarkers/COAs or analysis of the natural history study results should be included in the application. Explain the decision for selecting the statistical analysis methods—what methods were considered; why were the proposed methods chosen. Describe sample size considerations for validating the biomarkers and COAs, or disease natural history characterization proposed. Statistical analysis of convergent validity of COA measures and biomarkers is often an important component of trial readiness studies. Describe which biomarkers and COA measures will be tested for convergent validity if appropriate for the study.

Existing Clinical Networks

Applications should briefly describe the clinical network(s) that currently exist. For example, what infrastructure is already developed to enroll and conduct clinic visits for the proposed study?

For ancillary studies, briefly describe the aims of the parent study and the timeline of the parent study relative to the proposed ancillary study. The application should discuss the additional burden to the participants of the parent study and whether consent obtained from the participants is adequate to cover the ancillary study or if additional consent must be obtained. (See also Letters of Support)

Letters of Support

Provide letters of collaboration from individuals who will contribute in a substantive, meaningful way to the scientific development or execution of the project, whether or not salaries are requested. As appropriate, letters should document access to expertise, equipment and/or patients.

For ancillary studies, provide a letter of support from the PD/PI of the parent study that includes:

• A brief description of the aims of the parent study
• The timeline of the parent study relative to the proposed ancillary study

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the How to Apply- Application Guide.

Other Plan(s): 

All instructions in the How to Apply-Application Guide must be followed, with the following additional instructions:

• 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.

Appendix: Only limited Appendix materials are allowed. Follow all instructions for the Appendix as described in the How to Apply- Application Guide.

• No publications or other material, with the exception of blank questionnaires or blank surveys, may be included in the Appendix.

With the following modifications:

• For proposed ancillary studies, provide the protocol for the parent clinical trial or longitudinal study and the consent form for the parent study
• Meeting minutes or advice letters provided by the FDA regarding qualification or discussions from Critical Path Innovation Meetings (CPIM) or other early interaction meetings of the proposed biomarker(s), COA measure(s), or natural history studies

PHS Human Subjects and Clinical Trials Information

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 How to Apply- 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 How to Apply- Application Guide must be followed.

Delayed Onset Study

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 How to Apply- Application Guide must be followed.

PHS Assignment Request Form

All instructions in the How to Apply- Application Guide must be followed.

3. Unique Entity Identifier and System for Award Management (SAM)

See Part 2. 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

4. Submission Dates and Times

Part I. 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 Grants Policy Statement Section 2.3.9.2 Electronically Submitted Applications.

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 How to Apply-Application Guide.

5. Intergovernmental Review (E.O. 12372)

This initiative is not subject to intergovernmental review.

6. Funding Restrictions

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 Section 7.9.1 Selected Items of Cost.

Applications must be submitted electronically following the instructions described in the How to Apply 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 form. 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 NOFO for information on registration requirements.

The applicant organization must ensure that the unique entity identifier provided on the application is the same identifier used in the organization’s profile in the eRA Commons and for the System for Award Management. Additional information may be found in the How to Apply 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.

Use of Common Data Elements in NIH-funded Research

Many NIH ICs encourage the use of common data elements (CDEs) in basic, clinical, and applied research, patient registries, and other human subject research to facilitate broader and more effective use of data and advance research across studies.  CDEs are data elements that have been identified and defined for use in multiple data sets across different studies.  Use of CDEs can facilitate data sharing and standardization to improve data quality and enable data integration from multiple studies and sources, including electronic health records.  NIH ICs have identified CDEs for many clinical domains (e.g., neurological disease), types of studies (e.g. genome-wide association studies (GWAS)), types of outcomes (e.g., patient-reported outcomes), and patient registries (e.g., the Global Rare Diseases Patient Registry and Data Repository).  NIH has established the NIH CDE Repository to assist investigators in identifying NIH-supported CDEs when developing protocols, case report forms, and other instruments for data collection.  The Portal provides guidance about and access to NIH-supported CDE initiatives and other tools and resources for the appropriate use of CDEs and data standards in NIH-funded research.  Investigators are encouraged to consult the Portal and describe in their applications any use they will make of NIH-supported CDEs in their projects. 

Recipients or subrecipients must submit any information related to violations of federal criminal law involving fraud, bribery, or gratuity violations potentially affecting the federal award. See Mandatory Disclosures, 2 CFR 200.113 and NIH Grants Policy Statement Section 4.1.35.

Send written disclosures to the NIH Chief Grants Management Officer listed on the Notice of Award for the IC that funded the award and to the HHS Office of Inspector Grant Self Disclosure Program at [email protected].

Post Submission Materials

Applicants are required to follow the instructions for post-submission materials, as described in the policy

Section V. Application Review Information

1. Criteria

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.

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 scored review criteria and additional review criteria (as applicable for the project proposed). An application does not need to be strong in all categories to be judged likely to have a major scientific impact.

Reviewers will consider Factors 1, 2 and 3 in the determination of scientific merit, and in providing an overall impact score. In addition, Factors 1 and 2 will each receive a separate factor score. 

As applicable for the project proposed, reviewers will consider the following additional items while determining scientific and technical merit, but will not give criterion scores for these items, and should consider them in providing an overall impact score.

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.

2. Review and Selection Process

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s) convened by the Center for Scientific Review (CSR), 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.

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 Section 2.5.1. Just-in-Time Procedures. This request is not a Notice of Award nor should it be construed to be an indicator of possible funding.

Prior to making an award, NIH reviews an applicant’s federal award history in SAM.gov to ensure sound business practices. An applicant can review and comment on any information in the Responsibility/Qualification records available in SAM.gov. NIH will consider any comments by the applicant in the Responsibility/Qualification records in SAM.gov to ascertain the applicant’s integrity, business ethics, and performance record of managing Federal awards per 2 CFR Part 200.206 “Federal awarding agency review of risk posed by applicants.” This provision will apply to all NIH grants and cooperative agreements except fellowships.

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 Section 2.4.4 Disposition of Applications.

Section VI. Award Administration Information

1. Award Notices

A Notice of Award (NoA) is the official authorizing document notifying the applicant that an award has been made and that funds may be requested from the designated HHS payment system or office. The NoA is signed by the Grants Management Officer and emailed to the recipient’s business official.

In accepting the award, the recipient agrees that any activities under the award are subject to all provisions currently in effect or implemented during the period of the award, other Department regulations and policies in effect at the time of the award, and applicable statutory provisions.

Recipients must comply with any funding restrictions described in Section IV.6. Funding Restrictions. Any pre-award costs incurred before receipt of the NoA are at the applicant's own risk.  For more information on the Notice of Award, please refer to the NIH Grants Policy Statement Section 5. The Notice of Award and NIH Grants & Funding website, see Award Process.

Institutional Review Board or Independent Ethics Committee Approval: Recipient institutions must ensure that protocols are reviewed by their IRB or IEC. To help ensure the safety of participants enrolled in NIH-funded studies, the recipient must provide NIH copies of documents related to all major changes in the status of ongoing protocols.

2. Administrative and National Policy Requirements

The following Federal wide and HHS-specific policy requirements apply to awards funded through NIH:

• The rules listed at 2 CFR Part 200, Uniform Administrative Requirements, Cost Principles, and Audit Requirements for Federal Awards.
• All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the terms and conditions in the Notice of Award (NoA). The NoA includes the requirements of this NOFO. 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.

All federal statutes and regulations relevant to federal financial assistance, including those highlighted in NIH Grants Policy Statement Section 4 Public Policy Requirements, Objectives and Other Appropriation Mandates.

Recipients are responsible for ensuring that their activities comply with all applicable federal regulations.  NIH may terminate awards under certain circumstances.  See 2 CFR Part 200.340 Termination and NIH Grants Policy Statement Section 8.5.2 Remedies for Noncompliance or Enforcement Actions: Suspension, Termination, and Withholding of Support. 

Pursuant to the Cybersecurity Act of 2015, Div. N, § 405, Pub. Law 114-113, 6 USC § 1533(d), the HHS Secretary has established a common set of voluntary, consensus-based, and industry-led guidelines, best practices, methodologies, procedures, and processes.

Successful recipients under this NOFO agree that:

When recipients, subrecipients, or third-party entities have:

1. ongoing and consistent access to HHS owned or operated information or operational technology systems; and 
2. receive, maintain, transmit, store, access, exchange, process, or utilize personal identifiable information (PII) or personal health information (PHI) obtained from the awarding HHS agency for the purposes of executing the award.

Recipients shall develop plans and procedures, modeled after the NIST Cybersecurity framework, to protect HHS systems and data. Please refer to NIH Post-Award Monitoring and Reporting for additional information. 

Not Applicable

Consistent with the 2023 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.

4. Reporting

When multiple years are involved, recipients will be required to submit the Research Performance Progress Report (RPPR) annually and financial statements as required in the NIH Grants Policy Statement Section 8.4.1 Reporting. To learn more about post-award monitoring and reporting, see the NIH Grants & Funding website, see Post-Award Monitoring and Reporting.

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 Section 8.6 Closeout. NIH NOFOs outline intended research goals and objectives. Post award, NIH will review and measure performance based on the details and outcomes that are shared within the RPPR, as described at 2 CFR Part 200.301.

Section VII. Agency Contacts

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: https://www.era.nih.gov/need-help (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]

Alice Chen Grady, M.D.
National Center for Advancing Translational Sciences (NCATS)
Telephone: 301-827-2015
Email: [email protected]

Melissa Parisi, MD, PhD
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Telephone: 301-435-6880
Email: [email protected]

Examine your eRA Commons account for review assignment and contact information (information appears two weeks after the submission due date).

Zulema Eldridge
National Center for Advancing Translational Sciences (NCATS)
Telephone: 301.443.3066
Email: [email protected] 

Lauren Ruane
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Telephone: 301-402-6554
Email: [email protected]

Section VIII. Other Information

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 2 CFR Part 200.