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

Part 1. Overview Information
Part 2. Full Text of the 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

A. Background

The FDA Office of Orphan Products Development (OOPD) was created to identify and promote the development of orphan products. Orphan products are drugs, biologics, medical devices, and medical foods that are indicated for a rare disease or condition. The "Accelerating Access to Critical Therapies for ALS Act" was enacted on December 23, 2021 which established the FDA Rare Neurodegenerative Disease Grant Program, which is administered by OOPD. This Act allows the FDA to award grants and contracts to public and private entities to cover costs of research and development of interventions intended to prevent, diagnose, mitigate, treat or cure rare neurodegenerative diseases (including amyotrophic lateral sclerosis (ALS)) in adults and children. Neurodegenerative diseases occur when nerve cells in the brain or peripheral nervous system lose function over time and ultimately die. In general, they are incurable and debilitating conditions and are progressive. The term rare disease or condition is defined in 21 U.S.C. 360ee.

FDA has funded multiple awards beginning in fiscal year 2022 to help meet the intent of the ACT for ALS. FDA sought input from patients, researchers, nonprofit organizations, companies, and other stakeholders on regulatory science research gaps that could advance medical product development (Docket FDA-2022-N-2544). Specifically, input was sought for development of regulatory science tools or other research and development needs in the preclinical or clinical space. As a result of this feedback, additional funding opportunities were announced, and FDA continues to build on these important concepts.

With this new funding opportunity announcement (FOA), FDA will continue to address unmet funding needs identified for rare neurodegenerative diseases in adults and children. Specifically, FDA hopes to support natural history studies that improve the understanding of rare neurodegenerative diseases and enhance the use of approaches that will enrich clinical trial designs and increase future clinical trial participation (e.g., digital health technologies, disease appropriate developmental assessment tools, remote spirometry, novel biomarkers, and COAs).

The information obtained from a natural history study plays an essential role at every stage of product development and could be especially impactful in newly discovered rare diseases. Natural history studies are vital in identifying the patient population, understanding patient subtypes based on genotypic and/or phenotypic heterogeneity, identifying or developing study endpoints, COAs, biomarkers, and when appropriate, serving as external controls. It could be valuable for establishing early disease progression in high risk or known mutation carriers for neurodegeneration prior to the onset of symptoms and develop sensitive biomarkers of disease progression that will enable future clinical trials in pre-symptomatic individuals.

To ensure that natural history studies provide optimal support to rare disease product development, it is critical to have standardized approaches to ensure data quality. Natural history studies should have well-defined and documented protocols before study initiation, while potentially incorporating flexible and innovative approaches in study design as the understanding or treatment of the disease evolves. Further, given the limited number of patients affected by a given rare disease and the potential for patients to be geographically dispersed or considering enrollment in other natural history studies or clinical trials, collaborative and efficient approaches are fundamental. This FOA will support prospective, efficient, and innovative natural history studies for rare neurodegenerative diseases with a focus on collaborative and standardized approaches to ensure data quality and interpretability. FDA encourages applicants to refer to the "Rare Diseases: Natural History Studies for Drug Development, Guidance for Industry" for guidance on the conduct of a natural history study, considerations to enhance interpretability of study results, and discussion on data collection standards and data quality and integrity. FDA encourages applicants to refer to "Rare Diseases: Common Issues in Drug Development" for guidance on conducting more efficient and successful drug development programs. Applicants are also encouraged to refer to information on the Orphan Products Grants Program website before applying for this opportunity.

The development and/or validation of biomarkers for rare neurodegenerative diseases are essential for clinical trial design and identification of appropriate endpoints. Biomarkers are 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. A digital biomarker is a characteristic or set of characteristics, collected from digital health technologies, that is measured as an indicator of normal biological processes, pathogenic processes, or responses to an exposure or intervention, including therapeutic interventions. A biomarker is not an assessment of how an individual feels, functions, or survives. They can be used to diagnose disease or define disease subtypes, determine susceptibility/risk, assess prognosis, monitor disease, predict therapeutic response. FDA encourages applicants to refer to FDA Resources About Biomarkers and Qualification for biomarker FAQs and guidance.

The development and/or validation of clinical outcome assessments (COAs) are also essential for clinical trial design and identification of appropriate endpoints. A COA is a measure that describes or reflects how a patient feels, functions, or survives. Types of COAs include Patient-reported outcome (PRO) measures; Observer-reported outcome (ObsRO) measures; Clinician-reported outcome (ClinRO) measures; and Performance outcome (PerfO) measures. COAs are used to capture data which measure treatment benefit or risk in medical product clinical trials. FDA encourages applicants to refer to FDA Resources About COAs for FAQs and guidance.

B. Research Objectives

FDA is interested in supporting natural history studies in conjunction with COA and/or biomarker studies that enrich clinical trial designs to address the unmet need for the treatment of rare neurodegenerative diseases in children and adults. To that end, and based on the criteria outlined below, FDA has identified the following areas of interest for the purpose of this FOA:

1. Ability to exert a significant impact in the field of rare neurodegenerative diseases for future clinical trials.

2. Inclusion of high quality, interpretable data using well-defined protocols with a rigorous and standardized approach to data collection and analysis, utilization of common data elements, plans for minimization of bias, data sharing across sites, data dissemination and collaborative use of data.

3. Use of existing infrastructure, resources, and collaboration among stakeholders in industry, academia, and patient organizations.

Under this cooperative agreement, the application must propose science-based activities that will strengthen the development of medical products for rare neurodegenerative diseases in children and adults. The applicant will be required to track short- and long-term goals and objectives and demonstrate how the proposed activities relate to the FDA’s regulation of medical products.

The accessibility to the necessary infrastructure, resources, and collaborations to accomplish the proposed aims should be available at the time of application submission. Collections of new specimens and/or data from participants in an existing cohort are allowed and applicants are encouraged to include diversity in their sample populations.

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

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

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 FDA 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)

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)

Non-domestic (non-U.S.) Entities (Foreign Institutions) are eligible to apply.

Non-domestic (non-U.S.) components of U.S. Organizations are eligible to apply.

Foreign components, as defined in the HHS Grants Policy Statement, are 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 FDA 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.

• 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 registration; 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. Individuals from diverse backgrounds, including underrepresented racial and ethnic groups, individuals with disabilities, and women are always encouraged to apply for FDA 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.

Multiple PDs/PIs
The decision of whether to apply for a grant with a single PD/PI or multiple PDs/PIs is the responsibility of the investigators and applicant organizations and should be determined by the scientific goals of the project. Applications for grants with multiple PDs/PIs will require additional information, as outlined in the instructions below. More than one PD/PI (i.e., multiple PDs/PIs), may be designated on the application for projects that require a team science approach and therefore clearly do not fit the single-PD/PI model. Additional information on the implementation plans and policies and procedures to formally allow more than one PD/PI on individual research projects is available at http://grants.nih.gov/grants/multi_pi.

When multiple PDs/PIs are proposed, FDA requires one PD/PI to be designated as the "Contact PI, who will be responsible for all communication between the PDs/PIs and the FDA, for assembling the application materials outlined below, and for coordinating progress reports for the project. The contact PD/PI must meet all eligibility requirements for PD/PI status in the same way as other PDs/PIs but has no other special roles or responsibilities within the project team beyond those mentioned above.

Information for the Contact PD/PI should be entered in item 14 of the SF424 (R&R) form. All other PDs/PIs should be listed in the Research & Related Senior/Key Person Profile and assigned the project role of PD/PI. Please remember that all PDs/PIs must be registered in the eRA Commons prior to application submission. The Commons ID of each PD/PI must be included in the Credential field of the Research & Related Senior/Key Person component. Failure to include this data field will cause the application to be rejected. All projects proposing Multiple PDs/PIs will be required to include a new section describing the leadership plan approach for the proposed project.

Multiple PD/PI Leadership Plan
For applications designating multiple PDs/PIs, a new section of the research plan, entitled Multiple PD/PI Leadership Plan [item 7 of the PHS 398 Research Plan] must be included. A rationale for choosing a multiple PD/PI approach should be described. The governance and organizational structure of the leadership team and the research project should be described, and should include communication plans, process for making decisions on scientific direction, and procedures for resolving conflicts. The roles and administrative, technical, and scientific responsibilities for the project or program should be delineated for the PDs/PIs and other collaborators.

If budget allocation is planned, the distribution of resources to specific components of the project or the individual PDs/PIs should be delineated in the Leadership Plan. In the event of an award, the requested allocations may be reflected in a footnote on the Notice of Award (NoA).

Applications Involving a Single Institution
When all PDs/PIs are within a single institution, follow the instructions contained in the SF424 (R&R) Application Guide.

Applications Involving Multiple Institutions
When multiple institutions are involved, one institution must be designated as the prime institution and funding for the other institution(s) must be requested via a subaward to be administered by the prime institution. When submitting a detailed budget, the prime institution should submit its budget using the Research & Related Budget form. All other institutions should have their individual budgets attached separately to the Research & Related Subaward Budget Attachment(s) Form. See Section R.310 of the SF424 (R&R) Application Guide for further instruction regarding the use of the subaward budget form.

This NOFO does not require cost sharing as defined in the HHS Grants Policy Statement.

Applicant organizations may submit more than one application, provided that each application is scientifically distinct.

The FDA will not accept duplicate or highly overlapping applications under review at the same time per 2.3.7.4 Submission of Resubmission Application. This means that the FDA 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.

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.

It is critical that applicants follow the Research (R) Instructions in the SF424 (R&R) 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.

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:

Zahara Graves
Grants Management Specialist (Detail)
Email: [email protected]

and

Katherine Needleman
Director, Orphan Products Grants Program
Email: [email protected]

All page limitations described in the SF424 Application Guide and the Table of Page Limits must be followed, with the following exceptions or additional requirements:

For this specific FOA, the Research Strategy section is limited to 12 pages.

The following section supplements the instructions found in the SF424 (R&R) Application Guide and should be used for preparing an application to this NOFO.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions:

• Applications requesting multiple years of support must complete and submit a separate detailed budget breakdown and narrative justification for each year of financial support requested.
• If an applicant is requesting indirect costs as part of their budget, a copy of the most recent Federal indirect cost rate or F&A agreement must be provided as part of the application submission. This agreement should be attached to the RESEARCH & RELATED Other Project Information Component as line #12 'Other Attachments'.
• If the applicant organization has never established an indirect cost rate and/or does not have a negotiated Federal indirect cost rate agreement, a de minimis indirect cost rate of 10 percent (10%) of modified total direct costs (MTDC) will be allowed. MTDC means all direct salaries and wages, applicable fringe benefits, materials and supplies, services, travel, and subaward and subcontracts up to the first $25,000 of each subaward or subcontract. MTDC excludes equipment, capital expenditures, charges for patient care, rental costs, tuition remission, scholarships and fellowships, participant support costs and the portion of each subaward and subcontract in excess of $25,000.
• Indirect/F&A costs under grants to foreign and international organizations will be funded at a fixed rate of 8 percent of modified total direct costs (MTDC), exclusive of tuition and related fees, direct expenditures for equipment, and subawards in excess of $25,000. (With the exception of the American University of Beirut and the World Health Organization, which are eligible for full F&A cost reimbursement). Awards to domestic organizations with a foreign or international consortium participant may include 8 percent of MTDC, exclusive of tuition and related fees, direct expenditures for equipment, and subawards in excess of $25,000.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions:

Research Strategy:

The following sections should be included under the Research Strategy following the guidelines in Section V. Application Review Information:

1. Rationale

2. Study Design/Data Quality and Interpretability

3. Inclusion of Patient Input

4. Investigator(s), Infrastructure, and Financial Resources

5. Ability to Advance the Current Field

Rare Disease Prevalence:

The Rationale Section of the Research Strategy should also include a subsection with the specific heading Rare Neurodegenerative Disease Population/Prevalence. This subsection must include documentation that the disease or condition to be studied is a rare neurodegenerative disease. Specifically, neurodegenerative diseases occur when nerve cells in the brain or peripheral nervous system lose function over time and ultimately die. In general, they are incurable and debilitating conditions and are progressive. In addition to being neurodegenerative, the disease must also be rare. The term rare disease or condition is defined in 21 U.S.C. 360ee. Generally, FDA considers drugs, devices, and medical foods potentially eligible for grants under this grant program if they are indicated for a disease or condition that has a prevalence of fewer than 200,000 people in the United States or in the case of an acute disease (i.e., less than 1 year duration), an annual incidence of less than 200,000 per year. For studies proposing assessing multiple rare neurodegenerative diseases, supportive prevalence data for each rare neurodegenerative disease is required.

Additional information may be required upon request, for example, regarding population estimate and rationale. This additional information may be required, in part, to assure that human clinical trials of drugs are eligible to receive funding under the OOPD Grants Program. 21 U.S.C. 360ee(b)(1)(A). See Section VIII, Other Information - Required Federal Citations, for policies related to this announcement.

Support of Product Development:

The Rationale Section of the Research Strategy should also include a subsection with the heading Support of Product Development. This subsection should include an explanation of how the proposed study will address critical knowledge gaps, to remove major barrier(s) to progress in the field, exert a significant and broad impact on a specific rare neurodegenerative disease or multiple rare neurodegenerative diseases with similar pathophysiology, and meet data standards to inform rare neurodegenerative disease product development. If the proposal is for multiple rare neurodegenerative diseases, a plan as to how the applicant intends to proceed with product development (potentially in collaboration with multiple sponsors) should be provided in the grant application.

Study Monitoring Plan:

The Study Design/Data Quality and Interpretability Section of the Research Strategy should include a further subsection with the heading "Study Monitoring Plan." This subsection should include a proposed plan for monitoring, as applicable. The specific approach to monitoring will depend on features of the study to be conducted e.g., several levels of monitoring: Data and Safety Monitoring Board (DSMB), Study Monitoring Committee (SMC), and Independent Medical Monitor (IMM). Monitoring activities should be appropriate to the study, study phase, population, research environment, and degree of risk involved. Guidance is available at: https://www.fda.gov/media/116754/download. This section will detail the parties responsible for monitoring, what will be monitored, and the frequency (which will depend on such factors as the study design, and anticipated recruitment rate). The plan will specify individual and study "stopping guidelines" and other criteria for the monitors to follow. Guidance on these topics is available at: http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM127073.pdf

Letters of support: Letters of support should not be included as part of the Research Strategy and instead should be uploaded to line 9 on the PHS 398 Research Plan Form.

Letters of support should be included for the following areas:

1) Study Sites: The leader(s) of the existing clinical research institutions that will conduct the study should describe their site support, including relevant resources and study infrastructure, and an estimate of the number of patients with the target rare neurodegenerative disease(s) who would be eligible for the study;

2) Patient Engagement: There must be evidence that patient input has been obtained in a meaningful way. A current letter(s) from patient(s)/caregiver(s)/patient organizations describing early and ongoing engagement in trial design should be provided.

3) Intellectual Property: Information can be found in Code of Federal Regulations, Title 2, Part 200.315 (2 CFR 200.315), Intangible Property.

-- Intellectual and Material Property Plan (if applicable): Provide a plan for resolving intellectual and material property issues among participating organizations.

Resource Sharing Plan: 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 application forms packages.

Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the SF424 (R&R) Application Guide, with the following modification:

Generally, Resource Sharing Plans are expected, but they are not applicable for this FOA.

Appendix:

Only limited Appendix materials are allowed. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.

Do not use the Appendix to circumvent page limits.

The Appendices should include the following, as appropriate for the proposed study:

Protocol: The full final protocol must be provided.

Informed Consent: Consent forms, assent forms, and any other information given to a subject must be provided and must comply with all elements of Human Subject Research per 21 CFR 50.25.

When involving human subjects research, clinical research, and/or 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.

All instructions in the SF424 (R&R) Application Guide must be followed.

Foreign (non-U.S.) institutions must follow policies described in the HHS Grants Policy Statement and procedures for foreign institutions.

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, FDA’s electronic system for grants administration. eRA Commons 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. Late applications will not be accepted for this FOA.

Applicants are responsible for viewing their application before the due date in the eRA Commons to ensure accurate and successful submission.

Information on the submission process and a definition of on-time submission are provided in the SF424 (R&R) Application Guide.

This initiative is not subject to intergovernmental review.

All FDA awards are subject to the terms and conditions, cost principles, and other considerations described in the HHS Grants Policy Statement and 45 CFR 75, 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.

Awards issued under this FOA will be incrementally funded awards for each budget period.

Pre-award costs are allowable only as described in the HHS Grants Policy Statement.

Additional funding restrictions may be part of the Notice of Award.

Protection of Human Research Subjects

All institutions engaged in human subject research financially supported by HHS must file an assurance of protection for human subjects with the Office of Human Research Protections (OHRP) (45 CFR part 46). See Office of Human Research Protections for guidance on human subject protection issues. Federal regulations (45 CFR 46) require that applications and proposals involving human subjects must be evaluated with reference to the risks to the subjects, the adequacy of protection against these risks, the potential benefits of the research to the subjects and others, and the importance of the knowledge gained or to be gained.

The requirement to file an assurance applies to both awardee and collaborating performance site institutions. Awardee institutions are automatically considered to be engaged in human subject research whenever they receive a direct HHS award to support such research, even where all activities involving human subjects are carried out by a subcontractor or collaborator. In such cases, the awardee institution bears the responsibility for protecting human subjects under the award.

The awardee institution is also responsible for, among other things, ensuring that all collaborating performance site institutions engaged in the research hold an approved assurance prior to their initiation of the research. No awardee or performance site institution may spend funds on human subject research or enroll subjects without the approved and applicable assurance(s) on file with OHRP. An awardee institution must, therefore, have its own IRB of record and assurance. The IRB of record may be an IRB already being used by one of the performance sites, but it must specifically be registered as the IRB of record with OHRP.

For further information, applicants should review the section on human subjects in the application instructions as posted on the Grants.gov application Web site. The clinical protocol should comply with ICHE6 Good Clinical Practice Consolidated Guidance which sets an international ethical and scientific quality standard for designing, conducting, recording, and reporting trials that involve the participation of human subjects. All human subject research regulated by FDA is also subject to FDA's regulations regarding the protection of human subjects (21 CFR part 50 and 21 CFR part 56 and Guidance for Institutional Review Boards and Clinical Investigators). Applicants are encouraged to review the regulations, guidance, and information sheets on human subject protection and good clinical practice available at FDA's site on Clinical Trials and Human Subject Protection.

Key Personnel and Human Subject Protection Education

The awardee institution is responsible for ensuring that all key personnel receive appropriate training in their human subject protection responsibilities. Key personnel include all principal investigators, co-investigators, and performance site investigators responsible for the design and conduct of the study. HHS, FDA, and OOPD do not prescribe or endorse any specific education programs. Many institutions have already developed educational programs on the protection of research subjects and have made participation in such programs a requirement for their investigators. Other sources of appropriate instruction might include the online tutorials offered by the Office of Human Subjects Research, NIH at http://ohsr.od.nih.gov/ and by OHRP at https://www.hhs.gov/ohrp/education-and-outreach/index.html.

Within 30 days of the award, the principal investigator should provide a letter to FDA's grants management office that includes the names of the key personnel, the title of the human subjects protection education program completed for each key personnel, and a one-sentence description of the program. This letter should be signed by the principal investigator and cosigned by an institution official and sent to the Grants Management Specialist whose name appears on the official Notice of Grant Award (NGA).

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 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 FDA. 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 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 assigned grants management specialist and responsiveness by components of participating organizations, FDA. Applications that are incomplete, non-compliant and/or nonresponsive will not be reviewed.

Post-submission materials are those submitted after submission of the grant application but prior to objective review. They are not intended to correct oversights or errors discovered after submission of the application. FDA accepts limited information between the time of initial submission of the application and the time of objective review. Applicants must contact the assigned Grants Management Specialist to receive approval, prior to submitting any post submission materials. Acceptance and/or rejection of any post submission materials is at the sole discretion of the FDA. Any inquiries regarding post submission materials should be directed to the assigned Grants Management Specialist.

Only the review criteria described below will be considered in the review process.

FDA grants management and program staff will review all applications sent in response to this funding opportunity announcement. To be responsive, an application must be submitted in accordance with the requirements of this notice. Applications found to be non-responsive will receive notice that the application will not be reviewed.

Program Responsiveness Review Criteria

The following criteria will be used to decide whether or not an application is responsive to this RFA.

1. Applications must propose a prospective natural history study alone or in conjunction with COA and/or biomarker development/validation studies.

2. The Rationale Section of the Research Strategy section of the application must contain information documenting that the rare neurodegenerative disease or condition to be treated meets the definition of a rare disease or condition, as defined in 21 U.S.C. 360ee(b)(2). Prevalence calculations should be provided along with citations. For studies proposing to assess multiple rare neurodegenerative diseases, supportive prevalence data for each disease is required. Additionally, documentation that the disease is a rare neurodegenerative disease should be provided. Neurodegenerative diseases are those in which nerve cells in the brain or peripheral nervous system lose function over time and ultimately die. In general, they are incurable and debilitating conditions and are progressive.

3. The Rationale Section of the Research Strategy section of the application must include an explanation of how the proposed study will exert a significant impact on rare neurodegenerative diseases, address critical knowledge gaps, remove major barrier(s) to progress in the field, and meet data standards to inform rare neurodegenerative disease product development.

4. The requested time must not exceed 4 years.

5. Appropriate documentation is needed including the protocol and as applicable informed consent/assent forms. These should be submitted as appendices to the application.

6. Letters of support regarding study sites and patient engagement are also required.

7. Page limits, font size and margins should comply with the Application Guide, Electronic Submission of Grant Applications. (https://grants.nih.gov/grants/how-to-apply-application-guide.html), with the exceptions noted in the Page Limitations section above for Resubmissions.

8. Additional information may be required upon request after submission of an application to determine responsiveness, for example, regarding population estimate and rationale. This additional information may be required, in part, to assure that the proposal is eligible to receive funding under the OOPD grant program. 21 U.S.C. 360ee(b)(1)(A).

Applicants are strongly encouraged to contact FDA to resolve any questions about criteria before submitting their application. Please direct all questions of a technical or scientific nature to the OOPD program staff and all questions of an administrative or financial nature to the grants management staff (see Agency Contacts in Section VII of this document).

Responsive applications will be reviewed and evaluated for scientific and technical merit by a panel of internal and external experts in rare neurodegenerative diseases/natural history/biomarker/COA studies. Consultation with experts in the subject field including FDA experts may also occur during this phase of the review to determine whether the proposed study will provide acceptable data that could contribute to future product development or having a regulatory impact in the field. Funding decisions will be made by the Commissioner of Food and Drugs or his designee. By submitting an application in response to this RFA, applicants understand and agree that members of the objective review panel of experts may be provided access to non-public information contained in the grant application, as necessary for evaluation of the application and subject to necessary restrictions on the further disclosure of the information.

A score will be assigned to each application based on the scientific/technical review criteria. The review panel may advise the program staff about the appropriateness of the proposal to the goals of this OOPD grant program.

Reviewers will provide an overall impact score to reflect their assessment of the likelihood for the project to address an unmet need and to exert a sustained, significant influence on the research field(s) involved via efficient and innovative approaches, 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/technical merit.

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. In addition, an application with moderate correctable weaknesses in a criterion may still receive a high overall impact score because one or more of the other review criteria are critically important to the research and have significant strengths. The relative importance of strengths and weaknesses, not simply the number of strengths and weaknesses, are considered in developing the overall impact score.

The soundness of rationale in relation to the current understanding of the rare neurodegenerative disease(s) and the likelihood the proposal will facilitate future medical product development in rare neurodegenerative disease(s).

• Description of the state of existing knowledge, including literature citations and highlights of relevant preliminary studies, existing natural history studies, biomarker/COA endpoint development, standard of care, and treatment options.
• Explanation of knowledge gap(s) and critical barrier(s) to progress in the field that the proposed project will address.
• Explanation of how the proposed study will provide essential data for product development and/or approval.

The quality and appropriateness of the study design, research methodology, data collection, and data analyses to accomplish the specific aims of the proposed study and its potential to inform rare neurodegenerative disease clinical trial development.

• Description of the study including a clear hypothesis, study aims, study design, and how data will be collected, analyzed, and interpreted.
• Description of plans for ensuring data quality including, but not limited, to standardized data collection and analysis, minimization of bias, data entry, data access, data monitoring, data sharing and data dissemination.
• Description of plans for protecting the rights, safety, and welfare of study participants in compliance with federal law and how data will be collected according to Good Clinical Practice Guidelines.
• Discussion of challenges, potential problems, alternative strategies, and benchmarks for success anticipated to achieve the aims within a stated timeframe.

3. Inclusion of Patient Input:

The inclusion of patient and caregiver perspectives in the planning and design of the study to improve protocol design and medical product development.

• Description of plans to include early and ongoing patient/stakeholder input in the study (e.g., protocol design, data elements, feasibility, data sharing and dissemination).
• Description of plans to reduce patients' burden to participate the study, impact on daily living, and potential issues with trial design feasibility.

The probability of success of the proposed project given the environment in which the work will be done.

• Description of the competence of the PI(s), collaborators, and other support staff in conducting the proposed research, including their academic qualifications, research experiences, productivity, and any special attributes. If applicable, description of the rationale, leadership approach, governance, and organizational structure for a multi-PD/PI project.
• Description of the applicant's ability to recruit and complete the proposed study within budget and stated time limits, including a detailed recruitment plan and timeline for implementation of the project upon funding.
• Description of institutional support, equipment, and other resources, such as with existing research networks, industry, academia and/or patient organizations and resource sharing plans as appropriate.
• Description of any additional funds expected to be contributed by other sources (including the applicant) to the study prior to FDA grant funding and those to be used during the proposed funding period.

The ability of the project to advance current research or clinical practice paradigms towards future product development and to exert a significant influence on product development.

• Explanation of how the proposed study will exert a sustained, powerful impact on the research field, including if applicable whether the proposal has broader impact beyond the disease or condition being studied.
• Explanation of sustainability plans beyond the proposed funding period, including a description of plans for leveraging data and additional funding for use in further phases of development beyond the proposed funding period.

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.

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 and Pediatric Ethics.

When the proposed project involves human subjects, 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.

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.

Not Applicable

Not Applicable

Not Applicable

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.

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.

Applications will be evaluated for scientific and technical merit by (an) appropriate Objective Review Committee convened by the FDA, using the stated review criteria.

As part of the Objective Review, all applications:

• Will receive a written critique.

Appeals of objective review will not be accepted for applications submitted in response to this NOFO.

Applications will compete for available funds with all other recommended applications submitted in response to this NOFO. The following will be considered in making funding decisions:

• Scientific and technical merit of the proposed project as determined by objective review.
• Availability of funds.
• Relevance of the proposed project to program priorities.

Successful applicants will be notified of additional information that may be required or other actions leading to an award. The decision not to award a grant, or to award a grant at a particular funding level, is discretionary and is not subject to appeal to any FDA or HHS official or board.

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.

Recipients must comply with any funding restrictions described in Section IV.6. 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 NOFO will be subject to terms and conditions found in the HHS Grants Policy Statement.

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.

All FDA grant and cooperative agreement awards include the HHS Grants Policy Statement as part of the NoA.

If a recipient is successful and receives a Notice of Award, 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.

Should the applicant organization successfully compete for an award, recipients of federal financial assistance (FFA) from HHS will be required to complete an HHS Assurance of Compliance form (HHS 690) in which the recipient agrees, as a condition of receiving the grant, to administer programs in compliance with federal civil rights laws that prohibit discrimination on the basis of race, color, national origin, age, sex and disability, and agreeing to comply with federal conscience laws, where applicable. This includes ensuring that entities take meaningful steps to provide meaningful access to persons with limited English proficiency; and ensuring effective communication with persons with disabilities. Where applicable, Title XI and Section 1557 prohibit discrimination on the basis of sexual orientation, and gender identity, The HHS Office for Civil Rights provides guidance on complying with civil rights laws enforced by HHS. See https://www.hhs.gov/civil-rights/for-providers/provider-obligations/index.html and https://www.hhs.gov/civil-rights/for-individuals/nondiscrimination/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 FDA grant programs, please contact the Scientific/Research Contact that is identified in Section VII under Agency Contacts of this NOFO.

• For guidance on meeting the legal obligation to take reasonable steps to ensure meaningful access to programs or activities by limited English proficient individuals 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 information on an institution’s specific legal obligations for serving qualified individuals with disabilities, including reasonable accommodations and making services accessible to them, 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, see https://www.hhs.gov/civil-rights/for-individuals/sex-discrimination/index.html. For information about FDAs commitment to supporting a safe and respectful work environment, who to contact with questions or concerns, and what FDA's expectations are for institutions and the individuals supported on FDA-funded awards, please see FDA's Anti-Harassment and Inappropriate Conduct Policy.
• For guidance on administering programs in compliance with applicable federal conscience protection and associated anti-discrimination laws 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), FDA 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 and 2 CFR Part 200.206 Federal awarding agency review of risk posed by applicants. This provision will apply to all FDA grants and cooperative agreements except fellowships.

FDA considers the sharing of research resources developed through FDA-sponsored research an important means to enhance the value and further the advancement of research. When research resources have been developed with FDA funds and the associated research findings published, those findings must be made readily available to the scientific community.

Upon acceptance for publication, scientific researchers must submit the author’s final manuscript of the -reviewed scientific publication resulting from research supported in whole or in part with FDA funds. FDA defines the author's final manuscript as the final version accepted for journal publication, which includes all modifications from the publishing peer review process. The PMC archive is the designated repository for these manuscripts for use by the public, health care providers, educators, scientists, and FDA. Please see the FDA Public Access Policy.

Termination provisions in 2 CFR 200.340 (a) (1-4) are applicable to awards issued under this Notice of Funding Opportunity.

Additional terms and conditions regarding FDA regulatory and OC programmatic requirements may be part of the Notice of Award.

Reporting Requirements:

All FDA grants require both Financial and Performance reporting.

Financial Reporting:

A. Financial Expenditure Reports

A required Federal Financial Report (FFR) must be submitted annually. All annual FFRs must be submitted electronically using the Payment Management System (PMS). This includes all initial FFRs being prepared for submission and any revised FFRs being submitted or re-submitted to FDA. Paper expenditure/FFR reports will not accepted.

Annual FFRs must be submitted for each budget period no later than 90 days after the end of the calendar quarter in which the budget period ended. The reporting period for an annual FFR will be that of the budget period for the particular grant; however, the actual submission date is based on the calendar quarter. If a grant is under expanded authorities, the grantee must indicate the carryover amount in Section 12. Remarks of the annual FFR.

Performance Progress Reporting:

When multiple years (more than one budget period) are involved, awardees will be required to submit the Research Performance Progress Report (RPPR) annually as required in the Notice of Award. Annual RPPRs must be submitted using the RPPR module in eRA Commons. The annual RPPR must include a detailed budget. Annual RPPRs are due no later than 60 days prior to the start of the next budget period.

Failure to submit timely reports may affect future funding. Additional Financial and Performance Progress reports may be required for this award. Any additional reporting requirements will be listed under Section IV Special Terms and Condition of the Notice of Award.

Salary Caps:

None of the funds in this award shall be used to pay the salary of an individual at a rate in excess

of the current Executive Level II of the Federal Executive Pay Scale.

Certificates of Confidentiality 42 U.S.C. 241(d)

Awardees are responsible for complying with all requirements to protect the confidentiality of identifiable, sensitive information that is collected or used in biomedical, behavioral, clinical, or other research (including research on mental health and research on the use and effect of alcohol and other psychoactive drugs) funded wholly or in part by the Federal Government. See 42 U.S.C. 241(d). All research funded by FDA, in whole or in part, that is within the scope of these requirements is deemed to be issued a Certificate of Confidentiality through these Terms and Conditions. Certificates issued in this manner will not be issued as a separate document.

Awardees are expected to ensure that any investigator or institution not funded by FDA who receives a copy of identifiable, sensitive information protected by these requirements, understand they are also subject to the requirements of 42 U.S.C. 241(d). Awardees are also responsible for ensuring that any subrecipient that receives funds to carry out part of the FDA award involving a copy of identifiable, sensitive information protected by these requirements understand they are also subject to subsection 42 U.S.C. 241(d).

Acknowledgment of Federal Support:

When issuing statements, press releases, publications, requests for proposal, bid solicitations and other documents --such as tool-kits, resource guides, websites, and presentations (hereafter statements )--describing the projects or programs funded in whole or in part with FDA federal funds, the recipient must clearly state:

1. the percentage and dollar amount of the total costs of the program or project funded with federal money; and,

2. the percentage and dollar amount of the total costs of the project or program funded by non-governmental sources.

When issuing statements resulting from activities supported by FDA financial assistance, the recipient entity must include an acknowledgement of federal assistance using one of the following statements.

If the FDA Grant or Cooperative Agreement is NOT funded with other non-governmental sources:

This [project/publication/program/website, etc.] [is/was] supported by the Food and Drug Administration (FDA) of the U.S. Department of Health and Human Services (HHS) as part of a financial assistance award [FAIN] totaling $XX with 100 percent funded by FDA]/HHS. The contents are those of the author(s) and do not necessarily represent the official views of, nor an endorsement, by FDA/HHS, or the U.S. Government.

If the FDA Grant or Cooperative Agreement IS partially funded with other nongovernmental sources:

This [project/publication/program/website, etc.] [is/was] supported by the Food and Drug Administration (FDA) of the U.S. Department of Health and Human Services (HHS) as part of a financial assistance award [FAIN] totaling $XX with XX percentage funded by FDA/HHS and $XX amount and XX percentage funded by non-government source(s). The contents are those of the author(s) and do not necessarily represent the official views of, nor an endorsement, by FDA/HHS, or the U.S. Government.

The federal award total must reflect total costs (direct and indirect) for all authorized funds (including supplements and carryover) for the total competitive segment up to the time of the public statement. Any amendments by the recipient to the acknowledgement statement must be coordinated with FDA. If the recipient plans to issue a press release concerning the outcome of activities supported by FDA financial assistance, it should notify FDA in advance to allow for coordination.

Additional prior approval requirements pertaining to Acknowledgement of Federal Support, publications, press statements, etc. may be required, and if applicable, will be listed under Section IV Special Terms and Condition of the Notice of Award.

Prior Approval:

All prior approval requests must be submitted using the Prior Approval module in eRA Commons. Any requests involving budgetary issues must include a new proposed budget and a narrative justification of the requested changes. If there are any questions regarding the need or requirement for prior approval for any activity or cost, the grantee is to contact the assigned Grants Management Specialist prior to expenditure of funds.

For grant awards not covered under Expanded Authorities, Carryover and No Cost Extension (NCE) requests will require prior approval. All Carryover and NCE requests should be submitted using the Prior Approval module in eRA Commons. ****Please review the section on Expanded Authorities to determine if this award is covered/not covered under Expanded Authorities and whether prior approval is needed for carryover and no cost extension requests.****

The following activities require prior approval from FDA on all awards:

1. Change in Grantee Organization

2. Significant Rebudgeting

3. Change in Scope or Objectives

4. Deviation from Terms and Conditions of Award

5. Change in Key Personnel which includes replacement of the PD/PI or other key personnel as specified on the NoA.

6. Disengagement from the project for more than three months, or a 25 percent reduction in time devoted to the project, by the approved PD/PI. No individual may be committed to more than 100% professional time and effort. In the event that an individual's commitment exceeds 100%, the grantee must make adjustments to reduce effort. For FDA-sponsored projects, significant reductions in effort (i.e., in excess of 25% of the originally proposed level of effort) for the PD/PI and key personnel named on named on this Notice of Award must receive written prior approval from FDA.

Additional prior approval requirements may be required for this award, and if applicable, will be listed under Section IV Special Terms and Condition of the Notice of Award.

Audits and Monitoring:

Audit Requirements:

1. Recipients of Federal funds are subject to annual audit requirements as specified in 45 CFR 75.501 (https://www.ecfr.gov/cgi-bin/retrieveECFR?gp=1&SID=8040c4036b962cc9d75c3638dedce240&ty=HTML&h=L&r=PART&n=pt45.1.75#se45.1.75_1501). Grantees should refer to this regulation for the current annual Federal fund expenditure threshold level which requires audit.

2. Foreign recipients are subject to the same audit requirements as for-profit organizations (specified in 45 CFR 75.501(h) through 75.501(k).

3. For-profit and foreign entities can email their audit reports to [email protected] or mail them to the following address:

U.S. Department of Health and Human Services
Audit Resolution Division, Room 549D
Attention: Robin Aldridge, Director
200 Independence Avenue, SW
Washington, DC 20201

Monitoring:

Recipients are responsible for managing the day-to-day operations of grant-supported activities using their established controls and policies, as long as they are consistent with Federal, DHHS and FDA requirements. However, to fulfill their role in regard to the stewardship of Federal funds, FDA monitors our grants to identify potential problems and areas where technical assistance might be necessary. This active monitoring is accomplished through review of reports and correspondence from the recipient, audit reports, site visits, and other information available to FDA.

1. Desk review: FDA grants monitoring specialists will periodically reach out to recipients to request information for the completion of desk reviews. Requested information may include:

• Policies and procedures
• List of grant expenditures
• Accounting records
• Supporting documents (e.g., invoices, receipts, paystubs, timesheets, contracts, etc.)
• Financial statements
• Audit reports
• Other related documentation

2. Site visits: FDA will conduct site visits when necessary and will notify the recipient with reasonable advance notice of any such visit(s).

3. Foreign entities: All Foreign entities are subject to the same monitoring requirements as domestic entities. Foreign entities covered under immunity Executive Orders will provide supporting documents for monitoring requirements unless such an action is a violation of the Executive Orders. Recipients may discuss with the FDA to come up with an alternate approach to satisfy the award monitoring requirements.

All recipients will make reasonable efforts to resolve issues found, including audit findings. Successful resolutions to issues are important as they are part of the grant performance review. All recipients are responsible for submitting all requested information in an expeditious manner. Failure to submit timely reports and/or respond to inquiries from FDA may affect future funding or enforcement actions, including withholding, or conversion to a reimbursement payment method.

Financial Conflict of Interest (FCOI):

This award is subject to the Financial Conflict of Interest (FCOI) regulation at 42 CFR Part 50 Subpart F.

Closeout Requirements (when applicable):

A Final Research Performance Progress Report (FRPPR), Final Invention Statement HHS-568 (if applicable), Tangible Personal Property Report SF-428 (if applicable), and Statement of Disposition of Equipment (if applicable) must be submitted within 120 days after the expiration date of the project period. All closeout documents must be submitted electronically in eRA Commons.

The Final Federal Financial Report (FFR SF-425), must be submitted in PMS and indicate the exact balance of unobligated funds and may not reflect unliquidated obligations. There must be no discrepancies between the Final FFR expenditure data and FFR cash transaction data in the Payment Management System (PMS). The expended funds reported on the Final FFR must exactly match the disbursements and the charge advances in PMS. It is the recipient's responsibility to reconcile reports submitted to PMS and to the FDA.

Program Income:

The grantee is required to report any Program Income generated during the Project Period of this grant. Except for royalty income generated from patents and inventions, the amount and disposition of Program Income must be identified on lines 10 (l), (m), (n), and (o) of the grantee s Federal Financial Report (FFR) SF-425.

Examples of Program Income include (but are not limited to): fees for services performed during the grant or sub-grant period, proceeds from sale of tangible personal or real property, usage or rental fees, patent or copyright royalties, and proceeds from the sale of products and technology developed under the grant.

Any Program Income generated during the Project Period of this grant by the grantee or sub-grantee will be treated as identified below.

Treatment of Program Income:

Prohibition on certain telecommunications and video surveillance services or equipment:

(a) As described in CFR 200.216, recipients and subrecipients are prohibited to obligate or spend grant funds (to include direct and indirect expenditures as well as cost share and program) to:

(1) Procure or obtain,

(2) Extend or renew a contract to procure or obtain; or

(3) Enter into contract (or extend or renew contract) to procure or obtain equipment, services, or systems that use covered telecommunications equipment or services as a substantial or essential component of any system, or as critical technology as part of any system. As described in Pub. L. 115-232, section 889, covered telecommunications equipment is telecommunications equipment produced by Huawei Technologies Company or ZTE Corporation (or any subsidiary or affiliate of such entities).

i. For the purpose of public safety, security of government facilities, physical security surveillance of critical infrastructure, and other national security purposes, video surveillance and telecommunications equipment produced by Hytera Communications Corporation, Hangzhou Hikvision Digital Technology Company, or Dahua Technology Company (or any subsidiary or affiliate of such entities).

ii. Telecommunications or video surveillance services provided by such entities or using such equipment.

iii. Telecommunications or video surveillance equipment or services produced or provided by an entity that the Secretary of Defense, in consultation with the Director of the National Intelligence or the Director of the Federal Bureau of Investigation, reasonably believes to be an entity owned or controlled by, or otherwise, connected to the government of a covered foreign country.

Other:

This award is subject to the requirements of 2 CFR Part 25 for institutions to maintain an active registration in the System of Award Management (SAM). Should a consortium/subaward be issued under this award, a requirement for active registration in SAM must be included.

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 with cumulative total value greater than $10,000,000 must report and maintain information 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 the Federal Awardee Performance and Integrity Information System (FAPIIS)). Full reporting requirements and procedures are found in Appendix XII to 45 CFR Part 75.

You must administer your project 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 (including gender identity, sexual orientation, and pregnancy). This includes taking reasonable steps to provide meaningful access to persons with limited English proficiency and providing programs that are accessible to and usable by persons with disabilities. The HHS Office for Civil Rights provides guidance on complying with civil rights laws enforced by HHS. See https://www.hhs.gov/civil-rights/for-providers/providerobligations/index.html and https://www.hhs.gov/civil-rights/forindividuals/nondiscrimination/index.html.

• You must take reasonable steps to ensure that your project provides meaningful access to persons with limited English proficiency. For guidance on meeting your legal obligation to take reasonable steps to ensure meaningful access to your programs or activities by limited English proficient individuals, see https://www.hhs.gov/civilrights/for-individuals/special-topics/limited-english-proficiency/fact-sheetguidance/index.html and https://www.lep.gov.
• For information on your specific legal obligations for serving qualified individuals with disabilities, including providing program access, reasonable modifications, and taking appropriate steps to provide effective communication, 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, see https://www.hhs.gov/civil-rights/for-individuals/sexdiscrimination/index.html.
• For guidance on administering your project in compliance with applicable federal religious nondiscrimination laws and applicable federal conscience protection and associated anti-discrimination laws, see https://www.hhs.gov/conscience/conscienceprotections/index.html and https://www.hhs.gov/conscience/religiousfreedom/index.html.

Cooperative Agreement Terms and Conditions of Award

The following special terms of award are in addition to, and not in lieu of, otherwise applicable U.S. Office of Management and Budget (OMB) administrative guidelines, U.S. Department of Health and Human Services (HHS) grant administration regulations at 45 CFR Part 75, and other HHS, PHS, and FDA 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 FDA programmatic involvement with the recipients is anticipated during the performance of the activities. Under the cooperative agreement, FDA's 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 recipients for the project as a whole, although specific tasks and activities may be shared among the recipients and FDA as defined below.

Recipients 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 HHS, PHS, and FDA policies.

Program Steering Committee:

The Program Steering Committee will function as the advisory board of all grants awarded under this RFA. Each Program Steering Committee will include one representative from the award and will include FDA Scientific and Program Officer(s). Additional people relevant to the program aims and goals may be invited to attend meetings and participate in working groups by action of the Program Steering Committee or FDA.

Principal Investigator Responsibilities:

The PD(s)/PI(s) will have the primary responsibility for the scientific, technical, or programmatic aspects of the cooperative agreement and for day-to-day management of the project or program. The PD(s)/PI(s) will maintain general oversight for ensuring compliance with the financial and administrative aspects of the award, as well as ensuring that all staff have sufficient clearance and/or background checks to work on this project or program. This individual will work closely with designated officials within the recipient organization to create and maintain necessary documentation, including both technical and administrative reports; prepare justifications; appropriately acknowledge Federal support in publications, announcements, news programs, and other media; and ensure compliance with other Federal and organizational requirements.

Additionally, PD/PIs will:

1. Comply with all special terms and conditions of the grant, including those which state that future funding of the study will depend on recommendations from the OOPD program official. The scope of the recommendations will consider the following: (1) progress based on specific circumstances of the study; and (2) compliance with applicable FDA and HHS regulatory requirements for the trial.

2. Participate in milestone meetings (virtual or in person) and submit periodic milestone progress reports to FDA program staff in a standard form as agreed upon at the initiation, and by provide additional information as needed.

3. Ensure data and safety monitoring of a clinical trial is commensurate with the risks posed to study participants and with the size and complexity of the study and that monitoring systems are in place, that the quality of the monitoring activity is appropriate, and that the OOPD Program Official is informed of recommendations emanating from monitoring activities. These data and safety monitoring procedures must be in place to safeguard the well-being of study participants and to ensure scientific integrity. Monitoring must be performed on a regular basis throughout the subject accrual, treatment, and follow-up periods. The specific approach to monitoring will depend on features of the clinical trial to be conducted e.g., several levels of monitoring: Data and Safety Monitoring Board (DSMB), Study Monitoring Committee (SMC) and Independent Medical Monitor (IMM). Monitoring activities should be appropriate to the study, study phase, population, research environment, and degree of risk involved. Guidance is available at: https://www.fda.gov/media/116754/download

4. Participate in site visits or grant evaluations (in person or virtual) or attend meetings as requested by the FDA. Make the resources available for grant evaluation or site visits or inspections (in person or virtual) during and/or after the study if requested by FDA.

5. Submit data for quality assessment and/or validation in any manner if requested by FDA.

6. Serve as member of the Program Steering Committee.

7. Note that any publication or oral presentation regarding outcomes of this grant must undergo FDA/OC review and approval process. This process can take 30-90 days. Prior to submission of a manuscript, presentation, or abstract with FDA co-author(s) describing the results for publication, the PI should forward to the FDA a copy of the manuscript, presentation, or abstract to be submitted to review for any potential language that might reference, imply or infer any FDA endorsement of regulatory and/or policy changes related to the project. For publications without an FDA co-author but using FDA funds to support the grant, a courtesy review of the publication should be shared with FDA to ensure that any potential language that might reference, imply, or infer any FDA endorsement of regulatory and/or policy changes related to the project is not stated.

8. Assure that appropriate administrative and logistical support is provided to coordinate the project (including but not limited to facilitating the formation of working groups, scheduling and coordinating logistics of teleconferences and in-person meetings, and approval and tracking of research projects).

9. Oversee the implementation of the approved data and sharing plans.

10. Ensure compliance with the applicable mandatory regulations (including protection of human subjects) as required by specific research activities.

FDA Responsibilities:

1. An FDA Program Official (PO) will have substantial programmatic involvement as described below. The PO is the official responsible for the programmatic, scientific, and/or technical aspects of assigned applications and grants. The PO’s responsibilities include, but are not limited to, post-award monitoring of project/program performance, including review of progress reports and making site visits or grant evaluations; and other activities complementary to those of the Grants Management Officer (GMO). The PO and the GMO work as a team in many of these activities. The PO and GMO will be named in the Notice of Award.

2. One or more designated FDA program staff will have substantial involvement in the Program Steering Committee to ensure the objectives of the program are being met and participate in scientific/milestone meetings. The primary responsibility for the program resides with the awardee, although specific tasks and activities will be shared among the awardee and the FDA program staff.

3. FDA will provide periodic technical monitoring and/or direction of the work, including monitoring of data analysis, interpretation of analytical findings and their significance. The oversight may be in the form of telephone conversations, e-mails, or written correspondence between the PO/grants management officer or specialist and the PI. Information including, but not limited to, information regarding study progress, enrollment, problems, adverse events, changes in protocol, study monitoring activities, new collaborations, publications, financial and data leveraging, and changes in clinical guidelines based on the project will be requested. Periodic grant evaluations (teleconference or on-site) with officials of the grantee organization may also occur. OOPD may request information related to the impact of this study on future approvals and other outcomes such as publications or data leveraging. The results of these monitoring activities will be recorded in the official grant file and will be available to the grantee upon request consistent with applicable disclosure statutes and with FDA disclosure regulations.

4. FDA will assist and approve (as deemed appropriate) the substance of publications, co-authorship of publications and data release.

5. Evaluate the adherence of awardees to the approved data sharing plans and intellectual property plans.

6. Monitor the operations and progress of the project and make recommendations on overall project directions and allocations of project funds.

7. Decide on project continuation with input from the PI and/or any established committee, based on:

FDA reserves the right to terminate or curtail the award (or an individual component of the award) in the event of inadequate progress.

Dispute Resolution:

Any disagreements that may arise in scientific or programmatic matters (within the scope of the award) between award recipients and the FDA may be brought to Dispute Resolution. A Dispute Resolution Panel composed of three members will be convened. It will have three members: a designee of the Program Steering Committee chosen without FDA staff input, one FDA designee, and a third designee with expertise in the relevant area who is chosen by the other two; in the case of individual disagreement, the first member may be chosen by the individual awardee. This special dispute resolution procedure does not alter the awardee's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulation 42 CFR Part 50, Subpart D and DHHS regulation 45 CFR Part 16.

Note: The HHS Policy for Data Management and Sharing is effective for due dates on or after January 25, 2023.

Consistent with the HHS 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 HHS Grants Policy Statement. Upon the approval of a Data Management and Sharing Plan, it is required for recipients to implement the plan as described.

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 HHS 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 HHS Grants Policy Statement. FDA NOFOs outline intended research goals and objectives. Post award, FDA will review and measure performance based on the details and outcomes that are shared within the RPPR, as described at 45 CFR Part 75.301 and 2 CFR Part 200.301.

The Federal Funding Accountability and Transparency Act of 2006 (Transparency Act), includes a requirement for recipients of Federal grants to report information about first-tier subawards and executive compensation under Federal assistance awards issued in FY2011 or later. All recipients of applicable FDA grants and cooperative agreements are required to report to the Federal Subaward Reporting System (FSRS) available at www.fsrs.gov on all subawards over the threshold. See the HHS Grants Policy Statement for additional information on this reporting requirement.

In accordance with the regulatory requirements provided at 45 CFR 75.113 and 2 CFR Part 200.113 and Appendix XII to 45 CFR Part 75 and 2 CFR Part 200, 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 and 2 CFR Part 200 Award Term and Condition for Recipient Integrity and Performance Matters.

Monitoring Activities

The guidelines are intended to provide information for principal investigators who are conducting clinical trials. The procedures outlined herein are in addition to (and not in lieu of) Institutional Review Board (IRB), Office for Human Research Protections (OHRP), other Food and Drug Administration (FDA), and Good Clinical Practices requirements.

Oversight Activities

Documentation of assurances with the Office of Human Research Protection (OHRP) (see Section IV.5.A of this document) must be on file with the FDA grants management office before an award is made. Any institution receiving Federal funds must have an institutional review board (IRB) of record even if that institution is overseeing research conducted at other performance sites. To avoid funding studies that may not receive or may experience a delay in receiving IRB approval, documentation of IRB approval and Federal Wide Assurance (FWA) for the IRB of record for all performance sites must be on file with the FDA grants management office before an award to fund the study will be made.

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)

Grants.gov Customer Support (Questions regarding Grants.gov registration and Workspace)
Contact Center Telephone: 800-518-4726
Email: [email protected]

Katherine Needleman
Office of Orphan Products Development
Food and Drug Administration
10903 New Hampshire Avenue
Silver Spring, MD 20993-0002
Phone: 301-796-8660
E-mail: [email protected]

Zahara Graves
Office of Acquisitions & Grants Services (OAGS)
Food and Drug Administration
Email: [email protected]

Zahara Graves
Office of Acquisitions & Grants Services (OAGS)
Food and Drug Administration
Email: [email protected]

All awards are subject to the terms and conditions, cost principles, and other considerations described in the HHS Grants Policy Statement. Notice of Award, and 45 CFR 75, 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.

Awards are made under the authorization of Section 301 of the Public Health Service Act (42 USC 241), 21 U.S.C. 360ee, and under Federal Regulations 42 CFR Part 52, 45 CFR Part 75, and 2 CFR Part 200. All grant awards are subject to applicable requirements for clinical investigations imposed by sections 505, 512, and 515 of the act (21 U.S.C. 355, 360b, and 360e) or safety, purity, and potency for licensing under section 351 of the Public Health Service Act (42 U.S.C. 262), including regulations issued under any of these sections.

All human subject research regulated by FDA is also subject to FDA's regulations regarding the protection of human subjects (21 CFR Parts 50 and 56). Applicants are encouraged to review the regulations, guidance, and information sheets on human subject protection and Good Clinical Practice available on the Internet at http://www.fda.gov/oc/gcp/.

The applicant is referred to HHS regulations at 45 CFR 46.116 and 21 CFR 50.25 for details regarding the required elements of informed consent.