Foa_Content_of_RFA-FD-25-020.pdf

FDA Research OCT FY2025_1 Page 1 of 36

Department of Health and Human Services

Part 1. Overview Information

Participating Organization(s)

U.S. Food and Drug Administration (FDA)

NOTE: The policies, guidelines, terms, and conditions stated in this Notice of Funding Opportunity (NOFO) may differ from those used by the NIH. Where this NOFO provides specific written guidance that may differ from the general guidance provided in the grant application form, please follow the instructions given in this NOFO.

The FDA does not follow the NIH Page Limitation Guidelines or the NIH Review Criteria. Applicants are encouraged to consult with FDA Agency Contacts for additional information regarding page limits and the FDA Objective Review Process.

Components of Participating Organizations

Office of Orphan Products Development (OOPD)

Funding Opportunity Title

Reissue of RFA-FD-23-001- Clinical Studies of Orphan Products Addressing Unmet Needs of Rare Diseases (R01 Clinical Trials Required)

Activity Code

R01 Research Project Grant

Announcement Type

Reissue of RFA-FD-23-001

Related Notices

None

Number (FON)

RFA-FD-25-020

Companion Funding Opportunity

None http://www.fda.gov/ http://www.fda.gov/ForIndustry/DevelopingProductsforRareDiseasesConditions/default.htm http://grants.nih.gov/grants/funding/ac_search_results.htm?text_curr=r01&Search.x=0&Search.y=0&Search_Type=Activity

FDA Research OCT FY2025_1 Page 2 of 36

Number of Applications

See Part 2, Section III. 3. Additional Information on Eligibility.

Assistance Listing Number(s)

93.103

Purpose

The purpose of this Notice of Funding Opportunity (NOFO) is to fund clinical trials of products evaluating efficacy and/or safety in support of a new indication or change in labeling to address unmet needs in rare diseases or conditions. Additionally, through the funding of collaborative, efficient, and/or innovative clinical trials, FDA expects to increase the number of approved treatments for rare diseases and exert a broad and positive impact on rare disease drug development.

Goals

The goal of this Notice of Funding Opportunity (NOFO) is intended to support clinical trials of orphan products in all phases of product development (phase 1, 2 and/or 3) for rare diseases with unmet medical needs. These clinical trials should evaluate safety and/or efficacy of medical products in support of a new indication or a change in labeling.

Key Dates

Posted Date

July 11, 2025

Open Date (Earliest Submission Date)

August 22, 2025

Letter of Intent Due Date(s)

September 22, 2025 (Optional) September 21, 2026 (Optional) September 20, 2027 (Optional)

Application Due Date(s) October 21, 2025, by 11:59 PM Eastern Time

October 20, 2026, by 11:59 PM Eastern Time

October 19, 2027, by 11:59 PM Eastern Time.

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Applicants are encouraged to apply early to allow adequate time to make any corrections to errors found in the application during the submission process by the due date. Resubmissions ONLY Application Due Date(s): May 18, 2027; May 16, 2028 by 11:59 PM Eastern Time. See resubmission eligibility requirement below. Applicants should be aware that on-time submission means that an application is submitted error free (of both Grants.gov and eRA Commons errors) by 11:59 PM Eastern Time on the application due date.

All applications are due by 11:59 PM Eastern Time.

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

No late applications will be accepted for this Notice of Funding Opportunity (NOFO).

AIDS Application Due Date(s) Not Applicable

Scientific Merit Review

New Applications: February/March 2026, 2027, 2028 Resubmissions: June 2027, 2028

Earliest Start Date

July 2026

Expiration Date

May 31, 2028

Advisory Council Review Not Applicable

Due Dates for E.O.

12372

Not Applicable

Required Application Instructions Conformance to all requirements, both in the the Research (R) Instructions How to Apply - Application Guide and in the NOFO, is required and strictly enforced. Applicants must read and follow all application instructions in the How to Apply - Application Guide as well as any program-specific instructions noted in Section IV of this NOFO or an applicable related Notice posted to the Guide for Grants and Contracts.

When the program-specific instructions deviate from those in the How to Apply - Application Guide, follow the program-specific instructions.

Applications that do not comply with these instructions may be delayed or not accepted for review.

Table of Contents Part 1. Overview Information

Key Dates

Part 2. Full Text of Announcement

Section I. Notice of Funding Opportunity Description https://grants.nih.gov/grants/guide/url_redirect.htm?id=82400 https://grants.nih.gov/grants/guide/url_redirect.htm?id=82400 https://grants.nih.gov/grants/guide/url_redirect.htm?id=82400 http://grants.nih.gov/grants/guide/url_redirect.htm?id=11164 https://grants.nih.gov/grants/guide/url_redirect.htm?id=82400

FDA Research OCT FY2025_1 Page 4 of 36

Section II. Award Information

Section III. Eligibility Information

Section IV. Application and Submission Information

Section V. Application Review Information

Section VI. Award Administration Information

Section VII. Agency Contacts

Section VIII. Other Information

Part 2. Full Text of Announcement Section I. Notice of Funding Opportunity Description

1. Research Objectives

1.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 rare diseases or conditions. The term “rare disease or condition” is defined in 21 U.S.C. 360ee. For chronic diseases, FDA considers drugs, biologics, devices, and medical foods potentially eligible for grants under the Orphan Products Development (OPD) Clinical Trials Grants Program if they are indicated for a disease or condition that has a prevalence of fewer than 200,000 people in the United States. For acute diseases (i.e., less than 1 year duration), the annual incidence of the disease must be less than 200,000 per year. Diagnostics and vaccines are considered potentially eligible for such grants only if the U.S. population to whom they will be administered is fewer than 200,000 people in the U.S. per year.

There are over 10,000 rare diseases that affect ~30 million Americans but only a few hundred of these rare diseases currently have approved treatments. The Orphan Products Grants Program has been supporting clinical trial research since 1983 and more than 80 of the funded studies have facilitated the marketing approval of rare disease products. To address the remaining unmet need and the lack of treatments for the majority of rare diseases, FDA is focusing their efforts with this NOFO to facilitate drug development in safe yet efficient means by encouraging the use of established infrastructure and resources (e.g., clinical trial networks and data standardization, analytics, and sharing platforms), collaborative efforts between stakeholders (e.g., industry/academia/patient organizations), and early and ongoing patient engagement in trial design (e.g., study feasibility, assessment of important clinical outcomes).

Additionally, applications proposing innovative clinical trial designs (i.e., seamless, adaptive, basket, umbrella, platform trials) or innovative methods (i.e., data modeling and simulations) will be eligible for additional funding (see Section II below). These approaches are vital in expediting drug development and have the potential to make a broad and positive impact for rare diseases in general.

1.B. Research Objectives

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This NOFO is intended to support clinical trials of orphan products in all phases of product development (phase 1, 2 and/or 3) for rare diseases with unmet medical needs. These clinical trials should evaluate safety and/or efficacy of medical products in support of a new indication or a change in labeling.

Depending on the phase of development, these trials may need to include an appropriate comparator, such as a placebo, a concurrent external control, or a historical control. OOPD encourages applicants to refer to "Rare Diseases: Considerations for the Development of Drugs and Biological Products" for guidance on conducting more efficient and successful drug development programs. Applicants are also encouraged to refer to Guidance Documents for Rare Disease Drug Development for selected guidances relevant to rare disease drug development and information on the Orphan Products Grants Program website before applying for this opportunity.

To facilitate efficient product development, the use of shared, established infrastructure and resources and collaborative efforts between stakeholders in industry, academia, and patient organizations are highly encouraged under this NOFO. Additionally, patients living with a rare disease, or their caregivers have experiences and knowledge that contribute to important considerations in product development, such as with trial feasibility, thus early and ongoing patient engagement is also highly encouraged.

Innovative and Efficient Trial Approaches:

FDA is interested in supporting innovative and efficient trial designs and will allow for additional funding with justification for applications proposing the use of one or more of the following:

• Innovative trial designs such as seamless and adaptive trial designs, which compress the phases of a trial into one continuous trial, as well as basket, umbrella and platform trials, which allow for testing of multiple drugs and/or multiple diseases using a common infrastructure.

• Innovative methods using data simulations and modeling toward the study of safety and efficacy of a product.

These approaches may hold significant promise for the advancement of therapeutic treatments for rare diseases through all phases of product development. Early engagement with FDA review divisions to discuss the use of these innovative approaches is highly recommended prior to submitting a grant application (e.g., preIND, INTERACT, other meetings).

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

Section II. Award Information

Funding Instrument

Grant: A financial assistance mechanism providing money, property, or both to an eligible entity to carry out an approved project or activity.

Application Types Allowed

New Renewal Resubmission Revision

The OER Glossary and the How to Apply - Application Guide provide details on these application types. Only those application types listed here are allowed for this NOFO.

https://www.fda.gov/regulatory-information/search-fda-guidance-documents/rare-diseases-considerations-development-drugs-and-biological-products https://www.fda.gov/drugs/guidances-drugs/guidance-documents-rare-disease-drug-development#Rare https://www.fda.gov/industry/medical-products-rare-diseases-and-conditions/funding-opportunities-rare-disease-research https://www.fda.gov/industry/medical-products-rare-diseases-and-conditions/funding-opportunities-rare-disease-research https://www.fda.gov/drugs/cder-small-business-industry-assistance-sbia/small-business-and-industry-assistance-frequently-asked-questions-pre-investigational-new-drug-ind https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/otp-interact-meetings https://www.fda.gov/regulatory-information/search-fda-guidance-documents/formal-meetings-between-fda-and-sponsors-or-applicants-pdufa-products http://grants.nih.gov/grants/guide/url_redirect.htm?id=11116

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Clinical Trial?

Required: Only accepting applications that propose clinical trial(s).

Need help determining whether you are doing a clinical trial?

Funds Available and Anticipated Number of Awards

The number of awards is contingent upon Congressional appropriations to this FDA grants program and the submission of a sufficient number of meritorious applications.

Award(s) will provide one (1) year of support and include future recommended support for an additional three (3) years contingent upon annual appropriations, availability of funding, and satisfactory recipient performance.

Award Budget

Application budgets need to reflect the actual needs of the proposed project and should not exceed the following in maximum total costs (direct and indirect costs) and maximum years of support.

YR 01: $650,000

YR 02: $650,000

YR 03: $650,000

YR 04: $650,000

Applicants may request additional funding over the above listed maximums for innovative and efficient trial approaches. The additional funding request shall not exceed an additional $250,000 total costs per year (to a maximum total award cost of $900,000 per year) for up to 4 years. Justification for the additional funding request must be reflected in the budget request and will be reviewed annually by the program.

See Appendix Section below for definitions of types of studies eligible for additional funding (Section IV.2).

Award Project Period

The scope of the proposed project should determine the project period.

The maximum project period is four (4) years, however, the length of support will depend on the nature of the study.

For those studies with an expected duration of more than 1 year, a second, third, or fourth year of noncompetitive continuation of support will depend on the following factors: (1) Performance during the preceding year; (2) compliance with regulatory requirements of IND/investigational device exemption (IDE), if applicable; and (3) availability of Federal funds.

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

Section III. Eligibility Information Eligible Organizations https://grants.nih.gov/grants/guide/url_redirect.htm?id=82370 https://www.hhs.gov/sites/default/files/hhs-grants-policy-statement-april-2025.pdf

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Higher Education Institutions

• Public/State Controlled Institutions of Higher Education

• Private Institutions of Higher Education

Nonprofits Other Than Institutions of Higher Education

• Nonprofits with 501(c)(3) IRS Status (Other than Institutions of Higher Education)

• Nonprofits without 501(c)(3) IRS Status (Other than Institutions of Higher Education)

For-Profit Organizations

• Small Businesses

• For-Profit Organizations (Other than Small Businesses)

Local Governments

• State Governments

• County Governments

• City or Township Governments

• Special District Governments

• Indian/Native American Tribal Governments (Federally Recognized)

• Indian/Native American Tribal Governments (Other than Federally Recognized)

Federal Governments

U.S. Territory or Possession

Other

• Independent School Districts

• Public Housing Authorities/Indian Housing Authorities

• Native American Tribal Organizations (other than Federally recognized tribal governments)

• Faith-based or Community-based Organizations

• Regional Organizations

• Non-domestic (non-U.S.) Entities (Foreign Organizations)

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

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

Foreign components, as defined in the NIH Grants Policy Statement, are allowed.

Required Registrations Applicant Organizations

Applicant organizations must complete and maintain the following registrations as described in the How to Apply - Application Guide to be eligible to apply for or receive an award. All registrations must be completed prior to the application being submitted. Registration can take 6 weeks or more, so applicants should begin the registration process as soon as possible. Failure to complete registrations in advance of a due date is not a valid reason for a late submission, please reference the HHS Grants Policy Statement for additional information

• System for Award Management (SAM) Applicants must complete and maintain an active registration, which requires renewal at least annually. The renewal process may require as much time as the initial registration. SAM registration includes the assignment of a Commercial and Government Entity (CAGE) Code for domestic organizations which have not already been assigned a CAGE Code.

http://grants.nih.gov/grants/guide/url_redirect.htm?id=11118 https://grants.nih.gov/grants/guide/url_redirect.htm?id=82400 https://grants.nih.gov/grants/guide/url_redirect.htm?id=82400 https://grants.nih.gov/grants/guide/url_redirect.htm?id=82390

FDA Research OCT FY2025_1 Page 8 of 36 o 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.

o Unique Entity Identifier (UEI) - A UEI is issued as part of the SAM.gov registration process. The same UEI must be used for all registrations, as well as on the grant application.

• eRA Commons - Once the unique organization identifier is established, organizations can register with eRA Commons in tandem with completing their Grants.gov registrations; all registrations must be in place by time of submission. eRA Commons requires organizations to identify at least one Signing Official (SO) and at least one Program Director/Principal Investigator (PD/PI) account in order to submit an application.

• Grants.gov Applicants must have an active SAM registration in order to complete the Grants.gov registration.

Program Directors/Principal Investigators (PD(s)/PI(s))

All PD(s)/PI(s) must have an eRA Commons account. PD(s)/PI(s) should work with their organizational officials to either create a new account or to affiliate their existing account with the applicant organization in eRA Commons. If the PD/PI is also the organizational Signing Official, they must have two distinct eRA Commons accounts, one for each role. Obtaining an eRA Commons account can take up to 2 weeks.

Eligible Individuals (Program Director/Principal Investigator) Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) is invited to work with their organization to develop an application for support.

For institutions/organizations proposing multiple PDs/PIs, visit the Multiple Program Director/Principal Investigator Policy and submission details in the Senior/Key Person Profile (Expanded) Component of the How to Apply - Application Guide.

The PD/PI should be an established investigator in the scientific area in which the application is targeted and capable of providing both administrative and scientific leadership to the development and implementation of the proposed program. The PD/PI will be expected to monitor and assess the program and submit all documents and reports as required.

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 Research & Related (R&R) form. All other PDs/PIs should be listed in the (R&R) 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.

http://grants.nih.gov/grants/guide/url_redirect.htm?id=11176 https://grants.nih.gov/grants/guide/url_redirect.htm?id=11123 http://grants.nih.gov/grants/guide/url_redirect.htm?id=82300 https://grants.nih.gov/grants/guide/url_redirect.php?id=82400 http://grants.nih.gov/grants/multi_pi

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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 subcontract 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 G.310 of the SF424 (R&R) Application Guide for further instruction regarding the use of the subaward budget form.

2. Cost Sharing 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.

• An application that has substantial overlap with another application pending appeal of initial peer review (see 2.3.9.4 Similar, Essentially Identical, or Identical Applications).

Section IV. Application and Submission Information

1. Requesting an Application Package The application forms package specific to this opportunity must be accessed through ASSIST, Grants.gov Workspace or an institutional system-to-system solution. Links to apply using ASSIST or Grants.gov Workspace are available in Part 1 of this NOFO. See your administrative office for instructions if you plan to use an institutional system-to-system solution.

2. Content and Form of Application Submission It is critical that applicants follow the instructions in the Research (R) Instructions in the How to Apply - Application Guide except where instructed in this notice of funding opportunity to do otherwise.

Conformance to the requirements in the How to Apply - Application Guide is required and strictly enforced. Applications that are out of compliance with these instructions may be delayed or not accepted for review.

https://www.hhs.gov/sites/default/files/hhs-grants-policy-statement-april-2025.pdf http://grants.nih.gov/grants/guide/url_redirect.htm?id=82415 http://grants.nih.gov/grants/guide/url_redirect.htm?id=82423 https://grants.nih.gov/grants/guide/url_redirect.htm?id=82400

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Letter of Intent Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows FDA staff to estimate the potential review workload and plan the review. No responsiveness decision will be made based on the letter of intent.

By the date(s) 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), email 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 via electronic mail as a PDF file with the NOFO Number and the Institution's Name in the message subject heading to:

Katherine Needleman Director, Orphan Products Grants Program Email: OOPD_CTGrants@fda.hhs.gov

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

, with the following exceptions or additional requirements:

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

A resubmission application must include an Introduction Section of the Research Strategy (1 page maximum) addressing the most recent objective review critique (Summary Statement).

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

Applicable only to Resubmission, Renewal, and Revision Applications:

• For field 4. a. Federal Identifier - The Federal Identifier is required. Include only the IC and serial number of the previously assigned award number (e.g., use FD007777 from 1U01FD007777-01).

• For field 8. TYPE OF APPLICATION - select one of the following:

o Resubmission- Check this option when submitting a revised (altered or corrected) or amended application. Please see additional Resubmission requirements under the Research Strategy.

o Renewal - Check this option if you are requesting additional funding for a period subsequent to that provided by a current award. Please see additional Renewal requirements under the Research Strategy.

o Revision- Check this option for competing revisions and non-competing administrative supplements.

SF424(R&R) Project/Performance Site Locations All instructions in the How to Apply - Application Guide must be followed.

SF424(R&R) Other Project Information All instructions in the How to Apply - Application Guide must be followed.

SF424(R&R) Senior/Key Person Profile All instructions in the How to Apply - Application Guide must be followed.

mailto:OOPD_CTGrants@fda.hhs.gov https://grants.nih.gov/grants/guide/url_redirect.htm?id=82400 https://grants.nih.gov/grants/guide/url_redirect.htm?id=61134 https://grants.nih.gov/grants/guide/url_redirect.htm?id=82400 https://grants.nih.gov/grants/guide/url_redirect.htm?id=82400

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R&R Budget

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.

• Applications requesting additional funding (up to $250,000 total costs per year) for innovative and efficient trial approaches must submit a clear description and justification as to how they have met the requirements as outlined in the Appendix Section below (limited to 3 pages). This description and justification must be included as an appendix to the application. Applications not meeting these requirements may be requested to reduce their budget.

• 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 should be included and described in the budget justification section separate from FDA request justification. Details should be provided on total amounts, location of sources, and confirmation if these funds have been secured.

• 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.

R&R Subaward Budget All instructions in the How to Apply - Application Guide must be followed.

PHS 398 Cover Page Supplement All instructions in the How to Apply - Application Guide must be followed.

PHS 398 Research Plan All instructions in the How to Apply - Application Guide must be followed, with the following additional instructions:

Research Strategy:

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

http://grants.nih.gov/grants/guide/url_redirect.htm?id=12000 https://grants.nih.gov/grants/guide/url_redirect.htm?id=82400

FDA Research OCT FY2025_1 Page 12 of 36

1. Rationale

2. Study Design including 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 Disease Population/Prevalence.” This subsection should include documentation to support that the estimated prevalence of the orphan disease or condition in the United States is 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. (Please Note: Applications may be considered for the use of a product in an orphan subset of a non-rare disease or condition when the applicant can explain based on a characteristic or feature of the product (e.g., mechanism of action, toxicity profile, prior clinical experience) why the product will be limited to use in the subset of question. An orphan subset is not based on an unmet need, or how a sponsor may wish to study or indicate a product. The explanation for the orphan subset must make it clear to OOPD that the product would not be appropriate in the disease or condition outside of the subset, including pediatric subpopulations). For studies proposing assessing multiple rare diseases, supportive prevalence data for each rare 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 specific heading “Support of Product Development.” This subsection should include an explanation of how the proposed study will either help support product approval or provide essential data needed for product development. If the proposal is for multiple products or multiple rare 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.

Resubmissions:

FDA will not accept any application in response to this FOA that is essentially the same as one currently pending initial merit review unless the applicant withdraws the pending application. However, FDA will accept a resubmission application addressing the criteria in this announcement. A resubmission application must include an Introduction Section of the Research Strategy (1 page maximum) addressing the most recent objective review critique (Summary Statement). The Summary Statement issued from the Office of Orphan Products Development must be included as an Appendix in the resubmission application. A resubmission application must otherwise also be complete and stand-alone from previous versions. Resubmissions are intended for those applications that were previously submitted to OOPD, reviewed and received a score on the application. Note: Only previously submitted applications to the Orphan Products Clinical Trials Grants program that received a numeric score and that do not require an IND protocol amendment prior to application resubmission will be accepted.

https://uscode.house.gov/view.xhtml?req=granuleid:USC-2000-title21-section360ee&num=0&edition=2000 https://www.fda.gov/regulatory-information/search-fda-guidance-documents/clarification-orphan-designation-drugs-and-biologics-pediatric-subpopulations-common-diseases

FDA Research OCT FY2025_1 Page 13 of 36

Study Monitoring Plan:

The Study Design Section of the Research Strategy should include a subsection with the specific heading "Study Monitoring Plan." This subsection should include a proposed plan for monitoring. 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. 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, interventions 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

Renewals

For Renewal applications, the Research Strategy should include a brief Progress Report that summarizes Progress to Date and accomplishments achieved during the current funding period. The Progress Report should include a summary of the specific aims of the previous project period and the importance of the findings, progress made towards achievements, explanation on any significant changes to the specific aims and any new directions.

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 disease(s) who would be eligible for the study;

2) Product Availability: There must be evidence that the product(s) to be studied is available to the applicant in the form and quantity needed for the clinical trial proposed. A current letter(s) from the supplier as an appendix will be acceptable. If negotiations regarding the supply of the study product(s) are underway but have not been finalized at the time of application, please provide a letter indicating such in the application. Verification of adequate supply of study product(s) will be necessary before an award is made;

3) 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.

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

, with the following modification:

• All applications, regardless of the amount of direct costs requested for any one year, should address a Data Management and Sharing Plan.

Other Plan(s): Note: Effective for due dates on or after January 25, 2023, the Data Management and Sharing Plan will be attached in the Other Plan(s) attachment in FORMS-H application forms packages.

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

https://www.fda.gov/media/116754/download http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM127073.pdf

FDA Research OCT FY2025_1 Page 14 of 36

• All applicants planning research (funded or conducted in whole or in part by the FDA) that results in the generation of scientific data are required to comply with the instructions for the Data Management and Sharing Plan. All applications, regardless of the amount of direct costs requested for any one year, must address a Data Management and Sharing Plan.

Appendix:

Only limited Appendix materials are allowed. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide, with the following additional requirements:

Do not use the Appendix section to circumvent page limits.

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

1. Protocol: The full final protocol (IND/IDE submitted protocol) must be provided.

2. 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.

3. Innovative and Efficient Trial Approaches: Applications requesting additional funding (up to $250,000 total costs per year) for innovative and efficient trial approaches must submit a clear description and justification as to how the requirements as outlined below are met (limited to 3 pages):

• Innovative trial designs such as seamless and adaptive trial designs, which compress the phases of a trial into one continuous trial, as well as basket, umbrella and platform trials, which allow for testing of multiple drugs and/or multiple diseases using a common infrastructure.

• Innovative methods using data simulations and modeling toward the study of safety and efficacy of a product.

OOPD encourages applicants to refer to:

• "Interacting with the FDA on Complex Innovative Trial Designs" and "Adaptive Design Clinical Trials for Drugs and Biologics" for guidance on complex innovative designs and the use of data simulations and modeling for clinical trials intended to support the effectiveness and safety of drugs and biologics.

These approaches may hold significant promise for the advancement of therapeutic treatments for rare diseases through all phases of product development. Early engagement with FDA review divisions to discuss the use of these innovative approaches is highly recommended prior to submitting a grant application (e.g., preIND, INTERACT, other meetings).

Applications not meeting these requirements may be requested to reduce their budget.

4. Summary Statement: Resubmissions must provide the previous OOPD Summary Statement in an appendix section and may include a point-by-point rebuttal to those critiques.

PHS Human Subjects and Clinical Trials Information When involving human subjects research, clinical research, and/or FDA-defined clinical trials (and when applicable, clinical trials research experience) follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the How to Apply - Application Guide, with the following additional instructions:

If you answered "Yes" to the question “Are Human Subjects Involved?” on the R&R Other Project Information form, you must include at least one human subjects study record using the Study Record:

PHS Human Subjects and Clinical Trials Information form or Delayed Onset Study record.

Study Record: PHS Human Subjects and Clinical Trials Information

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

http://grants.nih.gov/grants/guide/url_redirect.htm?id=12000 https://www.fda.gov/regulatory-information/search-fda-guidance-documents/interacting-fda-complex-innovative-trial-designs-drugs-and-biological-products https://www.fda.gov/regulatory-information/search-fda-guidance-documents/adaptive-design-clinical-trials-drugs-and-biologics-guidance-industry https://www.fda.gov/regulatory-information/search-fda-guidance-documents/adaptive-design-clinical-trials-drugs-and-biologics-guidance-industry

FDA Research OCT FY2025_1 Page 15 of 36

Foreign Organizations Foreign (non-U.S.) organizations must follow policies described in the HHS Grants Policy Statement, and procedures for foreign organizations described throughout the How to Apply Application Guide.

4. Submission Dates and Times Part I. contains information about Key Dates and times. Applicants are encouraged to submit applications before the due date to ensure they have time to make any application corrections that might be necessary for successful submission. When a submission date falls on a weekend or Federal holiday, the application deadline is automatically extended to the next business day.

Organizations must submit applications to Grants.gov (the online portal to find and apply for grants across all Federal agencies). Applicants must then complete the submission process by tracking the status of the application in the eRA Commons, FDA's electronic system for grants administration. FDA 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 How to Apply - Application Guide.

5. Intergovernmental Review (E.O. 12372) This initiative is not subject to intergovernmental review.

6. Funding Restrictions All FDA awards are subject to the terms and conditions, cost principles, and other considerations described in the HHS Grants Policy Statement.

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

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.

https://www.hhs.gov/sites/default/files/hhs-grants-policy-statement-april-2025.pdf https://grants.nih.gov/grants/guide/url_redirect.html?id=82380 http://grants.nih.gov/grants/guide/url_redirect.htm?id=11128 http://grants.nih.gov/grants/guide/url_redirect.htm?id=11123 https://grants.nih.gov/grants/guide/url_redirect.htm?id=82400 https://grants.nih.gov/grants/guide/url_redirect.htm?id=82400 https://grants.nih.gov/grants/policy/nihgps/html5/section_10/10.10.1_executive_orders.htm https://www.hhs.gov/sites/default/files/hhs-grants-policy-statement-april-2025.pdf https://www.hhs.gov/sites/default/files/hhs-grants-policy-statement-april-2025.pdf https://www.hhs.gov/ohrp/index.html https://www.hhs.gov/ohrp/regulations-and-policy/regulations/45-cfr-46/index.html

FDA Research OCT FY2025_1 Page 16 of 36

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 study initiation. 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 a single IRB and assurance. The single IRB may be an IRB already being used by one of the performance sites, but it must specifically be registered as the single IRB 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).

7.