U.S. Food and Drug Administration (FDA)
NOTE: The policies, guidelines, terms, and conditions stated in this announcement may differ from those used by the NIH. Where this Funding Opportunity Announcement (FOA) provides specific written guidance that may differ from the general guidance provided in the grant application form, please follow the instructions given in this FOA.
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.
Office of Orphan Products Development (OOPD)
Funding Opportunity Title
Efficient and Innovative Natural History Studies Addressing Unmet Needs in Rare Diseases (R01) Clinical Trials Not Required
R01 Research Project Grant
Reissue RFA-FD-19-001 - Natural History Studies Addressing Unmet Needs of Rare Diseases: Orphan Products Research Project Grant (R01)
Funding Opportunity Announcement (FOA) Number
Companion Funding Opportunity
Catalog of Federal Domestic Assistance (CFDA) Number(s)
Funding Opportunity Purpose
The purpose of this funding opportunity announcement (FOA) is to support efficient and innovative natural history studies that advance medical product development in rare diseases/conditions with unmet needs. Through the support of natural history studies with high quality and interpretable data elements, FDA expects to address critical knowledge gaps, remove major barriers to progress in the field, exert a significant and broad impact on a specific rare disease or multiple rare diseases with similar pathophysiology, and facilitate rare disease product development.
February 17, 2021
Open Date (Earliest Submission Date)
December 17, 2021; December 15, 2023
Letter of Intent Due Date(s)
January 14, 2022; January 12, 2024
Application Due Date(s)
February 15, 2022; February 13, 2024: 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.
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.
Late applications will not be accepted for this FOA.
AIDS Application Due Date(s)
Scientific Merit Review
June 2022: June 2024
Advisory Council Review
Earliest Start Date
September 2022; September 2024
February 14, 2024
Due Dates for E.O. 12372
It is critical that applicants follow the Research (R) Instructions in the SF424 (R&R) Application Guide, except where instructed to do otherwise (in this FOA or in a Notice from the NIH Guide for Grants and Contracts). Conformance to all requirements (both in the Application Guide and the FOA) is required and strictly enforced. Applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions. Applications that do not comply with these instructions may be delayed or not accepted for review.
There are several options available to submit your application through Grants.gov to NIH and Department of Health and Human Services partners. You must use one of these submission options to access the application forms for this opportunity.
I. 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
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. Rare diseases, as generally defined in the US Orphan Drug Act (ODA), are diseases or conditions with a prevalence of fewer than 200,000 persons in the US. Approximately 30 million Americans are affected by 7,000 known rare diseases but only a few hundred of these rare diseases have approved treatments. Unlike common diseases, there is little existing knowledge on the initial manifestations, major symptoms and limitations of day-to-day function, which makes drug development challenging. To address this, it is critical to study the natural history of rare diseases.
Per the March 2019 FDA Draft Guidance for Industry and Other Stakeholders entitled, Rare Diseases: Natural History Studies for Drug Development, the natural history of a disease is traditionally defined as the course a disease takes in the absence of intervention in individuals with the disease, from the disease’s onset until either the disease’s resolution or the individual’s death. A natural history study is a preplanned observational study intended to track the course of the disease. Its purpose is to identify demographic, genetic, environmental, and other variables (e.g., treatment modalities, concomitant medications) that correlate with the disease’s development and outcomes. Natural history studies are likely to include patients receiving the current standard of care and/or emergent care, which may alter some manifestations of the disease.
Information obtained from a natural history study plays an essential role at every stage of product development, such as identifying the patient population, identifying or developing clinical outcome assessments and biomarkers, and when appropriate, serving as external controls. Natural history studies are observational/non-interventional in nature and may be retrospective or prospective.
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 is intended to support prospective or retrospective, efficient, and innovative natural history studies with a focus on collaborative and standardized approaches to ensure data quality and interpretability. OOPD 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 is interested in supporting natural history studies that address unmet needs in rare diseases. To that end, and based on the criteria outlined below, FDA has identified the following areas of interest for the purpose of this FOA:
· Ability to address unmet needs pertinent to stage of product development
For example, there may already be product(s) in the pipeline where a natural history study is needed to better understand patient subtypes based on genotypic and/or phenotypic heterogeneity, and to identify/develop biomarkers and clinical outcome measures. For diseases that are less well-characterized, a natural history study will provide insight on future product development by evaluating the major functional limitations and manifestations of the disease.
· Inclusion of high quality and interpretability of the data
For rare diseases, data integrity and reliability are of particular importance since the small and geographically dispersed patient populations often require multicenter and/or international studies. Studies should have well-defined protocols with a rigorous and standardized approach to data collection, such as delineation of the study population, the data elements to be collected, how and on what schedule (if prospective) such data will be collected, utilization of common data elements, plans for minimization of bias and data sharing across sites and a statistical analysis plan.
Use of data standards
FDA has specific data standards and terminology recommendations for marketing applications. Therefore, natural history data that will be used to support a marketing application should be collected according to these data standards. As rare disease drug development may take place in multiple countries, international data standards should also be considered. The use of globally unique identifiers (GUIDs), should be considered to avoid data duplication. See the FDA’s Study Data Standards Resources web page at https://www.fda.gov/forindustry/datastandards/studydatastandards/default.htm.
· Use of existing infrastructure and resources and collaboration among stakeholders in industry, academia and patient organizations
· Inclusion of patient engagement
Patients living with a rare disease or their caregivers, have experiences and knowledge that contribute to important considerations in generating data about the natural history of a disease.
· Use of innovative and efficient approaches to expedite future development
For example, use of adaptive study design, new and/or flexible methods/techniques of data collection, modeling and simulation of data.
· Ability to exert a broad impact in advancing multiple rare diseases sharing a similar pathophysiology
· Inclusion of future plans for data dissemination and collaborative use of data
See Section VIII. Other Information for award authorities and regulations.
Grant: A support mechanism providing money, property, or both to an eligible entity to carry out an approved project or activity.
Application Types Allowed
The OER Glossary and the SF424 (R&R) Application Guide provide details on these application types.
Optional: Accepting applications that do not propose clinical trial(s) involving investigational products under 21 CFR Part 312 or 21 CFR Part 812
Funds Available and Anticipated Number of Awards
The number of awards is contingent upon FDA appropriations 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 up to three (3) additional year(s) contingent upon annual appropriations, availability of funding and satisfactory awardee performance.
See Background for definitions of types of studies (Section I.1).
Prospective Natural History Studies
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) and maximum years of support:
YR 01: $400,000
YR 02: $400,000
YR 03: $400,000
YR 04: $400,000
Retrospective Natural History Studies or Survey Studies
YR 01: $150,000
YR 02: $150,000
See Background for definitions of types of studies (Section I.1).
Award Project Period
The scope of the proposed project should determine the project period.
Prospective Natural History Studies
The maximum project period is four (4) years, however, the length of the study will depend on the nature of the study.
Retrospective Natural History Studies
The maximum project period is two (2) years, however, the length of the study 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, as 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 FOA.
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:
o Hispanic-serving Institutions
o Historically Black Colleges and Universities (HBCUs)
o Tribally Controlled Colleges and Universities (TCCUs)
o Alaska Native and Native Hawaiian Serving Institutions
o 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)
· Small Businesses
· For-Profit Organizations (Other than Small Businesses)
· 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)
· U.S. Territory or Possession
· 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 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. Failure to complete registrations in advance of a due date is not a valid reason for a late submission.
· Dun and Bradstreet Universal Numbering System (DUNS) - All registrations require that applicants be issued a DUNS number. After obtaining a DUNS number, applicants can begin both SAM and eRA Commons registrations. The same DUNS number must be used for all registrations, as well as on the grant application.
· System for Award Management (SAM)– Applicants must complete and maintain an active registration, which requires renewal at least annually. The renewal process may require as much time as the initial registration. SAM registration includes the assignment of a Commercial and Government Entity (CAGE) Code for domestic organizations which have not already been assigned a CAGE Code.
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.
· eRA Commons - Applicants must have an active DUNS number to register in eRA Commons. Organizations can register with the eRA Commons as they are working through their SAM or Grants.gov registration, but all registrations must be in place by time of submission. eRA Commons requires organizations to identify at least one Signing Official (SO) and at least one Program Director/Principal Investigator (PD/PI) account in order to submit an application.
· Grants.gov – Applicants must have an active DUNS number and SAM registration in order to complete the Grants.gov registration.
Program Directors/Principal Investigators (PD(s)/PI(s))
All PD(s)/PI(s) must have an eRA Commons account. PD(s)/PI(s) should work with their organizational officials to either create a new account or to affiliate their existing account with the applicant organization in eRA Commons. If the PD/PI is also the organizational Signing Official, they must have two distinct eRA Commons accounts, one for each role. Obtaining an eRA Commons account can take up to 2 weeks.
Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) is invited to work with his/her organization to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for 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.
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.
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).
Involving a Single Institution
When all PDs/PIs are within a single institution, follow the instructions contained in the SF424 (R&R) Application Guide.
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 FOA 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. 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 funding opportunity announcement to do otherwise. Conformance to the requirements in the Application Guide is required and strictly enforced. Applications that are out of compliance with these instructions may be delayed or not accepted for review.
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 study
· Name(s), email address(es), and telephone number(s) of the PD(s)/PI(s)
· Names of other key personnel
·&nnbsp; 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 FOA Number and the Institution's Name in the message subject heading to:
Grants Management Specialist
Director, Orphan Products Grants Program
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 for the main proposal.
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 following section supplements the instructions found in the SF424 (R&R) Application Guide and should be used for preparing an application to this FOA.
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:
2. Study Design/Data Quality and Interpretability
3. Inclusion of Patient Input
5. Infrastructure and Financial Resources
6. Ability to Advance the Current Field
The Rationale Section of the Research Strategy should also include a subsection with the specific heading “Rare Disease Prevalence.” This subsection should include documentation to support that the estimated prevalence of the orphan disease or condition in the United States is less than 200,000 (or in the case of a potential vaccine or diagnostic, information to support that the product will be administered to fewer than 200,000 people in the United States per year). 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 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 disease or multiple rare diseases with similar pathophysiology, and meet data standards to inform rare disease 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 in collaboration with multiple sponsors should be provided in the grant application.
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, the 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 OOPD 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.
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 protocol adherence, data integrity and interim data monitoring, as applicable. This section will detail who is to be responsible for monitoring, what data will be monitored (i.e., performance and safety data), the timing of the first data review (e.g., "the first interim look will occur when the initial 20 participants have completed the 6 month follow-up visit"), and the frequency of interim reviews (which will depend on such factors as the study design, study related procedures and anticipated recruitment rate). The plan will specify "stopping guidelines" and other criteria for the monitors to follow in their review of the interim data. 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 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.
Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the SF424 (R&R) Application Guide, with the following modification:
· All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan.
Do not use the Appendix to circumvent page limits. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide with the following additional requirements:
The Appendices should include the following, as appropriate for the proposed study:
· Protocol: The full final protocol must be provided in an appendix section.
· Informed Consent: Consent forms, assent forms, and any other information given to a subject must be providedThe applicant is referred to HHS and FDA regulations at 45 CFR 46.116 and 21 CFR 50.25 for details regarding the required elements of informed consent.
· Summary Statement: Resubmissions must provide the previous OOPD Summary Statement in an appendix section and should include a point by point rebuttal to those critiques.
When involving FDA-defined 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 described throughout the SF424 (R&R) Application Guide.
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.
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.
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.
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). Applicants are advised to visit the OHRP Web site at http://www.hhs.gov/ohrp 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 (http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html).
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 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 https://www.fda.gov/science-research/science-and-research-special-topics/clinical-trials-and-human-subject-protection. .
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. For assistance with application submission, contact the Application Submission Contacts in Section VII.
All PD(s)/PI(s) must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile Component of the SF424(R&R) Application Package. Failure to register in the Commons and to include a valid PD/PI Commons ID in the credential field will prevent the successful submission of an electronic application to FDA. See Section III of this FOA for information on registration requirements.
The applicant organization must ensure that the DUNS number it provides on the application is the same number used in the organization’s profile in the eRA Commons and for the System for Award Management. Additional information may be found in the SF424 (R&R) Application Guide.
See more tips for avoiding common errors.
Upon receipt, applications will be evaluated for completeness and compliance with application instructions by the 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.
In unusual circumstances, additional information may be considered, on a case by case basis, for
inclusion in the objective expert panel review, however, the FDA cannot assure inclusion of any
information after the receipt date other than evidence of final IRB approval, and FWA or assurance.
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 an observational/non-interventional natural history study for rare diseases or conditions. These natural history studies can be either prospective or retrospective.
2. The Rationale Section of the Research Strategy section of the application must contain information documenting that the disease or condition to be treated meets the definition of a rare disease or condition, fewer than 200,000 people in the US, as defined in 21 U.S.C. 360ee. Prevalence calculations should be provided along with citations. For studies proposing to assess multiple rare diseases, supportive prevalence data for each rare disease is required.
3. The Rationale Section of the Research Strategy section of the application must 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 disease or multiple rare diseases with similar pathophysiology, and meet data standards to inform rare disease product development.
4. The requested time must not exceed 4 years for a prospective study or 2 years for a retrospective study.
5. Appropriate documentation is needed including the protocol and informed consent form. These should be submitted as appendices to the application. Letters of support regarding study sites and patient engagement are also required.
6. 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.
7. 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 experts in rare diseases/natural history 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 product approval. 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 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 disease(s) and the likelihood the proposal will facilitate medical product development to address an unmet medical need in rare disease(s) or provide highly significant improvements in treatment or diagnosis and assist or substantially contribute to market approval of product(s).
· Description of the state of existing knowledge, including literature citations and highlights of relevant preliminary studies, subgroups, existing natural history studies/data, standard of care, treatment options and relevant completed or ongoing studies.
· Explanation of the importance of knowledge gap(s) and critical barrier(s) to progress in the field such as lack of treatments that the proposed project will address.
· Explanation of how the proposed study will provide essential data needed 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 disease product development and make a broad impact in rare diseases in general.
· Description of the study including a clear rationale, study aims, study design, and data elements to be collected including how potential sources of bias will be minimized to maintain reliability/reproducibility and how quality data will be collected, analyzed, and interpreted.
· Description of methods to be used such as disease definition and disease criteria for entry into the study and justification, standard background care (e.g., concomitant medications, dietary therapy, assistive devices, supportive therapies), methods to be used for defining the natural history, procedures of measurement, sample collection and schedule of data collection.
· Discussion of challenges, potential problems, alternative strategies, and benchmarks for success anticipated to achieve the aims within a stated timeframe.
· Description and explanation of the use of innovative and efficient approaches, such as adaptive study design, new and/or flexible methods/techniques of data collection, modeling and simulation of data, common data elements and data extrapolation among rare diseases with similar pathophysiology, and collaborative means for data and resource sharing).
· Description of the statistical analysis plan for each specific aim and methods in adequate detail.
· Description of plans for complying with human subjects protection and study monitoring.
· Description of how data will be collected according to FDA standards for marketing applications and compliance to good clinical practice as applicable.
3. Inclusion of Patient Input:
The inclusion of patient and caregiver perspectives in the planning of the study to improve protocol design and medical product development through understanding of disease and treatment burden, impact on daily living, and potential issues with study feasibility.
· 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.
The qualifications of the Principal Investigator(s) (PIs), collaborators, and other support staff.
· 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. A study team member with expertise (e.g., statistical and epidemiologic training) in the design, conduct and analysis of long-term cohort studies should be included as appropriate.
· If applicable, description of the rationale, leadership approach, governance, and organizational structure for a multi-PD/PI project.
The probability of success of the proposed project given the environment in which the work will be done.
· Description of evidence of the ability of the applicant to implement the study when funded, recruit patients and complete the proposed study within its budget and within stated time limits with the infrastructure in place. A detailed timeline for implementation of the project should be provided.
· Description of evidence 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.
5B. Financial Resources:
· 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.
· Description of sustainability plans for acquiring additional funding, including plans for leveraging FDA funding for additional resources needed for continuing the proposed study and/or for further phases of development beyond 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 address unmet needs and exert a sustained, powerful influence in the field. Considerations include studies that have the potential to exert a broad impact in advancing multiple rare diseases sharing a similar pathophysiology.
· Explanation of how the innovative approaches to be developed or used would contribute to medical product development for the rare disease(s).
· Description of plans for sharing/dissemination of data to benefit rare disease community and inform medical product development, including a publication strategy and adherence to any relevant criteria for reporting.
· Explanation of sustainability plans beyond the proposed funding period, including a description of plans for leveraging data 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 providing and 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.
When the proposed project involves human subjects and/or FDA-defined clinical research, the committee will evaluate the proposed plans for the inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion (or exclusion) of individuals of all ages (including children and older adults) to determine if it is justified in terms of the scientific goals and research strategy proposed. For additional information on review of the Inclusion section, please refer to the Guidelines for the Review of Inclusion in Clinical Research.
Reviewers will assess whether materials or procedures proposed are potentially hazardous to research personnel and/or the environment, and if needed, determine whether adequate protection is proposed.
For Resubmissions, the committee will evaluate the application as now presented, taking into consideration the responses to comments from the previous objective review group and changes made to the project. Resubmission applications must include an Introduction addressing the previous objective review critique (Summary Statement). The Summary Statement issued from OOPD must also be included as an Appendix in the resubmission application.
As applicable for the project proposed, reviewers will consider each of the following items, but will not give scores for these items, and should not consider them in providing an overall impact score.
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 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).
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 Objective Review Committee using the stated review criteria.
As part of the objective review, all responsive applications:
· Will receive a written critique.
Appeals of objective review will not be accepted for applications submitted in response to this FOA.
Applications will compete for available funds with all other recommended applications submitted in response to this FOA. 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.
· Ability to start study.
· 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 grantee’s business official.
Awardees must comply with any funding restrictions described in Section IV.5. Funding Restrictions. Selection of an application for award is not an authorization to begin performance. Any costs incurred before receipt of the NoA are at the recipient's risk. These costs may be reimbursed only to the extent considered allowable pre-award costs.
Any application awarded in response to this FOA will be subject to terms and conditions found in the HHS Grants Policy Statement, this FOA, and Notice of Award.
All FDA grant and cooperative agreement awards include the HHS Grants Policy Statement as part of the NoA.
Recipients of federal financial assistance (FFA) from HHS must administer their programs in compliance with federal civil rights law that prohibit discrimination on the basis of race, color,
national origin, disability, age and, in some circumstances, religion, conscience, and sex. This
includes ensuring programs are accessible to persons with limited English proficiency. The HHS Office for Civil Rights provides guidance on complying with civil rights laws enforced by HHS. Please see
https://www.hhs.gov/civil-rights/for-providers/provider-obligations/index.html and http://www.hhs.gov/ocr/civilrights/understanding/section1557/index.html.
HHS recognizes that research projects are often limited in scope for many reasons that are nondiscriminatory, such as the principal investigator’s scientific interest, funding limitations, recruitment requirements, and other considerations. Thus, criteria in research protocols that target or exclude certain populations are warranted where nondiscriminatory justifications establish that such criteria are appropriate with respect to the health or safety of the subjects, the scientific study design, or the purpose of the research. For additional guidance regarding how the provisions apply to FDA grant programs, please contact the Scientific/Research Contact that is identified in Section VII under Agency Contacts of this FOA.
· Recipients of FFA must ensure that their programs are accessible to persons with limited English proficiency. HHS provides guidance to recipients of FFA on meeting their legal obligation to take reasonable steps to provide meaningful access to their programs by persons with limited English proficiency. Please see https://www.hhs.gov/civil-rights/for-individuals/special-topics/limited-english-proficiency/fact-sheet-guidance/index.html and https://www.lep.gov. For further guidance on providing culturally and linguistically appropriate services, recipients should review the National Standards for Culturally and Linguistically Appropriate Services in Health and Health Care at https://minorityhealth.hhs.gov/omh/browse.aspx?lvl=2&lvlid=53.
· Recipients of FFA also have specific legal obligations for serving qualified individuals with disabilities. Please see http://www.hhs.gov/ocr/civilrights/understanding/disability/index.html.
· HHS funded health and education programs must be administered in an environment free of sexual harassment. Please see https://www.hhs.gov/civil-rights/for-individuals/sex-discrimination/index.html; https://www2.ed.gov/about/offices/list/ocr/docs/shguide.html; and https://www.eeoc.gov/eeoc/publications/upload/fs-sex.pdf.
· Recipients of FFA must also administer their programs in compliance with applicable federal religious nondiscrimination laws and applicable federal conscience protection and associated anti-discrimination laws. Collectively, these laws prohibit exclusion, adverse treatment, coercion, or other discrimination against persons or entities on the basis of their consciences, religious beliefs, or moral convictions. Please see https://www.hhs.gov/conscience/conscience-protections/index.html and https://www.hhs.gov/conscience/religious-freedom/index.html.
Please contact the HHS Office for Civil Rights for more information about obligations and prohibitions under federal civil rights laws at https://www.hhs.gov/ocr/about-us/contact-us/index.html or call 1-800-368-1019 or TDD 1-800-537-7697.
In accordance with the statutory provisions contained in Section 872 of the Duncan Hunter National Defense Authorization Act of Fiscal Year 2009 (Public Law 110-417), 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 “Federal awarding agency review of risk posed by applicants.” This provision will apply to all FDA grants and cooperative agreements.
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 peer-reviewed scientific publication resulting from research supported in whole or in part with FDA funds to the NIH National Library of Medicine's (NLM) PubMed Central (PMC). 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.
Additional terms and conditions regarding FDA regulatory and OOPD programmatic requirements may be part of the Notice of Award.
All FDA grants require both Financial and Performance reporting.
A. Cash Transaction Reports
The Federal Financial Report (FFR) has a dedicated section to report Federal cash receipts and disbursements. For recipients, this information must be submitted quarterly directly to the Payment Management System (PMS) using the web-based tool. Quarterly reports are due 30 days following the end of each calendar quarter. The reporting period for this report continues to be based on the calendar quarter. Questions concerning the requirements for this quarterly financial report should be directed to the PMS.
B. Financial Expenditure Reports
A required Federal Financial Report (FFR) must be submitted annually. All annual FFRs must be submitted electronically using the Federal Financial Report (FFR) system located in the eRA Commons. 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.
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.
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.
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:
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 AuditResolution@hhs.gov 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
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 Federal Financial Report SF-425, 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 90 days after the expiration date of the project period. All closeout documents must be submitted electronically in eRA Commons.
The Final FFR must 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 reported on the grantee's report to the Payment Management System and the charge advances in PMS. It is the recipient's responsibility to reconcile reports submitted to PMS and to the FDA.
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.
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.
When multiple years are involved, awardees will be required to submit the Research Performance Progress Report (RPPR) annually and financial statements as required in the Notice of Award.
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.
The Federal Funding Accountability and Transparency Act of 2006 (Transparency Act), includes a requirement for awardees of Federal grants to report information about first-tier subawards and executive compensation under Federal assistance awards issued in FY2011 or later. All awardees of applicable 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 $25,000.
In accordance with the regulatory requirements provided at 45 CFR 75.113 and Appendix XII to 45 CFR Part 75, recipients that have currently active Federal grants, cooperative agreements, and procurement contracts from all Federal awarding agencies with a cumulative total value greater than $10,000,000 for any period of time during the period of performance of a Federal award, must report and maintain the currency of information reported in the System for Award Management (SAM) about civil, criminal, and administrative proceedings in connection with the award or performance of a Federal award that reached final disposition within the most recent five-year period. The recipient must also make semiannual disclosures regarding such proceedings. Proceedings information will be made publicly available in the designated integrity and performance system (currently FAPIIS). This is a statutory requirement under section 872 of Public Law 110-417, as amended (41 U.S.C. 2313). As required by section 3010 of Public Law 111-212, all information posted in the designated integrity and performance system on or after April 15, 2011, except past performance reviews required for Federal procurement contracts, will be publicly available. Full reporting requirements and procedures are found in Appendix XII to 45 CFR Part 75 – Award Term and Conditions for Recipient Integrity and Performance Matters.
The guidelines below are intended to provide information for principal investigators who are conducting clinical studies. 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.
It is an OOPD policy that data and safety monitoring of a natural history study is to be commensurate with the risks posed to study participants and with the size and complexity of the study. Risks imposed by natural history studies include mainly privacy issues and adverse events associated with invasive clinical procedures. The OOPD requires that a Grantee and any third party engaged in supporting the clinical research be responsible for oversight of data and safety monitoring, ensuring 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.
The program official will oversee grantees' activities periodically. The oversight may be in the form of telephone conversations, e-mails, or written correspondence between the program official/grants management officer or specialist and the principal investigator. Information including, but not limited to, information regarding study progress, enrollment, problems, changes in protocol, study oversight 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. To ensure that funded studies support the long-term goal of product approval, regulatory milestone meetings will be initiated as needed. OOPD may request information related to the impact of this study on future approvals/product development such as publications, data sharing, and data/financial leveraging. The results of these oversight 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. Also, the grantee organization must 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 project officer. The scope of the recommendations will consider the following: (1) progress toward enrollment, based on specific circumstances of the study; and (2) compliance with applicable FDA and HHS regulatory requirements for the natural history study.
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 registration, submitting and tracking an application, documenting system problems that threaten submission by the due date, post submission issues)
Finding Help Online: http://grants.nih.gov/support/ (preferred method of contact)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)
Customer Support (Questions regarding Grants.gov registration and Workspace)
Contact Center Telephone: 800-518-4726
Director, Orphan Products Grants Program
Office of Orphan Products Development
Food and Drug Administration
10903 New Hampshire Avenue
Silver Spring, MD 20993-0002
Office of Acquisitions & Grants Services (OAGS)
Food and Drug Administration
Office of Acquisitions & Grants Services (OAGS)
Food and Drug Administration
All awards are subject to the terms and conditions, cost principles, and other considerations described in the HHS Grants Policy Statement.
Awards are made under the authorization of Section 301 of the Public Health Service Act as amended (42 USC 241) and under Federal Regulations 42 CFR Part 52 and 45 CFR Part 75 and 92. 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, or 360e) or safety, purity, and potency for licensing under section 351 of the Public Health Service Act (the PHS Act) (42 U.S.C. 262), section 351 of the PHS Act, including regulations issued under any of these sections. The 21st Century Cures Act [Pub. L. No. 114-255] specifically authorized the FDA to fund prospectively planned and designed observational studies and other analyses conducted to assist in the understanding of the natural history of a rare disease or condition and in the development of a therapy.
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.
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