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.

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

Section 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. The term rare disease or condition is defined in 21 U.S.C. 360ee. As a practical way to implement the statutory definition, 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, not incidence, of fewer than 200,000 people in the United States. 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 7,000 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 70 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 FOA to facilitate and move new therapies along in drug development in safe yet efficient means by encouraging innovative clinical trial designs (e.g., adaptive, basket, umbrella trials), innovative methods (e.g., data modeling and simulations), 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). These methods are vital to efficient trials and data evaluation that can expedite drug development and have the potential to make a broad and positive impact for rare diseases in general.

This FOA is intended to support clinical studies of products for rare diseases with an unmet medical need. These well-controlled studies should evaluate safety and/or efficacy of medical products in support of a new indication or a change in labeling.

Use of innovative, efficient trial designs is encouraged under this FOA. Potential examples include seamless 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. Consideration should also be given to the use of real-world data, which could be used to design and conduct more efficient clinical trials. Analysis of real-world data can also, in certain cases, support medical product development and approval using novel analytical approaches. In addition, this FOA encourages applications that propose adaptive trial designs, simulations, and modeling used 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 tools is recommended prior to submitting a grant application.

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 FOA. Additionally, patients living with a rare disease or 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 Demonstration Projects (OPTIONAL): Applicants are encouraged to submit a stand-alone innovative demonstration project proposal in addition to their application that can be used as models for future drug development in rare diseases in one of the following areas: 1) innovative collaborations; 2) innovative patient recruitment/retention strategies; or 3) innovative methods using data simulation/modeling. Please note, selected proposals for this stand-alone section will be awarded additional funds based on merit as detailed below. The Demonstration Project should be submitted as a stand alone Appendix to the Application with a maximum of 5 pages.

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

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

For-Profit Organizations

• Small Businesses
• For-Profit Organizations (Other than Small Businesses)

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)
• U.S. Territory or Possession

Other

• Independent School Districts
• Public Housing Authorities/Indian Housing Authorities
• Native American Tribal Organizations (other than Federally recognized tribal governments)
• Faith-based or Community-based Organizations
• Regional Organizations
• Non-domestic (non-U.S.) Entities (Foreign Institutions)

Non-domestic (non-U.S.) Entities (Foreign Institutions) are eligible to apply.
Non-domestic (non-U.S.) components of U.S. Organizations are eligible to apply.
Foreign components, as defined in the HHS Grants Policy Statement, are allowed.

Applicant Organizations

Applicant organizations must complete and maintain the following registrations as described in the SF 424 (R&R) Application Guide to be eligible to apply for or receive an award. All registrations must be completed prior to the application being submitted. Registration can take 6 weeks or more, so applicants should begin the registration process as soon as possible. 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.

Multiple PDs/PIs

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

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

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

Multiple PD/PI Leadership Plan

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

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

Applications Involving a Single Institution

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

Applications Involving Multiple Institutions

When multiple institutions are involved, one institution must be designated as the prime institution and funding for the other institution(s) must be requested via a 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.

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 decisions 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 the Main Proposed clinical study
• Plan to submit Optional Innovative Demonstration Project, Name(s), email address(es), and telephone number(s) of the PD(s)/PI(s)
• Names of other key personnel
• Estimated grant budget request (provide a separate main proposal total budget from optional innovative demonstration project budget)
• 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:

Dan Lukash

Grants Management Specialist

Email: [email protected]

and

Katherine Needleman

Director, Orphan Products Grants Program

Email: [email protected]

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

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

Applicants submitting an Optional Innovative Demonstration Project must provide a description of how they will address that project (limited to 5 pages maximum) and must be attached as a stand alone appendix to the application.

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.
• Applications proposing an Innovative Demonstration Project must submit a separate detailed budget and justification in addition to the main proposal budget and justification. The Innovative Demonstration Project's budget and justification must be attached as a stand alone appendix to the application.
• 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.

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

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

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

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

1. Rationale

2. Study Design

3. Inclusion of Patient Input

4. Investigator(s)

5. Infrastructure and Financial Resources

6. 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 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 vaccine or diagnostic, information to support that the product will be administered to fewer than 200,000 people in the United States 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). 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 OPD 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 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, 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 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.

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 data monitoring. This section will detail who will be responsible for monitoring (i.e., a DSMB, an SMC, or the study investigator), what data will be monitored (i.e., performance and safety data only vs. efficacy data as well), 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, interventions 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) 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 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.

Appendix:

Only limited Appendix materials are allowed. Do not use the Appendix section 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 must include the following, as appropriate for the proposed study:

• Protocol: The full final protocol (IND/IDE submitted protocol) must be provided.
• Informed Consent: Consent forms, assent forms, and any other information given to a subject must be provided. The 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 may include a point by point rebuttal to those critiques.
• Applications requesting $500,000 or more in direct costs in any year (independent of the optional Innovative Demonstration Project) must attach as an appendix, the prior approval letter from the FDA, accepting the assignment of the application. Applications submitted without this approval will not be reviewed. Final budget determinations will be made during the grant review.
• Innovative Demonstration Project (OPTIONAL):
• Applicants submitting an optional Innovative Demonstration Project (5 pages maximum) must provide a description of how they will address the criteria of that project related to one of the three goals described below (see Scoring Criteria). This section is a stand-alone section from the rest of the application and will be scored separately for potential additional funding. Should this Innovative Demonstration Project not be funded, it should not affect the design and/or feasibility of the main proposal submitted. This section must be attached as a stand alone appendix to the application.
• Applications proposing an Innovative Demonstration Project must submit a separate detailed budget and justification in addition to the main proposal budget and justification. The Innovative Demonstration Project's budget and justification must be attached as a stand alone appendix.

When involving human subjects research, clinical research, and/or clinical trials (and when applicable, clinical trials research experience) follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the SF424 (R&R) Application Guide, with the following additional instructions:

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

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 part 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 an 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 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 OPD 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.

Important reminders:

All PD(s)/PI(s) must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile Component of the SF424(R&R) Application Package. Failure to register in the Commons and to include a valid PD/PI Commons ID in the credential field will prevent the successful submission of an electronic application to 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.

Applicants requesting $500,000 or more in direct costs in any year must provide a letter of request (separate from the Letter of Intent) to the Scientific/ Research Contact at least 4 weeks prior to the application deadline. Consortium/contractual facilities and administrative (F&A) costs do not count against the direct cost limit. Estimated direct costs, consortium/contractual F&A (if any), total costs and narrative budget justification for each year of the proposed project should be provided as well as a description of any funds expected to be contributed by other sources. Upon review, adequate requests will be issued a letter from the Scientific/Research Contact accepting the assignment of the application. This letter must be included as an appendix in the final grant application. Applications submitted without this approval will not be reviewed. Final budget determinations will be made during the grant review.

Please note: this request does not include the funding requested for the Optional Innovative Project. Only submit a request of $500,000 or more in direct costs if the main proposal's budget is above this limit.

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 review, however, the FDA cannot assure inclusion of any information after the receipt date other than evidence of final IRB approval, FWA or assurance, and certification of adequate supply of study product.

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.

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

1. Applications must propose clinical trials intended to provide safety and/or efficacy data for rare diseases or conditions. Applications must use the generic name of the proposed product(s).

2. The requested time must not exceed 4 years.

3. The Rationale Section of the Research Strategy must contain information documenting that the disease or condition to be treated meets the definition of a rare disease or condition, as defined in 21 U.S.C. 360ee. FDA generally considers drugs, devices, and medical foods potentially eligible for grants under the OPD grant program if they are indicated for a disease or condition that has a prevalence, not incidence, of fewer than 200,000 people in the United States.

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.

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 United States per year. 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. If a designation by the Office of Orphan Products Development has been received by the institution submitting the grant for the drug for the disease subject to the grant, the designation number and date of designation should be provided in this section.

4. There must be an explanation in the Rationale Section of the Research Strategy of how the proposed well-controlled study will support of a new indication or change in labeling of a product(s).

5. The study protocol proposed in the grant application (including studies of already approved products evaluating new orphan indications) is subject to 21 CFR 312.2b and 21 CFR 812.2 due to the use of it to support a new indication or change in labeling, with the exception noted below. The protocol must be submitted to the applicable FDA IND/IDE review division a minimum of 30 days before the grant application deadline. The IND must be active (not on clinical hold or exempted) or the IDE must be approved to qualify the application for review.

Only medical foods that do not need pre-market approval and medical devices that are classified as non-significant risk (NSR) are free from these IND/IDE requirements. Applicants studying an NSR device should provide a letter in the application from the FDA Center for Devices and Radiologic Health indicating the device is an NSR device.

Note: The final version of the protocol submitted to OOPD in the grant application is the protocol that MUST be submitted to an IND/IDE. The IND/IDE number and the date that the protocol was submitted to that IND/IDE should be included with the title of the project on the face page of the grant application.

6. If the sponsor of the IND/IDE is other than the principal investigator listed on the application, a letter from the sponsor permitting access to the IND/IDE must be submitted in both the IND/IDE and in the grant application. The name(s) of the Principal Investigator(s) named in the application and in the study protocol must be submitted to the IND/IDE.

7. Appropriate documentation is needed including the protocol and informed consent form. These should be submitted as appendices to the application. Letters of support regarding the availability of product, study sites, and patient engagement are also required.

8. 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 and optional Innovative Demonstration Project proposals.

9. 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 human clinical trials of drugs are eligible to receive funding under the OPD 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 OPD 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 the subject field of the specific application. Consultation with the proper 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 the OPD grant program.

Reviewers will provide an overall impact score to reflect their assessment of the likelihood for the project to exert a sustained, powerful influence on the research field(s) involved, in consideration of the following review criteria and additional review criteria (as applicable for the project proposed).

Reviewers will consider each of the review criteria below in the determination of scientific merit. 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.

1. Rationale:

The soundness of rationale in relation to the current understanding of the rare disease(s) and the likelihood the proposal will facilitate a well-controlled study in support of a new indication(s) for use or change in labeling of a product(s) to address unmet needs in a rare disease(s).

• Description of the state of existing knowledge, including literature citations and highlights of relevant preliminary studies and previous preclinical and/or clinical data, including the natural history of the disease(s) in relation to the proposed safety/efficacy evaluation.
• 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 to support a new indication or a change in labeling.

2. Study Design

The quality and appropriateness of the study design, research methodology, and data analyses to accomplish the specific aims of the proposed study and its potential to make a broad impact for rare diseases in general.

• Description of the study including a clear hypothesis, study aims, and experimental design including the appropriateness of endpoints for the proposed study population and how data will be collected, analyzed, and interpreted.
• Explanation of the trial design and how it will meet the objectives efficiently (e.g., the use of basket, umbrella, platform trials, etcetera should be explicitly stated).
• Description of how the study has the potential to provide a broad and positive impact for rare diseases.
• Description of the statistical analysis plan in adequate detail to show that the power of the study and data analyses will be sufficient to detect a meaningful benefit.
• Description of plans for ensuring data quality including but not limited to standardized data collection, data entry, data access, data monitoring, data sharing, and compliance to good clinical practice.
• Description of plans for complying with human subjects' protection and study monitoring.
• Discussion of challenges, potential problems, alternative strategies, and benchmarks for success anticipated to achieve the aims within a stated timeframe.

3. Inclusion of Patient Input:

The inclusion of patient and caregiver perspectives in the planning and design of the clinical study to improve protocol design and medical product development through understanding of disease and treatment burden, impact on daily living, and potential issues with trial design feasibility.

• Description of plans to include early and ongoing patient/stakeholder input in the study (e.g., protocol design, data elements, feasibility, data sharing).

4. Investigator(s):

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.
• If applicable, description of the rationale, leadership approach, governance, and organizational structure for a multi-PD/PI project.

5. Infrastructure and Financial Resources:

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

5A. Infrastructure Resources:

• Description of evidence of the ability of the applicant to recruit and complete the proposed study within its budget and within stated time limits, including a detailed timeline for implementation of the project upon funding.
• Description of institutional support, equipment, and other resources, such as with existing research networks, industry, academia and/or patient organizations and resource sharing plans as appropriate.
• Evidence that the product(s) to be studied is available to the applicant in the form and quantity needed for the clinical trial.

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.

Explanation of sustainability plans for acquiring additional funding for further phases of development beyond the proposed funding period, including a description of plans for leveraging FDA funding for additional resources needed for the proposed trial/overall development of the product(s).

6. Ability to Advance the Current Field:

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

• Explanation of how the proposed study will exert a sustained, powerful influence on the research field.
• Explanation of novel or improved concepts, approached or methodologies, instrumentation or interventions to be developed or used, such as with pharmacokinetic, pharmacodynamic or clinical study designed (e.g. adaptive design trials, modeling, or simulations), and/or outcome measures, and their advantages over existing approaches.
• Description of plans for sharing/dissemination of data following completion of study.
• 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.

This additional add-on project proposal section will be scored separately (by the criteria below) for overall feasibility and merit and must stand on its own and be independent of the main proposal scored above. It must include a separate budget and budget justification that clearly reflects the time and scope required to complete the proposal. The time and scope of this additional project may vary depending on the proposed project. The significance of the proposed project will be evaluated in terms of how it promotes innovative, efficient product development for the proposed rare disease(s) and how it could be used as a model for FDA and others in future drug development for rare diseases.

Areas of potential projects that OOPD will consider include the following. The scored review criteria are described in the bullets in the three sections below.

If proposing an innovative demonstration project, propose only one of the following areas per application:

1) Innovative Collaborations:

Use of the project to provide for innovative collaborative approaches that may serve as a model/example for use in future drug development for the proposed rare disease(s) or other rare diseases.

• Description of the collaboration or network (e.g. stakeholders involved, clinical sites including geographic diversity, expertise) and cooperative agreements to meet the goal.
• Description of how this project is innovative and will make rare disease product development more efficient.
• Description of the how this will provide a vital tool to decrease time or costs of current or future studies.
• Description of plans to manage the collaboration, monitor progress, meet timelines, and leverage the strategy for current and future phases of development.
• Significance and impact of the project as it relates, contributes, and advances rare disease product development.

2) Innovative Patient Recruitment/Retention Strategies:

Use of the project to develop innovative patient recruitment and or retention models that may serve as a model/example for use in future drug development for the proposed rare disease(s) or other rare diseases.

• Description of the tools and strategies that will be used to meet goals, such as maximal recruitment of patients, standardized data collection, and enhancement of protocol adherence.
• Description of the how these methods are innovative and will improve patient recruitment and/or retention in studies and provide an efficient method to evaluate the limited number of patients with rare diseases.
• Description of the how this will provide a vital tool to decrease time or costs of current or future studies.
• Description of plans to monitor progress, meet timelines, and leverage the strategy for current and future phases of development.
• Significance and impact of the project as it relates, contributes, and advances rare disease product development.

3) Innovative Methods Using Data Modeling/Simulation:

Use of the project to perform innovative data simulation/modeling that may serve as a model/example for use in future drug development for the proposed rare disease(s) or other rare diseases.

• Description how these methods will be performed and how it will inform clinical trial design for this study or future studies.
• Description of how the methods are innovative and will improve the organization of diverse data sets, optimization of product dosing based on individual physiology and genetics, and/or can provide a vital tool to help evaluate new treatments in rare diseases where patient populations are inherently difficult to study because of their small size.
• Description of how this will provide a vital tool to decrease time or costs of current or future studies.
• Description of plans to monitor progress, meet timelines, and leverage the strategy for current and future phases of development.
• Significance and impact of the project as it relates, contributes, and advances rare disease product development.

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

For research that involves human subjects but does not involve one of the categories of research that are exempt under 45 CFR Part 46, the committee will evaluate the justification for involvement of human subjects and the proposed protections from research risk relating to their participation according to the following five review criteria: 1) risk to subjects, 2) adequacy of protection against risks, 3) potential benefits to the subjects and others, 4) importance of the knowledge to be gained, and 5) data and safety monitoring for clinical trials.

For research that involves human subjects and meets the criteria for one or more of the categories of research that are exempt under 45 CFR Part 46, the committee will evaluate: 1) the justification for the exemption, 2) human subjects involvement and characteristics, and 3) sources of materials. For additional information on review of the Human Subjects section, please refer to the Guidelines for the Review of Human Subjects.

Inclusion of Women, Minorities, and Individuals Across the Lifespan

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.

Resubmission applications must include an Introduction addressing the previous objective review critique (Summary Statement). The Summary Statement issued from the Office of Orphan Products Development must also be included as an Appendix in the resubmission application.

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. The adequacy of the responses to comments from the most recent scientific review group will be assessed including the appropriateness of the improvements 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) appropriate Objective Review Committee, using the stated review criteria.

As part of the objective review, all applications:

• Will receive a written critique.

Appeals of objective review will not be accepted for applications submitted in response to this 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.
• 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 laws that prohibit discrimination on the basis of race, color, national origin, disability, age and, in some circumstances, religion, conscience, and sex. This includes ensuring programs are accessible to persons with limited English proficiency. The HHS Office for Civil Rights provides guidance on complying with civil rights laws enforced by HHS. Please see https://www.hhs.gov/civil-rights/for-providers/provider-obligations/index.html and http://www.hhs.gov/ocr/civilrights/understanding/section1557/index.html.

HHS recognizes that research projects are often limited in scope for many reasons that are nondiscriminatory, such as the principal investigator’s scientific interest, funding limitations, recruitment requirements, and other considerations. Thus, criteria in research protocols that target or exclude certain populations are warranted where nondiscriminatory justifications establish that such criteria are appropriate with respect to the health or safety of the subjects, the scientific study design, or the purpose of the research. For additional guidance regarding how the provisions apply to 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, including digital data, 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. In addition, investigators seeking FDA funding, in whole or in part, via a contract, grant, or assistance agreement must have an FDA-approved Data Management Plan a plan for digital data management and sharing prior to commencing any related services or work.

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.

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).

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

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 terms and conditions of award and the HHS Grants Policy Statement.

All new and continuing grants which have referenced INDs/IDEs must comply with all regulatory requirements necessary to keep the status of their IND/IDE active and in effect, that is, not on clinical hold.

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

It is an OOPD policy that data and safety monitoring of a clinical trial is to be commensurate with the risks posed to study participants and with the size and complexity of the study. 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.

FDA Requirements for Monitoring

The OOPD requires that each clinical trial it supports, regardless of phase, has data and safety monitoring procedures in place to safeguard the well-being of study participants and to ensure scientific integrity. Monitoring must be performed on a regular basis throughout the subject accrual, treatment, and follow-up periods.

The specific approach to monitoring will depend on features of the clinical trial to be conducted e.g., several levels of monitoring: Data and Safety Monitoring Board (DSMB), Study Monitoring Committee (SMC) and Independent Medical Monitor (IMM). Monitoring activities should be appropriate to the study, study phase, population, research environment, and degree of risk involved. Guidance is available at: https://www.fda.gov/media/116754/download

The program official will monitor grantees 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, adverse events, changes in protocol, study monitoring activities, new collaborations, publications, financial and data leveraging, and changes in clinical guidelines based on the project will be requested. Periodic grant evaluations (teleconference or on-site) with officials of the grantee organization may also occur. 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 and other outcomes such as publications or data leveraging. The results of these monitoring activities will be recorded in the official grant file and will be available to the grantee upon request consistent with applicable disclosure statutes and with FDA disclosure regulations. 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 program official. The scope of the recommendations will consider the following: (1) progress toward enrollment, based on specific circumstances of the study; (2) adequate supply of the product/device; and (3) compliance with applicable FDA and HHS regulatory requirements for the trial.

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

We encourage inquiries concerning this funding opportunity and welcome the opportunity to answer questions from potential applicants.

eRA Service Desk (Questions regarding ASSIST, eRA Commons, application errors and warnings, documenting system problems that threaten submission by the due date, and post-submission issues)

Finding Help Online: http://grants.nih.gov/support/ (preferred method of contact)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

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

Katherine Needleman
Director, Orphan Products Grants Program
Office of Orphan Products Development
Food and Drug Administration
10903 New Hampshire Avenue
WO32-5295
Silver Spring, MD 20993-0002
Phone: 301-796-8660
E-mail: [email protected]

Daniel Lukash
Office of Acquisitions & Grants Services (OAGS)
Food and Drug Administration
Telephone: 240-402-7596
Email: [email protected]

Daniel Lukash
Office of Acquisitions & Grants Services (OAGS)
Food and Drug Administration
Telephone: 240-402-7596
Email: [email protected]

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), 21 U.S.C. 360ee, and under Federal Regulations 42 CFR Part 52 and 45 CFR Part 75. All grant awards are subject to applicable requirements for clinical investigations imposed by sections 505, 512, and 515 of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 355, 360b, and 360e) or safety, purity, and potency for licensing under section 351 of the Public Health Service Act (42 U.S.C. 262), including regulations issued under any of these sections. All human subject research regulated by FDA is also subject to FDA's regulations regarding the protection of human subjects (21 CFR Parts 50 and 56).