See RFA for upcoming receipt dates.

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 submission due date.

A Letter of Intent is not required, is non-binding, and does not enter into the review of a subsequent application. However, 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.
Prospective applicants are asked to submit the letter of intent with information contained in the RFA by 11:59 PM Eastern Time at least 30 days before the application submission deadline.

The grants are available to any foreign or domestic, public or private, for-profit or nonprofit entity (including state and local units of government). Federal agencies may not apply.

Of the estimated FY funding of approximately $15 million, approximately $10 million will fund noncompeting continuation awards, and approximately $5 million will fund new awards, subject to availability of funds. Application budgets are not limited but need to reflect the actual needs of the proposed project.

Application budgets need to reflect the actual needs of the proposed project including both direct and indirect costs).

Applicants requesting $500,000 or more in direct costs in any year (independent of the optional Innovative Demonstration Project) 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. 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 attachment in the final grant application. Applications submitted without this approval will not be reviewed. Final budget determinations will be made during the grant review.

Note: 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. For the optional Innovative Demonstration Project Funding, the maximum amount requested shall not exceed $500,000 total costs per year. As with the overall application, it is expected that the time and scope of the project is reflected in the budget request and will be reviewed annually by the program.

The scope of the proposed project should determine the project period. The maximum project period is 4 years. However, the length of support will depend on the nature of the study.

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

Products that qualify for this grant program are drugs, biologics, medical devices, and foods for medical purposes that are indicated (used) for a disease or condition that affects fewer than 200,000 people in the United States. Diagnostics and vaccines will qualify for the program only if the United States population to whom they will be administered is fewer than 200,000 people 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.

No. A drug or biologic product does NOT have to hold orphan drug designation to be eligible for the grant program. The Background and Significance section of the application must contain information documenting the prevalence, not incidence, of the population to be served by the product is fewer than 200,000 individuals in the United States. The applicant should include a detailed explanation supplemented by authoritative references in support of the prevalence figure. However, if the prevalence calculations submitted in the application were not adequate and OOPD has questions that aren’t easily resolved during the initial review of the application, OOPD may recommend an official Orphan Drug Designation application to resolve the issues prior to review of the grant application.

Diagnostic tests and vaccines will qualify only if the population to whom they will be administered is fewer than 200,000 individuals in the United States per year. The orphan drug designation process is the mechanism by which sponsors of drugs and biologics for rare diseases may qualify for incentives of the Orphan Drug Act such as tax credits and marketing exclusivity. Orphan drug designation is encouraged, especially if there is a question as to whether the proposed disease or condition would be eligible for orphan drug status or in cases where the estimated prevalence of the population is close to 200,000.

Only well-controlled studies in support of a new indication or change in labeling of products to address unmet needs in rare diseases or conditions. Through the funding of efficient and innovative clinical studies evaluating safety and/or efficacy, FDA expects to increase the number of treatments for rare diseases with an unmet medical need and exert a broad and positive impact on rare disease drug development.

Use of innovative efficient trial designs is encouraged under the funding opportunity announcement. For example, 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. Early stages of product development can also hold significant promise for the advancement of curative treatments for rare diseases. Consideration should also be given to the use of real world data, which has the potential to allow for more efficient design and conduct of clinical trials in the health care setting to answer questions previously though infeasible. Real world data can also, in certain cases, be analyzed to support medical product development and approval using novel analytical approaches.Use of innovative efficient trial designs is encouraged under the funding opportunity announcement. 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.

Yes, an active (e.g., non-exempt and non-hold) IND/IDE is needed, except for medical foods that do not need premarket approval and medical devices that are classified as non-significant risk (NSR). Applicants studying an NSR device should provide a letter in the application from FDA's Center for Devices and Radiological Health indicating the device is an NSR device.

The purpose of this RFA is to fund well-controlled studies in support of a new indication or change in labeling of products to address unmet needs in rare diseases or conditions. 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 above.

The same version of the protocol that is submitted with the grant application 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 grant application for review. Be sure to indicate in the IND cover letter to the review division your intent of applying for an FDA Office of Orphan Products Development Clinical Trials grant and how the study will be used for future marketing approval and product development. This will allow the review division to assess the IND. To qualify for programmatic/scientific review, the study protocol proposed in the grant application must be deemed as safe to proceed under an active IND or IDE (i.e., not on clinical hold and not exempt).

No. The clinical protocol that is being submitted in the grant application for the product for the disease/condition being studied through the proposed trial must be submitted to the appropriate FDA review division a minimum of 30 days before the grant application deadline.

If you are not the sponsor on the IND/IDE, then you must have a formal collaborative agreement with the company or individual who is the official sponsor of the IND and should include documentation of such a relationship in your grant application.

Yes. The grants are available to any foreign or domestic, public or private, for-profit or nonprofit entity (including State and local units of government).
Foreign applications must indicate how the proposed project has specific relevance to the mission and objectives of FDA and has the potential for significantly advancing science in the United States.

Yes. 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 for guidance on human subject protection issues. Federal regulations (45 CFR 46) require that applications and proposals involving human subjects must be evaluated with reference to the risks to the subjects, the adequacy of protection against these risks, the potential benefits of the research to the subjects and others, and the importance of the knowledge gained or to be gained.

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

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

The clinical protocol should comply with 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. Responsibilities of Sponsor-Investigators can also be found in the online presentation which provides awareness to sponsors and investigators of important responsibilities to adequately conduct clinical trials. For further information, applicants should review the section on human subjects in the application instructions of the Request for Applications (RFA).

No. IRB approval is not required at the time of the submission of grant application. However, documentation of IRB approval for the single IRB of record must be on file with the FDA grants management office before an award to fund the study will be made.

Yes. The protocol should be submitted in the application as an appendix. Informed consent and assent forms should be provided as an appendix as well.

All applications must be submitted electronically through Grants.gov. The applications must be prepared using the SF424 (R&R) application forms along with the SF424 (R&R) Application Guide for this funding opportunity as well as any program-specific instructions. Please see the current RFA for receipt dates and information on how to apply.

The earliest submission date for the RFA is 60 days prior to the application submission deadline. A letter of intent is due (not required) a minimum of 30 days prior to the application due date. 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 funding opportunity.

>FDA grants management and program staff will review all applications. To be responsive, an application must be submitted in accordance with the requirements of the Request for Applications (RFA). Applications found to be non-responsive will be returned to the applicant without further consideration. Responsive applications will be peer reviewed and evaluated for scientific and technical merit by a panel of experts in the subject field of the specific application. Consultation with the relevant FDA review division 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. 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 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 as described in the RFA.

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

In addition, reviewers will evaluate the following additional items while determining scientific and technical merit:

• Budget and Period of Support
• Protections for Human Subject
• Inclusion of Women, Minorities, and Children
• Resource Sharing Plan
• Foreign Organizations
• Biohazards

See the RFA for further information.

Applicants will usually be notified of the review results via a summary statement approximately 6 months from the application deadline.

Once the grant applications are reviewed and scored by the ad hoc panel of experts, a cut-off score for funding will be established. Those applications within the anticipated fundable range will be ranked in order of their score with the earliest possible funding start date as specified in the RFA based on availability of funds.

All responsive applications will be issued scores and summary statements following the review of the applications. If your grant application received a favorable/competitive score you will be sent a cover memo and a Pre-Funding Certification Form (PCF) along with a copy of the Summary Statement. You will be required to complete and return the PCF and accompanying information (including your responses to the Summary Statement critiques, the current IRB approval letter, Federal Wide Assurance documentation and verification of product availability) by the date specified in the cover memo. This is not a guarantee that you will receive funding.

If you receive grant funding, you will receive a formal Notice of Grant Award. Your grant will be assigned an OOPD grant Project Officer (PO) who will be your main contact. You will be required to keep the PO informed throughout the grant of any issues and changes including request for approval of protocol changes by OOPD and the appropriate FDA Review Division under which the IND or IDE for the study is held, adverse events, changes in key study personnel, etc. If you have any questions or concerns about the grant or the study, you may contact the PO for assistance. Additionally, if you experience any difficulties in patient enrollment, OOPD may be able to assist or suggest options.

You will receive a congratulatory letter from the PO outlining your roles, responsibilities, and requirements as a grantee. You will be required to follow and be in compliance with Good Clinical Practices and Current Good Manufacturing Practices. You will be required to maintain regulatory requirements such as IRB approvals, up to date FWA, IND requirements including submission of IND annual reports and appropriate adverse event reporting, up to date clinicaltrials.gov information (for applicable or voluntarily registered trials), etc.

The program project officer will oversee grantees' activities periodically through telephone conversations, e-mails, or written correspondences. To assist in monitoring your grant, your PO will establish enrollment and progress goals for each funding year with you upon initial funding. You will also be required to submit Quarterly Reports and Annual Reports to OOPD to update OOPD on information such as study progress, enrollment, problems, changes in protocol, and study oversight activities. There will be at least one grant evaluation (teleconference or on-site) with officials of the grantee organization during the lifetime of your grant to ensure extramural funded studies, which involve human subjects, are consistent with grant agreement terms and human subjects’ protection requirements. To ensure that funded studies support the long-term goal of product approval, regulatory milestone meetings will be initiated as needed. OOPD should be contacted before any protocol changes are made (including Key Personnel and Performance Site changes). Publication of study results is encouraged.

In addition, OOPD may hold periodic interactive webinars as part of the Orphan Grantees Unite Initiative to connect grantees and provide a forum to share useful information.

Quarterly Reports will be required typically every three months from the date the grant was issued. 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. OOPD may request information related to the impact of this study on future approvals and other outcomes such as publications or data leveraging. For “applicable clinical trials” and voluntarily registered trials, updates on the ClinicalTrials.gov entry for the study will be requested.

Research Performance Progress Report (RPPR)s are required yearly for grants more than 1 year in length. These reports will include items such as progress made, budget information, updates on any revisions made, accomplishments, future goals, publications/presentations resulting from the award, and personnel updates.

A Final Report will be due within 90 days after the end date of the project period. Items that are needed include a Final Financial Status Report, Final Invention Statement Certification, and Final Performance/Progress report.

Questions regarding financial aspects of a proposed application and a funded grant should be addressed to:

Daniel Lukash, FDA/Office of Acquisitions & Grant Service

Telephone: 240-402-7596

E-mail: Daniel Lukash

Scientific and Research questions should be addressed to: Katherine Needleman, FDA/Office of Orphan Products Development

Telephone: 301-796-8660

E-mail: Katherine Needleman

Technical questions regarding submitting through grants.gov should be submitted to:

     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)

o   Finding Help Online: https://grants.nih.gov/support/index.html

o   Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

Grants.gov Customer Support (Questions regarding Grants.gov registration and submission, downloading forms and application packages)

o   Contact Center Telephone: 800-518-4726

o   Email: [email protected]