It is critical that applicants follow the 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. Rare diseases, as generally defined in the US Orphan Drug Act (ODA), are diseases or conditions with a prevalence of fewer than 200,000 persons in the US. Approximately 30 million Americans are affected by 7,000 known rare diseases but only a few hundred of these rare diseases have approved treatments. Unlike common diseases, there is little existing knowledge on the presentation, major limitations on day-to-day function, core unmet needs, and course of most rare diseases which makes drug development challenging. To address this, it is critical to study the natural history of rare diseases.

The natural history of a disease is traditionally defined as the natural course of a disease from the time immediately prior to its inception, progressing through its pre-symptomatic phase and different clinical stages to the point where the disease has ended without external intervention. A natural history study describes the course of a disease over time, identifying demographic, genetic, environmental, and other variables that correlate with its development and outcomes. These studies are likely to include patients receiving the current standard of care (e.g., supportive care, unapproved treatment options), which may alter some otherwise natural manifestations or course of the disease.

In a prospective study, data are generated after study initiation. Prospective studies allow implementation of predefined and consistent data collection, utilization of up-to-date medical terminology and standard of care, and the flexibility to collect additional data as the study evolves. However, prospective studies can be resource intensive and time consuming. The outcome of a prospective study hinges on the study design which is dictated by the existing knowledge of the rare disease at study initiation. In a retrospective study, data have already been generated prior to study initiation. Retrospective studies are most commonly reviews of existing medical records. The advantage of retrospective studies is to allow collection of natural history information in a relatively short period. Limitations of retrospective studies may include inconsistent data collection, outdated or non-uniform medical terminology and outdated standard of care.

This FOA is intended to support prospective or retrospective observational/non-interventional natural history studies with a substantial potential to further current or future product development.

Natural History studies eligible for this funding opportunity will support studies that characterize the natural history of rare diseases/conditions with the goal of providing data by innovative means to facilitate medical product development for patients living with rare diseases where unmet needs exist. Therefore, natural history studies at various stages of product development and/or disease knowledge are encouraged. For example, there may already be products in the pipeline that are seeking to develop/validate biomarkers or clinical outcome measures. Alternatively, where diseases are less well-characterized, there may be need to evaluate the major functional limitations and manifestations of the disease or identify genotypic and phenotypic subpopulations. Higher priority will be given to efficient natural history studies where the study has a potential to exert a broad impact in advancing multiple rare diseases sharing a similar pathophysiology.

Use of innovative models of natural history studies is highly encouraged under this FOA. Applications that propose simulations and modeling towards the study of safety and effectiveness of a product in conjunction with the natural history study will be a priority. Modeling and simulation allow for organization of diverse data sets, optimization of product dosing based on individual physiology and genetics, and 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. Innovative methods for data collection as well as data dissemination which can serve as a model for future studies is also highly encouraged.

Inclusion of patient and caregiver perspectives from the rare disease community is highly encouraged. Patients living with a rare disease or a family member who cares for them, have experiences and knowledge that can contribute to generating data about the natural progression of the disease.

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 in response to 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)

The grants are available to any foreign or domestic, public or private, for-profit or nonprofit entity (including State and local units of government).

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) (formerly CCR) 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 and SAM registration in order to complete the eRA Commons registration. Organizations can register with the eRA Commons as they are working through their SAM or Grants.gov registration. 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) Cover component. All other PDs/PIs should be listed in the Research & Related Senior/Key Person component 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 [Section 10 of the Research Plan Component in the SF424 (R&R)], 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 component. All other institutions should have their individual budgets attached separately to the Research & Related Subaward Budget Attachment(s) Form. See Section 4.8 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.

Buttons to access the online ASSIST system or to download application forms 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 instructions in the Research Instructions in the SF424 (R&R) Application Guide, including Supplemental Grant Application Instructions 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.

For information on Application Submission and Receipt, visit Frequently Asked Questions Application Guide, Electronic Submission of Grant Applications.

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

By the date(s) listed in Part 1. Overview Information, prospective applicants are asked to submit a letter of intent that includes the following information:

• Descriptive title of proposed activity
• Name(s), email address(es), and telephone number(s) of the PD(s)/PI(s)
• Names of other key personnel
• Participating institution(s)
• Number and title of this funding opportunity

The letter of intent should be sent via electronic mail as a PDF file with the 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.

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

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

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

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

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

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

• Applications requesting multiple years of support must complete and submit a separate detailed budget breakdown and narrative justification for each year of financial support requested.
• If an applicant is requesting indirect costs as part of their budget, a copy of the most recent Federal indirect cost rate or F&A agreement must be provided as part of the application submission. This agreement should be attached to the RESEARCH & RELATED Other Project Information Component as line #12 'Other Attachments'.
• If the applicant organization has never established an indirect cost rate and/or does not have a negotiated Federal indirect cost rate agreement, a de minimis indirect cost rate of 10 percent (10%) of modified total direct costs (MTDC) will be allowed. MTDC means all direct salaries and wages, applicable fringe benefits, materials and supplies, services, travel, and subaward and subcontracts up to the first $25,000 of each subaward or subcontract. MTDC excludes equipment, capital expenditures, charges for patient care, rental costs, tuition remission, scholarships and fellowships, participant support costs and the portion of each subaward and subcontract in excess of $25,000.

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.

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

1. Rationale

2. Study Design and Inclusion of Patient Input

3. Investigator(s)

4. Infrastructure and Resources

5. Ability to Advance the Current Field

Rare Disease Prevalence:

The Rationale Section of the Research Strategy should also include a further subsection with the heading Rare Disease Prevalence. This subsection should include documentation to support that the estimated prevalence of the orphan disease or condition in the United States is less than 200,000 (or in the case of a potential vaccine or diagnostic, information to support that the product will be administered to fewer than 200,000 people in the United States per year). For studies proposing assessing multiple rare diseases, supportive prevalence data for each rare disease is required.

Additional information may be required upon request, for example, regarding population estimate and rationale. This additional information may be required, in part, to assure that human clinical trials of drugs are eligible to receive funding under the 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 further subsection with the heading Support of Product Development. This subsection should include an explanation of how the proposed study will provide a broad impact in either helping support product approval or providing essential data needed for product development. If the proposal is for multiple products or multiple rare diseases, a plan as to how they intend to proceed with product development in collaboration with multiple sponsors is needed in the grant application.

Study Monitoring Plan:

The Study Design and Inclusion of Patient Input Section of the Research Strategy should include a further subsection with the heading "Study Monitoring Plan." This subsection should include a proposed plan for protocol adherence, data integrity and interim data monitoring, as applicable. This section will detail who is to be responsible for monitoring, what data will be monitored (i.e., performance and safety data), the timing of the first data review (e.g., "the first interim look will occur when the initial 20 participants have completed the 6 month follow-up visit"), and the frequency of interim reviews (which will depend on such factors as the study design, study related procedures and anticipated recruitment rate). The plan will specify "stopping guidelines" and other criteria for the monitors to follow in their review of the interim data. Guidance on these topics is available at: http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM127073.pdf

Letters of support:

Letters of support from the leader(s) of the existing clinical research institutions that will conduct the study indicating the sites that will be involved in the study, relevant resources and study infrastructure, and an estimate of the number of available eligible, relevant rare disease patients should also 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:

Do not use the Appendix to circumvent page limits. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide with the following additional instructions:

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

Protocol: The full final protocol must be provided in an appendix section.

Informed Consent: Consent forms, assent forms, and any other information given to a subject are part of the grant application and must be provided, even if in a draft form. The consent forms should be attached in an appendix section. 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.

An application that does not observe the required page limitations may be delayed or rejected in the review process. Applicants must follow the specific instructions on Appendix materials as described in the SF424 (R&R) Application Guide (See http://grants.nih.gov/grants/funding/424/index.htm).

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

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

Study Record: PHS Human Subjects and Clinical Trials Information

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

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

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

In unusual circumstances, additional information may be considered, on a case by case basis, for

inclusion in the objective expert panel review, however, the FDA cannot assure inclusion of any

information after the receipt date other than evidence of final IRB approval, and FWA or assurance.

This initiative is not subject to intergovernmental review.

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

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

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

All institutions engaged in human subject research financially supported by HHS must file an assurance of protection for human subjects with the Office of Human Research Protections (OHRP) (45 CFR part 46). Applicants are advised to visit the OHRP Web site at http://www.hhs.gov/ohrp for guidance on human subject protection issues. Federal regulations (45 CFR 46) require that applications and proposals involving human subjects must be evaluated with reference to the risks to the subjects, the adequacy of protection against these risks, the potential benefits of the research to the subjects and others, and the importance of the knowledge gained or to be gained (http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html ).

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

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

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

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 http://www.hhs.gov/ohrp/education/.

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 Applying Electronically. 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 contact the Scientific/ Research Contact at least 4 weeks prior to the application deadline. Approval for requests over $500,000 must be included as an attachment in the final submission. Applications submitted without this approval will not be reviewed.

Applicants are required to follow the instructions for post-submission materials, as described in NOT-OD-13-030.

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 notice. 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.

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

A score will be assigned to each application based on the scientific/technical review criteria. The review panel may advise the program staff about the appropriateness of the proposal to the goals of this 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. Factors taken into account will include the likelihood of the proposed project to address one or more important question(s) or knowledge gap(s) in the field, to remove a major barrier to progress in the field, to exert a significant and broad impact on the disease(s), and to inform clinical trial design and future product development for the rare disease(s).

An application does not need to be strong in all categories to be judged likely to have major scientific impact. For example, a project that by its nature is not innovative may be essential to advance a field. In addition, an application with moderate correctable weaknesses in a criterion may still receive a high overall impact score because one or more of the other review criteria are critically important to the research and have significant strengths. The relative importance of strengths and weaknesses, not simply the number of strengths and weaknesses, are considered in developing the overall impact score.

The soundness of rationale in relation to the current understanding of the rare disease(s) and the likelihood the proposal will facilitate medical product development to address an unmet medical need in a rare disease(s) or provide highly significant improvements in treatment or diagnosis and assist or substantially contribute to market approval of product(s).

• Description of the state of existing knowledge, including literature citations and highlights of relevant preliminary studies, subgroups, existing natural history studies/data, standard of care, treatment options and relevant completed or ongoing studies.
• Explanation of the importance of knowledge gap(s) and critical barrier(s) to progress in the field such as lack of treatments that the proposed project will address.
• Explanation of how the proposed study will either help support product approval or provide essential data needed for product development.

The quality and appropriateness of the study design, research methodology, data and data analyses to accomplish the specific aims of the proposed study. Patients and caregivers should be involved in the planning of the design and development of these studies. Their unique insights and experiences to provide data about the natural progression of the disease to inform rare disease medical product development programs.

• Description of the study including a clear hypothesis, study aims, and experimental design including how quality data will be collected, analyzed, and interpreted. If applicable, considerations include clear descriptions of methods to be used for diagnosing the proposed rare diseases(s) versus methods to be used for defining the natural history.
• Explanation of the use of novel designs to meet objectives more efficiently (innovative design, use of modeling/simulations, and data elements that inform product development for multiple diseases).
• Description of plans to include patient/stakeholder input in study design and data elements.
• Description of the statistical analysis plan for each specific aim and methods in adequate detail, as applicable.
• Description of plans for ensuring data quality including but not limited to standardized data entry, data access, data monitoring, and if applicable 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.

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.

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

• Description of evidence of the ability of the applicant to recruit and complete the proposed study within its budget and within stated time limits with the infrastructure in place including a timeline to implementation of the project.
• Description of evidence of institutional support, equipment, and other resources, such as with existing research networks, industry, academia and/or patient organizations and resource sharing plans as appropriate.

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

• Explanation of how the proposed study will exert a sustained, powerful influence on the research field. Considerations include studies that have the potential to exert a broad impact in advancing multiple rare diseases sharing a similar pathophysiology.
• Explanation of novel or innovative concepts or methodologies to be developed or used (e.g., modeling, simulations, development of biomarkers and/or clinical endpoints).
• Description of plans for sharing/dissemination of data following completion of study. Considerations include innovative methods for data collection as well as data dissemination which can serve as a model for future studies.
• Explanation of sustainability plans beyond the proposed funding period and for acquiring alternative/additional funding if needed.

1. Applications must propose a natural history study for rare diseases or conditions. These observational/non-interventional studies can be either prospective or retrospective.

2. The Rationale Section of the Research Strategy section of the application must contain information documenting that the disease or condition to be treated meets the definition of a rare disease or condition, fewer than 200,000 people in the US, as defined in 21 U.S.C. 360ee. Prevalence calculations should be provided along with citations. For studies proposing to assess multiple rare diseases, supportive prevalence data for each rare disease is required.

3. The Rationale Section of the Research Strategy section of the application must include an explanation of how the proposed study will either contribute to product approval or provide essential data needed for product development.

4. The requested time must not exceed 4 years for a prospective study or 2 years for a retrospective study.

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

6. Page limits, font size and margins should comply with the Application Guide, Electronic Submission of Grant Applications. (https://grants.nih.gov/grants/how-to-apply-application-guide.html).

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

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

For research that involves human subjects but does not involve one of the six 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 six categories of research that are exempt under 45 CFR Part 46, the committee will evaluate: 1) the justification for the exemption, 2) human subjects involvement and characteristics, and 3) sources of materials. For additional information on review of the Human Subjects section, please refer to the Guidelines for the Review of Human Subjects.

When the proposed project involves human subjects and/or FDA-defined clinical research, the committee will evaluate the proposed plans for the inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion (or exclusion) of children 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.

As applicable for the project proposed, reviewers will consider each of the following items, but will not give scores for these items, and should not consider them in providing an overall impact score.

Reviewers will assess whether the project presents special opportunities for furthering research programs through the use of unusual talent, resources, populations, or environmental conditions that exist in other countries and either are not readily available in the United States or augment existing U.S. resources.

Reviewers will comment on whether the following Resource Sharing Plans, or the rationale for not sharing the following types of resources, are reasonable: (1) Data Sharing Plan; (2) Sharing Model Organisms; and (3) Genomic Data Sharing Plan (GDS).

Reviewers will consider whether the budget and the requested period of support are fully justified and reasonable in relation to the proposed research.

Applications will be evaluated for scientific and technical merit by an Objective Review Committee using the stated review criteria.

As part of the objective review, all responsive applications:

• Will receive a written critique.

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

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

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

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

Recipients of federal financial assistance (FFA) from HHS must administer their programs in compliance with federal civil rights law. This means that recipients of HHS funds must ensure equal access to their programs without regard to a person’s race, color, national origin, disability, age and, in some circumstances, sex and religion. This includes ensuring your programs are accessible to persons with limited English proficiency. 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.

HHS provides general 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 http://www.hhs.gov/ocr/civilrights/resources/laws/revisedlep.html. The HHS Office for Civil Rights also provides guidance on complying with civil rights laws enforced by HHS. Please see http://www.hhs.gov/ocr/civilrights/understanding/section1557/index.html; and http://www.hhs.gov/ocr/civilrights/understanding/index.html. 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. Please contact the HHS Office for Civil Rights for more information about obligations and prohibitions under federal civil rights laws at http://www.hhs.gov/ocr/office/about/rgn-hqaddresses.html or call 1-800-368-1019 or TDD 1-800-537-7697. Also note it is an HHS Departmental goal to ensure access to quality, culturally competent care, including long-term services and supports, for vulnerable populations. 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 http://minorityhealth.hhs.gov/omh/browse.aspx?lvl=2&lvlid=53.

In accordance with the statutory provisions contained in Section 872 of the Duncan Hunter National Defense Authorization Act of Fiscal Year 2009 (Public Law 110-417), FDA awards will be subject to the Federal Awardee Performance and Integrity Information System (FAPIIS) requirements. FAPIIS requires Federal award making officials to review and consider information about an applicant in the designated integrity and performance system (currently FAPIIS) prior to making an award. An applicant, at its option, may review information in the designated integrity and performance systems accessible through FAPIIS and comment on any information about itself that a Federal agency previously entered and is currently in FAPIIS. The Federal awarding agency will consider any comments by the applicant, in addition to other information in FAPIIS, in making a judgement about the applicant’s integrity, business ethics, and record of performance under Federal awards when completing the review of risk posed by applicants as described in 45 CFR Part 75.205 Federal awarding agency review of risk posed by applicants. This provision will apply to all FDA grants and cooperative agreements.

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

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

Additional terms and conditions regarding FDA regulatory and FDA Office of Orphan Products Development 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 HHS Grants Policy Statement.

The Federal Funding Accountability and Transparency Act of 2006 (Transparency Act), includes a requirement for awardees of Federal grants to report information about first-tier subawards and executive compensation under Federal assistance awards issued in FY2011 or later. All awardees of applicable FDA grants and cooperative agreements are required to report to the Federal Subaward Reporting System (FSRS) available at www.fsrs.gov on all subawards over $25,000.

In accordance with the regulatory requirements provided at 45 CFR 75.113 and Appendix XII to 45 CFR Part 75, recipients that have currently active Federal grants, cooperative agreements, and procurement contracts from all Federal awarding agencies with a cumulative total value greater than $10,000,000 for any period of time during the period of performance of a Federal award, must report and maintain the currency of information reported in the System for Award Management (SAM) about civil, criminal, and administrative proceedings in connection with the award or performance of a Federal award that reached final disposition within the most recent five-year period. The recipient must also make semiannual disclosures regarding such proceedings. Proceedings information will be made publicly available in the designated integrity and performance system (currently FAPIIS). This is a statutory requirement under section 872 of Public Law 110-417, as amended (41 U.S.C. 2313). As required by section 3010 of Public Law 111-212, all information posted in the designated integrity and performance system on or after April 15, 2011, except past performance reviews required for Federal procurement contracts, will be publicly available. Full reporting requirements and procedures are found in Appendix XII to 45 CFR Part 75 Award Term and Conditions for Recipient Integrity and Performance Matters.

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

It is an OOPD policy that data and safety monitoring of a natural history study is to be commensurate with the risks posed to study participants and with the size and complexity of the study. Risks imposed by natural history studies include mainly privacy issues and adverse events associated with invasive clinical procedures. The OOPD requires that a Grantee and any third party engaged in supporting the clinical research be responsible for oversight of data and safety monitoring, ensuring that monitoring systems are in place, that the quality of the monitoring activity is appropriate, and that the OOPD Project Officer is informed of recommendations emanating from monitoring activities.

The program project officer will oversee grantees' activities periodically. The oversight may be in the form of telephone conversations, e-mails, or written correspondence between the project officer/grants management officer or specialist and the principal investigator. Information including, but not limited to, information regarding study progress, enrollment, problems, changes in protocol, and study oversight activities will be requested. Periodic grant evaluations (teleconference or on-site) with officials of the grantee organization may also occur. The results of these oversight activities will be recorded in the official grant file and will be available to the grantee upon request consistent with applicable disclosure statutes and with FDA disclosure regulations. Also, the grantee organization must comply with all special terms and conditions of the grant, including those which state that future funding of the study will depend on recommendations from the OOPD project officer. The scope of the recommendations will consider the following: (1) progress toward enrollment, based on specific circumstances of the study; and (2) compliance with applicable FDA and HHS regulatory requirements for the natural history study.

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

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

eRA Service Desk (Questions regarding ASSIST, eRA Commons registration, submitting and tracking an application, documenting system problems that threaten submission by the due date, post submission issues)

Finding Help Online: http://grants.nih.gov/support/ (preferred method of contact)

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

Grants.gov Customer Support (Questions regarding Grants.gov registration and submission, downloading forms and application packages)
Contact Center Telephone: 800-518-4726

Web ticketing system: https://grants-portal.psc.gov/ContactUs.aspx
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 Public Health Service Act as amended (42 USC 241) and under Federal Regulations 42 CFR Part 52 and 45 CFR Part 75 and 92. All grant awards are subject to applicable requirements for clinical investigations imposed by sections 505, 512, and 515 of the act (21 U.S.C. 355, or 360e) or safety, purity, and potency for licensing under section 351 of the Public Health Service Act (the PHS Act) (42 U.S.C. 262), section 351 of the PHS Act, including regulations issued under any of these sections. The 21st Century Cures Act [Pub. L. No. 114-255] specifically authorized the FDA to fund prospectively planned and designed observational studies and other analyses conducted to assist in the understanding of the natural history of a rare disease or condition and in the development of a therapy.

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

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