Required Application Instructions

It is critical that applicants follow the instructions in the SF424 (R&R) Application Guide, except where instructed to do otherwise. 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 natural history of a disease is 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. Natural history studies track the course of disease overtime, identifying demographic, genetic, environmental, and other variables that correlate with its development and outcomes in the absence of treatment. Thorough understanding of disease natural history is the foundation upon which a clinical development program for drugs, biologics, medical foods or medical devices is built.

Rare diseases, as defined in the US Orphan Drug Act (ODA), are diseases or conditions with a prevalence of fewer than 200,000 persons in the US. Though individually rare, together there are ~30 million Americans affected by 7,000 known rare diseases. Unlike common diseases, there is little existing knowledge on the natural history of most rare diseases, which makes natural history studies of particular importance for rare diseases product development. In January 2014, the FDA organized a Public Workshop on Complex Issues in Developing Drugs for Rare Diseases. During the workshop, the lack of natural history studies was reconfirmed by all stakeholders (patients, industry, researchers and the FDA) as one of the most common and urgent issues that hinder treatment development for rare diseases. The need for natural history studies was also emphasized in the recently published (August 17, 2015) draft FDA Guidance for Industry, Rare Diseases: Common Issues in Drug Development.

Natural History studies can be retrospective or prospective, and cross sectional or longitudinal and also include surveys.

In a retrospective study, data have already been generated prior to study initiation. Retrospective studies are most commonly reviews of medical records, such as patient charts. The advantage of retrospective studies is to allow collection of natural history information in a relatively short period of time. Limitations of retrospective studies include inconsistent data collection, outdated or non-uniform medical terminology and outdated standard of care which may alter disease natural history.

In a prospective study, data are generated after study initiation. Prospective studies allow implementation of a predefined and consistent data collection, up-to-date medical terminology and standard of care and the flexibility to collect additional data as the study evolves. However, prospective studies are resource intensive and can be lengthy. 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.

A cross-sectional study captures an overview of the disease course by evaluating patients at different stages of disease progression at a short, defined time period (i.e., one time point).

A longitudinal study follows a cohort of patients and describes disease progression over time, measured at more than one point in time.

A survey study collects and analyzes natural history data through questionnaires answered by patients, primary caregivers, and/or others. Survey studies typically do not involve clinical visits and provide a quick overview of the disease population. However, quality and accuracy of data may vary largely in survey studies.

Each type of natural history study has its own value and limitations. The application of natural history studies depends on the specific rare disease setting, particularly on existing knowledge and available treatments. For rare diseases with little existing knowledge, retrospective review of available cases or survey studies may be the first steps toward understanding disease natural history and to generate hypotheses for subsequent prospective studies. For rare diseases with some existing natural history knowledge, prospective natural history studies may best assist in drug development and identification of treatment options by formulating a sensitive clinical outcome measure, identifying subpopulations or developing biomarkers. For the small group of well-characterized rare diseases with approved treatments or improved standard of care, prospective studies can define the altered disease natural history under the current medical setting; thereby, providing reference for development of a more effective or safer treatment. Application and value of a natural history study also hinges on study design, protocol adherence and data quality. For rare diseases, data interpretability and consistency are of particular importance since the small and geographically dispersed patient populations often require multicenter and/or international studies. A standardized approach to data collection, i.e. utilization of common data elements, provides assurance of data quality and potentially broad applications of natural history studies. FDA recommends that applicants evaluate and use existing natural history resources, e.g., standardized tools, database platforms, etc., where applicable, to avoid duplication and to maximize efficient use of resources.

The objective of FDA's Orphan Products Natural History Grants Program is to support studies that characterize the natural history of rare diseases/conditions, identify genotypic and phenotypic subpopulations, and develop and/or validate clinical outcome measures, biomarkers and/or companion diagnostics. The ultimate goal of these natural history studies is to support clinical development of products for use in serious rare diseases or conditions where no current therapy exists or where the proposed product will be superior to the existing therapy. FDA provides grants for natural history studies that will either assist or substantially contribute to market approval of these products. Applicants must include in the application's Background and Significance section documentation to support that the estimated prevalence of the orphan disease or condition in the US 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 US per year), and an explanation of how the proposed study will either help support product approval or provide essential data needed for product development. Additional information may be required upon request, for example, regarding population estimate and rationale.

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:

• Hispanic-serving Institutions
• Historically Black Colleges and Universities (HBCUs)
• Tribally Controlled Colleges and Universities (TCCUs)
• Alaska Native and Native Hawaiian Serving Institutions
• 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). Federal agencies may not apply.

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.
• 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. The Project Director/Principal Investigator (PD/PI) will be solely responsible for planning, directing, and executing the proposed project.

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 grant 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 https://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 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, 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.

The FDA will not accept any application that is essentially the same as one currently pending initial objective review unless the applicant withdraws the pending application. FDA will not accept any application that is essentially the same as one already reviewed.

Applicants should apply electronically by visiting the web site www.grants.gov and following instructions under Apply for Grants. Users of grants.gov will be able to download a copy of the application package, complete it offline, and then upload and submit the application via the grants.gov web site. In order to apply electronically, the applicant must have a Data Universal Number System (DUNS) number, and register in the System for Award Management (SAM) database, in eRA Commons, and in grants.gov (further information below). A registration process with Grants.gov and eRA Commons is necessary before submission and applicants are highly encouraged to start the process at least four weeks prior to the grant submission date. PDs/PIs should work with their institutions/organizations to make sure they are registered in the eRA Commons.

Several additional separate actions are required before an applicant institution/organization can submit an electronic application, as follows:

1) Organizational/Institutional Registration in Grants.gov/Get Registered

• Your organization will need to obtain a DUNS number and register with System for Award Management (SAM) as part of the Grants.gov registration process.
• The DUNS number is a 9-digit identification number that uniquely identifies business entities.
• The SAM database is a government-wide warehouse of commercial and financial information for all organizations conducting business with the Federal Government. SAM integrates the eight current federal procurement systems and the Catalog of Federal Domestic Assistance into a single new, streamlined system. This now houses the CCR system.
• If your organization does not have a Taxpayer Identification Number (TIN) or Employer Identification Number (EIN), allow for extra time. A valid TIN or EIN is necessary for SAM registration.
• The SAM also validates the EIN against Internal Revenue Service records, a step that will take an additional one to two business days.

Direct questions regarding Grants.gov registration can be directed to:
Grants.gov Customer Support
Contact Center Phone: 800-518-4726
Email [email protected]

Registration steps, in detail, can be found at http://www07.grants.gov/applicants/organization_registration.jsp.

2) Organizational/Institutional Registration in the eRA Commons (https://commons.era.nih.gov/commons/registration/registrationInstructions.jsp)

• Direct questions regarding the Commons registration can be directed to:
  eRA Commons Help Desk
  Phone: 301-402-7469 or 866-504-9552 (Toll Free)
  Finding Help Online: https://grants.nih.gov/support/index.html
  Email [email protected]

3) Project Director/Principal Investigator (PD/PI) Registration in the eRA Commons: Refer to the eRA Commons System (COM) Users Guide.

• The individual(s) designated as PDs/PIs on the application must also be registered in the eRA Commons. In the case of multiple PDs/PIs, all PDs/PIs must be registered in the eRA Commons prior to the submission of the application.
• Each PD/PI must hold a PD/PI account in the Commons. Applicants should not share a Commons account for both an Authorized Organization Representative/Signing Official (AOR/SO) role and a PD/PI role; however, if they have both a PD/PI role and an Internet Assisted Review (IAR) role, both roles should exist under one Commons account. When multiple PDs/PIs are proposed, all PDs/PIs at the applicant organization must be affiliated with that organization. PDs/PIs located at another institution need not be affiliated with the applicant organization, but must be affiliated with their own organization to be able to access the Commons.
• This registration/affiliation must be done by the AOR/SO or their designee who is already registered in the Commons.
• Both the PD/PI(s) and AOR/SO need separate accounts in the eRA Commons since both are authorized to view the application image. Note that if a PD/PI is already registered in the eRA Commons, another registration to apply for an FDA opportunity is not necessary.

Several of the steps of the registration process could take four weeks or more. Therefore, applicants should immediately check with their business official to determine whether their organization/institution is already registered in both Grants.gov and the Commons. The FDA will accept electronic applications only from organizations that have completed all necessary registrations. Registration steps, in detail, can be found at https://commons.era.nih.gov/commons/registration/registrationInstructions.jsp.

Applicants must obtain the SF424 (R&R) application package associated with this funding opportunity using the Apply for Grant Electronically button in this FOA or following the directions provided at Grants.gov.

Please locate the current package each cycle to obtain the most up to date forms to download and submit. Forms may change between receipt dates.

It is critical that applicants follow the 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.

Special instructions for applicants who are submitting a renewal or revision
Applicants submitting a renewal or resubmission are required to enter the previous grant number into the Federal Identifier field in the SF424 (R&R) Cover Component form. Renewal and resubmission applications that do not include this number will receive an error message.

If an application for the same study was submitted in response to a previous request for application (RFA) but has not yet been funded, an application in response to this notice will be considered a request to withdraw the previous application. The applicant for a resubmitted application should address the issues presented in the summary statement from the previous review and include a copy of the summary statement itself as part of the resubmitted application. A resubmission application should be complete and stand alone from previous versions. An application that has received two prior disapprovals is not eligible for resubmission.

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.

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, with the following exceptions or additional requirements:

• For this specific FOA, the Research Strategy section is limited to 25 pages.
• See the following for page instructions: http://www.fda.gov/orphan.

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:

Page limitations of the PHS398 Research Plan component must be followed as outlined in the SF424 (R&R) Application Guide unless otherwise stated per FDA’s guidelines located at http://www.fda.gov/orphan. Although each section of the Research Plan component needs to be uploaded separately as a PDF attachment, applicants are encouraged to construct the Research Plan component as a single document, separating sections into distinct PDF attachments just before uploading the files. This approach will enable applicants to better monitor formatting requirements such as page limits. All attachments must be provided to FDA in PDF format, filenames must be included with no spaces or special characters, and a .pdf extension must be used.

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:

• Generally, Resource Sharing Plans are expected, but they are not applicable for this FOA.

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:

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.

Protocol

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

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 https://grants.nih.gov/grants/funding/424/index.htm).

When conducting clinical research, follow all instructions for completing PHS Inclusion Enrollment Report as described in the SF424 (R&R) Application Guide.

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 with the following additional instructions:

Applications from foreign organizations must:

• Request budgets in U.S. dollars.
• Prepare detailed budgets for all applications (that is, complete the Research & Related Budget component of the SF424).
• Not seek charge back of customs and import fees.
• Make every effort to comply with the format specifications, which are based upon a standard U.S. paper size of 8.5 x 11 within each PDF.
• Comply with Federal/FDA policies on human subjects, animals, and biohazards.
• Comply with Federal/FDA biosafety and biosecurity regulations. See Section VI.2., Administrative and National Policy Requirements.
• Indicate in the 398 Research Plan how the proposed project has specific relevance to the mission and objectives of FDA and has the potential for significantly advancing sciences in the United States.

Proposed research should provide special opportunities for furthering research programs through the use of unusual talent, resources, populations, or environmental conditions in other countries that are not readily available in the United States or that augment existing U.S. resources. The proposal must indicate how the proposed project has specific relevance to the mission and objectives of FDA and has the potential for significantly advancing sciences in the United States.

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. Once an application package has been successfully submitted through Grants.gov, any errors have been addressed, and the assembled application has been created in the eRA Commons, the PD/PI and the Authorized Organization Representative/Signing Official (AOR/SO) have two weekdays (Monday- Friday, excluding Federal holidays) to view the application image to determine if any further action is necessary.

• If everything is acceptable, no further action is necessary. The application will automatically move forward for processing after two business days, excluding Federal holidays.
• Prior to the submission deadline, the AOR/SO can Reject the assembled application and submit a changed/corrected application within the two day viewing window. This option should be used if it is determined that some part of the application was lost or did not transfer correctly during the submission process, the AOR/SO will have the option to Reject the application and submit a Changed/Corrected application. In these cases, please contact the eRA Help Desk to ensure that the issues are addressed and corrected. Once rejected, applicants should follow the instructions for correcting errors in Section 2.12 of the SF424 (R&R) Application Guide (https://grants.nih.gov/grants/funding/424/index.htm# ), including the requirement for cover letters on late applications. The Reject feature should also be used if you determine that warnings are applicable to your application and need to be addressed now. Remember, warnings do not stop further application processing. If an application submission results in warnings (but no errors), it will automatically move forward after two weekdays if no action is taken. Some warnings may need to be addressed later in the process. If the two day window falls after the submission deadline, the AOR/SO will have the option to Reject the application if, due to an eRA Commons or Grants.gov system issue, the application does not correctly reflect the submitted application package (e.g., some part of the application was lost or didn t transfer correctly during the submission process). The AOR/SO should first contact the eRA Commons Helpdesk to confirm the system error, document the issue, and determine the best course of action. FDA will not penalize the applicant for an eRA Commons or Grants.gov system issue with an eRA Commons Helpdesk ticket number.
• 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.

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.

NOTE: An on-time submission means that an application is successfully submitted to Grants.gov no later than 11:59 p.m. eastern time on the application due date.

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. FDA will not accept any application that is essentially the same as one already reviewed. However, the FDA will accept a resubmission application, but such application must include an Introduction (1 page maximum) addressing the critique from the previous review.

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 and responsiveness. Applications that are incomplete, non-compliant and/or nonresponsive will not be reviewed.

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

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 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. 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.

In their written critiques, reviewers will be asked to comment on each of the following criteria in addition to the Scientific/Technical Review Criteria outlined below, in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. Each of these criteria will be addressed and considered in assigning the overall score, and weighted as appropriate for each application. Note that an application does not need to be strong in all categories to be judged likely to have major scientific impact and thus deserve a meritorious priority score.

Investigators: Assessing the competence of the principal investigator(s) and key personnel to conduct the proposed research. This includes their academic qualifications, research experiences, productivity, and any special attributes.

Resources and Environment: Evaluating any special attributes or deficiencies relevant to the conduct of the proposed studies.

Budget: Evaluating whether all items of the requested budget are appropriate and justified.

Human Subjects and Monitoring: Evaluating possible physical, psychological, or social injury patients might experience as subjects in the proposed research. Discussing whether the rights and welfare of the individuals will be adequately protected. Assessing and reporting adverse events associated with imaging and/or invasive biomaterial collection procedures, especially those unexpected serious adverse events in the disease population. Evaluating the informed consent documents for protection of individuals and for data dissemination as well as the plan to monitor the integrity of the data collected and the compliance with the protocol.

Reviewers will consider each of the review criteria below in the determination of scientific merit giving one impact score per application.

1. The soundness of the rationale for the proposed study;

2. The quality and appropriateness of the study design, including the design of the monitoring and human subject protection plan;

3. If needed, the statistical justification for the number of patients chosen for the study, based on the proposed outcome measures, and the appropriateness of the statistical procedures for analysis of the results;

4. The adequacy of the evidence that the proposed number of eligible subjects can be recruited in the requested timeframe;

5. The qualifications of the investigator and support staff, and the resources available to them;

6. The adequacy of the justification for the request for financial support;

7. The adequacy of plans for complying with regulations for protection of human subjects and monitoring;

8. The ability of the applicant to complete the proposed study within its budget and within time limits stated in this FOA;

9. Provision of a plan to include patient/stakeholder input in study design and data elements of interest;

10. The soundness of rationale in relation to the understanding of the rare disease, description of prior and ongoing natural history studies and product development programs;

11. The adequacy of plans for ensuring data quality including but not limited to standardized data entry and compliance to good clinical practice;

12. The adequacy of plans for an interim report for prospective longitudinal studies;

13. If applicable, the adequacy for sustainability plans for study continuation beyond the proposed funding period and for acquiring alternative/additional funding if needed;

14. The adequacy for plans for data access and dissemination following completion of the study.

Eligibility requirements are as follows.

1. Applications must propose natural history studies intended to support product development.

Eligible natural history studies include, but are not limited to, those aimed to:

a. understand disease progression to identify and develop clinical outcome measures for product development;

b. understand genotypic and phenotypic variations to identify distinct subpopulations for precision medicine approaches;

c. develop and/or validate biomarkers to assist product development.

2. There must be an explanation in the Background and Significance section of how the proposed study will either contribute to a product approval or provide essential data needed for product development.

a. If the study intends to provide support to a specific product development under an active IND or IDE, the corresponding IND or IDE must be referenced.

b. An IND or IDE, however, is not required for an application to be eligible.

3. The Background and Significance 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, 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. Prevalence calculations should be provided along with citations.

4. The Background and Significance section must include the landscape of the disease including what the current treatment options and standard of care options are for this rare disease, what is being done in terms of product development currently for this rare disease, what competing natural history studies are ongoing, and how this study will progress the existing knowledge.

5. If a retrospective chart review or survey is being proposed, the scientific rationale section of the application should contain justification of why a retrospective study is proposed vs a prospective study for the rare disease and what impact this data will make on the field.

6. If a prospective study is being proposed, the study plan section must include details of a proposed interim analysis to be conducted to report on findings, progress, and need for continuing the study.

7. The requested budget must be within the limits, either $400,000 in total costs per year for up to 5 years for prospective studies, or $150,000 in total costs per year for up to 2 years for retrospective studies or survey studies.

8. The protocol and the informed consent form should be submitted in the application and included as an appendix.

9. Page limits, font size and margins should comply with the Application Guide, Electronic Submission of Grant Applications.

10. 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 grant program. 21 U.S.C. 360ee(b)(1)(A).

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

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.

For Resubmissions, the committee will evaluate the application as now presented, taking into consideration the responses to comments from the previous Objective Review Committee 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.

Applicants may submit a resubmission application, but such application must include an Introduction addressing the previous 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.

Resubmissions are intended for those applications that were previously submitted to OPD, reviewed and received a score on the application.

For Renewals, the committee will consider the progress made in the last funding period.

For Revisions, the committee will consider the appropriateness of the proposed expansion of the scope of the project. If the Revision application relates to a specific line of investigation presented in the original application that was not recommended for approval by the committee, then the committee will consider whether the responses to comments from the previous Objective Review Committee are adequate and whether substantial changes are clearly evident.

Active grants in regulatory compliance may be eligible to submit a competing supplement application. A competing supplement (also called Revision) is a request for additional funds for a current award to expand the scope of work. Competing supplements may be submitted throughout the fiscal year and will be permitted for this FOA to compete for funding. Please contact the OPD program contact for further information.

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.

Not Applicable.

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 applications:

• Will receive a written critique (Summary Statement).

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.

If the application is under consideration for funding, FDA may request information from the applicant prior to making the award.

A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant organization for successful applications. Once all administrative and programmatic issues have been resolved, 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.6. 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. 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. 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.

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.

Awardees will be required to provide

1. the final published article metadata to PubMed upon publication, and

2. the final published article to PubMed Central (PMC) within 12 months of its publication date.

Awardees should identify and submit to OOPD the PubMed Central Identification Number (PMCID) for any peer-reviewed publications associated with their grant to demonstrate compliance with the Public Access Policy. Failure to comply with the public access policy could result in withholding, suspension, or termination of funding for non-competing continuation awards or negatively influence future funding opportunities.

See the following for more information. http://www.fda.gov/ScienceResearch/AboutScienceResearchatFDA/ucm433459.htm

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 progress report, invention statement, and the expenditure data portion of the Federal Financial Report are required for closeout of an award (including when an award is relinquished, when a recipient changes institutions, or when an award is terminated), as described in the HHS Grants Policy Statement.

Also, 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.

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 OPD 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 OPD 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 OPD Project Officer is informed of recommendations emanating from monitoring activities.

Preliminary monitoring details including protocol adherence and data integrity should be submitted as part of the Research Plan portion of the grant application. OPD staff will ensure that any concerns with monitoring are resolved before the grant award is made.

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 site visits 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 OPD 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 or assurance) 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. In addition, if a grant is awarded, grantees will be informed of any additional documentation that should be submitted to FDA's IRB.

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: https://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 CenterTelephone: 800-518-4726
Email: [email protected]

Katherine Needleman
Food and Drug Administration (FDA)
10903 New Hampshire Avenue
WO32-5295
Silver Spring, MD 20993-0002
Telephone: 301-796-8660
Email: [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 PHS Act as amended (42 U.S.C. 241) and under applicable regulations at 42 CFR Part 52 and 45 CFR Parts 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.

This program is not subject to the intergovernmental review requirements of Executive Order 12372. FDA's research program is described in the Catalog of Federal Domestic Assistance (CFDA), No. 93.103 http://www.cfda.gov/.

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.

All awards will be subject to all policies and requirements that govern the research grant programs of the PHS as incorporated in the HHS Grants Policy Statement.