Required Application Instructions

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

This FOA invites researchers to submit applications for support of clinical projects that address critical needs for clinical trial readiness in rare neurological or neuromuscular diseases/conditions. Components of trial readiness may include knowledge of the course of disease necessary for selecting cohorts of patients with defined characteristics, and validation of clinical outcome measures or biomarkers appropriate for assessing response to the intervention. By supporting studies aimed at clinical trial readiness, the NINDS intends to accelerate the testing of candidate therapeutics and increase the likelihood of successful trials.

The NINDS supports basic, translational and clinical research on a broad range of diseases that are defined as rare (fewer than 200,000 patients in the U.S.). To optimize the design of clinical trials for these diseases, there needs to be sufficient understanding of the presentation and course of the disease. Furthermore, tools to select appropriate participants for the trial and to measure the effects of interventions must be sensitive, reliable, valid and responsive. These tools include clinical outcome assessment (COA) measures (including clinical scales and composite measures) and biomarkers (diagnostic, prognostic, predictive, pharmacodynamic or others). COA measures include clinician-, observer- and patient-reported outcome measures, and quantitative performance outcome measures. A biomarker can be a laboratory measurement of the concentration of biomolecule in a patient’s tissue or fluids, or it can be a measurable feature of the patient s tissues or organs that is informative of structure, composition or physiological functioning. Prior to launching clinical efficacy studies, however, sufficient testing is required to demonstrate that the assays and the biomarkers themselves are sensitive, reliable, and appropriate for use in future clinical trials. Without sufficient knowledge of the disease and suitable measurement tools, clinical trials may be inconclusive or misleading. For some of the rare diseases within the mission of NINDS, preclinical translational research has advanced and candidate therapeutics are currently being developed, but clinical trial readiness may be lagging. For these diseases, additional studies are needed to collect data essential for the design of clinical trials or to prepare research tools for use in trials.

The FDA has recently published Draft Guidance on common issues in drug development for rare diseases. This FOA is intended to support studies that address some of the issues in this guidance document including the needs for adequate understanding of the course of the disease, and reliable endpoints and outcome measures.

This FOA is intended to support clinical studies that address current obstacles to the design of upcoming clinical trials in rare neurological and neuromuscular diseases and conditions. The studies supported through this FOA should be clinical observational studies (cross-sectional or longitudinal), and no intervention studies will be supported through this FOA. Appropriate trial readiness projects can be stand-alone studies, or they can be ancillary to other, ongoing clinical studies. For example, a project could propose to validate new or improved COA measures or biomarkers by adding them as experimental outcomes in an ongoing trial or longitudinal study that is supported through other funding sources. Higher priority will be given to diseases/conditions that currently or soon will have multiple candidate therapeutics or devices ready for testing in clinical trials, but that lack critical components of trial readiness that are needed for moving forward. For these higher priority diseases, the justification should be made by the applicants that clinical trials could begin immediately after the completion of the trial readiness study to test the candidate therapeutics that will be available at that time. Disorders will be given lower priority if there is not a strong justification for the urgent need for trial readiness, based on the likelihood of available candidate therapeutics by the time the trial readiness study would be completed. Lower priority will also be given to diseases or conditions for which clinical trials are already ongoing, and advances in clinical trial design through more sensitive or reliable biomarkers or COA measures, or better characterization of disease cohorts would not significantly accelerate progress toward effective treatments.

Because of the limited number of patients with specific rare diseases or conditions available at any one clinical site, clinical trials evaluating the efficacy of candidate interventions often utilize networks or consortia of clinical sites with experience interacting with those patients. The consistent and reproducible use of validated COA measures or biomarkers at multiple clinical sites is essential for clinical trial success. Therefore, prior to planning a multi-site trial, it may be necessary to conduct a multi-site trial readiness study to determine whether COA measures or biomarkers are fit for purpose and whether it is feasible to collect the data under conditions expected for the upcoming trial. This FOA is intended to support clinical studies aimed at verifying that candidate COAs or biomarkers are suitable for use in upcoming multi-site clinical trials. If only single-site clinical trials are anticipated (e.g., the condition is so rare that all patients are seen at one site), it would be appropriate to conduct the clinical trial readiness study at that one site. However, this may be an unusual situation, and awards from this FOA are likely to support multi-site studies.

Applications to this FOA may propose studies to address gaps in knowledge regarding clinical presentation or progression of rare diseases that must be filled before planning for clinical trials. Such cohort characterization studies may be needed, for example, to determine trial eligibility criteria or to determine a stage of disease progression when the response to treatment may be more readily detected. Cohort characterization studies should be submitted to this FOA only if the data to be collected are needed for the design of a clinical trial or trials in the near future. Natural history studies aimed at testing hypotheses regarding the epidemiology, genetic associations, genotype/phenotype correlations, disease mechanisms or therapeutic target identification are outside the scope of this FOA and will not be supported. However, studies are encouraged that address clinical trial readiness and also collect patient samples that could be valuable for future hypothesis-testing studies supported through other FOAs.

It is not the intent of this FOA to support studies of biomarker discovery or assay characterization. In order to be considered for support through this FOA, the biochemical or molecular biomarker analytical assay(s) should be already characterized in terms of accuracy, precision, analytical sensitivity and specificity, effects of interfering substances, dynamic range and expected normal values. If the application involves the use of imaging, radiological or physiological biomarkers, methods for measuring the biomarkers should have been optimized in clinical studies (not necessarily the same rare disease patient population), and should be ready for use in a multi-site study at the time of application. Proposed studies may test the reproducibility of biomarker measurements at multiple clinical sites and the relationship between the biomarker measurement and patient survival, function or other disease-associated symptoms. Studies aimed at developing COA instruments may include cross-sectional evaluation to assess score reliability (test-retest or inter-rater) and construct validity, as well as longitudinal evaluation to assess responsiveness. Studies of patient-reported or person-centered outcomes should incorporate existing NIH- and NINDS-supported measurement tools, including NeuroQoL, PROMIS and Toolbox. Validation of these tools in specific rare disease populations, including the addition of disease-specific modules, is encouraged.

Studies are encouraged to collect the clinical data needed to apply to the FDA for qualification of biomarkers or COAs intended to be used in the regulatory review process. Researchers are encouraged to initiate the qualification process with the FDA prior to submitting an application to this FOA. Advice from the FDA on the development of the COA or biomarker should be included in the application, if available. The FDA provides additional information about the Drug Development Tools Qualification Program on its website.

Examples of studies intended to be supported through this FOA include, but are not limited to the following:

• Studies aimed at demonstrating that COA measures or significant biomarkers are fit for use in specific contexts relevant to upcoming multi-site clinical trials
• Studies to characterize rare disease patient cohorts regarding COA measures, biomarkers, genetic, epigenetic or physiological factors that will be used to stratify patients or determine inclusion/exclusion criteria in upcoming clinical trials
• Studies to characterize rare disease patient cohorts using candidate outcome measures to collect data needed for accurate power calculations or to determine the appropriate duration of upcoming clinical trials
• Studies to establish the variability of outcome measures in patient cohorts, for use as historical control groups for upcoming clinical trials
• Studies testing the responsiveness of biomarkers or COAs through the observation of patients who are receiving treatment as part of their clinical care, or ancillary to clinical trials that are supported through other sources of funding
• Studies to address knowledge gaps for clinical trial planning that also pilot innovative recruitment strategies for women, minorities and other underserved populations who would be candidates for participation in upcoming rare disease trials

Examples of studies that are considered not appropriate for this FOA include, but are not limited to the following:

• Natural history studies aimed at exploring disease pathophysiology, genetic or epigenetic mechanisms are outside the scope of this FOA. Studies of patient genetics or pathophysiology would be in scope only if characterization is necessary for stratifying trial participants or determining inclusion/exclusion criteria in upcoming clinical trials.
• Neither preclinical translational studies for the development of candidate therapeutics/devices nor clinical trials (defined in NOT-OD-15-015), will be supported through this FOA. NINDS has existing funding opportunities for translational studies that are applicable to rare diseases (see http://www.ninds.nih.gov/funding/areas/translational_research/). Support for clinical trials is available through other FOAs (see NINDS Exploratory Clinical Trials or NeuroNEXT).
• Applications that propose any animal studies will not be considered for funding.
• Studies of biomarker discovery should seek funding through the parent FOAs for research project grants.
• Applications that propose only to create or maintain patient registries will not be considered for funding. NINDS does not intend to provide support to maintain or acquire additional data on study participants beyond the end of the trial readiness grant.
• Applications that request support for infrastructure to establish new clinical trial networks are beyond the scope of this FOA. Applicants should leverage existing resources such as existing rare disease-focused networks or NeuroNEXT.

Prospective applicants are encouraged to discuss project suitability for this FOA with the NINDS Scientific/Research Contact listed in the Agency Contacts section below.

It is a goal of this initiative to support studies that fill knowledge gaps and verify the suitability of tools required for the design of upcoming clinical trials. The trial readiness study applicants may not necessarily be the researchers designing and conducting the future trials. To promote communication among these groups of researchers and to ensure uptake of the products of the trial readiness studies, each awardee should establish an external advisory committee. This committee should include relevant clinical trialists and other stakeholders in the success of rare disease clinical trials. Applicants are encouraged to include one or more patients or patient advocates on this advisory committee. The Advisory Committee should meet prior to the initiation of enrollment and periodically during the course of the study to provide comments and suggestions on the study protocol and to review progress and accomplishments. The NINDS Project Scientist for the Cooperative Agreement should be invited to attend all Advisory Committee meetings, but would not be a voting member of this committee.

Applicants should leverage existing research resources for their clinical trial readiness studies. Such resources may include existing clinical research networks such as NeuroNEXT or other existing networks that have successfully conducted studies of rare neurological or neuromuscular diseases. Leveraging the resources and support from advocacy groups, private research foundations, academic institutions, other government agencies and the NIH Intramural program are also encouraged. Researchers interested in conducting trial readiness studies through NeuroNEXT should contact the NINDS Office of Clinical Research early in process of designing the study.

Studies are also encouraged that leverage the resources of ongoing clinical trials or longitudinal studies supported through other Federal or private funds. Researchers may consider collecting data to characterize new or improved COA measures or biomarkers as ancillary studies to ongoing clinical trials or longitudinal studies.

Researchers should include in their applications quantitative milestones leading to the accomplishment of the goals (see Project Milestones and Timelines in the Section IV below on Application and Submission Information). The milestones will be used by the Program Director(s)/Principal Investigator(s), the Advisory Committee and NINDS Program Official and Project Scientist to facilitate monitoring of progress, and assessing the feasibility for completing the study.

NINDS Program Official will contact the applicant to discuss the proposed milestones prior to the award. The Program Official and Project Scientist will discuss with the Program Director(s)/Principal Investigator(s) any recommended changes to the research plan or suggestions from peer reviewers, and the plan will be revised as appropriate prior to the award. The Terms and Conditions for the award will include recruitment milestones expected to be met by specific time periods, accrual goals for women and minorities (as appropriate), and other milestones specific to the research project.

Studies aimed at testing whether COAs or biomarkers are fit for use in upcoming clinical trials should include quantitative milestones regarding the sensitivity, reliability and responsiveness of the COA or biomarker. For studies aimed at developing COAs or biomarkers that are qualified by the FDA for use in clinical trials, milestones should be based on the advice provided by the FDA in response to the initial consultation. Submission to the FDA of a full qualification package should also be among the milestones. For further information, see:

http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM230597.pdf

Under this Cooperative Agreement mechanism, NINDS Project Scientist will have substantial communication and involvement with researchers in decision making prior to award and during the conduct of the study to provide oversight of data and safety monitoring, ensure the timely completion of the proposed studies and to maximize the positive impact of the studies on upcoming clinical trials. The NINDS Program Official and Project Scientist should also be invited to participate in meetings of the steering committee, the Advisory Committee and meetings with the FDA.

Applicants are encouraged to consult with NINDS Scientific/Research Staff early on during the planning for an application. This early contact will provide an opportunity to discuss and clarify NINDS policies and guidelines, including the scope of project relative to the NINDS mission and intent of this FOA. These discussions also provide important information and guidance on how to develop an appropriate timeline and milestone plan, which are subject to peer review under this program.

NIH grants policies as described in the NIH 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 NIH 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)
• Eligible Agencies of the Federal Government
• U.S. Territory or Possession

Other

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

Non-domestic (non-U.S.) Entities (Foreign Institutions) are eligible to apply.
Non-domestic (non-U.S.) components of U.S. Organizations are eligible to apply.
Foreign components, as defined in the NIH 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. The NIH Policy on Late Submission of Grant Applications states that 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 NIH 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.

This FOA does not require cost sharing as defined in the NIH Grants Policy Statement.

Applicant organizations may submit more than one application, provided that each application is scientifically distinct.

The NIH will not accept duplicate or highly overlapping applications under review at the same time. This means that the NIH 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.
• An application that has substantial overlap with another application pending appeal of initial peer review (see NOT-OD-11-101).

Applicants must download 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.

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.

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 IC Staff to estimate the potential review workload and plan the review.

By the date 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), 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 to:

Emily Carifi, Ph.D.
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-0665
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. The application should include in the budget, support for the safety monitoring plan, and travel and/or teleconferences for the Advisory Committee meetings.

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

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

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

Research Strategy:

Rare Disease Status

The Significance section of the Research Strategy should include a paragraph with the heading Justification of Rare Disease . This section should provide a justification that the disease/condition being studied is rare in the U.S. This section may include one or more references confirming that the prevalence of the disease/condition that is the primary focus of the research application is 200,000 or fewer patients in the U.S.

Need for Clinical Trial Readiness

The Significance section of the Research Strategy should also include a further subsection with the heading Urgent Need for Clinical Trial Readiness . This subsection should describe the need for conducting the trial readiness study at this time. Applicants should describe the clinical trial design issues (e.g., biomarker or COA validation or qualification, data for power calculations, defining inclusion/exclusion criteria, determining the duration of the trial, etc.) that will be addressed by this trial readiness study. Describe the potential impact of the proposed studies in addressing significant needs in the design and increasing the likelihood of success of upcoming clinical trials.

This section should also contain the following:

• A brief description of the state of development of candidate therapeutics or devices for this rare disease (even if the current applicants are not involved in the development of those therapeutics/devices).
• Describe the expected timelines for the advance of therapeutics/devices to clinical trials.
• A brief description of the clinical trial(s) that would be enabled by the results of this trial readiness study. Provide letters of support from the researchers who expect to conduct upcoming trials.
• Briefly describe the currently available COA measures or biomarkers. If appropriate for the proposed study, describe how the study will result in advancements over the currently available measures/biomarkers. If the current measures/biomarkers are considered inadequate or insufficiently developed for use in upcoming trials, describe their limitations and how those limitations may compromise the success of upcoming trials. If the proposed trial readiness study is ancillary to an ongoing clinical trial or longitudinal study, describe that study and provide a letter of support from the study's lead PD(s)/PI(s). Explain how the trial readiness study will lead to improvements in the design of future trials above that of the ongoing study.
• Describe any gaps in knowledge regarding the course of the disease that must be addressed before clinical trials are planned.
• A brief description of significant current and/or potential support from companies or voluntary health organizations for clinical trial readiness studies or clinical trials for this disease.
• Studies aimed at testing whether candidate COA measures or biomarkers are fit for use in upcoming trials should describe the specific, expected context of use for the measures and plans for implementing them in upcoming trials. Consideration should be given for applying to the FDA for qualification of the COA measure or biomarker. Qualification may not be necessary or appropriate for all COA measures or biomarkers, but the rationale for the decision of whether or not to apply for qualification should be described in this section of the application.

Supporting Data for Entry

Applications that include the testing of biomarkers or outcome measures should provide, in the Approach section, a justification that the assays and methods for measurement are ready for use in a multi-site study at the time of application. For biochemical or molecular biomarkers, this justification should describe accuracy, precision, analytical sensitivity, analytical specificity including interfering substances, dynamic range and expected normal values. For imaging, radiological or physiological biomarkers, the justification should provide preliminary data on the accuracy, reproducibility, sensitivity and specificity as determined by study of a patient cohort (but not necessarily in the same rare disease). Standardized protocols for measuring the biomarker at the proposed clinical sites should be included in the appendix. A description of the equipment and expertise available at each clinical site, as related to the measurement of biomarkers or outcome measures, should be provided in the application. Plans for the training of personnel at each site in the use of the standardized protocols, data quality control strategies, reference standards and approaches for verifying instrument calibration at the clinical sites should also be described as appropriate.

Existing Clinical Networks

For ancillary studies, briefly describe the aims of the parent study and the timeline of the parent study relative to the proposed ancillary study. The application should discuss the additional burden to the participants of the parent study and whether consent obtained from the participants is adequate to cover the ancillary study or if additional consent must be obtained. (See also Letters of Support)

Advisory Committee
The Approach section of the Research Strategy should include a further subsection with the heading Advisory Committee . This subsection should describe plans for establishing an advisory committee for the study, composed of at least five members. The NINDS Project Scientist for the Cooperative Agreement should be invited to participate in all meetings of the committee, but would not be a voting member. The members should include researchers not directly involved in the study, either from academics or from industry, who may lead future clinical trials that would be enabled by this trial readiness study. Researchers conducting similar studies in other diseases may also have the appropriate expertise for this committee. Applicants should also consider including at least one patient or patient advocate among the members of the committee. . This subsection should also describe plans for an initial meeting of study investigators with the committee to seek comments and suggestions on the design of the study and approval of the study protocol, before enrollment begins. Also describe plans for regular meetings with the committee to review progress and solicit advice on course corrections. Describe how the advice from the committee will be incorporated into the management of the study. The Advisory Committee will not be responsible for data and safety monitoring (see Data and Safety Monitoring section below).

Project Milestones and Timelines

In this subsection under Approach, applicants should describe milestones to be used for measuring success in achieving each of the research plan’s aims. Specify the quantitative criteria for measuring success and related rationale. One or more milestones should be used for each aim. Specify the timeline for each milestone. There should be at least one milestone each year.

Examples of milestones include, but are not limited to the following:

• Institutional Review Board (IRB) and other regulatory approvals (Applicants are encouraged to use a central IRB.)
• Certification of clinical sites regarding the training of personnel on the study protocol, calibration of instruments, implementation of data management and safety monitoring protocols, etc.
• Approval of the research protocol by the Advisory Committee
• Patient enrollment (including gender, race and ethnicity, children) and clinic visit milestones for each grant year
• Go/no go decision points regarding biomarker or COA sensitivity, reliability and responsiveness

For studies aimed at FDA qualification of COAs or biomarkers, milestones should be based on the advice provided by the FDA in response to the initial consultation. Submission of a full qualification package should also be among the milestones. For further information, see:

http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM230597.pdf

Include a timeline that indicates IRB approval(s), meetings of the Advisory Committee, staging of patient visits, and expected completion for each of the milestones. Also describe the time frame of planning for clinical trials that will utilize the resulting products of the trail readiness study.

Applicants are encouraged to use a central IRB, rather than independent review at each participating institution.

Letters of Support

Provide a letter of support from the leader(s) of the existing clinical research network that will conduct the trial readiness study that indicates the sites involved in the network, relevant resources and study infrastructure, and an estimate of the number of eligible, relevant rare disease patients accessible through the network. For ancillary studies, provide a letter of support from the PD/PI of the parent study that includes a brief description of the aims of the parent study and indicates the timeline of the parent study relative to the proposed ancillary study.

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.

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

• Standardized protocols for measuring the biomarkers proposed
• For proposed ancillary studies, provide the protocol for the parent clinical trial or longitudinal study and the consent form for the parent study
• Guidance documents provided by the FDA regarding qualification of the proposed biomarker(s) or COA measure(s)

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

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

Foreign (non-U.S.) institutions must follow policies described in the NIH Grants Policy Statement, and procedures for foreign institutions described throughout the SF424 (R&R) Application Guide.

See Part I. Section III.1 for information regarding the requirements for obtaining a Dun and Bradstreet Universal Numbering System (DUNS) Number and for completing and maintaining an active System for Award Management (SAM) registration. Part I. Overview Information contains information about Key Dates. 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, NIH’s electronic system for grants administration. NIH 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. If a Changed/Corrected application is submitted after the deadline, the application will be considered late.

Applicants are responsible for viewing their application before the due date in the eRA Commons to ensure accurate and successful submission.

Information on the submission process and a definition of on-time submission are provided in the SF424 (R&R) Application Guide.

This initiative is not subject to intergovernmental review.

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

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

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. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Guidelines for Applicants Experiencing System Issues.

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 NIH. 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 Center for Scientific Review, NIH. Applications that are incomplete or non-compliant will not be reviewed.

Applicants requesting $500,000 or more in direct costs in any year (excluding consortium F&A) must contact a Scientific/ Research Contact at least 6 weeks before submitting the application and follow the Policy on the Acceptance for Review of Unsolicited Applications that Request $500,000 or More in Direct Costs as described in the SF424 (R&R) Application Guide.

Applicants are required to follow our Post Submission Application Materials policy.

Important Update: See NOT-OD-16-006 and NOT-OD-16-011 for updated review language for applications for due dates on or after January 25, 2016.

Only the review criteria described below will be considered in the review process. As part of the NIH mission, all applications submitted to the NIH in support of biomedical and behavioral research are evaluated for scientific and technical merit through the NIH peer review system.

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, and give a separate score for each. 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.

Does the project address an important problem or a critical barrier to progress in the field? If the aims of the project are achieved, how will scientific knowledge, technical capability, and/or clinical practice be improved? How will successful completion of the aims change the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field?

How strong is the justification in the application that the disease or condition meets the criteria of being rare (fewer than 200,000 patients in the U.S.)?

How does the project address a significant, unmet need for clinical trial readiness?

Is there overlap with ongoing efforts for clinical trial readiness for the same rare disease?

How will successful completion of the aims enable the design of one or more important clinical trials, and will the readiness study increase the likelihood of success of those trials?

How strong is the justification that there will be candidate therapeutics ready for testing in clinical trials at the time of completion of the proposed trial readiness study?

How strong is the justification for the urgency of the trial readiness study?

If the application proposes to conduct a study that is ancillary to an ongoing clinical trial or longitudinal study, how does the ancillary study have the potential to provide knowledge or test the readiness of outcome measures or biomarkers that will significantly advance the design of future trials beyond that of the existing study? How will the additional burden of the ancillary study affect the participants in the parent study? How does the consent obtained for participation in the parent study relate to consent for the ancillary study?

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the project? If Early Stage Investigators or those in the early stages of independent careers, do they have appropriate experience and training? If established, have they demonstrated an ongoing record of accomplishments that have advanced their field(s)? If the project is collaborative or multi-PD/PI, do the investigators have complementary and integrated expertise; are their leadership approach, governance and organizational structure appropriate for the project?

How does the expertise of the investigators qualify them for studying the rare disease/condition, managing the study, and analyzing the data with appropriate, rigorous statistical methods?

Does the application challenge and seek to shift current research or clinical practice paradigms by utilizing novel theoretical concepts, approaches or methodologies, instrumentation, or interventions? Are the concepts, approaches or methodologies, instrumentation, or interventions novel to one field of research or novel in a broad sense? Is a refinement, improvement, or new application of theoretical concepts, approaches or methodologies, instrumentation, or interventions proposed?

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Are potential problems, alternative strategies, and benchmarks for success presented? If the project is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed?

How well does the application describe plans to ensure that the study is scientifically rigorous, controls are in place to minimize bias, and that reporting is transparent?

How well will the milestones measure success in achieving the aims of the application?

How feasible are the milestones for participant enrollment relative to the timeline for completing the aims within the term of the grant?

How effectively will the milestones for the performance of COA measures or biomarkers establish appropriate go/no-go decisions points in preparing for clinical trials? Are the milestones appropriate for establishing the reliability, validity and responsiveness of the COA measures or biomarkers?

How strong is the justification that this study will provide critical knowledge or data for the design of a clinical trial that can begin immediately after the completion of the study?

How well characterized are the assays for biochemical or molecular biomarkers in terms of accuracy, precision, sensitivity, selectivity, dynamic range and expected normal values?

How well optimized and ready for implementation in a multi-site study are the methods for measuring imaging, radiological or physiological biomarkers and COAs?

How well does the application describe a plan to establish and meet regularly with an Advisory Committee with appropriate expertise, and to incorporate the advice from the committee in to the management of the study?

If the project involves human subjects and/or NIH-defined clinical research, are the plans to address 1) the protection of human subjects from research risks, and 2) inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion or exclusion of children, justified in terms of the scientific goals and research strategy proposed?

Will the scientific environment in which the work will be done contribute to the probability of success? Are the institutional support, equipment and other physical resources available to the investigators adequate for the project proposed? Will the project benefit from unique features of the scientific environment, subject populations, or collaborative arrangements?

Do the clinical sites provide access to a sufficient number of patients with the rare disease to support enrollment for the study?

How strong is the justification that all of the participating clinical sites have the appropriate expertise and equipment for measuring COAs and analyzing appropriate biomarkers?

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

For research that involves human subjects but does not involve one of the 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 NIH-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.

The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following five points: 1) proposed use of the animals, and species, strains, ages, sex, and numbers to be used; 2) justifications for the use of animals and for the appropriateness of the species and numbers proposed; 3) adequacy of veterinary care; 4) procedures for limiting discomfort, distress, pain and injury to that which is unavoidable in the conduct of scientifically sound research including the use of analgesic, anesthetic, and tranquilizing drugs and/or comfortable restraining devices; and 5) methods of euthanasia and reason for selection if not consistent with the AVMA Guidelines on Euthanasia. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animal Section.

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 scientific review group and changes made to the project.

Not Applicable

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 scientific review group are adequate and whether substantial changes are clearly evident.

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 assess the information provided in this section of the application, including 1) the Select Agent(s) to be used in the proposed research, 2) the registration status of all entities where Select Agent(s) will be used, 3) the procedures that will be used to monitor possession use and transfer of Select Agent(s), and 4) plans for appropriate biosafety, biocontainment, and security of the Select Agent(s).

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.

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

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s) convened by the NINDS, in accordance with NIH peer review policy and procedures, using the stated review criteria. Assignment to a Scientific Review Group will be shown in the eRA Commons.

As part of the scientific peer review, all applications:

• May undergo a selection process in which only those applications deemed to have the highest scientific and technical merit (generally the top half of applications under review) will be discussed and assigned an overall impact score.
• Will receive a written critique.

Applications will be assigned on the basis of established PHS referral guidelines to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications . Following initial peer review, recommended applications will receive a second level of review by the National Advisory Neurological Disorders and Stroke Council. The following will be considered in making funding decisions:

• Scientific and technical merit of the proposed project as determined by scientific peer review.
• Availability of funds.
• Relevance of the proposed project to program priorities.

After the peer review of the application is completed, the PD/PI will be able to access his or her Summary Statement (written critique) via the eRA Commons.

Information regarding the disposition of applications is available in the NIH Grants Policy Statement.

If the application is under consideration for funding, NIH will request "just-in-time" information from the applicant as described in the NIH Grants Policy Statement.

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 on the Award Conditions and Information for NIH Grants website. This includes any recent legislation and policy applicable to awards that is highlighted on this website.

All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the NoA. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General and Part II: Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Grantees, and Activities. More information is provided at Award Conditions and Information for NIH Grants.

Cooperative Agreement Terms and Conditions of Award

The following special terms of award are in addition to, and not in lieu of, otherwise applicable U.S. Office of Management and Budget (OMB) administrative guidelines, U.S. Department of Health and Human Services (DHHS) grant administration regulations at 45 CFR Parts 74 and 92 (Part 92 is applicable when State and local Governments are eligible to apply), and other HHS, PHS, and NIH grant administration policies.

The administrative and funding instrument used for this program will be the U01 cooperative agreement, an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH programmatic involvement with the awardees is anticipated during the performance of the activities. Under the cooperative agreement, the purpose of the NIH is to support and stimulate the recipients' activities by involvement in and otherwise working jointly with the award recipients in a partnership role; it is not to assume direction, prime responsibility, or a dominant role in the activities. Consistent with this concept, the dominant role and prime responsibility resides with the awardees for the project as a whole, although specific tasks and activities may be shared among the awardees and the NIH as defined below.

The PD(s)/PI(s) will have primary responsibility for:

• Defining of research objectives and approaches.
• Planning, conducting, analyzing, and publishing results, interpretations, and conclusion of their studies and for providing overall scientific and administrative leadership for the Research Project.
• Supervising of the clinical study with consistent emphasis on collaborative interactions among PD(s)/PI(s), advisory and steering committees, and NINDS representatives.
• Retaining custody of and maintaining primary rights to data and software developed under this award, subject to Government rights of access consistent with current DHHS, PHS, and NIH policies.

NIH Staff have substantial programmatic involvement that is above and beyond the normal stewardship role in awards, as described below:

NINDS staff involvement will include oversight of the IRB-approved protocol by the NINDS Program Official, documentation of adequate serious adverse event management and reporting, and regular communications with the PD/PI and staff; additional involvement generally includes participation in meetings of the advisory committee. Specifically:

• An NINDS Project Scientist working with the PD/PI will develop milestones for the study. Failure to meet the agreed upon milestones may result in reduced funding or early termination of the cooperative agreement. The NINDS retains the option to obtain periodic external peer review of progress.
• The NINDS Project Scientist will function as one of several co-investigators, collaborating and interacting as necessary with the PD(s)/PI(s) in accomplishing the overall goals of the Research Program.
• In addition, an NINDS Program Official will be responsible for the normal scientific and programmatic stewardship of the award and will be named in the award notice.
• If the proposed study should involve interaction with the FDA regarding biomarker or outcome measure qualification, the NINDS Project Scientist and/or Program Official(s) will be present at any meetings held with the FDA related to this NIH-funded protocol.

As with any award, even during the period recommended for support, continuation is conditional upon satisfactory progress. If, at any time, recruitment falls significantly below the projected milestones for recruitment, the NINDS will consider ending support and negotiating a phase-out of the award. The NINDS retains the option to obtain periodic external peer review of progress. Milestones will be established by the NINDS prior to the award of the grant based on recommendations from the primary review group. Feasibility milestones will be defined at the start of each trial and will be monitored closely by the NINDS Program Official. Achievement of these milestones will be evaluated by NINDS prior to releasing funding for each year of the award and failure to achieve these milestones may lead to study termination.

Areas of Joint Responsibility include:

• Clarifying, negotiating and finalizing the milestones and timelines.

Dispute Resolution

Any disagreements that may arise in scientific or programmatic matters (within the scope of the award) between award recipients and the NIH may be brought to Dispute Resolution. A Dispute Resolution Panel composed of three members will be convened. It will have three members: a designee of the Steering Committee chosen without NIH Staff voting, one NIH designee, and a third designee with expertise in the relevant area who is chosen by the other two; in the case of disagreement, the first member may be chosen by the individual awardee. This special dispute resolution procedure does not alter the awardee's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulation 42 CFR Part 50, Subpart D and DHHS regulation 45 CFR Part 16. Final decisions made by NINDS regarding a discontinuation are not appealable.

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 NIH Grants Policy Statement.

A final progress report, invention statement, and the expenditure data portion of the Federal Financial Report are required for closeout of an award, as described in the NIH 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 NIH 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. See the NIH Grants Policy Statement for additional information on this reporting requirement.

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

eRA Commons Help Desk (Questions regarding 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]

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Email: [email protected] (preferred method of contact)
Telephone: 301-945-7573

Glen H. Nuckolls, Ph.D.
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-5745
Email: [email protected]

Ernest Lyons, Ph.D.
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-9223
Email: [email protected]

Tijuanna Decoster, Ph.D.
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-9231
Email: [email protected]

Recently issued trans-NIH policy notices may affect your application submission. A full list of policy notices published by NIH is provided in the NIH Guide for Grants and Contracts. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part 52 and 45 CFR Part 75.