Part 1. Overview Information

Key Dates

All applications are due by 5:00 PM local time of applicant organization. 

Applicants are encouraged to apply early to allow adequate time to make any corrections to errors found in the application during the submission process by the due date.

No late applications will be accepted for this Notice of Funding Opportunity (NOFO).

It is critical that applicants follow the instructions in the Research (R) Instructions in the How to Apply - Application Guide, except where instructed to do otherwise (in this NOFO or in a Notice from NIH Guide for Grants and Contracts).

Conformance to all requirements (both in the How to Apply - Application Guide and the NOFO) is required and strictly enforced. Applicants must read and follow all application instructions in the How to Apply - Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the How to Apply - Application Guide, follow the program-specific instructions.

Applications that do not comply with these instructions may be delayed or not accepted for review.

There are several options available to submit your application through Grants.gov to NIH and Department of Health and Human Services partners. You must use one of these submission options to access the application forms for this opportunity.

1. Use the NIH ASSIST system to prepare, submit and track your application online.
2. Use an institutional system-to-system (S2S) solution to prepare and submit your application to Grants.gov and eRA Commons to track your application. Check with your institutional officials regarding availability.
   
   
3. Use Grants.gov Workspace to prepare and submit your application and eRA Commons to track your application.



Table of Contents
Part 1. Overview Information
Key Dates
Part 2. Full Text of Announcement
Section I. Notice of 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

Part 2. Full Text of Announcement

Section I. Notice of Funding Opportunity Description

The purpose of this Notice of Funding Opportunity (NOFO) is to encourage grant applications for the conduct of scientific research utilizing data from expanded access (EA) for investigational drugs or biological products as described in section 561 of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 360bbb). These applications will target intermediate size populations of patients living with amyotrophic lateral sclerosis (ALS) who are not eligible for ongoing clinical trials for the prevention, diagnosis, mitigation, treatment, or cure of ALS ("intermediate EA protocol for ALS").

Provision of the investigational drug or biological product under an intermediate EA protocol for ALS must not interfere with the initiation, conduct, or completion of clinical investigations that could support marketing approval or otherwise compromise the potential development of medical products for the prevention, diagnosis, mitigation, treatment, or cure of ALS.

Background

ALS is a rapidly progressive, ultimately fatal, neurodegenerative disease with over 32,000 estimated cases in the United States (U.S.) or a prevalence rate of 9.9 per 100,000 U.S. population. The disease affects both upper and lower motor neurons, leading to weakness and wasting of most skeletal muscles including the diaphragm. There is considerable variability in the phenotypic presentation and progression of ALS although the mean survival of people with diagnosis of ALS from symptom onset is 3-5 years. To date, treatment options for ALS remain severely limited. Currently, there are three disease-modifying drugs for ALS on the market in the U.S. Another drug was approved by the FDA in 2022, but was removed from the market by the manufacturer based on topline results from a phase III clinical trial that ended in 2023. Two of these drugs are approved for all forms of ALS, and one drug is approved for SOD1-linked, familial ALS. However, so far, these drugs only have modest effects on slowing progression of the disease, and there is no known treatment that prevents, halts or reverses the progression of ALS. Thus, the development of new effective treatments to prevent disease onset, make ALS a livable disease, or cure ALS is a pressing need.

To address this challenge, some people with ALS may be eligible to enroll in ongoing phase 3/efficacy clinical trials of investigational drugs and biological products for ALS.  However, trial sponsors typically set inclusion criteria that restrict participation to only a subset of people with ALS to increase the likelihood of detecting efficacy with feasible sample size and trial duration. Thus, a potentially large segment of people with ALS may be ineligible to participate in clinical trials because they do not meet these inclusion criteria.

EA, sometimes referred to as “compassionate use”, was established to provide treatment access to investigational medical products (i.e., drugs, biological products, medical devices) for people with serious, life-threatening diseases like ALS when no comparable or satisfactory therapy is available to diagnose, monitor, or treat the disease or condition. This pathway is defined and regulated by the FDA (see https://www.fda.gov/news-events/public-health-focus/expanded-access). Further, the FDA has not yet determined if these products are safe and effective for their intended use. One requirement of the EA pathway is that providing the investigational medical product under EA must not interfere with the initiation, conduct, or completion of clinical investigations that could support marketing approval of a medical product for the EA use, or otherwise compromise its potential development. An intermediate-size patient population EA protocol is generally used when more than one patient will be treated with an investigational drug/biological product under the EA (21 CFR 312.315), and can involve hundreds or even thousands of patients if appropriate.

Section 2 of the Accelerating Access to Critical Therapies for ALS Act (ACT for ALS; P.L. 117-79) established a grant program for scientific research utilizing data from EA to investigational drugs for ALS.

Objective

The objective of this NOFO is to support the conduct of scientific research utilizing data from intermediate-size patient population EA protocols for ALS (see https://www.fda.gov/news-events/expanded-access/expanded-access-categories-drugs-including-biologics).

Applicants should take note of the following special requirements and considerations:

• EA New Drug Application (IND): 
  • An intermediate-size patient population EA IND application must be submitted to the FDA by the day of submission of the grant application to the NINDS.
  • Approval notification from FDA, such as a "may proceed" email or letter, must be submitted to NINDS prior to funding
• The investigational drug or biological product must not be approved under a New Drug Application (NDA) or licensed under a Biologics License Application (BLA).
• Institutional Review Board (IRB) approval of the protocol and the informed consent document are not required at the time of application submission, but must be documented prior to funding and initiation of treatment of participants. As such, NINDS encourages investigators to begin these processes as early as possible.
• Applications must follow NINDS guidelines for monitoring clinical trials.
• The EA protocol will provide access to the investigational drug or biological product for people with ALS. The protocol must also generate data that will support research or development related to the prevention, diagnosis, mitigation, treatment, or cure of ALS. A description of the scientific research goal(s) informed by these data could include the investigational drug’s/biological product’s effect on biomarkers related to the pathophysiology of ALS or target engagement, the collection of safety or outcome information, such as survival or other significant medical events (e.g., hospitalization or need for ventilatory support), or patient experience data that are not specifically tied to assessing efficacy.
• Applications are required to include a description of how the proposed EA program will not interfere with participant enrollment in ongoing clinical trials for investigational therapies for the prevention, diagnosis, mitigation, treatment, or cure of ALS.
• Funding for the EA protocol will continue until one of the following events:  
  • Marketing authorization of the drug/biological product by the FDA
  • Withdrawal or termination of the IND for the investigational agent by the sponsor
  • Decision by the FDA to put the EA protocol on hold, e.g., should information emerge that alters the acceptability of the EA use
  • Scenarios such as: (a) failure to implement the study protocol, (b) a substantial shortfall in study participant follow-up, data reporting and dissemination, quality control, or other major breach of the protocol, (c) substantive changes in the agreed-upon protocol with which NINDS does not concur, (d) study participant safety or ethical issues that may dictate a premature termination, or (e) a change in the state of science that has a significant impact on the relevance of the question
  • The project period has ended. The consent process should clearly explain to the study participants that grant support for the EA protocol is limited to the project period.
• This NOFO strongly encourages the use of common data elements (CDEs). CDEs are data standards that have been identified and defined for use in multiple data sets across different studies.  
• This NOFO strongly encourages applications that include a plan for stakeholder engagement. Stakeholder engagement in clinical studies involves people with lived experiences (PWLE), health professionals, and the clinical research team working in active partnership at various levels across the continuum of clinical research. Applicants are strongly encouraged to establish relationships with PWLE(s) and/or advocacy groups and solicit their input (including during study design) on recruitment, the clinical meaningfulness of the question under study, the relevance of the proposed clinical outcomes, and approaches to minimizing the burden on study participants. Applicants are encouraged to facilitate continued respectful, equitable and bidirectional knowledge transfer during stakeholder engagement to build trust in communities that may be fearful of participating in clinical research because of stigmas and medical mistrust. Furthermore, engaging stakeholders in these ways may also improve participant retention and adherence to the study protocol.
• NINDS is committed to reducing the disproportionate burden of neurological disease borne by underserved groups of society, including racial and ethnic minority, rural, and socioeconomically disadvantaged populations. People from racial and ethnic minority groups and people living in rural areas are disproportionately affected by many medical conditions including ALS. Additionally, socioeconomically disadvantaged populations are more likely to be at risk for poorer health outcomes.  Therefore, ensuring appropriate inclusion of populations that experience health disparities is strongly encouraged. 

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

Investigators proposing NIH-defined clinical trials may refer to the Research Methods Resources website for information about developing statistical methods and study designs.

Section II. Award Information

NIH grants policies as described in the NIH Grants Policy Statement will apply to the applications submitted and awards made from this NOFO.

Section III. Eligibility Information

1. Eligible Applicants

All organizations administering an eligible parent award may apply for a supplement under this NOFO.

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)

Local 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)

Federal Government

• 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

Eligible applicants must be clinical trial sites that participate in a phase 2/3 or phase 3 efficacy clinical trial (designed to provide pivotal data to support a marketing application) supported by a small business concern that is the FDA-designated sponsor of a drug or biological product which is the subject of an IND under section 505(i) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 355(i)) to prevent, diagnose, mitigate, treat, or cure ALS. The definition of a small business concern can be found in section 3(a) of the Small Business Act (15 U.S.C. 632(a)).

Non-domestic (non-U.S.) Entities (Foreign Organizations) are not eligible to apply.

Non-domestic (non-U.S.) components of U.S. Organizations are not eligible to apply.

Foreign components, as defined in the NIH Grants Policy Statement, are not allowed. 

Applicant Organizations

Applicant organizations must complete and maintain the following registrations as described in the How to Apply - 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, please reference NIH Grants Policy Statement Section 2.3.9.2 Electronically Submitted Applications for additional information. 

• System for Award Management (SAM) – Applicants must complete and maintain an active registration, which requires renewal at least annually. The renewal process may require as much time as the initial registration. SAM registration includes the assignment of a Commercial and Government Entity (CAGE) Code for domestic organizations which have not already been assigned a CAGE Code.
  • 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.
  • Unique Entity Identifier (UEI) - A UEI is issued as part of the SAM.gov registration process. The same UEI must be used for all registrations, as well as on the grant application.
• eRA Commons - Once the unique organization identifier is established, organizations can register with eRA Commons in tandem with completing their Grants.gov registration; all registrations must be in place by time of submission. eRA Commons requires organizations to identify at least one Signing Official (SO) and at least one Program Director/Principal Investigator (PD/PI) account in order to submit an application.
• Grants.gov – Applicants must have an active 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 their organization to develop an application for support. Individuals from diverse backgrounds, including underrepresented racial and ethnic groups, individuals with disabilities, and women are always encouraged to apply for NIH support. See, Reminder: Notice of NIH's Encouragement of Applications Supporting Individuals from Underrepresented Ethnic and Racial Groups as well as Individuals with Disabilities, NOT-OD-22-019.

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 How to Apply - Application Guide.

2. Cost Sharing

This NOFO does not require cost sharing as defined in the NIH Grants Policy Statement Section 1.2 Definition of Terms.

3. Additional Information on Eligibility

Number of Applications

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, per NIH Grants Policy Statement Section 2.3.7.4 Submission of Resubmission Application. 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 NIH Grants Policy Statement 2.3.9.4 Similar, Essentially Identical, or Identical Applications).

Section IV. Application and Submission Information

1. Requesting an Application Package

The application forms package specific to this opportunity must be accessed through ASSIST, Grants.gov Workspace or an institutional system-to-system solution. Links to apply using ASSIST or Grants.gov Workspace are available in Part 1 of this NOFO. See your administrative office for instructions if you plan to use an institutional system-to-system solution.

2. Content and Form of Application Submission

It is critical that applicants follow the instructions in the Research (R) Instructions in the How to Apply - Application Guide except where instructed in this notice of funding opportunity to do otherwise. Conformance to the requirements in the How to Apply - Application Guide is required and strictly enforced. Applications that are out of compliance with these instructions may be delayed or not accepted for review.

Letter of Intent

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:

Amy Tsou, M.D.
Email: amy.tsou@nih.gov  

All page limitations described in the How to Apply – Application Guide and the Table of Page Limits must be followed.

The following section supplements the instructions found in the How to Apply – Application Guide and should be used for preparing an application to this NOFO.

All instructions in the How to Apply - Application Guide must be followed.

All instructions in the How to Apply - Application Guide must be followed.

All instructions in the How to Apply - Application Guide must be followed.

All instructions in the How to Apply - Application Guide must be followed.

R&R or Modular Budget

All instructions in the How to Apply - Application Guide must be followed.

Funds may be requested for:

• Payment to the manufacturer or sponsor for the costs related to the investigational drug or biological product of the intermediate EA protocol for ALS, as authorized under section 312.8(d) of title 21, Code of Federal Regulations (or successor regulations) (indirect costs not allowed)
• Costs incurred in providing such drug/biological product consistent with the research objectives of the grant (indirect cost not allowed)
• Costs associated with biospecimen collection and banking through BioSEND or other repository
• Costs to cover expenses incurred by participating clinical trial sites in conducting research with respect to such drugs/biological products including any analysis
• Personnel effort, support for study participant travel/meals, and other budget items within the overall budget cap to ensure that this goal of appropriate inclusion is met

R&R Subaward Budget

All instructions in the How to Apply - Application Guide must be followed.

All instructions in the How to Apply - Application Guide must be followed.

All instructions in the How to Apply - Application Guide must be followed, with the following additional instructions:

Introduction to Application: For Resubmission applications, an Introduction to Application is required in the Overall component.

Research Strategy:

Significance: Describe how data generated through the EA protocol for the investigational drug/biological product will advance research or development to support prevention, diagnosis, mitigation, treatment, or cure of ALS. 

• Biological and/or Clinical Relevance: Applications should not only describe the research goal(s), but also describe how achieving the goal(s) will advance our understanding of ALS by addressing the investigational drug's/biological product's effect on biomarkers related to the pathophysiology of ALS or target engagement, collection of safety or outcome information (such as survival or other significant medical events [e.g., hospitalization or need for ventilatory support]), or patient experience data not specifically tied to assessing efficacy.

Preliminary Studies: Present the scientific rationale for the research goal(s) to be supported by data generated through the intermediate EA protocol for ALS, including preliminary data, clinical and/or preclinical studies, or data on biological mechanisms.

Approach: 

Non-interference with Clinical Trials: Describe how the proposed intermediate EA protocol for ALS is designed to avoid 1) interfering with the initiation, conduct, or completion of clinical investigations that could support marketing approval or 2) otherwise compromise the potential development of medical products for the prevention, diagnosis, mitigation, treatment, or cure of ALS.

Outline how data will be obtained, analyzed, and interpreted with sufficient rigor to quantitatively assess project outcomes. Describe the use of the NIH/NINDS Common Data Elements and, as applicable, other NIH or external resources to standardize the collection of clinical data (see additional details below).

The summary of the proposed research should include a discussion of potential limitations and/or challenges in the protocol and strategies to address these concerns. 

The application should describe what (if any) non-traditional approaches to engage potential study participants for intervention delivery and data collection will be used to minimize burden (see section 2 below). 

• Use of CDEs in NIH-funded Research: Leading assessments and decision-making processes regarding adoption and implementation of data collection standards, a core set of CDEs and tools, and harmonization procedures including mapping to common data models to maximize comparability across the program and measurement modes. Data availability and data collection processes will differ across different types of studies, including, for example, studies with data extracted from electronic health records, studies with data collected in research clinic settings, and studies with data collected in community settings via digital technology (e.g., mobile app, wearables, etc.).NINDS strongly encourages the use of CDEs available at www.commondataelements.ninds.nih.gov (ALS CDE Project). Investigators should describe how standardization of data collection and data collection instruments will be used, including the use of existing NIH/NINDS CDEs. Investigators are expected to describe how they will use the NINDS CDEs and other data standards, creation of Case Report Forms (CRFs) and data dictionaries. Whenever applicable, investigators should use the standardized CRFs and other instruments identified by the NINDS CDE Project. If other CDEs are used/reused, describe how they will be used and mapped. The CDE Project has developed uniform formats by which clinical data can be systematically collected, analyzed, and shared across the research community. To maximize comparisons across datasets or studies and facilitate data integration and collaboration, researchers funded through this RFA are strongly encouraged to use the following standards and resources (where applicable):  
  • NIH CDE Repository
  • PROMIS
  • NeuroQOL
  • PhenX toolkit
  • PhenX Toolkit Social Determinants of Health (SDOH) Collections
  • NIH Toolbox
  • Clinical and Translational Science Award (CTSA) program
  • HL7 FHIR® (Fast Healthcare Interoperability Resources)
  • Standardized set of data classes, data elements, and associated vocabulary standards specified in the United States Core Data for Interoperability (USCDI) standards
  • FDA Digital Health Center of Excellence
• Stakeholder Engagement: this NOFO strongly encourages applications that include a plan for stakeholder engagement. Stakeholder engagement in clinical studies involves patients, families, their representatives, health professionals, and the clinical research team working in active partnership at various levels across the continuum of clinical research. Leveraging the resources and support from advocacy groups, private research foundations, academic institutions, other government agencies, and the NIH Intramural program are also strongly encouraged.

Letters of Support: If there will be subcontracts or service agreements for personnel or facilities, include documentation of such commitments, co-signed by a business official and the investigator at the participating center.

If there are agreements with collaborating industry partners, include documentation of the agreements, co-signed by a business official and an appropriate official at the company.

If there are manufacturing agreements, include a letter of intent or letter of authorization from the manufacturer, co-signed by a business official and an appropriate official at the company.

If CTSA resources will be utilized, include letter of support from each site CTSA program officer concurring with the specific plan for using these resources.

If some costs for the intermediate EA protocol for ALS are to be borne by sources other than NIH, include documentation of this support, signed by individuals who have the authority to make a commitment on behalf of the organization they represent.

Applicants are encouraged to include letters or other supporting documentation from relevant stakeholders (e.g., potential study participants, referring and treating physicians, patient advocacy groups) to show that they believe the study question to be important, consider the study design to be acceptable, and that patients were included as partners in the concept development and design of the EA program.

Resource Sharing Plan:

Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the How to Apply - Application Guide. 

• Applications proposing to collect biospecimens must use the BioSEND protocols and procedures, and all specimens collected and banked with BioSEND must come from individuals who have consented to banking and sharing broadly with academia and industry. Note that costs for collection are NOT included as a component of the NINDS Biomarkers Repository award to offset some of the cost of biospecimen banking. Therefore, costs for the biospecimen collection (collection kits, shipping kits to sites, shipping samples to BioSEND) are borne by the grantees utilizing this resource (see NOT-NS-15-046). Applicants planning projects in which biospecimens will be collected are strongly advised to consult the BioSEND website for more information about samples banked at the repository. In addition, applicants are advised to consult with BioSEND staff to obtain a quote for biospecimen banking costs (https://biosend.org/request_a_quote.html).
  • Please request a quote from BioSEND by filling out a quote form at https://biosend.org/request_a_quote.html. BioSEND staff will contact the PI(s). Applicants should include this information in the application.   
• Whenever applicable, the NINDS Human Cell and Data Repository (NHCDR) must be used to bank and distribute cells collected from participants in these studies. Note that costs for collection are NOT included as a component of the NHCDR award to offset some of the cost of biospecimen banking. Therefore, costs for the biospecimen collection (collection kits, shipping kits to sites, shipping samples to NHCDR) are borne by the grantees utilizing this resource. Applicants planning projects in which biospecimens will be collected are strongly advised to consult the NHCDR website for more information about samples banked at the repository. In addition, applicants are advised to consult with NHCDR staff to obtain a quote for biospecimen banking costs (https://nindsgenetics.org/contact-information/).

Other Plan(s):

All instructions in the How to Apply - Application Guide must be followed, with the following additional instructions:

• All applicants planning research (funded or conducted in whole or in part by NIH) that results in the generation of scientific data are required to comply with the instructions for the Data Management and Sharing Plan. All applications, regardless of the amount of direct costs requested for any one year, must address a Data Management and Sharing Plan. 
• To increase the value of its funded research, an ALS Knowledge Platform managed by the NINDS will serve as a data repository for data sharing and analysis through a cloud-based infrastructure. Applicants are expected to submit a complete de-identified dataset containing all variables collected in the intermediate EA protocol for ALS and a data dictionary within an agreed upon timeframe. Applicants are encouraged to make use of the NINDS CDEs for ALS, see https://www.commondataelements.ninds.nih.gov/amyotrophic%20lateral%20sclerosis. 

Only limited Appendix materials are allowed. Follow all instructions for the Appendix as described in the How to Apply - Application Guide.

Applicants should include with appendix materials a statement regarding the qualification of the drug/biological product sponsor as a small business concern as defined in section 3(a) of the Small Business Act (15 U.S.C. 632(a)).

When involving human subjects research, clinical research, and/or NIH-defined clinical trials (and when applicable, clinical trials research experience) follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the How to Apply - Application Guide, with the following additional instructions:

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

Study Record: PHS Human Subjects and Clinical Trials Information

All instructions in the How to Apply - Application Guide must be followed.

All applications must follow the instructions G.500 – PHS Human Subjects and Clinical Trials Information with additional instructions specific to this NOFO.

Section 2 - Study Population Characteristics

A goal of this initiative is to support studies that lead to findings applicable to all people affected by ALS. Therefore, it is important that the sex/gender, race, ethnicity, and age of the participants appropriately represent the ALS patient population of in the U.S.

In sections 2.4 “Inclusion of Women and Minorities” and 2.5 “Recruitment and Retention Plan” of the Human Subject form applications must address the following points in addition to the G.500 instructions.

2.4 Inclusion of Women and Minorities

• Provide data, if available, on the demographics of individuals affected by the condition under study in the catchment area for the clinical sites proposed in the application.
• Provide annual milestones for enrollment including numbers by sex/gender, race, and ethnicity.
• Describe how the planned enrollment will appropriately represent the sex/gender, race, ethnicity and age of the population of individuals in the U.S. affected by ALS.
• Identify the person/people in the research team that will carry out the proposed outreach and their qualifications or relevant abilities such as fluency in languages other than English and/or cultural sensitivity.

2.5 Recruitment and Retention Plan

• Describe how the proposed recruitment and retention plan is designed to overcome obstacles to study participation. Strategies to overcome obstacles include but are not limited to the following:
  • Describe the efforts that will be made to include underserved groups of society, including racial and ethnic minorities, rural, and socioeconomically disadvantaged populations impacted by ALS. 
  • Minimize the burden of participating in the study by reducing the frequency and/or duration of clinic visits and overall time required.
  • Select study sites with ample numbers and diversity of potential study participants.
  • Select study sites that minimize the travel of study participants.
  • Provide support for study participant transportation, accommodations and parking as needed.
  • Provide daycare for family members during study visits.
  • Allow for clinic visits in the evenings and/or during weekends.
  • Integrate remote data collection such as smartphone apps or wearables into the study design while also taking into consideration the need for access to broadband communication networks in rural areas.
  • Establish recruitment, enrollment, and/or data collection sites in the community at locations that are convenient, familiar, and trusted by potential study participants.
  • Have validated translations of consent forms and other relevant study documents available in languages that help ensure the achievement of the planned enrollment.
  • Include study personnel who are bilingual and culturally sensitive to the planned enrollment population. Consider enlisting the help of community ambassadors to build trust in the communities of potential study participants.
• In addition to the primary plan for recruiting sex/gender, racial, and ethnic group members, provide alternative/back-up strategies to be used if enrollment significantly deviates (more than 20% of any category for each annual milestone) from the planned numbers according to sex/gender, race or ethnicity. Back-up plans may, for example, propose to add research sites with access to additional individuals that are underrepresented in the enrollment.
• Describe what other research studies may be competing for recruitment of the same patient population at the same clinic sites that are proposed in the application. Describe plans for communicating to potential study participants the options available to them.  

Section 3 - Protection and Monitoring Plans

3.1 Protection of Human Subjects

Applicants should discuss how the consent process will clearly inform study participants that the grant support for EA for the investigational drug/biological product is limited to the project period.

3.1.2 Adequacy of Protection Against Risks

3.1.2b Protections Against Risks

A plan for interim analysis and stopping the study for evidence of harm, i.e., greater than expected mortality as well as serious adverse effects.

3.3 Data and Safety Monitoring Plan

Applicants should follow the NINDS Guidelines for Data and Safety Monitoring in Clinical Trials (https://www.ninds.nih.gov/funding/apply-funding/application-support-library/clinical-research-guidelines/ninds-guidelines-monitoring-clinical-trials) when developing their Data and Safety Monitoring Plan (DSMP).

3.5 Overall Structure of the Study Team

• Describe a Clinical Site Monitoring Plan including how site adherence to the protocol and consenting process will be ensured, who will be responsible for site monitoring, the frequency of planned monitoring activities, and the plan for handling deficiencies. Also describe plans for training and, if needed, certifying site personnel to complete study procedures.
• Describe a Data Management Plan including the methods and systems for data collection and quality control, and for ensuring data confidentiality and privacy.
• Describe the plans, if any, to use non-traditional data collection approaches (e.g., digital/mobile/sensor technologies and web-based systems) and why these are appropriate.
• Describe the composition and role of any advisory committees.
• Discuss the responsibilities, oversight and coordination of any centers or cores.
• Describe any subcontracts or service agreements for personnel or facilities.
• If applicable, include a statement regarding how Clinical and Translational Science Award (CTSA) program (http://ncats.nih.gov/ctsa) resources will be leveraged. Describe what CTSA services will be used at each participating CTSA site and how the use of the CTSA impacts the trial budget.

Delayed Onset Study

Note: Delayed onset does NOT apply to a study that can be described but will not start immediately (i.e., delayed start). All instructions in the How to Apply - Application Guide must be followed.

All instructions in the How to Apply - Application Guide must be followed.

3. Unique Entity Identifier and System for Award Management (SAM)

See Part 2. 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. 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. When a submission date falls on a weekend or Federal holiday, the application deadline is automatically extended to the next business day.

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 and time.  If a Changed/Corrected application is submitted after the deadline, the application will be considered late. Applications that miss the due date and time are subjected to the NIH Grants Policy Statement Section 2.3.9.2 Electronically Submitted Applications.

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 How to Apply – Application Guide.

5. Intergovernmental Review (E.O. 12372)

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 Section 7.9.1 Selected Items of Cost.

Applications must be submitted electronically following the instructions described in the How to Apply - Application Guide. Paper applications will not be accepted.

Applicants must complete all required registrations before the application due date. Section III. Eligibility Information contains information about registration.

For assistance with your electronic application or for more information on the electronic submission process, visit How to Apply – Application Guide. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Dealing with System Issues guidance. 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 form. 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 NOFO for information on registration requirements.

The applicant organization must ensure that the unique entity identifier provided on the application is the same identifier used in the organization’s profile in the eRA Commons and for the System for Award Management. Additional information may be found in the How to Apply - 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 and responsiveness by NINDS, NIH. Applications that are incomplete, non-compliant and/or non-responsive will not be reviewed.

Recipients or subrecipients must submit any information related to violations of federal criminal law involving fraud, bribery, or gratuity violations potentially affecting the federal award. See Mandatory Disclosures, 2 CFR 200.113 and NIH Grants Policy Statement Section 4.1.35.

Send written disclosures to the NIH Chief Grants Management Officer listed on the Notice of Award for the IC that funded the award and to the HHS Office of Inspector Grant Self Disclosure Program at grantdisclosures@oig.hhs.gov. 

Applicants are required to follow the instructions for post-submission materials, as described in the policy

IRB Communications (Optional – 5 pages max). Submissions that exceed this limit will not be accepted:

• This attachment should be entitled “IRB Communications.pdf”.
• Applicants should submit relevant approval letters and associated attachments.

FDA Documentation (if not provided in the application):

• This attachment should be entitled “FDA May Proceed Documentation.pdf”.
• Applicants must submit documentation such as a "may proceed" email or letter from the FDA for the intermediate EA protocol for ALS that is the subject of the grant application.

As part of “just-in-time” materials, the drug/biological product sponsor will be required to certify Small Business Concern eligibility under section 3(a) of the Small Business Act (15 U.S.C. 632(a)) prior to award.

Section V. Application Review Information

1. Criteria

Only the review criteria described below will be considered in the review process.  Applications submitted to the NIH in support of the NIH mission are evaluated for scientific and technical merit through the NIH peer review system.

A proposed Clinical Trial application may include study design, methods, and intervention that are not by themselves innovative but address important questions or unmet needs. Additionally, the results of the clinical trial may indicate that further clinical development of the intervention is unwarranted or lead to new avenues of scientific investigation.

Overall Impact

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).

Scored Review Criteria

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.

Significance

Does the project address an important problem or a critical barrier to progress in the field? Is the prior research that serves as the key support for the proposed project rigorous? 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?

Are the scientific rationale and need for a clinical trial to test the proposed hypothesis or intervention well supported by preliminary data, clinical and/or preclinical studies, or information in the literature or knowledge of biological mechanisms? For trials focusing on clinical or public health endpoints, is this clinical trial necessary for testing the safety, efficacy or effectiveness of an intervention that could lead to a change in clinical practice, community behaviors or health care policy? For trials focusing on mechanistic, behavioral, physiological, biochemical, or other biomedical endpoints, is this trial needed to advance scientific understanding?

Specific to this NOFO:

• How well will data generated through the EA protocol for the investigational drug/biological product inform our understanding of ALS by supporting research or development related to the prevention, diagnosis, mitigation, treatment, or cure of ALS?
• How well will the proposed intermediate EA protocol for ALS contribute data on the safety or other biologic effects of the intervention that could affect clinical practice should the intervention prove effective?
• How well does the application describe prior research that serves as the key support for the research goal(s) to be supported by data generated through the intermediate EA protocol for ALS? Examples of prior research may include preliminary data, clinical and/or preclinical studies, or information in the literature or knowledge of biological mechanisms. How well do these prior research efforts employ rigorous practices such as minimization of experimental biases, robust experimental design, transparent reporting of results and analysis, and careful interpretation?

Investigator(s)

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?

With regard to the proposed leadership for the project, do the PD/PI(s) and key personnel have the expertise, experience, and ability to organize, manage and implement the proposed clinical trial and meet milestones and timelines? Do they have appropriate expertise in study coordination, data management and statistics? For a multicenter trial, is the organizational structure appropriate and does the application identify a core of potential center investigators and staffing for a coordinating center?

Innovation

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?

Does the design/research plan include innovative elements, as appropriate, that enhance its sensitivity, potential for information or potential to advance scientific knowledge or clinical practice?

Approach

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Have the investigators included plans to address weaknesses in the rigor of prior research that serves as the key support for the proposed project? Have the investigators presented strategies to ensure a robust and unbiased approach, as appropriate for the work proposed? 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? Have the investigators presented adequate plans to address relevant biological variables, such as sex, for studies in vertebrate animals or human subjects?

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 individuals of all ages (including children and older adults), justified in terms of the scientific goals and research strategy proposed?

Does the application adequately address the following, if applicable

Study Design

Is the study design justified and appropriate to address primary and secondary outcome variable(s)/endpoints that will be clear, informative and relevant to the hypothesis being tested? Is the scientific rationale/premise of the study based on previously well-designed preclinical and/or clinical research? Given the methods used to assign participants and deliver interventions, is the study design adequately powered to answer the research question(s), test the proposed hypothesis/hypotheses, and provide interpretable results? Is the trial appropriately designed to conduct the research efficiently? Are the study populations (size, gender, age, demographic group), proposed intervention arms/dose, and duration of the trial, appropriate and well justified?

Are potential ethical issues adequately addressed? Is the process for obtaining informed consent or assent appropriate? Is the eligible population available? Are the plans for recruitment outreach, enrollment, retention, handling dropouts, missed visits, and losses to follow-up appropriate to ensure robust data collection? Are the planned recruitment timelines feasible and is the plan to monitor accrual adequate? Has the need for randomization (or not), masking (if appropriate), controls, and inclusion/exclusion criteria been addressed? Are differences addressed, if applicable, in the intervention effect due to sex/gender and race/ethnicity?

Are the plans to standardize, assure quality of, and monitor adherence to, the trial protocol and data collection or distribution guidelines appropriate? Is there a plan to obtain required study agent(s)? Does the application propose to use existing available resources, as applicable?

Data Management and Statistical Analysis

Are planned analyses and statistical approach appropriate for the proposed study design and methods used to assign participants and deliver interventions? Are the procedures for data management and quality control of data adequate at clinical site(s) or at center laboratories, as applicable? Have the methods for standardization of procedures for data management to assess the effect of the intervention and quality control been addressed? Is there a plan to complete data analysis within the proposed period of the award?

Specific to this NOFO:

• Which elements of the proposed intermediate EA protocol for ALS ensure a study design that will avoid interfering with the initiation, conduct, or completion of clinical investigations that could support marketing approval or otherwise compromise the potential development of medical products for the prevention, diagnosis, mitigation, treatment, or cure of ALS? How well will these elements of the study design work to prevent interference?
• How well does the application demonstrate robust methods for obtaining, analyzing, and interpreting data with rigor?
• How strong is the justification that the planned enrollment will appropriately represent the sex/gender, race, ethnicity and age of the population of individuals in the U.S. affected by ALS? How likely are the recruitment and retention strategies provided in the application to achieve the planned enrollment? How well described are the primary and back-up recruitment and retention strategies to reduce obstacles for the participants and to ensure enrollment of appropriate diverse cohorts of participants?
• How appropriate are the proposed use of NIH/NINDS CDEs and other NIH resources to standardize the collection of clinical data (as applicable)?
• If applicable, how appropriate are the non-traditional data collection approaches and the justification to use them?
• How appropriate are the descriptions of the composition and role of any advisory committees, and the responsibilities, oversight and coordination of any sites or centers ?
• How does the application show that patient groups and other relevant stakeholders view the question to be important and consider the study design to be acceptable?
• How well does the application address potential limitations and/or challenges in the protocol and how these will be addressed?

Environment

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?

If proposed, are the administrative, data coordinating, enrollment and laboratory/testing centers, appropriate for the trial proposed?

Does the application adequately address the capability and ability to conduct the trial at the proposed site(s) or centers? Are the plans to add or drop enrollment centers, as needed, appropriate?

If international site(s) is/are proposed, does the application adequately address the complexity of executing the clinical trial?

If multi-sites/centers, is there evidence of the ability of the individual site or center to: (1) enroll the proposed numbers; (2) adhere to the protocol; (3) collect and transmit data in an accurate and timely fashion; and, (4) operate within the proposed organizational structure?

Additional Review Criteria

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.

Study Timeline

Is the study timeline described in detail, taking into account start-up activities, the anticipated rate of enrollment, and planned follow-up assessment? Is the projected timeline feasible and well justified? Does the project incorporate efficiencies and utilize existing resources (e.g., CTSAs, practice-based research networks, electronic medical records, administrative database, or patient registries) to increase the efficiency of participant enrollment and data collection, as appropriate?

Are potential challenges and corresponding solutions discussed (e.g., strategies that can be implemented in the event of enrollment shortfalls)?

Protections for Human Subjects

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

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

Inclusion of Women, Minorities, and Individuals Across the Lifespan

When the proposed project involves human subjects and/or 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 individuals of all ages (including children and older adults) to determine if it is justified in terms of the scientific goals and research strategy proposed. For additional information on review of the Inclusion section, please refer to the Guidelines for the Review of Inclusion in Clinical Research.

Vertebrate Animals

The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following three points: (1) a complete description of all proposed procedures including the species, strains, ages, sex, and total numbers of animals to be used; (2) justifications that the species is appropriate for the proposed research and why the research goals cannot be accomplished using an alternative non-animal model; and (3) interventions including analgesia, anesthesia, sedation, palliative care, and humane endpoints that will be used to limit any unavoidable discomfort, distress, pain and injury in the conduct of scientifically valuable research. Methods of euthanasia and justification for selected methods, if NOT consistent with the AVMA Guidelines for the Euthanasia of Animals, is also required but is found in a separate section of the application. For additional information on review of the Vertebrate Animals Section, please refer to the Worksheet for Review of the Vertebrate Animals Section.

Biohazards

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.

Resubmissions

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.

Renewals

Not Applicable

Revisions

Not Applicable

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.

Applications from Foreign Organizations

Not Applicable.

Select Agent Research

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).

Resource Sharing Plans

Reviewers will comment on whether the Resource Sharing Plan(s) (i.e., Sharing Model Organisms) or the rationale for not sharing the resources, is reasonable.

Authentication of Key Biological and/or Chemical Resources:

For projects involving key biological and/or chemical resources, reviewers will comment on the brief plans proposed for identifying and ensuring the validity of those resources.

Budget and Period of Support

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

2. Review and Selection Process

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

As part of the scientific peer review, all applications 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 submitted in response to this NOFO. 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.

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 Section 2.5.1. Just-in-Time Procedures. This request is not a Notice of Award nor should it be construed to be an indicator of possible funding.

Prior to making an award, NIH reviews an applicant’s federal award history in SAM.gov to ensure sound business practices. An applicant can review and comment on any information in the Responsibility/Qualification records available in SAM.gov.  NIH will consider any comments by the applicant in the Responsibility/Qualification records in SAM.gov to ascertain the applicant’s integrity, business ethics, and performance record of managing Federal awards per 2 CFR Part 200.206 “Federal awarding agency review of risk posed by applicants.”  This provision will apply to all NIH grants and cooperative agreements except fellowships.

3. Anticipated Announcement and Award Dates

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. Refer to Part 1 for dates for peer review, advisory council review, and earliest start date.

Information regarding the disposition of applications is available in the NIH Grants Policy Statement Section 2.4.4 Disposition of Applications.

Section VI. Award Administration Information

1. Award Notices

A Notice of Award (NoA) is the official authorizing document notifying the applicant that an award has been made and that funds may be requested from the designated HHS payment system or office. The NoA is signed by the Grants Management Officer and emailed to the recipient’s business official.

In accepting the award, the recipient agrees that any activities under the award are subject to all provisions currently in effect or implemented during the period of the award, other Department regulations and policies in effect at the time of the award, and applicable statutory provisions.

Recipients must comply with any funding restrictions described in Section IV.6. Funding Restrictions. Any pre-award costs incurred before receipt of the NoA are at the applicant's own risk.  For more information on the Notice of Award, please refer to the NIH Grants Policy Statement Section 5. The Notice of Award and NIH Grants & Funding website, see Award Process.

Individual awards are based on the application submitted to, and as approved by, the NIH and are subject to the IC-specific terms and conditions identified in the NoA.

ClinicalTrials.gov: If an award provides for one or more clinical trials. By law (Title VIII, Section 801 of Public Law 110-85), the "responsible party" must register and submit results information for certain “applicable clinical trials” on the ClinicalTrials.gov Protocol Registration and Results System Information Website (https://register.clinicaltrials.gov). NIH expects registration and results reporting of all trials whether required under the law or not. For more information, see https://grants.nih.gov/policy/clinical-trials/reporting/index.htm

Institutional Review Board or Independent Ethics Committee Approval: Recipient institutions must ensure that all protocols are reviewed by their IRB or IEC. To help ensure the safety of participants enrolled in NIH-funded studies, the recipient must provide NIH copies of documents related to all major changes in the status of ongoing protocols.

Data and Safety Monitoring Requirements: The NIH policy for data and safety monitoring requires oversight and monitoring of all NIH-conducted or -supported human biomedical and behavioral intervention studies (clinical trials) to ensure the safety of participants and the validity and integrity of the data. Further information concerning these requirements is found at http://grants.nih.gov/grants/policy/hs/data_safety.htm and in the application instructions (SF424 (R&R) and PHS 398).

Investigational New Drug or Investigational Device Exemption Requirements: Consistent with federal regulations, clinical research projects involving the use of investigational therapeutics, vaccines, or other medical interventions (including licensed products and devices for a purpose other than that for which they were licensed) in humans under a research protocol must be performed under a Food and Drug Administration (FDA) investigational new drug (IND) or investigational device exemption (IDE).

2. Administrative and National Policy Requirements

The following Federal wide and HHS-specific policy requirements apply to awards funded through NIH:

• The rules listed at 2 CFR Part 200, Uniform Administrative Requirements, Cost Principles, and Audit Requirements for Federal Awards.
• All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the terms and conditions in the Notice of Award (NoA). The NoA includes the requirements of this NOFO. 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, Recipients, and Activities.
• If a recipient receives an award, the recipient must follow all applicable nondiscrimination laws. The recipient agrees to this when registering in SAM.gov. The recipient must also submit an Assurance of Compliance (HHS-690). To learn more, see the Laws and Regulations Enforced by the HHS Office for Civil Rights website. 
  • HHS recognizes that NIH research projects are often limited in scope for many reasons that are nondiscriminatory, such as the principal investigator’s scientific interest, funding limitations, recruitment requirements, and other considerations. Thus, criteria in research protocols that target or exclude certain populations are warranted where nondiscriminatory justifications establish that such criteria are appropriate with respect to the health or safety of the subjects, the scientific study design, or the purpose of the research. For additional guidance regarding how the provisions apply to NIH grant programs, please contact the Scientific/Research Contact that is identified in Section VII under Agency Contacts of this NOFO.

All federal statutes and regulations relevant to federal financial assistance, including those highlighted in NIH Grants Policy Statement Section 4 Public Policy Requirements, Objectives and Other Appropriation Mandates.

Recipients are responsible for ensuring that their activities comply with all applicable federal regulations.  NIH may terminate awards under certain circumstances.  See 2 CFR Part 200.340 Termination and NIH Grants Policy Statement Section 8.5.2 Remedies for Noncompliance or Enforcement Actions: Suspension, Termination, and Withholding of Support. 

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 (HHS) grant administration regulations at 2 CFR Part 200, and other HHS, PHS, and NIH grant administration policies.

The administrative and funding instrument used for this program will be the cooperative agreement, an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH programmatic involvement with the recipients is anticipated during the performance of the activities. Under the cooperative agreement, the NIH purpose is to support and stimulate the recipients' activities by involvement in and otherwise working jointly with the 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 recipients for the project as a whole, although specific tasks and activities may be shared among the recipients and NIH as defined below.

• “NINDS reserves the right to curtail the study (or an individual award) under a range of scenarios including but not limited to (a) failure to implement the study protocol, (b) a substantial shortfall in subject recruitment, follow-up, data reporting and dissemination, quality control, or other major breach of the protocol, (c) substantive changes in the agreed-upon protocol with which NINDS does not concur, (d) reaching a major study objective substantially ahead of schedule with persuasive statistical evidence, (e) human subject safety or ethical issues that may dictate a premature termination, or (f) a change in the state of science that has significant impact on the relevance of the question.

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

• The Program Director/Principal Investigator will have the primary responsibility to define research objectives and approaches and to plan, conduct, analyze and publish results, interpretation, and conclusions of their studies and for providing overall scientific and administrative leadership for the research project.
• The PD/PI will oversee all aspects of the organization and execution of the studies outlined in the application and approved by NINDS after peer review.
• Recipients have primary and lead responsibilities for the project as a whole, including any modification of study design, conduct of the study, quality control, data analysis and interpretation, preparation of publications, and collaboration with other investigators, unless otherwise provided for in these terms or by action of the primary leadership committee.
• Recipients will be responsible for reporting recruitment data to the NINDS Recruitment Planning & Monitoring System (RPMS).
• Recipients will be responsible for putting all study materials and procedure manuals into the public domain. Recipients are expected to publish and publicly disseminate results, data and other products of the study, concordant with governance policies and protocols. Publications and oral presentations of work performed under this agreement will require appropriate acknowledgment of support by the NINDS/NIH.
• Recipients will be responsible for obtaining prior written approval of the NINDS Grants Management Specialist in consultation with the NINDS Program Officer for any change in any of the key personnel identified in the Notice of Grant Award.
• Recipients(s) will retain custody of and have primary rights to the data and software developed under these awards, subject to Government policies regarding rights of access consistent with current DHHS, PHS, and NIH policies.

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

An NINDS Project Scientist will have substantial programmatic involvement that is above and beyond the typical stewardship role in other awards, as described below:

• Serve as a resource to provide scientific/programmatic support during the accomplishment of the research by participating in the design of the activities, advising in the selection of sources or resources (e.g., determining where a particular reagent can be found), provision of research resources and reagents available from NINDS recipients and contractors, advising in management and technical performance, or participating in the preparation of publications.
• Function as one of several co-investigators, collaborating and interacting as necessary with the PI in accomplishing the overall goals of the Research Program.
• Serve on the primary leadership committee.

An NINDS Program Official will have substantial programmatic involvement that is above and beyond the typical stewardship role in other awards, as described below:

• Oversee the adequacy of adverse event management and reporting and have regular communications with the PD/PI and study team, which may include attendance at the DSMB and related committee meetings.
• Review the progress of the study, and of each participating facility, through consideration of the annual reports, site visits, screening logs, etc. This review may include, but is not limited to, compliance with the study protocol, adherence to uniform data collection procedures, and the timeliness and quality of data reporting.
• Monitor progress of study milestones; as with any award, continuation, even during the period recommended for support, is contingent upon satisfactory progress. Progress will be monitored by NINDS. The schedule for these interim reviews will be based upon the duration of the intermediate EA protocol for ALS period. Continuation of funding will be dependent upon the recipient’s ability to show adequate progress towards milestone accomplishment.

A third NINDS Program Official from the Division of Clinical Research may serve as the NINDS liaison to the Data and Safety Monitoring Board (DSMB). All efforts will be made by the Sponsor, PI/PD and study team to communicate the following to the DSMB members with the goal of safeguarding participants of the expanded access trial:

• Data and/or DSMB reports from ongoing efficacy trials of the investigational medical product including safety data and/or recommendations for continuation, modification, or termination of the trial
• Substantive basic scientific or clinical therapeutic developments that affect the safety of participants or ethics of continuing the trial
• Any interval regulatory correspondence with the U.S. F.D.A. and/or Office of Human Research Protections (OHRP) impacting participant safety

Areas of Joint Responsibility include:

• A steering committee will be established to discuss interventions, follow up, quality control, protocol adherence, assessment of problems affecting the study and potential changes in the protocol, interim data safety and monitoring, final data analysis and interpretation, preparation of publications, and development of solutions. The PI/PD will serve on the steering committee with the NINDS Project Scientist, and other NINDS Program Officials. If a voting structure is introduced, the NINDS Project Scientist will be a voting member, and NINDS Program Officials may serve as non-voting members.
• Recipients will be required to accept and implement policies approved by the Steering Committee.

Dispute Resolution:

Any disagreements that may arise in scientific or programmatic matters (within the scope of the award) between recipients and NIH may be brought to Dispute Resolution. A Dispute Resolution Panel composed of three members will be convened: 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 individual disagreement, the first member may be chosen by the individual recipient. This special dispute resolution procedure does not alter the recipient's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulation 42 CFR Part 50, Subpart D and HHS regulation 45 CFR Part 16.

3. Data Management and Sharing

Consistent with the 2023 NIH Policy for Data Management and Sharing, when data management and sharing is applicable to the award, recipients will be required to adhere to the Data Management and Sharing requirements as outlined in the NIH Grants Policy Statement. Upon the approval of a Data Management and Sharing Plan, it is required for recipients to implement the plan as described.

4. Reporting

When multiple years are involved, recipients will be required to submit the Research Performance Progress Report (RPPR) annually and financial statements as required in the NIH Grants Policy Statement Section 8.4.1 Reporting.  To learn more about post-award monitoring and reporting, see the NIH Grants & Funding website, see Post-Award Monitoring and Reporting.

A final RPPR, invention statement, and the expenditure data portion of the Federal Financial Report are required for closeout of an award, as described in the NIH Grants Policy Statement Section 8.6 Closeout. NIH NOFOs outline intended research goals and objectives. Post award, NIH will review and measure performance based on the details and outcomes that are shared within the RPPR, as described at 2 CFR Part 200.301.

Section VII. Agency Contacts

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

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

Finding Help Online: https://www.era.nih.gov/need-help (preferred method of contact)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

General Grants Information (Questions regarding application instructions, application processes, and NIH grant resources)
Email: GrantsInfo@nih.gov (preferred method of contact)
Telephone: 301-480-7075

Grants.gov Customer Support (Questions regarding Grants.gov registration and Workspace)
Contact Center Telephone: 800-518-4726
Email: support@grants.gov

Amy Tsou, M.D.
National Institute of Neurological Disorders and Stroke (NINDS)
Division of Clinical Research
Email: amy.tsou@nih.gov

Emily Caporello, Ph.D.
National Institute of Neurological Disorders and Stroke (NINDS)
Division of Translational Research
Email: emily.caporello@nih.gov

Chief, Scientific Review Branch
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone:  301-496-9223
Email: nindsreview.nih.gov@mail.nih.gov

Chief Grants Management Officer
National Institute of Neurological Disorders and Stroke (NINDS)
Email: ChiefGrantsManagementOfficer@ninds.nih.gov

Section VIII. Other Information

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 2 CFR Part 200.