Department of Health and Human Services

Part 1. Overview Information

Participating Organization(s)

National Institutes of Health (NIH)

Components of Participating Organizations

National Institute of Neurological Disorders and Stroke (NINDS)

Funding Opportunity Title
NINDS Exploratory Clinical Trials for Small Business (R43/R44 Clinical Trial Required)
Activity Code

R43/R44 Small Business Innovation Research (SBIR) Grant - Phase I, Phase II, and Fast-Track

Announcement Type
Reissue of PAR-21-266
Related Notices

    See Notices of Special Interest associated with this funding opportunity

  • June 12, 2023 - Implementation of the NIH SBIR and STTR Foreign Disclosure Pre-award and Post-Award Requirements­­. See NOT-OD-23-139.
  • February 23, 2023 - Notice of Change to Minimum Performance Standards for SBIR and STTR Applicants­­. See NOT-OD-23-092.
  • August 31, 2022 - Implementation Changes for Genomic Data Sharing Plans Included with Applications Due on or after January 25, 2023. See Notice NOT-OD-22-198.
  • August 5, 2022 - Implementation Details for the NIH Data Management and Sharing Policy. See Notice NOT-OD-22-189.
Funding Opportunity Number (FON)
PAR-23-311
Companion Funding Opportunity
PAR-24-044 , R41/ R42 Small Business Technology Transfer (STTR) Grants - Phase I/ * Small Business Technology Transfer (STTR) Grants - Phase II
Assistance Listing Number
93.853
Notice of Funding Opportunity Purpose

The purpose of this notice of funding opportunity (NOFO) is to provide a vehicle for Small Business Concerns (SBCs) submitting Small Business Innovation Research (SBIR) grant applications for investigator-initiated exploratory clinical trials to the National Institute of Neurological Disorders and Stroke (NINDS). The projects must focus on products related to the mission and goals of the NINDS and may evaluate drugs, biologics, devices, or diagnostics, as well as surgical, behavioral or rehabilitation therapies.

Plan for Enhancing Diverse Perspectives

The NIH recognizes that diverse teams working together and capitalizing on innovative ideas and distinct perspectives outperform homogeneous teams. There are many benefits that flow from a diverse scientific workforce, including: fostering scientific innovation, enhancing global competitiveness, contributing to robust learning environments, improving the quality of the research, advancing the likelihood that underserved populations participate in, and benefit from research, and enhancing public trust.

To support the best science, the NIH encourages inclusivity in research. Examples of structures that promote diverse perspectives include but are not limited to:

  • Transdisciplinary research projects and collaborations among neuroscientists and researchers from fields such as computational biology, physics, engineering, mathematics, computer and data sciences, as well as bioethics.
  • Engagement from different types of institutions and organizations (e.g., research-intensive, undergraduate-focused, minority-serving, community-based).
  • Individual applications and partnerships that enhance geographic and regional heterogeneity.
  • Investigators and teams composed of researchers at different career stages.
  • Participation of individuals from diverse backgrounds, including groups traditionally underrepresented in the biomedical, behavioral, and clinical research workforce (see NOT-OD-20-031), such as underrepresented racial and ethnic groups, those with disabilities, those from disadvantaged backgrounds, and women.
  • Opportunities to enhance the research environment to benefit early- and mid-career investigators.

This NOFO requires a Plan for Enhancing Diverse Perspectives (PEDP), which will be assessed as part of the scientific and technical peer review evaluation. Applications that fail to include a PEDP will be considered incomplete and will be withdrawn.

Applicants are strongly encouraged to read the NOFO instructions carefully and view the available PEDP guidance material.

Key Dates

Posted Date
November 27, 2023
Open Date (Earliest Submission Date)
December 05, 2023
Letter of Intent Due Date(s)

30 days prior to the application due date

The following table includes NIH standard due dates marked with an asterisk.
Application Due Dates Review and Award Cycles
New Renewal / Resubmission / Revision (as allowed) AIDS - New/Renewal/Resubmission/Revision, as allowed Scientific Merit Review Advisory Council Review Earliest Start Date
January 05, 2024 * January 05, 2024 * Not Applicable March 2024 May 2024 July 2024
April 05, 2024 * April 05, 2024 * Not Applicable July 2024 August 2024 December 2024
September 05, 2024 * September 05, 2024 * Not Applicable November 2024 January 2025 April 2025
January 05, 2025 * January 05, 2025 * Not Applicable March 2025 May 2025 July 2025
April 05, 2025 * April 05, 2025 * Not Applicable July 2025 August 2025 December 2025
September 05, 2025 * September 05, 2025 * Not Applicable November 2025 January 2026 April 2026
January 05, 2026 * January 05, 2026 * Not Applicable March 2026 May 2026 July 2026
April 05, 2026 * April 05, 2026 * Not Applicable July 2026 August 2026 December 2026
September 05, 2026 * September 05, 2026 * Not Applicable November 2026 January 2027 April 2027

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.

Expiration Date
September 06, 2026
Due Dates for E.O. 12372

Not Applicable

Required Application Instructions

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

Conformance to all requirements (both in the Application Guide and the NOFO) 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.

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.


  4. Table of Contents

Part 2. Full Text of Announcement

Section I. Notice of Funding Opportunity Description

Purpose

NINDS is committed to advancing diagnostics and treatments for people burdened by neurological diseases, and the NINDS Small Business Innovation Research (SBIR) and Small Business Technology Transfer (STTR) programs have provided the small business community with critical seed funding to support the development of a wide variety of technologies and therapeutics for the diagnosis and treatment of neurological diseases. The SBIR/STTR Programs are structured in three phases. The main objective in SBIR/STTR Phase I is to establish the technical merit and feasibility of the proposed research and development (R&D) efforts, whereas in SBIR/STTR Phase II it is to continue the R&D efforts to advance the technology toward ultimate commercialization. At the conclusion of an SBIR/STTR Phase II, it is expected that the small business concern (SBC) will fully commercialize their product or technology using non-SBIR/STTR funds in Phase III.

The development of medical biotechnology products is often impeded by a significant funding gap (known as the “Valley of Death”). In particular, the development of regulated products such as therapeutics and medical devices often requires several years and substantial capital investments, due in part to the high costs of clinical trials.

This NOFO supports applications from Small Business Concerns (SBCs) for exploratory clinical trials that contribute to the justification for a future trial to establish definitive efficacy (such as a Phase 3 clinical trial or a Pivotal device trial). This includes Phase 1 and 2 studies of drugs and biologics, feasibility and preliminary efficacy studies of devices, as well as early studies of surgical, behavioral or rehabilitation therapies. This NOFO supports single-site and multi-site trials with up to three clinical sites. Applications must aim to generate data that inform further clinical development of the proposed intervention or diagnostic, and in the case of FDA-regulated clinical trials applications must demonstrate readiness by including FDA approval of the proposed study. The earliest clinical studies should be designed to provide important initial information regarding the intervention (e.g., safety, tolerability, dosing) or diagnostic. Midstage clinical studies will generally include randomization and blinding and should yield data that allow a clear go/no-go decision regarding whether the intervention should proceed to an efficacy trial. All applications must outline specific plans for future development in the event of promising results.

This NOFO is not intended to support the conduct of a clinical trial where the primary aim is to establish or confirm definitive efficacy. Applications to implement definitive efficacy trials (e.g., Phase 3 clinical trials of drugs or Pivotal device trials) should be submitted to NINDS Efficacy Clinical Trials (UG3/UH3). See https://grants.nih.gov/grants/guide/pa-files/PAR-21-237.html for more information.

This NOFO is not intended to support the conduct of clinical trials with more than three clinical sites. NINDS supports several clinical trial networks specifically designed to implement larger multi-site clinical trials. See https://www.ninds.nih.gov/Current-Research/Research-Funded-NINDS/Clinical-Research for more information.

Renewal applications of SBIR Phase II awards (i.e., SBIR Phase IIB) to conduct Phase I and II clinical studies should be submitted to NINDS Renewal Awards of SBIR Phase II Grants (Phase IIB) for Clinical Trials and Clinical Research (R44).

The goal of this NOFO is to assist applicants in pursuing the next appropriate milestone(s) necessary to advance a product/technology that requires Federal regulatory approval or to bring a complex research tool to market. To achieve this goal, the NOFO aims to facilitate the transition of clinical-stage projects to the commercialization stage by encouraging business relationships between NIH’s SBIR/STTR recipients and third-party investors and/or strategic partners.

Definitions

For this funding opportunity announcement Phase 1 and 2 clinical studies or trials refer to the common phases of a clinical trial. SBIR Phase I and II refer to the project phases of the SBIR program.

NIH defines a clinical trial as "a research study in which one or more human subjects are prospectively assigned to one or more interventions (which may include placebo or other control) to evaluate the effects of those interventions on health-related biomedical or behavioral outcomes."

Specific Objectives

Scientific/Technical Scope

Examples of appropriate studies under this NOFO include, but are not limited to, those designed to:

  • Evaluate and optimize the dose, formulation, safety, tolerability or pharmacokinetics of an intervention in healthy volunteers or the target population.
  • Evaluate whether an intervention produces sufficient evidence of short-term activity (e.g., biomarker activity, target engagement, dose-response trends, pharmacodynamic response) in a human "proof of concept" trial.
  • Select or rank the best of two or more potential interventions or dosing regimens to be evaluated in a subsequent trial, based on tolerability, biological activity, or preliminary clinical efficacy (e.g., futility trials).
  • For devices: Establish proof-of-principle and optimize techniques, operation, and usability of a device; inform the final device design decisions; and estimate the magnitude of treatment effect.

NINDS recognizes that devices can differ greatly in terms of basic form and function, physiological bases for therapy, degree of invasiveness, etc. A Pivotal device study, for example, could potentially be used in support of an off-label indication of an existing market approved device, or to provide evidence for a novel device design in support of a Pre-Market Approval (PMA), Humanitarian Device Exemption (HDE), 510(k) or 510(k) De Novo submission. Due to the broad scope of possible medical devices and the varied nature of the regulatory path, investigators considering applications to evaluate devices are strongly encouraged to contact Scientific/Research Staff as early as possible to discuss these issues and determine the suitability of their project for this funding mechanism.

Every facet of the United States scientific research enterprise—from basic laboratory research to clinical and translational research to policy formation–requires superior intellect, creativity and a wide range of skill sets and viewpoints. NIH’s ability to help ensure that the nation remains a global leader in scientific discovery and innovation is dependent upon a pool of highly talented scientists from diverse backgrounds who will help to further NIH's mission. Research shows that diverse teams working together and capitalizing on innovative ideas and distinct perspectives outperform homogenous teams. Scientists and trainees from diverse backgrounds and life experiences bring different perspectives, creativity, and individual enterprise to address complex scientific problems. There are many benefits that flow from a diverse NIH-supported scientific workforce, including: fostering scientific innovation, enhancing global competitiveness, contributing to robust learning environments, improving the quality of the research, advancing the likelihood that underserved or health disparity populations participate in, and benefit from health research, and enhancing public trust.  See the Notice of NIH's Interest in Diversity, NOT-OD-20-031. Moreover, fostering diversity by encouraging the participation of individuals from nationally underrepresented groups in the scientific research workforce is a longstanding interest of Congress, (e.g., Public Law 117–167, CHIPS and Science Act of 2022, P.L. 114-329, American Innovation and Competitiveness Act of 2017, P.L. 114-255, 21st Century Cures Act of 2016). Also, fostering and encouraging participation by socially and economically disadvantaged and women-owned small businesses in technological innovation is one of the goals of the SBIR and STTR programs (https://www.sbir.gov/sites/default/files/SBA%20SBIR_STTR_POLICY_DIRECTIVE_May2023.pdf).

Plan for Enhancing Diverse Perspectives

The NIH recognizes that diverse teams working together and capitalizing on innovative ideas and distinct perspectives outperform homogeneous teams. There are many benefits that flow from a diverse scientific workforce, including: fostering scientific innovation, enhancing global competitiveness, contributing to robust learning environments, improving the quality of the research, advancing the likelihood that underserved populations participate in, and benefit from research, and enhancing public trust.

To support the best science, the NIH encourages inclusivity in research. Examples of structures that promote diverse perspectives include but are not limited to:

  • Transdisciplinary research projects and collaborations among neuroscientists and researchers from fields such as computational biology, physics, engineering, mathematics, computer and data sciences, as well as bioethics.
  • Engagement from different types of institutions and organizations (e.g., research-intensive, undergraduate-focused, minority-serving, community-based).
  • Individual applications and partnerships that enhance geographic and regional heterogeneity.
  • Investigators and teams composed of researchers at different career stages.
  • Participation of individuals from diverse backgrounds, including groups traditionally underrepresented in the biomedical, behavioral, and clinical research workforce (see NOT-OD-20-031), such as underrepresented racial and ethnic groups, those with disabilities, those from disadvantaged backgrounds, and women.
  • Opportunities to enhance the research environment to benefit early- and mid-career investigators.

This NOFO requires a Plan for Enhancing Diverse Perspectives (PEDP), as described in NOT-MH-21-310, submitted as Other Project Information as an attachment (see Section IV). Applications that fail to include a PEDP will be considered incomplete and will be withdrawn.

Applicants are strongly encouraged to read the NOFO instructions carefully and view the available PEDP guidance materia. The PEDP lwill be assessed as part of the scientific and technical peer review evaluation.

Independent Third-Party Partners

As significant funding is often needed to take regulated clinical projects to market beyond initial clinical studies, we encourage applicants to develop business relationships between applicant SBCs and third-party investors/strategic partners who can provide substantial financing to help accelerate the commercialization of promising new products and technologies initiated with NIH SBIR or STTR funding. Third-party partners include, but are not limited to, another company, a venture capital firm, an “angel” investor, a foundation, a university, a research institution, a state or local government, or any combination of the above. In light of these goals, the NINDS strongly encourages applicants to establish business relationships with investors and/or strategic partners that have appropriate prior experience in the commercialization of emerging biomedical technologies.

That said, NINDS recognizes that companies developing products that have small potential revenue streams or that target small patient populations face additional barriers to market entry that make them less attractive to investors and strategic partners at preclinical or early clinical stages of development. Many of these technologies require complex clinical trial designs because of small and geographically dispersed patient populations.

For the purposes of this NOFO, NINDS has defined small markets as development of novel products that:

  • Address a rare disease, defined in the Rare Diseases Act of 2002 (Public Law 107-280) as a condition affecting fewer than 200,000 individuals in the United States; or
  • Qualify as a Humanitarian Use Device, defined as a medical device intended to benefit patients in the treatment or diagnosis of a disease or condition that affects or is manifested in fewer than 4,000 persons in the United States per year; or
  • Target a young pediatric population defined as including neonates (0-28 days), infants (<2 years), and/or children (2-12 years of age), as indicated in the FDA Premarket Assessment of Pediatric Medical Devices; or
  • Are complex research tools. This is instrumentation comprising several distinct parts that must work together. Very often the goal of such projects is to deliver turnkey products for researchers. For example, high density electroencephalography instrumentation includes electrode arrays, amplifiers, data analytic and data visualization software, etc. Another example is non-invasive near infrared imaging instrumentation, which might include photon sources and detectors, timing devices for delivering photons, amplifiers, and software. Some high throughput assay systems may fall into this category.

NINDS, as part of NIH, strives for rigor and transparency in all research it funds. For this reason, NINDS explicitly emphasizes the NIH application instructions related to rigor and transparency (https://grants.nih.gov/policy/reproducibility/guidance.htm) and provides additional guidance to the scientific community (https://www.ninds.nih.gov/Funding/grant_policy). For example, the biological rationale for the proposed experiments must be based on a robust and rigorous scientific rationale, which means that data supporting the scientific rationale should be collected via methods that minimize the risk of bias and be reported in a transparent manner. If previously published or preliminary studies do not meet these standards, applicants should address how the current study design addresses the deficiencies in rigor and transparency. Proposed experiments should likewise be designed in a manner that minimizes the risk of bias and ensures validity of experimental results.

The proposed clinical trial must be based on a robust and rigorous scientific rationale (e.g., derived from non-clinical in vivo and/or in vitro studies or preliminary clinical studies) that demonstrates that there is an adequate scientific foundation to justify the proposed trial. The proposed trial design must also use rigorous and transparent approaches.

Applicants should take note of the following:

(1) Consultation with NINDS: Applicants are encouraged to consult with NINDS Scientific/Research staff as plans for an application are being developed (see Section VII, Agency Contacts) and no later than 12 weeks prior to the anticipated application submission date. This early contact will provide an opportunity to clarify NINDS policies and guidelines as well as to discuss how to develop an appropriate project timeline and milestone plan, which is subject to peer review. As well, discussions regarding strategies for recruitment and inclusion of women and minorities as participants in research involving human subjects are available.

(2) Other Relevant Programs: NINDS supports several clinical trial networks specifically designed to implement multi-site clinical trials. See https://www.ninds.nih.gov/Current-Research/Research-Funded-NINDS/Clinical-Research for more information:

NeuroNEXT (http://www.neuronext.org): NINDS has a network called NeuroNEXT specifically designed to implement multicenter exploratory clinical trials (see https://www.neuronext.org/) and when appropriate, it is strongly preferred that such trials be performed within this network. Therefore, applying to this exploratory clinical trials NOFO, an applicant should follow the instructions on the above website to obtain feedback on the suitability of their trial for NeuroNEXT. An important advantage of NeuroNEXT is that it can provide clinical, statistical and logistical expertise in developing study protocols as well as a standing national network of experienced clinical sites prepared to enroll study participants.

StrokeNet (http://www.nihstrokenet.org): NINDS has a network called StrokeNet specifically designed to implement multicenter exploratory and efficacy trials in stroke prevention, treatment and rehabilitation (see http://www.nihstrokenet.org/). NINDS requires that all large stroke trials be considered for StrokeNet. Only under exceptional circumstances will NINDS consider funding such trials outside of the StrokeNet program (see https://grants.nih.gov/grants/guide/notice-files/NOT-NS-14-043.html). An important advantage of StrokeNet is that it can provide clinical, statistical and logistical expertise in developing study protocols as well as a standing national network of experienced clinical sites prepared to enroll study participants.

EPPIC-Net (https://www.ninds.nih.gov/Current-Research/Trans-Agency-Activities/NINDS-Role-HEAL-Initiative/NINDS-Role-HEAL-Initiative-EPPIC ): The Early Phase Pain Investigation Clinical Network (EPPIC-Net) seeks to enhance the treatment of acute and chronic pain and reduce reliance on opioids by accelerating early-phase clinical trials of non-addictive treatments for pain. EPPIC-Net has the capacity to quickly and efficiently conduct many simultaneous multisite studies. The network will conduct studies on a variety of treatments, including drugs and devices, as well as studies to better understand pain. Successful asset applicants do not receive funding but rather receive access to EPPIC-Net resources for conduct of the clinical trial for their asset. Intellectual property and products studied within EPPIC-Net remain the property of the asset owner.

SIREN (https://siren.network/): NINDS supports the SIREN network which performs clinical trials that impact the care of the patient with a neurological emergency other than stroke in the pre-hospital or emergency department setting. NINDS requires that all such trials be first considered for the SIREN network, though the study PI may come from outside of the network. The study PI will work with the SIREN network to write the protocol and lead the operations committee for the trial.

Before submitting an application to this NOFO, applicants should consult with NINDS scientific/research staff to obtain feedback on the suitability of their trial for one of these networks. An important advantage of the networks is their capacity to provide clinical, statistical, and logistical expertise in developing study protocols, as well as a standing national network of experienced clinical sites prepared to enroll study participants.

Trans-NIH Initiatives. NINDS participates in funding opportunities under the NIH HEAL Initiative® that support clinical trials focused on development of therapies and technologies directed at enhanced pain management. If eligible, companies are encouraged to apply through these funding opportunities. For more information visit: https://heal.nih.gov/.

NINDS Cooperative Agreement (U44) Translational Programs. NINDS has specific translational programs that utilize the SBIR cooperative agreement mechanism (U44), some of which allow preclinical and clinical trial activity within a single proposal. If eligible, companies are encouraged to apply through these programs. For more information visit: https://www.ninds.nih.gov/Current-Research/Research-Funded-NINDS/Translational-Research.

(3) NIH Resources: As appropriate, applicants are encouraged to make use of the following resources for clinical research including:

Applicants are strongly encouraged to leverage existing NINDS research resources for their studies whenever possible. Such resources may include biospecimens from NINDS Human Biospecimen and Data Repository (BioSEND) or informatics system. The NINDS BioSEND repository receives, processes, stores, and distributes biospecimen resources from NINDS funded studies that can be shared by the neuroscience research community, and currently banks a variety of biospecimens including DNA, plasma, serum, RNA, CSF, and saliva. The NINDS Human Cell and Data Repository provides 1) disease-relevant stem cell lines for biomarker discovery, and/or 2) the capacity to bank blood for the creation of new cell lines relevant to their disease of interest. Leveraging the resources and support from neurological disorder advocacy groups, private research foundations, academic institutions, other government agencies and the NIH Intramural program are also encouraged. Finally, applicants are encouraged to leverage the resources of ongoing clinical trials supported through other Federal or private funds.

Applications proposing to collect biospecimens are strongly recommended to 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. Therefore, most costs for the biospecimen banking are borne by the recipients  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 (email: biosend@iu.edu).

(4) IRB documentation: IRB approval is not required at the time of application submission, but is required prior to funding. As such, NINDS encourages investigators to begin these processes as early as possible. NINDS also will require documentation of any other necessary regulatory approvals (e.g., Recombinant DNA Advisory Committee) prior to funding. Applicants are encouraged to review the NIH policy concerning single IRB for multisite clinical trials (see https://grants.nih.gov/grants/guide/notice-files/NOT-OD-16-094.html and https://grants.nih.gov/grants/guide/notice-files/NOT-OD-17-076.html) as well as the sIRB requirement per the revised Common Rule at 45CFR46.114 https://www.hhs.gov/ohrp/regulations-and-policy/regulations/45-cfr-46/revised-common-rule-regulatory-text/index.html#46.114.

(5) Study Rationale: The rationale for a clinical trial must be based on (i) an unmet medical need; (ii) a plausible biological mechanism; and (iii) robust supporting data, e.g., from non-clinical (in vivo and/or in vitro data) studies or preliminary clinical studies that demonstrate there is an adequate scientific foundation to justify the proposed trial. The scientific premise for the trial should be based on preclinical and/or clinical data from rigorously performed studies (see http://grants.nih.gov/grants/guide/notice-files/NOT-OD-15-103.html). If previous research does not meet the rigor criteria outlined to an acceptable degree, applicants should address how the current study design addresses the deficiencies.

(6) Efficacy: This NOFO is not intended to support the conduct of a clinical trial where the primary aim is to establish or confirm definitive efficacy (although under certain circumstances, early studies of preliminary efficacy can be a secondary aim). While an exploratory clinical trial may examine clinical outcomes or biomarker outcomes as measures of "preliminary efficacy" as a secondary aim, it is important that it not appear to be an underpowered efficacy trial. Applications to implement definitive efficacy trials (e.g., Phase 3 trials of drugs or Pivotal device trials) should be submitted to PAR-21-237, NINDS Efficacy Clinical Trials. While an exploratory clinical trial may examine clinical outcomes or biomarker outcomes as measures of "preliminary efficacy" as a secondary aim, it is important that it not appear to be an underpowered efficacy trial.

(7) Effect Size: A drug or biologic trial will not be considered for funding under this NOFO when its primary objective is to estimate intervention effect size to be used in power calculations for a future efficacy clinical trial. Effect size estimates based on small or short-term studies are often unreliable. Power for an efficacy trial should be based on the smallest clinically meaningful effect size, which is often determined by surveying physicians or patients, or by comparison to the effect produced by existing interventions.

(8) Ancillary studies: Ancillary studies, defined as research undertaken to address scientific questions relevant to the parent study and that require access to data or records from the parent study, and/or involve collection of additional data, specimens, or records, are not permitted within the clinical trial application. Applicants are advised to discuss their ideas with Scientific/Research staff for direction on an appropriate funding mechanism.

(9) Secondary Aims: For drugs and biologics, issues of study feasibility and refinement of study procedures may be addressed as secondary aims in a clinical trial, but not as the primary aim. Examples of such secondary aims include

  • Determining the optimal measure (endpoint), its variability, and/or the optimal timing of outcome evaluations in the context of the intervention
  • Collecting information on the utility of questionnaires, rating scales, or biomarkers
  • Developing and refining data collection procedures.
  • Optimizing the administration of the study intervention.
  • Developing and refining standardized methods of assessing outcome.
  • Optimizing methods for identifying, recruiting, and retaining study participants.

For Early Feasibility or Traditional Feasibility studies of medical devices, issues of study feasibility and refinement of study procedures are expected to be addressed as primary aims in addition to providing initial clinical safety data at this stage. These may include:

  • Identifying appropriate modifications to the procedure or device to enable a subsequent Pivotal study on a finalized system;
  • Refining the intended use population;
  • Developing and refining data collection procedures;
  • Refining the non-clinical test plans or methodologies; and
  • Developing subsequent clinical study protocols.

(10) Multiple Trials: There may be several questions to be answered before a phase 3 efficacy trial can be designed and conducted. The proposed study is not required to address all potential questions, but the applicant should clearly detail the overall clinical development plan for the intervention, which could involve more than one exploratory trial.

(11) Innovative Designs: The use of innovative and efficient study designs is encouraged, such as adaptive dose-finding designs, designs incorporating plans for sample size recalculation, preliminary efficacy for devices, and futility designs. Applications for Phase 1 trials in the patient population are encouraged when appropriate (e.g., certain rare diseases), as are applications that encompass Phase 1 and Phase 2 studies (early proof of mechanism or proof of concept). Applications Phase 3 trials should be submitted under PAR-21-237, NINDS Efficacy Clinical Trials. For medical devices, Traditional Feasibility study designs may include, for example, single-arm studies, on-off interventions (patients as their own controls), device-device comparisons, device-drug comparisons, comparisons to historical controls, comparisons to performance criteria/goals, adaptive designs, and Bayesian designs.

(12) Pharmacometrics: Applications seeking to obtain data needed for pharmacometric modeling are encouraged, with the aim of enabling the optimal design of a future efficacy trial of an intervention.

(13) Innovative Technologies: Applicants are encouraged to consider utilizing (at least experimentally) digital/mobile/sensor technologies and web-based systems to facilitate data collection (including data collection in a continual, contextual, real-world setting rather than through a traditional milestone-based approach), as well as to enhance protocol adherence.

(14) Rare Diseases: Trials in rare diseases are encouraged, particularly in conditions for which definitive outcome measures and prior data from natural history studies are available. It is recognized that available patient pools may not be adequate to meet the sample size requirements typically seen in trials in more common disorders of the nervous system, and innovative trial designs, including crossover designs and adaptive designs, can be appropriately considered. Additionally, an assessment of clinical efficacy as a secondary outcome may be warranted for rare diseases where the available patient pool may not make a definitive efficacy trial feasible. Regardless of the design it is especially important to ensure that the study design and statistical analysis plans will meet the stated objectives, and allow for the most efficient evaluation of the limited subjects. The application should clearly demonstrate recruitment feasibility at the participating site and applicants are encouraged to fully engage patient advocacy groups or similar representatives of the affected disease community in study design, execution, and reporting.

(15) Relationships with Patient Groups: Applicants are strongly encouraged to establish relationships with patient groups and solicit their input 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 subjects

(16) Biomarkers: Applications are encouraged that evaluate preliminary efficacy based on early signals of activity on biomarkers or clinical endpoints, or that mechanistically test the activity of an intervention in terms of its presumed target(s). However, this NOFO is not appropriate for applications primarily intended to discover biomarkers.

Applications Not-Responsive to this NOFO:

Non-responsive applications will not be reviewed.

  • Applications primarily intended to discover biomarkers. For Biomarker funding opportunities at NINDS please visit: https://www.ninds.nih.gov/Current-Research/Focus-Tools-Topics/Biomarkers.
  • Applications for Phase 3 trials. These projects should be submitted under PAR-21-237, NINDS Efficacy Clinical Trials.
  • Applications for a clinical trial where the primary aim is to establish or confirm definitive efficacy. Applications to implement definitive efficacy trials (e.g., Phase 3 trials of drugs or Pivotal device trials) should be submitted to PAR-21-237, NINDS Efficacy Clinical Trials.
  • Trials where the primary objective is to estimate intervention effect size to be used in power calculations for a future efficacy clinical trial.
  • Multi-site clinical trials with more than three clinical sites. These trials may be supported through NINDS clinical trial networks, such as StrokeNet (http://www.nihstrokenet.org), NeuroNEXT (http://www.neuronext.org) and EPPIC-Net (https://www.ninds.nih.gov/Current-Research/Trans-Agency-Activities/NINDS-Role-HEAL-Initiative/NINDS-Role-HEAL-Initiative-EPPIC).
  • Preclinical activities to support filing of an IND or IDE followed by clinical trial activities supported by this IND/IDE.
  • Applications that fail to include a PEDP
  • Studies requiring an IND/IDE where the applicant has not demonstrated that their intervention falls into one of the following scenarios:

(a) The protocol has been submitted under an open IND and the IND is not under full or partial hold. Under this scenario, applicants must provide documentation such as a "may proceed" email or letter from the FDA.

(b) The protocol has been submitted as an original IDE or as a new study under an open IDE, and FDA has fully approved the IDE or IDE supplement. Under this scenario, applicants must provide documentation of an IDE or IDE supplement full approval letter from the FDA.

(c) The protocol has been submitted under an IND and is on full or partial hold. Under this scenario applicants must provide full documentation from the FDA on the reasons for hold and the FDA recommendations. Applicants should discuss how they intend to address the hold issues and when they believe they will have FDA approval to proceed with trial implementation.

(d) The protocol has been submitted as an original IDE or as a new study under an open IDE, and FDA has conditionally approved the IDE or IDE supplement. Under this scenario applicants must provide full documentation from the FDA on the conditions of approval. Applicants should discuss how they intend to address these conditions and when they believe they will have FDA approval to proceed with trial implementation.

(e) The protocol is exempt from an IND. Under this scenario applicants must provide a copy of the exemption letter from the FDA.

(f) The protocol is either exempt from the IDE regulations or does not require IDE approval because it is determined to be nonsignificant risk. Under this scenario applicants must provide either an IDE exemption letter or a copy of the risk determination letter from the FDA. For devices, if the IRB has determined that the device is Non-Significant Risk, documentation from the IRB is acceptable.

(g) The study is of a non-regulated intervention, including surgical and behavioral interventions. Provide a Non-Significant Risk documentation of your intervention from an IRB.

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

Funding Instrument

Grant: A support mechanism providing money, property, or both to an eligible entity to carry out an approved project or activity.

Application Types Allowed
New (Phase I, Fast-Track)
Renewal (Phase II)
Resubmission (All Phases)

New (SBIR Direct Phase II)

The OER Glossary and the SF424 (R&R) Application Guide provide details on these application types. Only those application types listed here are allowed for the NOFO.  

Clinical Trial?
Required: Only accepting applications that propose clinical trial(s)
Funds Available and Anticipated Number of Awards

The number of awards is contingent upon NIH appropriations and the submission of a sufficient number of meritorious applications.

Award Budget

Total funding support (direct costs, indirect costs, fee) normally may not exceed $295,924 for Phase I awards and $1,972,828 for Phase II awards. NIH has received a waiver from SBA, as authorized by statute, to exceed these total award amount hard caps for specific topics. The current list of approved topics can be found at https://sbir.nih.gov/funding.

Applications should not exceed $700,000 in total cost for Phase I, with no more than $500,000 total costs in any year, and $3,000,000 total costs for Phase II with no more $1,500,000 in total cost in any year.

Applicants are strongly encouraged to contact program officials prior to submitting any application in excess of the hard caps listed above and early in the application planning process. In all cases, applicants should propose a budget that is reasonable and appropriate for completion of the research project.

Award Project Period

Durations up to 2 years for Phase I and up to 3 years for Phase II may be requested.

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

Eligible Organizations

Only United States small business concerns (SBCs) are eligible to submit applications for this opportunity. A small business concern is one that, at the time of award of Phase I and Phase II, meets all of the following criteria:

  1. Is organized for profit, with a place of business located in the United States, which operates primarily within the United States or which makes a significant contribution to the United States economy through payment of taxes or use of American products, materials or labor;
  2. Is in the legal form of an individual proprietorship, partnership, limited liability company, corporation, joint venture, association, trust or cooperative, except that where the form is a joint venture, there must be less than 50 percent participation by foreign business entities in the joint venture;
  3. SBIR and STTR.  Be a concern which is more than 50% directly owned and controlled by one or more individuals (who are citizens or permanent resident aliens of the United States), other business concerns (each of which is more than 50% directly owned and controlled by individuals who are citizens or permanent resident aliens of the United States), an Indian tribe, ANC or NHO (or a wholly owned business entity of such tribe, ANC or NHO), or any combination of these; OR
  4. SBIR-only.  Be a concern which is more than 50% owned by multiple venture capital operating companies, hedge funds, private equity firms, or any combination of these.  No single venture capital operating company, hedge fund, or private equity firm may own more than 50% of the concern, unless that single venture capital operating company, hedge fund, or private equity firm qualifies as a small business concern that is more than 50% directly owned and controlled by individuals who are citizens or permanent resident aliens of the United States; OR
  5. SBIR and STTR.  Be a joint venture in which each entity to the joint venture must meet the requirements set forth in paragraph 3 (i) or 3 (ii) of this section. A joint venture that includes one or more concerns that meet the requirements of paragraph (ii) of this section must comply with § 121.705(b) concerning registration and proposal requirements.

4. Has, including its affiliates, not more than 500 employees.

If the concern is more than 50% owned by multiple venture capital operating companies, hedge funds, private equity firms, or any combination of these falls under 3 (ii) or 3 (iii) above, see Section IV. Application and Submission Information for additional instructions regarding required application certification.

If an Employee Stock Ownership Plan owns all or part of the concern, each stock trustee and plan member is considered an owner.

If a trust owns all or part of the concern, each trustee and trust beneficiary is considered an owner.

Definitions:

  • Hedge fund has the meaning given that term in section 13(h)(2) of the Bank Holding Company Act of 1956 (12 U.S.C. 1851(h)(2)). The hedge fund must have a place of business located in the United States and be created or organized in the United States, or under the law of the United States or of any State.
  • Portfolio company means any company that is owned in whole or part by a venture capital operating company, hedge fund, or private equity firm.
  • Private equity firm has the meaning given the term “private equity fund” in section 13(h)(2) of the Bank Holding Company Act of 1956 (12 U.S.C. 1851(h)(2)). The private equity firm must have a place of business located in the United States and be created or organized in the United States, or under the law of the United States or of any State.
  • Venture capital operating company means an entity described in § 121.103(b)(5)(i), (v), or (vi). The venture capital operating company must have a place of business located in the United States and be created or organized in the United States, or under the law of the United States or of any State.
  • ANC means Alaska Native Corporation.
  • NHO means Native Hawaiian Organization.


SBCs must also meet the other regulatory requirements found in 13 C.F.R. Part 121. Business concerns, other than investment companies licensed, or state development companies qualifying under the Small Business Investment Act of 1958, 15 U.S.C. 661, et seq., are affiliates of one another when either directly or indirectly, (a) one concern controls or has the power to control the other; or (b) a third-party/parties controls or has the power to control both. Business concerns include, but are not limited to, any individual (sole proprietorship) partnership, corporation, joint venture, association, or cooperative. The SF424 (R&R) SBIR/STTR Application Guide should be referenced for detailed eligibility information.
 

Small business concerns that are more than 50% owned by multiple venture capital operating companies, hedge funds, private equity firms, or any combination of these are NOT eligible to apply to the NIH STTR program.

     

Performance Benchmark Requirements
      

Phase I to Phase II Transition Rate Benchmark: In accordance with guidance from the SBA, the HHS SBIR/STTR Program is implementing the Phase I to Phase II Transition Rate benchmark required by the SBIR/STTR Reauthorization Act of 2011 and the SBIR and STTR Extension Act of 2022.The benchmark establishes a minimum number of Phase II awards the company must have received relative to a given number of Phase I awards received during the 5-fiscal year time period. The Transition Rate is calculated as the total number of SBIR and STTR Phase II awards a company received during the past 5 fiscal years divided by the total number of SBIR and STTR Phase I awards it received during the past 5 fiscal years excluding the most recently completed year. The Transition Rate requirement, agreed upon and established by all 11 SBIR agencies, was published for public comment in a Federal Register Notice on October 16, 2012 (77 FR 63410) and amended on May 23, 2013 (78 FR 30951).


For SBIR and STTR Phase I applicants that have received more than 20 Phase I awards over the past 5 fiscal years (excluding the most recently-completed fiscal year): Companies that do not meet or exceed the benchmark minimum Transition Rate of 0.25 will not be eligible to apply for a Phase I, Fast-Track, or Direct Phase II (if available) award for a period of one year from the date of the application submission. This requirement does not apply to companies that have received 20 or fewer Phase I awards over the prior 5-fiscal year period.

For application deadlines that fall on or after April 5, 2023: For SBIR and STTR Phase I applicants that have received more than 50 Phase I awards over the past 5 fiscal years (excluding the most recently-completed fiscal year): Companies that do not meet or exceed the benchmark minimum Transition Rate of 0.5 will not be eligible to receive more than 20 total Phase I and Phase II awards for a period of one year from the date on which such determination is made. This requirement does not apply to companies that have received 50 or fewer Phase I awards over the 5-fiscal year period.

On June 1 of each year, SBA will identify the companies that fail to meet minimum performance requirements. SBA calculates individual company Phase I to Phase II Transition Rates using SBIR and STTR award information across all federal agencies will notify companies and the relevant officials at the participating agencies. More information on the Phase I to Phase II Transition Rate requirement is available at SBIR.gov.

Phase II to Commercialization Benchmark: In accordance with guidance from the SBA, the HHS SBIR/STTR Programs are implementing the Phase II to Commercialization Rate benchmark for Phase I applicants, as required by the SBIR/STTR Reauthorization Act of 2011 and the SBIR and STTR Extension Act of 2022. The Commercialization Rate Benchmark was published in a Federal Register notice on August 8, 2013 (78 FR 48537), with a reopening of the comment period published on September 26, 2013 (78 FR 59410).

For companies that have received more than 15 Phase II awards from all agencies over the past 10 fiscal years (excluding the two most recently completed fiscal year): Companies that meet this criterion must show an average of at least $100,000 in revenues and/or investments per Phase II award or at least 0.15 (15%) patents per Phase II award resulting from these awards during the past 10- fiscal year period. Applicants that fail this benchmark will not be eligible to apply for New Phase I, Fast-track or Direct Phase II (if applicable) awards for a period of one year. This requirement does not apply to companies that have received 15 or fewer Phase II awards over the 10-fiscal year period, excluding the two most recently completed fiscal years.

For application deadlines that fall on or after April 5, 2023: For companies that have received more than 50 Phase II awards from all agencies over the past 10-fiscal years (excluding the two most recently completed Fiscal Year): Companies that meet this criterion must show an average of at least $250,000 of aggregated sales and investment per Phase II award over the past 10-fiscal year period. Applicants that fail this benchmark will not be eligible to receive more than 20 total Phase I and Phase II awards for a period of one year from the date on which such determination is made. This requirement does not apply to companies that have received 50 or fewer Phase II awards over the 10-fiscal year period, excluding the two most recently completed fiscal years.

For application deadlines that fall on or after April 5, 2023: For companies that have received more than 100 Phase II awards from all agencies over the past 10-fiscal years (excluding the two most recently completed Fiscal Year): Companies that meet this criterion must show an average of at least $450,000 of aggregated sales and investment per Phase II award over the past 10-fiscal year period. Applicants that fail this benchmark will not be eligible to receive more than 20 total Phase I and Phase II awards for a period of one year from the date on which such determination is made. This requirement does not apply to companies that have received 100 or fewer Phase II awards over the 10-fiscal year period, excluding the two most recently completed fiscal years.

Foreign Institutions

Non-domestic (non-U.S.) Entities (Foreign Institutions) 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, may be allowed.

Required Registrations

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 Grants Policy Statement Section 2.3.9.2 Electronically Submitted Applications states that failure to complete registrations in advance of a due date is not a valid reason for a late submission.

  • 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.
    • 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.
  • SBA Company Registry –See How to Apply – Application Guide for instructions on how to register and how to attach proof of registration to your application package. Applicants must have a UEI to complete this registration. SBA Company registration is NOT required before SAM, Grants.gov or eRA Commons registration.
  • 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.

Eligible Individuals (Program Director/Principal Investigator)

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 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 SF424 (R&R) Application Guide.

Under the SBIR program, for both Phase I and Phase II, the primary employment of the PD/PI must be with the small business concern at the time of award and during the conduct of the proposed project. For projects with multiple PDs/PIs, at least one must meet the primary employment requirement. Occasionally, deviations from this requirement may occur.
 

For the STTR program, the PD(s)/PI(s) may be employed with the SBC or the single, “partnering” non-profit research institution as long as s/he has a formal appointment with or commitment to the applicant SBC, which is characterized by an official relationship between the SBC and that individual. Such a relationship does not necessarily involve a salary or other form of remuneration The primary employment of the PD/PI must be with the SBC or the Research Institution (where they are PD/PI at) at the time of award and during the conduct of the proposed project. Each PD/PI must commit a minimum of 10% effort to the project.

The How to Apply – Application Guide should be referenced for specific details on eligibility requirements. For institutions/organizations proposing multiple PDs/PIs, see Multiple Principal Investigators section 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.

3. Additional Information on Eligibility

Number of Applications

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

NIH will not accept similar grant applications with essentially the same research focus from the same applicant organization. This includes derivative or multiple applications that propose to develop a single product, process, or service that, with non-substantive modifications, can be applied to a variety of purposes. Applicants may not simultaneously submit identical/essentially identical applications under both this funding opportunity and any other HHS funding opportunity, including the SBIR and STTR Parent announcements.

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).

A Phase I recipient  may submit a Phase II application either before or after expiration of the Phase I budget period, unless the awardee elects to submit a Phase I and Phase II application concurrently under the Fast-Track procedure. To maintain eligibility to seek Phase II or IIB support, a Phase I recipient  should submit a Phase II application, and a Phase II recipient  should submit a Phase IIB application, within the first six due dates following the expiration of the Phase I or II budget period, respectively.

Contractual/Consortium Arrangements

For SBIR:
In Phase I, normally, two-thirds or 67% of the research or analytical effort is carried out by the small business concern. The total amount of all consultant and contractual arrangements to third parties for portions of the scientific and technical effort is generally not more than 33% of the total amount requested (direct, F&A/indirect, and fee).

In Phase II, normally, one-half or 50% of the research or analytical effort is carried out by the small business concern. The total amount of consultant and contractual arrangements to third parties for portions of the scientific and technical effort is generally not more than 50% of the total Phase II amount requested (direct, F&A/indirect, and fee).

Deviations from these requirements may be considered on a case by case basis. Please contact a program officer for additional information. Deviations must be approved in writing by the Grants Management Officer (GMO) after consultation with the agency SBIR Program Manager/Coordinator.

A small business concern may subcontract a portion of its SBIR or STTR award to a Federal laboratory within the limits above. A Federal laboratory, as defined in 15 U.S.C. § 3703, means any laboratory, any federally funded research and development center, or any center established under 15 U.S.C. §§ 3705 & 3707 that is owned, leased, or otherwise used by a Federal agency and funded by the Federal Government, whether operated by the Government or by a contractor.

The basis for determining the percentage of work to be performed by each of the cooperative parties in Phase I or Phase II will be the total of the requested costs attributable to each party, unless otherwise described and justified in “Consortium/Contractual Arrangements” of the PHS 398 Research Plan component of SF424 (R&R) application forms.

Additional details are contained in the SF424 (R&R) SBIR/STTR Application Guide.

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 SBIR/STTR (B) 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 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:
Emily Caporello, Ph.D.
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-1778
Email: Emily.caporello@nih.gov

Page Limitations

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

Instructions for Application Submission

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.

SF424(R&R) Cover

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

SF424(R&R) Project/Performance Site Locations

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

SF424(R&R) Other Project Information

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

Other Attachments:

1. SBIR Application Certification for small business concerns majority-owned by multiple venture capital operating companies, hedge funds, or private equity firms

Applicant small business concerns that are majority-owned by multiple venture capital operating companies, hedge funds, or private equity firms (e.g. majority VCOC-owned) are required to submit a Certification at time of their application submission per the SBIR Policy Directive.  Follow the instructions below. 

Applicants small business concerns who are more than 50% directly owned and controlled by one or more individuals (who are citizens or permanent resident aliens of the United States), other business concerns (each of which is more than 50% directly owned and controlled by individuals who are citizens or permanent resident aliens of the United States), or any combination of these (i.e. NOT majority VCOC-owned) should NOT fill out this certification and should NOT attach it to their application package.

  1. Download the “VCOC Certification.pdf” at the NIH SBIR Forms webpage. 
  1. Answer the 3 questions and check the certification boxes.
  1. The authorized business official must sign the certification.
  1. Save the certification using the original file name.  The file must be named “SBIR Application VCOC Certification.pdf”.  DO NOT CHANGE OR ALTER THE FILE NAME.  Changing the file name may cause delays in the processing of your application.
  1. When you are completing the application package, attach this certification as a separate file by clicking "Add Attachments" located to the right of Other Attachments field on the “Research and Related Other Project Information” form.

 2. Fundraising Plan Documentation (ONLY for Phase 2, Direct to Phase 2, or Fast-Track applications; optional): Documents related to third-party-investors and their commitment (to be included in support of the Commercialization Plan)

Include documentation of support from third-party investors such as term sheets or redacted bank statements or other appropriate documents (other than letters of support). Collate all such documents in one pdf file (with the list of attached documents at the beginning). Use filename "Third-Party Investors". (Note that this filename will become a bookmark in the application.)

3. Regulatory Plan Documentation – Applications that do not include this will be withdrawn and not reviewed.

Applicants MUST provide a regulatory plan describing the regulatory pathway that is being or will be pursued and a timeline for achieving regulatory approval with discrete milestones, or clear reasoning indicating the trial uses a non-regulated intervention. Applicants should submit evidence that they have contacted the appropriate regulatory authority and that their research plan and objectives follow the relevant requirements or guidance of that authority. Examples that provide evidence of appropriate interactions are: 1) letters or emails between the SBC and the appropriate FDA Center personnel 2) meeting minutes concerning a pre-submission meeting or regarding a 510(k), IDE, PMA, HDE, BLA, IND, or NDA application.

The applicant must provide documentation indicating their intervention falls into one of the following scenarios:

(a) The protocol has been submitted under an open IND and the IND is not under full or partial hold. Under this scenario, applicants must provide documentation such as a "may proceed" email or letter from the FDA.

(b) The protocol has been submitted as an original IDE or as a new study under an open IDE, and FDA has fully approved the IDE or IDE supplement. Under this scenario, applicants must provide documentation of an IDE or IDE supplement full approval letter from the FDA.

(c) The protocol has been submitted under an IND and is on full or partial hold. Under this scenario applicants must provide full documentation from the FDA on the reasons for hold and the FDA recommendations. Applicants should discuss how they intend to address the hold issues and when they believe they will have FDA approval to proceed with trial implementation.

(d) The protocol has been submitted as an original IDE or as a new study under an open IDE, and FDA has conditionally approved the IDE or IDE supplement. Under this scenario applicants must provide full documentation from the FDA on the conditions of approval. Applicants should discuss how they intend to address these conditions and when they believe they will have FDA approval to proceed with trial implementation.

(e) The protocol is exempt from an IND. Under this scenario applicants must provide a copy of the exemption letter from the FDA.

(f) The protocol is either exempt from the IDE regulations or does not require IDE approval because it is determined to be nonsignificant risk. Under this scenario applicants must provide either an IDE exemption letter or a copy of the risk determination letter from the FDA. For devices, if the IRB has determined that the device is Non-Significant Risk, documentation from the IRB is acceptable.

(g) The study is of non-regulated intervention, including surgical and behavioral interventions. Provide a Non-Significant Risk documentation of your intervention from an IRB.

Applications that do not include this information will be withdrawn and not reviewed. Prior to grant award, recipients  who do not have an exemption from the FDA must provide any additional FDA correspondence regarding the status of the protocol to the NINDS, especially if the trial has been placed under full or partial hold.

4. Community Engagement and Research Inclusion (CERI) plan

In an Other Attachment entitled “Community Engagement and Research Inclusion (CERI) Plan”, all applicants must include a summary that proposes or describes how community engagement strategies and community-engaged research will be employed during the planning period; specifically five components, a) communities of interest, b) community partners (if applicable), c) partnership development, d) strategy for incorporation of input, and e) success evaluation metrics. The “Community(ies) of interest” includes people with lived experience (PWLE; lived experience as a member of a health disparity population  (HDP) community(ies)) who have or are at risk of developing neurological disorders as well as their caregivers.  Community partner(s) include those who represent communities of interest. Our working definition of community partner is a person(s), group, or organization with demonstrated experience leading, advocating, representing, or partnering on behalf of the interest of or perspectives of HDP communities. Examples of community partner(s) include: community champions, key informants, community advisory board, patient advisory board, advocacy organization, community organization, community health worker, FQHC social worker, HDP community faith leader, members of American Indian or Alaska Native tribes, etc. Applicants must describe an existing or proposed partnership that outlines the roles of community partners, the organizational and decision-making structure for the partnerships and the degree of recurring discussions between research team and community partners. Applicants should aim to incorporate input collected through CE strategies in at least two phases within the study: planning/design (i.e., participant outreach, IRB development, advisory board development, etc.), data collection (i.e., culturally appropriate materials, researcher/coordinators/practitioner HDP interviewer style/language, etc.), findings interpretation (i.e., HDP participant research attitudes, cultural context relevant to participant responses, etc.), or communication of findings (i.e., community newsletter, community seminar, health empowerment materials, etc.). Finally, the CERI plan should describe metrics to evaluate and assess meaningful community engagement. The CERI plan may be no more than 2 pages in length and should include a timeline and milestones for relevant components that will be considered as part of the review.

Examples of meaningful community engagement and community-engaged research elements to describe in the CERI plan include but are not limited to:

  • Ensuring that community partners and PWLE represent interests relevant to community of interest described within the study
  • Proposed roles of academic partners and community partners, including the composition and expertise of the community partners and stakeholders, the phase(s) (i.e., design, conduction, analysis, interpretation, and/or dissemination) of research the community partner will be engaged in, the program infrastructure and management of partnerships (e.g., memorandum of understanding) co-created with or approved by the community partner, if applicable
  • Obtaining and incorporating community partner/PWLE input regarding utilization of appropriate linguistic and cultural competence strategies within the study design (e.g., language translation, cultural adaptation) and ensuring representation of participants who have significant social, economic and/or linguistic disadvantage anticipated to participate in study
  • Describing how community partner/PWLE will be engaged at specific phases of the research study and a plan for how their input will be incorporated
  • Describing plans for regular recurring reflection/topic discussions with community partner/PWLE and how these discussions will serve goals of the project
  • Consideration for appropriate and equitable resources provided to community partner/PWLE based on their time and effort spent contributing to the study, as well as mutual benefit and recognition (i.e., publication authorship, conference presentation, work group representation, etc.)
  • Outlining methods and metrics to monitor community engagement efforts, including a description of how data will be collected within the framework of the grant activities
  • The anticipated or planned personal benefits including dissemination of information during and following the study, knowledge and empowerment of community partner/PWLE

5. Plan for Enhancing Diverse Perspectives (PEDP)

In an "Other Attachment" entitled "Plan for Enhancing Diverse Perspectives," all applicants must include a summary of strategies to advance the scientific and technical merit of the proposed project through expanded inclusivity. The PEDP should provide a holistic and integrated view of how enhancing diverse perspectives is viewed and supported throughout the application and can incorporate elements with relevance to any review criteria (significance, investigator(s), innovation, approach, and environment) as appropriate. Where possible, applicant(s) should align their description with these required elements within the research strategy section. The PEDP will vary depending on the scientific aims, expertise required, the environment and performance site(s), as well as how the project aims are structured. The PEDP may be no more than 1-page in length and should include a timeline and milestones for relevant components that will be considered as part of the review. Examples of items that advance inclusivity in research and may be part of the PEDP can include, but are not limited to:

  • Discussion of engagement with different types of institutions and organizations (e.g., research-intensive, undergraduate-focused, minority-serving, community-based).
  • Description of any planned partnerships that may enhance geographic and regional diversity.
  • Plan to enhance recruiting of women and individuals from groups historically underrepresented in the biomedical, behavioral, and clinical research workforce.
  • Proposed monitoring activities to identify and measure PEDP progress benchmarks.
  • Plan to utilize the project infrastructure (i.e., research and structure) to support career-enhancing research opportunities for diverse junior, early- and mid-career researchers.
  • Description of any training and/or mentoring opportunities available to encourage participation of students, postdoctoral researchers and co-investigators from diverse backgrounds.
  • Plan to develop transdisciplinary collaboration(s) that require unique expertise and/or solicit diverse perspectives to address research question(s).
  • Publication plan that enumerates planned manuscripts and proposed lead authorship.
  • Outreach and planned engagement activities to enhance recruitment of individuals from diverse groups as research participants including those from under-represented backgrounds.

For further information on the Plan for Enhancing Diverse Perspectives (PEDP), please see https://braininitiative.nih.gov/about/plan-enhancing-diverse-perspectives-pedp.

SF424(R&R) Senior/Key Person Profile Expanded

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

Clinical trials must be directed by PD(s)/PI(s) with experience in the conduct of clinical trials and expertise in the disease area. Such experience must be documented, including timely submission of primary publications from previous trials, ideally within one year of completion of subject follow-up. The application should also indicate the prior experience of other study team members who are Senior/Key Personnel in clinical trial design and implementation.

R&R Budget

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

Applicants should budget for the services of a Medical Safety Monitor (who should be independent of the study investigators) to provide timely review of Serious Adverse Events (SAEs). Additionally, if it is anticipated that the NINDS will decide to appoint a Data and Safety Monitoring Board (DSMB), applicants should expect an annual one-day, in-person meeting of the DSMB and should budget to allow up to 6 persons from the investigator team to attend. The travel expenses of DSMB members and the meeting room rental will be handled by NINDS.

If some trial costs are to be borne by sources other than NIH, these contributions must be presented in detail in the budget justification. These costs borne by third parties do not constitute cost-sharing as defined in the current NIH Grants Policy Statement and should not be presented as part of the requested budget.

PEDP implementation costs 

? Applicants may include allowable costs associated with PEDP implementation (as outlined in Grants Policy Statement section 7: https://grants.nih.gov/grants/policy/nihgps/html5/section_7/7.1_general.htm).

R&R Subaward Budget

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

PHS 398 Cover Page Supplement

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

PHS 398 Research Plan

SBIR/STTR Information Form

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

With the following additional instructions:

Research Strategy: The scientific rationale and preliminary data supporting the proposed clinical trial, including results from preclinical and clinical studies, and an overview of the current status of therapeutics for the disease, must be included in the application. Applicants should ensure that the data supporting the proposed trial meet the NIH scientific rigor guidelines (see http://grants.nih.gov/grants/guide/notice-files/NOT-OD-15-103.html). If a proposed trial plans to study the intervention(s) based upon preclinical mechanistic studies, results from such studies should be summarized and referenced. If preclinical data (e.g. animal studies) do not meet the rigor guidelines, the applicant should discuss the limitations of those data and any plans to address those gaps in knowledge through the current study design.

Significance and Biological Relevance: The significance of the proposed clinical trial must be clearly stated, and a discussion of the risks and benefits should be included. It is particularly important to discuss how results of the trial (positive or negative) will advance product development. The application should explain why the proposed trial is necessary to inform the design of a subsequent clinical trial for efficacy.

Preliminary Studies: The major findings of the preclinical and clinical studies that led to the proposed clinical trial should be presented and discussed in the context of the NIH rigor guidelines. Data from previous studies that support the proposed hypotheses and the feasibility of the trial should also be included. Study conceptualization and planning must be at a stage sufficient to allow for an assessment of the likelihood of trial success.

Approach: A concise summary of the proposed research plan should include:

  • A discussion of potential biases and/or challenges in the protocol and how they will be addressed.
  • Clear go/no-go criteria for proceeding with a subsequent efficacy clinical trial.
  • Evidence that relevant stakeholders (e.g. potential subjects, referring and treating physicians, patient groups) have equipoise, view the question to be important and consider the study acceptable. This evidence may be supported by letters from stakeholders (e.g., professional organizations or patient groups).

NINDS urges investigators to follow the NIH guidance for rigor and transparency in grant applications (https://grants.nih.gov/policy/reproducibility/guidance.htm) and NINDS research practices (https://www.ninds.nih.gov/funding/preparing-your-application/preparing-research-plan/rigorous-study-design-and-transparent-reporting). This will ensure that robust experiments are designed, potential experimenter biases are minimized, results and analyses are transparently reported, and results are interpreted carefully. These recommended research practices include, where applicable, expressing clear rationale for the chosen model(s) and primary/secondary endpoint(s), describing tools and parameters clearly, blinding, randomizing, ensuring adequate sample size, pre-specifying inclusion/exclusion criteria, appropriately handling missing data and outliers, implementing appropriate controls, preplanning analyses, and using appropriate quantitative techniques. It is also strongly recommended to indicate clearly the exploratory vs. confirmatory components of the study, consider study limitations, and plan for transparent reporting of all methods, analyses, and results so that other investigators can evaluate the quality of the work and potentially perform replications. Investigators should indicate whether data presented or cited in the application as key support for the proposed work were collected, analyzed, and reported in a rigorous and transparent manner as indicated above. A plan to address any ambiguity, weaknesses, or limitations in the prior research should be included in the application. Proposed experiments should similarly adhere to these high standards of rigor and transparency.

The plan should include the methods and systems for data collection and quality control, and for ensuring data confidentiality and privacy, and the process for locking the final dataset and providing for data sharing, as appropriate and consistent with achieving the goals of the program. 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.

Applicants must describe the rigor, robustness, and transparency of supporting data that are being used to justify the proposed trial and address any gaps identified. For all clinical trials, the rationale for the trial design, population(s) and hypotheses being tested, and control groups must be described. Potential biases and/or challenges in the study design and protocol should be identified and addressed. For Basic Experimental Studies involving Humans (BESH), the application should describe and address how the expected effect size relates to biologically meaningful differences. For exploratory (typically Phase I or II) clinical trials, the proposed study design should enable the rigorous assessment of outcomes focused on dosing, target engagement, safety, or other appropriate measures. For efficacy or effectiveness (typically Phase III or later) clinical trials, the proposal should account for clinical relevance of the expected effect size and include measures, such as blinding and randomization, to reduce the risk of systematic biases.

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 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 trial costs 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 from patient organizations or other supporting documentation to show that patients were included as partners in the concept development and design of the trial

Include letters of support documenting commitments from third-party investors. Letters of support from these institutional partners should indicate any actual or planned/conditional financial commitment as a specific dollar figure or range, consistent with the instructions provided under Section IV.2, Other Attachments, “Fundraising Plan Documentation”. Appropriate documentation of third-party investor commitment(s) may include a conditional letter of support stating that the third-party funding is contingent upon NIH selecting the application for an award.

SBIR-eligible public companies may include as part of their fundraising plan the issuance of stock. In such a case, the preferred documentation is a letter of support, signed by the Chairman of the Board of Directors, which stipulates the following: (1) the amount of capital raised from the issuance of stock; (2) the amount of capital that will be dedicated to the proposed project under this NOFO ; (3) sufficient information regarding the use of the dedicated capital to demonstrate a substantial, value-added contribution toward the development and commercialization of the product or service to be developed under this NOFO.

Resource Sharing Plans:

Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the SF424 (R&R) Application Guide.

Other Plan(s)

All instructions in the SF424 (R&R) 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 Small Business Innovation Research (SBIR) and Small Business Technology Transfer (STTR) applicants are required to address a Data Management and Sharing Plan, regardless of the amount of direct costs requested for any one year. However, SBIR and STTR recipients may retain the rights to data generated during the performance of an SBIR or STTR award for up to 20 years after the award date, per the Small Business Innovation Research (SBIR) and Small Business Technology Transfer (STTR) Program Policy Directive. An acceptable Data Management and Sharing plan can reference and incorporate these data rights. Further information about SBIR and STTR data rights are enumerated in the NIH GPS. The plan should include the methods and systems for data collection and quality control, and for ensuring data confidentiality and privacy, and the process for locking the final dataset, as appropriate and consistent with achieving the goals of the program. 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.

Appendix:

Note that Phase I SBIR/STTR Appendix materials are not permitted.  Only limited items are allowed in the Appendix of other small business applications.  The instructions for the Appendix of the Research Plan are described in the SF424 (R&R) Application Guide; any instructions provided here are in addition to the SF424 (R&R) Application Guide Instructions.

SBIR/STTR Information Form

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

Commercialization Plan (Fast-track and Phase II only):

b) Company: An objective of the SBIR and STTR programs is to foster and encourage participation in innovation and entrepreneurship by socially and economically disadvantaged persons and women-owned small businesses. Describe the company’s approach to recruiting prospective new and senior employees  from diverse backgrounds, including those that may be underrepresented in the entrepreneurial, biomedical, behavioral, or clinical research workforce . Such individuals may include, for example, individuals  from underrepresented racial and ethnic groups, individuals with disabilities, women, and individuals  from disadvantaged backgrounds. 

d) Intellectual Property (IP) Protection: Applicants are encouraged to prepare this section of the application in consultation with partnering institution's technology transfer officials, if applicable.

Applicants should describe the IP landscape surrounding their investigational drug, biologic or therapeutic device. Applicants should describe any known constraints that could impede the development of their investigational drug, biologic, or therapeutic device (e.g., certain restrictions under transfer or sharing agreements, applicants' previous or present IP filings and publications, similar technologies that are under patent and/or on the market, etc.) and how these issues could be addressed. If the applicants propose using an investigational drug, biologic, device, or technology whose IP is not owned by the small business, applicants should include a letter from any entities owning the IP indicating there will not be any limitations imposed on the studies or the product which would impede achieving the goals of this funding program.

If patents pertinent to the investigational drug, biologic, or therapeutic device being developed under this application have been filed, the applicant should indicate the details of filing dates, what types of patents are filed, and application status, and associated USPTO links, if applicable.

Applicants should discuss future IP filing plans. For a multiple-PD/PI, multiple-institution application, applicants should describe the infrastructure of each institution for bringing the technologies to practical application and for coordinating these efforts (e.g., licensing, managing IP) among the institutions, consistent with achieving the goals of the program. Applicants should clarify how IP will be shared or otherwise managed if there are multiple PD/PIs and institutions involved, consistent with achieving the goals of the program.

e) Finance Plan [this section replaces section e Finance Plan described in the SF424 Application Guide]. Applicants are expected to provide a Fundraising Plan including the following information:

  • A detailed and specific plan for securing substantial, independent third-party investor funds.
  • The type(s) of independent third-party investor funds (i.e., cash, convertible debt, etc.) that will be secured
  • The source(s) of independent third-party investor funds (e.g., venture capital, state funds) that will be secured
  • The total amount of independent third-party investor funds that will be secured
  • The anticipated schedule for receiving independent third-party investor funds, including any relevant terms and conditions if available

The NINDS considers the raising of independent third-party investor funds to be an important means to facilitate and accelerate the capital-intensive steps that are required to commercialize new products/technologies emerging from NIH-funded SBIR/STTR Phase II projects. As such, the NINDS expects that applicants will secure substantial independent third-party investor funds. NINDS recognizes that fundraising expectations for companies working in small markets may be unique. For the purposes of this NOFO, NINDS has defined small markets as development of novel products that:

  • Address a rare disease as defined in the Orphan Drug Act Amendment of 1984 as any disease or condition affecting fewer than 200,000 persons in the United States.
  • Qualify as a Humanitarian Use Device, defined as a medical device intended to benefit patients in the treatment or diagnosis of a disease or condition that affects or is manifested in fewer than 4,000 persons in the United States per year.
  • Target a young pediatric population defined as including neonates (0-28 days), infants (<2 years), and/or children (2-12 years of age), as indicated in the FDA Premarket Assessment of Pediatric Medical Devices.
  • Are complex research tools. This is instrumentation comprising several distinct parts that must work together. Very often the goal of such projects is to deliver turnkey products for researchers. For example, high density electroencephalography instrumentation includes electrode arrays, amplifiers, data analytic and data visualization software, etc. Another example is non-invasive near infrared imaging instrumentation, which might include photon sources and detectors, timing devices for delivering photons, amplifiers, and software. Some high throughput assay systems may fall into this category.

Examples of third-party investors include, but are not necessarily limited to, another company, a venture capital firm, an individual “angel” investor, a foundation, a university, a research institution, a state or local government, strategic or industry partner, or any combination of the above. Third-party investors generally should not include owners of the applicant SBC, their family members, and/or “affiliates” of the applicant SBC. Revenue will be considered on a case-by-case basis. Independent third-party investor funds generally does not include in-kind support and/or intangible assets. Applicants should clearly indicate within their third-party fundraising plan the total amount of funding that will be secured from the preferred sources listed above SBIR-eligible public companies may include as part of their fundraising plan the issuance of stock. In such a case, the preferred documentation is a letter of commitment, signed by the Chairman of the Board of Directors, which stipulates the following: (1) the amount of capital raised from the issuance of stock; (2) the amount of capital that will be dedicated to the proposed project under this NOFO; (3) sufficient information regarding the use of the dedicated capital to demonstrate a substantial, value-added contribution toward the development and commercialization of the product/technology to be developed under this NOFO (see instructions below under “Use of Third-Party Investment Funds”). Applicants are expected to document third-party investor funds (or plans for raising them) as concretely as possible. For example, plans to raise additional funds from venture capital and/or strategic partners should name specific companies and investors. Documentation should be included in the "Other Attachments" and "Letters of Support”. It is likely that several months will have elapsed between the time an application is submitted and the time it is peer reviewed and subsequently considered for possible funding. Accordingly, applicants should present a detailed summary of all past and/or planned (i.e., future/expected) third-party investor funds which clearly shows, relative to the estimated award date, when these funds have been and/or will be secured. For example, if the fundraising efforts of the SBC are in progress, and/or if the third-party investment is contingent upon NIH selecting the application for funding, then such plans should be clearly described in the Fundraising Plan. Applicants seeking further information regarding preferred sources and/or types of support that would demonstrate a third-party investor commitment are strongly encouraged to communicate with the Scientific/Research Contact(s) listed under Section VII.

h) Statement of Need Applicants must provide a concise “Statement of Need”. This statement is expected to provide answers to the questions listed below.

PHS Human Subjects and Clinical Trials Information

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

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

Study Record: PHS Human Subjects and Clinical Trials Information

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

With the following additional instructions:

Section 2 - Study Population Characteristics

2.4 Inclusion of Women and Minorities

The plan must also consider translation of all the study-related documents to enroll participants from communities that do not speak English. Considerations that may contribute to successful inclusion are appropriate site selection, patient- or community-engagement for the major elements of the project, use of focus groups that include women and members of racial and ethnic minority groups  to address barriers to inclusion, etc.

2.5 Recruitment and Retention Plan

Applicants should survey the potential clinical site to ensure that recruitment targets can be met. The survey questions will depend on the nature of the trial and the protocol-specified screening procedures but might include these:

Has the PD/PI previously recruited patients with this disease into a clinical trial?

Does this site have all necessary equipment to complete eligibility evaluations?

If not, how far (in miles) will patients need to travel to complete eligibility evaluations?

What is the total number of patients seen at this site in the past 12 months?

How many of these appear to meet the pre-screening eligibility criteria?

How many of these are likely to be found fully eligible and consent to be enrolled?

Does this site have experience enrolling and following with participants with limited English proficiency?

What plans are there to enroll people from diverse populations, people of different ages, races, and ethnicities?

2.7 Study Timeline

Applicants should provide detailed project performance and timeline objectives. The proposed milestones must include achievable goals for each stage of the project as follows:

Completion of start-up activities (finalization of protocol, contracting of sites, registration in ClinicalTrials.gov, completion of any final regulatory approvals, etc.)

Earliest possible enrollment date

Enrollment of 25%, 50%, 75% and 100% of the targeted sample size

Completion of all study data collection

Completion of primary endpoint and secondary endpoint data analyses

Completion of final study report

Publication of primary study results

Reporting of results in ClinicalTrials.gov

Submission of final public use dataset to NINDS

If an adaptive design is to be used, indicate when adaptions will be considered.

Section 3 - Protection and Monitoring Plans

3.3 Data and Safety Monitoring Plan (DSMP)

Applicants should refer to the NINDS Guidelines for Data and Safety Monitoring in Clinical Trials (https://www.ninds.nih.gov/Funding/Apply-Funding/Application-Support-Library/NINDS-Guidelines-Data-and-Safety-Monitoring) when describing their DSMP.

3.5 Overall Structure of the Study Team

Clinical Site Monitoring Plan. Describe a Clinical Site Monitoring Plan including how site adherence to the protocol and consenting process will be ensured, who is 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 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 (https://ctsacentral.org/) 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.

Section 4 - Protocol Synopsis

4.1 Study Design 

4.1.a Detailed Description

As applicable, state how the following resources for clinical research will be utilized:

NINDS Common Data Elements (https://www.commondataelements.ninds.nih.gov/#page=Default);

NeuroQOL (http://www.healthmeasures.net/explore-measurement-systems/neuro-qol);

NIH Toolbox (http://www.healthmeasures.net/explore-measurement-systems/nih-toolbox); and

PROMIS (http://www.healthmeasures.net/explore-measurement-systems/promis).

For later-stage exploratory studies, state the go/no-go criteria that will be used at the end of this exploratory trial to decide whether to proceed with a subsequent efficacy clinical trial.

4.3 Statistical Design and Power

Statistical Analysis Plan (SAP): Applicants should provide a SAP for analyses specified in the study protocol. In addition to items requested under Section 4 - Protocol Synopsis of the PHS Human Subjects and Clinical Trials Information form, include the rationale for how missing data will be handled; plans for interim analyses for safety, efficacy, and futility; rationale for recalculation of the sample size midway through the trial (if applicable); and other measures to ensure rigor and transparency of the analysis. Sufficient details should be provided in the SAP about any computer simulations used to investigate the operating characteristics of complex clinical trial designs (such as adaptive designs); to choose between alternative outcome measures; or to determine sample size, accounting for the impact of noncompliance, missing data, subject eligibility criteria, etc. It is particularly important to discuss the range of conditions that were considered in the simulation and why this range was considered appropriate, how robust the findings were across the range of conditions considered, and how the study will adjust for any design deficiencies (e.g., bias, loss of power) the simulations revealed.

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 SF424 (R&R) Application Guide must be followed.

PHS Assignment Request Form

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

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

See Part 1. Section III.1 for information regarding the requirement for obtaining a unique entity identifier and for completing and maintaining active registrations in System for Award Management (SAM), eRA Commons, and Grants.gov

4. Submission Dates and Times

Part I. Overview Information contains information about Key Dates and time. 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 the How to Apply – Application Guide.

5. Intergovernmental Review (E.O. 12372)

This initiative is not subject to intergovernmental review.

6. Funding Restrictions

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.

7. Other Submission Requirements and Information

Applications must be submitted electronically following the instructions described in the SF424 (R&R) SBIR/STTR 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.

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 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, and responsiveness by components of participating organizations, NIH. Applications that are incomplete, non-compliant and/or nonresponsive will not be reviewed.

Applications must include a PEDP submitted as Other Project Information as an attachment. Applications that fail to include a PEDP will be considered incomplete and will be withdrawn before review.

Post Submission Materials

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

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.

For this particular announcement, note the following:

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 and proposed product or service address an important problem, a critical barrier to progress, or unmet need 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 and commercialization of the resulting product or service change the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field? Does the proposed project have commercial potential to lead to a marketable product, process or service? In the case of Phase II, Fast-Track, and Phase II Competing Renewals, does the Commercialization Plan demonstrate a high probability of commercialization? How strong is the described market opportunity in the Commercialization Plan including: (i) the product or service being developed; (ii) target customers; and (iii) how the product will solve a demonstrated customer need?

Specific for this NOFO:

  • If preclinical data (e.g. animal studies) do not meet the rigor guidelines, how well does the application discuss the limitations of those data? How well will the current study design address those gaps in knowledge?
  • How convincing is the evidence that equipoise exists in the medical and patient communities and the intervention is ready for clinical development?
  • How essential is the proposed exploratory trial to inform the design and implementation of subsequent steps in the evaluation of the intervention?
  • For Renewal applications to complete the aims of the original trial: Has the rationale or significance of the trial changed (e.g., recent relevant findings or new treatments that would alter the trial impact)?
  • To what extent do the efforts described in the Plan for Enhancing Diverse Perspectives further the significance of the project? 

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?

Investigator(s)

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the project and will they devote sufficient effort to successfully complete the proposed aims? Do the PD(s)/PI(s) have appropriate experience and training to lead this project? If so, have they demonstrated an ongoing record of accomplishments in 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? For projects in later stages, does the team have expertise to commercialize the technology/service/product?

Specific for this NOFO:

  • To what extent will the efforts described in the Plan for Enhancing Diverse Perspectives strengthen and enhance the expertise required 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 proposed product or service represent an innovative approach to addressing an important problem, barrier to progress, or unmet need in research or clinical practice? Does the end product or service proposed in application challenge and seek to shift current research or clinical practice paradigms? Will the end product or service proposed have significant advantages over existing approaches or methodologies, instrumentation, or interventions or those in development?

In the case of Phase II, Fast-Track, and Phase II Competing Renewals, does the small business present a reasonable plan to create a temporal barrier against other companies aiming to provide a similar solution, including protecting the intellectual property relevant to the product and technology(ies) being studied or used during the project?

Specific for this NOFO:

 

  • How much of an advantage does the proposed technology/product offer over all existing approaches as well as those in development for the same indication regardless of therapeutic classes?
  • If the proposed technology/product is trying to improve over early generations that may or may not have been marketed, are the potential advantages truly significant?
  • To what extent will the efforts described in the Plan for Enhancing Diverse Perspectives meaningfully contribute to innovation? 

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 research aims appropriate for the current stage of development? Do the aims represent the necessary steps to further advance the development of the product or service? 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? For a Phase I application, are there clear, appropriate, measurable goals (milestones) that should be achieved prior to initiating Phase II? Have the investigators presented adequate plans to address relevant biological variables, such as sex, for studies in vertebrate animals or human subjects?

For a Phase I, will the strategy establish feasibility, and will particularly risky aspects be managed? Are there clear, appropriate, measurable goals (milestones) that should be achieved prior to initiating Phase II?

For a Fast-Track, are there clear, appropriate, measurable goals (milestones) that should be achieved prior to initiating Phase II? Will successful completion of the research aims significantly advance development of the proposed product or service toward eventual commercialization?

For a Phase II, will successful completion of the research aims significantly advance development of the proposed product or service toward eventual commercialization? How well did the applicant demonstrate progress toward meeting the Phase I objectives, demonstrating feasibility, and providing a solid foundation for the proposed Phase II activity?

Specific for this NOFO:

  • How well does the application outline specific plans for clinical development of the intervention beyond this exploratory clinical trial?
  • For later-stage exploratory trials: How appropriate are the go/no-go criteria for proceeding with a subsequent efficacy clinical trial?
  • How well does the application show evidence of involvement of patient groups in study design and recruitment plans?
  • How well does the project leverage the use of existing NIH tools and other resources, including partnership with existing research networks?
  • For renewal applications to complete the aims of the original trial:
    • Has the administration of the trial to date been appropriate?
    • Has recruitment proceeded at the expected rate, and if not, are the plans to reach the desired sample size appropriate?
    • Is the trial as designed and executed likely to achieve the stated aims?
  • Has recruitment proceeded at the expected rate, and if not, are the plans to reach the desired sample size appropriate?
  • Is the trial as designed and executed likely to achieve the stated aims?
  • Has appropriate consideration been given to utilizing the NINDS Common Data Elements? 
  • Are the timeline and milestones associated with the Plan for Enhancing Diverse Perspectives well-developed and feasible? 

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?

Environment

Will the scientific and business environment in which the work will be done contribute to the probability of success and eventual commercialization? Are the small business 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 arrangement?

For a Phase I, does the company have appropriate business expertise and resources, or have they identified appropriate business resources, to accomplish the aims of this project and support commercialization of the proposed product or service?

For a Phase II or Fast-Track, does the applicant have access to the business experts and resources needed to accomplish the aims of this project and to commercialize the proposed product or service?

Specific for this NOFO:

  • To what extent does the applicant SBC have the ability to address regulatory issues, either through their own staff members or through appropriate arrangements with external regulatory consultants?
  • To what extent will features of the environment described in the Plan for Enhancing Diverse Perspectives (e.g., collaborative arrangements, geographic diversity, institutional support) contribute to the success of the project?

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

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)?

Intellectual Property (IP)

How strong is the applicant's intellectual property (IP) portfolio/position (pertinent to the proposed project), and to what extent does the company have a reasonable strategy to protect its IP going forward?

Fundraising Plan

How well does the application support the ability of the SBC to establish relationships with third-party investors and/or strategic partners and secure substantial independent third-party investor funds as expected under this NOFO? NINDS expects companies working in small markets to secure independent third-party funding equal to or greater than one-third of the NINDS funds being requested throughout the project period. For all other projects, it is expected that the level of this independent third-party funding will be equal to or greater than the NINDS funds being requested throughout the Phase IIB Bridge Award project period.

How detailed is the documentation (e.g., term sheet) that has been provided by the applicant to corroborate the Fundraising Plan? To what extent has the applicant demonstrated that the third-party investor support will provide a substantial, value-added contribution toward the development and commercialization of the product/technology? For example, has the applicant described the specific activities that the third-party investor funds will support?

If the third-party investors have attached restrictions and/or triggers and/or milestones to future payments, then to what extent have these restrictions been clearly stipulated in the application? In general, have the terms of the future investment rounds been sufficiently described, thus demonstrating a high level of confidence in the SBC’s ability to execute the overall fundraising plan?

Phase II Applications

For Phase II Applications, how well did the applicant demonstrate progress toward meeting the Phase I (or Phase I-like) objectives, demonstrating feasibility, and providing a solid foundation for the proposed Phase II activity?

Phase I/Phase II Fast-Track Applications

For Phase I/Phase II Fast-Track Applications, reviewers will consider the following:

1. Does the Phase I application specify clear, appropriate, measurable goals (milestones) that should be achieved prior to initiating Phase II?

2. To what extent was the applicant able to obtain letters of interest, additional funding commitments, and/or resources from the private sector or non-SBIR/STTR funding sources that would enhance the likelihood for commercialization?

Commercialization (Phase II and Fast-Track Only)

For Phase II and Phase I/Phase II Fast-Track Applications, reviewers will consider the following:

How well does the applicant present the market opportunity, including market segments, that its product or technology will address? Does the applicant understand the barriers to commercialization of its product or service (e.g., regulatory approval, insurance reimbursement, competitive products, customer preferences)? Does the applicant have appropriate strategies to address these barriers?

Does the applicant provide appropriate post-SBIR product development and commercialization milestones and explain how it will achieve these milestones? Does the applicant present a plan for funding the development and commercialization of the product or service? If applicable, did the applicant obtain letters of interest or commitment for such funding and/or resources?

Are the small business executives, management team, and business experts well suited to advance the development and commercialization of the proposed product or service? If not, is there a plan in place to add the necessary expertise as the product advances towards commercialization?

Is there a sound strategy for driving product adoption and generating revenue from the product or service (e.g., product sales, licensing, partnerships)?

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 criteria: (1) description of proposed procedures involving animals, including species, strains, ages, sex, and total number to be used; (2) justifications for the use of animals versus alternative models and for the appropriateness of the species proposed; (3) interventions to minimize discomfort, distress, pain and injury; and (4) justification for euthanasia method if NOT consistent with the AVMA Guidelines for the Euthanasia of Animals. Reviewers will assess the use of chimpanzees as they would any other application proposing the use of vertebrate animals. 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.

Phase IIB Competing Renewals

Not Applicable

Revisions

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.

Additional Review Considerations

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 with Foreign Components

Reviewers will consider whether work to be performed outside of the United States is thoroughly justified, based on a rare and unique circumstance, and necessary to the overall completion of the project.

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) (e.g., 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 the Center for Scientific Review, 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 will receive a written critique.

Applications may undergo a committee 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.

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 appropriate national Advisory Council or Board. 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.
  • Security risk as assessed by the HHS Due Diligence Program (for due dates on or after September 5, 2023).

Disclosure Requirements Regarding Ties to Foreign Countries

Upon request applicants are required to disclose all funded and unfunded relationships with foreign countries, using the Required Disclosures of Foreign Affiliations or Relationships to Foreign Countries form (referred to as the “Disclosure Form” hereafter), for all owners and covered individuals. A “covered individual” is defined as all senior key personnel identified by the SBC in the application (i.e., individuals who contribute to the scientific development or execution of a project in a substantive, measurable way).

Upon request, applicants must submit the completed Disclosure Form and any additional agency-specific information electronically in eRA Commons via the Just-In-Time (JIT) process as described in the NIH Grants Policy Statement (GPS) Section 2.5.1 Just-in-Time Procedures. Applicants must continue to comply with NIH Other Support disclosure requirements as provided in NIH GPS Section 2.5.1 and may be required to provide similar information on the Disclosure Form for covered individuals identified in the application. If participating in this NOFO, SBC applicants applying to CDC and FDA will follow each agency’s policies for submitting additional documents during the pre-award process. Applicants that do not submit the completed Disclosure Form during the JIT process will be deemed noncompliant and not be considered for funding.

Denial of Awards

Applicants are encouraged to consider whether their entity’s relationships with foreign countries of concern will pose a security risk. Prior to issuing an award, NIH (and, CDC or, FDA, as applicable) will determine whether the SBC submitting the application:

  • has an owner or covered individual that is party to a malign foreign talent recruitment program;
  • has a business entity, parent company, or subsidiary located in the People’s Republic of China or another foreign country of concern; or
  • has an owner or covered individual that has a foreign affiliation with a research institution located in the People’s Republic of China or another foreign country of concern.

A finding of foreign involvement with countries of concern will not necessarily disqualify an applicant. NIH (and, CDC or, FDA, as applicable) will provide SBC applicants the opportunity to address any identified security risks prior to award. Final award determinations will be based on whether the applicant’s involvement falls within any of the following risk criteria, per the Act:

  • interfere with the capacity for activities supported by NIH, CDC, or FDA to be carried out;
  • create duplication with activities supported by NIH, CDC, or FDA;
  • present concerns about conflicts of interest;
  • were not appropriately disclosed to NIH, CDC, or FDA;
  • violate Federal law or terms and conditions of NIH, CDC, or FDA; or
  • pose a risk to national security.

NIH, CDC, and FDA will not issue an award under the SBIR/STTR program if the covered relationship with a foreign country of concern identified in this guidance is determined to fall under any of the criteria provided above, and the risk cannot be resolved.

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

If the application is under consideration for funding, NIH will request "just-in-time" (JIT) information from the applicant as described in the NIH Grants Policy Statement. SBIR and STTR applicants under consideration for award will be required to submit the SBA U.S. Small Business Administration (SBA) issued the Required Disclosures of Foreign Affiliations or Relationships to Foreign Countries form during the JIT process. Applicants that fail to submit a Disclosure Form will not be considered for funding.

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 recipient's business official.

Recipients must comply with any funding restrictions described in Section IV.6. Funding Restrictions. Selection of an application for award is not an authorization to begin performance. Any costs incurred before receipt of the NoA are at the recipient's risk. These costs may be reimbursed only to the extent considered allowable pre-award costs.

Any application awarded in response to this NOFO 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.

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

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, Recipients, and Activities, including of note, but not limited to:

If a recipient is successful and receives a Notice of Award, 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.

Should the applicant organization successfully compete for an award, recipients of federal financial assistance (FFA) from HHS will be required to complete an HHS Assurance of Compliance form (HHS Assurance of Compliance form (HHS 690)) in which the recipient agrees, as a condition of receiving the grant, to administer programs in compliance with federal civil rights laws that prohibit discrimination on the basis of race, color, national origin, age, sex and disability, and agreeing to comply with federal conscience laws, where applicable. This includes ensuring that entities take meaningful steps to provide meaningful access to persons with limited English proficiency; and ensuring effective communication with persons with disabilities. Where applicable, Title XI and Section 1557 prohibit discrimination on the basis of sexual orientation, and gender identity, The HHS Office for Civil Rights provides guidance on complying with civil rights laws enforced by HHS. See https://www.hhs.gov/civil-rights/for-providers/provider-obligations/index.html and https://www.hhs.gov/civil-rights/for-individuals/nondiscrimination/index.html.

HHS recognizes that research projects are often limited in scope for many reasons that are nondiscriminatory, such as the principal investigator’s scientific interest, funding limitations, recruitment requirements, and other considerations. Thus, criteria in research protocols that target or exclude certain populations are warranted where nondiscriminatory justifications establish that such criteria are appropriate with respect to the health or safety of the subjects, the scientific study design, or the purpose of the research. 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.

Please contact the HHS Office for Civil Rights for more information about obligations and prohibitions under federal civil rights laws at https://www.hhs.gov/ocr/about-us/contact-us/index.html or call 1-800-368-1019 or TDD 1-800-537-7697.

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

Report fraud, waste and abuse

The Office of Inspector General Hotline accepts tips from all sources about potential fraud, waste, abuse and mismanagement in Department of Health & Human Services programs. The reporting individual should indicate that the fraud, waste and/or abuse concerns an SBIR/STTR grant or contract, if relevant. Report Fraud.

Cooperative Agreement Terms and Conditions of Award

Not Applicable

3. Data Management and Sharing

Note: The NIH Policy for Data Management and Sharing is effective for due dates on or after January 25, 2023.

  • Consistent with the 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. SBIR and STTR recipients may retain the rights to data generated during the performance of an SBIR or STTR award for up to 20 years after the award date, per the Small Business Innovation Research (SBIR) and Small Business Technology Transfer (STTR) Program Policy Directive. An acceptable Data Management and Sharing plan can reference and incorporate these data rights. Further information about SBIR and STTR data rights are enumerated in the NIH GPS.

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.

NIH requires that SBIR/STTR recipients submit the following reports within 120 days of the end of the grant budget period unless the recipient is under an extension. 

Failure to submit timely final reports may affect future funding to the organization or awards with the same PD/PI. 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 200.301.

The Federal Funding Accountability and Transparency Act of 2006 (Transparency Act), includes a requirement for recipients of Federal grants to report information about first-tier subawards and executive compensation under Federal assistance awards issued in FY2011 or later.  All recipients 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 the threshold. See the NIH Grants Policy Statement for additional information on this reporting requirement.

In accordance with the regulatory requirements provided at 45 CFR Part 75 and 2 CFR Part 200, recipients that have currently active Federal grants, cooperative agreements, and procurement contracts from all Federal awarding agencies with a cumulative total value greater than $10,000,000 for any period of time during the period of performance of a Federal award, must report and maintain the currency of information reported in the System for Award Management (SAM) about civil, criminal, and administrative proceedings in connection with the award or performance of a Federal award that reached final disposition within the most recent five-year period. The recipient must also make semiannual disclosures regarding such proceedings. Proceedings information will be made publicly available in the designated integrity and performance system (currently FAPIIS). This is a statutory requirement under section 872 of Public Law 110-417, as amended (41 U.S.C. 2313).  As required by section 3010 of Public Law 111-212, all information posted in the designated integrity and performance system on or after April 15, 2011, except past performance reviews required for Federal procurement contracts, will be publicly available. Full reporting requirements and procedures are found in 45 CFR Part 75 and 2 CFR Part 200 – Award Term and Condition for Recipient Integrity and Performance Matters.

Recipient s will provide updates at least annually on implementation of the PEDP.

Disclosure of Foreign Relationships Reporting Requirements

Recipients are responsible for monitoring their relationships with foreign countries of concern post-award, for any changes that may impact previous disclosures. SBCs receiving an award under the SBIR/STTR program are required to submit an updated Disclosure Form to report any of the following changes to NIH (and, CDC or, FDA, as applicable) throughout the duration of the award:

  • any change to a disclosure on the Disclosure Form;
  • any material misstatement that poses a risk to national security; and
  • any change of ownership, change to entity structure, or other substantial change in circumstances of the SBC that NIH, CDC, and FDA determine poses a risk to national security.

Updated Disclosure Forms are required within 30 days of any change in ownership, entity structure, covered individual, or other substantive changes in circumstance, as described above. Recipients are required to upload these updated disclosures using the Additional Materials (AM) tool in eRA Commons. In addition, regular updates are required at the time of all SBIR/STTR annual, interim, and final Research Performance Progress Reports (RPPRs).

If the recipient reports a covered foreign relationship that meets any of the risk criteria prohibiting funding described in this NOFO, NIH, CDC, and FDA may withhold funding until the covered relationship has been dissolved. The recipient will be required to submit documentation verifying the relationship has been terminated. If the risk cannot be resolved, NIH, CDC, and FDA may deem it necessary to terminate the award for material failure to comply with the federal statutes, regulations, or terms and conditions of the federal award. Refer to NIH GPS Section 8.5.2 Remedies for Noncompliance or Enforcement Actions: Suspension, Termination, and Withholding of Support for more information. Recipients are encouraged to monitor their covered foreign relationships post-award and avoid entering into relationships, both funded and unfunded, that may pose a security risk and jeopardize their ability to retain their award.

Agency Recovery Authority and Repayment of Funds

An SBC will be required to repay all amounts received from NIH, CDC, and FDA under the award if either of the following determinations are made upon assessment of a change to their disclosure:

  • the SBC makes a material misstatement that NIH, CDC, and FDA determine poses a risk to national security; or
  • there is a change in ownership, change in entity structure, or other substantial change in circumstances of the SBC that NIH, CDC, and FDA determine poses a risk to national security.

The repayment requirements and procedures provided in Section 8.5.4 Recovery of Funds of the NIH GPS apply and may also be subject to additional noncompliance and enforcement actions as described in Section 8.5.2 of the GPS. Recipients are required to follow the repayment procedures provided in the Guidance for Repayment of Grant Funds to the NIH.

Section VII. Agency Contacts

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

Application Submission Contacts

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: 301-637-3015

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

SBA Company Registry (Questions regarding required registration at the SBA Company Registry and for technical questions or issues)
Website to Email: http://sbir.gov/feedback?type=reg

Scientific/Research Contact(s)

Emily Caporello, Ph.D.
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-1778
Email: Emily.caporello@nih.gov

Peer Review Contact(s)

Examine your eRA Commons account for review assignment and contact information (information appears two weeks after the submission due date).

Financial/Grants Management Contact(s)

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.

Authority and Regulations

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.

The SBIR Program is mandated by the Small Business Innovation Development Act of 1982 (P.L. 97-219), reauthorizing legislation (P.L. 99-443) P.L. 102-564, P.L. 112-81 (SBIR/STTR Reauthorization Act of 2011), as reauthorized and extended under P.L. 114-328, Section 1834, P.L. 115-232, and P.L. 117-183. The basic design of the NIH SBIR Program is in accordance with the Small Business Administration (SBA) SBIR Policy Directive.

The STTR Program is mandated by the Small Business Reauthorization Act of 1997 (P.L. 105-135), and reauthorizing legislation, P.L. 107-50, P.L. 112-81 (SBIR/STTR Reauthorization Act of 2011), as reauthorized and extended under P.L. 114-328, Section 1834, P.L. 115-232, and P.L. 117-183. The basic design of the NIH STTR Program is in accordance with the Small Business Administration (SBA)STTR Policy Directive.

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