Description:
Purpose
NINDS is committed to advancing treatments, tools, and diagnostics that benefit people burdened by neurological diseases through the NINDS Small Business Innovation Research (SBIR) and Small Business Technology Transfer (STTR) programs. 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). To achieve commercialization, some projects initiated with SBIR or STTR funding require considerable grant-in-aid financing beyond the SBIR/STTR Phase II award to achieve follow-on investment or commercialization. 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 or studies 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, first-in-human studies (as defined by the Food and Drug Administration), 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. Mid-stage 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.
In addition, 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 disparate patient populations.
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 tools intended for the neuroscience research market
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 previously funded SBIR or STTR Phase II projects to the commercialization stage by encouraging business relationships between NIH’s SBIR/STTR recipients and third-party investors and/or strategic partners. In particular, this NOFO will give competitive preference and funding priority to applications deemed likely to result in a commercial product as indicated by an applicant's ability to secure partnerships within a broad range of potential third-parties.
Specific Objectives
Independent Third-Party Partners
This NOFO is specifically intended to encourage 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. In particular, applicants are expected to leverage their previous NIH SBIR or STTR support, as well as the opportunity to compete for additional NINDS funding under this NOFO, to negotiate and attract third-party financing needed to advance a product or technology toward commercialization. The applicant’s ability to secure funds will provide a measure of commercial potential that is essential for the SBIR applications submitted to this NOFO. This commercial potential will be strongly considered in making funding decisions. It is anticipated that many of the partnerships between applicant SBCs and third-party partners will involve a considerable level of project due diligence, thereby increasing the likelihood of commercial success for the funded projects. 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.
NINDS expects companies working in small markets (as defined above) 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.
Scientific/Technical Scope
The technical and commercial objectives described in the SBIR Phase IIB application must represent an extension of the development efforts that were pursued in a previously funded NIH SBIR or STTR Phase II grant or contract.
Examples of appropriate studies under thisNOFO 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.
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.
NIH strongly encourages applications from PDs/PIs from broadly diverse backgrounds to bring diverse perspectives to the research enterprise. Diversity within the NIH-supported scientific workforce fosters innovation, enhances global competitiveness, and improves the quality of research and research outcomes. NIH is committed to supporting a sustainable and diverse biomedical research workforce (see Notice of NIH's Interest in Diversity, NOT-OD-20-031).
Fostering and encouraging applications from 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). To broaden the range of institutions training researchers entering the biomedical entrepreneurial workforce, NIH also strongly encourages applications with eligible PDs/PIs who are graduates or affiliates of institutions in Institutional Development Award (IDeA) states or Resource-Limited Institutions. (See Notice of Special Interest: Encouraging Small Businesses to Partner with Resource-Limited Institutions (RLIs) on Small Business Innovation Research (SBIR) and Small Business Technology Transfer (STTR) Program Applications, NOT-OD-23-179.)
Plan for Enhancing Diverse Perspectives
The NIH recognizes that teams comprised of investigators with diverse perspectives working together and capitalizing on innovative ideas and distinct viewpoints outperform homogeneous teams. There are many benefits that flow from a scientific workforce rich with diverse perspectives, 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 guided by the consideration of diverse perspectives. Broadly, diverse perspectives can include but are not limited to the educational background and scientific expertise of the people who perform the research; the populations who participate as human subjects in research studies; and the places where research is done.
This NOFO requires a Plan for Enhancing Diverse Perspectives (PEDP), which will be assessed as part of the scientific and technical peer review evaluation. Assessment of applications containing a PEDP are based on the scientific and technical merit of the proposed project. Consistent with federal law, the race, ethnicity, or sex (including gender identity, sexual orientation or transgender status) of a researcher, award participant, or trainee will not be considered during the application review process or when making funding decisions. Applications that fail to include a PEDP will be considered incomplete and will be administratively withdrawn before review.
The PEDP will be submitted as Other Project Information as an attachment (see Section IV). Applicants are strongly encouraged to read the NOFO instructions carefully and view the available PEDP guidance materials
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, minorities, and participation of individuals across the lifespan 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:
Clinical and Translational Science Award (CTSA) program (https://ncats.nih.gov/ctsa);
NeuroQOL (http://www.neuroqol.org);
NIH Toolbox (http://www.nihtoolbox.org);
PROMIS (http://www.nihpromis.org); and
NINDS Common Data Elements (http://www.commondataelements.ninds.nih.gov).
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.
(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
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
Applications Not-Responsive to this NOFO:
Non-responsive applications will not be reviewed.
Applications for Phase 3 trials and other trials where the primary aim is to establish or confirm definitive efficacy. These projects should be submitted under 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.
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.
