NINDS Exploratory Clinical Trials for Small Business (R43/R44 Clinical Trial Required)

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 FOA 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 studies of devices, as well as preliminary studies of surgical, behavioral or rehabilitation therapies. A wide range of trials at different stages of development are allowed, including first-in-human (as defined by the Food and Drug Administration), Phase 1 and 2 single-site studies, and Phase 2b multicenter studies in certain cases. 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 FOA 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 (U01). 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 Pre-Clinical Research (R44). The goal of this FOA 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 FOA aims to facilitate the transition of clinical-stage projects to the commercialization stage by encouraging business relationships between NIH’s SBIR/STTR awardees 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. Specific Objectives Scientific/Technical Scope Examples of appropriate studies under this FOA 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., 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. This PAR encourages applications from diverse teams of investigators, including team members that are underrepresented in the biomedical, behavioral, or clinical research workforce Fostering diversity by encouraging the participation of individuals from nationally underrepresented groups in the scientific research workforce is longstanding interest of Congress, and a key component of the NIH strategy to identify, develop, support, and maintain the quality of our scientific human capital (e.g., Public Law 114-329, American Innovation and Competitiveness Act of 2017, and Notice of NIH's Interest in Diversity, NOT-OD-20-031). Scientists and trainees from underrepresented backgrounds and life experiences bring different perspectives, creativity, and individual enterprise to address complex scientific problems. Increasingparticipation by socially andeconomically disadvantagedand women-owned small businesses isalsocritical to the success of the SBIR and STTR programs.  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 diverse patient populations. For the purposes of this FOA, 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. 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 are available. (2) Other Relevant Programs: NINDS supports clinical trial networks specifically designed to implement multi-site clinical trials, and when appropriate, it is strongly preferred that such trials be considered for implementation through one of these networks. 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 FOA, 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. Before submitting an application to this FOA, 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 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 opportunties. 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 grantees utilizing this resource (see NOT-NS-15-046). Applicants planning projects in which biospecimens will be collected are strongly advised to consult the BioSEND website for more information about samples banked at the repository. In addition, applicants are advised to consult with BioSEND staff to obtain a quote for biospecimen banking costs (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 FOA 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 trials of drugs or Pivotal device trials) should be submitted to PAR-18-422, 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 trial will not be considered for funding under this FOA 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. Creating clinical trial infrastructure 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 an 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)Adaptive Designs: The use of innovative and efficient study designs is encouraged, such as adaptive dose-finding designs, designs incorporating plans for sample size recalculation, and futility designs. Applications for Phase 1 trials in the patient population are encouraged when appropriate, as are applications that encompass Phase 1 and Phase 2a studies (early proof of mechanism or proof of concept). Applications for seamless Phase 2/3 trials should be submitted under PAR-18-422, 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 ultimate 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 other 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 sites 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). This FOA is not appropriate for applications primarily intended to discover biomarkers. Applications Not-Responsive to this FOA: 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 seamless Phase 2/3 trials. These projects should be submitted under PAR-18-422, 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-18-422, 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 Phase II stroke clinical trials (these should be submitted to StrokeNet http://www.nihstrokenet.org). Preclinical activities to support filing of an IND or IDE followed by clinical trial activities supported by this IND/IDE. 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.