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Purpose: To facilitate the cooperation and partnering of public and private funding organizations, universities, academic medical centers, research institutes, contract research organizations, biotechnology companies, and pharmaceutical companies, NINDS formed the Network for Excellence in Neuroscience Clinical Trials (NeuroNEXT: https://neuronext.org. NeuroNEXT has a Clinical Coordinating Center (CCC), a Data Coordinating Center (DCC) and a group of geographically distributed clinical sites. This clinical research network develops and conducts multiple, scientifically sound, possibly biomarker-informed exploratory clinical trials evaluating the most promising therapies, whether from academic, foundation or industry discoveries. Examples include Phase 2 clinical trials and clinical research studies aimed at validating biomarkers and clinical outcomes in preparation for clinical trials. A separate clinical trials network has been established and funded by NINDS to conduct clinical trials and biomarker studies for stroke treatment, prevention and recovery; thus NeuroNEXT has been established for the conduct of studies in neurological disorders other than stroke. NeuroNEXT provides a robust, standardized, and accessible infrastructure to facilitate rapid development and implementation of protocols in neurological disorders affecting adult and/or pediatric populations. While the network is not specific to one disease, it has the capacity to coordinate a cadre of specialist investigators to implement studies efficiently in response to disease-specific opportunities. The network is designed to increase the efficiency of clinical trials, to facilitate patient recruitment and retention, to increase the quality of neuroscience clinical trials, and to enable public-private partnerships. Applicants to this NOFO will be required to incorporate the NeuroNEXT infrastructure (www.neuronext.org) into their proposed study. Additional (ad-hoc) sites may be proposed to fulfill specific study requirements. All applicants will be required to use the master clinical trial agreements and central IRB that have been established for NeuroNEXT. This NOFO uses the U44 cooperative agreement mechanism and is open to eligible applicants, as defined in Section III. Academic researchers may wish to consider applying through OTA-24-013 f(Stage 1 Preliminary) and OTA-24-014 Stage 2 Protocol) “NeuroNEXT Clinical Trials ”. Since conducting the clinical trials needed for commercialization may be capital-intensive, this NOFO encourages business relationships between NIH's SBIR/STTR awardees and third-party investors and/or strategic partners. In particular, this NOFO will give competitive preferences and funding priority to applications deemed likely to result in a commercial product as indicated by an applicant's ability to secure independent third-party funds. Definitions: For this funding opportunity announcement, Phase I and II 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. Scope of the Program: This NOFO encourages Phase II SBIR applications for exploratory clinical trials of investigational agents (drugs, biologics, surgical therapies or devices) that may contribute to the justification for and provide the data required for designing a future trial, for biomarker validation studies, or for proof of mechanism clinical studies. Applications for drugs or biologics should be supported by compelling scientific evidence that the investigational agent proposed for study will reach/act upon the designated target or that its mechanism of action is such that it is expected to be of benefit in ameliorating a specific aspect of the disease. Neurologic diseases chosen for study must fall within the primary responsibility of NINDS (www.ninds.nih.gov/funding/areas/index.htm). Multi-site studies in stroke prevention, treatment and/or recovery are not appropriate for this FOA; those studies would be considered by NIH StrokeNet: http://www.nihstrokenet.org/. A separate clinical trial network also exists for the conduct of studies in neurological emergencies (SIREN: https://siren.network/). Studies on these topics should be directed to the dedicated networks. Studies primarily focused on biomarker validation may also apply to one of the NINDS Biomarker funding opportunities https://www.ninds.nih.gov/current-research/focus-tools-topics/focus-biomarkers-research. Applications proposing primarily phase 1 and 3 clinical trials should be directed to the exploratory clinical trial NOFO, PAR-22-142 (https://grants.nih.gov/grants/guide/pa-files/PAR-22-142.html) and the efficacy clinical trial NOFO, PAR-21-237 (https://grants.nih.gov/grants/guide/pa-files/PAR-21-237.html) respectively, or their reissues. 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 the target population. Validate biomarkers that are fit-for-purpose for a specific context of use and can be used in future clinical trials. Select or rank the best of two or more potential interventions or dosing regimens to be evaluated in a subsequent trial, based on tolerability, safety data, biological activity, or preliminary clinical efficacy (e.g., futility trials). Evaluate biological activity relative to clinical endpoints. For medical devices, in addition to providing initial clinical safety data, appropriate studies are those that inform the next phase of development, usually by finalizing the device design, establishing operator technique, and/or finalizing the choice of study endpoints for the design of a pivotal clinical trial. This NOFO is not intended to support the conduct of a clinical trial where the primary aim is to confirm efficacy of a proposed intervention. While NeuroNEXT is primarily intended for exploratory trials, the network will consider Phase II/III trials in rare diseases with a US prevalence of under 200,000 persons as defined in the Rare Diseases Act of 2002 (Public Law 107-280 (https://www.gpo.gov/fdsys/pkg/PLAW-107publ280/content-detail.html)). Phase 1b/2a trials requiring multi-center implementation can be considered under this NOFO. Working with NeuroNEXT is a cooperative venture between NINDS, the NeuroNEXT network and the applicant. NINDS will provide guidance to potential applicants with input from NINDS Program Staff and the NeuroNEXT Executive Committee. Potential applicants are strongly encouraged to contact NINDS Scientific/Research Contacts (see Agency Contacts, Section VII) to discuss the feasibility of conducting the proposed trial through the NeuroNEXT infrastructure before submitting an application. Pre-application consultation may include an introductory teleconference (at least 3 months prior to submission), followed by a conference call or in-person meeting with NINDS staff, as needed. Applicants should make note of the following: (1) Medical devices: The NIH recognizes that devices can vary greatly in terms of basic form and function, physiological bases for therapy, degree of Invasiveness, etc. Consequently, the appropriate pathway to market may require a traditional Feasibility and Pivotal study in support of an eventual Pre-Market Approval submission, or a more limited study to address specific issues in support of an FDA 510(k) or 510(k) De Novo submission. NINDS anticipates that the majority of device projects utilizing NeuroNEXT will be traditional Feasibility Studies in order to best leverage the advantages of the network. A Traditional Feasibility Study is a clinical investigation that is commonly used to capture preliminary safety and effectiveness information on a near-final or final device design to adequately plan a Pivotal Study. (2) Biomarker validation studies: Biomarkers are defined as a characteristic that is measured as an indicator of normal biological processes, pathogenic processes, or responses to an exposure or intervention, including therapeutic interventions. Categories of biomarkers include: Susceptibility/risk, diagnostic, monitoring, prognostic, predictive, pharmacodynamic/response, and safety. Biomarker studies should define their intended Context of Use (a statement that fully and clearly describes the way the biomarker will be used in future clinical trials). (3) Rare diseases: Applications in rare diseases are encouraged while recognizing that available patient pools may not be adequate to meet the sample size requirements normally required to establish the efficacy of an intervention. NINDS acknowledges that innovative, non-traditional trial designs including adaptive designs may be appropriate in rare disease studies. Regardless of the design it is especially important to ensure that the study design and statistical analysis plans 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. Applications Not Responsive to this NOFO Nonclinical studies of disease mechanism or therapeutic mechanism of action studies Animal studies Single site studies Research focused entirely on natural history studies Applications considered non-responsive will be withdrawn prior to review. This NOFO requires a Community Engagement and Research Inclusion (CERI) Plan which will be assessed as part of the scientific and technical peer review evaluation. Assessment of applications containing a CERI Plan are based on descriptions of how community engagement strategies and community-engaged research will be employed during the planning period of the proposed study; 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. Applications that fail to include a CERI Plan will be considered incomplete and will be administratively withdrawn before review. The CERI Plan will be submitted as Other Project Information as an attachment (see Section IV). Applicants are strongly encouraged to read the NOFO instructions carefully.