NIH StrokeNet Small Business Innovation Clinical Trials and Biomarker Studies for Stroke Treatment, Recovery, and Prevention (U44)

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 in the advancement of interventions for stroke prevention, treatment, and rehabilitation, NINDS has formed the NIH Stroke Clinical Trials Research Network (NIH StrokeNet, http://www.ninds.nih.gov/research/clinical_research/NINDS_stroke_trials_network.htm). The NIH StrokeNet comprises a National Clinical Coordinating Center (NCC), a National Data Management Center (NDMC) and 25 geographically distributed Regional Coordinating Centers (RCC) with over 350 affiliated stroke centers.

The NIH StrokeNet network will consider the breadth of cerebrovascular disease, beginning with patients identified with an acute stroke through stroke rehabilitation and primary and secondary stroke prevention for pediatric and adult patients.

The network will provide a robust, standardized, and accessible infrastructure to facilitate rapid development and implementation of NINDS-funded stroke trials. The network is designed to increase the efficiency of stroke clinical trials by facilitating patient recruitment and retention, supporting novel methodologies and streamlined approaches to accelerate the development of promising stroke therapies, and enabling comparison between approaches.

This FOA is restricted to small business applicants.  For-profit organizations and non-profits other than Institutions of Higher Education may wish to consider applying through PAR-17-277, NIH StrokeNet Clinical Trials for Stroke Treatment, Recover and Prevention Infrastructure Resource Access (X01).  Others may consider use of PAR-17-274, NIH StrokeNet Clinical Trials and Biomarker Studies for Stroke Treatment, Recovery and Prevention (U01).  It is recommended that all prospective applicants contact NINDS Scientific/Research staff before submitting an application. 

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

NINDS has established the NIH StrokeNet to facilitate and streamline the execution of clinical trials in stroke. Thus, it is expected that all multi-center clinical trials for stroke treatment, prevention, and recovery supported by NINDS will be considered for implementation through the NIH StrokeNet. 

This FOA encourages and provides a mechanism for the submission of applications for multi-center exploratory and confirmatory clinical trials focused on promising interventions, including pragmatic trials performed in large numbers of patients with minimal alteration from clinical practice and low per-patient costs.  Also eligible are biomarker- and outcomes-validation studies that are immediately preparatory to trials in stroke prevention, treatment, or recovery.  Exploratory clinical trials must include a clearly defined go/no-go pathway toward advancement to a future Phase 3 trial. In addition, the network will support studies to validate biomarkers with demonstrated promise to inform Phase 2 clinical trials.  It is NINDS’ intention that the NIH StrokeNet will maintain a balanced portfolio of studies in each of these three areas, defined as follows:

• Primary and secondary prevention stroke trials – studies of agents, devices, or strategies to prevent recurrent stroke in survivors of stroke or transient ischemic attack (TIA), or to prevent first stroke in high-risk populations.
• Emergent management or acute stroke treatment trials – studies of agents, devices, or strategies to intervene during the acute phase of stroke with the goal of reducing brain injury and promoting optimal patient recovery; may include pre-hospital as well as emergency department or in-patient approaches; includes all stroke types.
• Neuro-recovery and rehabilitation stroke trials – studies of agents, devices, or strategies to improve long-term recovery, including cognitive, behavioral and/or motor function or quality of life outcomes, and/or to reduce the time to optimal recovery in patients after the acute period.  

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 exploratory studies (for example, early dose ranging studies with biomarker outcome, early proof of mechanism or proof of concept trials) are encouraged when appropriate.   For medical devices, Early Feasibility and Traditional Feasibility study designs may include single-arm case series, on-off interventions (patients as own controls), device-device comparisons, comparisons to historic controls, comparisons to performance controls, or adaptive/Bayesian designs. 

Priority of proposed network trials deemed by peer review to be highly meritorious will be based on factors including infrastructure capacity and availability of patient populations considering current ongoing trials within the network.  Applicants may submit a proposed study at any time but timing of funding and initiation of the study will be determined by the NINDS with input from the NIH StrokeNet leadership as necessary to assure that studies can be conducted within the proposed timeline included in the research plan of the application. 

While additional sites outside of the NIH StrokeNet network of RCC's may be required, NINDS expects that any confirmatory (Phase 3) trial conducted within the network will utilize most or all of the Regional Coordinating Centers.  Exploratory trials and biomarker validation studies are expected to use at least 5 RCC's and should be feasible within the network with the addition of relatively few non-NIH StrokeNet sites (note that the applicant institution, if not a NIH StrokeNet site, may be included as a performance site in the study). The final number of sites needed for a proposed study will be determined following a feasibility assessment by the NIH StrokeNet. 

Exploratory Trials

Examples of appropriate exploratory studies under this FOA include, but are not limited to, multi-center studies designed for the following purposes:

• To evaluate and optimize the dose, formulation, safety, tolerability, or pharmacokinetics of an intervention in the target population.
• To evaluate whether an intervention produces sufficient evidence of short-term activity (e.g., biomarker activity, pharmacodynamic response, target engagement, dose-response trends) in a human “proof of concept” trial.
• To 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).
• To 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.

Confirmatory (Phase 3) Trials

Confirmatory trials are conducted to provide a definitive answer regarding the safety and efficacy of an intervention or to compare the effectiveness of two or more interventions.  The proposed research must address a scientifically important question, provide valuable information to the existing knowledge base, and have public health relevance.  The trial design should ensure that high quality, complete data regarding the primary outcome will be collected in the most efficient manner in terms of time, resources, and burden to subjects. Secondary outcomes should be included only when they are anticipated to provide important supportive or explanatory data. The necessity of each secondary endpoint must be justified in light of cost and burden.  Pragmatic trials requiring minimal data collection and low cost per subject are encouraged. 

Biomarker and Clinical Endpoint Studies

Biomarkers, especially neuroimaging markers of vascular pathology, brain ischemia, or recovery after injury, have been developed for stroke research.  The potential applications of biomarkers include guiding early neuroprotective and reperfusion interventions, monitoring neuroplasticity in stroke recovery, and expediting therapy development.  Some biomarkers have been validated in multi-center studies, but their full potential to advance research awaits standardization and adoption across a clinical trials network. Similarly, for certain stroke trials the “road block” to evaluating a therapeutic approach may be the lack of a valid clinical endpoint.

This FOA encourages the submission of studies to validate biomarkers or clinical outcomes with demonstrated promise to inform Phase 2 clinical trials.  Depending on the scientific questions posed, biomarker studies supported under this program might be stand-alone protocols or could be embedded within a network stroke trial.  Studies designed for biomarker discovery are not suitable for this FOA.

Implementation

Applicants should make note of the following:

(1) Working with the NIH StrokeNet is a cooperative venture between NINDS, the NIH StrokeNet and the applicant. Potential applicants will be provided guidance by NINDS Program Staff and the NIH StrokeNet Executive and Steering Committees. Potential applicants are strongly encouraged to contact NINDS Scientific/Research Contacts (see Section VII. Agency Contacts) in order to discuss the appropriateness of the proposed study to be conducted within the NIH StrokeNet.  Prior to submission of the grant, applicants will be encouraged to work closely with the NIH StrokeNet Investigators in developing their research plan, assessing the feasibility of the study, and developing an appropriate budget to conduct the research.  The additional interaction with the network is intended to harness the scientific clinical trial expertise in the network and to establish early collaborations necessary for successful conduct of the research plan. Potential applicants are strongly encouraged to start the process early and allow ample time (i.e., 4-6 months) to prepare and submit a competitive NIH StrokeNet project application.

(2) Applicants to this FOA will be required to incorporate the NIH StrokeNet infrastructure (http://www.ninds.nih.gov/research/clinical_research/NINDS_stroke_trials_network.htm) into their proposed study, including central coordination through the NCC, data management through the NDMC, and subject recruitment and trial implementation at the RCCs and affiliated sites. It is not required that all sites participate in every trial. Additional (ad hoc) performance sites that are not currently NIH StrokeNet sites may be proposed to fulfill specific study requirements. All applicants and ad-hoc non-NIH StrokeNet sites will be required to use the master clinical trial agreements and central IRB that have been established for the NIH StrokeNet.

(3) Following peer review, the operational clinical protocol for trials selected for funding will be finalized by the NIH StrokeNet protocol working group and are expected to incorporate recommendations that may come from the peer review process. The NIH StrokeNet team was established by NINDS based on peer- and Council review to form a group of outstanding clinical trial experts from the fields of neurology and statistics with a proven record of developing high quality protocols.  Final protocols will be reviewed and approved by NINDS prior to funding the application.

(4) This FOA is intended to support studies in patients, not healthy volunteers. Applications to conduct exploratory trials in healthy volunteers should be submitted in response to a separate announcement, PAR-17-122 (https://grants.nih.gov/grants/guide/pa-files/PAR-17-122.html).  All trials proposing use of an investigational agent or device must have an active IND or IDE or documentation of exemption at the time of submission of the application (see https://grants.nih.gov/grants/guide/notice-files/NOT-NS-11-018.html).

(5)  Device trials: 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 may require a more limited study to address specific issues in support of an FDA 510(k) or 510(k) De Novo submission. Clinical studies involving devices may utilize the entire NIH StrokeNet network, or a more limited subset of centers selected based on appropriate expertise for the given device. Investigators are encouraged to contact the NINDS Scientific/Research Contact as early as possible to discuss how the NIH StrokeNet network may best be utilized in support of their specific device project. NINDS anticipates that the majority of device projects utilizing the NIH StrokeNet will be traditional Feasibility Studies in order to optimally leverage network advantages.  An Early Feasibility Study should be designed [in accordance with FDA’s draft guidance, “Investigational Device Exemptions (IDE) for Early Feasibility Medical Device Clinical Studies, Including Certain First in Human (FIH) Studies”, see http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm277670.htm] to allow for early clinical evaluation of devices to provide proof of principle and initial clinical safety data while device design and operations are still in development. 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.

(6) Rationale:  Exploratory and confirmatory clinical trials proposed for this network must anchor their rationale in (1) an unmet medical need; (2) a plausible biological mechanism; (3) rigorous preclinical (in vitro and/or in vivo) data; and/or (4) early clinical data. The individual weight given to each of these four criteria should be carefully assessed in the context of the specific application; there is no requirement to provide support from all four areas. The major findings of the studies, whether preclinical or clinical, that led to the proposed clinical trial should provide a compelling rationale that the proposed intervention will be effective. Data from preclinical and pilot studies demonstrating the need for and the feasibility of the trial should be presented when available. While the NINDS recognizes that animal models for stroke prevention, treatment, and recovery may be of limited informative value, the applicant should consider the rigor of any animal studies being used as support (https://grants.nih.gov/grants/guide/notice-files/NOT-NS-11-023.html).  Preclinical data (such as from animal studies) that do not sufficiently meet the rigor guidelines or are not sufficiently associated with the human condition may be inadequate to support the rationale for the study. 

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

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

• Clinical and Translational Science Award (CTSA) program (https://www.ctsacentral.org/);
• 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/).

(9) Mobile Technologies: Applicants are strongly encouraged to consider utilizing (at least experimentally) mobile technologies to facilitate data collection and protocol adherence on the part of research participants and study site staff.

(10) Plan for Full Commercialization:  Applications considered under this FOA must outline a specific plan for future development in the case of a successful clinical trial. All applicants are expected to describe a realistic plan (extending beyond the SBIR Phase II), which outlines how and when full commercialization can be accomplished.

Since conducting the clinical trials needed to commercialize these products may be capital-intensive, this FOA encourages 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 funding. 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.   

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