NINDS Renewal Awards of SBIR Phase II Grants (Phase IIB) for Clinical Trials and Clinical Research (R44 Clinical Trial Optional)

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 SBC will fully commercialize their product or technology using non-SBIR/STTR funds in Phase III.

Some projects initiated with SBIR or STTR funding require considerable financing beyond the SBIR/STTR Phase II award to achieve commercialization. The development of medical biotechnology products is often impeded by a significant funding gap, known as the "Valley of Death," between the end of the SBIR/STTR Phase II award and the commercialization stage. In particular, the development of therapeutics and medical devices often requires several years and substantial capital investments, due in part to the costs associated with conducting clinical trials. Traditionally, large pharmaceutical and biotechnology companies, as well as venture capital firms, have provided the resources needed to conduct the clinical studies required to fully develop and commercialize biomedical products and technologies initiated with SBIR/STTR funding. More recently, however, many investors in life science technologies have shown a bias toward financing the continued development of relatively mature technologies at established companies, rather than the higher-risk, emerging technologies under development at many small businesses.

This FOA supports SBIR Phase IIB applications from Small Business Concerns (SBCs) for clinical trials or clinical research that contribute to the justification for a future trial to establish efficacy (such as a Phase 3 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.  Applications must aim to generate data that inform further clinical development of the proposed intervention or diagnostic. The earliest studies should be designed to provide important initial information regarding the intervention (e.g., safety, tolerability, dosing) or diagnostic. Later-stage 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.

Since conducting the clinical trials needed for commercialization may be capital-intensive, the FOA aims to facilitate the transition of SBIR Phase II projects to the commercialization stage by encouraging business relationships between NIH's SBIR/STTR awardees and third-party investors and/or strategic partners. In particular, this FOA 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 substantial independent third-party funds (i.e. third-party funds that equal or exceed the NINDS funds being requested throughout the Phase IIB project period).

These funds can come from a variety of sources and a number of public and private organizations are taking steps to provide additional resources to advance a greater number of early-stage technologies toward commercialization. Importantly, many of these organizations are not only providing financial support but also establishing programs to provide commercialization guidance. For example, in the area of drug development, a number of major pharmaceutical firms have developed corporate venture funds focused on supporting projects in the pre-clinical stages of development, and some of these firms have established technology incubators to provide regulatory guidance. In addition, a growing number of universities are creating venture funds to support innovative technologies developed by their resident investigators, and numerous state-sponsored technology funds have also been created across the U.S. to support start-up companies. Taken together, these programs can provide additional financing and commercialization support for SBIR awardees that have received initial seed funding and a rigorous technical evaluation through the NIH peer review process. As such, a major goal of this FOA is to provide a platform to incentivize partnerships between NIH-funded SBIR/STTR awardees and a broad range of potential third-party investors.

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. SBIR Phase IIB awards must be based on a previously successful SBIR or STTR Phase II award.

Specific Objectives

Independent Third-Party Investor Funds

This FOA 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 FOA, to negotiate and attract third-party financing needed to advance a product or technology toward commercialization. The applicant's ability to secure independent third-party investor funds that equal or exceed the total amount of the NINDS funds being requested over the entire Phase IIB project period will provide a measure of the commercial potential that is essential for the SBIR applications submitted to this FOA. This potential will be strongly considered in making funding decisions. It is anticipated that many of the partnerships between applicant SBCs and third-party investors will involve a considerable level of project due diligence by the private sector, thereby increasing the likelihood of commercial success for the funded projects. 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.

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 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).
• To evaluate biological activity relative to clinical endpoints.
• 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.

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 three 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) - supports early phase clinical trials in neurological disorders other than stroke.
• StrokeNet (www.nihstrokenet.org) - supports early phase as well as phase III clinical trials in stroke prevention, acute treatment, and recovery.

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.

(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://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).

(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).

(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, and it is recognized that available patient pools may necessitate innovative trial designs to allow for the most efficient evaluation of the limited subjects available for study. 

(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.    

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