NINDS Renewal Awards of SBIR Phase II Grants (Phase IIB) for Exploratory Clinical Trials and Clinical Research (R44)
- 001: Funding Opportunity Description
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 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 exploratory clinical trials 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). 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 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. 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 in response 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.
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.
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).
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) Other Relevant Programs:
NINDS has a network called NeuroNEXT specifically designed to implement multi-site exploratory clinical trials (see http://www.neuronext.org/) and when appropriate, it is strongly preferred that such trials be performed within this network. Therefore, before submitting an application to this FOA, applicants 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.
NINDS has also recently initiated a network to advance stroke research through multi-site clinical trials focused on key interventions in stroke prevention, treatment and recover www.nihstrokenet.org. The NETT (Neurological Emergencies Treatment Trials) is available to support large simple trials to reduce the burden of very acute injuries and illnesses affecting the brain, spinal cord, and peripheral nervous system (http://www.nett.umich.edu/nett/welcome).
(2) 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-13-278, NINDS Investigator-Initiated Phase 3 Clinical Trials.
(3) Effect Size: A trial will not be considered 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.
4) Secondary Aims: For drugs and biologics, issues of study feasibility and refinement of study procedures may be addressed as secondary aims in an exploratory 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.
(5) Multiple Trials: There may be multiple questions remaining to be answered before a Phase 3 trial can be designed and conducted. The proposed study is not required to address all potential questions.
(6) Exploratory IND/Early Feasibility studies: Applicants may propose Exploratory IND studies as defined by the FDA (http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm078933.pdf) or early feasibility studies of devices as defined by the FDA (http://www.fda.gov/downloads/medicaldevices/deviceregulationandguidance/guidancedocuments/ucm279103.pdf).
- Applicants are encouraged to evaluate preliminary efficacy based on early signals of activity on biomarkers or clinical endpoints, or mechanistically test the activity of an intervention in terms of its presumed target(s). However, in the absence of a suitable biomarker, clinical outcomes may be used.
- It is not the purpose of this FOA to encourage applications to discover biomarkers.
(8) 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). For a Phase 2 trial of a drug or biologic, specific plans for the next steps of the therapy's development (such as a future efficacy trial) must be succinctly stated. Applications for seamless Phase 2 and Phase 3 trials should be submitted to PAR-13-278, NINDS Investigator-Initiated Phase 3 Clinical Trials. 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.
(9) Simulations: Computer simulations are sometimes used to investigate the operating characteristics of complex clinical trial designs (such as adaptive designs), to choose between alternative outcome measures, or to determine sample size, by taking into account the impact of noncompliance, missing data, and subject eligibility criteria, etc.
(10) 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.
(11) Rare Diseases: Trials in rare diseases are encouraged, and it is recognized that available patient pools may not be adequate to meet the sample size requirements typically seen in Phase 3 trials. Innovative trial designs, including crossover designs and adaptive designs, may allow for the most efficient evaluation of the limited subjects available for study. For trials in rare diseases, it is especially important to ensure that the study design will meet the stated objectives, and the approach should carefully be justified. Applicants proposing Phase 3 studies aiming to demonstrate evidence of efficacy to support a licensing application are encouraged to contact the FDA to gain concurrence on the trial design. Applicants are also advised to contact NINDS Scientific/Research staff early in the planning process.
(12) 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.
(13) Regulatory Approvals: As per NINDS policy (http://grants.nih.gov/grants/guide/notice-files/NOT-NS-11-018.html), at the time of grant submission, if the intervention is a drug, biologic, or device, applicants must provide documentation from the FDA providing information on one of the following three scenarios:
(a) The protocol has been submitted under an open IND/IDE and the IND/IDE 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 under an IND/IDE 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.
(c) The protocol is exempt from an IND/IDE. Under this scenario applicants must provide a copy of the exemption letter from the FDA. For devices, if the IRB has determined that the device is Non-Significant Risk, documentation from the IRB is acceptable.
Applications that do not include this information will be considered incomplete. Prior to grant award, awardees who do not have an exemption from the FDA must provide any additional FDA correspondence regarding the status of the protocol to the NINDS, especially if the trial has been placed under full or partial hold.
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.
(14) 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).
(15) Mobile Technologies: Applicants are 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.
(16) 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). 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.