- 001: Funding Opportunity Description
The SBIR/STTR Programs were recently reauthorized by the United States Congress with the SBIR/STTR Reauthorization Act of 2011(P.L. 112-81). One change that was made to the SBIR program in this reauthorization was the authority for certain participating federal agencies to ‘issue a Phase II award to a small business concern that did not receive a Phase I award for that research/research & development. This is a so-called ‘Direct-to-Phase II’ SBIR award. This authority would permit SBCs to submit Direct-to-Phase-II SBIR applications, if the small business had performed the Phase I stage-type of research through other funding sources. The legislative rationale for permitting the Direct-to-Phase II award is to allow a SBC that has already built a technology prototype and tested its feasibility (i.e. completed Phase-I-type R&D) to move directly into a Phase-II-type R&D that tests the functional viability of the prototype according to scientific methods and potential for commercial development. The Direct-to-Phase-II SBIR mechanism eliminates the need for the SBCs to propose additional small feasibility studies, if the technology is ready for the Phase II stage of development. The Direct-to-Phase II authority is not available to the STTR program.
The purpose of this funding opportunity announcement (FOA) is to support Direct-to-Phase II exploratory clinical trials at the NINDS. For this FOA, the small business has demonstrated the scientific and technical merit and feasibility of the prototype stage of developing a biomedical technology that has commercial potential. The goal of this FOA is to enable a small business that has accomplished the objectives of a Phase I SBIR grant through non-SBIR funds to initiate the Phase II SBIR stage of development, without needing to perform more early stage, Phase-I-SBIR-type research.
This FOA will also not accept ‘regular’ Phase II submissions from SBCs that have received a Phase I SBIR or STTR award from NIH or any other agency that participates in the SBIR/STTR programs. For this FOA, it is expected that the technology, prototype, or method will have passed the proof of principle stage and that the product has demonstrated feasibility and supports a Phase II effort. Data or evidence of the capability, completeness of design, and efficacy must be provided in the application, along with the rationale for selection of the criteria used to validate the technology, prototype, or method, similar to a Phase I final report required in standard Phase II applications.
This FOA supports Direct-to-Phase II SBIR 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 clinical trial or a Pivotal device trial). This includes Phase 1 and 2 clinical 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 clinical studies, and Phase 2b multicenter clinical studies. Applications should 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 should consider 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 PAR-13-278 "NINDS Investigator-Initiated Phase 3 Clinical Trials". Fast-Track applications or 'regular' Phase II submissions from SBCs that have received a Phase I SBIR from NIH or any other agency should be submitted to PAR-12-073. Renewal applications of SBIR Phase II awards (i.e. SBIR Phase IIB) to conduct Phase I and II clinical studies should be submitted to PAR-14-208.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.
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) 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.
(3) 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.
(4) 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.
(5) 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).
(6) Regulatory Approvals: As per NINDS policy (http://grants.nih.gov/grants/guide/notice-files/NOT-NS-11-018.html), to be considered in scope at the time of grant submission, if the intervention is a drug, biologic, or device, applicants should be able to provide information from the FDA 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.
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.
- Applicants 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). 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 clinical trials in the patient population are encouraged when appropriate, as are applications that encompass Phase 1 and Phase 2a clinical studies (early proof of mechanism or proof of concept). Applications for seamless Phase 2/3 clinical trials should be submitted under 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 clinical 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 clinical 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) 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).
(14) 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.
(15) 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.