NIDDK Exploratory Clinical Trials for Small Business (R44)

This Funding Opportunity Announcement (FOA) supports applications from Small Business Concerns (SBCs) for exploratory clinical trials that contribute to the justification for a future trial to establish definitive efficacy (such as a Phase 3 clinical trial or a pivotal device trial). This includes Phase 1 and 2 clinical studies of drugs, biologics and biotechnology products, feasibility studies of devices, as well as preliminary clinical 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. The earliest studies should be designed to provide important initial information regarding the intervention (e.g., safety, tolerability, dosing, usability, acceptability). 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 a definitive efficacy trial. This FOA is not intended to support the conduct of a clinical trial where the primary aim is to establish or confirm definitive efficacy (pivotal trials).

The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) will allow SBIR clinical trial applications through this FOA and will no longer accept clinical trial applications to prior small business announcements (see NOT-DK-16-030).

The mission of the NIDDK is to conduct and support medical research and research training and to disseminate science-based information on diabetes and other endocrine and metabolic diseases; gastrointestinal and liver diseases, nutritional disorders, and obesity; and kidney, urologic, and hematologic diseases, to improve people’s health and quality of life. 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. More recently, however, many investors in life science technologies have shown a preference 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. As a result, many small businesses need to have clinical data to attract sufficient third-party investment.

Definitions

For this funding opportunity announcement, Phase 1 and 2 clinical studies or trials refer to the common phases of a clinical trial. SBIR or STTR Phase I and II refer to the project phases of the SBIR/STTR programs.

Examples of appropriate studies under this FOA include, but are not limited to, those designed to:

• Evaluate and optimize the dose, formulation, safety, tolerability, usability, acceptability 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 therapeutic approaches or dosing regimens to be evaluated in a subsequent trial, based on tolerability, biological activity, or preliminary clinical efficacy.

NIDDK 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 a new 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 FOA.

NIDDK will prioritize applications to develop novel interventions and discourages submission of applications to develop "me-too" strategies. NIDDK will also prioritize applications to develop interventions for indications for which there are no or few effective therapies or prevention strategies. While repurposing of already approved interventions may be supported under this FOA, NIDDK will not support studies meant to support label expansion.

Applicants should take note of the following:

(1) 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, whenever possible, on the Minimal Clinically Important Difference (MCID). The MCID is the smallest change in a treatment outcome that a patient would identify as important; it is often determined by surveying patients or their physicians.

(2) 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:

• Collecting information on the utility of questionnaires, rating scales, or biomarkers
• Developing and refining standardized methods of assessing outcome
• Optimizing methods for identifying, recruiting, and retaining study participants
• Creating clinical trial infrastructure

(3) 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 but the applicant should clearly detail the total clinical development plan.

(4) Regulatory Approvals: If the intervention is a drug, biologic, or device, applicants should be able to provide information from the FDA on one of the following two scenarios:

(a) The protocol for the study and population proposed 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 for the study and population proposed is exempt from an IND/IDE for the specific protocol, device, and patient population. Under this scenario, applicants must provide a copy of the exemption letter from the FDA, prior to funding. For devices, if the IRB has determined that the device is Non-Significant Risk, documentation from the IRB is acceptable, prior to funding.

Full IRB approval is not required at the time of application submission, but is required prior to funding. As such, NIDDK encourages investigators to begin these processes as early as possible. NIDDK also will require documentation of any other necessary regulatory approvals (e.g., Recombinant DNA Advisory Committee) prior to funding.

(5) Biomarkers:

• Applications are encouraged that utilize 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.
• This FOA is not intended to support biomarker discovery.

(6) 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). 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.

(7) 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.

(8) Rare Diseases: Trials in rare diseases are encouraged. Innovative trial designs, including crossover designs and adaptive designs and N of one trials, 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.

(9) 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. See Section IV. 2. Letters of Support.

(10) 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 )
• NIH Toolbox (http://www.nihtoolbox.org)
• PROMIS (http://www.nihpromis.org)

(11) Mobile Technologies: Applicants are encouraged to consider utilizing (at least experimentally) mobile technologies (e.g., wireless or remote) to facilitate data collection and protocol adherence on the part of research participants and study site staff.

(12) Consultation with NIDDK: Applicants are encouraged to consult with NIDDK 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 NIDDK 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.

(13) Applicants citing preclinical research should ensure it meets high scientific rigor guidelines (for reference see  http://grants.nih.gov/reproducibility/index.htm).

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