NeuroNEXT Small Business Innovation in Clinical Trials (U44 Clinical Trial Optional)

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, NINDS has formed the Neurology Network of Excellence in Clinical Trials (NeuroNEXT, www.NeuroNEXT.org). NeuroNEXT has a Clinical Coordinating Center (CCC), a Data Coordinating Center (DCC) and a group of 25 geographically distributed clinical sites. This clinical research network develops and conducts multiple, scientifically sound, possibly biomarker-informed exploratory clinical trials evaluating the most promising therapies, whether from academic, foundation or industry discoveries.  Examples include Phase 2 clinical trials and clinical research studies aimed at validating biomarkers and clinical outcomes in preparation for clinical trials. A separate clinical trials network has been established and funded by NINDS to conduct clinical trials and biomarker studies for stroke treatment, prevention and recovery; thus NeuroNEXT has been established for the conduct of studies in neurological disorders other than stroke.

NeuroNEXT provides a robust, standardized, and accessible infrastructure to facilitate rapid development and implementation of protocols in neurological disorders affecting adult and/or pediatric populations.  While the network is not specific to one disease, it has the capacity to coordinate a cadre of specialist investigators to implement studies efficiently in response to disease-specific opportunities. 

The network is designed to increase the efficiency of clinical trials, to facilitate patient recruitment and retention, to increase the quality of neuroscience clinical trials, and to enable public-private partnerships.

This FOA uses the U44 cooperative agreement mechanism and is open to eligible applicants, as defined in Section III. Academic researchers may wish to consider applying through PAR-16-155 "NeuroNEXT Clinical Trials (U01)". For-profit organizations and Non-profits other than Institutions of Higher Education may wish to consider applying through PAR-15-195 "NeuroNEXT Infrastructure Resource Access (X01)" or any reissue if they wish to gain access to the network infrastructure but do not require funds for trial costs.

Since conducting the clinical trials needed for commercialization may be capital-intensive, this FOA encourages business relationships between NIH's SBIR/STTR awardees and third-party investors and/or strategic partners. In particular, this FOA will give competitive preferences and funding priority to applications deemed likely to result in a commercial product as indicated by an applicant's ability to secure independent third-party funds.

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:

This FOA encourages Fast Track, Phase II, and Phase IIB SBIR applications for exploratory clinical trials of investigational agents (drugs, biologics, surgical therapies or devices) that may contribute to the justification for and provide the data required for designing a future trial, for biomarker validation studies, or for proof of mechanism clinical studies. Applications for drugs or biologics should be supported by compelling scientific evidence that the investigational agent proposed for study will reach/act upon the designated target or that its mechanism of action is such that it is expected to be of benefit in ameliorating a specific aspect of the disease. Neurologic diseases chosen for study must fall within the primary responsibility of NINDS (www.ninds.nih.gov/funding/areas/index.htm). Multi-site studies in stroke prevention, treatment and/or recovery are not appropriate for this FOA; those studies would be considered by NIH StrokeNet: http://www.nihstrokenet.org/.

Applications in rare diseases are encouraged while recognizing that available patient pools may not be adequate to meet the sample size requirements normally required to establish the efficacy of an intervention. NINDS acknowledges that innovative, non-traditional trial designs including adaptive designs may be appropriate in rare disease studies. While NeuroNEXT is primarily intended for exploratory trials, the network will consider Phase II/III trials in diseases with a US prevalence of under 5,000 persons.

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 the target population.
• 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.
• 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).
• Evaluate biological activity relative to clinical endpoints.

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.

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.

Fast Track Studies should implement clear go-no go criteria for continuing to the next Phase II SBIR. When possible, all studies should also include go-no go criteria for proceeding to the next trial phase after the Phase II award.  These should be biomarker-informed wherever possible. https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DrugDevelopmentToolsQualificationProgram/ucm370262.htm

This FOA is not intended to support the conduct of a clinical trial where the primary aim is to confirm efficacy of a proposed intervention.

Implementation:

Applicants should make note of the following:

(1) Applicants to this FOA will be required to incorporate the NeuroNEXT infrastructure (www.neuronext.org) into their proposed study. Additional (ad-hoc) sites may be proposed to fulfill specific study requirements. All applicants will be required to use the master clinical trial agreements and central IRB that have been established for NeuroNEXT.

(2) Rationale: Exploratory trials primarily test hypotheses in relatively small programs so that the acceptable risk and uncertainty are higher than in later stage programs. Exploratory clinical trials to address an unmet medical need or to improve current standards of care must anchor their rationale in:

• A plausible biological mechanism;
• Non-clinical (in vitro and/or in vivo) data; and/or
• Early clinical data.

The individual weight should be carefully assessed in the specific context of the application at hand; there is no requirement to provide support from all three areas. 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.

(3) Secondary Aims:

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, but are not limited to, the following:

• 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,
• 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.

(4) 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 NeuroNEXT Network, or a more limited subset of centers selected based on appropriate expertise for the given device. Investigators are encouraged to contact NINDS Scientific/Research Staff as early as possible to discuss how the NeuroNEXT network may best be utilized in support of their specific device project.

NINDS anticipates that the majority of device projects utilizing NeuroNEXT will be traditional Feasibility Studies in order to best leverage the advantages of the network. 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. If an Early Feasibility Study is proposed, it 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", 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. 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.

(5) NIH Resources:

As appropriate, applicants are encouraged to make use of the following resources for clinical research including:

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

(b) NeuroQOL (http://www.neuroqol.org);

(c) NIH Toolbox (http://www.nihtoolbox.org);

(d) PROMIS (http://www.nihpromis.org); and

(e) NINDS Common Data Elements (http://www.commondataelements.ninds.nih.gov).

(6) 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.

Working with NeuroNEXT is a cooperative venture between the applicant, NINDS, and the NeuroNEXT network. NINDS will provide guidance to potential applicants with input from NINDS Program Staff and the NeuroNEXT Executive Committee. Potential applicants are strongly encouraged to contact NINDS Scientific/Research Contacts (see Agency Contacts, Section VII) in order to discuss the feasibility of conducting the proposed trial through the NeuroNEXT infrastructure before submitting an application. Pre-application consultation may include an introductory teleconference (at least 3 months prior to submission), followed by additional communication with NINDS staff, if needed.

The operational clinical protocol and actual budget for trials under this FOA will be constructed after peer review and then reviewed by NINDS for funding consideration. Funding decisions will also be based on a study's fit for the network relative to other proposed and ongoing trials. The award and continuation of funding are subject to milestones to be specified in the notice of grant award according to NINDS policies. 

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