HHS SBIR PAR-08-235 1

The NINDS Translational Research Program is specifically focused on pre-clinical therapy development necessary to begin clinical testing of therapeutic candidates for neurological disorders. This program supports the pre-clinical development of drugs, biologics, and devices including activities from the identification of a therapeutic lead to Investigational New Drug (IND) or Investigational Device Exemptions (IDE) application to the Food and Drug Administration (FDA).

The scope of the Phase I portion of a Fast-Track in the program includes all activities in the pre-clinical therapy development pipeline, and the Phase I can be structured in any way necessary to support subsequent pre-clinical development tasks during the Phase II project.

However, the Phase II awards in the program support milestone-driven projects that begin with identified candidate therapeutics and proceed through Investigational New Drug (IND) or Investigational Device Exemptions (IDE). Therefore, the primary purpose of the Phase I awards is, when appropriate, to support preliminary steps in therapy development that are outside the scope of the Phase II projects.

Phase I awards include, but are not limited to:

• Creation and validation of screening assays for therapy development. The assays may be intended for primary or secondary screening efforts at any level of throughput.

• Creation of animal models of neurological disorders for therapy development. Animal models that will be used for basic research are outside the scope of the program.

• Identification of candidate therapeutics, including primary or secondary screening efforts at any level of throughput. Primary screening efforts are not supported by the U01 and U54 cooperative agreement mechanisms in the NINDS Translational Research Program.

• Development of preliminary proof-of-principle data on the efficacy of candidate therapeutics.

The scope of a Phase II award in the program is the same whether it is based on a previously successful Phase I in the regular SBIR program or if it is part of a Fast-Track application.

For entry to the program, projects must have one or more identified therapeutic leads and convincing proof-of-principle on efficacy demonstrated in credible models of the disease or against defined disease targets.

When appropriate, projects must include lead optimization for disease-related activity and for pharmacological and toxicological properties consistent with the intended use of the therapy, which is the subject of a special review criterion. In cases where no lead optimization is proposed, there must be a demonstration that sufficient optimization for the disease target and intended use have been conducted previously.

In addition to optimization, projects may include pre-clinical efficacy testing, predictive ADMET (absorption, distribution, metabolism, excretion, and toxicology) testing, formulation, manufacture, pharmacology, toxicology, and IND or IDE submission. Applications must include feasible plans for achieving a complete IND or IDE application for submission to the FDA within the project period. Because the project must be sufficiently advanced at entry to achieve regulatory submission by the end of the project period, the program does not support early-stage therapeutic discovery activities such as high throughput screening.

Due to the unique requirements of the NINDS Cooperative Program in Translational Research, applicants are strongly encouraged to consult with NINDS Program Staff as plans for an application are being developed. This early contact will provide an opportunity to clarify the applicant's understanding of program goals and guidelines, including the scope of projects within the program and the requirement that project objectives be milestone-driven. These discussions also provide important information and guidance on how to develop an appropriate milestone plan, which is subject to peer review under this program. Pre-application consultation includes both an introductory call to discuss the scope and goals of the program and a conference call with NINDS staff. Pre-application consultation on translational research cooperative agreements require adequate lead time before an application receipt date in order for applicants to have sufficient time to consider advice and perspective from NINDS program staff. For this reason, the introductory call should be completed at least 10 weeks before a receipt date and the conference call at least 8 weeks before a receipt date.

Shortly after receipt, applications will be examined by NINDS Program Staff to determine if they are within the scope of this FOA. PDs/PIs for applications that are outside the scope will be asked to consider whether their proposed studies fall within the scope of other FOAs. If an application is responsive to a different FOA that will be reviewed by the NIH Center for Scientific Review, it is likely the review will be delayed one round. Applications that are not within the scope of any existing FOAs will be withdrawn from further consideration.

The NINDS Cooperative Program in Translational Research Small Business Awards provides funding through the U44 cooperative agreements mechanism. As a cooperative agreement, implementation will involve participation of NINDS program staff in the planning and execution of these therapy-directed projects. The U44 cooperative agreements support translational research projects that are focused on a single problem or approach to therapy development for a neurological disorder, or a group of closely related neurological disorders. Consortium agreements are permitted.

Milestones: Phase II applications must include proposed yearly go/no-go milestones that are the subject of a special review criterion. During the execution of the project, NINDS staff will assess progress toward and achievement of milestones. Achievement of these milestones will be evaluated by NINDS prior to releasing funding for each year of the award. Guidance for preparation of milestone plans will be provided by NINDS in pre-application teleconferences and is available at http://www.ninds.nih.gov/funding/research/translational/DevelopingMilestones.htm.

Collaboration among awardees will be encouraged and facilitated by NINDS program staff. Investigators will have the opportunity to share data, materials, and expertise. It is expected that lessons learned and techniques developed within one disease community will be relevant to the efforts of other communities.