Participating Organization(s)	National Institutes of Health (NIH)
Components of Participating Organizations	National Center for Advancing Translational Sciences (NCATS)
Funding Opportunity Title	Limited Competition for NIH-Industry Pilot Program: Discovering New Therapeutic Uses for Existing Molecules (UH3)
Activity Code	UH3 Exploratory/Developmental Cooperative Agreement Phase II
Announcement Type	New
Related Notices	May 12, 2014 - This RFA has been reissued as PAR-14-211. September 6, 2012 - See Notice NOT-TR-12-010. Annoucing a Technical Assistance Webinar. July 20, 2012 - See Notice NOT-TR-12-008. Clarification for the NIH-Industry Pilot Program providing clarification regarding application requirements
Funding Opportunity Announcement (FOA) Number	RFA-TR-12-005
Companion Funding Opportunity	PAR-12-203, Pre-application for the NIH-Industry Pilot Program, Discovering New Therapeutic Uses for Existing Molecules (X02); RFA-TR-12-004, Limited Competition for the NIH-Industry Pilot Program: Discovering New Therapeutic Uses for Existing Molecules (UH2/UH3)
Number of Applications	See Section III. 3. Additional Information on Eligibility.
Catalog of Federal Domestic Assistance (CFDA) Number(s)	93.350
Funding Opportunity Purpose	The National Center for Advancing Translational Sciences (NCATS) seeks to develop a therapeutics discovery pilot program that will explore new therapeutic uses for proprietary drug candidates (Agents) across a broad range of human diseases. This innovative program will match Agents and associated data from pharmaceutical company partners with the best ideas for new therapeutic uses from the biomedical research community. PAR-12-203 encourages X02 pre-applications for the NIH-Industry Pilot Program: Discovering New Therapeutic Uses for Existing Molecules. The X02 pre-application is the first step in the application process for RFA-TR-12-004 and RFA-TR-12-005; applicants must read both of the companion FOAs. The X02 pre-applications will be evaluated by outside scientific experts. Investigators whose X02 pre-applications are judged to be the most meritorious will be notified of the opportunity to submit a UH3 application under this FOA or a UH2/UH3 application under RFA-TR-12-004. The UH3 will support milestone-driven Phase IIa proof of concept trials to assess the potential clinical efficacy of an Agent, made available for this program by the pharmaceutical partners, for its potential new use in the proposed disease population. The project period for the UH3 is up to two years.

Posted Date	June 12, 2012
Open Date (Earliest Submission Date)	November 17, 2012
Letter of Intent Due Date	Not Applicable
Application Due Date(s)	December 17, 2012, by 5:00 PM local time of applicant organization.
AIDS Application Due Date(s)	Not Applicable.
Scientific Merit Review	March 2013
Advisory Council Review	May 2013
Earliest Start Date(s)	June 2013
Expiration Date	December 18, 2012
Due Dates for E.O. 12372	Not Applicable

Required Application Instructions

It is critical that applicants follow the instructions in the SF 424 (R&R) Application Guide, except where instructed to do otherwise (in this FOA or in a Notice from the NIH Guide for Grants and Contracts). Conformance to all requirements (both in the Application Guide and the FOA) is required and strictly enforced. Applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions. Applications that do not comply with these instructions may be delayed or not accepted for review.

Part 1. Overview Information
Part 2. Full Text of the Announcement
Section I. Funding Opportunity Description
Section II. Award Information
Section III. Eligibility Information
Section IV. Application and Submission Information
Section V. Application Review Information
Section VI. Award Administration Information
Section VII. Agency Contacts
Section VIII. Other Information

Background

In April 2011, NIH convened an NIH-Industry Roundtable that included a group of senior leaders and experts from the pharmaceutical industry, government, academia, and the non-profit sector to explore opportunities to foster new NIH-industry partnerships that facilitate drug rescue and repurposing. Some of the challenges that were identified include: resource implications (the time and resources for a pharmaceutical company to maintain, update, and organize their compound libraries for drug rescue and repurposing); patent considerations (off-patent compounds or compounds whose patents are close to expiring, may not be attractive to industry because the financial return and market incentives for the product may be limited); and transactional hurdles related to developing, negotiating and implementing appropriate legal agreements among the parties, including addressing such concerns as intellectual property rights and liability. The Roundtable participants agreed that more can and should be done to increase engagement and partnerships in drug rescue and repurposing and to enhance the success of these efforts. In response to one of the recommendations from the meeting, NCATS has developed an NIH-Industry Pilot Program: Discovering New Therapeutic Uses for Existing Molecules.

This Program will fund research to identify new therapeutic uses of proprietary drug candidates (compounds and biologics), made available by pharmaceutical company partners, to benefit public health. NCATS is especially interested in projects that address areas of unmet medical need. NCATS plans to initiate the research program as a pilot with a limited set of high-quality drug candidates (Agents) contributed by the pharmaceutical company partners. If the pilot is successful, the Program may be expanded to include additional pharmaceutical or biotechnology company partners, Agents, and new therapeutics discovery projects.

Research Objectives

The Program intends to support innovative ideas from the biomedical research community for the discovery of potential therapeutic uses of these Agents in previously unexplored disease areas. Proof of concept studies can include, as examples, use of an Agent as a stand-alone intervention or as an adjunctive intervention (if there is no evidence of drug-drug interactions with the proposed standard of care treatment). Strategies to inform the selection of patients for proposed new uses of the Agents are of interest.

For this FOA, Phase IIa proof of concept trials are defined as studies designed to explore new hypotheses and to assess whether the Agent demonstrates an early signal of efficacy in the targeted patient population, typically 150 subjects or less. In addition to clinical benefit, Phase IIa trials also include assessments of safety, tolerability, and PD/PK response of the Agent.

UH3 objectives

The UH3 activities will include exploratory, phase IIa proof of concept trials designed to establish the relationship between the magnitude and duration of target modulation and clinical efficacy of the Agent in the proposed disease population. The inclusion of biomarkers in the design of the study is encouraged, when appropriate: e.g., the inclusion of PK/PD biomarkers to assess target engagement, exposure and functional pharmacological activity of the Agent (see, Morgan P., et. al, Drug Discov. Today (2012), doi:10.1016/j.drudis.2011.12.020), or the use of molecular markers of disease, pharmacogenomics, or other biomarkers as patient selection strategies. The goals of the Phase IIa proof of concept trials are to determine that the Agent modulates the target/mechanism and shows potential for efficacy in the proposed disease population, thereby de-risking further clinical development of the Agent for a new therapeutic use that has not previously been explored. The duration of the UH3 project period is up to two years.

In cases where the proof of concept studies are successful, it is anticipated that the pharmaceutical company partner will pursue further clinical development of the Agent for the new therapeutic use, including requisite Phase III clinical trials, ultimately commercializing the novel therapeutic intervention for the new disease indication whenever feasible.

Application Process

The submission of an X02 pre-application is a necessary first step in applying for an award under this FOA or the companion FOA, RFA-TR-12-004 (UH2/UH3); applicants must also read both companion FOAs prior to submitting an X02 pre-application. Pre-applications submitted in response PAR-12-203 will be evaluated by outside scientific experts. X02 applicants will receive feedback on the scientific merit, technical feasibility, administration and management plans, and overall potential for impact of the science proposed in the pre-application Investigators whose X02 pre-applications are identified as being highly meritorious and relevant to program priorities will be notified of the opportunity to submit a UH3 application.

X02 applicants invited to submit a UH3 application must contact the pharmaceutical company partner for the Agent that was selected for studies in the X02 pre-application, and execute an appropriate Confidential Disclosure Agreement (see template CDAs). Under the CDA, the applicant and pharmaceutical company partner will exchange confidential information (e.g., additional information on the Agent and studies to test the proposed new therapeutic use of the Agent), as deemed necessary, to initiate discussions. Subsequently, it is anticipated that a Collaborative Research Agreement (CRA) between the applicant and the pharmaceutical company partner will be the vehicle through which the applicant obtains permission to work with the Agent on the research project plan for the UH3 application. The applicant must provide the NIH with documentation of access to the Agent and associated data needed for filing an investigator-sponsored Investigational New Drug (IND) Application and for conducting the proposed clinical trial (e.g., an executed CRA).

Partnership Information

A key component of this FOA is the formation of collaborative partnerships between the biomedical research community and industry partners. NCATS has executed a Memorandum of Understanding (MOU) with each of the pharmaceutical company partners to provide a framework under which specific proprietary Agents will be provided by these partners to the program awardees. Template agreements have been developed for this program: Confidential Disclosure Agreements (CDAs) and Collaborative Research Agreements (CRAs) between the pharmaceutical company partner and the applicant. These template agreements have been developed to streamline interactions among the parties for the Program, and it is anticipated that applicants will use the agreements. Investigators should work with their institutional technology transfer or sponsored research office to finalize the terms and conditions of the CDA and CRA for the selected Agent prior to submission of a UH3 application. A successful UH3 application will be contingent on the applicant’s ability to provide the NIH with documentation of access to the selected Agent and associated data needed for filing an investigator-sponsored IND in order to conduct the proposed clinical trials (e.g., an executed CRA or letter from the pharmaceutical partner).

Agents Available for the Program

The list of Agents and non-confidential information can be found at http://www.ncats.nih.gov/research/reengineering/rescue-repurpose/therapeutic-uses/directory.html.

Timeline for the Program

August 14, 2012	Submission date for X02 pre-application
September 2012	Evaluation of pre-application by outside experts
Late September 2012	Notification of opportunity to submit a full UH2/UH3 or UH3 application
December 17 2012	Submission date for UH2/UH3 applications
March 2013	Scientific merit review for UH2/UH3 applications
May 2013	NCATS Advisory Council review of applications
July 2013	Earliest possible start date for awarded grants

Funding Instrument	Cooperative Agreement
Application Types Allowed	New The OER Glossary and the SF 424 (R&R) Application Guide provide details on these application types.
Funds Available and Anticipated Number of Awards	NCATS intends to commit up to $20 million in FY 2013 to fund six to eight UH2/UH3 or UH3 awards in response to this FOA and the companion FOA (RFA-TR-12-004). Future year amounts will depend on annual appropriations.
Award Budget	Application budgets are not limited, but need to reflect actual needs of the proposed project.
Award Project Period	The total project period for a UH3 application submitted in response to this FOA may not exceed two years.

NIH grants policies as described in the NIH Grants Policy Statement will apply to the applications submitted and awards made in response to this FOA.

This FOA is a limited competition for those applicants who submitted a pre-application in response to PAR-12-203 [X02] and have been notified of the opportunity to submit a UH3 application.

Not Applicable.

Applicant organizations must complete the following registrations as described in the SF 424 (R&R) Application Guide to be eligible to apply for or receive an award. Applicants must have a valid Dun and Bradstreet Universal Numbering System (DUNS) number in order to begin each of the following registrations.

• Central Contractor Registration (CCR) must maintain an active registration, to be renewed at least annually
• Grants.gov
• eRA Commons

All Program Directors/Principal Investigators (PD(s)/PI(s)) must also work with their institutional officials to register with the eRA Commons or ensure their existing eRA Commons account is affiliated with the eRA Commons account of the applicant organization.

All registrations must be completed by the application due date. Applicant organizations are strongly encouraged to start the registration process at least 4-6 weeks prior to the application due date.

This FOA is a limited competition for those applicants who submitted an X02 pre-application in response to PAR-12-203 [X02] and have been notified of the opportunity to submit a UH3 application.

For these UH3 applications, the PD/PI must be the same PD/PI listed on the X02 pre-application. For UH3 applications proposing multiple PD(s)/PI(s), the contact PD/PI must be the same PD/PI listed as the contact on the X02 pre-application. The contact PD/PI is strongly encouraged to continue the multiple PD(s)/PI(s) leadership identified in the X02 pre-application if notified of the opportunity to submit a UH3 application.

NIH Intramural Research Program (IRP) investigators are eligible to apply for the UH3 FOA, subject to the availability of intramural funds to support the project. IRP investigators can apply as PD(s)/PI(s), as multiple PD/PIs in conjunction with extramural investigators (http://grants.nih.gov/grants/multi_pi/index.htm), or as collaborators with extramural academic or biotechnology company investigators. Intramural Research Investigators cannot request extramural funds. For more information, see Section 6, Other Submission Requirements and Information.

This FOA does not require cost sharing as defined in the NIH Grants Policy Statement.

Applicant organizations may submit more than one application, provided that each application is scientifically distinct.

NIH will not accept any application in response to this FOA that is essentially the same as one currently pending initial peer review unless the applicant withdraws the pending application. NIH will not accept any application that is essentially the same as one already reviewed.

Applicants must download the SF424 (R&R) application package associated with this funding opportunity using the Apply for Grant Electronically button in this FOA or following the directions provided at Grants.gov.

It is critical that applicants follow the instructions in the SF424 (R&R) Application Guide, except where instructed in this funding opportunity announcement to do otherwise. Conformance to the requirements in the Application Guide is required and strictly enforced. Applications that are out of compliance with these instructions may be delayed or not accepted for review.

For information on Application Submission and Receipt, visit Frequently Asked Questions Application Guide, Electronic Submission of Grant Applications.

The forms package associated with this FOA includes all applicable components, mandatory and optional. Please note that some components marked optional in the application package are required for submission of applications for this FOA. Follow all instructions in the SF424 (R&R) Application Guide to ensure you complete all appropriate optional components.

All page limitations described in the SF424 Application Guide and the Table of Page Limits must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions:

Specific Instructions for Preparing a UH3 Application

1. The selected Agent and new therapeutic use should be the same as proposed in the X02 pre-application.

2. UH3 applications are limited to 12 pages for the Research Strategy section including milestones, timeline and future plans.

3. See Section 6, Other Submission Requirements and Information for additional information.

Specific Aims

The one-page Specific Aims section should include the following information:

1. Define the aims of the Phase IIa proof of concept clinical trial.

a. The aims should include proposed clinical trials to determine target modulation and efficacy.

b. The clinical data resulting from the UH3 component should provide sufficient evidence that the drug candidate is safe and well-tolerated for sustained administration in the proposed dose range, modulates the target/mechanism and a biomarker of PD effect, and has a signal of efficacy in the disease population.

Research Strategy

Within the 12-page Research Strategy, provide the following information:

1. Background & Significance

a. Identify the Agent, its known pharmacologic mechanism of action or target, and route of administration.

b. State the biological rationale or hypothesis for the new therapeutic use of the Agent

c. Indicate the disease, clinical population, and public health need that will be addressed by the proposed new use of the Agent.

1). Address the global burden of disease, which patients will benefit, how they will benefit, how use of the Agent will be superior to current therapy options, and potential for impact on public health.

2. Preliminary Studies

a. The Preliminary Studies will contain, but are not limited to, data and information that validate the feasibility of conducting studies to address the specific aims.

1). Evidence that the target or specific pathway is involved in the disease pathology.

2). Any additional relevant information on the Agent (e.g., availability of pharmacokinetics (PK) and pharmacodynamics (PD) markers, any exclusions or restrictions in the Agent's use).

• Summary information for the Agent, available at http://www.ncats.nih.gov/research/reengineering/rescue-repurpose/therapeutic-uses/directory.html, will be provided to the NIH peer review committee members and does not need to be detailed in this application.

3). Data to support the selection of dose and exposure of the Agent based on available PD/PK biomarkers or functional pharmacological activity.

4). Information on the risk/benefit of the Agent to patients and the operational feasibility of conducting clinical trials to address the specific aims.

3. Approach

a. Describe and justify the design of the Phase IIa proof of concept trial to assess activity of the Agent to change the disease state in the proposed patient group.

1). Describe the use of PK and PD biomarkers, when available, to select the dose and exposure of the Agent at the target site of action, binding at the target, or expression of functional pharmacological activity of the Agent at the target site of action.

2). Specify the duration of studies, based on safety data available for the Agent, and whether the new use of the Agent is for treatment of an acute or chronic disease.

3). Specify dose range, route of administration, and amount of Agent needed based on the formulation available for the selected Agent.

4). Discuss plans for timely filing of an IND and expedited Institutional Review Board (IRB) approval.

b. Define the patient selection strategy.

• Include the use of molecular markers of disease, pharmacogenomics, or other biomarkers, when applicable.

c. Define the clinical end points or outcome measures and the power calculations that determine the size of the trial.

1). The sample size, power, and duration of the trial should be justified for the specific disease population.

2). Discuss alternative statistical plans to show potential therapeutic benefit in Phase IIa proof of concept trials with small sample size.

4. Milestones and Timeline

a. The application must include clearly-specified, well-defined milestones, go/no go decision points, and timelines for assessing progress.

• Assess operational feasibility and resources needed: human subjects protection approval and monitoring necessary to complete the work of the UH3 (e.g., IND, IRB approval, Data and Safety Monitoring Plan approval), access to and number of patients, patient selection criteria, availability of the Agent, and formulation.

b. Provide a clear description of the timeline, interim milestones and go/no decision points during the course of the clinical trial.

• Enrollment rate (e.g., number of subjects meeting eligibility criteria for enrollment per month, criteria for terminating the study if minimum recruitment milestones are not met by the mid-point of the study).
• Futility analysis (e.g., what are the criteria for conducting an interim analysis for futility, failure to separate from placebo).
• Decision points for terminating the trial (e.g., safety, tolerability, patient acceptability issues).
• See regular reporting as specified in the Terms and Conditions.

c). Identify any impediments that could require an addendum to the research plan, milestones, or timeline with a discussion of alternative approaches.

d). Provide detailed quantitative criteria by which milestone achievement will be assessed.

e). Provide a detailed timeline for the anticipated attainment of each milestone and the overall goal.

5. Future Plans

a. Describe the commercial potential of the Agent as a development candidate and potential challenges for commercialization of the Agent for the new disease indication.

The following sections are not part of the Research Strategy but must be included in the application:

Protection of Human Subjects

Address Human Subjects protections for any clinical research anticipated in the period of the grant, as described in the PHS 398 application instructions. Human subjects protection should be detailed for the proposed Phase IIa proof of concept trial. Describe in detail known information and possible contingencies regarding potential risks and benefits to participation, and plans to obtain informed consent. Include anticipated plans for data and safety monitoring commensurate with potential risks inherent in Phase Ib and IIa clinical trials.

Inclusion of Women and Minorities, Inclusion of Children

Provide description of plans for adequate inclusion of minorities and women in the clinical sample, or justify any exclusions. Include a targeted/planned enrollment table for each of the planned studies involving human subjects. Provide description of plans for adequate inclusion of children in the clinical sample, or justify any exclusions. Inclusion plans should be provided separately for each stage of the award.

Letters of Support

Include a letter of support from the pharmaceutical company partner documenting: access to the Agent and associated data needed for filing an investigator-sponsored IND for the Agent to conduct the proposed clinical trials (e.g., a letter indicating that a CRA has been executed, that the PD/PI has the right to cross-reference specific sections of the pharmaceutical company partner's IND/Drug Master File, etc.).

Resource Sharing Plan

Individuals are required to comply with the instructions for the Resource Sharing Plans (Data Sharing Plan, Sharing Model Organisms, and Genome Wide Association Studies (GWAS)) as provided in the SF424 (R&R) Application Guide, with the following modifications:

• All applications, regardless of the amount of direct costs requested for any one year, should include a Data Sharing Plan.
• Positive or negative data from NIH supported clinical trials should be made available to the research community through ClinicalTrials.gov, publications, or public website, consistent with achieving the goals of the Program. The applicant should address a plan and timeline for sharing clinical trials data.

Appendix

Appendices are not allowed for this FOA and will not be accepted. Do not use the other attachments section.

Part I. Overview Information contains information about Key Dates. Applicants are encouraged to submit in advance of the deadline to ensure they have time to make any application corrections that might be necessary for successful submission.

Organizations must submit applications via Grants.gov, the online portal to find and apply for grants across all Federal agencies. Applicants must then complete the submission process by tracking the status of the application in the eRA Commons, NIH’s electronic system for grants administration.

Applicants are responsible for viewing their application in the eRA Commons to ensure accurate and successful submission.

Information on the submission process and a definition of on-time submission are provided in the SF424 (R&R) Application Guide.

This initiative is not subject to intergovernmental review.

All NIH awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

Pre-award costs are allowable only as described in the NIH Grants Policy Statement.

Applications must be submitted electronically following the instructions described in the SF 424 (R&R) Application Guide. Paper applications will not be accepted.

Applicants must complete all required registrations before the application due date. Section III. Eligibility Information contains information about registration.

For assistance with your electronic application or for more information on the electronic submission process, visit Applying Electronically.

Important reminders:
All PD(s)/PI(s) must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile Component of the SF 424(R&R) Application Package. Failure to register in the Commons and to include a valid PD/PI Commons ID in the credential field will prevent the successful submission of an electronic application to NIH.

The applicant organization must ensure that the DUNS number it provides on the application is the same number used in the organization’s profile in the eRA Commons and for the Central Contractor Registration (CCR). Additional information may be found in the SF424 (R&R) Application Guide.

See more tips for avoiding common errors.

Upon receipt, applications will be evaluated for completeness by the Center for Scientific Review and responsiveness by NCATS. Applications that are incomplete and/or nonresponsive will not be reviewed.

In order to expedite review, applicants are requested to notify the NCATS Referral Office by email at [email protected] when the application has been submitted. Please include the FOA number and title, PD/PI name, and title of the application:

Bonnie B. Dunn, PhD
Scientific Review Officer
Office of Grants Management and Scientific Review
National Center for Advancing Translational Sciences
National Institutes of Health
6701 Democracy Blvd., Room 1066
Bethesda, MD 20892-4874
Courier service zip code 20817
301-435-0824 (direct line)
301-435-0811 (Office of Review)
Email: [email protected]

Milestones and Timeline

Prior to funding an application, the Program Official will contact the applicant to discuss the proposed UH3 milestones and potential changes suggested by NIH staff or the NIH review panel. The Program Official and the applicant will negotiate and agree on a final set of approved UH3 milestones. These milestones will be the basis for judging progress towards and completion of the interim milestones in the UH3 stage.

Data and Safety Monitoring

All NIH supported clinical trials, including Phase I trials, require monitoring (NIH Guidance on Data and Safety Monitoring for Phase I and Phase II Trials NOT-OD-00-038). Although a general DSMP may be appropriate for the initial grant application, NIH staff must review and approve a detailed DSMP with required supporting material prior to the start of any trial. Early discussions with NIH staff are encouraged to prevent delays. The proposed level of monitoring should be commensurate with risk. For many studies, the grantee manages data and safety monitoring. In specific cases, NIH may establish and manage independent data and safety monitoring boards (DSMBs) for trials that utilize NIH grant resources. For Phase IIa proof of concept trials, this level of monitoring may be appropriate if the studies have multiple clinical sites, are blinded (masked), or employ particularly high-risk interventions or vulnerable populations. In these cases, NIH establishes a charter, appoints members and an executive secretary, provides conflict of interest vetting, and supports the activities of the DSMB. The NIH is responsible for continuing oversight even if monitoring is delegated to the grantee. All other NIH Policies related to clinical research, including trials, will also apply to the UH3 award.

Documentation of access to the Agent proposed for use in the UH3 studies

Consistent with achieving the goals of the Program, the applicant must provide the NIH with documentation of access to the Agent, which was proposed in the X02 pre-application, and associated data needed for conducting the proposed pre-clinical studies and for filing an investigator-sponsored IND in order to conduct the proposed clinical trials (e.g., an executed CRA or letter from the pharmaceutical partner).

Additional Instructions for NIH Intramural Research Program (IRP) Applicants

1. IRP investigators can apply as PD(s)/PI(s), as multiple PD(s)/PI(s) in conjunction with extramural investigators (http://grants.nih.gov/grants/multi_pi/index.htm), or as collaborators with extramural academic or biotechnology company investigators, pending the availability of intramural funds to support the project.

2. IRP investigators and laboratories cannot request extramural funds.

3. An official letter from the Scientific Director, which indicates approval of the IRP scientist's role as PD/PI or as collaborator in the project, must be included as a letter of support in the UH3 application. The letter must specify the Scientific Director's commitment of intramural research funds to support the IRP investigator's proposed UH3 project or project component.

4. Justification must be provided for all proposed personnel (Federal employees and contract staff) who will be committing effort on the project although no funds are requested in the application. Applicants should indicate the number of person-months devoted to the project, even though no extramural funds are requested for salary and fringe benefits.

5. If selected, NIH IRP scientists, in conjunction with their respective technology transfer representative, will need to contact the pharmaceutical company partner participating in this Program for the selected Agent to: execute a CDA to exchange confidential information, and negotiate a PHS Cooperative Research and Development Agreement (CRADA), Clinical Trials CRADA, or other similar type of agreement, to incorporate, as appropriate, the terms of the CRA.

6. If selected, NIH intramural scientists will participate in this program as PD(s)/PI(s) in accord with the Terms and Conditions provided in this FOA. Intellectual property will be managed in accord with established policy of the NIH.

7. Should an extramural application include the collaboration with an IRP scientist, no extramural funds may be requested to support the IRP scientist or IRP laboratory.

Applicants are required to follow the instructions for post-submission materials, as described in NOT-OD-10-115,

Only the review criteria described below will be considered in the review process. As part of the NIH mission, all applications submitted to the NIH in support of biomedical and behavioral research are evaluated for scientific and technical merit through the NIH peer review system.

Reviewers will provide an overall impact/priority score to reflect their assessment of the likelihood for the project to exert a sustained, powerful influence on the research field(s) involved, in consideration of the following review criteria and additional review criteria (as applicable for the project proposed).

Reviewers will consider each of the review criteria below in the determination of scientific merit, and give a separate score for each. An application does not need to be strong in all categories to be judged likely to have major scientific impact. For example, a project that by its nature is not innovative may be essential to advance a field.

Significance

Does the project address an important problem or a critical barrier to progress in the field? If the aims of the project are achieved, how will scientific knowledge, technical capability, and/or clinical practice be improved? How will successful completion of the aims change the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field? Does the proposed project have the potential for influence with regard to a new therapeutic use for the Agent in a disease or disorder for which there is no current treatment or clinical outcome, or for which the current standard of care has considerable disadvantages or very limited utility? Is there a strong biological rationale for the indicated therapeutic use?

Investigator(s)

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the project? If Early Stage Investigators or New Investigators, or in the early stages of independent careers, do they have appropriate experience and training? If established, have they demonstrated an ongoing record of accomplishments that have advanced their field(s)? If the project is collaborative or multi-PD(s)/PI(s), do the investigators have complementary and integrated expertise; are their leadership approach, governance and organizational structure appropriate for the project? What are the qualifications, experience, and commitment of the personnel involved in the proposed therapeutics discovery project? Do the PD(s)/PI(s) have the scientific and organizational vision and experience to serve effectively as the Director(s) of the project? Is there evidence of sufficient management capabilities that include fiscal administration, personnel management, planning, and budgeting? Does the investigative team have the requisite competencies and experience with clinical trials recruitment and execution? Do the PD(s)/PI(s) demonstrate relevant experience and knowledge of the public-private partnerships?

Innovation

Does the application challenge and seek to shift current research or clinical practice paradigms by utilizing novel theoretical concepts, approaches or methodologies, instrumentation, or interventions? Are the concepts, approaches or methodologies, instrumentation, or interventions novel to one field of research or novel in a broad sense? Is a refinement, improvement, or new application of theoretical concepts, approaches or methodologies, instrumentation, or interventions proposed?

Approach

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Are potential problems, alternative strategies, and benchmarks for success presented? If the project is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed? What is the evidence for the biological hypothesis for the proposed new use of the Agent (its pharmacologic mechanism of action or target) and relevance of the biology to therapeutic intervention in the proposed disease that suggests likelihood of successful completion of Phase IIa proof of concept trials during the two-year project period? Are procedures in place for quality control and quality assessment of the clinical procedures? Are data management and support procedures developed sufficiently to allow tracking of clinical trial data? Have the PD(s)/PI(s) provided an operational plan for managing the necessary collaborations between and among clinical plan investigators and the pharmaceutical company partner? Is a plan in place for timely submission of an IND application for the clinical trial, expedited IRB review and approval, and timely patient recruitment? What is the likelihood of the proposed project in meeting the goals under the compressed two-year timeline of the FOA?

If the project involves clinical research, are the plans for 1) protection of human subjects from research risks, and 2) inclusion of minorities and members of both sexes/genders, as well as the inclusion of children, justified in terms of the scientific goals and research strategy proposed?

Environment

Will the scientific environment in which the work will be done contribute to the probability of success? Are the institutional support, equipment and other physical resources available to the investigators adequate for the project proposed? Will the project benefit from unique features of the scientific environment, subject populations, or collaborative arrangements? Are facilities adequate for the overall functions of the project and to implement the goals of the program? Is there evidence for institutional commitment to the program, including provision of space, and other measures of institutional commitment? Are the research environment and resources, including equipment and facilities, adequate? Does the scientific environment indicate the potential for a multi-disciplinary approach involving teams of investigators? Is a team in place to rapidly implement the proposed trial?

As applicable for the project proposed, reviewers will evaluate the following additional items while determining scientific and technical merit, and in providing an overall impact/priority score, but will not give separate scores for these items.

Milestones and Timeline

Are appropriate, evaluative milestones provided for the UH3 stages clearly defined? Are the UH3 milestones feasible, well developed and quantifiable with regard to the specific aims? Is the timeline feasible for the UH3? Are the go/no go decision points, recruitment goals, and timelines appropriate for the Phase IIa proof of concept trial in the UH3?

Protections for Human Subjects

For research that involves human subjects but does not involve one of the six categories of research that are exempt under 45 CFR Part 46, the committee will evaluate the justification for involvement of human subjects and the proposed protections from research risk relating to their participation according to the following five review criteria: 1) risk to subjects, 2) adequacy of protection against risks, 3) potential benefits to the subjects and others, 4) importance of the knowledge to be gained, and 5) data and safety monitoring for clinical trials.

For research that involves human subjects and meets the criteria for one or more of the six categories of research that are exempt under 45 CFR Part 46, the committee will evaluate: 1) the justification for the exemption, 2) human subjects involvement and characteristics, and 3) sources of materials. For additional information on review of the Human Subjects section, please refer to the Human Subjects Protection and Inclusion Guidelines.

Inclusion of Women, Minorities, and Children

When the proposed project involves clinical research, the committee will evaluate the proposed plans for inclusion of minorities and members of both genders, as well as the inclusion of children. For additional information on review of the Inclusion section, please refer to the Human Subjects Protection and Inclusion Guidelines.

Vertebrate Animals

The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following five points: 1) proposed use of the animals, and species, strains, ages, sex, and numbers to be used; 2) justifications for the use of animals and for the appropriateness of the species and numbers proposed; 3) adequacy of veterinary care; 4) procedures for limiting discomfort, distress, pain and injury to that which is unavoidable in the conduct of scientifically sound research including the use of analgesic, anesthetic, and tranquilizing drugs and/or comfortable restraining devices; and 5) methods of euthanasia and reason for selection if not consistent with the AVMA Guidelines on Euthanasia. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animal Section.

Biohazards

Reviewers will assess whether materials or procedures proposed are potentially hazardous to research personnel and/or the environment, and if needed, determine whether adequate protection is proposed.

Resubmissions

Not Applicable.

Renewals

Not Applicable.

Revisions

Not Applicable.

As applicable for the project proposed, reviewers will consider each of the following items, but will not give scores for these items, and should not consider them in providing an overall impact/priority score.

Applications from Foreign Organizations

Not Applicable.

Select Agent Research

Reviewers will assess the information provided in this section of the application, including 1) the Select Agent(s) to be used in the proposed research, 2) the registration status of all entities where Select Agent(s) will be used, 3) the procedures that will be used to monitor possession use and transfer of Select Agent(s), and 4) plans for appropriate biosafety, biocontainment, and security of the Select Agent(s).

Resource Sharing Plans

Reviewers will comment on whether the following Resource Sharing Plans, or the rationale for not sharing the following types of resources, are reasonable: 1) Data Sharing Plan; 2) Sharing Model Organisms; and 3) Genome Wide Association Studies (GWAS).

Reviewers will also comment on whether the applicant has addressed a plan and timeline for sharing positive or negative clinical trials data (e.g., through ClinicalTrials.gov, publications, or public website.

Budget and Period of Support

Reviewers will consider whether the budget and the requested period of support are fully justified and reasonable in relation to the proposed research.

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s), convened by the NCATS, in accordance with NIH peer review policy and procedures, using the stated review criteria. Review assignments will be shown in the eRA Commons.

As part of the scientific peer review, all applications:

• May undergo a selection process in which only those applications deemed to have the highest scientific and technical merit (generally the top half of applications under review) will be discussed and assigned an overall impact/priority score.
• Will receive a written critique.

Appeals of initial peer review will not be accepted for applications submitted in response to this FOA.

Applications will be assigned to NCATS with potential secondary assignment based on the proposed disease population to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications submitted in response to this FOA. Following initial peer review, recommended applications will receive a second level of review by the NCATS Advisory Council. The following will be considered in making funding decisions:

• Scientific and technical merit of the proposed project as determined by scientific peer review.
• Availability of funds.
• Relevance of the proposed project to program priorities.

After the peer review of the application is completed, the PD(s)/PI(s) will be able to access his or her Summary Statement (written critique) via the eRA Commons.

Information regarding the disposition of applications is available in the NIH Grants Policy Statement.

If the application is under consideration for funding, NIH will request "just-in-time" information from the applicant as described in the NIH Grants Policy Statement.

A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant organization for successful applications. The NoA signed by the grants management officer is the authorizing document and will be sent via email to the grantee’s business official.

Awardees must comply with any funding restrictions described in Section IV.5. Funding Restrictions. Selection of an application for award is not an authorization to begin performance. Any costs incurred before receipt of the NoA are at the recipient's risk. These costs may be reimbursed only to the extent considered allowable pre-award costs.

Any application awarded in response to this FOA will be subject to the DUNS, CCR Registration, and Transparency Act requirements as noted on the Award Conditions and Information for NIH Grants website.

All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the NoA. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General and Part II: Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Grantees, and Activities. More information is provided at Award Conditions and Information for NIH Grants.

Cooperative Agreement Terms and Conditions of Award

The following special terms of award are in addition to, and not in lieu of, otherwise applicable U.S. Office of Management and Budget (OMB) administrative guidelines, U.S. Department of Health and Human Services (DHHS) grant administration regulations at 45 CFR Parts 74 and 92 (Part 92 is applicable when State and local Governments are eligible to apply), and other HHS, PHS, and NIH grant administration policies.

The administrative and funding instrument used for this program will be the cooperative agreement, an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH programmatic involvement with the awardees is anticipated during the performance of the activities. Under the cooperative agreement, the NIH purpose is to support and stimulate the recipients' activities by involvement in and otherwise working jointly with the award recipients in a partnership role; it is not to assume direction, prime responsibility, or a dominant role in the activities. Consistent with this concept, the dominant role and prime responsibility resides with the awardees for the project as a whole, although specific tasks and activities may be shared among the awardees and the NIH as defined below.

The PD(s)/PI(s) will have the primary responsibility for:

• Determining the experimental research approaches, designing protocols, setting project milestones and go/no go decision points, and conducting the project within the guidelines of the FOA.
• Submitting an investigator-sponsored IND, assuming responsibility for the development, assembly, and submission of all required regulatory documents, and providing all required information to NIH staff. This includes but is not limited to all communications with the FDA (or other regulatory authority) and the IRB.
• Compliance with all federal regulations and NIH policies, including those related to clinical research and clinical trials. Adherence to NIH requirements for clinical trial monitoring, including oversight by an independent NIH Data and Safety Monitoring Board (DSMB) if required by NIH.
• Ensuring the timely submission of the clinical trial protocol, consent form, and periodic reports for the project to the NIH as required. Ensuring timely submission of all information and documents required by NIH for oversight of the project and data and safety monitoring.
• Submitting required documents, including adverse events or unanticipated problems, to the FDA or OHRP in a timely manner as required by regulation, and submitting these reports to NIH staff at the time of submission to the appropriate agency.
• Inviting external scientist(s) to serve as advisors on the Steering Committee as needed, in consultation with the NIH Program Official, NIH Project Scientist, and pharmaceutical company partner.
• The PD(s)/PI(s) will chair the Steering Committee, organize and circulate a written agenda in advance of conference calls and meetings, and prepare and circulate minutes that delineate decisions and action items resulting from the calls or meetings.
• Adhering to Steering Committee policies and accepting the participation and assistance of NIH staff in accordance with the guidelines described in the NIH staff responsibilities in the Terms and Conditions of Award.
• Providing periodic reports to the Steering Committee summarizing: the progress of the project; obstacles encountered and solutions; monthly recruitment updates; and quarterly milestones updates. The reports should be provided in a format decided upon by the Steering Committee.
• Retaining custody of and have primary rights to the data and software developed under these awards, subject to Government rights of access consistent with current HHS, PHS, and NIH policies, consistent with the terms of the CRA.

NIH staff have substantial programmatic involvement that is above and beyond the normal stewardship role in awards, as described below:

The Project Scientists will:

• Have substantial scientific/programmatic involvement during conduct of this cooperative agreement, through technical assistance, advice, and coordination above and beyond normal program stewardship of grants.
• Coordinate with the awardees in monitoring issues relating to: design of the activities, recruitment, adherence to protocols, adjustment of study protocols, and management and technical performance.
• Participate in all Steering Committee activities, including conference calls, subcommittees and special committees.
• Participate in the review of clinical research protocols and data safety monitoring plans, and depending on their level of complexity and risk, recommend further review by the NIH DSMB or another monitoring body.
• Participate in weekly project update meetings with the PD/PI.

The Program Official will:

• Be responsible for the normal scientific and programmatic stewardship of the award.
• Participate in all Steering Committee meetings and conference calls.
• Monitor recruitment status of the trial on an ongoing basis.
• Monitor performance through consideration of quarterly meetings of the Steering Committee and annual reports, site visits, and compliance with NIH procedures.
• Approve modifications to the research plan and/or study protocol(s), in consultation with the Steering Committee, based on emerging data and/or other issues that impact progress of the project.
• Determine if the awardee has met/achieved milestones for the project.
• Reserve the right to obtain periodic external peer review, and recommend reviewers for, an assessment of progress and achievement of milestones.
• Ensure timely registration of Phase I and Phase II trials in ClinicalTrials.gov.
• Reserve the right to terminate or curtail a UH3 project for any of the following reasons: (1) inadequate progress in meeting the pre-negotiated milestones and timelines; (2) risk to subject safety; (3) slow accrual; (4) data from a futility analysis; or (5) failure to comply with the Terms and Conditions of Award.

Areas of Joint Responsibility include:

Steering Committee:

Each awardee's project will have a Steering Committee. The Steering Committee will serve as the operational governing board for the project. The Steering Committee will include: the PD(s)/PI(s), key personnel, the pharmaceutical company collaborator or consultant as an ex officio member, the NIH Project Scientist, the NIH Program Official, and external scientist(s).

The Steering Committee will:

• Participate in monitoring scientific progress of the UH3 research project plan, assessing recruitment, progress of the go/no go milestones, and assessing whether go/no go criteria have been met.
• Convene quarterly meetings (in person or by video or audio teleconference) to monitor progress on the research project plan and to address issues or activities that impact the project. At least one in person meeting should be held annually in the Washington, D.C. area to allow attendance of NIH staff.
• Hold teleconferences to address operational issues on a monthly basis, or as dictated by the needs of the study.
• Establish workgroups for specific tasks as the Steering Committee deems appropriate. The workgroups will make recommendations to the Steering Committee.
• Ensure timely publication of abstracts and scientific articles to make results of projects and inventions available, including negative data regarding new therapeutic uses.
• Ensure timely submission of Phase I and Phase II data to ClinicalTrials.gov.
• Participate in monitoring of intellectual property arising from the project.

Dispute Resolution:

Any disagreements that may arise in scientific or programmatic matters (within the scope of the award) between award recipients and the NIH may be brought to Dispute Resolution. A Dispute Resolution Panel composed of three members will be convened. It will have three members: a designee of the Steering Committee chosen without NIH staff voting, one NIH designee, and a third designee with expertise in the relevant area who is chosen by the other two; in the case of individual disagreement, the first member may be chosen by the individual awardee. This special dispute resolution procedure does not alter the awardee's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulation 42 CFR Part 50, Subpart D and DHHS regulation 45 CFR Part 16.

When multiple years are involved, awardees will be required to submit the Non-Competing Continuation Grant Progress Report (PHS 2590) annually and financial statements as required in the NIH Grants Policy Statement.

A final progress report, invention statement, and the expenditure data portion of the Federal Financial Report are required for closeout of an award, as described in the NIH Grants Policy Statement.

The Federal Funding Accountability and Transparency Act of 2006 (Transparency Act), includes a requirement for awardees of Federal grants to report information about first-tier subawards and executive compensation under Federal assistance awards issued in FY2011 or later. All awardees of applicable NIH grants and cooperative agreements are required to report to the Federal Subaward Reporting System (FSRS) available at www.fsrs.gov on all subawards over $25,000. See the NIH Grants Policy Statement for additional information on this reporting requirement.

We encourage inquiries concerning this funding opportunity and welcome the opportunity to answer questions from potential applicants.

Grants.gov Customer Support (Questions regarding Grants.gov registration and submission, downloading or navigating forms)
Contact Center Phone: 800-518-4726
Email: [email protected]

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Telephone 301-710-0267
TTY 301-451-5936
Email: [email protected]

eRA Commons Help Desk (Questions regarding eRA Commons registration, tracking application status, post submission issues)
Phone: 301-402-7469 or 866-504-9552 (Toll Free)
TTY: 301-451-5939
Email: [email protected]

We encourage inquiries and welcome the opportunity to answer questions from potential applicants.

For technical questions regarding the FOA (mechanisms, partnerships, application content or scientific management of the cooperative agreements), please contact:

Christine Colvis, Ph.D.
Therapeutics Discovery Program
National Center for Advancing Translational Sciences, NIH
6701 Democracy Blvd., Democracy I, Rm. 924
Bethesda MD 20892-4874 (Regular mail)
Bethesda MD 20817 (FedEx)
Telephone: See Contact List
Email: [email protected]
Mailbox: [email protected]

FAQs: http://www.ncats.nih.gov/research/reengineering/rescue-repurpose/therapeutic-uses/therapeutics-faq.html

Heng Xie, M.D., M.P.H., Ph.D.
Supervisory Medical Officer
Division of Clinical Innovation
National Center for Advancing Translational Sciences, NIH
6701 Democracy Blvd., Democracy I, Rm. 908
Bethesda MD 20892-4874 (Regular mail)
Bethesda MD 20817 (FedEx)
Telephone: 301-443-8063
Fax: 301-480-3661
Email: [email protected]

For questions related to proposed new therapeutic uses of the Agents in specific disease areas, Institute or Center contacts can be found at http://www.ncats.nih.gov/research/reengineering/rescue-repurpose/therapeutic-uses/contacts.html

Bonnie B. Dunn, Ph.D.
Office of Grants Management and Scientific Review
National Center for Advancing Translational Sciences (NCATS)
6701 Democracy Boulevard, Room 1066, MSC 4874
Bethesda, MD 20892-4874
Bethesda, MD 20817 (for Express/Courier Service)
Telephone: 301-435-0824 (direct line)
Telephone: 301-435-0811 (Office of Review)
Email: [email protected]

Susan Lowenthal
Office of Grants Management
National Center for Advancing Translational Sciences (NCATS)
6701 Democracy Blvd, Room 1051
Bethesda, MD 20892 (20817 for express delivery)
Telephone: 301-435-0848
Fax: 301-480-3777
Email: [email protected]

Amy McGuire
Office of Grants Management
National Center for Advancing Translational Sciences (NCATS)
6701 Democracy Boulevard, Room 1051, MSC 4874
Bethesda, MD 20892
Bethesda, MD 20817 (for Express/Courier Service)
Telephone: 301-435-0853
Fax: 301-480-3777
Email: [email protected]

Recently issued trans-NIH policy notices may affect your application submission. A full list of policy notices published by NIH is provided in the NIH Guide for Grants and Contracts. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

Awards are made under the authorization of Sections 301, 479 and 480 of the Public Health Service Act as amended (42 USC 241, 287 and 287a) and under Federal Regulations 42 CFR Part 52 and 45 CFR Parts 74 and 92.