Department of Health and Human Services

Part 1. Overview Information
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 (UH2/UH3)

Activity Code

UH2/UH3 Stage 1 (Feasibility)/Stage 2 (Implementation) Cooperative Agreement

Announcement Type

New

Related Notices

  • 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-12-004

Companion Funding Opportunity

PAR-12-203, Pre-application for the NIH-Industry Pilot Program, Discovering New Therapeutic Uses for Existing Molecules (X02); RFA-TR-12-005, Limited Competition for the NIH-Industry Pilot Program:  Discovering New Therapeutic Uses for Existing Molecules (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 experts.

Investigators whose X02 pre-applications are judged to be the most meritorious will be notified of the opportunity to submit a UH2/UH3 application under this FOA or a UH3 application under RFA-TR-12-005

The UH2/UH3 is a two stage application. 

The UH2 (Stage 1) will support milestone-driven feasibility studies to validate the biological relevance of the Agent's pharmacologic mechanism/target in pre-clinical disease models and Phase Ib trials for a period that may vary from three months up to one year.  UH2 studies should establish a link between the Agent's mechanism/target and the biology of the proposed disease. UH2 projects that have met the scientific milestones and feasibility requirements will be eligible for rapid transition to the second UH3 stage after NIH administrative review. 

The UH3 (Stage 2) 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 stage is up to two years.

 
Key Dates
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.

Table of Contents

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

Part 2. Full Text of Announcement

Section I. Funding Opportunity Description

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 stand-alone intervention or as 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 Ib and Phase IIa trials are defined as follows.  Phase Ib trials are defined as studies usually conducted in the target patient population to establish feasibility (e.g., target engagement, PD/PK, optimal dosing of the Agent) for a Phase IIa proof of concept trial.  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.

UH2 feasibility objectives (Stage 1)

The UH2 activities will generally include pre-clinical studies and/or Phase Ib clinical trials using the selected Agent to provide sufficient evidence in the biological rationale for the proposed therapeutic use, identify the dose or exposure of the Agent in the proposed patient group, and inform patient selection.  Investigators should consider the use of pharmacokinetic (PK) and pharmacodynamic (PD) biomarkers to assess the selection of doses and exposure of the Agent at the target site of action, binding at the target, and expression of functional pharmacological activity of the Agent at the target site of action (see, Morgan P., et. al, Drug Discov. Today (2012), doi:10.1016/j.drudis.2011.12.020). Because the Agents have previously been studied in human subjects, it is imperative that the proposed studies rapidly assess feasibility and biological rationale for testing the selected Agent for the new therapeutic use.  The duration of the UH2 project period is anticipated to vary in time from three months up to one year based on data needed to establish validity of the biological rationale and feasibility for a proof of concept trial (as specified in the specific aims of the UH2 project).

UH3 implementation objectives (Stage 2)

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, above); 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 and is expected to begin as soon as the UH2 milestones and feasibility requirements are met (see Milestones and UH2/UH3 Transition under Section 6, Other Submission Requirements and Information).  NIH approval for transition of the project to the UH3 stage will be contingent on reaching the milestones and feasibility requirements specified in the Notice of Award for successful completion of the work proposed in the UH2 stage, and NIH review of updated IND information, a human subjects protection plan, and a data and safety monitoring plan.

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-12-005 (UH3); applicants must also read both companion FOAs prior to submitting an X02 pre-application.  Pre-applications submitted in response to PAR-12-203 will be evaluated by outside 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 UH2/UH3 application.

X02 applicants notified of the opportunity to submit a UH2/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 UH2/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 UH2/UH3 application.  A successful UH2/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 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).   

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 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


Section II. Award Information
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

NIH intends to commit up to $20 million in FY2013 to fund six to eight UH2/UH3 or UH3 awards in response to this FOA and the companion FOA (RFA-TR-12-005). 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 duration of the UH2/UH3 project period will not exceed three years.  The duration of the project period is anticipated to vary between three months up to one year for the UH2, and up to two years for the UH3.  Funding of the UH3 award will be determined by successful completion of UH2 scientific milestones as determined by the NIH. 

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.

Section III. Eligibility Information

1.Eligible Applicants

Eligible Organizations

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 UH2/UH3 application.

Foreign Institutions

Not Applicable.

Required Registrations

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.

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.

Eligible Individuals (Program Director/Principal Investigator)

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 UH2/UH3 application.

For these UH2/UH3 applications, the PD/PI must be the same PD/PI listed on the X02 pre-application.  For UH2/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 submit a UH2/UH3 application.

NIH Intramural Research Program (IRP) investigators are eligible to apply for the UH2/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(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.  Intramural Research Investigators cannot request extramural funds.  For more information, see Section 6, Other Submission Requirements and Information.    

2. Cost Sharing

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

3. Additional Information on Eligibility

Number of Applications

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.

Section IV. Application and Submission Information

1. Requesting an Application Package

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.

2. Content and Form of Application Submission

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.

Required and Optional Components

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.

Page Limitations

All page limitations described in the SF424 Application Guide and must be followed, with the following exceptions or additional requirements:

PHS 398 Research Plan Component

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

Specific Instructions for Preparing a Combined UH2/UH3 Application

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

2. The UH2/UH3 must be submitted as a single application but the approach should be clearly organized into two stages:  UH2 (Stage 1) and UH3 (Stage 2). 

3. UH2/UH3 applications are limited to up to 12 pages for the UH2 and up to 12 pages for the UH3 pages for the Research Strategy section including milestones, timeline, and future plans. 

4. Applications will be assigned a single impact/priority score. 

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

Specific Aims

The one-page Specific Aims section should include Aims delineated for the UH2 (Stage 1) and UH3 (Stage 2) components:

1. UH2 (Stage 1)

a. Define the aims of the pre-clinical studies, if any are proposed.

b. Define the aims of the Phase Ib clinical trials.

2. UH3 (Stage 2)

a. Define the aims of the Phase IIa proof of concept trial.

1). The aims should address target modulation and efficacy.

2). 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 Research Strategy, provide the following information for the UH2 (Stage 1) and UH3 (Stage 2) Components.  Separate the information for each Component for Approach and Milestones:

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). Data to support the selection and relevance of the proposed models to assess the efficacy of the Agent in the new disease area (e.g., choice of assays, models, species, outcome or endpoints selected).

3). 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). 

3. Approach

UH2 (Stage 1)

a. Provide an overall plan to assess the validity of the biological hypothesis for use of the Agent in the new disease area. 

1). Describe and justify the selection of the approach(es) to demonstrate activity of the Agent (e.g., pre-clinical disease models, disease assays, or patient-derived samples).

2). Consider 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 and route of administration of Agent.

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

5). Note that pre-clinical animal studies may not be necessary in all cases and their inclusion should be tied to a go/no go decision to test the Agent in the proposed patient group. 

b. Provide a plan for Phase Ib trials to link the Agent's mechanism of action (target or pathway) to disease pathophysiology or changing the disease state in the proposed patient group.   

1). Describe the design to assess the safety, dosing, and tolerability of the Agent in the proposed patient population.

2). Describe the use of PK and PD biomarkers, when available, to assess: dose and exposure of the Agent at the target site of action; binding at the target; and expression of functional pharmacological activity of the Agent at the target site of action.

3). Identify the inclusion of any clinical endpoints or outcome measures.

4). Identify the length of the study, number of subjects, amount of Agent needed, and formulation.

UH3 (Stage 2) 

a. Provide an overall plan for the Phase IIa proof of concept trial

1). Specify the duration of studies, based on safety data available for the Agent.

2). Specify dose range, route of administration, and amount of Agent needed.

3). Discuss plans for submitting an IND protocol amendment, if appropriate.

b. Define the patient selection strategy.

1). Consider the use of molecular markers of disease, pharmacogenomics, or other biomarkers, when applicable. 

c. Define the clinical end points and the power calculations that determine the size of the Phase IIa proof of concept trial.

1). The sample size, power, and duration of the Phase IIa proof of concept trials should be justified for the specific disease population. 

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

4. Milestones and Timeline

The application must include clearly-specified, well-defined milestones, go/no go decision points, and timelines for assessing progress in both the UH2 and UH3 stages, including specific milestones and timeline for progressing from the UH2 stage to the UH3 stage.  Milestones and the timeline for each stage must be provided in a separate heading at the end of the Approach section for each UH2 and UH3 component.  More detailed information about Milestones can be found under Section 6, Other Submission Requirements and Information.

a. UH2 (Stage 1) Milestones and criteria for UH2/UH3 transition must: 

1). Identify and justify the scientific milestones, go/no go decisions, and timeline to advance studies of the Agent to the UH3 stage (Phase IIa proof of concept trial).

b. UH3 (Stage 2) Milestones must:

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

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

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

4). 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.  Anticipated protections should be separated for any proposed Phase Ib and Phase IIa proof of concept trials in the UH2 and UH3 stages. Some information may not be available, as the design of the Phase IIa proof of concept trial and the selection criteria (stratification strategy) for the target population in the UH3 may not be clear until milestones have been achieved in the UH2.  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 draft targeted/planned enrollment table for each of the planned trials 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 conducting the proposed pre-clinical studies and 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:

Appendix

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

Foreign Institutions

Applicants may have subcontracts with foreign institutions if they provide novel approaches or patient populations. If included, foreign (non-US) institutions must follow policies described in the NIH Grants Policy Statement, and procedures for foreign institutions described throughout the SF424 (R&R) Application Guide.

3. Submission Dates and Times

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.

4. Intergovernmental Review (E.O. 12372)

This initiative is not subject to intergovernmental review.

5. Funding Restrictions

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.   

6. Other Submission Requirements and Information

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 therapeutics.discovery@nih.gov 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: dunnbo@mail.nih.gov

Milestones and UH2/UH3 Transition

1. Prior to funding an application, the Program Official will contact the applicant to discuss the proposed UH2 and 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 UH2 milestones which will be specified in the Notice of Award.  These milestones will be the basis for judging the successful completion of the work proposed in the UH2 stage and progress towards interim milestones in the UH3 stage. 

2. For funded UH2 applications, projects that have met the scientific milestones and feasibility requirements will be eligible for rapid transition to the second UH3 stage after NIH administrative review.  The PD(s)/PI(s) will submit a progress report to both the Grants Management Specialist and the Program Official upon completion of the UH2 milestones and any revisions to the proposed UH3 aims.  Prior to initiation of a Phase IIa proof of concept  trial in the UH3 stage, an updated human subjects protection plan (e.g., IND protocol amendment, IRB approval of amendments to the protocol or consent form) and a detailed data and safety monitoring plan (DSMP) must be approved by NIH.  Receipt of this progress report will trigger an administrative program review that will determine whether or not the UH3 should be awarded.   

3. The release of UH3 funds will be based on successful completion of the approved scientific milestones, program priorities, and the availability of funds. UH3 milestones will be the basis for

judging progress towards and completion of 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 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 both the UH2 and UH3 phase of award.

Documentation of access to the Agent proposed for use in the UH2/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 UH2/UH3 application.  The letter must specify the Scientific Director's commitment of intramural research funds to support the IRP investigator's proposed UH2/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 providing the selected Agent made available through this FOA 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.

Post Submission Materials

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

Section V. Application Review Information

1. Criteria

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.

Overall Impact

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).

Scored Review Criteria

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 two stages of 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? Are procedures in place for quality control and quality assessment of the preclinical and 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 preclinical and clinical plan investigators, and the pharmaceutical company partner? Have the PD(s)/PI(s) discussed a plan for timely submission of an IND application for the clinical trials, expedited IRB review and approval, and timely patient recruitment? Is there a plan for moving expeditiously to Phase IIa proof of concept trials once a new therapeutic use has been assessed for biological validity and feasibility? What is the likelihood of the proposed project in meeting the goals under the compressed timelines 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 studies? 

Additional Review Criteria

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 UH2 and UH3 stages clearly defined? Are the UH2 and UH3 milestones feasible, well developed and quantifiable with regard to the specific aims of each stage?  Is the timeline feasible for the UH2 and UH3 stages?  Are the go/no go decision points, recruitment goals, and timelines appropriate for the UH2 and UH3 stages? Are adequate criteria provided in the UH2 stage to assess milestone completion and operational feasibility of studying the Agent in the targeted patient population, in order to make a decision to advance studies of the Agent to a Phase IIa proof of concept trial in the UH3 stage?

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.     

Additional Review Considerations

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.

2. Review and Selection Process

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s), convened by 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:

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:

3. Anticipated Announcement and Award Dates

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.

Section VI. Award Administration Information

1. Award Notices

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.

2. Administrative and National Policy Requirements

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:

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

The Project Scientists will:

The Program Official will:

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 each awardee’s 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:

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.

3. Reporting

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. 

Section VII. Agency Contacts

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

Application Submission Contacts

Grants.gov Customer Support (Questions regarding Grants.gov registration and submission, downloading or navigating forms)
Contact Center Phone: 800-518-4726
Email: support@grants.gov

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Telephone 301-435-0714
TTY 301-451-5936
Email: GrantsInfo@nih.gov

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: commons@od.nih.gov

Scientific/Research Contact(s)

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)
Phone: See Contact List
Email: ccolvis@mail.nih.gov
Mailbox: Therapeutics.Discovery@nih.gov

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)
Phone: 301-443-8063
Fax: 301-480-3661
Email: XieHe@mail.nih.gov

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.

Peer Review Contact(s)

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
Phone: 301-435-0824 (direct line)
Phone: 301-435-0811 (Office of Review)
Email: dunnbo@mail.nih.gov

Financial/Grants Management Contact(s)

Susan Lowenthal
Office of Grants Management
National Center for Advancing Translational Sciences, NIH, DHHS
6701 Democracy Blvd, Room 1051
Bethesda, MD 20892 (20817 for express delivery)
Phone: 301-435-0848
Fax: 301-480-3777
Email: lowenths@mail.nih.gov

Amy McGuire
Office of Grants Management
National Center for Advancing Translational Sciences, NIH, DHHS
6701 Democracy Blvd, Room 1043
Bethesda, MD 20892 (20817 for express delivery)
Phone: (301-435-0853
Fax: 301-480-3777
Email: mcguirear@mail.nih.gov

Section VIII. Other Information

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.

Authority and Regulations

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.


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