Required Application Instructions

It is critical that applicants follow the instructions in the SF424 (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

In June 2012, NCATS issued its first Funding Opportunity Announcements (FOAs) which were for an NIH-Industry Pilot Program: Discovering New Therapeutic Uses for Existing Molecules. The pilot was designed to increase engagement and partnerships between academia and industry in drug repurposing and to enhance the success of these efforts. These objectives were met using several innovative strategies. When the FOAs were published, information about investigational Agents (new molecular entities (NMEs) and biologics) from pharmaceutical companies was made publicly available. Also made publicly available were template collaborative research agreements (CRAs) and template confidential disclosure agreements (CDAs) that would be executed between the NIH applicant and the pharmaceutical company providing the Agent. The use of the template CDAs and CRAs in the pilot program led to rapid establishment of pharmaceutical-academic collaborations. The increased awareness and availability of these Agents to the research community resulted in submissions to NIH of almost 160 pre-applications for a wide array of diseases.

This robust response from both the pharmaceutical industry and from the research community was a strong indicator of a high level of enthusiasm for the pilot. Based on these indicators as well as feedback obtained through a Request for Information (RFI; http://grants.nih.gov/grants/guide/notice-files/NOT-RM-13-021.html), and surveys of awardees, the pharmaceutical companies, and NIH Components, NCATS is issuing this new round of Funding Opportunity Announcements (FOAs).

FOA	Type of research supported	Period of support (maximum)
X02	Requisite preapplication (no research supported)	N/A
UH3	Phase 2a Clinical Trial	2 years
UH2/UH3	UH2: Pre-clinical and/or Phase 1b; UH3: Phase 2a Clinical Trial	1 year for UH2 and 2 years for UH3
UH2/UH3 Pediatrics*	UH2: Pre-clinical, Phase 1a Clinical Trial, pediatric toxicology, and Phase 1b; UH3: Phase 2a Clinical Trial	2 years for UH2 and 2 years for UH3

* In general, pediatric populations to be considered for this FOA refer to disease populations for which there is no adult equivalent and therefore, there is no adult population in which the drug could be tested prior to testing in children. However, trials in pediatric or juvenile populations for indications that also have an adult population (e.g., type 2 diabetes, autism, osteoarthritis) may be considered if there is a strong scientific rationale that justifies why phase 2a trials in the pediatric population are required even though an adult patient population exists.

This FOA intends to support innovative ideas from the biomedical research community for the discovery of potential therapeutic uses of those Agents that are amenable to exploration/use in previously unexplored disease areas unique to pediatric populations. In general, pediatric populations to be considered for this FOA refer to disease populations for which there is no adult equivalent and therefore, there is no adult population in which the drug could be tested prior to testing in children. However, trials in pediatric or juvenile populations for indications that also have an adult population (e.g., type 2 diabetes, autism, osteoarthritis) may be considered if there is a strong scientific rationale that justifies why phase 2a trials in the pediatric population are required even though an adult patient population exists (e.g., the target in the pediatric population may differ from that in the adult or treatment of children may reduce progression or severity of the disease). Agents pharmaceutical companies will consider for use in pediatric populations are listed in the Table of Agents for Pediatric Indications. Applicants need to refer to the "Additional Characteristics" row of the more detailed Agent information chart for the agent of interest to determine the type(s) of pediatric diseases the pharmaceutical company will consider (e.g., only trials in pediatric populations for which there is no adult population; or trials for diseases/conditions that have a pediatric and adult population, if the trials in a pediatric population are scientifically justified). Applicants exploring therapies for diseases that occur in both children and adults should consider applying in response to one of the companion FOAs focusing on adult populations PAR-14-211 or PAR-14-212.

Some of the compounds in the Table of Agents will be more amenable to exploration/use in pediatric populations than others based on the Biopharmaceutical Classification System (BCS), adult safety data, expected palatability issues, bioavailability and other criteria. A pediatric oral formulation will need to be an 1) oral solution/suspension, which is recommended for children ages 6 to 11, or 2) a small tablet/capsule, which should be considered for ages 12 to 18 years. An extemporaneous formulation of an Agent that could be prepared immediately prior to dosing is another option. Those Agents that have the potential to be used in a pediatric disease are indicated in the Table of Agents for Pediatric Indications.

This FOA is for a Feasibility/Implementation Cooperative Agreement (UH2/UH3) that allows one additional year of support in the UH2 feasibility stage (compared to the companion FOA PAR-14-212 for adult indications). The extra year of support [for a total of two years of support for the UH2 (for pediatric indications only)] is for required Phase 1a and juvenile toxicity testing.

Proposed human trials can include: 1) use of an Agent as a stand-alone intervention, or 2) as an adjunctive intervention with existing standard of care (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 1a trials are defined as initial studies in healthy adult volunteer subjects or the pediatric rare disease subjects; or other initial studies (using the proposed pediatric formulation) to determine the metabolic and pharmacological actions and the side effects (including those associated with increasing drug doses, or drug-drug interactions in cases where the agents will be tested as adjunctive treatment), as required by the FDA. A Phase 1b trial is defined as studies usually conducted in the target pediatric patient population to establish feasibility (e.g., target engagement, pharmacokinetic/pharmacodynamic (PK/PD), initial dosing of the Agent) prior to a Phase 2a trial. Phase 2a clinical trials provide data on the relationship of dosing and response for the particular intended use (including trials on the impact of dose ranging on safety, biomarkers, and proof of concept), in a small number of the targeted pediatric-patient population. In addition to clinical benefit, Phase 2a trials also include assessments of safety, tolerability, and PK/PD response of the Agent.

UH2 feasibility objectives (Stage 1)

The UH2 activities for this FOA will generally include pre-clinical studies including juvenile animal studies to assess the potential drug toxicity in one or more species and/or Phase 1a and Phase 1b clinical trials using the selected Agent to identify the dose or exposure of the Agent in the pediatric patient group, and inform patient selection. FDA's Guidance on Nonclinical Safety Evaluation of Pediatric Drug Products should be considered in designing pre-clinical toxicity studies (http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm079247.pdf). 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. The duration of the UH2 project period is anticipated to vary in time from one to two years based on data needed to establish safety in children, dose selection/exposure, and additional data needed to transition to the Phase 2a clinical trial (as specified in the specific aims of the UH2 project).

UH3 implementation objectives (Stage 2)

The UH3 activities will include exploratory, milestone-driven Phase 2a trials designed to demonstrate that the Agent modulates the target and has the potential to yield the desired clinical outcome in the proposed pediatric disease population and assess its potential for further clinical development. 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; or the use of molecular markers of disease, pharmacogenomics, or other biomarkers as patient selection strategies. 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. 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 Phase 2a clinical trials are successful, it is anticipated that the pharmaceutical company partner will have first right of refusal to pursue further clinical development of the Agent for the new therapeutic use, including requisite Phase 3 clinical trials, ultimately commercializing the novel therapeutic intervention for the new disease indication whenever feasible.

National Center for Advancing Translational Sciences (NCATS)

NCATS will consider co-funding projects that address a disease for which there is no or inadequate treatment and for which there is strong scientific rationale. NCATS is particularly interested in rare diseases.

National Institute on Aging (NIA)

NIA will consider funding projects consistent with its mission of reducing the burden of diseases and conditions associated with aging.

National Institute of Alcohol Abuse and Alcoholism (NIAAA)

Currently, there are only a few FDA-approved drugs to treat alcohol use disorder (AUD). Given the heterogeneity of this disorder, the modest effect size of approved medications, and the numerous targets involved with AUDs, development of new, effective medications to treat AUD is a top priority for NIAAA. NIAAA will consider funding projects to investigate the use of existing molecules to treat AUD.

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

NICHD will consider funding projects with a pediatric focus, particularly pediatric rare and neglected diseases.

National Institute on Drug Abuse (NIDA)

Currently, there are no FDA-approved medications to treat substance use disorders (SUDs) involving stimulants (cocaine and methamphetamine), although there are approved medications for SUDs involving opiates. The development of medications to treat SUDs is a top priority for NIDA. NIDA will consider funding projects to investigate the use of existing molecules to treat SUDs involving cocaine, methamphetamine, cannabis, nicotine, or opiates.

National Institute on Deafness and Other Communication Disorders (NIDCD)

NIDCD will consider funding projects focused on communication disorders of hearing (including tinnitus), balance, taste, smell, voice, speech and language, including biomedical and behavioral problems associated with people who have these communication impairments or disorders.

National Institute of Dental and Craniofacial Research (NIDCR)

NIDCR will consider funding projects to treat conditions affecting the oral cavity or that improve dental and craniofacial health.

National Institute of Mental Health (NIMH)

NIMH will consider funding projects that focus on the treatment and prevention of psychiatric disorders in adults and children and are consistent with the NIMH’s emphasis on the experimental therapeutic approach. Consistent with the Research Domain Criteria (RDoC), NIMH is particularly interested in testing novel interventions that focus on operationally defined, empirically-supported functional domains or symptom(s) of psychiatric disorders in subjects that share the same underlying disease processes.

National Institute of Neurologic Disease and Stroke (NINDS)

NINDS will consider funding projects consistent with its mission of reducing the burden of neurologic disease.

Food and Drug Administration (FDA)

FDA will consider co-funding projects that meet rare disease criteria per the Orphan Drug Act.

The submission of an X02 pre-application is a necessary first step in applying for an award under this FOA or the companion FOAs. Applicants must also read the companion FOAs prior to submitting an X02 pre-application. Pre-applications submitted to PAR-14-213 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 of X02 pre-applications that are identified as being highly meritorious and relevant to NIH program priorities will be provided contact information for the appropriate pharmaceutical company based on the Agent or mechanism of action identified in their X02 pre-application. The X02 applicants and pharmaceutical company partner will jointly decide whether a UH2/UH3 application should be submitted.

X02 applicants put in contact with the pharmaceutical company partner for the Agent that was selected for studies in the X02 pre-application, are expected to 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. Through the CDA X02 applicants will have access to the additional information and data on the Agent, but will not have access to the Agent itself. 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 if an award is made. 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).

A key aspect 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 with the pharmaceutical company partner for the selected Agent, prior to submitting a UH2/UH3 application. A complete UH2/UH3 application is 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).

The list of Agents and non-confidential information can be found at

http://www.ncats.nih.gov/research/reengineering/rescue-repurpose/therapeutic-uses/directory2014.html

June 15, 2014	X02 Letters of Intent (LOIs) due
July 15, 2014	Due date for X02 pre-application
August 2014	Evaluation of pre-application by outside experts
Late September/Early October 2014	Notification of opportunity to submit a full UH2/UH3 application
January 16, 2015	Due date for UH2/UH3 applications
February/March 2015	Scientific merit review for UH2/UH3 applications
May 2015	Advisory Councils for review of applications
July 2015	Earliest possible start date for awarded grants

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.

Higher Education Institutions

• Public/State Controlled Institutions of Higher Education
• Private Institutions of Higher Education

The following types of Higher Education Institutions are always encouraged to apply for NIH support as Public or Private Institutions of Higher Education:

• Hispanic-serving Institutions
• Historically Black Colleges and Universities (HBCUs)
• Tribally Controlled Colleges and Universities (TCCUs)
• Alaska Native and Native Hawaiian Serving Institutions
• Asian American Native American Pacific Islander Serving Institutions (AANAPISIs)

Nonprofits Other Than Institutions of Higher Education

• Nonprofits with 501(c)(3) IRS Status (Other than Institutions of Higher Education)
• Nonprofits without 501(c)(3) IRS Status (Other than Institutions of Higher Education)

For-Profit Organizations

• Small Businesses
• For-Profit Organizations (Other than Small Businesses)

Governments

• State Governments
• County Governments
• City or Township Governments
• Special District Governments
• Indian/Native American Tribal Governments (Federally Recognized)
• Indian/Native American Tribal Governments (Other than Federally Recognized)
• Eligible Agencies of the Federal Government including the NIH Intramural Research Program
• U.S. Territory or Possession

Other

• Independent School Districts
• Public Housing Authorities/Indian Housing Authorities
• Native American Tribal Organizations (other than Federally recognized tribal governments)
• Faith-based or Community-based Organizations
• Regional Organizations

This FOA is a limited competition for applicants whose X02 pre-applications submitted in response to PA-14-213 were identified as being highly meritorious and relevant to NIH program priorities; X02 applicants will have contacted the appropriate pharmaceutical company to exchange data under a CDA and both parties will have decided that a Pediatrics UH2/UH3 application should be submitted.

Non-domestic (non-U.S.) Entities (Foreign Institutions) are not eligible to apply.
Non-domestic (non-U.S.) components of U.S. Organizations are not eligible to apply.
Foreign components, as defined in the NIH Grants Policy Statement, are allowed.

Applicant Organizations

Applicant organizations must complete and maintain the following registrations as described in the SF 424 (R&R) Application Guide to be eligible to apply for or receive an award. All registrations must be completed prior to the application being submitted. Registration can take 6 weeks or more, so applicants should begin the registration process as soon as possible. The NIH Policy on Late Submission of Grant Applications states that failure to complete registrations in advance of a due date is not a valid reason for a late submission.

• Dun and Bradstreet Universal Numbering System (DUNS) - All registrations require that applicants be issued a DUNS number. After obtaining a DUNS number, applicants can begin both SAM and eRA Commons registrations. The same DUNS number must be used for all registrations, as well as on the grant application.
• System for Award Management (SAM) (formerly CCR) Applicants must complete and maintain an active registration, which requires renewal at least annually. The renewal process may require as much time as the initial registration. SAM registration includes the assignment of a Commercial and Government Entity (CAGE) Code for domestic organizations which have not already been assigned a CAGE Code.
• NATO Commercial and Government Entity (NCAGE) Code Foreign organizations must obtain an NCAGE code (in lieu of a CAGE code) in order to register in SAM.
• eRA Commons - Applicants must have an active DUNS number and SAM registration in order to complete the eRA Commons registration. Organizations can register with the eRA Commons as they are working through their SAM or Grants.gov registration. eRA Commons requires organizations to identify at least one Signing Official (SO) and at least one Program Director/Principal Investigator (PD/PI) account in order to submit an application.
• Grants.gov Applicants must have an active DUNS number and SAM registration in order to complete the Grants.gov registration.

Program Directors/Principal Investigators (PD(s)/PI(s))

All PD(s)/PI(s) must have an eRA Commons account. PD(s)/PI(s) should work with their organizational officials to either create a new account or to affiliate their existing account with the applicant organization in eRA Commons. If the PD/PI is also the organizational Signing Official, they must have two distinct eRA Commons accounts, one for each role. Obtaining an eRA Commons account can take up to 2 weeks.

Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) is invited to work with his/her organization to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH support.

For institutions/organizations proposing multiple PDs/PIs, visit the Multiple Program Director/Principal Investigator Policy and submission details in the Senior/Key Person Profile (Expanded) Component of the SF424 (R&R) Application Guide.

This FOA is a limited competition for applicants whose X02 pre-applications submitted in response to PA-14-213 were identified as being highly meritorious and relevant to NIH program priorities; X02 applicants will have contacted the appropriate pharmaceutical company to exchange data under a CDA and both parties will have decided that a Pediatrics UH2/UH3 application should be submitted.

For these Pediatric 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 to 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.

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 that is essentially the same as one already reviewed within the past thirty-seven months (as described in the NIH Grants Policy Statement), except for submission:

• To an RFA of an application that was submitted previously as an investigator-initiated application but not paid;
• Of an investigator-initiated application that was originally submitted to an RFA but not paid; or
• Of an application with a changed grant activity code.

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.

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

The forms package associated with this FOA includes all applicable components, required 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.

The following section supplements the instructions found in the SF424 (R&R) Application Guide and should be used for preparing an application to this FOA.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed.

Project Summary/Abstract: To ensure protection of intellectual property, applicants should discuss with the pharmaceutical company and the institutional technology transfer office, the appropriate level of detail to be provided in the UH2/UH3 application title and abstract since that information will be publicly available for awarded projects.

Other Attachments: Attach Agent information for the Agent selected for use in the project, available at http://www.ncats.nih.gov/research/reengineering/rescue-repurpose/therapeutic-uses/directory2014.html, and title it "Agent Information".

All instructions in the SF424 (R&R) Application Guide must be followed.

The PD/PI on the UH2/UH3 application must be the same PD/PI for the X02 pre-application.

All instructions in the SF424 (R&R) Application Guide must be followed.

If the applicant institution is an NIH Institute or Center, funds may not be requested for an extramural component/collaborator in the application.

All instructions in the SF424 (R&R) Application Guide must be followed.

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

Specific Aims: The Specific Aims section should include Aims delineated for the UH2 (Stage 1) and UH3 (Stage 2) stages:

1. UH2 (Stage 1)

a. Define the aims of the pre-clinical studies.

b. Define the aims of the Phase 1a and Phase 1b clinical trials.

2. UH3 (Stage 2)

a. Define the aims of the Phase 2a clinical 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 modulates the target/mechanism and a biomarker of PD effect, and has the potential to yield the desired clinical outcome in the pediatric disease population.

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

1. Background & Significance

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

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

c. Indicate the disease that is unique to the pediatric population, and public health need that will be addressed by the proposed new use of the Agent. If the disease/condition exists in both children and adults, include strong scientific justification for testing the Agent in a pediatric patient population instead of testing in an adult patient population (e.g., the target in the pediatric population may differ from that in the adult or treatment of children may reduce progression or severity of the disease).

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 public health impact.

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 pediatric disease pathology.

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

3). Any additional relevant data/information on the Agent (e.g., availability of pharmacokinetics (PK) and pharmacodynamics (PD) markers, any exclusions or restrictions in the Agent's use) supporting dose and dose schedule for the Agent in the proposed new disease area.

3. UH2 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 Agent activity (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. Provide/describe juvenile toxicity data results, if available. Describe proposed pre-clinical juvenile toxicity studies to support clinical trials in children, if these have not been completed. Investigators should consider FDA's Guidance on Nonclinical Safety Evaluation of Pediatric Drug Products in designing pre-clinical toxicity studies (http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm079247.pdf).

3). Specify dose range of the Agent using the company-specified route of administration. Discuss any known or expected issues with oral formulations (solubility/permeability, taste/bitterness).

4). Discuss plans and personnel resources available for timely filing of an IND and rapid Institutional Review Board (IRB) approval.

• Applicants are strongly encouraged to consider requesting a pre-IND meeting with FDA (Type B meeting) prior to submitting their UH2/UH3 application. Guidance on FDA meetings is located at this link: http://www.fda.gov/downloads/Drugs/Guidances/ucm153222.pdf.

5). Pre-clinical animal safety studies should be tied to a go/no go decision to test the Agent in the proposed pediatric-patient group.

b. Provide a plan for Phase 1a safety studies in healthy volunteers and Phase 1b trials to determine appropriate dosing for the proposed pediatric-patient group.

1). Describe the design to assess the safety, dosing, and tolerability including palatability of the Agent (if oral) in the proposed pediatric-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 (dosing schedule and time to obtain data endpoints), number of subjects, plans for patient recruitment, clinical monitoring and oversight, and data management.

5). Provide an estimate for the amount of Agent needed and the formulation.

6.) Describe plans for clinical data management.

4. UH2 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 stage.

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

a. Identify and justify the scientific milestones, go/no go decisions, and timeline to advance studies of the Agent to the UH3 stage (Phase 2a clinical trial).

1). Discuss how data generated in the UH2 studies will be assessed to determine the risk/benefit of the Agent to patients: safety (i.e., proposed clinical starting dose based on the No Observed Adverse Effect Level [NOAEL] established in the pre-clinical safety studies), tolerability, bioavailability/PK, and PD (duration of action, relationship between dose/exposure and PD).

2). Indicate plans and timing for an amendment to the IND for the proposed UH3 clinical trial.

3). 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 (DSMP) approval), access to and number of pediatric patients (include discussion of other trials that may be recruiting from the same patient pool), patient selection criteria, availability of the Agent, and formulation.

5. UH3 Approach

UH3 (Stage 2)

a. Provide an overall plan for the Phase 2a clinical trial.

1). 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.

2). Specify dose range, PD parameters used to perform dose ranging, route of administration and dosage form, and amount of Agent needed.

b. Define the patient selection strategy.

1). Describe a plan for the involvement of Patient Advocacy Groups (PAGs) in the project. If PAGs are not included, provide a rationale for their exclusion.

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

c. Define the primary end points and justify the number of patients chosen for the Phase 2a study (based on the proposed outcome measures and the appropriateness of the statistical methods).

1). The sample size and duration of the Phase 2a clinical trials should be justified for the specific pediatric disease population.

2). Discuss alternative statistical methods to show efficacy in Phase 2a clinical trials with small sample sizes.

3). Provide evidence that the proposed number of eligible subjects can be recruited in the requested timeframe.

4). Provide assurance that the proposed study can be completed within its budget and within the time limits stated in this FOA.

5.) Describe plans for clinical data management.

6. Administration and Management

a. Provide an operational plan for managing the pre-clinical studies and clinical trials necessary to fully develop a new use for the Agent.

1). Describe institutional and/or project personnel experience with FDA regulatory processes.

2). Explain the proposed contribution of each of the key participants in achieving the objectives of the project.

3). It will be important for the PD/PI to describe experience in meeting milestones.

b. Explain the proposed contribution of each of the administrative components to achieving the objectives of the program.

c. Describe relevant experience and knowledge of public-private partnerships.

d. Describe the team's experience in the methods and approaches for design and implementation of human clinical trials and readiness to test the hypothesis.

e. Describe the team's requisite competencies and experience with clinical trials recruitment and execution and ability to recruit and enroll patients in the target disease population.

7. UH3 (Stage 2) 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 stage.

The UH3 milestones must:

a. Provide a clear timeline, interim milestones, and go/no decision points for the clinical trial.

1). 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).

2). Decision points for terminating the trial (e.g., safety, tolerability, patient acceptability issues, including palatability and the ability to swallow the dosage form).

3). See regular reporting as specified in the Terms and Conditions.

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

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

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

8. 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.

Protection of Human Subjects: Address Human Subjects protections for any clinical research anticipated in the period of the grant, as described in the SF 424 (R&R) application instructions. Anticipated protections should be separated for any proposed Phase 1b and Phase 2a clinical trials in the UH2 and UH3 stages. Some information may not be available, as the design of the Phase 2a clinical 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 1b and 2a 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 exclusion(s). 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: Applicants must 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, and the PD/PI has the right to cross-reference specific sections of the pharmaceutical company partner's IND/Drug Master File, etc.).

If multiple institutions are involved in an application, a letter of support should be included from each institution.

For Intramural Scientists, an official letter from the Scientific Director, which indicates approval of the intramural 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 intramural investigator's proposed UH2/UH3 project or project component.

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 modification:

• All applications, regardless of the amount of direct costs requested for any one year, should address 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 trial data.

Appendix: Do not use the Appendix to circumvent page limits. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.

When conducting clinical research, follow all instructions for completing Planned Enrollment Reports as described in the SF424 (R&R) Application Guide.

When conducting clinical research, follow all instructions for completing Cumulative Inclusion Enrollment Report as described in the SF424 (R&R) Application Guide.

Part I. Overview Information contains information about Key Dates. Applicants are encouraged to submit applications before the due date to ensure they have time to make any application corrections that might be necessary for successful submission.

Organizations must submit applications to 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. NIH and Grants.gov systems check the application against many of the application instructions upon submission. Errors must be corrected and a changed/corrected application must be submitted to Grants.gov on or before the application due date. If a Changed/Corrected application is submitted after the deadline, the application will be considered late.

Applicants are responsible for viewing their application before the due date 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 SF424 (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 SF424(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. See Section III of this FOA for information on registration requirements.

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 System for Award Management. 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. Applications that are incomplete 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.

Applicants requesting $500,000 or more in direct costs in any year (excluding consortium F&A) must contact NIH program staff at least 6 weeks before submitting the application and follow the Policy on the Acceptance for Review of Unsolicited Applications that Request $500,000 or More in Direct Costs as described in the SF424 (R&R) Application Guide.

All NIH supported clinical trials, including Phase I trials, require monitoring (NIH Guidance on Data and Safety Monitoring for Phase 1 and Phase 2 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 2a 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.

The requests by NIH intramural scientists will be limited to the incremental costs required for participation. As such, these requests will not include any salary and related fringe benefits for career, career conditional or other Federal employees (civilian or uniformed service) with permanent appointments under existing position ceilings or any costs related to administrative or facilities support (equivalent to Facilities and Administrative or F&A costs). These costs may include salary for staff to be specifically hired under a temporary appointment for the project, consultant costs, equipment, supplies, travel, and other items typically listed under Other Expenses. Applicants should indicate the number of person-months devoted to the project, even if no funds are requested for salary and fringe benefits.

If selected, appropriate funding will be provided by the NIH Intramural Program. NIH intramural scientists will participate in this program as PDs/PIs in accord with the Terms and Conditions provided in this FOA. Intellectual property will be managed in accord with established policy of the NIH in compliance with Executive Order 10096, as amended, 45 CFR Part 7; patent rights for inventions developed in NIH facilities are NIH property unless NIH waives its rights.

Should an extramural application include the collaboration with an intramural scientist, no funds for the support of the intramural scientist may be requested in the application. The intramural scientist may submit a separate request for intramural funding as described above.

If selected, NIH intramural 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.

Applicants are required to follow the instructions for post-submission materials, as described in NOT-OD-13-030.

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.

This initiative invites ideas for new therapeutic uses of existing molecules (Agents) from pharmaceutical company partners. Through this program, applicants will not have access to the Agents unless an award is made. However, applicants have been provided information on the Agent through a CDA with the pharmaceutical partner.

Reviewers will provide an overall impact 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/PI, 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 drug development, clinical trials planning, recruitment and execution in pediatric populations? Does the investigative team have an experienced individual/office/organization to effectively manage regulatory aspects of the project? 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? Although the Agent itself was not accessible to the PD/PI, 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? Does the evidence adequately support the hypothesis? If the applicant is proposing studies in a pediatric population for a disease/condition that exists in both children and adults, is there sufficient scientific justification for testing the Agent in a pediatric patient population instead of testing in an adult patient population? Are procedures in place for quality control and quality assessment of the preclinical and clinical study implementation? 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 investigators and the pharmaceutical company partner? Have the PD(s)/PI(s) discussed a plan for regulatory guidance in writing and timely submission of an IND application for the clinical trials, IRB review and approval, and timely patient recruitment? Is there a plan to incorporate relevant Patient Advocacy Groups (PAGs)? If PAGs are not included, is there rationale to support their exclusion? Is there a plan for moving expeditiously to Phase 2a clinical trials once a new therapeutic use has been assessed for safety and tolerability? What is the likelihood of the proposed project in meeting the goals under the compressed timelines of the FOA? Has the PD/PI provided evidence that the proposed number of eligible subjects can be recruited in the requested timeframe? Does the applicant have the ability to complete the proposed phase 2a clinical trial within the 2-year project period of the UH3?

If the project involves human subjects and/or NIH-defined clinical research, are the plans to address 1) the protection of human subjects from research risks, and 2) inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion or exclusion 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 to implement the goals of the project and for the overall functions of the project, including regulatory submissions, rapid IRB approval, and safety monitoring? 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?

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 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? 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 2a clinical 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 Guidelines for the Review of Human Subjects.

Inclusion of Women, Minorities, and Children

When the proposed project involves human subjects and/or NIH-defined clinical research, the committee will evaluate the proposed plans for the inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion (or exclusion) of children to determine if it is justified in terms of the scientific goals and research strategy proposed. For additional information on review of the Inclusion section, please refer to the Guidelines for the Review of Inclusion in Clinical Research.

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 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 evaluate and comment on the 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 NCATS, in accordance with NIH peer review policy and procedures, using the stated review criteria. Assignment to a Scientific Review Group 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 score.
• Will receive a written critique.

Applications will be assigned 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 appropriate national Advisory Council or Board. 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/PI 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, SAM Registration, and Transparency Act requirements as noted on the Award Conditions and Information for NIH Grants website.

Milestones and UH2/UH3 Transition

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.

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 Food and Drug Administration (FDA)/or other regulatory authority and the IRB.
• Complying with all federal regulations and NIH policies, including those related to clinical research and clinical trials.
• Adhering 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 Office of Human Research Protections (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 in the UH2 and UH3 stages; obstacles encountered and solutions; monthly recruitment updates; and quarterly progress on milestones or milestone updates. The reports should be provided in a format decided upon by the Steering Committee.
• Providing an interim report, due at completion of the UH2 milestones to the NIH, as specified in the Notice of Award.
• Retaining custody of and having 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 as a voting member; however, NIH voting membership will not exceed one-third of the total committee membership.
• Participate in the review of clinical research protocols and clinical 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 throughout the UH2 and/or UH3 stages of the project.
• Determine if the awardee has met the milestones and feasibility requirements for transition of the project from the UH2 to the UH3 stage.
• 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 UH2 or UH3 project for any of the following reasons: (1) inadequate progress in meeting the pre-negotiated milestones and timelines; (2) failure to meet the go/no go milestone(s) for transition from the UH2 to UH3; (3) risk(s) to subject s safety; (4) slow accrual; (5) data from a futility analysis; or (6) 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 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 (voting), the NIH Program Official (ex officio), and external scientist(s).

The Steering Committee will:

• Participate in monitoring scientific progress of the UH2 and UH3 research project plan, assessing recruitment and progress of the go/no go milestones.
• 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. Applicants should consider holding at least one in person meeting 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 1 and Phase 2 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 annual Non-Competing Progress Report (PHS 2590 or RPPR) 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.

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 2a clinical 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.

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

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

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Christine Colvis, Ph.D.
National Center for Advancing Translational Sciences (NCATS)
Telephone: 301-451-3903
Email: [email protected]

Linda Brady, Ph.D.
National Institute of Mental Health (NIMH)
Telephone: 301-443-3563
Email: [email protected]

Jill Heemskerk, Ph.D.
National Institute of Mental Health (NIMH)
Telephone: 301-443-0081
Email: [email protected]

Janet Cyr, Ph.D.
National Institute on Deafness and Other Communication Disorders (NIDCD)
Telephone: 301-402-3458
Email: [email protected]

Ivan Montoya M.P.H., MD
National Institute on Drug Abuse (NIDA)
Telephone: 301-443-8639
Email: [email protected]

Larry Refolo, Ph.D.
National Institute on Aging (NIA)
Telephone: 301-594-7576
Email: [email protected]

Joanne Fertig, Ph.D.
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Telephone: 301-443-0635
Email: [email protected]

Patricia Walicke, M.D., Ph.D.
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-1779
Email: [email protected]

Anne Zajicek, M.D., Pharm.D.
National Institute of Child Health and Human Development (NICHD)
Telephone: 301-435-6865
Email: [email protected]

R. Dwayne Lunsford, Ph.D.
National Institute of Dental and Craniofacial Research (NIDCR)
Telephone: 301-594-2421
Email: [email protected]

Katherine Needleman, Ph.D.
U.S. Food and Drug Administration (FDA)
Telephone: 301-796-8664
Email: [email protected]

Barbara Mroczkowski, Ph.D.
National Cancer Institute (NCI)
Telephone: 301-496-4291
Email: [email protected]

John W Thomas, Ph.D.
National Heart, Lung, and Blood Institute (NHLBI)
Telephone: 301-435-0065
Email: [email protected]

Patricia J. Noel, Ph.D.
National Heart, Lung, and Blood Institute (NHLBI)
Telephone: 301-435-0202
Email: [email protected]

Simhan Danthi, Ph.D.
National Heart, Lung, and Blood Institute (NHLBI)
Telephone: 301-451-5170
Email: [email protected]

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

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

Sheri Hild, Ph.D.
National Center for Advancing Translational Sciences (NCATS)
Telephone: 301-435-0811 (Office of Scientific Review)
Email: [email protected]

Jenelle Wiggins
National Center for Advancing Translational Sciences (NCATS)
Telephone: 301-435-0843
Email: [email protected]

Rebecca Claycamp
National Institute of Mental Health (NIMH)
Telephone: 301-443-2811
Email: [email protected]

Chris Myers
National Institute on Deafness and Other Communication Disorders (NIDCD)
Telephone: 301-435-0713
Email: [email protected]

Ericka Wells
National Institute on Drug Abuse (NIDA)
Telephone: 410-254-1853
Email: [email protected]

Jillian Morris
National Institute on Aging (NIA)
Telephone: 301-496-8986
Email: [email protected]

Judy Fox
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Telephone: 301-443-4704
Email: [email protected]

Tijuanna DeCoster, Ph.D.
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-9231
Email: [email protected]

Bryan Clark
National Institute of Child Health and Human Development (NICHD)
Telephone: 301-435-6975
Email: [email protected]

Diana Rutberg
National Institute of Dental and Craniofacial Research (NIDCR)
Telephone: 301-594-4798
Email: [email protected]

Garcia Nelson
National Cancer Institute (NCI)
Telephone: 240-276-5613
Email: [email protected]

Kimberly Stanton
National Heart, Lung, and Blood Institute (NHLBI)
Telephone: 301-435-0166
Email: [email protected]

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Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part 52 and 45 CFR Parts 74 and 92.