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

Clinic Testing Therapeutic/Indication Pairing Strategies (U01 Clinical Trial Required)

Activity Code

U01 Research Project – Cooperative Agreements

Announcement Type

New

Related Notices
  • NOT-OD-18-009 - Reminder: FORMS-E Grant Application Forms and Instructions Must be Used for Due Dates On or After January 25, 2018.
Funding Opportunity Announcement (FOA) Number

PAR-18-332

Companion Funding Opportunity

None

Catalog of Federal Domestic Assistance (CFDA) Number(s)

 93.350 

Funding Opportunity Purpose

This Funding Opportunity Announcement (FOA) invites applications for support of clinical studies to repurpose existing drugs or biologics (therapeutics) that have already completed at least a Phase l trial for a different indication by the time an award is made. The hypothesis for proposed studies must be developed using innovative processes to identify the therapeutic/indication pair. Examples include independent crowdsourcing strategies (e.g., http://www.ncats.nih.gov/ntu/therapeutics/current, http://openinnovation.astrazeneca.com/, or any website that lists experimental drugs or biologics), or computational algorithms.

Projects should be supported by scientific evidence that modulation of a therapeutic target will have a positive impact on the disease/condition.

The U01 award may be used for Phase I and/or Phase II clinical trials for a new therapeutic use to establish substantial evidence of efficacy and to establish evidence of safety for the new use.   

Key Dates
Posted Date

October 20, 2017

Open Date (Earliest Submission Date)

January 5, 2018

Letter of Intent Due Date(s)

January 5, 2018

Application Due Date(s)

Standard dates, by 5:00 PM local time of applicant organization. All types of non-AIDS applications allowed for this funding opportunity announcement are due on these dates.

Applicants are encouraged to apply early to allow adequate time to make any corrections to errors found in the application during the submission process by the due date.

AIDS Application Due Date(s)

Not Applicable

Scientific Merit Review
Advisory Council Review
Earliest Start Date
Expiration Date

November 6, 2020

Due Dates for E.O. 12372

Not Applicable

Required Application Instructions

It is critical that applicants follow the Research (R) 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.


There are several options available to submit your application through Grants.gov to NIH and Department of Health and Human Services partners. You must use one of these submission options to access the application forms for this opportunity.

  1. Use the NIH ASSIST system to prepare, submit and track your application online.
  2. Use an institutional system-to-system (S2S) solution to prepare and submit your application to Grants.gov and eRA Commons to track your application. Check with your institutional officials regarding availability.

  3. Use Grants.gov Workspace to prepare and submit your application and eRA Commons to track your application.
  4.  

    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

    The purpose of this FOA is to support clinical studies to evaluate a therapeutic/indication pair for drug repurposing. The repurposing hypothesis should be generated using a developed method that is publicly available. Examples include independent crowdsourcing strategies [e.g., http://www.ncats.nih.gov/ntu/assets/current, http://openinnovation.astrazeneca.com/, or any website that lists experimental therapies (drugs or biologics)], or computational algorithms. 

    Background

    Discoveries that clarify the molecular basis of disease provide unprecedented opportunities to translate research findings into new medicines. However, developing a new medicine takes an enormous amount of time, money and effort, mainly due to bottlenecks in the therapeutic development process. Delays and barriers mean that translation of a promising experimental therapy into an approved drug often takes a decade or more.  NCATS intends to support strategies that reduce delays, decrease costs and improve success rates.

    Drug repurposing/repositioning is one such strategy. Many existing experimental drugs, FDA approved drugs, and biologics already have been tested in humans, and detailed information is available about their pharmacology, formulation, and potential toxicity. By building upon previous research and development efforts, new uses for existing experimental drugs or FDA approved drugs can be advanced to testing in clinical trials more quickly than starting from scratch. If a new therapy receives regulatory approval, it can be efficiently integrated into clinical practice.

    NCATS focuses not on specific diseases, but what is common among them and the translational science process. NCATS mission is focused on process improvements (new technologies/approaches to accelerate the process of getting more treatments to patients), by developing and deploying solutions that can be used by all translational science researchers. In doing so, NCATS complements other NIH ICs that also support translational research in disease-specific areas.

    For this funding opportunity announcement (FOA), NCATS is interested in clinical studies that demonstrate utility of an approach for identifying new therapeutic/indication pairs. The strategy should be applicable to other diseases, so that successful use of the method can improve the efficiency of predicting new indications for existing therapeutics.

    Research Objectives and Scope

    This FOA intends to support clinical testing of innovative ideas for the discovery of new therapeutic uses of existing drugs/biologics in previously unexplored diseases. Proposed human trials can include: 1) use of an existing drug or biologic as a stand-alone intervention; or 2) use of an existing drug or biologic 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).  In either case, this initiative will support clinical trials on a therapeutic/indication pair, which was identified with a published or publicly available computational algorithm, or publicly available independent crowdsourcing strategy to identify a new therapeutic/indication. The method should already be published or publicly available, so it can be disseminated to improve data usability for future repurposing studies.

    Phase II clinical trials may be proposed for a common disease. If needed, Phase I clinical trials may also be included for the new indication for a common disease.  Rare disease trials should follow Draft FDA Guidance: “Rare Diseases: Common Issues in Drug Development Guidance for Industry”. Specifically, one or more adequate and well-controlled clinical trial(s) may be conducted in a rare disease population.

    Strategies to inform the selection of patients for proposed new uses of the therapeutic area are of interest.

    For this FOA NCATS will use the following definitions:

    • Crowdsourcing: Crowdsourcing occurs when an investigational drug is publicly posted for investigators to propose ideas for new therapeutic uses. Generally, crowdsourcing is an approach used for investigational therapeutics, not therapeutics approved by the FDA, since approved drugs already are known to the public.
    • Computational algorithm: A computational algorithm is the business end of bioinformatics. A computational algorithm will mine existing data and identify therapeutic/indication pairs for experimental investigation.
    • Published or publicly available method: A published method is generally one that is in a peer-reviewed publication. A publicly available method could be available via a website or a commercially available product. The publicly available strategy does not need to be free, but it should be available to investigators that would like to use it.
    • Phase I clinical studies are conducted in the target patient population to evaluate safety, determine a safe dose range, and identify side effects prior to conducting a Phase II clinical trial.
    • Phase II clinical trials are conducted in a larger patient population, typically 150 subjects or less for trials in adults. The purpose of the Phase II clinical study is to provide a preliminary signal of efficacy.
    • Rare Disease: A disease or condition that affects fewer than 200,000 people in the U.S.
    • Common Disease: Any disease or condition that is not a rare disease.
    • Clinical trials for Rare Disease: Due to small numbers of available patients, the terms Phase I, II and III clinical trials may not always be appropriate.  Therefore, well-controlled studies in a rare disease population may be proposed to demonstrate substantial evidence of efficacy in treating or preventing the condition and to establish evidence of safety for that use. Evidence of efficacy for a rare disease may be established in one or more adequate and well-controlled clinical trials in the identified population. See Rare Disease: Common Issues in Drug Development Guidance for Industry for more information:  http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM458485.pdf

    Clinical trials should use the selected therapeutic in its existing formulation/route of administration. The only exception is for pediatric indications, which may need to be formulated as a solution/suspension for oral administration (ages 6 to 11) or a small tablet/capsule (ages 12 to 18). Palatability issues also may have to be addressed for pediatric administration.

    Phase I clinical trials may be needed for the new indication, depending on what is already known about the drug. Projects that propose early stage Phase I clinical trials for the new therapeutic use are expected to be completed within 12 months and should be designed to accomplish the following:

    • Inform patient selection criteria.
    • Identify an appropriate dose(s), drug exposure at the target site to use in the proposed patient group, and evaluate safety, and tolerability prior to conducting a Phase II clinical trial in a larger population.

    Transition from Phase I to Phase II clinical trials is dependent on meeting Phase I milestones, listed in the Notice of Grant Award. Progress from the dose-finding safety and tolerability clinical trial to the Phase II efficacy signal trial is generally assessed at the transition from year 1 to year 2 of the award. Phase II clinical activities will include milestone-driven trials that are designed to detect a preliminary signal of efficacy to inform a decision on progressing to the next phase of development. The total clinical trial period is up to three years.

    Due to small numbers of available patients, the terms Phase I, II and III clinical trials may not always be appropriate for rare disease studies. NCATS can support milestone-driven rare disease trials to establish evidence that establishes safety and efficacy for a total clinical trial period up to three years. See Rare Disease: Common Issues in Drug Development Guidance for Industry for more information: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM458485.pdf. Applicants are strongly encouraged to have prior consultation with NCATS staff regarding the determination of whether proposed activities meet the criteria for Phase III rare disease or condition trials.

    Organizations involved in the research project must be identified at the time of application. Prior to application, the applicant organization must provide documentation that they have or will have access to the drug/biologic that will be used in clinical studies. To help ensure rapid transition to future Phase II clinical trials, the therapeutic must have completed Phase I clinical testing in humans for a different indication by the time an award is made.

    Because the abstracts will be published upon award of a grant, applicants are encouraged to discuss with collaborators and their institutional technology transfer office to ensure the abstract content will not constitute disclosure of intellectual property and proprietary information.  

    NCATS strongly encourages applicants to involve patients or their representatives in the planning of the trial, as appropriate.

    The following will not be considered for support under this FOA:

    • Support for pre-clinical studies.
    • Applications that propose repurposing projects that are solely the result of traditional experimental methods.
    • Applications for drug development that are the next logical step in an existing project.
    • Projects that are the result of a standard literature search or database search with no improved efficiency.
    • Projects that follow a previously demonstrated pathway.
    • Projects that are not truly a new use of an existing therapy (e.g., clinicaltrials.gov lists other trials for the therapeutic/indication).
    • Repurposing ideas that result solely from physically screening a library of drugs to identify the therapeutic/indication pair.
    • Applications that do not include documentation of access to the clinical supply.
    • Applications that propose testing a drug or biologic that has not already been tested in at least a Phase I clinical trial for a different indication.
    • Applications that propose to test a formulation of a drug/biologic that is different from what has been tested in phase I studies previously. The only exception is for pediatric indications, which may need to be formulated as a solution/suspension for oral administration (ages 6 to 11) or a small tablet/capsule (ages 12 to 18). Palatability issues also may have to be addressed for pediatric administration.
    • Projects that propose testing the effectiveness of a dietary supplement.
    • Applications that propose phase III clinical trial activities for a common disease or condition.

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

    Section II. Award Information
    Funding Instrument

    Cooperative Agreement: A support mechanism used when there will be substantial Federal scientific or programmatic involvement. Substantial involvement means that, after award, NIH scientific or program staff will assist, guide, coordinate, or participate in project activities. See Section VI.2 for additional information about the substantial involvement for this FOA.

    Application Types Allowed

    New

    Resubmission

    Revision

    The OER Glossary and the SF424 (R&R) Application Guide provide details on these application types.

    Clinical Trial?

    Required: Only accepting applications that propose clinical trial(s)

    Need help determining whether you are doing a clinical trial?

    Funds Available and Anticipated Number of Awards

    The number of awards is contingent upon NIH appropriations and the submission of a sufficient number of meritorious applications.

    Award Budget

    Application budgets need to reflect the actual needs of the proposed project. In a disease agnostic pool of applications, the budget for individual projects is highly dependent on the disease area and methods proposed. The budget is expected to be not more than $3,000,000 direct costs/year.

    Award Project Period

    The project period may be up to three years.  

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

    Section III. Eligibility Information
    1. Eligible Applicants
    Eligible Organizations

    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)
    • 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
    Foreign Institutions

    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.

    Required Registrations

    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.

    Eligible Individuals (Program Director/Principal Investigator)

    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.

    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.

    The NIH will not accept duplicate or highly overlapping applications under review at the same time.  This means that the NIH will not accept:

    • A new (A0) application that is submitted before issuance of the summary statement from the review of an overlapping new (A0) or resubmission (A1) application.
    • A resubmission (A1) application that is submitted before issuance of the summary statement from the review of the previous new (A0) application.
    • An application that has substantial overlap with another application pending appeal of initial peer review (see NOT-OD-11-101).  
    Section IV. Application and Submission Information
    1. Requesting an Application Package

    Buttons to access the online ASSIST system or to download application forms are available in Part 1 of this FOA. See your administrative office for instructions if you plan to use an institutional system-to-system solution.

    2. Content and Form of Application Submission

    It is critical that applicants follow the Research (R) 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.

    Letter of Intent

    Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows IC staff to estimate the potential review workload and plan the review.

    By the date listed in Part 1. Overview Information, prospective applicants are asked to submit a letter of intent that includes the following information:

    • Descriptive title of proposed activity
    • Name(s), address(es), and telephone number(s) of the PD(s)/PI(s)
    • Names of other key personnel
    • Participating institution(s)
    • Number and title of this funding opportunity

    The letter of intent should be sent to:

    Carol Lambert, Ph.D.
    Telephone: 301-435-0814
    Fax: 301-435-0824
    Email: lambert@mail.nih.gov

    Page Limitations

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

    Instructions for Application Submission

    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.

    SF424(R&R) Cover

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

    SF424(R&R) Project/Performance Site Locations

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

    SF424(R&R) Other Project Information

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

    SF424(R&R) Senior/Key Person Profile

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

    R&R or Modular Budget

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

    The Budget should include:

    • resources for conduct and completion of the clinical trial, including funding for orderly close-out of clinical sites, and preparation of a final study report.
    • site assessment and protocol training, prior to initiation of a clinical trial.
    R&R Subaward Budget

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

    PHS 398 Cover Page Supplement

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

    Cover Letter: Applicants who consult with NCATS staff should attach a letter that summarizes the discussion during prior consultation and documentation of the determination of whether proposed activities meet the criteria for Phase III rare disease or condition trials. The letter may be obtained from the appropriate NCATS scientific/research contact and included as an attachment to the SF424 (R&R) Cover.

    PHS 398 Research Plan

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

    Specific Aims: Applicants must provide a single specific aims attachment that summarizes the following.

    I. Scientific rationale and clinical need for a trial.

    II. Indication under study

    III. Potential impact

    IV. Summary of the study design

    A. Study Phase(s)

    • ·    Define the aims of the Phase I dosing, safety and tolerability clinical trial, if such a trial is proposed for the new indication.
    • ·    Define the aims of the preliminary efficacy signal, Phase II clinical trial. The aims should address target modulation and efficacy.
    • ·    Rare disease clinical trials: Define the aims of the well-controlled study/studies to demonstrate safety and efficacy in a defined disease population.

    Research Strategy: Within the Research Strategy, provide the following information for the clinical trial segments. Refer to but do not duplicate information submitted on the PHS Human Subjects Clinical Trial Information Form.

    I. Background & Significance (Overall)

    • State or cite the method that was used for identifying the new therapeutic/indication pair (independent crowdsourcing strategy or computational algorithm), and the impact on the field of study if the method is validated.
    • State the biological rationale for the clinical trial and overall plan to assess validity of the hypothesis for using the drug or biologic for a new indication.
    • Identify the uniqueness of the therapeutic/indication pair, pharmacologic mechanism of action or target, route of administration, how the new therapeutic use is superior to current therapies, novelty of this target class for the tested therapeutic, and/or how the mechanism of action of the therapeutic has been understudied for the indication.
    • Describe previous and current indications for which the drug or biologic has been or is being tested. 
    • Briefly describe the patient population, unmet medical need, global burden of disease, which patients will benefit, how they will benefit, and potential public health impact if the proposed research successfully translates to the clinic.
    • Address any ways that the project will improve the success or efficiency of translational science.

    II. Preliminary Studies: Preliminary studies include any data and information that validates feasibility for studies that address the specific aims.

    • Evidence that the target or specific pathway is involved in the disease pathology.
    • Data that supports the selection of clinical trial endpoints for assessing drug or biologic activity, or clinical outcome assessments that measure patient symptoms, overall mental state, or effects of a disease or condition on how the patient functions. Learn more: http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DrugDevelopmentToolsQualificationProgram/ucm284077.htm
    • Any additional relevant information on the therapeutic [e.g., availability of pharmacokinetics (PK) and pharmacodynamics (PD) markers, any exclusions or restrictions for use of the therapeutic], supporting dose and dose schedule for the therapeutic in the proposed new disease area.

    III. Phase I trial: Provide an overall plan to assess the validity of the biological hypothesis for use of the therapeutic in the new disease area.

    A.  Provide a plan for the Phase I trial [if a dose-finding safety and tolerability clinical trial is needed for the new patient group prior to conducting a Phase II clinical trial in a larger population)].

    • ·    Specify dose range of the therapeutic.
    • ·    Describe the approach and personnel resources available for clinical trial document preparation and timely filing of an IND and rapid Institutional Review Board (IRB) approval.  If a multisite trial is proposed, a single or central IRB should be used. https://grants.nih.gov/grants/guide/notice-files/NOT-OD-16-094.html
    • ·    Describe the use of PK and PD biomarkers, when available, to assess: dose and exposure of the therapeutic at the target site of action; binding at the target; and expression of functional pharmacological activity of the therapeutic at the target site of action.

    IV. Phase II clinical trial

    A. Provide an overall plan for the preliminary efficacy signal Phase II clinical trial.

    • ·    Describe the trial design, based on available safety data for the therapeutic. 

    B. Define the patient selection strategy.

    • ·    Consider the use of molecular markers of disease, pharmacogenomics, or other biomarkers, when applicable.
    • ·    Describe a plan for the involvement of Patient Advocacy Groups (PAGs) in the protocol design and recruitment strategy. If PAGs are not included, provide a rationale for their exclusion.

    C. Specify dose range, PD parameters used to perform dose ranging, route of administration (new formulations and changes in route are not allowed except for pediatric indications), and amount of therapeutic needed.

    D. Justify the number of patients chosen for the Phase II trial (based on the proposed outcome measures and the appropriateness of the statistical methods).

    • ·    The sample size and duration of the Phase II clinical trials should be justified for the specific disease population.
    • ·    Provide assurance that the proposed study can be completed within its budget and within the time limits stated in this FOA.

    V. Rare disease clinical trial, if applicable

    A.  Provide a well-controlled clinical trial plan that is designed to show substantial evidence that there is safety and efficacy, and the benefits to patients significantly outweigh any risks.

    • ·    Define the study duration and choice of subpopulations (when relevant), and number of subjects. Additionally, study design may include the following:
    • ·    Clinically meaningful patient assessment tools and endpoints.
    • ·    Outcome measures that are more specific or sensitive to changes in manifestations of the disease or can more quickly demonstrate safety or efficacy than existing measures.
    • ·    New or optimized biomarkers that may provide proof-of-concept, guide dose selection, allow early identification of safety concerns, or provide supportive evidence of efficacy.
    • ·    Data elements: Which disease manifestations are likely to develop, and when; which are likely to persist; and which disease signs predict development of the most important disease manifestations?

    VI. Administration and Management

    A. Provide an operational plan for managing clinical trials necessary to fully develop a new use for the therapeutic.

    • ·    Describe how the team's collective experience in the methods and approaches for design and implementation of clinical trials and readiness to test the hypothesis will provide synergy that promotes successful completion of the project.
    • ·    Describe how the team's collective requisite competencies and experience with clinical trials recruitment and execution and ability to recruit and enroll patients in the target disease population will provide synergy that promotes successful completion of the A Project manager, study coordinator(s) or other person responsible for the day-to-day trial management must be named in the application, and their experience with similar trials should be described in the administration and management plan, if a biosketch is not included.

    VII. Future Plans:

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

    Letters of Support:

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

    Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans 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.

    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.

    PHS Human Subjects and Clinical Trials Information

    When involving NIH-defined human subjects research, clinical research, and/or clinical trials follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the SF424 (R&R) Application Guide, with the following additional instructions:

    If you answered “Yes” to the question “Are Human Subjects Involved?” on the R&R Other Project Information form, you must include at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials Information form or a Delayed Onset Study record.

    Study Record: PHS Human Subjects and Clinical Trials Information

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

    This grant submission should include a complete set of clinical trial documents, demonstrating that the applicant institution and all study sites are ready to start enrollment as soon as an award is made.

    Section 2 - Study Population Characteristics

    2.5 Recruitment and Retention Plan: (No more than 4 pages). In addition to the form instructions, the following information is required for this specific FOA.

    A.  Recruitment and Referral sources: Include a census of the population available and rate of new cases at the proposed sites.

    B.  Enrollment rate (e.g., number of subjects meeting eligibility criteria for enrollment per month, criteria for conducting a futility analysis if minimum recruitment milestones are not met by the mid-point of the study).

    C.  Discuss potential recruitment delays or challenges, and alternative strategies that can be implemented if there are adverse outcomes or enrollment shortfalls (e.g., additional outreach procedures, alternate/back-up referral sources).

    D.  Procedures to monitor enrollment and track/retain participants for follow-up assessments.

    E.  Evidence to support the feasibility of enrollment, including descriptions of prior experiences and yield from research efforts using similar referral sources and/or strategies.

    F.  Strategies to ensure a diverse, representative sample.

    G.  A description of how the trial will be organized and managed, including the plans to identify and select additional collaborators, if applicable.

    H.  Decision points for terminating the trial (e.g., safety and tolerability issues).

    Study Timeline . Milestones (Required for this specific FOA): Include milestones and a timeline for each clinical trial stage. The milestones must provide a clear timeline, interim milestones, and go/no go decision points for the clinical trial. Include decision points for proceeding from a Phase I dosing and tolerability trial to a Phase II efficacy signal clinical trial, if a dosing trial is proposed. Milestones should be specific, quantifiable, and scientifically justified. Timelines for the following should also be included.

    A.  Finalization of clinical protocol IRB and DSMB approvals.

    B.  Completion of regulatory approvals

    C.  Registration in ClinicalTrials.gov

    D.  Screening Initiation

    E.  Enrollment and randomization timeline

    F.  Completion of data collection: This must be completed during the project period.

    G.  Completion of primary, secondary, and exploratory endpoint data analyses.

    H.  Completion of final study report.

    I.  Reporting of results in ClinicalTrials.gov

    Section 4 Protocol Synopsis

    4.6. Will the study use an FDA-regulated intervention? Due to the scope of this FOA, applicants must answer yes.

    4.6.a. If yes, describe the availability of Investigational Product (IP) and Investigational New Drug (IND)/Investigational Device Exemption (IDE) status (Required): The applicant organization must provide documentation that they have or will have access to the selected therapeutic that is manufactured according to U.S. Food and Drug Administration chemistry, manufacturing, and controls standards and Good Manufacturing Practices, and access to any data (e.g., Investigator's Brochure, study reports, ability to cross reference the Drug Master File) needed for obtaining regulatory approval, and for conducting the proposed clinical trials.

    A.  Regulatory status: 1) Indicate whether an FDA-approved therapeutic is available for purchase; 2) whether a new IND is not needed as documented through communication with FDA; 3) for studies where asset is provided by a pharmaceutical partner a letter should be provided indicating that a Collaborative Research Agreement or equivalent will be executed, and the PD/PI has the right to cross-reference specific sections of the pharmaceutical company partner's IND/Drug Master File, etc.

    B.  The Resource Access Plan should address any additional complexities associated with materials and data obtained from foreign sources, if applicable.

    C.  For projects that propose using a therapeutic owned by a small company, the applicant must explain how risks will be mitigated for federal investment. Include a plan to access the clinical material needed during the proposed project period, if an NIH award is made.

    D.  If the drug or biologic to be tested is not marketed, and evidence that a Phase I trial for a different indication has been conducted on the drug or biologic (publication, clinicaltrials.gov registration number, etc.) is not available, include documentation from the therapeutic provider that clearly states that a Phase I trial for a different indication has been completed and indicates by whom the trial was conducted.

    Delayed Onset Study

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

    PHS Assignment Request Form

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

    3. Unique Entity Identifier and System for Award Management (SAM)

    See Part 1. Section III.1 for information regarding the requirement for obtaining a unique entity identifier and for completing and maintaining active registrations in System for Award Management (SAM), NATO Commercial and Government Entity (NCAGE) Code (if applicable), eRA Commons, and Grants.gov

    4. Submission Dates and Times

    Part I. Overview Information contains information about Key Dates and times. 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. When a submission date falls on a weekend or Federal holiday, the application deadline is automatically extended to the next business day.

    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 and time.  If a Changed/Corrected application is submitted after the deadline, the application will be considered late. Applications that miss the due date and time are subjected to the NIH Policy on Late Application Submission.

    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.

    5. Intergovernmental Review (E.O. 12372)

    This initiative is not subject to intergovernmental review.

    6. 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.

    7. Other Submission Requirements and Information

    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. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Guidelines for Applicants Experiencing System Issues. For assistance with application submission, contact the Application Submission Contacts in Section VII.

    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 and compliance with application instructions by the Center for Scientific Review, NIH. Applications that are incomplete or non-compliant will not be reviewed.

    Requests of $500,000 or more for direct costs in any year

    Applicants requesting $500,000 or more in direct costs in any year (excluding consortium F&A) must contact a Scientific/ Research Contact 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.

    Prior Consultation with NCATS staff

    Consultation with NCATS staff at least 8 weeks prior to the application due date is strongly encouraged including new and resubmission applications. NCATS staff will consider whether the proposed clinical trial meets the definition of a phase III clinical trial activity for a rare disease or condition. NCATS staff will not evaluate the technical and scientific merit of the proposed trial; technical and scientific merit will be determined during peer review using the review criteria indicated in this FOA. If the request is for an activity for a rare disease or condition phase III trial, the applicant will be informed that the project could be supported by NCATS. If the applicant requests support for up to the end of a phase II CT for a common disease, the applicant will be informed that this policy does not apply and that the project could be supported by NCATS.  If the request is, in part or in full, for support for a phase III CT activity for a disease or condition other than a rare disease or condition, the potential applicant will be informed that NCATS cannot fund the activities and, as appropriate, strongly encouraged to seek other funding opportunities to support the phase III activities. A letter that summarizes the discussion during prior consultation and documentation of the determination may be obtained from the appropriate the NCATS scientific/research contact and included as an attachment to the SF424 (R&R) Cover.

    Post Submission Materials

    Applicants are required to follow the instructions for post-submission materials, as described in the policy.

    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.

    A proposed Clinical Trial application may include study design, methods, and intervention that are not by themselves innovative but address important questions or unmet needs. Additionally, the results of the clinical trial may indicate that further clinical development of the intervention is unwarranted or lead to new avenues of scientific investigation.

    Overall Impact

    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).

    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? Is there a strong scientific premise for the project? 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? 

    Are the scientific rationale and need for a clinical trial to test the proposed hypothesis or intervention well supported by preliminary data, clinical and/or preclinical studies, or information in the literature or knowledge of biological mechanisms? For trials focusing on clinical or public health endpoints, is this clinical trial necessary for testing the safety, efficacy or effectiveness of an intervention that could lead to a change in clinical practice, community behaviors or health care policy? For trials focusing on mechanistic, behavioral, physiological, biochemical, or other biomedical endpoints, is this trial needed to advance scientific understanding?

    Specific to this FOA: Are the milestones clinically significant? Does the milestone plan measure endpoints or outcomes that are meaningful to the patient population? Are milestones and go/no go decisions clearly defined and appropriate to validate significance of the new therapeutic use?  

    Investigator(s)

    Are the PD(s)/PI(s), collaborators, and other researchers well suited to the project? If Early Stage Investigators or those 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?

    With regard to the proposed leadership for the project, do the PD/PI(s) and key personnel have the expertise, experience, and ability to organize, manage and implement the proposed clinical trial and meet milestones and timelines? Do they have appropriate expertise in study coordination, data management and statistics? For a multicenter trial, is the organizational structure appropriate and does the application identify a core of potential center investigators and staffing for a coordinating center?

    Specific to this FOA: Has an individual who will be responsible for day-to-day management of the trial been named? Do they have the right experience for managing the proposed project? Are effort levels sufficient to support completion of the work within the project period?  

    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? 

    Does the design/research plan include innovative elements, as appropriate, that enhance its sensitivity, potential for information or potential to advance scientific knowledge or clinical practice?

    Specific to this FOA: How novel is the therapeutic/indication pair?  How novel is the clinical trial?  

    Approach

    Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Have the investigators presented strategies to ensure a robust and unbiased approach, as appropriate for the work proposed? 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? Have the investigators presented adequate plans to address relevant biological variables, such as sex, for studies in vertebrate animals or human subjects? 

    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?

    Does the application adequately address the following, if applicable:

    Study Design 

    Is the study design justified and appropriate to address primary and secondary outcome variable(s)/endpoints that will be clear, informative and relevant to the clinical and statistical hypothesis being tested? Is the scientific rationale/premise of the study based on previously well-designed preclinical and/or clinical research? Given the methods used to assign participants and deliver interventions, is the study design adequately powered to answer the research question(s), test the proposed hypothesis/hypotheses, and provide interpretable results? Is the trial appropriately designed to conduct the research efficiently? Are the study populations (size, gender, age, demographic group), proposed intervention arms/dose, and duration of the trial, appropriate and well justified?   

    Are potential ethical issues adequately addressed? Is the process for obtaining informed consent or assent appropriate? Is the eligible population available? Are the plans for recruitment outreach, enrollment, retention, handling dropouts, missed visits, and losses to follow-up appropriate to ensure robust data collection? Are the planned recruitment timelines feasible and is the plan to monitor accrual adequate? Has the need for randomization (or not), masking (if appropriate), controls, and inclusion/exclusion criteria been addressed? Are differences addressed, if applicable, in the intervention effect due to sex/gender and race/ethnicity? 

    Are the plans to standardize, assure quality of, and monitor adherence to, the trial protocol and data collection or distribution guidelines appropriate? Is there a plan to obtain required study agent(s)?

    Data Management and Statistical Analysis 

    Are planned analyses and statistical approach appropriate for the proposed study design and methods used to assign participants and deliver interventions? Are the procedures for data management and quality control of data adequate at clinical site(s) or at center laboratories, as applicable? Have the methods for standardization of procedures for data management to assess the effect of the intervention and quality control been addressed? Is there a plan to complete data analysis within the proposed period of the award?   

    Specific to this FOA:  Are there quantifiable measures for making go/no-go decisions? Is there a plan to complete data analysis within the proposed period of the award within the milestone and timeline plan? 

    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?

    If proposed, are the administrative, data coordinating, enrollment and laboratory/testing centers appropriate for the trial proposed?

    Does the application adequately address the capability and ability to conduct the trial at the proposed site(s) or center(s)? Are the plans to add or drop enrollment centers, as needed, appropriate?

    If international site(s) is/are proposed, does the application adequately address the complexity of executing the clinical trial?

    If multi-sites/centers, is there evidence of the ability of the individual site or center to: (1) enroll the proposed numbers; (2) adhere to the protocol; (3) collect and transmit data in an accurate and timely fashion; and (4) operate within the proposed organizational structure?

    Specific to this FOA: Is there likely to be an adequate disease population to complete the clinical trial enrollment goals at the proposed sites?  

    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 score, but will not give separate scores for these items.

    Study Timeline

    Is the study timeline described in detail, taking into account start-up activities, the anticipated rate of enrollment, and planned follow-up assessment? Is the projected timeline feasible and well justified? Does the project incorporate efficiencies and utilize existing resources (e.g., CTSAs, practice-based research networks, electronic medical records, administrative database, or patient registries) to increase the efficiency of participant enrollment and data collection, as appropriate?

    Are potential challenges and corresponding solutions discussed (e.g., strategies that can be implemented in the event of enrollment shortfalls)?   

    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 criteria: (1) description of proposed procedures involving animals, including species, strains, ages, sex, and total number to be used; (2) justifications for the use of animals versus alternative models and for the appropriateness of the species proposed; (3) interventions to minimize discomfort, distress, pain and injury; and (4) justification for euthanasia method if NOT consistent with the AVMA Guidelines for the Euthanasia of Animals. Reviewers will assess the use of chimpanzees as they would any other application proposing the use of vertebrate animals. 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

    For Resubmissions, the committee will evaluate the application as now presented, taking into consideration the responses to comments from the previous scientific review group and changes made to the project

    Renewals

    Not Applicable

    Revisions

     For Revisions, the committee will consider the appropriateness of the proposed expansion of the scope of the project. If the Revision application relates to a specific line of investigation presented in the original application that was not recommended for approval by the committee, then the committee will consider whether the responses to comments from the previous scientific review group are adequate and whether substantial changes are clearly evident.

    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 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)  Genomic Data Sharing Plan (GDS).

    Authentication of Key Biological and/or Chemical Resources:

    For projects involving key biological and/or chemical resources, reviewers will comment on the brief plans proposed for identifying and ensuring the validity of those resources.

    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. 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 NCATS Advisory Council. The following will be considered in making funding decisions:

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

    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. Refer to Part 1 for dates for peer review, advisory council review, and earliest start date.

    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 terms and conditions found on the Award Conditions and Information for NIH Grants website.  This includes any recent legislation and policy applicable to awards that is highlighted on this website.

    Additionally, NCATS may specify special reporting requirements for the proposed clinical trial to be included under NCATS-specific terms and conditions in the NoA.

    For example: If the proposed clinical trial has elevated risks, NCATS may require closer programmatic monitoring and it may be necessary to require the awardee to provide more frequent information and data as a term of the award (e.g., to clarify issues, address and evaluate concerns, provide documentation).  All additional communications and information related to programmatic monitoring must be documented and incorporated into the official project file.

    Individual awards are based on the application submitted to, and as approved by, the NIH and are subject to the IC-specific terms and conditions identified in the NoA. 

    ClinicalTrials.gov: If an award provides for one or more clinical trials. By law (Title VIII, Section 801 of Public Law 110-85), the "responsible party" must register and submit results information for certain “applicable clinical trials” on the ClinicalTrials.gov Protocol Registration and Results System Information Website (https://register.clinicaltrials.gov). NIH encourages registration of all trials whether required under the law or not. For more information, see http://grants.nih.gov/ClinicalTrials_fdaaa/ 

    Institutional Review Board or Independent Ethics Committee Approval: Grantee institutions must ensure that the application as well as all protocols are reviewed by their IRB or IEC. To help ensure the safety of participants enrolled in NIH-funded studies, the awardee must provide NIH copies of documents related to all major changes in the status of ongoing protocols. 

    Data and Safety Monitoring Requirements: The NIH policy for data and safety monitoring requires oversight and monitoring of all NIH-conducted or -supported human biomedical and behavioral intervention studies (clinical trials) to ensure the safety of participants and the validity and integrity of the data. Further information concerning these requirements is found at http://grants.nih.gov/grants/policy/hs/data_safety.htm and in the application instructions (SF424 (R&R) and PHS 398). 

    Investigational New Drug or Investigational Device Exemption Requirements: Consistent with federal regulations, clinical research projects involving the use of investigational therapeutics, vaccines, or other medical interventions (including licensed products and devices for a purpose other than that for which they were licensed) in humans under a research protocol  must be performed under a Food and Drug Administration (FDA) investigational new drug (IND) or investigational device exemption (IDE). 

    Milestones: Future support of a study funded under this FOA is contingent upon adequate participant recruitment based on projected milestones.    

    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.

    Recipients of federal financial assistance (FFA) from HHS must administer their programs in compliance with federal civil rights law. This means that recipients of HHS funds must ensure equal access to their programs without regard to a person’s race, color, national origin, disability, age and, in some circumstances, sex and religion. This includes ensuring your programs are accessible to persons with limited English proficiency.  HHS recognizes that research projects are often limited in scope for many reasons that are nondiscriminatory, such as the principal investigator’s scientific interest, funding limitations, recruitment requirements, and other considerations. Thus, criteria in research protocols that target or exclude certain populations are warranted where nondiscriminatory justifications establish that such criteria are appropriate with respect to the health or safety of the subjects, the scientific study design, or the purpose of the research.

    For additional guidance regarding how the provisions apply to NIH grant programs, please contact the Scientific/Research Contact that is identified in Section VII under Agency Contacts of this FOA. HHS provides general guidance to recipients of FFA on meeting their legal obligation to take reasonable steps to provide meaningful access to their programs by persons with limited English proficiency. Please see http://www.hhs.gov/ocr/civilrights/resources/laws/revisedlep.html. The HHS Office for Civil Rights also provides guidance on complying with civil rights laws enforced by HHS. Please see http://www.hhs.gov/ocr/civilrights/understanding/section1557/index.html; and http://www.hhs.gov/ocr/civilrights/understanding/index.html. Recipients of FFA also have specific legal obligations for serving qualified individuals with disabilities. Please see http://www.hhs.gov/ocr/civilrights/understanding/disability/index.html. Please contact the HHS Office for Civil Rights for more information about obligations and prohibitions under federal civil rights laws at http://www.hhs.gov/ocr/office/about/rgn-hqaddresses.html or call 1-800-368-1019 or TDD 1-800-537-7697. Also note it is an HHS Departmental goal to ensure access to quality, culturally competent care, including long-term services and supports, for vulnerable populations. For further guidance on providing culturally and linguistically appropriate services, recipients should review the National Standards for Culturally and Linguistically Appropriate Services in Health and Health Care at http://minorityhealth.hhs.gov/omh/browse.aspx?lvl=2&lvlid=53.

    In accordance with the statutory provisions contained in Section 872 of the Duncan Hunter National Defense Authorization Act of Fiscal Year 2009 (Public Law 110-417), NIH awards will be subject to the Federal Awardee Performance and Integrity Information System (FAPIIS) requirements.  FAPIIS requires Federal award making officials to review and consider information about an applicant in the designated integrity and performance system (currently FAPIIS) prior to making an award.  An applicant, at its option, may review information in the designated integrity and performance systems accessible through FAPIIS and comment on any information about itself that a Federal agency previously entered and is currently in FAPIIS.  The Federal awarding agency will consider any comments by the applicant, in addition to other information in FAPIIS, in making a judgement about the applicant’s integrity, business ethics, and record of performance under Federal awards when completing the review of risk posed by applicants as described in 45 CFR Part 75.205 “Federal awarding agency review of risk posed by applicants.”  This provision will apply to all NIH grants and cooperative agreements except fellowships.

    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 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; but they must consider and incorporate constructive feedback on improvements to scientific rigor received from the Clinical Trial Oversight Committee (CTOC).
    • 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.
    • Ensure timely submission of Phase I and Phase II clinical trial data to ClinicalTrials.gov.
    • 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 CTOC as needed, in consultation with the NIH Program Official, NIH Project Scientist, and pharmaceutical company partner (if applicable).
    • The PD(s)/PI(s) will chair the CTOC, 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.
    • Hold teleconferences with NIH to address operational issues on a monthly basis, or as dictated by the needs of the study.
    • 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 or progress on the milestones.
    • Adhering to relevant 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.
    • Hold teleconferences with NIH to address operational issues on a monthly basis, or as dictated by the needs of the study. Providing monthly written reports to the CTOC summarizing: the progress of the project; obstacles encountered and solutions; monthly recruitment updates. The reports should be provided in a format decided upon by the CTOC.
    • Providing a progress report, due 60 days prior to completion of the budget period 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.
    • Addressing all study design, operational and logistical issues, and safety, regulatory, ethical, and conflict of interest concerns raised by NCATS staff.
    • Complying with the clinical terms of award as articulated in the Notice of Award (NoA), such that no funds may be drawn down from the payment management system and no obligations may be made against federal funds for any research involving human subjects until a revised NoA is received.
    • Ensure timely publication of abstracts and scientific articles to make results of projects and inventions available, including negative data regarding new therapeutic uses.

    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 CTOC activities, including conference calls.
    • 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 DSMB or another monitoring body.
    • Participate in 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 project update meetings and conference calls.
    • Monitor recruitment status of the trial on an ongoing basis.
    • Monitor performance through consideration of quarterly meetings of the CTOC, annual reports, and compliance with NIH procedures.
    • Approve modifications to the research plan and/or study protocol(s), in consultation with the CTOC, based on emerging data and/or other issues that impact progress of the project.
    • Reserve the right to obtain periodic external review and select reviewers for an assessment of progress and achievement of milestones.
    • Reserve the right to terminate or curtail a project for any of the following reasons: (1) inadequate progress in meeting the pre-negotiated milestones and timelines; (2) risk(s) to subject’s safety; (3) slow accrual; (4) data from a futility analysis; or (5) failure to comply with the Terms and Conditions of Award.

    Areas of Joint Responsibility include:

    Clinical Trial Oversight Committee (CTOC):

    Each awardee's project will have a CTOC. The CTOC will include: the PD(s)/PI(s), key personnel, the NIH Project Scientist (voting), the NIH Program Official (ex officio), and any external scientist(s) that the PI invites.

    The CTOC will:

    • Recommend changes to the experimental design, clinical trial plan, to address obstacles encountered and solutions and compliance with relevant policies and regulations.
    • 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 member chosen by the individual awardee, one NIH designee, and a third designee with expertise in the relevant area who is chosen by the other two. 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. Follow 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.

    3. Reporting

    When multiple years are involved, awardees will be required to submit the Research Performance Progress Report (RPPR) annually and financial statements as required in the NIH Grants Policy Statement.

    A final RPPR, 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.

    In accordance with the regulatory requirements provided at 45 CFR 75.113 and Appendix XII to 45 CFR Part 75, recipients that have currently active Federal grants, cooperative agreements, and procurement contracts from all Federal awarding agencies with a cumulative total value greater than $10,000,000 for any period of time during the period of performance of a Federal award, must report and maintain the currency of information reported in the System for Award Management (SAM) about civil, criminal, and administrative proceedings in connection with the award or performance of a Federal award that reached final disposition within the most recent five-year period.  The recipient must also make semiannual disclosures regarding such proceedings. Proceedings information will be made publicly available in the designated integrity and performance system (currently FAPIIS).  This is a statutory requirement under section 872 of Public Law 110-417, as amended (41 U.S.C. 2313).  As required by section 3010 of Public Law 111-212, all information posted in the designated integrity and performance system on or after April 15, 2011, except past performance reviews required for Federal procurement contracts, will be publicly available.  Full reporting requirements and procedures are found in Appendix XII to 45 CFR Part 75 – Award Term and Conditions for Recipient Integrity and Performance Matters.

    Section VII. Agency Contacts

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

    Application Submission Contacts

    eRA Service Desk (Questions regarding ASSIST, eRA Commons registration, submitting and tracking an application, documenting system problems that threaten submission by the due date, post submission issues)
    Finding Help Online: http://grants.nih.gov/support/ (preferred method of contact)
    Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

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

    GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
    Email: GrantsInfo@nih.gov (preferred method of contact)
    Telephone: 301-945-7573

    Scientific/Research Contact(s)

    Bobbie Ann Austin, Ph.D.
    National Center for Advancing Translational Sciences (NCATS)
    Telephone: 301-435-0824
    Email: Bobbie.Austin@nih.gov

    Peer Review Contact(s)

    Carol Lambert, Ph.D.
    National Center for Advancing Translational Sciences (NCATS)
    Telephone: 301-435-0814
    Email: Lambert@mail.nih.gov

    Financial/Grants Management Contact(s)

    Gloria Velez
    National Center for Advancing Translational Sciences (NCATS) 
    Telephone: 301-435-0875
    Email: gloria.velez@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 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 Part 75.

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