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.

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

Purpose

NCATS is issuing a Funding Opportunity Announcement (FOA) that supports clinical testing of new therapeutic uses for experimental drugs or biologics (Assets) across a broad range of human diseases in adult and pediatric populations. This innovative program matches researchers with a selection of pharmaceutical industry assets to test ideas for new therapeutic uses with the ultimate goal of identifying promising new treatments for patients. The program was designed to enable efficient 3-way drug repositioning partnerships among academic, government, and pharmaceutical partners.

A U01 award may support clinical trial activities through the end of Phase II for all diseases or conditions, and through the end of Phase III for a rare disease or condition. For this FOA, a rare disease is defined as a disease or condition that affects fewer than 200,000 people in the U.S. Applicants that wish to apply for support for a Phase III equivalent trial in a rare disease population must include a letter of permission from NCATS in the U01 application. Learn more: NOT-TR-18-025.

An X02 pre-application is the first step in the application process for partnering with a pharmaceutical company under PAR-18-909. NCATS serves as a matchmaker between investigators with new therapeutic use ideas and asset providers. It is up to those parties to decide to work together on a full application for funding. Applicants must obtain a letter of support from a pharmaceutical partner, who will provide access to IND-enabling paperwork and drug product if the project is selected for funding. Such applicants may submit a U01 application under this FOA.

Background

Discovering New Therapeutic Uses for Existing Molecules (New Therapeutic Uses) is a collaborative therapeutics program. It was designed to enable efficient 3-way drug repositioning partnerships among academic, government, and pharmaceutical partners. This innovative program matches researchers with a selection of Pharmaceutical Industry Assets to test ideas for new therapeutic uses of those Assets, with the ultimate goal of identifying promising new treatments for patients. Strategies used to accomplish this include posting limited confidential information about investigational Assets [new molecular entities (NMEs) and biologics] offered by pharmaceutical companies to a public website. This facilitates crowdsourcing of ideas for new therapeutic uses from academic medical centers or companies in the form of grant applications to NCATS. The program has shortened the time needed to establish collaborations to 3 to 4 months (from the typical 9 months to a year), by publicly posting template confidential disclosure agreements (CDAs) and collaborative research agreements (CRAs) that are executed between the applicant institution and the pharmaceutical company partner that provides the Asset for testing a new therapeutic use.

Research Objectives and Scope

This funding opportunity announcement (FOA) intends to support the testing of innovative ideas for the discovery of new therapeutic uses of existing Assets in previously unexplored diseases. Applicants may apply to this FOA for either adult or pediatric indications.

The U01 may support some or all the following:

Clinical trials may be proposed using the selected company Asset in its existing formulation/route of administration to identify the dose or exposure of the Asset in the proposed patient group. Proposed human trials may include: 1) use of an Asset as a stand-alone intervention, or 2) as an adjunctive intervention with an existing treatment (if there is no evidence of drug-drug interactions with the proposed standard of care treatment).

One year of support may be provided for a Phase I clinical trial (if needed). Applicants must propose a Phase II clinical trial, an adaptive design clinical trial that overlaps Phase II, or any phase trial for a rare disease. Generally, support is for two years for a Phase II trial for a common disease, or up to three years of support (total) for an adaptive design clinical trial. For rare diseases not specifically addressing clinical trial phases, up to three years of support are recommended. Four years of support (total) may be provided for a rare or common disease, if it is well justified for the patient population and the letter of support from an Asset provider indicates availability of the Asset for that period of time.

Adult indications: Refers to new uses of existing Assets in previously unexplored diseases that impact adults. Planned clinical trials for adult indications should use the selected therapeutic in its existing formulation/route of administration.

• Phase I clinical trials (optional): Phase I clinical studies are conducted with the Asset in the target patient population to inform patient selection criteria, evaluate safety and tolerability, determine a safe dose range, and identify side effects prior to conducting a Phase II clinical trial. Phase I clinical trials are milestone-driven, with prior NCATS milestone review and approval.
• Phase II clinical trials (required): Phase II trials are conducted to demonstrate that the Asset modulates the target and has the potential to yield the desired clinical outcome in the proposed patient population a preliminary signal of efficacy. Phase II clinical trials are conducted in a larger patient population, typically 150 subjects or less for trials in adults. Phase II clinical trials are milestone-driven, with prior NCATS milestone review and approval.
• Adaptive design clinical trial: Investigators should refer to FDA draft guidance for a complete definition of an adaptive design clinical trial for drugs and biologics. https://www.fda.gov/downloads/drugs/guidances/ucm201790.pdf

Pediatric indications: Refers to new uses of existing Assets in previously unexplored diseases that are unique to pediatric populations (a disease/disorder with no adult equivalent that could be tested prior to testing in children). However, trials in pediatric 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 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). Planned clinical trials for a pediatric indication may need an Asset to be formulated for a pediatric population. Examples include formulation 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 trials for pediatric indications (optional): Phase I pediatric trials include pediatric rare disease subjects with no adult equivalent; or other initial studies (testing a proposed pediatric formulation); or 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 Assets will be tested as adjunctive treatment), as required by the FDA. Phase I pediatric trials include studies conducted in the target pediatric patient population to establish feasibility [e.g., target engagement, pharmacokinetic/pharmacodynamic (PK/PD), initial dosing of the Asset] prior to a Phase II trial. Phase I clinical trials are milestone-driven, with prior NCATS milestone review and approval.
• Phase II clinical trials (required): Phase II trials for pediatric indications provide data on the relationship of dosing and response for the 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 II trials also include assessments of safety, tolerability, and PK/PD response of the Asset. Phase II clinical trials are milestone-driven, with prior NCATS milestone review and approval.

Common disease: Any disease that is not a rare disease.

Rare disease: A rare disease is a disease or condition that affects fewer than 200,000 people in the U.S. 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.

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

• require pre-clinical work to demonstrate efficacy.
• require non-clinical safety studies.
• designed to address all the regulatory requirements for assessing adverse drug-drug interactions as a combination product.
• propose to test a drug or biologic that is not on the list of Assets for the current application cycle. See the current Industry-Provided Asset list.
• are not a new use of an existing therapy (e.g., clinicaltrials.gov lists other trials for the therapeutic/indication).
• do not document access to the Asset from the pharmaceutical partner.
• propose to test a formulation of an Asset that is different than what the pharmaceutical company partner is providing. The only exception is for pediatric indications, which may need to be formulated as a solution/suspension for oral administration or a small tablet/capsule. Palatability issues also may have to be addressed for pediatric administration.
• propose testing the effectiveness of a dietary supplement.
• propose Phase III clinical trials for a common disease or condition.
• propose one trial that tests more than one publicly posted Asset.

Partnership Information

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 Assets 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 these agreements. Investigators must 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 Asset, prior to submitting a U01 application.

This initiative invites ideas for new therapeutic uses of existing molecules (Assets) from pharmaceutical company partners. Applicants will not have access to the Assets unless an award is made. However, applicants will have been provided information on the Asset through a CDA with the pharmaceutical partner. CDAs should be executed within 30 days of receiving pharmaceutical company contact information from the NIH. Delays in executing the CDA will reduce the amount of time an applicant will have access to Asset information and may cause delays in assembling the full U01 application. A sample timeline is below. However, applicants should discuss timelines with the pharmaceutical partner with which they are working.

Application stage	Reference timeframe
X02 application is submitted.	See receipt dates.
Contact information for pharmaceutical partner is sent to the most meritorious applications.	Approximately 2 months after receipt of X02.
CDA is executed.	Applicant should contact pharmaceutical partner to initiate execution of a CDA within one week of receiving contact information; the CDA execution takes approximately 2-8 weeks to complete.
Data are exchanged by applicant and pharmaceutical company partner.	Approximately 1 week.
Joint decision is made about submitting a full application.	Approximately 8 weeks
CRA process and grant writing occur	Please note that the CRA process takes a minimum of 12 weeks, even with template agreements, and cannot start until CDAs are signed.
Final research plan is reviewed by both parties.	2 weeks prior to receipt date.
Letter of support is provided by industry partner, if a partnership was established.	At least 1 week prior to receipt date.
Full U01 application is submitted with letter of support from the pharmaceutical partner.	See receipt dates.

Assets Available for the Program

The list of Assets and non-confidential information can be found here. Some of the compounds in the Table of Assets 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. Assets that pharmaceutical companies will consider for use in pediatric populations are listed in the Table of Assets for Pediatric Indications. Applicants need to refer to the "Additional Characteristics" row of the more detailed Asset information chart for the Asset of interest to determine the type(s) of pediatric diseases the pharmaceutical company partner will consider.

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

NIH grants policies as described in the NIH Grants Policy Statement will apply to the applications submitted and awards made from 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
• 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 X02 pre-applicants that: 1) submitted a pre-application to PAR-18-909; 2) were put in contact with a pharmaceutical partner, 3) exchanged data under a confidential disclosure agreement; and subsequently 4) obtained a letter of support from a pharmaceutical partner.

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.

It is strongly encouraged for U01 applications that the PD/PI not be changed from that listed on the X02 pre-application. For U01 applications proposing multiple PD(s)/PI(s), it is strongly encouraged that the contact PD/PI be the same PD/PI listed as the contact PD/PI on the X02 pre-application. The contact PD/PI is strongly encouraged to continue the multiple PD(s)/PI(s) leadership described in the X02 pre-application, if a successful partnership with a pharmaceutical company is established and a U01 application is submitted.

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.

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).

Applicant organizations may include only one publicly posted Asset in an application. The Asset in an application may be tested against multiple indications as a basket trial. More than one application may be submitted from an institution, if the hypothesis is scientifically distinct.

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.

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.

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: 301-480-3660
Email: [email protected]

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

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.

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

• Describe institutional and/or project personnel experience with FDA regulatory processes.
• It will be important for the PD/PI to describe experience in meeting clinical and regulatory milestones.
• Describe relevant experience and knowledge of public-private partnerships.

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.

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

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

Cover Letter: Applicants who wish to apply for a Phase III clinical trial for a rare disease should consult with NCATS staff to determine whether the planned trial meets the definition of a Phase III rare disease and determine whether it could be supported by NCATS (NOT-TR-18-025). A letter should be attached that summarizes the discussion about whether the proposed activities meet the criteria for Phase III rare disease trials. The letter may be obtained from the appropriate NCATS scientific/research contact and included as an attachment to the SF424 (R&R) Cover. Applicants who are applying for funds to support a Phase I or Phase II trial for a common disease are also encouraged to consult with NCATS staff but do not need to include a cover letter summarizing such prior consultation.

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 describes the aims of the project.

• Scientific rationale and clinical need for a trial
• Indication under study
• Potential impact
• Summary of the study design that is organized by 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 safety/toxicity, 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: Applicants are encouraged to incorporate the feedback on the previous X02 application in the research strategy of the U01 application. However, the U01 application must not contain an introduction to respond to the feedback; the U01 is not a resubmission or a renewal of the X02.

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.

Background and Significance (Overall)

• Identify the Asset, its known pharmacologic mechanism of action or target, and route of administration.
• Describe previous and current indications for which the Asset has been or is being tested.
• Identify the uniqueness of the Asset, pharmacologic mechanism of action or target, how the new therapeutic use is superior to current therapies, novelty of this target class for the tested therapy, and/or how the mechanism of action of the therapy has not been studied or is understudied for the indication.
• State the biological rationale and overall plan to assess validity of the hypotheses for the therapeutic potential of modulating the Asset’s target or mechanism of action.
• Briefly describe the global burden of disease, which patients will benefit, how they will benefit, how use of the Asset is superior to current therapies, 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.
• For adult indications, indicate the disease, clinical population and public health need that will be addressed by the proposed new use of the Asset.
• For pediatric indications, indicate the disease that is unique to the pediatric population, clinical population, and public health need that will be addressed by the proposed new use of the Asset. If the disease/condition exists in both children and adults, include strong scientific justification for testing the Asset 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).

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

The Preliminary data may include the following elements.

• Evidence that the target or specific pathway is involved in the disease pathology.
• Data that supports the clinical trial design, such as 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.
• Any additional relevant information on the Asset [e.g., availability of pharmacokinetics (PK) and pharmacodynamics (PD) markers, any exclusions or restrictions in the Asset's use].
• Data that have addressed intrinsic/extrinsic factors in the new patient population that differ from the human data that is already available for the Asset.
• Data that established precision medicine approaches to inform the selection of patients for the proposed new use of the Asset. Include the following types of studies (when needed):
• Studies have established the right dose, the right duration, the right time of treatment, or the right patients to treat in a new population (or sub population), when the data available from prior studies was not sufficient to support the proposed clinical trial.
• Data that justify the selected dose range dose and schedule of the Asset. For pediatric indications, discuss the proposed route of administration and discuss any known or expected issues with oral formulations (solubility/permeability, taste/bitterness).
• Brain and penetrance studies (for neurological indications) when such data was not available for prior indication.
• Data on safety margins for toxicity that may be different in the new study population (e.g., longer term toxicity studies were completed for the new indication).
• Juvenile animal data in one or more species (for pediatric indications) that address FDA's Guidance on Nonclinical Safety Evaluation of Pediatric Drug Products. Learn more.
• Data on risk factors that impact the new population.
• Clinical Trial Feasibility data: Data that indicate how fast or slow enrollment will occur, identifies appropriate inclusion and exclusion criteria, and/or demonstrates feasibility for enrollment goals to be achieved at the geographical sites represented.

Applicants are strongly encouraged to consider requesting a pre-IND meeting with FDA (Type B meeting) prior to submitting the U01 application to understand regulatory requirements that they need to meet. Guidance on FDA meetings is located at this link.

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

• 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)].
• Define the aims of the Phase I dosing, safety and tolerability clinical trial, if such a trial is proposed.
• Specify dose range, dose schedule, duration of administration, and time to obtain data points.
• 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 Asset at the target site of action.
• Describe the design to assess the safety, dosing, and tolerability of the Asset in the proposed patient population, using the company-specified route of administration and formulation. For pediatric indications, address palatability of the Asset (if oral) in the proposed pediatric-patient population.
• Provide an estimate for how much Asset is needed and, for pediatric indications, the formulation.

Phase II clinical trial

• Define the aims of the Phase II preliminary efficacy signal. The aims should demonstrate that the Asset modulates the target and has potential to yield the desired clinical outcome/effectiveness in the patient population.
• Describe the trial design, based on available safety data for the Asset.
• Define the primary end points and justify the number of patients chosen for the Phase II trial (based on the proposed outcome measures and the appropriateness of the statistical design).
• Specify the dose range, PD parameters used to perform dose ranging, duration of studies and whether the new use of the Asset is for treatment of an acute or chronic disease, route of administration, and amount of Asset needed.
• Provide assurance that the proposed study can be completed within its budget and within the time limits stated in this FOA.
• Provide evidence such as track record of the trial sites that the proposed number of eligible subjects can be recruited in the requested timeframe, and that the proposed study can be completed within its budget, and within the time limits stated in this FOA.

Rare disease clinical trial, if applicable

• 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.
• Please explain if any outcome measures being used 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?

Letters of Support:

Applicants must include a letter of support from the pharmaceutical company partner documenting: access to the Asset and associated data needed for filing an investigator-sponsored IND for the Asset 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.). Applications that lack this letter will not progress to review.

Please note that resubmissions need an updated letter of support from the participating pharmaceutical partner, who is under no obligation to make an Asset available for longer than one application cycle.

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

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:

Only limited Appendix materials are allowed. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.

When involving NIH-defined human subjects research, clinical research, and/or clinical trials (and when applicable, clinical trials research experience) 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 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 with the following additional instructions:

Section 2 - Study Population Characteristics

2.5 Recruitment and Retention Plan

In addition to the form instructions, the following information is required for this specific FOA.

• 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 recruitment strategy, or provide a rationale for their exclusion
• Recruitment and Referral sources: Include a census of the population available and rate of new cases at the proposed sites.
• 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).
• 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).
• Procedures to monitor enrollment and track/retain participants for follow-up assessments.
• Evidence to support the feasibility of enrollment, including descriptions of prior experiences and yield from research efforts using similar referral sources and/or strategies.
• Strategies to ensure a diverse, representative sample. A description of how the trial will be organized and managed, including the plans to identify and select additional collaborators, if applicable.

2.7 Study Timeline

Applicants must include an overall study timeline and key milestones. These milestones should encompass the tasks required prior to, during the actual trial work, and final report.

Elements that should be included for each year include a goal, followed by 1) Measure, 2) Milestone, 3) Go/No Go Criteria, 4) Quantitative Criteria for Success, and 5) Estimated completion dates.

Milestones should be specific, quantifiable, and scientifically justified. The following elements should be incorporated into the milestones.

• 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).
• Decision points for terminating either phase of the trial (e.g., safety, tolerability, patient acceptability issues), including, for pediatric indications, palatability, if applicable, and appropriateness of the dosage form).
• Identify any impediments that could require an addendum to the research strategy, milestones, or timeline with a discussion of alternative approaches.
• Provide detailed quantitative criteria by which milestone achievement will be assessed. Document power calculations, use of DSMB approaches to safety and toxicity, stopping rules, and contingency plans to deal with recruitment shortfalls.

This document will be carefully reviewed by NCATS prior to final approval.

Delayed Onset Study

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

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

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

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.

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. 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.

Prior Consultation with NCATS staff

For applicants who wish to apply for funds for a Phase III trial on a rare disease, consultation with NCATS staff at least 8 weeks prior to the application due date is strongly encouraged. This applies to both 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 and whether NCATS could support the trial. 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 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, 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 NCATS scientific/research contact and included as an attachment to the SF424 (R&R) Cover.

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

Important Update: See NOT-OD-18-228 for updated review language for due dates on or after January 25, 2019.

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.

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.

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?

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?

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? How novel is the therapeutic/indication pair?

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?

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?

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)?

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.

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.

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.

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.

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.

Not Applicable.

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.

Not Applicable.

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).

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).

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.

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 to this FOA. Following initial peer review, recommended applications will receive a second level of review by the NCATS Advisory Council. The following will be considered in making funding decisions:

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

After the peer review of the application is completed, the PD/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.

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 expects 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).

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 Part 75, 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.

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.

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

eRA Service Desk (Questions regarding ASSIST, eRA Commons, application errors and warnings, documenting system problems that threaten on-time submission, and 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)

General Grants Information (Questions regarding application processes and NIH grant resources)
Email: [email protected] (preferred method of contact)
Telephone: 301-945-7573

Grants.gov Customer Support (Questions regarding Grants.gov registration and Workspace)
Contact Center Telephone: 800-518-4726
Email: [email protected]

Bobbie Ann Mount, Ph.D.
National Center for Advancing Translational Sciences (NCATS)
Telephone: 301-435-0824
Email: [email protected]

Carol Lambert, Ph.D.
National Center for Advancing Translational Sciences (NCATS)
Telephone: 301-435-0814
Email: [email protected]

Gloria Velez
National Center for Advancing Translational Sciences (NCATS)
Telephone: 301-435-0875
Email: [email protected]

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

Awards are made under the authorization of Sections 301 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.