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

Alcoholic hepatitis (AH) is a clinical syndrome of acute liver failure prevalent in people with decades of heavy alcohol use, for which there are no effective treatments. Research in developing new interventions for AH has been challenging, given its high mortality rate, heterogeneity in clinical presentation, complexity of interacting pathophysiologic mechanisms, the difficulties of recruiting and retaining patients with alcohol use disorders, and the lack of animal models that mimic AH in humans.

In response to the urgent public health significance of AH, in 2012 the NIAAA launched the Translational Research in Alcoholic Hepatitis program, which established four individually operating consortia each consisting of a set of integrated projects ranging from basic research to clinical studies. The original AH program made a number of exciting discoveries and made steady progress towards its scientific and programmatic goals including establishing a consensus statement on disease definition and common data elements.

To further accelerate AH intervention development, the NIAAA seeks to consolidate and integrate the existing AH program into the Clinical and Translational Network. This consolidation is aimed to increase the efficiency and effectiveness of the program by streamlining processes for designing, initiating and conducting clinical trials, reducing administrative redundancy, facilitating complementary interactions across the Network and making optimal use of scientific innovations.

The consolidated AH Network consists of the following components:

Clinical component: consists of up to 9 collaborative U01 clinical centers conducting common multi-center clinical phase 2b trials and observational studies in patients with AH; some of these centers will also conduct the U01 Clinical Pilot Trials of intervention-development related issues.

Data Coordinating Center: serves as the Network data management center and biorepository, provides biostatistical and logistical support, coordinates various trans-Network activities as well as standardizes approaches, procedures and data formats to minimize resources/effort duplication.

Translational component: consists of up to 10 U01 studies aimed on improving various aspects of AH diagnosis and intervention.

Basic and pre-clinical component: consists of to-be-determined number of basic and pre-clinical studies aimed to discover novel mechanisms of AH pathogenesis and/or tools for clinical development.

These four components will be individually awarded through the respective FOAs indicated below:

1. Clinical component under RFA AA 18-002 (collaborative U01) (up to 9 awards) and RFA AA 18-005 (U01) (this FOA) (up to 9 awards);
2. Data Coordinating Center under RFA AA 18-004 (U24) (up to 2 awards);
3. Translational component under RFA AA 18-003 (U01) (up to 10 awards);
4. Basic/Pre-clinical component under RFA AA 18-006 (UH2/UH3).

Through this FOA, applications are sought to conduct investigator-initiated single-center feasibility and pilot studies to optimize critical elements for full-scale clinical trials including agent(s), dosing, enrollment and adherence, data collection and appropriate outcome and follow-up. The overall objectives of these studies are to generate sufficient data for 1) informing go/no-go decisions about further testing of the candidate interventions and 2) optimization of the design of the late-stage clinical trials for obtaining meaningful results.

To meet these objectives, projects should address the core clinical trial design issues, including the feasibility, tolerability, acceptability, safety, and preliminary indications of effectiveness of therapeutic interventions. The pilot studies are expected to involve a small number of patients and will not achieve statistical significance, but may lead to new clinical trial design to increase the success rates of drug efficacy studies. Despite their outcomes, the pilot studies will provide information of high utility to the field by informing decisions about whether further testing is warranted and by filling gaps in scientific knowledge. Both novel investigational drugs and rescued or repurposed drugs are appropriate for this announcement.

Some examples of research topics appropriate for this FOA include, but are not limited to:

• Evaluating and optimizing the dose, formulation, safety, tolerability of an intervention in the target population;
• Assessing pharmacokinetics of the studied agents and establishing relationships between the dose, schedule, exposure and effect;
• Evaluating the feasibility of recruitment, retention, assessments, and reporting of adverse events;
• Identifying inclusion and exclusion criteria to be applied in phase 2b and above clinical trials;
• Developing and refining data collection procedures;
• Determining the best methods for identifying, stratifying, and recruiting study subjects;
• Obtaining sufficient evidence of short-term improvement in patients to justify an efficacy trial;
• Evaluating strategies for recruitment and retention to overcome logistical barriers and disparities in clinical trial participation among racial/ethnic minorities, socioeconomic and other diverse populations.

This FOA may support activities related to the conduct of the pilot studies, including, but not limited to:

• Regulatory activities to support the implementation of the trial;
• Training of study personnel related to the conduct of the trial;
• Enrollment and recruitment of study participants;
• Data collection, management, and quality control for the trial;
• Laboratory work and data analysis;
• Study management and oversight;
• Other related post-enrollment activities;
• Preparation of the final study report.

Other requirements of this FOA:

Because the pilot studies are expected to involve a small number of patients and have a shorter duration, applicants must propose two pilot trial designs to be conducted sequentially over the funding period. Applicants must provide a clear scientific premise and compelling rationale for pursuing the proposed pilot studies and development of the intervention. Pilot projects must be distinct from a cross-Network common clinical trial.

All applications are required to use the Network master agreements and to share data and biospecimens with other collaborating sites within the AH Network. Prior arrangement needs to be made and specified in the submitted application so that pilots will be coordinated with the ongoing clinical trial and observational studies, and statistical and data management support will be provided by Data Coordinating Center unit (DCC).A letter of support from one or more of the NIAAA approved collaborating sites is required.

Given the complexity of the research projects, it is expected that each award will support multidisciplinary teams composed of scientists with diverse expertise. The PD/PIs are strongly encouraged to include Early Stage investigators in the proposed research projects to provide them with exposure to and experience in clinical research methods and laboratory techniques.

NIAAA will consider clinical research grant applications that focus on already established patient cohorts within the NIAAA-supported Alcoholic Hepatitis Translational and Clinical Network in California, Indiana, Kentucky, Massachusetts, Minnesota, Ohio, Pennsylvania, Texas and Virginia. NIAAA does not intend to expand the cohort beyond these locations.

It should be noted that related translational projects, such as those examining whether the intervention engages the target/mechanism or identifying biomarkers, are supported separately by the U01 translational component mechanism (RFA AA 18-003).

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 in response to this FOA.

Higher Education Institutions

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

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

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

Nonprofits Other Than Institutions of Higher Education

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

For-Profit Organizations

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

Governments

• State Governments
• County Governments
• City or Township Governments
• Special District Governments
• Indian/Native American Tribal Governments (Federally Recognized)
• Indian/Native American Tribal Governments (Other than Federally Recognized)
• Eligible Agencies of the Federal Government
• 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

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

Applicant Organizations

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

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

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

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

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

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

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

Only one application per institution (normally identified by having a unique DUNS number or NIH IPF number) is allowed

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).

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, including Supplemental Grant Application Instructions 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:

Abraham P. Bautista, Ph.D.
National Institute on Alcohol Abuse and Alcoholism (NIAAA
Telephone: 301-443-9737
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 with additional requirements:

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

Facilities & Other Resources

The description of the resources and environment should address how the study utilizes existing infrastructure or utilizes other available resources to increase the efficiency of participant recruitment and data collection

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

The PD(s)/PI(s) should document expertise needed to successfully design and conduct the proposed studies and prior experience with studies in AH including clinical trials under an FDA IND or other types of clinical research studies. The experience of all key personnel must be carefully documented.

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

The budget should be largely planned on a fee-for-service basis with detailed per-patient costs and may include clinical trial costs such as study-related procedures/materials. The budget will not include costs which are already covered by the U01 clinical trials and observational studies award.

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, with the following additional instructions:

Research Strategy

Clinical Significance: Applicants must provide a clear and compelling rationale for pursuing the proposed pilot studies and development of the intervention, as well as for other critical aspects of the trial design. The clinical significance of the future clinical trial must be clearly stated. It is particularly important that there be discussion of how the results of the proposed research (positive or negative) will guide decisions about whether a subsequent study is feasible or justified, and/or provide evidence that additional studies must be completed before proceeding to a full-scale trial.

Prior Studies and Rationale for Development: The major findings of the preclinical and/or clinical studies that led to the proposed research should be described. Characteristics of any preliminary research results provided in support of the proposed project, whether conducted by the applicant or others, should be described in the application so that peer reviewers may evaluate the strength of the supporting evidence. The applicant should also discuss the limitations of those data.

Study Design: Applicants must propose two pilot trial designs to be conducted sequentially over the funding period. A summary of the proposed protocol for each pilot study of the application should be presented in the Research Strategy and must include data to justify the selection of the study intervention; a description of the target population, description of all assessments and outcomes addressing the primary and secondary research questions; statistical methods such as sample size justification, study outcome measures and final analyses, methods of bias control and methods for handling missing data. All applications must include clearly-specified, well-defined milestones, go/no go decision points, and timelines for assessing progress.

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.

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

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 and responsiveness by components of participating organizations, NIH. Applications that are incomplete, non-compliant and/or nonresponsive will not be reviewed.

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

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

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

Reviewers will provide an overall impact 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?

Despite their outcomes, will the proposed pilot studies provide information of high utility to the field by informing decisions about whether further testing is warranted and by filling gaps in scientific knowledge? Will the proposed studies adequately inform an effective design of a randomized clinical trial to treat AH? Is there an adequate description on the significance of biological variables, such as, sex for studies on human subject?

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?

If established, have they demonstrated a prior experience with studies in AH including clinical trials under an FDA IND or other types of clinical research studies?

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?

Are there innovative approaches to the scientific question(s), research design, or implementation? Are appropriate biomarkers and alternative outcomes proposed in the design of the study?

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?

Does the application propose two pilot trial designs to be conducted sequentially over the funding period? Does the application address the core clinical trial design issues, including the feasibility, tolerability, acceptability, safety, and preliminary indications of effectiveness of therapeutic interventions in AH? Are there adequate pre-clinical or clinical data to justify the scientific questions proposed? Do the proposed recruitment plans include a viable approach to recruitment of participants and anticipated rates of progression for the proposed pilot studies? Are there backup plans in case the primary recruitment plan fails? Does the application include Data Management and Quality Control; Data and Safety Monitoring Plan; statistical methods such as sample size justification, study outcome measures and final analyses, methods of bias control and methods for handling missing data? Does the application provide plans how pilot projects will be coordinated with the ongoing clinical trials and observational studies, and statistical and data management support will be provided by Data Coordinating Center unit (DCC)? Does the application include plans to share data and biospecimens with other collaborating sites within the AH Network? Does the application include clearly-specified, well-defined milestones, go/no go decision points, and timelines for assessing progress?

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?

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?

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.

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.

Not Applicable

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{NIAAA}, 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.

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

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 NIAAA 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.

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 OMB administrative guidelines, HHS grant administration regulations at 45 CFR Part 75 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 U01, an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH programmatic involvement with the awardees is anticipated during the performance of the activities. Under the cooperative agreement, the NIH purpose is to support and stimulate the recipients' activities by involvement in and otherwise working jointly with the award recipients in a partnership role; it is not to assume direction, prime responsibility, or a dominant role in the activities. Consistent with this concept, the dominant role and prime responsibility resides with the awardees for the project as a whole, although specific tasks and activities may be shared among the awardees and the NIH as defined below.

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

• The Program Director(s)/Principle Investigator(s) (PD(s)/PI(s)-will be primarily responsible for defining the objectives and approaches, planning, conduct, analysis, and publication of results, interpretations, and conclusions of studies conducted under the terms and conditions of the cooperative agreement award.
• The PD(s)/PI(s) will establish a Steering Committee to implement, coordinate, and manage the project(s). Awardee(s) will name investigators to serve as members on a Steering Committee and other subcommittees. Awardees will be required to accept and implement the common protocol(s) and procedures approved by the Steering Committee.
• The PD(s)/PI(s) will establish procedures, where applicable, for all participating institutions in coordinated awards to comply with FDA regulations for studies involving investigational agents or devices and to comply with the requirements of 45 CFR Part 46 for the protection of human subjects, and the NIH policy requirements for the inclusion of women, minorities and children.
• PD(s)/PI(s) for each U01 clinical trial center will have the responsibility for medical safety and protection of study participants.
• PD(s)/PI(s) for each U01 clinical trial center have the responsibility to submit a detailed Data and Safety Monitoring Plan (DSMP) for each clinical trial conducted under this award to the Program Official from NIAAA for approval. The DSMP should be developed using NIAAA Data and Safety Monitoring Plan Requirements for NIAAA-funded Clinical Trials at https://www.niaaa.nih.gov/ResearchInformation/ExtramuralResearch/ResourcesAppGrantees/guidelines.htm.
• The PD(s)/PI(s) will accept close coordination and participation of the NIAAA Project Scientist in those aspects of scientific and technical management of the study as stated in these terms and conditions.
• The PD(s)/PI(s) will retain custody of and primary rights to their data developed under the award, subject to current Government policies regarding rights of access consistent with current DHHS, PHS, and NIH policies.
• Each Network project will receive a separate award, and the Principal Investigator(s) will have control over the project’s operating budget.
• PD(s)/PI(s) will be responsible for themselves and their staff in maintaining confidentiality of the information as developed by the Network, including, without limitation, study protocols, data analysis, conclusions, etc. per policies approved by the Steering Committee as well as any confidential information received by third party collaborators.
• The PD(s)/PI(s) will be responsible for maintaining collaborative interactions between investigators, Steering Committee, NIAAA Scientist, and External Advisory Board.
• The PD(s)/PI(s) will have the responsibility of submitting annual progress reports to the NIAAA to inform on the progress of the project(s) conducted under this award, including advances, obstacles and steps taken to remedy them, and a summary of any NIAAA-approved changes and departures from the approved study protocol, as well as any human-subjects issues.
• When appropriate, and in accordance with NIH policies, as well as NIAAA policies, awardees will be expected to collaborate on all aspects of research activities including to share novel reagents, biomaterials, methods and models and resources; as well as to share both positive and negative results that would help guide the research activities of other Network members.
• The PD(s)/PI(s) will agree to establish agreements among themselves through Steering Committee to address the following issues:
• Procedures for safeguarding confidential information, including without limitation, any data generated by the Network as well as information and/or data received from external collaborators;
• Procedures for addressing ownership of intellectual property that result from aggregate multi-party data;
• Procedures for sharing biospecimens among Network members that operationalizes material transfer in an efficient and expeditious manner;
• Procedures for reviewing publications and determining authorship.
• Awardees must agree to comply with the processes and goals as delineated within the FOA.

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

The cooperative agreement will be assigned an NIAAA Project Scientist (PS) who will have substantial programmatic involvement that is above and beyond the normal stewardship role in awards and will be named in the award notice. This includes helping to maintain the overall scientific balance in the program commensurate with new research and emerging research opportunities, facilitating communication and coordination among the awardees, and ensuring that the activities of the awardees are consistent with the mission of the NIAAA and AH Network. Specifically, the PS will have primary responsibility for:

• participating in the definition of objectives and approaches, and in planning, conducting, analyzing, and publishing results, interpretations, and conclusions of their studies. However, the dominant role and prime responsibility for the activity reside with the awardee(s) for the project as a whole, but not necessarily for each task;
• serving as a resource to aid in resolving scientific and regulatory issues as they arise;
• cooperation or coordination with, or assistance to, awardees in performing project activities, e.g., development of research protocols; data collection, analyses, and interpretations; or re-direction of objectives during the course of a project;
• overseeing adverse event management and reporting, and having regular communications with the PD/PI and study team, which may include attendance at the safety monitoring meetings (or DSMB) and related External Advisory Board meetings or Steering Committee meetings;
• advising and assisting reprogramming efforts, including options to modify, halt or close any cooperative agreement for reasons including but not limited to: a) patient safety; b) failure to achieve enrollment and completion milestones, c) emergence of already conclusive study results and d) emergence of new information that diminishes the scientific importance of the study question;
• serving as a resource with respect to other ongoing NIH activities that may be relevant to this study to facilitate compatibility and avoid unnecessary duplication of effort;
• participation on committees (other than peer review, see below) as a voting member or in other functions in helping to guide the course of long-term projects or activities;
• participation in the presentation of research results, including publications from the project.

These activities could result in a real and/or perceived bias about the project that might prohibit independent evaluation of the progress of the award. Accordingly, the NIAAA PS will not:

• attend peer review meetings of Renewal/Revision/Administrative extension applications unless IC waiver obtained per IC procedures for management of concern about bias;
• have decision-making authority on matters of budgetary and funding actions, grants management actions, and management of intellectual property.

Additionally, an agency Program Officer and Grants Management Specialist will be responsible for the normal program stewardship and administrative oversight of the cooperative agreement and will be named in the award notice.

The release of each annual funding by NIAAA will be based on the review by NIAAA officials of progress made towards achieving the research goals, interim objectives and milestones. NIAAA reserves the right to terminate or curtail a study (or any individual award) in the event of inadequate progress, poor quality, or other major breach of the approved project. Final decisions will be made based on established institute procedures.

The specific timelines, interim objectives and funding levels agreed to by the awardee and the NIAAA shall be included in the terms and conditions of award. Given the nature of product development, it is recognized that timelines and interim objectives may require revision and renegotiation during the course of the project period.

Areas of Joint Responsibility include:

Steering Committee (SC) is the main governing body of the AH Network that integrates the efforts of all Network awardees and provides oversight of collaborative activities. The SC will be composed of the following voting members: all PD(s)/PI(s) representing each AH Network U01/U24/UH2/UH3 award; and the NIAAA Project Scientist.

Chairs of the SC. Two principle investigators with advanced expertise will be selected to serve as co-chairs of the SC by the NIAAA, in consultation with PIs in the AH Network. The co-chairs of the SC, in collaboration with the Project Scientist, will perform the following duties:

• provide leadership to the Committee by conducting the SC meetings and prioritizing meeting agenda;
• serve as the Network and SC’s contact persons to external oversight committees and NIAAA;
• appoint ad hoc committees as needed;
• submit annual Network Progress Reports to the External Advisory Board on behalf of the SC;
• coordinate operational management and mediate internal conflict resolution.

Primary responsibilities of the Steering Committee include, but are not limited to, the following activities:

• establishing Network policies and procedures;
• establishing policies and procedures for reviewing and recommending changes in underperforming projects in order to meet the goals of AH Network, and making recommendations to the NIAAA for replacing the project with more promising ones with revised scope and adjusted budget (increase in the budget will not be permitted);
• establishing policies and procedures for reviewing a potential UH2/UH3 grant submission of a project to be conducted in collaboration with the Network; advising NIAAA on the proposal’s suitability for the Network;
• evaluating protocols proposed by the Network investigators and developing consensus protocols;
• establishing a Data and Safety Monitoring Board for clinical studies as appropriate to ensure protection of human subjects;
• promoting and fostering the inclusion of women and ethnic minorities in clinical studies and assuring the completeness of informed consent;
• tracking and reporting, with the assistance from DCC, the Network research progress and assuring that the results of laboratory research and clinical studies are published in peer-reviewed journals in a timely manner and in accordance with the publication policies of the Network;
• planning one face-to-face meeting every 12 months during the Network project period;
• working with the DCC and the Network on questionnaires and other data recording forms, establishing and maintaining quality control among recipients, standardization of data management, and cooperation on the publication of results.

The SC is expected to meet in-person an average of twice a year and by teleconference monthly (potentially more frequently during the start-up phase of the network). Each voting member will have one vote. Decisions will be made by consensus or majority vote when needed. Additional non-voting members will include representatives from sub-committees and working groups. Additional non-voting members may participate on the SC in an advisory capacity on an as needed basis and decided by the existing voting committee members. Additional NIH staff members may participate in SC meetings as non-voting members as needed (for example to provide additional expertise).

Subcommittees of the SC will be established as necessary, but will include, at a minimum: 1) Publications and Presentations, 2) Clinical, and 3) Translational subcommittees. The Publications and Presentations Subcommittee will facilitate and supervise preparation of collaborative manuscripts prior to submission for publication. The clinical sub-committee will oversee and guide clinical trials and observational studies. The translational sub-committee will coordinate the translational research effort across the Network.

Data Safety and Monitoring Board will review interim results periodically as established in the data and safety monitoring plan in accordance with NIAAA policies for monitoring purpose. The DSMB will provide feedback to the Network Steering Committee, IRB, and NIAAA.

External Advisory Board appointed by the NIAAA in consultation with the SC will oversee the Network and provide annual reviews of progress to the SC and NIAAA and advise the SC on research design issues and data quality analysis.

Single Institutional Review Board of Record (sIRB) is expected to streamline IRB approvals, provide the ethical review, and maintain patient safety while reducing the inefficiencies and burden of each clinical site conducting their own IRB review (see NOT-OD-17-027, https://grants.nih.gov/grants/guide/notice-files/NOT-OD-17-027.html).

Dispute Resolution:

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

When multiple years are involved, awardees will be required to submit the 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 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)
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Grants.gov Customer Support (Questions regarding Grants.gov registration and submission, downloading forms and application packages)
Contact Center Telephone: 800-518-4726
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GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Email: [email protected] (preferred method of contact)
Telephone: 301-945-7573

Svetlana Radaeva, Ph.D.
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Telephone: 301.443.1189
Email: [email protected]

Ranga Srinivas, Ph.D.
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Telephone: 301-451-2067
Email: [email protected]

Judy Fox
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Telephone: 301-443-4704
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.