Participating Organization(s)	National Institutes of Health (NIH)
Components of Participating Organizations	National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Funding Opportunity Title	Translational Research in Alcoholic Hepatitis (U01)
Activity Code	U01 Research Project Cooperative Agreements
Announcement Type	New
Related Notices	August 23, 2017 - This RFA has been reissued as RFA-AA-18-002. August 23, 2017 - This RFA has been reissued as RFA-AA-18-003.
Funding Opportunity Announcement (FOA) Number	RFA-AA-12-007
Companion FOA	None
Number of Applications	See Section III. 3. Additional Information on Eligibility.
Catalog of Federal Domestic Assistance (CFDA) Number(s)	93.273
FOA Purpose	The National Institute on Alcohol Abuse and Alcoholism (NIAAA) invites cooperative agreement applications (U01) from single institutions or consortia of institutions to conduct research in the areas of Alcoholic Hepatitis (AH). The major goal of this research initiative is to expedite the translation of emerging findings that could advance the development of new or existing treatments for AH. A close collaboration between basic scientists and clinicians to further improve the understanding of the mechanisms underlying AH, and translate that knowledge into novel therapies is essential for this research activity. This initiative is specifically directed at AH and not at alcoholic fibrosis/cirrhosis and/or complications of portal hypertension.

Posted Date	November 23, 2011
Open Date (Earliest Submission Date)	January 15, 2012
Letter of Intent Due Date	January 15, 2012
Application Due Date(s)	February 15, 2012, by 5:00 PM local time of applicant organization.
AIDS Application Due Date(s)	Not Applicable
Scientific Merit Review	May/June 2012
Advisory Council Review	August 2012
Earliest Start Date(s)	September 1, 2012
Expiration Date	February 16, 2012
Due Dates for E.O. 12372	Not Applicable

Required Application Instructions

It is critical that applicants follow the instructions in the SF 424 (R&R) Application Guide, except where instructed to do otherwise (in this FOA or in a Notice from the NIH Guide for Grants and Contracts). Conformance to all requirements (both in the Application Guide and the FOA) is required and strictly enforced. Applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions. Applications that do not comply with these instructions may be delayed or not accepted for review.

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

The National Institute on Alcohol Abuse and Alcoholism (NIAAA) invites cooperative agreement applications (U01) from single institutions or consortia of institutions to conduct research in the areas of Alcoholic Hepatitis (AH). The major goal of this research initiative is to expedite the translation of emerging findings that could advance the development of new or existing treatments for AH. A close collaboration between basic scientists and clinicians to further improve the understanding of the mechanisms underlying AH, and translate that knowledge into novel therapies is essential for this research activity. This initiative is specifically directed at AH and not at alcoholic fibrosis/cirrhosis and/or complications of portal hypertension.

Background

Alcoholic hepatitis, one of the most serious forms of alcohol-induced liver disease, is characterized by progressive necro-inflammation of the liver resulting in a high, short-term mortality rate: up to 40 percent of patients with severe AH die within 6 months after the onset of the clinical syndrome. In the long-term, patients who survive an episode of AH have a 70 percent probability of developing cirrhosis. Therefore, more effective therapies are urgently needed to decrease the high mortality and morbidity rates of AH.

The exact incidence of AH is unknown. However, its prevalence is about 20 percent among alcoholics who underwent liver biopsy. AH typically affects heavy-drinking alcoholics, but it may also occur in moderate drinkers after a single episode of binge drinking, suggesting the role of factors other than alcohol in individual susceptibility to AH. Studies have shown that various environmental and host factors such as genetics, nutrition, co-existing diseases, age, gender and race/ethnicity may be involved in the incidence and severity of AH. However, the exact cause(s) that triggers the development and exacerbation of AH remains unknown.

The management of patients with AH relies upon the assessment of the severity of the disease and can be very challenging because of the rapid development of a variety of potentially life-threatening complications, and lack of effective therapies. Patients with AH often develop systemic inflammatory response syndrome together with microcirculatory disturbance and systemic hemodynamic derangements, resulting in multi-organ failure. Liver failure, sepsis, hepatorenal syndrome and gastrointestinal bleeding are the main causes of death. Other associated diseases include hepatic encephalopathy, acute pancreatitis and pneumonia. Such a diverse range of organ-specific and universal pathologies illustrates the complexities to be addressed and understood before successful therapeutic strategies can be developed.

Current therapeutic approaches typically include abstinence from alcohol, the correction of malnutrition and specific drug treatment. Unfortunately, despite intense testing of many medications, none of them have proven effective and uniformly recommended for patients with AH. Various clinical trials of different drugs have produced controversial results further fueling debates on their roles in the management of AH. However, there is growing optimism that new combined therapies incorporating the simultaneous or sequential use of different drugs to timely target multiple pathological mechanisms may provide better clinical outcomes than currently available monotherapies. A deeper and more mechanistic knowledge of AH pathogenesis is critical for developing new treatment strategies.

The etiology of AH is multifactorial, thus it is likely that several pathological mechanisms contribute to disease phenotype and outcome. Evidence from both clinical and animal studies demonstrates that the activation of liver immunity that modulates the body's response to alcohol affects hepatic inflammation, repair and protection signals, all of which are of great importance in the genesis of AH. Endotoxin and pro-inflammatory cytokines were suggested as the main effector molecules in the initiation and progression of liver injury and inflammation in AH. In addition, many other mechanisms such as alcohol and lipid metabolism, oxidative stress and the production of reactive oxygen species contribute to disease evolution.

Despite impressive progress in the field, a comprehensive understanding of the driving forces behind AH has been challenging due mainly to liver complexity. While most current studies focus on a single gene or pathway in a single cell type, the liver consists of many different cell types, all of which may elicit different responses to up- or down-regulate certain factor(s). Indeed, the disappointing results of clinical trials investigating the efficacy of anti-TNFa therapy were attributed, in part, to its pleiotropic effects on inflammatory, degenerative and regenerative processes, depending on cell type and local microenvironment.

Cross talk between various systems is central to health or disease state. For example, growing evidence indicates that cytokines and complement system in the liver are involved not only in the balanced regulation of innate and adaptive immune responses, but also in the control of cellular growth and apoptosis, suggesting an overlap between liver regeneration and inflammation. Therefore, to understand AH as a whole, it is important to identify process-specific networks in all cell types present in the liver along with their regulatory mechanisms, then find the biological pathways that connect these different networks into a functioning organ, and finally examine how they behave with temporal and environmental changes. This can be achieved through bioinformatics approaches that combine biological and clinical knowledge with diverse high-throughput data and computer algorithms.

The emerging tendency to move from reductionism towards systems biology, and the lack of animal models that mimic AH in humans, emphasize the need of close collaborations between basic science and clinical research groups. While animal models allow well-controlled mechanistic studies of certain specific pathological processes of AH development, their inability to adequately recapitulate human disease and their lack of relevant clinical outcome measures (histology versus functional deficits and death) slow the translation of scientific innovations into therapeutics. On the other hand, human data are difficult to interpret because of unclear causal relationships between pathological changes. Close cooperation between basic scientists and clinician researchers would help design animal studies with translation challenges in mind and would provide quick feedback on the clinical implementations of new laboratory discoveries. Therefore, this two-way communication is necessary for improving the understanding of the underlying disease mechanisms and translating that knowledge into novel therapies.

To this end, the current FOA encourages innovative cooperative agreement applications (U01) to expedite the translation of emerging findings that could advance the development of new or existing therapeutics for AH treatment. This initiative is also intended to stimulate collaboration between basic and clinical scientists in the conceptualization and proof of concept of proposed treatment strategies. Under this FOA, applicants may submit preclinical as well as clinical studies of new or existing pharmacological and/or non-pharmacological treatment options that have theoretical or empirical evidence of efficacy to treat AH. Preclinical applications may include studies collecting data on drug’s dose-ranging, pharmacokinetics, toxicology, as well as studies investigating mechanisms responsible for unexpected outcomes and phenomena from past clinical trials. Animal studies focusing on identifying potential targets for intervention are encouraged, but the results of those studies must be evaluated in clinically relevant situations to demonstrate their direct validity for human disease. These studies should create ground-breaking ideas for future treatment approaches or extend previous discoveries toward new directions or applications.

Research examples include but are not limited to those listed below:

• Test new drugs available for the treatment of other inflammatory diseases, or new combinations of existing medications, which may be promising candidates for the treatment of AH (e.g., validate the utility of pentoxyfylline, and investigate the efficacy of combined therapy with corticosteroids). Develop immunomodulatory and anti-chemokine therapy for AH, and evaluate drug delivery mechanisms to the liver or specific liver organelles (e.g., mitochondria).
  
  
• Investigate the role of nutrition as a cofactor in the development/progression of AH. Define environmental and host factors that alter susceptibility to AH and impact disease outcomes, such as cellular regulatory and immune response genes and signaling pathways involved in inflammation, cell proliferation and apoptosis, the role of epigenetics, hepatocyte-derived HMGB1 signaling and osteopontin in the pathogenesis of AH, the role of TLR4 signaling and dendritic cell abnormalities in acute AH, and the role of alcohol metabolism on hepatic lipid accumulation.
  
  
• Identify and validate molecular signatures of AH associated with certain disease phenotype (e. g. mild, severe, with/without complications) and of their responses to therapy. Investigate metabolomics and metagenomics in AH mechanisms, biomarkers, therapeutic targets. Identify and validate predictors of severity and survival in AH that can be used for disease management, or evaluation of pharmacokinetics and pharmacodynamics of targeted therapies.
  
  
• Develop novel computational approaches for integrating existing biological and toxicological knowledge into data analysis algorithms for drug response studies.
  
  
• Explore the role of alcohol-induced changes in organ-to-organ interactions (e.g., the liver-gut axis) for the onset and progression of AH. Dissect the complexity of intercellular and intracellular communications among different liver cell types and their spatial/temporal relationships at different stages of disease and during treatment and establish mechanistic links between inflammatory mediators and hepatocyte regeneration/death.

Organization

The NIAAA envisions a multisite consortium that consists of research project components and an administrative component.

The multisite research project components will be formed from a multidisciplinary team of collaborating basic and clinical research groups possessing unique and complementary expertise to synergize each other in accomplishing a common goal. The consortia will work on a cluster of interactive individual research projects that evaluate a single topic both in humans and in a basic laboratory setting with a goal of better understanding mechanisms of alcoholic hepatitis, development of new therapies, or biomarkers, etc. All projects should be highly translational, with a goal of rapid translation of basic science findings into clinical practice. Each application will originate from the Program Director(s)/Principal Investigator(s) research institution and awards will be made to individual institutions.

An administrative component, lead by the Consortium Coordinator, would be responsible for the scientific integrity, productivity, and overall coordination of the consortium. The Administrative Component will include an Administrative and Project Management Plans and this component will also be responsible for the collaborative responsibilities such as the functions of the Scientific Advisory Panel and the overseeing of a Steering Committee to help develop protocols, evaluate progress and results, recommend changes to the study, if necessary, and suggest future directions. The Steering Committee is also responsible for scientific enrichment activities for the benefit of the consortium and the scientific research community. In addition, the Steering Committee will be responsible for organizing an annual meeting of the consortia investigators.

The Consortium Coordinator is the scientist who should have a working knowledge of the multiple measures being undertaken in the consortium, and is responsible for assembling and integrating the collaborative research, and the overall performance of the project. Because a substantial level of effort will be necessary to manage a project of this magnitude, the Consortium leader is expected to make a major commitment to directing, managing and executing the goals and collaborative nature of the project.

The Consortium Coordinator's application will be the lead application of the consortium and should include an Administrative Section, listing all the components, together with the Administrative Management Plan and Plan for Data Sharing and Intellectual Property, consistent with achieving the goals of the program. This application should discuss the theme and goals of the consortium and should explicitly describe the interactions and benefits of the proposed collaboration between projects. The application should also include a comprehensive budget of the whole consortium in addition to its own individual budget. It is acceptable for the Consortium Coordinator to submit a research project component in addition to the lead application.

Administrative and Project Management Plans: The Consortium Coordinator must include an Administrative Management Plan, and should address the integration among individual projects and plans for how the information will be integrated into the solution of the overall question being addressed. The application must include a Project Management Plan, including an ongoing evaluation plan, to ensure consistent forward progress of the project. The mechanism to add new participating investigators and dealing with members whose association with the project has not been productive should be documented in the application. The plan should also include proposed methods for conflict resolution among the participating sites and information dissemination both within the collaborative projects and to the scientific community. Furthermore, the application will include a mechanism to consider and respond to concerns of the scientific community directly affected by the operation and impact of the project.

Plan for Data Sharing and Intellectual Property: NIH expects applicants who respond to this FOA to develop and propose specific plans for sharing the data and materials generated through the large-scale collaborative project, consistent with achieving the goals of the program. This would entail addressing the interests of the Government in the availability of, and access to, the results of publicly funded research. The initial review group will comment on the proposed plans. In addition, as one of the criteria for award, NIAAA staff will also consider the adequacy of the plans. Because advancing research in this field is a critical and important aspect of this FOA and can be achieved through broad dissemination of data and research resources, the proposed sharing and data release plans, after negotiation with the applicants when necessary, will be made a condition of the award. The members of the consortium should disclose their ties to profit-making organizations to aid the project in avoiding conflict of interest situations. Applicants are also reminded that the grantee institution is required to disclose each subject invention to NIAAA within two months after the inventor discloses it in writing to grantee institution personnel responsible for patent matters.

Funding Instrument	Cooperative Agreement
Application Types Allowed	New The OER Glossary and the SF 424 (R&R) Application Guide provide details on these application types.
Funds Available and Anticipated Number of Awards	NIAAA intends to commit $4 million in Total Costs in FY 2012 to fund one or more consortium, dependent on the availability of funds.
Award Budget	Each consortium may request up to $2 million in total cost and the Administrative Core is capped at $25,000 direct cost.
Award Project Period	The total project period for an application submitted in response to this funding opportunity announcement may not exceed five years.

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

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

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 eligible to apply.
Non-domestic (non-U.S.) components of U.S. Organizations are eligible to apply.
Foreign components, as defined in the NIH Grants Policy Statement, are allowed.

Applicant organizations must complete the following registrations as described in the SF 424 (R&R) Application Guide to be eligible to apply for or receive an award. Applicants must have a valid Dun and Bradstreet Universal Numbering System (DUNS) number in order to begin each of the following registrations.

• Central Contractor Registration (CCR) must maintain an active registration, to be renewed at least annually
• Grants.gov
• eRA Commons

All Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) must also work with their institutional officials to register with the eRA Commons or ensure their existing eRA Commons account is affiliated with the eRA Commons account of the applicant organization.

All registrations must be completed by the application due date. Applicant organizations are strongly encouraged to start the registration process at least 4-6 weeks prior to the application due date.

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 PD(s)/PI(s), visit the Multiple Program Director(s)/Principal Investigator(s) Policy and submission details in the Senior/Key Person Profile (Expanded) Component of the SF 424 (R&R) Application Guide.

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

Applicant organizations may submit more than one application, provided that each application is scientifically distinct.

NIH will not accept any application in response to this FOA that is essentially the same as one currently pending initial peer review unless the applicant withdraws the pending application. NIH will not accept any application that is essentially the same as one already reviewed.

Applicants must download the SF424 (R&R) application package associated with this funding opportunity using the Apply for Grant Electronically button in this FOA or following the directions provided at Grants.gov.

It is critical that applicants follow the instructions in the SF424 (R&R) Application Guide, except where instructed in this funding opportunity announcement to do otherwise. Conformance to the requirements in the Application Guide is required and strictly enforced. Applications that are out of compliance with these instructions may be delayed or not accepted for review.

For information on Application Submission and Receipt, visit Frequently Asked Questions Application Guide, Electronic Submission of Grant Applications.

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 research
• Name, address, and telephone number of the PD(s)/PI(s)
• Names of other key personnel
• Participating institutions
• Number and title of this funding opportunity

The letter of intent should be sent to:

Abraham Bautista, Ph.D.
Director, Office of Extramural Activities
National Institute on Alcohol Abuse and Alcoholism
5635 Fishers Lane, Room 2089
Bethesda, MD 20892
Rockville, MD 20852 (for express/courier service, non-USPS)
Telephone: (301) 443-9737
Email: bautista@mail.nih.gov

The forms package associated with this FOA includes all applicable components, mandatory and optional. Please note that some components marked optional in the application package are required for submission of applications for this FOA. Follow all instructions in the SF424 (R&R) Application Guide to ensure you complete all appropriate optional components.

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

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

Individuals are required to comply with the instructions for the Resource Sharing Plans (Data Sharing Plan, Sharing Model Organisms, and Genome Wide Association Studies (GWAS) as provided in the SF424 (R&R) Application Guide.

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

Foreign (non-US) institutions must follow policies described in the NIH Grants Policy Statement, and procedures for foreign institutions described throughout the SF424 (R&R) Application Guide.

Part I. Overview Information contains information about Key Dates. Applicants are encouraged to submit in advance of the deadline to ensure they have time to make any application corrections that might be necessary for successful submission.

Organizations must submit applications via Grants.gov, the online portal to find and apply for grants across all Federal agencies. Applicants must then complete the submission process by tracking the status of the application in the eRA Commons, NIH’s electronic system for grants administration.

Applicants are responsible for viewing their application in the eRA Commons to ensure accurate and successful submission.

Information on the submission process and a definition of on-time submission are provided in the SF424 (R&R) Application Guide.

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 SF 424 (R&R) Application Guide. Paper applications will not be accepted.

Applicants must complete all required registrations before the application due date. Section III. Eligibility Information contains information about registration.

For assistance with your electronic application or for more information on the electronic submission process, visit Applying Electronically.

Important reminders:
All PD(s)/PI(s) must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile Component of the SF 424(R&R) Application Package. Failure to register in the Commons and to include a valid PD(s)/PI(s) Commons ID in the credential field will prevent the successful submission of an electronic application to NIH.

The applicant organization must ensure that the DUNS number it provides on the application is the same number used in the organization’s profile in the eRA Commons and for the Central Contractor Registration (CCR). Additional information may be found in the SF424 (R&R) Application Guide.

See more tips for avoiding common errors.

Upon receipt, applications will be evaluated for completeness by the Center for Scientific Review and responsiveness by components of participating organizations, NIH. Applications that are incomplete and/or nonresponsive will not be reviewed.

In order to expedite review, applicants are requested to notify the NIAAA Referral Office by email at srinivar@mail.nih.gov when the application has been submitted. Please include the FOA number and title, PD(s)/PI(s) name, and title of the application.

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

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/priority score to reflect their assessment of the likelihood for the project to exert a sustained, powerful influence on the research field(s) involved, in consideration of the following review criteria and additional review criteria (as applicable for the project proposed).

Reviewers will consider each of the review criteria below in the determination of scientific merit, and give a separate score for each. An application does not need to be strong in all categories to be judged likely to have major scientific impact. For example, a project that by its nature is not innovative may be essential to advance a field.

Significance

Does the project address an important problem or a critical barrier to progress in the field? If the aims of the project are achieved, how will scientific knowledge, technical capability, and/or clinical practice be improved? How will successful completion of the aims change the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field?

Investigator(s)

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the project? If Early Stage Investigators or New Investigators, or in the early stages of independent careers, do they have appropriate experience and training? If established, have they demonstrated an ongoing record of accomplishments that have advanced their field(s)? If the project is collaborative or multi-PD(s)/PI(s), do the investigators have complementary and integrated expertise; are their leadership approach, governance and organizational structure appropriate for the project?

Innovation

Does the application challenge and seek to shift current research or clinical practice paradigms by utilizing novel theoretical concepts, approaches or methodologies, instrumentation, or interventions? Are the concepts, approaches or methodologies, instrumentation, or interventions novel to one field of research or novel in a broad sense? Is a refinement, improvement, or new application of theoretical concepts, approaches or methodologies, instrumentation, or interventions proposed?

Approach

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Are potential problems, alternative strategies, and benchmarks for success presented? If the project is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed?

If the project involves clinical research, are the plans for 1) protection of human subjects from research risks, and 2) inclusion of minorities and members of both sexes/genders, as well as the inclusion of children, justified in terms of the scientific goals and research strategy proposed?

Environment

Will the scientific environment in which the work will be done contribute to the probability of success? Are the institutional support, equipment and other physical resources available to the investigators adequate for the project proposed? Will the project benefit from unique features of the scientific environment, subject populations, or collaborative arrangements?

As applicable for the project proposed, reviewers will evaluate the following additional items while determining scientific and technical merit, and in providing an overall impact/priority score, but will not give separate scores for these items.

Integration and Collaboration

Do the scientific aims of the application significantly complement other projects within the consortium and advance the overarching goals of the consortium? Is there evidence of significant collaboration with other projects or components in the consortium?

Protections for Human Subjects

For research that involves human subjects but does not involve one of the six categories of research that are exempt under 45 CFR Part 46, the committee will evaluate the justification for involvement of human subjects and the proposed protections from research risk relating to their participation according to the following five review criteria: 1) risk to subjects, 2) adequacy of protection against risks, 3) potential benefits to the subjects and others, 4) importance of the knowledge to be gained, and 5) data and safety monitoring for clinical trials.

For research that involves human subjects and meets the criteria for one or more of the six categories of research that are exempt under 45 CFR Part 46, the committee will evaluate: 1) the justification for the exemption, 2) human subjects involvement and characteristics, and 3) sources of materials. For additional information on review of the Human Subjects section, please refer to the Human Subjects Protection and Inclusion Guidelines.

Inclusion of Women, Minorities, and Children

When the proposed project involves clinical research, the committee will evaluate the proposed plans for inclusion of minorities and members of both genders, as well as the inclusion of children. For additional information on review of the Inclusion section, please refer to the Human Subjects Protection and Inclusion Guidelines.

Vertebrate Animals

The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following five points: 1) proposed use of the animals, and species, strains, ages, sex, and numbers to be used; 2) justifications for the use of animals and for the appropriateness of the species and numbers proposed; 3) adequacy of veterinary care; 4) procedures for limiting discomfort, distress, pain and injury to that which is unavoidable in the conduct of scientifically sound research including the use of analgesic, anesthetic, and tranquilizing drugs and/or comfortable restraining devices; and 5) methods of euthanasia and reason for selection if not consistent with the AVMA Guidelines on Euthanasia. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animal Section.

Biohazards

Reviewers will assess whether materials or procedures proposed are potentially hazardous to research personnel and/or the environment, and if needed, determine whether adequate protection is proposed.

Resubmissions

Not Applicable.

Renewals

Not Applicable.

Revisions

Not Applicable.

As applicable for the project proposed, reviewers will consider each of the following items, but will not give scores for these items, and should not consider them in providing an overall impact/priority score.

Applications from Foreign Organizations

Reviewers will assess whether the project presents special opportunities for furthering research programs through the use of unusual talent, resources, populations, or environmental conditions that exist in other countries and either are not readily available in the United States or augment existing U.S. resources.

Select Agent Research

Reviewers will assess the information provided in this section of the application, including 1) the Select Agent(s) to be used in the proposed research, 2) the registration status of all entities where Select Agent(s) will be used, 3) the procedures that will be used to monitor possession use and transfer of Select Agent(s), and 4) plans for appropriate biosafety, biocontainment, and security of the Select Agent(s).

Resource Sharing Plans

Reviewers will comment on whether the following Resource Sharing Plans, or the rationale for not sharing the following types of resources, are reasonable: 1) Data Sharing Plan; 2) Sharing Model Organisms; and 3) Genome Wide Association Studies (GWAS).

Budget and Period of Support

Reviewers will consider whether the budget and the requested period of support are fully justified and reasonable in relation to the proposed research.

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s), convened by the NIAAA in accordance with NIH peer review policy and procedures, using the stated review criteria. Review assignments will be shown in the eRA Commons.

As part of the scientific peer review, all applications:

• 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/priority 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 National Advisory Council on Alcohol Abuse and Alcoholism. 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(s)/PI(s) will be able to access his or her Summary Statement (written critique) via the eRA Commons.

Information regarding the disposition of applications is available in the NIH Grants Policy Statement.

If the application is under consideration for funding, NIH will request "just-in-time" information from the applicant as described in the NIH Grants Policy Statement.

A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant organization for successful applications. The NoA signed by the grants management officer is the authorizing document and will be sent via email to the grantee’s business official.

Awardees must comply with any funding restrictions described in Section IV.5. Funding Restrictions. Selection of an application for award is not an authorization to begin performance. Any costs incurred before receipt of the NoA are at the recipient's risk. These costs may be reimbursed only to the extent considered allowable pre-award costs.

Any application awarded in response to this FOA will be subject to the DUNS, CCR Registration, and Transparency Act requirements as noted on the Award Conditions and Information for NIH Grants website.

All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the NoA. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General and Part II: Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Grantees, and Activities. More information is provided at Award Conditions and Information for NIH Grants.

Cooperative Agreement Terms and Conditions of Award

The following special terms of award are in addition to, and not in lieu of, otherwise applicable U.S. Office of Management and Budget (OMB) administrative guidelines, U.S. Department of Health and Human Services (DHHS) grant administration regulations at 45 CFR Parts 74 and 92 (Part 92 is applicable when State and local Governments are eligible to apply), and other HHS, PHS, and NIH grant administration policies.

The administrative and funding instrument used for this program will be the cooperative agreement, an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH programmatic involvement with the awardees is anticipated during the performance of the activities. Under the cooperative agreement, the NIH purpose is to support and stimulate the recipients' activities by involvement in and otherwise working jointly with the award recipients in a partnership role; it is not to assume direction, prime responsibility, or a dominant role in the activities. Consistent with this concept, the dominant role and prime responsibility resides with the awardees for the project as a whole, although specific tasks and activities may be shared among the awardees and the NIH as defined below.

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

• Defining the research objectives, approaches and details of the projects within the guidelines of the RFA AA-12-007 as well as execution of the proposed project;
• Cooperating with NIAAA programmatic, technical, and administrative staff;
• Administratively managing the U01;
• Participating in all Steering Committee activities;
• Accepting and implementing the policies and procedures developed by the Steering Committee;
• Providing information about progress in annual reports and data in any other manner determined by the Steering Committee to be necessary.
• The timely submission of all abstracts, manuscripts and reviews (co)authored by members of the grant and supported in part or in total under this Cooperative Agreement. Publications or oral presentations of work performed under this Cooperative Agreement will require appropriate acknowledgement of NIAAA support.

Awardees will retain custody of and have primary rights to the data and software developed under these awards, subject to Government rights of access consistent with current DHHS, PHS, and NIH policies.

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

A Program Official from NIAAA will serve as the NIH Project Scientist and will have substantial programmatic involvement as described below. The NIH Project Scientist will:

• Serve as a liaison between the consortium, the Steering Committee and the NIAAA;
• Facilitate coordination of project activities during the course of the project and serve as a resource of scientific and policy information related to the goals of the consortium 's research;
• Participate in data analyses, interpretations, and where warranted, co-authorship of the publication of results of studies conducted through the consortium;
• Retain the option to recommend, with the advice of the Scientific Advisory Board, the withholding or reduction of support from any cooperative agreement that substantially fails to achieve its goals, or fails to comply with the Terms and Conditions of the award.

A separate NIAAA Program Official will be responsible for the normal scientific and programmatic stewardship of the award and will be named in the award notice.

Areas of Joint Responsibility include:

External Scientific Advisory Panel: The External Scientific Advisory Panel, which consists of non-Consortium affiliated scientists and other experts appointed by the Consortium Coordinator in consultation with NIAAA Project Scientist, will oversee the Consortium and provide annual reviews of progress and advice the Steering Committee on research design issues and data quality analysis.

Steering Committee: The Steering Committee will serve as the main governing body for awardees of this program. The Steering Committee will develop standards for data collection, nomenclature, scientific methodologies, and collaborative protocols; monitor and evaluate the progress of clinical and mechanistic studies; and ensure that results are reported in the scientific literature in a timely manner and widely disseminated to medical professionals. All awardees will be required to accept and implement policies approved by the Steering Committee.

The Steering Committee will be composed of the Consortium Coordinator, the PD(s)/PI(s) of the research project components, and the NIAAA Project Scientist. A Chairperson will be elected by majority vote from among non-government voting members. The Steering Committee may also invite other individuals (including external experts and representatives of NIH Institutes/Centers) to participate as non-voting members if their expertise is required for specific discussions. The Steering Committee is expected to meet in-person early in the first year of the project, and annually throughout the project period, and teleconferences are expected to occur on at least a quarterly basis throughout the project period.

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 Non-Competing Continuation Grant Progress Report (PHS 2590) annually and financial statements as required in the NIH Grants Policy Statement.

A final progress report, invention statement, and the expenditure data portion of the Federal Financial Report are required for closeout of an award, as described in the NIH Grants Policy Statement.

The Federal Funding Accountability and Transparency Act of 2006 (Transparency Act), includes a requirement for awardees of Federal grants to report information about first-tier subawards and executive compensation under Federal assistance awards issued in FY2011 or later. All awardees of applicable NIH grants and cooperative agreements are required to report to the Federal Subaward Reporting System (FSRS) available at www.fsrs.gov on all subawards over $25,000. See the NIH Grants Policy Statement for additional information on this reporting requirement.

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

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

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Telephone 301-710-0267
TTY 301-451-5936
Email: GrantsInfo@nih.gov

eRA Commons Help Desk(Questions regarding eRA Commons registration, tracking application status, post submission issues)
Phone: 301-402-7469 or 866-504-9552 (Toll Free)
TTY: 301-451-5939
Email: commons@od.nih.gov

Svetlana Radaeva, Ph.D.
Division of Metabolism and Health Effects
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Telephone: 301-443-1189
Email: sradaeva@mail.nih.gov

Ranga V Srinivas, Ph.D.
Chief, Extramural Project Review Branch
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Telephone: (301) 451 2067
Email: srinivar@mail.nih.gov

Judy Fox
Chief, Grants Management Branch
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Telephone: (301) 443-4704
Email: jfox@mail.nih.gov

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 Parts 74 and 92.