Part 1. Overview Information

Key Dates

All applications are due by 5:00 PM local time of applicant organization. 

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

No late applications will be accepted for this Notice of Funding Opportunity (NOFO).

It is critical that applicants follow the instructions in the Research (R) Instructions in the How to Apply - Application Guide, except where instructed to do otherwise (in this NOFO or in a Notice from NIH Guide for Grants and Contracts).

Conformance to all requirements (both in the Application Guide and the NOFO) is required and strictly enforced. Applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions.

Applications that do not comply with these instructions may be delayed or not accepted for review.

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

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



Table of Contents
Part 1. Overview Information
Key Dates
Part 2. Full Text of Announcement
Section I. Notice of Funding Opportunity Description
Section II. Award Information
Section III. Eligibility Information
Section IV. Application and Submission Information
Section V. Application Review Information
Section VI. Award Administration Information
Section VII. Agency Contacts
Section VIII. Other Information

Part 2. Full Text of Announcement

Section I. Notice of Funding Opportunity Description

Background

Advanced Alcohol-associated Liver Disease (ALD), that includes severe Alcohol-associated Hepatitis (sAH) and decompensated alcohol-associated cirrhosis (deAC), is a serious and potentially fatal consequence of long-term alcohol misuse and Alcohol Use Disorder (AUD). Between 2000-2019, ALD-related deaths increased by 47%. The number of patients with advanced ALD who were listed for liver transplant increased by 63% from 2007 to 2017. The high mortality rates of advanced ALD increase the strain on hospitals and intensive care units and place additional financial burdens on both patients and healthcare providers due to extended hospital stays, specialized treatments, and organ transplant procedures. Management of advanced ALD is, therefore, a major unmet need in the hepatology field.

AH is a severe, sub-acute clinical manifestation of ALD with high short-term mortality rate of 30% within 3 months of diagnosis. Most AH patients have concomitant underlying cirrhosis that increases the risk of decompensation and results in low survival rates. For example, studies from the Department of Veterans Affairs (VA) demonstrate that patients with co-existed both diseases have a death rate of greater than 60 percent over a 4-year period, with most of the deaths occurring in the first year. 

The clinical and laboratory features of deAC  are similar to  sAH. DeAC occurs when the liver is unable to carry out its normal function leading to ascites, encephalopathy, jaundice, coagulopathy and gastrointestinal bleeding. All of these features can also occur in sAH with or without cirrhosis. Currently, there are no effective treatments for the above two severe clinical conditions. Research in developing new interventions for sAH and deAC 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 in clinical trials, and the lack of animal models that mimic sAH and deAC in humans.

Currently, there are no FDA approved treatments for sAH and deAC. A growing body of evidence from retrospective observational studies indicates that treatment of the underlying AUD improves clinical outcomes among this patient population both in terms of severity and mortality. However, proactive clinical trials demonstrating effectiveness are lacking. Moreover, the integration of ALD-AUD treatment lacks established guidelines, creating uncertainty regarding when, how, and which treatment regimens to apply. This absence of evidence-based data raises important questions about the effectiveness and optimal strategies for addressing AUD within the context of ALD treatment.

This research program will address these questions by conducting an ALD-AUD integrated treatment clinical trial. The trial will evaluate whether active treatment of AUD will reduce progression of liver disease and improve liver-related outcomes. In addition, the program will continue and expand the collection and usage of biospecimens in order  to provide a basis for performing additional ancillary and mechanistic studies to understand factors influencing the course of liver disease and alcohol relapse. 

The program will leverage the existing AlcHepNet infrastructure and resources for the upcoming clinical trial. Initially funded in 2012 as four separate consortia, AlcHepNet was consolidated into a unified entity in 2018. In the next cycle, AlcHepNet will enhance network experience by incorporating specialties essential for holistic care, thereby expanding the team’s breadth. The structure of AlcHepNet is aimed to increase the efficiency by streamlining processes for designing and conducting clinical trials, reducing administrative redundancy, facilitating complementary interactions across the Network and making optimal use of scientific innovations.

The purpose of AlcHepNet is to improve biomedical, psychosocial and quality of life outcomes for patients with advanced ALD. 

This Clinical Center RFA (U01) runs in parallel with a companion RFA soliciting U24 applications for a Data Coordinating Center (DCC).

Purpose and Objectives

The AlcHepNet will conduct integrated treatment clinical trials focused on advanced alcohol-associated  liver disease (ALD), including severe alcohol-associated hepatitis (sAH) and alcohol-associated cirrhosis (deAC).

Important gaps in knowledge and hurdles to patient care with advanced ALD  that could be addressed include but are not limited to:

• Effect of integrated treatments targeting both AUD and ALD on ALD patients’ survival.
• Potential drug-related hepatotoxicity of current AUD medications in patients with ALD.
• Hurdles to practical approaches (treatment duration, endpoints, outcome measures, etc.) to conducting clinical trials that combine AUD and ALD.
  • Interventional methods and techniques may include, but are not limited to, pharmacologic agents, behavioral, cognitive, and device-based approaches, or a combination thereof.
  • The experimental arm for AUD in the integrated clinical trial should involve an active AUD treatment that assesses whether treating AUD leads to favorable outcomes for liver disease. This approach should be compared to the standard method, which involves asking questions about alcohol consumption and referring patients to addiction specialists.

To achieve the goals of the program, the RFAs require that AlcHepNet

• Conduct a multi-center multi-disciplinary clinical trial designed to study safety and efficacy of interventions targeting both AUD and liver disease.

First-in-human clinical trials or clinical studies where the objective is to elucidate the pathogenesis of the disease or identify potential therapeutic targets for future clinical trial are considered not responsive to this RFA.

Investigators and the Data Coordinating Center will work towards providing open access of its data for researchers outside AlcHepNet.

Network Organization

The AlcHepNet will bring together the Clinical Component (consisting of up to 6 Clinical Site Centers) and the Data Coordinating Center (DCC) to form a cooperative research platform for performing the multi-site common protocol clinical trial and local ancillary studies in patients with advanced ALD. The AlcHepNet will also be supported by NIAAA, the Steering Committee and its subcommittees, Data and Safety Monitoring Board (DSMB), and other committees as needed. The responsibilities of each component of the Network are described in the Terms and Conditions of Award.

Clinical component: will consist of up to 6 collaborative U01 clinical centers conducting the common multi-center clinical trial and local site-specific ancillary studies. They will be responsible for proposing protocols, participating in their overall development, conducting the research, and disseminating research findings. The Clinical Center sites will be reimbursed on a per-capita basis for enrollment and biospecimen collection under the common protocol via subcontract with the DCC. Clinical site budgets will fund local infrastructure, salaries, and the cost of local study protocols.

Data Coordinating Center: one DCC will serve as the Network data management center and central biorepository, provides biostatistical and logistical support, coordinate various trans-Network activities as well as standardizes approaches, procedures and data formats to minimize resources/effort duplication. The DCC is expected to facilitate the sharing of data and biospecimens to the broader research community upon study completion via establishing a Data Commons into the public domain.

Clinical component and DCC will be individually awarded through the respective NOFOs indicated below:

1. Clinical component under RFA-AA-24-004 (collaborative U01) (this NOFO) (up to 6 awards)
2. Data Coordinating Center under RFA-AA-24-005 (U24) (1 award)

Objectives and Specific Requirements for Clinical Centers (CC)

All CC will recruit and treat a sufficient number of participants, implement the common protocol clinical trial and site-specific ancillary studies, where proposed, according to the manual of operations, collect the outcome data specified in the protocol and provide study data to the DCC.

Specific requirements for clinical center U01 applications:

• The collaborative clinical U01s must share identical specific aims, a specific protocol across the sites and be organized as such to increase sample size, accelerate recruitment, and increase sample diversity and representation.
• Each U01 must have 2 principal investigators, one representing hepatology and one representing addiction medicine.
• The program should provide a mechanism for cross-site coordination, quality control, database management, statistical analysis, and reporting in conjunction with the DCC.
• Each individual CC U01 application should provide a demonstrated track record in clinical trial enrollment and capacity to achieve milestones.
• Each U01 application should include the Research Plan, Data and Safety Monitoring Plan, Clinical Protocol Synopsis, Statistical Analysis Plan for Clinical Trial, and Milestone Plan.
• All U01 applications to this RFA should be designed to maximize the use of the existing expertise and resources from the NIAAA-supported AH program and other outside research resources where it is possible to leverage existing data and infrastructure.
• All U01 CCs are required to use a central IRB.
• Each U01 application may propose site-specific ancillary study that leverage the common protocol data and biospecimens by identifying important research questions involving understanding and management of advanced ALD that require use of this unique shared longitudinal resource to adequately answer.

Responsibilities of the Clinical Centers (CC)

CC responsibilities include study design and conduct, protocol development and implementation, and data and biospecimen collection, as described in detail below. In addition, the CCs are responsible for assuring Good Clinical Practice (GCP) and adequate protections of human subjects and disseminating research findings in coordination with the DCC. All CCs are required to participate in a cooperative and interactive manner with one another and with the DCC.

Study Design, Protocol Development and Implementation

Each CC will be responsible for conducting local ancillary studies as originally proposed in their awarded U01 application, as well as contributing to the development of and adherence to the common protocol for integrated treatment clinical trial and biospecimen collection efforts to support network-wide studies at the direction of the DCC and Steering committee. Once the common protocol clinical trial has been launched, each CC will be expected to enroll according to the enrollment plan to meet milestones within each funding year, as indicated in Notice of Award.

Data/Biospecimen Collection and Reimbursement

The CCs will be responsible for collecting, storing, and analyzing the data and/or biospecimens necessary for completion of the local studies as proposed in the U01 application, and for transferring data and biospecimens collected under the common protocol to the DCC for management and collation. The CC sites will be reimbursed on a per-capita basis for enrollment and biospecimen collection under the common protocol via subcontract with the DCC, but do not receive funding to perform the local ancillary studies from the DCC. Personnel and related infrastructure costs to conduct local studies at the CCs must be budgeted for in the CC application. Applicants should note that only research-related costs above those incurred as part of usual clinical care are eligible to be covered by CC award funds and/or reimbursement via reimbursement funds from the DCC. It is anticipated that approximately $450,000 direct costs per year in reimbursement funds will be included in the DCC award and made available for reimbursement to the CCs.

Human Subjects Protection

CCs must agree to use of the single Institutional Review Board (sIRB) selected by the DCC for the common protocol clinical trial, consistent with NIH policies regarding multi-site studies involving human subjects.

CCs are expected to oversee the preparation of informed consent templates, recruitment brochures, and other study-related patient materials for the local studies, and ensuring that all participating sites within the CC are trained on local site-specific human subjects procedures including the informed consent process, AlcHepNet policies, applicable regulations, and Good Clinical Practice (GCP). The CCs will also be responsible for ensuring that study execution is compliant with the local and common protocols, manual of procedures, AlcHepNet policies, applicable regulations and guidelines throughout the duration of the program. CCs are responsible for monitoring enrollment and data quality among their participating subsites, and identifying and reporting to the DCC any study-related issues as early as possible. As needed, the CCs will work with the DCC to develop corrective and preventative action plans in consultation with the NIAAA.

CCs will also be responsible for assuring local study compliance with the Health Insurance Portability and Accountability Act (HIPAA) in accordance with 45 CFR Parts 160, 162, and 164 or corresponding regulations for any participating international Clinical Centers; Implementation and supervision of the revised Common Rule (45 Part 46), including the use of a single-IRB review for federally-funded, multi-institutional studies conducted in the United States. In addition, the CCs will be expected to register and report results of local clinical studies in ClinicalTrials.gov as required by NIH policy and 42 CFR Part 11.

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

Diversity

It is expected that the clinical centers will seek to recruit prospective research team members from diverse backgrounds, including individuals from underrepresented groups.  For more information, see  NOT OD 20-031 (Notice of NIH's Interest in Diversity) and NOT OD 22-019 (Reminder: Notice of NIH's Encouragement of Applications Supporting Individuals from Underrepresented Ethnic and Racial Groups as well as Individuals with Disabilities).

Individuals from underrepresented groups are encouraged to pursue opportunities to serve as key contributors to the biomedical research . In addition, research teams are encouraged to include investigators from various disciplines/departments and specialties.

NIAAA is especially interested in clinical centers which cover patient populations experiencing health disparities.

Plan for Enhancing Diverse Perspectives (PEDP)

• This NOFO requires a Plan for Enhancing Diverse Perspectives (PEDP) as described in NOT-MH-21-310, submitted as Other Project Information as an attachment (see Section IV).
• Applicants are strongly encouraged to read the NOFO instructions carefully and view the available PEDP guidance material. The PEDP will be assessed as part of the scientific and technical peer review evaluation, as well as considered among programmatic matters with respect to funding decisions.

Non-Responsive Applications

The following  applications will be considered non-responsive and will be withdrawn prior to review: 

• Application proposing clinical sites that did not achieve a minimum enrollment milestone of 50% (or 16 subjects) in the most recent AlcHepNet clinical trial at the time of interim analysis (January 31, 2022).  
• Applications proposing the introduction or testing of a new drug candidate for the treatment of ALD.
   

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

Investigators proposing NIH-defined clinical trials may refer to the Research Methods Resources website for information about developing statistical methods and study designs.

Section II. Award Information

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

Section III. Eligibility Information

1. Eligible Applicants

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)

Local 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)

Federal Governments

• 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 Organizations) 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 not 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. Failure to complete registrations in advance of a due date is not a valid reason for a late submission, please reference NIH Grants Policy Statement Section 2.3.9.2 Electronically Submitted Applications for additional information

• System for Award Management (SAM) – 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.
  • Unique Entity Identifier (UEI) - A UEI is issued as part of the SAM.gov registration process. The same UEI must be used for all registrations, as well as on the grant application.
• eRA Commons - Once the unique organization identifier is established, organizations can register with eRA Commons in tandem with completing their Grants.gov registrations; all registrations must be in place by time of submission. 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 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 their organization to develop an application for support. Individuals from diverse backgrounds, including underrepresented racial and ethnic groups, individuals with disabilities, and women are always encouraged to apply for NIH support. See, Reminder: Notice of NIH's Encouragement of Applications Supporting Individuals from Underrepresented Ethnic and Racial Groups as well as Individuals with Disabilities, NOT-OD-22-019.

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 How to Apply Application Guide.

The application is required to be submitted as a multiple PD(s)/PI(S), and at least one of PD(s)/PI(s) must be a current AlcHepNet awardee funded through RFA-AA-18-002. 

2. Cost Sharing

This NOFO does not require cost sharing as defined in the NIH Grants Policy Statement NIH Grants Policy Statement Section 1.2 Definition of Terms.

3. Additional Information on Eligibility

Number of Applications

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

The NIH will not accept duplicate or highly overlapping applications under review at the same time, per NIH Grants Policy Statement Section 2.3.7.4 Submission of Resubmission Application. 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 NIH Grants Policy Statement 2.3.9.4 Similar, Essentially Identical, or Identical Applications).

This RFA requires applications to contain at least two senior/key personnel of different clinical specialties - hepatology and alcohol addiction medicine. One of those specialty areas should be represented by the contact PD/PI, with the second specialty area represented by an investigator who is designated as a multiple PD/PI. More than one senior/key personnel from each of the two specialty areas may be included. Those listed as PD(s)/PI(s) should have demonstrated experience in clinical research studies involving ALD patient populations.

Section IV. Application and Submission Information

1. Requesting an Application Package

The application forms package specific to this opportunity must be accessed through ASSIST, Grants.gov Workspace or an institutional system-to-system solution. Links to apply using ASSIST or Grants.gov Workspace are available in Part 1 of this NOFO. See your administrative office for instructions if you plan to use an institutional system-to-system solution.

2. Content and Form of Application Submission

It is critical that applicants follow the instructions in the Research (R) Instructions in the How to Apply - Application Guide except where instructed in this notice of funding opportunity 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.

Letter of Intent

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

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

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

The letter of intent should be sent to:

Philippe Marmillot, Ph.D.
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Telephone: 301-443-2861
Email: philippe.marmillot@nih.gov

Page Limitations

All page limitations described in the How to Apply – Application Guide and the Table of Page Limits must be followed.

The following section supplements the instructions found in the How to Apply – Application Guide and should be used for preparing an application to this NOFO.

SF424(R&R) Cover

All instructions in the How to Apply Application Guide must be followed.

SF424(R&R) Project/Performance Site Locations

All instructions in the How to Apply Application Guide must be followed.

SF424(R&R) Other Project Information

All instructions in the How to Apply Application Guide must be followed.

Facilities and other resources

Each application in a set of linked collaborative U01s must describe the facilities and resources available for that application. It is expected that this section of the application will be different in each of the linked applications. Applicants should especially focus on the unique resources at their institution and any sub-contracts which lend themselves to the completion of the project.

Other Attachments

The following attachments must be included as a part of the collaborative agreement application. Attachments permit expansion but not duplication of certain elements that cannot be appropriately described in the Research Strategy. All attachments listed below must be provided or the application will not be peer reviewed.

1. Clinical Protocol Synopsis for Clinical Trial

Clinical Protocol Synopses must be provided as attachments called "Clinical Protocol Synopsis for Clinical Trial.pdf" (12 pages).

The synopsis will provide a concise snapshot of the overall study. It will be considered by reviewers, in addition to the components of the regular application. The synopsis is meant to supplement the information provided in the Research Strategy and must not duplicate information there. The Clinical Protocol Synopsis should represent the protocol that would be implemented at each site. It is meant to summarize the necessary elements of the clinical trial.

Clinical Protocol Synopses are expected to include the following information:

• Protocol Title
• Focus of the Study
• Objectives: A brief description of objectives, including the primary objective and secondary objectives (in a few sentences).
• Study Design: A brief description of the study design
• Intervention to Be Tested: A description of the intervention to be tested, and a brief description of the protocol to be followed in each arm of the trial and the adherence assessment. Specify concomitant interventions, if applicable.
• Primary and Important Secondary Endpoints: Specify the endpoints for the primary and, if applicable, important secondary endpoints.
• Provide schedule of clinical and laboratory evaluations.
• Study Population: A brief description of the study population, including the sample size, gender, age, demographic group, required health status, and geographic location.
• Enrollment Sites: A list of enrollment/participating sites and their expected enrollment. Briefly describe plans for IRB approval.
• Statistical Design and Power: Specify the number of subjects to enroll, the expected effect size, event rate, power and the statistical methods (per protocol, intent-to-treat) to compare groups with respect to the primary outcome measure. Specify criteria for intervention discontinuation and stopping guidelines.
• Group Assignment: Methods of assignment of participants to study groups and of randomization.
• Subject Participation Duration: Time it will take for each individual participant to complete all subject visits.
• A Recruitment and Retention Plan for Research Study Participants describing the following: 1) the planned recruitment methods including use of contact lists, databases or other pre-screening resources, advertisements, outreach, media/social media and referral networks or groups; 2) if there are known participant or study-related barriers to accrual or participation (based on literature or prior experience), please list these barriers and describe plans to address them to optimize success; 3) contingency plans for participant accrual if enrollment significantly lags behind accrual benchmarks; 4) participant retention and adherence strategies; 5) possible competition from other trials for study participants; 6) safeguards for vulnerable populations as appropriate;

2. 

1. Milestones and Timeline Plan for Clinical Trial

Linked applications must provide an identical Milestones and Timeline Plans across sites, submitted as pdf attachments with the title “Milestones and Timeline for Clinical Trial” (2 pages) that include the following information:

• Completion of regulatory approvals;
• Enrollment of the first subject;
• Enrollment of 30%, 65% and 90% of the projected recruitment;
• Completion of data collection time period;
• Completion of primary endpoint and secondary endpoint data analyses time period;
• Completion of final study report.

The Terms and Conditions will include site activation and recruitment milestones, accrual goals and any other identified requirements for completion of the approved research. Each participating site will need to include achievement of specific milestones for clinical trial in its annual progress report in order to provide clear indicators of a site project's continued success or developing difficulties. Release of funding for each year of the award will be contingent upon achieving the stated milestones; failure to achieve these milestones may lead to award restrictions or termination.

2.  Plan for Enhancing Diverse Perspectives

• In an "Other Attachment" entitled "Plan for Enhancing Diverse Perspectives," all applicants must include a summary of strategies to advance the scientific and technical merit of the proposed project through expanded inclusivity
• The PEDP should provide a holistic and integrated view of how enhancing diverse perspectives is viewed and supported throughout the application and can incorporate elements with relevance to any review criteria (significance, investigator(s), innovation, approach, and environment) as appropriate.
• Where possible, applicant(s) should align their description with these required elements within the research strategy section
• The PEDP will vary depending on the scientific aims, expertise required, the environment and performance site(s), as well as how the project aims are structured
• The PEDP may be no more than 1-page in length and should include a timeline and milestones for relevant components that will be considered as part of the review

 Examples of items that advance inclusivity in research and may be part of the PEDP can include, but are not limited to:

• Discussion of engagement with different types of institutions and organizations (e.g., research-intensive, undergraduate-focused, minority-serving, community-based).
• Description of any planned partnerships that may enhance geographic and regional diversity.
• Plan to enhance recruiting of women and individuals from groups historically underrepresented in the biomedical, behavioral, and clinical research workforce.
• Proposed monitoring activities to identify and measure PEDP progress benchmarks.
• Plan to utilize the project infrastructure (i.e., research and structure) to support career-enhancing research opportunities for diverse junior, early- and mid-career researchers.
• Description of any training and/or mentoring opportunities available to encourage participation of students, postdoctoral researchers and co-investigators from diverse backgrounds.
• Plan to develop transdisciplinary collaboration(s) that require unique expertise and/or solicit diverse perspectives to address research question(s).
• Publication plan that enumerates planned manuscripts and proposed lead authorship.
• Outreach and planned engagement activities to enhance recruitment of individuals from diverse groups as research participants including those from underrepresented backgrounds.

For further information on the Plan for Enhancing Diverse Perspectives (PEDP), please see https://braininitiative.nih.gov/about/plan-enhancing-diverse-perspectives-pedp

The following additional documents must be included as attachments:

• The informed consent templates;
• Copies of data collection forms, questionnaires or other relevant materials;
• Documentation of co-funding of clinical trials from partners, if applicable.

SF424(R&R) Senior/Key Person Profile

All instructions in the Ho to Apply Application Guide must be followed.

• Each application must include only its own personnel and respective biographical sketches.

The PD(s)/PI(s) of the clinical trial/observational study must be experienced in the conduct of clinical studies and have prior experience with studies in AUD and 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. Most clinical trials will require a multidisciplinary team (clinician, data manager, study coordinator(s), etc.) and the application should reflect their roles and responsibilities in the design and implementation of the study protocol

R&R or Modular Budget

All instructions in the How to Apply Application Guide must be followed.

PEDP implementation costs

• Applicants may include allowable costs associated with PEDP implementation (as outlined in the Grants Policy Statement section 7: https://grants.nih.gov/grants/policy/nihgps/html5/section_7/7.1_general.htm).

R&R Subaward Budget

All instructions in the How to Apply Application Guide must be followed.

• Each application must include only its own budget If clinical sub-sites are involved, they should be supported by the fee for service mechanism. Sub-contracts from the clinical center sites to sub-sites are not allowed.
• All applications must provide detailed scientific and operational plans as well as funding needs for the entire trial and data analysis period. Reviewers of the application(s) will evaluate the entire project.
• U01 application budget should reflect support for personnel and infrastructure costs of CC to conduct the common protocol clinical trial and local ancillary studies.
• For other Investigators/Staff, the person-months should be commensurate with the effort required for the proposed personnel activities. This should include support for clinical research support staff, e.g., clinical coordinators, at the participating sites with demonstrated clinical research experience to facilitate the day-to-day clinical study operations of the CCs including: managing collaborations with other clinical research coordinators; obtaining informed consent; processing, storage, and shipping of human biospecimens; a comprehensive knowledge of GCP study conduct; development and monitoring of study enrollment accrual benchmarks; completion of case report forms; administration of agreements with sub-sites CCs, the DCC, and other research collaborators.
• Applications may include the cost of local site-specific ancillary studies.
• Other expenses as appropriate to complete the proposed studies. Applicants should note that only research-related costs above those incurred as part of usual clinical care are eligible to be covered by grant funds and/or reimbursement via reimbursement costs from the DCC.
• Include budget support for key investigators and personnel to travel to biennial two-day meetings of Network investigators in Bethesda, Maryland.
• If parts of the costs of the trial are to be provided by sources other than NIAAA, these contributions must be presented in detail in the budget justification.

Note: Do not include budget support for the DSMB.

PHS 398 Cover Page Supplement

All instructions in the How to Apply Application Guide must be followed.

PHS 398 Research Plan

All instructions in the How to Apply Application Guide must be followed, with the following additional instructions:

Research Strategy

The Research Strategy must be identical across linked collaborative U01 applications, with the exception of the subsection under the header "Elements Unique to This Site." All variations in the Research Strategy between sites, no matter how minor, should be highlighted in a subsection of the Research Strategy with the heading "Elements Unique to This Site" (estimated to be no more than 1 page of the Research Strategy Section). In this subsection, PD(s)/PI(s) should describe, for example, how the research site has a unique role in the collaboration, such as data coordination, etc. Any site that contracts out some portions of this work should list this fact under "Elements Unique to This Site," and provide a full description of the nature, purpose, and oversight of this contractual arrangement.

The Research Strategy should be organized in a manner that will facilitate peer review. The body of the application must present an overview of the state of the science, current status and relevance of the proposed clinical studies, a discussion of the specific protocol, and the approach to data collection, analysis and dissemination.

Applications must conform with current guidelines, taking care to address important elements related to Significance, Approach, and Innovation.

Applications should provide the overall goals for the entire application and indicate separately Specific Aims to be accomplished in the clinical trial.

Applicants are requested to clearly address the following aspects:

• Provide a clear statement of the question(s) that the study will address and its importance;
• Describe the scientific rationale and clinical need for the study, including an assessment of previous preclinical and/or clinical studies and their quality;
• Describe the potential for the study results to impact knowledge, clinical practice or health care policy;
• Describe the overall strategy, methodology and analyses to be used to accomplish the goals and specific aims of the study;
• Describe the recruitment and retention strategy;
• Describe the intervention to be tested and the protocol to be followed in each arm of the trial, including a discussion of potential biases or challenges in the protocol and how they will be addressed;
• Describe the process to be used for obtaining informed consent;
• Describe statistical methods and power for the study design;
• Describe plans for acquisition and handling of study agent(s);
• Describe the process that will be used for attaining all necessary FDA or other applicable regulatory agency approvals necessary to the conduct of the trial;
• Describe the study organization and administration, and include a communication plan. The study organization plan can include, but is not necessarily limited to: a description of committee structures needed to manage the complexity of the clinical trial; the role of any internal or external advisory committees; the oversight, responsibilities, and coordination of any sites or cores proposed; and the role of any sub-contractors or providers of services, personnel, or facilities. The plan should explain how the DCC will coordinate activities on clinical trial implementation. The communication plan should include a description of the coordination between the separate components including NIAAA and identify the key channels used to reach and inform each stakeholder group and receive feedback.
• Describe plans to implement and monitor Good Clinical Practices (GCP) and Good Laboratory Practices (GLP) as appropriate.
• PD/PI must describe the strong leadership abilities and proficiency in managing large, multi-component programs without duplicating information in the biosketches.

In this section, there should be sufficient description of the items listed above to permit thorough evaluation of the proposed study. Technical details contained in the Clinical Protocol Synopsis, Statistical Analysis Plan, and Milestones and Timeline Plan can be referenced from within the Research Strategy section in order to avoid duplicating text.

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the  How to Apply Application Guide.

Other Plan(s): Note: Effective for due dates on or after January 25, 2023, the Data Management and Sharing Plan will be attached in the Other Plan(s) attachment in FORMS-H application forms packages.

All instructions in the How to Apply Application Guide must be followed, with the following additional instructions:

• All applicants planning research (funded or conducted in whole or in part by NIH) that results in the generation of scientific data are required to comply with the instructions for the Data Management and Sharing Plan. All applications, regardless of the amount of direct costs requested for any one year, must address a Data Management and Sharing Plan.
• Applications that include human subject research are expected to describe basic plans for submitting grant-related human subjects data to the NIAAA-sponsored data repository, as described in NOT-AA-23-001 and NOT-AA-23-002.

Appendix: Only limited Appendix materials are allowed. Follow all instructions for the Appendix as described in the How to Apply Application Guide.

• No publications or other material, with the exception of blank questionnaires or blank surveys, may be included in the Appendix.

PHS Human Subjects and Clinical Trials Information

When involving human subjects research, clinical research, and/or NIH-defined clinical trials (and when applicable, clinical trials research experience) follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the How to Apply Application Guide, with the following additional instructions:

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

Study Record: PHS Human Subjects and Clinical Trials Information

All instructions in the How to Apply Application Guide must be followed.

Section 4 - Protocol Synopsis

4.1.a. Detailed Description

The synopsis will provide a concise snapshot of the overall study. It will be considered by reviewers, in addition to the components of the regular application. The synopsis is meant to supplement the information provided in the Research Strategy and must not duplicate information there. The Clinical Protocol Synopsis should represent the protocol that would be implemented at each site. It is meant to summarize the necessary elements of the clinical trial.

Clinical Protocol Synopses are expected to include the following information:

• Protocol Title
• Focus of the Study
• Objectives: A brief description of objectives, including the primary objective and secondary objectives (in a few sentences).
• Study Design: A brief description of the study design
• Intervention to Be Tested: A description of the intervention to be tested, and a brief description of the protocol to be followed in each arm of the trial and the adherence assessment. Specify concomitant interventions, if applicable.
• Primary and Important Secondary Endpoints: Specify the endpoints for the primary and, if applicable, important secondary endpoints.
• Provide schedule of clinical and laboratory evaluations.
• Study Population: A brief description of the study population, including the sample size, gender, age, demographic group, required health status, and geographic location.
• Enrollment Sites: A list of enrollment/participating sites and their expected enrollment. Briefly describe plans for IRB approval.
• Statistical Design and Power: Specify the number of subjects to enroll, the expected effect size, event rate, power and the statistical methods (per protocol, intent-to-treat) to compare groups with respect to the primary outcome measure. Specify criteria for intervention discontinuation and stopping guidelines.
• Group Assignment: Methods of assignment of participants to study groups and of randomization.
• Subject Participation Duration: Time it will take for each individual participant to complete all subject visits.
• A Recruitment and Retention Plan for Research Study Participants describing the following: 1) the planned recruitment methods including use of contact lists, databases or other pre-screening resources, advertisements, outreach, media/social media and referral networks or groups; 2) if there are known participant or study-related barriers to accrual or participation (based on literature or prior experience), please list these barriers and describe plans to address them to optimize success; 3) contingency plans for participant accrual if enrollment significantly lags behind accrual benchmarks; 4) participant retention and adherence strategies; 5) possible competition from other trials for study participants; 6) safeguards for vulnerable populations as appropriate;

 4.3 Statistical Design and Power

These documents should provide details on the analyses described in the protocol, including a detailed description of how the statistical analysis of the primary and secondary endpoints will be performed, how the sample size was determined, how missing data will be handled, plans for interim analyses for safety, efficacy and futility, plans for recalculation of the sample size midway through the study (if applicable), etc. Applications should include plans to account for participant drop-out.

Delayed Onset Study

Note: Delayed onset does NOT apply to a study that can be described but will not start immediately (i.e., delayed start). All instructions in the How to Apply Application Guide must be followed.

PHS Assignment Request Form

All instructions in the How to Apply Application Guide must be followed.

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

See Part 2. Section III.1 for information regarding the requirement for obtaining a unique entity identifier and for completing and maintaining active registrations in System for Award Management (SAM), NATO Commercial and Government Entity (NCAGE) Code (if applicable), eRA Commons, and Grants.gov

4. Submission Dates and Times

Part I. 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 Grants Policy Statement Section 2.3.9.2 Electronically Submitted Applications.

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 How to Apply – Application Guide.

5. Intergovernmental Review (E.O. 12372)

This initiative is not subject to intergovernmental review.

6. Funding Restrictions

All NIH awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

Pre-award costs are allowable only as described in the NIH Grants Policy Statement Section 7.9.1 Selected Items of Cost.

7. Other Submission Requirements and Information

Applications must be submitted electronically following the instructions described in the How to Apply 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 How to Apply – Application Guide. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Dealing with System Issues guidance. 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 form. 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 NOFO for information on registration requirements.

The applicant organization must ensure that the unique entity identifier provided on the application is the same identifier used in the organization’s profile in the eRA Commons and for the System for Award Management. Additional information may be found in the How to Apply Application Guide.

See more tips for avoiding common errors.

Applications must include annual milestones. Applications that fail to include annual milestones will be considered incomplete and will be withdrawn. Applications must include a PEDP submitted as Other Project Information as an attachment. Applications that fail to include a PEDP will be considered incomplete and will be withdrawn before review.

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.

Post Submission Materials

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

Any instructions provided here are in addition to the instructions in the policy.

Section V. Application Review Information

1. Criteria

Only the review criteria described below will be considered in the review process.  Applications submitted to the NIH in support of the NIH mission are evaluated for scientific and technical merit through the NIH peer review system.

For this particular NOFO, note the following:

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

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

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

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.

2. Review and Selection Process

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 policies and practices, 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 will receive a written critique.

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.

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

Applications will be assigned on the basis of established PHS referral guidelines to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications submitted in response to this NOFO. Following initial peer review, recommended applications will receive a second level of review by the appropriate national Advisory Council or Board. The following will be considered in making funding decisions:

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

3. Anticipated Announcement and Award Dates

After the peer review of the application is completed, the PD/PI will be able to access his or her Summary Statement (written critique) via the eRA Commons. Refer to Part 1 for dates for peer review, advisory council review, and earliest start date.

Information regarding the disposition of applications is available in the NIH Grants Policy Statement Section 2.4.4 Disposition of Applications.

Section VI. Award Administration Information

1. Award Notices

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

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

Recipients must comply with any funding restrictions described in Section IV.6. 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 NOFO 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.

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

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

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

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

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

2. Administrative and National Policy Requirements

All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the NoA. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: Generaland Part II: Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Recipients, and Activities, including of note, but not limited to:

• Federalwide Standard Terms and Conditions for Research Grants
• Prohibition on Certain Telecommunications and Video Surveillance Services or Equipment
• Acknowledgment of Federal Funding

If a recipient is successful and receives a Notice of Award, in accepting the award, the recipient agrees that any activities under the award are subject to all provisions currently in effect or implemented during the period of the award, other Department regulations and policies in effect at the time of the award, and applicable statutory provisions.

If a recipient receives an award, the recipient must follow all applicable nondiscrimination laws. The recipient agrees to this when registering in SAM.gov. The recipient must also submit an Assurance of Compliance (HHS-690). To learn more, see the HHS Office for Civil Rights website.

HHS recognizes that NIH 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 NOFO.

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 2 CFR Part 200.206 “Federal awarding agency review of risk posed by applicants.” This provision will apply to all NIH grants and cooperative agreements except fellowships.

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 (HHS) grant administration regulations at 2 CFR Part 200, 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 recipients 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 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 recipients for the project as a whole, although specific tasks and activities may be shared among the recipients and 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). Recipient(s) will name investigators to serve as members on a Steering Committee and other subcommittees. Recipientswill 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 and NIAAA Project Scientist.
• 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, recipients 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.
• Recipients must agree to comply with the processes and goals as delineated within the NOFO.

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 recipients, and ensuring that the activities of the recipients are consistent with the mission of the NIAAA and AlcHepNet. Specifically, the PS will have primary responsibility for:

• participating in the definition of objectives and approaches, and in planning, conducting, analyzing, and advising on the publication of results, interpretations, and conclusions of their studies. However, the dominant role and prime responsibility for the activity reside with the recipient(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, recipients 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 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 recipientand 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 AlcHepNet that integrates the efforts of all Network recipients and provides oversight of collaborative activities. The SC will be composed of the following voting members: all PD(s)/PI(s) representing each AlcHepNet U01/U24 award; and the NIAAA Project Scientist.

Chair of the SC.  Principal investigator with advanced expertise will be selected to serve as chair  of the SC by the NIAAA, in consultation with PIs in the AlcHepNet. The chair 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;
• 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 AlcHepNet;
• 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 andminorities 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 bienniallly and by teleconference as decided  by the members of the Steering Committee. 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) Ancillary Studies. 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 the  clinical trials. The ancillary study sub-committee will coordinate the site-specific ancillary studies 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.

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 recipient. This special dispute resolution procedure does not alter the recipient'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.

3. Data Management and Sharing

Consistent with the 2023 NIH Policy for Data Management and Sharing, when data management and sharing is applicable to the award, recipients will be required to adhere to the Data Management and Sharing requirements as outlined in the NIH Grants Policy Statement. Upon the approval of a Data Management and Sharing Plan, it is required for recipients to implement the plan as described.

4. Reporting

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

Recipients will provide updates at least annually on implementation of the PEDP.

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. NIH NOFOs outline intended research goals and objectives. Post award, NIH will review and measure performance based on the details and outcomes that are shared within the RPPR, as described at 2 CFR Part 200.301.

The Federal Funding Accountability and Transparency Act of 2006 as amended (FFATA), includes a requirement for recipients of Federal grants to report information about first-tier subawards and executive compensation under Federal assistance awards issued in FY2011 or later.  All recipients 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 the threshold.  See the NIH Grants Policy Statement for additional information on this reporting requirement.

In accordance with the regulatory requirements provided at 2 CFR Part 200.113 and Appendix XII to 2 CFR Part 200, 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 2 CFR Part 200 – Award Term and Condition for Recipient Integrity and Performance Matters.

Section VII. Agency Contacts

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

eRA Service Desk (Questions regarding ASSIST, eRA Commons, application errors and warnings, documenting system problems that threaten submission by the due date, and post-submission issues)

Finding Help Online: https://www.era.nih.gov/need-help (preferred method of contact)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

General Grants Information (Questions regarding application instructions, application processes, and NIH grant resources)
Email: GrantsInfo@nih.gov (preferred method of contact)
Telephone: 301-480-7075

Grants.gov Customer Support (Questions regarding Grants.gov registration and Workspace)
Contact Center Telephone: 800-518-4726
Email: support@grants.gov

Zhigang (Peter) Gao, M.D.
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Telephone: 301.443.6106
Email:  gaozh@mail.nih.gov

Ranga Srinivas, Ph.D.
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Telephone: 301-451-2067
Email: srinivar@mail.nih.gov

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

Section VIII. Other Information

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

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 2 CFR Part 200.