National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Reissue of RFA-AA-19-005
August 23, 2019- Clarifying Competing Application Instructions and Notice of Publication of Frequently Asked Questions (FAQs) Regarding Proposed Human Fetal Tissue Research. See Notice NOT-OD-19-137
The purpose of this Funding Opportunity Announcement (FOA) is to invite cooperative agreement applications for research that advances promising compounds through the drug development pipeline for the treatment of Alcohol Use Disorder (AUD) or Alcohol-Related Organ Damage (AROD), or the combination of AUD and AROD.
NIAAA is seeking applications for medications development research projects from for-profit and not-for-profit entities, including academic institutions, pharmaceutical and biotechnology companies, private and public foundations, and small businesses able to demonstrate significant resource commitment to the proposed project.
The aim of this FOA is to move candidate compounds through any single phase, or multiple phases of the development spectrum.
For compounds focused on treating AUD or the combination of AUD and AROD, projects may start with lead optimization (late discovery) and go through Phase 2 proof-of-concept studies.
For AROD, studies may start with lead optimization, but only go as far as Phase 1 safety tolerability trials.
In all cases the goal of the proposed candidate compound must ultimately be the submission to the FDA. All candidate compounds must be patentable and have a plausible path to commercialization. Within these phases of drug development, each proposed project should have a defined entry and exit point. Applicants are strongly encouraged to contact the NIAAA Division of Medications Development Staff or Division of Metabolism and Health Effects Staff prior to submitting an application to this FOA.
January 16, 2020
February 26, 2020
March 26, 2020
All applications are due by 5:00 PM local time of applicant organization. All types of non-AIDS applications allowed for this funding opportunity announcement are due on the listed date(s).
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 funding opportunity announcement.
Conformance to all requirements (both in the Application Guide and the FOA) is required and strictly enforced. Applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions.
Applications that do not comply with these instructions may be delayed or not accepted for review.
There are several options available to submit your application through Grants.gov to NIH and Department of Health and Human Services partners. You must use one of these submission options to access the application forms for this opportunity.
Alcohol Use Disorder (AUD) is a global health problem, affecting more than 78 million adults world-wide, including over 15 million adult Americans and resulting in a myriad of medical, psychological, social, economic, and personal problems. AUD ranks among the leading causes of decreased disability-adjusted life-years and ranks third in preventable causes of death in the United States. The total economic cost to society in the United States is a staggering $249 billion each year.
During the past two decades, progress has been made in developing medications to treat AUD. Currently, there are three Food and Drug Administration (FDA)-approved medications for the treatment of alcohol dependence: disulfiram, oral and long-term injectable naltrexone, and acamprosate. In addition, nalmefene recently has been approved in Europe. However, given the heterogeneous nature of AUD, many individuals show only limited or no response to these medications. Because of this, developing and evaluating new, more robust and safe medications to treat AUD remains a top priority for NIAAA.
AUD is associated with end-organ damage to multiple systems including the liver, heart, pancreas, lung, brain, kidney, bone and skeletal muscles, endocrine and immune systems as well as with the development of certain cancers and birth defects. The World Health Organization estimates that in 2016, of the 3 million alcohol-related deaths around the world, 21% involved digestive disorders, and 19% involved cardiovascular diseases. To avert such an enormous human and economic burden, effective therapies to prevent and treat Alcohol-Related Organ Damage (AROD) are urgently needed. There are currently no FDA-approved therapies for alcohol-related organ damage. Despite impressive scientific advances in basic research, the development of effective AROD therapies has been challenging, particularly due to the multi-factorial and unique actions of alcohol on living tissue as well as incomplete understanding of the natural history of AROD. Therefore, to catalyze drug development for AROD, the NIAAA is issuing this Funding Opportunity Announcement, which offers researchers funding to advance promising therapies by supporting IND-enabling and first in human testing of well characterized therapeutic candidates.
In AROD, improvement in the long-term survival following treatment of the organ damage depends on abstinence from alcohol and requires AUD treatment. Although combination therapies of different drugs to target AROD and AUD have been used to help the patients, a dual-targeting approach could serve as an emerging important model to expedite new therapies for comorbid diseases of alcohol addiction. Generation of dual-targeting drugs, where a single chemical entity can act on multiple molecular targets to have positive effects on both AROD and mechanisms regulating alcohol-seeking behavior may be of great relevance to the treatment of AUD patients with co-occurring AROD. }
The purpose of this RFA is accelerate the pace of medications development by focusing on moving candidate compounds through the drug development pipeline. This will be accomplished by using a cooperative agreement between NIAAA and outside entities to include both profit and non-profit organizations.
Stages of Medication Development
AUD and AUD/AROD:
For medications that treat AUD, or AUD and AROD, applications can focus at any point along the drug development pipeline from lead optimization through Phase 2. This includes: lead optimization (late discovery); pre-clinical investigational new drug (IND)-enabling studies (e.g., clinical toxicology; Good Manufacturing Practice (GMP) manufacturing; and pharmacokinetics; animal efficacy studies as long as candidate compound is patentable and has a plausible path to commercialization); Phase 1 human studies (e.g., safety, tolerability, dosing, alcohol interaction); Phase 2 studies (.e., proof-of-concept human laboratory and clinical trials).
For AROD, applications can focus at any point along the drug development pipeline from lead optimization through Phase 1. Phase 2 studies will not be considered.
The defined entry and exit points along the drug development pipeline will depend on the developmental status of the candidate compound. For example, some candidate compounds may only need one or a few IND-enabling studies, while other compounds may need an entire pre-IND package. The development stage of other compounds may require completing the IND package, securing an IND and conducting Phase 1 human safety tolerability study. Still other compounds, focused on treating AUD or both AUD and AROD, may have completed the Phase 1 study and be ready to begin a Phase 2 proof-of-concept trial.
Candidate compounds may be either a new chemical entity or a repurposed drug that has been that has been reformulated and is eligible for FDA approval. All IND-enabling and Phase 1 studies should be conducted consistent with FDA guidelines (https://www.fda.gov/downloads/drugs/guidances/ucm073246.pdf). Proposed Phase 2 studies should consider FDA guidance https://www.fda.gov/files/drugs/published/Alcoholism---Developing-Drugs-for-Treatment.pdf .
NIAAA is interested in exploring new targets for medications development. With our increased understanding of biological mechanisms underlying AUD, more than 35 promising targets have been shown to alter alcohol drinking behavior. The targets that are of particular interest to NIAAA are as follows: vasopressin 1b antagonist, hypocretin (orexin) receptor antagonist, nociception/orphanin FQ (NOP) receptor agonist/antagonist, kappa opioid receptor antagonist, Corticotropin releasing factor (CRF)1 antagonist, glucocorticoid receptor antagonist, glutamate NMDA modulator, glutamate transporter 1 enhancer, fatty acid amide hydrolase (FAAH) inhibitor, monoacylglycerol lipase (MAGL) inhibitor, potassium channel activator, nicotinic a3ß4 partial agonist and a7 agonist/positive allosteric modulator, phosphodiesterase inhibitor, GABAB receptor positive allosteric modulator, GABAA receptor modulator, glucagon-like peptide 1 (GLP-1) agonist, ghrelin receptor (GHS-R1A) antagonist, sigma receptor antagonist. Neurokinin1 antagonist, neuropeptide Y2 antagonist, Neuropeptide Y1 antagonist, Adrenoceptor beta antagonist, Agmatinase inhibitor. Other targets also will be considered if they have been validated. New chemical entities are NIAAA's highest priority. Repurposed compounds will be considered if they are reformulations of existing drugs and eligible for patenting and commercial development.
Though the cellular and molecular mechanisms causing and promoting alcohol-related organ damage have yet to be determined, a large body of evidence now shows that AROD share some common mechanisms which may be useful targets for drug development. For example, inflammatory mediators are involved in hepatitis, pancreatitis, pulmonary, renal, brain and vascular disorders associated with alcohol abuse. Oxidant stress caused by alcohol metabolism is a common element in cellular injury in liver, pancreas, lung, and brain. In addition, many alcohol-related medical disorders are associated with increased expression of genes favoring growth arrest and apoptosis, along with extracellular matrix formation and remodeling resulting in the failure of tissue repair and the progression to chronic diseases. Given that our knowledge of mechanisms of AROD is incomplete, therapies shown to alleviate AROD convincingly in animals, without known mechanism and meeting the other entry criteria, will be considered.
AUD and AROD
Recent advances in basic research suggest that overlapping mechanisms of organ damage and addiction processes involve dysregulation of inflammation. In light of the relatively incomplete knowledge of mechanisms of both types of pathology, effective therapies consisting of a single chemical entity and supported by convincing evidence in animal models, without known mechanism, will be considered.
Entry Criteria for the Following Stages of Medications Development
Applicants who propose candidate compounds need to minimally satisfy the following conditions:
1) The candidate compounds must be adequately characterized (e.g., structure/identity, selectivity, other modality-specific characteristics).
2) The candidate compound should be patentable and have a plausible path to commercialization.
3) Applicants must show ownership agreement (i.e., license agreement, MOU) of intellectual property rights to proposed candidate compound.
NIAAA is interested in studies from any subset of the following stages of drug development:
A. Examples of Pre-Clinical IND-Enabling Studies:
1) Medicinal chemistry studies to further optimize the candidate compound
2) Toxicology (acute and repeated dose) and if applicable, genotoxicity, carcinogenicity, reproduction, and immunotoxicity studies.
3) Pharmacokinetics (absorption, distribution, metabolism, and excretion [ADME])
4) Formulation development and chemical synthesis under GMP
5) Animal efficacy studies if candidate compound is patentable and has a plausible path to commercialization
B. Examples of Human Phase 1 Studies
1) Pharmacokinetics (ADME)
2) Single and multiple ascending dosing
4) Target engagement
5) If applicable, alcohol interaction
6) If applicable, abuse liability
C. Examples of Human Phase 2 Studies (with patient population) -- for AUD or AUD/AROD targets only
1) Human laboratory trials
2) Proof-of-concept clinical trials
Delineation of milestones is a key characteristic of this FOA. A milestone is defined as a scheduled event in the project timeline, signifying the completion of a major project stage or activity. Milestones are to be performance-based to achieve completion of the study on time and on budget. Investigators should design a series of milestones for completion of the study and provide contingency plans to proactively confront potential delays or disturbances in attaining the milestones. Investigators should design relevant milestones that reflect essential progress of the proposed research.
Continuation of the award is conditional upon satisfactory progress and subject to availability of funds. If, at any time, progress falls significantly below the projected milestones, NIAAA will consider ending support and negotiating an orderly phase-out of the award and retains, as an option, periodic external peer review of progress. NIAAA staff will closely monitor progress at all stages, milestones, accrual, and safety.
Before human studies can be conducted, an IND or IND exemption must be obtained. In most cases, a pre-IND meeting with the FDA is strongly encouraged. A Clinical Research Organization, or other regulatory support, may be helpful in compiling relevant data and facilitating this pre-IND meeting and subsequent interactions with the FDA. Applications may include a budget to support such activities.
In conducting Phase 2 human studies, NIAAA encourages data collection assessments capturing demographics, daily drinking (before and during treatment), AUD diagnosis (and/or characterization of problematic drinking), alcohol craving, alcohol-related consequences, comorbidities (i.e., substance use, medical, psychiatric), medication adherence, and potential mechanisms and moderators of treatment effect.
It is expected that applicants will be attentive to NIH policies related to Rigor and Reproducibility.
Studies that are not intended to support FDA submissions (e.g. INDs, NDA, use patents) are not appropriate for this RFA and should be submitted to the appropriate parent NIH FOA.
Medications development research in minority and underserved populations (e.g., African Americans, Asians, Hispanics, Native Americans, Alaska Natives, Native Hawaiians, Pacific Islanders) is sparse. Thus, investigators are encouraged to include these populations in their medications development clinical studies in sufficient numbers to determine whether there are unique circumstances that should be considered in future research.
Applicants are strongly encouraged to contact the NIAAA Division of Medications Development or Division of Metabolism and Health Effects prior to submitting to this FOA.
Applications deemed non-responsive to the RFA will not be reviewed.
NIAAA will not accept AIDS-related research applications in response to this FOA.
The OER Glossary and the SF424 (R&R) Application Guide provide details on these application types. Only those application types listed here are allowed for this FOA.
NIAAA intends to commit $5.0M in FY 2020 to fund 4 awards.
For AUD treatment candidate compounds and combination AUD and AROD Phase 2 candidate compounds, budgets must not exceed $1.0 M in direct costs per year.
For Alcohol-related organ damage (AROD) treatment candidate compounds and combination AUD and AROD candidate compounds from lead optimization through Phase 1, budgets must not exceed $1.0 M in direct costs per year for IND enabling studies and $500,000 direct cost per year for clinical Phase 1.
The scope of the proposed project should determine the project period. The maximum project period is 5 years.
Higher Education Institutions
The following types of Higher Education Institutions are always encouraged to apply for NIH support as Public or Private Institutions of Higher Education:
Nonprofits Other Than Institutions of Higher Education
Non-domestic (non-U.S.) Entities (Foreign Institutions) are not eligible to apply.
Non-domestic (non-U.S.) components of U.S. Organizations are not eligible to apply.
Foreign components, as defined in the NIH Grants Policy Statement, are not allowed.
Applicant organizations must complete and maintain the following registrations as described in the SF 424 (R&R) Application Guide to be eligible to apply for or receive an award. All registrations must be completed prior to the application being submitted. Registration can take 6 weeks or more, so applicants should begin the registration process as soon as possible. The NIH Policy on Late Submission of Grant Applications states that failure to complete registrations in advance of a due date is not a valid reason for a late submission.
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.
For institutions/organizations proposing multiple PDs/PIs, visit the Multiple Program Director/Principal Investigator Policy and submission details in the Senior/Key Person Profile (Expanded) Component of the SF424 (R&R) Application Guide.
This FOA does not require cost sharing as defined in the NIH Grants Policy Statement.
The NIH will not accept duplicate or highly overlapping applications under review at the same time. This means that the NIH will not accept:
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 FOA. See your administrative office for instructions if you plan to use an institutional system-to-system solution.
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:
The letter of intent should be sent to:
Dr. Abraham Bautista
All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions:
Facilities & Other Resources: The application must describe in detail how the funds requested to NIAAA will be leveraged with current resources. It should include all the strengths and resources that the grantee organization and, if pertinent, its collaborators will be contributing towards accomplishing the research plan.
For applications which propose resource(s)at one or more collaborating organization(s), the application should contain a specific description of each resource, how it will facilitate the project goals, and an outline of the projected timeline for resource receipt and utilization. The resources provided by the collaborating organization(s) should represent a significant contribution to the project.
All instructions in the SF424 (R&R) Application Guide must be followed.
Research Strategy: the research strategy should include the following subsections:
A. Significance: Clinical Importance and Feasibility
B. Supporting Data for Entry
C. Detailed Plans for Approach (Including Milestones and Timelines)
D. Intellectual Property (IP) Strategy
Clinical Importanceand Feasibility:
If the therapy is an improvement over an earlier generation agent(s) that has not been marketed, discuss what advantages the new agent has. Include results from previous clinical trials with related agents.
Discuss how the proposed project relates to therapy development efforts underway in academia and industry, regardless of therapeutic class. What are the distinct advantages to the new, proposed therapy considering other investigational agents that might be entering the clinical pipeline soon?
B. Supporting Data for Entry
The Supporting Data for Entry section contains, but is not limited to, comprehensive data to justify that the application meets the entry criteria, as well as data that demonstrate the feasibility of conducting studies to address the specific aims, for example:
(1) Describe what is known about the candidate compound such as structure/identity, selectivity/specificity, bioactivity, stability, bioavailability, and other modality- specific characteristics.
(2) Discuss feasibility of production and reproducibility of production of the candidate.
C. Detailed Plans for Approach (Including Milestones)
In this section applicants should detail the planned approach. Describe milestones to be used for measuring success in achieving each of the research plan's objectives. One or more milestones should be used for each objective. For each milestone provide details on methods, assumptions, experimental designs, and data analysis plans (if the results are quantitatively measured). Specify the quantitative criteria for measuring success and the rationale for the quantitative criteria. Quantitative criteria should be robust and be consistent with the state-of-the-art in the field. Most of the time the quantitative criteria for success in the milestones will also be used for making go/no-go decisions and this should be specified. There should be at least one milestone proposed for completion at the end of each year.
Approach could include but is not limited to:
Describe experimental design. If the studies proposed are planned to be done in a Contract Research Organization (CRO), Contract Manufacturing Organizations (CMO), list the name(s) of the CRO(s) for the activities.
Present a plan for the preparatory work for IND-enabling studies such as Chemistry, Manufacturing, and Controls (CMC) activities, preliminary safety studies, validation of target engagement assays to support future human clinical trials, final characterization of the manufactured material intended for preclinical IND-enabling toxicology studies, etc.
Present a plan for preclinical studies consistent with FDA regulatory guidance.. These include IND-enabling toxicology, tumorigenicity evaluations as needed, immunogenicity evaluations as needed, biodistribution studies as needed, large animal study to assess biocompatibility of means of clinical delivery of the candidate, validation of appropriate assays for target engagement markers to enable human use, etc.
For critical preclinical studies, like definitive verification of the activities of the candidate (if needed) in preclinical efficacy studies, and/or pharmacokinetics-pharmacodynamics studies, provide the following:
The choice of models, assays, and clinically-relevant endpoints (primary, secondary, and exploratory when applicable) for these studies;
Information on study design, power analyses and associated assumptions for sample size estimation (e.g., what is considered a minimal change predictive of clinically meaningful change, variance known in the in vivo assay described in supporting data, expected treatment effect size), and detailed procedures of how blinding and randomization will be done;
Data handling rules such as criteria for inclusion and exclusion of data;
Plans for data analysis and interpretation;
Outline any differences between how these analyses will be performed and those used to develop the Entry Criteria (outlined above) for the candidate. Provide a rationale for any changes.
D. Intellectual Property Strategy
Applicants are encouraged to prepare this section in consultation with their institutions’ technology transfer officials.
Applicants should describe the IP landscape surrounding their therapy. Applicants should describe any known constraints that could impede the development of their therapy (e.g., certain restrictions under transfer or sharing agreements, applicants' previous or present IP filings and publications, similar therapies that are under patent protection and/or on the market, etc.) and how these issues could be addressed. If the applicant proposes using an agent(s) whose IP is not owned by the applicant's institution, either an investigational therapeutic, FDA-approved therapeutic, or other licensed product, the applicant should address any questions of freedom to develop consistent with achieving the goals of the program which is to pursue FDA approval. Applicants should include a letter (see Letters of Support) from the entity who owns the IP indicating they will provide the agent(s), if there are any limitations on the studies that can be performed with that agent(s), agreement about public disclosure of results (including negative results), and whether there is an agreement already in place.
If patents pertinent to the therapy being developed under this application have been filed, the applicant should indicate the details of filing dates, what type of patents are filed, and application status, and associated United States Patent and Trademark Office (USPTO) database links, if applicable.
Applicants should discuss future IP filing plans. For a multiple PD/PI, multi-institution application, applicants should describe the infrastructure of each institution for bringing the technologies to practical application and for coordinating these efforts (e.g., licensing, managing IP) among the institutions. Applicants should clarify how IP will be shared or otherwise managed if there are multiple PD/PIs and institutions involved, as appropriate and consistent with achieving the goals of the program.
Letters of Support: Applicants should include letters of support from consultants, contractors, and collaborators.
If research will be performed at more than one institution, include a letter of support from each institution clarifying how intellectual property will be shared or otherwise managed across the institutions.
If collaborating with a private entity, include a letter of support that addresses any agreement to provide agent(s), any limits on the studies that can be performed with said agent(s), any limitations on sharing of data (including negative results), and whether a licensing agreement(s) is in place. This letter should come from a high official within the private entity who has authority to speak on these issues.
The following modifications also apply:
If you answered “Yes” to the question “Are Human Subjects Involved?” on the R&R Other Project Information form, you must include at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials Information form or Delayed Onset Study record.
Study Record: PHS Human Subjects and Clinical Trials Information
All instructions in the SF424 (R&R) Application Guide must be followed.
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 SF424 (R&R) Application Guide must be followed.
See Part 1. Section III.1 for information regarding the requirement for obtaining a unique entity identifier and for completing and maintaining active registrations in System for Award Management (SAM), NATO Commercial and Government Entity (NCAGE) Code (if applicable), eRA Commons, and Grants.gov
Part I. Overview Information contains information about Key Dates and times. Applicants are encouraged to submit applications before the due date to ensure they have time to make any application corrections that might be necessary for successful submission. When a submission date falls on a weekend or Federal holiday, the application deadline is automatically extended to the next business day.
Organizations must submit applications to Grants.gov (the online portal to find and apply for grants across all Federal agencies). Applicants must then complete the submission process by tracking the status of the application in the eRA Commons, NIH’s electronic system for grants administration. NIH and Grants.gov systems check the application against many of the application instructions upon submission. Errors must be corrected and a changed/corrected application must be submitted to Grants.gov on or before the application due date and time. If a Changed/Corrected application is submitted after the deadline, the application will be considered late. Applications that miss the due date and time are subjected to the NIH Policy on Late Application Submission.
Applicants are responsible for viewing their application before the due date in the eRA Commons to ensure accurate and successful submission.
Information on the submission process and a definition of on-time submission are provided in the SF424 (R&R) Application Guide.
This initiative is not subject to intergovernmental review.
All NIH awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.
Pre-award costs are allowable only as described in the NIH Grants Policy Statement.
Applications must be submitted electronically following the instructions described in the SF424 (R&R) Application Guide. Paper applications will not be accepted.
Applicants must complete all required registrations before the application due date. Section III. Eligibility Information contains information about registration.
For assistance with your electronic application or for more information on the electronic submission process, visit 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.
All PD(s)/PI(s) must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile Component of the SF424(R&R) Application Package. Failure to register in the Commons and to include a valid PD/PI Commons ID in the credential field will prevent the successful submission of an electronic application to NIH. See Section III of this FOA for information on registration requirements.
The applicant organization must ensure that the DUNS number it provides on the application is the same number used in the organization’s profile in the eRA Commons and for the System for Award Management. Additional information may be found in the SF424 (R&R) Application Guide.
See more tips for avoiding common errors.
Upon receipt, applications will be evaluated for completeness and compliance with application instructions by the Center for Scientific Review and responsiveness by components of participating organizations, NIH. Applications that are incomplete, non-compliant and/or nonresponsive will not be reviewed.
In order to expedite review, applicants are requested to notify the NIAAA Referral Office by email at firstname.lastname@example.org when the application has been submitted. Please include the FOA number and title, PD/PI name, and title of the application.
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.
In addition, for applications involving clinical trials:
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.
Does the project address an important problem or a critical barrier to progress in the field? Is the prior research that serves as the key support for the proposed project rigorous? 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?
In addition, for applications involving clinical trials
Are the scientific rationale and need for a clinical trial to test the proposed compound well supported by preliminary data, clinical and/or preclinical studies, or information in the literature or knowledge of biological mechanisms? ? For trials focusing on clinical or public health endpoints, is this clinical trial necessary for testing the safety, efficacy or effectiveness of an intervention that could lead to a change in clinical practice, community behaviors or health care policy?. For trials focusing on mechanistic, behavioral, physiological, biochemical, or other biomedical endpoints, is this trial needed to advance scientific understanding?
Specific to this FOA:
Arethe Clinical Impact and Feasibility of the agent adequately described? If the therapy is an improvement over an earlier generation agent(s) that has not been marketed, what advantages does the new agent have? Are previous clinical trials with related agents adequatelydiscussed? Is the discussion appropriately presented onhow the proposed project relates to therapy development efforts underway in academia and industry, regardless of therapeutic class? If appropriate, are the plans outlined for the first clinical proof-of-concept study and feasibility of conducting the trial(s) adequately discussed?
Are the PD(s)/PI(s), collaborators, and other researchers well suited to the project? If Early Stage Investigators or those in the early stages of independent careers, do they have appropriate experience and training? If established, have they demonstrated an ongoing record of accomplishments that have advanced their field(s)? If the project is collaborative or multi-PD/PI, do the investigators have complementary and integrated expertise; are their leadership approach, governance and organizational structure appropriate for the project?
In addition, for applications involving clinical trials
With regard to the proposed leadership for the project, do the PD/PI(s) and key personnel have the expertise, experience, and ability to organize, manage and implement the proposed clinical trial and meet milestones and timelines? Do they have appropriate expertise in study coordination, data management and statistics? For a multicenter trial, is the organizational structure appropriate and does the application identify a core of potential center investigators and staffing for a coordinating center?
Does the application challenge and seek to shift current research or clinical practice paradigms by utilizing novel theoretical concepts, approaches or methodologies, instrumentation, or interventions? Are the concepts, approaches or methodologies, instrumentation, or interventions novel to one field of research or novel in a broad sense? Is a refinement, improvement, or new application of theoretical concepts, approaches or methodologies, instrumentation, or interventions proposed?
In addition, for applications involving clinical trials
Does the design/research plan include innovative elements, as appropriate, that enhance its sensitivity, potential for information or potential to advance scientific knowledge or clinical practice?
Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Have the investigators included plans to address weaknesses in the rigor of prior research that serves as the key support for the proposed project? Have the investigators presented strategies to ensure a robust and unbiased approach, as appropriate for the work proposed? Are potential problems, alternative strategies, and benchmarks for success presented? If the project is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed? Have the investigators presented adequate plans to address relevant biological variables, such as sex, for studies in vertebrate animals or human subjects?
Specific to this FOA:
Did the study meets the entry criteria, including describing what is known about the candidate compound structure/identity, selectivity/specificity, bioactivity, stability, bioavailability, and other modality specific characteristics.
Were the feasibility of production and reproducibility of production of the candidate compound adequately discussed? Is thedescription of milestones that will be used for measuring success in achieving each of the research plan's objectives sufficiently detailed? Did the PD/PI adequately describe quantitative criteria for measuring success? If applicable,howwelldetailedis the description of the Contract Research Organization (CRO) and/or Contract Manufacturing Organizations (CMO), including their proposed activities for the study? Are there adequate details demonstrating that preclinical studies areconsistent with or per regulatory guidance i ncluding IND-enabling toxicology, tumorigenicity evaluations as needed, immunogenicity evaluations as needed, biodistribution studies as needed, large animal study to assess biocompatibility of means of clinical delivery of the candidate, validation of appropriate assays for target engagement markers to enable human use, etc?
Regarding the Section on Entry Criteria:
Is the candidate compound adequately characterized (e.g., structure/identity, selectivity, and other modality-specific characteristics)?
Regarding the Section on Milestones:
Are the milestones robust and justifiable, i.e., associated with clear, quantitative criteria for success that allow go/no go decisions ? Are the timelines proposed for achieving the milestones realistic and inclusive of necessary steps, but also efficient without adding unnecessary steps?
In addition, for applications involving clinical trials
Does the application adequately address the following, if applicable:
Is the study design justified and appropriate to address primary and secondary outcome variable(s)/endpoints that will be clear, informative and relevant to the hypothesis being tested? Is the scientific rationale/premise of the study based on previously well-designed preclinical and/or clinical research? Given the methods used to assign participants and deliver interventions, is the study design adequately powered to answer the research question(s), test the proposed hypothesis/hypotheses, and provide interpretable results? Is the trial appropriately designed to conduct the research efficiently? Are the study populations (size, gender, age, demographic group), proposed intervention arms/dose, and duration of the trial, appropriate and well justified?
Are potential ethical issues adequately addressed? Is the process for obtaining informed consent or assent appropriate? Is the eligible population available? Are the plans for recruitment outreach, enrollment, retention, handling dropouts, missed visits, and losses to follow-up appropriate to ensure robust data collection? Are the planned recruitment timelines feasible and is the plan to monitor accrual adequate? Has the need for randomization (or not), masking (if appropriate), controls, and inclusion/exclusion criteria been addressed? Are differences addressed, if applicable, in the intervention effect due to sex/gender and race/ethnicity?
Are the plans to standardize, assure quality of, and monitor adherence to, the trial protocol and data collection or distribution guidelines appropriate? Is there a plan to obtain required study agent(s)? Does the application propose to use existing available resources, as applicable?
Data Management and Statistical Analysis
Are planned analyses and statistical approach appropriate for the proposed study design and methods used to assign participants and deliver interventions? Are the procedures for data management and quality control of data adequate at clinical site(s) or at center laboratories, as applicable? Have the methods for standardization of procedures for data management to assess the effect of the intervention and quality control been addressed? Is there a plan to complete data analysis within the proposed period of the award?
If the project involves human subjects and/or NIH-defined clinical research, are the plans to address 1) the protection of human subjects from research risks, and 2) inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion or exclusion of individuals of all ages (including children and older adults), justified in terms of the scientific goals and research strategy proposed?
Will the scientific environment in which the work will be done contribute to the probability of success? Are the institutional support, equipment and other physical resources available to the investigators adequate for the project proposed? Will the project benefit from unique features of the scientific environment, subject populations, or collaborative arrangements?
In addition, for applications involving clinical trials
If proposed, are the administrative, data coordinating, enrollment and laboratory/testing centers, appropriate for the trial proposed?
Does the application adequately address the capability and ability to conduct the trial at the proposed site(s) or centers? Are the plans to add or drop enrollment centers, as needed, appropriate?
If multi-sites/centers, is there evidence of the ability of the individual site or center to: (1) enroll the proposed numbers; (2) adhere to the protocol; (3) collect and transmit data in an accurate and timely fashion; and, (4) operate within the proposed organizational structure?
Specific to applications proposing clinical trials
Is the study timeline described in detail, taking into account start-up activities, the anticipated rate of enrollment, and planned follow-up assessment? Is the projected timeline feasible and well justified? Does the project incorporate efficiencies and utilize existing resources (e.g., CTSAs, practice-based research networks, electronic medical records, administrative database, or patient registries) to increase the efficiency of participant enrollment and data collection, as appropriate?
Are potential challenges and corresponding solutions discussed (e.g., strategies that can be implemented in the event of enrollment shortfalls)?
For research that involves human subjects but does not involve one of thecategories 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 categories of research that are exempt under 45 CFR Part 46, the committee will evaluate: 1) the justification for the exemption, 2) human subjects involvement and characteristics, and 3) sources of materials. For additional information on review of the Human Subjects section, please refer to the Guidelines for the Review of Human Subjects.
When the proposed project involves human subjects and/or NIH-defined clinical research, the committee will evaluate the proposed plans for the inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion (or exclusion) of individuals of all ages (including children and older adults) to determine if it is justified in terms of the scientific goals and research strategy proposed. For additional information on review of the Inclusion section, please refer to the Guidelines for the Review of Inclusion in Clinical Research.
The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following criteria: (1) description of proposed procedures involving animals, including species, strains, ages, sex, and total number to be used; (2) justifications for the use of animals versus alternative models and for the appropriateness of the species proposed; (3) interventions to minimize discomfort, distress, pain and injury; and (4) justification for euthanasia method if NOT consistent with the AVMA Guidelines for the Euthanasia of Animals. Reviewers will assess the use of chimpanzees as they would any other application proposing the use of vertebrate animals. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animal Section.
Reviewers will assess whether materials or procedures proposed are potentially hazardous to research personnel and/or the environment, and if needed, determine whether adequate protection is proposed.
If applicable, the reviewers will evaluate the strength of the applicant's intellectual property (IP) portfolio/position (pertinent to the proposed project). Is the Intellectual Development Strategy described in detail including current patents, patent filings and future plans for IP filings, any known constraints that could impede the development of the compound (e.g., certain restrictions under transfer or sharing agreements, applicants' previous or present IP filings and publications, similar therapies that are under patent protection and/or on the market, etc.) and how these issues could be addressed?
Reviewers will assess the information provided in this section of the application, including 1) the Select Agent(s) to be used in the proposed research, 2) the registration status of all entities where Select Agent(s) will be used, 3) the procedures that will be used to monitor possession use and transfer of Select Agent(s), and 4) plans for appropriate biosafety, biocontainment, and security of the Select Agent(s).
Reviewers will comment on whether the following Resource Sharing Plans, or the rationale for not sharing the following types of resources, are reasonable: (1) Data Sharing Plan; (2) Sharing Model Organisms; and (3) Genomic Data Sharing Plan (GDS).
For projects involving key biological and/or chemical resources, reviewers will comment on the brief plans proposed for identifying and ensuring the validity of those resources.
Reviewers will consider whether the budget and the requested period of support are fully justified and reasonable in relation to the proposed research.
Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s) convened by NIAAA, in accordance with NIH peer review policy and procedures, using the stated review criteria. Assignment to a Scientific Review Group will be shown in the eRA Commons.
Information regarding the disposition of applications is available in the NIH Grants Policy Statement.
A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant organization for successful applications. The NoA signed by the grants management officer is the authorizing document and will be sent via email to the grantee’s business official.
Awardees must comply with any funding restrictions described in Section IV.5. Funding Restrictions. Selection of an application for award is not an authorization to begin performance. Any costs incurred before receipt of the NoA are at the recipient's risk. These costs may be reimbursed only to the extent considered allowable pre-award costs.
Any application awarded in response to this FOA will be subject to terms and conditions found on the Award Conditions and Information for NIH Grants website. This includes any recent legislation and policy applicable to awards that is highlighted on this website.
Institutional Review Board or Independent Ethics Committee Approval: Grantee institutions must ensure that protocols are reviewed by their IRB or IEC. To help ensure the safety of participants enrolled in NIH-funded studies, the awardee must provide NIH copies of documents related to all major changes in the status of ongoing protocols.
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: Grantee 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 awardee must provide NIH copies of documents related to all major changes in the status of ongoing protocols. Data and Safety
Monitoring Requirements: The NIH policy for data and safety monitoring requires oversight and monitoring of all NIH-conducted or -supported human biomedical and behavioral intervention studies (clinical trials) to ensure the safety of participants and the validity and integrity of the data. Further information concerning these requirements is found at http://grants.nih.gov/grants/policy/hs/data_safety.htm and in the application instructions (SF424 (R&R) and PHS 398).
Investigational New Drug or Investigational Device Exemption Requirements: Consistent with federal regulations, clinical research projects involving the use of investigational therapeutics, vaccines, or other medical interventions (including licensed products and devices for a purpose other than that for which they were licensed) in humans under a research protocol must be performed under a Food and Drug Administration (FDA) investigational new drug (IND) or investigational device exemption (IDE).
Recipients of federal financial assistance (FFA) from HHS must administer their programs in compliance with federal civil rights law. This means that recipients of HHS funds must ensure equal access to their programs without regard to a person’s race, color, national origin, disability, age and, in some circumstances, sex and religion. This includes ensuring your programs are accessible to persons with limited English proficiency. HHS recognizes that research projects are often limited in scope for many reasons that are nondiscriminatory, such as the principal investigator’s scientific interest, funding limitations, recruitment requirements, and other considerations. Thus, criteria in research protocols that target or exclude certain populations are warranted where nondiscriminatory justifications establish that such criteria are appropriate with respect to the health or safety of the subjects, the scientific study design, or the purpose of the research.
In accordance with the statutory provisions contained in Section 872 of the Duncan Hunter National Defense Authorization Act of Fiscal Year 2009 (Public Law 110-417), NIH awards will be subject to the Federal Awardee Performance and Integrity Information System (FAPIIS) requirements. FAPIIS requires Federal award making officials to review and consider information about an applicant in the designated integrity and performance system (currently FAPIIS) prior to making an award. An applicant, at its option, may review information in the designated integrity and performance systems accessible through FAPIIS and comment on any information about itself that a Federal agency previously entered and is currently in FAPIIS. The Federal awarding agency will consider any comments by the applicant, in addition to other information in FAPIIS, in making a judgement about the applicant’s integrity, business ethics, and record of performance under Federal awards when completing the review of risk posed by applicants as described in 45 CFR Part 75.205 “Federal awarding agency review of risk posed by applicants.” This provision will apply to all NIH grants and cooperative agreements except fellowships.
For additional guidance regarding how the provisions apply to NIH grant programs, please contact the Scientific/Research Contact that is identified in Section VII under Agency Contacts of this FOA. HHS provides general guidance to recipients of FFA on meeting their legal obligation to take reasonable steps to provide meaningful access to their programs by persons with limited English proficiency. Please see https://www.hhs.gov/civil-rights/for-individuals/special-topics/limited-english-proficiency/index.html. The HHS Office for Civil Rights also provides guidance on complying with civil rights laws enforced by HHS. Please see https://www.hhs.gov/civil-rights/for-individuals/section-1557/index.htmlhttps://www.hhs.gov/civil-rights/for-providers/laws-regulations-guidance/index.html. Recipients of FFA also have specific legal obligations for serving qualified individuals with disabilities. Please see https://www.hhs.gov/civil-rights/for-individuals/disability/index.html. Please contact the HHS Office for Civil Rights for more information about obligations and prohibitions under federal civil rights laws at https://www.hhs.gov/ocr/about-us/contact-us/index.htmlor call 1-800-368-1019 or TDD 1-800-537-7697. Also note it is an HHS Departmental goal to ensure access to quality, culturally competent care, including long-term services and supports, for vulnerable populations. For further guidance on providing culturally and linguistically appropriate services, recipients should review the National Standards for Culturally and Linguistically Appropriate Services in Health and Health Care at http://minorityhealth.hhs.gov/omh/browse.aspx?lvl=2&lvlid=53.
The following special terms of award are in addition to, and not in lieu of, otherwise applicable U.S. Office of Management and Budget (OMB) administrative guidelines, U.S. Department of Health and Human Services (DHHS) grant administration regulations at 45 CFR Part 75, and other HHS, PHS, and NIH grant administration policies.
The administrative and funding instrument used for this program will be the cooperative agreement, an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH programmatic involvement with the awardees is anticipated during the performance of the activities. Under the cooperative agreement, the NIH purpose is to support and stimulate the recipients' activities by involvement in and otherwise working jointly with the award recipients in a partnership role; it is not to assume direction, prime responsibility, or a dominant role in the activities. Consistent with this concept, the dominant role and prime responsibility resides with the awardees for the project 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:
NIAAA staff have substantial scientific and programmatic involvement that is above and beyond the normal stewardship role in awards, as described below:
An NIAAA Project Scientist will be assigned to the project with substantial scientific and programmatic involvement during the conduct of this activity through technical assistance, advice and coordination that is above and beyond the normal stewardship role in awards. The Project Scientist will provide additional expertise that is needed for proper scientific management of the award. This includes assisting the PI/PD in the development of a project milestone plan at the outset of the project, approving the final milestone language for incorporation into the award notice, enhancing the project's progress by providing access to various NIH resources, when appropriate, providing technical assistance, advice, and coordination to the project, although the dominant role and responsibilities for the activities funded by the U01 reside with the PI/PD. Project Scientist may not attend peer review meetings.
NIAAA Program Staff designated as the Program Official/Director will be responsible for the normal scientific and programmatic stewardship of the awards and will be named in the summary statement and the Notice of Award (NoA), and will be the primary contact with the PI/PD. NIAAA Program Official/Director may recommend withholding of support, suspension, or termination of the award for lack of adherence to required policies and/or procedures, and lack of adherence to the goals of the FOA. The Program Officer/Director may terminate or curtail the study (or an individual award) in the event of (a) failure to develop or implement a mutually agreeable collaborative protocol, (b) substantial shortfall in participant recruitment, follow-up, data reporting, quality control, or other major breach of the protocol, (c) substantive changes in the agreed-upon protocol with which NIAAA cannot concur, (d) reaching a major study endpoint substantially before schedule with persuasive statistical significance, or (e) human subject ethical issues that may dictate a premature termination.
The Program Officer will be responsible for assessing the progress of the project towards accomplishment of milestones, and for recommending the level of continued funding.
Go/No-Go milestones (typically a minimum of one per funding year) will be established by the PI/PD in collaboration with NIAAA Program Director and NIAAA Project Scientist at the start of the project and updated as needed. The application must include milestones with quantitative success criteria for each year of funding. Each year the PI/PD must submit milestone progress reports for independent evaluation by NIAAA Program Director and NIAAA Project Scientist.
PLEASE NOTE: If a funded project does not make sufficient progress toward the agreed upon milestones at any stage, funding for the project may be discontinued.
For a Phase 1 clinical trial, the following are required for approval for trial commencement (defined as signing of informed consent by first prospective participant):
An NIAAA Extramural/Program Staff may not have a dual role as Project Scientist and Program Officer/Director.
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. One member will be selected by the awardee, a second member will be selected by NIAAA and a third designee with expertise in the relevant area will be chosen by the other two. This special dispute resolution procedure does not alter the awardee's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulation 42 CFR Part 50, Subpart D and DHHS regulation 45 CFR Part 16.
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 agreementsare required to report to the Federal Subaward Reporting System (FSRS) available at www.fsrs.gov on all subawards over $25,000. See the NIH Grants Policy Statement for additional information on this reporting requirement.
In accordance with the regulatory requirements provided at 45 CFR 75.113 and Appendix XII to 45 CFR Part 75, recipients that have currently active Federal grants, cooperative agreements, and procurement contracts from all Federal awarding agencies with a cumulative total value greater than $10,000,000 for any period of time during the period of performance of a Federal award, must report and maintain the currency of information reported in the System for Award Management (SAM)about civil, criminal, and administrative proceedings in connection with the award or performance of a Federal award that reached final disposition within the most recent five-year period. The recipient must also make semiannual disclosures regarding such proceedings.Proceedings information will be made publicly available in the designated integrity and performance system (currently FAPIIS). This is a statutory requirement under section 872 of Public Law 110-417, as amended (41 U.S.C. 2313). As required by section 3010 of Public Law 111-212, all information posted in the designated integrity and performance system on or after April 15, 2011, except past performance reviews required for Federal procurement contracts, will be publicly available. Full reporting requirements and procedures are found in Appendix XII to 45 CFR Part 75 – Award Term and Conditions for Recipient Integrity and Performance Matters.
Finding Help Online:http://grants.nih.gov/support/(preferred method of contact)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)
General Grants Information (Questions regarding application instructions, application processes, and NIH grant resources)
Email:GrantsInfo@nih.gov(preferred method of contact)
Grants.gov Customer Support(Questions regarding Grants.gov registration and Workspace)
Contact Center Telephone: 800-518-4726
Joanne B. Fertig, Ph.D.
Division of Medications Development
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Kathy Jung, Ph,D.
Division of Metabolism and Health Effects
National Institute on Alcohol and Alcoholism
Telephone: 301 443-8774
Ranga Srinivas, Ph.D.
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
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