Department of Health
and Human Services (HHS)
and Human Services (HHS)
EXPIRED
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
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).
NIAAA is seeking applications for medications development research projects from both for-profit and not-for-profit entities, including academic institutions, pharmaceutical and biotechnology companies, private and public foundations, small businesses not eligible for the SBIR/STTR program and single entities able to demonstrate significant resource commitment to the proposed project. A resource commitment from a single entity could, for example, consist of salary support for key personnel or production and formulation of clinical trial material.
The aim of this FOA is to move candidate compounds through Investigational New Drug (IND) requirements, Phase 1 human safety, tolerability, and dosing studies, and Phase 2 human laboratory and proof-of-concept trials. Within these phases of drug development, each proposed project should have a defined entry and exit point. Finally, this FOA will support animal studies to prove efficacy if the candidate compound is patentable and has a plausible path to commercialization. Applicants are strongly encouraged to contact the NIAAA Division of Medications Development Staff prior to submitting to this FOA.
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.
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.
Alcohol Use Disorder 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 efficacious and safe medications remains a top priority for NIAAA.
The purpose of this RFA is accelerate the pace of grant-funded medications development for AUD 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.
Applications can focus at any point along the drug development pipeline, including: 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); and Phase 2 studies (i.e., proof-of-concept human laboratory and clinical trials) of either a new chemical entity or an already marketed therapeutic compound. IND-enabling and Phase 1 studies should be conducted consistent with FDA guidelines (https://www.fda.gov/downloads/drugs/guidances/ucm073246.pdf).
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 a few IND-required studies, while other compounds may have already completed the IND requirements and can start the Phase 2 trials.
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, metabotropic glutamate receptor type 5 antagonist and type 2/3 agonist, glutamate NMDA modulator, glutamate transporter 1 enhancer, AMPA/kainate antagonist, fatty acid amide hydrolase (FAAH) inhibitor, monoacylglycerol lipase (MAGL) inhibitor, potassium channel activator, nicotinic a3 4 partial agonist and a7 agonist/positive allosteric modulator, phosphodiesterase inhibitor, GABAB receptor positive allosteric in modulator, GABAA receptor modulator, glucagon-like peptide 1 (GLP-1) agonist, rapamycin complex 1 (mTORC1) inhibitor, ghrelin receptor (GHS-R1A) antagonist, sigma receptor antagonist, neuropeptide’s agonist/antagonist, pannex-1 channel blocker, PPARa agonist, PPAR agonist, and monoamine stabilizer. Other targets also will be considered if they have been shown to alter alcohol drinking behavior in animal models. Exploration of new types of candidate compounds addressing these targets, both novel and repurposed compounds, is a high priority.
Medications that have been extensively investigated are no longer a priority. These include, but are not limited to, naltrexone, acamprosate, topiramate, and ondansetron. Applicants are strongly encouraged to contact the NIAAA Division of Medications Development Staff prior to submitting to this FOA.
In addition to focusing on individuals with AUD only, development of effective pharmacologic treatments for individuals with co-occurring psychiatric disorders, especially post-traumatic stress disorder (PTSD), is a high priority for NIAAA. Compared with non-comorbid individuals, people with comorbid disorders tend to have a more severe clinical impairment, higher rate of psychosocial and medical problems, higher utilization of health service, higher suicide rate, and lower quality of life.
Entry Criteria for the Following Stages of Medications Development:
Applicants who propose candidate compounds need to minimally satisfy the following conditions:
NIAAA is interested in studies from the following stages of drug development:
A. Pre-Clinical IND-Enabling Studies
B. Human Phase 1 Studies
C. Human Phase 2 Studies (with patient population)
Milestones
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, and should determine dates at which the study will have achieved targeted accrual at predefined increments.
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, the 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.
Special Considerations
Before Phase 2 human studies can be conducted, an IND or IND exemption must be obtained. In some cases, a pre-IND meeting with the FDA may be needed. 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.
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.
Studies on medications development for the treatment of Alcohol Use Disorder that include patients with HIV and AIDS-related topics, treatments and outcomes will be considered non-responsive to this FOA
Resubmissions from RFA-AA-18-009
The OER Glossary and the SF424 (R&R) Application Guide provide details on these application types.
Need help determining whether you are doing a clinical trial?
The number of awards is contingent upon NIH appropriations and the submission of a sufficient number of meritorious applications
NIAAA intends to commit $3.0M in FY 2019 to fund 4 awards.
No more than $1.0 million direct costs per year may be requested for applications proposing IND enabling studies. No more than $500,000 direct costs per year for applications that propose only Phase 2 human laboratory and proof-of-concept clinical trials. No more than $1.5 million may be requested by applications that proposing both IND enabling studies and Phase 2 human laboratory and proof-of-concept clinical trials.
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
For-Profit Organizations
Governments
Applicant organizations
Applicant organizations must complete and maintain the following registrations as described in the SF 424 (R&R) Application Guide to be eligible to apply for or receive an award. All registrations must be completed prior to the application being submitted. Registration can take 6 weeks or more, so applicants should begin the registration process as soon as possible. The NIH Policy on Late Submission of Grant Applications states that failure to complete registrations in advance of a due date is not a valid reason for a late submission.
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:
Buttons to access the online ASSIST system or to download application forms are available in Part 1 of this FOA. See your administrative office for instructions if you plan to use an institutional system-to-system solution.
For information on Application Submission and Receipt, visit Frequently Asked Questions Application Guide, Electronic Submission of Grant Applications.
Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows IC staff to estimate the potential review workload and plan the review.
By the date listed in Part 1. Overview Information, prospective applicants are asked to submit a letter of intent that includes the following information:
The letter of intent should be sent to:
Dr. Abraham Bautista
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Telephone: 301-443-9737
Email: [email protected]
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 a grantee and 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 section 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
A. Significance
Clinical Importance and 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?
Briefly outline the plans for the first clinical proof-of-concept study and comment on feasibility of conducting the trial(s).
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) Present data showing the minimal effective dose, optimal effective dose, time and duration of treatment. These should have been determined in relevant in vivo assays using clinically relevant functional and/or anatomical outcome measures, and/or in vivo target engagement assays, using a candidate that is sufficiently pure. [This normally should have been done using the clinically intended route of administration and special formulations if proposed (such as slow release, liposomes, nanoparticles, etc.), unless justified to use other routes of administration in which case the dose-response must have been reliably bridged by pharmacokinetics measurements]. Present data on pharmacokinetics, CNS penetration (if applicable), and pharmacokinetics-pharmacodynamics relationship. NIAAA encourages discussion of rigor, control of bias, and transparency of reporting in order to ensure robustness and reproducibility of the observed results.
(3) 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 milestone 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 that are consistent with 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:
D. Intellectual Property Strategy
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. Applicants should include a letter (see Letters of Support) from the entity who owns the IP indicating whether 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 proposed resources (e.g., funds, personnel power, materials, in-kind resources) are expected to provide a significant contribution to the project.
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.Foreign (non-U.S.) institutions must follow policies described in the NIH Grants Policy Statement, and procedures for foreign institutions described throughout the SF424 (R&R) Application Guide.
See Part 1. Section III.1 for information regarding the requirement for obtaining a unique entity identifier and for completing and maintaining active registrations in System for Award Management (SAM), NATO Commercial and Government Entity (NCAGE) Code (if applicable), eRA Commons, and Grants.gov
Part I. Overview Information contains information about Key Dates and times. Applicants are encouraged to submit applications before the due date to ensure they have time to make any application corrections that might be necessary for successful submission. When a submission date falls on a weekend or Federal holiday , the application deadline is automatically extended to the next business day.
Organizations must submit applications to Grants.gov (the online portal to find and apply for grants across all Federal agencies). Applicants must then complete the submission process by tracking the status of the application in the eRA Commons, NIH’s electronic system for grants administration. NIH and Grants.gov systems check the application against many of the application instructions upon submission. Errors must be corrected and a changed/corrected application must be submitted to Grants.gov on or before the application due date and time. If a Changed/Corrected application is submitted after the deadline, the application will be considered late. Applications that miss the due date and time are subjected to the NIH Policy on Late Application Submission.
Applicants are responsible for viewing their application before the due date in the eRA Commons to ensure accurate and successful submission.
Information on the submission process and a definition of on-time submission are provided in the SF424 (R&R) Application Guide.
This initiative is not subject to intergovernmental review.
All NIH awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement .
Pre-award costs are allowable only as described in the NIH Grants Policy Statement.
Applications must be submitted electronically following the instructions described in the SF424 (R&R) Application Guide. Paper applications will not be accepted.
Applicants must complete all required registrations before the application due date. Section III. Eligibility Information contains information about registration.
For assistance with your electronic application or for more information on the electronic submission process, visit Applying Electronically. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Guidelines for Applicants Experiencing System Issues. For assistance with application submission, contact the Application Submission Contacts in Section VII.
Important reminders:
All PD(s)/PI(s) must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile Component of the SF424(R&R) Application Package. Failure to register in the Commons and to include a valid PD/PI Commons ID in the credential field will prevent the successful submission of an electronic application to NIH. See Section III of this FOA for information on registration requirements.
The applicant organization must ensure that the DUNS number it provides on the application is the same number used in the organization’s profile in the eRA Commons and for the System for Award Management. Additional information may be found in the SF424 (R&R) Application Guide.
See more tips for avoiding common errors.
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 hypothesis or intervention well supported by preliminary data, clinical and/or preclinical studies, or information in the literature or knowledge of biological mechanisms? For trials focusing on clinical or public health endpoints, is this clinical trial necessary for testing the safety, efficacy or effectiveness of an intervention that could lead to a change in clinical practice, community behaviors or health care policy? For trials focusing on mechanistic, behavioral, physiological, biochemical, or other biomedical endpoints, is this trial needed to advance scientific understanding?
Did the PD/PI describe the Clinical Importance and Feasibility of the agent? 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 provided and discussed? Did the PD/PI discuss how the proposed project relates to therapy development efforts underway in academia and industry, regardless of therapeutic class? Are the plans outlined for the first clinical proof-of-concept study and feasibility of conducting the trial(s) 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?
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?
Did the study meets the entry criteria, including a) compound structure/identity, selectivity/specificity, bioactivity, stability, bioavailability, and other modality specific characteristics; and b) is the compound patentable and does it have a plausible path to commercialization
Was the feasibility of production and reproducibility of production of the candidate compound discussed? Is there a description of milestones that will be used for measuring success in achieving each of the research plan's objectives? Did the PD/PI describe quantitative criteria for measuring success? If applicable, was a description provided of the Contract Research Organization (CRO) and/or Contract Manufacturing Organizations (CMO), including their proposed activities for the study? Are preclinical studies described consistent with or per regulatory guidance including 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:
#160;
Is the candidate compound adequately characterized (e.g., structure/identity, selectivity, and other modality-specific characteristics)? Is the candidate compound patentable and does it have a plausible path to commercialization?
Regarding the Section on Milestones:
Are the milestones robust and 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?
Specific to applications involving clinical trials
Does the application adequately address the following, if applicable:
Study Design
Is the study design justified and appropriate to address primary and secondary outcome variable(s)/endpoints that will be clear, informative and relevant to the 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?
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 international site(s) is/are proposed, does the application adequately address the complexity of executing the clinical trial?
If multi-sites/centers, is there evidence of the ability of the individual site or center to: (1) enroll the proposed numbers; (2) adhere to the protocol; (3) collect and transmit data in an accurate and timely fashion; and, (4) operate within the proposed organizational structure?
Study Timeline
In addition, for applications involving 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 the categories of research that are exempt under 45 CFR Part 46, the committee will evaluate the justification for involvement of human subjects and the proposed protections from research risk relating to their participation according to the following five review criteria: 1) risk to subjects, 2) adequacy of protection against risks, 3) potential benefits to the subjects and others, 4) importance of the knowledge to be gained, and 5) data and safety monitoring for clinical trials.
For research that involves human subjects and meets the criteria for one or more of the 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.
For Resubmissions, the committee will evaluate the application as now presented, taking into consideration the responses to comments from the previous scientific review group and changes made to the project.
Not Applicable
Not Applicable
Intellectual Property
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 whether the project presents special opportunities for furthering research programs through the use of unusual talent, resources, populations, or environmental conditions that exist in other countries and either are not readily available in the United States or augment existing U.S. resources.
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.
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.
Individual awards are based on the application submitted to, and as approved by, the NIH and are subject to the IC-specific terms and conditions identified in the NoA. ClinicalTrials.gov: If an award provides for one or more clinical trials. By law (Title VIII, Section 801 of Public Law 110-85), the "responsible party" must register and submit results information for certain "applicable clinical trials" on the ClinicalTrials.gov Protocol Registration and Results System Information Website (https://register.clinicaltrials.gov). NIH expects registration of all trials whether required under the law or not. For more information, see http://grants.nih.gov/ClinicalTrials_fdaaa/
Institutional Review Board or Independent Ethics Committee Approval: Grantee institutions must ensure that the application as well as all protocols are reviewed by their IRB or IEC. To help ensure the safety of participants enrolled in NIH-funded studies, the awardee must provide NIH copies of documents related to all major changes in the status of ongoing protocols. Data and Safety Monitoring Requirements: The NIH policy for data and safety monitoring requires oversight and monitoring of all NIH-conducted or -supported human biomedical and behavioral intervention studies (clinical trials) to ensure the safety of participants and the validity and integrity of the data. Further information concerning these requirements is found at http://grants.nih.gov/grants/policy/hs/data_safety.htm and in the application instructions (SF424 (R&R) and PHS 398).
Investigational New Drug or Investigational Device Exemption Requirements: Consistent with federal regulations, clinical research projects involving the use of investigational therapeutics, vaccines, or other medical interventions (including licensed products and devices for a purpose other than that for which they were licensed) in humans under a research protocol must be performed under a Food and Drug Administration (FDA) investigational new drug (IND) or investigational device exemption (IDE).
Milestones
Prior to funding an application, NIAAA Program staff will contact the applicant to discuss the proposed milestones and any changes suggested by the NIAAA review panel or NIAAA Program staff. A final set of milestones will be specified in the Notice of Award.
Progress towards achievement of the final set of milestones will be evaluated by NIAAA Program staff. NIAAA Program staff may consult as necessary with independent consultants with relevant expertise. If justified, future year milestones may be revised based on data and information obtained during the previous project period. If, based on the progress report, a funded project does not meet the milestones, funding for the project may be discontinued. In addition to milestones, the decision regarding continued funding will also be based on the overall robustness of the entire data package that adequately allows an interpretation of the results (regardless if they have been captured in the milestones), overall progress, NIAAA portfolio balance and program priorities, competitive landscape, and availability of funds.
NIAAA emphasizes the importance of the robustness and reproducibility of experimental results. In some cases, conducting additional critical experiments will be important for NIAAA to have confidence in making a funding decision. Therefore, NIAAA Program staff, in consultation with the PD/PI, may add experiments that need to be conducted prior to or during the award as an additional milestone(s). In some cases, these studies will be supported by additional funds from NIAAA.
Recipients of federal financial assistance (FFA) from HHS must administer their programs in compliance with federal civil rights law. This means that recipients of HHS funds must ensure equal access to their programs without regard to a person’s race, color, national origin, disability, age and, in some circumstances, sex and religion. This includes ensuring your programs are accessible to persons with limited English proficiency. HHS recognizes that research projects are often limited in scope for many reasons that are nondiscriminatory, such as the principal investigator’s scientific interest, funding limitations, recruitment requirements, and other considerations. Thus, criteria in research protocols that target or exclude certain populations are warranted where nondiscriminatory justifications establish that such criteria are appropriate with respect to the health or safety of the subjects, the scientific study design, or the purpose of the research.
For additional guidance regarding how the provisions apply to NIH grant programs, please contact the Scientific/Research Contact that is identified in Section VII under Agency Contacts of this FOA. HHS provides general guidance to recipients of FFA on meeting their legal obligation to take reasonable steps to provide meaningful access to their programs by persons with limited English proficiency. Please see 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.html; and https://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.html or call 1-800-368-1019 or TDD 1-800-537-7697. Also note it is an HHS Departmental goal to ensure access to quality, culturally competent care, including long-term services and supports, for vulnerable populations. For further guidance on providing culturally and linguistically appropriate services, recipients should review the National Standards for Culturally and Linguistically Appropriate Services in Health and Health Care at http://minorityhealth.hhs.gov/omh/browse.aspx?lvl=2&lvlid=53.
In accordance with the statutory provisions contained in Section 872 of the Duncan Hunter National Defense Authorization Act of Fiscal Year 2009 (Public Law 110-417), NIH awards will be subject to the Federal Awardee Performance and Integrity Information System (FAPIIS) requirements. FAPIIS requires Federal award making officials to review and consider information about an applicant in the designated integrity and performance system (currently FAPIIS) prior to making an award. An applicant, at its option, may review information in the designated integrity and performance systems accessible through FAPIIS and comment on any information about itself that a Federal agency previously entered and is currently in FAPIIS. The Federal awarding agency will consider any comments by the applicant, in addition to other information in FAPIIS, in making a judgement about the applicant’s integrity, business ethics, and record of performance under Federal awards when completing the review of risk posed by applicants as described in 45 CFR Part 75.205 Federal awarding agency review of risk posed by applicants. This provision will apply to all NIH grants and cooperative agreements except fellowships.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:
All aspects of their study, including any modification of study design, conduct of the study, quality control, data analysis and interpretation, preparation of publications, dissemination of data, tools, and technologies, and collaboration with other investigators. The awardee agrees to accept close coordination, cooperation, and participation of NIAAA staff in those aspects of scientific and technical management of the study as stated in these terms and conditions.
Meeting NIAAA policy requiring that studies be monitored commensurate with the degree of potential risk to study subjects and the complexity of the study.
Upon implementation of the protocol, ensuring that each site, whether a single institution or a consortium of institutions, will follow the procedures required by the protocol regarding study conduct and monitoring, data collection, and quality control.
Support or other involvement of industry or any other third party in the study--e.g., participation by the third party; involvement of project resources or citing the name of the project or the NIAAA support; or special access to project results, data, findings, or resources--may be advantageous and appropriate. However, except for licensing of patents or copyrights, support or involvement of any third party will occur only following notification of and concurrence by NIAAA.
Awardees are expected to publish and publicly disseminate results, data, and other products of the study, concordant with governance policies and protocols. Publications and oral presentations of work performed under this agreement will require appropriate acknowledgment of support by the NIAAA/NIH.
Obtaining prior written approval of the NIAAA Grants Management Specialist in consultation with the NIAAA Program Officer for any change in any of the key personnel identified in the Notice of Grant Award.
Awardees will retain custody of and have primary rights to the data and software developed under these awards, subject to Government rights of access consistent with current DHHS, PHS, and NIH policies.
NIH staff have substantial programmatic involvement that is above and beyond the normal stewardship role in awards, as described below:
The NIH Project Scientist will be extramural staff from NIAAA, who will have substantial involvement above and beyond the normal program stewardship of the award. The NIH Project Scientist is a partner within the research team representing the government's interest in the substantive work of the research team with the following responsibilities:
Have substantial scientific/programmatic involvement during conduct of this cooperative agreement, through technical assistance, advice,
Coordinate with the awardees in monitoring issues relating to: design of the activities, recruitment, adherence to protocols, adjustment of study protocols, and management and technical performance.
Participate in all Steering Committee activities, including conference calls, subcommittees and special committees.
Have access to data generated under this Cooperative Agreement and may periodically review the data and progress reports. NIAAA staff may use information obtained from the data for the preparation of internal reports on the activities of the study. However, awardees will retain custody of and have primary rights to all data developed under these awards, subject to Government rights of access consistent with HHS, PHS, and NIH policies.
Provide guidance and support in the development, assembly, and submission of all required regulatory documents, e.g., those regarding the use of investigational drugs, to the Food and Drug Administration.
Will not be involved in funding decisions and will not be allowed to attend review meetings of conflicted applications.
The NIH Program Official will be an NIAAA Staff who will be responsible for the normal scientific and programmatic stewardship of the award. Additional responsibilities include:
Participate in all Steering Committee meetings and conference calls.
Monitor recruitment status of the trial on an ongoing basis.
Monitor performance through consideration of quarterly meetings of the Steering Committee and annual reports, site visits, and compliance with NIH procedures.
Approve modifications to the research plan and/or study protocol(s) based on emerging data and/or other issues that impact progress of the project.
Determine if the awardee has met/achieved milestones throughout the project.
Determine if the awardee has met the milestones and feasibility requirements for transition of the project to the next year or stage of funding.
Reserve the right to obtain periodic external peer review, and recommend reviewers for, an assessment of progress and achievement of milestones.
Ensure timely registration of Phase I and Phase II trials in ClinicalTrials.gov.
Reserve the right to terminate or curtail the study (or an individual award) in the event of (a) failure to implement the study protocol, (b) a substantial shortfall in milestone achievement (e.g., participant recruitment, follow-up, data reporting and dissemination, quality control, or other major breach of the protocol), (c) substantive changes in the agreed-upon protocol with which NIAAA does not concur, (d) reaching a major study objective substantially before schedule with persuasive statistical evidence, or (e) human subject ethical issues that may dictate a premature termination.
Oversee the adequacy of adverse event management and reporting, and have regular communications with the PD/PI and study team.
Will be involved in funding decisions and attend review meetings of applications submitted in response to this FOA.
The NIAAA Staff will not have dual roles as Project Scientist and Program Officer.
Dispute Resolution:
Any disagreements that may arise in scientific or programmatic matters (within the scope of the award) between award recipients and the NIH may be brought to Dispute Resolution. A Dispute Resolution Panel composed of three members will be convened. It will have three members: a designee of the Steering Committee chosen without NIH staff voting, one NIH designee, and a third designee with expertise in the relevant area who is chosen by the other two; in the case of individual disagreement, the first member may be chosen by the individual awardee. This special dispute resolution procedure does not alter the awardee's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulation 42 CFR Part 50, Subpart D and DHHS regulation 45 CFR Part 16.
The Federal Funding Accountability and Transparency Act of 2006 (Transparency Act), includes a requirement for awardees of Federal grants to report information about first-tier subawards and executive compensation under Federal assistance awards issued in FY2011 or later. All awardees of applicable NIH grants and cooperative agreements are required to report to the Federal Subaward Reporting System (FSRS) available at www.fsrs.gov on all subawards over $25,000. See the NIH Grants Policy Statement for additional information on this reporting requirement.
In accordance with the regulatory requirements provided at 45 CFR 75.113 and Appendix XII to 45 CFR Part 75, recipients that have currently active Federal grants, cooperative agreements, and procurement contracts from all Federal awarding agencies with a cumulative total value greater than $10,000,000 for any period of time during the period of performance of a Federal award, must report and maintain the currency of information reported in the System for Award Management (SAM) about civil, criminal, and administrative proceedings in connection with the award or performance of a Federal award that reached final disposition within the most recent five-year period. The recipient must also make semiannual disclosures regarding such proceedings. Proceedings information will be made publicly available in the designated integrity and performance system (currently FAPIIS). This is a statutory requirement under section 872 of Public Law 110-417, as amended (41 U.S.C. 2313). As required by section 3010 of Public Law 111-212, all information posted in the designated integrity and performance system on or after April 15, 2011, except past performance reviews required for Federal procurement contracts, will be publicly available. Full reporting requirements and procedures are found in Appendix XII to 45 CFR Part 75 Award Term and Conditions for Recipient Integrity and Performance Matters.
Finding Help Online: http://grants.nih.gov/support/ (preferred method of contact)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)
General Grants Information (Questions regarding application processes and NIH grant resources)
Email: [email protected] (preferred method of contact)
Telephone: 301-945-7573
Grants.gov Customer Support (Questions regarding Grants.gov registration and Workspace)
Contact Center Telephone: 800-518-4726
Email: [email protected]
Raye Z. Litten, Ph.D.
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Telephone: 301-443-0636
Email: [email protected]
Ranga Srinivas, Ph.D.
National Institute of Alcohol Abuse and Alcoholism (NIAAA)
Telephone: 301-451-2067
Email: [email protected].
Mr. Jeffrey Thurston
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Telephone: 301-443-9801
Email: [email protected]