Department of Health
and Human Services (HHS)
and Human Services (HHS)
EXPIRED
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
New
None
93.273
This funding opportunity announcement (FOA) focuses on sensitivity and tolerance mechanisms underlying the development of alcohol use disorder. The intent of this FOA is to: (1) develop hypotheses about cellular, molecular or network mechanisms that regulate sensitivity and tolerance to alcohol, and (2) develop quantitative models to predict the development of tolerance and the progression to alcohol use disorder. These objectives will be accomplished with a Phased Innovation (R21/R33) mechanism, clinical trial required, in which secondary data analysis or pilot studies can occur during the R21 phase, and research testing the hypotheses can be expanded in the R33 phase. The transition to the R33 phase will be determined by NIAAA program staff after evaluation of the achievement of specific milestones set for the R21 phase. Applicants interested in animal studies on the mechanisms of tolerance may consider FOA (PAR-18-659) or in the genetic basis of tolerance may consider FOA (PA-18-660).
July 10, 2019
Not Applicable
Standard dates apply by 5:00 PM local time of applicant organization. All types of non-AIDS applications allowed for this funding opportunity announcement are due on these dates.
The first standard application due date for this FOA is October 1?6, 2019.
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.
Standard AIDS dates apply by 5:00 PM local time of applicant organization. All types of AIDS and AIDS-related applications allowed for this funding opportunity announcement are due on these dates.
The first AIDS application due date for this FOA is January 7, 2020
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.
Standard dates apply
Standard dates apply
Standard dates apply
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.
Background
While many Americans imbibe in alcoholic beverages, for some, drinking becomes problematic, potentially leading to an alcohol use disorder (AUD). The response to the initial alcohol experiences, sometimes known as sensitivity, may predict AUD later in life. Low sensitivity is associated with high probability of developing an AUD. Following initial exposure, responses to alcohol change with subsequent drinking. Alcohol tolerance is a complex phenomenon in which increased alcohol intake is required to achieve a given effect, e.g., the feeling of intoxication, and is a defining feature of AUD. Stated in another way, tolerance decreases the effect of a defined alcohol dose. Alcohol sensitivity and tolerance vary in the population, yet, research on underlying mechanisms is sparse and findings are disparate. Experimental subjects vary in age, sex, racial or ethnic background, previous alcohol exposure, drinking context and genetics. Response variables are often subjective, while objective measures are not comparable between studies. The goal of this FOA is to build a framework for the systematic analysis of the factors that contribute to alcohol sensitivity and tolerance and the mechanisms that regulate tolerance and transition to AUD.
In contrast to the scarcity of studies directly addressing mechanisms of tolerance, there is an abundance of behavioral and physiological data from subjects with AUD, and thus alcohol tolerance. Clinical studies include retrospective data regarding the need to increase the number of drinks over time for the same effect. The clinical studies usually focus on the withdrawal, relapse and re-instatement phases of AUD, but the same models and data can inform tolerance and progression to AUD.
The physiological nature of tolerance has been classified as either metabolic or functional. Metabolic tolerance describes changes in efficiency or capacity to metabolize ethanol resulting in a decrease in the blood alcohol concentration following a given dose of alcohol. Functional tolerance refers to lessened response to alcohol independent of the rate of metabolism of alcohol. Little is known about the interplay between metabolic and functional tolerance, as many of the molecules that metabolize alcohol in the liver are expressed in the nervous system.
Functional tolerance is further defined based upon the duration of alcohol exposure.
Different time frames for the forms of tolerance suggest separate underlying mechanisms. Tolerance diminishes after periods of abstinence, and thus, an individual may experience multiple episodes of tolerance. The dependence of the alcohol responses on previous periods of alcohol exposure, context(s), and abstinence has not been systematically studied under the framework of tolerance, nor have relationships between acute, rapid or chronic tolerance been well studied. It is unknown whether the common mechanisms mediate multiple forms of tolerance.
Sensitivity and tolerance are assessed by multiple methods. For human subjects, measurements include self-reported number of drinks to achieve intoxication, cortisol levels, or electrophysiological changes. Brain imaging studies have combined blood (or breath) alcohol concentration with self-reported assessment of intoxication, performance on cognitive and memory tasks with blood oxygen level-dependent response and functional connectivity measures. Recent studies of tolerance measured drinking and blood alcohol concentrations in complex motor and cognitive tasks, such as driving simulators.
The development of tolerance requires a compensatory response. Behavioral tolerance describes tolerance in response to specific cues. Thus, an individual or research subject may exhibit tolerance to alcohol in one context (i.e. bar), but not in another (i.e. workplace). The repeated pairing of the situational cues with alcohol represents Pavlovian conditioning. With behavioral tolerance, the cues alone can elicit the compensatory response, and the tolerance can be extinguished after repeated presentation of cues in absence of alcohol. Behavioral tolerance contributes to the dependence, withdrawal and abstinence phases of AUD.
Alcohol responses and tolerance capacity widely vary among humans and are influenced by multiple factors, including genetics, sex, race/ethnicity, behavioral context, and age. A spectrum of responses is observed, yet the underlying mechanisms for individual variability are not known. Drinking patterns of individual subjects within a cohort are not reported, but rather the mean and variance. However, the blood alcohol concentration is often measured and correlated with alcohol intake on an individual basis, providing an indication of variability within the study population. Similarly, self-report surveys highlight drinking patterns (or maximum number of drinks per day) and analyze individual perception of intoxication, but often the reports are not accompanied by objective measurements of functional outcomes or genetic variation. In summary, individual differences in the research subjects and the measurements of response and tolerance have been overlooked, and the translation and interpretation of the results do not converge into common mechanisms and neural circuits.
Specific Areas of Research Interest
This FOA encourages studies that identify the mechanisms of sensitivity and tolerance in AUD in relation to other variables (e. g. sex, behavioral context, age) through an R21/R33 mechanism. The R21 phase is the first two (2) years of the application, while the R33 spans the following three (3) years.
There is little convergence of published parameters, drinking models and patterns, and assessment paradigms. The R21 phase supports re-analysis of data from human experimental paradigms leading to AUD, with the goal of developing new hypotheses and common experimental framework(s) to characterize the sensitivity and tolerance (including individual variations). While tolerance may not have been the goal of the previous research, measurements of blood alcohol concentrations, in addition to the behavioral or physiological measurements, may provide insight into the mechanisms of tolerance. Re-analysis of these data and new pilot studies, through the lens of understanding sensitivity and tolerance, have the potential to provide preliminary data to develop and test new hypotheses about the roles of sensitivity and tolerance in AUDs in the R33 phase. Study topics include, but are not limited to, the following:
Studies that determine the effects of sex, age, race/ethnicity, environmental context, metabolites, and dose on the response (sensitivity) to alcohol
Studies that define common parameters leading to the acquisition of chronic tolerance, including factors that define response heterogeneity (genetics, epigenetic modifications, biomarkers (including metabolites), sex, race/ethnicity, and age)
Studies that define overall exposure regimen (i.e. oral, intravenous, low dose, voluntary choice, binge drinking, self-administration, and periods of abstinence) and the effects of prediction and control (learning mechanisms) in alcohol tolerance, persistence, and extinction
Development and testing of quantitative models describing the relationship between sensitivity and tolerance, defining relationships between acute, rapid and chronic tolerance, and identify common and distinct mechanisms of sensitivity and forms of tolerance
Examination of behavioral responses and neural circuitry following repeated periods of tolerance and abstinence and relationship to AUD and relapse
Studies of adaptation of neural circuits of behavioral, emotional, and cognitive measures during acquisition and loss of tolerance, including molecular and cellular changes. Adaptations leading to the allostatic static within a neural circuit or across neural circuits due to tolerance is of high programmatic priority
Interactions of neural circuitry of the physiological responses of tolerance and the neural circuitry of AUD and relapse, including methods of electrophysiology and functional magnetic resonance imaging
Studies that utilize state-of-the-art multi-omics approaches in humans to identify and validate molecular signaling, cellular and extracellular interactions, and epigenetic mechanisms, underlying sensitivity and tolerance to alcohol
Studies that examine the interactions of metabolic and functional forms of tolerance, with special consideration to molecules involved in alcohol metabolism that are expressed in the brain
Milestones
Studies are encouraged to use existing data from one or more Program Directors/Principal Investigators to develop hypotheses of the roles of sensitivity and tolerance in AUD. Projects should include the following:
Clear milestones for the R21 phase and related scientific goals for the R33 phase
Identification of previous studies and data that will be used to generate or support hypotheses about sensitivity or tolerance. The heterogeneity of previous samples (i.e. subjects that did not meet criterion for AUD or relapse) should be considered
Development of hypotheses of cellular and molecular mechanisms, signal transduction pathways, or network models for chronic tolerance
The objectives for the R33 phase should be based on the findings from the R21 phase. Examples of the goals for the R33 phase include, but are not limited to:
Generation of a quantitative model that predicts the influence of sensitivity or tolerance on the development of AUD
Identification of the neurobiological mechanisms of sensitivity and tolerance
Identification of points of prevention or intervention of alcohol abuse or alcohol use disorder, based on the sensitivity or tolerance criteria or mechanisms of acquisition of tolerance
Identification of the molecular genetic bases for the individual differences in sensitivity and tolerance
Studies of pharmacological targets or drug candidates for prevention of alcohol use disorder based on mechanisms of tolerance
Notes on priorities
Applications of cross-tolerance effects of alcohol with other drugs of abuse or multiple substances are not appropriate for this FOA. Studies that include a focus on environmental moderators of sensitivity or tolerance (e.g. fetal alcohol spectrum disorder, teratogens, or adverse childhood experiences) will not be considered appropriate to this FOA. Applicants are strongly encouraged to consult the Scientific/Research Contact listed below to discuss the alignment of their proposed work with the objectives of this FOA.
Grant: A support mechanism providing money, property, or both to an eligible entity to carry out an approved project or activity.
The OER Glossary and the SF424 (R&R) Application Guide provide details on these application types.
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The number of awards is contingent upon NIH appropriations and the submission of a sufficient number of meritorious applications.
For the R21 phase, the combined budget for direct costs during the two-year project period may not exceed $275,000 with no more than $200,000 requested in a single year. For the R33 phase, the direct costs should not exceed $500,000 per year.
The project period is limited to 2 years for the R21 phase and up to 3 years for the R33 phase. The total project period may not exceed 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:
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.
All instructions in the SF424 (R&R) Application Guide must be followed.
Specific Aims: Applicants must provide a single attachment of Specific Aims to include both the R21 and R33 phases.
Research Strategy: In preparing the R21/R33 application, investigators should consider that the application will be assigned a single overall impact score. Thus, clarity and completeness of the application regarding specific goals and the feasibility of each phase and the Milestones are critical. The Research Strategy should contain separate sections for both the R21 and R33 phases. It is not necessary to repeat information or details in the R33 section that are described in the R21 section.
Milestones and R21/R33 Transition
Applicants must propose a well-defined set of measurable milestones to achieve by the end of the R21 phase (R21), as well as milestones for the R33 phase. Examples of milestones for the R21 phase include, but are not limited to:
Analyses of previously acquired data from human and animal studies of alcohol (ab)use or dependence to identify (1) relationships of sensitivity or tolerance with future alcohol (ab)use, or (2) mechanisms of sensitivity or tolerance
Additional data acquisition or analysis from current studies to address roles of sensitivity and tolerance
Identification of common parameters of sensitivity or tolerance between human subjects and animal studies.
The objectives for the R33 phase should be based on the findings from the R21 phase. Examples of the goals for the R33 phase include, but are not limited to:
Generation of a quantitative model that predicts the influence of sensitivity or tolerance on the development of AUD
Identification of the neurobiological mechanisms of sensitivity and tolerance
Identification of points of prevention or intervention of alcohol abuse or alcohol use disorder, based on the sensitivity or tolerance criteria or mechanisms of acquisition of tolerance
Identification of the molecular genetic bases for the individual differences in sensitivity and tolerance
Studies of pharmacological targets or drug candidates for prevention of alcohol use disorder based on mechanisms of tolerance
Milestones should be specific, quantifiable, and scientifically justified; they should not be simply a restatement of the specific aims. Transition to the R33 phase is contingent upon programmatic review that will include, but is not limited to, satisfactory demonstration that the R21 milestones have been achieved. Transition to the R33 phase is not guaranteed for all grants awarded under this FOA.
The following modifications also apply:
Applications that include human subjects research are expected to describe basic plans for submitting grant-related human subjects data to the NIAAA-sponsored repository, as described in NOT AA-18-010.
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 with the following additional instructions:
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 How to Apply Application Guide. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Dealing with System Issues guidance. For assistance with application submission, contact the Application Submission Contacts in Section VII.
Important reminders:
All PD(s)/PI(s) must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile 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, NIH. Applications that are incomplete or non-compliant will not be reviewed.
In order to expedite review, applicants are requested to notify the NIAAA Referral Office by email at [email protected] when the application has been submitted. Please include the FOA number and title, PD/PI name, and title of the application.
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.
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.
For this particular announcement, note the following:
The R21/R33 phased innovation grant supports investigation of novel scientific ideas or new interventions, model systems, tools, or technologies that have the potential for significant impact on biomedical or behavioral and social sciences research. An R21/R33 grant application need not have preliminary data, extensive background material or preliminary information; however, they may be included if available. Appropriate justification for the proposed work can be provided through literature citations, data from other sources, or, when available, from investigator-generated data. Accordingly, reviewers will emphasize the conceptual framework, the level of innovation, and the potential to significantly advance our knowledge or understanding. Reviewers will assign a single impact score for the entire application, which includes both the R21 and R33 phases.
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?
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?
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?
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?
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?
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?
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?
Milestones
Are the R21 milestones clearly defined? Are the milestones feasible, well-developed, and objectively measurable with regard to specific goals and accomplishments? Are adequate criteria provided for the R21 phase that can be utilized to determine milestone completion before proceeding to the next phase of the project? Is it clear how the R33 phase of the study will develop and expand once the R21 milestones are achieved?
Study Timeline
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 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
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 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.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.
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 instructions, 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]
Elizabeth M Powell, PhD
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Telephone: 301-443-0786
Email: [email protected]
Ranga Srinivas, PhD
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Telephone: 301-451-2067
Email: [email protected]
Judy Fox
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Telephone: 301-443-4704
Email: [email protected]