Participating Organization(s)	National Institutes of Health (NIH)
Components of Participating Organizations	National Institute on Drug Abuse (NIDA)
Funding Opportunity Title	Predictive Animal Models for Smoking Cessation Medications (U54)
Activity Code	U54 Specialized Center- Cooperative Agreements
Announcement Type	New
Related Notices	None
Funding Opportunity Announcement (FOA) Number	RFA-DA-11-014
Companion FOA	None
Number of Applications	See Section III. 3. Additional Information on Eligibility.
Catalog of Federal Domestic Assistance (CFDA) Number(s)	93.279
FOA Purpose	This FOA, issued by the National Institute on Drug Abuse, National Institutes of Health, solicits grant applications for a multi-project research program to develop a weighted battery of animal behavioral tests for preclinical development of smoking cessation medications. This research program seeks to significantly improve the predictive validity of in vivo screening of drug candidates.  Since people smoke for many different reasons - withdrawal relief, pleasure, taste, improvement in concentration, weight control, stress control, irritability reduction, etc. - one approach to generating predictive models is to assess effects of effective anti-smoking pharmacotherapies on specific components of tobacco dependence. Applications are expected to include animal behavior tests only. The critical part of this initiative is the establishment of a biostatistical/computational modeling core and individual project nodes, arranged according to behavioral paradigms being studied. The behavioral assessments used to model various domains of tobacco dependence should capture essential features of these processes. Funding would be provided through a cooperative center agreement mechanism (U54). Applications will be solicited for centers that include core and node activities. Applicants are responsible for arranging the agreements between different laboratories which will service all centers activities, including the statistical/administrative core as well as the behavioral nodes activities.

Posted Date	February 4, 2011
Letter of Intent Due Date	March 1, 2011
Application Due Date(s)	March 31, 2011
AIDS Application Due Date(s)	Not Applicable.
Scientific Merit Review	June/July 2011
Advisory Council Review	August 2011
Earliest Start Date(s)	September 2011
Expiration Date	April 1, 2011
Due Dates for E.O. 12372	Not Applicable

Required Application Instructions

It is critical that applicants follow the instructions in the PHS398 Application Guide except where instructed to do otherwise (in this FOA or in a Notice from the NIH Guide for Grants and Contracts). Conformance to all requirements (both in the Application Guide and the FOA) is required and strictly enforced. While some links are provided, applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions. Applications that do not comply with these instructions may be delayed or not accepted for review.

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

Purpose:

Despite major developments in computed model systems, in vitro models and ex vivo models, in vivo animal testing is still a necessary part of drug development. This funding opportunity announcement (FOA) invites applications from investigators interested in participating in a National Institute on Drug Abuse (NIDA) effort to develop a weighted battery of animal behavioral tests to function as a screening system for preclinical development of smoking cessation medications. The critical part of this initiative is the establishment of a biostatistical/computational modeling core and individual project nodes, arranged according to the behavioral paradigms being studied. This research program seeks to significantly improve the predictive validity of in vivo screening of drug candidates. Funding would be provided through a cooperative center agreement mechanism (U54). The objectives of the program are (i) to obtain standardized data on the responses to existing first-line pharmacotherapies, that have been approved by FDA as aids for smoking cessation (i.e. varenicline, bupropion ), and second-line pharmacotherapies(i.e. clonidine, nortriptyline), in a range of animal behavioral tests that capture different domains of drug addiction/dependence, and (ii) to use these data to develop a battery with improved predictive validity for in vivo screening of anti-smoking drug candidates, as well as to make data broadly available (e.g., through the Neuroscience Information Framework (NIF)) to advance future research and discovery in this area. Applications proposing new animal models or tests will not be considered.

Background:

Because of the importance of tobacco-dependence treatment to national tobacco control efforts, the National Cancer Institute and the National Institute on Drug Abuse (NIDA) convened a meeting in January 2007, entitled Translational Medication Development for Nicotine Dependence Workshop. Participants from industry, academia and government agencies provided their views on the greatest opportunities for accelerating the translational efforts in the area of nicotine dependence. One of the challenges in medications development for addictive disorders is to determine the predictive validity of preclinical and clinical pharmacology models of various aspects of drug dependence. Although animal models of addictive disorders show convergent and face validity, it may not be possible to establish predictive validity due to an absence of effective medications to treat certain addictive disorders, e.g., cocaine dependence. However, establishing predictive validity of models for nicotine dependence is an exception as several approved medications exist. In fact, the current situation gives us an unprecedented opportunity to develop validated models of approved medications and expand the research agenda to address critical questions that may serve as a template for future studies in all addictions. Because addiction involves cognitive, affective, behavioral, and genetic components, research with effective smoking cessation medications can help to map the mechanisms of action of these agents. This may lead to insights into the nature of addiction, as well as provide signatures of medication effects. Novel chemical structures could then be profiled against currently available medications to determine their (novel) pharmacological profile.

Several pharmacotherapies are, in fact, available to support treatment of nicotine (tobacco) dependence, including ones with an overt nicotinic mechanism of action, such as nicotine replacement therapies and varenicline (Chantix , Champix ), others, in which nicotinic mechanisms may be a component, such as bupropion (Zyban ), and still others, for which there is no obvious nicotinic component to their action (e.g., the second-line medication clonidine, an α2 adrenergic agonist). Each of these drugs significantly improves the quit-rate compared to placebo. With these currently available medications, however, only about 20% of smokers are able to maintain long-term abstinence, and more efficacious pharmacotherapies need to be developed promptly.

Research Scope:

Basic research into the mechanisms of nicotine addiction has the benefit of the availability of a wide array of preclinical animal behavioral models and tests. A number of these tests have seen extensive use as research tools, and as a result they are known to have utility in studying the mechanisms and processes related to addiction and drug abuse relapse. In addition, some of these models, such as drug-self administration and drug discrimination, have demonstrated translational utility in providing preclinical data in support of the development of varenicline. However, given that varenicline is the only smoking cessation pharmacotherapy to have been developed through the typical pharmaceutical industry drug discovery approach, there is little evidence for the predictive validity of any of these models for medication development for drug addiction. Indeed, since inadequate efficacy remains a significant cause of failure in the drug development process, improvements in the ability to predict efficacy at various stages across the drug development process are warranted. The intent of this FOA is to fund a multi-project center(s) to undertake the screening of anti-smoking medications with various mechanisms of action, known to demonstrate efficacy in humans, in animal behavioral tests capturing cognitive, affective, behavioral reward/reinforcement, etc., components of tobacco dependence in humans. Although addiction is frequently and preferentially conceptualized in terms of reward and reinforcement, this initiative seeks to collect data simultaneously in other domains that may be relevant to drug addiction and drug abuse relapse, for example, (i) reward and positive reinforcement, (ii) anxiety, stress and emotionality/withdrawal (iii) impulsivity and compulsivity, (iv) cognition and (v) emotional memory among others. For each of these domains, there exist well-established tests that have validity within the domain (e.g., for reward and reinforcement reward enhancement, self-administration, reinstatement; for anxiety, stress and emotionality startle, pre-pulse inhibition, precipitated withdrawal; for impulsivity and compulsivity 5-choice serial reaction time task, delayed reward tasks; for cognition novel object recognition, conditioned stimulus effects; for emotional memory fear conditioning).

The purpose of this initiative is to support research to estimate if individually and/or collectively these tests are predictive of medication efficacy in clinical trials. It is important to note that the examples given above are not intended to be directive or exclusive, and other models may be worthy of validation in this effort. In general, the tests chosen should be ones that have been used pre-clinically, so that reliability of the data generated has been established and that there exists some conceptual understanding of what the test measures. In addition, while considering tests for the reward and positive reinforcement domain, investigators must be aware that certain animal behavioral tests appear not to generate reliable data with nicotine, and these should not be proposed (e.g., conditioned place preference, nicotine-primed reinstatement). Equally, it is important to highlight the fact that this initiative is not intended as a mechanism to support the development of new behavioral models, assays or tests, or to uncover novel behavioral processes or neurobiological mechanisms. Nor is it intended to be directed only to investigators who work in the drug addiction field. Indeed, NIDA welcomes the interest of investigators who have expertise with animal models that have not seen wide use in addiction research (e.g., potentiated startle, elevated plus maze), but that might be useful as part of a screening battery. Whereas individual projects within the center will be supported to generate data in one to several of these domains, a center core facility will be needed to be responsible for coordination of in-depth data analyses and modeling (assessment of whether overall data have predictive validity through weighed factor analyses, etc.) for each behavioral paradigm across multiple doses of first and second line medications.

In general, applicants must provide the rationale for:

Selecting the model system. For both target identification and target validation in vivo studies, small rodents remain the first choice. The rationale for selecting the particular species, strain, gender and age of the animals must be provided and these should be accessible to the general scientific community. A detailed description of the animal characteristics such as a definition of study population using a common strain and individual commercial stock designations of each animal provider, diet, housing conditions, microbial status and handling should be described. Before using compounds in animal systems, detailed information about the cross reactivity of the compounds with the target in the species of interest is necessary. For example, lower binding affinity in mice would require higher dosing which, in turn, might compromise target specificity and affect the results of testing. In addition, other interspecies differences should be taken into consideration. Bupropion is metabolized differently in the rat compared to human and mouse. Therefore, applicants need to specify how they will address this and similar species differences (e.g., comparison of dosing with bupropion compared to its metabolite over a sufficient dose/time range).

Selecting the tests for the behavioral parameter(s)/domain(s) to be studied. The proposed test must be validated for its specificity and selectivity to measure clinically relevant symptom(s) or physiological parameters. It is expected that, regardless of the test or battery chosen for testing, investigators will propose an approach that is sensitive to the need for relatively high throughput in vivo assessment. Approaches that require lengthy training or assessment periods will be deemed not feasible for in vivo screening.

Selecting the dose and route of administration for the medications being tested. A drug administration and dose regimen that is adapted to the pharmacokinetic properties of the drug, and to the duration of the study requires careful consideration. The rationale for dosing the animal must be evident from appropriate pharmacodynamic and pharmacokinetic assays, published in the literature or obtained in applicants laboratories. The route of administration is important not only because of animal welfare, but also out of consideration that the oral route is the desired route of administration in humans. Hence, oral dosing is preferable whenever possible. Frequent subcutaneous, intraperitoneal or intravenous injections lead to considerable stress in the animals and could influence test outcome. Assistant application devices, such as minipumps, should be avoided wherever possible, as they require surgery, additional control groups and can cause technical complications. For testing, a minimum of 3 doses of first and second line medications should be proposed. All of the medications are to be screened in each model proposed for evaluation.

Selecting the experimental design. Demonstrate the reconciliation between statistical needs for the detection of biological effects and constraints of animal welfare, cost and time. A detailed discussion about the use of appropriate statistics must be provided, including the evidence that applicants consulted a statistician to obtain information about the sufficient group size, and the appropriate statistical method to be applied for data analysis for each behavioral test and adapting the statistical approach for combining data across behavioral tests in developing an optimized predictive screening system. See further discussion below under Center and Node Responsibilities

The objectives of the program are (i) to obtain standardized data on the responses to existing first-line pharmacotherapies that have been approved for the treatment of tobacco dependence, (i.e. varenicline, bupropion , and second-line pharmacotherapies (i.e. clonidine, nortriptyline), in a range of animal behavioral models, and (ii) to use these data to develop a behavioral battery that improves predictive validity of in vivo models for screening of novel anti-smoking drug candidates. The proposed experiments need to be designed to include testing of each medication over a sufficient dose range and time-of-exposure range to ensure pharmacokinetic requirements are met.

Center and Node Responsibilities:

The U54 Center must include an administrative/statistical node to conduct data analysis and modeling, along with individual project nodes, arranged according to behavioral domains being studied, for example, (i) reward and positive reinforcement, (ii) anxiety, stress and emotionality/withdrawal, (iii) impulsivity and compulsivity, (iv) cognition and (v) emotional memory. It is likely that each domain will be represented by a separate node, but it is possible that a single node might have the capability of representing more than one domain. Each node (e.g., laboratory) will collect standardized data on responding to first and second-line pharmacotherapies across an agreed upon range of doses and time-of-exposure. An essential part of the application will be a description of the analytical and modeling capabilities of the central computing node. The process by which data will be collected among disparate behavioral nodes must be described in detail. This is especially important when behavioral nodes exist at sites separate from the central node.

Funding Instrument	Cooperative Agreement: A support mechanism used when there will be substantial Federal scientific or programmatic involvement. Substantial involvement means that, after award, scientific or program staff will assist, guide, coordinate, or participate in project activities.
Application Types Allowed	New The OER Glossary and the PHS398 Application Guide provide details on these application types.
Funds Available and Anticipated Number of Awards	NIDA intends to commit an estimated total of $2,500,000 to fund 1-2 grants.
Award Budget	Application budgets are not limited, but need to reflect actual needs of the proposed project.
Award Project Period	The maximum period is 5 years.

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

Higher Education Institutions:

• Public/State Controlled Institutions of Higher Education
• Private Institutions of Higher Education

The following types of Higher Education Institutions are always encouraged to apply for NIH support as Public or Private Institutions of Higher Education:

• Hispanic-serving Institutions
• Historically Black Colleges and Universities (HBCUs)
• Tribally Controlled Colleges and Universities (TCCUs)
• Alaska Native and Native Hawaiian Serving Institutions

Nonprofits Other Than Institutions of Higher Education

• Nonprofits with 501(c)(3) IRS Status (Other than Institutions of Higher Education)
• Nonprofits without 501(c)(3) IRS Status (Other than Institutions of Higher Education)

For profit Organizations

• Small Businesses
• For-Profit Organizations (Other than Small Businesses)

Governments

• State Governments
• County Governments
• City or Township Governments
• Special District Governments
• Indian/Native American Tribal Governments (Federally Recognized)
• Indian/Native American Tribal Governments (Other than Federally Recognized)
• Eligible Agencies of the Federal Government
• U.S. Territory or Possession

Other

• Independent School Districts
• Public Housing Authorities/Indian Housing Authorities
• Native American tribal organizations (other than Federally recognized tribal governments)
• Faith-based or Community-based Organizations
• Regional Organizations

Foreign (non-U.S.) components of U.S. Organizations are not allowed.

Applicant organizations must complete the following registrations as described in the PHS398 Application Guide to be eligible to apply for or receive an award. Applicants must have a valid Dun and Bradstreet Universal Numbering System (DUNS) number in order to begin each of the following registrations.

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

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

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

Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Project Director/Principal Investigator (PD/PI) is invited to work with his/her organization to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH support.

For institutions/organizations proposing multiple PDs/PIs, visit the Multiple Program Director/Principal Investigator Policy and submission details in the Senior/Key Person Profile (Expanded) Component of the PHS398 Application Guide.

Applications with Multiple PDs/PIs

When multiple PD/PIs are proposed, use the Face Page-Continued page to provide items 3a 3h for all PD/PIs. NIH requires one PD/PI be designated as the contact PD/PI for all communications between the PD/PIs and the agency. The contact PD/PI must meet all eligibility requirements for PD/PI status in the same way as other PD/PIs, but has no special roles or responsibilities within the project team beyond those mentioned above. The contact PD/PI may be changed during the project period. The contact PD/PI should be listed in block 3 of Form Page 1 (the Face Page), with all additional PD/PIs listed on Form Page 1-Continued. When inserting the name of the PD/PI in the header of each application page, use the name of the Contact PD/PI, et. al. The contact PD/PI must be from the applicant organization if PD/PIs are from more than one institution.

All individuals designated as PD/PI must be registered in the eRA Commons and must be assigned the PD/PI role in that system (other roles will not give the PD/PI the appropriate access to the application records). Each PD/PI must include their respective eRA Commons ID in the eRA Commons User Name field.

All projects proposing Multiple PDs/PIs will be required to include a new section describing the leadership plan approach for the proposed project.

Multiple PD/PI Leadership Plan: For applications designating multiple PDs/PIs, a new section of the research plan, entitled Multiple PD/PI Leadership Plan must be included. A rationale for choosing a multiple PD/PI approach should be described. The governance and organizational structure of the leadership team and the research project should be described, and should include communication plans, process for making decisions on scientific direction, and procedures for resolving conflicts. The roles and administrative, technical, and scientific responsibilities for the project or program should be delineated for the PDs/PIs and other collaborators.

If budget allocation is planned, the distribution of resources to specific components of the project or the individual PDs/PIs should be delineated in the Leadership Plan. In the event of an award, the requested allocations may be reflected in a footnote on the Notice of Award.

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

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

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

Applicants are required to prepare applications according to the current PHS 398 application forms in accordance with the PHS 398 Application Guide.

It is critical that applicants follow the instructions in the PHS398 Application Guide, except where instructed in this funding opportunity announcement to do otherwise. Conformance to the requirements in the Application Guide is required and strictly enforced. Applications that are out of compliance with these instructions may be delayed or not accepted for review.

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

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

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

The letter of intent should be sent to: NIDALetterofIntent@mail.nih.gov

Applicants are encouraged to send the letter of intent by email to the email address above but as an alternative the letter may also be sent to:

Director - DA-11-014
Office of Extramural Affairs
National Institute on Drug Abuse/NIH/DHHS
6001 Executive Boulevard, Suite 4243, MSC 9550
Bethesda, MD 20892-9550
Rockville, MD 20852 (for express/courier service)

Applications must be prepared using the PHS 398 research grant application forms and instructions for preparing a research grant application. Submit a signed, typewritten original of the application, including the checklist, and three signed photocopies in one package to:

Center for Scientific Review
National Institutes of Health
6701 Rockledge Drive, Room 1040, MSC 7710
Bethesda, MD 20892-7710 (U.S. Postal Service Express or regular mail)
Bethesda, MD 20817 (for express/courier service; non-USPS service)

At the time of submission, two additional paper copies of the application and all copies of the appendix files must be sent to:

Director - DA-11-014
Office of Extramural Affairs
National Institute on Drug Abuse/NIH/DHHS
6001 Executive Boulevard, Suite 4243, MSC 9550
Bethesda, MD 20892-9550
Rockville, MD 20852 (for express/courier service)

All page limitations described in the PHS398 Application Guide must be followed with the following exceptions or additional requirements:

• 12 pages for Overview of the Cooperative Research Center
• 12 pages for a description of the administrative/statistical node. An essential part of the application will be a description of the analytical and modeling capabilities of the central computing node. The process by which data will be collected among disparate behavioral nodes must be described in detail. This is especially important when behavioral nodes exist at sites separate from the central node.
• 12 pages for a description of each individual project node. The number of project nodes per Cooperative Center is not specified but the Overview (see above) should explain the rationale for the number and type of behavioral domains being studied. Moreover, it is likely that each domain will be represented by a separate node, but it is possible that a single node might have the capability of representing more than one domain
• Specific aims for each of the above sections and for each project node is limited to one page.

All instructions in the PHS398 Application Guide must be followed, with the following additional instructions:

Resource Sharing Plan

Individuals are required to comply with the instructions for the Resource Sharing Plans (Data Sharing Plan, Sharing Model Organisms, and Genome Wide Association Studies (GWAS)) as provided in the PHS398 Application Guide, with the following modifications:

• All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan.

Appendix

Do not use the appendix to circumvent page limits. Follow all instructions for the Appendix (please note all format requirements) as described in the PHS398 Application Guide,

Not Applicable

Part I. Overview Information contains information about Key Dates. 

Information on the process of receipt and determining if your application is considered on-time is described in detail in the PHS398 Application Guide.

Applicants may track the status of the application in the eRA Commons, NIH’s electronic system for grants administration.

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 received on or before the due dates in Part I. Overview Information. .

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

Special Requirements

Investigators funded under this FOA are expected to federate their data supported by this FOA through the Neuroscience Information Framework (NIF), consistent with achieving the goals of this program. NIF is sponsored by the NIH Blueprint for Neuroscience Research to enhance neuroscience research by enabling discovery and access to research data and tools worldwide through a resource registry and concept based query system. (see http://www.neuinfo.org). Data sharing plans that applicants submit are expected to incorporate federation of data with NIF.

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

Only the review criteria described below will be considered in the review process. As part of the NIH mission, all applications submitted to the NIH in support of biomedical and behavioral research are evaluated for scientific and technical merit through the NIH peer review system.

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

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

Significance

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

Investigator(s)

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

Innovation

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

Approach

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

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

Environment

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

In addition to the above review criteria, the following criteria will be addressed and considered in determining scientific merit and score.

Individual Projects:

• Are the experimental design and methods adequate to achieve the research objectives?
• Has the selection of the model system been justified adequately?
• Has the behavioral test been validated for specificity and selectivity is it high throughput?
• Have the dose and route of administration been justified adequately?
• Are the scientific qualifications and time commitments of the PIs of the individual projects appropriate?

Core Resources:

• Are the analytical and modeling capabilities of the central computing core adequate to achieve the goals of the project?
• Do the core resources effectively and efficiently support the research activities in a manner that cannot be supported through available resources?
• Is each node justified as essential for the conduct of project research?
• Are the qualifications of core managers adequate?

Overall Program Organization:

• Are the scientific qualifications, scientific and administrative leadership capabilities, and the time commitment of the PD adequate?
• Is the planning and evaluation process adequate, including?
• Do the organization and leadership of the separate project nodes promote and facilitate scientific interactions and the effective use of core facilities?
• Are tangible institutional commitments that will enable and facilitate the research objectives adequate?

A single impact/priority score will be assigned to the Multi-Component Translational Research Project application as a whole after discussing all of the review elements. The score will be based on the overall quality of the research projects, the overall effectiveness and adequacy of core resources, and the overall program organization and capability.

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

Protections for Human Subjects

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

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

Inclusion of Women, Minorities, and Children 

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

Vertebrate Animals

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

Biohazards

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

Resubmissions

Not Applicable.

Renewals

Not Applicable.

Revisions

Not Applicable.

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

Applications from Foreign Organizations

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

Select Agent Research

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

Resource Sharing Plans

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

Budget and Period of Support

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

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

As part of the scientific peer review, all applications:

• May undergo a selection process in which only those applications deemed to have the highest scientific and technical merit (generally the top half of applications under review), will be discussed and assigned an overall impact/priority score.
• Will receive a written critique.

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

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

After the peer review of the application is completed, the PD/PI will be able to access his or her Summary Statement (written critique) via the eRA Commons. 

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

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

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

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

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

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

A. Background Guidance

In general, applicants must provide the rationale for:

1)    Selecting the model system. For both target identification and target validation in vivo studies, small rodents remain the first choice. The rationale for selecting the particular species, strain, gender and age of the animals must be provided and these should be accessible to the general scientific community. Before using compounds in animal systems, detailed information about the cross reactivity of the compounds with the target in the species of interest is necessary. For example, lower binding affinity in mice would require higher dosing which, in turn, might compromise target specificity and affect the results of testing. In addition, other interspecies differences should be taken into consideration. Bupropion is metabolized differently in the rat compared to human and mouse. Therefore, applicants need to specify how they will address this and similar species differences (e.g., comparison of dosing with bupropion compared to its metabolite over a sufficient dose/time range).

• Reverse validity approach. It is expected that, regardless of the test or battery chosen for testing, investigators will propose a reverse validity approach, which begins with drugs that are known to be effective in human clinical studies (e.g., varenicline, bupropion) to validate and refine animal models.
• High throughput. It is expected that, regardless of the test or battery chosen for testing, investigators will propose an approach that is sensitive to the need for relatively high throughput in vivo assessment. Approaches that require lengthy training or assessment periods will be deemed not feasible for purposes of screening smoking cessation medications.
• Selecting the dose and route of administration for the medications being tested. A drug administration and dose regimen that is adapted to the pharmacokinetic properties of the drug, and to the duration of the study requires careful consideration. The rationale for dosing the animal must be evident from appropriate pharmacodynamic and pharmacokinetic assays, published in the literature or obtained in applicants laboratories. The route of administration is important not only because of animal welfare, but also out of consideration that the oral route is the desired route of administration in humans. Hence, oral dosing is preferable whenever possible. Frequent subcutaneous, intraperitoneal or intravenous injections lead to considerable stress in the animals and could influence test outcome. Assistant application devices, such as minipumps, should be avoided wherever possible, as they require surgery, additional control groups and can cause technical complications. For testing, a minimum of 3 doses of first and second line medications should be proposed. All of the medications are to be screened in each model proposed for evaluation.
• Selecting the experimental design. Demonstrate the reconciliation between statistical needs for the detection of biological effects and constraints of animal welfare, cost and time. A detailed discussion about the use of appropriate statistics must be provided, including the evidence that applicants consulted a statistician to obtain information about the sufficient group size, and the appropriate statistical method to be applied for data analysis for each behavioral test and adapting the statistical approach for combining data across behavioral tests in developing an optimized predictive screening system.
• The objectives of the program are (i) to obtain standardized data on the responses to existing first-line pharmacotherapies that have been approved for the treatment of tobacco dependence, (i.e. varenicline, bupropion (US DHHS/PHS 2008) and second-line pharmacotherapies,(i.e. clonidine, nortriptyline), in a range of animal behavioral models, and (ii) to use these data to develop a behavioral battery that improves predictive validity of in vivo models for screening of novel anti-smoking drug candidates. The proposed experiments need to be designed to include testing of each medication over a sufficient dose range and time-of-exposure range to ensure pharmacokinetic requirements are met.

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

The PD/PI will have the primary responsibility for defining the details for the development of a weighted behavioral battery for medications discovery and development research project within the guidelines of FOA-DA-11-014 and for performing the scientific activities. The PI will agree to collaboration and to accept close coordination, cooperation, and participation of NIH staff and advisors in those aspects of scientific and technical management of the project as described under the Cooperative Agreement Terms and Conditions of Award.

The PI will:

• Determine experimental approaches, design protocols, set project milestones and conduct experiments;
• Endeavor to meet or exceed stated milestones;
• Provide goals for throughput, quality, and cost to NIDA as requested (usually at the outset of the award and in monthly progress reports to the Steering Committee, but also at other times as requested by NIDA program staff);
• Ensure that the results of the research effort meet or exceed the quality standards and costs agreed upon at the time of award;
• Submit data for quality assessment in any manner specified by the Steering Committee or the Panel of Scientific Consultants;
• Submit periodic progress reports in a standard format, as agreed upon by the Steering Committee and the Panel of Scientific Consultants;
• Ensure that the data are deposited in the appropriate public databases and that resources developed as part of this project are made publicly available according to NIH policies;
• Adhere to the general NIH policies regarding sharing resources, data release, and resource sharing, as well as the specific data and resource-sharing policies proposed in the application, as modified by any negotiation prior to award or that might be established by the Steering Committee during the course of this activity;
• Accept and implement any other common policies, guidelines and procedures that are developed and approved by the Steering Committee and the Panel of Scientific Consultants;
• Inform the NIDA Program Director and of all major interactions with members of the Steering Committee;
• Attend a yearly Steering Committee meeting with the Panel of Scientific Consultants. 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 HHS, PHS, and NIH policies.

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

For RFA-DA-11-014, the NIDA Project Scientist will have substantial scientific/programmatic involvement during the conduct of this activity through technical assistance, advice and coordination. However, the role of the NIDA Project Scientist will be to facilitate and not to direct the activities. It is anticipated that decisions in all collaborative activities will be reached by consensus of the Steering Committee, of which the PI is a member, and that the NIDA Project Scientist will participate in this process. The NIDA Project Scientist shall participate as a member of the Steering Committee and will have one vote.

The Project Scientist will:

• Participate (with the PI and the other Steering Committee members) in the group process of setting research priorities for the research project, deciding optimal research approaches and protocol designs, and contributing to the adjustment of research protocols or approaches as warranted. The Project Scientist will assist and facilitate the group process and not direct it;
• Negotiate goals for throughput, quality, and cost with the awardee, as necessary;
• Serve as a liaison between the awardee and the Panel of Scientific Consultants;
• Attend all Steering Committee meetings as a voting member and assist in developing operating guidelines, quality control procedures, and consistent policies for dealing with recurrent situations that require coordinated action;
• Periodically report progress to the Director of NIDA;
• Lend relevant expertise and overall knowledge of NIH-sponsored research to facilitate the selection of scientists not affiliated with the awardee institutions who are to serve on the Panel of Scientific Consultants and the Steering Committee;
• Serve as liaison between the Steering Committee and the Panel of Scientific Consultants;
• Serve on subcommittees of the Steering Committee, as appropriate; to provide advice in the management and technical performance of the investigation;
• Assist in promoting the availability of resources developed in the course of this project to the scientific research community-at large;
• Participate in data analyses, interpretations, and where warranted, authoring of the publication of results of studies conducted as part of the research project;
• Assist awardees in the development, if needed, of policies for dealing with situations that require coordinated action;
• Retain the option to recommend, with the advice of the Panel of Scientific Consultants, the withholding or reduction of support from any cooperative agreement that substantially fails to achieve its goals according to the milestones agreed to at the time of award, or fails to maintain the state of the art in the production of mouse knockout mutants or fails to comply with the Terms and Conditions of the award.

Areas of Joint Responsibility include:

The Steering Committee will serve as the main governing board of the awarded research project. The Steering Committee membership will include the PI of the awarded cooperative agreement and the NIH Project Scientist. Additional members may be added by action of the Steering Committee.

The Steering Committee will:

• Discuss progress in meeting the goals of the cooperative agreement research project;
• Discuss potential modifications of the goals of the research project;
• Develop recommendations for uniform procedures and policies necessary to meet the goals of the project. Adoption of procedures and policies developed by the Steering Committee will require concurrence by the Panel of Scientific Consultants;

Each full member will have one vote; the total votes of the NIH Project Scientist-members of the Steering Committee will constitute a minority of the votes. Awardee members of the Steering Committee will be required to accept and implement policies approved by the Steering Committee.

Panel of Scientific Consultants:

A Panel of Scientific Consultants (PSC) will be responsible for reviewing and evaluating the progress of the research project toward meeting its goals. The PSC will provide recommendations to the Director of NIDA. The Panel will be composed of four to six senior scientists with relevant expertise who are not PIs of a cooperative agreement involved in the research project. The Panel of Scientific Consultants will be appointed by the NIDA Director. The membership of the Panel of Scientific Consultants may be enlarged permanently, or on an ad hoc basis, as needed.

The Panel of Scientific Consultants will meet at least once a year and by conference call 2 to 3 times per year. During part of this meeting, there will be a joint meeting with the Steering Committee to allow the PSC members to interact directly with the awardees. Annually, the PSC will make recommendations to the NIH regarding progress present advice to the NIDA Director about changes, if any, which may be necessary.

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 regulations 42 CFR Part 50, Subpart D and HHS regulations 45 CFR Part 16.

When multiple years are involved, awardees will be required to submit the Non-Competing Continuation Grant Progress Report (PHS 2590) annually and financial statements as required in the NIH Grants Policy Statement.

A final progress report, invention statement, and Financial Status Report are required when an award is relinquished when a recipient changes institutions or when an award is terminated.

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

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

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

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

Elena Koustova, Ph.D.
Division of Basic Neuroscience and Behavioral Research
National Institute on Drug Abuse (NIDA)
Telephone: 301-496-8768
Email: koustovae@mail.nih.gov

Paul Schnur, Ph.D.
Division of Basic Neuroscience and Behavioral Research
National Institute on Drug Abuse (NIDA)
Telephone: 301-435-1316
Email: pschnur@mail.nih.gov

Mark Swieter, Ph.D.
Office of Extramural Affairs
National Institute on Drug Abuse (NIDA)
Telephone: 301-435-1389
Email: mswieter@mail.nih.gov

Cheryl Nathaniel
Grants Management Branch
National Institute on Drug Abuse (NIDA)
Telephone: 202-526-0108
Email: nathanic@mail.nih.gov

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

Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part 52 and 45 CFR Parts 74 and 92.

Special Considerations

HIV/AIDS Counseling and Testing Policy for the National Institute on Drug Abuse: In light of recent significant advances in rapid testing for HIV and in effective treatments for HIV, NIDA has revised its 2001 policy on HIV counseling and testing. NIDA-funded researchers are strongly encouraged to provide and/or refer research subjects to HIV risk reduction education and education about the benefits of HIV treatment, counseling and testing, referral to treatment, and other appropriate interventions to prevent acquisition and transmission of HIV. This policy applies to all NIDA funded research conducted domestically or internationally. For more information see http://grants.nih.gov/grants/guide/notice-files/NOT-DA-07-013.html.

National Advisory Council on Drug Abuse Recommended Guidelines for the Administration of Drugs to Human Subjects: The National Advisory Council on Drug Abuse (NACDA) recognizes the importance of research involving the administration of drugs with abuse potential, and dependence or addiction liability, to human subjects. Potential applicants are encouraged to obtain and review these recommendations of Council before submitting an application that will administer compounds to human subjects. The guidelines are available on NIDA's Web site at http://www.nida.nih.gov/about/organization/nacda/CouncilStatement.html.