It is critical that applicants follow the Research (R) Instructions in the SF424 (R&R) 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. 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 the 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

The Step Up for SUD Initiative provides short-term funding to conduct experiments aiming to expand the range of drug targets and mechanisms for SUD therapies. In addition, it will allow for in-kind access to biomedical product development expertise, business strategy and commercialization support, and assistance in the company/startup formation, as needed. Applications to test new therapeutic ideas (a new mechanism/ target class for SUD or a new SUD indication for a validated mechanism/ target class), especially for cocaine, methamphetamine, or cannabis use disorders are encouraged.

Basic science/basic research, also called pure research or fundamental research, refers to the highly skilled, usually academic laboratory-based, research that is needed to understand the cellular or molecular mechanisms underlying a disorder. Although basic research aims to further scientific knowledge through understanding of the function of newly discovered molecules, phenomena, or processes, it is the keystone of the drug discovery process, which allows scientists to uncover defective biological pathways that can be targeted to treat a condition. Over the past 20 years basic research has identified neural substrates and pathways implicated in reward and addiction. However, the application of this basic knowledge to the development of effective medications to treat SUD has largely been ineffective. Currently, there are medications approved by the Food and Drug Administration (FDA) for use as an aid to smoking cessation treatment and to treat opioid use disorder, but the options for both are still limited. Moreover, there are no FDA-approved medications for cocaine, methamphetamine, or cannabis use disorders. Thus, the development of safe and effective medications to treat these disorders is an urgent public health need. Basic scientists are encouraged to more productively contribute to addressing this need.

The modern drug development paradigm rests firmly on the ability to capitalize on scientific discovery, and scientific advances made by the NIDA-funded basic scientists are seemingly offering extraordinary opportunities for the development of medications to treat SUDs. These include the discovery of genes and proteins, receptors, neurotransmitters, neuromodulators, and brain circuits associated with drug abuse, as well as risk and protective factors for the SUD onset and progression. However, most of the work of converting a discovery into a therapeutic cannot and is not expected to be done within an organization engaged in fundamental research, such as university. The discoveries need to exit the academic environment to begin pre-clinical and clinical development, thus, significantly limiting the opportunities for the basic scientists to shepherd their ideas into drugs and to meaningfully contribute to product development process. It is possible that the aggregate number of new drugs is a fraction of the potential yield from universities and research institutes. Key challenges that hinder participation of basic scientists in the drug development include insufficient funding for validation and translation studies, lack of the drug development expertise or internal R&D resources, limited knowledge of business strategy and development, and difficulty identifying the right partners at the right time. This FOA is poised to tackle the challenges through this nimble, short-term funding opportunity.

The long and winding process to transform an idea into a drug is wrought with difficulties, compounded by the high risk of biomedical product development and resulting low investment for its early stages. As a result, too few possibilities created by basic researchers can be supported. The challenge for government funders, such as NIDA, is to look within the translation gap to find a solution that can be implemented through better efficiency, collaboration and synergistic activities. This FOA highlights a novel funding model adopted to incorporate the best formal product development practices and "lean"/agile ideas to engage the basic scientists and to spark the development of new therapeutics for SUD patients.

The canonical view of innovation process as a linear sequence of activities whose value can be judged only at the end is being replaced with a segmented, outcome-based approach. The progressive value buildup model stipulates how to relate the entry and exit points along the drug development continuum to the achievements along the way, and what needs to be done to demonstrate commercial value at each step. It means that the basic scientist - inventor of a new technology, including new drug targets and new compounds - does not have to participate in the entire drug R&D process but can still productively contribute to the creation of the viable therapeutics. One stage (or one step up to reach a value inflection point) needs to be accomplished successfully to create enough value to become attractive to partners (e.g. pharma companies) for potential hand-off. Because basic (exploratory) science is sometimes produced to a different standard than is needed for commercialization, with emphasis on novelty rather than the rigorous validation and proof of concept needed for the uptake by investors and pharmaceutical industry, this funding opportunity is designed to allow for brief experimentation to align the world-class disease biology expertise in SUD with the interest of investors and industry to create (financial) value.

For each project funded under this FOA, the NIDA will assemble an NIH expert panel called a Project Development Team (PDT) comprising of Program Official (PO), Science Officer (SO), the PD/PI and appropriate NIH expert consultants. Together, the team will create a credible thesis for how the PD/PI will address an important SUD issue in a transformative way, differentiate from other approaches, and create a path for progressively de-risking that opportunity. The PDT will help the PD/PI establish an overall strategy for the project, including identifying the critical value inflection point to determine what needs to be done in the preceding stage to make the technology attractive to the potential partners.

The Step Up for SUD Initiative also aims to address another challenge for translating the academic discoveries, namely, the comprehensive capture of negative results. It is acknowledged that negative data fit poorly to current publishing and citation paradigms. As the result, only the successful accounts of research are primarily published, leading to confirmation bias. NIDA believes that proper archiving of negative results will benefit the community at large and improve the scientific knowledge about potential SUD drug targets. The applicants are expected to take deliberative measures to publicize the outcomes, including negative, of this funding.

Scope

The single major contributor to the cost of the drug research and development is the high project attrition rate. While the attrition due to poor bioavailability and pharmacokinetics was recently noticeably reduced, attrition due to insufficient efficacy remains constant and persistent. This indicates that more effective target selection continues to be the major challenge. Target selection is based on integrating the understanding of multiple factors, including disease biology, pharmacological tractability of the target, safety risks and commercial opportunities.

The main focus of research activities funded through this FOA is drug target validation. For the purpose of this FOA, target is defined as molecular entity present in living systems that, upon interaction with therapeutic agents of their byproduct, results in modified biological responses that lead to therapeutic outcomes. The interaction between a drug and its target leads directly or indirectly to observable clinical outcomes. While the main focus of this initiative is on target validation, the applications could be submitted to explore any early discovery stage (e.g. assay development, hit identification/ confirmation) up to the lead optimization stage. Proposals for the more advanced drug discovery and development efforts are not responsive to this FOA and are supported by NIDA through multiple available FOAs.

The proposed studies could include, but not limited to, the following:

• Validation of targets for SUD treatment;
• Experiments to assure data robustness (e.g., reproducing the key (including published) in vitro and in vivo finding in at least 2 duplicate studies using same material, doses, readouts);
• Determination of biological criteria for hit designation;
• Determination of approach for hit-to-lead discovery;
• Developing the target-specific screening paradigms and decision trees;
• Development and validation of in vitro and in vivo assays;
• General mechanism of action (MOA) and selectivity testing;
• Composing drug product concepts (e.g., Target Product Profile (TPP));
• Compound screening (including FDA-approved drugs for other indications, drugs approved outside of US, etc.) to yield hits and leads;
• Business case preparation work;
• Experiments to strengthen the intellectual property (IP) position.

Applications to test new therapeutic ideas (a new mechanism/ target class for SUD or a new SUD indication for a validated mechanism/ target class), especially the ones enabled by the growing availability of the broader armamentarium of treatment modalities are encouraged. Monoclonal antibodies, recombinant proteins, nucleus acid-based therapeutics and viral vectors have expanded the druggable target space compared with traditional small-molecule drugs alone.

Through this FOA, the development of pharmacotherapeutics, not diagnostics or devices, will be supported. Applications focusing solely on generation of new animal models, development of new human laboratory models or mechanistic studies of the neurobiology of addiction are considered non-responsive for this FOA and maybe withdrawn.

To apply, the structured information supporting target hypothesis generation must be provided. This is explicitly described in Section IV. The use of Target Development Level (TDL) classification scheme which categorizes proteins into four groups with respect to the depth of investigation from a clinical chemical and biological standpoint is encouraged.

Since the goal of this FOA is to validate new drug targets, the creation and protection of intellectual property (IP) that will make drug target candidates attractive to potential licensing and commercialization partners are a significant consideration in designing research strategies. The Principal Investigator (PI)'s institutions retain their assignment of IP rights and gain assignment of IP for drug target candidates or drug candidates developed through this FOA. It is expected that the PI institutions will take responsibility for patent filings, maintenance and licensing efforts toward commercialization. The PD/PI is expected to work closely with technology transfer/business development officials at his or her institution to ensure that royalty agreements, patent filings, and all other necessary IP arrangements are completed. Award recipients will be encouraged to identify and foster relationships with potential licensing and commercialization partners, consistent with the goals of this funding opportunity announcement.

The outcomes sought by NIDA will include an increase in the number of robustly validated targets; building several packages of pre-clinical in vitro and in vivo evidence; developing good quality tool molecules to enable the SUD drug discovery efforts; and building capacity in early SUD drug discovery and high-quality scientific collaboration.

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

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

o Hispanic-serving Institutions

o Historically Black Colleges and Universities (HBCUs)

o Tribally Controlled Colleges and Universities (TCCUs)

o Alaska Native and Native Hawaiian Serving Institutions

o Asian American Native American Pacific Islander Serving Institutions (AANAPISIs)

Nonprofits Other Than Institutions of Higher Education

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

For-Profit Organizations

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

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
• Non-domestic (non-U.S.) Entities (Foreign Institutions)

Non-domestic (non-U.S.) Entities (Foreign Institutions) are eligible to apply.
Non-domestic (non-U.S.) components of U.S. Organizations are eligible to apply.
Foreign components, as defined in the NIH Grants Policy Statement, are allowed.

Applicant Organizations

Applicant organizations must complete and maintain the following registrations as described in the SF 424 (R&R) Application Guide to be eligible to apply for or receive an award. All registrations must be completed prior to the application being submitted. Registration can take 6 weeks or more, so applicants should begin the registration process as soon as possible. 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.

• Dun and Bradstreet Universal Numbering System (DUNS) - All registrations require that applicants be issued a DUNS number. After obtaining a DUNS number, applicants can begin both SAM and eRA Commons registrations. The same DUNS number must be used for all registrations, as well as on the grant application.
• System for Award Management (SAM) Applicants must complete and maintain an active registration, which requires renewal at least annually. The renewal process may require as much time as the initial registration. SAM registration includes the assignment of a Commercial and Government Entity (CAGE) Code for domestic organizations which have not already been assigned a CAGE Code.
• o NATO Commercial and Government Entity (NCAGE) Code Foreign organizations must obtain an NCAGE code (in lieu of a CAGE code) in order to register in SAM.
• eRA Commons - Applicants must have an active DUNS number to register in eRA Commons. Organizations can register with the eRA Commons as they are working through their SAM or Grants.gov registration, but all registrations must be in place by time of submission. eRA Commons requires organizations to identify at least one Signing Official (SO) and at least one Program Director/Principal Investigator (PD/PI) account in order to submit an application.
• Grants.gov Applicants must have an active DUNS number and SAM registration in order to complete the Grants.gov registration.

Program Directors/Principal Investigators (PD(s)/PI(s))

All PD(s)/PI(s) must have an eRA Commons account. PD(s)/PI(s) should work with their organizational officials to either create a new account or to affiliate their existing account with the applicant organization in eRA Commons. If the PD/PI is also the organizational Signing Official, they must have two distinct eRA Commons accounts, one for each role. Obtaining an eRA Commons account can take up to 2 weeks.

Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) is invited to work with 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 SF424 (R&R) Application Guide.

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.

The NIH will not accept duplicate or highly overlapping applications under review at the same time. This means that the NIH will not accept:

• A new (A0) application that is submitted before issuance of the summary statement from the review of an overlapping new (A0) or resubmission (A1) application.
• A resubmission (A1) application that is submitted before issuance of the summary statement from the review of the previous new (A0) application.
• An application that has substantial overlap with another application pending appeal of initial peer review (see NOT-OD-11-101).

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.

It is critical that applicants follow the Research (R) Instructions in the SF424 (R&R) 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 activity
• Name(s), address(es), and telephone number(s) of the PD(s)/PI(s)
• Names of other key personnel
• Participating institution(s)
• Number and title of this funding opportunity

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

Applicants are encouraged to send the letter of intent by email to the above email address. As an alternative, letters may also be sent to:

Office of Extramural Policy and Review
National Institute on Drug Abuse/NIH/DHHS
6001 Executive Boulevard, Suite 4243, MSC 9550
Bethesda, MD 20892-9550

All page limitations described in the SF424 Application Guide and the Table of Page Limits must be followed.

The following section supplements the instructions found in the SF424 (R&R) Application Guide and should be used for preparing an application to this FOA.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions:

Specific Aims:

The Specific Aims section should include Aims appropriate for the FOA goals and the U18 award duration.

Research Strategy: The Research Strategy section should include the following specific subsections, as described below.

Clinical Impact in treating SUDs:

1. Briefly describe the current state of knowledge of the etiology, clinical characteristics, and current and projected prevalence of the particular SUD;

2. Briefly discuss available treatments, including all treatment modalities and their limitations;

3. Discuss how the proposed project relates to therapeutic development efforts underway in academia and industry.

Biological Rationale for Target Selection:

The structured information supporting the target hypothesis generation must be under the title Target Selection Rationale. The following information must be provided:

1. Intended biological target/pathway;

2. Target expression in relevant human cells/tissues;

3. Evidence of disease-target association based on clinical observations;

4. Relevant in vitro models;

5. Relevant in vivo models;

6. Target commercial viability; and

7. Target Development Level.

Correspondingly, the following information must be also provided:

1. For Intended biological target/pathway, describe the target and whether it should be blocked or activated. Describe the cellular/physiological process being modulated.

2. For Target expression in relevant human cells/tissues, describe target expression in terms of tissue and cell diversity as well as techniques used to measure expression. Describe expression in both disease-affected and normal conditions.

3. For Evidence of disease-target association based on clinical observations, provide the evidence that links this target to the SUD indication. Mention the genetic linkage to SUD, with the special emphasis on equivalent modification of protein levels in response to disease status and outcome, if applicable.

4. For Relevant in vitro models, describe what can be modeled in vitro and in which cellular system. If the target can be assayed in a relevant cell-based system, describe the robustness of this assay. Discuss access to the primary human material to investigate the target biology (expression/function).

5. For Relevant in vivo models, describe the in vivo system. If target validation is based on knockdown/deletion studies, describe the appropriate controls and discuss if those studies are complemented by the small molecule or antibody studies demonstrating the same phenotype. Discuss if the in vivo model is relevant to SUD, and how well it models or predicts human condition.

6. For Target commercial viability, present information about any existing target modulators used clinically, available commercially or identified in literature.

7. For Target Development Level, use the Target Development Level (TDL) classification scheme which categorizes proteins into four groups with respect to the depth of investigation from a clinical chemical and biological standpoint (https://ncats.nih.gov/pubs/features/idg-proteins).

Testing Strategy (Approach):

Innovation:

• Comment on the novelty of proposed approach, target, pathway, assays or models.

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the SF424 (R&R) Application Guide, with the following modification:

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

Appendix:

Only limited Appendix materials are allowed. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.

When involving human subjects research, clinical research, and/or NIH-defined clinical trials (and when applicable, clinical trials research experience) follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the SF424 (R&R) Application Guide, with the following additional instructions:

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

Study Record: PHS Human Subjects and Clinical Trials Information

All instructions in the SF424 (R&R) Application Guide must be followed.

Delayed Onset Study

Note: Delayed onset does NOT apply to a study that can be described but will not start immediately (i.e., delayed start).

All instructions in the SF424 (R&R) Application Guide must be followed.

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.

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 and responsiveness by NIDA, NIH. Applications that are incomplete, non-compliant and/or nonresponsive will not be reviewed.

Applicants are required to follow the instructions for post-submission materials, as described in the policy. Any instructions provided here are in addition to the instructions in the policy.

Only the review criteria described below will be considered in the review process.

Applications submitted to the NIH in support of the NIH mission are evaluated for scientific and technical merit through the NIH peer review system.

For this announcement, note the following:

• The FOA is to support early stage, high-risk, high-reward, projects. Applications funded through this cooperative agreement initiative will be subjected to substantial risk oversight and management by the NIH/NIDA Program Officials.

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

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

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?

Specific to the FOA:

How significant an advantage does the proposed drug target or drug candidate offer over other treatments currently under development for SUDs? How strong are the data supporting the choice of drug target or drug candidate for the SUD indication? Are the proposed drug target or the drug candidates sufficiently active in assays that are relevant to the SUD indication?

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?

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?

Would the proposed drug target or drug candidate be expected to give significantly better clinical outcome than what has been observed in previous efforts focused on the same target?

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?

What is the likelihood that completion of the research objectives will lead to a successful development for an effective therapy for SUDs (i.e., is there a clear path into the clinic)?

Are the proposed studies appropriate, feasible, and consistent with the proposed drug target or drug candidate, and likely to advance the project to the desired endpoint within the proposed timeframe?

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?

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 score, but will not give separate scores for these items.

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.

Not Applicable

Not Applicable

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 score.

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.

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

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 score.
• Will receive a written critique.

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

Applications will be assigned to the appropriate NIH Institute or Center. Applications 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. Refer to Part 1 for dates for peer review, advisory council review, and earliest start date.

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

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’s business official.

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

Any application awarded in response to this FOA will be subject to terms and conditions found on the Award Conditions and Information for NIH Grants website. This includes any recent legislation and policy applicable to awards that is highlighted on this website.

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

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.

Recipients of federal financial assistance (FFA) from HHS must administer their programs in compliance with federal civil rights law. This means that recipients of HHS funds must ensure equal access to their programs without regard to a person’s race, color, national origin, disability, age and, in some circumstances, sex and religion. This includes ensuring your programs are accessible to persons with limited English proficiency. HHS recognizes that research projects are often limited in scope for many reasons that are nondiscriminatory, such as the principal investigator’s scientific interest, funding limitations, recruitment requirements, and other considerations. Thus, criteria in research protocols that target or exclude certain populations are warranted where nondiscriminatory justifications establish that such criteria are appropriate with respect to the health or safety of the subjects, the scientific study design, or the purpose of the research.

For additional guidance regarding how the provisions apply to NIH grant programs, please contact the Scientific/Research Contact that is identified in Section VII under Agency Contacts of this FOA. HHS provides general guidance to recipients of FFA on meeting their legal obligation to take reasonable steps to provide meaningful access to their programs by persons with limited English proficiency. Please see https://www.hhs.gov/civil-rights/for-individuals/special-topics/limited-english-proficiency/index.html. The HHS Office for Civil Rights also provides guidance on complying with civil rights laws enforced by HHS. Please see https://www.hhs.gov/civil-rights/for-individuals/section-1557/index.html; and https://www.hhs.gov/civil-rights/for-providers/laws-regulations-guidance/index.html. Recipients of FFA also have specific legal obligations for serving qualified individuals with disabilities. Please see https://www.hhs.gov/civil-rights/for-individuals/disability/index.html. Please contact the HHS Office for Civil Rights for more information about obligations and prohibitions under federal civil rights laws at https://www.hhs.gov/ocr/about-us/contact-us/index.html or call 1-800-368-1019 or TDD 1-800-537-7697. Also note it is an HHS Departmental goal to ensure access to quality, culturally competent care, including long-term services and supports, for vulnerable populations. For further guidance on providing culturally and linguistically appropriate services, recipients should review the National Standards for Culturally and Linguistically Appropriate Services in Health and Health Care at http://minorityhealth.hhs.gov/omh/browse.aspx?lvl=2&lvlid=53.

In accordance with the statutory provisions contained in Section 872 of the Duncan Hunter National Defense Authorization Act of Fiscal Year 2009 (Public Law 110-417), NIH awards will be subject to the Federal Awardee Performance and Integrity Information System (FAPIIS) requirements. FAPIIS requires Federal award making officials to review and consider information about an applicant in the designated integrity and performance system (currently FAPIIS) prior to making an award. An applicant, at its option, may review information in the designated integrity and performance systems accessible through FAPIIS and comment on any information about itself that a Federal agency previously entered and is currently in FAPIIS. The Federal awarding agency will consider any comments by the applicant, in addition to other information in FAPIIS, in making a judgement about the applicant’s integrity, business ethics, and record of performance under Federal awards when completing the review of risk posed by applicants as described in 45 CFR Part 75.205 Federal awarding agency review of risk posed by applicants. This provision will apply to all NIH grants and cooperative agreements except fellowships.

Cooperative Agreement Terms and Conditions of Award

The following special terms of award are in addition to, and not in lieu of, otherwise applicable U.S. Office of Management and Budget (OMB) administrative guidelines, U.S. Department of Health and Human Services (DHHS) grant administration regulations at 45 CFR Parts 75, and other HHS, PHS, and NIH grant administration policies.

The administrative and funding instrument used for this program will be the cooperative agreement, an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH programmatic involvement with the awardees is anticipated during the performance of the activities. Under the cooperative agreement, the NIH purpose is to support and stimulate the recipients' activities by involvement in and otherwise working jointly with the award recipients in a partnership role; it is not to assume direction, prime responsibility, or a dominant role in the activities.

Consistent with this concept, the dominant role and prime responsibility resides with the awardees for the project as a whole, although specific tasks and activities may be shared among the awardees and the NIH as defined below. The PD/PI will be responsible for:

• Determining experimental approaches, designing protocols, conducting experiments, participating in kick-off meeting and analyzing and interpreting research data for studies funded through this Initiative.
• Presenting project updates (including raw data, when requested) in conference calls.
• With the Project Development Team, assisting in the development of a project milestone/value inflection point plan at the outset of the project.
• Coordinating and participating with NIH staff and NIH-contracted consultants in all aspects of scientific and technical management of the project.
• Collaborating and communicating effectively with NIH staff and NIH consultants to achieve project goals.
• Adhering to goals and strategies for target validation, screening throughput, and quality control, established by the PDT.
• Ensuring that all data and assay protocols developed as a part of this project are deposited in a centralized NIDA database according to the timeline agreed upon by the PDT.
• Adhering to NIH policies, including those regarding data release, intellectual property, and publications.
• Implementing all scientific and policy decisions approved by the PDT and the NIDA program officials.
• Preparing all results of the studies supported through this FOA for publication in the Project Outcomes Section of all Final and Interim Research Performance Progress Reports (RPPRs) and making them available to the general public via the NIH RePORTER in accordance to NOT-OD-18-103. It is important for investigators to consider the following points to address those that are appropriate when describing the results:
• Experimental Design:

o The selected models and endpoints (animal and/or cellular)

o For in vitro assays, pharmacological relevance and assay quality typically determined according to the Z factor

o For in vivo studies, provide details of the animals used, including species, strain and sub strain, sex, age or developmental stage, and weight

o The selected controls

o Randomization and blinding

o Route and timing of intervention delivery/dosing

o Sample size estimation, data handling, and power calculation

o Statistical methods used in analysis and interpretation of results

• Results:

o Independent validation/replication, if available

o Robustness and reproducibility of the observed results

o Dose-response

o Verification that interventional drug or biologic reached and engaged the target

o Outcomes measures with specifying the primary outcome measure that was used to determine the sample size

• Interpretation of Results:

o Discussion of effect size in relation to potential clinical impact

o Potential conflicts of interest

• Business Value Proposition Reporting:

o If it is appropriate for the project, report the evaluation of the commercial value and the risk structure of the development by providing the following:

• Target product profile (TPP) that includes therapeutic concept, medical need, and competitive edge
• Establishment of technical or clinical feasibility
• Intellectual property
• A final risk analysis considering the compound, mechanism, TPP and competitive risk
• Working closely with his/her institution's technology transfer officials to ensure that royalty agreements, patent filings, and all other necessary intellectual property arrangements are completed in a timely manner

An NIH Scientific Officer will be assigned to the project, with substantial scientific involvement that is above and beyond the normal stewardship role in awards, as described below:

• Identifying and providing the PDT with consultants who can provide strategic and technical guidance.
• Coordinating and participating in PDT meetings to discuss project status, planning, and implementation.
• With the PDT, assisting in the development of a project goals/plan at the outset of the project.
• Providing a perspective on the priorities of NIDA.
• Facilitating collaboration and data exchange among the awardee, and NIH-contracted consultants, Enhancing the project progress by providing access to various NIH resources when appropriate.
• Providing technical assistance, advice, and coordination to the project, although the dominant role and responsibilities for the activities funded by this award reside with the awardee.
• Serving as scientific liaison among the awardee and other NIH program staff.

Areas of Joint Responsibility include:

• Project Development Team (PDT): This team will collaboratively set strategic direction and guide the work flow for the project on an ongoing basis. The PDT will meet every two weeks via teleconference to analyze and interpret data from the PD/PI and to formulate the subsequent experimental plan. The PDT will propose milestones and produce progress reports for evaluation by the program staff as needed.
• The members of this collaborative effort are all made aware of the requirement for confidentiality due to the intent of the awardee to pursue commercialization of any qualified outcomes. Contractors and consultants of NIH will be made aware of the confidential nature of work done under this collaborative effort. The handling and disposition of this confidential data and business privileged information may be covered by the Trade Secrets Act, 18 U.S.C. Section 1905.

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 External Oversight Committee chosen without NIH staff voting, one NIH designee, and a third designee with expertise in the relevant area who is chosen by the other two; in the case of individual disagreement, the first member may be chosen by the individual awardee. This special dispute resolution procedure does not alter the awardee's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulation 42 CFR Part 50, Subpart D and DHHS regulation 45 CFR Part 16.

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

A final RPPR, invention statement, and the expenditure data portion of the Federal Financial Report are required for closeout of an award, as described in the NIH Grants Policy Statement.

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.

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

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

Finding Help Online: http://grants.nih.gov/support/ (preferred method of contact)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

General Grants Information (Questions regarding application instructions, application processes, and NIH grant resources)
Email: GrantsInfo@nih.gov (preferred method of contact)
Telephone: 301-945-7573

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

Elena Koustova, PhD, MBA
National Institute on Drug Abuse (NIDA)
Telephone: 301-496-8768
Email: koustovae@mail.nih.gov

Ram Arudchandran, Ph.D.
National Institute on Drug Abuse (NIDA
Telephone: 301-827-6889
Email: ramachandran.arudchandran@nih.gov

Dharmendar Rathore, PhD
National Institute on Drug Abuse (NIDA)
Telephone: 301-402-6965
Email: dharmendar.rathore@nih.gov

Amy Connolly
National Institute on Drug Abuse (NIDA)
Telephone: (301) 827-4457
Email: connolla@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 Part 75.