Participating Organization(s)	National Institutes of Health (NIH)
Components of Participating Organizations	National Institute of Mental Health (NIMH) National Institute on Alcohol Abuse and Alcoholism (NIAAA) National Institute on Drug Abuse (NIDA)
Funding Opportunity Title	National Cooperative Drug Discovery/Development Groups (NCDDG) for the Treatment of Mental Disorders, Drug or Alcohol Addiction (UM1)
Activity Code	UM1 Multi-Component Research Project Cooperative Agreements
Announcement Type	Reissue of PAR-11-206
Related Notices	May 9, 2014 - See Notice NOT-MH-14-014. Notice of Expiration of this PAR. April 21, 2014 - This PAR has been reissued as PAR-14-184. May 30, 2013 (NOT-OD-13-074) - NIH to Require Use of Updated Electronic Application Forms for Due Dates on or after September 25, 2013. Forms-C applications are required for due dates on or after September 25, 2013.
Funding Opportunity Announcement (FOA) Number	PAR-13-087
Companion Funding Opportunity	PAR-13-086, U19 Research Program Cooperative Agreements
Number of Applications	See Section III. 3. Additional Information on Eligibility.
Catalog of Federal Domestic Assistance (CFDA) Number(s)	93.242, 93.273, 93.279
Funding Opportunity Purpose	The purpose of the National Cooperative Drug Discovery/Development Group (NCDDG) Program is to create multidisciplinary research groups or partnerships for the discovery of pharmacological agents to treat and to study mental illness, drug or alcohol addiction. The objectives of this program are to: accelerate innovative drug discovery; develop pharmacologic tools for basic and clinical research on mental disorders, or drug or alcohol addiction; develop and validate models for evaluating novel therapeutics for mental disorders; and support early phase human clinical testing to rapidly assess the safety and efficacy of promising drug candidates and new indications for IND-ready agents for the treatment of mental disorders or alcohol addiction. The National Institute of Mental Health (NIMH), the National Institute on Drug Abuse (NIDA), and the National Institute on Alcohol Abuse and Alcoholism (NIAAA) encourage applications to advance the discovery, preclinical development, and proof of concept testing of new, rationally based candidate agents to treat mental disorders or drug or alcohol addiction, and to develop novel ligands as tools to further characterize existing or to validate new drug targets. Partnerships between academia and industry are strongly encouraged.

Posted Date	January 11, 2013
Open Date (Earliest Submission Date)	January 22, 2013
Letter of Intent Due Date(s)	30 days before the application due date
Application Due Date(s)	February 22, 2013; June 24, 2013; October 24, 2013; February 24, 2014; June 22, 2014; October 22, 2014; February 22, 2015; June 22, 2015; October 22, 2015, by 5:00 PM local time of applicant organization.
AIDS Application Due Date(s)	Not Applicable
Scientific Merit Review	June, October, and February, annually
Advisory Council Review	October, January, and May, annually
Earliest Start Date	December, April, and July, annually
Expiration Date	(Now Expired April 21, 2014 per issuance of PAR-14-184), Originally October 23, 2015
Due Dates for E.O. 12372	Not Applicable

This FOA uses NIH’s new Application Submission System & Interface for Submission Tracking (ASSIST) for the electronic preparation and submission of multi-project applications through Grants.gov to NIH. Applications to this FOA must be submitted electronically; paper applications will not be accepted. ASSIST replaces the Grants.gov downloadable forms currently used with most NIH opportunities and provides many features to enable electronic multi-project application submission and improve data quality, including: pre-population of organization and PD/PI data, pre-submission validation of many agency business rules and the generation of data summaries in the application image used for review.

Required Application Instructions

It is critical that applicants follow the 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) and where instructions in the Application Guide are directly related to the Grants.gov downloadable forms currently used with most NIH opportunities. 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

The intent of this Funding Opportunity Announcement (FOA) is to encourage applications from academic, biotechnology, or pharmaceutical industry investigators interested in participating with the National Institute of Mental Health (NIMH), the National Institute on Drug Abuse (NIDA), or the National Institute on Alcohol Abuse and Alcoholism (NIAAA) in a National Cooperative Drug Discovery/Development Group (NCDDG) program. The objectives of this program are to advance the discovery, preclinical development, and proof of concept testing of new, rationally based candidate agents to treat mental disorders or drug or alcohol addiction and to develop novel ligands as tools to advance biological research on the function of genes, cells, and biochemical pathways implicated in the etiology and pathophysiology of mental disorders, drug or alcohol addiction, and as potential new therapeutics. Partnerships between academia and industry are strongly encouraged.

Each NCDDG program should consist of a multi-disciplinary team of scientists with appropriate expertise to further the development and evaluation of novel compounds. Scientists from both academia and pharmaceutical industry are encouraged to participate within an NCDDG; scientists from foreign institutions and NIH Intramural laboratories may participate in some aspects (see Instructions for NIH Intramural Researchers for details). It is anticipated that the interaction of academic and non-profit research institutions with industry and NIH via the NCDDG model will: 1) accelerate the discovery and development of new therapeutics for mental disorders, drug or alcohol addiction; 2) increase the availability of pharmacologic research tools (including imaging agents) for basic and clinical research; 3) facilitate the development and validation of models and pharmacodynamic (PD) measures to evaluate novel therapeutics for mental disorders; 4) increase the availability of new IND-ready compounds and agents suitable for testing in humans; and 5) facilitate the development and validation of new clinical measures or biomarkers suitable for use in human proof of concept trials of novel therapeutics for mental disorders or alcohol addiction.

The goal of the NCDDG program is not to duplicate or compete with the private sector but to complement and accelerate the development of research tools for new molecular targets implicated in mental disorders, drug or alcohol addiction, and effective compounds and agents for the prevention and treatment of psychiatric and addictive disorders, as well as core features of these illnesses, especially in areas of unmet medical need.

Significant advances in neuroscience, genetics, and basic behavioral science, together with technological developments, have provided a rich knowledge base for understanding pathophysiology, identifying new molecular targets for drug discovery, and developing rational pharmacotherapies for the treatment of psychiatric and substance abuse disorders. With the wealth of potential new drug targets, the opportunity exists to accelerate the process of target validation and medication discovery to make great strides toward novel and effective treatments for mental disorders, drug or alcohol addiction.

A UM1 application can include no more than two projects. Applications proposing two or more Research Projects along with Scientific and/or Administrative Core components should respond to the companion FOA utilizing the U19 mechanism (see PAR-13-086).

NIMH's objectives and interests for the NCDDG program

NIMH’s objective for the NCDDG program is to establish public-private partnerships to conduct innovative, high impact research focused on the discovery of pharmacological agents targeting novel molecular targets implicated in the pathophysiology of mood and anxiety disorders, schizophrenia, eating disorders, obsessive-compulsive disorder, fragile x, autism, and other mental illnesses.

NIMH-relevant NCDDG research projects should focus on novel interventions that interrogate a molecular or clinical target that is linked to a biological mechanism or pathophysiology of the proposed mental disorder (see TR Insel, Next-Generation Treatments for Mental Disorders, Sci Transl Med 4, 1-9, 2012, http://stm.sciencemag.org/content/4/155/155ps19.full.pdf?sid=76964b41-811e-47a7-af12-369ffb476042).

It is expected that the majority of NCDDG applications will be aimed at pharmacological treatment development for mental disorders. However, in recognition of the emerging therapeutic potential of neuroplasticity or neuromodulation approaches that directly engage brain circuits (e.g., deep brain stimulation (DBS), regional transcranial magnetic stimulation (rTMS)), the NIMH welcomes innovative therapeutic development applications that are focused on targeting of specific circuits.

Research projects directed towards ameliorating clinical dimensions of pathophysiology embedded in DSM diagnostic entities, but not typically identified as the primary target of current clinical therapeutics, are also encouraged. See the Research Domain Criteria (RDOC) webpage and proceedings of the RDoC domain workshops (working memory, negative valence systems (i.e., aversive motivational dimensions), positive valence systems, cognitive systems, social process systems, and arousal/regulatory systems) for more details.

NIMH will accept UM1 projects or components ranging from ligand discovery and testing in preclinical models to human proof of concept studies of novel agents. Examples include, but are not limited to:

• Ligand discovery for therapeutics development and as research tools (e.g., imaging probes) for novel molecular targets implicated in mental illnesses;
• Preclinical testing of novel compounds in disease-based models;
• Development and validation of novel, disease-based models including combined genetic and environmental manipulations and/or novel behavioral or physiological measures for evaluating therapeutic compounds. Measures with potential translational utility from preclinical to first in human studies are particularly encouraged;
• Initial Good Laboratory Practice (GLP) toxicology, safety pharmacology, and pharmacokinetics to support an Investigational New Drug (IND) application to the Food and Drug Administration (FDA) to begin human clinical testing;
• Phase I studies (first in human pharmacology experiments) that include PD/pharmacokinetic (PK) biomarkers to assess target engagement, pharmacological or physiological effect, safety, and tolerability;
• Phase Ib studies in the proposed disease population to confirm target engagement, determine optimal dosing, exposure, functional pharmacological activity, and tolerability of the novel agent. See AF Cohen, Developing drug prototypes: pharmacology replaces safety and tolerability? Nature Reviews Drug Discovery 9, 856-865, 2010, http://www.nature.com/nrd/journal/v9/n11/pdf/nrd3227.pdf;
• Phase IIa (experimental medicine) studies designed to establish the relationship between the magnitude and duration of target modulation and potential for clinical efficacy in the proposed disease population (linking biological/molecular mechanism of a novel intervention to clinical effect);
• The inclusion of biomarkers in the design of the study is encouraged, when appropriate: e.g., PD biomarkers to assess functional pharmacological activity of the agent or the use of pharmacogenetic or other biomarkers as patient selection strategies;
• The Phase IIa proof of concept study should provide sufficient data for projects to be "de-risked" to attract public or private funding for further clinical and commercial development;
• For proof of concept studies, priority will be given to novel agents that are IND-ready with pre-clinical profiles suggesting the possibility of therapeutic effect in mental disorders. Testing of novel indications for already approved agents will be considered, based on feasibility, strong theoretical rationale, and unmet clinical or medical need.

NIDA's objectives and interests for the NCDDG program

NIDA's interests are in the discovery of ligands that constitute important research tools and/or medication candidates to advance the development of pharmacotherapies for drug addiction treatment. Over the past decade or so, there have been major advances in our understanding of the protein targets, neural circuitry, and behavioral phenomena associated with addiction, and in the effects of drugs of abuse on CNS processes associated with addictive behavior, such as synaptic plasticity. The initial targets for most drugs of abuse are known and have been shown to be predominantly either G-protein coupled receptors, such as the dopamine receptor, an indirect site of action for cocaine and amphetamine, or ligand gated ion channels, such as the nicotinic cholinergic receptors (nAChRs), a target for nicotine. Drug addiction also involves activation of intracellular signaling proteins that can affect the response to drugs of abuse, and there is clear evidence for the involvement of numerous, specific neurotransmitter systems in addiction. Genetic polymorphisms are likely to lead to variation in the biological activity in many of these protein targets, which may be relevant to individual variability in response to drugs of abuse and, ultimately, to vulnerability to addiction. Given that research has discovered some of the mechanisms through which addictive drugs act in the CNS, numerous potentially viable targets for medications are known and, for the most part, well characterized. Hence the opportunity exists for the development of new ligands for target validation studies and potentially for development as pharmacotherapies.

From NIDA's perspective, the NCDDG is a ligand discovery and translational initiative in which the objective is the development of molecules with a particular profile of action as prototypes for medications to treat addiction or as tools to advance research in the treatment development domain. A number of cellular and animal models are currently available for ligand discovery efforts relevant to drug addiction treatment research. It is therefore expected that groups will include a program to evaluate the efficacy of novel ligands in appropriate models. Components of NIDA-relevant NCDDG research projects could include, but are not limited to: (1) assessment of the behavioral profile of novel ligands in tests of reinforcement, relapse and withdrawal; (2) tests of the ability of novel ligands to modulate cellular processes of plasticity in reward-relevant regions of the brain; (3) assessment of ligand efficacy on G-protein coupled receptors and ligand gated ion channel activation; and 4) receptor activation effects on down-stream intracellular systems or in modulating the release of addiction-relevant neurotransmitters. Projects that propose integrating two or more of these approaches also are encouraged.

Two targets, the mu-opiate receptor and the dopamine transporter, have been extensively pursued in medication discovery efforts related to opiate and cocaine addiction, respectively. Given the clinical availability of mu-opiate agonists, partial agonists and antagonists and the large number of NIDA-supported grants already focusing on the dopamine transporter, NIDA is not interested in supporting NCDDG projects with a focus on these two targets. Applicants are encouraged to focus on the discovery of truly novel ligands through the pursuit of targets such as orexin (hypocretin) and nicotinic acetylcholine receptor subtypes. A more extensive list of targets for consideration can be found below.

NIAAA's objectives and interests for the NCDDG program

NIAAA's interests for the NCDDG program are in the discovery of novel ligands that may lead to the development of medications for the treatment of alcohol dependence and addiction, and ligands to be used as tools to research biological processes contributing to compulsive drinking. The focus of proposed research projects should follow that described above by NIMH, but should be relevant to the mission of NIAAA. Applicants are strongly encouraged to discuss applications involving toxicity, safety and pharmacokinetic as well as proof of concept studies of novel compounds with NIAAA staff listed in Section VII - Agency Contact(s) Scientific/Research Contacts.

Compounds currently approved by the Food and Drug Administration for treating alcohol dependence have distinct mechanisms of action and target distinct behavioral aspects of problem alcohol consumption. Disulfiram (Antabuse), an aldehyde dehydrogenase inhibitor leads to a systemic build up of acetaldehyde when alcohol is ingested. This is experienced as an unpleasant intoxication and creates an aversion to consuming alcohol. Naltrexone, an opiate receptor antagonist, is thought to diminish alcohols positive reinforcing effects, particularly in people with mu opiate receptor polymorphisms. Acamprosates therapeutic mechanism of action is unclear, but it is thought that acamprosate attenuates the enhanced glutamatergic transmission during alcohol withdrawal and may work best at alleviating craving and relapse in abstinent patients. Each medication has been found to be highly effective in some patients, yet other patients fail to respond to them. Thus, there is a need for the development of medications that interact at additional targets, and that treat additional behavioral facets of alcoholism.

Current pharmaceutical strategies for treating alcohol use disorders are broadly designed towards developing agents that: a) modify alcohol intoxication, reduce the pleasurable effects of alcohol or increase the aversive effects, b) reduce craving or the urge to drink, c) reduce the signs and symptoms of acute and protracted withdrawal syndromes, and d) treat co-morbid psychiatric illnesses or reduce psychological distress which contributes to elevated alcohol consumption. Alcohol's multiple biological effects, and the many physical and behavioral alterations that occur following chronic alcohol use and abuse, offer opportunities for developing additional pharmacotherapies.

NCDDG is an opportunity to identify and develop compounds towards both existing and new molecular targets having the potential to treat alcohol use disorders, or to facilitate and enhance basic and clinical research on identifying the neurobiological and behavioral processes that contribute to the transition from voluntary to compulsive drinking. Aspects of alcohol consumption and alcohol-seeking are modulated through the actions of neurotransmitter receptors and transporters, ion channels, neuromodulators, hormones, and intracellular signaling networks. Thus, there are a number of potential target sites for which new pharmaceutical agents may be developed, such as effectors of opioid, serotonin, dopamine, glutamate, GABA, cannabinoid, and adenosine receptors, modulators of neuropeptide systems (NPY, CRF, substance P), and agents that alter signal transduction pathways (such as protein kinase effectors, protein phosphatase inhibitors, G-protein regulators and calcium signaling disruptors).

Cellular models may be used as initial screening tools to evaluate the molecular properties of candidate compounds. However, it is further expected that the more promising compounds will be tested and evaluated in established animal models of behavioral aspects of alcoholism, such as drinking, dependence, craving and reinstatement models (see Drug Discovery Today: Disease Models 2: 313, 2005). As no single compound is expected to address all of the behavioral aspects and consequences of alcoholism, projects that propose integrating two or more behavioral testing paradigms are especially sought.

The identification and pursuit of agents towards novel targets previously un-recognized or understudied for the treatment of alcohol abuse disorders are especially encouraged. In particular, NIAAA encourages applications focusing on agents that alleviate craving and dysphoria during protracted abstinence, and agents effective in patients who have co-morbid psychiatric illnesses (e.g., schizophrenia, bipolar disorder). Applications that essentially propose to further extend the testing of established or well-studied compounds and strategies are not appropriate for this FOA.

In summary, the NCDDG Program will support broad, innovative, multidisciplinary, multi-project approaches to the discovery of new, rationally based treatments and research tools for mental disorders, drug or alcohol addiction. Since the creative talents in the required scientific disciplines are rarely available in a single institution, a multi-institutional, group approach involving academic, nonprofit, commercial, and/or industrial institutions is envisioned. Academic and pharmaceutical scientists are strongly encouraged to form partnerships that take full advantage of their combined intellectual and material resources for drug discovery, lead optimization, model development, and clinical testing. Further, the interaction of academic and non-profit research institutions with pharmaceutical industry and NIH is expected to facilitate subsequent development and marketing of new pharmacologic treatments, although these latter activities are not within the scope of this FOA. Molecular targets for drug discovery, and the sources and types of chemical entities to be investigated, will be selected by the applying group. Both novel mechanism of action and disease-oriented approaches are of interest.

The objective of this FOA is to establish NCDDG Groups to conduct innovative, high impact research focused on the discovery and testing of chemical entities for novel molecular targets implicated in the pathophysiology of mental disorders, or drug or alcohol addiction. The NCDDG serves as a vehicle for pharmaceutical and academic scientists to pool intellectual and material resources for the translation of basic science findings into the conceptualization, discovery, and evaluation of new chemical entities. Groups are encouraged to select molecular targets for drug discovery based on recent findings in basic and clinical neuroscience, genetics, and proteomics relevant to the understanding of mental disorders, drug or alcohol addiction.

Molecular targets that applicants may wish to consider include, but are not limited to, the following.

Please contact program staff listed in Section VII - Agency Contact(s) Scientific/Research Contacts to determine program priorities and molecular targets of interest to the participating NIH Institutes.

• Receptors: adenosine; adrenergic: alpha 1, alpha 2; cannabinoid: CB1, CB2; corticotropin releasing hormone: CRF R1, CRF R2; dopamine: D1, D3, D4, D5; estrogen; GABA A subunits; GABA ion channel; GABA B; glutamatergic, glycine site; metabotropic glutamate subtypes and other glutamate receptor subtypes; muscarinic subunits; neurokinin receptors: NK1, NK2, NK3; heteromeric neuronal nicotinic receptor subunits; NMDA subunits; opioid receptors: mu, delta, kappa; serotonin: 5-HT1A, 5-HT1B, 5-HT1D, 5-HT2A, 5-HT2C, 5-HT5, 5-HT6, 5-HT7; orexin (hypocretin); oxytocin; vasopressin receptors; intracellular targets;
• Voltage gated ion channels: Ca, Na, K M current proteins; ion channel modulators;
• Receptor interacting proteins, trafficking proteins;
• Multi-target compounds: rational design of single chemical entities with the ability to modulate multiple targets simultaneously, using novel chemistries and scaffolds;
• Transporters: vesicular ACh; GABA; glutamate; glycine; glutamine; NET; VMAT I/II, excitatory amino acid transporters;
• Markers for glia, glial activation, and glial cell death;
• Enzymes: choline acetyltransferase; dopamine beta-hydroxylase; GABA transaminase; glutamic acid decarboxylase; glutaminergic; phosphodiesterases; tyrosine hydroxylase;
• Intracellular targets: gene expression/transcription markers; markers of neurogenesis or neuronal cell death; markers of mitochondrial function; lipid metabolism; neuroinflammatory markers: cytokines, COX inhibitors; peptidases; phosphatases; phospholipases; protein kinases; neurotrophins; endothelial and other growth factors.
• Neuroplasticity or neuromodulation: approaches that directly engage or target specific brain circuits (e.g., DBS, rTMS);
• Enhancement or restoration of core components of mental or drug or alcohol abuse disorders, such as deficits in cognition, attention, or other executive functions, social cognition, motivation, negative symptoms, audiogenic seizures, etc.

Potential ligands of interest to NIMH, NIDA and NIAAA might be identified by their receptor properties (e.g., positive or negative allosteric modulators, functionally selective ligands, partial agonists, agonists, or antagonists), solubility, pharmacokinetics, oral or CNS bioavailability, or other characteristics to support their use as research tools or candidates for drug development.

The identification of lead compounds and refining them for medication development are important goals of this initiative. Generally this can involve classical approaches of medicinal chemistry using structure-activity relationship (SAR) rationales. The use of chemical libraries, structural biology and computer modeling of molecular targets to screen for compounds with activity at selected targets are also examples of appropriate approaches. If applicants do choose to conduct library screening, they are encouraged to focus on targeted libraries rather than random structural screening. Screening of existing libraries (e.g., G-protein receptor-focused) that will not require significant synthetic resources is encouraged. Note that the pharmaceutical industry has reduced its reliance on combinatorial chemistry approaches due to general lack of success. Although NIDA, NIMH and NIAAA will not rule out the use of combinatorial chemistry in NCDDG projects, applicants proposing them should provide appropriate justification that this approach to compound synthesis is desirable.

It is anticipated that the interaction of academic and non-profit research institutions with NIH and pharmaceutical industry will facilitate timely evaluation and development of preclinical and clinical research tools, models, and novel therapeutics. Applicants should outline proposed plans for further development of promising compounds or clinical candidates that are generated and/or tested by the NCDDG program.

Note:

For applicants seeking additional sources of support for preclinical development activities such as toxicology and safety pharmacology assessment, bulk synthesis, GMP manufacturing, or formulation development, the Bridging Interventional Development Gaps (BrIDGs) Program (http://www.ncats.nih.gov/research/reengineering/bridgs/bridgs.html), offers investigators access to preclinical development resources on a competitive basis. Applicants are encouraged to contact BrIDGs staff about ways in which they can apply for and access resources provided by the program prior to submitting an application to the NCDDG FOA.

Funding Instrument	Cooperative Agreement: A support mechanism used when there will be substantial Federal scientific or programmatic involvement. Substantial involvement means that, after award, NIH scientific or program staff will assist, guide, coordinate, or participate in project activities.
Application Types Allowed	New Renewal Resubmission Revision The OER Glossary and the SF424 (R&R) Application Guide provide details on these application types.
Funds Available and Anticipated Number of Awards	The number of awards is contingent upon NIH appropriations and the submission of a sufficient number of meritorious applications.
Award Budget	Application budgets are not limited, but need to reflect actual needs of the proposed project.
Award Project Period	The total project period may not exceed five 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
• 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)

Non-domestic (non-U.S.) Entities (Foreign Institutions) are not eligible to apply.
Non-domestic (non-U.S.) components of U.S. Organizations are not eligible to apply.

Foreign components, as defined in the NIH Grants Policy Statement, are allowed.

Applicant organizations must complete the following registrations as described in the SF424 (R&R) 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.

• System for Award Management (SAM) must maintain an active entity registration (formerly CCR registration), to be renewed at least annually. Use the SAM.gov Manage Entity function to manage your entity registrations. See the Grants Registration User Guide at SAM.gov for additional information.
• Grants.gov
• eRA Commons

All Program Directors/Principal Investigators (PD(s)/PI(s)) and component Project Leads that are not yet registered in eRA Commons must work with their institutional officials to register. Also, institutional officials at the applicant organization should ensure that the eRA Commons account for the contact PD/PI is affiliated with their organization.

eRA Commons accounts are necessary to use ASSIST to prepare and submit applications.

All registrations must be completed by the application due date. Applicant organizations are strongly encouraged to start the registration process at least 6 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 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.

NIH will not accept any application that is essentially the same as one already reviewed within the past thirty-seven months (see NIH Grants Policy Statement), except for submission:

1. To an RFA of an application that was submitted previously as an investigator-initiated application but not paid;

2. Of an investigator-initiated application that was originally submitted to an RFA but not paid; or

3. Of an application with a changed grant activity code.

Applicants can access the SF424 (R&R) application package associated with this funding opportunity using the Apply for Grant Electronically button in this FOA or following the directions provided at Grants.gov.

Applicants will use NIH’s ASSIST system, rather than Grants.gov’s downloadable forms, to prepare and submit applications through Grants.gov to NIH.

It is critical that applicants follow the instructions in the SF424 (R&R) Application Guide, except where instructed in this funding opportunity announcement to do otherwise and where instructions in the Application Guide are directly related to the Grants.gov downloadable forms currently used with most NIH opportunities. 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.

For information on Application Submission and Receipt, visit Frequently Asked Questions Application Guide, Electronic Submission of Grant Applications.

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

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

• Descriptive title of proposed research
• 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:

Linda Brady, Ph.D.
Division of Neuroscience and Basic Behavioral Science
National Institute of Mental Health
6001 Executive Boulevard, Room 7204, MSC 965
Bethesda, MD 20892-9645
Rockville, MD 20852-9645 (for express/courier service)
Telephone: (301) 443-3563
Email: lbrady@mail.nih.gov

Applications submitted to this FOA will be made up of a collection of application components. All applications will include an Overall component that provides information regarding the application as a whole, as well as a combination of additional component types. Applicants should select the appropriate application component types in ASSIST when preparing applications. Note, eRA Commons accounts are necessary to use ASSIST to prepare and submit applications.

Component Types Available in ASSIST	Research Strategy/Program Plan Page Limits
Overall	12
Project	12 per project

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

The following table provides instruction clarification for the information required in the Overall component of a multi-project application versus information required for all other components included in the application.

Form	Overall component	All other components
SF424 (R&R) cover	Complete entire form	Complete only the following fields: 1. Applicant Information 2. Type of Applicant (optional) 3. Descriptive Title of Applicant’s Project 4. Proposed Project Start/Ending Dates
Project /Performance Site Location(s)	Enter primary site only. A summary of Project/Performance Sites in the Overall section of the assembled application image in eRA Commons compiled from data collected in the other components will be generated upon submission.	List all performance sites that apply to the specific component. Note: The Project Performance Site form allows up to 300 sites, prior to using additional attachment for additional entries.
Budget	The only budget information included in the Overall component is the Estimated Project Funding section of the SF424 (R&R) cover. A budget summary in the Overall section of the assembled application image in eRA Commons compiled from detailed budget data collected in the other components will be generated upon submission.	Budget forms appropriate for the specific component will be included in the application package. Note: The R&R Budget form included in many of the component types allows for up to 100 Senior/Key Persons in section A and 100 Equipment Items in section C prior to using attachments for additional entries. All other SF424 (R&R) instructions apply.
Research & Related Senior/Key Person Profile	Include only the Project Director/Principal Investigator (PD/PI) and any multi-PDs/PIs (if applicable to this FOA) for the entire application. A summary of Senior/Key Persons followed by their Biographical Sketches in the Overall section of the assembled application image in eRA Commons will be generated upon submission.	Use Project Role of Other with Category of Project Lead and provide a valid eRA Commons ID in the Credential field in the Project Director/Principal Investigator section. List Senior/Key persons that are working in multiple components in each relevant component. Include a single 4-page Biographical Sketch for each Senior/Key person covering the entire application regardless of the number of components in which they participate. If more than 100 Senior/Key persons are included in a component, the Additional Senior Key Person attachments should be used.
Research & Related Other Project Information	Follow standard instructions.	Human Subjects: Answer only the Are Human Subjects Involved? and Is the Project Exempt from Federal regulations? questions. Vertebrate Animals: Answer only the Are Vertebrate Animals Used? question. Project Narrative: Optional
PHS 398 Cover Page Supplement	Note: Human Embryonic Stem Cell lines from other components should be repeated in cell line table in Overall component.	Enter Human Embryonic Stem Cells in each relevant component.
PHS 398 Research Plan	For Resubmission and Revision applications, an Introduction to Application is required in the Overall component.	For Resubmission and Revision applications, an Introduction to Application is allowed for each component.
PHS 398 Research Plan	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 SF424 (R&R) 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. Data from the NCDDG program should be made available to the research community through publications, or public website, consistent with achieving the goals of the Program. Positive or negative data from NIH supported clinical trials should be made available to the research community through ClinicalTrials.gov, publications, or public website, consistent with achieving the goals of the Program. The applicant should address a plan and timeline for sharing chemical synthesis, preclinical and clinical trials data. Appendix: Do not use the Appendix to circumvent page limits. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.

Each NCDDG UM1 application must include the following components:

• Overall
• Research Project: No more than two

Applications proposing two or more Research Projects with Scientific and Administrative Core components should respond to the companion FOA utilizing the U19 mechanism (see PAR-13-086).

Senior/Key Personnel (Overall)

The PD/PI will be expected to devote at least 1.8 person months of effort to the NCDDG program. It is anticipated that the NCDDG Groups will include outstanding scientists from diverse scientific disciplines within neuroscience, neuropharmacology, neurobiology, medicinal chemistry, clinical neuroscience, clinical trials, mental disorders research, drug or alcohol addiction research, radiochemistry, and/or pharmacokinetics into synergistic research teams without regard to institutional affiliation.

Pharmaceutical partners should include key personnel who have authority within the company to allocate resources to ensure successful completion of the proposed discovery and development efforts.

Budget (Overall)

This program strongly encourages resource contributions (financial and in-kind), of the partners within the NCDDG (e.g., biotechnology, pharmaceutical, or disease foundations) for IND-directed toxicology and safety studies, and for phase I and IIa studies. Private sources of funding should be identified in the application to support Good Manufacturing Practice (GMP) synthesis, formulation, and/or IND filing costs.

PHS 398 Research Plan (Overall)

Research Strategy: The Research Strategy should provide the following details:

• The NCDDG Program objectives and goals should be relevant to and compatible with the NIMH, NIDA, or NIAAA priorities in Section I - Funding Opportunity Description. Applicants should describe their plans to accommodate the stated NCDDG requirements, criteria, and NIMH, NIDA, or NIAAA involvement. The development of analogs of established or well-studied agents for the treatment of mental disorders, drug or alcohol abuse is not appropriate for this FOA.
• An overview of the proposed NCDDG Group, its central theme and goals; this overview should describe the general objectives, and explain the proposed contribution of each of the individual Research Project(s) towards achieving the objectives of the Group.
• A clear description of how each component Research Project is required for the attainment of the NCDDG Program's objectives, including available professional and technical personnel to permit efficient and successful conduct of the proposed research, and description of the contribution of each to fulfillment of group objectives.
• A clear description of the strategy for decision-making regarding identification and evaluation of promising drug candidates for development.
• Evidence that each component Research Project and the Group as a whole have available facilities required for conduct of the proposed research.
• A plan to assure the maintenance of close collaboration and effective communication among members of the group. Letters of commitment to this plan by all Research Project Leaders are not part of the Research Strategy and should be attached separately (see Letters of Support below). Include plans for scheduling group meetings, notifying group members (including NIMH, NIDA, or NIAAA), and documenting and disseminating group meeting proceedings.
• Include a statement that awardees must agree to the "Cooperative Agreement Terms and Conditions of Award" in Section VI.2.A "Award Administration Information".
• Description of the steps that will be taken to ensure successful completion of the NCDDG research should a key member leave the Group.
• Timeline and Milestones: A Timeline and Milestones section must be included in the Research Strategy section for the overall NCDDG. The timeline should describe the expected progression of the research activities for the overall NCDDG, Research Projects over the life of the project. Project milestones should be identified along the timeline. Milestones should be well described, quantifiable, and scientifically justified. The milestones should be regarded as criteria for evaluating the progress and direction of the research project and should not be just a restatement of the specific aims. During the project period, the applicant will be expected to refer to these milestones in annual progress reports. The funding institute will use the milestones, the annual progress reports, and other measures of productivity and success to judge the progress, impact, and value of the program.
• Applicants are strongly encouraged to detail the current status of lead compounds and key lead optimization goals for a development program (e.g., http://www.nimh.nih.gov/research-funding/therapeutics/compound_report_card.pdf) as well as go-no-go criteria in a testing funnel for advancing compounds across stages (http://www.nimh.nih.gov/research-funding/therapeutics/example_testing_funnel.pdf in the Overall Component strategy.
• There is increasing awareness among neurological disease communities that to assess the predictive value of preclinical research, sufficient information must be provided regarding study design and execution, experimental subjects, data analyses, and interpretation. Examples of the critical elements of a well-designed study are summarized at http://www.ninds.nih.gov/funding/transparency_in_reporting_guidance.pdf. Applicants are urged to consider these elements when describing supporting data and designing the proposed studies.

Letters of Support: Include letters of commitment to the collaboration and communication plan (described in the Research Strategy) by all Research Project Leaders.

The application may include up to two research projects.

When preparing your application in ASSIST, use Component Type Project .

PHS 398 Research Plan (Research Projects)

Research Strategy: The Research Strategy t for each individual Research Project must address:

• The major goals and objectives of the project and their relationship to the overall effort of the NCDDG.
• The status of current research efforts, the limitations of existing approaches, and how the research questions posed relate to the objectives of the particular project and the NCDDG as a whole.
• The feasibility of the proposed experiments, the advantages of new methodologies (if any), the potential pitfalls, alternative approaches, the means of assessing success of the research to meet the objectives of the project and the NCDDG as a whole.
• Identify measurable milestones and a time line of the research activities for the Research Project over the life of the project. Milestones should be well described, quantifiable, and scientifically justified. The milestones should be regarded as criteria for evaluating the progress and direction of the Research Project and should not be just a restatement of the specific aims.

An NIH intramural researcher collaborating on an NCDDG must obtain the approval of his/her NIH Institute Scientific Director for participating under the terms and conditions of the FOA. A copy of that letter of approval must be provided (see below).

NIH intramural researchers submitting an Individual Research Project as a part of an NCDDG must follow the procedures for Individual Research Projects as described below:

SF424 (R&R) Cover (Overall)

The NIH Institute should be listed in the Applicant Information section. The Scientific Director who provided approval should be listed as the Contact.

Research & Related Other Project Information (Overall)

Other Attachments. The Individual Research Project PD/PI must obtain the approval of his/her NIH Institute Scientific Director for participating as a component of the NCDDG under the terms and conditions of the FOA. A copy of that letter of approval must be provided as an attachment in the Other Attachments section. The file should be named Scientific Director Approval.pdf to facilitate appropriate bookmarking in the final application image.

R&R Budget (Overall)

The individual budget pages should supply the time and effort for each project participant, but no other budget figures should be included. The resources available for the Research Project and the research environment should be carefully described, but no budget figures should be included. The NIH Institute Scientific Director, as part of the letter of approval for participation, must verify the amount of intramural resources that will be allocated to the project described in the application, and provide assurance that the conduct of the project will comply with the DHHS regulations for research involving human subjects (if applicable) and with the PHS policy on vertebrate animal research.

Research Plan (Overall)

Letters of Support. A copy of the letter of approval of the NIH Institute or Center Scientific Director should be uploaded.

Part I. Overview Information contains information about Key Dates. Applicants are encouraged to submit applications before the deadline to ensure they have time to make any application corrections that might be necessary for successful submission.

Organizations must submit applications via 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.

Applicants are responsible for viewing their application before the deadline in the eRA Commons to ensure accurate and successful submission.

Information on the submission process and a definition of on-time submission are provided in the SF424 (R&R) Application Guide.

This initiative is not subject to intergovernmental review.

All NIH awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

Pre-award costs are allowable only as described in the NIH Grants Policy Statement.

Applications must be submitted electronically following the instructions described in the SF424 (R&R) Application Guide. Paper applications will not be accepted.

Applicants must complete all required registrations before the application due date. Section III. Eligibility Information contains information about registration.

For assistance with your electronic application or for more information on the electronic submission process, visit Applying Electronically.

Important reminders:
All PD(s)/PI(s) and component Project Leads 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.

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 (SAM). 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 by the Center for Scientific Review, NIH. Applications that are incomplete will not be reviewed.

In order to expedite review, applicants are requested to notify the NIMH Referral Office by email at NIMHReferral@mail.nih.gov when the application has been submitted. Please include the FOA number and title, PD/PI name, and title of the application.

Applicants requesting $500,000 or more in direct costs in any year (excluding consortium F&A) must contact NIH program staff at least 6 weeks before submitting the application and follow the Policy on the Acceptance for Review of Unsolicited Applications that Request $500,000 or More in Direct Costs as described in the SF424 (R&R) Application Guide.

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 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 NCDDG program that by its nature is not innovative may be essential to advance a field.

Significance

Does the NCDDG address an important problem or a critical barrier to progress in the field? If the aims of the proposed NCDDG program 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? To what degree does the proposed plan for discovery and testing of novel treatments, research tools, preclinical models, and clinical studies support the needs for the targeted disease? What is the likelihood that it will produce and significantly advance a new candidate therapeutic for development?

Investigator(s)

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the Research Projects and overall NCDDG program? 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? Have collaborations been established or consultants identified to provide the appropriate depth and breadth of expertise required for the project? Has the PD/PI demonstrated leadership in development, implementation, and management of comprehensive research programs? Are there adequate plans for ensuring effective intra-Group communication, interaction, cohesiveness, and coordination among the PD/PI, Research Project Leaders and NIH Project Scientists? Do the investigators state their willingness to collaborate extensively and share information fully?

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? Is the target or mechanism under investigation for drug or therapeutics discovery novel? Will new paradigms for drug discovery, models, or candidate therapeutics emerge for the targeted disease?

Approach

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the Research Projects and overall NCDDG program? 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 NCDDG 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? If preclinical testing is proposed, are the designs sufficiently detailed and rationalized and are such studies relevant to the clinical development path? Are the scientific disciplines represented in Research Projects adequate to achieve the NCDDG Program objectives? Is there a sound scientific rationale for the proposed molecular or clinical targets? Are targets, screens, and preclinical models relevant to therapeutic discovery for mental disorders and/or drug or alcohol addiction? Are the proposed Phase 1 clinical studies for mental disorders designed to assess target engagement, optimal dosing, safety, and tolerability? Are the proposed Phase 1b/IIa clinical studies for mental disorders designed to establish the relationship between the magnitude and duration of target modulation and potential for clinical efficacy in the proposed study population? Are the proposed PD biomarkers to assess functional pharmacological activity of the novel agent or the use of pharmacogenetic or other biomarkers as patient selection strategies appropriate to the proposed clinical studies of mental disorders? If pharmaceutical partnerships are proposed, how will they facilitate the development and evaluation of candidate drugs or therapeutics, tools for clinical research, and model validation for testing therapeutics?

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? Does the clinical research team demonstrate a track record in successfully recruiting subjects into clinical trials and research studies and completing proposed studies within projected timelines?

As applicable for the NCDDG 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.

Timelines and Milestones

Are appropriate, evaluative go/no go decision-making points and quantitative milestones provided and clearly defined? Are the milestones feasible and quantifiable for the specific aims of the Research Projects and overall NCDDG program? Are the timelines appropriate for the Research Projects and overall NCDDG program? Are definitive go/no-go milestone studies appropriately powered and are statistical analyses clearly described? Are the recruitment goals appropriate for the proposed clinical studies?

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 NCDDG 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

For Resubmissions, the committee will evaluate the application as now presented, taking into consideration the responses to comments from the previous scientific review group and changes made to the project.

Renewals

For Renewals, the committee will consider the progress made in the last funding period..

Revisions

For Revisions, the committee will consider the appropriateness of the proposed expansion of the scope of the project. If the Revision application relates to a specific line of investigation presented in the original application that was not for recommended approval by the committee, then the committee will consider whether the responses to comments from the previous scientific review group are adequate and whether substantial changes are clearly evident.

As applicable for the NCDDG 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.

Applications from Foreign Organizations

Not Applicable

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.

Criterion scores will not be assigned for individual Research Projects.

Significance

Does this study address an important problem? If the aims of the application are achieved, how will scientific knowledge or clinical practice be advanced? What will be the effect of these studies on the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field?

Approach

Are the conceptual framework, design, and methods adequately developed, well integrated, and appropriate to the aims of the project? Are the scientific disciplines represented in Research Projects adequate to achieve the objectives? Does the applicant acknowledge potential problem areas and consider alternative tactics? Is the plan to optimize lead structures adequate to ensure that the most efficacious drug will result? If pharmaceutical partnerships are proposed, how will they facilitate the discovery and development of candidate drugs or therapeutics and evaluation of research tools or models?

Innovation

Does the Research Project employ novel concepts, approaches or methods? Are the aims original and innovative? Does the project challenge existing paradigms or develop new tools, methodologies, or technologies?

Investigator

Are the Research Project Leader and key personnel appropriately trained and well suited to direct or carry out this work? Is the Project Leader's time commitment sufficient to achieve the goals? Is the work proposed appropriate to the experience level of the key personnel and other researchers? Have collaborations been established or consultants identified to provide the appropriate depth and breadth of expertise required for the project? Does the PD/PI have previous experience or the ability to manage an integrated scientific enterprise? Do other members of the Group have experience that will facilitate achieving the desired research outcomes?

Environment

Does the technical and scientific environment in which the work will be done contribute to the probability of success? Does the proposed work take advantage of unique features of the technical and scientific expertise and employ effective collaborations?

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s), convened by the NIMH, 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.

Applications will be assigned on the basis of established PHS referral guidelines to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications. Following initial peer review, recommended applications will receive a second level of review by the appropriate National Advisory Council. 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’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 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.

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 74 and 92 (Part 92 is applicable when State and local Governments are eligible to apply), and other HHS, PHS, and NIH grant administration policies.

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

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

• The PD/PI will have primary authority and responsibility to define objectives and approaches and to plan and conduct the proposed research. She/he will assume responsibility and accountability to the applicant organization and to the NIMH, NIDA and/or NIAAA for performance and proper conduct of all research supported in the NCDDG, including the NIH intramural component, if applicable, in accordance with the Terms and Conditions of Award. The PD/PI will be a member of the Steering Committee.
• Intramural research scientists participating as Research Project Leaders or collaborators have the same rights and responsibilities as other members of the Group (see below for Participation of NIH Intramural Scientists).
• The Awardee Institution and/or Research Project Leader's Institution will retain primary custody of and have primary rights to data as specified under either the NIMH, NIDA and/or NIAAA approved Intellectual Property Patent Rights Agreements for New Chemical Entities (described below) or the data and research resource sharing plans (described above). The Government, via the NIMH, NIDA or NIAAA Project Scientist(s), will have access to data generated under this cooperative agreement and may periodically review the data consistent with current DHHS, PHS, and NIH policies. Timely publication of major findings by the Group members is encouraged. Publication or oral presentation of work done under this agreement will require appropriate acknowledgment of NIMH, NIDA or NIAAA support, including the assigned cooperative agreement award number.
• Ownership of compound libraries and/or combinatorial libraries for drug discovery acquired during the course of the research rests with the Group. Prior to award, the Group(s) must formulate a plan for final disposition of the compounds and ownership rights in the event that the compounds are transferred to other parties who make discoveries using them. This plan is to be approved by NIMH, NIDA or NIAAA.
• It is the intention that new chemical entities be fully evaluated as potential candidate drugs for mental health disorders, drug or alcohol addiction or as potential research tools, after the Group has concluded its evaluation and before the compounds are transferred to other parties for evaluation in other therapeutic areas. The Groups must follow the NIMH, NIDA or NIAAA approved Intellectual Property Patent Rights Agreements for New Chemical Entities (described below) or the data and research resource sharing plans (described above).

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

The Project Scientist(s) interacts scientifically with the Group and may provide appropriate assistance, including assisting in research planning, suggesting studies within the scope of the Group's objectives and research activities, presenting experimental findings to the Group from published sources or from relevant contract projects, participating in the design of experiments agreed to by the Group, participating in the analysis of results, and advising in management and technical performance. The Project Scientist(s) will be a member(s) of the Steering Committee. However, the total membership by NIH staff will not exceed one-third (1/3) of the membership of the Steering Committee. In all cases, the role of NIMH, NIDA, or NIAAA will be to assist and facilitate and not to direct activities.

The NIMH, NIDA, or NIAAA Project Scientist(s) can recommend to their Institutes to utilize their drug development resources (e.g., CNS receptor screening, chemical synthesis, and toxicology services) in support of the NCDDG Group research activities if such resources are required on an occasional basis. The following is a list of resources that are readily available and may be supplied if they become desirable during performance. It is not anticipated that requests of services will be considered as a continuing need.

• Reference compounds for standardization of test systems, as analytical standards, and for related purposes.
• Data from testing conducted in resource contract laboratories.
• Laboratory testing capacity, whenever appropriate and possible, in NIMH's and NIDA's current contract based preclinical testing programs or in the NIH Rapid Access to Interventional Development (NIH-RAID) program. The Group is expected to provide sufficient test material for such testing.
• Additional needed resources such as test materials and information that may not otherwise be available to the Group.

Phase I and IIa projects may be reviewed by the appropriate NIH Institute's Data and Safety Monitoring Board (DSMB) to ensure the safety of participants and the validity and integrity of the data. The study protocol(s) and consent form(s) will be reviewed by the DSMB prior to initiation of the project. The DSMB will review study reports from the NCDDG group on a regular basis to monitor subject enrollment and retention, safety, quality of data collection, and integrity of the study. Based on its review, the DSMB has the authority to stop the study after it has started.

Additionally, an NIMH, NIDA, or NIAAA Program Official will be responsible for the normal scientific and programmatic stewardship of the award, including monitoring implementation of the data and research resource sharing plans and will be named in the award notice.

Participation of NIH Intramural Scientists. An NIH intramural scientist may not serve as the PD/PI of an NCDDG but may participate in a Group as a Project Leader, collaborator, or consultant. However, an Intramural scientist may not receive salary, equipment, supplies, or other remuneration from awards resulting from this FOA. The Intramural scientist must obtain written approval of his/her NIH Institute Scientific Director for the amount of resources that may be allocated to the project. The approval must also specify that the conduct of the project will comply with the DHHS regulations for research involving human subjects (if applicable) and with the PHS policy on vertebrate animal research. The participation of an intramural scientist is independent of and unrelated to the role of the NIMH, NIDA and/or NIAAA Project Scientist. For NCDDG applications that include NIH intramural components, the intramural resource level will be included in the total cost of the overall application. The involvement of Intramural scientists needs to be consistent with NIH Policy, http://www1.od.nih.gov/oir/sourcebook/ethic-conduct/ethical-conduct-toc.htm.

Areas of Joint Responsibility include:

Steering Committee:

A governing Steering Committee composed of the PD/PI, Research Project Leaders, Core Directors, NIH Project Scientist(s), and NIH Program Official (as a non-voting member will be established in each NCDDG to assist in monitoring and developing the scientific content and direction of the program.

The Steering Committee members will meet periodically to review and monitor progress, plan and design research activities, and establish priorities. The frequency of meetings, not fewer than two per year, will be determined by the PI/PD who will be responsible for scheduling the time and place (in person or by video or audio teleconference) and for preparing concise proceedings or minutes (two or three pages) which will be delivered to the members of the Group within 2 weeks of the meeting.

a. The principal end products of NCDDG activities for NIMH and NIAAA are expected to include: 1) the discovery and testing of new chemical entities, optimization of lead compounds, IND-directed toxicology, safety pharmacology to support phase I studies, identification of clinical candidates for the treatment of mental disorders or alcohol addiction, and/or phase II efficacy studies; 2) research tools; and 3) preclinical models to evaluate novel therapeutics. Cost-sharing is encouraged for IND-directed toxicity and safety studies of drug candidates. Private sources of funding should be identified for GMP synthesis, formulation, IND filing costs, and toxicology and safety studies exceeding 28 days in duration.

b. The principal end products of NCDDG activities for NIDA are expected to include: 1) the discovery of ligands for target validation studies and potentially for development as pharmacotherapies for drug addiction, 2) as research tools to advance research in the treatment development domain, and 3) preclinical models to evaluate novel therapeutics. Studies required for IND-targeted preclinical development (GMP synthesis, formulation, toxicology) are generally beyond the scope of this FOA for NIDA. Such development through the NIH RAID program or private venture capital is encouraged.

c. NIMH and/or NIAAA will retain the option to cross-file or independently file an application for an investigational clinical trial (e.g., an IND application to the United States Food and Drug Administration) of any clinical research tool or invention resulting from these NIH supported cooperative agreements. Reports of data generated by the Group or any of its members required for inclusion in IND applications and for cross-filing purposes shall be submitted promptly by the Principal Investigator to the NIH Institute Project Scientist upon request. Such reports shall include background information, methods, results, and conclusions.

Dispute Resolution:

Any disagreements that may arise in scientific or programmatic matters (within the scope of the award) between award recipients and the NIH may be brought to Dispute Resolution. A Dispute Resolution Panel composed of three members will be convened. It will have three members: a designee of the Steering Committee chosen without NIH staff voting, one NIH designee, and a third designee with expertise in the relevant area who is chosen by the other two; in the case of individual disagreement, the first member may be chosen by the individual awardee. This special dispute resolution procedure does not alter the awardee's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulation 42 CFR Part 50, Subpart D and DHHS regulation 45 CFR Part 16.

Intellectual Property and Patent Rights for New Chemical Entities

Since the discovery of new pharmacological treatments for mental disorders, drug or alcohol addiction is a major objective of this effort and active involvement by pharmaceutical laboratories is encouraged and may be facilitated by the existence of appropriate patent coverage, it is essential that applicants provide plans to address the handling of intellectual property for new chemical entities for the treatment of mental disorders, drug or alcohol addiction under this FOA.

Successful applicants are required to supply the following confidential materials to the NIMH, NIDA and/or NIAAA Program Officials listed under Section VII. Agency Contacts.

1. Each applicant Group must provide a detailed description of the approach to be used for handling intellectual property and for licensing where appropriate, in particular where the invention may involve investigators from more than one institution. Procedures must be described for resolution of legal problems should they arise. Your attention is drawn to the NIH Extramural Technology Transfer Policies and Documents [http://grants.nih.gov/grants/intell-property.htm].

2. A formal statement of Intellectual Property among all Group members and their institutions as well as a detailed description of procedures to be followed for resolution of legal problems which may develop, must be signed and dated by the organizational official authorized to enter into intellectual property arrangements for each Group member and member institution. The signed agreement must be submitted prior to award to the appropriate NIMH, NIDA and/or NIAAA staff at the addresses provided under Section VII. Agency Contacts.

3. A plan must be developed for disposition of combinatorial and compound libraries generated in Research Projects focused on discovery of new chemical entities as clinical candidates for drug development in conformance with Section VI.2.A - Cooperative Agreement Terms and Conditions of Award and consistent with achieving the goals of the program. The signed document must be submitted prior to award to the appropriate NIMH, NIDA and/or NIAAA staff at the addresses provided under Section VII. Agency Contacts.

4. Prior to the award, the PD/PI and each Project Leader must provide a signed statement of acceptance of the participation of NIMH, NIDA or NIAAA staff during performance of the award as outlined under "NIH Staff Responsibilities" in Section VI.2.A - Cooperative Agreement Terms and Conditions of Award.

Note: Do NOT submit documents 1-4 above with the application. However, awards will not be made until these documents are received and approved by NIMH, NIDA or NIAAA.

When multiple years are involved, awardees will be required to submit the annual non-competing progress report (PHS 2590 or RPRR) and financial statements, as required in the NIH Grants Policy Statement.

A final progress report, 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.

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

Grants.gov Customer Support (Questions regarding Grants.gov registration and submission, downloading or navigating forms)
Contact Center Phone: 800-518-4726
Email: support@grants.gov

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

Linda Brady, Ph.D.
National Institute of Mental Health
Telephone: (301) 443-3563
Email: lbrady@mail.nih.gov

Questions about proof of concept studies for novel interventions or IND-ready therapeutics for mental disorders in adult populations should be directed to:

Mi Hillefors, M.D., Ph.D.
National Institute of Mental Health
Telephone: (301) 443-2738
Email: hillefom@mail.nih.gov

Questions about proof of concept studies for novel interventions or IND-ready therapeutics for mental disorders in children and adolescents should be directed to:

Margaret Grabb, Ph.D.
National Institute of Mental Health
Telephone: (301) 443-3563
Email: mgrabb@mail.nih.gov

David Shurtleff, Ph.D.
National Institute on Drug Abuse
Telephone: (301) 435-0891
Email: dshurtle@mail.nih.gov

Mark Egli, Ph.D.
National Institute on Alcohol Abuse and Alcoholism
Telephone: (301) 594-6382
Email: megli@mail.nih.gov

David Armstrong, Ph.D.
National Institute of Mental Health
Telephone: (301) 443-3534
Email: armstrda@mail.nih.gov

Rebecca Claycamp, M.S., CRA
National Institute of Mental Health
Telephone: (301) 443-2811
Email: rclaycam@mail.nih.gov

Pam Fleming
National Institute on Drug Abuse
Telephone: (301) 443-6710
Email: pfleming@mail.nih.gov

Judy Fox
National Institute on Alcohol Abuse and Alcoholism
Telephone: (301) 443-4704
Email: jfox@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.