Participating Organization(s)	National Institutes of Health (NIH)
Components of Participating Organizations	National Institute of Mental Health (NIMH)
Funding Opportunity Title	Research to Improve the Care of Persons at Clinical High Risk for Psychotic Disorders (R01)
Activity Code	R01 Research Project Grant
Announcement Type	New
Related Notices	August 21, 2013: Removed reference to ASSIST in section IV.3, since ASSIST is currently only available for multi-project applications.
Funding Opportunity Announcement (FOA) Number	RFA-MH-14-211
Companion Funding Opportunity	RFA-MH-14-210, Collaborative R01 Research Project RFA-MH-14-212, R34 Clinical Trial Planning Grant Program
Number of Applications	See Section III. 3. Additional Information on Eligibility.
Catalog of Federal Domestic Assistance (CFDA) Number(s)	93.242
Funding Opportunity Purpose	Given the highly disruptive and disabling nature of psychotic disorders, early intervention has been recommended as a means of preventing psychosis onset among at-risk individuals, as well as averting other adverse outcomes such as mood syndromes, substance abuse disorders, and functional decline in social, academic, and vocational domains. This funding opportunity announcement, along with the companion announcements, aims to support research that will inform a step-wise approach to early psychosis intervention in the United States. The goals of this initiative are to encourage applications that (1) test the effectiveness of interventions that target symptomatic and functional difficulties associated with clinical risk states for psychosis; (2) test hypotheses regarding mediators/mechanisms of action of these interventions; (3) create an evidence base to inform stepped-care models of early psychosis intervention; and (4) determine the feasibility for implementing such approaches in community-based treatment settings.

Posted Date	August 7, 2013
Open Date (Earliest Submission Date)	December 6, 2013
Letter of Intent Due Date(s)	December 6, 2013
Application Due Date(s)	January 6, 2014, by 5:00 PM local time of applicant organization. Applicants are encouraged to apply early to allow adequate time to make any corrections to errors found in the application during the submission process by the due date.
AIDS Application Due Date(s)	Not Applicable
Scientific Merit Review	April 2014
Advisory Council Review	August 2014
Earliest Start Date	September 30, 2014
Expiration Date	January 7, 2014
Due Dates for E.O. 12372	Not Applicable

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). 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

Approximately 100,000 young persons in the United States experience a first episode of psychosis every year. During the same interval, it is estimated that over one million children and adolescents may experience problems in thinking, mood, and social functioning suggestive of a pre-psychosis risk state. Given the highly disruptive and disabling nature of psychotic disorders, early intervention has been recommended as a means of preventing psychosis onset among at-risk individuals, as well as averting other adverse outcomes such as mood syndromes, substance abuse disorders, and functional decline in social, academic, and vocational domains. Efficacy trials suggest that targeted preventive interventions can reduce psychosis risk over 12 months to a greater extent than routine monitoring or non-specific treatment. Increasing the effectiveness of preventive interventions, and extending the benefits of pre-emptive treatment beyond 12 months, should be a major focus of clinical research. More clinical trial data are necessary to determine the risks and benefits of various forms of intervention prior to psychosis onset, and the likelihood that promising interventions can be brought to scale. Accordingly, the goals of this initiative are to (1) test the effectiveness of interventions that target symptomatic and functional difficulties associated with clinical risk states for psychosis; (2) test hypotheses regarding mediators/mechanisms of action of these interventions; (3) create an evidence base to inform stepped-care models of early psychosis treatment; and (4) determine the feasibility for implementing such approaches in community treatment settings within the United States.

Over the past two decades, several hundred published reports have explored the construct of a clinical high risk (CHR) state for psychosis. Research conducted in Australia, Europe, and North America has established the predictive validity of risk criteria based on the presence of attenuated psychotic symptoms, transient psychotic episodes, or trait vulnerability combined with functional deterioration. A recent meta-analysis of transition to psychosis among approximately 2,500 individuals who met CHR criteria reported mean transition rates of 22% at 1 year, 29% at 2 years, and 32% at 3 years. A separate study reporting outcomes for CHR persons who did not develop overt psychosis over an extended period found that many experience ongoing problems with attenuated positive symptoms (41% at 2 years) as well as persistent functional disability. Accumulating evidence of poor or marginal recovery over time spurred a shift in the CHR research agenda approximately 10 years ago, with increasing emphasis placed on randomized controlled trials (RCTs) to explore indicated prevention approaches.

Since 2002, eleven RCTs have been conducted to test the efficacy of psychological, pharmacologic, nutritional, and multi-component psychosocial interventions for preventing psychosis onset among help-seeking persons who meet CHR criteria. Meta-analyses of these studies suggest that cognitive-behavioral therapy exerts a moderate effect on transition to psychosis at 12 months (50% risk reduction compared to supportive counseling), and that multi-component treatment, including family therapy, also delays or reduces transition to psychotic illness at one year. Although no clear evidence supports pharmacological interventions for persons at high clinical risk, one study suggests a potentially beneficial effect of nutritional supplementation (i.e., omega-3 fatty acids). While groundbreaking, efficacy trials have not generated knowledge that is readily translatable to clinical practice in U.S. community care settings.

Additional RCTs are required to expand knowledge regarding effective interventions during the CHR period, and to build an evidence base to support high quality community care. Clinical staging or stepped care models have been suggested as a framework for future effectiveness studies . In these models, first-line interventions are selected according to a person’s position along a continuum of illness, with changes in therapy (i.e., stepping up or down) depending on outcomes attained with initial treatment. Step-wise care requires reliable strategies for determining an individual’s illness state; evidence-based treatments of differing intensity that match the person’s risk state; and procedures for monitoring clinical progress against pre-determined response criteria (e.g., stabilization, recovery, or worsening). The current initiative aims to support research that will inform a step-wise approach to CHR care in the context of the U.S. healthcare system. Anticipated outcomes from this program of research might include, but are not limited to:

• Interventions of varying complexity, intensity, and duration that address symptoms, problems, functional impairments, or underlying substrates (e.g., neurocognitive deficits, attribution bias, etc.) that characterize different CHR states;
• Empirical data regarding the effectiveness, risks, and benefits of various forms of stage-specific intervention; and
• Information regarding the feasibility of implementing promising therapies for CHR in community treatment settings in the United States

This Funding Opportunity Announcement (FOA) solicits research grant applications for randomized controlled trials that will test the effectiveness of interventions for CHR states within a stepped care framework. To accomplish this goal, the initiative will support RCTs that (a) segment the CHR population according to degree of psychosis vulnerability; (b) select well-specified CHR subgroups for study; (c) test interventions that address defining features of the selected CHR subgroup; and (d) determine the effectiveness of stage-specific treatments based on a priori definitions of recovery, stabilization, and worsening. In aggregate, this program of research will inform a step-wise approach to CHR care that features lower intensity/lower risk treatments as first-line interventions, with decisions regarding discharge, maintenance therapy, or step-up to more intensive care based on objective measures of treatment outcome.

Responsive applications will select study samples on the basis of validated interview measures that assess key CHR features, e.g., the Comprehensive Assessment of At-Risk Mental States; the Structured Interview for Prodromal Syndromes , or the Bonn Scale for the Assessment of Basic Symptoms . In addition, the application must specify which methods will be applied to segment the CHR population into coherent subgroups. Several strategies have been proposed for stratifying the CHR population according to early versus later stages of psychosis risk ; severity of attenuated positive symptoms and functional impairments, and neurocognitive status . Other approaches to risk stratification are permissible, including biomarkers or biosignatures of emerging illness. In all cases, however, the applicant must justify the choice of stratification method on empirical grounds, and provide evidence that subgroup classification can be accomplished reliably. Investigators should have a history of successfully working with populations at clinical high risk for psychosis. Applications should include information demonstrating the investigator’s capacity to identify, recruit, and randomize individuals who meet CHR subgroup criteria in numbers sufficient to support a well-powered RCT. Investigators should also demonstrate experience in clinical trials management.

For the purposes of this FOA, applicants may propose novel approaches to CHR treatment or phase-specific adaptations of interventions with established efficacy for other conditions or illness phases. In either case, applicants should propose interventions that target the illness or disability features that characterize the selected CHR subgroup. Interventions may be psychological, rehabilitative, or pharmacologic in nature. Whatever the intervention, the application should specify which psychological constructs, neurocognitive operations, or biological variables (i.e., mechanisms") are thought to underlie CHR illness or disability. Applicants must describe how the proposed intervention is expected to impact hypothesized mechanisms, and how this relationship will be measured. Depending on the nature of the intervention, the targets and change mechanisms might involve specific neurobiological entities (e.g. brain circuits) or psychological or behavioral processes. Applications should justify the plan for assessment of targeted mechanisms using valid measures that are as objective and direct as is feasible (e.g., using neurophysiological and/or behavioral measures or laboratory tasks that have been previously validated as reflecting underlying behavioral, psychological or neural targets/mechanisms, as appropriate and feasible). When relevant, investigators are encouraged to conceptualize their research using the constructs and units of analysis defined in the Research Domain Criteria framework (http://www.nimh.nih.gov/research-priorities/rdoc/index.shtml ).

Proposed treatments should be justified on conceptual and empirical grounds with pilot data that demonstrate feasibility as well as the potential for clinical benefit. The clinical trial should be designed to provide a definitive test of an intervention’s effectiveness and to evaluate whether changes in hypothesized mechanisms are associated with subsequent changes in functional outcomes. For novel approaches to CHR treatment, there should be sufficient pilot data supporting the approach. In cases where pilot data are lacking, investigators should consider applying to the companion intervention development FOA, RFA-MH-14-212, Research to Improve the Care of Persons at Clinical High Risk for Psychotic Disorders (R34).

Applicants are not required to propose interventions for more than one CHR subgroup. That is, RCTs focusing on a single step of care for a well-defined subgroup will be considered responsive to this FOA. However, it is also acceptable to propose tests of multi-step interventions where second-line treatments are offered to individuals who do not respond to initial interventions. RCTs that propose tests of multi-step interventions should consider sequential multiple assignment randomized trial (SMART) designs to test the value of adaptive treatment approaches.

Applications must propose subgroup-specific primary and secondary endpoints based on a priori definitions of (1) recovery, (2) stabilization, and (3) worsening. The RCT should be powered to detect clinically significant differences between treatment and control groups on the primary outcome of interest. Primary and secondary outcome measures for the RCT should be selected on the basis of recovery criteria relevant to the selected CHR subgroup. For example, reversal of moderate attenuated psychotic symptoms, or restoration of normal social/academic performance, are reasonable recovery outcomes for persons in an early or low-severity CHR state. Alternately, reducing the intensity of attenuated positive symptoms and averting transition to psychosis are acceptable outcomes for individuals in a late or moderately severe CHR state. Finally, rapid remission of psychosis is a logical clinical endpoint for interventions that address brief limited intermittent psychotic symptoms or are intended to reverse an initial psychotic episode. Although studies may lack sufficient power to evaluate psychosis conversion as a primary outcome, transition to active psychosis should be operationalized and tracked as a secondary outcome in all investigations.

Finally, while it is acceptable for RCTs to occur within the context of academic or CHR research-based clinics, applicants must recognize that the ultimate goal of this initiative is to test practical interventions that could be feasibly implemented and sustained in community treatment settings in the United States. Consequently, applicants are encouraged to (a) anticipate the characteristics of real-world community settings that could affect uptake of effective treatments and (b) take these features into account when developing and testing intervention strategies. Responsive applications will include information related, but not limited, to the feasibility of methods for segmenting the CHR population into coherent subgroups, staff training and supervision requirements, practical approaches for monitoring treatment fidelity, resource requirements, and practical measures of quality and outcome.

Funding Instrument	Grant: A support mechanism providing money, property, or both to an eligible entity to carry out an approved project or activity.
Application Types Allowed	New The OER Glossary and the SF424 (R&R) Application Guide provide details on these application types.
Funds Available and Anticipated Number of Awards	NIMH intends to commit approximately $5 million in FY 2014 to fund an estimate of 5-6 awards in response to this FOA and the companion announcements.
Award Budget	Application budgets are not limited, but need to reflect the actual needs of the proposed project.
Award Project Period	The total project period for an application submitted in response to this FOA 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)

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) (formerly CCR) 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.
• 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 and SAM registration in order to complete the eRA Commons registration. Organizations can register with the eRA Commons as they are working through their SAM or Grants.gov registration. 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 and should work with their organizational officials to either create a new account or to affiliate an existing account with the applicant organization’s eRA Commons account. 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.

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

• To an RFA of an application that was submitted previously as an investigator-initiated application but not paid;
• Of an investigator-initiated application that was originally submitted to an RFA but not paid; or
• Of an application with a changed grant activity code.

Applicants must download 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.

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. 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 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:

Amy B. Goldstein, PhD
National Institute of Mental Health
6001 Executive Blvd.
Room 7133, MSC 9633
Bethesda, MD 20892-9633
Email: [email protected]

Office: 301-496-7227
Fax: 301-443-4045
Address for FedEx, UPS, etc:
6001 Executive Blvd, RM 7144
Rockville MD, 20852

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

The forms package associated with this FOA includes all applicable components, required and optional. Please note that some components marked optional in the application package are required for submission of applications for this FOA. Follow all instructions in the SF424 (R&R) Application Guide to ensure you complete all appropriate optional components.

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, with the following additional instructions:

Research Strategy: As part of the research strategy, applications should present: (1) an empirically justified approach to specifying and stratifying the clinical high risk population that is reliable and valid; (2) an approach to intervention that targets specific mechanisms of illness; (3) functional outcome measures related to mechanisms of illness; and (4) operationalized definitions of recovery, stabilization and worsening, with specific outcome measures for each.

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 modification:

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

Consistent with NIH efforts to establish and promote the use of common standardized measures and methods, the harmonization of data across sites, and the sharing of data with the wider research community, applications are expected to include a Data Sharing Plan that addresses:

• Plans for dissemination of standardized assessment battery and methods
• Plans for data dictionary preparation and careful documentation of data collected
• List of key elements for data sharing
• Data sharing schedule/timeline (i.e., release of data)
• Plan for post-award disposition of data. Applicants are encouraged to submit a final, de-identified dataset to the NIMH Limited Access Dataset Repository.

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.

When conducting clinical research, follow all instructions for completing Planned Enrollment Reports as described in the SF424 (R&R) Application Guide.

When conducting clinical research, follow all instructions for completing Cumulative Inclusion Enrollment Report as described in the SF424 (R&R) Application Guide.

Foreign (non-U.S.) institutions must follow policies described in the NIH Grants Policy Statement, and procedures for foreign institutions described throughout the SF424 (R&R) Application Guide.

The ultimate aim of this initiative is to test interventions that can be feasibly implemented in the United States. As a result, while foreign institutions are eligible to apply, foreign investigators should collaborate with a US investigator in the submission of an application and, in the application, describe how data collected in the foreign site will be relevant to, and will inform, the US healthcare system.

Part I. Overview Information contains information about Key Dates. 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.

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. If a Changed/Corrected application is submitted after the deadline, the application will be considered late.

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

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

This initiative is not subject to intergovernmental review.

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

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

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

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

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

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 by the Center for Scientific Review and responsiveness by NIMH, NIH. Applications that are incomplete and/or nonresponsive will not be reviewed.

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

Applicants are required to follow the instructions for post-submission materials, as described in NOT-OD-13-030.

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

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

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

Significance

Does the project address an important problem or a critical barrier to progress in the field? If the aims of the project are achieved, how will scientific knowledge, technical capability, and/or clinical practice be improved? How will successful completion of the aims change the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field? Does the application address strategies for increasing the effectiveness of preventive interventions for psychosis risk states, or extending the benefits of pre-emptive treatment beyond 12 months? Do the investigators propose an approach to intervention that, if effective, could substantially improve symptomatic and functional difficulties associated with risk states for psychosis? Would the research contribute meaningfully to an evidence base that would, ultimately, inform stepped-care models of early psychosis intervention? If shown to be effective, are the interventions to be tested feasible; i.e., could the interventions tested be brought to scale and delivered in community treatment settings? Will the study, as designed, provide important information for future program development, even if the results are negative? (i.e., fast-fail principles)

Investigator(s)

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the project? If Early Stage Investigators or New Investigators, or in the early stages of independent careers, do they have appropriate experience and training? If established, have they demonstrated an ongoing record of accomplishments that have advanced their field(s)? If the project is collaborative or multi-PD/PI, do the investigators have complementary and integrated expertise; are their leadership approach, governance and organizational structure appropriate for the project? Do the investigators have a history of successfully working with populations at clinical high risk for psychosis? Does the investigative team have a demonstrated record of successfully identifying, recruiting, and randomizing CHR individuals in other research studies? Do the investigators demonstrate expertise in clinical trials management?

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 intervention approach proposed novel? Are novel strategies or methods used in stratifying subgroups?

Approach

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Are potential problems, alternative strategies, and benchmarks for success presented? If the project is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed? Does the application include an approach to selecting study samples that is based on validated interview measures of psychosis risk? Is the methodology selected for segmenting the CHR population specified, reliable, and valid? Does the intervention target psychological constructs, neurocognitive operations, or biological variables that are thought to underlie CHR illness or disability? Are there clearly specified strategies for measuring the relationship between mechanism of illness and functional and symptomatic outcomes? Does the plan for assessment of targeted mechanisms use valid measures that are as objective and direct as is feasible? For novel interventions, are there sufficient pilot data regarding impact on psychological constructs, neurocognitive operations, or biological variables that are thought to underlie CHR illness or disability? Does the application include operationalized definitions of recovery, stabilization, and worsening? Does the application include an operationalized definition of, and an approach for tracking, transition to psychosis? If the RCT tests a multi-step intervention, has the investigator considered sequential multiple assignments randomized trial (SMART) designs to test the value of adaptive treatment approaches? Is there sufficient power to detect differences between treatment and control groups on the primary outcome of interest? Does the application anticipate the characteristics of 'real world' community settings that could impact uptake of effective treatments? To what extent are these factors taken into account when developing and testing intervention strategies? Is information provided with respect to the feasibility of methods for segmenting the CHR population in coherent subgroups, staff training and supervision requirements, practical approaches to monitoring treatment fidelity, resource requirements, and practical measures of quality and outcome?

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

Environment

Will the scientific environment in which the work will be done contribute to the probability of success? Are the institutional support, equipment and other physical resources available to the investigators adequate for the project proposed? Will the project benefit from unique features of the scientific environment, subject populations, or collaborative arrangements? Does the application take into account 'real world' community settings that could affect uptake of effective treatments?

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.

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 Guidelines for the Review of Human Subjects.

Inclusion of Women, Minorities, and Children

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

Vertebrate Animals

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

Biohazards

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

Resubmissions

Not Applicable

Renewals

Not Applicable

Revisions

Not Applicable

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

Applications from Foreign Organizations

Reviewers will assess whether the project presents special opportunities for furthering research programs through the use of unusual talent, resources, populations, or environmental conditions that exist in other countries and either are not readily available in the United States or augment existing U.S. resources. To what extent will data generated by the foreign organization be relevant to intervention implementation within US healthcare systems?.

Select Agent Research

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

Resource Sharing Plans

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

Budget and Period of Support

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

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

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 Mental Health 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, SAM 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

Not Applicable

When multiple years are involved, awardees will be required to submit the annual Non-Competing Progress Report (PHS 2590 or RPPR) 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.

eRA Commons Help Desk (Questions regarding eRA Commons registration, submitting and tracking an application, documenting system problems that threaten submission by the due date, post submission issues)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

Web ticketing system: https://public.era.nih.gov/commonshelp
TTY: 301-451-5939
Email: [email protected]

Grants.gov Customer Support (Questions regarding Grants.gov registration and submission, downloading forms and application packages)
Contact Center Telephone: 800-518-4726

Web ticketing system: https://grants-portal.psc.gov/ContactUs.aspx
Email: [email protected]

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Telephone: 301-710-0267
TTY: 301-451-5936
Email: [email protected]

Amy B. Goldstein, PhD
National Institute of Mental Health
Telephone: 301.496.7227
Email: [email protected]

David Armstrong, Ph.D.
National Institute of Mental Health (NIMH)
Telephone: 301-443-3534
Email: [email protected]

Tamara Kees
National Institute of Mental Health
Telephone: 301-443-8811
Email: [email protected]

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.