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

Purpose

The purpose of this FOA is to support research to test the therapeutic value of treatment, preventive, and services strategies for which there is already evidence of efficacy, for use in community and practice settings and to test hypotheses regarding moderators, mediators, and mechanisms of action of these interventions. This FOA supports research to evaluate the effectiveness of pharmacologic, psychosocial (psychotherapeutic and behavioral), device based, rehabilitative and combination interventions that show promise, compared to existing treatment approaches, for improving symptomatic and functional outcomes for mental disorders. Studies that address either acute or longer-term therapeutic effects are encouraged. This FOA also supports clinical trials to test patient-, provider-, organizational-, or systems -level services interventions to improve service access, engagement, quality, coordination, or delivery, with the goal of improved outcomes for individual patients and as well as larger populations. The intervention research covered under this announcement is explicitly focused on practice-relevant questions. This FOA is intended to support research on interventions/services models that have potential to substantially impact practice and public health in terms of the magnitude of likely improvements in key outcomes (e.g., clinical benefit, safety/tolerability profile, value and efficiency, or scalability potential), as compared to existing approaches.

Research Objectives

In general, prior to effectiveness testing, results from more highly controlled studies provide empirical support regarding the intervention's efficacy and the mechanism that underlies clinical benefit (i.e., evidence that the intervention engages its intended neurobiological or psychological targets, and changes in these targets lead to functional improvement and clinical benefit). Consistent with the NIMH experimental therapeutics approach (http://www.nimh.nih.gov/about/director/2012/experimental-medicine.shtml), this FOA is intended to support effectiveness trials that not only to test the intervention effects on outcomes of interest, but also explicitly inform understanding regarding whether the intervention engages associated change mechanisms that were previously identified under more controlled, efficacy conditions, thereby reconfirming the intervention targets and testing whether previously identified change mechanisms are operative in the effectiveness context (see NIMH web page on Clinical Trials). In this manner, the results of the effectiveness trial will advance knowledge regarding therapeutic change mechanisms and have utility regardless of trial outcomes (e.g., in the event of negative results, information about whether the intervention was successful at engaging its targets can facilitate interpretation).

Depending on the nature of the intervention, the "targets" or mechanism of action might involve specific neurobiological entities (e.g. brain circuits) or psychological or behavioral processes (e.g., attention bias, cognitive control, stress regulation). For studies that involve preventive or therapeutic interventions, NIMH encourages research that takes into account RDoC or RDoC-like constructs when defining the subject eligibility (inclusion), intervention targets or mechanisms, and outcomes, as appropriate and feasible in the effectiveness setting (see the RDoC webpage http://www.nimh.nih.gov/research-funding/rdoc/nimh-research-domain-criteria-rdoc.shtml for more details). In the case of services interventions, targets might involve consumer or provider behaviors that are intervened on in order to improve access, engagement, quality or outcomes of treatments and services.

With appropriate justification, there could be an exception to the requirement for strong efficacy evidence before an intervention is tested in an effectiveness trial. To reduce the alarming fall-off in effect sizes from efficacy to effectiveness studies, and to expedite translation from intervention development to practice-ready interventions, this FOA encourages investigators to conduct rigorous trials in community settings as early as possible in the intervention development sequence. Depending on the intervention type and measurement involved, and with strong justification, this announcement seeks trials with high internal validity, albeit with community therapists and typical community patients in community settings, as an alternative to traditional early efficacy trials (e.g., in laboratory settings).

Research responsive to this announcement must involve trials with prospective data collection in which patients are assigned to specific intervention conditions. While random allocation to intervention conditions is expected in most cases, depending on the study question, practical constraints, and ethical considerations, quasi-experimental designs with non-randomized comparison groups might be appropriate, with strong justification. Studies that address questions regarding the impact of interventions using only archival or observational/naturalistically collected data are not considered responsive to this FOA; applicants are encouraged to contact Scientific/Research staff with questions regarding responsive trial designs and alternative FOAs.

Comparison or control conditions may include treatment-as-usual or other standard or experimental interventions of proven efficacy. However, placebo or sham interventions might be used where appropriately justified, for example, in studies of augmentation strategies (blinded) added to existing treatments (generally open-label). In contrast to efficacy trials, it is anticipated that effectiveness trials might not be double-blind; while self- and clinician-ratings can be informative and may reasonably be collected, unless otherwise justified, raters responsible for key outcome measures should be blinded as to subjects' treatment assignment. Primary outcome measures should be validated and generally accepted by the field. Given the emphasis on practice relevant questions, outcomes of interest extend beyond symptom reduction to include short- and long-term assessment of changes in functioning across domains (such as school, work, family, peer functioning) for children, adolescents, and adults, and also might include other outcomes of interest to key stakeholders (e.g., efficiency, value, or other factors related to the eventual implementation of new intervention and services approaches).

Given the focus on practice-relevant questions in community and practice settings, collaborations between academic researchers and clinical or community practice partners or networks are expected. . When possible, studies should capitalize on existing infrastructure (e.g., practice-based research networks such as the NIMH-sponsored Mental Health Research Network (MHRN), electronic medical records, administrative data bases, patient registries, institutions with Clinical and Translational Science Awards) to increase the efficiency of participant recruitment (i.e., more rapid identification and enrollment) and to facilitate the collection of moderator data (e.g., clinical characteristics, biomarkers), longer-term follow-up data, and broader, stakeholder-relevant outcomes (e.g., mental health and general health care utilization, value and efficiency of intervention approaches).

Effective prevention and treatment of mental illness have the potential to reduce morbidity and mortality associated with intentional injury (i.e., suicide attempts and deaths, see: www.suicide-research-agenda.org). Lack of attention to the assessment of these outcomes has limited our understanding regarding the degree to which effective mental health interventions might offer prophylaxis. Accordingly, where feasible and appropriate, NIMH encourages effectiveness research that, includes assessment of suicidal behavior in order to advance understanding of how effective prevention and treatment of mental disorders might impact suicide relevant outcomes.

It is expected that most projects should request and be completed in a 3- or 4- year budget period. Applicants are strongly encouraged to contact Scientific/Research staff in advance if they anticipate requesting 5 years of support. Studies that build in efficiencies to expedite enrollment and the delivery of practice-relevant results will be considered of higher priority by the NIMH.

Potential applicants are strongly encouraged to contact Scientific/Research contacts as far in advance as possible to discuss the match between potential research applications and current NIMH priorities and relevant funding mechanisms.

Information about the mission, strategic plan and research interests of the NIMH can be found at the NIMH website (http://www.nimh.nih.gov/) including http://www.nimh.nih.gov/research-priorities/strategic-objectives/index.shtml. Applicants are also strongly encouraged to review the information on the NIMH website focused on clinical trials http://www.nimh.nih.gov/funding/clinical-trials-for-researchers/index.shtml.

Please note, per NOT-MH-14-007 NIMH will not accept R01, R21, or R03 applications that include clinical trials of potential therapies for mental disorders, under the NIH parent R01 Funding Opportunity Announcement (FOA) PA-13-302, NIH parent R21 FOA PA-13-303, and NIH Parent R03 FOA PA-13-304, and subsequent reissuances of these FOAs.

Priorities and Considerations for Effectiveness Trials Research

Given the resources necessary to launch large-scale trials and conduct intervention research in community/practice settings, studies must be justified in terms of potential clinical/public health impact; potential to inform understanding of targets/mechanisms of action and personalized strategies; and use of innovative platforms (e.g. registries) and designs (e.g., time and cost efficiencies for enrolling representative patient samples via networks or other existing infrastructure). NIMH strongly discourages large scale trials designed to detect incremental gains in established effects; expensive trials of on-patent medications without demonstrated superiority over off-patent medications; and trials adapting currently available treatments for new subpopulations without strong empirical justification.

This FOA is intended to support effectiveness research as follows:

• Trials that address a knowledge gap that is widely recognized as a substantial obstacle to the treatment or prevention of mental illness and focus on a problem with substantial public health significance, in terms of the condition's prevalence and associated morbidity, functional disability, mortality, costs or other barriers to the receipt of treatment or services.
• Effectiveness research for which the results have the potential to change clinical practice (i.e., consumer, provider or payer behavior) or organizational- or systems-level processes and public health (e.g., in terms of illness prognosis, quality of life, academic or employment outcomes, mortality).
• Trials that not only address the effectiveness of the intervention or service delivery approach, but also explicitly address whether the intervention engages the target(s)/mechanism(s) presumed to underlie the intervention effects (the mechanism that accounts for changes in clinical/functional outcomes, changes in provider behavior, etc.), such that the results will be informative regardless of the effectiveness outcomes and will contribute to understanding of change mechanisms and inform the development and refinement of more potent and efficient interventions.
• Research on the effectivess of scalable interventions and service delivery approaches that could be broadly implemented using typically available resources (e.g., training infrastructure, skilled providers), typical service structures (including health care financing), and typical service use patterns.
• Effectiveness research that is informed by collaborations among academic researchers, community practice partners/providers, consumers, and relevant policy makers, as appropriate, in a manner that informs the trial and helps to ensure the results will have utility.
• Prospective effectiveness trials that examine questions that cannot be addressed more efficiently with other less time- and resource-intensive strategies, such as secondary analyses or meta-analyses of existing databases, observational data, or electronic medical records.
• Trials that utilize existing infrastructure (e.g., practice-based research networks, electronic medical records, administrative data bases, patient registries), as feasible, to increase the efficiency of participant recruitment and data collection.
• Trial designs that are maximally efficient for testing the study hypotheses, including studies that incorporate innovative elements (e.g., adaptive sequential randomization, equipoise stratification), as appropriate, that enhance thesensitivity and potential for yielding interprestable results.
• Effectiveness trials that can contribute to advancing the personalization of mental health careandinclude collection of clinical and biological variables (e.g., blood for genetic analysis, other potential biomarkers), as appropriate, that might be used to inform or test algorithms for more prescriptive approaches.ntribute information to larger databases for future use?
• NIMH encourages effectiveness trials that include collection of data and biospecimens in a manner that will promote appropriate sharing and integration into larger databases (e.g., use of common data elements; https://www.phenxtoolkit.org/). Accordingly, NIMH encourages the use of standardized instruments (including assessments of suicidal beahavior, as appropriate) and collection of data in a manner that will allow other researchers to analyze the data, including conducting meta-analyses.

Examples of clinical trials that would be considered responsive to the goals of this FOA include but are not limited to:

• Large scale, pragmatic trials (treatment, prevention, or rehabilitation) using pharmacologic, psychosocial, and other approaches individually or in combination, including studies that examine the balance between effectiveness and safety and studies that compare the efficiency and value of alternate intervention approaches.
• Trials designed to demonstrate that a therapeutic signal and mechanisms of action detected in preliminary work hold up when the intervention's effectiveness is tested on a larger scale in community settings (with community therapists and a heterogeneous sample) while maximizing internal validity, e.g., by using objective/observational methods to measure moderators, mediators, mechanisms, fidelity, and clinical benefits.
• Trials that incorporate tailoring variables (e.g., clinical data, biomarkers) into participant assignment algorithms and employ sequential randomization and iterative evaluation of treatment effects to test prescriptive intervention approaches (e.g., MOST/SMART adaptive treatment designs).
• Trials that examine the utility and efficiency of modular or stepped-care approaches for matching treatment components of varying intensity to patient's preferences or areas of greatest need.
• Studies that incorporate risk information to stratify and assign participants to preventive interventions in community practice settings (e.g., schools, primary care).
• Trials that examine the utility of technology-based approaches to significantly improve the delivery of interventions and services or improve access to and quality of mental health care.
• Trials that test or compare patient-, provider- or systems-level services interventions designed to promote service access, use, engagement, and retention or improve quality or outcomes of care, including approaches to reduce empirically documented outcome disparities experienced by people in specific subgroups.
• Studies that test diffusion strategies (i.e., dissemination and implementation) to improve adoption of evidence-based treatments in practice settings.
• Studies that test provider-, organizational-, or systems- level interventions to increase the uptake, fidelity, and sustained use of evidence-based MH interventions (e.g., studies comparing approaches to provider training and supervision).

Examples of studies that are not responsive to this FOA and will not be reviewed include the following:

• Applications whose scope of work involves examing intervention effectiveness without studying whether the intervention engages the target(s) presumed to underlie benefits and without examining whether intervention-induced changes in targets are associated with clinical benefit.
• Adaptations of existing interventions in the absence of a compelling justification and in the absence of a clear experimental therapeutics approach to examining how the intervention engages the adaptation target (see the NAMHC Workgroup Report, "From Discovery to Cure: Accelerating the Development of New and Personalized Interventions for Mental Illnesses http://www.nimh.nih.gov/about/advisory-boards-and-groups/namhc/reports/fromdiscoverytocure.pdf", see Recommendation 2.4.1, page 19, for additional guidance regarding the empirical justification for intervention adaptations and augmentations.)
• Studies conducted in academic research laboratories as opposed to effectiveness studies in community practice clinics/settings (e.g., studies in research clinics that involve research therapists or other features that are not representative of typical practice settings and substantially impact generalizability).
• Trials using patented medications that lack superior efficacy or safety relative to currently available off-patent medications.
• Studies of stigma or health literacy interventions that do not explicitly study the impact on mental health service access, engagement, quality and/or outcomes of care.

Applicants must include all information described in the FOA instructions in Section IV.2 (Instructions for Application Submissions; Other Attachments; PHS 398 Research Plan; Research Strategy). Incomplete applications will not be reviewed.

Updated priorities for NIMH clinical trials research are detailed on the NIMH Clinical Trials website. Intervention research that addresses objectives outlined in the NIMH Strategic Plan and NIMH Strategic Research Priorities is encouraged. Additional priorities for intervention research are detailed in the NAMHC Workgroup Report "From Discovery to Cure: Accelerating the Development of New and Personalized Interventions for Mental Illnesses." Research on services interventions that addresses objectives outlined in Objective 4 of the NIMH Strategic Plan and NIMH Strategic Research Priorities is encouraged. Additional Priorities for services research are outlined in the NAMHC Workgroup Report "The Road Ahead: Partnerships to Transform Services."

Scale and Scope of Studies Covered Under this Announcement

This FOA is intended to support trials that are statistically powered to provide a definitive answer regarding the study intervention's effectiveness in comparison to usual care practices or alternative intervention/services approaches. The study should also be designed to address hypotheses regarding predictors and moderators of effectiveness and questions regarding the action of mediators and mechanisms that underlie clinical benefit.

Please see the NIMH Clinical Trial web page for FOAs covering other stages of intervention research.

While this FOA provides support for fully-powered effectiveness studies via the R01 grant mechanism, accrual of participants and data collection at multiple sites via subcontracts is permissible, with appropriate provisions for cross-site coordination and quality control. Such a study with multiple sites through subcontracts is strongly encouraged to use a centralized IRB. Applicants interested in submitting multi-site effectiveness trials (e.g., to answer primary effectiveness questions and key questions regarding moderators/mechanisms, to ensure geographic and demographic diversity) are directed to RFA-MH-16-415 "Clinical Trials to Test the Effectiveness of Treatment, Preventive, and Services Interventions (Collaborative R01)".

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

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

For institutions/organizations proposing multiple PDs/PIs, visit the Multiple Program Director/Principal Investigator Policy and submission details in the Senior/Key Person Profile (Expanded) Component of the SF424 (R&R) Application Guide.

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

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

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

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

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, including Supplemental Grant Application Instructions 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:
Email: [email protected]

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

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

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

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

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

Facilities and Other Resources: The description of the resources and environment should address how the study utilizes existing infrastructure (e.g., CTSAs, practice-based research networks, electronic medical records, administrative data bases, patient registries) or utilizes other available resources to increase the efficiency of participant recruitment and data collection or provide a justification in the event that such efficiencies cannot be incorporated.

Other Attachments: Applicants must upload a single attachment that includes the following information relevant to the proposed clinical trial Applicants should use the headers below in their description. This attachment must be no more than 4 pages. Applications that exceed this limit will not be reviewed.

I. Participant Recruitment and Retention Procedures: Applications must provide a clear description of:

• Recruitment and Referral sources, including detailed descriptions of the census/rate of new cases and anticipated yield of eligible participants from each source;
• Procedures that will be used to monitor enrollment and track/retain participants for follow-up assessments;
• Strategies that will be used to ensure a diverse, representative sample;
• Potential recruitment/enrollment challenges and strategies that can be implemented in the event of enrollment shortfalls (e.g., additional outreach procedures, alternate/back-up referral sources);
• Evidence to support the feasibility of enrollment, including descriptions of prior experiences and yield from research efforts employing similar referral sources and/or strategies.

II. Study Milestones and Timeline: Applications must provide a clear description of:

• Objective, quantifiable, and scientifically justified study milestones; and
• A proposed timeline for reaching important study milestones such as: (a) finalizing the study procedures and training participating clinical site staff; (b) finalizing the intervention manual and assessment protocols, including fidelity measures/procedures, where applicable; (c) enrolling 25%, 50%, 75% and 100% of the sample; (d) completing all subject follow-up assessments and data collection activities, including data quality checks; (e) analyzing and interpreting results; and (f) preparing de-identified data and relevant documentation to facilitate data sharing, as appropriate. The proposed milestones should describe projected specific, measureable and achievable progress throughout the project period, which can be used as an indicator of success.

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

As appropriate, Senior/Key Personnel should demonstrate their experience and expertise at collaborating with community practice partners/providers, consumers, and relevant policy makers to conduct effectiveness studies.

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: The Research Strategy should include the following information. Applications should not duplicate information provided in the attachment described in Section IV.2, "SF424 (R&R) Other Project Information," unless needed to provide context.

Significance:

• Justify the practical effect of the intervention or service approach in terms of the estimated hypothesized effect size (in terms of key outcomes, such as clinical benefit, safety/tolerability, value and efficiency, or scalability), compared with already available approaches. Address the potential impact of the intervention/service delivery approach in terms of both (1) the empirical basis for the anticipated effect size (e.g., citing data regarding the magnitude of the association between the target and the clinical endpoint of interest and/or effect sizes obtained in prior efficacy studies), and (2) the clinical meaningfulness of the anticipated increment in effects compared to existing approaches.
• Address the degree to which the proposed intervention/service delivery approach is scalable and could be disseminated into practice, given typically available resources (e.g., trained, skilled providers), typical service structures (including MH financing), and typical service use patterns.

Innovation:

• Highlight how innovative research strategies and design/analytic elements (e.g., adaptive sequential randomization, equipoise stratification) are incorporated, as appropriate, in order to enhance the study's potential for yielding practice-relevant information.

Approach:

• Detail the plan to explicitly address whether the intervention engages the mechanism that is presumed to underlie the intervention effects (the mechanism that account for changes in clinical/ functional outcomes, changes in provider behavior, etc.). Include the following: (1) a conceptual framework that clearly identifies the target(s)/mechanism(s) and the empirical evidence linking the target(s)/mechanism(s) to the clinical symptoms, functional deficits, or patient-, provider- or system-level behaviors/processes that the intervention seeks to improve; (2) plans for assessing engagement of the target(s)/mechanism(s) using valid measures that are as direct and objective as is feasible in the effectiveness context, including the specific measures, the assessment schedule, and the justification for the assessment strategy (e.g., evidence regarding the validity and feasibility of the proposed measures in the effectiveness context); and (3) an analytic strategy and corresponding power calculations for data analyses that will be used to examine whether the intervention engages the target(s) and whether intervention-induced changes in the target(s) are associated with clinical benefit (i.e., mediation). In the case of multi-component interventions, the application should specify the conceptual basis, assessment plan, and analytic strategy, as detailed above, for the target(s)/mechanism(s) corresponding to each intervention component, as appropriate in the effectiveness context.
• When appropriate, for studies that involve preventive or therapeutic interventions, detail how the study takes into account RDoC or RDoC-like constructs when defining the subject eligibility (inclusion), intervention targets or mechanisms, and outcomes, as feasible in the effectiveness setting.
• Describe provisions for the assessment and monitoring of the fidelity of intervention delivery via procedures that are feasible and valid for use in community practice settings.
• As appropriate, describe plans to involve collaborations and/or input from community practice partners/providers, consumers, and relevant policy makers in a manner that informs the research and helps to ensure the results will have utility.
• Incorporate outcome measures that are validated and generally accepted by the field, including stakeholder-relevant outcomes (e.g., functioning, health services use), as appropriate.
• As relevant, address how the trial contributes to advancing the personalization of mental health care and describe the collection of clinical and biological variables (e.g., blood for genetic analysis, other potential biomarkers) that might be used to examine moderators or inform/test algorithms for more prescriptive approaches. Address statistical power to test for moderators and/or the potential to contribute information regarding potential moderators to larger databases for future use.
• For studies that involve the assessment of patient-level outcomes, plans are expected that describe the assessment of suicidal behavior and related outcomes using strategies that can facilitate integration and sharing of data (e.g., see NOT-MH-15-009 and https://www.phenxtoolkit.org/ for constructs and corresponding assessment strategies), as appropriate, or provide a rationale for excluding such measures if they are not included. Accordingly, the application should provide the rationale for the selection of suicide-related constructs and corresponding assessment instruments (e.g., measures of ideation, attempts), the time periods assessed (e.g., lifetime history, current), and the assessment schedule for administration (e.g., baseline, during intervention, post-intervention, follow up), taking into account the nature of the target population, participant burden, etc. The application should also address provisions for clinical management when suicidal behavior is reported. In situations where it is not appropriate or feasible to include assessment of suicide outcomes due to the nature of the intervention (e.g., services interventions that target provider behavior or systems-level factors), the target population (e.g., very young children), or unique issues related to participant burden or safety/monitoring concerns, the application should provide an appropriate justification for excluding these assessments.

Protections of Human Subjects: Describe key features of a safety monitoring plan including plans for efficient IRB review and approval including the use of centralized IRB models when multiple clinical sites are planned.

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

In order to advance the goal of widespread data sharing among researchers, investigators funded under this FOA are expected to share those data via the National Database for Clinical Trials related to Mental Illness (NDCT; http://ndct.nimh.nih.gov/; see NOT-MH-14-015 and NOT-MH-15-012). Established by the NIH, NDCT is a secure informatics platform for scientific collaboration and data-sharing that enables the effective communication of detailed research data, tools, and supporting documentation. NDCT links data across research projects through its Global Unique Identifier (GUID) and Data Dictionary technology. Investigators funded under this FOA are expected to use these technologies to submit data to NDCT.

To accomplish this objective, it will be important to formulate a) an enrollment strategy that will obtain the information necessary to generate a GUID for each participant, and b) a budget strategy that will cover the costs of data submission. The NDCT web site provides two tools to help investigators develop appropriate strategies: 1) the NDCT Budgeting Spreadsheet http://ndct.nimh.nih.gov/preplanning/budget - a customizable Excel worksheet that includes tasks and hours for the Program Director/Principal Investigator and Data Manager to budget for data sharing; and 2) plain language text to be considered in your informed consent http://ndct.nimh.nih.gov/preplanning/informed-consent. Investigators are expected to certify the quality of all data generated by grants funded under this FOA prior to submission to NDCT and review their data for accuracy after submission. Submission of descriptive/raw data is expected semi-annually (every January 15 and July 15); submission of all other data is expected at the time of publication, or prior to the end of the grant, whichever occurs first (see Data Sharing Expectation http://ndct.nimh.nih.gov/preplanning/#tab-1 for more information); Investigators are expected to share results, positive and negative, specific to the cohorts and outcome measures studied by using the Study functionality(see http://ndct.nimh.nih.gov/results). The NDCT Data Sharing Plan is available for review on the NDCT web site (http://ndct.nimh.nih.gov/wp-content/uploads/NDCT_Data_Sharing_Policy_20141002.pdf ). NDCT staff will work with investigators to help them submit data types not yet defined in the NDCT Data Dictionary http://ndct.nimh.nih.gov/submit/data-dictionary.

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.

It is strongly recommended that complete intervention protocols and manuals be included in the appendix.

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.

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. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Guidelines for Applicants Experiencing System Issues.

Important reminders:

All PD(s)/PI(s) must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile Component of the SF424(R&R) Application Package. Failure to register in the Commons and to include a valid PD/PI Commons ID in the credential field will prevent the successful submission of an electronic application to NIH. See Section III of this FOA for information on registration requirements.

The applicant organization must ensure that the DUNS number it provides on the application is the same number used in the organization's profile in the eRA Commons and for the System for Award Management. Additional information may be found in the SF424 (R&R) Application Guide.

See more tips for avoiding common errors.

Upon receipt, applications will be evaluated for completeness and compliance with application instructions by the Center for Scientific Review and responsiveness by NIMH, NIH. Applications that are incomplete, non-compliant 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.

Use of Common Data Elements in NIH-funded Research

NIMH encourages the use of common data elements (CDEs) in basic, clinical, and applied research, patient registries, and other human subject research to facilitate broader and more effective use of data and advance research across studies. CDEs are data elements that have been identified and defined for use in multiple data sets across different studies. Use of CDEs can facilitate data sharing and standardization to improve data quality and enable data integration from multiple studies and sources, including electronic health records. NIH ICs have identified CDEs for many clinical domains (e.g., neurological disease), types of studies (e.g. genome-wide association studies (GWAS)), types of outcomes (e.g., patient-reported outcomes), and patient registries (e.g., the Global Rare Diseases Patient Registry and Data Repository). NIH has established a "Common Data Element (CDE) Resource Portal" (http://cde.nih.gov/) to assist investigators in identifying NIH-supported CDEs when developing protocols, case report forms, and other instruments for data collection. The Portal provides guidance about and access to NIH-supported CDE initiatives and other tools and resources for the appropriate use of CDEs and data standards in NIH-funded research. Investigators are encouraged to consult the Portal and describe in their applications any use they will make of NIH-supported CDEs in their projects.

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

Important Update: See NOT-OD-16-006 and NOT-OD-16-011 for updated review language for applications for due dates on or after January 25, 2016.

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.

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 justify the practical effect of the intervention or service approach in terms of the estimated hypothesized effect size (in terms of key outcomes, such as clinical benefit, safety/tolerability, value and efficiency, or scalability), compared with already available approaches? Does the application adequately address both (1) the empirical basis for the anticipated effect size (e.g., citing data regarding the magnitude of the association between the target and the clinical endpoint of interest and/or effect sizes obtained in prior efficacy studies), and (2) the clinical meaningfulness of the anticipated increment in effects compared to existing approaches?

If the approach is successful, is it scalable and could it be disseminated into practice given typically available resources (e.g., trained, skilled providers), typical service structures (including health care financing), and typical service use patterns?

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?

As appropriate, does the trial involve collaborations and/or input from community practice partners/providers, consumers, and relevant policy makers in a manner that informs the research and helps to ensure the results will have utility?

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

Does the design/research plan include innovative elements (e.g., adaptive sequential randomization, equipoise stratification), as appropriate, that enhance its sensitivity and potential for information?

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?

Is the study designed to explicitly address whether the intervention engages the mechanism that is presumed to underlie the intervention effects (the mechanism that accounts for changes in clinical/ functional outcomes, changes in provider behavior, etc.)? Does the application include (1) a well-supported conceptual framework that clearly identifies the target(s)/mechanism(s) and the empirical evidence linking the target(s)/mechanism(s) to the clinical symptoms, functional deficits, or patient-, provider- or system-level behaviors/processes that the intervention seeks to improve; (2) well justified plans for assessing engagement of the target(s)/mechanism(s), including the specific measures, the assessment schedule, and the justification for the assessment strategy (e.g., evidence regarding the validity and feasibility of the proposed measures in the effectiveness context); and (3) an appropriate analytic strategy and corresponding power calculations for data analyses that will be used to examine whether the intervention engages the target(s) and whether intervention-induced changes in the target(s) are associated with clinical benefit (i.e., mediation)? Is the study sufficiently powered to examine mediators of intervention effects? In the case of multi-component interventions, does the application specify the conceptual basis, assessment plan, and analytic strategy, as detailed above, for the target(s)/mechanism(s) corresponding to each intervention component, as appropriate in the effectiveness context?

When appropriate, for studies that involve preventive or therapeutic interventions, does the study take into account RDoC or RDoC-like constructs when defining the subject eligibility (inclusion), intervention targets or mechanisms, and outcomes, as feasible in the effectiveness setting?

Does the application include provisions for the assessment and monitoring of the fidelity of intervention delivery via procedures that are feasible and valid for use in community practice settings?

Are proposed outcome measures validated and generally accepted by the field; are stakeholder-relevant outcomes included, as appropriate (e.g., functioning, health services use)?

Are the trial design and description of the research protocol consistent with CONSORT guidelines , as appropriate?

Will the trial contribute to advancing the personalization of mental health care? Does it include collection of clinical and biological variables (e.g., blood for genetic analysis, other potential biomarkers), as appropriate, that might be used to inform or test algorithms for more prescriptive approaches? Will the study have either adequate statistical power to test for moderators or the potential to contribute information to larger databases for future use?

If the project involves human subjects and/or NIH-defined clinical research, are the plans to address 1) the protection of human subjects from research risks, and 2) inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion or exclusion of children, justified in terms of the scientific goals and research strategy proposed?

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

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

Milestones and Timeline

Is the study timeline described in detail, taking into account start-up activities, the anticipated rate of enrollment, and planned follow-up assessments? Is the project timeline feasible and well justified?

Are appropriate, evaluative milestones clearly defined for the aims associated? Are the milestones feasible and quantifiable with regard to the specific aims and timeline? Are potential challenges and corresponding solutions discussed (e.g., strategies that can be implemented in the event of enrollment shortfalls)?

Does the project incorporate efficiencies and utilize existing resources (e.g. CTSAs, practice-based research networks, electronic medical records, administrative data bases, or patient registries) to increase the efficiency of participant enrollment and data collection, as appropriate?

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.

When the proposed project involves human subjects and/or NIH-defined clinical research, the committee will evaluate the proposed plans for the inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion (or exclusion) of children to determine if it is justified in terms of the scientific goals and research strategy proposed. For additional information on review of the Inclusion section, please refer to the Guidelines for the Review of Inclusion in Clinical Research.

Not Applicable

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

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

Not Applicable

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

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

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

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

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. The proposed milestones may be modified in negotiations with NIMH program officials before an initial award is made, and during the review of annual non-competitive renewal applications. Agreed upon milestones will be included in the Notice of Award, and unmet milestones will be considered in the review and approval of these annual renewals.

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

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

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 Research Performance Progress Report (RPPR) annually 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.

Recruitment Reporting and Trial Registration

NIMH requires reporting of recruitment milestones for participants in clinical trials as noted at https://grants.nih.gov/grants/guide/notice-files/NOT-MH-05-013.html. While trials in response to this FOA may not seek 150 subjects or more (the level at which this reporting has been required), we expect reporting for all trials, even those with less than 150 subjects.

The NIMH expects the registration and results reporting for all NIMH-supported clinical trials in ClinicalTrials.gov, regardless of whether or not they are subject to FDAAA (see https://grants.nih.gov/ClinicalTrials_fdaaa/at-a-glance.htm). We plan to include language regarding this expectation in the notice of grant award.

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

eRA Service Desk (Questions regarding ASSIST, eRA Commons 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)

Finding Help Online: https://grants.nih.gov/support/index.html
Email: [email protected]

Grants.gov Customer Support (Questions regarding Grants.gov registration and submission, downloading forms and application packages)
Contact CenterTelephone: 800-518-4726
Email: [email protected]

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Email: [email protected] (preferred method of contact)

Telephone: 301-710-0267

For Studies involving therapeutic and preventive interventions:

Joel Sherrill, Ph.D.
National Institute of Mental Health (NIMH)
Telephone: 301-443-2477
Email: [email protected]

For Studies involving services interventions:

Denise Juliano-Bult, M.S.W.
National Institute of Mental Health (NIMH)
Telephone: 301-443-1638
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 (NIMH)
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 Part 75.