Part I Overview Information


Department of Health and Human Services

Participating Organizations
National Institutes of Health (NIH), (http://www.nih.gov)

Components of Participating Organizations
National Institute of Mental Health (NIMH), (http://www.nimh.nih.gov)

Title:  Biosignature Discovery for Personalized Treatment in Depression (U01)

Announcement Type
New

Update: The following update relating to this announcement has been issued:

Request For Applications (RFA) Number: RFA-MH-10-040

Catalog of Federal Domestic Assistance Number(s)
93.242

Key Dates
Release Date: September 16, 2009
Letters of Intent Receipt Date:  December 14, 2009
Application Receipt Date:  January 13, 2010
Peer Review Date: March 2010
Council Review Date: May 2010
Earliest Anticipated Start Date: July 1, 2010  
Additional Information To Be Available Date (Url Activation Date): Not Applicable
Expiration Date: January 14, 2010

PRE-APPLICATION TELECONFERENCE (Change of date, now October 1, 2009 - see NOT-MH-09-019)

NIMH will hold a pre-application teleconference on Monday, September 28th from 10:30 am-12:30 pm (EST) to which all prospective applicants are invited. This is a technical assistance teleconference conducted by NIMH staff involved in managing this program to explain the goals and objectives of this initiative and answer questions from the attendees. Participating in the teleconference is neither required nor necessary for a successful application. It is intended to be an opportunity to clarify the objectives of the initiative. Potential applicants are encouraged to submit their questions or comments to biosignatures@mail.nih.gov in advance of the call.  Applicants interested in participating in the technical assistance call should send a message to the mailbox above to obtain a dial in number.

Due Dates for E.O. 12372

Not Applicable

Additional Overview Content

Executive Summary

Table of Contents


Part I Overview Information

Part II Full Text of Announcement

Section I. Funding Opportunity Description
1. Research Objectives

Section II. Award Information
1. Mechanism(s) of Support
2. Funds Available

Section III. Eligibility Information
1. Eligible Applicants
    A. Eligible Institutions
    B. Eligible Individuals
2.Cost Sharing or Matching
3. Other - Special Eligibility Criteria

Section IV. Application and Submission Information
1. Address to Request Application Information
2. Content and Form of Application Submission
3. Submission Dates and Times
    A. Receipt, Review and Anticipated Start Dates
         1. Letter of Intent
    B. Sending an Application to the NIH
    C. Application Processing
   D.  Application Assignment
4. Intergovernmental Review
5. Funding Restrictions
6. Other Submission Requirements

Section V. Application Review Information
1. Criteria
2. Review and Selection Process
    A. Additional Review Criteria
    B. Additional Review Considerations
    C. Resource Sharing Plan(s)
3. Anticipated Announcement and Award Dates

Section VI. Award Administration Information
1. Award Notices
2. Administrative and National Policy Requirements
     A. Cooperative Agreement Terms and Conditions of Award
3. Principal Investigator Rights and Responsibilities
4. NIH Responsibilities
5. Collaborative Responsibilities
6. Arbitration Process
7. Reporting

Section VII. Agency Contact(s)
1. Scientific/Research Contact(s)
2. Peer Review Contact(s)
3. Financial/ Grants Management Contact(s)

Section VIII. Other Information - Required Federal Citations

Part II - Full Text of Announcement


Section I. Funding Opportunity Description


1. Research Objectives

Purpose

The purpose of this funding opportunity announcement (FOA) is to support exploratory research to discover panels of promising potential biomarkers (i.e., biosignatures) that are predictive of treatment outcomes in major depressive disorder (MDD) and to establish a data resource for the genetic study of MDD.  This research is relevant to NIMH’s ultimate goal of developing and testing personalized approaches to the care of mental illness as articulated in NIMH’s Strategic Plan Objective 3 http://www.nimh.nih.gov/about/strategic-planning-reports/index.shtml.

Effective interventions are available for the treatment of depression, but there is considerable individual variation in treatment outcomes.  Many patients do not derive sufficient benefit from the first treatment they receive and require multiple sequentially delivered treatments, or concurrent administration of multiple treatments.  In clinical practice, many patients who do not respond to the first treatment do not return to explore other treatment options that might eventually be effective.

This FOA will advance research on the individualized treatment of depression by systematically assessing panels of promising potential biomarkers of treatment outcomes. To this end, NIMH intends to fund a randomized clinical trial comparing treatment interventions with putatively distinctive mechanisms in a well-characterized cohort of adult patients (age 18-65 years) diagnosed with MDD. 

Background

Despite the heterogeneity in treatment outcomes, treatment guidelines for MDD remain mostly non-specific due to the lack of empirically validated personalized interventions.  Some progress has been made in identifying potential predictors and moderators of treatment outcomes, but no specific algorithm for individualizing care has been developed and tested for efficacy.

This initiative will support the systematic collection, storage, and/or analysis of biomaterials and biological, behavioral, and clinical data as promising biomarkers of treatment outcomes.  Treatment outcomes of interest include both treatment-induced benefits and adverse effects.  There is a particular interest in identifying biomarkers that add predictive value beyond traditional clinical characteristics.

Data collected should cover a range of mechanistic levels; these could include developmental and family history and neurobiological and behavioral measures. Specific and clear hypotheses based on present knowledge and state of technology will be an important component of a successful application. However, because technological and scientific advances are being made at a rapid pace, investigators are encouraged to be forward thinking in their plan for the collection of biomaterials that may be of critical value in the future.  Specifically, whole blood and other biomaterials should be collected and stored (e.g., pre- and post-treatment samples, creation of immortalized cell lines) as a community resource for exploratory analyses to identify pharmacogenetic, epigenomic, metabolomic, proteomic, and/or transcriptomic biomarker profiles related to treatment outcomes in this and in future validation studies by the research community.

The outcomes examined could include overall treatment response, specific treatment-induced benefits, adverse effects, and exploratory endpoints.  The study design should include a systematic search for biological, behavioral, and clinical panels that predict treatment outcomes, especially in the early phase of treatment (days, weeks).  Applications are encouraged from clinical networks capable of rapidly collecting biological, behavioral, and clinical data from large numbers of patients, and that include collaborators with state-of-the-art expertise in advanced technologies for biomarker collection and analyses (e.g., epigenomics, proteomics, metabolomics, transcriptomics).

Research Scope

NIMH intends to fund a randomized clinical trial comparing treatment interventions with putatively distinctive mechanisms.  As an example, such a trial may include a serotonergic antidepressant, a non-serotonergic antidepressant, and psychotherapy.  The study should recruit adult patients to undergo in-depth clinical diagnostic evaluations and provide information on a wide range of potential biomarkers (e.g., biological materials, anatomical and physiological measurements, and behavioral testing).  These well-characterized patients would then be randomly assigned to one of the treatment arms.  A broad set of clinical outcome measures should be included in the trial.  Multivariate statistical analytic approaches should be proposed to evaluate outcomes against baseline assessments to systematically search for clinical and biological predictors and moderators of overall treatment efficacy or adverse events.

The ultimate goal of this initiative is to identify a personalized treatment algorithm to be tested in a future clinical validation trial.  While responsive applications are expected to be primarily exploratory in nature, applicants are expected to justify the choice of each proposed biomarker based on available technologies, existing data, and scientific rationale.  It is expected that there will be both theoretical and empirical support for the initial set of biomarkers to be studied; applicants are also encouraged to be efficient and flexible in their experimental design so as to permit expansion of data collection and/or analysis based on feedback from the NIMH Project Team and Implementation Working Group.   The NIMH Project Team is a team of senior extramural NIMH staff with expertise and experience in clinical trial design and implementation, genetic, behavioral, and clinical biomarker technology, and database coordination.  The Implementation Working Group will consist of 6-8 senior scientists who will be asked to give guidance on the final study design as well as reviewing and monitoring progress.  See further details in Section VI.2.A Cooperative Agreement Terms and Conditions of Award.  

The population for investigation will consist of patients (age 18-65 years) with MDD.  Applicants should fully describe the patient sample that will be appropriate for this biomarker discovery trial.  Applicants should consider and justify the clinical co-morbidities included or excluded in this study.  Because the goal is to identify biomarkers that will be predictive in a real-world population and useful for individualized clinical decision-making, some heterogeneity in the subject population is to be expected.

The sample sizes in this study should be large enough to allow sufficient statistical power for discriminating between treatment modalities on primary clinical indicators and for conducting informative explorative analyses of potential predictors and moderators of treatment outcomes.  In addition to addressing such variables in the context of group differences, the sensitivity and specificity for predicting variance in individual cases should be considered.  Applications should include specific power analyses and justifications where appropriate.

A case may be made to include smaller contrast groups of normal subjects or unaffected relatives for baseline comparisons to discriminate stable/trait markers of depressive illness from those markers that would change in a predictable fashion with treatment.  In order to maximize resources, applicants should consider whether there are cost-efficient study randomization/stratification designs that may not require collection of all assessments from all subjects.

Research Design

This initiative will support a biomarker discovery trial to set the stage for future validation studies by a broader group of investigators to test combinations of biomarker panels as predictive indicators of clinical response, differential response to specific treatments, or adverse effects.  Therefore, the current trial should be designed to capture a wide range of potential biomarkers within a fairly compressed time frame.  Approximately 6 months should be allotted at the beginning of the project period for final modifications to the design and scope of the study.  These modifications will be discussed and agreed upon by the selected investigative team, NIMH staff, and an external Implementation Working Group established by NIMH.

The clinical trial itself should be initiated during the second half of the first year of the project. The expectation is that data collection and preliminary analyses will be accomplished during Years 2 and 3.  The fourth year can then be utilized for: exploratory analyses of samples collected during the course of the trial; bioinformatics analyses to identify which biological, behavioral, or clinical variables or combinations of variables predict treatment outcomes; empirical development of algorithms to inform personalized treatment; and dissemination of results and broad sharing of data generated by this initiative to drive the design of future validation studies.

Biological, Behavioral, and Clinical Measures

In this FOA, “biomarker panels” or “biosignatures” refers to reliable, quantifiable measures gathered across time that assess validated phenotypes associated with MDD.  The biomarker panels are dynamic, not static, and can potentially capture phases of the disease from pre-clinical to post-treatment.  Variables could include assessment of clinical symptoms or functional domains of function (e.g., properties of the neural circuitry and/or molecular mechanisms underlying core clinical components, biochemical or physiological measures), and exploratory biomarkers.

Examples of variables that applicants might consider collecting and/or exploring at baseline and at specific time points during treatment include, but are not limited to:

It is anticipated that a number of clinical variables will be included in the study database, to be analyzed as potential predictors and moderators of treatment outcomes in conjunction with the behavioral and biological markers.  It is anticipated that, while certain markers may have predictive value that is specific in nature, a panel of bio-behavioral-clinical markers (biosignature) will ultimately be most informative.

Behavioral tasks used for assessment purposes should have demonstrated reliability and their relevance to mechanisms underlying depression should be clearly justified. For behavioral testing and imaging data collection, it would be acceptable if a subset of the subjects undergo imaging, as long as all subjects are tested behaviorally on the cognitive and /or affective tasks.  To promote utility in the field, it would be advantageous if the tasks and measurements included are ultimately transportable to clinical settings.  

It is incumbent on the applicant to provide the rationale and justification for all proposed potential biomarkers and treatment interventions based on the state-of-the-science of the pathogenesis and treatment of MDD.

For the successful applicant, the variables to be measured may be expanded or otherwise modified in consultation with NIMH staff and/or an implementation working group once the application is funded, but prior to the commencement of the trial.

See Section VIII, Other Information - Required Federal Citations, for policies related to this announcement.

Section II. Award Information


1. Mechanism of Support

This funding opportunity will use the NIH Cooperative Agreement (U01) award mechanism.  In the cooperative agreement mechanism, the Project Director/Principal Investigator (PD/PI) retains the primary responsibility and dominant role for planning, directing, and executing the proposed project, with NIH staff being substantially involved as a partner with the Principal Investigator, as described under the Section VI. 2. Administrative Requirements, "Cooperative Agreement Terms and Conditions of Award.”

This FOA uses “Just-in-Time” information concepts. It also uses the non-modular budget formats described in the PHS 398 application instructions (see http://grants.nih.gov/grants/funding/phs398/phs398.html).

2. Funds Available

NIMH expects to commit approximately $6 million in total costs in Fiscal Year 2010 to fund one or more applications in response to this FOA.  The total project period and costs for an application submitted in response to this FOA may not exceed four years or $6 million total costs per year, which will include facilities & administrative costs by consortium participants

Because the nature and scope of the proposed research will vary from application to application, it is anticipated that the size and duration of each award will also vary. Although the financial plans of the NIMH provide support for this program, awards pursuant to this funding opportunity are contingent upon the availability of funds and the receipt of a sufficient number of meritorious applications.

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.

Section III. Eligibility Information


1. Eligible Applicants

1.A. Eligible Institutions

The following organizations/institutions are eligible to apply:

Foreign institutions are not eligible to apply. However, investigators from Foreign institutions may participate (under subcontractual arrangements) on an application submitted by a PI from an eligible institution within the U.S.

1.B. Eligible Individuals

Any individual with the skills, knowledge, and resources necessary to carry out the proposed research as the PD/PI is invited to work with his/her institution 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.

More than one PD/PI, or multiple PDs/PIs, may be designated on the application for projects that require a “team science” approach and therefore clearly do not fit the single-PD/PI model. Additional information on the implementation plans, policies and procedures to formally allow more than one PD/PI on individual research projects is available at http://grants.nih.gov/grants/multi_pi. All PDs/PIs must be registered in the NIH eRA Commons prior to the submission of the application (see http://era.nih.gov/ElectronicReceipt/preparing.htm for instructions).

The decision of whether to apply for a grant with a single PD/PI or multiple PDs/PIs is the responsibility of the investigators and applicant organizations, and should be determined by the scientific goals of the project. Applications for grants with multiple PDs/PIs will require additional information, as outlined in the instructions below. When considering multiple PDs/PIs, please be aware that the structure and governance of the PD/PI leadership team as well as the knowledge, skills and experience of the individual PDs/PIs will be factored into the assessment of the overall scientific merit of the application.  Multiple PDs/PIs on a project share the authority and responsibility for leading and directing the project, intellectually and logistically. Each PD/PI is responsible and accountable to the grantee organization, or, as appropriate, to a collaborating organization, for the proper conduct of the project or program, including the submission of required reports. For further information on multiple PDs/PIs, please see http://grants.nih.gov/grants/multi_pi.

2. Cost Sharing or Matching

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

3. Other-Special Eligibility Criteria

Number of Applications. Applicants may submit more than one application, provided they are scientifically distinct.

Resubmissions.  Resubmission applications are not permitted in response to this FOA. 

Renewals.  Renewal applications are not permitted in response to this FOA.  

Section IV. Application and Submission Information


1. Address to Request Application Information

The PHS 398 application instructions are available at http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format. Applicants must use the currently approved version of the PHS 398. For further assistance contact GrantsInfo, Telephone (301) 435-0714, Email: GrantsInfo@nih.gov.

Telecommunications for the hearing impaired: TTY 301-451-5936.

2. Content and Form of Application Submission

Applications must be prepared using the most current PHS 398 research grant application instructions and forms. Applications must have a D&B Data Universal Numbering System (DUNS) number as the universal identifier when applying for Federal grants or cooperative agreements. The D&B number can be obtained by calling (866) 705-5711 or through the web site at http://www.dnb.com/us/. The D&B number should be entered on line 11 of the face page of the PHS 398 form.

The title and number of this funding opportunity must be typed in item (box) 2 only of the face page of the application form and the YES box must be checked.

SPECIAL INSTRUCTIONS

Applications with Multiple PDs/PIs 

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

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

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

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

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

Additional information is available in the PHS 398 grant application instructions.

3. Submission Dates and Times

Applications must be received on or before the receipt date described below (Section IV.3.A). Submission times N/A.

3.A. Receipt, Review and Anticipated Start Dates
Letters of Intent Receipt Date:  December 14, 2009
Application Receipt Date:  January 13, 2010
Peer Review Date:  March 2010
Council Review Date:  May 2010
Earliest Anticipated Start Date:  July 1, 2010

3.A.1. Letter of Intent

Prospective applicants are asked to submit a letter of intent that includes the following information:

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.

The letter of intent is to be sent by the date listed in Section IV.3.A.

The letter of intent should be sent to:

Benedetto Vitiello, M.D.
Division of Services and Intervention Research
National Institute of Mental Health
6001 Executive Boulevard, Room 7147, MSC 9633
Bethesda, MD 20892-9633
Telephone:  (301) 443-3357
Email: bvitiell@mail.nih.gov

3.B. Sending an Application to the NIH

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

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

Personal deliveries of applications are no longer permitted (see http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-040.html).

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

Jean G. Noronha, Ph.D.
Division of Extramural Activities
National Institute of Mental Health
6001 Executive Boulevard, Room 6154, MSC 9609
Bethesda, MD  20892-9609
Rockville, MD  20852 (for express/courier service)
Telephone:  (301) 443-3367
FAX:  (301) 443-4720
Email:  jnoronha@mail.nih.gov

3.C. Application Processing

Applications must be received on or before the application receipt date described above (Section IV.3.A.). If an application is received after that date, the application may be delayed in the review process or not reviewed.  Upon receipt, applications will be evaluated for completeness by the CSR and for responsiveness by the reviewing Institute Incomplete and/or non-responsive applications will not be reviewed.

The NIH will not accept any application in response to this funding opportunity that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. However, when a previously unfunded application, originally submitted as an investigator-initiated application, is to be submitted in response to a funding opportunity, it is to be prepared as a NEW application. That is, the application for the funding opportunity must not include an Introduction describing the changes and improvements made, and the text must not be marked to indicate the changes from the previous unfunded version of the application.

Information on the status of an application should be checked by the Principal Investigator in the eRA Commons at: https://commons.era.nih.gov/commons/.

4. Intergovernmental Review

This initiative is not subject to intergovernmental review.

5. Funding Restrictions

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

Pre-award costs are allowable. A grantee may, at its own risk and without NIH prior approval, incur obligations and expenditures to cover costs up to 90 days before the beginning date of the initial budget period of a new award if such costs: 1) are necessary to conduct the project, and 2) would be allowable under the grant, if awarded, without NIH prior approval. If specific expenditures would otherwise require prior approval, the grantee must obtain NIH approval before incurring the cost. NIH prior approval is required for any costs to be incurred more than 90 days before the beginning date of the initial budget period of a new award.

The incurrence of pre-award costs in anticipation of a competing or non-competing award imposes no obligation on NIH either to make the award or to increase the amount of the approved budget if an award is made for less than the amount anticipated and is inadequate to cover the pre-award costs incurred. NIH expects the grantee to be fully aware that pre-award costs result in borrowing against future support and that such borrowing must not impair the grantee's ability to accomplish the project objectives in the approved time frame or in any way adversely affect the conduct of the project (see NIH Grants Policy Statement http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part6.htm.)

6. Other Submission Requirements

The objectives and goals for the proposed study should be relevant to and compatible with the scientific priorities stated in the Research Objectives section of this funding opportunity.  Applicants should describe their plans to accommodate stated requirements, criteria, and NIMH involvement.  The research teams that respond to this FOA are expected to include outstanding scientists with diverse expertise relevant to achieving the study’s aims, such as experience conducting clinical trials research (including genetic and/or neurobiological approaches where appropriate), with exceptional data management and analysis skills, and with appropriate statistics/biostatistics resources.  Evidence of expertise in these areas must be documented in the research grant application.

Follow the PHS 398 Instructions for preparing an application (PHS 398 grant application instructions).  In addition, provide the following:  an Overview/General Approach section prior to the Research Plan. 

Research Plan, Including Page Limitations

In combination, the Overview/General Approach and Research Plan components of the research section must not exceed 40 pages.

Specific issues to be addressed in the General Approach and Research Plan components of the application are presented below.

Overview/General Approach

This section should not exceed 10 pages and should provide the following details:

The overview should describe the project’s general approach to conducting the research.  It should demonstrate the applicants’ mastery of the extant literature relating to mechanisms and treatment of MDD, clinical trials research, diverse materials and methods for selecting and analyzing biological materials, and multi-disciplinary approaches to the evaluation of biomarkers.

Research Plan

The research plan should describe (a) the specific aims, goals, and objectives of the project, (b) background and significance, (c) the status of current research efforts (preliminary studies), and (d) the research design and methods proposed for the investigation.  Please refer to specific sub-sections listed below when preparing the research design and methods section.  In addition, the applicant should discuss the advantages of new methodologies or technological advances (if any), alternative approaches, and the feasibility of the proposed research. 

Justification of biomarkers: Detailed attention should be given to the applicants’ selection of potential biomarkers and to the analyses required for biomarkers with the most promise.  Study design should specify details about the expertise, and capacity for biomarker data collection at individual sites.

Sample collection, handling, and storage: Whole blood and biomaterials should be collected and stored for future analyses.  The applicants are expected to submit a data sharing plan that addresses how all data (genotypes and phenotypes) would be available to meet the program goal of establishing a global resource for the genetic study of mental disorders in the NIMH Human Genetics Initiative (http://nimhgenetics.org/).

Data sharing: To meet the program goals of this project, an explicit plan for rapid and broad sharing of all de-identified biomarker, clinical, and other primary data generated in this project would be needed to permit analyses by the wider scientific community (see below).

Justification of sample: Detailed attention should be given to patient characteristics, characteristics of the diagnosis, sample size, and appropriate power calculations.

Justification of sites: Detailed attention should be given to the human and technical resources available at each site and their appropriateness to the study design.  In addition, the number of sites proposed and the ability/track record of the sites individually and collectively to enroll the appropriate type of subjects within the project timeframe should be detailed.

Data analysis/Outcomes of interest: Investigators should describe feasible and scientifically appropriate methods for assessing empirical relationships between treatment outcomes and biomarkers, including those that would be expected to remain stable regardless of depression status (e.g., in episode or remitted) and those that would be expected to change during the course of treatment in a manner that might parallel improvement in mood, cognition, and behavior.  Clinical outcomes should be assessed with contemporary psychometric and measurement methods.  Behavioral, anatomical and physiological measures should have demonstrated reliability.  Bioanalytical/statistical expertise appropriate to this type of hypothesis driven/exploratory research and complex data sets must be demonstrated.

Inclusion of a Coordinating Center and Data Center: Detailed attention should be given to selection of the administrative and scientific Coordinating Center and the study Data Center (if different than the Coordinating Center).  Experience in coordinating large multisite clinical trials, experience with the full range of biological and clinical measures to be collected, experience in establishing databases, and experience in ensuring appropriate training and monitoring of study progress should be detailed.

Processes for maintaining collaboration: A plan to assure the maintenance of close collaboration and effective communication among members of the multisite research team should be included.  Letters of commitment to this plan by all key personnel at each of the proposed sub-contract sites should be included.  Include plans for:  scheduling Steering Committee meetings (two per year) and monthly conference calls; communicating with group members, the NIMH (including Project Scientists, Program Official, and the Project Team), and the Implementation Working Group members; and documenting and disseminating group meeting proceedings.

Awardees must agree to the "Cooperative Agreement Terms and Conditions of Award" in Section VI.2.A "Award Administration Information."

Appendix Materials

All paper PHS 398 applications submitted must provide appendix material on CDs only. See http://grants.nih.gov/grants/guide/notice-files/NOT-OD-08-031.html.

Include five identical CDs in the same package with the two applications sent to Jean Noronha in the NIMH Division of Extramural Activities. 

Do not use the Appendix to circumvent the page limitations of the Research Plan component. An application that does not observe the required page limitations may be delayed in the review process.

Resource Sharing Plan(s)

NIH considers the sharing of unique research resources developed through NIH-sponsored research an important means to enhance the value of, and advance research. When resources have been developed with NIH funds and the associated research findings published or provided to NIH, it is important that they be made readily available for research purposes to qualified individuals within the scientific community. If the final data/resources are not amenable to sharing, this must be explained in Resource Sharing section of the application. See http://grants.nih.gov/grants/policy/data_sharing/data_sharing_faqs.htm.

(a) Data Sharing Plan: Regardless of the amount requested, investigators are expected to include a brief 1-paragraph description of how final research data will be shared. Applicants are encouraged to discuss data-sharing plans with their NIH program contact. See Data-Sharing Policy or http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-032.html.

Plan for Sharing of Biomarker Data and Clinical Trials DatasetsThe biomarker data and biomaterials generated in this project will constitute a national scientific resource for the research community, and should be made available to the research community no more than 6 months after the last subject’s study visit has been completed.  It is expected that all genetic data generated in this project (i.e., DNA, immortalized cell lines, genotypes, phenotypes) will be made part of a global resource for the genetic study of mental disorders through the NIMH Human Genetics Initiative (http://nimhgenetics.org/). It is anticipated that public access to the clinical trial data will be accomplished by preparation of well-documented de-identified dataset(s) consisting of all data obtained.  It is anticipated that the study data management team will be responsible for preparation of these dataset(s) according to guidelines provided by NIMH Project Scientist(s), Program Official, and Project Team members for organization, documentation, and preservation of participant privacy.  It is expected that the clinical trial datasets will reside with the biomarker datasets (e.g., biochemical, genetic, imaging, physiological, behavioral data) and biomaterials through existing databases (e.g., http://ndg.sfn.org/; http://ndg.sfn.org/eavXSearch.aspx?db=10&cl=81). 

Prior to award, the PD/PI and NIMH will develop and finalize a data sharing agreement that will specify timelines and criteria for:  rapid deposition of data and biomaterials generated in this project; access to de-identified data; conditions for research use; and procedures for vetting requests for access to biomaterials and primary data maintained in the data coordinating center and/or other NIH or public databases.  It is further anticipated that the timelines, criteria, and procedures for access to the dataset(s) and biomaterials generated in this project will be further developed and finalized with the PI/PD(s) and NIMH Project Scientist(s) and Program Official and specified in the data sharing agreement.

(b) Sharing Model Organisms: Regardless of the amount requested, all applications where the development of model organisms is anticipated are expected to include a description of a specific plan for sharing and distributing unique model organisms and related resources, or state appropriate reasons why such sharing is restricted or not possible. See Sharing Model Organisms Policy, and NIH Guide NOT-OD-04-042.

(c) Genome-Wide Association Studies (GWAS): Regardless of the amount requested, applicants seeking funding for a genome-wide association study are expected to provide a plan for submission of GWAS data to the NIH-designated GWAS data repository, or provide an appropriate explanation why submission to the repository is not possible.  A genome-wide association study is defined as any study of genetic variation across the entire genome that is designed to identify genetic associations with observable traits (such as blood pressure or weight) or the presence or absence of a disease or condition.  For further information see Policy for Sharing of Data Obtained in NIH Supported or Conducted Genome-Wide Association Studies, NIH Guide NOT-OD-07-088, and http://grants.nih.gov/grants/gwas/.

Section V. Application Review Information


1. Criteria

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

2. Review and Selection Process

Applications that are complete and responsive to the FOA will be evaluated for scientific and technical merit by an appropriate peer review group convened by the NIMH in accordance with NIH peer review procedures (http://grants1.nih.gov/grants/peer/), using the review criteria stated below.

As part of the scientific peer review, all applications will:

The following will be considered in making funding decisions:

The mission of the NIH is to support science in pursuit of knowledge about the biology and behavior of living systems and to apply that knowledge to extend healthy life and reduce the burdens of illness and disability.  As part of this mission, applications submitted to the NIH for grants or cooperative agreements to support biomedical and behavioral research are evaluated for scientific and technical merit through the NIH peer review system. 

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

Core Review Criteria.  Reviewers will consider each of the five review criteria below in the determination of scientific and technical 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 this study identify potentially significant biomarkers to explore? If the aims of the application are achieved, how will scientific knowledge about biomarker panels (biosignatures) be advanced?  What will be the effect of these studies on the design of future validation trials of biomarkers for personalizing treatment of MDD?

Investigator(s).  Are the PD/PIs, collaborators, and other researchers well suited to the project?  If Early Stage Investigators or New Investigators, 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? Is there an appropriate level of bioanalytical/biostatistical expertise to manage the complex data sets?  Are the Coordinating and Data Centers appropriately experienced to successfully carry out this multisite clinical trial, including instrument and database development, cross-site training and reliability, site monitoring, etc.?  Does the research team have the expertise, to collect, manage, and analyze the required biological samples, biological and behavioral measurements, neuroanatomical, and/or physiological data, and standardized clinical evaluations?  Are appropriately trained clinicians available to deliver both pharmacological and psychotherapeutic treatments with respect to random assignment?  Do the applicants provide evidence of expertise in implementing and conducting a large multi-site clinical trial, given the complex data collection, data analysis and remote and centralized data management systems?

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?  In addition, does the project explore previously under-studied potential biomarkers? Does the project address an innovative hypothesis or critical barrier to progress in the field of biomarker discovery?  Does the project extend beyond already known subgroup analyses of patients treated for MDD?

Approach.  Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project?  Has the trial been designed to reduce the impact of placebo effect?  Are potential problems, alternative strategies, and benchmarks for success presented?   If the project is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed? If the project involves clinical research, are the plans for 1) protection of human subjects from research risks, and 2) inclusion of minorities and members of both sexes/genders, as well as the inclusion of children, justified in terms of the scientific goals and research strategy proposed?

Is the duration of the trial adequate for assessing the prediction of clinically relevant outcomes?  It is expected that the treatment trial will last at least 12 weeks.  Is a plan included to allow for longer term follow up beyond the project period, contingent on the availability of future funds?  Do the applicants include a data analysis plan that describes the approach to estimate the predictive value of individual biological, behavioral, or clinical variables of interest and of combinations of variables?  Is the risk of false positive results in this largely exploratory research adequately addressed? Are the number of and appropriateness of the clinical sites used to recruit the study sample as well as sites that might be included for specialized expertise (e.g., a data analysis center or a highly skilled neurophysiology lab) adequately justified?  Do the applicants provide evidence that a sufficiently large sample can be recruited within the project’s three-year time frame for recruitment and data collection, and that the subjects will accept treatment randomization? For the behavioral tasks used for assessment purposes do the applicants demonstrate reliability and clearly justify their relevance to mechanisms underlying depression?  Do the applicants provide the rationale and justification for all proposed potential biomarkers and treatment interventions based on the state-of-the-science of the pathogenesis and treatment of MDD?

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?  Are the proposed clinical sites appropriate for this study?  Do the proposed clinical sites have a track record for meeting or exceeding recruitment targets?  Do the proposed clinical sites have a track record for separating drug response from placebo?  Does the scientific environment of each subcontract, if present, provide a compelling justification for the need to be included in the U01?

Additional Review Criteria.  As applicable for the project proposed, reviewers will consider the following additional items in the determination of scientific and technical merit, but will not give separate scores for these items.

Management of the Project. Does the PD/PI’s management plan ensure that there will be sufficient coordination and communication among the members of the U01 for this project, including collaborating clinical site(s), consortia, and/or coordinating/data center(s), and resolving conflicts?  Are there adequate plans for ensuring effective intra-Group collaboration, effective communication, and coordination among the PI/PD, Key Personnel, NIMH Project Scientists, and Implementation Working Group?  Are plans included for scheduling Steering Committee meetings and conference calls, notifying group members, and documenting and disseminating group meeting proceedings?  Were letters of commitment to this plan supplied by all key personnel?

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.

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.

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.

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

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

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 (http://grants.nih/gov/grants/policy/data_sharing/data_sharing_guidance.htm) including the Plan for Sharing of Biomarker Data and Clinical Trials Datasets (detailed above); 2) Genome Wide Association Studies (GWAS) (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-07-088.html).

3. Anticipated Announcement and Award Dates

Not applicable.

Section VI. Award Administration Information


1. Award Notices

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.

If the application is under consideration for funding, NIH will request "just-in-time" information from the applicant. For details, applicants may refer to the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General.

A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant organization. The NoA signed by the grants management officer is the authorizing document. Once all administrative and programmatic issues have been resolved, the NoA will be generated via email notification from the awarding component to the grantee business official.

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. See Also Section IV.5. Funding Restrictions.

2. Administrative and National Policy Requirements

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 (http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part4.htm) and Part II Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Grantees, and Activities (http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_part9.htm).

The following Terms and Conditions will be incorporated into the award statement and will be provided to the Principal Investigator as well as to the appropriate institutional official, at the time of award.

2.A. Cooperative Agreement Terms and Conditions of Award

The following special terms of award are in addition to, and not in lieu of, otherwise applicable OMB administrative guidelines, HHS grant administration regulations at 45 CFR Parts 74 and 92 (Part 92 is applicable when State and local Governments are eligible to apply), and other HHS, PHS, and NIH grant administration policies.

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

2.A.1. Principal Investigator Rights and Responsibilities

a. PI/PD will have the primary authority and responsibility to define objectives and approaches and to plan and conduct the proposed study.  The PI/PD will assume responsibility and accountability to the applicant organization and to the NIMH for performance and proper conduct of the research supported in accordance with the Terms and Conditions of Award. 

b. The awardee Institution will retain primary custody of and rights to the data and software developed under these awards, subject to Government rights of access consistent with current HHS, PHS, and NIH policies; however, data will be put into the public domain no more than 6 months after the last subject’s last study visit as specified under the data sharing and research resource sharing plans (also see below).  The Government, via the NIMH Project Scientist(s), will have access to primary data generated under this cooperative agreement and may periodically review the data, consistent with current DHHS, PHS, and NIH policies.

The data from this cooperative agreement will be analyzed and interpreted first by the collaborators in the project.  However, since the biomarker datasets and biomaterials generated in this project constitute a national scientific resource for the research community, the biomarker datasets and biomaterials should be made available to the research community no more than 6 months after the last subject’s study visit has been completed.  It is expected that all genetic data generated in this project (i.e., DNA, immortalized cell lines, genotypes, phenotypes) will be made part of a global resource for the genetic study of mental disorders through the NIMH Human Genetics Initiative (http://nimhgenetics.org/). It is anticipated that public access to the clinical trial data will be accomplished by preparation of well-documented de-identified dataset(s) consisting of all data obtained. 

It is anticipated that the study data management team will be responsible for preparation of these dataset(s) according to guidelines provided by NIMH Project Scientist(s), Program Official, and Project Team members for organization, documentation, and preservation of participant privacy.  It is expected that the clinical trial datasets will reside with the physical biomarker datasets and biomaterials. Prior to award, to meet the goals of the program, the PD/PI and NIMH will develop and finalize a data sharing agreement that will specify timelines and criteria for: rapid deposition of data and biomaterials generated in this project; access to de-identified data; conditions for research use; and procedures for vetting requests for access to biomaterials and primary data maintained in the data coordinating center and/or other NIH or public databases.  It is further anticipated that the timelines, criteria, and procedures for access to the dataset(s) and biomaterials generated in this project will be further developed and finalized with the PI/PD(s) and NIMH Project Scientist(s) and Program Official and specified in the data sharing agreement.

c. The PI/PD will be responsible for planning and participating collaboratively with NIMH under this cooperative agreement.  Through participation in meetings of the Steering Committee (of which the PI is a voting member and as defined below) for this project and conference calls, the awardees will work with the NIMH Project Scientist(s), the NIMH Project Team, and the Implementation Working Group (both groups defined below) to finalize the study design, to finalize the collection of specific biomarker panels and biomaterials, to play a key role in the development and implementation of a protocol, and in the establishment of quality control, monitoring and reporting procedures.

d. Given the scale and scope of this project, and the likely size and diversity of the research team, the PI should establish a transparent process for proposing and developing scientific manuscripts, including appropriate mechanisms for determining authorship, in consultation with the co-investigators and the project Steering Committee.  

2.A.2. NIH Responsibilities

The NIMH Project Scientist(s) will have substantial programmatic involvement that is above and beyond the normal stewardship role in awards, as described below.

a. The Project Scientist(s) will have scientific involvement in the conduct of this research activity, through membership on the Steering Committee, described further below. The Project Scientist(s) interacts scientifically with the Steering Committee and may provide appropriate assistance, including assisting in research planning, suggesting studies within the scope of the study’s objectives and research activities, presenting experimental findings to the Steering Committee from published sources, relevant NIMH and FNIH Biomarker Consortium programs, or from relevant NIMH contract projects.

b. The Project Scientist(s) will serve as a voting member of the Steering Committee.

c. The Project Scientist(s) will ensure that the scientific goals of NIMH are reflected in the design of experiments agreed to by the Steering Committee, participating in the analysis and reporting of results, and advising in management and technical performance.

d. In all cases, the role of NIMH Project Scientist(s) will be to assist and facilitate and not to direct activities. 

The NIMH Project Team, a team of senior extramural NIMH staff with expertise and experience in clinical trial design and implementation, genetic, behavioral, and clinical biomarker technology, and database coordination, will assist in overseeing progress and coordination of the biomarker studies for this project. 

The project will be reviewed by the NIMH Data and Safety Monitoring Board (DSMB) to ensure the safety of participants and the validity and integrity of the data.  The study protocol(s) and consent form(s) will be reviewed by the NIMH DSMB prior to initiation of the project.  Study data will be reviewed by the NIMH DSMB according to the Board’s review schedule, currently three times per year, at approximately 4-month intervals. The DSMB is an independent panel of experts in clinical trials that are appointed by NIMH to monitor multisite trials that are conducted under cooperative agreements or contract mechanisms.  The DSMB will receive a report from the study data management and statistical center usually about 4-6 weeks before each review date.  The study team’s submission to the DSMB is expected to follow the established reporting format and template that will be provided to the data management/statistical team.  It is expected that NIMH DSMB procedures for presenting data to the Board will be followed and that NIMH staff will represent the study to the Board.  In general, the report will include the major variables necessary for monitoring subject enrollment and retention, safety, quality of data collection, and integrity of the study.  Based on its review, the DSMB has the authority to prevent the study from starting or to stop the study after it has started.

In addition to the NIMH Project Scientist(s), an Institute Program Official will be named in the award notice.  The Program Official will be responsible for the normal scientific and programmatic stewardship of the award, including monitoring implementation of the subject recruitment plan and data and research resource sharing plans and will be an ex officio (non-voting) member of the Steering Committee.  

2.A.3. Collaborative Responsibilities

A Steering Committee composed of the PD/PI, Research Project Leaders, NIMH Project Scientist(s), NIMH Program Official, member of the NIMH Project Team, will be established to serve as the governing board for the award. 

The Steering Committee will have overall responsibility for the study and will make modifications in the protocols, as necessary.  The NIMH Project Scientist(s) will have a single vote on the project Steering Committee; the NIMH Program Official and NIMH Project Team representative will be non-voting members.  Each key investigator in the grant will have one vote, as agreed and specified in detail after the grant is awarded.  Other personnel deemed relevant by the PD/PI and NIMH may be added to the Steering Committee after the project’s inception. 

The project Steering Committee will collaboratively establish by-laws that specify the functioning of the Steering Committee, possible need for subcommittees, or workgroups for specific tasks, and publication and authorship policies.  The NIMH Project Scientist(s) may not chair any committee or subcommittee.  Decisions will be made by majority vote of a quorum, with an attempt for consensus when possible.  PI/PD members of the Steering Committee will be required to accept and implement policies approved by the Steering Committee.  Any project Steering Committee member who considers a committee decision unacceptable may appeal by following the arbitration procedure described below. 

The Steering Committee members will meet not fewer than twice per year and will hold monthly conference calls, as needed for the duration of the study.  The PD/PI will be responsible for scheduling the time and place, notifying group members including the NIMH Project Scientist(s) and Program Official, and for preparing concise proceedings or minutes which will be disseminated to members of the Group within 14 days of the meeting or conference call.  Each full member will have one vote.

Responsibilities of the Steering Committee members include:

a.     Collaboratively finalizing the study plan, including design, assessment instruments, biomarker and biomaterials component protocols, detailed implementation procedures, and data sharing and data analysis plans.

b.     Abiding by and directing the study plan agreed to by the project Steering Committee taking into account the recommendations of the NIMH Project Scientist(s), NIMH Project Team, and Implementation Working Group.

c.     Monitoring the study and developing and implementing quality control procedures.

d.     Conserving grant funds in the service of the common objectives and of the research plan agreed on by the project Steering Committee.

e.     Facilitating the analysis of data and the rapid data release to the scientific community (see data sharing and research resource sharing plans described above); submitting data on time in the form and on the schedule agreed to by the Steering Committee.

f.      Evaluating and reporting study results: defining rules regarding access to data and publication of findings from analyses of the data set.

The Implementation Working Group:  An Implementation Working Group will be responsible for making recommendations about the final design of the clinical trials and exploratory biomarker studies, providing ongoing direction for collection, handling, and storage of biomarker data and biomaterials for the program, and for reviewing and monitoring progress over time. The group will consist of 6-8 senior scientists who are not directly involved in the project.  The NIMH Project Team will appoint members to the Implementation Working Group.

Progress Reviews.  Progress of the project will be reviewed by the NIMH Project Scientist(s), Program Official, Project Team, and the Implementation Working Group at the annual Steering Committee meeting and at the time of each continuation application to assure that satisfactory progress is being made in achieving the project objectives, especially with respect to enrollment, collection, handling, and storage of biomarker data and biomaterials for the program, and that the site(s) are following the procedures and analyses recommended and approved by the Steering Committee.

2.A.4. Dispute Resolution

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

By acceptance of these awards, the awardees agree to abide by decisions and policies of the project Steering Committee and the other terms and conditions listed above or referenced in the Notice of Grant Award.

3. Reporting

Awardees will be required to submit the Non-Competing Continuation Grant Progress Report (PHS 2590) annually and financial statements as required in the NIH Grants Policy Statement.

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

Section VII. Agency Contacts


We encourage your inquiries concerning this funding opportunity and welcome the opportunity to answer questions from potential applicants. Inquiries may fall into three areas: scientific/research, peer review, and financial or grants management issues:

1. Scientific/Research Contacts:

Benedetto Vitiello, M.D.
Division of Services and Intervention Research
National Institute of Mental Health
6001 Executive Boulevard, Room 7147, MSC 9633
Bethesda, MD 20892-9633
Telephone:  (301) 443-3357
Email: bvitiell@mail.nih.gov

Linda Brady, Ph.D.
Division of Neuroscience and Basic Behavioral Science
National Institute of Mental Health
6001 Executive Boulevard, Room 7204, MSC 9632
Bethesda, MD 20892-9632
Telephone: (301) 443-3563
Email: lbrady@mail.nih.gov

Margaret Grabb, Ph.D.
Division of Developmental Translational Research
Division of Neuroscience and Basic Behavioral Science
National Institute of Mental Health
6001 Executive Boulevard, Room 7201, MSC 9645
Bethesda, MD 20892-9645
Rockville, MD 20852 (for express or courier service)
Telephone: (301) 443-3563
Email: mgrabb@mail.nih.gov

Mi Hillefors, M.D., Ph.D.
Division of Adult Translational Research and Treatment Development
National Institute of Mental Health
6001 Executive Boulevard, Room 7125, MSC 9632
Bethesda, MD 20892-9632
Telephone: (301) 443-2738
Email: mi.hillefors@nih.gov

Thomas Lehner, Ph.D.
Division of Neuroscience and Basic Behavioral Science
National Institute of Mental Health
6001 Executive Boulevard, Room 7189, MSC 9632
Bethesda, MD 20892-9632
Telephone: (301) 443-9869
Email: tlehner@mail.nih.gov

Janine Simmons, M.D., Ph.D.
Division of Neuroscience and Basic Behavioral Science
National Institute of Mental Health
6001 Executive Boulevard, Room 7179, MSC 9632
Bethesda, MD 20892-9632
Telephone: (301) 443-6652
Email: simmonsj@mail.nih.gov

2. Peer Review Contacts:

David Armstrong, Ph.D.
Division of Extramural Activities
National Institute of Mental Health
6001 Executive Boulevard, Room 6138, MSC 9606
Bethesda, MD 20892-9606
Telephone: (301) 443-3534
Email: armstrda@mail.nih.gov

3. Financial or Grants Management Contacts:

Victoria Carper, MPA
Divisional of Extramural Activities
National Institute of Mental Health
6001 Executive Boulevard, Room 6118, MSC 9605
Bethesda, MD  20892-9605
Telephone: (301) 443-3858
FAX: (301) 480-6885
Email: carpervictoria@nih.gov

Section VIII. Other Information


Required Federal Citations

Use of Animals in Research:
Recipients of PHS support for activities involving live, vertebrate animals must comply with PHS Policy on Humane Care and Use of Laboratory Animals (http://grants.nih.gov/grants/olaw/references/PHSPolicyLabAnimals.pdf) as mandated by the Health Research Extension Act of 1985 (http://grants.nih.gov/grants/olaw/references/hrea1985.htm), and the USDA Animal Welfare Regulations (http://www.nal.usda.gov/awic/legislat/usdaleg1.htm) as applicable.

Human Subjects Protection:
Federal regulations (45CFR46) require that applications and proposals involving human subjects must be evaluated with reference to the risks to the subjects, the adequacy of protection against these risks, the potential benefits of the research to the subjects and others, and the importance of the knowledge gained or to be gained (http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm).

Data and Safety Monitoring Plan:
Data and safety monitoring is required for all types of clinical trials, including physiologic toxicity and dose-finding studies (phase I); efficacy studies (Phase II); efficacy, effectiveness and comparative trials (Phase III). Monitoring should be commensurate with risk. The establishment of data and safety monitoring boards (DSMBs) is required for multi-site clinical trials involving interventions that entail potential risks to the participants (NIH Policy for Data and Safety Monitoring, NIH Guide for Grants and Contracts, http://grants.nih.gov/grants/guide/notice-files/not98-084.html).

Sharing Research Data:
Investigators submitting an NIH application seeking $500,000 or more in direct costs in any single year are expected to include a plan for data sharing or state why this is not possible (http://grants.nih.gov/grants/policy/data_sharing).

Investigators should seek guidance from their institutions, on issues related to institutional policies and local IRB rules, as well as local, State and Federal laws and regulations, including the Privacy Rule. Reviewers will consider the data sharing plan but will not factor the plan into the determination of the scientific merit or the priority score.

Policy for Genome-Wide Association Studies (GWAS):
NIH is interested in advancing genome-wide association studies (GWAS) to identify common genetic factors that influence health and disease through a centralized GWAS data repository. For the purposes of this policy, a genome-wide association study is defined as any study of genetic variation across the entire human genome that is designed to identify genetic associations with observable traits (such as blood pressure or weight), or the presence or absence of a disease or condition. All applications, regardless of the amount requested, proposing a genome-wide association study are expected to provide a plan for submission of GWAS data to the NIH-designated GWAS data repository, or provide an appropriate explanation why submission to the repository is not possible. Data repository management (submission and access) is governed by the Policy for Sharing of Data Obtained in NIH Supported or Conducted Genome-Wide Association Studies, NIH Guide NOT-OD-07-088. For additional information, see http://grants.nih.gov/grants/gwas/

Access to Research Data through the Freedom of Information Act:
The Office of Management and Budget (OMB) Circular A-110 has been revised to provide access to research data through the Freedom of Information Act (FOIA) under some circumstances. Data that are (1) first produced in a project that is supported in whole or in part with Federal funds and (2) cited publicly and officially by a Federal agency in support of an action that has the force and effect of law (i.e., a regulation) may be accessed through FOIA. It is important for applicants to understand the basic scope of this amendment. NIH has provided guidance at http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm. Applicants may wish to place data collected under this funding opportunity in a public archive, which can provide protections for the data and manage the distribution for an indefinite period of time. If so, the application should include a description of the archiving plan in the study design and include information about this in the budget justification section of the application. In addition, applicants should think about how to structure informed consent statements and other human subjects procedures given the potential for wider use of data collected under this award.

Inclusion of Women And Minorities in Clinical Research:
It is the policy of the NIH that women and members of minority groups and their sub-populations must be included in all NIH-supported clinical research projects unless a clear and compelling justification is provided indicating that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing clinical research should read the "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); a complete copy of the updated Guidelines is available at http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm. The amended policy incorporates: the use of an NIH definition of clinical research; updated racial and ethnic categories in compliance with the new OMB standards; clarification of language governing NIH-defined Phase III clinical trials consistent with the new PHS Form 398; and updated roles and responsibilities of NIH staff and the extramural community. The policy continues to require for all NIH-defined Phase III clinical trials that: a) all applications or proposals and/or protocols must provide a description of plans to conduct analyses, as appropriate, to address differences by sex/gender and/or racial/ethnic groups, including subgroups if applicable; and b) investigators must report annual accrual and progress in conducting analyses, as appropriate, by sex/gender and/or racial/ethnic group differences.

Inclusion of Children as Participants in Clinical Research:
The NIH maintains a policy that children (i.e., individuals under the age of 21) must be included in all clinical research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them.

All investigators proposing research involving human subjects should read the "NIH Policy and Guidelines" on the inclusion of children as participants in research involving human subjects (http://grants.nih.gov/grants/funding/children/children.htm).

Required Education on the Protection of Human Subject Participants:
NIH policy requires education on the protection of human subject participants for all investigators submitting NIH applications for research involving human subjects and individuals designated as key personnel. The policy is available at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.

Human Embryonic Stem Cells (hESC):
Criteria for federal funding of research on hESCs can be found at http://stemcells.nih.gov/index.asp and at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html. Only research using hESC lines that are registered in the NIH Human Embryonic Stem Cell Registry will be eligible for Federal funding (http://escr.nih.gov). It is the responsibility of the applicant to provide in the project description and elsewhere in the application as appropriate, the official NIH identifier(s) for the hESC line(s) to be used in the proposed research.

NIH Public Access Policy Requirement:
In accordance with the NIH Public Access Policy (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-08-033.html) investigators must submit or have submitted for them their final, peer-reviewed manuscripts that arise from NIH funds and are accepted for publication as of April 7, 2008 to PubMed Central (http://www.pubmedcentral.nih.gov/), to be made publicly available no later than 12 months after publication. As of May 27, 2008, investigators must include the PubMed Central reference number when citing an article in NIH applications, proposals, and progress reports that fall under the policy, and was authored or co-authored by the investigator or arose from the investigator’s NIH award.  For more information, see the Public Access webpage at http://publicaccess.nih.gov/.

Standards for Privacy of Individually Identifiable Health Information:
The Department of Health and Human Services (DHHS) issued final modification to the "Standards for Privacy of Individually Identifiable Health Information", the "Privacy Rule", on August 14, 2002. The Privacy Rule is a federal regulation under the Health Insurance Portability and Accountability Act (HIPAA) of 1996 that governs the protection of individually identifiable health information, and is administered and enforced by the DHHS Office for Civil Rights (OCR).

Decisions about applicability and implementation of the Privacy Rule reside with the researcher and his/her institution. The OCR website (http://www.hhs.gov/ocr/) provides information on the Privacy Rule, including a complete Regulation Text and a set of decision tools on "Am I a covered entity?" Information on the impact of the HIPAA Privacy Rule on NIH processes involving the review, funding, and progress monitoring of grants, cooperative agreements, and research contracts can be found at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-025.html.

URLs in NIH Grant Applications or Appendices:
All applications and proposals for NIH funding must be self-contained within specified page limitations. For publications listed in the appendix and/or Progress report, internet addresses (URLs) must be used for publicly accessible on-line journal articles.  Unless otherwise specified in this solicitation, Internet addresses (URLs) should not be used to provide any other information necessary for the review because reviewers are under no obligation to view the Internet sites. Furthermore, we caution reviewers that their anonymity may be compromised when they directly access an Internet site.

Healthy People 2010:
The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2010," a PHS-led national activity for setting priority areas. This FOA is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople.

Authority and Regulations:
This program is described in the Catalog of Federal Domestic Assistance at http://www.cfda.gov/ and is not subject to the intergovernmental review requirements of Executive Order 12372. 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 52 and 45 CFR Parts 74 and 92. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement. The NIH Grants Policy Statement can be found at http://grants.nih.gov/grants/policy/policy.htm.

The PHS strongly encourages all grant recipients to provide a smoke-free workplace and discourage the use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care, or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people.

Loan Repayment Programs:
NIH encourages applications for educational loan repayment from qualified health professionals who have made a commitment to pursue a research career involving clinical, pediatric, contraception, infertility, and health disparities related areas. The LRP is an important component of NIH's efforts to recruit and retain the next generation of researchers by providing the means for developing a research career unfettered by the burden of student loan debt. Note that an NIH grant is not required for eligibility and concurrent career award and LRP applications are encouraged. The periods of career award and LRP award may overlap providing the LRP recipient with the required commitment of time and effort, as LRP awardees must commit at least 50% of their time (at least 20 hours per week based on a 40 hour week) for two years to the research. For further information, please see: http://www.lrp.nih.gov.


Weekly TOC for this Announcement
NIH Funding Opportunities and Notices


Office of Extramural Research (OER) - Home Page Office of Extramural
Research (OER)
  National Institutes of Health (NIH) - Home Page National Institutes of Health (NIH)
9000 Rockville Pike
Bethesda, Maryland 20892
  Department of Health and Human Services (HHS) - Home Page Department of Health
and Human Services (HHS)
  USA.gov - Government Made Easy


Note: For help accessing PDF, RTF, MS Word, Excel, PowerPoint, Audio or Video files, see Help Downloading Files.