RESEARCH ON INTERVENTIONS FOR ANOREXIA NERVOSA (RIAN) RELEASE DATE: November 3, 2003 RFA Number: RFA-MH-04-002 (This RFA has been reissued, see RFA-MH-05-009) Department of Health and Human Services (DHHS) PARTICIPATING ORGANIZATION: National Institutes of Health (NIH) (http://www.nih.gov/) COMPONENTS OF PARTICIPATING ORGANIZATION: National Institute of Mental Health (NIMH) (http://www.nimh.nih.gov/) CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBER(S): 93.242 LETTER OF INTENT RECEIPT DATE: December 22, 2003 APPLICATION RECEIPT DATE: January 22, 2004 THIS RFA CONTAINS THE FOLLOWING INFORMATION o Purpose of this RFA o Research Objectives o Mechanism(s) of Support o Funds Available o Eligible Institutions o Individuals Eligible to Become Principal Investigators o Special Requirements o Where to Send Inquiries o Letter of Intent o Submitting an Application o Supplementary Instructions o Peer Review Process o Review Criteria o Receipt and Review Schedule o Award Criteria o Required Federal Citations PURPOSE OF THIS RFA The purpose of this Request for Applications (RFA) is to evaluate intervention(s) for treatment of anorexia nervosa (AN). To accomplish this goal the National Institute of Mental Health (NIMH) will support development of a collaborative network of qualified institutions. The infrastructure created through this network will have the capacity to conduct a moderate to large-scale evaluation of promising intervention(s) for AN. It is also intended to serve as a resource for future ancillary studies. This network for Research in Anorexia Nervosa (RIAN) will be supported under a cooperative agreement (U01) mechanism for multi-site clinical trials. RESEARCH OBJECTIVES Background A recent NIH workshop "The Development of Research Priorities for the Treatment of Anorexia Nervosa: Overcoming Existing Barriers" (summarized at http://www.nimh.nih.gov/events/ansummary.cfm) was held to discuss both the serious nature of the disorder and the obstacles that hinder progress in research on AN. The essential features of AN are a refusal to maintain a normal body weight, an intense fear of gaining weight, and a significant distortion in an individual’s perception of the shape or size of his or her body. AN is a rare yet often chronic disorder frequently complicated by extensive comorbidity and a high mortality rate consequent to malnutrition and/ or suicide. AN often co-exists with other forms of psychopathology including depression, anxiety disorders, personality disorders and substance-use disorders and has serious medical co-morbidity (e.g., osteopenia and osteoporosis, cardiovascular complications, fluid and electrolyte changes and disruption in immune functioning). Despite its gravity, very little is known about the effective treatment, and ultimately, the prevention of AN. The existing literature is comprised primarily of small, brief efficacy studies marked by substantial attrition and limited follow-up. Additional information is needed regarding the most effective types of interventions, the most appropriate approaches for different age groups, and the best systems for delivery. Psychosocial and pharmacological treatments should be studied across different settings (e.g., inpatient, outpatient, day treatment) and should target both the short and long-term phases of the illness, including the prevention of relapse. Given that the overwhelming majority of participants in research have been Caucasian females, there is a need to evaluate specialized interventions strategies for ethnic minority groups and for males. Developmentally informed interventions specifically targeting youths should also be examined. Clinical observations and limited epidemiological research have also suggested that persons with AN are at greater risk for suicidal behavior and death. Improved research approaches for better assessment and management of suicidal risk among persons with this disorder are needed. Ethical issues associated with the use of certain research designs (e.g., no-treatment control groups) are a concern in intervention research. This may necessitate that only active treatments can be compared in the context of this RFA. The paucity of evidence about the effectiveness of interventions in AN can be explained, at least in part, by the substantial methodological challenges associated with small sample sizes (due to the relative rarity of the disorder), difficulties with patient recruitment, high attrition, and problems with patient compliance. Obstacles to delivering successful interventions in the community (including limited insurance coverage to pay for inpatient or long-term treatments) must also be considered when designing a research project to ensure that the findings obtained will be practical for translation to community practice. To address these challenges, the collaboration of a network of committed investigators with access to patients with AN is essential. Objectives and Scope The primary aim of the network is to facilitate a moderate to large-scale evaluation of promising treatment(s) for AN, including a long-term follow-up of research participants. The RIAN network will have the capacity to improve sample size, accelerate recruitment, and increase population diversity and representation beyond what could be accomplished at a single site. Each site will have its own principal investigator and it is expected that these investigators will jointly submit (as a group of U01s) a study plan similar to that which is required in Collaborative R01s for Clinical and Services Studies of Mental Disorders and AIDS. (http://grants.nih.gov/grants/guide/pa-files/PA-01-123.html). The sites will share common entrance criteria and assessment protocols, as well as a common standardized intervention protocol. One site will serve as a coordinating center that will manage the overall operations of the network. A Steering Committee will provide scientific oversight and will be the principal decision-making body for the study. Data management and analyses will be supported separately by NIMH. This RFA also aims to provide research education and training for junior investigators and/or established investigators willing to redirect their effort to research in AN. Below are examples of research areas and questions that could advance scientific knowledge regarding interventions for AN. The list is not exhaustive, and it is expected that additional important research topics may be identified. o Disorder-specific adaptations of treatments that have been successfully used to treat other disorders, including theory-based modifications of interventions that are efficacious with other disorders. o Pharmacological intervention studies focused on resolution of primary symptoms and consequent weight restoration. o Evaluations of strategies aimed at increasing compliance and minimizing drop-outs. o Research on family interventions for adolescents. o Studies of more effective relapse prevention procedures and maintenance or booster therapies. o Rigorous tests of multimodal interventions in the inpatient, outpatient, or partial hospitalization settings. o Studies that test developmentally-informed interventions for children and adolescents. o Interventions that incorporate alternate systems of delivery and therapeutic approaches (schools, nutritionists, psychologists, psychiatrists, etc.) alone or in combination. o Interventions that include a focus on specialized strategies for understudied groups, including ethnic minority groups and females. o Research targeting approaches to better assessing and managing suicide risk among persons with this disorder. MECHANISM OF SUPPORT This RFA will use NIH cooperative agreement (U01) award mechanism. This RFA is a one-time solicitation. The anticipated award date is September 2004. Future unsolicited, R01 applications based on this project will compete with all investigator-initiated applications and will be reviewed according to the customary peer review procedures. The NIH (U01) is a cooperative agreement award mechanism. In the cooperative agreement award mechanism, the Principal Investigator 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 "Cooperative Agreement Terms and Conditions of Award". FUNDS AVAILABLE The NIMH intends to commit approximately $1,250,000 total costs, in FY 2004, to fund one network comprised of multiple new cooperative agreement awards in response to this RFA. An applicant may request a project period of up to 5 years. Please note that F&A costs on a subcontract are included in the total cost limit. Although the financial plans of the NIMH provide support for this program, awards pursuant to this RFA are contingent upon the availability of funds and the receipt of a sufficient number of meritorious applications. ELIGIBLE INSTITUTIONS You may submit (an) application(s) if your institution has any of the following characteristics: o For-profit or non-profit organizations o Public or private institutions, such as universities, colleges, hospitals, and laboratories o Units of State and local governments o Eligible agencies of the Federal government o Domestic or foreign institutions/organizations o Faith-based or community-based organizations INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS Each site will have its own principal investigator (PI). Any individual with the skills, knowledge, and resources necessary to carry out the proposed research is invited to work with their 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 programs. SPECIAL REQUIREMENTS This RFA will provide support for a network comprised of multiple sites for participant recruitment and study. Each site should be able to contribute to the development of a common detailed protocol, assemble and train a research team, recruit and enroll eligible patients, collect and transmit data to a data management center, conduct common interventions and follow patients over extended periods of time. Prior to submission, investigators of a collaborating network should agree on the proposed research plan and the procedures for site organization and coordination. One site of a network should be designated as the coordinating center. It will have oversight over all other sites regarding operations of the RIAN network. It can be located at one of the clinical sites as long as it functions with independent operation and authority. The principal investigator at the coordinating center should have prior experience conducting multi-site trials. Individual sites will need resources to collect and transmit research data to the data management center. The coordinating center should be able to provide assistance with the research design and statistical analyses. The data management center will be supported separately by the NIMH. It will manage the multi-site database and conduct statistical analyses in coordination with the investigators. Each of the proposed clinical sites should provide documentation of their recruitment history for similar conditions as well as an estimate of participant flow for the particular group of AN patients whom they plan to enroll. A rationale for the sample size and number of sites should be provided. Cooperative Agreements Terms and Conditions of Award These special Terms of Award are in addition to and not in lieu of otherwise applicable Office of Management and Budget (OMB) administrative guidelines, Department of Health and Human Services (DHHS) grants administration regulations in 45 CFR part 74 and 92, and other HHS, PHS, and NIH grant administration policy statements. Under the cooperative agreement, the NIMH purpose is to support and/or stimulate the recipients activities by involvement in and otherwise working jointly with the awards recipients in a partner role, but it is not to assume direction, prime responsibility, or a dominant role in the activity. Consistent with the above concept, the dominant role and prime responsibility for the activity reside with the awardees for the project as a whole, although specific tasks and activities in carrying out the study will be shared between the awardees and the NIMH scientific collaborators or designee. 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 below or referenced in the Notice of Grant Award. Under the cooperative agreement, a relationship will exist between the awardees and the NIMH, in which the performers of the activities are responsible for the requirements and conditions described below and agree to accept program assistance from NIMH staff collaborators in achieving project objectives. Failure of the awardees to meet the performance requirements, including these special terms and conditions of award, or significant changes in level of performance, may result in a reduction of budget, withholding of support, suspension and/or termination of the awards. 1. Awardee Rights and Responsibilities The awardees have the primary authority and responsibility for defining objectives and approaches and for planning, conducting, analyzing, and publishing results, interpretations, and conclusions of the study. The awardees shall retain custody of and primary rights to the data developed under this award, subject to Government rights of access and consistent with current HHS, PHS, and NIH policies; however, the data base will be put into the public domain no more than 36 months after the last wave of data has been cleaned. The awardees will be responsible for planning and participating collaboratively with NIMH under this cooperative agreement. Through participation in meetings of the Steering Committee for this project and conference calls, the awardees will work with the NIMH staff collaborators in the implementation of a multi- site protocol, and in the establishment of quality control and monitoring procedures which are to be reported in non-competing continuation applications. Management of the multi-site database and final statistical analyses will be conducted at the data management center. However, some capability of data management functions will need to be present at each site. These functions will include: (1) ongoing monitoring of the data collected at the site for clarity, completion, and accuracy as compared with the source documents; (2) transferring of data to the central database by batching, copying, and mailing the data, or faxing them to the data management center; and (3) addressing possible queries from the data management center about the data. Investigators at the collaborating sites will have initial access to the data for analyses, interpretation and reporting. However since the creation of the data set is funded through public monies and because the data set will constitute a national scientific resource for the research community, a de- identified data set will be made available to the large research community no more than 36 months after the last wave of data have been cleaned. 2. NIMH Responsibilities At least one NIMH staff collaborator or a designee will have scientific involvement in the conduct of this activity, above and beyond normal program stewardship, through membership on the project Steering Committee. The participation of NIMH staff collaborator(s) is intended to assist the project Steering Committee in its efforts to ensure that the broad scientific goals of NIMH are reflected in the implementation, and reporting of results of the studies. Specifically, the staff collaborator(s) will participate in decisions about study design, instrumentation, and clinical assessment. The NIMH staff collaborator(s) will participate in all major project meetings and may cooperate with the awardees as author or co-author of resulting publications in accordance with publication policies developed by the Steering Committee of this project. Publications involving NIMH staff must follow NIH and NIMH publication policies. In addition to the NIMH staff collaborator(s), an NIMH Project Officer will be responsible for normal stewardship, and will provide technical assistance, programmatic monitoring, and assistance in the coordination of the overall project, but will not be a voting member of the project Steering Committee. After the initial year, for which the NIMH requires a mid-year report, progress of the project will be reviewed by the NIMH Project Officer annually at the time of each continuation application. These reports will be assessed to assure that satisfactory progress is being made in achieving the project objectives, especially with respect to enrollment and quality of data collection, and that the site is following the procedures recommended and approved by the project Steering Committee. The NIMH will appoint an independent panel of experts in clinical trials to constitute a Data Safety and Monitoring Board (DSMB). The DSMB will report to the NIMH. The DSMB will monitor safety, quality of data collection, and integrity of the study. The costs of the DSMB will come from an NIMH source independent of the cooperative agreement. The study data will be reviewed by the DSMB every 3-6 months. The DSMB will receive a report from the data management and statistical center usually about 4 weeks before each review date. Such a report will include the major variables necessary for monitoring safety and quality of data collection and integrity of the study. As study protocol and consent forms are relevant to safety and quality of data, the DSMB will also review these documents before the onset of the study. Based on this review, the DSMB has the authority to prevent the study from starting or to stop the study after it has started. 3. Collaborative Responsibilities The project Steering Committee will be the principal decision-making body for the study. It will have overall responsibility for the study and will make modifications in the protocols as necessary. The NIMH staff collaborator(s) will jointly have one vote on the project Steering Committee. Each awardee will jointly have one vote, although up to three persons from each site may be members of the project Steering Committee. A representative of the contracted database management component will participate on the Steering Committee, but will not be a voting member. A quorum will require one NIMH staff collaborator or designee and at least four representatives, each from one of the participating sites. The project Steering Committee will elect a chairperson, and may establish additional by-laws, subcommittees, or workgroups for specific tasks, including a Publications Committee to develop policies on publication and authorship. An NIMH staff collaborator may not chair any committee or subcommittee. Membership on the project Steering Committee becomes effective for the site upon receipt of the notice of award. Decisions will be made by majority vote of a quorum, with an attempt for consensus when possible. Any project Steering Committee member who considers a committee decision unacceptable may appeal by following the arbitration procedure described below. The project Steering Committee will meet annually, and convene through telephone conferences or in person, as needed, for the duration of the study. Responsibilities of the project Steering Committee members (collaborators) include: (1) collaboratively finalizing the study plan, including design, assessment instruments, component protocols, and detailed implementation procedures; (2) abiding by and directing the study plan determined by the project Steering Committee; (3) monitoring the study and developing and implementing quality control procedures; (4) conserving grant funds in the service of the common objectives and of the research plan agreed on by the project Steering Committee; (5) facilitating the analysis of data and the eventual release to the larger scientific community (see Public Domain below); submitting data on time in the form and on the schedule determined by the project Steering Committee; (6) evaluating and reporting study results: defining rules regarding access to data and publication of findings from analyses of the data set; and (7) abiding by all scientific, practical, and policy decisions of the project Steering Committee. 4. Arbitration Procedures If a decision related to a scientific or programmatic issue between the awardees and the NIMH staff collaborator(s) or NIMH is not acceptable to the awardee(s), the awardee may, within 30 days of notification of the decision, request a review by an arbitration panel composed of one arbitrator nominated by the awardee(s), one nominated by NIH, and one chosen by the first two nominees. This panel will make a decision within 60 days of the request. Failure to comply with the decision of the panel may result in termination of support for the awardee(s) by NIMH. This arbitration procedure in no way affects the right by the awardee(s) to appeal any adverse action in accordance with PHS regulations at 42 CFR Part 50, subpart D, and HHS Grant Administration Regulations at 45 CFR Part 74, section 304, and HHS regulations at 45 Parts 16 and 75. WHERE TO SEND INQUIRIES We encourage inquiries concerning this RFA 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: o Direct your questions about scientific/research issues to: Linda Street, Ph.D. Division of Services and Intervention Research National Institute of Mental Health 6001 Executive Boulevard, Room 7160, MSC 9635 Bethesda, MD 20892-9635 Telephone: (301) 443-0651 FAX: 301-594-6784 Email: Lstreet@nih.gov o Direct your questions about peer review issues to: Michael Kozak, Ph.D. Division of Extramural Activities National Institute of Mental Health 6001 Executive Boulevard, Room 6138, MSC 9609 Bethesda, MD 20892-9608 Telephone: (301) 443-1340 FAX: (301) 443-4720 Email: kozakm@mail.nih.gov o Direct your questions about financial or grants management matters to: Joy R. Knipple Division of Extramural Activities National Institute of Mental Health 6001 Executive Boulevard, Room 6115, MSC 9605 Bethesda, MD 20892-9605 Telephone: (301) 443-8811 FAX: (301) 443-6885 Email: jknipple@nih.gov LETTER OF INTENT Prospective applicants are asked to submit a letter of intent that includes the following information: o Descriptive title of the proposed research o Name, address, and telephone number of the Principal Investigator o Names of other key personnel o Participating institutions o Number and title of this RFA 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 at the beginning of this document. The letter of intent should be sent to: Linda Street, Ph.D. Division of Services and Intervention Research National Institute of Mental Health 6001 Executive Boulevard, Room 7160, MSC 9635 Bethesda, MD 20892-9635 Telephone: (301) 443-0651 FAX: 301-594-6784 Email: Lstreet@nih.gov SUBMITTING AN APPLICATION Applications must be prepared using the PHS 398 research grant application instructions and forms (rev. 5/2001). Applications must have a DUN and Bradstreet (D&B) Data Universal Numbering System (DUNS) number as the Universal Identifier when applying for Federal grants or cooperative agreements. The DUNS number can be obtained by calling (866) 705-5711 or through the web site at http://www.dunandbradstreet.com/. The DUNS number should be entered on line 11 of the face page of the PHS 398 form. The PHS 398 document is available at http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format. For further assistance contact GrantsInfo, Telephone (301) 710-0267, Email: GrantsInfo@nih.gov. SUPPLEMENTARY INSTRUCTIONS The general instructions in the PHS 398 form should be followed with exceptions as noted below. Each application should include the following three sections and give headings as follows: 1) Research Plan, 2) Operations, and 3) Training Capabilities. The combined page limit for these three sections may not exceed 30 pages, however, the Research Plan for the coordinating center application may include up to three extra pages to describe its unique content. Research Plan This section should include a description of the proposed intervention study. It should describe the design and conduct of the treatments that are to be tested by all institutions of a particular collaborating network. Where there are even minor variations in the research plan or operations between sites, these should be highlighted in a subsection with the heading, Elements Unique to this Site . The application should characterize the full range of expertise needed to successfully carry out this research and indicate how this expertise will be obtained. It should describe overall managerial and administrative responsibilities and the functions of the Steering Committee. The description of the intervention study should include the rationale, methods, experimental design, time line of objectives to be accomplished, plans for data acquisition and a general analytical plan. The experimental hypotheses proposed should be supported by preliminary data sufficient to warrant testing in a moderate to large-scale multi-site study. Realistic estimates of patient enrollment and effect size of interventions should be made to support estimates of statistical power to address these hypotheses. The steps involved with multi-site collaboration should be illustrated including methods for cross-site training of the intervention and assessment instruments and procedures for measuring protocol adherence. Outcomes should include quality of life, social adaptation, comorbidity of medical and psychiatric diagnoses and costs or cost- effectiveness of care. Particular attention should be directed at strategies for participant retention and for long-term follow-up. Mediators and moderators of outcome should also be evaluated. Operations This section should include the functions to be performed by individual sites and the integration of procedures across multiple sites. This section may include both shared or common elements and those that are unique to each site. Each of the proposed clinical sites should provide documentation of their recruitment history for similar conditions as well as an estimate of participant flow for the particular group of AN patients whom they plan to enroll. A rationale for the sample size and number of sites should be provided. The application should provide specific plans for enrolling and retaining these participants as well as strategies for recruiting a participant pool that is sufficiently representative with regard to sex, ethnicity, race or socioeconomic status. These plans might include a description of relevant materials to be prepared, treatment center staffing goals, staff training and community outreach. Some or all of the sites should be located in communities with diverse populations. The application should describe the number and types of trials competing for similar patients at each clinical site. Finally, applicants must demonstrate an awareness of the effects of the research design on their ability to recruit and retain AN patients. Applications must include a description of the available infrastructure and facility, including necessary clinic and/or laboratory equipment. Evidence of departmental and institutional support, documented by letters to the investigator, must be provided. Coordinating Center Application: For the one site designated as the Coordinating Center, it should propose an organizational structure and provide for it in the budget. Statistical consultation for design and analysis issues should be available to the coordinating center. The duties, functions, and integration of the coordinating center and clinical sites should also be described. Training Capabilities Applicants should describe how the RIAN grants will provide research education and training for junior investigators and/or established investigators willing to redirect their effort to research in AN. Budget The following issues should be considered and addressed in the Budget Justification section: Allowable costs in NIH cooperative agreements are governed by rules set forth in the NIH Grants Policy Statement (http://grants.nih.gov/grants/policy/nihgps_2001/) and as stated on the Notice of Grant Award. Under these rules the PI may exercise flexibility to meet unexpected requirements by rebudgeting or requesting approval to rebudget among categories within the total direct cost budget of the RIAN grant (as shown on the Notice of Grant Award), within the ceilings set in these guidelines. Items fundable through a RIAN cooperative agreement may include: 1. Personnel: Principal investigator and other senior investigators, junior investigators, research coordinator, data coordinator and others (time and effort as needed, with appropriate justification). 2. Support services directly related to the project: e.g., project-specific supplies, duplication costs, dedicated telephone line. 3. Clinical costs: Cost of clinical care that is directly related to the research project, and is not covered by other sources. Cost of pharmaceuticals to be used in the study, other pharmacy and laboratory costs, as justified by the research protocol. 4. Travel: Travel for the principal investigator and one co-investigator for a yearly network meeting; additional travel for training in multi-site protocols as needed. The following items are not fundable through a RIAN grant: Costs of routine clinical care that are not directly related to the research project, or are covered by other sources, rent, administrative or secretarial services. USING THE RFA LABEL: The RFA label available in the PHS 398 (rev. 5/2001) application form must be affixed to the bottom of the face page of the application. Type the RFA number on the label. Failure to use this label could result in delayed processing of the application such that it may not reach the review committee in time for review. In addition, the RFA title and number must be typed on line 2 of the face page of the application form and the YES box must be marked. The RFA label is also available at: http://grants.nih.gov/grants/funding/phs398/label-bk.pdf. SENDING AN APPLICATION TO THE NIH: 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 Bethesda, MD 20817 (for express/courier service) At the time of submission, two additional copies of the application and all copies of the appendix materials must be sent to: Jean Noronha, Ph.D. Division of Extramural Activities National Institute of Mental Health 6001 Executive boulevard, Room 6154, MSC 9609 Bethesda, MD 20892-9663 Rockville, MD 20852 (for express/courier service) Telephone: (301) 443-3367 FAX: (301) 443-4720 Email: jnoronha@mail.nih.gov APPLICATION PROCESSING: Applications must be received on or before the application receipt date listed in the heading of this RFA. If an application is received after that date, it will be returned to the applicant without review. Although there is no immediate acknowledgement of the receipt of an application, applicants are generally notified of the review and funding assignment within 8 weeks. The Center for Scientific Review (CSR) will not accept any application in response to this RFA 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 an RFA, it is to be prepared as a NEW application. That is, the application for the RFA 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. PEER REVIEW PROCESS Upon receipt, applications will be reviewed for completeness by the CSR and responsiveness by the National Institute of Mental Health. Incomplete and/or non-responsive applications will not be reviewed. Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened by the National Institute of Mental Health in accordance with the review criteria stated below. As part of the initial merit review, all applications will: o Undergo a process in which only those applications deemed to have the highest scientific merit, generally the top half of the applications under review, will be discussed and assigned a priority score o Receive a written critique o Receive a second level review by the National Advisory Mental Health Council REVIEW CRITERIA The goals of NIH-supported research are to advance our understanding of biological systems, improve the control of disease, and enhance health. In the written comments, reviewers will be asked to evaluate the application in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. The scientific review group will address and consider each of the following criteria in assigning the application’s overall score, weighting them as appropriate for each application. o Significance o Approach o Innovation o Investigator o Environment The application does not need to be strong in all categories to be judged likely to have major scientific impact and thus deserve a high priority score. For example, an investigator may propose to carry out important work that by its nature is not innovative but is essential to move a field forward. SIGNIFICANCE: Does this study address an important aspect of treatment of AN? If the aims of the application are achieved, how will scientific knowledge be advanced? What will be the effect of these studies on the concepts or methods that drive this field? Will the knowledge gained contribute to improved care? APPROACH: Are the conceptual framework, design, methods, sample size and analyses adequately developed, well-integrated, and appropriate to the aims of the intervention study? Have the investigators accounted for the difficulties in enrollment, retention and follow-up? Does the applicant acknowledge other potential problem areas and consider alternative tactics? Are specific achievable performance objectives described for development of the network? Are the training and activities of research personnel adequately described? INNOVATION: Does the project employ novel concepts, approaches or methods? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? INVESTIGATOR: Is the investigator appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the principal investigator and other researchers (if any)? Does the investigator at the coordinating center have experience in planning and conducting collaborative multi-center studies? ENVIRONMENT: Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed site(s) have a sufficient flow of participants? What is the experience of the institution(s) in enrollment for clinical trials? Is there evidence of institutional support? ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, the following items will be considered in the determination of scientific merit and the priority score: COLLABORATION: Is there a feasible mechanism for collaboration to achieve scientific integration of research procedures, overall managerial and administrative responsibilities, appropriate quality control and reliability assurance, and planning for data management, analysis and reporting of results? COORDINATING CENTER: Does the coordinating center plan describe the leadership of the project and have clearly defined administrative responsibilities? Does the coordinating center have the necessary scientific consultation available (e.g., in biostatistics)? TRAINING: Is there an adequate plan to provide training to junior investigators and/or established investigators who are willing to redirect their effort to research in AN? PROTECTION OF HUMAN SUBJECTS FROM RESEARCH RISK: The involvement of human subjects and protections from research risk relating to their participation in the proposed research will be assessed. (See criteria included in the section on Federal Citations, below). INCLUSION OF WOMEN, MINORITIES AND CHILDREN IN RESEARCH: The adequacy of plans to include subjects from both genders, all racial and ethnic groups (and subgroups), and children as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. (See Inclusion Criteria in the sections on Federal Citations, below). CARE AND USE OF VERTEBRATE ANIMALS IN RESEARCH: If vertebrate animals are to be used in the project, the five items described under Section f of the PHS 398 research grant application instructions (rev. 5/2001) will be assessed. ADDITIONAL REVIEW CONSIDERATIONS SHARING RESEARCH DATA: Applicants requesting more than $500,000 in direct costs in any year of the proposed research must include a data sharing plan in their application. The reasonableness of the data sharing plan or the rationale for not sharing research data will be assessed by the reviewers. However, reviewers will not factor the proposed data sharing plan into the determination of scientific merit or priority score. http://grants.nih.gov/grants/policy/data_sharing BUDGET: The reasonableness of the proposed budget and the requested period of support in relation to the proposed research. RECEIPT AND REVIEW SCHEDULE Letter of Intent Receipt Date: December 22, 2003 Application Receipt Date: January 22, 2004 Peer Review Date: May/June 2004 Council Review: September 2004 Earliest Anticipated Start Date: September 2004 AWARD CRITERIA Award criteria that will be used to make award decisions include: o Scientific merit (as determined by peer review) o Availability of funds o Programmatic priorities REQUIRED FEDERAL CITATIONS 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). The establishment of data and safety monitoring boards (DSMBs) is required for multi-site clinical trials involving interventions that entail potential risk to the participants. (NIH Policy for Data and Safety Monitoring, NIH Guide for Grants and Contracts, June 12, 1998: http://grants.nih.gov/grants/guide/notice-files/not98-084.html). SHARING RESEARCH DATA: Starting with the October 1, 2003 receipt date, 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, 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. 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 - Amended, October, 2001," published in the NIH Guide for Grants and Contracts on October 9, 2001 (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); a complete copy of the updated Guidelines are 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 RESEARCH INVOLVING HUMAN SUBJECTS: The NIH maintains a policy that children (i.e., individuals under the age of 21) must be included in all human subjects research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them. This policy applies to all initial (Type 1) applications submitted for receipt dates after October 1, 1998. 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 that is available at 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 proposals for research involving human subjects. You will find this policy announcement in the NIH Guide for Grants and Contracts Announcement, dated June 5, 2000, at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html. PUBLIC 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 public 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 PA 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. 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). Those who must comply with the Privacy Rule (classified under the Rule as covered entities ) must do so by April 14, 2003 -(with the exception of small health plans which have an extra year to comply). 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. Unless otherwise specified in an NIH solicitation, Internet addresses (URLs) should not be used to provide information necessary to 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 RFA 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 or Health Systems Agency review. 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.

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