AUTISM RESEARCH CENTERS OF EXCELLENCE: THE STAART PROGRAM Release Date: March 6, 2002 RFA: RFA-MH-03-005 National Institute of Mental Health (NIMH) (http://www.nimh.nih.gov/) National Institute of Child Health and Human Development (NICHD) (http://www.nichd.nih.gov/) National Institute of Neurological Disorders and Stroke (NINDS) (http://www.ninds.nih.gov/) National Institute on Deafness and Other Communication Disorders (NIDCD) (http://www.nidcd.nih.gov/) National Institute of Environmental Health Sciences (NIEHS) (http://www.niehs.nih.gov/) LETTER OF INTENT RECEIPT DATE: June 27, 2002 APPLICATION RECEIPT DATE: August 29, 2002 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 Peer Review Process o Review Criteria o Receipt and Review Schedule o Award Criteria o Required Federal Citations PURPOSE OF THIS RFA The National Institutes of Health Autism Coordinating Committee (NIH/ACC) is implementing the aspects of the Children's Health Act of 2000 that relate to support of autism research by NIH. The NIH/ACC is composed of the NIH Institutes currently funding autism research: NIMH, NICHD, NINDS, NIDCD, and NIEHS. An important aspect of these activities is the establishment of Centers of Excellence in Autism Research, and in this RFA the participating institutes invite research grant applications for such Centers. The first round of competition for this type of center support was initiated by RFA-MH- 02-001 (http://grants.nih.gov/grants/guide/rfa-files/RFA-MH-02-001.html). This RFA initiates a second round of competition under the same guidelines, except for deadlines, that governed the first round. These Centers will constitute a cohesive program, operating under an NIH cooperative agreement, which will be called the STAART Centers Program (Studies to Advance Autism Research and Treatment). The primary goal of the STAART initiative is to establish several research centers, each of which will bring together expertise, infrastructure and resources focused on major questions about autism. The research issues to be addressed will include causes, diagnosis, early detection, prevention, and treatment, with approaches such as developmental neurobiology, genetics, and psychopharmacology being represented. Centers should use innovative research designs and state-of-the-art technologies. Centers should draw upon established basic and clinical scientists to form unique collaborations optimally suited to address the research questions posed. Achieving high levels of expertise and resources may require multi-institutional consortia to be formed. Centers are expected to provide an environment and core resources that will enhance ongoing research by bringing together biomedical, behavioral, and clinical science investigators to study autism. The centers will provide investigators with well-characterized patients and control subjects, family information, and other scientific resources that will facilitate research projects. Each center should develop in accordance with available expertise, interests, and resources, but should also be responsive to national needs related to autism. Although the types of activities that should be included are indicated in these guidelines, specific approaches to accomplish them are left to applicants. In addition to the self-contained activities of individual centers, the STAART Centers Program will conduct collaborative studies among centers which will be overseen by a Steering Committee for the Program involving representation from each center and from NIH. The STAART Centers Program will be funded through an NIH Cooperative Agreement mechanism, the goal of which is to maximize the collaborative utilization of the unique resources in infrastructure, expertise, and clinical recruitment that will be created. Investigators interested in applying for support of autism research using mechanisms other than this RFA should see NIH PA-01-051 (http://grants.nih.gov/grants/guide/pa-files/PA-01-051.html) for a description of NIH's broad support of autism spectrum research. RESEARCH OBJECTIVES Background o Organization of initiatives relevant to the STAART Program. Public Law 106-310, The Children's Health Act of 2000, authorizes the Director of NIH, acting through the Director of the National Institute of Mental Health (NIMH), to expand autism research activities in general and to support the planning and establishing of no fewer than five Centers of Excellence in Autism Research. This RFA solicits applications for such center support under the STAART Centers Program. o Appropriateness of proposed research for center support rather than R01 support. The NIH has long supported a variety of autism research projects through R01, P01, small grant, and career development mechanisms. Those types of support will continue, and many new and continuing projects will be more appropriate for those mechanisms. What distinguishes a research program that is appropriate for STAART support from a research program that is better supported through a series of R01 grants? The STAART Program, funded through the U54 mechanism, supports major multidisciplinary research programs, consisting of interdependent and interrelated subprojects, cores, and infrastructure. "Multidisciplinary" is defined as having subprojects representing different disciplines, approaches, and expertise exploring a common or unifying theme. This feature alone does not constitute a rationale for the use of a center mechanism, since many individual investigator- initiated research grants (R01s) are multidisciplinary in nature. Meaningful and committed interactions among the disciplines must be evident. "Interdependent" means that materials, results, data, patient populations, or methodologies are shared among the subprojects. Results of one subproject may well affect the understanding and interpretation of data from another project and thereby influence the nature of the research being performed in one or more of the other subprojects. The feasibility of the research proposed on any subproject might be significantly diminished if that subproject were submitted as a traditional individual research grant (R01) application. However, diminished feasibility is not, in itself, justification for inclusion of an independent subproject in a Centers application. In addition, each subproject must have goals and objectives that focus on the common unifying theme to be considered interrelated. In all cases, the necessity for concurrent funding of the subprojects and cores must be specified and fully justified (e.g., longitudinal study on a unique and difficult to acquire subject population; the data must be collected from the same subjects in a time-dependent fashion; the data from one subproject directly impact the conduct of the research on one or more of the other subprojects). Core support must be justified as providing essential resources to the center's projects. Goals of the STAART Centers Program Even given the promising growth of the clinical and basic research fields relevant to autism, and the interaction among investigators in the field that has been cultivated by sustained NIH support of the Network on the Neurobiology and Genetics of Autism, 10 Collaborative Programs of Excellence in Autism (CPEA) program, the STAART Centers Program will represent a substantial increase in the scope of the scientific enterprise related to this disorder, particularly as it provides a specific emphasis on and direct funding for treatment research. An application for STAART support must include at least one proposed treatment project, and to be funded a STAART Center must include at least one fundable treatment project. The primary goal of the present initiative is to support cohesive teams of accomplished investigators focused on basic and clinical issues related to autism. STAART support will provide investigators within each center the opportunity to pursue common goals and objectives, work as an integrated, interactive research team, and develop the resources, equipment, or administrative support needed to operate an interdisciplinary center. This type of multidisciplinary, multi-faceted research is of paramount importance in elucidating the etiology, pathophysiology, and evidence-based treatment of autism. It is expected that the STAART Centers will produce innovative, potentially high-impact approaches to fundamental research problems. It is also anticipated that STAART Centers will attract outstanding investigators who have not been part of the autism field. Examples of scientific areas that could be appropriate foci for STAART Centers activities are: o development of new or improved treatments, in behavioral/psychosocial, pharmacological, and other biological modalities - testing safety & efficacy of treatments now used - translation of basic research into novel therapies - pharmacogenetics - pharmacokinetics - development of new outcome measures o development of methods for early diagnosis and screening, including biological and behavioral indices for early detection o investigation of neural bases and pathways for abnormal behaviors o investigation of potential environmental etiologies and risk factors including - prenatal - infectious - toxic - immunizations o description and characterization of co-morbidities, and how they relate to etiology, pathology, and prevention: for example, brain - gut connection, gastrointestinal abnormalities, epilepsy, obsessive-compulsive disorder o neuroimaging investigations using functional magnetic resonance imaging, brain mapping, other new technologies to determine neuroanatomic and localized functional abnormalities and how they change over time o genetic studies including gene-environment interactions, candidate genes, and genotype-phenotype correlations o studies of language and disorders of communication o interventional, descriptive, and neuroimaging studies which utilize a related comparison group such as fragile X, obsessive-compulsive disorder, mental retardation, tuberous sclerosis, Williams syndrome o development of novel animal models These are examples and by no means all inclusive. There are many other potential areas of study that applicants might choose to emphasize. The Children's Health Act. As noted above, the Children's Health Act contains specific provisions regarding the centers it mandates. All of these will be considered in the review of the Centers applications. The relevant text of the Act is as follows: "(1) IN GENERAL. The Director [of NIH] shall under subsection (a)(1) make awards of grants and contracts to public or nonprofit private entities to pay all or part of the cost of planning, establishing, improving, and providing basic operating support for centers of excellence regarding research on autism. "(2) RESEARCH. Each center under paragraph (1) shall conduct basic and clinical research into autism. Such research should include investigations into the cause, diagnosis, early detection, prevention, control, and treatment of autism. The centers, as a group, shall conduct research including the fields of developmental neurobiology, genetics, and psychopharmacology. "(3) SERVICES FOR PATIENTS.- "(A) IN GENERAL. A center under paragraph (1) may expend amounts provided under such paragraph to carry out a program to make individuals aware of opportunities to participate as subjects in research conducted by the centers. "(B) REFERRALS AND COSTS. A program under subparagraph (A) may, in accordance with such criteria as the Director may establish, provide to the subjects described in such subparagraph, referrals for health and other services, and such patient care costs as are required for research. "(C) AVAILABILITY AND ACCESS. The extent to which a center can demonstrate availability and access to clinical services shall be considered by the Director in decisions about awarding grants to applicants which meet the scientific criteria for funding under this section. "(4) COORDINATION OF CENTERS; REPORTS.- The Director shall, as appropriate, provide for the coordination of information among centers under paragraph (1) and ensure regular communication between such centers, and may require the periodic preparation of reports on the activities of the centers and the submission of the reports to the Director. "(5) ORGANIZATION OF CENTERS.- Each center under paragraph (1) shall use the facilities of a single institution, or be formed from a consortium of cooperating institutions, meeting such requirements as may be prescribed by the Director. "(6) NUMBER OF CENTERS; DURATION OF SUPPORT.- "(A) IN GENERAL.- The Director shall provide for the establishment of not less than 5 centers under paragraph (1). "(B) DURATION.- Support for a center established under paragraph (1) may be provided under this section for a period not to exceed 5 years. Such period may be extended for 1 or more additional periods not exceeding 5 years if the operations of such center have been reviewed by an appropriate technical and scientific peer review group established by the Director and if such group has recommended to the Director that such period should be extended." The specific provisions of this RFA are intended to implement these provisions of the Act. For example, the requirement of the Act that each center shall conduct basic and clinical research is interpreted in this RFA to mean that it is mandatory for applications to include both clinical and basic studies to be considered responsive to this RFA. For this purpose, clinical research is considered to be research involving individuals with autism that deals with biomedical and/or behavioral aspects of the disorder. Basic research is considered to be studies dealing with normative processes in people, animals, or in vitro preparations. As another example, the Act indicates a spectrum of targeted research topics that are appropriate for centers. For the review of STAART applications, a principal criterion for evaluation will be the extent to which the center projects directly, and as comprehensively as possible, address these topics. However, although a comprehensive representation of these topics is desirable, it is expected that a given proposed center may have only a limited capacity to address certain topics. Thus, it is expected that each funded center will address a majority of these topics with substantive, high-quality research proposals and will develop additional capacity for more comprehensive efforts over time. o Collaborative studies. In addition to these issues that are focused on individual centers, a major goal of the STAART Centers Program is to establish a major research network that, as a whole, will be capable of implementing large treatment, diagnostic, genetic, neuroscientific and other studies, which are not currently feasible. To accomplish this, the U54 mechanism is being used to support the centers, and there will be active involvement of NIH staff in coordinating collaborative studies that will be defined and implemented after the initial centers are funded. Also, there will be funds from the overall funding pool that will be designated for collaborative studies so that appropriate budget supplements and/or increases can be distributed to the participating centers. However, it is expected that each center will contribute reasonable subject recruitment and follow-up functions to these collaborative studies without budget supplementation. It is expected that the STAART-wide collaborative studies will emerge from common scientific interests among the funded centers. Therefore, it is appropriate for applicants to describe studies they would be particularly interested in that might utilize the resources of the STAART Centers Program. Such a study might, for example, be a pharmacological or psychosocial treatment study or an investigation of early signs of autism that would not have sufficient power without the resources of the program. ORGANIZATION OF STAART CENTERS Each STAART Center will have a Center Director (the Center Principal Investigator) who will make scientific and administrative decisions relating to the center, will oversee identification and selection of key personnel, and will be responsible for allocation and monitoring of STAART funds. These responsibilities and decisions will be undertaken with the advice of the executive committee and the External Consultants Committee described below. There will also be a Co-Director. The Director and Co-Director should have a demonstrated capability to organize, administer and direct the center. It is expected that the Director and Co-Director will have a substantial investment in the center and be its scientific leaders. Thus, each should have a minimum total (including core and project commitments) time commitment of 20% to the STAART Center. Each center will have a team of appropriate investigators, a set of research projects, a collection of support cores, and appropriate infrastructure and institutional support that will allow the proposed center to accomplish the goals of the STAART Centers Program. STAART support is not intended to be a substitute for individual grant support. It is, therefore, expected that project and core leaders will have independent, peer-reviewed research support. Neither should the STAART Center be the primary source of research funding for the investigators associated with the Center. It is desirable for STAART-supported research to complement other funded research related to autism taking place at the applicant institution, including activities supported by R01, P01, P30, P50, and other mechanisms. Investigators with the qualifications to be members of the research team, and to contribute to such a unique enterprise, may be located in different geographic locations. Therefore, collaborations among different institutions are encouraged, if scientifically appropriate. The proposed team will be responsible for the definition of the research goals and objectives of the research enterprise, as well as ongoing activities. Each STAART Center applicant must demonstrate the ability to perform the necessary administrative, clinical, and information utilization functions. A possible structure is outlined below, in which these functions are organized into new cores that would be established with STAART funding. However, there are no mandatory cores, and applicants may propose other ways of accomplishing these functions, such as integrating them with already existing structures. Also, other cores may be proposed. There should be institutional resources set in place to provide the components that make the site(s) competitive for Center of Excellence support. There should be substantive departmental and institutional support for and commitment to the proposed center. Applications should provide a description of the clinical populations, patient, family, and control subject information, tissue resources, genetics resources, and other resources that will be involved as part of the team's clinical research component. It is anticipated that resources and projects that are in place due to funding from sources other than the STAART Program will synergistically interact with STAART infrastructure, cores, and projects. The application should explain how STAART support would facilitate the development and significance of related projects that may not be an integral component of the STAART itself. In such cases, it will also be necessary to address, in detail, questions of possible overlap of support from other grants or funding sources. STAART Centers must commit to cooperate fully and to share data concerning patients, control subjects and specimen resources within the STAART Centers Program, and with the broad scientific community, as specified by NIH. Cores A core is a shared central laboratory or clinical research facility, service, or resource. Each core is directed by a faculty investigator (the Core Director) with substantial expertise related to the core. Two important and related considerations are (1) the degree to which currently funded investigators within or outside the center will use and will benefit from core resources and (2) the degree to which the resources will promote new and/or expanded autism research efforts locally, regionally or nationally. Applicants should document and describe briefly the projects, both existing and planned, whether funded by the center or not, that will depend upon resources provided by the cores (clinical cores, in particular). o Administrative core. The successful operation of each STAART Center will require the integration of the activities of several projects and cores, as well effective organization of the efforts of scientific and professional personnel from a variety of disciplines and subspecialties. This requires the presence of an administrative structure to organize the flow of information, distribution of effort, allocation of resources, and to implement other necessary administrative functions. This will require an administrative core or its equivalent. The administrative requirements of each STAART Center will necessitate the assistance of an administrator with business management expertise. It is important that such an individual be identified and directly involved with the fiscal and administrative aspects of the STAART application and grant. It is expected that the STAART Center administrative structure will facilitate the following: 1) coordination and integration of STAART components and activities 2) planning and review of utilization of funds 3) provide support and advice for the STAART Director in his/her oversight of the activities of the center 4) interact with the scientific and lay communities to develop relevant goals for the STAART Center within the immediate environment of the Center 5) interact with other STAART Centers and the centers' NIH Science Officers to develop trans-STAART research projects. The Science Officer is the NIH representative who implements the NIH aspects of the Cooperative Agreement in each center. An executive committee (composed of core directors, project leaders, and the administrator) will be established in each center to assist the Center Director and Co-Director in making scientific and administrative decisions. The executive committee should be encouraged to seek outside advice and consultation, both from within the institution and from other institutions, in its monitoring and development of the scientific content and direction of the program. An External Consultants Committee to each STAART Center, consisting of scientists from outside of the institution or consortium, will also be established. Unless already appointed, External Consultants Committee members should not be recruited until the NIH review process is complete. This committee will be used to evaluate the programs of the center, research progress, the effectiveness of communications within the center, and any other activities for which outside expertise is required or desirable. The committee should meet annually and prepare a report including recommendations to assist the center. The NIH Science Officer for that center and the Program Officer for the STAART Program should be invited to attend each meeting as observers. A copy of the advisory committee report should be sent to the appropriate NIH Science Officer and to the Program Officer. o Clinical core. The STAART Center will provide well-characterized patients, patient and family information, and biological samples from persons with autism and appropriate control subjects for center research projects and for collaborative research projects across the STAART Centers Program. The clinical core serves the functions of patient and control subject recruitment, evaluation, and diagnosis; establishing and maintaining a subject registry; longitudinal follow up of patient and control subjects; acquisition of clinical and laboratory data; and data coordination and biostatistical analysis (if not included as a function of the administrative core or a separate data core). A research database that maintains confidentiality of all patient and control subject records should be established at each STAART Center. A clinical core may perform a limited amount of developmental work, but should not directly be used as a mechanism to fund research per se. The developmental work allowable in a clinical core must be directly related to the function of the core. It may be directed toward improving and expanding the core functions, e.g., improving existing diagnostic strategies, or developing additional methodologies, techniques or services. Proposed developmental work should be described as completely as possible in the application. Planning for patient and appropriate control subject recruitment should include sensitivity to ethical concerns, research design and biostatistical analysis. While conducting clinical treatment trials is one function of a clinical core, it should not be the major effort of the core. The application should include a description of the types (with specific examples) of research projects and clinical trials that will use the core and what benefits will obtain to other research activities from the existence of the clinical core. The proposed procedures for allocating access to patient and control subjects across the STAART projects within the center should be described. It is important to note that the only patient care costs that can appropriately be supported by STAART funds are those that are essential for research activities. Thus, it is important for each application, whether or not a clinical core is proposed, to describe the local resources available, the institutional commitment to maintaining clinical resources, and the way in which the already existing and the planned resources would be used to provide recruitment, referral, and information resources for patients and their families. The aspects of the Act relevant to these issues should be directly and comprehensively addressed in the application. Applicants must demonstrate a data management capability either by creating a feasible data core or by having a clearly defined data management section in the administrative or clinical core. In any case, data management should also include biostatistical consulting to the scientific members of the center. o Scope of appropriate subject populations. STAART studies can appropriately focus on any of the autism spectrum disorders and on either children or adults with these disorders or at risk for these disorders, and comparison groups appropriate for the scientific questions proposed, for example, people with fragile X, obsessive compulsive disorder, Williams syndrome, mental retardation, schizophrenia, or normally developing children or adults. The primary criteria for determining inclusion of a particular subject pool are scientific. That is, the applicant must justify the inclusion of particular subject groups as being of scientific interest and as being justified given the hypothesis being tested, the experimental design, and feasibility issues. Efforts to recruit diverse population subgroups including children, minorities and women must be outlined. o Neuropathology and genetics activities. It is anticipated that the STAART Centers Program will offer important opportunities for enhanced collaborative collection of materials and data in the areas of genetics and neuropathology. Although, not every center may wish to propose substantive cores or projects in these areas, each center applicant should indicate, through core and project proposals, or through a statement of intent included in the application, their intention to participate in collaborative STAART activities in these areas. Possible Additional Cores The STAART Centers Program will support additional cores that provide opportunities for scientific accomplishments beyond those attainable solely through support of the suggested cores. It is important to note that support should not be requested for cores that only replace or centralize resources supported on individual project grants. In a Center grant application, it is not sufficient for the principal investigator merely to identify such centralized resources. Rather, it must be demonstrated exactly how each core would augment or enhance the present capabilities of the investigators and make possible new activities. There should be a thorough discussion of the project(s) that will use resources of additional cores. Genetics Data Sharing in the STAART Program NIH has a strong interest in the sharing of data and other resources produced through its funding, and has long-standing policies in this area (for the most recent statement, see the NIH Grants Policy Statement, page II-62, "Unique Research Resources," published in October 1998, related to the distribution of unique research resources produced with DHHS funding (http://grants.nih.gov/grants/policy/nihgps/). More specific policies have been promulgated from time to time to address the needs of particular areas of research. For example, NIH has worked with journals and databases to encourage the rapid placement of unpublished DNA sequence data and crystallographic coordinates into public databases. The National Human Genome Research Institute has a policy that all genomic data, whether published or not, should be shared as rapidly as possible and placed in the public domain http://www.nhgri.nih.gov/Grant_info/Funding/Statements/RFA/new_data_release.h tml. For grantees engaged in large-scale sequencing, the policy specifies data release within 24 hours of generation http://www.nhgri.nih.gov/Grant_info/Funding/Statements/RFA/data_release.html. After extensive discussion with mental health and human genetics researchers and advocacy members, a Genetics Workgroup of the National Advisory Mental Health Council (NAMHC) recommended that the National Institute of Mental Health (NIMH) draft a policy that provides for the sharing of genetic materials after a 12- to 18-month proprietary period. The workgroup report is available at http://www.nimh.nih.gov/research/genetics.htm. It was also recommended that this policy include all elements of the guidelines developed by NIH and the Department of Energy (DOE) to address the special needs of genome research (http://www.nhgri.nih.gov/Grant_info/Funding/Statements/data_release.html). Sharing within the scientific community of genetic material and data collected in large-scale human genetic studies has been a guiding principle of NIMH's Human Genetics Initiative http://zork.wustl.edu/nimh/. Each application for STAART support must include a plan for the sharing of genetic materials and data. This plan will be evaluated during the peer review of the application. This sharing plan should address the issues raised in the following paragraphs. The timeline for sharing of genetic data will be compatible with the timeline for sharing of other types of data as described under SPECIFIC REQUIREMENTS - TERMS AND CONDITIONS OF AWARD, under 6. Public Domain of Data (below). Creation of high-quality lymphoblastoid cell lines from blood samples establishes an infinitely renewable source of DNA for subsequent genetic analyses. In addition, these biological materials will be an invaluable resource for future studies that employ genetic maps of much higher density (e.g., those with single nucleotide polymorphisms as a basis) and that employ efficient technologies to study gene function and expression. Cell lines are an essential resource to permit broad sharing of data and biomaterials for genetic analyses in the wider scientific community. Therefore, it is expected that permanent cell lines will be established for subjects studied in STAART projects and that these will be shared with the scientific community. Any proposed use of cell lines in STAART projects other than for sharing will require a compelling scientific rationale in the application. Appropriate arrangements should be included in the proposed sharing plan. It is expected that the information to be shared includes clinical, diagnostic, and pedigree structure information (excluding all personal identifiers), in addition to cell lines and DNA. It is expected that the data sharing plan will include the following elements: 1) the creation of comprehensive and verified databases that contain clinical, diagnostic, pedigree structure, and genotypic information collected and produced in the STAART Center; 2) the establishment of high-quality cell lines, from which DNA will be extracted and stored, for all subjects studied from whom blood samples have been obtained; 3) mechanisms by which all databases and biological materials (DNA samples, cell lines) are widely distributed to qualified investigators in the scientific community; 4) a protocol and criteria for wide dissemination of these data and materials; and 5) a timetable for distribution. The plan will be considered part of the scientific methodology for carrying out the research and, as such, the adequacy of the plan will be considered in determining whether the project shall be funded. The sharing plan as approved, after negotiation with the applicant when necessary, will be a condition of the award. It is NIH's position that dissemination of data and biomaterials via individual laboratories and Web sites is not sufficient, as it would force interested investigators to have to search several different data collections to make use of the results. In addition, differences in protocols across projects for creating databases, establishing cell lines, and extracting DNA may make it impossible for researchers to combine information for integrated genetic analyses. It is highly preferable that data and materials generated in such grants should be placed in common, accessible cell repositories and databases that are widely available to investigators in the scientific community. Such data management and cell repository facilities include the NIMH Center for Genetic Studies (http://zork.wustl.edu/nimh/) and the Autism Genetic Resources Exchange (AGRE; http://www.agre.org/). General Data Sharing Policies and Data Coordination Facility for the STAART Centers Program It is expected that the STAART Program will become a valuable resource for research advances in the study of autism. The data generated by this resource will be extremely important and their impact will be optimized only by implementing successful data sharing policies and data storage and management infrastructure. The specifics of the policies that will eventually be implemented will be determined among the funded centers and NIH staff in meetings and negotiations conducted after the initial group of centers is funded. These policies will include a variety of types of data and materials. It is anticipated that the STAART Program will establish and support a centralized data management facility that will collect, store, coordinate and distribute data from all member centers. This will facilitate the standardization and usefulness of the information collected at the various sites. A separate RFA for proposals to establish and operate the centralized data facility will be issued in the future. RESEARCH PROJECTS Applications must include a minimum of three and a maximum of six proposed research projects. The research projects should be proposed for five years of funding and incorporate the latest techniques and propose studies that will advance our understanding of the basic and clinical underpinnings of autism in areas such as etiology, genetics, pathogenesis, epidemiology, diagnosis, therapeutic interventions, patient management, and care giver issues. The projects should be similar in quality and scope to moderately sized R01 grants and subprojects of program project grants. For projects using patients, it is essential that the expectations for numbers of subjects be clearly stated and that the proposed source of these subjects be identified so that the overall picture of subject recruitment and availability can be critically evaluated for the entire center. It is preferable that the center projects demonstrate a high level of interrelatedness among themselves. The rationale for inclusion in the center, rather than implementing these as individually supported projects (e.g., via R01 support) should be provided. In order for an application to receive funding as a STAART Center, there must be at least 3 fundable research projects, at least one of which must be a treatment study. MEETINGS In order to assure active collaboration with other STAART Centers, the Director, Co-Director, project directors, and other key personnel should attend STAART Centers Program annual meetings and other ad hoc meetings that may be called to share research findings and plan for collaborative research projects or to refine and standardize operating procedures among the Centers. The STAART application should include funds for this travel. In the first year of STAART funding for each center, funding should be requested for an additional initial meeting of Center Directors and key personnel with NIH staff to decide on common diagnostic procedures, research tools, and to implement decision-making processes that are appropriate for the cooperative agreement mechanism. MECHANISM OF SUPPORT This RFA will use the National Institutes of Health (NIH) specialized cooperative research center (U54) award mechanism, an "assistance" mechanism (rather than an "acquisition" mechanism) in which substantial NIH scientific and/or programmatic involvement with the awardee is anticipated during performance of the activity. Under the cooperative agreement, the NIH purpose is to support and/or stimulate the recipient's activity by involvement in and otherwise working jointly with the award recipient in a partner role, but it is not to assume direction, prime responsibility, or a dominant role in the activity. Details of the responsibilities, relationships, and governance of the studies to be funded under cooperative agreements are discussed below under Terms and Conditions of Award. Potential applicants may obtain the NICHD U54 Specialized Cooperative Research Center Grant Guidelines at http://www.nichd.nih.gov/funding/mechanism/u54_guide.cfm. With certain exceptions, specified below, the information provided there is applicable to this RFA, including the preparation of applications. Applicants should request five years of support. It is anticipated that competitive renewal applications for a second 5-year period will be allowed. Individual projects that are developed as outgrowths of a STAART Center grant and are no longer an integral part of the center should seek independent funding. USE OF THE COOPERATIVE AGREEMENT MECHANISM The use of a Cooperative Agreement Mechanism for this RFA is intended to enhance coordination among STAART Centers in order to increase the impact of the STAART Centers Program on the public health issues of autism and to better achieve the goals of the Children's Health Act. The U54 mechanism implements a process of NIH coordination, guidance, and ongoing evaluation. For example, it will permit NIH participation in a process of standardizing diagnostic and other tools across the STAART Centers in collaboration with the Center Directors and investigators. It will permit awardee and NIH participation in the Steering Committee (described below) that will make decisions about collaborative studies that will use the resources of multiple centers, thus exceeding the capabilities present in any one center. FUNDS AVAILABLE Each center application may request a maximum of $1.2 million per year direct costs. Facilities and Administration (F&A) costs on subcontracts will be listed as direct costs on budget pages as is the usual NIH practice, but they will not count against the cap of $1.2 million. The estimated total funds (direct and F&A costs) available for support for all awards made under this and subsequent RFAs for the STAART Centers Program are anticipated to be $12 million per year. This total amount will be used to fund the complement of at least 5 centers, a data coordination center, and collaborative projects among the centers. The number of centers funded through the two rounds of competition will be at least 5 and the total number will depend upon the merit of the applications received and the funds available. The award of grants pursuant to this RFA is contingent upon the availability of funds for this purpose. Only applications of sufficiently high merit will be funded. The majority of the $12 million pool of funds will be distributed to successful center applicants to support the activities specific to each center. A separate portion of this pool of funds will be distributed to centers to fund specific cooperative projects among the centers, and another portion of the pool will be used to fund a data coordination center for which there will be a separate RFA in the future. The exact nature of the cooperative studies will be determined by the Steering Committee of the STAART Centers Program. Investigator-initiated requests for competitive supplements will not be allowed in the STAART Program. 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 Applications prepared for this competition may propose multi-institutional consortium arrangements. While the applicant institution must be domestic, foreign institutions may be involved in a consortium. For example, a project within the center may be located at a foreign institution and supported through a subcontract. INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS 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 TERMS AND CONDITIONS OF AWARD As part of the U54 Cooperative Center Grant process, the following Terms and Conditions of Award and details of the arbitration procedures pertaining to the scope and nature of the interaction between the NIH staff and the participating awardees will be incorporated into the Notice of Grant Award and provided to the Principal Investigator and the institutional official at the time of award. These procedures will be in addition to the customary programmatic and financial negotiations that occur in the administration of grants. Cooperative agreements are assistance mechanisms subject to the same administrative requirements as grants. The special Terms and Conditions of Award are in addition to, and not in lieu of, otherwise applicable OMB administrative guidelines, HHS Grant Administration Regulations at 45 CFR Part 74 and 92, and other HHS, PHS, and NIH grant administration policies and procedures. Cooperative Agreements are subject to the administrative requirements outlined in pertinent OMB, HHS, PHS, and NIH guidelines, with particular emphasis on HHS regulations at 42 CFR Part 52 and 45 CFR Part 74. Facilities and Administrative Cost (indirect cost) award procedures will apply to cooperative agreement awards in the same manner as for grants. The administrative and funding instrument used for this program is a Cooperative Agreement (U54), an "assistance" mechanism (rather than an "acquisition" mechanism) in which substantial NIH scientific and/or programmatic involvement with the awardee is anticipated during performance of the activity. Under the cooperative agreement, the NIH purpose is to support and/or stimulate the recipient's activity by involvement in and otherwise working jointly with the award recipient in a partner role, but it is not to assume direction, prime responsibility, or a dominant role in the activity. Consistent with this concept, the dominant role and prime responsibility for the activity resides with the awardee(s) for the project as a whole, although specific tasks and activities in carrying out the studies will be shared among the awardees and an NIH Science Officer. 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 Awardees have primary authorities and responsibilities to define objectives and approaches, and to plan, conduct, analyze, and publish results, interpretations, and conclusions of their studies. The primary responsibilities of the awardees are to: o Define the research objectives o Design the necessary research protocols o Conduct specific studies o Analyze and interpret research data o Propose protocol modifications as required o Establish an External Consultants Committee to the center o Participate in STAART collaborative projects approved by the Steering Committee o Serve on the STAART Steering Committee o Agree to sharing of data and biological materials in accordance with approved data sharing plans o Agree to participate according to Steering Committee policies in a centralized data facility that will be established o Interact with the FDA concerning clinical investigations, when appropriate o Provide information to the NIH Science Officer and NIH Program Officer concerning progress o Maintain career development opportunities to encourage new investigators to work in the field of autism research o Abide by all scientific, practical and policy decisions of the Steering Committee Awardees will retain custody of and primary rights to their data and intellectual property developed under the award subject to current government policies regarding rights of access as consistent with current HHS, PHS, and NIH policies and subject to the terms and conditions of this RFA. 2. NIH Responsibilities NIH Science Officers: NIH Science Officers will be NIH program staff who will have substantial scientific involvement during the conduct of this activity, through technical assistance, advice, and coordination above and beyond normal program stewardship for grants. Each center will have a designated NIH Science Officer, and a given individual may be the NIH Science Officer for more than one center. The NIH Science Officers will be selected by the NIH/ACC. The degree of involvement by the NIH Science Officers will include the following: o Assist in avoiding unwarranted duplication of effort across centers; help coordinate collaborative research efforts that involve multiple centers o Review and comment on critical stages in the research program before subsequent stages are implemented o Assist in the interaction between the awardee and the FDA, when appropriate o Assist in the interaction between the awardee and investigators of other institutions as well as between the awardee and potential commercial sponsors o Retain the option of recommending termination of studies if technical performance falls below acceptable standards, or when specific lines of research cannot be effectively pursued in a timely manner o Retain the option to recommend additional research endeavors within the constraints of the approved research and negotiated budget o Serve on the STAART Steering Committee NIH Program Officer: NIH will appoint a Program Officer who will have program oversight responsibilities for each center and for the entire STAART Program. This individual will not be a Science Officer(s). The Program Officer will: o Have the option to recommend withholding support to a participating institution if technical performance requirements are not met o Exercise the normal stewardship responsibilities of an NIH Program Officer o Carry out continuous review of all activities to ensure objectives are being met o Will not be a member of the STAART Steering Committee 3. Data Safety and Monitoring Board NIH will establish a Data Safety and Monitoring Board (specifics below). 4. Collaborative Responsibilities/Steering Committee Overall coordination of the Program, consistent with the stated intent of the RFA, will be done by a Steering Committee consisting of the Directors of each of the participating centers, the PI of the Data Coordination Center, and NIH Science Officers. Each Center Director (or designee) will have one vote. Science Officers may vote, and their total votes will count 1/2 as much as the total votes of the Center Directors. Center membership on the Steering Committee becomes effective upon issuance of the Notice of Grant Award. The Steering Committee may establish additional by-laws, subcommittees, or workgroups for specific tasks. Science Officers may not chair any committee or subcommittee. The Steering Committee meetings will be convened at least once yearly. The purpose of these meetings is to assess scientific progress, identify new research opportunities, establish priorities, and discuss strategy. Decisions will be made by a majority vote of a quorum, with an attempt for consensus when possible. A quorum is the presence of a majority of the Center Directors and at least one Science Officer. The Steering Committee can convene through telephone conference or in person. Outside consultants/experts may be asked to participate in these discussions as nonvoting advisors. Collaborative projects among the STAART Centers will require Steering Committee approval. The Steering Committee may also be used to endorse research instruments that will be used across multiple centers. Responsibilities of the Steering Committee members include: o Finalizing collaborative study plans, including design, assessment instruments, component protocols, and detailed implementation procedures o Abiding by and directing the study plan for collaborative projects determined by the Steering Committee o Monitoring collaborative studies and developing and implementing quality control procedures o Conserving grant funds in the service of the common objectives and of the research plan agreed on by the Steering Committee o 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 Steering Committee o Evaluating and reporting study results: defining rules regarding access to data and publication of findings from analyses of the data set o Abiding by all scientific, practical, and policy decisions of the Steering Committee Any Center Director who considers a Steering Committee decision unacceptable may appeal by following the arbitration procedure described below. 5. Arbitration Process When agreement between an awardee and NIH staff or between awardees cannot be reached on scientific/programmatic issues that may arise after the award is made, an arbitration panel will be formed. The arbitration panel will consist of one person selected by the Directors of the Centers, one person selected by the NIH, and a third person selected by both NIH staff and the Directors. The decision of the arbitration panel, by majority vote, will be binding. The special arbitration procedure in no way affects the right of an awardee 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. 6. Public Domain of Data The data from this cooperative agreement will first be available to be analyzed and interpreted by the collaborators in the project. 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, the awardees will make data of all types available to the larger research community no more than 24 months from the date after which the final wave of data for a particular project have been collected and cleaned. More rapid sharing of data is encouraged. 7. Scientific Advisory Board The Steering Committee will appoint a Scientific Advisory Board of independent experts in the research areas represented among the centers. This board will advise the Steering Committee on the scientific aspects of STAART activities, including providing review of collaborative studies that will need to be approved by the Steering Committee before being implemented. 8. Funding of Collaborative Projects Collaborative projects developed by the Steering Committee will be submitted to the NIH Program Officer for potential funding after the Steering Committee has obtained feedback from the Scientific Advisory Board. The Program Officer will make a final decision based on Steering Group deliberations, Scientific Advisory Board feedback to the Steering Group, Steering Group responses to that feedback, and Program Officer consultations with individual outside experts. The Program Officer may decide to have a collaborative project submitted by the Steering Group as a competitive supplement that undergoes NIH-organized peer review prior to the Program Officer's final decision. 9. Progress Reviews Progress of the project will be reviewed annually by the NIH Program Officer at the time each continuation application is considered for funding to assure that satisfactory progress is being made in achieving the project objectives and that each site is following the procedures recommended and approved by the Steering Committee. During the first year of funding, and during subsequent years, if deemed necessary by the Program Officer, reviews will be more frequent. Should problems arise in the conduct of the study, the NIH Program Officer may require that the awardee submit quarterly reports on progress and fiscal matters. By acceptance of this award, the awardee agrees 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. WHERE TO SEND INQUIRIES We encourage inquiries concerning this RFA and welcome the opportunity to answer questions from potential applicants. In addition, the NIH will establish an internet site at: http://www.nimh.nih.gov/grants/autismcentersrfa.cfm in order to provide answers to commonly asked questions from potential applicants and to post points of clarification regarding this RFA. 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: Steve Foote, Ph.D. Division of Neuroscience and Basic Behavioral Science National Institute of Mental Health 6001 Executive Boulevard, Room 7204, MSC-9645 Bethesda, MD 20892-9645 Rockville, MD 20852(For express/overnight services) Telephone: (301) 443-3563 FAX: (301) 443-1731 Email: sfoote@mail.nih.gov L.R. Stanford, Ph.D. National Institute of Child Health and Human Development 6100 Executive Boulevard, Room 4B09, MSC 7510 Bethesda, MD 20892-7510 Telephone: (301) 496-1383 FAX: (301) 496-3791 Email: lstanfor@mail.nih.gov Deborah Hirtz M.D. Clinical Trials, Division of Extramural Research National Institute of Neurological Disorders and Stroke 6001 Executive Boulevard, Room 2212, MSC 9523 Bethesda, MD 20892-9523 Telephone: (301) 496-5821 FAX: (301) 480-1080 Email: dh83f@nih.gov Judith A. Cooper, Ph.D. Scientific Programs Branch Division of Extramural Research National Institute on Deafness and Other Communication Disorders 6120 Executive Boulevard, Room 400C, MSC-7180 Bethesda, MD 20892-7180 Telephone: (301) 496-5061 FAX: (301) 402-6251 Email: Judith_Cooper@nih.gov Cindy P. Lawler, Ph.D. Division of Extramural Research and Training National Institute of Environmental Health Sciences P.O. Box 12233, MD EC-23 Research Triangle Park, NC 27709 Telephone: (919) 316-4671 FAX: (919) 541-5064 Email: lawler@niehs.nih.gov Direct your questions about financial or grants management matters to: Carol J. Robinson Grants Management Branch Division 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) 443-6885 Email: crobinson@mail.nih.gov Mary E. Daley Grants Management Branch National Institute of Child Health and Human Development Building 6100, Room 8A17, MSC 7510 Bethesda, MD 20892-7510 Telephone: (301) 496-1305 FAX: (301) 402-0915 Email: md74u@nih.gov Gladys Melendez-Bohler, M.S. Grants Management Branch National Institute of Neurological Disorders and Stroke 6001 Executive Boulevard, Room 3290, MSC 9537 Bethesda, MD 20892-9537 Telephone: (301) 496-3929 Fax: (301) 402-0219 Email: gb13y@nih.gov Sara Stone Grants Management Branch National Institute on Deafness and Other Communication Disorders 6120 Executive Boulevard, Room 400B, MSC-7180 Bethesda, MD 20892-7180 Telephone: (301) 402-0909 FAX: (301) 402-1758 Email: Sara_Stone@nih.gov Laura Williams-Boyd Grants Management Branch National Institute of Environmental Health Sciences P.O. Box 12233, MD EC-23 Research Triangle Park, NC 27709 Telephone: (919) 541-7629 FAX: (919) 541-2860 Email: willia27@niehs.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 is to be sent to Dr. Steve Foote at the address listed under INQUIRIES. SUBMITTING AN APPLICATION Applications must be prepared using the PHS 398 research grant application instructions and forms (rev. 5/2001). The PHS 398 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. Applicants are strongly encouraged to call one of the NIH program staff listed under INQUIRIES with any questions regarding the responsiveness of their proposed project to the goals of this RFA. Applications for the U54 grant are to be prepared in a manner consistent with the information presented in this RFA. Applicants may also wish to consult the NICHD U54 Cooperative Specialized Research Center Grant Guidelines, available from the contacts listed under INQUIRIES below, and at: http://www.nichd.nih.gov/funding/mechanism/u54_guide.cfm. SPECIFIC INSTRUCTIONS FOR PREPARING AN APPLICATION Applications are to be submitted on Form PHS 398 (http://grants.nih.gov/grants/funding/phs398/phs398.html). All instructions and guidelines accompanying the PHS 398 are to be followed, with the exception of the sections modified by the specific instructions described below. Also, applicants can obtain any updated information about preparing an application at: http://www.nimh.nih.gov/grants/autismcentersrfa.cfm. In lieu of the preprinted Table of Contents outline on Form Page 3 of PHS 398, a Table of Contents should be prepared listing all of the major sections described below and paginated to enable reviewers to find specific information readily. The Table of Contents should contain the information described below. It should be divided into the following sections: Section I - General Information, Section II - Research Plan, and Section III - Appendix. The following guidelines will provide directions and descriptions for preparing each section. Major areas to be listed and paginated in the Table of Contents are underlined. SECTION I - GENERAL INFORMATION A. FACE PAGE Complete all items on the application's face page. This is Form Page 1 of the application; number succeeding pages consecutively. On line 2, enter the appropriate Request for Applications (RFA) number and title, and mark the YES box. B. DESCRIPTION AND PERSONNEL On Form Page 2, describe briefly the research program, indicate the emphasis of the component research projects, and identify the purposes of the proposed cores. List key scientific and technical personnel participating in the Center. Use continuation pages as necessary, numbering consecutively. C. TABLE OF CONTENTS Prepare the Table of Contents as noted above. The major areas to be listed are enumerated in these instructions. D. BUDGET ESTIMATES Prepare a series of composite Budget Tables for the center as requested below. A separate detailed budget is required for each research project and for each core unit. 1. Composite Budget a. Use Form Page 4, "DETAILED BUDGET FOR INITIAL BUDGET PERIOD," of the PHS 398 to present the total direct cost budget for all requested support for the first year. For each category, such as "PERSONNEL," "EQUIPMENT," etc., list the amount requested for each research project and for each core unit. If consortium arrangements have been made involving other institutions or organizations, include total costs (direct and F&A) associated with such third party participation in the "CONSORTIUM/CONTRACTUAL COSTS" category. Costs for purchased services should be itemized under "OTHER EXPENSES." b. Use Form Page 5, "BUDGET FOR ENTIRE PROPOSED PROJECT PERIOD," of the PHS 398 to prepare a budget, by category, that provides direct cost totals for each year of requested support. 2. Individual Project and Core Budgets a. First year (use Form Page 4 of PHS 398 for each) b. Total project period (use Form Page 5 of PHS 398 for each) Consortium Budgets (if applicable) should be presented as described in Item 1 (Composite Budget), including a budget for the entire proposed project period. Total Direct and F&A costs of sub-awardees are to be shown under "CONSORTIUM/CONTRACTUAL COSTS" on individual research project or core budgets and a detailed consortium budget is to be inserted following the appropriate research project or core budgets. Budget Justifications: Describe the specific functions of key scientific and technical personnel, consultants, collaborators, and support staff. For all years, explain and justify any unusual items such as major equipment or alterations and renovations. For future years of support requested, justify any significant increases in any category over the first 12-month budget period. Identify such significant increases with asterisks against the appropriate amounts. E. BIOGRAPHICAL SKETCH Biographical sketches are required for all key scientific and technical personnel participating in the research projects and core units as listed on Form Page 2. Beginning with the Center Director, and following in alphabetical order, submit biographical sketches as described in the "Instructions for Form PHS- 398," using Form Page 6. F. RESOURCES Complete the "RESOURCES" section on Form Page 8 of the PHS 398 for the overall Center. Briefly describe the features of the institutional environment that are or would be relevant to the effective implementation of the proposed program. As appropriate, describe available resources, such as clinical and laboratory facilities, participating and affiliated units, patient populations, geographical distribution of space and personnel, and consultative resources. Use continuation pages as needed. SECTION II - RESEARCH PLAN Include a detailed Table of Contents with pagination (numeric only) at the beginning of Section II. Identify each research project or core unit by title, and assign each research project a number (I, II, III) and each core unit a capital letter (A,B,C) that reflects the order in which the research projects and core units are presented in the application research plan. For each research project and core unit, provide the name of the Principal Investigator or Core Director, and biographical sketches for personnel not identified previously. REVISED APPLICATIONS: In order for revised applications to be accepted for review, there must be substantial changes in the content of the application. Include an Introduction to Revised Application (3-page limit; insert just before the Introductory Overview) that summarizes the substantial additions, deletions, and changes, and responds to the criticisms and issues raised in the summary statement. The changes in the Research Plan must be clearly marked by appropriate bracketing, indenting, or changing of typography, unless the changes are so extensive as to include most of the text. This exception should be explained in the Introduction to Revised Application. Do not underline or shade changes. The Preliminary Studies/Progress Report sections should incorporate any work done since the prior version was submitted. For each core or project that is substantially revised, an additional, one-page Introduction to Revised Application can be inserted just before the Research Project Plan or just before the individual core description. Acceptance of a revised application automatically withdraws the prior version, since two versions of the same application cannot be simultaneously pending. A. INTRODUCTORY OVERVIEW (20-page limit) Provide an overview of the entire proposed center describing the central theme and goals. Describe how the overall center can achieve its major objectives. Explain the proposed contribution of each of the projects in achieving the objectives of the center. Furthermore, the administrative arrangements and support necessary to effect the research should be carefully described in the application. Shared resources should be described. In addition, provide detailed information on collaborations, recruitment, facilities and resources. 1. Purpose and Objectives of the Center. Discuss the philosophy and objectives of the Center and general plans for the proposed grant period. Discuss the composite research program, highlighting its central theme. List by title and investigator the component research projects and core units, showing the interrelationship between the research projects and the core units and their relationship to the central theme. Describe relevant history leading up to the Center application. 2. Administration, Organization, and Operation of the Center. Include information on the support and commitment of the parent institution for the Center, the authority of the Center Director, the use of advisory committees, and the method of determining core access and space assignment. Describe organizational framework and provide an organizational chart. 3. Assurances and Collaborative Agreements. Any arrangements for collaborative and cooperative endeavors or subcontracting should be highlighted. Letters of Intent to Collaborate and Letters of Agreement from consultants should be referenced here and included at the end of the appropriate research project or core unit. B. PROGRESS REPORT/PRELIMINARY DATA (5-page limit) This section should be used to present, in condensed form, previously published and/or preliminary data that are relevant to proposed center activities and research projects that will be unique to the center and will involve collaboration across projects and/or cores within the center. Since individual projects, and preliminary data relevant to them, will be described in the following section, only those collaborative activities/projects that bear directly on the proposed center activities should be summarized here. For ongoing projects or existing cores, list relevant publications published or accepted for publication during the past five-years. The list of publications does not count against the page limit. C. RESEARCH PROJECT DESCRIPTION Identify each project by a Roman numeral (I, II, III ) and a title. For each component research project, a full description is to be provided following the format presented in Form PHS 398. Begin the presentation of each component research project on a separate cover page. For each project, include the following information: 1. Introductory Information a. Indicate: Project Title Project Principal Investigator, title, location Other investigators, consultants, and collaborators, titles (Associate Professor, Postdoctoral Fellow, student). b. Abstract of Research Plan (use Form Page 2 of PHS 398) 2. Research Project Plan (Do not exceed 25 pages for Sections a-d): Discuss the purpose and nature of the project and its relevance to the application's overall theme. Address the following: a. Specific Aims b. Background and Significance c. Preliminary Studies d. Research Design and Methods. In addition to usual contents of this section, describe the research project's use of core unit services, including need for the services, and the advantages and cost effectiveness of core unit usage for the project. e. Human Subjects. For research involving human subjects, this section must address the inclusion of women, minorities and their subgroups, and children as research subjects, following relevant policy announcements. f. Vertebrate Animals g. Consultants h. Collaborative arrangements, including pertinent letters of assurance and intent. i. Literature Cited D. CORE DESCRIPTIONS Identify each proposed core unit by a letter (A, B, C...) and a title (Administrative, Molecular/Cellular...). For each core unit, a full description is to be provided following the format presented below. Do not exceed a total of 25 pages for each core description. 1. Overall Introduction (Do not exceed 3 pages, excluding the summary table) Identify the proposed core units by title; briefly summarize the overall objectives of each core unit; present the organizational framework or chart; highlight the decision-making process for use of core unit services described; and present plans for quality control. Complete a summary table for the first year of the proposed grant by showing the quantitative use (percent) of each core unit by the component research projects, presented in a format such as that suggested in Table II (see below). Begin the presentation of each core unit on a separate cover page. For each proposed core, address cost effectiveness and plans for quality control, as appropriate. For each core, or its equivalent in the center, include the following information: 2. Administrative Core Unit (if applicable) a. Objective b. Staffing: Description of key professional and support staff functions c. Resources: Description of space and physical resources d. Services Provided: Describe current and projected services to other core units and research projects, and the center as a whole 3. Research Core Units a. Objective b. Staffing: Brief description of scientific, technical, as well as support staff functions c. Resources d. Administration: Description of overall management of the research core unit e. Justification: Description of services provided and their bearing on productivity and quality, as well as documentation of cost-effectiveness and quality control f. Utilization: Indicate past and/or current usage (e.g., assays performed, animals supplied, etc.) and list projects proposed for core usage, identified by full title, such as displayed in sample format shown in Table II at http://www.nichd.nih.gov/funding/mechanism/u54_guide.cfm#appendix1 g. If core service involves human subjects (e.g., recruitment; screening), discuss the inclusion of women, minorities and their subgroups, and children as research subjects, following relevant policy announcements (see RFA for references) E. CHECKLIST - As required in Form PHS 398 SECTION III - APPENDIX Include materials as appropriate (see PHS 398). Other Support and Core Usage information should be provided in the format shown in sample Tables I and II at http://www.nichd.nih.gov/funding/mechanism/u54_guide.cfm#appendix1. SUBMISSION INSTRUCTIONS 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, 2 additional copies of the application, including all 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 courier/express service) Telephone: (301) 443-3367 FAX: (301) 443-4720 Email: jnoronha@mail.nih.gov APPLICATION PROCESSING: Applications must be received by 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. 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. The CSR will not accept any application that is essentially the same as one already reviewed. This does not preclude the submission of substantial revisions of applications already reviewed, but such applications must include an Introduction addressing the previous critique. All applications will initially be assigned to NIMH. Following review, all of the participating institutes will make decisions about their respective roles in funding and in the distribution of the responsibilities of NIH staff. These decisions will be based on the relevance of scientific activities in specific centers to institute missions and the expertise of NIH staff. Applicants from institutions that have a General Clinical Research Center (GCRC) funded by the NIH National Center for Research Resources may wish to identify the GCRC as a resource for conducting the proposed research. If so, a letter of agreement from either the GCRC Program Director or Principal Investigator should be included with the application. PEER REVIEW PROCESS Upon receipt, applications will be reviewed for completeness by the CSR and for responsiveness to this RFA by NIH program staff. Incomplete and/or non- responsive applications will be returned to the applicant without further consideration. 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 NIH in accordance with the review criteria stated below. As part of the initial merit review, all applications will: o Receive a written critique 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, may be discussed and assigned a priority score o Receive a second level review by the appropriate Institute's National Advisory 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 discuss the following aspects of your application in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals: o Significance o Approach o Innovation o Investigator o Environment The scientific review group will address and consider each of these criteria in assigning your application's overall score, weighting them as appropriate for each application. Your 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, you may propose to carry out important work that by its nature is not innovative but is essential to move a field forward. 1. Significance. Does this study address an important problem? 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? 2. Approach. Are the conceptual framework, design, methods, and analyses adequately developed, well-integrated, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics? 3. Innovation. Does the project employ novel concepts, approaches or method? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? Special emphasis will be placed on integration of basic and clinical research components relevant to autism into promising synergistic proposals. 4. Investigator. Are the investigators appropriately trained and well suited to carry out this work? 5. Environment. Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed experiments take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of institutional support? The initial review group will also examine: The appropriateness of proposed project budget and duration; the adequacy of plans to include children and both genders and minorities and their subgroups as appropriate for the scientific goals of the research and plans for the recruitment and retention of subjects; the provisions for the protection of human and animal subjects; and the safety of the research environment. ADDITIONAL REVIEW CRITERIA SPECIFIC TO STAART CENTERS PROGRAM Listed below are additional review criteria to be used in the evaluation of STAART Center applications; these criteria will be applied to applications by evaluating preliminary work to organize the center, history of autism research by the applicants, and plans for implementation of the proposed program. Applicants should clearly demonstrate the ways in which the STAART Center would contribute to the growth of local research programs, support on-going projects, cooperate with other STAART Centers in collaborative research, and attract both senior and new investigators to autism research. A. Center as a Whole 1) The potential for impact of the STAART Center on the progress of autism research locally and nationally. 2) Extent of "centerness," i.e., does the center as a whole serve a purpose greater than the sum of the individual components? 3) Effectiveness of the proposed center in meeting the requirements of the Children's Health Act. B. Cores 1) How effective is the overall organization of the proposed cores in relation to the center's total research program? 2) Will each core enhance collaborative and/or interdisciplinary research within the STAART Center and the wider research community? 3) Would any proposed optional cores duplicate existing resources or services? If so, are the requested new resources justified? 4) Is the core useful to multiple projects? each core must provide essential facilities or service for two or more subprojects judged to have substantial scientific merit. 5) The quality of the facilities or services provided by this core (including procedures, techniques, and quality control and criteria for prioritization of usage). 6) The qualifications, experience, and commitment of the personnel involved in the core. C. Projects Projects will be evaluated by the standard NIH criteria listed above and by their integration into the center and their potential contributions to other projects in the center. It should be noted that each meritorious subproject will receive a priority score and that these ratings will appear in the summary statement. Individual subprojects judged as "Not Recommended for Further Consideration" (because the proposed research is not significant and substantial when judged against the above criteria, or there are other significant concerns) will be deleted from the center. It is anticipated that inclusion of a 'weak' or 'non-essential' project in the application will reflect poorly on the overall program. In addition, NIH retains the right to delete individual projects when making final funding decisions regarding STAART Center applications, for example, those that score below the current R01 funding level. It will be mandatory for each successful application to include at least 3 fundable research projects. At least one of the fundable projects must be a treatment study dealing with a topic such as outcome measures, treatment development, innovative treatment possibilities, effects of pretreatment measures on treatment selection, treatment efficacy or a similar topic. D. Data Management 1) Are data management and support procedures developed sufficiently to allow STAART investigators to access and utilize data, for example, data from the clinical core? Does the center provide statistical design and support to STAART investigators? 2) Is there a sound plan to manage and utilize clinical and neuropathological data? Are adequate safeguards to protect patient confidentiality addressed? Are staffing, hardware and software adequate? E. Program Administration 1) Does the PI have the scientific and organizational vision and experience to serve effectively as the Center Director? 2) Is there evidence of management capabilities for the Center that include fiscal administration, procurement, property and personnel management, planning, and budgeting? F. Facilities 1) Are facilities adequate for the overall functions of the center and to implement the goals of the STAART Centers Program? G. Institutional Commitment 1) Is there evidence for institutional commitment to the program, including provision of funding, space, faculty positions for autism research and other essential STAART functions, and/or commitments for construction or renovation? 2) Are the research environment and resources, including equipment and facilities, adequate? Is there potential for interaction with scientists from other departments and components? A site visit is not a required part of the review process. Applicants should ensure that their written applications are complete and self-contained. RECEIPT AND REVIEW SCHEDULE Letter of Intent Receipt Date: June 27, 2002 Application Receipt Date: August 29, 2002 Scientific Review Date: February/March 2003 Advisory Council Date: May 2003 Earliest Date of Award: July 1, 2003 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 MONITORING PLAN AND DATA SAFETY AND MONITORING BOARD: Research components involving Phase I and II clinical trials must include provisions for assessment of patient eligibility and status, rigorous data management, quality assurance, and auditing procedures. In addition, it is NIH policy that all clinical trials require data and safety monitoring, with the method and degree of monitoring being commensurate with the risks (NIH Policy for Data Safety and Monitoring, NIH Guide for Grants and Contracts, June 12, 1998: http://grants.nih.gov/grants/guide/notice-files/not98-084.html). For the STAART Centers Program, an independent panel of experts, constituting a Data Safety and Monitoring Board, will be appointed by NIH to monitor safety, quality of data collection, and integrity of the study. The costs of the DSMB will come from an NIH source independent of the cooperative agreement. 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 AMENDMENT "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. HUMAN EMBRYONIC STEM CELLS (hESC): Criteria for federal funding of research on hESCs can be found at http://grants.nih.gov/grants/stem_cells.htm 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 (see http://escr.nih.gov). It is the responsibility of the applicant to provide the official NIH identifier(s)for the hESC line(s)to be used in the proposed research. Applications that do not provide this information will be returned without review. 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. 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 Nos 93.242 (NIMH), 93.865 (NICHD), 93.853 (NINDS), 93.173 (NIDCD), and 93.113 (NIEHS). Awards are made under authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and administered under NIH grants policies and Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. The Public Health Service strongly encourages all grant and contract recipients to provide a smoke-free workplace and promote the non-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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