NIGMS CENTERS OF EXCELLENCE IN COMPLEX BIOMEDICAL SYSTEMS RESEARCH RELEASE DATE: April 29, 2003 RFA: GM-03-009 National Institute of General Medical Sciences (NIGMS) (http://www.nigms.nih.gov/) CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBER(S): 93.309, 93.821, 93.859, 93.862 Letter of Intent Receipt Date: September 3, 2003 Application Receipt Dates: October 14, 2003 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 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 This document re-announces the National Institute of General Medical Sciences (NIGMS) RFA for the establishment of new academic Centers of Excellence in Complex Biomedical Systems Research (CE/CBSR) that was published in the NIH Guide on January 26, 2001. The goal of the CE/CBSR program is to promote institutional development of pioneering research and training programs focused on quantitative, systems level analysis of biological phenomena of biomedical importance within the NIGMS mission. NIGMS supports fundamental inquiries focused on cell biology and biophysics, genetics and developmental biology, human physiology in the areas of trauma, burn, inflammation, and multiorgan failure, and pharmacology and anesthesiology. NIGMS does not support research focused on diseases that are the domain of other Institutes and Centers within the NIH. The CE/CBSR program also is responsive to the Biomedical Information Science and Technology Initiative (BISTI) and its call for National Programs of Excellence in Biomedical Computing (NPEBC). Non-exclusive examples of appropriate research foci of CE/CBSR Centers are the organization and dynamic behaviors of subcellular, cellular, and developing systems, the relationship of genetic and environmental variation to the expression of phenotype, and the understanding of organ system responses to injury and stress. Approaches might include computationally- based modeling; e.g., of processes such as the cell cycle, pattern formation during embryogenesis, the flux of substrates and intermediates in metabolism, system wide responses to pharmaceuticals, and cellular stress responses. Statistical and other mathematical tools may be used to analyze the genetic architecture of complex traits, and network analysis may be applied to understanding the integrated systemic host responses to trauma, burn, or other injury. The P50 Center Grant mechanism will support the development of multi- investigator teams capable of engaging biomedical complexity with a scope of activities not possible with other funding mechanisms. Activities will encompass research and training, as well as workshops, symposia, and other forms of outreach. Centers will support research activities that may include the development of new instrumentation and methods, bioinformatics infrastructure, and new theoretical frameworks. Training activities may include programs in computational and information sciences. Partnering with undergraduate institutions, especially those with substantial numbers of underrepresented minority students, is encouraged. RESEARCH OBJECTIVES Background The biomedical sciences have undergone a fundamental shift in both the conceptual and technical approaches that can be brought to bear on certain problems of profound importance. These problems center on the understanding of the behavior of biological systems whose function is the product of spatial and temporal ordering of myriad interacting components. Examples of first attempts to understand these phenomena can be found at all levels of biological organization, including the modeling of the genetic circuitry of bacteriophage lambda regulation, the modeling of the yeast cell division cycle, and the quantitation of cellular processes such as metabolic flux and response to stress. At higher levels of organization, modeling approaches are being used to understand the orderly development of biological pattern in model organisms such as Drosophila. At the clinical level, new approaches are being explored to understand the integrated activity of tissues and organs. Part of the impetus for systems-scale approaches rests on recent advances in acquiring data of the necessary quality and quantity to permit computer based modeling. Among the most striking recent examples is the availability of complete DNA sequences for a number of organisms, including humans. This advance has made it feasible to generate a truly comprehensive "parts list" for any organism and to track changes over time. Potentially, the enumeration of all the informational units of the genomes (protein coding regions, regulatory elements), their processed forms, and their positional significance, should be possible and, for some microorganisms, close at hand. The challenges are substantial. A significant fraction of newly identified coding regions have no known relatives in existing indices of function, and the identification of regulatory elements presents a significant informatics challenge. Much progress is being made in adapting existing methods (such as gene inactivation) to high-throughput functional analysis, and developing newer computational approaches grounded in evolutionary theory. A higher order problem presents itself in understanding how the genome-encoded components and the "stuff" of the living state (metabolites, ions, water) are constituted in networks of interacting molecules with particular distributions in time and space. Advances in imaging techniques and analytic methods promise to yield copious quantitative and spatial data on specific molecules in biological systems. Knowledge of the network and changes in its components over time, and the local rules by which the individual components distribute material and information will substantially advance our knowledge. At the organismal level, phenotype must take into account the relationships and interactions of biological and environmental variables. Basic biological systems, including gene sequences, structures, and pathways that direct metabolism and development vary within individuals, among individuals, among populations, and among species. Advances in complex systems level understanding must ultimately include models that account for this variation. Medical, biotechnological, and other uses of biological information increasingly depends on our ability to understand the principles and dynamics that explain the behavior of the system as a whole. Whether the goal is to understand the consequences of disease or injury, or to identify particular molecular targets for drug interventions, or to modify the metabolism of microorganisms to produce medicines, the challenge is "predictability." Predicting how the system of interest will respond to an intervention is a computational problem. For biological systems this challenge is daunting. The effort to get a quantitative "handle" on biological systems and their integrated behavior requires diverse expertise. In particular, contributions from the computational disciplines of engineering, physics, and computer science are needed. The development of new theoretical frameworks will in large part be a mathematical endeavor. As modeling and simulation studies advance in sophistication, there will be a demand for better quality and increased quantities of data, and therefore the development of new instrumentation and methods. The organization and representation of these new data streams, and their integration with preexisting knowledge, will challenge current capabilities in bioinformatics. The organization of projects incorporating multidisciplinary approaches and the recruitment and training of skilled personnel are not simple undertakings, and these CE/CBSR Centers grants are designed to support these activities. In addition to research contributions, successful Centers will provide their home institutions with the means to implement organizational and professional changes that will make interdisciplinary research in complex biological systems and bioinformatics attractive career options for both established and entry level investigators. The institutions will receive the resources to recruit new investigators who have the skills needed to develop new methods and tools, and to develop appropriate training programs in computational and information sciences. In addition, the Centers will disseminate expertise and knowledge through workshops and symposia, and, because the Centers will be pioneering a new era in biological sciences, they will provide outreach activities to undergraduate institutions, including minority-serving institutions. NIGMS currently supports the analysis of complex biological systems through investigator-initiated research project grants, using the R01, P01, R21, and other appropriate grant mechanisms. However, the resources needed to conduct the multi-faceted, multi-disciplinary projects that may be required to achieve significant advances in these complex areas may be beyond the scope of the typical R01 or P01 grant. Therefore, this RFA presents an opportunity for applicants to assemble large teams of investigators from diverse disciplines that may not be possible with other funding mechanisms. High priority will be given to projects that integrate multi-investigator, multi-disciplinary approaches with a high degree of interplay between computational and experimental approaches. Innovation is critical. A variety of organizational models are possible, and it is not the purpose of this announcement to prescribe any particular one. Current initiatives related to CE/CBSR can be found in prior NIGMS program announcements: http://www.nigms.nih.gov/funding/complex_systems.html. Some groups interested in the scope of this RFA might find the P01 mechanism more suited to the scale of their efforts; they should consult the prior announcement at the URL: http://grants.nih.gov/grants/guide/pa-files/ PA-98-077.html. Scope of Research The NIGMS intends to support Centers of Excellence in Complex Biomedical Systems for research areas that 1) are central to its mission, and 2) focus on developing new computational approaches to biomedical complexity. Research areas that historically have been computationally based (e.g., molecular structure and modeling) are excluded as a focus of this Center program. Research projects focusing on disease processes and their specific organ systems are not eligible. NIGMS mission areas for which Centers of Excellence in Complex Biomedical Systems Research would be particularly appropriate include, but are not limited to, the following: o Pattern formation and developmental processes in model systems (e.g., Drosophila, C. elegans, etc.) o Metabolic networks and the control of the flux of substrates, intermediates, and products in cell physiology o Signaling networks and the regulatory dynamics of cellular processes such as cell cycle and apoptosis, and response to environmental stress o Supramolecular machines, such as the replisome, spliceosome, and molecular motor assemblies in cell division and motility o Organ system networks involved in multi-organ failure in shock, trauma, and burn injury o Genetic architecture of biological complexity related to inherited variation and environmental fluctuations. NIGMS strongly encourages investigators who propose to develop applications to discuss their ideas with NIGMS program staff prior to submission to ensure that applications will be responsive to the NIGMS mission and intent for this program. Center Developmental Activities Centers will likely support the development of new mathematical tools, theory, and technologies that foster computational solutions. Examples are network theoretical structures for understanding genetic and physiological regulatory circuitry, systems of equations allowing the description of signaling dynamics, analytical tools to discover the relationship of genotypic variation to phenotype, and computer models of morphological changes during development. The substantial bioinformatics challenge of engaging large data streams and developing models has been highlighted in the BISTI report (http://www.nih.gov/about/director/060399.htm): "To make optimal use of information technology, biomedical researchers need, first of all, the expertise to marry information technology to biology in a productive way. New hardware and software will be needed, together with deepened support and collaboration from experts in allied fields. Inevitably, those needs will grow as biology moves increasingly from a bench-based to a computer-based science, as models replace some experiments and complement others, as lone researchers are supplemented by interdisciplinary teams. The overarching need is for an intellectual fusion of biomedicine and information technology." To this end, Centers may include bioinformatics tool development that could include DNA sequence feature search programs, specialized databases, development of data sharing and representation formats, and data mining algorithms, etc.. The plan may also include the design of new instrumentation that may be required, for example, to obtain time series measurements of multiple parameters of cell and tissue function, including spatial information by imaging technologies. Centers will be expected to provide national leadership in complex systems research. To do so, they will be expected to support training and outreach activities that will insure the flow of information and expertise both into and out of the Center. One reason for the current lack of adequately qualified personnel is that there are too few appropriate environments available to support training. The establishment of Centers under this program is intended to help to alleviate this shortage by serving as an academic focus for systems approaches. To maximize their impact, Centers should integrate the training of young investigators and broaden the training of established investigators. Graduate students and postdoctoral fellows should participate in the research. Additional training activities that leverage strengths of the institution and the research program of the Center are encouraged. Such training could be at the undergraduate, graduate, or professional levels. The NIGMS strongly urges the inclusion of partnering programs that will help minority-serving institutions to develop capabilities in these new arenas. Workshops, visiting investigatorships, and courses that may develop from Center activities will serve the wider community of investigators and their institutions by disseminating scientific knowledge and organizational information. Center Directors may be asked to join a committee to provide feedback on the success of the CE/CBSR program. MECHANISM OF SUPPORT This RFA will use the NIH P50 Specialized Center Grant mechanism. As an applicant you will be solely responsible for planning, directing, and executing the proposed project. This RFA is a one-time solicitation. Future unsolicited, competing-continuation applications based on this project will compete with all investigator-initiated applications and will be reviewed according to the customary peer review procedures. The anticipated award date is July 1, 2004. Applications submitted in response to the previous RFA announcements of this program, and unfunded, may be revised and resubmitted for this RFA. This RFA uses just-in-time concepts and the non-modular budgeting formats. This program does not require cost sharing as defined in the current NIH Grants Policy Statement at http://grants.nih.gov/grants/policy/nihgps_2001/part_i_1.htm. FUNDS AVAILABLE The NIGMS intends to commit approximately $6 million in FY04 to fund 2-3 new P50 Center grants in response to this RFA. An applicant may request a project period of up to 5 years and a budget for direct costs of up to $2M per year, exclusive of facilities and administrative costs for collaborating institutions. Funds for initial large equipment may be requested in excess of this $2M limit if prior approval is obtained from staff responsible for scientific/research issues, listed below, prior to application submission. Because the nature and scope of the proposed research will vary from application to application, it is anticipated that the size and duration of each award will also vary. Although the financial plans of the NIGMS provide support for this program, awards pursuant to the RFA are contingent upon the availability of funds and the receipt of a sufficient number of meritorious applications. In any event, the total length of support for any P50 Center under this program will be limited to a maximum of ten years. ELIGIBLE INSTITUTIONS You may submit an application if your institution is a domestic organization and has any of the following characteristics: o 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 Foreign institutions are not eligible to apply. 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 Centers will receive an administrative site visit during the third year of the first grant cycle. The fifth year of funding will depend on the outcome of that administrative review, and the Principal Investigator (PI) will receive advice about NIGMS interest in accepting a competing renewal application to extend the initial award. The Principal Investigator of Center Grant must commit a minimum effort of 30%. The Center will be expected to have a Board of Advisors, drawn from experts outside the project. These advisors will meet annually to review and provide guidance on Center activities. While a description of the Board's activities should be included in the application, potential members of the Board should not be named, contacted, or selected until an award has been made. This stipulation will allow a wider pool of potential reviewers of the application. Costs for activities of the Board of Advisors should be included in the budget. The NIH is interested in ensuring that the information about new methods, technologies, computer software, and high-throughput functional data that are developed through this program become readily available to the research community for further research and development. Such sharing will eventually lead to information and products that improve the health of the public. For this reason, applicants should develop and propose specific plans for sharing of data, materials, and software generated through the grant, taking into consideration the Guidance issued by NIH http://ott.od.nih.gov/ and http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-032.html. To the extent that established public databases have the capability for collecting and disseminating the data that would be collected under the grant, it is NIGMS's strong preference that a plan for the rapid deposition of data into such public databases be described in the application. The scientific review group will comment on the proposed plan for sharing and data release. The adequacy of the plan will also be considered by NIH staff as one of the criteria for award. The proposed sharing plan, after negotiation with the applicant when necessary, will be made a condition of the award. Evaluation of renewal applications will include assessment of the effectiveness of data, materials, and software release. 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: James J. Anderson, Ph.D. Center for Bioinformatics and Computational Biology National Institute of General Medical Sciences, NIH 45 Center Drive, Room 2AS-25A, MSC 6200 Bethesda, MD 20892-6200 Telephone: (301) 594-0943 FAX: (301) 480-2228 Email: andersoj@nigms.nih.gov o Direct your questions about peer review issues to: Helen R. Sunshine, Ph.D. Office of Scientific Review National Institute of General Medical Sciences, NIH 45 Center Drive, Room 3AN.12F, MSC 6200 Bethesda, MD 20892-6200 Telephone: (301) 594-2881 FAX: (301) 480-8506 Email: sunshinh@nigms.nih.gov o Direct your questions about financial or grants management matters to: Joseph Ellis Grants Administration Branch National Institute of General Medical Sciences, NIH 45 Center Drive, Room 2AN-32C, MSC 6200 Bethesda, MD 20892-6200 Telephone: (301) 594-5135 FAX: (301) 480-1969 E-mail: ellisj@nigms.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 the 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 NIGMS 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: James J. Anderson, Ph.D. Center for Bioinformatics and Computational Biology National Institute of General Medical Sciences 45 Center Drive, Room 2AS-25A, MSC 6200 Bethesda, MD 20892-6200 Telephone: (301) 594-0943 FAX: (301) 480-2228 Email: andersoj@nigms.nih.gov 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 Grants Info, Telephone (301) 435-0714, Email: GrantsInfo@nih.gov. SUPPLEMENTAL INSTRUCTIONS: The applicant should identify clearly in the abstract and more fully in the research plan the new approaches and collaborations, and the specific biological questions that are to be explored as a result of the establishment of the Center. The synergies to be achieved through the establishment of multi-disciplinary teams and novel collaborations should be fully described. The P50 grant application should specify the administrative and organizational structure(s) that will be used to support the research. It is anticipated that the Center projects will be multi-disciplinary and will draw on a variety of resources. Thus, a well thought out and carefully described organization will be required. The PI is responsible for ensuring that scientific goals are met, and for developing and managing a decision-making structure and process that will allow resources to be allocated (and reallocated, if necessary) to meet those goals. Projects of the complexity, both scientific and managerial, that NIGMS anticipates will characterize these Centers will require a substantial amount of the PI's effort to achieve success. Therefore, the PI will be required to devote at least 30% effort to the leadership and implementation of the Center. If core facilities or shared resources are required, these should be described, as should their management and service to the research projects. The applicant should explain how different components of the organization, including key personnel, will interact, why they are essential to accomplishing the research, and how the combined resources create capabilities that are more than the sum of the parts. "Centers-without-walls" are welcome under this solicitation. If any of the components are physically separated from each other (i.e., located in different departments or institutions), the applicant should address how interactions will be facilitated. NIGMS is not specifying a specific organizational structure (e.g., specific numbers of projects and cores) in this RFA, preferring that applicants develop the structure that would best promote the research. However, applicants should note that the effectiveness of the proposed structure will be a criterion of the evaluation prior to an award and will be monitored after an award is made. A timeline for the project should be presented. This timeline should outline how the project's goals can be met within the time frame of a CE/CBSR grant. The timeline also will assist the investigators, NIGMS, and its advisors in evaluating progress toward the project's goals. For those projects for which the investigator deems it appropriate to do so, NIGMS encourages applicants to present explicit, quantitative milestones. If the Center is to be organized into projects, then the page limits specified in the PHS 398 form for sections a-d of the Research Plan will apply for each project. If, however, the Center is to integrate its activities in such a way that describing individual projects would not be helpful, then the limit for the narrative section (a-d) is 40 pages. Please note that there is no requirement to submit this maximum number of pages; instead, concise, articulate applications are desired. NIGMS encourages applicants to devise a strategy for the Center's training and outreach components that best take advantage of the research program, the investigators' talents, and other institutional resources, to offer unique and substantial training opportunities for students and other investigators. The CE/CBSR will therefore augment programs previously developed by NIGMS (see http://grants.nih.gov/grants/guide/pa-files/PAR-99-146.html, http://grants.nih.gov/grants/guide/pa-files/PA-98-082.html) for expanding the cadre of investigators working in computational biology. 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 applications 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, including all appendices, must be sent to: Helen R. Sunshine, Ph.D. Office of Scientific Review National Institute of General Medical Sciences 45 Center Drive, Room 3AN-12F, MSC 6200 Bethesda, MD 20892-6200 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. 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. Unfunded applications submitted for a previous version of this RFA may be submitted as revised applications that will include an Introduction describing the changes and improvements made, with text clearly marked to indicate the changes. PEER REVIEW PROCESS Upon receipt, applications will be reviewed for completeness by CSR and for responsiveness by the NIGMS. Incomplete 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 the NIGMS in accordance with the review procedures 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, will be discussed and assigned a priority score. o Receive a second level review by the NIGMS 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. 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. If the P50 Center Grant application includes distinct subprojects, the scientific merit of each will be assessed, based on its merit as an independent effort and its potential importance/contribution to the success of the overall effort (the projects will not receive separate scores, however). SIGNIFICANCE: Does the 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? 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? 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 principal 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 the other researchers? 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 including any needed expansion of facilities, improvement of infrastructure, and relief from other academic duties where necessary? ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, the application will also be reviewed with respect to the following: o Quality and appropriateness of the management plan, including the effectiveness of the management structure and the PI's ability to lead and coordinate the activities. Do the individual components exhibit a high degree of interrelatedness and synergy? Are the proposed core facilities (if any) essential to the success of the center? o Adequacy of plans for a Board of Advisors to provide scientific and managerial oversight. o Quality of the proposed training plan and outreach activities and their likely effectiveness in meeting community needs, including provisions for engaging under-represented minorities. Will this center serve as a model for cross-disciplinary interactions? 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 CONSIDERATIONS DATA SHARING: The adequacy of the proposed plan to share data. 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: September 3, 2003 Application Receipt Date: October 14, 2003 Peer Review Date: February – March 2004 Council Review: May, 2004 Earliest Anticipated Start Date: July 1, 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 MONITORING PLAN AND DATA AND SAFETY 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 and Safety Monitoring, NIH Guide for Grants and Contracts, June 12, 1998: http://grants.nih.gov/grants/guide/notice-files/not98-084.html). 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. 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 RFA 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 Nos. 93.309, 93.821, 93.859, and 93.862 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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