INFLAMMATORY BOWEL DISEASE GENETICS RESEARCH CONSORTIUM Release Date: July 24, 2001 RFA: RFA-DK-02-011 (Reissued as RFA-DK-06-504) National Institute of Diabetes and Digestive and Kidney Diseases (http://www.niddk.nih.gov) Letter of Intent Receipt Date: October 17, 2001 Application Receipt Date: November 20, 2001 PURPOSE The Division of Digestive Diseases and Nutrition (DDN) of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) invites Cooperative Agreement Applications for a single Genetic Analysis, DNA and cell line repository and Data Coordinating Center (DCC) and for multiple inflammatory bowel disease (IBD) Genetic Research Centers (GRC) to participate in the development and implementation of studies to identify genes which are associated with Crohn’s disease and ulcerative colitis. The DCC and GRCs will work together cooperatively as a Consortium. The primary objective(s) of this investigation will be identification of genes or genomic regions that are associated with increased risk of IBD and with specific phenotypic manifestations, such as early age of onset, location, complications, rate of progression, response to therapy or susceptibility to environmental risk factors. To achieve this objective, two different types of centers will form a consortium consisting of centers which will work together with staff from NIDDK to achieve the study objectives. There will be a single Genetic Analysis, DNA and cell line repository and Data Coordinating Center (DCC). This center will be responsible for the collection, management and support of analysis of both the genetic and clinical data. The DCC will coordinate communication and research with the GRCs. The DCC may apply both existing and novel methods for data collection and genetic analysis. The DCC will play a key role in the logistics of the planning and development stage. In addition to assisting the GRCs in finalizing the study protocols, the DCC will establish the data acquisition, transfer, and management system, develop procedures for ensuring subject and control confidentiality and safety, develop procedures for quality control, training, and certification, develop and produce a manual of operations, and supervise the orderly collection and transmission of data. To achieve the aims of the study, the DCC will also be responsible for the creation and maintenance of a DNA and cell line repository containing appropriate patient and control samples that are required to achieve aims of specific research studies. It is anticipated that the repository may be maintained through a contract mechanism from the DCC. In addition, the DCC may propose cost-efficient methods to provide services, such as genotyping, to GRCs. Although a DCC and GRC may exist at the same institution, the two types of centers will require separate applications and these will be evaluated independently, by criteria outlined below. The GRCs will be composed of one or more sites having investigators with expertise in genetics and inflammatory bowel disease which will participate in the collection of data and genetic materials from appropriate groups of patients and propose and execute individual research projects. It is envisioned that the GRC will need to concentrate on details of study design, including the development of phenotypic criteria and realistic estimates of the appropriate number of well-characterized selected patient, family and control subjects to achieve the goals of the study. The GRCs will have full responsibility for identifying, recruiting and enrolling the necessary number of study participants to meet the study goals and bring the study to completion. The GRCs will collect and transmit genetic, familial and clinical data as delineated in the Manual of Operation. As a part of this solicitation, each GRC will propose one or more genetic studies which are aimed at the overall objective, stated above, and which will effectively use the resources of the consortium. 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 Request for Application (RFA), Inflammatory Bowel Disease Genetics Research Consortium, is related to the priority areas of chronic disease and childhood illnesses. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople/. ELIGIBILITY REQUIREMENTS Applications may be submitted from either domestic or foreign institutions, for-profit and non-profit organizations, public and private, such as universities, colleges, hospitals, laboratories, units of State and local governments, and eligible agencies of the federal government. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as Principal Investigators. All current policies and requirements that govern the research grant programs of the National Institutes of Health (NIH) will apply to grants awarded under this RFA. Among the disciplines and expertise that may be appropriate for this program are gastroenterology, pediatrics, genetics, and epidemiology. Within the Consortium an institution may apply for both a GRC and the DCC, however, each component must have separate application with a specific plan of how the independent operation of each unit of the GRC and DCC will be maintained. MECHANISM OF SUPPORT This RFA will use the NIH cooperative clinical research (U01) award mechanism of support, an assistance mechanism (rather than as 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 stimulate the recipients activity by involvement in the activity and otherwise working jointly with the award recipients 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 study to be funded under cooperative agreements are discussed below under Terms and Conditions of Award. The total project period for an application submitted in response to this RFA may not exceed 5 years. This is a one time solicitation. At this time, the NIDDK has not determined whether or how this solicitation will be continued beyond the present RFA. The anticipated award date is July 2002. FUNDS AVAILABLE The NIDDK intends to commit approximately $2 million in total costs (direct plus Facilities and Administrative (F & A) costs) in FY 2002 to fund approximately six IBD Genetics Research Center (GRC) applications and one Genetic Analysis, DNA and cell line repository and Data Coordinating Center (DCC) application in response to this RFA. Applicants for the GRCs may request a project period up to five years and a budget for total costs (direct plus F & A) of up to $225,000/year. Applicants for the DCC may request a project period up to five years and a budget for total costs (direct plus F & A) of up to $650,000/year. However, exceptions to these guidelines will be accepted if, for example, a single GRC consists of a cooperative group located at multiple clinical sites. Because the nature and scope of the research proposed in response to this RFA may vary, it is anticipated that the size of each award may vary in all years. Future year costs will be distributed based on the recommended protocols, database development, patient sample acquisition costs, and research protocols proposed and approved by the Steering and Planning Committee. Although the financial plans of the NIDDK provide support for this program, awards pursuant to this RFA are contingent upon the availability of funds and the receipt of a sufficient number of applications of outstanding scientific and technical merit. Designated funding levels are subject to change at any time prior to final award, due to unforeseen budgetary, administrative, or scientific developments. RESEARCH OBJECTIVES Background The human inflammatory bowel diseases, ulcerative colitis (UC) and Crohn’s disease (CD) are relatively common chronic diseases of the gastrointestinal tract that cause significant morbidity and high utilization of health care resources. The etiology and pathogenesis of these diseases remains elusive and therapy is imperfect. A wealth of clinical and basic research information concerning IBD and related animal models has appeared in the literature in recent years. Multiple hypotheses regarding pathogenesis are currently under investigation, including, among others, possible host immune defects, differences in mucosal barrier function and mucosal repair, and interactions between the host with the GI mucosal flora. IBD may be associated with distinctly different phenotypic characteristics which may be due to differences in underlying host susceptibility and differences in environmental factors. There is substantial evidence that genetic factors are important in IBD. Multiple lines of evidence based on twin studies, familial risk and segregation analysis have suggested that IBD is a complex, non- Mendelian genetic disorder. Between 8% and 30% of patients have a positive family history. Based on concordance in twin studies, a much greater role for genetic factors has been suggested for Crohn’s disease than ulcerative colitis. However, the pattern of inheritance in IBD does not appear to be Mendelian. Further, the majority of patients with both diseases do not have a family history of IBD. Multiple genes have been examined using a candidate gene approach. While HLA loci are associated with IBD in specific populations, the role of HLA genes does not appear to be dominant. Multiple groups of investigators have carried out genome wide scans using microsatellite markers in families with IBD, and a number of loci have been identified with significant, reproducible Lod scores on chromosomes 16, 12 and 1. The most widely studied locus on chromosome 16, IBD1, has been recently shown to represent mutations in the gene Nod2, about which relatively little is known at the present time. There are numerous animal models of gastrointestinal inflammation, some spontaneous and some experimentally induced or related to selective gene inactivation, which have also suggested that gastrointestinal inflammatory disease is under complex genetic control and possibly intimately related to interactions of the host with the resident microbial flora. It is expected that the identification of genetic loci that are critical in gastrointestinal inflammation in the mouse will accelerate the identification of syntenic regions in humans that may contribute to IBD, although studies of murine genetics do not fall within the scope of this solicitation. The long term goal of this solicitation is a detailed characterization of the genetic susceptibility and resistance loci for IBD, which hopefully will lead to a better understanding of disease pathogenesis, environmental modifying factors, rational design of specific pharmaceutical or biological therapies, accurate diagnostic testing for risk of IBD, and better rationale for selection of available therapies and prognosis. Research Goals and Scope It is the intent of this solicitation to invite applications from investigators with diverse scientific interests, who wish to apply their expertise to the discovery of gene sequences associated with the development of IBD. The specific goals of this solicitation are: (1) to encourage novel approaches to identification of genes and interacting environmental factors that contribute to IBD pathogenesis through a coordinated genetic analysis and data collection center (2) to facilitate collaborative interactions among scientists by formation of a cooperative consortium for genetic research (3) to facilitate the recruitment of representative patients and families with well- characterized IBD for prospective studies to delineate genomic regions associated with the development and progression of disease(s), (4) to establish a resource for genetic studies of IBD by creating a DNA and cell line repository, and (5) to improve outcomes in people having or at risk for IBD through genetic research. It is anticipated that the study will take place in up to six GRCs and one DCC over a period of five years. Study Design It is anticipated that over the five-year period, several cohorts of patients, families and control subjects will be studied by the Principal Investigators. The individual GRCs and the DCC participating in the cooperative study should conduct mutually agreed upon protocols for characterization of study subjects and for genetic analytic strategies. The GRCs will also conduct independent analyses, and will have exclusive access to data from their study populations for a period of time, to be determined by the Steering and Planning Committee (see below). The Steering and Planning Committee, will also develop policies and procedures that permit utilization of the DNA and cell line repository by other investigators who are not members of the consortium. The design of the final research protocol for implementation, including the eligibility criteria for the final study population and the studies to be undertaken, will be effected by the Steering and Planning Committee (see below), which will take into consideration protocols submitted and evaluated by the Scientific Review Group during the review process. Study Components 1. IBD Genetic Research Centers (GRCs) A GRC is an institution that is actively involved in the recruitment and evaluation of patients, family members and control subjects and the initiation of individual, center-specific genetic studies taking advantage of special patient populations. The GRC should consist of an interdisciplinary team of investigators and appropriate personnel, such as a research coordinator and clerical staff. GRCs will be required to submit familial, phenotypic, diagnostic, medical therapeutic and genetic data as well as blood samples for the DNA and cell line repository to the DCC. The GRC must work in concert with the DCC to implement procedures for uniform data collection, handling and transmittal of data, as well as data audits and other data quality control procedures, as established by the study protocol. The GRC will be required to share data and patient specimens derived from collaborative studies. The Principal Investigator and Co-Investigators in each GRC should be skilled in collaborative clinical investigation. It is anticipated that the GRCs will conduct independent analyses and will have exclusive access to data from their study populations for a period of time to be determined by the Steering and Planning Committee. Individual, center-specific projects may be conducted through the auspices of the DCC. The GRCs and DCC will develop uniform procedures and data sharing policies, and independently and collectively allocate resources and personnel for the performance of independent, center- specific analyses and studies. 2. Genetic Analysis, DNA and cell line repository and Data Coordinating Center (DCC) There will be a single DCC. This center will be responsible for the collection, management and analysis of both the genetic and clinical data and coordinating communication and research with the Participating Investigating Centers. The DCC is encouraged to propose to use both existing and novel methods for data collection and genetic analysis. The DCC will play a key role in the logistics of the planning and development stage. It is anticipated that in the proposal, criteria for standardization of patient, family member and control population selection criteria and genetic studies, and data collection for the investigations to be performed will be outlined. In addition to assisting the GRCs in finalizing the study protocols, the DCC will establish the data acquisition, transfer, and management system, develop procedures for ensuring subject and control confidentiality and safety, develop procedures for quality control, training, and certification, develop and produce a manual of operations, and supervise the orderly collection and transmission of data. The DCC should be prepared to assume a key role in overseeing implementation and adherence to the study protocols, and assuring quality control of the data collected. To achieve the aims of the study, the DCC will also be responsible for the creation and maintenance of a DNA and cell line repository containing appropriate patient and control samples that are required to achieve aims of specific research studies. It is anticipated that the repository may be maintained through a contract mechanism from the DCC. In addition, the DCC will have overall responsibility for genotyping and may propose cost-efficient methods to provide services to GRCS. Although a DCC and GRC may exist at the same institution, the two types of centers will require separate applications and these will be evaluated independently, by criteria outlined below. The DCC will be expected to provide appropriate molecular biologic, biostatistical, data management, and coordination and genetic analysis expertise, as well as supporting the special independent studies proposed by the individual GRCs and approved by the Steering and Planning Committee (see below). Sub-contracting of various aspects of the DCC to other institutions with special expertise may be included in the application. The DCC also will be expected to generate appropriately detailed reports to the Steering and Planning Committee and to the NIDDK staff (see below) at regular intervals, and will be responsible for the logistics and planning of the meeting of these committees and their subcommittees. 3. Steering and Planning Committee The primary governing body of the study will be the Steering and Planning Committee comprised of each of the Principal Investigators of the GRCs and the DCC, the Chairperson of the Steering and Planning Committee, and the NIDDK Project Coordinator (described in detail under Terms and Conditions). The NIDDK staff will initially appoint an interim chairperson prior to the first meeting of the Steering Committee. 4. Project Coordinator The NIDDK will appoint a Project Coordinator, within the Division of Digestive Diseases and Nutrition, to assist the Steering and Planning Committee in carrying out the proposed studies (described in detail under Terms and Conditions). The Project Coordinator will provide scientific support to awardees activities, including protocol development, quality control, interim data monitoring, final data analysis and interpretation, preparation of publications, and overall performance monitoring. SPECIAL REQUIREMENTS Terms and Conditions of Award The following terms and conditions will be incorporated into the award statement and provided to the Principal Investigator(s) as well as the institutional official at the time of award. These special Terms of Award are in addition to and not in lieu of otherwise applicable OMB administrative guidelines, HHS Grant Administration Regulations at 45 CFR Parts 74 and 92, the NIH Grant Policy statement. The administrative and funding instrument used for this program is a cooperative agreement (U01), 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 the NIDDK Project Scientists. 1) Awardees Rights and Responsibilities o The awardee(s) will have lead responsibilities in all aspects of their protocols, including any modification of study design, conduct of the study, quality control, data analysis and interpretation, preparation of publications, and collaboration with other investigators, unless otherwise provided for in these terms or by action of the Steering Committee. Modifications of protocols will be approved by the Steering Committee. o Awardees will retain custody of and have primary rights to their data developed under these awards, subject to Government rights of access consistent with current HHS, PHS, and NIH policies. The collaborative protocol and governance policies will call for the continued submission of data centrally to the DCC for a collaborative database, the submission of copies of the collaborative data sets to each principal investigator upon completion of the study, procedures for data analysis, reporting and publication, and procedures to protect and ensure the privacy of medical and genetic data (if any) and records of individuals. The NIDDK Project Scientist, on behalf of the NIDDK, will have the same access, privileges and responsibilities regarding the collaborative data as the other members of the Steering Committee. o The DCC will be involved in collaborations with the NIDDK and the GRCs during all phases of the research studies and will maintain the specimen repository. Thus, the awardee is expected to work cooperatively with GRCs and sponsoring organizations in a multi-center study and oversee the implementation of and adherence to a common protocol, as well as assure quality control of the data collected and storage of collected tissue specimens. In addition to organizing and attending regular meetings, the DCC will be expected to maintain close communications with the NIDDK Project Scientist and the Principal Investigators of the GRCs. o Awardees are encouraged to publish and to publicly release and disseminate results, data and other products of the study, concordant with the study protocol and governance and the approved plan for making data and materials available to the scientific community and the NIDDK. However, during or within three years beyond the end date of the project period of NIDDK support, unpublished data, unpublished results, data sets not previously released, or other study materials or products are to be made available to any third party only with the approval of the Steering Committee. o Support or other involvement of industry or any other third party in any study performed by the Consortium-- e.g., participation by the third party, involvement of project resources or citing the name of the project or the NIDDK support, or special access to project results, data, findings or resources -- may be advantageous and appropriate. However, except for licensing of patents or copyrights, support or involvement of any third party will occur only following notification to, and concurrence by, NIDDK. o Upon completion of the project, the DCC is expected to put all study design materials and procedure manuals into the public domain and/or make them available to other investigators, according to the approved plan for making data and materials available to the scientific community and the NIDDK, for the conduct of research at no charge other than the costs of reproduction and distribution. 2) NIDDK Staff Responsibilities The NIDDK will name a Project Scientist from within the Division of Digestive Diseases and Nutrition whose function will be to assist the Steering Committee in carrying out the study. The Project Scientist will have one vote for all key study group subcommittees. The Project Scientist will have substantial scientific-programmatic involvement in quality control, interim data analysis, safety monitoring, and final data analysis and interpretation, preparation of publications, and coordination and performance monitoring. The dominant role and prime responsibility for these activities resides with the awardees for the project as a whole, although specific tasks and activities in carrying out the studies will be shared among the awardees and the NIDDK Project Scientist. The NIDDK reserves the right to terminate or curtail the study (or an individual award) in the event of (a) failure to develop or implement a mutually agreeable collaborative protocol, (b) substantial shortfall in participant recruitment, follow-up, data reporting, quality control, or other major breach of the protocol, (c) substantive changes in the agreed-upon protocol with which NIDDK cannot concur, (d) reaching a major study endpoint substantially before schedule with persuasive statistical significance, or (e) human subject ethical issues that may dictate a premature termination. 3) Collaborative Responsibilities The Steering Committee, composed of each of the Principal Investigators of the DCC and the GRCs, the NIDDK Project Scientist, and the Chairman of the Steering Committee, will be the main governing board of the studies. This committee will have the primary responsibility for approval of the common protocols, facilitating the conduct of participant follow-up, monitoring completeness of data collection and timely transmission of data to the DCC, and reporting the study results. It will also be responsible for establishing study policies in such areas as access to patient data, ancillary studies, publications and presentations, and performance standards. Each member of the Steering Committee will have one vote and all major scientific decisions will be determined by a majority vote of the Steering Committee. A Chairperson will be chosen from among the Steering Committee members (but not the NIDDK Project Scientist), or alternatively, from among experts in the field of IBD who are not participating directly in the study. Subcommittees will be established for specific purposes as needed, such as for ancillary studies, publications and presentations, quality control, recruitment, protocol adherence, among others. Each Consortium GRC Awardee and the DCC Awardee agree to the governance of the study through the Steering Committee. The Steering Committee voting membership shall consist of the Principal Investigators of the GRCs and the DCC, and the NIDDK Project Scientist. Meetings of the Steering Committee will ordinarily be held by telephone conference calls or in the Washington DC Metropolitan Area. The NIDDK Project Scientist (and the other cited NIDDK scientists) may work with awardees on issues coming before the Steering Committee and, as appropriate, other committees, e.g., issues of recruitment, intervention, follow-up, quality control, standards and methods, adherence to protocol, assessment of problems affecting the study and potential changes in the protocol, interim data and safety monitoring, final data analysis and interpretation, preparation of publications, and development of solutions to major problems such as insufficient participant enrollment. Regardless of the number of NIH staff participating in technical advisory roles, the NIDDK will be limited to one vote on the Steering Committee. 4) Arbitration Any disagreement that may arise in scientific/programmatic matters (within the scope of the award), between award recipients and the NIDDK may be brought to arbitration. An arbitration panel will be composed of three members one selected by the Steering Committee (with the NIDDK member not voting) or by the individual awardee in the event of an individual disagreement, a second member selected by NIDDK, and the third member selected by the two prior members. This special arbitration procedure in no way affects the awardee"s right to appeal an adverse action that is otherwise appealable in accordance with the PHS regulations at 42 CFR part 50, Subpart D and HHS regulation at 45 CFR part 16, or the rights of NIDDK under applicable statutes, regulations and terms of the award. INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS 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 biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification are 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 research involving human subjects should read the UPDATED "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research," published in the NIH Guide for Grants and Contracts on August 2, 2000 (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-048.html), a complete copy of the updated Guidelines are available at http://grants.nih.gov/grants/funding/women_min/guidelines_update.htm. The revisions relate to NIH defined Phase III clinical trials and require: a) all applications or proposals and/or protocols to 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) all investigators to report accrual, and to conduct and report analyses, as appropriate, by sex/gender and/or racial/ethnic group differences. INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of NIH 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 was published in the NIH Guide for Grants and Contracts, March 6, 1998, and is available at the following URL address: http://grants.nih.gov/grants/guide/notice-files/not98-024.html Investigators also may obtain copies of these policies from the officials listed under INQUIRIES. Program staff may also provide additional relevant information concerning the policy. 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. This policy announcement is found in the NIH Guide for Grants and Contracts Announcement dated June 5, 2000, at the following website: http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.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. Reviewers are cautioned that their anonymity may be compromised when they directly access an Internet site. 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. LETTER OF INTENT Prospective applicants are asked to submit, by October 17, 2001, a letter of intent that includes a descriptive title of the proposed research, the name, address, and telephone number of the Principal Investigator, the identities of other key personnel and participating institutions, whether the application is for a GRC or the DCC, and the number and title of the RFA in response to which the application may be submitted. 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 NIDDK staff to estimate the potential review workload and avoid conflict of interest in the review. The letter of intent is to be sent to the Chief, Review Branch at the address listed under INQUIRIES, below. APPLICATION PROCEDURES The research grant application form PHS 398 (rev. 5/01) is to be used in applying for these grants. These forms are available at most institutional offices of sponsored research and from the Division of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301/710-0267, email: GrantsInfo@nih.gov. The PHS 398 application kit is also available on the Internet at http://grants.nih.gov/grants/forms.htm Application Requirements Applicants must describe plans to accommodate the stated program requirements, criteria, and staff involvement. Applicants must address points discussed in the SPECIAL REQUIREMENTS section of this RFA. 1. GRC Applications Applicants for the GRCs should respond with research protocols involving multicenter participation to address the objectives of the study and to reach the study goals. It is anticipated that applicants will develop criteria for studying specific subgroups of patients with IBD. Applicants should outline the rationale and background of the proposed studies, study design and protocols, eligibility criteria, type of patients, family members and control subjects to be included in the studies, and initial power analyses in their applications. For each of the clinical protocols, the GRC applicants should discuss the characteristics and number of potential participants that would be available from their own geographic region. It is anticipated that GRC applicants will propose a varying number of studies, but the submitted research plan should remain within the 25 page limit. Genetic studies involving individual subjects and groups of people necessarily involve information that should be kept highly confidential. It will be critical that at all phases of the study, the investigators understand and minimize the risks involved in such genetic research, protecting both individual subjects and research participants in groups, and optimize procedures for obtaining informed consent. An application for a GRC should provide evidence that the investigators are capable of recruiting a sufficient number of participants for the proposed studies, and initiating and completing independent studies consistent with the overall goals of this RFA. Applicants for GRCs should describe the target population from which they expect to recruit the required number of patients, family members and control subjects as study participants, and plans for recruitment of women, minorities, and children, as required. In addition, applicants for a GRC will submit proposals and power analyses for cost-effective strategies to address their individual study questions, taking advantage of their particular geographic locations and patient populations. Proposed provisions to ensure confidentiality and to optimize informed consent procedures must be presented in the application. There should be evidence of strong institutional support for the GRC, including adequate space in which to conduct clinical and research activities and office space for staff. An organizational structure for the GRC should be set forth in the application, delineating lines of authority and responsibility for dealing with problems in all general areas as well as stated willingness to follow commonly agreed upon protocols. The principal investigator should indicate their willingness to participate in a per patient basis for operational costs of patient specimen acquisition and processing. There must be ability to interact with the DCC and transmit and edit data. The applicant should include a succinct discussion of previous relevant research efforts. Applicants for GRCs should consider the economies of scale to be gained and cost effectiveness of strategies of research plans involving large numbers of patients. The applicant should also discuss in detail the recruitment strategies to procure the expected number of study participants. Specific plans for recruitment of minority participants and children must also be discussed. The applicant should indicate willingness to participate in the Consortium concept outlined in this solicitation, participate in the Steering Committee meetings and abide by its decisions, and indicate prior experience in collaborative, multi-center research. 2. DCC Applications A separate complete application is required from institutions applying to be the DCC. Applicants for the DCC component are not required to be a GRC site within the Consortium, however applicants for the DCC are also encouraged to submit an application for a GRC. It is anticipated that there may be considerable areas of overlap if both applications are submitted from the same group of investigators. Applicants must describe plans to achieve the stated Objectives and Scope, Special Requirements, and Terms and Conditions of Award stated in this RFA. In addition, applicants should document their willingness to participate on the Steering Committee and appropriate subcommittees, work cooperatively with other members of the Steering Committee, and follow the common protocol established cooperatively by the Steering Committee. It is expected that the PI of the DCC would carry out a significant leadership role in the consortium. Applicants must also address the following regarding responsibilities and requirements for the DCC: Participation in the design of the genetic analyses to be undertaken, development of research studies and development of the manual of operation, data collection forms, and questionnaires, Development and implementation of systems for communication among Steering Committee members, and among study sites, Data collection, editing, processing, analysis, and reporting, Monitoring of adherence to the research plan and of data quality, Establishment of procedures that insure the safety and confidentiality of all records. Specific experience in coordinating or monitoring studies of IBD is highly desirable, but if this does not exist collaboration with experts in IBD is strongly encouraged. The applicant for the DCC must delineate a plan for development and operation of a DNA and cell line repository. The applicant for the DCC should also address any issues regarding common services, such as genotyping, that could be provided to the various participating GRCs. Applications may not exceed 25 pages for sections a - d, excluding appendices, which may contain copies of pertinent forms or examples of correspondence useful for coordinating tasks. BUDGET AND RELATED ISSUES Applicants should complete the budget information as directed in the PHS 398 application form. 1. GRC Applications GRCs should consider the following issues regarding budgets. A central concept is that a core clinical effort will be required to maintain the infrastructure required to accurately phenotype patients and acquire clinical specimens. Based on this approach, it is estimated that the individual GRCs will require a minimum level of effort to sustain the organizational aspects of this aspect of the study. Therefore, individual GRCs should submit requests for a CORE BUDGET. It is anticipated that this core budget will cover a minimum ten percent effort for the principal investigator, and a small percent effort for other key personnel (nurse, technician, clinic coordinator, secretary), and travel costs for one or two individuals to attend consortium meetings up to four times a year in Bethesda, MD. Depending on the sample size requirements, it may be necessary for GRCs to subcontract to other clinical sites to obtain a sufficient number of patients and specimens for analysis. The core budget will include per patient costs for obtaining specimens from patients to forward to the DNA and cell line repository. These costs should be justified appropriately in budgets and may be distributed into subcontracts. Escalation is allowed at three percent for future years. Costs for clinical care are not permitted. In addition to the core budget, each GRC will be provided funds for implementation of research studies. The precise number of protocols conducted will be determined by the Consortium Steering Committee and will depend on availability of funds. It is anticipated that one or more studies may originate at each center. Allowable total costs for each GRC (core costs, costs per patient to conduct the protocols, and indirect costs) will vary. However, it is anticipated that the average total costs for each GRC will be $225,000 per year. The Consortium awards will be subject to administrative review annually. 2. DCC applications Applicants for the DCC should prepare budgets for five 12-month periods (not to exceed $650,000 total cost per year) that roughly correspond with the standard coordinating center responsibilities outlined in other sections of this RFA. In the first year, DCC applicants should include all costs associated with the organization of all administrative aspects of the Consortium to be developed and with the initiation of at least one research protocol. For subsequent years, applicants may assume that multiple research studies will be active, i.e. either in the protocol development, implementation, or analysis and writing phase. The DCC will be subject to administrative review annually. SUBMISSION INSTRUCTIONS The RFA label available in the PHS 398 (rev. 7/01) application form must be stapled to the bottom of the face page of the application and must display the RFA number DK-02-011. A sample RFA label is available at http://grants.nih.gov/grants/funding/phs398/label-bk.pdf. Please note this is in the pdf format. 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. 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 time of submission, two additional copies of the application must be sent to: Francisco O. Calvo, Ph.D. Chief, Review Branch Division of Extramural Activities, NIDDK 6707 Democracy Blvd. Room 752, MSC 5452 Bethesda, MD 20892-5452 (Courier use ZIP 20817) Telephone: (301) 594-8885 FAX: (301) 480-3505 Applications must be received by November 20, 2001. 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 previously reviewed, but such applications must include an introduction addressing the previous critique. REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed for completeness by the CSR and responsiveness by the NIDDK. 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 the NIDDK in accordance with the review criteria stated below. As part of the initial merit review, a process will be used by the initial review group in which applications receive a written critique and 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, assigned a priority score, and receive a second level review by the National Diabetes and Digestive and Kidney Diseases Advisory Council. REVIEW CRITERIA All applications will be reviewed according to the criteria listed below. The reviewers will be asked to evaluate the following aspects of the application in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. Each of these criteria will be addressed and considered in assigning the overall score, weighting them as appropriate for each application. Note that 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. o Significance: The application should address the problem outlined in the RFA. The application should demonstrate how the study will advance scientific and/or medical knowledge. o Approach: The adequacy of the proposed conceptual framework, design, methods, and analyses. The acknowledgement of potential problem areas and the consideration of alternative tactics. Since the final study design(s) will be developed collaboratively by the Steering Committee for the protocols, the peer review group will focus on evidence that the applicant has carefully thought about the issues involved and possesses the knowledge necessary to contribute meaningfully to the final design, including understanding of the scientific, ethical, and practical issues underlying the proposed study. o Innovation: The applicant should demonstrate how the project challenges existing paradigms or develops new methodologies or technologies. o Investigator: The investigator should be appropriately trained and well suited to carry out this work. The proposed study should be appropriate to the experience level of the principal investigator and other researchers (if any). There should be evidence of prior experience in working collaboratively to carry out a clinical study or standard protocol as well as evidence of willingness to work cooperatively on the Steering Committee to develop and follow a unified protocol. o Environment: The environment in which the work will be done should contribute to the probability of success. The proposed protocol should take advantage of unique features of the scientific environment and employ useful collaborative arrangements. There should be evidence of institutional support. In addition to the above criteria, in accordance with NIH policy, all applications will also be reviewed with respect to the following: o The adequacy of plans to include both genders, minorities and their subgroups as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. o The reasonableness of the proposed budget and duration in relation to the proposed research o The adequacy of the proposed protection for humans or the environment, to the extent they may be adversely affected by the project proposed in the application. The initial review group will also examine the safety of the research environment. Applicants are encouraged to submit and describe their own ideas about how best to meet the goals of the cooperative study and their specific protocols. The evaluation of applications for GRCs and the DCC will be based primarily on the scientific merit of the proposed studies, as defined above. Specific criteria for review of applications will also include: For both Participating Investigating Centers and the Genetic Analysis and Data Coordinating Center: 1. The scientific merit of the proposed study design(s) to address the objectives of the RFA, including strategies for patient identification and recruitment, and data collection and management, as outlined in the RFA. 2. Adequacy of the facilities and space. 3. Understanding and awareness of the scientific, ethical, and practical issues underlying the proposed studies and appropriateness of plans to deal with them. 4. Evidence of the degree of institutional commitment and support for the proposed program, including the relative position of the proposed project staff within the applicant"s organizational structure. 5. Willingness to carry out a commonly agreed upon study protocol, and to share patient data and specimens derived from collaborative studies. 6. Adequacy of plans to ensure accurate collection, confidentiality and timely transmission of study data. 7. The organizational and administrative structure of the proposed program. For GRCs: 1. Documentation of the specific competence and previous experience of professional, technical, and administrative staff pertinent to the operation of a GRC in previous collaborative clinical investigations. Evaluation will include the following: familiarity with and experience in recruiting participants in a study, handling laboratory specimens, working in collaboration with other investigators under a common protocol, ability to implement study procedures, and meticulous and expeditious handling of study data. 2. Documentation of access to patient population(s) from which a substantial number of participants can be recruited in sufficient numbers to meet the goals specified in the RFA. 3. Ability to recruit representative minority populations and children, as required. 4. Adequacy of proposed sample sizes and strategies for cost effective patient recruitment and data collection. For the DCC: 1. Documentation of the specific competence and experience of professional, technical, and administrative staff pertinent to both the molecular biologic, biostatistical and data coordination aspects of the proposed study. Prior experience in similar studies, in the collection of data and patient specimens from multiple locations, as well as experience in monitoring the quality and timeliness of such data, should be demonstrated. 2. Demonstrable knowledge of the potential problems associated with the conduct of this study and possible solutions must be demonstrated. 3. Suitability of proposed data management and data analytic plans. 4. Ability to design, implement and maintain a distributed data entry system for the GRCs. 5. The approach to and likelihood of soliciting cooperation from the participating GRCs and exercising appropriate leadership in matters of study design and protocol revisions, and data acquisition, management, and analysis. Specific plans for ensuring standardization and quality control of data collection across all study sites are required. 6. The adequacy of the proposed technical hardware. 7. Provision of cost-effective strategies for genotyping large populations and reliable estimates of genotyping costs for the contemplated joint and independent large-scale, high-throughput studies. 8. Ability to organize and provide oversight for a DNA and cell line repository suitable for the proposed studies for the consortium. SCHEDULE Letter of Intent Receipt Date: October 17, 2001 Application Receipt Date: November 20, 2001 Peer Review Date: March/April 2002 Council Review: May 2002 Earliest Anticipated Start Date: July 2002 AWARD CRITERIA Award criteria that will be used to make award decisions include: o Scientific and technical merit of the application for a GRC or a DCC. o The multi-disciplinary nature of the proposed studies (GRC). o Demonstration of expertise to manage, design and coordinate multicenter clinical research studies, including handling and storage of laboratory specimens (DCC). o The quality of response to the special requirements stated in this RFA. o Relevance to the overall programmatic balance and priorities of the NIDDK and sufficient compatibility of features proposed in the research plan and qualifications of the investigators to make a collaborative program within the Consortium a reasonable likelihood. o Availability of funds. o Access to patients including children and minority individuals. o A demonstrated willingness on the part of the investigators to work as part of the Consortium and with the NIDDK Project Scientist. INQUIRIES Inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Stephen P. James, M.D. Division of Digestive Diseases and Nutrition National Institute of Diabetes and Digestive and Kidney Diseases 6707 Democracy Blvd. Room 675, MSC 5450 Bethesda, MD 20892-5450 Telephone: (301) 594-7680 FAX: (301) 480-8300 Email: sj158p@nih.gov Direct inquiries regarding review matters to: Francisco O. Calvo, Ph.D. Chief, Review Branch Division of Extramural Activities National Institute of Diabetes and Digestive and Kidney Diseases 6707 Democracy Blvd. Room 752, MSC 5452 Bethesda, MD 20892-5452 Telephone: (301) 594-8885 FAX: (301) 480-3505 Email: fc15y@nih.gov Direct inquiries regarding fiscal matters to: Ms. Carolyn Kofa Grants Management Specialist Division of Extramural Activities National Institute of Diabetes and Digestive and Kidney Diseases 6707 Democracy Blvd. Room 727, MSC 5456 Bethesda, MD 20892-5456 Telephone: (301) 594-7687 FAX: (301) 480-3504 Email: ck104i@nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.848. Awards are made under authorization of the Public Health Service Act, Title IV, Part A (Public Law 78-410, as amended by Public Law 99-158, 42 USC 241 and 285) and administered under PHS grants policies and Federal Regulations 42 CFR 52 and 45 CFR Part 74. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. The PHS 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.

Weekly TOC for this Announcement
NIH Funding Opportunities and Notices


NIH Office of Extramural Research Logo
   Department of Health and Human Services (HHS) - Home Page Department of Health
and Human Services (HHS) 		  USA.gov - Government Made Easy
NIH... Turning Discovery Into Health®


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