and Human Services (HHS)
EXPIRED
GENOMICS OF TRANSPLANTATION COOPERATIVE RESEARCH PROGRAM RELEASE DATE: December 11, 2003 RFA Number: RFA-AI-04-002 (This RFA has been reissued, see RFA-AI-05-022) Department of Health and Human Services (DHHS) PARTICIPATING ORGANIZATION: National Institutes of Health (NIH) (http://www.nih.gov) COMPONENT OF PARTICIPATING ORGANIZATION: National Institute of Allergy and Infectious Diseases (NIAID) (http://www.niaid.nih.gov) CATALOGUE OF FEDERAL DOMESTIC ASSISTANCE NUMBERS: No. 93.855, Immunology, Allergy, and Transplantation Research No. 93.856, Microbiology and Infectious Diseases Research LETTER OF INTENT RECEIPT DATE: February 16, 2004 APPLICATION RECEIPT DATE: March 15, 2004 THIS RFA CONTAINS THE FOLLOWING INFORMATION o Purpose of this RFA o Research Objectives o Mechanisms of Support o Funds Available o Eligible Institutions o Individuals Eligible to Become Principal Investigators o Special Requirements o Where to Send Inquiries o Letter of Intent o Submitting an Application o Supplementary Instructions o Peer Review Process o Review Criteria o Receipt and Review Schedule o Award Criteria o Required Federal Citations PURPOSE OF THIS RFA The purpose of this RFA is to solicit applications from single institutions or consortia of institutions to establish cooperative interdisciplinary research programs for large-scale, broad-scope genomic studies in clinical transplantation, including solid organ, tissue, and cell transplantation. The goals of this program are to identify and characterize gene polymorphisms and gene expression patterns that: (1) correlate with and/or predict transplantation outcomes; (2) delineate immune responses relating to the onset and severity of acute and chronic graft rejection; (3) predict responses to immunosuppressive therapeutics to allow tailoring of therapy; and (4) elucidate the genetic basis of variability in graft survival between populations. The long-term goal of the program is to understand the genetic basis of immune-mediated graft rejection and differences in transplant outcomes, and thereby provide a rational basis for the development of more effective treatment and prevention strategies to improve long-term graft survival and provide a better quality-of-life for transplant recipients. BACKGROUND Transplantation is the preferred therapy for the majority of end-stage organ diseases, and, in 2002, almost 25,000 organ transplants were performed in the United States. One-year graft and patient survival rates have improved dramatically during the past 15 years, and approach 90% for many organs. A major factor contributing to this short-term improvement is the development of more efficacious immunosuppressive agents that prevent or treat acute rejection. However, long-term graft survival has not improved appreciably since the early 1980s, due, in large part, to a poor understanding of the mechanisms of chronic graft failure. Improving transplantation outcomes requires a greater understanding of the genetic basis of the immune response to organ and tissue allografts. Decades of research focused on the extraordinary genetic polymorphism of the major histocompatibility complex (MHC) and its role in graft survival have provided valuable insights into the relative risk for graft failure of MHC gene disparities between donors and recipients. In recent years, investigators have also demonstrated intriguing associations between transplant outcomes and polymorphisms in a variety of genes encoding cytokines (TNF-alpha, TGF-beta, IFN-gamma, lymphotoxin, IL-1, IL-4, IL-6 and IL-10), adhesion molecules (ICAM- 1, L-selectin, and E-selectin), and co-stimulatory/regulatory molecules (B7 and CTLA-4). Similarly, the efficacy and toxicity of immunosuppressive agents such as steroids and Tacrolimus in some transplant patients have correlated with polymorphisms in the multidrug resistance gene (MDR1). Genetic variations between genders and races may also influence transplantation outcomes. A recent review of transplants performed worldwide indicated that recipients of solid organs from female donors have poorer outcomes than recipients of organs from male donors. Similarly, while one-year graft survival is equivalent for African-Americans and Caucasians, the three-year graft survival rate is significantly lower for African-Americans. In the few studies addressing this health disparity, adverse transplantation outcomes among African-Americans were correlated with certain gene polymorphisms, which lead to higher production of inflammatory cytokines and increased expression of costimulatory molecules compared to Caucasians. Overall, studies delineating the contributions of gene polymorphisms or gene expression variation in transplantation outcomes have been relatively few and limited in scope. Large-scale, broad-scope studies of gene polymorphisms and expression in donor organs and recipients will help elucidate the genetic basis of immune response differences and risk factors, such as gender and race, that result in acute and chronic graft rejection. In addition, these studies should lead to the development of safer and more efficacious immunosuppressive therapies. During the past decade, genomic research has benefited from significant technological advances in measuring and identifying gene expression, and in determining genotypes, single nucleotide polymorphisms (SNPs), microsatellite polymorphisms, and SNP haplotypes. In addition, the initial sequencing of the human genome has created new opportunities and challenges to apply these technologies to decipher the biological significance of genes, gene expression, and polymorphisms as they relate to human diseases, including the clinical outcomes of organ and cell transplantation. Furthermore, knowledge gained through the International HapMap Project (http://www.genome.gov/10001688), which is charting genetic variations within the human genome that contribute to many diseases, will inform efforts in transplantation genomics. Recently, researchers have also made tremendous advances in SNP and microsatellite polymorphism discovery within immune response genes, underscoring the timeliness of undertaking larger, targeted efforts in transplantation genomics. In May 2003, NIAID convened a multidisciplinary Expert Panel on the genomics of transplantation to discuss the state-of-the-science in complex-trait disease genomics, identify areas of research emphasis, and identify gaps in knowledge and scientific opportunities to fill these gaps. This RFA is based, in part, on the Panel’s recommendations and will initiate a cooperative research program, which may be expanded in future years, to apply genomics research to critical scientific questions in organ, tissue, and/or cell transplantation. Understanding the mechanisms of graft rejection and responses to therapy should allow prediction of outcomes and thus have a major impact on the development of new immunosuppressive therapeutics and tailoring of existing therapeutic strategies. In addition, these studies should facilitate identification of genetic markers to be used as diagnostic and prognostic tools. RESEARCH OBJECTIVES This RFA will initiate the establishment of a cooperative research program in transplantation genomics, supporting collaborative multidisciplinary teams with expertise in various disciplines, including transplantation medicine, genetics, immunology, molecular biology, pharmacogenomics, biostatistics, and bioinformatics. This RFA calls for the use of recipient and donor samples, as well as clinical data, for large-scale, broad-scope, prospective and/or retrospective genomic studies in clinical transplantation. The research focus may address: (1) the identification of unique immune response genes or gene expression patterns during acute and chronic graft rejection; (2) the identification of genetic variation in response to immunosuppressive therapeutics; and/or (3) the identification of SNPs, SNP haplotypes, or microsatellite polymorphisms that correlate with and/or predict differences in transplant outcomes in individuals due to race or gender. The primary research focus must be transplantation genomics. However, a minor proteomics component, if an integral part of the proposed genomics studies, may be included. Development or optimization of bioinformatics and statistical tools will be necessary to: (1) facilitate sharing of data among investigators; (2) analyze multi-dimensional genomic data with clinical data; and (3) evaluate multigenic and varied therapeutic effects, particularly given the challenges due to the limited numbers and heterogeneous character of the patients and patient groups. Clinical trials of interventional agents or strategies, or interventional or observational clinical studies associated with the proposed genomic studies must have independent financial support and will not be supported under this RFA. Proposed mechanistic studies associated with clinical trials supported by industry are particularly encouraged, but clinical trials supported by any source, public or private, are eligible. Examples of relevant research may include, but are not limited to the following areas: o Determination of gene expression profiles of donor organs and recipients prior to transplantation, before clinical signs of rejection, and during acute and chronic rejection; o Development of surrogate biomarkers of acute and chronic graft rejection; o Identification of unique SNPs, SNP haplotypes, and microsatellite polymorphisms in both donors and recipients, and correlation of these genetic variations with responses to immunosuppressive therapy.; o Determination of gene polymorphisms and/or expression patterns associated with race, age, and/or gender in graft rejection and responses to immunosuppressive therapeutics; o Identification of DNA sequence-mediated regulation of gene expression associated with graft survival/rejection; and o Development of noninvasive diagnostic/prognostic tests based on gene expression that will predict or confirm acute and chronic rejection. This RFA will not support: o Clinical trials, interventional or observational clinical studies. However, applicants may request support for clinical procedures to obtain patient samples provided that these procedures are justified and not included in associated clinical trial; o Studies investigating the effects of HLA disparities between recipients and donors; or o Hematopoietic stem cell transplantation (HSCT) studies, including HSCT engraftment, unless HSCT is a component of organ or non-hematopoietic tissue transplantation, or the focus of the genomics studies is graft-versus-host disease. In addition, genomic studies of anti-tumor responses in HSCT are not within the scope of this RFA. MECHANISM OF SUPPORT This RFA will use the NIH cooperative agreement (U01) and/or the NIH multi- project cooperative agreement (U19), "assistance" mechanisms, rather than "acquisition" mechanisms. The applicant 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 September 1, 2004. Applications that are not funded in the competition described in this RFA may be resubmitted as NEW investigator-initiated applications using the standard receipt dates for NEW applications described in the instructions to the PHS 398 application. The NIH U01 and U19 are cooperative agreements award mechanism in which the Principal Investigator retains the primary responsibility and dominant role for planning, directing, and executing the proposed project, with NIH staff being substantially involved as a partner with the Principal Investigator, as described under the section "Cooperative Agreement Terms and Conditions of Award." Essential elements of the multi-project cooperative agreement mechanism (U19) include: 1) a minimum of two interrelated individual research projects organized around a central theme; 2) collaborative efforts and interaction among independent projects and their investigators to achieve a common goal; 3) a single principal investigator who will be scientifically and administratively responsible for the group effort; 4) a single applicant institution that will be legally and financially responsible for the use and disposition of funds awarded; and 5) where necessary, support for core resources or facilities, each of which shall be utilized by at least two research projects in order to facilitate the research effort. The total project period for applications submitted in response to this RFA may not exceed five years. Applicants for U19 grants must follow special application guidelines in the NIAID Brochure entitled INSTRUCTIONS FOR APPLICATIONS FOR MULTI-PROJECT AWARDS; this brochure is available via the WWW at: http://www.niaid.nih.gov/ncn/grants/multibron.htm. FUNDS AVAILABLE The NIAID, intends to commit approximately $2,000,000 in FY 2004 to fund 1 to 3 new cooperative agreements in response to this RFA. An applicant may request a project period of up to five years. 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 NIAID provide support for this program, awards pursuant to this RFA are contingent upon the availability of funds and the receipt of a sufficient number of meritorious applications. At this time, the NIAID has not determined whether or how this solicitation will be continued beyond the present RFA. ELIGIBLE INSTITUTIONS The applicant may submit (an) application(s) if the institution has any of the following characteristics: o For-profit or non-profit organizations o Public or private institutions, such as universities, colleges, hospitals, and laboratories o Units of State and local governments o Eligible agencies of the Federal government o Domestic or foreign institutions/organizations 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 Applicants are encouraged to contact NIAID Program staff well in advance of the application submission date to discuss the proposed research program. This contact allows staff to assess responsiveness to this RFA and provide appropriate guidance as needed. 1. Description of Research Projects Applications must propose clear research plan(s) and project goal(s) to be completed during the award period. The applicant must clearly state the interim objectives to be achieved during the project, identify impediments or critical decision points that could require a revision in the work plan, and provide a detailed timeline for the attainment of each goal. The application must also demonstrate the scientific and technical expertise required to design, conduct and analyze mechanistic studies responsive to this RFA. 2. Development of a Productive Collaborative Program Each U01 or U19 application must demonstrate the organization’s ability to participate effectively in the NIAID Genomics of Transplantation Cooperative Research Program. The application must include a written commitment to: participate in the NIAID Genomics of Transplantation Cooperative Research Program; serve on the Steering Committee; adhere to the decisions reached by the Steering Committee; and accept the participation and assistance of NIH staff in accordance with the guidelines outlined under Cooperative Agreement Terms and Conditions of Award: NIH Staff Responsibilities. For a U19 multi-project cooperative agreement, the application must provide: a clear and concise plan, in narrative and diagrammatic form, that depicts the interrelationships among the research groups, their relevant experience/expertise, and the contribution of each to fulfillment of the objectives of this RFA; an organizational chart of the U19 cooperative group showing the name, organization, and scientific discipline of the PI and of all key scientific and technical personnel. If the application is from a consortium of institutions, the applicant must provide a plan to assure the maintenance of close cooperation and effective communication among members of the U19 cooperative group. For U01 and U19 cooperative agreements, the application must provide a clear and concise research plan demonstrating a multi-disciplinary approach including, but not necessarily limited to, expertise in transplantation research, genomics, and biostatistics/bioinformatics. 3. Studies with Human Samples Although clinical trials will not be supported under this RFA, human samples and clinical data will be utilized in the research supported by this program. Research samples may be derived from ongoing clinical trials or completed clinical trials in which samples were maintained for the expressed purpose of future genetic research. Support for clinical procedures to obtain samples that are not part of an associated clinical trial or study (e.g., additional biopsies) must be clearly described and justified. Applications should address plans for human subjects, including definition(s) of the population(s), plans for recruitment and retention; informed consent forms (including describing descriptions of plans for subject confidentiality, deposition of information into a database, and follow-up with participants); plans for stored or shared samples (and the prior informed consents permitting this); or use of any established sample sets. It is highly recommended that proposed consent forms for the genomics studies have clear language that (1) distinguishes mechanistic studies from the clinical trials with which they may be linked; (2) clarifies and ensures that subjects can refuse to participate in the mechanistic genomics study and still participate in the clinical trial; and (3) stipulates that there will be no charges to the subjects for the additional studies. Any incentives provided to subjects to participate in the mechanistic studies (if in addition to those under the clinical trial or study) should be clearly described and justified. Applications must include documentation of the ability to acquire human samples and clinical data for the proposed studies. The NIH brochure entitled "Research on Human Specimens: Are You Conducting Research Using Human Subjects?" may also be of use to applicants (http://www-cdp.ims.nci.nih.gov/policy.html). OHRP guidance on Repositories, Tissue Storage Activities and Data Banks should also be considered http://www.hhs.gov/ohrp/humansubjects/guidance/reposit.htm IRB approval of the consent form(s) is not required at the time of submission of the application. However, at a minimum, a draft of the consent form to be used for the genomics studies must be included, as well as the consent form for the associated clinical trial, if different. 4. Establishment of Database Applications must include proposed plans for data management including: data access by investigators participating in the project; data analysis; statistical/bioinformatics support; and where applicable, establishment of a database(s). Timely release of data to the NIH-supported and/or public databases is expected in accordance with the guidelines set by the Steering Committee and the NIH data sharing policy available at: http://grants.nih.gov/grants/policy/data_sharing/. 5. Statistical Considerations Methods of data analysis and power calculations must be included. Include a justification for the required sample size. A restatement of the sample size calculations from an associated clinical trial is insufficient. Applications must describe the statistical procedures that will be used to analyze the data. If appropriate to your application, discuss whether it is necessary to perform the genomic studies on all subjects enrolled in the parent trial or whether a sample would be sufficient. It is strongly recommended that a statistician be part of the research team and active in preparation of the proposal. Documentation of the appropriate statistical expertise should also be included in the application where applicable. 6. Studies with Associated Clinical Trials The complete clinical protocol and informed consent form(s) for the associated clinical trial must be included with the application as an appendix. While drafts of the consent forms at participating sites are not required, it would be useful to include them if they are available. NIH will treat as confidential any scientific, pre-clinical, clinical, or formulation data and information that the sponsor deems to be proprietary and confidential. In order to ensure coordination between the genomic studies and the associated clinical trial, the principal investigator and his or her academic institution, the sponsor(s) of the clinical trial (including drug companies, if applicable), and the IND sponsor, if not one of the above, must provide written agreements for the conduct of the proposed studies as presented in the application. 7. Steering Committee The NIAID will establish a Steering Committee within 60 days of award to serve as the governing body of the Cooperative Research Program. At a minimum, the Steering Committee will be composed of the U01/U19 Principal Investigators, a subproject investigator of U19 awards, and the NIAID Scientific Coordinator. Each member of the Steering Committee will have one vote. The NIAID may identify and appoint an outside scientific advisory panel, of which up to two members will serve on the Steering Committee as non-voting members. A Chairperson will be selected by the Steering Committee from among the non- federal Committee members. Subcommittees of the Steering Committee may be established as necessary. The Steering Committee will meet two times annually in Bethesda, MD. Proposed budgets should include funds to cover travel costs for these meetings. Each Steering Committee member will be expected to participate in all meetings and activities, e.g., conference calls and special subcommittees as required. 8. Memorandum of Understanding Prior to award, the applicant must provide to the funding institute a memorandum of understanding signed by the applicant, an appropriate representative of the applicant institution, the principal investigator of the associated clinical trial, and an appropriate representative of the financial sponsor of the associated clinical trial, and IND holder if different. This memorandum will indicate agreement and will outline the specifics of the agreement for the following areas: 1) data from the genomic studies (including ownership, analysis, access, and release), 2) access to the data from the associated clinical trial (how/when) that are needed to analyze the genomic studies, including procedures for prevention of unblinding of the parent trial, 3) documentation of quality assurance procedures for both the parent trial and the genomic studies, and documentation of Data Safety Monitoring procedures for the parent trial, especially for efficacy trials, 4) ownership of intellectual property developed during the genomic studies, and 5) publication of the results of the genomic studies. COOPERATIVE AGREEMENT TERMS AND CONDITIONS OF AWARD The following terms and conditions will be incorporated into the award statement and provided to the Principal Investigator 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 part 74 and 92, and other HHS, PHS, and NIH Grant Administration policy statements. Cooperative agreements are subject to the administrative requirements outlined in OMB circulars A-102 and A-110. All pertinent HHS, PHS, and NIH grant regulations, policies and procedures, with particular emphasis on PHS regulations at 42 CFR Part 52 and HHS regulations at 45 CFR Part 74, are applicable. These special terms and conditions pertaining to the scope and nature of the interaction between the NIAID and the investigators will be incorporated in the Notice of Grant Award. However, these terms will be in addition to, not in lieu of, the customary programmatic and financial negotiations that occur in the administration of cooperative agreements. The administrative and funding instrument used for this program is the cooperative agreement (U01) or multiproject cooperative agreement (U19), an "assistance", rather than an "acquisition", mechanism, in which substantial NIH scientific and/or programmatic involvement with the awardee is anticipated during the 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 awardees for the project as a whole, although specific tasks and activities in carrying out the research will be shared among the awardees and the NIAID Scientific Coordinator through the Steering Committee. 1. Monitoring Clinical Studies When clinical studies or trials are a component of the research proposed, NIAID policy requires that studies be monitored commensurate with the degree of potential risk to study subjects and the complexity of the study. AN UPDATED NIAID policy was published in the NIH Guide on July 8, 2002 and is available at: http://grants.nih.gov/grants/guide/notice-files/NOT-AI-02-032.html. The full policy, including terms and conditions of award, is available at: http://www.niaid.nih.gov/ncn/pdf/clinterm.pdf. 2. Awardee Rights and Responsibilities Awardees will have primary responsibility for defining the research objectives, approaches and details of the projects within the guidelines of the RFA and for performing the scientific activity. Specifically, awardees have primary responsibility as described below. The Principal Investigators will: determine and coordinate the project activities scientifically and administratively; set project goals and timelines to achieve the proposed goals; accept and implement common guidelines approved by the Steering Committee; submit data to NIH-supported and/or public databases in accordance with policies agreed upon and established by the Steering Committee and the NIH data sharing policy available at: http://grants.nih.gov/grants/policy/data_sharing/; attend Steering Committee meetings and serve as a voting member of the Steering Committee; and participate in the cooperative nature of the group. It is recognized that goals may require revision and re-negotiation during the course of the project period. Release of each funding increment by NIAID will be based on an NIAID review of progress towards achieving the previously agreed upon research goals. Awardees will retain custody of and have primary rights to the data developed under these awards, subject to Government rights of access consistent with current HHS, PHS, and NIH policies. NIAID intends to support the peer-reviewed studies proposed in the awarded grant applications. However, under special circumstances (e.g. duplicative or overlapping specific aims between two awardees), the Steering Committee will establish guidelines and review procedures, and will evaluate and determine opportunities for collaboration, redirection or modification of the peer- reviewed or new projects when applicable and necessary. This policy is in keeping with the terms and conditions of the cooperative agreement mechanism. The awardee will implement the approved memorandum of understanding that will indicate agreement and will outline the specifics of the agreement for the following areas: 1) data from the genomic studies (including ownership, analysis, access, and release), 2) access to the data from the associated clinical trial (how/when) that are needed to analyze the genomic studies, including procedures for prevention of unblinding of the parent trial, 3) documentation of quality assurance procedures for both the parent trial and the genomic studies, and documentation of Data Safety Monitoring procedures for the parent trial, especially for efficacy trials, 4) ownership of intellectual property developed during the genomic studies, and 5) publication of the results of the genomic studies. 3. Studies with Human Samples Although clinical trials will not be supported under this RFA, human samples and clinical data will be utilized in the research supported by this program. The NIAID Program Director will facilitate compliance with NIH policies for monitoring activities commensurate with the degree of potential risk to human subjects. The NIAID policy including terms and conditions of award is available at: http://www.niaid.nih.gov/ncn/pdf/clinterm.pdf. The NIH brochure entitled "Research on Human Specimens: Are You Conducting Research Using Human Subjects?" may also be of use to applicants (http://wwwcdp.ims.nci.nih.gov/policy.html). OHRP guidance on Repositories, Tissue Storage Activities and Data Banks should also be considered http://www.hhs.gov/ohrp/humansubjects/guidance/reposit.htm 4. NIAID Staff Responsibilities NIAID staff assistance will be provided by a Program Director from the Transplantation Basic Sciences Section, Transplantation Immunobiology Branch, Division of Allergy, Immunology and Transplantation (DAIT), who will serve as NIAID's Scientific Coordinator and will be a voting member of the Steering Committee. The NIAID Scientific Coordinator will have substantial scientific/programmatic involvement during the conduct of this activity through technical assistance, advice and coordination above and beyond normal program stewardship for grants, as described below. During performance of the award, the NIAID Scientific Coordinator, with assistance from other scientific program staff who are designated based on the research topic and their relevant expertise, may provide appropriate assistance, advice, and guidance by: participating in the design of the activities; advising in the selection of sources or resources; coordinating or participating in the collection and/or analysis of data; advising in management and technical performance; or participating in the preparation of publications. However, the role of NIAID will be to facilitate and not to direct the activities. It is anticipated that decisions in all activities will be reached by consensus and the NIAID staff will be given the opportunity to offer input into this process. The manner of reaching this consensus and the final decision-making authority will rest with the Principal Investigator and the Steering Committee. In addition, the NIAID Program Director will be responsible for normal programmatic monitoring and stewardship for the award. Other appropriate NIAID program staff assistance will be coordinated by the Program Director. The NIAID Program Director will approve changes in proposed research objectives and redirection of research projects. The NIAID reserves the right to terminate or curtail a study (or any individual award) in the event of (a) substantial shortfall in participant recruitment, follow-up, data reporting, quality control, or other major breach of the protocol; (b) substantive changes in the consensus protocol to which the NIAID does not agree; (c) reaching a major study endpoint substantially before schedule with persuasive statistical significance; or (d) human subject ethical issues that may dictate a premature termination. An NIAID Program Director will be assigned to perform normal program stewardship responsibilities for this award. The Program Director may serve as the Scientific Coordinator. 5. Organizational Changes Certain organizational changes require the prior written approval of the NIAID Program Director. These changes include the addition or replacement of an investigator, component, or research base that is associated with the studies. A change in the PI, or in any key personnel identified on the Notice of Award, must have the prior written approval of the NIAID Grants Management Specialist in consultation with the NIAID Program Director. 6. Collaborative Responsibilities The Steering Committee A Steering Committee will serve as the governing board of the cooperative group of researchers. At a minimum, voting membership of the Steering Committee will include the NIAID Scientific Coordinator, each U01/U19 Principal Investigator, one sub-project investigator from each U19 award, and selected scientists other than the awardees when additional expertise is required for committee breadth and balance. The Steering Committee will appoint additional members by majority vote. In addition, the NIAID may appoint up to two members of an NIAID scientific advisory panel to the Steering Committee as non-voting members. Federal votes cannot exceed 25%. Awardee members of the Steering Committee will be required to accept and implement common guidelines and procedures approved by the Steering Committee. The NIAID Scientific Coordinator will schedule the meetings of the Steering Committee and actively assist the Chair in developing the meeting agendas. The Committee will meet at least twice the first year and annually thereafter. At least one of the meetings in the first year and the annual meetings will be in Bethesda, MD. Subcommittees may be established by the Steering Committee as necessary. The NIAID Scientific Coordinator will ensure coordination of the Steering Committee’s activities and implementation of the group’s recommendations. The Steering Committee or a designated subcommittee will prepare an annual report containing the following information: progress of ongoing and newly- initiated projects; manuscripts published, in press, and in preparation; presentations at regional, national, and international meetings; other activities of the group; data submitted to databases; and future plans. The first such report will be submitted to the NIAID Scientific Coordinator not later than 13 months after the initial notice of award, and yearly thereafter. The Steering Committee will: o Serve as the main governing board; o Evaluate progress of the transplantation genomics projects and provide guidance to investigators regarding study implementation and conduct; o Establish protocols and subcommittees for evaluation, review, recommendation and modification of peer-reviewed, new, or ongoing genomic studies from consortium members and/or new collaborators; o Establish standards for data collection, analysis, and data management; o Establish centralized data and statistical analysis cores as needed; o Review and provide recommendations for human subjects protection issues; o Consider the representative views of other researchers in the program; o Advise NIH on scientific opportunities, emerging needs, and impediments; o Ensure the timely release of data to the NIH supported and/or public databases; o Prepare Annual Reports; and o Develop guidelines for publication of collaborative project results Cooperation with Other NIH-Sponsored Programs In order to most efficiently utilize research resources and rapidly exchange scientific information to promote transplantation genomics objectives, it is anticipated that cooperation or opportunities to collaborate with other NIAID funded programs, such as the Cooperative Clinical Trial in Pediatric Transplantation, will be initiated in future years and will be coordinated and facilitated by the NIAID Program Director. 7. Arbitration Any disagreement that may arise on scientific or programmatic matters (within the scope of the award), between award recipients and the NIAID may be brought to arbitration. An arbitration panel will be composed of three members - one selected by the Steering Committee (with the NIAID representation not voting) or by the individual awardee in the event of an individual disagreement, a second member selected by NIAID, and the third member selected by the two prior selected 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. 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 questions about scientific/research issues to: Crystal Y. Koh, Ph.D. Division of Allergy, Immunology, and Transplantation National Institute of Allergy and Infectious Diseases Room Number 3026, MSC-6601 6610 Rockledge Drive Bethesda, MD 20892-6601 Telephone: (301) 496-5598 FAX: (301) 480-0693 Email: [email protected] o Direct questions about peer review issues to: Edward W. Schroder, Ph.D. Chief, Microbiology and Immunology Review Branch Scientific Review Program, DEA, NIAID, NIH, DHHS 6700-B Rockledge Drive MSC 7616 Bethesda, MD 20892-7616 Zip code for express couriers: 20817 Phone: 301-435-8537 FAX: 301-402-2638 e-mail: [email protected] o Direct questions about financial or grants management matters to: Ann Devine Division of Extramural Activities National Institute of Allergy and Infectious Diseases Room number 2118, MSC-7614 6700-B Rockledge Drive Bethesda, MD 20892-7614 Telephone: (301) 402-5601 FAX: (301) 480-3780 Email: [email protected] LETTER OF INTENT Prospective applicants are asked to submit a letter of intent that includes the following information: o Descriptive title of the proposed research o Name, address, and telephone number of the Principal Investigator o Names of other key personnel o Participating institutions o Number and title of this RFA Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows NIAID 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: Edward W. Schroder, Ph.D. Chief, Microbiology and Immunology Review Branch Scientific Review Program, DEA, NIAID, NIH, DHHS 6700-B Rockledge Drive MSC 7616 Bethesda, MD 20892-7616 Zip code for express couriers: 20817 Phone: 301-435-8537 FAX: 301-402-2638 e-mail: [email protected] SUBMITTING AN APPLICATION Applications must be prepared using the PHS 398 research grant application instructions and forms (rev. 5/2001). Applications must have a DUN and Bradstreet (D&B) Data Universal Numbering System (DUNS) number as the Universal Identifier when applying for Federal grants or cooperative agreements. The DUNS number can be obtained by calling (866) 705-5711 or through the web site at http://www.dunandbradstreet.com/. The DUNS number should be entered on line 11 of the face page of the PHS 398 form. The PHS 398 document is available at http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format. For further assistance contact GrantsInfo, Telephone (301) 710-0267, Email: [email protected]. SUPPLEMENTARY INSTRUCTIONS: It is highly recommended that the appropriate NIAID program contact be consulted before submitting the letter of intent and during the early stages of preparation of the application. (See program contact under INQUIRIES). Applicants for U19 cooperative agreements must follow special application guidelines in the NIAID Brochure entitled INSTRUCTIONS FOR APPLICATIONS FOR MULTI-PROJECT AWARDS; this brochure is available from NIAID listed under INQUIRIES via the WWW at: http://www.niaid.nih.gov/ncn/grants/multibron.htm. This brochure presents specific instructions for sections of the PHS 398 (rev. 5/01) application form that should be completed differently than usual. For all other items in the application, follow the usual instructions in the PHS 398. See the SPECIAL REQUIREMENTS section above for additional application requirements and instructions. USING THE RFA LABEL: The RFA label available in the PHS 398 (rev. 5/2001) application form must be affixed to the bottom of the face page of the application. Type the RFA number on the label. Failure to use this label could result in delayed processing of the application such that it may not reach the review committee in time for review. In addition, the RFA title and number must be typed on line 2 of the face page of the application form and the YES box must be marked. The RFA label is also available at: http://grants.nih.gov/grants/funding/phs398/label-bk.pdf. SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten original of the application, including the Checklist, and three signed, photocopies, in one package to: Center For Scientific Review National Institutes of Health 6701 Rockledge Drive, Room 1040, MSC 7710 Bethesda, MD 20892-7710 Bethesda, MD 20817 (for express/courier service) At the time of submission, two additional exact copies of the grant application and all five sets of any appendix material must be sent to: Edward W. Schroder, Ph.D. Chief, Microbiology and Immunology Review Branch Scientific Review Program, DEA, NIAID, NIH, DHHS 6700-B Rockledge Drive MSC 7616 Bethesda, MD 20892-7616 Zip code for express couriers: 20817 Applications that are not received as a single package on or before March 15, 2004 or that do not conform to the instructions contained in PHS 398 (rev. 5/01) Application Kit (as modified in, and superseded by, the NIAID BROCHURE ENTITLED "INSTRUCTIONS FOR APPLICATIONS FOR MULTI-PROJECT AWARDS"), will be judged non-responsive and will be returned to the applicant. 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. However, when a previously unfunded application, originally submitted as an investigator-initiated application, is to be submitted in response to an RFA, it is to be prepared as a NEW application. That is, the application for the RFA must not include an Introduction describing the changes and improvements made, and the text must not be marked to indicate the changes from the previous unfunded version of the application. Concurrent submission of an R01 and a Component Project of a Multi-project Application: Current NIH policy permits a component research project of a multi-project grant application to be concurrently submitted as a traditional individual research project (R01) application. If, following review, both the multi-project application and the R01 application are found to be in the fundable range, the investigator must relinquish the R01 and will not have the option to withdraw from the multi-project grant. This is an NIH policy intended to preserve the scientific integrity of a multi-project grant, which may be seriously compromised if a strong component project(s) is removed from the program. Investigators wishing to participate in a multi-project grant must be aware of this policy before making a commitment to the Principal Investigator and awarding institution. PEER REVIEW PROCESS Upon receipt, applications will be reviewed for completeness by the CSR and responsiveness by the NIAID. Incomplete and/or non-responsive applications will be returned to the applicant without further consideration. Applications requesting support for clinical trials of interventional agents or strategies, as well as for interventional or observational clinical studies will be non-responsive and returned without review. 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 NIAID in accordance with the review criteria stated below. As part of the initial merit review, all applications will: o Undergo a selection process in which only those applications deemed to have the highest scientific merit, generally the top half of applications under review, will be discussed and assigned a priority score o Receive a written critique o Receive a second level review by the National Advisory Allergy and Infectious Diseases 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 the 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 the 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. SIGNIFICANCE: Does this study address an important problem? If the aims of the application are achieved, how will scientific knowledge be advanced? What will be the effect of these studies on the concepts or methods that drive this field? 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 investigator appropriately trained and well-suited to carry out this work? Is the work proposed appropriate to the experience level of the principal investigator and other researchers (if any)? ENVIRONMENT: Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed experiments take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of institutional support? The general review criteria for U19 multi-project cooperative agreement applications are presented in the NIAID brochure entitled "INSTRUCTIONS FOR APPLICATIONS FOR MULTI-PROJECT AWARDS at http://www.niaid.nih.gov/ncn/grants/multibron.htm. ADDITIONAL REVIEW CRITERIA: In addition, the following review criteria will be considered in the determination of scientific merit and priority score: 1. Scientific merit of hypothesis-driven or discovery-based genomic studies that correlate with clinical outcomes. 2. Adequacy of multidisciplinary approach to conduct synergistic, basic and/or applied research to achieve the goals of Genomics of Transplantation Cooperative Research Program. 3. Technical and administrative feasibility of plans to conduct studies with human samples. 4. Database and statistical considerations: adequacy of proposed methods of data analysis and power calculations, and proposed plans and personnel for data management including data access by investigators participating in the project, statistical/bioinformatics support, and where applicable, establishment of a database(s). 5. 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) 6. 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). 7. 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 SHARING RESEARCH DATA: Applicants requesting more than $500,000 in direct costs in any year of the proposed research are expected to include a data sharing plan in their application. The reasonableness of the data sharing plan or the rationale for not sharing research data will be assessed by the reviewers. However, reviewers will not factor the proposed data-sharing plan into the determination of scientific merit or priority score. (See instructions and URL to policy in the Federal Citations, below.) 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: February 16, 2004 Application Receipt Date: March 15, 2004 Scientific Peer Review Date: June, 2004 Advisory Council Review: August, 2004 Earliest Anticipated Start Date: September, 2004 AWARD CRITERIA Award criteria that will be used to make award decisions include: o Scientific merit of the proposed project as determined by peer review o Availability of funds o Programmatic priorities REQUIRED FEDERAL CITATIONS HUMAN SUBJECTS PROTECTION: Federal regulations (45CFR46) require that applications and proposals involving human subjects must be evaluated with reference to the risks to the subjects, the adequacy of protection against these risks, the potential benefits of the research to the subjects and others, and the importance of the knowledge gained or to be gained. http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm DATA AND SAFETY MONITORING PLAN: Data and safety monitoring is required for all types of clinical trials, including physiologic, toxicity, and dose- finding studies (phase I); efficacy studies (phase II), efficacy, effectiveness and comparative trials (phase III). The establishment of data and safety monitoring boards (DSMBs) is required for multi-site clinical trials involving interventions that entail potential risk to the participants. (NIH Policy for Data Safety and Monitoring, NIH Guide for Grants and Contracts, June 12, 1998: http://grants.nih.gov/grants/guide/notice-files/not98-084.html). SHARING RESEARCH DATA: Starting with the October 1, 2003 receipt date, investigators submitting an NIH application seeking more than $500,000 or more in direct costs in any single year are expected to include a plan for data sharing or state why this is not possible. http://grants.nih.gov/grants/policy/data_sharing Investigators should seek guidance from their institutions, on issues related to institutional policies, local IRB rules, as well as local, state and Federal laws and regulations, including the Privacy Rule. Reviewers will consider the data sharing plan but will not factor the plan into the determination of the scientific merit or the priority score. INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH: It is the policy of the NIH that women and members of minority groups and their sub-populations must be included in all NIH-supported clinical research projects unless a clear and compelling justification is provided indicating that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing clinical research should read the AMENDMENT "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research - Amended, October, 2001," published in the NIH Guide for Grants and Contracts on October 9, 2001 (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); a complete copy of the updated Guidelines are available at http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm The amended policy incorporates: the use of an NIH definition of clinical research; updated racial and ethnic categories in compliance with the new OMB standards; clarification of language governing NIH-defined Phase III clinical trials consistent with the new PHS Form 398; and updated roles and responsibilities of NIH staff and the extramural community. The policy continues to require for all NIH-defined Phase III clinical trials that: a) all applications or proposals and/or protocols must provide a description of plans to conduct analyses, as appropriate, to address differences by sex/gender and/or racial/ethnic groups, including subgroups if applicable; and b) investigators must report annual accrual and progress in conducting analyses, as appropriate, by sex/gender and/or racial/ethnic group differences. INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS: The NIH maintains a policy that children (i.e., individuals under the age of 21) must be included in all human subjects research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them. This policy applies to all initial (Type 1) applications submitted for receipt dates after October 1, 1998. All investigators proposing research involving human subjects should read the "NIH Policy and Guidelines" on the inclusion of children as participants in research involving human subjects that is available at http://grants.nih.gov/grants/funding/children/children.htm REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS: NIH policy requires education on the protection of human subject participants for all investigators submitting NIH proposals for research involving human subjects. This policy announcement is in the NIH Guide for Grants and Contracts Announcement, dated June 5, 2000, at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html. PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT: The Office of Management and Budget (OMB) Circular A-110 has been revised to provide public access to research data through the Freedom of Information Act (FOIA) under some circumstances. Data that are (1) first produced in a project that is supported in whole or in part with Federal funds and (2) cited publicly and officially by a Federal agency in support of an action that has the force and effect of law (i.e., a regulation) may be accessed through FOIA. It is important for applicants to understand the basic scope of this amendment. NIH has provided guidance at http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm. Applicants may wish to place data collected under this 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 Catalogue of Federal Domestic Assistance at http://www.cfda.gov/ in the following citations: No. 93.855, Immunology, Allergy, and Transplantation Research and No. 93.856, Microbiology and Infectious Diseases Research. Awards are made under authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and administered under NIH grants policies and Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. The NIH Grants Policy Statement is available at http://grants.nih.gov/grants/policy/policy.htm. This document includes general information about the grant application and review process; information on the terms and conditions that apply to NIH Grants and cooperative agreements; and a listing of pertinent offices and officials at the NIH. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement. 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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