CLINICAL TRIALS IN ORGAN TRANSPLANTATION (CTOT) RELEASE DATE: December 9, 2003 RFA Number: RFA-AI-04-003 (Reissued as RFA-AI-08-015) Department of Health and Human Services (DHHS) PARTICIPATING ORGANIZATION: National Institutes of Health (NIH) (http://www.nih.gov) COMPONENTS OF PARTICIPATING ORGANIZATION: National Institute of Allergy and Infectious Diseases (NIAID) (http://www.niaid.nih.gov) National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (http://www.niddk.nih.gov) National Heart, Lung and Blood Institute (NHLBI) (http://www.nhlbi.nih.gov) CATALOGUE OF FEDERAL DOMESTIC ASSISTANCE NUMBERS: No. 93.855, Immunology, Allergy, and Transplantation Research No. 93.856, Microbiology and Infectious Diseases Research No. 93.849, Kidney Diseases, Urology and Hematology Research No. 93.837, Heart and Vascular Diseases Research No. 93.838, Lung Diseases Research No. 93.839, Blood Diseases and Resources 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 Mechanism(s) of Support o Funds Available o Eligible Institutions o Individuals Eligible to Become Principal Investigators o Special Requirements o Where to Send Inquiries o Letter of Intent o Submitting an Application o Supplementary Instructions o Peer Review Process o Review Criteria o Receipt and Review Schedule o Award Criteria o Required Federal Citations PURPOSE OF THIS RFA The Division of Allergy, Immunology, and Transplantation (DAIT) of the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH) invites applications from consortia of 2 or more institutions to participate in a clinical studies program of immune-mediated pathologic processes in organ transplantation. The purpose of this program is to support a cooperative, multi-site consortium for interventional or observational clinical studies, accompanied by mechanistic studies, to enhance our understanding of and ultimately reduce the immune-mediated morbidity and mortality of organ transplantation. These studies will be carried out in pediatric and adult candidates for and recipients of organ transplants as multi-center clinical trials that will (1) evaluate new therapeutic regimens to overcome immunologic barriers to graft acceptance and/or long-term graft and patient survival, (2) evaluate approaches to the treatment or prevention of immune-mediated complications of transplantation; (3) investigate the underlying mechanisms of action of the pathologic processes, agents or regimens under study; (4) develop diagnostic tests for and/or surrogate biomarkers that will facilitate routine surveillance, early diagnosis and ongoing monitoring of those processes that contribute to post-transplant morbidity and mortality. Studies of hematopoietic stem cell transplantation (HSCT) are excluded, unless HSCT is a component of a study of organ transplantation. Studies of islet transplantation for treatment of type I diabetes are also excluded. RESEARCH OBJECTIVES Organ or tissue replacement is the treatment for end-stage organ failure when other therapies have failed or are not available, and when the person affected by organ failure is deemed likely to benefit from organ transplantation. The benefits of organ transplantation, as evidenced by prolonged survival and/or improved quality of life, have been clearly demonstrated for children and adults suffering from a wide range of congenital and acquired diseases. However, normal life expectancy and health-related quality of life are rarely, if ever, restored by organ transplantation. Although 1-year survival after organ transplantation has improved markedly over the last 15 years, there has been little success in reversing the decline in long-term graft and patient survival that is seen in recipients of any organ transplant, in whom the prevalence of morbidities such as systemic hypertension, diabetes mellitus, renal insufficiency, and malignancy remain high as compared with the general population. The barriers to short and long-term success of transplant procedures are predominantly the result of incompatibility between donor and recipient, acute and chronic rejection, and complications of long-term pharmacologic immune suppression. Responsive applications to this RFA will propose multi-center clinical trials and/or observational studies, with associated mechanistic studies, that will improve our understanding of and/or evaluate interventions to reduce the immune-mediated morbidity and mortality of organ transplantation. Examples of conditions to be studied include, but are not limited to: 1. Pre-existing immunologic barriers (such as anti-HLA antibodies or ABO incompatibility) to successful transplantation. 2. Chronic, progressive allograft destruction (e.g., allograft nephropathy, obliterative bronchiolitis) after organ transplantation. 3. Immunomodulatory interventions targeting innate immunity and/or autoimmunity in transplant donors or recipients. 4. New, less toxic immunosuppressive agents or regimens, or innovative approaches to develop donor-specific tolerance. 5. Prevention or treatment of post-transplant lymphoproliferative disorder and malignancy. 6. Susceptibility to and prevention of the adverse consequences (e.g., nephropathy, systemic hypertension, diabetes mellitus, malignancy) of current post-transplant immunosuppressive regimens. Proposals must include a plan for associated mechanistic studies. These mechanistic studies will be weighed equally with the clinical studies in the review of applications. Collaboration with other NIAID initiatives in the performance of mechanistic studies is encouraged, and will be facilitated by NIAID program staff. Mechanistic studies may include, but are not limited to: 1. The underlying mechanisms of action of the therapeutic approaches under investigation. 2. Development, evaluation, and validation of diagnostic tests for and/or surrogate markers of the relevant immunologic processes that will facilitate routine surveillance, early diagnosis and ongoing monitoring of those processes that contribute to post transplant morbidity and mortality. The use of non-invasive or minimally invasive approaches is strongly encouraged. 3. Development of assays to define and monitor immunoreactivity in order to guide real-time dose adjustments of the immunosuppressive regimen. 4. Identify genetic determinants of outcome or response to therapy in tissue and organ transplant recipients. Studies may use samples from sources other than the subjects participating in the consortium’s clinical studies. Applicants must identify the source of patient materials required for the mechanistic studies and provide documentation of the availability of the appropriate number and type of patient materials and the willingness of the source to make such samples available to the investigators. As in the case of the proposed clinical protocol, award of the Cooperative Agreement does not imply that any proposed mechanistic studies will be implemented. Actual studies to be performed will be selected or designed by the Mechanistic Studies Subcommittee and approved by the Steering Committee. When research involves human specimens, an NIH brochure is available to assist investigators in understanding how human subjects regulations (45CFR46) apply to their research: Research on Human Specimens: Are You Conducting Research Using Human Subjects? http://www.cdp.ims.nci.nih.gov/policy.html. Creative approaches to overcoming the statistical or epidemiologic challenges of a small and heterogeneous patient group are encouraged. For each study performed within the cooperative group, all participating clinical sites will utilize uniform study designs and standardized data collection procedures. Proposals for animal studies of any sort, including xenotransplantation studies, will not be accepted. Interventions may target recipients and/or donors. MECHANISM OF SUPPORT This RFA will use the NIH cooperative agreement (U01). 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 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 is a cooperative agreement 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." The total project period for applications submitted in response to this RFA may not exceed five years. At this time, the NIAID has not determined whether and how this solicitation will be continued beyond the present RFA. This RFA uses just-in-time concepts. It also uses the modular budgeting format. (see http://grants.nih.gov/grants/funding/modular/modular.htm). Specifically, if the investigator is submitting an application with direct costs in each year of $250,000 or less, use the modular format. This program does not require cost sharing as defined in the current NIH Grants Policy Statement at http://grants.nih.gov/grants/policy/nihgps_2001/part_i_1.htm FUNDS AVAILABLE The participating IC(s) intends to commit approximately $7.8 million in FY 2004 to fund 3 to 5 new grants in response to this RFA. An applicant may request a project period of up to 5 years and a budget for direct costs of up to $2 million per year. 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 IC(s) provide support for this program, awards pursuant to this RFA are contingent upon the availability of funds and the receipt of a sufficient number of meritorious applications. ELIGIBLE INSTITUTIONS 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 his/her 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. These contacts help to ensure that applicants have a clear understanding of the goals, policies and priorities of this RFA. They also will allow staff to assess responsiveness to this RFA and provide appropriate guidance as needed, with regard to this initiative as well as other NIAID initiatives in transplantation research. Applicants must demonstrate the scientific expertise required to design, conduct, and analyze all mechanistic studies. Alternatively, the applicant may propose that some mechanistic studies be performed in collaboration with other existing NIAID-funded research groups or core facilities. Successful applicant consortia will be merged to create a single consortium of institutions and investigators that will develop a scientific agenda and collaborative program of clinical and mechanistic studies. The study organization will include the following: a Steering Committee; a Mechanistic Studies Subcommittee; other subcommittees created as deemed necessary by the Steering Committee; an independent Data and Safety Monitoring Board (DSMB) appointed by NIAID; and a separately-funded data coordination and management center (DCMC) that will be directed by NIAID. The Steering Committee will be the main governing body of the CTOT group. The Steering Committee will develop a scientific agenda for the group, and prioritize study protocols in accordance with this agenda. All major scientific decisions will be determined by a majority vote of the Steering Committee. The Steering Committee will have primary responsibility for the general organization of the studies and for finalizing and approving common clinical protocols. The Steering Committee will be responsible for the conduct and monitoring of studies and reporting study results. For each study, one PI will take the lead responsibility for drafting the protocol, although the Steering Committee and the NIAID Scientific Coordinator will provide input. A Mechanistic Studies Subcommittee (see Collaborative Responsibilities , below) will review and approve or modify the proposed mechanistic studies. Each investigational or therapeutic protocol will be implemented in as many participating sites as are needed and appropriate for the individual study, with a minimum of 2 sites participating in each study. As specific protocols are developed, support will depend on the availability of funds. For clinical sites, funds will be provided on a per patient basis. All participating clinical sites must be willing to accept this funding arrangement. Start up costs for clinical research resources that must be in place prior to enrollment of subjects may be exempt from this requirement, subject to approval by the Steering Committee and the NIAID Program Director. Clinical protocols must be approved by local institutional review boards and the NIAID Transplant DSMB before initiation. The exact number of protocols supported in the five-year program will depend on the nature and extent of the investigations approved by the Steering Committee. A database will be developed to support epidemiological studies and other clinical studies. Investigators in the CTOT group will be encouraged to develop collaborations with other laboratory and basic research investigators, as well as with industry. Any collaboration with industry will be developed with the assistance of the DAIT Office of Clinical Activities (OCA) and conducted under a DAIT Clinical Trials Agreement. Any specific collaboration involving the resources or protocols of the CTOT group will require approval by the Steering Committee. 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. The administrative and funding instrument used for this program is cooperative agreement (U01), 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. 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. Recipient institutions must agree as a term of award to accept per-patient funding for clinical activities. Start up costs for clinical research resources that must be in place prior to enrollment of subjects may be exempt from this requirement, subject to approval by the Steering Committee and the NIAID Program Director. 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. This award provides support for one or more NIH-defined Phase III clinical trials. The NIH Policy for research supported as an NIH Phase III Clinical Trial has been updated in Section III.B. of the NIH Guidelines on the Inclusion of Women and Minorities as Subjects in Clinical Research , updated August 1, 2000 (URL listed below under REQUIRED FEDERAL CITATIONS). A description of plans to conduct analyses, as appropriate, by sex/gender and/or racial/ethnic groups must be included in clinical trial protocols and the results of the subset analyses must be reported to NIH in Progress Reports, Competitive Renewal Applications, and in the required Final Progress Report, as stated in Section III.B. of the Guidelines. 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. Each PI will be a voting member of the Steering Committee and will be required to participate in all Steering Committee activities and to follow the policies and procedures that are developed by the Steering Committee. The PIs will be required to provide primary study data to NIAID for management, quality control, and analysis. The awardees will retain custody of and have primary rights to all data developed under these awards, subject to Government rights of access consistent with HHS, PHS, and NIH policies. The PIs responsibilities regarding Steering Committee membership, protocol development and conduct, and data coordination and management are described under Collaborative Responsibilities. 3. NIAID Staff Responsibilities An NIAID Program Director will be responsible for the normal program stewardship, including monitoring program progress, approving changes and concurring in proceeding into study implementation stage. The Government, via the NIAID Program Director, will have access to data generated under this Cooperative Agreement and may periodically review the data and progress reports. NIAID staff may use information obtained from the data for the preparation of internal reports on the activities of the study. However, awardees will retain custody of and have primary rights to all data developed under these awards. Program Review The NIAID Program Director, together with the DCMC and the Steering Committee, will review the progress of each participating institution through consideration of the annual reports, site visits, patient logs, etc. This review may include, but is not limited to, compliance with the study protocol, meeting patient enrollment targets, adherence to uniform data collection procedures, and the timeliness and quality of data reporting. The NIAID reserves the right to terminate or curtail any 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. Organizational Changes Certain organizational changes require the prior written approval of the NIAID Program Director. These changes include the addition or replacement of a physician, scientific investigator, affiliate, component, or research base that is associated with this study. 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. The NIAID Program Director may also serve as the NIAID Scientific Coordinator. NIAID Scientific Coordinator NIAID staff assistance will be provided by the Clinical Transplantation Section Chief, DAIT, who will serve as or designate the NIAID Scientific Coordinator. 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. The NIAID Scientific Coordinator will serve as a voting member of the Steering Committee and will participate in all Committee activities. The NIAID Scientific Coordinator will also serve on the Mechanistic Studies Subcommittee. Protocol Development As a member of the Steering Committee, the NIAID Scientific Coordinator will serve as a resource with respect to the design of the protocol and will, along with the DCMC, assist the Steering Committee in protocol development. Publication and Presentation of Study Findings The NIAID Scientific Coordinator may contribute, through review, comment, analysis, and/or co-authorship, to reporting results of the study to the investigator community and other interested scientific and lay organizations. Co-authorship by the NIAID Scientific Coordinator will be subject to approval in accordance with NIH policies regarding staff authorship of publications resulting from extramural awards. Regulatory Affairs The Chief of Regulatory Affairs/OCA/DAIT will be responsible for providing guidance and assistance in the development, assembly, and submission of all required regulatory documents, e.g. those regarding the use investigational drugs, to the Food and Drug Administration. 4. Collaborative Responsibilities Steering Committee. A Steering Committee will be established to serve as the main governing body of the cooperative research program. At a minimum, the Steering Committee will be composed of the following individuals: the NIAID Scientific Coordinator; the Principal Investigators; one additional Senior Investigator from each successful applicant consortium; the PI of the DCMC; and the Chair of the Mechanistic Studies Subcommittee (see below). A Senior Investigator is the person responsible for on-site scientific direction and implementation of the consensus protocols at his/her participating institution. Senior Investigators must be physicians with substantial experience in organ transplantation and in the design, implementation, and evaluation of clinical trials. Each PI may designate one Senior Investigator to serve on the Steering Committee. The designated Senior Investigator may not be from the same institution as the PI, and will serve on the Steering Committee for 12 months. At the last steering committee of each 12-month period, the PIs will indicate the designated Senior Investigators who will serve during the next 12-month period. Additional members, voting or non- voting, may be added to the steering committee by majority vote of the Steering Committee; non-voting members may be added at the discretion of the NIAID Program Director. All major scientific decisions will be determined by the Steering Committee, with each Principal Investigator, Senior Investigator, Chair of the Mechanistic Studies Subcommittee, and the NIAID Scientific Coordinator having one vote. The NIAID and the DCMC are limited to one vote each on the Steering Committee. The first two meetings of the Steering Committee will be convened by the NIAID Scientific Coordinator. At the second meeting, the group will elect a Chairperson from among the Steering Committee members; the NIAID Scientific Coordinator and the PI of the DCMC are not eligible to be the Steering Committee Chair. The Committee will meet in person or by teleconference at least four times during the first 12 months of the study and at least twice annually thereafter. This Committee will have primary responsibility for developing the common clinical protocols, approving the design and implementation of all mechanistic studies (via the mechanistic studies subcommittee), facilitating the conduct and monitoring of all clinical trials and mechanistic studies, analyzing and interpreting study data, and reporting study results. Studies will not be approved if the NIAID or the Steering Committee determines that it will not be feasible to accrue patients within the specified time frame. In addition, the steering committee will develop mechanisms for monitoring accrual performance and criteria for continued participation by each participating institution in the consortium. The Steering Committee will review the budget and expenditures at least once each year at a face-to-face meeting. Clinical trials and mechanistic studies will proceed into the implementation stage only with the concurrence of both the Steering Committee and the NIAID Program Director. Each Steering Committee member will be expected to participate in all Steering Committee activities, e.g., meetings, conference calls, special subcommittee activities, etc. as may be necessary. The Steering Committee shall appoint a Mechanistic Studies Subcommittee, as described below. Other Subcommittees may be appointed, as required, by the Steering Committee. The steering committee or a designated sub-committee will prepare an annual report containing the following information: Progress in ongoing and newly- initiated clinical trials and mechanistic studies; subject accrual and protocol compliance at all participating clinical sites; manuscripts published, in press, and in preparation; presentations at regional, national, and international meetings; and budget review. The first such report will be presented at a joint meeting of the steering committee and mechanistic studies subcommittee not later than 13 months after the initial notice of award, and yearly thereafter. The NIAID Scientific Coordinator will not participate substantively in the development or submission of the annual report, and will serve as the primary NIAID staff member responsible for review of the report by the sponsoring agency. Mechanistic Studies Subcommittee. The Steering Committee shall appoint a Mechanistic Studies Subcommittee to review and approve or modify proposed mechanistic studies. Each PI shall select two representatives from his/her consortium as voting members of the Mechanistic Studies Subcommittee. In addition, the NIAID Scientific Coordinator shall serve as a voting member. The Mechanistic Studies Subcommittee may ask the Steering Committee to appoint additional Mechanistic Studies Subcommittee members if additional expertise in a specific area is needed. The Mechanistic Studies Subcommittee shall elect a Chair from among its non-Federal members. The Chair shall serve as a voting member of the Steering Committee. The Subcommittee will meet at least twice yearly and its members will be expected to participate in all meetings, conference calls, and other Subcommittee activities. Data and Safety Monitoring Board (DSMB). An independent DSMB, appointed by the NIAID, will review progress at least annually and report their findings to the NIAID Program Director. Clinical protocols and mechanistic studies will be subject to review by the DSMB, in an advisory capacity, prior to implementation. The DSMB review will focus on the safety, ethics, and scientific and statistical integrity of the studies. Data Coordination and Management. Data Coordination and Management will be carried out by a separately funded Data Coordination and Management Center (DCMC). Each participating institution will be responsible for providing primary study data to NIAID via the DCMC for management, quality control, and analysis, using procedures and standards determined by the Steering Committee and the DCMC. The NIAID will provide, via its program staff and the DCMC, the following: technical assistance and data management services to the participating institutions with respect to quality control, uniformity of data collection, management of the collective database, and data analysis; centralized data collection and management; and quality assurance. Specific analyses to be performed will be directed by the Steering Committee. In the event of a specific safety concern, the DSMB may also request specific analyses from the DCMC. The results of those analyses will be delivered to the Steering Committee, which is responsible for determining how the results are interpreted, whether the results should influence ongoing data collection, and how the findings should be disseminated. All participating sites will have access to all data originating from their sites. The awardees will retain custody of and have primary rights to all data developed under these awards, subject to Government rights of access consistent with HHS, PHS, and NIH policies. Although the participating institutions will be closely involved with these centralized data collection and management services, the participating institutions will be responsible for on-site data collection and transmittal. Publication and Presentation of Study Findings. Timely publication of major findings is encouraged. Publications and oral presentations of work performed under this agreement will require appropriate acknowledgment of the participating institutions and NIAID support. Analyses to be performed using the collective data from all participating institutions will be determined and directed by the Steering Committee. Participating institutions wishing to perform analyses of local data will inform the Steering Committee of any such analyses prior to initiation in order to avoid duplication. Review and approval by the Steering Committee will be required for all analyses prior to publication or presentation according to criteria that will be developed by the Steering Committee. The Steering Committee may establish a Publications Subcommittee to carry out this function. Monitoring Study Progress. The Steering Committee will establish mechanisms for assessing the performance of the participating institutions, including institutions participating in consortia arrangements, with particular attention to accrual of adequate numbers of eligible patients, timely submission and quality of required data and conscientious observance of protocol requirements. 5. 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 or by the individual awardee in the event of an individual disagreement, a second member selected by the NIAID, and the third member with expertise in the relevant area and selected by the two prior members will be formed to review any scientific or programmatic issue that is significantly restricting progress. While the decisions of the Arbitration Panel are binding, these special arbitration procedures will in no way affect the awardee's right to appeal an adverse action in accordance with PHS regulations at 42 CFR Part 50, subpart D, and HHS regulations 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: Nancy D. Bridges, M.D. Chief, Clinical Transplantation Section Division of Allergy, Immunology, and Transplantation National Institute of Allergy and Infectious Diseases Tel (301) 496-5598 Email: nbridges@niaid.nih.gov Judith Massicot-Fisher, Ph.D. National Heart, Lung, and Blood Institute Telephone: (301) 435-0510 FAX: (301) 480-1454 Email: massicoj@nhlbi.nih.gov Catherine M. Meyers, M.D. Director, Inflammatory Renal Diseases Program Division of Kidney, Urologic & Hematologic Diseases National Institute of Diabetes and Digestive and Kidney Diseases Tel (301) 451-4901 Email: Cm420i@nih.gov 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: es170m@nih.gov 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: ad22x@nih.gov LETTER OF INTENT Prospective applicants are asked to submit a letter of intent that includes the following information: o Descriptive title of the proposed research o Name, address, and telephone number of the Principal Investigator o Names of other key personnel o Participating institutions o Number and title of this RFA Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows IC staff to estimate the potential review workload and plan the review. The letter of intent is to be sent by the date listed at the beginning of this document. The letter of intent should be sent to: 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: es170m@nih.gov SUBMITTING AN APPLICATION Applications must be prepared using the PHS 398 research grant application instructions and forms (rev. 5/2001). Applications must have a DUN and Bradstreet (D&B) Data Universal Numbering System (DUNS) number as the Universal Identifier when applying for Federal grants or cooperative agreements. The DUNS number can be obtained by calling (866) 705-5711 or through the web site at http://www.dunandbradstreet.com/. The DUNS number should be entered on line 11 of the face page of the PHS 398 form. The PHS 398 document is available at http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format. For further assistance contact GrantsInfo, Telephone (301) 710-0267, Email: GrantsInfo@nih.gov. SUPPLEMENTARY INSTRUCTIONS: See also the SPECIAL REQUIREMENTS section above. Research plans should be in the form of detailed concept proposals, organized as specific aims, background and significance, preliminary studies, and research design and methods (sections A-D). Proposals must be presented in sufficient detail to allow reviewers to judge significance, approach, innovation, and environment. The ability of the applicant consortium to perform the clinical and mechanistic studies should be clear. Methods of data analysis and sample size justification for the proposed clinical study, as well as scientific rationale for the mechanistic proposed mechanistic studies must be included. However, submission of a detailed, final clinical protocol is neither required nor encouraged, as the choice of studies to be performed and final protocol development will be accomplished subsequent to award, under the guidance of the Steering Committee. The research plan for both required proposals (see below) should not exceed 40 pages. The application must include two (2) concept proposals for clinical studies that meet the objectives and scope of this RFA. One proposal must be organ specific, while the other must be designed to address a transplant-related immunologic problem that may be studied in a diverse group of organ recipients (e.g., renal transplant recipients and heart transplant recipients, or liver transplant recipients and lung transplant recipients, or any other combination of recipients of different organs). Each of the 2 proposals may propose a clinical intervention, or one of the two protocols may be observational in design. Each clinical proposal must be accompanied by mechanistic studies designed to expand our understanding of the basic mechanisms of alloimmunity, innate immunity in the transplant setting, and/or graft dysfunction. Descriptions of proposed mechanistic studies are to include: identification of and rationale for the immune, genetic, and/or surrogate markers selected, including data from animal and/or human studies; a description of the source, quantity, and number of patient samples required; methodologies proposed to collect and analyze samples; and a discussion of how the results of the proposed mechanistic studies will improve the capacity to utilize immune, genetic and/or surrogate markers to predict patient outcome. The applicant should state clearly how anticipated study results can be expected to contribute to improvements in patient/graft survival. Additional requirements are as follows: 1. The applicant institution and each institution participating in the consortium must document their experience and capacity to recruit and retain study participants, and provide a description of the population currently available for each proposal. Furthermore, the applicant and participating institutions must explicitly state that the approved trials within the CTOT group will have priority over any subsequent non-CTOT group study in organ transplantation. Exemptions from this agreement will require approval by the NIAID and the Steering Committee. 2. The application must identify the single applicant organization that will be legally and financially responsible and accountable for the use and disposition of funds awarded on the basis of this RFA to other institutions participating in the consortium, and show availability of personnel and facilities capable of performing and supporting the administrative functions necessary. 3. The application must name a single PI who will have scientific responsibility for the application as a whole, including all consortium- related research activities. The PI must be a physician with substantial experience in organ transplantation and in the design, implementation, and evaluation of clinical trials. The applicant consortium must contain two or more participating institutions. Consortium member institutions may be clinical participants, in which case they must have a UNOS-certified program in organ transplantation, or they may be mechanistic study participants, in which case they must have demonstrated expertise in the research techniques necessary for the proposed study. Applications must name a single Senior Investigator for each participating institution in the consortium who will be responsible for on-site clinical and scientific implementation, direction and management of the clinical protocols, and the coordination of requirements for mechanistic studies of underlying mechanisms and immune/surrogate markers. A letter from each Senior Investigator, indicating a commitment to participate and the qualifying characteristics of his/her institution, must be included with the application. 4. The applicant must provide a clear and concise plan, in narrative and diagrammatic form, that depicts the interrelationships among the members of the consortium, their relevant experience/expertise, and the contribution of each to fulfillment of the objectives of this RFA, as well as an organizational chart of the consortium showing the name, organization, and scientific discipline of the PI and of all key scientific, technical and administrative personnel. 5. The application must provide a plan to ensure the maintenance of close cooperation and effective communication among members of the consortium; letters of commitment to this plan from all participating institutions; and evidence of the capability of the applicant organization and each institution in an applicant consortium to participate and interact effectively in cooperative, multi-center clinical trials. 6. The application must include a written commitment from the PI, and from the Senior Investigators of participating sites, to accept the participation and assistance of NIAID staff in accordance with the guidelines outlined under "Cooperative Agreement Terms and Conditions of Award: NIAID Staff Responsibilities." The application must also include a written commitment to the cooperative organization and willingness to adhere to the decisions reached by that Committee, including following the consensus protocols and mechanistic studies. 7. All costs required for the proposed protocols and mechanistic studies must be included in the application and must be fully justified. These include the additional costs of clinical research associated with the proposed protocols, costs for patient recruitment and follow-up, mechanistic studies, data collection, and participation in on-site quality assurance audits. Requested budgets should also include: (1) travel to the Bethesda, MD area for four 1- day Steering Committee meetings during the first 12 months, and twice annually thereafter, for the Principal Investigator and one Senior Investigator for each participating consortium, and (2) travel to the Bethesda, MD area for meetings of the Mechanistic Studies Subcommittee for the two representatives from each consortium, to coincide with steering committee meetings. 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 must be received on or before March 15, 2004. Applications that are not received as a single package on the receipt date 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. 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 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. 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. o Significance o Approach o Innovation o Investigator o Environment The application does not need to be strong in all categories to be judged likely to have major scientific impact and thus deserve a high priority score. For example, an investigator may propose to carry out important work that by its nature is not innovative but is essential to move a field forward. SIGNIFICANCE: Does this study address an important 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? ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, the following items will be considered in the determination of scientific merit and the priority score: Mechanistic studies will be weighed equally with the clinical studies in the review of applications. For the Principal Investigator: 1. Evidence of commitment and contributions to the field of organ transplantation, and of ability to provide the leadership necessary to achieve multi-site adherence in a clinical research protocol. For Participating Clinical Sites: 1. Demonstrated knowledge of clinical organ transplantation, and a documented commitment to the study of clinical aspects organ transplantation by the investigators and their institutions. 2. Evidence of successful experience in recruitment and retention of research subjects in multicenter clinical studies, and particularly studies of clinical organ transplantation. 3. Documentation of center transplant volume adequate to contribute (among all organ recipient groups) at least 10 adult or 5 pediatric subjects per year to the proposed studies. 4. Evidence of prior experience in working collaboratively in carrying out a clinical study protocol. For Sites Performing Mechanistic Studies: 1. Evidence of expertise in and prior experience with conduct of mechanistic studies pertaining to the immunologic areas under study using specimens of human origin. 2. A documented commitment to the study of the basic immunologic aspects of organ transplantation by the investigators and their institutions. PROTECTION OF HUMAN SUBJECTS FROM RESEARCH RISK: The involvement of human subjects and protections from research risk relating to their participation in the proposed research will be assessed. (See criteria included in the section on Federal Citations, below) INCLUSION OF WOMEN, MINORITIES AND CHILDREN IN RESEARCH: The adequacy of plans to include subjects from both genders, all racial and ethnic groups (and subgroups), and children as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. (See Inclusion Criteria in the sections on Federal Citations, below). CARE AND USE OF VERTEBRATE ANIMALS IN RESEARCH: If vertebrate animals are to be used in the project, the five items described under Section f of the PHS 398 research grant application instructions (rev. 5/2001) will be assessed. ADDITIONAL CONSIDERATIONS 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 and Safety Monitoring, NIH Guide for Grants and Contracts, June 12, 1998: http://grants.nih.gov/grants/guide/notice-files/not98-084.html). SHARING RESEARCH DATA: Starting with the October 1, 2003 receipt date, investigators submitting an NIH application seeking 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 PARTICIPANTSNIH 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. HUMAN EMBRYONIC STEM CELLS (hESC): Criteria for federal funding of research on hESCs can be found at http://stemcells.nih.gov/index.asp and at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html. Only research using hESC lines that are registered in the NIH Human Embryonic Stem Cell Registry will be eligible for Federal funding (see http://escr.nih.gov). It is the responsibility of the applicant to provide, in the project description and elsewhere in the application as appropriate, the official NIH identifier(s) for the hESC line(s)to be used in the proposed research. Applications that do not provide this information will be returned without review. PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT: The Office of Management and Budget (OMB) Circular A-110 has been revised to provide public access to research data through the Freedom of Information Act (FOIA) under some circumstances. Data that are (1) first produced in a project that is supported in whole or in part with Federal funds and (2) cited publicly and officially by a Federal agency in support of an action that has the force and effect of law (i.e., a regulation) may be accessed through FOIA. It is important for applicants to understand the basic scope of this amendment. NIH has provided guidance at http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm. Applicants may wish to place data collected under this PA in a public archive, which can provide protections for the data and manage the distribution for an indefinite period of time. If so, the application should include a description of the archiving plan in the study design and include information about this in the budget justification section of the application. In addition, applicants should think about how to structure informed consent statements and other human subjects procedures given the potential for wider use of data collected under this award. 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 PA 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; No. 93.856, Microbiology and Infectious Diseases Research; No. 93.849, Kidney Diseases, Urology and Hematology Research; No. 93.837, Heart and Vascular Diseases Research; No. 93.838, Lung Diseases Research; and No. 93.839, Blood Diseases and Resources 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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