COOPERATIVE CLINICAL TRIAL IN PEDIATRIC TRANSPLANTATION RELEASE DATE: March 26, 2002 RFA: AI-02-004 January 12, 2007 - This RFA has been reissued as (RFA-AI-07-006). National Institute of Allergy and Infectious Diseases (http://www.niaid.nih.gov) LETTER OF INTENT RECEIPT DATE: September 10, 2002 APPLICATION RECEIPT DATE: October 11, 2002 THIS RFA CONTAINS THE FOLLOWING INFORMATION o Purpose of this RFA o Research Objectives o Mechanism(s) of Support o Funds Available o Eligible Institutions o Individuals Eligible to Become Principal Investigators o Special Requirements o Where to Send Inquiries o Letter of Intent o Submitting an Application o Supplemental 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) invites applications from consortia of institutions to participate in a multi-center cooperative clinical trial program to improve graft acceptance and patient/graft survival in pediatric kidney transplant recipients up to 21 years of age. The goal of this research program is to support multi-center cooperative clinical trials in pediatric renal transplantation that will: (1) evaluate new therapeutic regimens to enhance long-term graft survival; (2) investigate the underlying mechanisms of action of the agents under study; (3) develop diagnostic tests to predict graft rejection; and (4) develop surrogate biomarkers for acute and chronic rejection. This Request for Applications (RFA) is a renewal of a previous RFA, AI-98-012. RESEARCH OBJECTIVES Background Kidney transplantation remains the therapy of choice for children with end- stage renal disease. Although dialysis offers an alternative treatment, the morbidity and side effects of this treatment remain significant. While the differences in one-year and five-year graft survival between children and adults are less pronounced than when the Cooperative Clinical Trial in Pediatric Transplantation (CCTPT) was established in 1994, children still do not achieve the long-term graft survival rates of adults who receive cadaveric renal transplants. This disparity in long-term graft survival is very problematic for young children; graft loss requires that the patient be returned to the transplant waiting list and dialysis with its attendant morbidity and side effects. In addition, young children are unlikely to achieve a normal life span or an acceptable quality-of-life because they will possibly receive a second and even a third or fourth transplant in their lifetimes. Although many factors have been implicated in the difference in graft survival between pediatric and adult kidney transplant recipients, the most important appears to be the pediatric immune system. In contrast to adults, children require higher doses of immunosuppressive therapy to prevent rejection. This difference is reflected in higher total T lymphocyte counts and increased responses to mitogen stimulation as compared with adults. These measures are associated with more frequent and vigorous episodes of graft rejection that are not as responsive to therapy as in adults, resulting in a higher rate of graft loss. Higher doses of the immunosuppressive drug, cyclosporine A (CsA), must be administered to achieve effective blood levels because the shorter intestinal length of children results in reduced absorption. In addition, children must also receive CsA more frequently as they metabolize it faster. These elevated doses of CsA induce hyperlipidemia, which increases the risk of atherosclerotic cardiovascular disease. A serious problem, unique to the pediatric population, is growth retardation, a well- documented side effect of the corticosteroids that are part of the standard immunosuppressive regimen. Growth retardation can lead to psychological problems and the inability to lead a normal life. It is most problematic for the very young transplant recipients, as they will never achieve normal stature. Therefore, changes in standard immunosuppression or the use of new treatment regimens that reduce or abolish the need for global immunosuppression hold the promise of improving graft survival and reducing adverse side effects. Such approaches include the use of new, less toxic induction therapies, such as anti-IL-2 receptor antibodies to replace cyclosporine or the use of less toxic replacements for steroids. The CCTPT provides the infrastructure to conduct these clinical trials, perform studies of underlying mechanisms, and develop immune and surrogate markers of graft acceptance, rejection and function. Research Objectives and Scope The purpose of this RFA is to support a program of multi-site, cooperative clinical trials in pediatric kidney transplantation to improve graft and patient survival. All participating clinical sites will utilize uniform controlled study designs and standardized data collection procedures. Pediatric patients up to 21 years of age may be studied, with the specific age groups to be determined by the design of the common protocols. Specifically, applications must propose: 1. Clinical trials to evaluate the safety and efficacy of new and innovative therapeutic approaches to induce donor-specific tolerance with or without standard immunosuppression, including temporary or permanent withdrawal of standard immunosuppression. 2. Clinical trials to evaluate the safety and efficacy of new, less toxic immunosuppressive agents or regimens to prevent rejection or new approaches to reduce the number of immunosuppressive agents required to prevent rejection. 3. Adjunct studies of the underlying mechanisms of action of the therapeutic approaches under investigation, including changes in immune response, measures of donor-specific responsiveness and/or tolerance; and 4. Adjunct studies to develop, evaluate, and validate sensitive immune and/or surrogate markers of short- and long-term graft survival and rejection, with particular emphasis on defining clinically relevant predictors of acute and chronic rejection. The use of non-invasive approaches is highly encouraged. Applications that contain any of the following will not be accepted: transplantation of multiple organs (e.g. combined kidney-pancreas transplantation), transplantation of organs other than kidneys, xenotransplantation, or transplantation in animal models. MECHANISM OF SUPPORT This RFA will use the NIH Cooperative Agreement (U01). The 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" 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 total project period for applications submitted in response to this RFA may not exceed five (5) years. At this time, the NIAID has not determined whether and how this solicitation will be continued beyond the present RFA. FUNDS AVAILABLE NIAID intends to commit approximately $2,500,000 in FY 2003 to fund approximately two (2) new and/or competitive continuation grants in response to this RFA. An applicant may request a project period of up to five years and a budget for direct costs of up to $1,250,000 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 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, it is not known if this RFA will be reissued. ELIGIBLE INSTITUTIONS Domestic institutions may submit applications if they have 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 INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS Individuals with the skills, knowledge, and resources necessary to carry out the proposed research are invited to work with their institutions 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 The study organization will consist of the following: a Steering Committee, an Adjunct Studies Subcommittee, a Data and Safety Monitoring Board, and a data coordination and management plan that will be direct by NIAID. These are described further in the "Terms and Conditions of Award". 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 (PI) 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" mechanism (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's 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. 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. Terms and Conditions of Award will be included with awards. NIAID policy was announced in the NIH Guide on February 24, 2000 and is available at: https://grants.nih.gov/grants/guide/notice-files/NOT-AI-00-003.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 AI-02-004 and for performing the scientific activities. The PI's responsibilities regarding Steering Committee membership, protocol development and conduct, and data coordination and management are described under Collaborative Responsibilities. In brief, the 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 PI 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. 3. NIAID Staff Responsibilities Program Director NIAID staff assistance will be provided by the Chief of the Transplantation Immunobiology Branch, Division of Allergy, Immunology and Transplantation, or designate, who will serve as the Program Director, responsible for normal program stewardship and administration. The Program Director may also serve as, or appoint, the Scientific Coordinator. 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 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. 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. Regulatory Affairs The Program Director may also be the responsible person for Investigational New Drug (IND) Applications, as applicable. The NIAID reserves the right to terminate or curtail the 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. Scientific Coordinator The NIAID Scientific Coordinator will have substantial scientific involvement during the conduct of this activity through technical assistance, advice and coordination above and beyond normal program stewardship for grants. 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 Adjunct 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 assist the Steering Committee in protocol development. Study Materials The NIAID Scientific Coordinator will be determine the mechanism(s) for acquisition and distribution of those study materials involved in the consensus protocols developed by the Steering Committee. The Scientific Coordinator will also assist 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. Monitoring Study Performance The NIAID Scientific Coordinator will provide assistance to the Steering Committee in the development of mechanisms and procedures for monitoring study performance. This includes participation in periodic on-site monitoring with respect to compliance with protocol specifications, quality control and accuracy of data recording, and patient accrual. Data Coordination and Management The NIAID Scientific Coordinator will be responsible for ensuring the provision of centralized data management and coordination assistance. Under the direction of the Steering Committee, the NIAID Scientific Coordinator will provide 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. 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. 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 NIAID Scientific Coordinator, the Principal Investigators, and one additional Senior Investigator from each consortium rotating on an annual basis. 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 pediatric kidney transplantation and in the design, implementation, and evaluation of clinical trials. All major scientific decisions will be determined by the Steering Committee, with each Principal Investigator, Senior Investigator, Chair of the Adjunct Studies Subcommittee, and the NIAID Scientific Coordinator having one vote. The Steering Committee will elect a Chairperson from among its non-Federal members during the first meeting of the Committee, to be convened by the NIAID Program Director. The Committee will meet at least twice during the first 12 months of the study and annually thereafter. This Committee will have primary responsibility for developing the common clinical protocols, approving the design and implementation of all adjunct studies, facilitating the conduct and monitoring of all clinical trials and adjunct studies, analyzing and interpreting study data, and reporting study results. Clinical trials and adjunct 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. Participating institutions will be required to accept and implement the consensus protocols and procedures approved by the Steering Committee. The Steering Committee shall appoint an Adjunct Studies Subcommittee, as described below. Other Subcommittees may be appointed, as required, by the Steering Committee. Adjunct Studies Subcommittee The Steering Committee shall appoint an Adjunct Studies Subcommittee to design, implement, and evaluate: (1) studies of the underlying mechanisms of action of the therapeutic approaches under investigation and (2) studies to develop, evaluate and validate immune and/or surrogate markers of kidney graft survival and rejection. Each PI shall select two representatives from his/her consortium as voting members of the Adjunct Studies Subcommittee. In addition, the NIAID Scientific Coordinator shall serve as a voting member. The non-federal members of the Adjunct Studies Subcommittee shall elect its Chair, who shall serve as a voting member of the Steering Committee. The Subcommittee will meet annually in conjunction with Steering Committee meetings and its members will be expected to participate in all meetings, conference calls, and other Subcommittee activities. Data and Safety Monitoring Board An independent Data and Safety Monitoring Board, to be appointed by the NIAID, will review progress at least annually and report to the NIAID Program Director. Clinical protocols and adjunct studies will be subject to review by the Data and Safety Monitoring Board, in an advisory capacity, prior to implementation. Data Coordination and Management Each participating institution will be responsible for providing NIAID with all primary study data for management, quality control, and analysis using procedures and standards determined by the Steering Committee. Under the direction of the Steering Committee, the NIAID will provide 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. The NIAID will be responsible for ensuring the provision of centralized data collection, management, and quality assurance. Specific analyses to be performed will be directed by the NIAID with the input of the Steering Committee. 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 data will be available to all awardees. 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, applicants should include in their budget requests only support for on-site data collection and transmittal. Publication and Presentation of Study Findings Early 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, selected by the two prior members. The Panel 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 your questions about scientific/research issues to: Shiv A. Prasad, Ph.D. Division of Allergy, Immunology, and Transplantation National Institute of Allergy and Infectious Diseases Room 5125, MSC-7640 6700-B Rockledge Drive Bethesda, MD 20892-7640 (20817 for express delivery) Telephone: (301) 496-5598 FAX: (301) 402-2571 E-Mail: sprasad@niaid.nih.gov o Direct your questions about peer review issues, address the letter of intent, and mail two copies of the application and all five sets of appendices to: Priti Mehrotra, Ph.D. Division of Extramural Activities National Institute of Allergy and Infectious Diseases Room 2100, MSC-7610 6700-B Rockledge Drive Bethesda, MD 20892-7610 (20817 for express/courier delivery) Telephone: (301) 435-9369 FAX: (301) 402-2638 E-Mail: pmehrotra@niaid.nih.gov o Direct your questions about financial or grants management matters to: Maryellen Connell Division of Extramural Activities National Institute of Allergy and Infectious Diseases Room 2123, MSC-7610 6700-B Rockledge Drive Bethesda, MD 20892-7610 (20817 for express/courier delivery) Telephone: (301) 402-5576 Fax: (301) 480-3780 E-Mail: mconnell@niaid.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 must be sent by September 10, 2002 to: Priti Mehrotra, Ph.D. Division of Extramural Activities National Institute of Allergy and Infectious Diseases Room 2100, MSC-7610 6700-B Rockledge Drive Bethesda, MD 20892-7610 (20817 for express/courier delivery) Telephone: (301) 435-9369 FAX: (301) 402-2638 E-Mail: pmehrotra@niaid.nih.gov SUBMITTING AN APPLICATION Applications must be prepared using the PHS 398 research grant application instructions and forms (rev. 5/2001). The PHS 398 is available at https://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format. For further assistance contact GrantsInfo, Telephone (301) 710-0267, E-mail: GrantsInfo@nih.gov. SUPPLEMENTAL INSTRUCTIONS Minimum Requirements for Application To promote the development of a collaborative program among the award recipients, a minimum number of issues must be addressed in the application, as outlined below. 1. The application must include two (2) proposed protocols for clinical trials that meet the objectives and scope of this RFA, as well as a discussion of the rationale for the patient population, the statistical calculations and considerations in determining sample size, the study design and the therapeutic approach(es) selected for study, and an assessment of how anticipated study results can be expected to contribute to improvements in patient/graft survival. One protocol may use new or innovative approaches, and one may focus on the modification of standard therapeutic approaches. Award of the Cooperative Agreement does not imply that any of the proposed protocols will be implemented. Because the actual protocols will be selected by the Steering Committee, the final clinical trials implemented by the CCTPT may not reflect any single protocol submitted in response to this RFA. 2. The application must include at least one (1) proposed hypothesis-driven adjunct study of the underlying mechanisms of action of the proposed protocols, including: the rationale for the adjunct studies proposed in terms of feasibility, validity, and sensitivity/specificity; the specific aspects of immune response and function to be measured; a description of the patient samples required, including time and frequency of collection, number and quantity of samples required and methodologies to be used to analyze patient samples, including new and non-invasive techniques for collection and analysis; and a discussion of how the results of the adjunct studies will contribute to further understanding of the clinical effects of the therapeutic approaches under investigation. As in the case of the proposed clinical protocols, award of the Cooperative Agreement does not imply that any proposed adjunct studies will be implemented. Actual studies to be performed will be selected or designed by the Adjunct Studies Subcommittee and approved by the Steering Committee. 3. The application must include at least one proposed adjunct study to develop, evaluate, and validate sensitive immune and/or surrogate markers of short- and long-term graft survival and/or rejection. One of the overall goals of these adjunct studies is to develop predictors of rejection prior to organ damage. Descriptions of proposed adjunct studies are to include: identification of and rationale for the immune and/or surrogate markers selected, including published 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 adjunct studies will improve the capacity to utilize immune and surrogate markers to predict graft acceptance, changes in graft function, rejection and patient survival. It is not a requirement that these adjunct studies be associated with the clinical protocols proposed in the application. Studies may use patient samples from the proposed protocols or from other sources. Applications must identify the source of patient materials required for the adjunct 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 adjunct studies will be implemented. Actual studies to be performed will be selected or designed by the Adjunct Studies Subcommittee and approved by the Steering Committee. 4. The applicant institution and each institution participating in the consortium must: document their experience and capacity to recruit and retain pediatric study participants up to 21 years of age; provide a description of the population currently available for each proposed protocol; and describe proposed mechanisms for monitoring accrual performance and criteria for continued participation by each participating institution. The ability to meet enrollment objectives may be documented by recruitment for prior CCTPT studies or other studies sponsored by Federal or non-Federal organizations. 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. Furthermore, applicant and participating institutions must agree that the approved trials within the CCTPT will have priority over any subsequent non-CCTPT trial in pediatric kidney transplantation. Exemptions from this agreement require approval by the NIAID and the Steering Committee. 5. 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 participating institutions and other institutions participating in the consortium, and show availability of personnel and facilities capable of performing and supporting the administrative functions necessary. 6. 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 pediatric kidney transplantation and in the design, implementation, and evaluation of clinical trials. In addition, 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 adjunct studies of underlying mechanisms and immune/surrogate markers. 7. Applications must demonstrate the scientific expertise required to design, conduct, and analyze all adjunct studies. Such expertise may be provided by a single scientist serving the entire consortium or more than one such scientist depending upon the proposed clinical protocols and adjunct studies. 8. The application must name a Project Coordinator who is an individual with substantial technical/administrative experience in managing patient enrollment, patient follow-up, and multi-source data collection for clinical studies. Each participating institution associated with an applicant consortium must also name such a Project Coordinator. 9. The application 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; 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; and a mechanism for selecting and replacing key professional or technical personnel. 10. The application must provide a plan to assure the maintenance of close cooperation and effective communication among members of the consortium, including letters of commitment to this plan from all participating institutions. 11. The application should discuss the capability of the applicant organization and each institution in an applicant consortium to participate and interact effectively in cooperative, multi-center clinical trials. 12. The application must include a written commitment to accept the participation and assistance of NIAID staff in accordance with the guidelines outlined under "Terms and Conditions of Award: NIAID Staff Responsibilities." The application must also include a written commitment to the cooperative organization and willingness to serve on the Steering Committee and to adhere to the decisions reached by that Committee, including following the consensus protocols and adjunct studies. 13. All costs required for the proposed protocols and adjunct 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, adjunct studies, data collection, and participation in on-site quality assurance audits. Requested budgets should also include: (1) travel to the Bethesda, MD area for two 2-day Steering Committee meetings during the first 12 months, and annually thereafter, for the Principal Investigator and one Senior Investigator for each institution participating in the consortium, and (2) travel to the Bethesda, MD area for annual one-day meetings of the Adjunct Studies Subcommittee for the two representatives from each consortium. 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: https://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 (20817 for express/courier delivery) 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: Priti Mehrotra, Ph.D. Division of Extramural Activities National Institute of Allergy and Infectious Diseases Room 2100, MSC-7610 6700-B Rockledge Drive Bethesda, MD 20892-7610 (20817 for express/courier delivery) Telephone: (301) 435-9369 FAX: (301) 402-2638 E-Mail: pmehrotra@niaid.nih.gov 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 contacts under INQUIRIES). APPLICATION PROCESSING: Applications must be received by October 11, 2002. If an application is received after that date, it will be returned to the applicant without review. 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. The Center for Scientific Review (CSR) will not accept any application in response to this RFA that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. The CSR will not accept any application that is essentially the same as one already reviewed. This does not preclude the submission of substantial revisions of applications already reviewed, but such applications must include an Introduction addressing the previous critique. 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 Receive a written critique o Undergo a process in which only those applications deemed to have the highest scientific merit, generally the top half of the applications under review, will be discussed and assigned a priority score o Receive a second level review by the 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 your application in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals: o Significance o Approach o Innovation o Investigator o Environment The scientific review group will address and consider each of these criteria in assigning your application's overall score, weighting them as appropriate for each application. Your application does not need to be strong in all categories to be judged likely to have major scientific impact and thus deserve a high priority score. For example, you may propose to carry out important work that by its nature is not innovative but is essential to move a field forward. (1) SIGNIFICANCE: Does your study address an important problem? If the aims of your application are achieved, how do they advance scientific knowledge? What will be the effect of these studies on the concepts or methods that drive this field? (2) APPROACH: Are the conceptual framework, design, methods, and analyses adequately developed, well integrated, and appropriate to the aims of the project? Do you acknowledge potential problem areas and consider alternative tactics? (3) INNOVATION: Does your project employ novel concepts, approaches or methods? Are the aims original and innovative? Does your project challenge existing paradigms or develop new methodologies or technologies? (4) INVESTIGATOR: Are you appropriately trained and well suited to carry out this work? Is the work proposed appropriate to your experience level as the principal investigator and to that of other researchers (if any)? (5) ENVIRONMENT: Does the scientific environment in which your 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, your application will also be reviewed with respect to the following: o PROTECTIONS: The adequacy of the proposed protection for humans to the extent they may be adversely affected by the project proposed in the application. o INCLUSION: 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 included in the section on Federal Citations, below) o DATA SHARING: The adequacy of the proposed plan to share data within the CCTPT. o BUDGET: The reasonableness of the proposed budget and the requested period of support in relation to the proposed research. However, this will not be part of the overall score. o APPLICABILITY: The potential for widespread clinical application of the proposed clinical trials. o TOXICITY REDUCTION: The use of immunosuppressive protocols that are less toxic than the current therapies. o RECRUITMENT: The ability of the applicant consortium to recruit and retain pediatric study participants up to 21 years of age. Details may be found above, under "B. Minimum Requirements for Application." o ADJUNCT STUDIES: The merit of the proposed adjunct studies, the innovation of the methods used, and the ability to procure sufficient numbers of samples for statistically valid analyses. RECEIPT AND REVIEW SCHEDULE Letter of Intent Receipt Date: September 10, 2002 Application Receipt Date: October 11, 2002 Scientific Peer Review Date: February, 2003 Advisory Council Review: June, 2003 Earliest Anticipated Start Date: August, 2003 AWARD CRITERIA Award criteria that will be used to make award decisions include: o Scientific merit (as determined by peer review) o Availability of funds o Programmatic priorities. REQUIRED FEDERAL CITATIONS MONITORING PLAN AND DATA SAFETY AND MONITORING BOARD: Research components involving Phase I and II clinical trials must include provisions for assessment of patient eligibility and status, rigorous data management, quality assurance, and auditing procedures. In addition, it is NIH policy that all clinical trials require data and safety monitoring, with the method and degree of monitoring being commensurate with the risks (NIH Policy for Data Safety and Monitoring, NIH Guide for Grants and Contracts, June 12, 1998: https://grants.nih.gov/grants/guide/notice-files/not98-084.html). INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH: It is the policy of the NIH that women and members of minority groups and their sub-populations must be included in all NIH-supported clinical research projects unless a clear and compelling justification is provided indicating that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing clinical research should read the 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 (https://grants.nih.gov/grants/guide/notice- files/NOT-OD-02-001.html); a complete copy of the updated Guidelines are available at https://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 https://grants.nih.gov/grants/funding/children/children.htm. REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS: NIH policy requires education on the protection of human subject participants for all investigators submitting NIH proposals for research involving human subjects. You will find this policy announcement in the NIH Guide for Grants and Contracts Announcement, dated June 5, 2000, at https://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 https://grants.nih.gov/grants/stem_cells.htm and at https://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html. Only research using hESC lines that are registered in the NIH Human Embryonic Stem Cell Registry will be eligible for Federal funding (see http://escr.nih.gov). It is the responsibility of the applicant to provide the official NIH identifier(s)for the hESC line(s)to be used in the proposed research. Applications that do not provide this information will be returned without review. PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT: The Office of Management and Budget (OMB) Circular A-110 has been revised to provide public access to research data through the Freedom of Information Act (FOIA) under some circumstances. Data that are (1) first produced in a project that is supported in whole or in part with Federal funds and (2) cited publicly and officially by a Federal agency in support of an action that has the force and effect of law (i.e., a regulation) may be accessed through FOIA. It is important for applicants to understand the basic scope of this amendment. NIH has provided guidance at https://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm. Applicants may wish to place data collected under this PA in a public archive, which can provide protections for the data and manage the distribution for an indefinite period of time. If so, the application should include a description of the archiving plan in the study design and include information about this in the budget justification section of the application. In addition, applicants should think about how to structure informed consent statements and other human subjects procedures given the potential for wider use of data collected under this award. URLs IN NIH GRANT APPLICATIONS OR APPENDICES: All applications and proposals for NIH funding must be self-contained within specified page limitations. Unless otherwise specified in an NIH solicitation, Internet addresses (URLs) should not be used to provide information necessary to the review because reviewers are under no obligation to view the Internet sites. Furthermore, we caution reviewers that their anonymity may be compromised when they directly access an Internet site. HEALTHY PEOPLE 2010: The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2010," a PHS-led national activity for setting priority areas. This RFA is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople. AUTHORITY AND REGULATIONS This program is described in the Catalogue of Federal Domestic Assistance 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 https://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. 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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