BLOOD AND MARROW TRANSPLANT CLINICAL RESEARCH NETWORK Release Date: January 4, 2001 RFA: RFA-HL-01-004 (Limited competition request for competing applications, see NOT-HL-05-119) National Heart, Lung, and Blood Institute (http://www.nhlbi.nih.gov/index.htm) National Cancer Institute (http://www.nci.nih.gov/) Letter of Intent Receipt Date: February 21, 2001 Application Receipt Date: March 19, 2001 PURPOSE The National Heart, Lung, and Blood Institute and the National Cancer Institute invite applications to participate in a Blood and Marrow Transplant Clinical Research Network (Network) of interactive clinical research groups. This network will promote the efficient comparison of novel treatment methods and management strategies of potential benefit for children and adults undergoing blood or marrow transplantation. The objective of these Requests for Applications (RFAs) is to establish and maintain (1) the infrastructure required for a network of up to twenty core clinical centers to perform multiple clinical trials for persons undergoing a hematopoietic stem cell transplant and (2) a Data Coordinating Center for the network. The project period for the Blood and Marrow Transplant Clinical Research Network will be five years. There will be an administrative review after approximately three years to determine if the network has been performing important comparative studies as envisioned. If so, the announcement of a competitive renewal for an additional five years is anticipated. Thus the network is expected to be funded for a maximum of ten years. 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, "Blood and Marrow Transplant Clinical Research Network," is related to the priority areas of chronic disabling conditions, cancer, and clinical prevention services. Potential applicants may obtain a copy of Healthy People 2010" at http://www.health.gov/healthypeople/. ELIGIBILITY REQUIREMENTS Applications may be submitted from organizations located in the United States of America. This geographic constraint is necessary because of the need for close communication among members of the program, the requirement for frequent steering committee meetings, and the necessity of site visits for data verification. For-profit and non-profit organizations, public and private, such as universities, colleges, hospitals, laboratories, units of state and local governments, and eligible agencies of the federal government may apply. The disciplines and expertise that will be sought for this program include but are not limited to the areas of pediatrics, infectious disease, internal medicine, hematology, oncology, immunology, pharmacology, therapeutic development, biostatistics and clinical trials management. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as Principal Investigators. All current policies and requirements that govern the research programs of the National Institutes of Health (NIH) will apply to grants awarded under this RFA. Awards for a Core Clinical Center and a Data Coordinating Center under this RFA will not be made to the same Principal Investigator to ensure that data analysis is conducted independently of data acquisition. The same institution may apply for both a Core Clinical Center and the Data Coordinating Center award, but the applications for each must be from different individuals. MECHANISM OF SUPPORT This RFA will use the cooperative agreement (U01) administrative and funding mechanism of support. Under the cooperative agreement, the NIH assists, supports, and/or stimulates, and is substantially involved with recipients in conducting a study by facilitating performance of the effort in a "partner" role. Details of the responsibilities, relationships, and governance of a study funded under a cooperative agreement are discussed later in this document. The project period for applications submitted in response to this RFA will be five years. An administrative review will be conducted in approximately the third year of the network to determine whether or not the network program should be announced for another five-year funding period. The total project period for this program will be no longer than 10 years. The anticipated award date is September 30, 2001. Awards for Core Clinical Centers are limited to $405,000 total costs per year. (Total costs include Facility & Administrative costs, also called indirect costs or overhead.) This includes up to $150,000 total costs to support core activities and up to $255,000 total costs for per-patient costs. The award for the Data Coordinating Center will comprise total costs per year for routine data center functions. In addition to a well documented budget for data coordinating activities, Data Coordinating Center applicants should request a line item of additional funds of $500,000 total costs per year specifically for biologic reagents, centralized laboratory costs and enrollment of additional patients or those from non-Core centers. FUNDS AVAILABLE An estimated sixteen awards for Core Clinical Centers and one award for a Data Coordinating Center will be made under this RFA. A maximum of $40 million (total costs) over a five-year period will be awarded. Because the nature and scope of the research proposed in response to this RFA may vary, it is anticipated that the size of an award may also vary in all years. Funds for patient-related costs will be restricted and released concordant with patient enrollment. Future year costs will be distributed based on the recommended protocols. Although the financial plans of NHLBI and NCI provide support for this program at levels of $6 million and $2 million per year, respectively, awards pursuant to this RFA are contingent upon the availability of funds and the receipt of a sufficient number of meritorious applications. Designated funding levels are subject to change at any time prior to final award, due to unforeseen budgetary, administrative, or scientific developments. RESEARCH OBJECTIVES Background Several new developments in the field of allogeneic hematopoietic stem cell transplantation have substantially decreased transplant-related morbidity and promise to make major improvements in both the safety and efficacy of transplantation, allowing transplantation to be extended to more patients. Use of matched unrelated marrow donors, unrelated cord blood units, and partially matched family donors have greatly expanded the options for patients who lack an HLA identical sibling donor. Use of stem cells mobilized and collected from peripheral blood rather than harvested from bone marrow speeds engraftment and may improve treatment outcome. Manipulation of the transplant to adjust the dose of stem cells and lymphocytes to optimum numbers (graft engineering) may also be beneficial. The use of non- myeloablative transplants (mini-transplants) promises to extend the safe application of stem cell allografts to individuals over 60 years and to patients with non-lethal hematologic diseases. Recently identified human minor histocompatibility antigens may provide another variable for predicting the severity of graft-versus-host disease. There is an urgent need to evaluate these promising new therapeutic approaches to hematopoietic stem cell transplantation and to disseminate the findings to health care professionals, patients and the public. Each year, thousands of patients undergo hematopoietic stem cell transplants in the United States, yet few of these patients are offered the option to enroll in a research protocol to study and improve the outcome of this life-saving but toxic and expensive procedure. There are several reasons why a blood and marrow transplant clinical research network would accelerate clinical research and evaluate new approaches to transplantation. The heterogeneity of hematopoietic stem cell transplant patients makes it difficult to accumulate a large number of comparable patients in one center. Multi-center trials will reduce the number of patients needed at each clinical center and allow accrual to be completed more rapidly. Further, a common treatment protocol will reduce variables that contribute to patient outcome and allow valid comparisons between treatments. Finally, the Network approach will increase the number of comparative trials that are conducted by providing a framework for rapid initiation of important studies, a focus on randomized studies, and efficient use of pooled clinical expertise and data management resources. Organization of the Blood and Marrow Transplant Clinical Research Network The Blood and Marrow Transplant Clinical Research Network (Network) will be a cooperative network of sixteen Core Clinical Centers, one Data Coordinating Center, the National Heart, Lung, and Blood Institute (NHLBI) and the National Cancer Institute (NCI). Core Clinical Centers will be responsible for proposing protocols that could be adopted by the Network, guiding protocol development, enrolling patients, analyzing results, and disseminating research findings. All Core Clinical Centers will be required to participate in a cooperative and interactive manner with one another and with the Data Coordinating Center. Transplant centers have the option to form a consortium and apply as a single entity for a Core Clinical Center award. In the case of a consortium, there will be one Principal Investigator who will serve on the Steering Committee and represent the other centers, and the maximum total costs per year will be limited to $405,000. A centralized Data Coordinating Center will support the activities of the Network. These include developing protocols, devising novel comparative study designs, providing sample size calculations and statistical advice, developing data forms, performing data analyses, coordinating the activities of the Steering Committee, Protocol Review Committee, and Data and Safety Monitoring Board, and overall study coordination and quality assurance. In addition, in order to hasten accrual in phase III protocols, the Coordinating Center with NHLBI and NCI and the Steering Committee will have the responsibility to identify qualified and interested investigators at non-Core centers who wish to enroll patients on these protocols. Arrangements for data collection and reimbursement of trial-related data collection costs at non-Core centers will be the responsibility of the Data Coordinating Center. The Data Coordinating Center will also be responsible for obtaining biologic reagents, organizing correlative laboratory studies, arranging for storage of patient samples, and procuring other resources as required by the clinical protocols. A Steering Committee will be the main governing body of the Network and, at a minimum, will be composed of the principal investigators of the Core Clinical Centers and the Data Coordinating Center and the NHLBI and NCI Project Scientists. The Steering Committee Chairperson, who will be someone other than an NHLBI or NCI staff member and may be someone other than a principal investigator, will be selected by NHLBI and NCI. The Core Clinical Centers, the Data Coordinating Center, NHLBI and NCI each will have one vote. The (Chairperson) will vote in the case of ties. The Steering Committee may meet as often as three to six times in the first 12 months of the Network, and two to four times per year thereafter. All major scientific decisions will be determined by majority vote of the Steering Committee. The Steering Committee will have primary responsibility for the general organization of the Network, finalizing common clinical protocols, facilitating the conduct and monitoring of the studies, and reporting study results. Topics for the protocols will be proposed and prioritized by the Steering Committee with input from the wider transplant community. For each protocol, one investigator (or small group) will take the lead responsibility for drafting the protocol along with the Data Coordinating Center, although the Steering Committee will provide input and will be responsible for assuring development of a common protocol to be implemented by other Clinical Centers. Subcommittees of the Steering Committee will be established as necessary; for example, it is envisioned that a Publications and Presentations Committee will prioritize, facilitate and supervise preparation and review of manuscripts prior to submission for publication. Subcommittees to oversee reporting of graft versus host disease and establishment of an infectious diseases registry are also envisioned. Data collections will be monitored in a manner consistent with Guidelines for Data Quality Assurance in Clinical trials and Observational Studies http://www.nhlbi.nih.gov/funding/policies/dataqual.htm. An independent Protocol Review Committee, established by NHLBI and NCI with input from the Steering Committee, will provide peer review for each protocol. A Data and Safety Monitoring Board (DSMB), similarly established, will monitor patient safety and review performance of each study approximately semi-annually. As a part of its monitoring responsibility, the DSMB will submit recommendations to NHLBI and NCI regarding the continuation of each study and prepare a report for principal investigators to provide to their institutional review boards (IRBs.) It is anticipated that each protocol will be implemented in at least two or more of the Core Clinical Centers. As specific protocols are developed, support will depend on the availability of funds and will be provided on a per patient basis. All the Core Clinical Centers must be willing to pursue this funding arrangement for each new protocol conducted. Clinical protocols must be approved by local IRBs and the Protocol Review Committee before initiation. The exact number of protocols supported in the 5 year program will depend on the nature and extent of the investigations proposed by the Steering Committee. Both short and long term projects should be considered. Research Scope The objective of this RFA is to establish a Network that will accelerate research in hematopoietic stem cell transplantation by comparing novel therapies to existing ones. Therapeutic trials may involve investigational drugs, drugs already approved but not currently used, and drugs currently used. The NIH encourages randomization; non-randomized trials will be supported in exceptional cases only. Randomization may be between different doses/graft compositions/modes of novel treatment or novel treatment versus standard therapy. Proposed studies must be ready for multi-center testing. Some examples of research questions appropriate for this RFA include, but are not limited to the following: Trial of sources of stem cells (cord blood transplants versus marrow, and/or versus mPBSC; mismatched family or unrelated donor). Trial of graft engineering (making a graft of specific subsets of cells like stem cells, T cells, and natural killer cells) versus a standard transplant. Trial of ex vivo expansion of stem cells (from peripheral blood or cord blood) versus conventional transplants, or comparing different methods of expansion, or mixed cord blood units. Trial of mini-transplants (has a less toxic conditioning regimen; relies on donor cells to stabilize engraftment) in older patients or with diseases where a toxic conditioning regimen is not needed such as sickle cell disease, thalassemia or Fanconi anemia versus a conventional transplant. Trial of conditioning regimens or other aspects of preparative or supportive therapy versus standard of care. Trial of red cell or platelet growth factors versus none to improve engraftment and survival. Trial of new immunosuppressive drugs, monoclonal antibodies, or cytokines versus standard of care immunosuppression. Trial of IL-11 in stimulating engraftment and preventing disease recurrence. Trial of IL-7 in preventing post transplant infections and relationship to GvHD. Trial of donor leukocyte infusions prophylactically versus as treatment for relapse, infections, or secondary malignancies. Trial of virus-specific ex vivo activated T cells versus standard therapy. Trial of general versus specific immunomodulation. Patient management trial: hematopoietic stem cell transplant versus chemotherapy for acute leukemia.* Patient management trial: effect of prior interferon or STI-571 therapy on the outcome of hematopoietic stem cell transplantation for chronic myelogenous leukemia.* Patient management trial: trial of stem cell transplants in patients with autoimmune disease versus high dose chemotherapy alone.* Patient management trial: trial of hematopoietic stem cell transplant versus conventional treatment for sickle cell disease.* * All patient management trials must be accompanied by a letter of collaboration from the chief of the clinical division responsible for referring the patients, for example oncology, rheumatology, or hematology. In addition, the Network will conduct patient management trials in collaboration with other groups that have an interest in the subject patient population, for example the cancer cooperative groups. These are examples only. Applicants are not limited to the subjects mentioned above and are encouraged to submit other topics pertinent to the objectives of the RFA. Research Plan Core Clinical Center applicants should propose a research plan that includes one protocol as a model for the network. The protocol should be short term and capable of completion within 18 to 36 months. Priority will be given to randomized studies. The protocols should demonstrate knowledge in the field of hematopoietic stem cell transplantation, ask clinically relevant questions, and require sufficient subjects to necessitate the use of a multi- center network. Applicants should provide preliminary results that justify the proposed end points and sample size. The research plan should follow the instructions in the PHS 398 application form which can be found at http://grants.nih.gov/grants/forms.htm. For the protocol, include a two to three page description of the rationale, research aims, outcome measures, and study design; a description of the patient populations with an estimate of the expected distribution of male and female patients, ages, and assurances of the applicant's access to the patient populations. Identify any competing protocols and provide an algorithm to explain patient allocation among them. Core Clinical Center applicants should indicate for each protocol how many patients are available in the applicant’s center and how many will be required from the network. The center’s estimate of eligible patients should be based on the actual number of transplants performed in the year 2000. Please complete the following table by providing the number of patients transplanted at your institution in the year 2000 in each category. Transplants in 2000 - Related - Mismatched Related - Unrelated - Autologous ----------------------------------------------------------------------------- Marrow - - - - ----------------------------------------------------------------------------- mPBSC - - - - ----------------------------------------------------------------------------- Cord Blood - - - - ----------------------------------------------------------------------------- Pediatric - - - - ----------------------------------------------------------------------------- Adult - - - - ----------------------------------------------------------------------------- Malignant - - - - ----------------------------------------------------------------------------- Non-malignant - - - - ----------------------------------------------------------------------------- On protocol - - - - ----------------------------------------------------------------------------- Randomized - - - - ----------------------------------------------------------------------------- Multi Center - - - - ----------------------------------------------------------------------------- It is the intent of this network that multiple trials will be conducted during the five year project period. It is anticipated that in the initial year, two trials will be selected from the studies proposed by the successful applicants. However, a decision to fund a particular Core Clinical Center will not commit the Network to develop that center’s clinical protocol. Nevertheless, awardees must agree to actively enroll patients in at least two Network trials. Applicants should plan that after the first year at least three trials will begin enrolling patients each year. All applicants should propose a strategy to streamline protocol development and acceptance among centers, given this ambitious pace for initiating trials. Initiation of trials in future years will depend on satisfactory progress in previous trials. Data Coordinating Center applicants should propose one clinical protocol from the perspective of study design, implementation, coordination and data analysis. Include a plan for recruiting patients from non-Core centers for studies that warrant it. Indicate appropriate objective measures of primary and secondary outcome. Describe methods to standardize reporting of graft versus host disease, propose a registry to track serious infectious complications, show plans to undertake quality of life studies and present an innovative approach for performing randomized studies at an early stage of investigation. Such approaches include, but are not limited to, use of internal pilot studies, methods for early stopping for futility or benefit, methods of adaptive trial redesign and other recently developed methods which will increase the efficiency of trial conduct. Development of new methods is encouraged. The entire application for Core Clinical Centers including protocols should not exceed the Form 398 Research Plan instructions of 25 pages. The Data Coordinating Center application may include an additional 5 pages to accommodate the clinical protocol proposal. SPECIAL REQUIREMENTS Terms and Conditions of Award The cooperative agreement is an award instrument establishing an "assistance" relationship (in contrast to an "acquisition" relationship) between NHLBI, NCI and a recipient, in which substantial NHLBI and NCI scientific and/or programmatic involvement with the recipient is anticipated during performance of the activity. The NHLBI and NCI purpose is to support and/or stimulate the recipient's activity by involvement in and otherwise facilitating the activity in a "partner" role, but avoiding a dominant role, direction, or prime responsibility. The terms and conditions below elaborate on these actions and responsibilities, and the awardee agrees to work with the NHLBI and NCI Project Scientists toward achieving the project objectives. It is anticipated that these terms and conditions will enhance the relationship between the NHLBI and NCI staff and the principal investigator(s), and will facilitate the successful conduct and completion of the study. 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 other HHS, PHS, and NIH grant administrative policy statements. The terms will be as follows: A. Awardee Rights and Responsibilities The Blood and Marrow Transplant Clinical Research Network (Network) will be a cooperative network of sixteen Core Clinical Centers, one Data Coordinating Center, the National Heart, Lung, and Blood Institute (NHLBI) and the National Cancer Institute (NCI). Core Clinical Centers will be responsible for proposing protocols that could be adopted by the Network, guiding protocol development, enrolling patients, analyzing results, and disseminating research findings. All Core Clinical Centers will be required to participate in a cooperative and interactive manner with one another and with the Data Coordinating Center. A centralized Data Coordinating Center will support the activities of the Network. These include developing protocols, devising novel comparative study designs, providing sample size calculations and statistical advice, developing data forms, performing data analyses, coordinating the activities of the Steering Committee, Protocol Review Committee, and Data and Safety Monitoring Board, and overall study coordination and quality assurance. In addition, in order to hasten accrual in phase III protocols, the Coordinating Center with NHLBI and the Steering Committee will have the responsibility to identify qualified and interested investigators at non-Core centers who wish to enroll patients on these protocols. Arrangements for data collection and reimbursement of trial-related data collection costs at non-Core centers will be the responsibility of the Data Coordinating Center. The Data Coordinating Center will also be responsible for obtaining biologic reagents, organizing correlative laboratory studies, arranging for storage of patient samples, and procuring other resources as required by the clinical protocols. 1. Development of Network Research Agenda and Protocols It is the responsibility of the awardee(s) to develop the details of the research design, including definition of objectives and approaches, the planning, implementation, and analysis of studies, any modification of study design, quality control, collaboration with other investigators, and the publication of results, interpretations, and conclusions of studies, unless otherwise provided for in these terms or by action of the Steering Committee. Modifications and ancillary protocols will be approved by the Data and Safety Monitoring Board. Ancillary studies will not be funded by this grant mechanism. 2. Coordination and Internal Oversight of Network Activities Awardee(s) agree to the governance of the study through a Steering Committee. Meetings of the Steering Committee will ordinarily be held in the Washington, D.C. metropolitan area or by telephone conference call. Funds should be requested for the Chair of the Steering Committee as part of the Data Coordinating Center budget. The Steering Committee, with the assistance of the Data Coordinating Center, is responsible for coordinating protocol development, protocol submission, study conduct, quality control and study monitoring, drug ordering, data management, statistical analysis, protocol amendments/status changes, adherence to requirements regarding investigational drug management and federally mandated regulations, and protocol and performance reporting. The Data Coordinating Center will be responsible for communication with the appropriate NHLBI and NCI staff. The Steering Committee Chairperson, who will be someone other than an NHLBI or NCI staff member and may be someone other than a principal investigator, will be selected by NHLBI and NCI. The Core Clinical Centers, the Data Coordinating Center, NHLBI and NCI each will have one vote. The (Chairperson) will vote in the case of ties. The Steering Committee may meet as often as three to six times in the first 12 months of the Network, and two to four times per year thereafter. All major scientific decisions will be determined by majority vote of the Steering Committee. 3. Protocol Submission and Approval A protocol is the detailed written plan of a clinical experiment. Formal protocol review and NHLBI and NCI approval prior to activation are required. A Protocol Review Committee (PRC), independent from study investigators and appointed by the Directors, NHLBI and NCI, will meet at regular intervals to review proposed protocols. The Steering Committee may recommend members for the PRC. Meetings will ordinarily be held in the Washington, D.C. metropolitan area. The NHLBI or NCI Project Scientist shall serve as Executive Secretary for the PRC. The Executive Secretary will provide the study chairman with the Protocol Review Committee's consensus review that describes recommended modifications and other suggestions, as appropriate. Every effort should be made to expedite the protocol approval process. Protocols should adhere to recent NIH polices including inclusion of women/minorities, children, http://grants.nih.gov/grants/funding/women_min/guidelines_update.htm and http://grants.nih.gov/grants/funding/children/children.htm and http://orwh.od.nih.gov/pubs/outreach.pdf. The data monitoring plan should also be consistent with recent guidelines http://www.nhlbi.nih.gov/funding/policies/dataqual.htm as should the plans for analysis for gender/minority for NIH defined Phase III trials. The major considerations relevant to protocol review by the PRC include: (a) the strength of the scientific rationale supporting the study, (b) the medical importance of the question being posed, (c) the avoidance of undesirable duplication with other ongoing studies, (d) the appropriateness of study design including interim monitoring plans if appropriate, (e) a satisfactory projected accrual rate and follow-up period, (f) patient safety, (g) compliance with federal regulatory requirements, (h) adequacy of data management, (i) appropriateness of patient selection, evaluation, assessment of toxicity, response to therapy and follow-up, (j) adherence to NIH guidelines as detailed above. 4. Network Compliance with Federally Mandated Regulatory Requirements The Network must comply with all FDA regulatory requirements for studies involving investigational devices and agents and NIH policies applying to the conduct of research involving human subjects and be consistent with Office of Human Research Protections guidelines http://www.hhs.gov/ohrp/. These regulations include but are not limited to CFR 21 Parts 50, 56 and 312 and CFR 45 Part 46. Awardees are required to follow established Network procedures for complying with the federally mandated regulations. Each awardee must: a. have a current approved multiple project assurance number on file with OHRP or obtain a single project assurance; b. have IRB approval for each protocol, amendment, and informed consent document prior to patient entry and at least annually thereafter, as appropriate for the degree of risk of the protocol, as stipulated by 45 CFR 46; c. provide the Data Coordinating Center with a current FDA Form 1572 and curriculum vitae for study investigators; d. provide evidence that each patient (or legal representative) has given written informed consent prior to entry on study; e. assure timely reporting of all serious and unexpected toxicities to the Data Coordinating Center, who will report them to NHLBI, NCI and other parties as appropriate; f. establish and maintain an on-site audit program according to Network procedures; and g. comply with all FDA monitoring and reporting requirements for investigational agents and devices. h. Data Collection and Management The Network shall establish and implement mechanisms for data collection and management that are: (a) adequate for quality control and analysis, and (b) as simple as possible in order to encourage maximum participation of physicians entering patients and to avoid unnecessary expenses. Awardees are required to follow Network procedures for data collection and management which will be developed by the Steering Committee. 6. Quality Control and Monitoring of Therapeutic and Diagnostic Modalities The Steering Committee shall establish and implement mechanisms for quality control of therapeutic and diagnostic modalities employed in its trials. Awardees are required to follow Network procedures for quality control. Quality control should include an initial determination of patient eligibility by the Data Coordinating Center prior to study enrollment. In addition, quality control procedures should include at a minimum concurrent or retrospective review to assure compliance with the protocol for radiation therapy, and consistency of evaluation of graft versus host disease, infectious disease reporting, determination of relapse versus graft failure, and other key endpoints. 7. Study Monitoring and Quality Assurance The Network shall establish and implement mechanisms for study monitoring and quality assurance. Awardees are required to follow Network procedures for study monitoring. The Network is responsible for assuring accurate and timely knowledge of the progress of each study through: a. tracking and reporting of patient accrual and adherence to defined accrual goals; b. ongoing assessment of case eligibility and availability; c. timely medical review and assessment of patient data; d. rapid reporting of treatment-related morbidity and measures to ensure communication of this information to all parties; e. interim evaluation and consideration of measures of outcome as consistent with patient safety and good clinical trials practice; f. timely communication of results of studies; and g. an on-site monitoring program. The NHLBI/NCI is responsible for ensuring that all participating sites receive routine audits by the Data Co-ordinating Center. In the event that an awardee fails to comply with these guidelines, the accrual of new patients to the Network's protocols at the affected site shall be suspended immediately upon notice of the determination. The suspension will remain in effect until the awardee conducts the required audit and the audit report or remedial action is accepted by the NHLBI and NCI. The Data Coordinating Center and NHLBI/NCI will be responsible for notifying any affected site of the suspension. During the suspension period, no funds from this award may be provided to the site for new accruals, and no charges to the award for new accruals will be permitted. 8. Performance Review of Participating Centers The Network shall establish and follow policies and procedures for credentialing participating institutions and conducting periodic review of the performance of each participating site. This review should examine patient accrual, data accuracy and timeliness, protocol compliance, long-term patient follow-up and audit results. NHLBI/NCI will make adjustments in center budgets based on accrual and performance. 9. Quality Assurance and Quality Control of Data Management. The Data Coordinating Center must follow procedures developed by the Network for quality assurance and quality control of data collected by the Network and for the prevention and/or identification of false or otherwise unreliable data. These procedures must be approved by NHLBI and NCI. If there is any indication through the quality assurance and/or quality control programs, or through any other means, of a pattern of non-compliance with protocol or regulatory requirements or a finding of possible alteration of data, these findings must be reported to NHLBI and NCI. 10. Reporting Requirements Reporting requirements will be in agreement with Network procedures, NHLBI and NCI policies, and FDA regulations. Interim reports of each activated and ongoing study shall appear in the minutes of each Network meeting and shall include specific data on patient accrual as well as, when appropriate, detailed reports of treatment-associated morbidity. Monthly accrual and screening information must be provided by the Data Monitoring Center to the NHLBI and NCI Project Scientists for all active studies. A system for providing such information in a timely manner should be in place. Awardees must provide screening data to the Data Coordinating Center in accordance with Network procedures. Annual scientific progress reports will be submitted by each awardee to the NHLBI and NCI. New reporting requirements should also be implemented http://grants.nih.gov/grants/funding/women_min/guidelines_update.htm. 11. Data and Safety Monitoring Board (DSMB) A Data and Safety Monitoring Board will (DSMB) be appointed by the Directors, NHLBI and NCI to provide overall monitoring of interim data and safety issues. The Steering Committee may suggest members for the DSMB. There will be a single DSMB for all studies conducted by the Network. Members who are lead investigators from institutions enrolling patients in a protocol under DSMB review will be required to recuse themselves for that review. The DSMB will meet semi-annually, usually in Bethesda, MD. The NHLBI or NCI Project Scientist shall serve as Executive Secretary for the DSMB. 12. Adverse Event Procedures In order to comply with FDA regulations, the awardee must promptly notify the Data Coordinating Center Principal Investigator or designee, and the NHLBI and NCI Project Scientists of serious and unexpected adverse events as instructed in the protocol. 13. Protocol Closure The Network shall establish and implement mechanisms for interim monitoring of results and accrual. If the Network wishes to close accrual to a study prior to meeting the initially established accrual goal, the request should be referred to the DSMB for review and to NHLBI and NCI for concurrence prior to implementation of the decision by the Network. It is recommended that statistical guidelines for early closure be presented as explicitly as possible in the protocol in order to facilitate these decisions. 14. Industry or Third-party Involvement Support or other involvement of industry or any other third party in the study -- e.g., participation by the third party; involvement of project resources or citing the name of the project or the NHLBI and NCI support; or special access to project results, data, findings or resources -- may be advantageous and appropriate. Joint projects and cost-sharing arrangements with industry are encouraged. Arrangements will be worked out on a case-by-case basis by the Network leadership and collaborating companies. Arrangements will in all cases conform to federal regulations and any applicable NHLBI and NCI policies on interactions among industry, cooperative trials networks, and NHLBI and NCI. In all cases, details of any financial or other arrangements between the Network and industrial companies must be approved by NHLBI and NCI. 15. Release of Study Data Awardees will retain custody of and have primary rights to the data developed under these awards, subject to Government rights of access consistent with current federal policies. The collaborative protocol and governance policies will require submission of data to the coordinating center for a collaborative database; specify procedures for data analysis, reporting and publication; and include procedures to protect and ensure the privacy of medical and genetic data and records of individuals. Copies of the collaborative data sets will be provided to each principal investigator after publication of study results. Each Awardee will comply with the approved data release plan. Awardees are encouraged to publish and to publicly release and disseminate results, data and other products of the study, concordant with the study protocol and governance and the approved plan for making data and materials available to the scientific community, NHLBI and NCI. No later than three years beyond the end date of the project period, unpublished data, data sets not previously released, or other study materials or products are to be made available to any interested party at no charge other than the costs of reproduction and distribution. At the end of the project, the Data Coordinating Center is expected to electronically place all study protocols and procedure manuals in the public domain and/or make them available to other interested parties at no charge other than the costs of reproduction and distribution, according to the approved plan for making data and materials available to the scientific community. 16. Termination or Curtailment The NHLBI and NCI reserve the right to terminate or curtail the Network, a protocol, or an individual award in the event of (a) failure to develop or implement a mutually agreeable collaborative protocol, (b) substantial shortfall in participant recruitment, follow-up, data reporting, quality control, or other major breach of the protocol, (c) substantive changes in the agreed-upon protocol with which NHLBI and NCI cannot concur, (d) reaching a major study endpoint substantially before schedule with persuasive statistical significance, or (e) human subject concerns that may dictate a premature termination. 17. Procedures in the Event of Scientific Misconduct It is the responsibility of the grantee institution to notify NHLBI/NCI of potential conflicts of interest with Network protocols as published in FINANCIAL CONFLICTS OF INTEREST AND RESEARCH OBJECTIVITY: ISSUES FOR INVESTIGATORS AND INSTITUTIONAL REVIEW BOARDS http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-040.html. If a duly authorized governmental or institutional body issues a final determination that scientific misconduct has occurred or if the awardee determines that other events have occurred which have significantly affected the quality or integrity of the Network data or patient safety, the awardee is responsible for notifying the Network's Data Coordinating Center who will notify the DSMB, the NHLBI and NCI, the collaborating investigators, and other sponsors of the affected work. Investigators will notify their IRBs. The awardee is also responsible, if the events described above have occurred, for ensuring that submitted but unpublished abstracts and manuscripts are corrected, if possible. If publication deadlines have passed or if abstracts and/or manuscripts containing the affected data have already been published, the awardee is responsible, within 90 days after learning of the event(s) significantly affecting the quality of the Network data or patient safety, for submitting to NHLBI and NCI a re-analysis of the results deleting the false or otherwise unreliable data, and disclosing within the text the reason(s) for the re-analysis. The awardee must submit the re-analysis for publication. The NHLBI and NCI may disseminate information about the re- analysis as broadly as it deems necessary. The awardee must use its best efforts to notify all scientists, research laboratories, and other organizations to which the awardee has sent research materials affected by false or otherwise unreliable data. True copies of data files and other supporting documentation from studies affected by scientific misconduct or other findings affecting the quality or integrity of data or patient safety shall be made available to the NHLBI and NCI in a timely manner upon the request of the Grants Management Officers, NHLBI and NCI. The NHLBI and NCI reserve the right to re-analyze, to publish, or to distribute its analyses of these data when it is in the interest of the public health. Prior to release, publication or distribution of such analyses, the NHLBI and NCI will provide such analyses to the awardee(s). 18. Notification of Patients of Protocol-related Information In order for there to be an appropriate response in the event the NHLBI and NCI determine, either while a protocol is active or (if relevant) during the lifetime of the subjects following protocol closure, that a medically important toxicity or side effect is associated with protocol-directed treatment or that the medical care of one or more subjects may have been compromised by scientific misconduct or other finding affecting the integrity of the data or patient safety at the awardee institution or at a third-party institution, funded or unfunded, the awardee shall assure that the institution(s) responsible for these subject(s') accrual, whether funded or unfunded, will have procedures in place: a) to contact each subject individually at his or her last known address on file with the institution and encourage subjects to notify the institution of any changes of address and b) which give each subject contacted appropriate information and the right to communicate with an appropriate institutional representative and, in the event of misconduct, to meet with a physician not connected with the clinical trial or study in which the subject has participated. The procedure must provide for informing the subjects fully of the consequences of the toxicity or misconduct for their care and well-being, if any, and the availability of follow-up; and their opportunity to examine any portion of their medical records relevant to the potential effect of the toxicity or side effect upon them or that may be affected by scientific misconduct or other findings affecting the quality or integrity of the data or patient safety. Under regulations in CFR 45 Part 74.53, NHLBI and NCI have right of access to research records pertinent to studies conducted with NHLBI and NCI funding. In exceptional circumstances, such as a public health emergency, institutions may be required to provide subject names and treatments to the NHLBI and NCI in a format which allows direct notification of the patient by the NHLBI and NCI. 19. There will be an administrative review by NHLBI and NCI after approximately three years to determine if the network and each of its components has been performing as envisioned in terms of patient recruitment and implementation of protocols of importance to the field. 20. All major scientific decisions will be determined by majority vote of the Steering Committee. 21. Awardees must agree to actively enroll patients in at least two Network trials. 22. Each clinical center shall be prepared for a yearly audit/site visit by the Data Coordinating Center. 23. NHLBI/NCI will make adjustments in center budgets based on accrual and performance. B. NHLBI and NCI Staff Responsibilities The role of NHLBI and NCI staff as described throughout these terms and conditions of award is to assist and facilitate, but not to direct, research activities. This cooperative agreement is part of a larger program of cooperative clinical trials in the NHLBI and NCI. 1. NHLBI and NCI Staff Interactions One NHLBI and one NCI staff member will be members of the Steering Committee. Because of the Network's diverse research agenda and the number of tasks that have to be accomplished for the Network to realize its goals, a number of NHLBI and NCI scientists from several organizational units may also interact with the Network. These staff scientists may include but are not limited to individuals with expertise in clinical trial design, recruitment, data collection, management, and monitoring, biostatistics, use of investigational agents, knowledge of other relevant ongoing studies, the ability to establish liaisons with other clinical cooperative groups and those with expertise in protocol-related and medical matters relating to the diseases under study. While one NHLBI and one NCI Project Scientist will be members of the Steering Committee; they or another NHLBI and/or NCI scientist may serve on other study committees when deemed appropriate by NHLBI and NCI. NHLBI and NCI staff scientists will review and provide advice regarding mechanisms established by the Network for quality control of therapeutic and diagnostic modalities employed in its trials. Staff will review and approve the mechanisms established by the Network for study monitoring including the Network's on-site auditing program. Staff may attend the on-site audits conducted by the Network as observers. The frequency of observer participation will be determined by the NHLBI and NCI. NHLBI and NCI staff scientists will review mechanisms established by the Network for data management. When deemed appropriate, staff will make recommendations to ensure that data collection and management procedures are: (a) adequate for quality control and analysis; (b) as simple as appropriate in order to encourage maximum participation of physicians entering patients and to avoid unnecessary expense; and (c) generally compatible with the standard formats for electronic data reporting to NHLBI and NCI. The NHLBI and NCI will have access to all data although they remain the property of the awardee institution. Data must also be available for external monitoring as required by FDA regulations. 2. Involvement in Investigational Drug and Device Management The NHLBI and NCI have the option to cross file or independently file an IND on investigational agents evaluated in trials supported under cooperative agreements. This requirement applies to drugs not developed in the NCI drug development program. In the case of investigational devices, the NHLBI and NCI, Network investigators, and the device supplier will decide collaboratively which organization will hold the IDE. NHLBI and NCI staff with experience in regulatory affairs or technology transfer must review and approve agreements regarding investigational agents between the Network and third-parties. 3. NHLBI and NCI Attendance at Network Meetings NHLBI and NCI Project Scientists will attend the regular Network Steering Committee meetings, will serve as the executive secretary for the PRC and DSMB, and will be invited to Network leadership and subcommittee meetings. 4. Facilitating Collaboration with other Cooperative Groups NHLBI and NCI Project Scientists will take an active role in promoting the timely completion of important studies, for example by encouraging and facilitating intergroup collaboration when appropriate, or by assisting in the identification and mobilization of additional resources. C. Arbitration Any disagreement that may arise in scientific/programmatic matters (within the scope of the award), between award recipients and the NHLBI and NCI may be brought to arbitration. An arbitration panel will be composed of three members--one selected by the Steering Committee (with the NHLBI and NCI members not voting) or by the individual awardee in the event of an individual disagreement, a second member selected by NHLBI and NCI, and the third member selected by the two other members. This panel will review the area of disagreement and recommend an appropriate course of action to the Directors, NHLBI and NCI. This special arbitration procedure in no way affects the awardee's right to appeal an adverse action that is otherwise appealable in accordance with the federal regulations at 42 CFR part 50, Subpart D and 45 CFR part 16, or the rights of NHLBI and NCI under applicable statutes, regulations and terms of the award. The Network will not expend NHLBI or NCI funds to conduct any study disapproved by NHLBI or NCI unless the disapproval has been overturned by the arbitration process outlined above. INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of the NIH that women and members of minority groups and their sub-populations must be included in all NIH-supported biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification are provided indicating that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing research involving human subjects should read the updated "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research," published in the NIH Guide for Grants and Contracts on August 2, 2000 http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-048.html; a complete copy of the updated Guidelines are available at http://grants.nih.gov/grants/funding/women_min/guidelines_update.htm:. The revisions relate to NIH defined Phase III clinical trials and require: a) all applications or proposals and/or protocols to provide a description of plans to conduct analyses, as appropriate, to address differences by sex/gender and/or racial/ethnic groups, including subgroups if applicable; and b) all investigators to report accrual, and to conduct and report analyses, as appropriate, by sex/gender and/or racial/ethnic group differences. INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of the NIH that children (i.e., individuals under the age of 21) must be included in all human subjects research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them. This policy applies to all initial (Type 1) applications and applications submitted for receipt dates after October 1, 1998. All investigators proposing research involving human subjects should read the NIH Policy and Guidelines on the Inclusion of Children as Participants in Research Involving Human Subjects that was published in the NIH Guide for GRANTS and Awards, March 6, 1998, and is available at the following URL address: http://grants.nih.gov/grants/guide/notice-files/not98-024.html. Investigators also may obtain copies of these policies from the program staff listed under INQUIRIES. Program staff may also provide additional relevant information concerning the policy. LETTER OF INTENT Prospective applicants are asked to submit by February 21, 2001, a letter of intent that includes a descriptive title of the proposed research, the name, address, and telephone number of the Principal Investigator, the identities of other key personnel and participating institutions, and the number and title of the RFA in response to which the application may be submitted. Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows NHLBI and NCI staff to estimate the potential review workload and plan the review. The letter of intent is to be faxed or mailed to Dr. Deborah Beebe at the address listed under INQUIRIES. APPLICATION PROCEDURES The research grant application form PHS 398 (rev. 4/98) is to be used in applying for these grants. These forms are available at most institutional offices of sponsored research or may be obtained from the Division of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301-710-0267, E-mail: GrantsInfo@nih.gov. The PHS 398 application kit is also available on the Internet at http://grants.nih.gov/grants/forms.htm. The entire application for Core Clinical Centers including protocols should not exceed the Form 398 Research Plan instructions of 25 pages. The Data Coordinating Center application may include an additional 5 pages to accommodate the clinical protocol proposal. Material to Include in Core Clinical Center Applications: To promote development of a collaborative program among the award recipients, the issues discussed below need to be addressed in each application for a Core Clinical Center and will be considered during the review of the application. This material is in addition to the submission of a research plan, as described in the section entitled Research Scope and should be included within the 25 page limit. Patient Access. Core Clinical Center applicants must have access to at least 35 patients per year undergoing an allogeneic blood or marrow transplant. Provide the information requested regarding patient numbers by completing Table 1. It is not anticipated that all patients will be enrolled in research protocols at any one time. It is possible that an individual patient may be enrolled in more than one study. Centers should estimate the number of patients that will be eligible for Network protocols, provide information on competing protocols, and present a strategy for allocating patients between them. Study population. The application should include a description of the pool of potential study participants--the age range, ethnic/racial distribution, estimated distribution of patients with different diseases and type of transplant. The Network should include as patients racial/ethnic minorities, children and women in ratios that at least approximate the incidence of the diseases being studied and provide sufficient clinical events to perform subgroup analyses. Patient-related costs. Specific laboratory tests specifically required by clinical protocols will be included as a part of the per patient costs of each Core Clinical Center. (Costs for tests that are a routine part of patients clinical care should not be included and may not be paid from grant funds.) Plans to release data. Awardees will retain custody of and have primary rights to the data developed under these awards, subject to Government rights of access consistent with current federal policies. The collaborative protocol and governance policies will require submission of data to the coordinating center for a collaborative database; specify procedures for data analysis, reporting and publication; and include procedures to protect and ensure the privacy of medical and genetic data and records of individuals. Copies of the collaborative data sets will be provided to each principal investigator after publication of study results. Each Awardee will comply with the approved data release plan. Awardees are encouraged to publish and to publicly release and disseminate results, data and other products of the study, concordant with the study protocol and governance and the approved plan for making data and materials available to the scientific community, NHLBI and NCI. No later than three years beyond the end date of the project period, unpublished data, data sets not previously released, or other study materials or products are to be made available to any interested party at no charge other than the costs of reproduction and distribution. At the end of the project, the Data Coordinating Center is expected to electronically place all study protocols and procedure manuals in the public domain and/or make them available to other interested parties at no charge other than the costs of reproduction and distribution, according to the approved plan for making data and materials available to the scientific community. Willingness to participate in the Network. Applicants should state their general support of collaborative research and interaction with other Core Clinical Centers, the Data Coordinating Center, NHLBI and NCI through the network. Centers must be willing to initiate randomized studies of promising therapy as soon as it is warranted. Centers must state their willingness to participate in Network trials even if the protocols they proposed are not selected for implementation. Applicants should discuss their willingness to accept per patient reimbursement (capitation) for each protocol as decided by the Steering Committee. Budget and Related Issues for Core Clinical Centers Core Clinical Center applicants should consider the following additional issues regarding budgets. The underlying concept of the Network is that a core effort is essential to maintain the infrastructure required to perform prospective multi-institution clinical trials. Based on this approach, it is estimated that the Core Clinical Centers will require a minimum level of effort to sustain the organizational aspects of the Network. In addition to the core budget, each Core Clinical Center will be provided funds for implementation of protocols on a per patient-enrolled basis. Funds for per patient costs will be restricted for this purpose. Costs for a required part of the patient’s treatment may not be requested from the grant. Costs for tests and treatment not part of the usual procedure may be requested. Allowable total costs for each clinical center (core costs, costs per patient to conduct the protocols, and facility and administrative costs) will be limited to $405,000 a year. The precise number of protocols conducted over the 5 years will be determined by the Network Steering Committee and will depend on availability of funds. Each clinical center must participate in at least two protocols per year. The initiation of two protocols is expected in the first year, and at least four new trials are expected to begin enrolling patients in future years. Initiation of trials in future years will depend on satisfactory progress in previous trials. Applicants for the Core Clinical Centers are requested to present the following information: For each year, the Clinical Centers should include the core budget costs and patient care costs. The core budget which is limited to $150,000 total costs is expected to cover a minimum 10% effort for the principal investigator, a small percent effort for other key personnel (nurse, technician, clinic coordinator, secretary), and travel costs for two people to attend 4 Network meetings per year in Bethesda, MD. Total costs for the core budget may be escalated at three percent for future years. Actual patient care costs will be determined by the specific protocols implemented at each center. For application purposes, $255,000 (total costs) should be entered on the patient care cost line on the budget page. This amount will be restricted for this purpose. Funds released will reflect protocol-specific costs as protocols are implemented. For the purpose of the review, centers should provide separate budgets for each clinical protocol they propose. These budgets should be developed on a cost per patient basis and include all direct and any applicable facilities and administrative costs. Costs of recruiting and following patients, costs for drugs or procedures, and costs for laboratory tests should be part of the per patient cost of conducting a protocol. Applications should identify the potential source(s) and cost for any drugs or procedures that are being considered for clinical protocols. The yearly budget for each protocol should include the number of patients available for the proposed protocol at the applicant’s center. Investigators should prepare budgets only for their own center to conduct the proposed trial, and not for the entire Network. However, the budget should state the total number of patients required from the entire network to complete each proposed trial. Continuation and level of funding for each Core Clinical Center will be based on actual recruitment and overall performance. Awards will be subject to administrative review annually. The entire Network will be reviewed after approximately three years. Material to Include in Data Coordinating Center Applications: To promote development of a collaborative program among the award recipients, the issues discussed below need to be addressed in each application for a Data Coordinating Center and will be considered during the review of the application. This material is in addition to the submission of a research plan, as described in the section entitled Research Scope and should be included within the 25 page limit. The Data Coordinating Center application may include an additional 5 pages to accommodate the clinical protocol proposal as noted above. Qualifications and experience. Applicants for the Data Coordinating Center must demonstrate knowledge in the area of hematopoietic stem cell transplantation and demonstrated experience coordinating multi-center clinical trials in all phases: protocol and manual of operations development, staff training in study procedures, data form development, patient recruitment strategies, data collection and management, quality assurance, data analysis, distributed data entry, electronic communications including web site development and management, administrative management and coordination. The experience of key personnel should be described. Study design and management. Data Coordinating Center applicants should discuss various aspects of study design that would be important in developing clinical protocols, for example: eligibility criteria; baseline and outcome measures; methods of randomization; important considerations for sample size and power calculations; methods and frequency of data collection and entry; monitoring accuracy of data collection including at least yearly site visits; quality control procedures including training and certification for multiple protocols, some of which may occur simultaneously; managing, labeling and handling of patient samples (see below); and plans for statistical analysis. Applicants should provide a time line for protocol development and a strategy for reducing the time required to initiate patient enrollment in new studies. Experience in and plans for development and use of novel statistical study designs should be described. Applicants should describe their familiarity with hematopoietic stem cell transplantation. Plans for coordinating the Data Safety Monitoring Board and the Protocol Review Committee should be included. Patient enrollment at Core Clinical Centers. Propose a method for screening eligible patients at Core Centers and identifying causes of non-enrollment. Describe previous experience with strategies to improve accrual in randomized clinical studies. Patient enrollment at outside centers. In order to produce the fastest possible accrual to phase III studies it is desirable that studies be accessible to as many patients as possible. The applicant should include a plan to identify interested non-Core transplant centers, evaluate their ability to enroll patients to a specific protocol, collect data from these centers, conduct onsite data audits at these centers, and provide per capita reimbursement for enrollment to these centers . Patient samples. The applicant should delineate how laboratory specimens required for specific studies will be handled and be prepared to submit plans for identifying a central laboratory(ies), establishing a specimen repository, or obtaining other services as needed for specific protocols. The costs of obtaining protocol-specific tests or services will be budgeted as a part of the per patient costs of each Clinical Center. (Costs for tests that are a routine part of the patients clinical care should not be included and may not be paid from grant funds.) The costs of specimen shipment as well as laboratory data acquisition and management will be a part of the budget of the Data Coordinating Center. An estimated shipping and handling costs per year for specimens should be included in the budget of the Data Coordinating Center. Central source of drugs and investigational agents. The applicant should describe in general terms plans to obtain needed drugs, biologic reagents, or devices and describe their experience with studies of investigational agents. Budget and Related Issues for Data Coordinating Center Applicants: Applicants for the Data Coordinating Center should prepare budgets for five 12 month periods that roughly correspond with the standard coordinating center responsibilities outlined in other sections of this RFA. For budget purposes, Data Coordinating Center applicants should assume that in the first year, all administrative aspects of the Network will be organized and two protocols will be developed and started. For subsequent years, applicants should assume that at least four new protocols will be initiated each year. Data Coordinating Center applicants should include costs for managing the DSMB and the Protocol Review Committee including the cost of three meetings per year in Bethesda. In addition, funds for reimbursing non-Core centers for patient accrual as well as appropriate oversight should be included. The Data Coordinating Center should budget $50,000 for expenses related to support for the chair of the Steering Committee. It is estimated that in addition to the standard data coordinating center responsibilities the potential per patient reimbursement, laboratory tests and services, and biologic reagents may cost an additional $500,000 total per year. The award will be subject to administrative review annually. There will be an administrative review by NHLBI and NCI after approximately three years to determine if the network and each of its components has been performing as envisioned in terms of patient recruitment and implementation of protocols of importance to the field. It is expected that all protocols will be performed in a manner consistent with United States Food and Drug Administration guidelines. APPLICATIONS NOT CONFORMING TO THESE GUIDELINES WILL BE CONSIDERED UNRESPONSIVE TO THIS RFA AND WILL BE RETURNED WITHOUT FURTHER REVIEW. The RFA label available in the PHS 398 application form must be affixed to the bottom of the face page of the application. 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, to identifying the application as a response to this RFA, check "YES" in item 2 of page 1 of the application and enter the title " Blood and Marrow Transplant Clinical Research Network HL- 01-004. Submit a signed, typewritten original of the application and three signed photocopies, in one package to: CENTER FOR SCIENTIFIC REVIEW NATIONAL INSTITUTES OF HEALTH 6701 ROCKLEDGE DRIVE, ROOM 1040 - MSC 7710 BETHESDA, MD 20892-7710 BETHESDA, MD 20817 (for express/courier service) At the time of submission, two additional copies of the application must be sent to Dr. Deborah Beebe at the listing under INQUIRIES. Applications must be received by March 19, 2001. If an application is received after this date it will be returned to the applicant without review. The Center for Scientific Review (CSR) will not accept any application in response to this RFA that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. This does not preclude the submission of substantial revisions of an application already reviewed, but such applications must include an introduction addressing the previous critique. REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed for completeness by the CSR and for responsiveness by NHLBI and NCI staff. Incomplete and/or nonresponsive applications will be returned to the applicant without further review. Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened by the Division of Extramural Affairs, NHLBI, in accordance with the review criteria stated below. The roster of the initial review group will be available via the NHLBI home page approximately two weeks prior to the review. As part of the initial merit review, all applications will receive a written critique and undergo a review in which only those applications deemed to have the highest scientific merit will be discussed and assigned a priority score. The National Heart, Lung and Blood Advisory Council and the National Cancer Advisory Board will perform a second level of review. Applications will be judged primarily on the scientific quality of the application, however, the scientific merit of the proposed research plan will not be the sole criterion for selection of a Clinical Center. Applicants are encouraged to present their own ideas on how best to meet the goals of the Network, but they are expected to address issues identified under APPLICATION PROCEDURES of the RFA. Review Criteria for Core Clinical Center Applications Research plan. Appropriateness of proposed protocols, need for the network to accomplish the proposed protocol, relevance and importance of the research questions, preliminary results that justify the proposed end points and sample size, and likelihood that accrual could be accomplished in three years. Qualifications and experience. The expertise, training, and experience of the investigators and staff in blood and marrow transplantation clinical trials, evidence of understanding of randomized, multi-center trials, administrative abilities of the Principal Investigator, study nurse and/or data coordinator, and the time they plan to devote to the program for the effective function of the Clinical Research Network. Patient access and study population. The availability of at least 35 allogeneic transplants at the applicant’s institution per year; the number that will be eligible for Network protocols; plans for the recruitment and retention of subjects; plans to ensure appropriate representation by ethnic group, age, and gender; the description of competing protocols, and the strategy for allocating patients between them. Willingness to participate in the Network. Applicant institution’s history of collaborative research, depth of commitment, willingness to randomize patients, and ability to work with other Network Centers, NHLBI, and NCI. Institutional resources for patient care and follow-up. Adequacy of institutional resources including personnel, space, and special laboratory facilities. The reasonableness of the proposed budget and duration in relation to the proposed research. The adequacy of the proposed protection for humans, animals or the environment, to the extent they may be adversely affected by the project proposed in the application. Further considerations for the review include: access to patients, multi disciplinary nature of the proposed studies, the discussion of considerations relevant to this RFA, and a demonstrated willingness on the part of the investigators to work as part of the Clinical Research Network and with the NHLBI and NCI Project Scientists. Review Criteria for Data Coordinating Center Applications Research plan. Demonstrates understanding of the scientific, statistical, logistical, and technical issues underlying multi-center studies, including issues relating to treatment and management of transplant subjects; and demonstrates leadership in study design and statistics, data acquisition and management, data quality control, data analysis, handling and quality control of laboratory specimens, and network coordination. Qualifications and experience. The expertise, training, and experience of the investigators and staff, including the administrative abilities of the Principal Investigator, co- investigator, and the time they plan to devote to the program for the effective coordination of the Clinical Research Network. Study management. The administrative, supervisory, and collaborative arrangements for achieving the goals of the program, including willingness to cooperate with the participating Clinical Centers and the NHLBI and NCI. This includes the ability to assist Core Clinical Centers with recruitment problems, and identify and subcontract with non-Core clinical centers to meet accrual goals. Willingness to participate in the Network. Applicant institution’s history of collaborative research, depth of commitment, and ability to work with other Network Centers, NHLBI, and NCI. Environment. Facilities, equipment, and organizational structure to effectively coordinate Clinical Research Network activities and assist Clinical Centers in implementing the Clinical Research Network protocols, providing for specialized laboratory testing, and collecting data. This includes but is not limited to development of repositories, conduct of lab tests and studies, and obtaining study drugs or investigational agents. The reasonableness of the proposed budget and duration in relation to the proposed research. The adequacy of the proposed protection for humans, animals or the environment, to the extent they may be adversely affected by the project proposed in the application. Further considerations for the review include: plans for access to patients, multi disciplinary nature of the proposed studies, the discussion of considerations relevant to this RFA, and a demonstrated willingness on the part of the investigators to work as part of the Clinical Research Network and with the NHLBI and NCI Project Scientists. Schedule Letter of Intent Receipt Date: February 21, 2001 Application Receipt Date: March 19, 2001 Council Review: August/September, 2001 Anticipated Award Date: September 30, 2001 AWARD CRITERIA Factors that will be considered in making awards include: a) the scientific merit of the proposed program as determined by peer review, the multi disciplinary nature of the proposed studies, and the quality of meeting the special requirements stated in this RFA; b) relevance to the overall programmatic balance and priorities of NHLBI and NCI, and sufficient compatibility of features proposed in the research plan and qualifications of the investigators to make a collaborative program within the Network a reasonable likelihood; c) the inclusion by the network of gender and minority participants in a manner consistent with the disease prevalence in question in the U.S. population; and d) the availability of funds. INQUIRIES Inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Dr. Charles M. Peterson Division of Blood Diseases and Resources National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Suite 10018, MSC 7950 Bethesda, Maryland 20892-7950 Telephone: (301) 435-0050 FAX: (301) 480-0868 E-mail: petersoc@nih.gov Dr. Roy S. Wu Division of Cancer Treatment & Diagnosis National Cancer Institute Executive Plaza North, Room 734 6130 Executive Boulevard Bethesda, MD 20892 Telephone: (301) 496-8866 FAX: (301) 480-4663 Email: Wur@ctep.nci.nih.gov Direct inquiries regarding review matters, send letter of intent, and two copies of the application to: Dr. Deborah Beebe Division of Extramural Affairs National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Suite 7178, MSC 7924 Bethesda, Maryland 20892-7924 (20817 for express mail) Telephone: (301) 435-0270 FAX: (301) 480-3541 E-mail: BeebeD@nhlbi.nih.gov Direct inquiries regarding fiscal matters to: Jane Davis Grants Operations Branch Division of Extramural Affairs National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Suite 7174, MSC 7926 Bethesda, MD 20892-7926 Telephone: (301) 435-0166 FAX: (301) 480-3310 E-mail: davisj@nih.gov Authority and Regulations This program is described in the Catalog of Federal Domestic Assistance, No. 93.839. Awards are made under authorization of the Public Health Service Act, Title IV, Part A (Public Law 78-410, amended by Public Law 99-158, 42 USC 241 and 285) and administered under NIH grants policies and Federal Regulations 42 CFR 52 and 45 CFR Part 74. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or a Health Systems Agency Review. The NIH strongly encourages all grant and contract recipients to provide a smoke-free workplace and promote the non-use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care or early childhood development services are provided to children. This is consistent with the NIH mission to protect and advance the physical and mental health of the American people.

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