PEDIATRIC BRAIN TUMOR CLINICAL TRIALS CONSORTIUM Release Date: February 20, 1998 RFA: CA-98-007 P.T. 34; K.W. 0705055, 0715035, 0740020 National Cancer Institute Letter of Intent Receipt Date: May 1, 1998 Application Receipt Date: July 10, 1998 PURPOSE The Cancer Therapy Evaluation Program (CTEP) of the Division of Cancer Treatment and Diagnosis (DCTD) at the National Cancer Institute (NCI) invites applications for cooperative agreements (U01) from institutions to participate in establishing a multidisciplinary network of highly specialized investigators to efficiently evaluate technically challenging and innovative treatment approaches for children with brain tumors. This Pediatric Brain Tumor Clinical Trials Consortium (PBTCTC) will conceive, develop, and conduct collaborative Pilot and Phase I and II clinical evaluations of promising new therapeutic agents or approaches for the treatment of primary central nervous system (CNS) malignancies in pediatric patients. The Consortium will consist of up to 8 Participant Member Institutions selected by peer review for their documented ability to develop and conduct clinical trials of innovative treatment approaches and for their multidisciplinary expertise in supporting innovative brain tumor clinical research. The consortium is to have a single Operations, Statistics, and Data Management Center, also selected by peer review. The PBTCTC will be constituted from these separate funded awardees. Participant Member Institutions will be responsible jointly for proposing and conducting clinical evaluations of new treatment approaches, while the Operations, Statistics, and Data Management Center will be responsible for providing operational and data management/analysis support to implement Consortium protocols in a timely manner. The ultimate objective of the proposed awards is to stimulate collaborative efforts to evaluate technically challenging treatment approaches that have promise in terms of improving outcome for children with brain tumors. HEALTHY PEOPLE 2000 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2000," a PHS-led national activity for setting priority areas. This Request for Applications (RFA), Pediatric Brain Tumor Clinical Trials Consortium, is related to the priority area of cancer. Potential applicants may obtain a copy of "Healthy People 2000" (Full Report: Stock No. 017-001-00474-0 or Summary Report: Stock No. 017-001-00473-1) through the Superintendent of Documents, Government Printing Office, Washington, DC 20402-9325 (telephone 202/512-1800). ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic non-profit and for-profit organizations, public and private, such as universities, colleges, hospitals, laboratories, units of State and local governments, and eligible agencies of the Federal government. Applications from minority individuals, women, and persons with disabilities are encouraged. Eligible institutions may apply for either of the following types of awards: (1) Participant Member Institutions; and/or (2) Operations, Statistics, and Data Management Center. Participant Member Institution and Operations, Statistics, and Data Management Center applications must be submitted separately. Participant Member Institutions must document their multidisciplinary expertise in conducting innovative brain tumor clinical research and the ability to develop and conduct clinical trials of innovative treatment approaches (including the application of sophisticated imaging technologies for response and toxicity analysis). Operations, Statistics, and Data Management Center applicants must document their ability to coordinate multi-institutional clinical trials of children with cancer. Detailed requirements are listed below in Terms and Conditions of Award, Awardee Rights and Responsibilities. MECHANISM OF SUPPORT The administrative and funding instrument to be used for this program will be a cooperative agreement (U01), an "assistance" mechanism, in which substantial NCI scientific and/or programmatic collaboration with the awardee is anticipated during performance of the activity. Under the cooperative agreement, the NCI purpose is to support and/or stimulate the recipient's activity by working jointly with the award recipient in a partner role, but is not to assume direction, prime responsibility, or a dominant role in the activity. Details of the responsibilities, relationships, and governance of the study to be funded under cooperative agreements(s) are discussed later in this document under the section "Terms and Conditions of Award". Awards and level of support depend on receipt of a sufficient number of applications of high scientific merit. Although this program is provided for in the financial plans of the NCI, awards pursuant to this RFA are contingent upon the availability of funds for this purpose. The total project period for each application submitted in response to the RFA may not exceed five years. The earliest anticipated award date is April 01, 1999. At this time, the NCI has not determined whether or how this solicitation will be continued beyond the present RFA. If there is sufficient continuing program need, NCI may invite the recipients of awards under this RFA to submit competitive continuation cooperative agreement applications for review. FUNDS AVAILABLE Approximately $2,000,000 in total costs per year for five years will be committed to specifically fund applications submitted in response to this RFA. It is anticipated that awards will be made to up to eight Participant Member Institution applicants and to a single Operations, Statistics, and Data Management Center applicant. Approximately $1,000,000 total costs will be allocated for support of 8 anticipated Participant Member Institutions. It is anticipated that one award for the Operations, Statistics, and Data Management Center will be made for approximately $1,000,000. In that award, it is expected that $150,000 will be restricted for a Discretionary Fund for laboratory studies including pharmacokinetic evaluations and the shipping of patient specimens. It is also expected that approximately $400,000 will be restricted for partial support of research procedures required to meet study objectives (e.g., specialized imaging studies), with these funds provided to the Operations, Statistics, and Data Management Center for distribution to Participant Member Institutions based on patient accrual. DEFINITIONS AWARDEE - The organization to which a cooperative agreement is awarded and which is responsible and accountable to NCI for the use of funds provided and for performance of the cooperative agreement-supported project. COOPERATIVE AGREEMENT - An assistance mechanism in which substantial NCI programmatic involvement with the recipient is anticipated during performance of the planned activity. CTEP PROTOCOL REVIEW COMMITTEE - A committee composed of the professional staff of the CTEP and additional consultants from other NCI divisions, and chaired by the Associate Director, CTEP, that reviews and approves every protocol supported through Cooperative Agreements with CTEP as well as protocols involving DCTD investigational drugs. DISCRETIONARY FUND - A fixed portion ($150,000) of the award to the Operations, Statistics, and Data Management Center that will be allocated according to the instructions of the Steering Committee. Appropriate uses may include funding for laboratory projects (e.g., pharmacokinetic studies, tumor biology studies). When appropriate expertise for protocol-required laboratory projects is not available among PBTCTC Participant Member Institutions, Discretionary Funds may be provided to non-member investigators to support the required work. NCI IMAGING RESEARCH COORDINATOR - The Diagnostic Imaging Program, DCTD, NCI staff member who interacts scientifically with the Applicant/Awardee Institutions concerning imaging research opportunities. NCI PROGRAM DIRECTOR - The CTEP extramural Program staff member (cited in the INQUIRIES SECTION) who will coordinate DCTD interactions and provide guidance for the overall program within the NCI. He/she is available for consultation during preparation of applications, as well as throughout the course of the research conducted under these cooperative agreements. He/she also serves in a back-up role for the NCI Scientific Coordinator. NCI RADIATION ONCOLOGY RESEARCH COORDINATOR - The Radiation Research Program, DCTD, NCI staff member who interacts scientifically with the Applicant/Awardee Institutions concerning radiation oncology research opportunities. NCI SCIENTIFIC COORDINATOR - The Clinical Investigations Branch, CTEP, DCTD, NCI staff member who interacts scientifically with the Applicant/Awardee Institutions. OPERATIONS, STATISTICS AND DATA MANAGEMENT CENTER - The administrative unit that coordinates all the Consortium activities. Responsibilities include administrative management, committee management and coordination, protocol development and submission, study conduct, implementing a quality assurance program including quality control, statistical analyses, adherence to requirements regarding NCI drug accountability and FDA, OPRR, and HHS regulations, and monitoring protocol and institutional performance. Statistical responsibilities include experimental design, participation in study planning and coordination, collection and analysis of patient and laboratory data, data management and analysis, data monitoring, and reporting of data. The Center may be separate from the sites for the Participant Member Institutions, or may be located at one of these sites. Additionally, the Center may have the statistics/data management center located at an institution different from the Operations Center, but the award itself will be made to a single institution. PARTICIPANT MEMBER INSTITUTION - An institution that submits an individual cooperative agreement application for conducting clinical trials as part of the PBTCTC. The Participant Member Institution may conduct clinical trials and participate in correlative laboratory studies. PATIENT STUDIES RESEARCH FUND - A restricted portion (approximately $400,000) of the award to the Operations, Statistics, and Data Management Center that will be allocated according to the instructions of the Steering Committee and are to be disbursed on a capitation basis. These funds are to support special clinical research costs for patients accrued onto Consortium clinical trials and are to be disbursed on a capitation basis. It is anticipated that for each Consortium protocol, the capitation formula for institutional reimbursement required to offset specific research expenses will be developed by the Steering Committee. The capitation formula will be subject to NCI review and approval prior to implementation. A primary anticipated use of these funds is to supplement Participant Member Institutions for costs related to specialized imaging studies required to meet Consortium protocol study endpoints. Other specialized clinical research studies are also appropriate uses for these funds (e.g., institutional costs related to sample collection and shipping required for pharmacokinetic studies and for correlative biology studies on tumor tissues, provide supplements for additional patient accrual and for auditing of clinical trials). PEDIATRIC BRAIN TUMOR CLINICAL TRIALS CONSORTIUM (PBTCTC) - The consortium of Participant Member Institutions and the Operations, Statistics and Data Management Center that have been awarded separate cooperative agreement (U01s). PRINCIPAL INVESTIGATOR - The single individual designated by the awardee institution who is responsible for the scientific and technical direction of the project. The Principal Investigator (PI) provides the scientific leadership for the Participant Member Institution and coordinates the Consortium-required efforts of other investigators from his/her institution. PROJECT COORDINATOR - The person who submits the application for the Operations, Statistics, and Data Management Center and who is responsible for the operational activities of the consortium through his/her role as PI of the Operations, Statistics, and Data Management Center. The Project Coordinator will be expected to have substantial pediatric oncology clinical trials experience. PROTOCOL CHAIRPERSON - The person who is primarily responsible for the development, coordination and monitoring of a specific clinical protocol. PROTOCOL COMMITTEE - The committee composed of the requisite multi-disciplinary expertise that is responsible for development, implementation, and reporting of the individual clinical trials of the PBTCTC. STEERING COMMITTEE - The committee that will be the main oversight body of the PBTCTC. It will be composed of at least the following: Participant Member Institution PIs, representatives from the Operations, Statistics, and Data Management Center (to include the Project Coordinator and a statistical/data management representative), a patient/family representative, and a non-voting representative of each of the brain tumor committees of the pediatric Cooperative Groups. NCI advisory members to the Steering Committee will include the NCI Program Director, the NCI Scientific Coordinator, the NCI Imaging Research Coordinator, the NCI Radiation Oncology Research Coordinator, and the NCI Adult CNS Consortium Scientific Coordinator. STEERING COMMITTEE CHAIRPERSON - A member of the Steering Committee (cannot be the NCI Program Director or the NCI Coordinator) elected by the Steering Committee who will coordinate the activities of the Consortium with the Operations, Statistics, and Data Management Center, and chair the biannual meetings of the Consortium (after the first meeting, which will be convened by the NCI) to be held at the NCI. The chairperson shall prepare and distribute the agendas for each meeting. TUMOR AND TISSUE REPOSITORY - A central resource supported by funds from the Operations, Statistics, and Data Management Center for the storage of tumor specimens and biological fluids from patients entered onto PBTCTC clinical trials for future correlative studies. The location(s) of the repository will be determined by the Steering Committee, and concepts such as "virtual tumor banks" may be employed by the Consortium (provided that there is central decision making concerning use of all stored materials). RESEARCH GOALS AND SCOPE Background In the 1980s, pediatric brain tumors surpassed childhood acute lymphoblastic leukemia as the primary cause of cancer-related deaths among children. During the past 20 years therapeutic advances resulting in improved survival for children with brain tumors have been limited, with 5-year survival rates increasing only slightly from 54% to 60%. Furthermore, for some specific pediatric brain tumor diagnoses (e.g., brain stem gliomas and glioblastoma multiforme) long-term survival rates remain below 20%, and even for those diagnoses for which curative therapy exists, long-term sequelae (especially neuropsychological) are troubling. New clinical research opportunities exist for evaluation in children with brain tumors. These include novel cytotoxic drugs, drug resistance inhibitors, radiation enhancers, radiosurgery techniques, antiangiogenic agents, signal transduction inhibitors, antisense oligonucleotides, differentiating agents, immune modulators, antibody-based approaches, regional delivery techniques, oncolytic viruses, and new approaches to gene therapy. However, timely evaluations of emerging therapeutic and diagnostic technologies for children with brain tumors are difficult because no single institution sees enough children with brain tumors to conduct timely clinical studies of these new therapeutic concepts (implying the need for multi-institutional collaborations). The NIH- supported pediatric Clinical Trials Cooperative Groups are well-positioned to provide definitive evaluations of treatment approaches that use technologies that have been disseminated to both large and small centers. However, evaluations of new agents and innovative treatment approaches for children with brain tumors present challenges that call for exceptional expertise and coordination which are achievable in only a limited number of institutions. For example, new radiation therapy and neurosurgical approaches often require special equipment and skills that are currently not widely available. Additionally, sophisticated neuro- imaging studies are becoming increasingly important in evaluating response to treatment as well as treatment-associated toxicity (e.g., MR spectroscopy to evaluate cellular response to therapy, PET imaging for evaluation of drug distribution and metabolism, PET imaging for evaluation of treatment-associated changes in tumor metabolism, and specialized methods for noninvasive imaging of gene therapy and cellular therapies). An additional complexity for new drug evaluation in children with brain tumors are the interactions among investigational anti-cancer agents and anticonvulsants and/or corticosteroids, since these interactions virtually mandate pharmacokinetic monitoring and dose- finding within the context of phase II studies. Given the above, clinical trial designs of innovative treatment strategies for children with brain tumors should include extensive patient analyses to understand the mechanism of action of agents under investigation and to evaluate patient responses. This RFA will address these challenges to progress in childhood brain tumor clinical research by establishing a consortium of institutions with the requisite multimodality and research expertise to rapidly conduct the initial clinical trials of novel treatment approaches for children with brain tumors, prior to definitive evaluations of these approaches by the pediatric Cooperative Groups. Objectives and Scope The purpose of the proposed awards is to establish a Pediatric Brain Tumor Clinical Trials Consortium for the expeditious evaluation of innovative therapies in children with brain tumors. The NCI is seeking multidisciplinary and multi institutional teams of exceptionally skilled clinical investigators from non- profit and for-profit research organizations who will interact with CTEP in a concerted way to conceive, create, and evaluate new approaches to therapy of pediatric CNS malignancies. It is anticipated that the pilot studies and phase I and II clinical trials conducted by the Consortium will require the specialized abilities of experienced neurosurgeons, neuro-oncologists, radiation oncologists, and neuro-imagers with access to the latest generation of imaging equipment. The novel treatment approaches studied by the Consortium will be selected by the Steering Committee based on research opportunities identified by Consortium investigators. These opportunities may have been developed within institutions participating in the PBTCTC, within the NCI, by other academic investigators, or by the pharmaceutical/ biotechnology sector. Laboratory studies to monitor patients (e.g., pharmacokinetics, pharmacodynamics) or to measure a particular biological response that may provide information relevant to the success or failure of the therapy administered are encouraged. It is anticipated that these studies will be included in the protocols to be created by the PBTCTC. Tissue specimens or biological fluids should be collected by the Participant Member Institutions for use in patient monitoring studies or donation to the PBTCTC Tumor and Tissue Repository for future correlative laboratory studies. The Pediatric Brain Tumor Clinical Trials Consortium will consist of approximately 8 Participant Member Institutions and an Operations, Statistics, and Data Management Center, each funded through separate cooperative agreements (see Definitions). The Consortium will be expected to accrue 80-100 patients per year to 3-4 clinical trials evaluating innovative and technically challenging therapeutic strategies. Thus, each applicant to be a Participant Member Institution must demonstrate the ability to recruit a minimum of 10-12 patients per year with childhood brain tumors to the innovative treatment studies that will be sponsored by the Consortium. In addition, applicants should describe areas of clinical and laboratory expertise resident at their institution that could serve as a basis for the development of clinical protocols by the Consortium. In the period immediately following the award of funds, NCI will sponsor a meeting at which the Principal Investigators of each awarded U01 (Participant Member Institutions and Operations, Statistics, and Data Management Center) and NCI staff will meet to discuss the operational features of the PBTCTC, including development of by-laws, organizational structure, and standard operating procedures (to be based on the proposed procedures and by-laws drafted by the Operations, Statistics, and Data Management Center). The ideas for clinical trials provided in the cooperative agreement applications as well as ideas generated after the formation of the Consortium will be presented, discussed and prioritized. Protocols will then be created, reviewed by the Steering Committee and submitted to the NCI for review and approval to ensure they are within the scope of peer review and for safety considerations, as required by Federal regulations. Such high priority clinical trials will begin after receiving final NCI approval. SPECIAL REQUIREMENTS A. Terms and Conditions of Award The administrative and funding instrument used for this program is a cooperative agreement (U01), an "assistance" mechanism in which substantial NIH scientific and/or programmatic involvement with the awardee is anticipated during performance of the activity. Under the cooperative agreement, the NIH purpose is to support and/or stimulate the recipient's activity by involvement in and otherwise working jointly with the award recipient in a partner role, but it is not to assume direction, prime responsibility, or a dominant role in the activity. Consistent with this concept, the dominant role and prime responsibility for the activity resides with the awardee(s) for the project as a whole, although specific tasks and activities in carrying out the studies will be shared among the awardees and the NCI staff. The role of the NCI staff as described throughout these terms and conditions of award is to facilitate and assist but not to direct research activities. This cooperative agreement is part of a larger program of investigational agent development in the NCI. Each of the NCI staff listed below has very specific and well defined responsibilities in terms of investigational agent development and the role of DCTD as a drug sponsor as defined in CFR 21 part 312. Under the cooperative agreement, a relationship will exist between the recipient of these awards and the NCI, in which the performers of the activities are responsible for the requirements and conditions described below, and agree to accept program assistance from the NCI Program Director and/or the NCI Coordinator in achieving project objectives. Failure of an awardee to meet the performance requirements, including these special terms and conditions of award, or significant changes in the level of performance, may result in a reduction of budget, withholding of support, suspension and/or termination of the award. These Terms and Conditions 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 administration policy statements. B. Awardee Rights and Responsibilities It is the responsibility of the PBTCTC to develop the details of the clinical and laboratory research design, including definition of objectives and approaches, planning, implementation, analysis, and publication of results, interpretations and conclusions of studies. The PBTCTC shall, with CTEP assistance, develop Pilot and Phase I and II protocols for clinical cancer research relating to childhood brain tumors in accord with the research interests, abilities and goals of the PBTCTC, and submit them to CTEP for review as appropriate prior to their implementation. The first responsibility of successful PBTCTC Participant Member Institution Applicants and the successful Operations, Statistics, and Data Management Center applicant will be to participate in a meeting convened by NCI staff to establish by-laws and standard operating procedures for the PBTCTC and to identify the initial clinical trials to be conducted by the PBTCTC. Specific Rights and Responsibilities for the Operations, Statistics, and Data Management Center and for the Participant Member Institutions are separately described below. Operations, Statistics, and Data Management Center Rights and Responsibilities: The PBTCTC Operations, Statistics, and Data Management Center, under the leadership of the Project Coordinator and with CTEP assistance, is responsible for coordinating protocol development, protocol submission, study conduct, quality assurance including quality control and study monitoring, 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 Project Coordinator from the PBTCTC Operations, Statistics, and Data Management Center will assist the Steering Committee Chairperson in seeing that the PBTCTC is able to fulfill its clinical research mission and to meet its administrative and regulatory obligations. Specific responsibilities of the Operations, Statistics, and Data Management Center include: 1. Preparation of an initial proposal for an organizational structure for the Consortium, including a draft charter/by-laws for the Consortium. The organizational structure should include the Scientific Committees that the Consortium will need to support its research objectives (e.g., Neuro-imaging Committee, Neuro-oncology Committee, Neuro-pathology Committee, Neurosurgical Committee, Radiation Oncology Committee). Following the development or modification of the proposed organizational structure and Consortium by-laws for the PBTCTC and its ratification at the initial meeting of the Steering Committee, the Operations, Statistics, and Data Management Center will be responsible for maintaining these and for submitting approved amendments/revisions to NCI and to PBTCTC Participant Member Institutions. 2. Establishment of procedures for submission of PBTCTC protocols to the CTEP Protocol and Information Office in a timely fashion for review and approval by NCI. Protocols involving NCI sponsored agents should be preceded by a written Letter of Intent (LOI) from the PBTCTC to the CTEP LOI Coordinator declaring interest in conducting a particular study. The LOI shall describe the hypothesis to be investigated, the general design of the contemplated trial plus relevant information on accrual capabilities to document feasibility. Protocols will be developed and submitted and studies will be conducted in accordance with the DCTD "Investigator's Handbook" (available upon request from the Program Director at the address below or available at the CTEP Web page at the following URL: http://ctep.info.nih.gov/handbook/index.html). The Operations, Statistics, and Data Management Center staff will communicate the results of the NCI review of protocols to the PBTCTC Participant Member Institutions and to relevant PBTCTC Committees. The PBTCTC will not expend NCI funds to conduct any study disapproved by CTEP unless CTEP's disapproval has been modified by the arbitration process outlined below. 3. Establishment of mechanisms for study monitoring. The PBTCTC is responsible for assuring accurate and timely knowledge of the progress of each study through: a) establishing procedures for assigning dose level (for phase I/dose escalation studies) at the time a new patient is entered, and assuring that the required observation period has elapsed before beginning a higher dose level; b) registration, tracking and reporting of patient accrual and adherence to defined accrual goals; appropriate attempts to accrue patients who fulfill NIH Guidelines for accrual of women and minorities to clinical trials with appropriate documentation and reporting of accrual as specified by NIH Guidelines; c) ongoing assessment of case eligibility and evaluability; d) timely medical review and assessment of patient data; e) rapid reporting of treatment-related morbidity (adverse drug reactions) and measures to ensure communication of this information to all parties; f) interim evaluation and consideration of measures of outcome, as consistent with patient safety and good clinical trials practice for pilot and phase I and II studies; 4. Establishment of mechanisms for quality assurance and quality control of therapeutic and diagnostic modalities employed in PBTCTC trials. Quality control at a minimum must consist of: a) Pathology: Verification of pathologic diagnosis in cases where known variability in the accuracy of histologic diagnosis is a potentially serious problem and where pathology data may provide important prognostic information. b) Radiation Therapy: Review (either concurrent or retrospective) of port films and compliance with protocol-specified doses for individual patients, where relevant. Determination of adequacy of radiation delivery with the assistance of the Radiological Physics Center (RPC), whose functions usually include equipment dosimetry, periodic institutional visits and other aspects of physics review. c) Chemotherapy: Review of submitted data with determination of protocol compliance in dose administration and dosage modification. d) Neurosurgery: Assessment of adequacy of protocol-specified surgical procedures where relevant (e.g., through review of operative notes and study- specific surgical forms). e) Diagnostic Imaging: Central review of claimed responses and adequacy of imaging. During the 5-year award period, a program for electronic submission, storage, and review of imaging studies should be developed and implemented by the Operations, Statistics, and Data Management Center. e) On-site Auditing: Establishment of an on-site monitoring program utilizing the NCI audit guidelines as a model which assures that a sampling of records at each Consortium institution participating in the clinical trials is audited at least once during each 3 year period. The on-site audit will address issues of data verification, protocol compliance, compliance with regulatory requirements for the protection of human subjects and investigational agent accountability. Any serious problems with data verification or compliance with Federal regulations must be reported to the NCI Program Director immediately. Otherwise, written reports must be submitted within four weeks of each audit to the NCI Program Director. Audit schedules are to be provided to the NCI Program Director annually in the non-competing continuation (Type 5) applications. 5. Establishment of procedures to ensure that data collection and management are: (i) adequate for quality control and analysis; (ii) as simple as appropriate in order to encourage maximum participation of physicians entering patients and to avoid unnecessary expense; and (iii) coordinated across the participating institutions. Clinical trials data should be submitted electronically, where feasible. 6. Establishment of procedures for the effective interaction of the statistical expertise of the Operations, Statistics, and Data Management Center with Study Committee investigators such that appropriate Statistical plans for PBTCTC pilot and phase I and II studies are developed. 7. Establishment of procedures for assuring that PBTCTC investigators performing trials involving DCTD Investigational Agents are NCI-registered investigators (Form 1572) and for assuring that the PBTCTC is in compliance with CTEP requirements described in the DCTD Investigators' Handbook for storage and accounting for investigational agents {including NCI/HHS Drug Accountability Records (DAR) procedures}, and is in compliance with FDA requirements for investigational agents. 8. Establishment of procedures to meet the Office for Protection from Research Risks (OPRR) requirements for the protection of human subjects. These include methods for assuring that each institution at which investigators are conducting Consortium trials has a current, approved assurance on file with the OPRR; that each protocol is reviewed by the responsible Institutional Review Board (IRB) prior to patient entry; that each protocol is reviewed annually by the IRB so long as the protocol is active; and that each patient (or legal representative) gives written informed consent prior to entry on study. These should be reviewed at the time of each audit. 9. Establishment of a system for assuring timely reporting of all serious and unexpected toxicities to the Investigational Drug Branch (IDB), CTEP according to CTEP guidelines (mailed annually to all registered investigators). This requires reporting Adverse Event Reactions (AERs) by telephone to the IDB Drug Monitor within 24 hours of the event and requires a written report to follow within 10 working days. 10. Maintaining and managing the Discretionary Fund including dispensing the funds for Steering Committee and NCI approved laboratory studies accompanying clinical protocols. 11. Managing and coordinating the acquisition and shipping of protocol-specified tumor specimens and biological fluids (with relevant clinical data) to the appropriate laboratories for testing. 12. Managing and coordinating the PBTCTC Tumor and Tissue Repository for storing specimens for future correlative laboratory studies approved by the Steering Committee. 13. Maintaining and managing the Patient Studies Research Fund to support special clinical research costs for patients accrued onto Consortium clinical trials. Funds will be disbursed on a capitation basis. It is anticipated that for each Consortium protocol, the capitation formula for institutional reimbursement required to offset specific research expenses will be developed by the Steering Committee. The capitation formula will be subject to NCI review and approval prior to implementation. 14. Establishment of policies and procedures, in collaboration with the PBTCTC Steering Committee and NCI program staff, for assessing performance of PBTCTC member institutions, with particular attention to accrual of adequate number of eligible patients onto consortium trials, timely submission of required data, conscientious observance of protocol requirements, study development and leadership, authorship and participation in group leadership. This mechanism will include a procedure for recommending to NCI Program staff an adjustment of institutional funds within the consortium as appropriate for the level of participation in consortium activities, including (but not limited to) accrual. 15. Submitting annual progress reports to the NCI that will describe activities and accomplishments during the previous year of the Consortium in general and of the Operations, Statistics, and Data Management Center. The report should include summary data on protocol performance by each Consortium member as well as plans and proposed budget for the coming year. 16. Establishment of procedures for the timely publication of major findings. Publication or oral presentation of work done under this agreement will require appropriate acknowledgment of NCI support. The NCI will have access to all data generated under this cooperative agreement and may periodically review the data. The awardee will retain custody and primary rights to the data consistent with current HHS, PHS and NIH policies. 17. Working with the Steering Committee Chairperson to organize biannual meetings of the consortium to review PBTCTC progress, establish priorities, and plan future activities. Relevant responsibilities include: (i) arranging for appropriate meeting space and accommodations for Consortium attendees; (ii) developing and distributing meeting agendas; and (iii) preparing summaries after each meeting to be sent to Consortium members and NCI program staff. Additional meetings between NCI staff and the Project Coordinator and Steering Committee Chairperson (and other PBTCTC members as appropriate) will be held if necessary. 18. Establishment of procedures for routine electronic communication between the Operations, Statistics, and Data Management Center and PBTCTC members at Participant Member Institutions to facilitate protocol development and study monitoring and to facilitate the work of the various discipline Committees of the PBTCTC. 19. Serving as the liaison between the NCI program staff and the Participant Member Institutions. Participant Member Institutions Rights and Responsibilities Include: 1. Participating in the Pediatric Brain Tumor Clinical Trials Consortium, as evidenced by participating in research design and protocol development, participating in the scientific Committees of the Consortium, accruing eligible patients to PBTCTC studies, and by following and implementing the operating procedures of the Consortium. 2. Serving as Protocol Chairs. For each specific clinical protocol, a single Protocol Chairperson from a Participant Member Institution will be selected to function as the scientific coordinator for that protocol. He/she will assume responsibility for the development of the protocol and for monitoring the protocol during the actual performance of the clinical trial in accordance with PBTCTC policies and procedures. 3. Service on the Scientific Committees for the various disciplines that the PBTCTC will need to support its research objectives (e.g., Neuro-imaging Committee, Neuro-oncology Committee, Neuro-pathology Committee, Neurosurgical Committee, Radiation Oncology Committee). 4. Implementing the core data collection method and strategy collectively developed by the PBTCTC Steering Committee. It is the responsibility of each Participant Member Institution to ensure that protocol-specified data are submitted in a timely manner to the Operations, Statistics, and Data Management Center. Clinical trials data will be submitted electronically, where feasible. 5. Complying with mechanisms for quality assurance and quality control of therapeutic and diagnostic modalities employed in PBTCTC trials. Institutional responsibilities for quality control include, but are not limited to, the following: a) Pathology: Submission of appropriate materials to allow verification of pathologic diagnosis, when relevant. b) Radiation Therapy: Submission of appropriate materials to allow review (either concurrent or retrospective) of port films and compliance with protocol- specified doses for individual patients, when relevant. c) Chemotherapy: Submission of appropriate data to allow determination of protocol compliance in dose administration and dosage modification. d) Neurosurgery: Submission of appropriate information to allow review of protocol-specified neurosurgical procedures. e) Diagnostic Imaging: Submission of appropriate imaging studies to allow central review of claimed responses and adequacy of imaging. During the 5-year award period, a program for electronic submission, storage, and review of imaging studies should be developed by the Operations, Statistics, and Data Management Center and implemented within each Participant Member Institution. e) On-site Auditing: Participation in the on-site monitoring program established by the Operations, Statistics, and Data Management Center which assures that a sampling of records at each Consortium institution participating in the clinical trials is audited at least once during each 3 year period. 6. Implementing the procedures established by the Operations, Statistics, and Data Management Center for assuring that PBTCTC investigators performing trials involving DCTD Investigational Agents are NCI registered investigators (Form 1572) and for assuring that the PBTCTC is in compliance with CTEP requirements described in the DCTD Investigators' Handbook for storage and accounting for investigational agents (including NCI/HHS Drug Accountability Records (DAR) procedures), and is in compliance with FDA requirements for investigational agents. 7. Implementing the procedures established by the Operations, Statistics, and Data Management Center to meet the Office for Protection from Research Risks (OPRR) requirements for the protection of human subjects. These include methods for assuring that each institution at which investigators are conducting Consortium trials has a current, approved assurance on file with the OPRR; that each protocol is reviewed by the responsible Institutional Review Board (IRB) prior to patient entry; that each protocol is reviewed annually by the IRB so long as the protocol is active; and that each patient (or legal representative) gives written informed consent prior to entry on study. 8. Implementing the procedures established by the Operations, Statistics, and Data Management Center for assuring timely reporting of all serious and unexpected toxicities to the Investigational Drug Branch (IDB), CTEP. 9. Acquisition and submission of protocol-specified tumor specimens, biological fluids and relevant clinical data to the appropriate laboratories where these specimens will be tested or stored for future studies. When additional tumor specimens or biological fluids are available, research specimens should be maintained in the PBTCTC Tumor and Tissue Repository for future correlative studies. 10. Serving as a resource for the conduct of protocol-specified laboratory projects (e.g., pharmacokinetic studies, tumor biology studies). The PBTCTC Steering Committee will establish a process for the selection of the laboratories to perform these studies. These projects may be supported using the Discretionary Funds of the Operations, Statistics, and Data Management Center or by independent funding. 11. Participating in PBTCTC procedures for the timely publication of major findings. Publication or oral presentation of work done under this agreement will require appropriate acknowledgment of NCI support. The NCI will have access to all data generated under this cooperative agreement and may periodically review the data. The awardee will retain custody and primary rights to the data consistent with current HHS, PHS and NIH policies. 12. Appropriately participating in the biannual meetings of the PBTCTC (and in other meetings as deemed necessary for performance of PBTCTC activities). 13. Appropriately using Discretionary Funds awarded by the Operations, Statistics, and Data Management Center to conduct laboratory studies accompanying PBTCTC clinical protocols. 14. Submitting an annual progress report to the NCI that describe activities and accomplishments during the previous year, and that includes plans and proposed budget for the coming year. C. NCI Staff Responsibilities It is expected that the dominant role and prime responsibility for the activity will reside with the awardee(s) for the project as a whole, although specific tasks and activities in carrying out the studies will be shared among the awardees and the NCI Program Director and NCI Scientific Coordinator. The NCI Program Director and Scientific Coordinator will be the main NCI contacts for all facets of the scientific interaction with the awardees and will provide advice to the awardee on specific scientific and/or analytic issues in addition to programmatic issues. NCI Program Staff Responsibilities will include: 1. Convening a meeting after awards are made at which the Principal Investigators of each awarded U01 (Participant Member Institutions and Operations, Statistics, and Data Management Center) and NCI staff will meet to discuss the operational features of the PBTCTC. At this meeting, the Chair of the Steering Committee will be selected, and a process will be identified for rapid establishment of PBTCTC by-laws and standard operating procedures (based on the proposed procedures and by-laws drafted by the Operations, Statistics, and Data Management Center). At this meeting, the initial clinical trials for PBTCTC evaluation will be identified as well. 2. Interacting with the Participant Member Institutions and Operations, Statistics, and Data Management Center on a regular basis to monitor Consortium progress. Monitoring may include: regular communications with the PIs and staff, periodic site visits for discussions with awardee research teams, response audits to confirm activity reported from a PBTCTC clinical trial, observation of field data collection and management techniques, fiscal review, and attendance at PBTCTC meetings. The NCI retains, as an option, periodic external review of progress. 3. Serving as a resource with respect to other ongoing NCI activities that may be relevant to the PBTCTC research efforts to identify promising new leads, to facilitate compatibility with other NCI research projects, and to avoid unnecessary duplication of effort. 4. CTEP Assistance in Protocol Development: The protocol must be a detailed written plan of a clinical experiment mutually acceptable to the PBTCTC and to the CTEP Protocol Review Committee (PRC). Communication at the various stages of protocol development is encouraged as necessary to promote protocol development and implementation. It is recommended that protocols utilizing NCI- sponsored agents be preceded by a written Letter of Intent (LOI) from the PBTCTC declaring interest in conducting a particular study. The PRC will formally review the LOI. Following review, the NCI Scientific Coordinator will provide a Program response to the PBTCTC and will address the following issues: (a) the existence and nature of concurrent clinical trials in the area of research, pointing out possible duplication of effort; (b) information including relevant pharmacokinetic and pharmacodynamic data concerning investigational agents; (c) availability of investigational agents; (d) the PRC's assessment of the scientific rationale and value of the proposed study, its design, and statistical requirements; and (e) the implementation of the study, if indicated. The LOI mechanism is designed for preliminary review and is recommended to expedite protocol development and implementation and to facilitate agreement on study priority and design (for further discussion of these mechanisms see the DCTD Investigator's Handbook, pp 32-35: available on request from the NCI Program Director at the address below, or available at the CTEP Web page at the following URL: http://ctep.info.nih.gov/handbook/index.html). 5. CTEP Review of Proposed Protocols: All PBTCTC protocols, including protocols utilizing agents not sponsored by NCI, will be reviewed by the PRC, which meets weekly and is chaired by the Associate Director, CTEP. Ad hoc reviewers, external to NCI, will be utilized when deemed appropriate by the PRC chairperson. Following the review of the protocol by the PRC, the NCI Scientific Coordinator will provide the PBTCTC with a consensus review that describes recommended modifications and other suggestions, as appropriate (see the DCTD Investigator's Handbook, for further information regarding protocol review at CTEP). The major considerations relevant to Protocol Review by CTEP include: (a) the strength of the scientific rationale supporting the study; (b) the medical importance of the question being posed; (c) the avoidance of unnecessary duplication with other ongoing studies; (d) the appropriateness of study design; (e) consistency with development plans for particular IND agents; (f) a satisfactory projected accrual rate and follow-up period; (g) patient safety; (h) compliance with federal regulatory requirements; (i) adequacy of data management; (j) appropriateness of patient selection, evaluation, assessment of toxicity, response to therapy and follow-up; and (k) method of monitoring and reporting to NCI to be used. If a proposed protocol is disapproved, the specific reasons for lack of approval will be communicated in writing by the NCI Scientific Coordinator to the PBTCTC as a consensus review within 30 days of protocol receipt by the NCI. NCI will not provide investigational drugs or permit expenditure of NCI funds for a protocol that it has not approved. The NCI Scientific Coordinator will be available to assist the PBTCTC in developing a mutually acceptable protocol, consistent with the research interests, abilities and strategic plans of the PBTCTC and of the NCI. 6. CTEP Involvement in Imaging Research: The NCI Imaging Research Coordinator will advise the PBTCTC Steering Committee and the NCI Scientific Coordinator with respect to ongoing NCI activities and research opportunities related to the imaging of pediatric brain tumors. He/she will participate in CTEP review of PBTCTC protocols with imaging components and will assist the NCI Science Coordinator in the overall review of PBTCTC imaging research activities and accomplishments. 7. CTEP Involvement in Radiation Oncology Research: The NCI Radiation Oncology Research Coordinator will advise the PBTCTC Steering Committee and the NCI Scientific Coordinator with respect to ongoing NCI activities and research opportunities related to radiation therapy for childhood brain tumors. He/she will participate in CTEP review of PBTCTC protocols with radiation therapy components and will assist the NCI Science Coordinator in the overall review of PBTCTC radiation oncology research activities and accomplishments. 8. CTEP Involvement in Protocol Closure: Protocol closure is primarily the responsibility of the PBTCTC and the specific Protocol Committee. The NCI Program Director and Scientific Coordinator will also monitor protocol progress and may request protocol closure to further patient accrual for the following reasons: (a) insufficient accrual rate; (b) accrual goal met; (c) poor protocol performance; (d) patient safety or regulatory concerns; (e) study results are already conclusive; and (f) emergence of new information that diminishes the scientific importance of the study question. NCI will not provide investigational agents or permit expenditures of NCI funds for a study after requesting closure (except for patients already on-study). 9. PBTCTC meetings: The NCI Scientific Coordinator, Program Director, Imaging Research Coordinator, and Radiation Oncology Research Coordinator will attend biannual PBTCTC meetings to discuss relevant scientific information, to discuss progress in the clinical trials, and to discuss the status of newly available investigational agents and other research opportunities in order to plan future activities. 10. CTEP involvement in Investigational New Drug Applications: a. The NCI will be willing to consider filing or cross-filing an IND for investigational drugs evaluated in the Pilot and Phase I and II Clinical Trials. This would apply to drugs not developed in the NCI drug development program. b. The NCI Program Director assisted by the Chief, Regulatory Affairs Branch (RAB), CTEP will advise investigators of specific requirements and changes in requirements concerning IND sponsorship that the FDA may mandate. Investigators performing trials under cooperative agreements will be expected, in cooperation with the NCI, to comply with all FDA monitoring and reporting requirements for investigational agents. c. Investigators performing NCI funded Pilot and Phase I and II Clinical Trials will be advised by the NCI Scientific Coordinator and Program Director of potential studies that will be relevant to new avenues of cancer therapy. When this involves investigational agents, the NCI Scientific Coordinator assisted by the Chief, RAB, CTEP will advise the investigators of the specific clinical information that will be needed from the clinical trials for that information to be acceptable to the FDA for inclusion in a new drug application (NDA). 11. CTEP Review of Federally Mandated Regulatory Requirements: The Chief, Clinical Trials Monitoring Branch (CTMB), through the NCI Scientific Coordinator, will advise the PBTCTC regarding mechanisms to meet FDA regulatory requirements for studies involving DCTD-sponsored investigational agents and the Office for Protection from Research Risks (OPRR) requirements for the protection of human subjects by PBTCTC institutions. (See AWARDEE RIGHTS AND RESPONSIBILITIES, above). For specific Pilot and Phase I and II trials with NCI-sponsored investigational agents selected by the CTEP Protocol Review Committee, the NCI has contracted for a Clinical Trials Monitoring Service (CTMS) to document regulatory compliance, to maintain a computerized data base and to produce periodic routine reports of the results, and special reports as necessary. 12. Access to Data: The NCI will have access to all data generated under this cooperative agreement and may periodically review the data. Data must also be available for external monitoring as required by NCI's Drug Master File Agreement with the FDA relative to the responsibility of the NCI as an IND agent sponsor. Data from studies of non-NCI-sponsored agents must be available for external monitoring as described in the policies and procedures established by the PBTCTC for on-site auditing of clinical trials data. The awardee (and industry sponsor, if any) will retain custody and primary rights to the data consistent with current HHS, PHS and NIH policies. 13. CTEP Review of Progress: Performance of each PBTCTC will be reviewed at least annually by the NCI Program Director and Scientific Coordinator on the basis of the information provided at the semi-annual and other meetings, in the annual progress reports and in the data summary reports submitted to the IDB Drug Monitor or by CTMS reports. In addition, periodic accrual information may be requested from the PBTCTC by the NCI Scientific Coordinator for all active studies when deemed appropriate. Insufficient patient accrual or progress, or noncompliance with the terms of award, including these Terms and Conditions of Award, may result in a reduction of budget, withholding of support, suspension or termination of the award. D. Collaborative Responsibilities 1. Service on the Steering Committee: The Steering Committee will be composed of at least the following: Participant Member Institution PIs, representatives from the Operations, Statistics, and Data Management Center (to include the Project Coordinator and a statistical/data management representative), the NCI Program Director and NCI Coordinator, a patient/family representative, and a non- voting representative of each of the brain tumor committees of the pediatric Cooperative Groups. The Steering Committee is responsible for the development and approval of the PBTCTC organizational structure and Consortium by-laws. The Steering Committee will have primary responsibility to design research activities, to establish priorities, and to develop and provide preliminary approval of protocols (prior to submission to NCI and final NCI approval), and to review progress. The Steering Committee will also establish a process for the selection of the laboratories to perform protocol-associated laboratory studies and will authorize the spending of funds from the Discretionary Fund and the Patient Studies Research Fund. The Chairperson of the Steering Committee will be selected from among the Principal Investigators of the Participant Member Institutions at their initial meeting. The Steering Committee Chairperson will assist the Operations, Statistics, and Data Management Center in coordinating Steering Committee activities, including preparing for PBTCTC meetings, documenting actions taken and progress in written reports to the NCI Program Director, and providing periodic supplementary reports to designated NCI staff upon request. E. Arbitration Any disagreement that may arise on scientific/programmatic matters (within the scope of the award), excluding patient safety issues or regulatory compliance, between award recipients and the NCI may be brought to arbitration. An arbitration panel composed of one awardee nominee, one NCI nominee, and a third member with clinical trials expertise chosen by the other two nominees will be formed to review the CTEP decision and recommend an appropriate course of action to the Director, DCTD. The arbitration procedures in no way affect the awardee's right to appeal an adverse determination under the terms of 42 CFR Part 50, Subpart D, and 45 CFR Part 16. 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 subpopulations must be included in all NIH supported biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification is provided 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 4928 of Public Law 103-43). All investigators proposing research involving human subjects should read the "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research," which have been published in the Federal Register of March 28, 1994 (FR 59 14508-14513) and in the NIH guide for Grants and Contracts, Volume 23, Number 11, March 18, 1994. Investigators also may obtain copies of the policy 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 May 1, 1998, 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. The letter of intent should indicate if an application is planned for the Operations, Statistics, and Data Management Center or is planned for a Participant Member Institution. Although a letter of intent is not required, is not binding, and does not enter into the review of subsequent applications, the information is helpful in planning for the review of applications. It allows NCI staff to estimate the potential review workload and to avoid conflict of interest in the review. The letter of intent is to be sent to: Ms. Diane Bronzert Division of Cancer Treatment and Diagnosis National Cancer Institute 6130 Executive Boulevard, Room 734, MSC 7432 Bethesda, MD 20892-7432 Rockville, MD 20852 (for express/courier service) Telephone: (301) 496-8866 FAX: (301) 480-4663 Email: BRONZERTD@CTEP.NCI.NIH.GOV APPLICATION PROCEDURES The research grant application form PHS 398 (rev. 5/95) is to be used in applying for these cooperative agreements. These forms are available at most institutional offices of sponsored research and 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, email: asknih@od.nih.gov. Line 2 of the application where the RFA is identified must indicate if an application is for the Operations, Statistics, and Data Management Center or is for a Participant Member Institution. Because the Terms and Conditions of Award discussed above will be included in all awards issued as a result of this RFA, it is critical that each applicant include specific plans for responding to these terms. Plans must describe how the applicant will comply with staff involvement. PBTCTC Operations, Statistics, and Data Management Center applicants must demonstrate in their applications the ability to meet the RESEARCH OBJECTIVES of the RFA. For the PBTCTC Operations, Statistics, and Data Management Center, the Research Plan (Items a-d, PHS 398 form) should not exceed 50 pages. To promote the development of a collaborative program among the award recipients and to assure that issues related to the RESEARCH OBJECTIVES of the RFA are adequately considered, a number of issues need to be addressed in their applications as discussed below. Applicants for the PBTCTC Operations, Statistics, and Data Management Center should describe: 1. the qualifications and pediatric oncology clinical research experience of the Project Coordinator, and the qualifications and experience of other key personnel. Previous experience with the design and administration of multi- institutional clinical trials with extensive data collection requirements should be described. 2. their ability to support the design and conduct of clinical trials for children with cancer, with emphasis on clinical trials for patients with brain tumors (including documentation of previous experience), including the following: A. their plans for coordinating protocol development in a timely manner. B. their plans for data collection and management, including a description of facilities and data management resources and personnel. Electronic submission of clinical trials data will be expected for Consortium studies, and plans for electronic data submission should be detailed. C. their statistical approach for pilot and phase I and II clinical trials for children with brain tumors, and for correlating research studies with treatment outcomes in clinical trials. D. their experience with and plans for multi-institutional study monitoring and for interactions with the Protocol Chair during the period that the studies are being conducted. E. their experience with and plans for quality assurance and quality control, including: pathology, neurosurgery, radiation therapy, chemotherapy delivery, neuro-imaging, and plans for on-site monitoring. Specifically concerning neuro- imaging, applicants should describe their capabilities and plans for central collection and review of neuro-imaging studies, including plans for electronic submission and storage of neuro-imaging studies during the five year funding period. F. their experience with and plans for compliance with regulatory requirements, including: (i) reporting of adverse drug reports for clinical trials involving investigational agents; (ii) establishment of procedures to meet the Office for Protection from Research Risks (OPRR) requirements for the protection of human subjects; (iii) and assuring that PBTCTC investigators performing trials involving DCTD Investigational Agents are NCI registered investigators (Form 1572) and for assuring that the PBTCTC is in compliance with CTEP requirements described in the DCTD Investigators' Handbook for storage and accounting for investigational agents {including NCI/HHS Drug Accountability Records (DAR) procedures}. G. their plans for assuring rapid publication of data obtained in PBTCTC clinical trials and laboratory studies. H. their experience with and plans for administering correlative laboratory studies, including: (i) coordinating the acquisition and shipping of protocol- specified tumor specimens, biological fluids and relevant clinical data to the appropriate laboratories; (ii) maintaining effective collaboration between laboratory and clinical investigators and the Operations, Statistics, and Data Management Center within the consortium; and (iii) evaluating and analyzing laboratory data with respect to treatment delivered or treatment outcome. 3. their ability for fiscal management of the Discretionary Fund and the Patient Studies Research Fund. 4. their plans for effective interaction and communication among Participant Member Institutions within the consortium, with the pediatric Cooperative Groups, and with the NCI (including plans for PBTCTC meetings and for effective electronic communication between meetings). 5. their plans for an organizational structure for the Consortium, including a draft charter/by-laws (to be included in the Appendix of the application) for the Consortium. The organizational structure should include a description of the mechanisms by which appropriate input will be obtained from representatives of the various disciplines that the Consortium will need to support its research objectives (e.g., Neuro-imaging, Neuro-oncology, Neuro-pathology, Neurosurgery, Radiation Oncology, etc.). The Operations, Statistics, and Data Management Center budget should include the following: o Costs for protocol development and implementation (including required personnel). o Costs for data collection and management (including required personnel). o Costs for statistical support and analysis. o Patient Studies Research Funds (approximately $400,000 total costs) to be dispersed to support institutional research costs, including: (i) collection and shipping of tissue specimens; (ii) performance of special neuro-imaging research studies; (iii) additional patient accrual and data monitoring; and (iv) other protocol-specified laboratory tests to be performed at accruing institutions. o Costs for quality assurance, including: pathology review, radiation therapy review, neurosurgical review, neuro-imaging review (using electronic submission and storage of protocol-mandated neuro-imaging studies), and on-site auditing. o Travel funds for 2-3 representatives from the Operations, Statistics, and Data Management Center to attend the biannual PBTCTC meetings. o Travel funds for the Steering Committee patient/family representative and the Cooperative Group representatives to attend the biannual PBTCTC meetings (6 trips total). o A Discretionary Fund (approximately $150,000 total costs) for laboratory studies including correlative molecular studies on tumor specimens and pharmacokinetic evaluations. PBTCTC Participant Member Institution applicants must demonstrate in their applications the ability to meet the RESEARCH OBJECTIVES of the RFA. To promote the development of a collaborative program among the award recipients and to assure that issues related to the RESEARCH OBJECTIVES of the RFA are adequately considered, a number of issues need to be addressed in their applications as discussed below. 1. Applicants should describe the clinical and/or basic research experience, training, time availability, research competence, and commitment to PBTCTC participation of the PI and investigators in the following disciplines: A. pediatric neuro-oncology; B. radiation oncology; C. neurosurgery; D. neuro-imaging; and E. neuropathology, as evidenced by past clinical research contributions and current research efforts relating to childhood (and/or adult) brain tumors. Relating to the above disciplines, applicants should also address the following topics: A. plans for institutional neuropathology support for tumor classification and for banking and distribution of patient specimens for concurrent and future studies. Ability to collect and ship patient specimens (e.g, tumor and biological fluids) to other members of the PBTCTC for the conduct of protocol- mandated tests or to a central tumor repository under the guidelines established by the PBTCTC should be described. Institutional neuropathology research projects relevant to childhood brain tumors should be described. B. the institutional availability of state-of-the-art imaging such as MRI, functional MRI, MRS, SPECT, and PET and the institutional commitment for utilizing these methodologies in the conduct of PBTCTC studies when such imaging studies are required. Institutional imaging research projects relevant to childhood brain tumors should be described. C. the institutional availability of state-of-the-art radiotherapy (e.g., for delivery of stereotactic radiotherapy and brachytherapy) and the institutional commitment to utilize these techniques in the conduct of PBTCTC studies when required. Institutional radiotherapy research projects relevant to childhood brain tumors should be described. D. the institutional availability of state-of-the-art neurosurgical facilities and expertise, and the institutional commitment to utilize these in the conduct of PBTCTC studies when required. Institutional neurosurgery research projects relevant to childhood brain tumors should be described. 2. Patient Accrual: o Applicants should document their ability to recruit a minimum of 10-12 evaluable patients per year with brain tumors who would be candidates for pilot and phase I and II clinical trials. Recent institutional accrual of children with brain tumors to pilot and phase I and II clinical trials should be provided. o Applicants should state their commitment to enter eligible patients onto clinical trials being performed through the Consortium and acknowledge that these clinical trials have the highest priority. Applicants should describe their plans to prioritize patients with brain tumors between Consortium studies and other trials. 3. Applicants should document their ability to meet the data collection and regulatory requirements necessary for clinical research for children with brain tumors, including: o institutional data management resources and plans for utilizing these resources for the conduct of PBTCTC clinical trials. Specific documentation of their institutions's ability to comply with electronic submission of clinical trials data should be included. o provisions for the protection of human subjects. o plans for inclusion of females and minorities. o drug control procedures as required for utilization of NCI-supplied experimental agents. 4. Applicants should describe the clinical and laboratory areas of scientific expertise resident at their institution that are applicable to innovative therapies for pediatric brain tumors, discuss and document the expertise (funded grants, publications, etc.), and describe the unique research contributions that the applicant would bring to the Consortium. Applicants should indicate in which of these research areas they would be willing to either lead Consortium clinical studies or would be willing to conduct correlative studies (e.g., pharmacokinetic and pharmacodynamic monitoring or imaging research studies) for Consortium protocols. 5. Applicants should describe the availability of appropriate facilities and equipment including clinical, computer and data management, laboratory facilities, and facilities for processing patient specimens for PBTCTC laboratory studies and for the PBTCTC Tumor and Tissue Repository. Note: Applicants from institutions that have a General Clinical Research Center (GCRC) funded by the NIH National Center for Research Resources may wish to identify the GCRC as a resource for conducting the proposed research. If so, a letter of agreement from either the GCRC Program Director or Principal Investigator must be included with the application. 6. Applicants should include as an Appendix a description of a clinical research project congruent with the Research Objectives of the RFA and based upon expertise and research findings from their institution. The description should be limited to no more than 5 pages, and the CTEP Letter of Intent format should be used. This format is described in Appendix VII of the DCTD "Investigator's Handbook" (available upon request from the Program Director at the address below or available at the CTEP Web page at the following URL: http://ctep.info.nih.gov/handbook/index.html). All costs required for these studies must be included in the applications and must be fully justified. These costs include the additional costs of clinical research associated with Pilot and Phase I and Phase II studies including costs for patient accrual, sample handling, laboratory studies, quality assurance, data management and data analysis, study monitoring, and travel. Each Participant Member Institution budget should include the following: o Support for personnel from the requisite participating subspeciality areas (Neuro-imaging, Neuro-oncology, Neuro-pathology, Neurosurgery, and Radiation Oncology). o Support for institutional data management activities. o Support for travel to the PBTCTC biannual meeting (approximately eight individual trips per year to be divided between the two PBTCTC biannual meetings). It is likely that one meeting each year will include representatives of multiple disciplines from each Participant Member Institution, while the other meeting will be restricted to 1 or 2 attendees from each Participant Member Institution. The RFA label available in the application form PHS 398 must be affixed to the bottom of the face page. 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 number and title must be typed on line 2a of the face page of the application form and the YES box must be marked. The Social Security Number (SSN) of the Principal Investigator should be provided along with the applicant's name at the top of the Personal Data form page only (PHS Form 398, page KK). The SSN should not be listed on the face page of the application, nor provided elsewhere in the application, e.g., top of each application page. When submitting competing renewal applications using the PHS 398 grant application kit, do not complete or submit the Personnel Report form page (JJ). This form page will be requested, if necessary, at the time of award. Submit a signed, typewritten original of the application, including the Checklist, and three signed, exact 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 also be sent to: Ms. Toby Friedberg Division of Extramural Activities National Cancer Institute 6130 Executive Boulevard, Room 636, MSC 7401 Bethesda, MD 20892 Rockville, MD 20852 (for express/courier service) Applications must be received by July 10, 1998. If an application is received after that date, it will be returned. 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 follow the guidance in the PHS 398 application instructions for the preparation of revised applications, including an introduction addressing the previous critique. REVIEW CONSIDERATIONS All applications will be judged on the basis of the documented ability of the investigators to meet the RESEARCH OBJECTIVES of the RFA as listed under Review Criteria. A. Review Procedures Upon receipt, applications will be reviewed for completeness by CSR and responsiveness by the NCI. Incomplete applications will be returned to the applicant without further consideration. Applications that are judged non- responsive will be returned by the NCI. Applications will be reviewed by an NCI peer review group on the basis of relative competitiveness. The NCI will withdraw from further competition those applications judged to be noncompetitive for award and notify the applicant and institutional business official. Those applications judged to be both competitive and responsive will be further evaluated, using the review criteria stated below, for scientific and technical merit by an appropriate peer review group convened by the Division of Extramural Activities, NCI. The second level of review will be provided by the National Cancer Advisory Board. B. Review Criteria Applications for the Operations, Statistics, and Data Management Center will be reviewed on the basis of the following criteria: o Qualifications and research experience of the Project Coordinator and the key personnel including, but not limited to, previous experience with design and administration of multi-institutional clinical trials (particularly for children with cancer) with extensive data collection requirements. o Adequacy of plans for the timely development and implementation of multi- institutional clinical trials for children with brain tumors. o Adequacy of the available facilities and data management and statistical resources and personnel. o Evidence of competence with regard to clinical trials administration, to include: experimental design and statistical analysis; quality assurance and quality control; study monitoring; data collection and management (including plans for electronic submission of clinical trials data); and compliance with regulatory requirements. Specifically concerning neuro-imaging, the adequacy of plans for central collection and review of neuro-imaging studies using electronic submission and storage. o Evidence of competence with regard to fiscal administration for distribution and management of funds involving multi-site studies. o Adequacy of experience with and plans for administering correlative laboratory studies, including coordination of the acquisition and shipping specimens, maintenance of effective collaboration between laboratory and clinical investigators and the Operations, Statistics, and Data Management Center within the consortium, evaluation and analysis of laboratory data with respect to treatment delivered or treatment outcome. o Adequacy of plans for effective communication and coordination between the Participant Member Institutions and the Operations, Statistics and Data Management Center and with the NCI. o Plans for the organizational structure of the Consortium, including its draft charter/by-laws. Applications for Participant Member Institutions will be reviewed on the basis of the following criteria: o The overall qualifications of applicant institutions to meet the requirements for participation listed under APPLICATION PROCEDURES. o Clinical and/or basic research experience, training, time availability, and research competence and commitment of the PI and investigators in the following disciplines: a) pediatric neuro-oncology; b) radiation oncology; c) neurosurgery; d) neuro-imaging; and e) neuropathology, as evidenced by past clinical research contributions and current research efforts relating to childhood (and/or adult) brain tumors. o Availability of sufficient numbers of evaluable patients with brain tumors for the conduct of pilot and phase I and II clinical trials, and adequacy of institutional commitment to enter eligible patients onto PBTCTC clinical trials. o Adequacy of plans for pathology support for tumor classification and for submission of tumor specimens for banking for concurrent or future correlative studies. o Availability of state-of-the-art imaging such as MRI, functional MRI, MRS, SPECT, and PET and ability to appropriately utilize these methodologies in the conduct of PBTCTC studies. o Adequacy of state-of-the-art radiotherapy (e.g., for delivery of stereotactic radiotherapy and brachytherapy) and ability to appropriately utilize these techniques in the conduct of PBTCTC studies. o Adequacy of state-of-the-art neurosurgical facilities and expertise, and ability to appropriately utilize these in the conduct of PBTCTC studies. o Adequacy of data management resources and facilities. o Adequacy of provisions for the protection of human subjects. o Adequacy of the plans for inclusion of females and minorities. o Submitted clinical protocol proposals will be reviewed as examples of ideas and/or research designs of applicant Institutions. These may be commented upon by peer reviewers as they illustrate the overall capability of the applicant to contribute to the research objectives of the Consortium. The specific proposals themselves will not be considered major elements in the evaluation, since PBTCTC protocols will reflect the input and expertise of investigators from multiple institutions, including those at the Operations, Statistics and Data Management Center. The reviewers will also judge the appropriateness of the proposed budget and duration in relation to the scientific merit and feasibility of the proposed research. AWARD CRITERIA Applications considered by the National Cancer Advisory Board will be considered for award based upon (a) scientific and technical merit; (b) availability of funds; and (c) programmatic priorities. Letter of Intent Receipt Date: May 1, 1998 Application Receipt Date: July 10, 1998 Review by National Cancer Advisory Board: February 1999 Anticipated Award Date: April 1999 INQUIRIES Written and telephone inquiries concerning the objectives and scope of this RFA and inquiries about whether or not specific proposed research would be responsive are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding scientific issues to: Dr. Malcolm Smith Division of Cancer Treatment and Diagnosis National Cancer Institute 6130 Executive Boulevard, Room 741, MSC 7436 Bethesda, MD 20892-7436 Telephone: (301) 496-2522 FAX: (301) 402-0557 Email: smithm@CTEP.NCI.NIH.GOV For programmatic information: Ms. Diane Bronzert Division of Cancer Treatment Diagnosis and Centers National Cancer Institute 6130 Executive Boulevard, Room 734, MSC 7432 Bethesda, MD 20892-7432 Telephone: (301) 496-8866 FAX: (301) 480-4663 Email: BRONZERTD@CTEP.NCI.NIH.GOV Direct inquiries regarding fiscal matters to: Ms. Crystal Wolfrey Grants Administration Branch National Cancer Institute 6120 Executive Boulevard, Room 243, MSC 7150 Bethesda, MD 20892-7150 Telephone: (301) 496-7800, ext. 282 FAX: (301) 496-8601 Email: WOLFREYC@GAB.NCI.NIH.GOV AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No 93.395, Cancer Treatment Research. Awards are made under the authorization of the Public Health Service Act, Title IV, Part A (Public Law 78-410, as amended, Public Law 99-158, 42 USC 241 and 285) and administered under HHS grants policies. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. The PHS strongly encourages all grant and contract recipients to provide a smoke- free workplace and promote the non-use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people.
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