Full Text CA-93-03 THERAPEUTIC STUDIES OF PRIMARY CENTRAL NERVOUS SYSTEM MALIGNANCIES IN ADULTS NIH GUIDE, Volume 21, Number 41, November 13, 1992 RFA: CA-93-03 P.T. 34 Keywords: Cancer/Carcinogenesis Nervous System Biological Response Modifiers Chemotherapeutic Agents National Cancer Institute Letter of Intent Receipt Date: January 15, 1993 Application Receipt Date: March 10, 1993 PURPOSE The Cancer Therapy Evaluation Program (CTEP) and the Radiation Research Program (RRP) of the Division of Cancer Treatment (DCT) at the National Cancer Institute (NCI) invite applications for cooperative agreements (U01) from consortia of institutions to perform Phase I and II clinical evaluations of promising new chemotherapeutic or biologic agents for the treatment of primary central nervous system (CNS) malignancies and to perform ancillary laboratory studies of aspects of CNS tumor biology with potential clinical implications. Integrated packages of individual applications are encouraged, with the lead institution of a proposed consortium indicating which participating institutions will provide organizational support, scientific leadership, laboratory capabilities, and/or patient resources. Each consortium of institutions will be referred to as a CNS Consortium (CNSC) for the purpose of this RFA. 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 RFA, Therapeutic Studies of Primary Central Nervous System Malignancies in Adults, 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 "Healthy People 2000" (Summary Report: Stock No. 017-001-00473-1) through the Superintendent of Documents, Government Printing Office, Washington, DC 20402-9325 (telephone 202/783-3238). ELIGIBILITY REQUIREMENTS Applications may be submitted by North American non-profit and for-profit organizations, public and private, such as universities, colleges, hospitals, laboratories, units of State and local governments, DCT clinical trials cooperative groups, and eligible agencies of the Federal government. Applications from minority individuals and women are encouraged. It is essential that applications be submitted as an integrated package from a team or consortium (CNSC) of medical institutions (a minimum of three) that agree to work together with a single Project Leader and a single administration, and submit applications that will be reviewed in relation to the consortium. Together, the institutions in the consortium would encompass experience in investigational drug clinical trials, access to sufficient numbers of primary CNS tumor patients to enter a minimum of 60-80 fully evaluable cases per year onto Phase I and II protocols, expertise in laboratory investigation of the biology of human gliomas, and access to a Central Operations Office for coordination of research activities and data analysis. Except under unusual circumstances, the Central Operations Office/Coordinating Center would be expected to reside at the Project Leader's institution. Detailed requirements are listed below in Terms of Cooperation, Responsibilities of Awardees. The members of each proposed consortium should together fulfill the criteria listed below. A. Requirements for the Consortium (CNSC) as a whole: 1. A commitment to participate in multi-institutional protocols and documentation of facilities and professional personnel available, committed, and expert in conducting brain tumor clinical trials. This includes assignment of appropriate specialist collaborators including, but not limited to, medical oncologists, radiation therapists, neurologists, neurosurgeons, neuroradiologists, and neuropathologists. 2. A Central Operations Office/Coordinating Center for biostatistical support, collection, analysis, reporting, and quality control of data from Phase I and II trials and related laboratory investigations. Detailed requirements will be found in RESEARCH OBJECTIVES, DEFINITIONS. 3. The applicant CNSC and each of its participating clinical institutions must have adequate central data collection and processing capabilities and the capability to meet FDA and HHS requirements for the conduct of research using investigational agents. 4. Each CNSC, a minimum of three institutions, must have the demonstrated capability of accruing a minimum of 60 fully evaluable, histologically confirmed high-grade glioma patients per year who would be appropriate candidates for Phase I or Phase II clinical trials, and who have acceptable performance status and organ function to enter such trials. In the case of a consortium (CNSC) with more than three clinical member institutions, a minimum of 20 such evaluable patients per institution per year will be required. 5. The CNSC (consortium) must demonstrate an active laboratory program at one or more of its participant institutions that utilizes human glioma specimens or cell lines and would be able to take advantage of additional clinical specimens (and accompanying clinical data) to perform correlative studies bearing on the clinical behavior of CNS tumors and/or their response to therapeutic interventions. Experience with gliomas and/or other human CNS tumors must be documented by a record of publications or peer-reviewed grant support. 6. The CNSC must demonstrate laboratory capabilities among one or more of its participant institutions sufficient to perform at least two comprehensive pharmacokinetic studies per year of selected Phase I or Phase II drugs being evaluated by the consortium. Experience with pharmacokinetic data analysis and correlation of these data with clinical drug response must be documented, as must familiarity with the latest technology for the detection and quantitation of drugs and their metabolites in physiological fluids and tissues. (see RESEARCH OBJECTIVES, RESEARCH GOALS AND SCOPE below) B. Each participant institution in the CNSC must have a mechanism to collect and ship patient specimens to other members of the CNSC and other consortia under the guidelines established for the individual studies. Institutions involved in laboratory studies must have the capability to receive and conduct research studies on patient specimens not only from within their own centers, but also from other members of the CNSC and other consortia funded by this U01. There must also be a mechanism in place for the collection and transfer of patient and laboratory data to the Central Operations Office/Coordinating Center for analysis. C. Each institution participating in the clinical trials of the consortium must meet the following requirements: 1. Experienced full-time physician investigators associated with the project who have demonstrated expertise in Phase I/II studies. 2. A multi-disciplinary neuro-oncology team with clinician members representing expertise in the disciplines of medical and radiation oncology, neurology/neurosurgery, neuropathology and neuroradiology. 3. Adequate physician, nursing and data management resources to comply with all data reporting requirements of NCI-sponsored Phase I and II trials. 4. Patient populations to support adequate patient accrual (criteria determined by the consortium) with annual monitoring to assure continued enrollment of patients on Phase I and II trials. 5. Availability of state-of-the-art instrumentation for neurologic magnetic resonance imaging and for radiation therapy. 6. Appropriate drug control procedures as required for utilization of NCI-supplied experimental agents. 7. Capability of meeting FDA requirements in A3 above. MECHANISM OF SUPPORT Awards will be made as cooperative agreements, which create an assistance relationship with substantial NCI programmatic involvement with the recipients during the performance of the project, as outlined in this RFA. The cooperative agreement mechanism is used when the NCI wishes to stimulate investigator interest and proposes to advise or assist in an important and opportune area of research. Support of this program will be through the Cooperative Agreement (U01), an assistance mechanism in which substantial NCI programmatic involvement with the recipient during performance of the planned activity is anticipated. The nature of NCI staff involvement is described in Terms of Cooperation, Nature of Participation by NCI Staff. Applicants will be responsible for the planning, direction, and execution of the proposed project. Except as otherwise stated in this RFA, awards will be administered under PHS grants policy as stated in the Public Health Service Grants Policy Statement, DHHS Publication No. (OASH) 90-50,000, revised October 1, 1990. This RFA is a one-time solicitation. If it is determined that there is a sufficient continuing program need, the NCI will invite recipients of awards under this RFA to submit competitive continuation cooperative agreement applications for review according to the procedures described in Review Considerations, Part A. FUNDS AVAILABLE Approximately $1,500,000 in total costs per year for four years will be committed to specifically fund applications submitted in response to this RFA. It is anticipated that six to nine individual awards will be made to the members of one to three consortia. This funding level is dependent on the receipt of a sufficient number of applications of high scientific merit. The total project period for applications submitted in response to the present RFA may not exceed four years. Although this program is provided for in the financial plans of the NCI, the award of cooperative agreements pursuant to this RFA is also contingent upon the continuing availability of funds for this purpose. RESEARCH OBJECTIVES A. Background Primary malignant brain tumors are responsible for approximately 12,000 deaths annually in the US. Astrocytomas of various histologic grades make up 65-70 percent of all primary, central nervous system (CNS) tumors. Other malignant histologies such as medulloblastomas, ependymomas, oligodendrogliomas, and CNS lymphomas make up an additional 15-20 percent of all cases. Standard treatment with surgery, radiation therapy, and chemotherapy has been shown to improve short term survival by two- to threefold, but in spite of aggressive, multimodality therapy and despite the fact that the majority of these cancers rarely metastasize, high-grade gliomas are nearly 100 percent lethal, and average survival usually ranges between 9-18 months. Surgery, radiation therapy, chemotherapy, and immunotherapy are limited in their effectiveness by the susceptibility of adjacent, normal brain to the adverse effects of treatment and by extensively infiltrating and/or resistant nests of malignant cells, and perhaps by other phenomena such as relative incapacity of the immune effector system and the brain's poor capacity for repair. In addition, clinical trials have been hampered by the fact that tumor status, the adverse sequelae of therapy, and the effects of ancillary treatments (such as steroids) are very difficult to segregate when assessed either by clinical examination or conventional diagnostic imaging. Clinical investigations of new means to treat such tumors are needed. Collaborative interactions between clinicians and laboratory scientists and between clinicians and diagnostic imagers are essential features of these investigations. The special skills of experienced tumor neurosurgeons, neuro-oncologists, radiation therapists, and neuroradiologists with access to the latest generation of imaging equipment will be required. NCI is therefore seeking multidisciplinary and multiinstitutional teams of talented scientists from non-profit and for-profit research organizations who will interact with the Cancer Therapy Evaluation Program (CTEP) and Radiation Research Program (RRP) in a concerted way to conceive, create, and evaluate new approaches to therapy of CNS malignancies. Scientific approaches should be broad and reflect the creativity and capabilities of team participants, including surgical, medical, radiotherapeutic, diagnostic imaging, laboratory and statistical skills. New clinical research opportunities exist with the development of novel cytotoxic drugs, radiation sensitizers, differentiating agents, immune modulators, monoclonal antibodies, and new approaches to gene therapy. Among the agents and techniques currently under development that appropriately might be studied by such a consortium are: temozolomide, the topoisomerase-1 inhibitors, taxol and its analogues, inhibitors of cytokines such as suramin or the TNF-` inhibitor pentoxifylline, differentiation-inducers, newer polyamine analogs, inhibitors of O6-methylguanine-DNA methyltransferase or mdr-1/P-glycoprotein or other drug resistance inhibitors, antisense oligonucleotides, monoclonal antibodies to appropriate cellular targets such as gangliosides, the novel bioreductive agent SR-4233, which is cytotoxic to hypoxic cells preferentially, and others, alone and in potential combination with sophisticated regional approaches such as brachytherapy, radiosurgery, or other modalities. Team objectives and approaches will be investigator-originated but consistent with program aims of improving the survival and quality of life for persons with primary CNS malignancies and providing fundamental insights into the biology of these tumors. B. Definitions COOPERATIVE AGREEMENT - An assistance mechanism in which substantial NCI programmatic involvement with the recipient is anticipated during performance of the planned activity. CENTRAL NERVOUS SYSTEM CONSORTIUM (CNSC) - The consortium of institutions (minimum of three members) who are submitting research grant applications together to conduct Phase I/II clinical trials and ancillary laboratory studies. Each CNSC also contains an application for a Central Operations Office/Coordinating Center. Each consortium will consist of talented and experienced individuals in multiple disciplines (e.g. medical oncology, neurosurgery, neurology, radiotherapy, radiobiology, pharmacology, molecular biology, pathology, biostatistics). CENTRAL OPERATIONS OFFICE/COORDINATING CENTER - An administrative unit that coordinates all CNSC activities. Responsibilities include administrative management, coordination of protocol development and submission, study conduct, quality control and protocol performance monitoring, statistical analyses, adherence to requirements regarding NCI drug accountability and FDA, OPRR and HHS regulations, and protocol and institutional performance reporting. 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 Central Operations Office/Coordinating Center may consist of a consortium with the statistics center located at another institution. PROJECT LEADER - The person who submits the application for the Central Operations Office/Coordinating Center and who is responsible for the CNSC as a whole. The consortium of participant institutions must agree to work together with the Project Leader. The Project Leader is responsible for coordinating the CNSC activities scientifically and administratively. The Project Leader may be the principal investigator on a participant institution application. PARTICIPANT INSTITUTION - The individual research grant application from an institution who is participating in the CNSC. The participant institution may conduct clinical trials and/or laboratory studies. PRINCIPAL INVESTIGATOR - The person who submits the single application for the participant institution and who is responsible for performance of the key personnel of that application. The Principal Investigator provides the scientific leadership for the participant institution. PROGRAM DIRECTOR - The staff member from the Cancer Therapy Evaluations Program, Division of Cancer Treatment (cited in the INQUIRIES SECTION) who coordinates NCI interactions, interacts scientifically with the CNSC, and provides guidance for the overall program within the NCI. C. RESEARCH GOALS AND SCOPE The primary goal of this initiative is to stimulate clinical research in the treatment of primary CNS malignancies in adult patients by providing support for consortia of institutions to perform Phase I and II clinical evaluations of promising new chemotherapeutic or biologic agents. A secondary goal is to utilize the consortia as a mechanism for sharing human brain tumor specimens among investigators conducting laboratory studies relevant to the biology, clinical behavior, or therapy of CNS tumors, particularly malignant gliomas. Clinical trials will take advantage of new developments in drug and radiation resistance, radiation sensitization, biological response modification, immune modulation, induction of apoptosis, differentiation induction, therapeutic irradiation techniques, induction or suppression of specific gene function, or other innovative approaches. Each CNSC will be formed for the purpose of: (1) sharing expertise of researchers in multiple disciplines; (2) conducting joint phase I and II clinical trials to provide adequate patient populations and timely completion; and (3) sharing of tumor specimens and data useful in the conduct of clinical pharmacologic and correlative laboratory studies. Participant institutions in the proposed consortium may be involved in clinical trials and/or laboratory studies. It is anticipated that one to three consortia will be established, comprising three to nine institutions. Each CNSC will select the specific agents to be tested in accord with their scientific interest and expertise and will develop a series of appropriate Phase II or Phase I trials with supporting protocol documents. Each applicant CNSC should submit as examples one or more draft clinical protocols as supplements to the Central Operations Office/Coordinating Center (Project Leader) and the participant institution applications. The CNSC, along with the assistance of the NCI Program Director, will develop a plan for prioritization of investigational trials. The NCI may provide NCI-sponsored IND agents or provide assistance to the awardee(s) by sponsoring or cross-referencing INDs for selected agents. Each CNSC must have documented numbers of patients with CNS tumors and a history of accrual of patients to clinical trials adequate for two-six phase I or II trials (60- 180 patients) per year. It is expected that all of the CNSC institutions together will be able to complete approximately six phase I or phase II trials (180 patients) per year. In addition, proposed consortia must have: (1) adequate radiotherapy support for clinical trials utilizing radiation in combination with other modalities; (2) adequate central data collection and processing capabilities as well as biostatistical expertise; (3) adequate pathology support for both institutional tumor classification and central neuropathology review and for banking and distribution of tumor tissues for concurrent and future laboratory studies; (4) mechanisms to collect and store patient specimens for laboratory studies being conducted by institutions in the CNSC; (5) expertise in antineoplastic drug pharmacology/pharmacokinetics. The correlative laboratory research program in a CNSC should address at least one field of research into the biology of human malignant gliomas with some potential for future clinical relevance. Examples of research fields for laboratory studies include: molecular genetics and cytogenetics, gene function and expression, signal transduction pathways, radiobiology, growth regulation, metabolism, differentiation and gene modulation by investigational agents, intracellular metabolism, mechanisms of drug resistance in tumor cells, CNS pharmacokinetics, invasion and spread, cytokine production or interactions, immune function and antigen expression, or other aspects that may have clinical implications or lead to new therapeutic approaches. Investigators are not limited to the above areas of laboratory experimentation. Correlative laboratory studies need not be directly related to individual clinical Phase I/II trials but should attempt to utilize the large clinical database that will be generated by the consortium to identify potential correlates of tumor behavior, and laboratory studies should be based on strong and testable hypotheses. A clear rationale should be given for the experimental design and technological methodologies selected. Preliminary data from appropriate tumor models or analysis of patient specimens should be provided to support the feasibility of each study. The laboratory assays must utilize tumor specimens from patients and there should be an established plan for prioritization of specimen distribution to collaborating laboratories. Participating institutions primarily involved in laboratory studies may accrue patients on CNSC clinical trials if the minimum clinical resources are in place (See Eligibility Requirements). The cooperative approach outlined in this RFA allows for interactions among successful applicants, with the assistance of NCI extramural staff, to perform Phase I and Phase II trials of anticancer agents and ancillary laboratory studies. This mechanism retains the decision-making prerogatives of the Principal Investigator and his/her colleagues, but at the same time, permits the active participation of NCI in research activities. (See Terms of Cooperation) SPECIAL REQUIREMENTS A. Terms of Cooperation The cooperative agreements will require cooperation between an NCI Program Director and the Project Leader(s) of the CNSC(s). The NCI Program Director will assist in coordinating the activities of the CNSC as defined below and in facilitating exchange of information. These Terms of Cooperation 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. Nature of Participation by NCI Staff The role of the CTEP and RRP staff as described throughout these terms of cooperation is to assist and facilitate 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 CTEP staff listed below has very specific and well defined responsibilities in terms of investigational agent development and the role of DCT as a drug sponsor as defined in 21 CFR Part 312. 1. CTEP and RRP as a Scientific Resource for NCI-supported Phase I and II Clinical Trials Investigations The NCI Program Director (cited in the INQUIRIES SECTION) will serve as a resource available to the CNSC for scientific information with respect to treatment regimens and clinical trial design. The Cancer Expert, RRP, will serve as a resource for specific scientific information with respect to radiation therapy and diagnostic imaging of CNS tumors. The NCI Program Director will assist the CNSC as appropriate in developing information concerning the scientific basis for specific trials and also will be responsible for advising the CNSC of the nature and results of relevant trials being carried out nationally or internationally. The NCI Program Director will sponsor an initial strategy meeting with the awardees to review the research plans proposed to ensure that they are compatible with the overall goals of the RFA, to ensure avoidance of duplication of effort, and to ensure the most effective use of available resources, including investigational agents. The NCI Program Director will also sponsor strategy meetings semi-annually or as needed, to be attended by investigators in the CNSC and other investigators as appropriate. At these meetings relevant information will be reviewed, national research goals discussed, and the outstanding research questions established and prioritized by the CNSC investigators. The Program Director will also provide updated information on the efficacy and toxicity of investigational new agents supplied to the CNSC under an Investigational New Drug (IND) Application sponsored by the DCT. 2. CTEP Assistance in Protocol Development The protocol must be a detailed written plan of a clinical experiment mutually acceptable to the proposing CNSC 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. All protocols should be preceded by a written Letter of Intent (LOI) from the CNSC declaring interest in conducting a particular study. The LOI should be sent to the CTEP LOI Coordinator who receives, logs in and schedules LOIs for review by the PRC (see Section - Responsibilities of Awardees). The PRC will formally review the LOI. Following review, the NCI Program Director will provide a Program response to the CNSC 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, including biologic response modifiers; (d) the scientific rationale and value of the proposed study, the design, the 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 (see the DCT Investigator's Handbook, pp 32-35, available on request from Dr. Richard Kaplan at the address below, for further discussion of these mechanisms). 3. CTEP Review of Proposed Protocols CNSC protocols will be reviewed by the PRC which meets weekly. It 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 Program Director will provide the CNSC with a consensus review that describes recommended modifications and other suggestions, as appropriate (see the DCT 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 to be used. If a proposed protocol is disapproved, the specific reasons for lack of approval will be communicated in writing by the NCI Program Director to the CNSC 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 Program Director will be available to assist the CNSC in developing a mutually acceptable protocol, consistent with the research interests, abilities and strategic plans of the CNSC and of the NCI. Disagreements arising pursuant to protocol approval will be submitted to an arbitration panel to determine the suitability of a protocol that has been disapproved. An arbitration panel composed of one CNSC nominee, one NCI nominee, and a third member with oncologic 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, DCT. These special arbitration procedures in no way affect the awardee's right to appeal an adverse determination in accordance with PHS regulations at 42 CFR Part 50, Subpart D, and HHS regulations at 45 CFR Part 16. The CNSC will not expend NCI funds to conduct any study disapproved by CTEP unless CTEP's disapproval has been modified by the arbitration process outlined above. 4. CTEP Review of Quality Control and Study Monitoring The Head, Quality Assurance and Compliance Section (QACS), Regulatory Affairs Branch (RAB), CTEP will review and provide advice, through the NCI Program Director, regarding mechanisms established by the CNSC for quality control of therapeutic and diagnostic modalities employed in its trials. (See RESPONSIBILITIES OF AWARDEES). The Head, QACS will review the CNSC procedures and policies for study monitoring including the awardees' on-site monitoring program (See 8. CTEP Review of Federally Mandated Regulatory Requirements). 5. CTEP Review of Data Management and Analysis The Chief, Biometrics Research Branch (BRB), CTEP will review CNSC mechanisms for data management and analysis. (See RESPONSIBILITIES OF AWARDEES). When deemed appropriate, The Chief, BRB will make recommendations to the CNSC, through the NCI Program Director, 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) sufficiently uniform across the CNSC participants. 6. CTEP Involvement in Protocol Closure The NCI Program Director will monitor protocol progress. When a study involves a DCT IND agent, the Head , QACS and the Investigational Drug Branch (IDB) Physician (Drug Monitor) who is assigned to each DCT IND agent to coordinate its development will also monitor progress. The NCI Program Director may request that a protocol study be closed to accrual for reasons including: (a) insufficient accrual rate; (b) accrual goal met; (c) poor protocol performance; (d) patient safety and 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). For any study, whether involving an investigational drug or not, NCI will establish an arbitration process for investigators who wish to appeal protocol closure. This process will be identical to that described above for protocol disapproval. 7. CTEP involvement in Investigational New Drug Applications a. The NCI will have the option to cross file or independently file an IND on investigational drugs evaluated in the 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, 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 Phase I and II Clinical Trials will be advised by the NCI Program Director of potential studies that will be relevant to new avenues of cancer therapy. When this involves investigational agents, the NCI Program Director 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). 8. CTEP Review of Federally Mandated Regulatory Requirements The Head, QACS, through the NCI Program Director, will advise the CNSC regarding mechanisms to meet FDA regulatory requirements for studies involving DCT-sponsored investigational agents and the Office for Protection from Research Risks (OPRR) requirements for the protection of human subjects by the CNSC institutions. (See RESPONSIBILITIES OF AWARDEES, below) For specific Phase I and II trials with NCI-sponsored investigational agents, 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. For Phase I studies, CTEP determines that the CTMS monitoring described above is necessary using the following guidelines: (a) Introduction of drug into humans for the first time; (b) Early Phase I studies using a single agent; (c) Concern for safety of patients; (d) PRC expresses concern with excessive toxicity. Phase II studies may also be monitored as noted above if PRC expresses concern with excessive toxicity. For these trials, awardees may be visited by the CTMS contractor three times a year. Phase II studies may also be monitored if PRC expresses concern with excessive toxicity. For these Phase I and II trials, awardees may be visited by the CTMS contractor three times a year. The required biweekly data submissions to the CTMS are described under RESPONSIBILITIES OF AWARDEES Section 9.d. For Phase II trials with DCT IND agents not requiring the above described monitoring, NCI will delegate to the awardee the task of providing an independent audit of each research study. The NCI's Clinical Trials Monitoring Service (CTMS) contractor shall be used to conduct these audits. The staff of QACS will perform random audits of the awardee to assure that the awardee is performing the delegated audit duties. Audit schedules and final audit reports will be provided to QACS, CTEP. Institutional responsibilities for monitoring are described below under RESPONSIBILITIES OF AWARDEES Section 9.c. 9. 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. The awardee will retain custody and primary rights to the data consistent with current HHS, PHS and NIH policies. 10. CTEP Review of Progress Performance of each CNSC will be reviewed at least annually by the NCI Program Director on the basis of the information provided at the CTEP sponsored 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 CNSC by the NCI Program Director for all active studies when deemed appropriate. Insufficient patient accrual or progress, or noncompliance with the terms of award, including these Terms of Cooperation, may result in a reduction of budget, withholding of support, suspension or termination of the award. RESPONSIBILITIES OF AWARDEES It is the responsibility of the CNSC 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 CNSC shall, with CTEP assistance, develop Phase I and II protocols for clinical cancer research in accord with the research interests of the CNSC, abilities and goals, and submit them to CTEP (either to the LOI Coordinator or to the CTEP Protocol and Information Office, the receiving office for all protocols sent to CTEP) for review as appropriate prior to their implementation. 1. Protocol Development It is anticipated that decisions in all CNSC activities will be reached by consensus of the collaborating member institutions under the leadership of the CNSC Project Leader. The Project Leader shall designate a Protocol Chairperson for each proposed study. The Project Leader along with coordinating Central Operations Office/Coordinating Center staff will be responsible for communication with the appropriate CTEP staff. 2. The CNSC Central Operations Office/Coordinating Center The CNSC Central Operations Office/Coordinating Center, under the leadership of the Project Leader and with CTEP assistance, 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. All the scientific and administrative decisions related to the CNSC funded activities and made by the CNSC institutions or affiliates will be coordinated by the Project Leader with the assistance of the CNSC Central Operations Office/Coordinating Center. 3. Protocol Submission The CNSC Central Operations Office/Coordinating Center, under the leadership of the Project Leader, will submit CNSC protocols to the CTEP Protocol and Information Office in a timely fashion for review and approval by NCI. All protocols should be preceded by a written Letter of Intent (LOI) from the CNSC 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 "DCT GUIDELINES FOR MULTICENTER INVESTIGATIONAL AGENT STUDIES" (available upon request from Dr. Richard Kaplan at the address below). The Project Leader, with the assistance of the Central Operations Office/Coordinating Center staff, will communicate the results of the NCI review of protocols to the CNSC participating institutions. 4. Prioritization of Studies The CNSC Project Leader and the Principal Investigators of the participant institutions will develop, together with the NCI Program Director, mutually acceptable plans for prioritization of clinical protocols, laboratory studies, and distribution of clinical specimens and tissues. 5. Quality Control The CNSC will establish mechanisms for quality control of therapeutic and diagnostic modalities employed in its 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 flow sheets with determination of protocol compliance in dose administration and dosage modification. d) Neurosurgery: Assessment of adequacy of protocol-specified surgical procedures (where relevant) through review of operative notes and study-specific surgical forms. e) Diagnostic Imaging: Central review of claimed responses and adequacy of imaging. 6. Study Monitoring The CNSC will establish mechanisms for study monitoring. The CNSC is responsible for assuring accurate and timely knowledge of the progress of each study through: a) establishing procedures for assigning dose level at the time a new patient is entered, and assuring that the required observation period has elapsed before beginning a higher dose level; b) tracking and reporting of patient accrual and adherence to defined accrual goals; 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; g) timely communication of results of studies; and h) an on-site monitoring program (see 9c below). i) establishing data management support capabilities which assure that data will be submitted via electronic transfer to the NCI's Clinical Trials Monitoring Service (CTMS) when required. (See 9d below) 7. Data Management and Analysis The CNSC will develop procedures to ensure that data collection and management are: (1) adequate for quality control and analysis; (2) as simple as appropriate in order to encourage maximum participation of physicians entering patients and to avoid unnecessary expense; and (3) sufficient across the participating institutions. 8. Investigational Drug Management Investigators performing trials under cooperative agreements must be NCI registered investigators (form 1572) and will be expected to implement CTEP requirements described in the DCT Investigators' Handbook for storage and accounting for investigational agents, to abide by NCI/HHS Drug Accountability Records (DAR) procedures, and to comply with all FDA requirements for investigational agents. 9. CNSC Compliance with Federally Mandated Regulatory Requirements The CNSC is responsible for establishing procedures for all participating institutions to comply with FDA regulations for studies involving investigational agents and OPRR requirements for the protection of human subjects. These procedures are: a) methods for assuring that each institution where investigators are conducting CNSC trials has a current, approved assurance on file with the OPRR; that each protocol is reviewed and approved by the responsible Institutional Review Board (IRB) prior to patient entry; that each protocol is reviewed at least annually by the IRB so long as the protocol is active; that each investigator is registered with the Drug Management and Authorization Section (DMAS), CTEP, with a current 1572 form on file; and that each patient (or legal representative) gives written informed consent prior to entry on study. b) a system for assuring timely reporting of all serious and unexpected toxicities to the IDB, CTEP according to CTEP guidelines (mailed annually to all registered investigators). This requires reporting Adverse Drug Reactions (ADRs) by telephone to the IDB Drug Monitor within 24 hours of the event and requires a written report to follow within 10 working days. c) an on-site monitoring program which assures that a sampling of records at each participating institution is audited at least two times during the cooperative agreement period. The on-site audit will address issues of data verification and 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 Head, QACS immediately. Otherwise, written reports must be submitted within six weeks of each audit. All audit schedules are to be provided to the Head, QACS at least four weeks prior to the date of the audit. d) For the specific Phase I and Phase II trials that require monitoring by the CTMS three times a year, information must be provided via electronic transfer to the CTMS at two week intervals and includes: notification of each patient entered onto a Phase I or II protocol within the previous two week period, and all data obtained on each registered patient within the previous two weeks as specified by the NCI/DCT Standard Case Report Form and the individual protocol. e) implementation of the CTEP requirements described in the DCT Investigators Handbook for storage and accounting for investigational agents provided under DCT sponsorship. 10. Progress Review The CNSC will establish a mechanism for assessing performance of its members, with particular attention to accrual of adequate number of eligible patients onto consortium trials, timely submission of required data, conscientious observance of protocol requirements, authorship and participation in group leadership. This mechanism will include a procedure for recommending an adjustment of institutional funds within the consortium as appropriate for the level of participation in consortium activities, including (but not limited to) accrual. 11. Attendance at Meetings The CNSC Project Leader and appropriate representative(s) of the CNSC participating institutions, shall meet twice a year with the NCI Program Director to review CNSC progress, establish priorities, and plan future activities. Additional meetings between the NCI Program Director and the Project Leader will be held if necessary. 12. Reporting Requirements Reporting requirements will be in agreement with FDA regulations and NCI procedures. Annual progress reports will be submitted to the NCI and will include at a minimum summary data on protocol performance by the awardee and each participating institution. In addition, data summary reports will be requested prior to the due date of the annual report to the FDA required of IND sponsors. The types of reports required are determined by CTEP at the time of protocol review. They are: (a) Quarterly Data Updates (QDA) for late Phase I trials not CTMS monitored; (2) Annual Data Updates (ADU) for late Phase I/Phase II combination studies sent to Protocol Chairman to summarize clinical data and progress; (3) Study summaries sent annually to summarize clinical data for Phase II studies. A system for providing such information in a timely manner must be in place. 13. Publication of Data Timely publication of major findings is encouraged. Publication or oral presentation of work done under this agreement will require appropriate acknowledgement 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. SPECIAL INSTRUCTIONS FOR PREPARATION OF COOPERATIVE AGREEMENT APPLICATIONS The grant application form PHS 398 (rev. 9/91) is to be used for the cooperative agreement application. The general instructions, e.g., for format and budget issues, included in the application packet must be followed. Because the Terms of Cooperation 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. All costs required for these studies must be included in the application and must be fully justified. These costs include the additional costs of clinical research associated with Phase I and Phase II studies including costs for patient accrual, sample handling, laboratory studies, quality assurance, data management and data analysis, study monitoring, travel, an on-site audit program and the biweekly electronic data submissions to the NCI's Clinical Trials Monitoring Service when required. For Phase II trials with DCT IND agents for which the awardee is responsible for providing the on-site monitoring, the awardee shall contract with the NCI's Clinical Trials Monitoring Service for the performance of audits. The awardee(s) will be expected to provide two audits per institution during the cooperative period and to request funding accordingly. Funds requested for the audit program will be restricted for this purpose only. The on-site audit requirements are described in the above section entitled SPECIAL REQUIREMENTS, TERMS OF COOPERATION, RESPONSIBILITIES OF AWARDEE. Each CNSC should anticipate the need to attend two meetings per year to share data and to coordinate activities. Travel funds for two representatives from the Central Operations Office/Coordinating Center and one or two representative(s) from each participant clinical and/or laboratory member institution should be included in the budget. SPECIAL INSTRUCTIONS TO APPLICANTS REGARDING IMPLEMENTATION OF NIH POLICIES CONCERNING INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH STUDY POPULATIONS NIH policy is that applicants for NIH clinical research grants and cooperative agreements will be required to include minorities and women in study populations so that research findings can be of benefit to all persons at risk of the disease, disorder or condition under study; special emphasis should be placed on the need for inclusion of minorities and women in studies of diseases, disorders and conditions which disproportionately affect them. This policy is intended to apply to males and females of all ages. If women or minorities are excluded or inadequately represented in clinical research, particularly in proposed population-based studies, a clear compelling rationale should be provided. The composition of the proposed study population must be described in terms of gender and racial/ethnic group. In addition, gender and racial/ethnic issues should be addressed in developing a research design and sample size appropriate for the scientific objectives of the study. This information should be included in the form PHS 398 in Section 1-4 of the Research Plan AND summarized in Section 5, Human Subjects. Applicants/offerors are urged to assess carefully the feasibility of including the broadest possible representation of minority groups. However, NIH recognizes that it may not be feasible or appropriate in all research projects to include representation of the full array of United States racial/ethnic minority populations (i.e., Native Americans (including American Indians or Alaskan Natives), Asian/Pacific Islanders, Blacks, Hispanics). The rationale for studies on single minority population groups should be provided. For the purpose of this policy, clinical research includes human biomedical and behavioral studies of etiology, epidemiology, prevention (and preventive strategies), diagnosis, or treatment of diseases, disorders or conditions, including but not limited to clinical trials. The usual policies concerning research on human subjects also apply. Basic research or clinical studies in which human tissues cannot be identified or linked to individuals are excluded. However, every effort should be made to include human tissues from women and racial/ethnic minorities when it is important to apply the results of the study broadly, and this should be addressed by applicants. For foreign awards, the policy on inclusion of women applies fully; since the definition of minority differs in other countries, the applicant must discuss the relevance of research involving foreign population groups to the United States' populations, including minorities. If the required information is not contained within the application, the application will be returned. Peer reviewers will address specifically whether the research plan in the application conforms to these policies. If the representation of women or minorities in a study design is inadequate to answer the scientific question(s) addressed AND the justification for the selected study population is inadequate, it will be considered a scientific weakness or deficiency in the study design and will be reflected in assigning the priority score to the application. All applications for clinical research submitted to NIH are required to address these policies. NIH funding components will not award grants or cooperative agreements that do not comply with these policies. LETTER OF INTENT Prospective applicants are asked to submit by January 15, 1993, a letter of intent that includes a descriptive title of the proposed research, the name, address, and telephone number of the Project Leader, 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 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: Dr. Richard Kaplan Cancer Therapy Evaluation Program Division of Cancer Treatment National Cancer Institute Executive Plaza North, Room 734 6130 Executive Boulevard Bethesda, MD 20892 Telephone: (301) 496-8866 FAX: (301) 480-4663 APPLICATION PROCEDURES The research grant application form PHS 398 (rev. 9/91) is to be used in applying for cooperative agreements. These forms are available at most institutional offices of sponsored research; from the Office of Grants Inquiries, Division of Research Grants, National Institutes of Health, Room 449, Westwood Building, 5333 Westbard Avenue, Bethesda, MD 20892, telephone (301) 496-7441; and from the NCI Program Director named below. The Central Operations Office/Coordinating Center as lead institution should submit a research grant application in which they should list the anticipated participant institutions, and include proposed clinical protocols in the Appendix. (The Central Operations Office/Coordinating Center application must be a separate document from any application from a participant institution; if a single institution will be applying for both participation in clinical and/or laboratory studies and as the Central Operations Office/Coordinating Center, two applications will be necessary.) Each participant institution should submit an individual research grant application and should indicate the Central Operations Office/Coordinating Center of the CNSC consortium in which they intend to participate. Participant institutions conducting clinical trials should include copies of the proposed CNSC clinical protocols in the Appendix. The grant application should describe the nature of their participation and justify budget requests for the protocols. 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. Submit a signed, typewritten original of the application, including the Checklist, and three signed, exact photocopies, in one package: Division of Research Grants National Institutes of Health Westwood Building, Room 240 Bethesda, MD 20892** At the time of submission, two additional copies of the application must also be sent to: Referral Officer Division of Extramural Activities National Cancer Institute Westwood Building, Room 838 5333 Westbard Avenue Bethesda, MD 20892 Applications must be received by March 10, 1993. If an application is received after that date, it will be returned. The Division of Research Grants (DRG) will not accept any application in response to this announcement that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. The DRG will not accept any application that is essentially the same as one already reviewed. This does not preclude the submission of substantial revisions of applications already reviewed, but such applications must include an introduction addressing the previous critique. REVIEW CONSIDERATIONS A. REVIEW PROCEDURES Upon receipt, applications will be reviewed for completeness by DRG 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. An application judged to be non-responsive to this RFA may be submitted as an investigator initiated regular research grant (R01) or program project grant (P01) at the next receipt date. The application would require modification in accordance with either the R01 or P01 guidelines. The new application would not be considered an application for a Cooperative Agreement, nor would it be considered a response to an RFA. Questions concerning the relevance of proposed research to the RFA may be directed to program staff as described in the INQUIRIES section below. Applications may be triaged 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 1. Applications for the Central Operations Office/Coordinating Center will be reviewed on the basis of the following criteria: o Scientific, technical, and medical significance and originality of proposed research as reflected in the protocols, research plans and strategies that address the clinical and laboratory considerations in the CNSC as a whole. o Qualifications and research experience of the Project Leader, Principal Investigators, and the key personnel including, but not limited to, previous experience with design and administration of multi-institutional clinical trials and correlative laboratory studies. o Appropriateness and adequacy of the experimental approach and methodology proposed to carry out the CNSC objectives including: o adequacy of plans for the development, implementation and analysis of multi-institutional clinical trials o adequacy of plans for correlative laboratory studies and evaluation of the data with respect to treatment administration or treatment outcome o adequacy of statistical approach for correlating research studies with treatment outcomes in clinical trials o Adequacy of plans for effective collaboration between laboratory and clinical investigators and the Central Operations Office/Coordinating Center within the consortium. Documentation of commitment of the Program Leader and each Principal Investigator and of key personnel to the goals of the CNSC. o Adequacy of the available facilities and data management resources and personnel. Evidence of the competence of the Central Operations Office/Coordinating Center with regard to the mechanisms for CNSC administration, experimental design, quality control, study monitoring, data management and reporting, statistical analysis, and compliance with regulatory requirements. o Demonstration of access to sufficient numbers of evaluable patients for Phase I and II clinical trials and followup by the CNSC (see Eligibility Requirements) and access to adequately processed tissue samples from a proportion of these patients. o Plans for effective interaction and coordination among participant institutions within the consortium, with other consortia working on CNS tumors, and with the NCI. 2. Applications for participant institutions will be reviewed on the basis of the following criteria: o The overall qualifications of applicant institutions to meet the eligibility requirements for participant institutions (see Eligibility Requirements) o Scientific merit and feasibility of the proposed research. o Appropriateness and adequacy of the experimental approach and methodology proposed to carry out the research. o Demonstration of availability of and access to sufficient numbers of evaluable patients for the conduct of phase I and II clinical trials. Evidence of ability to accrue patients to clinical trials. o Clinical and/or basic research experience, training, time availability, and research competence of the investigators involved. o Adequacy of plans for pathology support for tumor classification and for banking and distribution of patient specimens for concurrent and future studies. o Availability of state-of-the-art imaging equipment, especially MRI. The availability of MRS, SPECT, PET and other imaging techniques will be considered favorable additional assets. o Adequacy of state-of-the-art radiotherapy equipment. The availability of equipment for stereotactic radiosurgery and brachytherapy is not required, but would also be considered as assets to the application. o Adequacy of the available facilities and data management resources. o Adequacy of provisions for the protection of human subjects. o Adequacy of the plans for inclusion of females and minorities. 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 The anticipated date of award is September 1993. In addition to the technical merit of the application, NCI will consider how well the CNSC and participant institution met the goals and objectives of the program as described in the RFA. 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 strongly encouraged and should be directed to program staff listed below. The program staff welcome the opportunity to clarify any issues or questions from potential applicants. Direct inquiries regarding programmatic issues to: Dr. Richard Kaplan, Senior Investigator Cancer Therapy Evaluation Program Division of Cancer Treatment National Cancer Institute Executive Plaza North, Room 734 Bethesda, MD 20892 Telephone: (301) 496-8866 FAX: (301) 480-4663 Direct inquiries regarding fiscal matters to: Ms. Katharine Schulze Grants Administration Branch National Cancer Institute Executive Plaza South, Room 242 Bethesda, MD 20892 Telephone: (301) 496-7800, ext. 16 FAX: (301) 496-8601 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 Sections 301, 410, and 411, Part A (Public Law 78-410, 42 USC 241 as amended, Public Law 99-158, 42 USC 285a) and administered under PHS grants policies and Federal Regulations at 42 CFR Part 52 and 45 CFR Part 74. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. .

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