CONSORTIUM THERAPEUTIC STUDIES OF PRIMARY CENTRAL NERVOUS SYSTEM MALIGNANCIES IN ADULTS RELEASE DATE: January 16, 2003 RFA: CA-04-001 (Reissued as RFA-CA-08-504) National Cancer Institute (NCI) (http://www.nci.nih.gov/) LETTER OF INTENT RECEIPT DATE: February 21, 2003 APPLICATION RECEIPT DATE: March 28, 2003 This RFA is a reissue of RFA CA-97-002, which was published in the NIH Guide on November 22, 1996. THIS RFA CONTAINS THE FOLLOWING INFORMATION o Purpose of this RFA o Research Objectives o Mechanism of Support o Funds Available o Eligible Institutions o Individuals Eligible to Become Principal Investigators o Special Requirements o Where to Send Inquiries o Letter of Intent o Submitting an Application o Peer Review Process o Review Criteria o Receipt and Review Schedule o Award Criteria o Required Federal Citations PURPOSE OF THIS RFA The purpose of this RFA is for the Cancer Therapy Evaluation Program (CTEP) and the Radiation Research Program (RRP) of the Division of Cancer Treatment and Diagnosis (DCTD) at the National Cancer Institute (NCI) to invite the members of the North American Brain Tumor Consortium (NABTC) and the New Approaches to Brain Tumor Therapy (NABTT) consortium to submit new or competing continuation cooperative agreement applications. Each consortium of institutions will be referred to as a Central Nervous System Consortium (CNSC) for the purpose of this RFA. Members from both CNSCs will again be expected to perform Phase I and II clinical evaluations of promising new therapeutic agents or approaches for the treatment of primary CNS malignancies in adult patients, especially glioblastoma multiforme and other high-grade gliomas, and to perform ancillary laboratory studies of aspects of CNS tumor biology with potential clinical implications. The NCI desires to continue its support of talented scientists who will interact with other members of the consortium, and with NCI in a concerted way to conceive, create, and evaluate new approaches to the therapy of CNS tumors. The NCI anticipates continued funding of two CNSCs. Separate applications are requested from each current full and provisional member institution interested in continuing participation in their respective CNSC. Applications will only be accepted from current full and provisional member institutions of NABTC or NABTT. Each CNSC will include a single Central Operations Office/Coordinating Center responsible for meeting the administrative/regulatory requirements of the Consortium and for collecting/analyzing clinical data from participating institutions, a Pharmacokinetics Center, and a cohort of Participant Member Institutions providing patient resources. The proposed Central Operations Office/Coordinating Center of each CNSC should indicate which participating institutions will provide organizational support, scientific leadership, laboratory capabilities, and/or patient resources as well as pharmacokinetics expertise/facilities. Applications should indicate whether they are for the Central Operations Office/Coordinating Center, Pharmacokinetics Center, or Participant Member Institution providing patient resources. While a single application may propose only one of these roles, eligible institutions may submit separate applications for one or more of these different roles. It is anticipated that there will be only one application for the Central Operations Office/Coordinating Center of each CNSC. It is also anticipated that there will be only one application for the Pharmacokinetics Center of each CNSC. RESEARCH OBJECTIVES A. Background Primary malignant brain tumors are diagnosed in approximately 35,000 adults annually in the US and have been increasing in incidence, especially in the elderly. Meaningful therapeutic improvement has been made for the less common histologic types such as ependymomas, oligodendrogliomas, and CNS lymphomas. However, for the largest category, astrocytomas of various grades, little progress has been made. Aggressive multimodality therapy has been shown to improve short term survival by two- to three-fold, but average survival for patients with high-grade gliomas is only 9-15 months and, despite the fact that these cancers rarely metastasize, they remain essentially 100 percent lethal. Limited therapeutic success is related to many factors, including the unique biology of high-grade gliomas and the susceptibility of adjacent normal brain to adverse effects of treatment. There have also been few identified agents with therapeutic activity, which may well reflect inherent resistance to conventional classes of agents. However, in part, it may also reflect the fact that relatively few compounds had received thorough clinical evaluation to the standards now in place in the CNSCs. Brain tumor clinical trials are particularly challenging in that tumor status, the adverse sequelae of therapy, and the effects of ancillary treatments (such as steroids) are difficult to segregate when assessed either by clinical examination or conventional diagnostic imaging. Optimal response evaluation and management of these patients continues to require complex and well coordinated interdisciplinary management involving neurosurgeons, neurologists, medical and radiation oncologists, neuroradiologists, and neuropathologists, so that relatively few programs have been optimally suited to undertake such trials. Clinical investigations of new strategies to treat such tumors are needed. Collaborative interactions between clinicians and laboratory scientists and between clinicians, diagnostic imagers, and pathologists are essential features of these investigations. NCI is therefore interested in continuing support for multidisciplinary and multi- institutional teams of talented scientists from research organizations who will interact with CTEP and 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 expertise in neurosurgery, medical oncology, neurology, radiation oncology, neuroradiology, laboratory medicine and biostatistics. New clinical research opportunities exist with the development of novel cytotoxic drugs, drug resistance inhibitors, radiation enhancers and new radiation delivery technology, radiosurgery, antiangiogenic agents, signal transduction inhibitors, immune modulators, regional delivery techniques, and new approaches to gene therapy. 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, particularly high-grade gliomas, 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 currently existing as either NABTC or NABTT who are submitting research grant applications to conduct Phase I/II clinical trials and ancillary laboratory studies. Each CNSC contains a Central Operations Office/Coordinating Center, a Pharmacokinetics Center, and a minimum of five Participant Member Institutions providing patient resources. Each consortium will consist of talented and experienced individuals in multiple disciplines (e.g. medical oncology, neurosurgery, neurology, radiation oncology, radiobiology, pharmacology, molecular biology, neuropathology, neuroradiology, and 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, OHRP 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 be comprised of a small consortium of institutions where for example the operations and statistical components are at different institutions. The lead institution for this small consortium must be a current full or provisional member of NABTC or NABTT. PHARMACOKINETICS CENTER - A central unit that performs or oversees performance of pharmacokinetic (PK) testing in support of clinical trials for the CNSC. Because of the complexity of performing timely PK analysis on specimens from multiple trials at multiple sites, applicants should thoroughly describe the logistics of sample acquisition and registration. This description would be particularly important if the PK studies are to be performed at more than one site. The PK Center may be comprised of a small consortium of institutions where for example different studies are performed at different institutions. The lead institution for this small consortium must be a current full or provisional member of NABTC or NABTT. It is anticipated that the Pharmacokinetics Center (as well as other CNSC components) may want to pursue laboratory projects other than PK projects directly linked to the clinical protocols. While this is encouraged, very limited support is available as discussed under "Research Goals and Scope". GROUP LEADER- The person who submits the application for the NABTT or NABTC Central Operations Office/Coordinating Center and who is responsible for the CNSC as a whole. The consortium of Participant Member Institutions must agree to work together with the Group Leader. The Group Leader is responsible for coordinating the CNSC activities scientifically and administratively. The Group Leader may also be the principal investigator on a Participant Member Institution application. The Group Leader need not be the Chair of the Steering Committee. PARTICIPANT MEMBER INSTITUTION - The individual research grant application from an institution that is participating in the CNSC at a clinical member institution or the Pharmacokinetics Center. The Participant Member Institution may conduct clinical trials and/or laboratory studies. PRINCIPAL INVESTIGATOR - The person who submits the single application for the Participant Member Institution and who is responsible for performance of the key personnel of that application. The Principal Investigator (PI) provides the scientific leadership for the Participant Member Institution. PROTOCOL CHAIRPERSON – The CNSC representative who is responsible for the overall design, performance, interpretation and publishing of a particular study for the CNSC. NCI SCIENTIFIC COORDINATOR - The Senior Investigator, Clinical Investigations Branch, CTEP, DCTD, NCI, (cited in the INQUIRIES SECTION) who interacts scientifically with the Applicant/Awardee Institutions. INVESTIGATIONAL DRUG BRANCH INVESTIGATOR - The Senior Investigator, Investigational Drug Branch, CTEP, DCTD, NCI, who is assigned to a particular DCTD IND agent and assists in the coordination of its development. NCI PROGRAM DIRECTOR - The extramural grants staff member, Clinical Grants and Contracts Branch, CTEP, DCTD, NCI, (cited in the INQUIRIES SECTION) who will coordinate DCTD interactions and provide guidance for the overall program within the NCI. He/she also serves in a back-up role for the NCI Scientific Coordinator. STEERING COMMITTEE - Each consortium's steering committee will be composed of the Group Leader, PIs, and the NCI Scientific Coordinator, and will be the main oversight body of the consortium. DISCRETIONARY FUND - A fixed portion ($125,000) of the award to the Central Operations Office/Coordinating Center that will be allocated according to the instructions of the Steering Committee. Appropriate uses may include seed funding for laboratory projects, shipment of samples, supplementation of existing budgets for patient accrual or special clinical costs, auditing of clinical trials, or other purposes. 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, particularly malignant gliomas, by providing support for consortia of institutions to take advantage of promising new developments and perform Phase I and II clinical evaluations of innovative approaches or agents. A secondary goal is to utilize the consortia as a mechanism for sharing human brain tumor specimens collected to a high quality control standard, and associated with clinical data, in order to facilitate collaborative NCI programs of molecular and genetic characterization of human gliomas. It is anticipated that two consortia will continue to be funded. Each CNSC will exist for the purpose of: (1) conducting multi-institutional phase I and II clinical trials to provide adequate patient populations and timely completion; (2) sharing expertise of researchers in multiple disciplines; and (3) sharing of tumor specimens and data useful in the conduct of clinical pharmacologic and correlative laboratory studies. Each CNSC will select the specific agents to be tested in accord with their scientific interest and expertise and will continue to develop a series of appropriate phase I or phase II trials with supporting protocol documents. Each applicant institution should submit documentation of participation in the CNSC in terms of patient accrual, study activation, study leadership, and correlative studies. Each application should document and describe the number of patients accrued, studies activated, correlative studies conducted, abstracts presented, and paper published. Each application should also document papers in press, abstracts to be presented, and studies pending as well participatory and accrual targets for the proposed cooperative agreement. Each CNSC must be able to document access to adequate numbers of patients with CNS tumors and a history of accrual of patients to clinical trials adequate to support 6-8 phase I or II trials per year. See below for more specific accrual requirements. In addition, the CNSC taken as an organization 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 collaborative laboratory studies, including immediately processed frozen tumors; (5) expertise in antineoplastic drug pharmacology/pharmacokinetics; (6) expertise in neuroimmunology relevant to potential clinical trials; and (7) capability for electronic exchange of patient imaging data, with appropriate protections, to support future research in new methods for identifying target effects of new agents. Each CNSC, with the assistance of the NCI Scientific Coordinator and Program Director, will develop a plan for prioritization of investigational trials. The NCI will provide assistance in design of trials and may provide NCI-sponsored IND agents or provide assistance to the awardee(s) by sponsoring or cross-referencing INDs for selected agents. Each CNSC is also encouraged to carry out some of its trials with agents or other interventions that are not sponsored by NCI. The correlative laboratory research program in a CNSC should have demonstrable capabilities to carry out correlative 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, blood-brain barrier research, mechanisms of invasion and spread, microenvironment, cytokine production or interactions, immune function and antigen expression, or other aspects that may have clinical implications or lead to new therapeutic approaches. It is not expected that funding for these clinical consortia will be adequate to support to completion high quality laboratory projects (other than pharmacokinetic projects directly linked to the clinical protocols). Some funding for laboratory pilot studies will be available through the CNSC Discretionary Fund. However, the expectation is that investigators from within the consortium membership will have in place or will seek other funding for laboratory projects that can draw upon and utilize the substantial tissue and clinical data resources of the CNSCs. The CNSCs will be encouraged to establish scientific interactions with Brain Tumor SPOREs and centers with funded Program Project Grants for brain tumor research. Such arrangements could be expected to leverage the relative strengths and funding of these differently focused NCI-supported programs. The intent is that each CNSC should establish under these cooperative agreements an infrastructure that will promote this type of interaction. 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. Laboratory studies should naturally be based on strong and testable hypotheses. It is not expected that funding for these clinical consortia will be adequate to support to completion high quality imaging projects (other than imaging projects directly linked to the clinical protocols). Some funding for pilot studies will be available through the CNSC Discretionary Fund. However, the expectation is that investigators from within the consortium membership will have in place or will seek other funding for imaging projects that can draw upon and utilize clinical data and image resources of the CNSCs. The intent is that each CNSC should establish under these cooperative agreements an infrastructure that will promote this type of interaction. 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 therapeutic approaches 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 in such areas as access to NCI investigational agents, potential collaborations, when appropriate, between the two adult CNSCs and/or the Pediatric Brain Tumor Consortium, and development of various standards that promote efficient clinical research, including integration of novel imaging technology into early clinical trials. (See Terms and Conditions of Award) SUPPLEMENTAL REQUIREMENTS The Central Operations Office/Coordinating Center as lead institution should submit a research grant application which lists the anticipated participant institutions, and include examples of ongoing and proposed new clinical protocols. (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, more than one application 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 of which they are a participating member site. Participant institutions conducting clinical trials may include copies of specific proposed CNSC clinical protocols in the Appendix, but this is not mandatory. For the Central Operation Office/Coordinating Center application only, there is a limit of 75 pages for the Research Plan sections A-D of the application. However, all other sections of applications for the Central Operation Office/Coordinating Center must adhere to the page limits in the PHS 398 instructions. All sections of applications for the Pharmacokinetics Center and Participant Member Institution providing patient resources must adhere to the page limitations in the PHS 398 instructions. Because the Terms and Conditions of Award discussed below 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 NCI staff involvement. The CNSC and the members of each proposed Consortium must demonstrate in the application the ability to meet the following requirements: 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 oncologists, neurologists, neurosurgeons, neuroimagers, neuropathologists, and neuroimmunologists. 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 below. 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 5 institutions, must have the demonstrated capability of accruing a minimum of 60-80 fully evaluable patients with histologically confirmed high-grade gliomas 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 5 clinical member institutions, a minimum of 15-20 such evaluable patients per institution per year will be required. 5. Each CNSC must demonstrate an active program at one or more of its participant institutions that utilizes human glioma specimens or cell lines and conducts laboratory studies relevant to the biology, clinical behavior, or response to therapeutic interventions of CNS tumors, particularly malignant gliomas. Experience with gliomas and/or other human CNS tumors must be documented by a record of publications or peer-reviewed grant support. 6. Each CNSC must demonstrate laboratory capabilities among one or more of its participant institutions sufficient to perform up to 5 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. 7. Each CNSC must demonstrate that at least 2 of its participating member sites will be capable of collecting and sharing human frozen brain tumor specimens collected to a high quality control standard from 20 or more gliomas per year, along with appropriate longitudinal clinical data, in support of collaborative NCI programs of molecular and genetic characterization of human gliomas. 8. Each CNSC must demonstrate among its investigator membership expertise in clinically relevant aspects of neuroimmunology and the development of immunologic therapeutics. 9. Each CNSC must have a plan in place for ongoing evaluation of institutional (member) performance in the context of consortium goals and for bringing on potential new sites 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 RFA. 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 advanced neuro-imaging and for radiation therapy, as well as available instrumentation for exchange of imaging data to a planned future central imaging center for the CNS consortia. 6. Appropriate drug control procedures as required for utilization of NCI-supplied experimental agents. 7. Capability of meeting FDA requirements in A3 above. 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, and travel. 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. MECHANISM OF SUPPORT This RFA will use the NIH U01 award mechanism. The NIH U01 is a cooperative agreement award mechanism in which the Principal Investigator retains the primary responsibility and dominant role for planning, directing, and executing the proposed project, with NIH staff being substantially involved as a partner with the Principal Investigator, as described under the section "Cooperative Agreement Terms and Conditions of Award". FUNDS AVAILABLE NCI intends to commit approximately $3.3 million in total costs for FY 2004 to fund two CNSCs. Applicants may request a project period of up to five years. Because the nature and scope of the proposed research will vary from application to application, it is anticipated that the size and duration of each award will also vary. Although the financial plans of NCI provide support for this program, awards pursuant to this RFA are contingent upon the availability of funds and the receipt of a sufficient number of meritorious applications. ELIGIBLE INSTITUTIONS Only current full and provisional members of either NABTC or NABTT are eligible to apply. INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS Any individual with the skills, knowledge, and resources necessary to carry out the proposed research is invited to work with their eligible institution to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH programs. SPECIAL REQUIREMENTS Cooperative Agreement Terms and Conditions of Award The administrative and funding instrument used for this program is a cooperative agreement (U01), an "assistance" mechanism (rather than an "acquisition" mechanism) in which substantial NIH scientific and/or programmatic involvement with the awardee is anticipated during 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 for the project as a whole, although specific tasks and activities in carrying out the studies will be shared among the awardee and the NCI Project Scientist. The role of the Cancer Therapy Evaluation Program (CTEP) 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 CTEP 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. 1. Awardees Rights and Responsibilities It is the responsibility of each CNSC (as represented by the Protocol Chairperson) to develop the details of the research design, including definition of objectives and approaches, planning, implementation, analysis, and publication of results, interpretations and conclusions of studies. A protocol is the detailed written plan of a clinical experiment. The protocol must be mutually acceptable to the CNSC and to the CTEP Protocol Review Committee (PRC), which must review and approve every protocol. The CNSC Central Operations Office/Coordinating Center, under the leadership of the Group 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 Group Leader with the assistance of the CNSC Central Operations Office/Coordinating Center. a. Clinical Trial Conduct The clinical trials must be conducted in accordance with the instructions in the INVESTIGATOR'S HANDBOOK, A Manual for Participants in Clinical Trials of Investigational Agents Sponsored by the Division of Cancer Treatment and Diagnosis, National Cancer Institute (URL: http://ctep.cancer.gov/handbook/) The Investigator's Handbook contains information on the following: Protocol Development and Submission Ordering Investigational Drugs from NCI Accountability and Storage of Investigational Drugs Reporting of Results to CTEP [including the Clinical Trials Monitoring Service (CTMS) and the Clinical Data Update System (CDUS)] Reporting Adverse Drug Reactions [including Adverse Event Expedited Reporting System (AdEERS) and the Common Toxicity Criteria (CTC)] Monitoring and Quality Assurance All Protocols utilizing investigational agents must include the NCI Standard Protocol Language (http://ctep.cancer.gov/guidelines/templates.html) and be conducted in accordance with the terms of the Intellectual Property Option to Collaborator. The Intellectual Property Option to Collaborator document may be accessed at http://ctep.cancer.gov/industry/ipo.html or may be obtained from the Regulatory Affairs Branch, CTEP, DCTD, NCI at 301-496-7912. b. Protocol Development and submission 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 Group Leader. The Group Leader shall designate a Protocol Chairperson for each proposed study. The Group Leader along with coordinating Central Operations Office/Coordinating Center staff will be responsible for communication with the appropriate CTEP staff. The CNSC Central Operations Office/Coordinating Center, under the leadership of the Group Leader, will submit CNSC protocols to the CTEP Protocol and Information Office in a timely fashion for review and approval by NCI. All protocols involving NCI sponsored agents should be preceded by an electronic Letter of Intent (LOI) from the CNSC to the CTEP LOI Coordinator declaring interest in conducting a particular study and using the suggested format described in the INVESTIGATOR'S HANDBOOK in Appendix VII, GUIDELINES FOR SUBMITTING LOIs - Letter of Intent/ INVESTIGATIONAL DRUG TRIAL. The LOI Submission Form is available at http://ctep.CANCER.GOV/guidelines/index.html. 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 of expeditious completion of the proposed study. The LOI must describe the rationale for correlative studies. If funding for correlative studies is not through the CNSC, the LOI must indicate the source of funding or plans to secure funding. LOIs may be submitted in response to a CTEP solicitation of proposals to conduct clinical trials with specific NCI-held IND agents or at any time through the investigator's own initiative. The LOI is reviewed by CTEP Protocol Review Committee for scientific merit and need based on the development plan. The LOI may be rejected, approved with the requirement for recommendations to be incorporated, or fully approved. If the LOI is approved, the CNSC must, with CTEP assistance, develop protocols and submit them for PRC review within 30-45 days of LOI approval (timeline determined at time of LOI approval). For some novel agents, CTEP may provide protocol templates to reduce the effort of multiple investigators duplicating similar efforts in repetitive aspects of protocol development. The protocol should define the scientific objectives and experimental approaches for the specific agent for which CTEP holds an IND. The protocol should define for reference, procedures for pharmacokinetic and other correlative studies. For all protocols, whether or not employing an NCI-supplied agent, the CNSC must designate a Protocol Chairperson for each proposed study. The Protocol Chairperson will be responsible for communication with the appropriate CTEP staff. The PI is responsible for coordinating protocol development, protocol submission, study conduct, quality control and study monitoring, drug ordering, data management and analysis, protocol amendments/status changes, adherence to requirements for reporting serious adverse events and adherence to requirements regarding investigational drug management and federally mandated regulations and protocol and performance reporting. The CNSC must electronically submit (as .doc or .pdf files) protocols to the CTEP Protocol and Information Office, the receiving office for all protocols sent to CTEP, for review as appropriate, prior to their implementation. Protocols will be developed and submitted and studies will be conducted in accordance with the INVESTIGATOR'S HANDBOOK. The Group 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. c. Protocol Review, Revision and Implementation Communication between the CNSC and CTEP at the various stages of protocol development and conduct is encouraged as necessary to promote efficient and well informed protocol development and implementation. The PRC will review each protocol (generally within 2 weeks of submission) and the Protocol Chairperson will receive electronically a Consensus Review (generally within 3 weeks of submission). Numbered comments may include comments requiring a response, recommendations and/or comments concerning the consent requiring a response, as well as recommendations and/or comments from the industrial cosponsor, if any. Each numbered comment must be addressed point by point in a cover letter that accompanies the revised protocol. For CTEP-sponsored agents, the revised protocol and cover letter must be received by the PIO within 2-4 weeks of the date on the Consensus Review (which will correspond with the date the Review is sent by e-mail to the Protocol Chairperson). The reasonable time to respond to the Consensus Review will be determined by CTEP based on the extent and complexity of required revisions. If the CNSC has not received the Consensus review within 4 weeks from protocol submission, the PI should contact the PIO. Access to e-mail and ability to attach, send and receive documents (for example, protocols, amendments, and correspondence) via e-mail is required. Protocols can only be activated after review and approval by the Institutional Review Board (Form OMB No.0990-0263 Protection of Human Subjects: Assurance Identifications/IRB Certification/Declaration of Exemption (Common Rule) must be submitted. See OHRP website http://www.hhs.gov/ohrp/assurances/assurances_index.html under Related Forms and Procedures) the PRC, and the CTEP Coordinator and only after receipt of the protocol approval letter from NCI. The specific requirements of Protocol Submission, Review and Approval are described in the INVESTIGATOR'S HANDBOOK. The CNSC must notify the Protocol and Information Office in writing of each study status change at the time of status change. (For definition of study status see the INVESTIGATOR'S HANDBOOK). d. Study Conduct and Monitoring The CNSC and each awardee institution is responsible for the ensuring accurate and timely progress of each study and reporting of results to CTEP as the study sponsor through: 1) screening, registering and treating the planned number of patients on study in the time frame agreed to at the time of LOI or protocol approval; 2) appropriate patient follow-ups beyond that specified in the protocol (e.g., after adverse events, progressive disease or patient withdrawal); 3) 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, and assuring the all the relevant parties (nursing and pharmacy staff) are notified of the current dose level and assigned dose level for an individual patient; 4) 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; 5) ongoing assessment of patient eligibility and evaluability; 6) timely medical review and assessment of patient data; by the study chairperson and PI Investigator; 7) rapid reporting of serious treatment-related morbidity (adverse event reactions) electronically through AdEERS in compliance with FDA regulations and measures to ensure communication of this information to all parties [http://ctep.cancer.gov/reporting/adeers.html]; 8) interim evaluation and consideration of measures of outcome, as consistent with patient safety and good clinical trials practice; 9) conduct of pharmacokinetics and other laboratory correlative studies throughout the course of the clinical trial, to facilitate optimal utilization of data generated by such research efforts; and 10) timely communication of interim and final results of studies to CTEP and timely preparation, submission and publication of manuscripts to ensure communication to the scientific community. e. Data Management, Analysis and Reporting The CNSC and each awardee will develop procedures to ensure that data collection and management have: a) acceptable quality assurance standards; and b) procedures that are as simple as appropriate in order to encourage maximum participation of physicians entering patients and to avoid unnecessary expense. Quality assurance at a minimum must consist of: 1) 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. 2) Radiation Therapy: Review (either concurrent or retrospective) of simulation and port films as well as compliance with protocol-specified doses and target volumes for individual patients, where relevant. Determination of adequacy of radiation delivery with respect to treatment equipment, treatment planning, and quality assurance. 3) Chemotherapy: Review of pharmacy orders, investigational drug record keeping, drug administration, flow sheets and drug distribution with determination of protocol compliance in dose administration and dosage modification. 4) Surgery: Assessment of adequacy of protocol-specified surgical procedures (where relevant) through review of operative notes and study-specific surgical forms. 5) Imaging: Assessment of adequacy of protocol-specified imaging procedures. This would include (1) methods for acquisition and display of images; (2) methods for monitoring quality of image interpretation including quantitative measurement of lesions; and (3) methods of data archiving and retrieval as appropriate to specific studies. 6) Laboratory: For pharmacokinetic and correlative studies, quality assurance procedures for the laboratory assays must be established. These may include such elements as assay validation procedures, calibration curves, check samples, standards for accepting or rejecting data such as Shewart charts, positive and negative controls, etc., as well as external quality assurance if it is available. Procedures for ensuring patient privacy and sample tracking must be established by the CNSC 7) Reporting of pharmacokinetic results: For certain specific CTEP investigational agents, pharmacokinetic data results may be required to be reported to the Clinical Trials Monitoring Service (CTMS) using case report forms available from Theradex. It is anticipated that most studies will involve assays in (near) real time during the course of the study. The schedule for sample assay should be established in the written protocol (e.g., for each patient in real time, or for a cohort of patients at a particular dose, or after each nth patient as appropriate for a specific study). 8) Reporting of correlative studies results: The performance of correlative studies, including the number of patients studied; the number of samples; imaging studies or other procedures done; the number of samples or other procedures completed with results; and overall conclusions of these studies to date should be reported to the CDUS or CTMS as determined by the written protocol. f. Investigational Drug Management Investigators performing trials in the CNSCs must be NCI registered investigators (Form FDA 1572) and will be expected to implement CTEP requirements described in the 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. g. Compliance with Federally Mandated Regulatory Requirements Each awardee is responsible for establishing procedures to comply with FDA regulations for studies involving investigational agents and Office for Human Research Protections (OHRP) requirements for the protection of human subjects, and NIH requirements for data and safety monitoring of clinical trials http://grants.nih.gov/grants/guide/notice-files/not98-084.html with additional description at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-038.html. These procedures are: 1) Methods for ensuring that the each awardee institution has a current, approved assurance on file with the OHRP; that each protocol is reviewed and approved by the responsible Institutional Review Board (IRB) and CTEP PRC prior to patient entry; that each protocol is reviewed at least annually by the IRB so long as the protocol is active; that amendments are approved by the IRB; 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. In the case of multi-center protocols, the PI must assure that full IRB approval is obtained prior to patient entry at any subcontracted institution, that yearly reapprovals are conducted in a timely fashion and that amendments and serious adverse events are properly reported to each subcontracted institution's IRB. The PI must maintain documentation of initial approval, yearly reapproval, amendment reviews and reporting of serious adverse events for all participating institutions. 2) A system for ensuring 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). http://ctep.cancer.gov/reporting/adeers.html. This will require reporting Adverse Event Reactions (AERs) through AdEERS and/or by telephone to the responsible IDB Senior Clinical Investigator within 24 hours of the event and requires a written report to follow within 10 working days. (See 2. NCI Staff Responsibilities for definition of responsible IDB Senior Clinical Investigator Physician.) 3) A described system for ensuring that data safety monitoring is performed in accordance with NIH requirements h. Reporting Requirements: 1) Routine Protocol Reporting. Reporting requirements will be in agreement with FDA regulations and NCI procedures. The timely and accurate reporting of data from investigational drug trials to the sponsor in a format that is easily integrated is a critical responsibility for Good Clinical Practice and is an important responsibility of investigators doing research with IND drugs. The receipt of these data in a timely fashion is not an arbitrary requirement. The information contained in them is the material, which informs CTEP of the progress of the development of the drug, ensures safety and suggests promising new directions. The material is required by CTEP to meet its obligations under FDA regulations to (a) monitor the study and (b) submit regular reports of current findings to that agency. 2) All trials conducted by the CNSCs will require NCI-sponsored data monitoring. Some trials will require monitoring by the Clinical Trials Monitoring Services (CTMS). Information must be provided to the CTMS at two week intervals and includes: registration of each patient entered onto the protocol within the previous two week period, and all data obtained on each registered patient within the previous two weeks. Investigators are reminded that a course does not need to be complete to submit interval data to CTMS, as this system is designed to accept partial information and additional information for each case report form as it is generated. Most of trials performed by the CNSCs will have data submission via the Clinical Data Update System (CDUS), with less frequent reporting requirements (monthly or quarterly rather than biweekly). This reporting system is generally used for studies later in the development of a specific agent when substantial safety information suggests that frequent oversight by the IND sponsor is less critical for patient safety. 3) Adverse Events Reporting CNSC investigators must promptly report adverse events (AEs) in accordance with the NCI Guidelines for Adverse Event Reporting found at the following URL: http://ctep.cancer.gov/reporting/adeers.html. CTEP has developed operational definitions of Adverse Events (AEs) that apply to anticancer drug trials. These definitions are described in the Common Toxicity Criteria, Version 2.0 (CTC v2.0) available at the following URL: http://ctep.cancer.gov/reporting/ctc.html. Additional information about reporting adverse events is included in the CTC Manual and other CTC sources at: http://ctep.cancer.gov/reporting/ctc.html. The prompt reporting of AEs to CTEP is the responsibility of each investigator engaged in clinical research with investigational drugs supplied by the NCI and of the PI for the award. It should be noted that verbal/telephone communication of all new adverse events as well as all life-threatening (Grade 4, unless otherwise defined in the specific protocol) or lethal (Grade 5) adverse events is mandated for this process and facilitates discussion and assessment by both sponsor and investigator. See the above referenced URL for specific requirements for Adverse Event Reporting. These should be detailed in the text of the protocols using the CTEP table and additional protocol specific information. All adverse events for NCI-sponsored trials are reported using CTC Version 3.0 as documented in the protocol. i. On-site Audits: These will be carried out at appropriate intervals at all participating performance sites, in accordance with policies for CTEP-sponsored trials, as outlined in the INVESTIGATORS HANDBOOK. j. Publication of Data: Timely publication of major findings is encouraged. 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, will periodically review the data and may perform special analyses of the data. The awardees will retain custody and primary rights to the data consistent with current HHS, PHS, and NIH policies. k. Intellectual Property Awardees agree to promptly notify the NCI and the commercial Collaborator, if appropriate, in writing of any inventions, discoveries or innovations made by the Awardees' investigators or any other employees or agents of Awardees, whether patentable or not, which are conceived and/or first actually reduced to practice in the performance of this study using the commercial Collaborator's Agent (hereinafter "Awardee Inventions"). Awardees agree to notify NCI and Collaborator in writing upon the filing of any patent applications related to the research with the Agent. Awardees agree to grant to Collaborator: (i) a paid-up nonexclusive, nontransferable, royalty-free, world-wide license to all Awardee Inventions for research purposes only; and (ii) a time-limited first option to negotiate an exclusive, world-wide royalty-bearing license for all commercial purposes, including the right to grant sub-licenses, to all Awardee Inventions on terms to be negotiated in good faith by Collaborator and Awardees. Collaborator shall notify Awardees, in writing, of its interest in obtaining an exclusive license to any Awardee Invention within six (6) months of Collaborator's receipt of written notice of such Awardee Invention(s). In the event that Collaborator fails to so notify Awardees, or elects not to obtain an exclusive license, then Collaborator's option shall expire with respect to that Awardee Invention, and Awardees will be free to dispose of its interests in such Awardee Invention in accordance with Awardee policies. If Awardee and Collaborator fail to reach agreement within ninety (90) days, (or such additional period as Collaborator and Awardees may agree) on the terms for an exclusive license for a particular Awardee Invention, then for a period of six (6) months thereafter Awardee shall not offer to license the Awardee Invention to any third party on materially better terms than those last offered to Collaborator without first offering such terms to Collaborator, in which case collaborator shall have a period of thirty (30) days in which to accept or reject the offer. Awardees agree that notwithstanding anything herein to the contrary, any inventions, discoveries or innovations, whether patentable or not, which are not Subject Inventions as defined in 35 USC 201(e),* arising out of any unauthorized use of the Collaborator's Agent and/or any modifications to the Agent, shall be the property of the Collaborator (hereinafter "Collaborator Inventions"). Awardees will promptly notify the NCI and Collaborator in writing of any such Collaborator Inventions and, at Collaborator's request and expense, Awardees will request permission from the NIH*, if necessary, to cause to be assigned to Collaborator all right, title and interest in and to any such Collaborator Inventions and provide Collaborator with reasonable assistance to obtain patents (including causing the execution of any invention assignment or other documents). Awardees may also be conducting other more basic research using the Agent under the authority of a separate Material Transfer Agreement (MTA), or other such agreement with the NCI or Collaborator. Inventions arising there under shall be subject to the terms of the separate MTA, and not to this clause. * 35 USC 201 (e): The term 'subject invention' means any invention of the contractor conceived or first actually reduced to practice in the performance of work under a funding agreement: Provided, That in the case of a variety of plant, the date of determination (as defined in section 41(d) (FOOTNOTE 1) of the Plant Variety Protection Act (7 U.S.C. 2401(d))) must also occur during the period of contract performance. 2. 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 Scientific Coordinator who will provide expert advice to the awardee on specific scientific and/or analytic issues as described below. The NCI Program Director will be the contact point for interactions with the awardee related to monitoring of the award. The NCI Program Director will also serve in a back-up role for the NCI Scientific Coordinator. An Investigational Drug Branch Senior Clinical Investigator is assigned to each DCTD IND agent to assist in the coordination of its development. The role of CTEP 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 CTEP 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. In general NCI staff will be expected to serve as a resource with respect to other ongoing NCI activities that may be relevant to the protocol to facilitate compatibility and avoid unnecessary duplication of effort. NCI staff will provide advice in the management and technical performance of the investigations, coordinating clearances for investigational agents held by NCI. NCI staff will also review and approve protocols to insure they are within the scope of peer review and for safety considerations, as required by Federal regulations. NCI staff will monitor protocol progress, and may request that a protocol study be closed to accrual for reasons described below (see CTEP Involvement in Protocol Closure). Specific NCI responsibilities include: a. Provision of NCI-sponsored Investigational Agents and Responsibilities of IND Sponsor CTEP will supply some of the investigational agents to be studied and will be the IND Sponsor for these agents. CTEP will submit Investigational New Drug Applications to the FDA permitting DCTD to act as a drug sponsor. As a sponsor of an investigational drug, DCTD, and specifically CTEP, is responsible for seeing that clinical trials proceed safely and rationally from the initial dose-finding studies through the definitive evaluation of the new drug in the treatment of one or more specific cancers. b. CTEP as a Scientific Resource for NCI-supported Phase I and II Clinical Investigations and CTEP Assistance in Protocol Development The NCI Scientific Coordinator and the responsible Investigational Drug Branch investigator will serve as a resource available to the Principal Investigator (PI) for specific scientific information with respect to treatment regimens and clinical trial design. The NCI Scientific Coordinator and/or responsible Investigational Drug Branch investigator will advise the PI of potential studies that will be relevant to new avenues of cancer therapy. The NCI Scientific Coordinator and/or the responsible Investigational Drug Branch investigator will work collaboratively with the PI and Protocol Chairperson to define the objectives and experimental approaches. The NCI Scientific Coordinator and/or responsible Investigational Drug Branch investigator will assist the PI as appropriate in developing information concerning the scientific basis for specific trials and also will advise the PI of the nature and results of relevant trials being carried out under NCI sponsorship. The NCI Scientific Coordinator and/or responsible Investigational Drug Branch investigator will also provide updated information on the efficacy and toxicity of investigational new agents supplied to the PI under an Investigational New Drug (IND) Application sponsored by the DCTD. CTEP provides each investigator working with agents under CTEP IND with copies of all serious adverse event reports filed with the FDA for that agent. Because several portions of protocols are based on generic information about the agent under study, the Investigational Drug Branch investigator will endeavor to provide protocol templates with agent specific information and other generic information to the investigators. This facilitates both protocol writing and protocol review. c. Protocol Review The CTEP Protocol Review Committee (PRC), must review and approve every protocol proposed for the CNSCs, whether or not they involve DCTD investigational agents. The PRC, which meets weekly, is chaired by the Associate Director, CTEP, and is comprised of professional staff of the DCTD including the Investigational Drug Branch investigators, Clinical Investigations Branch disease coordinators, biostatisticians, Radiation Research Program staff, and NCI experts in surgery, diagnostic radiology, and cancer biomarker research, regulatory staff, pharmacy staff and ad hoc reviewers external to NCI when deemed appropriate by the PRC chairperson. The major considerations include: 1) the strength of the scientific rationale supporting the study; 2) the medical importance of the question being posed; 3) the probability that the trial design will provide a clear answer to the questions posed, 4) the avoidance of unnecessary duplication with other ongoing studies; 5) the appropriateness of study design with respect to development of any IND agent; 6) a satisfactory projected accrual rate and follow-up period; 7) patient safety; 8) plans for compliance and track record of compliance with federal regulatory requirements; 9) adequacy of data management; 10) appropriateness of patient selection, evaluation, assessment of toxicity, response to therapy and follow-up 11) clarity of methods and quality assurance measures for correlative studies Following the review of the protocol by the PRC, the responsible Investigational Drug Branch investigator will provide the PI with a consensus review. The consensus review summarizes the PRC review and describes required or recommended modifications and other suggestions, as appropriate. (See the INVESTIGATOR'S HANDBOOK, for further information regarding protocol review at CTEP). If a proposed protocol is disapproved, the specific reasons for lack of approval will be communicated to the PI as a consensus review within 30 days of protocol receipt by the NCI. The NCI Scientific Coordinator and/or responsible Investigational Drug Branch investigator will be available to assist the PI in developing a mutually acceptable protocol, consistent with the research interests, abilities and strategic plans of the PI and of the NCI. An arbitration system, as detailed below, will be available to resolve disagreements between the NCI and the awardee. NCI will not provide investigational agents or permit expenditure of NCI funds for a protocol that it has not approved unless CTEP's disapproval has been modified by the arbitration process outlined below. The PRC will also formally review Letters of Intent (LOI) for CTEP- supplied investigational agents. Following LOI review, the responsible Investigational Drug Branch investigator will provide a Program response to the PI and will address the following issues for approved LOI: 1) the existence and nature of concurrent clinical trials in the area of research, pointing out possible duplication of effort; 2) information including relevant pharmacokinetic and pharmacodynamic data concerning investigational agents; 3) availability of investigational agents; 4) the scientific rationale and value of the proposed study, the design, the statistical requirements; 5) the projected accrual rate; 6) correlative laboratory studies; and 7) the implementation of the study, if indicated. The LOI mechanism is designed for preliminary review and is recommended to expedite protocol development and implementation, to avoid duplication and to facilitate agreement on study priority and design (see the DCTD INVESTIGATORS HANDBOOK, available at web site http://ctep.cancer.gov/handbook/. d. CTEP Review of Federally Mandated Regulatory Requirements The NCI Scientific Coordinator and/or 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. The NCI Scientific Coordinator and/or 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). The Chief, Clinical Trials Monitoring Branch (CTMB) will review protocols to determine if the awardee's mechanisms for meeting FDA regulatory requirements for studies involving DCTD-sponsored investigational agents and the Office Human Research Protection (OHRP) requirements for the protection of human subjects are sufficient. These comments are incorporated into the protocol consensus review. (See Awardee's Rights and Responsibilities). As sponsor for investigational agents and the funding agency for cancer clinical trials, FDA regulations require the DCTD to maintain a monitoring program. Furthermore, DHHS regulations require monitoring plans for all clinical trials done under NIH sponsorship. The NCI must ensure that research data generated under its sponsorship are of high quality, reliable and verifiable. On-site monitoring is a requirement for investigators conducting clinical trials under NCI sponsorship. The Clinical Trials Monitoring Branch of CTEP provides direct oversight of the monitoring programs which includes auditing. The purpose of the audit is to document the accuracy of submitted data and to verify investigator's compliance with protocol and regulatory requirements. One of the objectives of conducting site visits is to bring the FDA regulatory requirements which affect various aspects of the conduct of clinical studies to the attention of individual investigators. The examination/audit will include, but may not be limited to the following: 1) Full and non-contingent Institutional Review Board (IRB) approvals and reapprovals; 2) copies of the IRB approval, including approvals for all amendments; 3) copies of the annual reports on the progress of the study and copies of IRB reapprovals for studies continuing beyond the first anniversary of the IRB approval date; 4) written informed consent obtained on the form approved by the IRB and the documentation of written informed consent for all the patients entered onto a study. The informed consent form signed by the patient at the time of study entry must be the most current version available from the IRB; 5) adherence to the protocol details; 6) adverse events and medical records to review classification of adverse experiences and the reporting to the IRB and the NCI of unusual or unexpected events, as well as events defined as requiring expedited reporting (serious and unexpected events) and all adverse events reported in case report forms; 7) record keeping and record retention in accordance with the regulatory requirements; 8) investigational agent accountability. e. CTEP Involvement in Protocol Closure The NCI Scientific Coordinator and/or responsible Investigational Drug Branch investigator and the Chief, CTMB will monitor protocol progress. The NCI Program Director or the responsible Investigational Drug Branch investigator may request that a protocol be closed to accrual for reasons including: 1) insufficient accrual rate; 2) accrual goal met; 3) poor protocol performance; 4) patient safety and regulatory concerns; 5) study results are already conclusive; 6) emergence of new information that diminishes the scientific importance of the study question; and 7) failure to collect or transmit data in a timely manner. NCI will not provide investigational agents or permit expenditures of NCI funds for a study after requesting closure (except for patients already on-study). If disagreements develop over NCI- recommended study closure for reasons other than patient safety or regulatory concerns, NCI will establish an arbitration process to resolve disagreements between the NCI and the awardee. f. Access to Data The NCI will have real-time access to all data generated under this cooperative agreement, will periodically review the data and may perform special data analyses. 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 of and primary rights to the data consistent with current HHS, PHS, and NIH policies. g. CTEP Review of Progress Progress will be reviewed annually by the NCI Scientific Coordinator and the NCI Program Director on the basis of the information provided at the semi-annual meetings, in the continuation application, and in the study summary reports submitted to CTEP via CDUD or CTMS. In addition, periodic accrual information may be requested from the PI 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 Special Terms and Conditions of Award, may result in a reduction of budget, withholding of support, suspension or termination of the award. 3. Collaborative Responsibilities Steering Committee The Steering Committee for each CNSC will be composed of the Group Leader, Principal Investigators of Participant Member Institutions, and NCI Scientific Coordinator. The Group Leader will serve as Chairperson of the Steering Committee. He/she is responsible for coordinating the Committee activities, for preparing meeting agendas, and for scheduling and chairing meetings. The Steering Committee has primary responsibility to design research activities, establish priorities, and develop and provide preliminary approval of protocols (prior to submission to NCI and final NCI approval). The Steering Committee will also authorize the spending of funds from the Discretionary Fund. Appropriate uses may include funding for pilot laboratory studies, shipment of specimens, and supplementing existing budgets for patient accrual and auditing of clinical trials. The Steering Committee Chairperson will document actions taken and progress in written reports to the NCI Program Director, and will provide periodic supplementary reports to designated NCI staff upon request. The collaborative protocols will be developed by the Steering Committee. Data will be submitted centrally to the Central Operations Office/Coordinating Center. Protocols will define rules regarding access to data and publications. Awardees will be required to accept and implement the common protocol and procedures approved by the Steering Committee. An independent advisory board can be helpful in assisting the consortia in prioritizing their programs, in serving as an independent monitoring committee for particularly challenging studies, etc. 4. Arbitration Any disagreement that may arise on scientific/programmatic matters (within the scope of the award), between award recipients and the NCI may be brought to arbitration. An arbitration panel will be composed of three members - one selected by the Steering Committee (with the NCI representation not voting) or by the individual awardee in the event of an individual disagreement, a second member selected by NCI, and the third member selected by the two prior selected members. This special arbitration procedure in no way affects the awardee's right to appeal an adverse action that is otherwise appealable in accordance with the PHS regulations at 42 CFR Part 50, Subpart D and HHS regulation at 45 CFR Part 16. WHERE TO SEND INQUIRIES We encourage inquiries concerning this RFA and welcome the opportunity to answer questions from potential applicants. Inquiries may fall into three areas: scientific/research, peer review, and financial or grants management issues: Direct your questions about scientific/research issues to: Richard Kaplan, M.D. (NCI CNSC Scientific Coordinator) Chief, Clinical Investigations Branch Cancer Therapy Evaluation Program Division of Cancer Therapy and Diagnosis 6130 Executive Boulevard, Room 7025, MSC 7436 Bethesda, MD 20892-7436 Telephone: (301) 496-2522 FAX: (301) 402-0557 Email: kaplanr@ctep.nci.nih.gov or Steven Krosnick, M.D. (NCI CNSC Program Director) Clinical Grants and Contracts Branch Cancer Therapy Evaluation Program Division of Cancer Therapy and Diagnosis 6130 Executive Boulevard, Room 7009, MSC 7432 Bethesda, MD 20892-7432 Telephone: (301) 496-8866 FAX: (301) 480-4663 Email: krosnicks@ctep.nci.nih.gov Direct your questions about peer review issues to: Referral Officer Division of Extramural Activities National Cancer Institute 6116 Executive Boulevard, Room 8041, MSC 8329 Bethesda, MD 20892-8329 Telephone: (301) 496-3428 FAX: (301) 402-0275 Email: ncirefof@dea.nci.nih.gov Direct your questions about financial or grants management matters to: Ms. Kelli Oster National Cancer Institute Executive Plaza South, Room 243 6120 Executive Boulevard MSC 7150 Bethesda, MD 20892-7150 Telephone: (301) 496-8627 FAX: (301) 496-8601 E-mail: ko31u@nih.gov LETTER OF INTENT Prospective applicants are asked to submit a letter of intent that includes the following information: o Descriptive title of the proposed research (indicate whether the application represents the Central Operations Office/Coordinating Center, the Pharmacokinetics Center, or a Participant Member Institution providing patient resources) o Name, address, and telephone number of the Principal Investigator o Names of other key personnel o Participating institutions (included under the application, not the CNSC as a whole) o Number and title of this RFA Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows NCI staff to estimate the potential review workload and plan the review. The letter of intent is to be sent by the date listed at the beginning of this document. The letter of intent should be sent to: Steven Krosnick, M.D. (NCI CNSC Program Director) Clinical Grants and Contracts Branch Cancer Therapy Evaluation Program Division of Cancer Therapy and Diagnosis 6130 Executive Boulevard, Room 7009, MSC 7432 Bethesda, MD 20892-7432 Telephone: (301) 496-8866 FAX: (301) 480-4663 Email: krosnicks@ctep.nci.nih.gov SUBMITTING AN APPLICATION Applications must be prepared using the PHS 398 research grant application instructions and forms (rev. 5/2001). The PHS 398 is available at http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format. For further assistance contact GrantsInfo, Telephone (301) 435-0714, Email: GrantsInfo@nih.gov. USING THE RFA LABEL: The RFA label available in the PHS 398 (rev. 5/2001) application form must be affixed to the bottom of the face page of the application. Type the RFA number on the label. Failure to use this label could result in delayed processing of the application such that it may not reach the review committee in time for review. In addition, the RFA title and number must be typed on line 2 of the face page of the application form and the YES box must be marked. The RFA label is also available at: http://grants.nih.gov/grants/funding/phs398/label-bk.pdf. SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten original of the application, including the Checklist, and three signed photocopies, in one package to: Center for Scientific Review National Institutes of Health 6701 Rockledge Drive, Room 1040, MSC 7710 Bethesda, MD 20892-7710 Bethesda, MD 20817 (for express/courier service) At the time of submission, two additional copies of the application must be sent to: Referral Officer Division of Extramural Activities National Cancer Institute 6116 Executive Blvd., Room 8041, MSC-8329 Rockville, MD 20852 (express courier) Bethesda MD 20892-8329 APPLICATIONS HAND-DELIVERED BY INDIVIDUALS TO THE NATIONAL CANCER INSTITUTE WILL NO LONGER BE ACCEPTED. This policy does not apply to courier deliveries (i.e. FEDEX, UPS, DHL, etc.) (http://grants.nih.gov/grants/guide/notice-files/NOT-CA-02-002.html) This change in practice is effective immediately. This policy is similar to and consistent with the policy for applications addressed to Centers for Scientific Review as published in the NIH Guide Notice http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-012.html. APPLICATION PROCESSING: Applications must be received by the application receipt date listed in the heading of this RFA. If an application is received after that date, it will be returned to the applicant without review. The Center for Scientific Review (CSR) will not accept any application in response to this RFA that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. The CSR will not accept any application that is essentially the same as one already reviewed. This does not preclude the submission of substantial revisions of applications already reviewed, but such applications must include an Introduction addressing the previous critique. PEER REVIEW PROCESS Upon receipt, applications will be reviewed for completeness by the CSR and for responsiveness by the NCI program staff. Incomplete applications will be returned to the applicant without further consideration. Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened by the Division of Extramural Activities (DEA) at NCI in accordance with the review criteria stated below. As part of the initial merit review all applications will: o Receive a written critique o Undergo a process in which only those applications deemed to have the highest scientific merit, generally the top half of the applications under review, will be discussed and assigned a priority score o Receive a second level review by the National Cancer Advisory Board. REVIEW CRITERIA The goals of NIH-supported research are to advance our understanding of biological systems, improve the control of disease, and enhance health. In the written comments, reviewers will be asked to discuss the following aspects of an application in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals: o Significance o Approach o Innovation o Investigator o Environment The scientific review group will address and consider each of these criteria in assigning an application's overall score, weighting them as appropriate for each application and type of submission (i.e., Central Operations Office/Coordinating Center, the Pharmacokinetics Center, or Participant Member Institutions providing patient resources). An application does not need to be strong in all categories to be judged likely to have major scientific impact and thus deserve a high priority score. For example, you may propose to carry out important work that by its nature is not innovative but is essential to move a field forward. (1) SIGNIFICANCE: Does the research plan address an important problem? If the aims of the application are achieved, how do they advance scientific knowledge? What will be the effect of these studies on the concepts or methods that drive this field? (2) APPROACH: Are the conceptual framework, design, methods, and analyses adequately developed, scientifically meritorious, well integrated, feasible and appropriate to the aims of the multi- institutional project? Are potential problem areas acknowledged and alternative tactics considered? Are there plans for effective collaboration between laboratory and clinical investigators and the Central Operations Office/Coordinating Center within the consortium as well as with outside groups such as other consortia and NCI researchers focusing on CNS tumors? Within the CNSC, though not necessarily at each institution, is there a plan for developing one or more laboratory programs that can utilize the resources provided by the CNSC's clinical trials? Is there an established plan for prioritization and distribution of specimens to collaborating laboratories? Does the Center Operations Office/Coordinating Center demonstrate effective plans for administration, experimental design, quality control, study monitoring, data management and reporting, statistical analysis, and compliance with regulatory requirements? Do Participant Member Institutions conducting clinical trials demonstrate plans for accrual, care, and follow-up of sufficient numbers of evaluable patients for CNSC Phase I and II clinical trials? Additionally, are there plans for data collection and data transfer to the Central Operations Office/Coordinating Center? Do Participant Member Institutions conducting clinical trials also demonstrate plans for pathology support for tumor classification as well as distribution of patient specimens for concurrent and future studies? Does the Pharmacokinetics Center demonstrate the feasibility and scientific merit of proposed studies and of plans to carry out pharmacokinetic analyses in a timely and effective manner? (3) INNOVATION: Does the application propose novel concepts, strategies, approaches, or methods? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? (It is understood that dose finding and efficacy-seeking clinical trials may not be innovative. However, innovative study designs may be proposed that consider the unique biology and environment of high-grade gliomas within the central nervous system. Also, proposed correlative studies may use innovative approaches to better understand the mechanism of action of an intervention as well as for the evaluation or prediction of patient response.) (4) INVESTIGATOR: Are the Group Leader, Principal Investigators, and the key personnel appropriately trained and well suited to carry out this work? Are the qualifications and research experience of the Group Leader, Principal Investigators, and the key personnel appropriate for the respective design and administration of multi-institutional clinical, pharmacokinetic, and correlative laboratory oncology studies? Is there evidence of commitment of the Group Leader, of each Principal Investigator and of multidisciplinary key personnel to the goals of the CNSC? (5) ENVIRONMENT: Does the scientific environment in which the proposed work will be done contribute to the probability of success? Do the proposed experiments take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of institutional support? Does the Central Operations Office/Coordinating Center demonstrate adequacy of the available facilities, data management resources, and personnel? Does the Central Operations Office/Coordinating Center also demonstrate evidence of the competence with regard to administration, experimental design, quality control, study monitoring, data management and reporting, statistical analysis, and compliance with regulatory requirements? Do both the Central Operations Office/Coordinating Center and participant Member Institutions conducting clinical trials demonstrate access to sufficient numbers of evaluable patients with gliomas for Phase I and II clinical trials, the capacity to follow these patients successfully, and access to adequately processed tissue samples from a proportion of these patients? Do Participant Member Institutions conducting clinical trials demonstrate adequate expertise in the areas of medical or neuro- oncology, surgery, radiation oncology, imaging, pathology, and data management to carry out and/or care for patients on clinical trials? Is there adequate state-of-the-art radiotherapy and imaging equipment? (The availability of equipment for stereotactic radiosurgery and brachytherapy as well as MRS, PET and other advanced imaging techniques will be considered favorable additional assets for a Participant Member Institution conducting clinical trials, although not required for this application.) Does the Pharmacokinetics Center demonstrate adequacy of equipment and resources to carry out pharmacokinetic analyses in a timely and effective manner, as well as appropriate experience of the personnel? ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, your application will also be reviewed with respect to the following: PROTECTIONS: The adequacy of the proposed protection for humans, animals, or the environment, to the extent they may be adversely affected by the project proposed in the application. INCLUSION: The adequacy of plans to include subjects from both genders, all racial and ethnic groups (and subgroups), and children as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. (See Inclusion Criteria included in the section on Federal Citations, below) DATA SHARING: The adequacy of the proposed plan to share data. BUDGET: The reasonableness of the proposed budget and the requested period of support in relation to the proposed research. RECEIPT AND REVIEW SCHEDULE o Letter of Intent Receipt Date: February 21, 2003 o Application Receipt Date: March 28, 2003 o Peer Review Date: June-July 2003 o Council Review: September 2003 o Earliest Anticipated Start Date: December 2003 AWARD CRITERIA Award criteria that will be used to make award decisions include: o Scientific merit (as determined by peer review) o Availability of funds o Programmatic priorities. REQUIRED FEDERAL CITATIONS MONITORING PLAN AND DATA SAFETY AND MONITORING BOARD: Research components involving Phase I and II clinical trials must include provisions for assessment of patient eligibility and status, rigorous data management, quality assurance, and auditing procedures. In addition, it is NIH policy that all clinical trials require data and safety monitoring, with the method and degree of monitoring being commensurate with the risks (NIH Policy for Data Safety and Monitoring, NIH Guide for Grants and Contracts, June 12, 1998: http://grants.nih.gov/grants/guide/notice-files/not98-084.html). Clinical trials supported or performed by NCI require special considerations. The method and degree of monitoring should be commensurate with the degree of risk involved in participation and the size and complexity of the clinical trial. Monitoring exists on a continuum from monitoring by the principal investigator/project manager or NCI program staff or a Data and Safety Monitoring Board (DSMB). These monitoring activities are distinct from the requirement for study review and approval by an Institutional review Board (IRB). For details about the Policy for the NCI for Data and Safety Monitoring of Clinical trials see: http://deainfo.nci.nih.gov/grantspolicies/datasafety.htm. For Phase I and II clinical trials, investigators must submit a general description of the data and safety monitoring plan as part of the research application. See NIH Guide Notice on "Further Guidance on a Data and Safety Monitoring for Phase I and II Trials" for additional information: http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-038.html. Information concerning essential elements of data safety monitoring plans for clinical trials funded by the NCI is available: http://www.cancer.gov/clinical_trials/. INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH: It is the policy of the NIH that women and members of minority groups and their sub-populations must be included in all NIH-supported clinical research projects unless a clear and compelling justification is provided indicating that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing clinical research should read the AMENDMENT "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research - Amended, October, 2001," published in the NIH Guide for Grants and Contracts on October 9, 2001 (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); a complete copy of the updated Guidelines are available at http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_ 2001.htm. The amended policy incorporates: the use of an NIH definition of clinical research; updated racial and ethnic categories in compliance with the new OMB standards; clarification of language governing NIH-defined Phase III clinical trials consistent with the new PHS Form 398; and updated roles and responsibilities of NIH staff and the extramural community. The policy continues to require for all NIH- defined Phase III clinical trials that: a) all applications or proposals and/or protocols must provide a description of plans to conduct analyses, as appropriate, to address differences by sex/gender and/or racial/ethnic groups, including subgroups if applicable; and b) investigators must report annual accrual and progress in conducting analyses, as appropriate, by sex/gender and/or racial/ethnic group differences. REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS: NIH policy requires education on the protection of human subject participants for all investigators submitting NIH proposals for research involving human subjects. You will find this policy announcement in the NIH Guide for Grants and Contracts Announcement, dated June 5, 2000, at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html. A continuing education program in the protection of human participants in research in now available online at: http://cme.nci.nih.gov/. HUMAN EMBRYONIC STEM CELLS (hESC): Criteria for federal funding of research on hESCs can be found at http://grants.nih.gov/grants/stem_cells.htm and at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html. Guidance for investigators and institutional review boards regarding research involving human embryonic stem cells, germ cells, and stem cell-derived test articles can be found at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-044.html. Only research using hESC lines that are registered in the NIH Human Embryonic Stem Cell Registry will be eligible for Federal funding (see http://escr.nih.gov). It is the responsibility of the applicant to provide the official NIH identifier(s)for the hESC line(s) to be used in the proposed research. Applications that do not provide this information will be returned without review. PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT: The Office of Management and Budget (OMB) Circular A-110 has been revised to provide public access to research data through the Freedom of Information Act (FOIA) under some circumstances. Data that are (1) first produced in a project that is supported in whole or in part with Federal funds and (2) cited publicly and officially by a Federal agency in support of an action that has the force and effect of law (i.e., a regulation) may be accessed through FOIA. It is important for applicants to understand the basic scope of this amendment. NIH has provided guidance at http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm. Applicants may wish to place data collected under this RFA in a public archive, which can provide protections for the data and manage the distribution for an indefinite period of time. If so, the application should include a description of the archiving plan in the study design and include information about this in the budget justification section of the application. In addition, applicants should think about how to structure informed consent statements and other human subjects procedures given the potential for wider use of data collected under this award. URLs IN NIH GRANT APPLICATIONS OR APPENDICES: All applications and proposals for NIH funding must be self-contained within specified page limitations. Unless otherwise specified in an NIH solicitation, Internet addresses (URLs) should not be used to provide information necessary to the review because reviewers are under no obligation to view the Internet sites. Furthermore, we caution reviewers that their anonymity may be compromised when they directly access an Internet site. HEALTHY PEOPLE 2010: The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2010," a PHS-led national activity for setting priority areas. This RFA is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople/. AUTHORITY AND REGULATIONS: This program is described in the Catalog of Federal Domestic Assistance No. 93.395 and is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. Awards are made under authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and administered under NIH grants policies described at http://grants.nih.gov/grants/policy/policy.htm and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. The PHS strongly encourages all grant recipients to provide a smoke- free workplace and discourage the use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care, or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people.


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