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Full Text CA-95-011 COOPERATIVE GROUP FOR BREAST AND COLO-RECTAL CANCER CLINICAL TRIALS NIH GUIDE, Volume 24, Number 19, May 26, 1995 RFA: CA-95-011 P.T. 34 Keywords: Clinical Trial Cancer/Carcinogenesis 0715036 Digestive System National Cancer Institute Letter of Intent Receipt Date: June 23, 1995 Application Receipt Date: August 25, 1995 PURPOSE The Division of Cancer Treatment (DCT), National Cancer Institute (NCI) invites applications for cooperative agreements to establish a surgically oriented, Clinical Trials Cooperative Group (henceforth termed the Group) that will perform multi-institutional clinical trials in adult patients with breast and colo-rectal cancer. The Group will be expected to conduct a broad spectrum of innovative therapeutic clinical trials that will advance the care of these patients. The NCI's Clinical Trials Cooperative Groups consist of researchers at affiliated institutions who jointly develop and conduct cancer treatment clinical trials in multi-institutional settings. They are a major component of the extramural research effort of the Division of Cancer Treatment. Each Group is supported to continually generate new trials compatible with its particular areas of interest and expertise, as well as with national priorities for cancer treatment research. Unlike most other major National Institutes of Health (NIH) cooperative clinical trials efforts, Group structure and funding are not usually linked to any specific clinical trial(s). This mechanism thus has the potential for considerable flexibility in resource allocation, and for the rapid testing of promising new cancer therapies in large patient populations, since the apparatus for conducting such trials is constantly in place. The Groups have been instrumental in the development of new standards of cancer patient management and sophisticated clinical investigation techniques. Further information on the DCT Clinical Trials Cooperative Groups can be found in the CLINICAL TRIALS COOPERATIVE GROUP PROGRAM GUIDELINES, available from the NCI Program Director listed under INQUIRIES. HEALTHY PEOPLE 2000 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2000," a PHS-led national activity for setting priority areas. This Request for Applications (RFA), Cooperative Group for Breast and Colo-Rectal Cancer Clinical Trials, is related to the priority area of cancer. Potential applicants may obtain a copy of "Healthy People 2000" (Full Report: Stock No. 017-001-00474-0 or Summary Report: Stock No. 017-001-00473-1) through the Superintendent of Documents, Government Printing Office, Washington, DC 20402-9325 (telephone 202-783-3238). ELIGIBILITY REQUIREMENTS Applications may be submitted by North American, for-profit and non-profit organizations, public and private, such as universities, colleges, hospitals, laboratories, units of State and local governments, and eligible agencies of the Federal government. In addition, health maintenance organizations (HMOs) are eligible. Foreign organizations outside North America are not eligible to apply. Applications that include minority individuals and women as Principal Investigators are encouraged. Eligible institutions may apply for one or more of the following types of awards: o Headquarters/Operations Office o Main Members o Statistical and Data Management Center Separate applications must be submitted for each type of award. Each Headquarters/Operations Office applicant must identify in both a cover letter and in the body of the application a single Statistical and Data Management Center with which it is proposing to collaborate. Each applicant for a Main Member award must identify in both a cover letter and in the body of the application the Headquarters/Operations Office with which the applicant is proposing to work. Each applicant for a Statistical and Data Management Center must identify both in a cover letter and in the body of the application the Headquarters/Operations Office with which the applicant is proposing to collaborate. It is the responsibility of potential applicants for the three components of the Group - Headquarters/Operations Office, Main Members and Statistical and Data Management Center - to identify themselves to each other and to establish affiliations. Main Member institutions can be members of other Cooperative Groups, but the research performed by the Main Member in other Groups can not overlap with the workscope of this RFA, and this should be made clear in the application. For this RFA, Main Member applicants can only affiliate with one Headquarters/Operations Office applicant. Each applicant for a Headquarters/Operations Office Group must demonstrate the ability to recruit and support adequate membership to ensure the ability to mount multiple, concurrent large scale (sample size > 1000 patients) randomized clinical trials in different prognostic subsets in breast and colo-rectal cancer. Each Main Member applicant must demonstrate the capability to accrue a minimum of 30 new patients per year. MECHANISM OF SUPPORT The administrative and funding instrument to be used for this RFA will be the cooperative agreement (U10), an assistance mechanism, in which substantial NCI scientific and/or programmatic involvement with the awardee is anticipated during performance of the activity. Under the cooperative agreement, the NCI's purpose is to support and/or stimulate the recipient's activity by involvement in and otherwise working jointly with the award recipient in a partner role, but it is not to assume direction, prime responsibility, or a dominant role in the activity. The U10 cooperative agreements are cooperative research programs between the Sponsoring Institute and participating principal investigators and institutions whose research is usually conducted through established protocols in multi-institutional settings. Details of the responsibilities, relationships, and governance of the study to be funded under this cooperative agreement are discussed later in this RFA under the section Terms and Conditions of Award. Because the nature and scope of the research proposed in response to this RFA may vary, it is anticipated that the size of the award(s) will vary also. The total project period for applications submitted in response to the present RFA may not exceed five years. The anticipated award date is March 1, 1996. Although this program is provided for in the financial plans of the NCI, awards pursuant to this RFA are contingent upon the availability of funds for this purpose. This RFA is a one-time solicitation. However, if it is determined that there is sufficient continuing program need, the NCI will invite recipients of awards under this RFA to submit competitive continuation cooperative agreement applications for review according to the CLINICAL TRIALS COOPERATIVE GROUP PROGRAM GUIDELINES, available from the NCI Program Director listed under INQUIRIES. FUNDS AVAILABLE Approximately $9 Million total costs will be available in fiscal year 1996 for the first year of support for awards made under this RFA. It is anticipated that only one Cooperative Group will be supported by awards via this RFA in fiscal year 1996. The level of support will be dependent upon the number of applications of high merit received and the availability of funds. Funding beyond the initial budget period will be contingent on the continued availability of funds for this purpose and the continued progress of the awardee and the Group as a whole. RESEARCH OBJECTIVES Background Breast cancer afflicts more than 180,000 women annually in the U.S. while cancer of the large bowel (colon-rectum) was estimated to occur in 75,000 men and in 74,000 women in 1994. Jointly, these two tumor sites represent nearly one third of all adult cancers and are estimated to cause death in over 102,000 Americans each year. Despite the obvious anatomic differences, the therapeutic approach developed for these cancers is analogous in many respects as is the need for improvement of our standard therapies. Early detection leads to better outcome, but screening tools remain suboptimal. Initial treatment is usually surgical, although improved understanding of tumor progression has led to the use of less radical surgical procedures. Involvement of lymph nodes portends systemic involvement, and thus reflects the need for adjuvant systemic treatment. Although effective adjuvant treatment is available, many patients still relapse despite such treatment. The advent of newer, biologic markers has defined subsets of node negative patients that have a high risk of relapse, and therefore merit consideration for adjuvant therapy. Advanced disease remains largely incurable so that its treatment is presently geared towards palliation of symptoms and enhancement of quality of life, and finally, chemoprevention is under study for both. As better genetic definition of high risk becomes available for breast and colo-rectal cancer, the need for effective preventive options is likely to increase. The current treatments used for breast and bowel cancer vary according to disease stage but are often characterized by a multimodality approach. Since early stage disease can often be cured by surgery alone, the emphasis in this setting has centered on conservative surgery, utilizing radiation, in some instances, to control microscopic disease. For more advanced tumors at higher risk of systemic spread, chemotherapy in both diseases and hormonal maneuvers in breast cancer have improved survival rates at 5 to 10 years by approximately 10 to 15 percent. However, the past twenty years of trials with systemic therapies have demonstrated that progress is usually incremental, and large phase III trials are often needed to detect small, yet meaningful, benefits. These characteristics make it evident that the cooperative efforts of specialists within institutions and partnerships among many different centers are required if further therapeutic advances in these tumors are to be achieved. Practitioners of general surgery are often involved early in the diagnosis and detection of these malignancies so that assuring them a key role in this Group should enhance its ability to perform innovative treatment and prevention trials. Improvements in our understanding of tumor promotion, growth, and metastases have occurred over the past decade in the fields of breast and bowel cancer. In order to translate this knowledge into clinical benefit, a collaboration between laboratory scientists and clinical researchers is required. The NCI is therefore seeking a surgically oriented, multidisciplinary and multi-institutional team of talented scientists from academic and community medical centers to form a Clinical Trials Cooperative Group that will interact with the Cancer Therapy Evaluation Program (CTEP) staff in a concerted way to conceive, create, and evaluate new approaches to the treatment of breast and bowel cancers. Furthermore, NCI is encouraging this Group to include women scientists and members of minority groups, who are recognized experts, in positions of both scientific and administrative leadership. Although new treatment ideas will come from diverse arenas such as pharmaceutical industry research and single institution trials, the NCI wishes this Group to have among its members sufficient academic research institutions capable of performing phase I and II trials, so that original ideas can be brought to the Group to serve as the basis for phase III comparisons. Scientific approaches should be broad and reflect the creativity and capabilities of team participants, including surgical, medical, radiotherapeutic, laboratory, diagnostic imaging, and statistical skills. Team objectives and approaches will be investigator-originated but consistent with program aims of improving the survival and quality of life for persons with breast and bowel cancers or those at risk for these diseases. Other A. Objectives and Scope The purpose of this RFA is to stimulate the development of innovative phase III clinical trials for the treatment of early stage breast and colo-rectal cancer. Phase I, II, and even phase III trials in metastatic disease are acceptable as long as the goal in developing these studies is to advance the treatment of early stage disease. Furthermore, a focus on surgical expertise is required so that innovative surgical treatments, such as laparoscopic abdominal surgery, guided axillary dissection and rectum sparing approaches, can be fully explored. Highlighting surgical participation also ensures the inclusion in the Group of medical "gatekeepers" who are ideally situated for participation in early detection, diagnostic, and preventive strategies. In addition, this surgical orientation should facilitate the collection of adequate tumor tissue and serum specimens for tumor banking and studies of the genetic and molecular changes with, or predisposing to, breast or colo-rectal cancer. Examples of potential innovative therapeutic approaches include: tumor vaccines and monoclonal antibodies against tumor-specific antigens, and monoclonal antibodies against tumor neovasculature; evaluation of retinoids, vitamin D analogs and other differentiating agents; testing of new chemotherapeutic agents such as topoisomerase I inhibitors, taxanes, thymidylate synthase inhibitors, edatrexate, and navelbine; development of pilot trials using intermediate endpoints for prevention of breast and bowel cancer; exploration of critical markers which indicate treatment sensitivity or resistance (e.g., cerbB-2, p53, tumor angiogenesis markers, thymidylate synthase) and detection of genetic changes in high risk individuals (BRCA-1, BRCA-2, HNPCC/MSH2); surgical studies of laparoscopic techniques for bowel resection vs. standard procedures, rectal-sparing approaches, trials studying the role of axillary dissection, surgical approaches to in situ breast cancer, and studies of the role of menstrual timing for breast surgery. In order to accomplish these research objectives, the scope of activities of this Clinical Trials Cooperative Group should include: 1. the ability of the membership to accrue large numbers of patients with early stage breast and colo-rectal cancer; 2. scientific leadership in these diseases including both clinical and laboratory expertise; 3. a statistical office with leadership that has proven experience in designing, conducting and analyzing phase I-III clinical trials. 4. a membership performance review program that emphasizes productivity as measured by both high quality record-keeping and adequate accrual; 5. a tumor banking system that facilitates integration of correlative studies into the overall research effort; 6. detailed methods for assuring inclusion in these trials of adequate numbers of women and minority patients; 7. the capability to perform pilot trials in metastatic disease preparatory to phase III adjuvant trials; 8. clinical research in diagnostic, epidemiologic, cost-effectiveness, quality of life, cancer control, and prevention trials, although not required, can serve to enhance Group science and the applicability of the research. Interest and expertise in these areas will enhance the application; 9. integration of members of the patient advocate community into appropriate Group committees and activities; 10. capability in dealing with regulatory responsibilities such as Investigational New Drug (IND) issues and drug shipments and handling; and 11. quality assurance and quality control programs that will ensure both a high quality of clinical research and patient safety. B. Organization The Group will consist of three major operational components: the Headquarters/Operations Office, the Statistical and Data Management Center, and the Participating Investigators' Institutions. Each component has general responsibilities in meeting the goals and objectives outlined above or in completing tasks necessary to accomplish those goals. The Group will be governed by a written constitution and bylaws, which should describe membership criteria for inclusion and exclusion, procedures for selecting Group leadership and other details of governance, and will be led by a chairperson who is ultimately responsible to the membership and to the NCI for the content and conduct of the Group's research program. Beyond this requirement, the structure and management of the Group is the responsibility of the Group itself to determine. The following sections describe the responsibilities and functions of each of the three operational components. 1. Headquarters/Operations Office The Headquarters/Operations office is the direct responsibility of the Group chairperson. It provides executive leadership and day-to-day administrative management of the Group. Through this office the chairperson implements the Group's scientific and organizational policies. Specific roles and responsibilities include the following: a. Provide general scientific oversight, assuring development of research plans for each disease and/or modality in the Group's repertoire and the maintenance of a clear sense of the Group's overall research priorities. b. Develop and provide to the Group membership and to NCI, a Constitution and By-Laws specifying Group structure and management, procedures for the selection of the Group Chair and other leadership, terms of office, criteria for membership, and other details of governance of the Group. c. Provide, to the membership and to the NCI, policies and procedures for the conduct of the Group's activities. d. Serve as the Group's communication and information dissemination hub for investigators and institutions within the Group and individuals and organizations outside of the Group. e. Provide overall management of the Group's resources, assuring allocation to high priority projects and to the most productive activities and members. f. Provide logistical and financial support to the Group's scientific committees, monitor their productivity, and provide for the election/appointment of their leadership. g. Provide organizational and logistical support for the Group's meetings. h. Conduct periodic review of the performance and membership status of each Main Member/Affiliate according to criteria established by the Group; this review should examine scientific contributions, patient accrual and follow-up, data accuracy and timeliness, protocol compliance, audit results, and adherence to regulatory requirements. i. Establish a Data and Safety Monitoring Committee (DSMC) for Phase III trials in accordance with NCI Guidelines, and provide organizational and logistical support to the DSMC. j. Develop procedures for study monitoring to assure compliance with protocol design and protection of patients from research risks. This medical review should be coordinated with the quality assurance and quality control programs managed by the Statistical and Data Management Center. k. Encourage and provide financial support for the integration of community participation (patients and patient advocates)in the Group's activities by including them in Group meetings and on appropriate committees. l. Foster and monitor the inclusion of women and ethnic minorities in the Group's clinical trials. m. Provide logistical and clerical support to the process of protocol development; develop and implement standards for protocol format. n. Assure internal Group and CTEP review and approval of protocol concepts, final protocol documents, informed consents and study amendments; advise CTEP of changes in protocol status. o. Produce and maintain current and accurate Group records. p. Oversee Group compliance with regulatory requirements concerning the use of investigational agents, the reporting of adverse events, and the protection of human research subjects (see also t. and u. below). q. Provide guidance to the membership regarding clinical trials practices, including ethical issues involved in clinical research and conflict of interest considerations. r. Track the progress of the Group's research and assure that results of Group trials are published in appropriate peer-reviewed literature in a timely manner and in accordance with Group publication policies. s. Assist member institutions in the process of preparing competing renewal applications. t. Verify that all membership sites have an approved Cooperative Project Assurance (CPA), or Multiple Project Assurance (MPA) as required on file with the Office for Protection from Research Risks (OPRR), DHHS. Physicians in private practice must have an approved Non-Institutional Investigator Agreement (NIA) on file with the Headquarters/Operations Office. u. Monitor and maintain appropriate records of protocols, informed consents, assurances and annual certifications of Institutional Review Board (IRB) review and approval (HHS Optional Form 310) for all Main Members and Affiliates. v. Manage and allocate financial resources from the Developmental Fund. The purpose of the Developmental Fund is to provide the Group leadership with resources to support new initiatives, special high-priority projects, and limited funding for candidate members. w. Provide third party payments to relevant participating Affiliates that do not hold cooperative agreements from the NCI. 2. Statistical and Data Management Center A Group's statistical and data management staff are integral collaborators in all stages of study development, conduct, analysis and reporting. In addition, the Statistical and Data Management Center funded by this RFA will have responsibility for the Group's quality control and quality assurance programs including the development and implementation of an on-site audit program. The general operational responsibilities usually assumed by this component include: a. Ensure study feasibility and appropriateness of study design with respect to stated study objectives. b. Ensure that there are clear and consistent definitions of study objectives, eligibility criteria, primary analysis endpoints, evaluation criteria (such as toxicity and response definitions) and guidelines for removal of patients from protocol therapy. c. Develop non-standard designs when necessary to achieve specific study objectives. d. Take primary responsibility for the establishment and conduct of quality control and on-site auditing. The Statistical Office will conduct the Group's on-site monitoring program and will be responsible for adherence to the NCI/CTMB GUIDELINES FOR ON-SITE MONITORING OF CLINICAL TRIALS FOR COOPERATIVE GROUPS AND CCOP RESEARCH BASES available from the NCI Program Director or from the Clinical Trials Monitoring Branch (CTMB), CTEP upon request. The Statistical Office will provide logistical and financial support for the Group's quality control programs. e. Implement plans for monitoring of study data, including planned interim analyses of studies and timely reporting to the DSMC of all toxicities. Interim study reports should be prepared according to Group policies in this regard. In general, reports of accrual, eligibility, evaluability, and toxicity should be made for each open study on at least a semi-annual basis. f. Implement appropriate registration, randomization procedures, and accrual tracking procedures. g. Design, develop and implement forms required to collect Group study data. h. Provide for all aspects of the collection and management of Group study data, especially quality and timeliness of data submission. i. Contribute to all decisions regarding the conduct of Group studies. j. Perform statistical analyses that use state-of-the art methodology and provide unbiased results. k. Co-author articles and abstracts based on protocol results and other Group data where appropriate; publish on methodologic issues in cancer clinical trials. 3. Participating Investigators/Membership Categories Investigators participating in Group research may come from a wide variety of academic and practice settings. Recognizing current realities of oncologic practice, the NCI provides various mechanisms of financial support for motivated investigators, including the Main Member (and its designated Affiliates) cooperative agreement (awarded directly by the Division of Cancer Treatment, NCI), the Community Clinical Oncology Program (CCOP) cooperative agreement (awarded directly by the Division of Cancer Prevention and Control, NCI), third-party payments (subcontracts or purchased service agreements) for Affiliate member institutions which do not hold cooperative agreement awards (awarded through the Headquarters/Operations Office) and the other special initiative programs such as the High Priority Trials Program and the Minority Initiative Program (awarded through the Headquarters/Operations Office). Participating investigators may receive additional funds through the Headquarters Office for the conduct of administrative, scientific, laboratory or high priority tasks which are within the workscope of the Group. The Group shall establish policies and procedures for credentialling participating institutions and conducting periodic review of the performance and membership status of all membership sites. This review should examine scientific contributions, patient accrual, data accuracy and timeliness, protocol compliance, procedures for lifetime tracking and follow-up of patients, and audit results. Reimbursement for the costs of participating in Group research must be linked to the quality of institutional performance. a. Main Members Main Member institutions can be North American, for profit and non-profit organizations, public and private, such as universities, colleges, hospitals, laboratories, units of State and local governments, and eligible agencies of the Federal Government. In addition, health maintenance organizations (HMOs) are eligible. In addition to patient accrual, substantial importance is placed on scientific and administrative contributions to the Group. The Group shall establish its own specific criteria for membership and a formal process for application. In most Groups, institutions are initially admitted for membership on a provisional basis. Eligibility for institutional cooperative agreement awards is limited to institutions which have been granted full membership by the Group, and continued NCI funding is contingent upon maintenance of satisfactory membership status. Investigators at Main Member institutions are expected to: 1) Actively participate in the Group's scientific committees. 2) Serve as Study Chairs responsible for the development and conduct of specific Group studies. 3) Contribute their independent laboratory and clinical research experience to the Group. 4) Actively participate in Group meetings. 5) Accrue a minimum of 30 patients annually to Group protocols. 6) Submit timely and accurate patient data to the statistical office. 7) Author manuscripts and abstracts to disseminate the results of Group studies. 8) Participate in the Group's on-site audit program. 9) Serve on Group administrative committees. 10) Periodically serve on NCI site visit teams and peer review committees. 11) Develop community outreach programs that involve patients and patient advocates in the Group's research in a productive and meaningful manner. This effort should be coordinated with the Headquarters/Operations Office. 12) Foster and monitor accrual of women and ethnic minorities to Group trials. 13) Assume responsibility for all Group activities conducted at his/her own institution and at Affiliate institutions (see b. below for Affiliate membership criteria). b. Affiliate Members Two categories of Affiliate membership will be permitted: 1) In category 1, Affiliate Members are proposed by Main Member institutions and represent sites of scientific or clinical expertise that are judged by the Main Member institution to contribute significantly to the quality of that institution's programs. Thus, Main Members seeking to sponsor Affiliates should be able to demonstrate reasonable geographic proximity to the Affiliate institution and past evidence of successful clinical collaboration in order to guarantee that the Main Member will be able to provide adequate oversight of the Affiliate Member. In addition, Affiliate Members are required to accrue a minimum of 10 eligible patients annually. They should also demonstrate quality record-keeping and strict adherence to all regulatory and human subjects requirements for clinical trials. This necessitates that all Affiliates have an assurance which is approved by OPRR and that its IRB is willing to assume responsibility for all the investigators associated with the Affiliate. If an Affiliate does not have an IRB and wishes to make an arrangement with the IRB of another Affiliate or Main Member, such arrangements must be approved by OPRR. In addition, all Affiliate investigators who are in private practice must complete a Non-Institutional Investigator Agreement which is co-signed by the responsible IRB and is on file at the Group Headquarters/Operations Office. Reimbursement of Affiliates in category 1 will be via a capitation (per patient research-cost reimbursement) system. Overall data quality as well patient accrual will be utilized in determining reimbursement for research costs. The specific criteria for determining reimbursement are the responsibility of the Main Member, but must be consistent with the overall performance review guidelines for Group membership as determined by the Headquarters/Operations Office. However, reimbursement of Affiliates will be capped at an amount equivalent to the research costs for 30 patients annually. Once an Affiliate has demonstrated the ability to accrue patients at this level, it should be encouraged to apply for Main Member status. On-site auditing of Affiliates may be the responsibility of the Main Member, and/or the Statistical Office depending on the auditing plan developed by the Statistical and Data Management Center, and shall be in accordance with the NCI-CTMB GUIDELINES FOR ON-SITE MONITORING OF CLINICAL TRIALS FOR COOPERATIVE GROUPS AND CCOP RESEARCH BASES. Affiliates will be responsible for directly registering all patients onto study protocols through the Group Headquarters/Operations Office, thus assuring that accrual can be accurately tracked by Affiliate site. Finally, all nominations for Affiliate status should be reviewed by the Group Membership Committee and endorsed by the process established by the Group. 2) In category 2, institutions which do not have either geographic proximity to a Main Member or can not find a Main Member sponsor may request to become an Affiliate Member directly through the Headquarters/Operations Office. The patient accrual and record keeping requirements are identical to those mentioned above for Affiliate Members in category 1. Reimbursement for research costs will also follow the same capitation scheme. The specific criteria for determining reimbursement will be the responsibility of the Headquarters/Operations Office. Reimbursement will be capped at 30 patients annually in order to encourage Affiliate Members performing at this high level to seek Main Member status. On-site auditing will be the responsibility of the Statistical and Data Management Center, and must be in accordance with the NCI-CTMB GUIDELINES FOR ON-SITE MONITORING OF CLINICAL TRIALS FOR COOPERATIVE GROUPS AND CCOP RESEARCH BASES. All nominations for Affiliate status in category 2 should be reviewed by the Group Membership Committee and endorsed by the process established by the Group. They should also demonstrate quality record-keeping and strict adherence to all regulatory and human subjects requirements for clinical trials. This necessitates that all category 2 Affiliates have an assurance which is approved by OPRR and that the IRB is willing to assume responsibility for all the investigators associated with the Affiliate. If an Affiliate does not have an IRB and wishes to make an arrangement with the IRB of another Affiliate or Main Member, such arrangements must be approved by OPRR. In addition, all Affiliate investigators who are in private practice must complete a Non-Institutional Investigator Agreement which is co-signed by the responsible IRB and is on file at the Group Headquarters/Operations Office. Category 2 Affiliates may include: a) High Priority Trials Initiative Participants The High Priority Trials Initiative was implemented by NCI in order to increase accrual to designated studies by providing financial support for study-related research to otherwise unfunded investigators. In addition, the Office of Cancer Communications, NCI, promotes the designated trials, and clinical trials research in general, through public relations activities designed to educate physicians and the public regarding opportunities to participate in clinical trials research. High Priority Trials investigators affiliate with the Cooperative Group through the Operations Office. They submit data in the same format and according to the same standards as any other Member or Affiliate investigator. Quality control is assured by the usual Group monitoring and evaluation procedures. b) Minority Initiative Program CTEP initiated the Minority Initiative Program in 1990 to increase the accrual of minority patients onto clinical trials and to investigate the basis for observed differences in cancer outcome among ethnic groups. Through this program additional funds are made available to Cooperative Group headquarters or statistical offices to help support these goals. Specific group activities are proposed by individual Groups and reviewed annually by CTEP. Activities supported through this program include capitation awards for increases in minority accrual, translation of patient education materials into languages other than English, training for investigators in minority accrual, and the recruitment of translators and patient advocates to help with accrual and follow-up of minority patients. c. Community Clinical Oncology Program (CCOP) Participants CCOP participants are funded by the Division of Cancer Prevention and Control (DCPC). They are community-based organizations which participate in Group treatment protocols and cancer control research studies based in the Groups or in cancer centers. DCPC periodically publishes a Request for Applications (RFA) for CCOP funds in which the application process, eligibility and funding criteria are described. CCOP participants affiliated with a Cooperative Group have access to Group protocols approved by and for CCOP accrual and submit data in the same format and according to the same standards and are audited as any Main or Affiliate Members. Group operations/statistics offices are funded by DCPC through separate research base awards to support the additional administrative responsibilities for and analysis of the data supplied by CCOP members. Duplicative funds should not be requested in applications to be funded by DCT. C. Scientific/Administrative Considerations Definitive clinical trials should usually constitute the major portion of a Group's activities; they should always serve as the ultimate goal of preliminary developmental trials. It is essential that important, original, and feasible treatment questions be posed, that study questions be answerable in a reasonable period of time, and that the methodology of each study be sound. Proper integration of diagnostic or other support modalities is essential, with standards of quality control as rigorous as those applied to treatment modalities. It is anticipated that decisions in all Group activities will be reached by consensus of the collaborating investigators under the leadership of the Cooperative Group Chairperson. Studies will be conducted in accordance with the CLINICAL TRIALS COOPERATIVE GROUP PROGRAM GUIDELINES, the INVESTIGATOR'S HANDBOOK, the GUIDELINES FOR THE CONDUCT OF INTERGROUP STUDIES, and the NCI-CTMB GUIDELINES FOR ON-SITE MONITORING OF CLINICAL TRIALS FOR COOPERATIVE GROUPS AND CCOP RESEARCH BASES. In most Groups the process of study generation begins at the level of a disease or modality committee, which develops specific experiments ultimately embodied in Group protocols. This proven organizational approach provides a forum for investigators who share a common area of interest, and an arena in which various ideas must compete if they are to gain the status of a Group study. The Group and its research committees should develop, articulate, and follow a comprehensive research plan which summarizes the Group's specific objectives and lines of investigation for each disease or modality that it chooses to study. The purpose of this plan is to focus attention on long-term goals, and to aid the Group in prioritization of competing research ideas. The plan will frequently include small developmental/pilot studies, Phase II studies, as well as large-scale Phase III efforts, all designed to take advantage of the Group's experience, expertise, resources, and clinical opportunities. These comprehensive research plans for each disease and/or modality committee will be a major focus of the peer review process. The multi-center nature of Group trials presents a variety of challenging methodologic problems regarding assurance of quality and consistency in study conduct. The need for formal mechanisms of medical review and quality control is obvious and Groups have developed a number of approaches to these issues. Quality control are a complex topics spanning the entire range of diagnostic and therapeutic modalities employed by each Group. Generalization concerning optimal quality control is impossible. Cost and benefit are obviously important factors in this assessment. Examples of the kinds of considerations to be applied follow: 1. Radiation therapy quality control may involve either simultaneous (rapid turnaround) or retrospective review of port films and compliance with protocol-specified doses for individual patients. Minimal standards for acceptability of equipment may be required. Each radiation therapy facility that treats patients on Group studies undergoes periodic physics review and equipment calibration by the Radiological Physics Center (RPC). The RPC in Houston, TX has supplied each Group's radiation therapy quality control office with the physics data necessary to conduct its case-level review. 2. Chemotherapy quality control is usually carried out through retrospective review of submitted flow sheets, with determination of protocol compliance in dose administration and dosage modification. The criteria vary considerably from study to study and from Group to Group and depend heavily on the specific research questions addressed. 3. Surgical quality control includes assessment by surgeons of the adequacy of protocol-specified surgical procedures through review of the operative notes, study-specific surgical forms, and pathology reports. Standards of acceptability for specialized surgical equipment, or requirements for participation in workshops may be necessary in some instances. Where appropriate, surgical modality committees may wish to draft handbooks of acceptable guidelines for surgical procedures used in studies. 4. Pathology review is usually retrospective and may be either by a committee within the Group or by an external reference panel. Pathology review is not required by CTEP for all cases, but should be required by the Group when known variability in the accuracy of histologic diagnosis is a potentially serious problem or when pathology data may provide important prognostic information. 5. Appropriate quality control for other therapeutic and diagnostic modalities are as essential to good data quality as those described above. Standardization of decentralized laboratory procedures (e.g., hormone receptor determinations) is an important case in point. 6. Assuring the safety of individual patients participating in each study, in maximizing their likelihood of exposure to optimal treatment, and in general, ensuring that the interests of patient participants are not subsidiary to those of the scientific investigation is critical to Group science. The continual assessment of the progress of studies necessary to achieve these ends is referred to in this document as study monitoring. All clinical treatment research carries with it the obligation to ensure optimal therapy for participating patients, and optimal conduct of the research such that the patients' participation is meaningful. In this context accurate and timely knowledge of the progress of each study is a critical Group responsibility and includes the following: a. Precise tracking of patient accrual to individual studies by Main Member or Affiliate site and the mechanisms to ensure adherence to defined accrual goals; b. Ongoing assessment of patient eligibility and evaluability and correction of specific problems in this regard; c. Adequate measures to ensure timely submission of protocol-required data for individual patients; d. Adequate measures to ensure timely medical review and assessment of these individual patients' data; e. Rapid reporting of treatment-related morbidity in individual patients and measures to ensure communication of this information to all parties to whom it is important, including the NCI and the Group Data and Safety Monitoring Committees; f. Prompt assessment of the significance of such information in the context of the entire study's experience; g. Interim evaluation and consideration of measures of outcome (although to the extent consistent with patient safety and good clinical trials practice such interim analyses should be minimized in frequency; access by participating investigators to interim outcome data should be limited as much as possible.) 7. Quality Control and On-site auditing A related need is for verification of the accuracy of data submitted from individual investigators to the Group. This need overlaps considerably with the obligation of the DCT as a sponsor of investigational agents to ensure visits to each site where NCI-sponsored clinical trials are performed, for the specific purpose of: a) auditing medical records, and b) assuring compliance with regulatory requirements of the Food and Drug Administration (FDA), including appropriate storage and handling of investigational agents. Each Group is therefore required to establish a system of periodic on-site audits of each Main Member/Affiliate, with CTEP oversight of the audit program. This dual responsibility of the Groups and the DCT is referred to as the on-site audit program. (see the NCI-CTMB GUIDELINES FOR ON-SITE MONITORING OF CLINICAL TRIALS FOR COOPERATIVE GROUPS AND CCOP RESEARCH BASES. a. Regulatory Obligation As a sponsor for investigational new agents, the DCT is required by FDA regulations to maintain an on-site audit program. Through formal agreements with the FDA, the DCT has delegated much of this responsibility to the Groups, although CTEP oversees the program. The specific purposes of the audit programs are to document the accuracy of data submitted to the Group, and to verify investigator compliance with the regulatory requirements for all clinical investigations. b. Data Verification/Protocol Compliance By comparison of submitted data with information contained in the patient's actual medical records, this component of the on-site audit program seeks to assure accuracy and completeness of Group information integral to the assessment of: o Patient eligibility; o Compliance with protocol-defined therapy; o Endpoint evaluation o Treatment related toxicity; o Protocol-required laboratory and diagnostic evaluations; o Overall quality of record keeping; o Concomitant therapy or other information which might affect study results but is not recorded on submitted study forms. c. Regulatory Requirements This component of the on-site audit program is intended to assess: o Documentation of Institutional Review Board (IRB) approvals, reapprovals, and protocol amendments; o Documentation of an IRB-approved, properly signed and dated informed consent document for each case audited, that includes an adequate description of the rules and benefits as contained in the model informed consent submitted to the NCI; o Security of investigational drug handling; o Adequacy of NCI drug accountability records (DAR). d. Procedures The Group must establish and follow an on-site audit program and audit procedures, in accordance with NCI-CTMB GUIDELINES FOR ON-SITE MONITORING OF CLINICAL TRIALS FOR COOPERATIVE GROUPS AND CCOP RESEARCH BASES. Each Main Member and designated Affiliate must be visited at least once every 36 months but remains at yearly risk of an audit. Audits are conducted by peer investigators within the Group. A percentage of Main Members/Affiliates are co-site visited by CTEP Quality Assurance staff or their agents. Protocols to be reviewed are selected by the Group in accordance with the above guidelines. A sample of investigational agent studies is always included when the Main Member or Affiliate has accrued patients to such studies. Individual cases are then randomly selected by the statistical office for review. A preliminary report must be faxed to CTMB within one working day of the audit. A final report of each audit is sent by the Group to CTMB within ten weeks of the audit. CTMB staff review the audit findings as well as the Group's evaluation and response. e. Group Evaluation and Response The discovery of actual fraud or other serious research misconduct during a Group audit has been rare. However, problems covering a wide spectrum of severity and type are often found; most are appropriately dealt with by constructive suggestions and are usually remedied through education of investigators and data managers. Notification of NCI is required in the event of findings suggestive of intentional misrepresentation of data and/or disregard for regulatory safequards, as well as other matters of sufficient seriousness. In such instances, the NCI/CTMB staff should be notified by telephone immediately, since other Federal agencies may require notification. Procedures for immediate suspension of accrual at the Main Member/Affiliate may be required. After reviewing the audit report and the Group's response, the CTMB staff may recommend further action to the Group or the NCI may take action independently. In cases of suspected fraud or other serious problem of compliance with regulatory requirements, CTEP may request formal investigation by the Office of Research Integrity (ORI, PHS, DHHS) or the Office for Protection from Research Risks (OPRR, NIH). f. Data and Safety Monitoring Committees For Phase III trials, the NCI has required the Groups to establish Data and Safety Monitoring Committees (DSMCs) that are independent of study leadership, are clearly free of conflicts of interest, and have formally documented policies and procedures which are approved by NCI. The main objectives of the independent DSMC are to: 1) Ensure that patients in the trial are protected and that their interests are not made secondary to the interests of scientific investigations. 2) Ensure that evaluation of interim results and decision-making about continuation, modification, termination of accrual and reporting of results are made competently based on thorough evaluation. 3) Ensure that the credibility of trial reports and ethics of trial conduct are above reproach with no actual or possible appearance of professional or financial conflicts of interest. 4) Enable physicians entering patients to remain free of knowledge of interim efficacy and toxicity data. This permits physicians to continue to approach their patients honestly and avoids the need to modify informed consent based on non-statistically-significant interim results. 5) Enable study leadership to remain free of knowledge of interim efficacy and toxicity data so that they may deal honestly with their peers in encouraging them to enter patients in the study and so that they do not put themselves, or the study, at risk by indirectly divulging interim results. SPECIAL REQUIREMENTS The research goals described in this RFA are part of a larger program of investigational agent development in the NCI. Each of the CTEP staff and CTEP Branches listed in the terms and conditions of award have very specific and well defined responsibilities in terms of investigational agent development and the role of DCT as a drug sponsor as defined in CFR 21 Part 312. The clinical development of new anticancer agents is a highly important utilization of Group resources, when carried out as a component of an overall strategy for study of a given disease. The Groups are a vital component of the research apparatus necessary for the clinical development of the many new investigational agents sponsored by the DCT. The DCT responsibilities for this development are shared by all Branches of CTEP. The Investigational Drug Branch (IDB) is responsible for 1) planning within CTEP and with members of the extramural community overall strategies for new agent studies in specific tumor types; and 2) coordinating and monitoring the trials of new agents developed by the DCT. The Pharmaceutical Management Branch (PMB) provides for the distribution of investigational new agents for which DCT is the sponsor. The Regulatory Affairs Branch (RAB) maintains close contact and ongoing dialogue with the pharmaceutical industry and with the Food and Drug Administration in order to ensure that new agent development complies with Federal regulations and proceeds in a coordinated way. The Clinical Investigations Branch (CIB) is involved in prioritizing evaluations of investigational agents compared to alternative research questions. The Biometric Research Branch (BRB) assesses proposed designs for evaluating the benefits of investigational agents. The Clinical Trials Monitoring Branch (CTMB) verifies adherence by the Groups to the quality assurance procedures of investigational agent trials. The Office of the Associate Director (OAD) integrates the efforts of the Branches. Terms and Conditions of Award These special Terms of Award are in addition to and not in lieu of otherwise applicable OMB administrative guidelines, HHS Grant Administration Regulations at 45 CFR Parts 74 and 92, and other HHS, PHS, and NIH Grant Administration policy statements. The administrative and funding instrument used for this program is a cooperative agreement (U10), 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(s) for the project as a whole, although specific tasks and activities in carrying out the studies will be shared among the awardees and the NCI Program Staff. A. Awardee Rights and Responsibilities The awardee's programmatic responsibilities for the conduct of the research supported by this cooperative agreement are described in the CLINICAL TRIALS COOPERATIVE GROUP PROGRAM GUIDELINES; the INVESTIGATOR'S HANDBOOK, (a Manual for Participants in Clinical Trials of Investigational Agents Sponsored by the Division of Cancer Treatment, National Cancer Institute); and the NCI-CTMB GUIDELINES FOR ON-SITE MONITORING OF CLINICAL TRIALS FOR COOPERATIVE GROUPS AND CCOP RESEARCH BASES, and any subsequent modifications of these documents. Specific portions of these documents, as enumerated in the following sections, are incorporated by reference as terms of award. These documents are available from the Cancer Therapy Evaluation Program (CTEP) upon request. Throughout these Terms and Conditions of Award "Participant" refers to all awardees as well as all institutions and/or individual investigators, both funded and unfunded, with whom they are participating or collaborating. 1. Development of Cooperative Group Research Agenda and Protocols It is the responsibility of the Cooperative Group (henceforth termed the Group) in accordance with its constitution, bylaws, policies and procedures 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. The Group shall, with CTEP assistance, develop Group research goals in accord with national research goals and develop protocols for clinical cancer research in accord with the Group's research interests, abilities and goals. The Group Chairperson shall designate other Group investigators to serve as Protocol Chairpersons for each proposed study. Protocols will be developed in accordance with the instructions in the CLINICAL TRIALS COOPERATIVE GROUP PROGRAM GUIDELINES, and the INVESTIGATOR'S HANDBOOK. The INVESTIGATOR'S HANDBOOK is reference handbook for all investigators who use DCT-sponsored investigational agents in their clinical trials, irrespective of funding mechanism. The INVESTIGATOR'S HANDBOOK describes, in accordance with NCI-FDA agreements: o Requirements for Protocol Development and Submission o Ordering Investigational Drugs from NCI o Responsibility for Reporting of Results to CTEP o Adverse Event Procedures o Accountability and Storage of Investigational Drugs o Monitoring and Quality Assurance 2. Coordination of Group Activities In accordance with the Group constitution, bylaws, policies and procedures, the Group Headquarters (or Statistical/Data Management Office as appropriate), under the leadership of the Group Chairperson 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 Group funded activities and made by the participating institutions will be coordinated by the Group Chairperson with the assistance of the staffs of the Headquarters, Statistical Office, and/or Data Management Office. The Group Chairperson or designee will be responsible for communication with the appropriate CTEP staff. 3. Protocol Submission Prior to protocol implementation, the Group Headquarters, under the leadership of the Group Chairperson, will submit the protocols for review to CTEP, or its designated Contractor, in accordance with the instructions in the NCI's INVESTIGATOR'S HANDBOOK and the CLINICAL TRIALS COOPERATIVE GROUP PROGRAM GUIDELINES. It is required that all Phase III protocols be preceded by Concept Review letter describing the hypothesis to be investigated, the general design of the contemplated trial plus relevant information on accrual capabilities to document feasibility. A letter of intent (LOI) must be submitted for all Phase II trials that include a DCT investigational agent. These two mechanisms for preliminary review are required to expedite protocol development and implementation and to facilitate agreement on study priority and design (see the INVESTIGATOR'S HANDBOOK, pp32-35, for further discussion of these mechanisms). The Group Chairperson, with the assistance of the Group Headquarter's staff, will communicate the results of the NCI review of protocols to the participating institutions. 4. Group Compliance with Federally Mandated Regulatory Requirements The Group must be in compliance with all Food and Drug Administration (FDA) regulatory requirements for studies involving investigational agents and NIH policies applying to the conduct of research involving human subjects. These regulations include but are not limited to Title 21 CFR 50,56 and 312 and Title 45 CFR 46. Participants are required to follow established Group procedures for complying with the Federally mandated regulations. a. The Group must be able to demonstrate that each participant has a current approved assurance number on file with the NIH Office for Protection from Research Risks (OPRR). b. The Group must be able to demonstrate that each protocol and informed consent is approved by the responsible Institutional Review Board (IRB) prior to patient entry, and that each investigator has a current FDA Form 1572 and curriculum vitae on file with the Pharmaceutical Management Branch, (PMB), CTEP. c. The Group must be able to demonstrate that each patient (or legal representative) gives written informed consent prior to entry on study. d. The Group must assure timely reporting of all serious and unexpected toxicities to CTEP. e. The Group must establish and maintain an on-site audit program in compliance with the NCI-CTMB GUIDELINES FOR ON-SITE MONITORING OF CLINICAL TRIALS FOR COOPERATIVE GROUPS AND CCOP RESEARCH BASES. f. The Group must have a method of providing, upon CTEP request, summary efficacy and toxicity data to be included in DCT's annual report to the FDA for each investigational agent. g. The Group must implement the CTEP requirements for storage and accounting for investigational agents provided under DCT sponsorship. 5. Investigational Drug Management Investigators performing Group trials are expected, in cooperation with the NCI, to comply with all FDA monitoring and reporting requirements for investigational agents. When new avenues of cancer therapy involving investigational drugs are pursued, the clinical information should be acceptable to the FDA for inclusion in a new drug application (NDA). 6. Quality Control and Study Monitoring a. The Group shall establish and implement mechanisms for quality control of therapeutic and diagnostic modalities employed in its trials. Participants are required to follow Group procedures for quality control. Quality control at a minimum should 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 port films and compliance with protocol-specified doses for individual patients. Determination of adequacy of radiation delivery with assistance of the Radiological Physics Center (RPC), whose functions usually include equipment dosimetry, periodic institutional visits and other aspects of physics review. 3) Chemotherapy: Review of flow sheets with determination of protocol compliance in dose administration and dosage modification. 4) Surgery: Assessment of adequacy of protocol-specified surgical procedures through review of operative notes and study-specific surgical forms. b. The Group shall establish and implement mechanisms for study monitoring and quality assurance. Participants are required to follow Group procedures for study monitoring. The Group is responsible for assuring accurate and timely knowledge of the progress of each study through: 1) tracking and reporting of patient accrual and adherence to defined accrual goals; 2) ongoing assessment of case eligibility and evaluability; 3) timely medical review and assessment of patient data; 4) rapid reporting of treatment-related morbidity and measures to ensure communication of this information to all parties; 5) interim evaluation and consideration of measures of outcome as consistent with patient safety and good clinical trials practice; 6) timely communication of results of studies; and 7) an on-site monitoring program. The awardee is responsible for ensuring that all Main Members and Affiliates have routine audits in accordance with the NCI-CTMB GUIDELINES FOR ON-SITE MONITORING OF CLINICAL TRIALS FOR COOPERATIVE GROUPS AND CCOP RESEARCH BASES and that the results of audits are reported to the NCI in accordance with the guidelines. In the event that the NCI determines that the awardee failed to comply with these guidelines, the accrual of new patients to the Group's protocols at the affected Main Member/Affiliate shall be suspended immediately upon notice of the NCI determination. The suspension will remain in effect until the awardee conducts the required audit and the audit report or remedial action is accepted by the NCI. The awardee will be responsible for notifying any affected Main Member/Affiliate of the suspension. During the suspension period, no funds from this award may be provided to the Main Member/Affiliate for new accruals, and no charges to the award for new accruals will be permitted. The NCI will also notify an institution that is the direct recipient of a cooperative agreement from the NCI if it is necessary to suspend accrual at that institution or at a third party institution supported under that institution's cooperative agreement. c. Quality Assurance and Quality Control of Data The awardee must follow NCI-approved procedures developed by the Group for the prevention and/or identification of false or otherwise unreliable data and for quality assurance of data collected by the Group. The awardee must follow Group procedures for the assurance of data quality and quality control in accordance with Group guidelines and NCI policies. In the event that there is a finding through the quality assurance and/or quality control programs of any indication of a pattern of non-compliance with protocol or regulatory requirements or a finding of possible alteration of data, these findings must be reported in accordance with the NCI-CTMB GUIDELINES FOR ON-SITE MONITORING OF CLINICAL TRIALS FOR COOPERATIVE GROUPS AND CCOP RESEARCH BASES. The awardee must follow policies developed by the Group and approved by the NCI for auditing the accuracy of scientific data submitted by Group participants. 7. Data Management and Analysis The Group shall establish and implement mechanisms for data management and analysis that ensure that data collection and management procedures are: (a) adequate for quality control and analysis; (b) as simple as appropriate in order to encourage maximum participation of physicians entering patients and to avoid unnecessary expense; and (c) sufficiently uniform across Groups. Participants are required to follow Group procedures for data management and analysis. 8. Data and Safety Monitoring Committees The Group must establish and maintain a Data and Safety Monitoring Committee (DSMC) for Phase III clinical trials. The policies and procedures of the DSMC must be approved by the NCI. The Group must comply with the approved policies and procedures of the DSMC. 9. Protocol Closure The Group shall establish and implement mechanisms for interim monitoring of results and monitoring protocol progress. If the Group wishes to close accrual to a study prior to meeting the initially established accrual goal, the interim results and other documentation should be made available to NCI staff for review and concurrence prior to implementation of the decision by the Group. It is recommended that statistical guidelines for early closure be presented as explicitly as possible in the protocol in order to facilitate these decisions. In the event that the DSMC has recommended early closure, DSMC procedures regarding notification of CTEP must be followed. 10. Protocol Reporting Requirements Reporting requirements will be in agreement with FDA regulations and NCI procedures. Interim reports of each activated and ongoing study shall appear in the minutes of each Group meeting and shall include specific data on patient accrual as well as, when appropriate, detailed reports of treatment-associated morbidity. Quarterly accrual information must be provided by the Headquarters or Statistical Office as appropriate to NCI for all active studies. A system for providing such information in a timely manner should be in place. Participants must provide accrual data to the Group in accordance with Group procedures. 11. Adverse Event Procedures In order to be in compliance with FDA regulations, all recipients of NCI support for clinical trials, including Groups responsible for coordinating and monitoring such trials, must promptly notify the NCI and any other sponsors of the trial of adverse events (i.e., adverse drug reactions) according to directions provided in the adverse event reporting section of the protocol. The awardee will notify all institutions/investigators participating in this project, funded or unfunded, about the above requirement and about the institutions'/ investigators' responsibility to report adverse events as specified in the protocol. The awardee will promptly notify the Investigational Drug Branch (IDB) Drug Monitor for DCT-sponsored investigational agents and the NCI Program Director for other agents, of serious or life-threatening events, as instructed in the protocol. 12. Performance Review The Group shall establish and follow policies and procedures for credentialling participating institutions and conducting periodic review of the performance and membership status of each Main Member/Affiliate. This review should examine scientific contributions, patient accrual, data accuracy and timeliness, protocol compliance, long-term patient follow-up and audit results. This mechanism will include a procedure for the Group Chair to recommend an adjustment of funds within the Group as appropriate for the level of participation in Group activities, including (but not limited to) accrual. This procedure can be either prospective (i.e., reimbursement by the case) or retrospective (financial adjustment at the time a non-competing continuation [Type 5] award is made). 13. Procedures in the Event of Scientific Misconduct If a duly authorized governmental or institutional body issues a final determination that scientific misconduct has occurred or if the awardee determines that other events have occurred which have significantly affected the quality or integrity of the Group data or patient safety, the awardee is responsible for notifying the Group Data and Safety Monitoring Committee (DSMC), the CTMB, the collaborating investigators, the appropriate Institutional Review Boards (IRBs), and other sponsors of the affected work. The awardee is also responsible, if the events described above have occurred, for ensuring that submitted but unpublished abstracts and manuscripts are corrected, if possible. If publication deadlines have passed or if abstracts and/or manuscripts containing the affected data have already been published, the awardee is responsible, within 90 days after learning of the event(s) significantly affecting the quality of the Group data or patient safety, for submitting to NCI a re-analysis of the results deleting the false or otherwise unreliable data, and disclosing within the text the reason(s) for the reanalysis. The awardee must submit the reanalysis for publication. The NCI may disseminate information about the reanalysis as broadly as it deems necessary. The awardee must use its best efforts to notify all scientists, research laboratories, and other organizations to which the awardee has sent research materials affected by false or otherwise unreliable data. True copies of data files and other supporting documentation from studies affected by scientific misconduct or other findings affecting the quality or integrity of data or patient safety shall be made available to the NCI in a timely manner upon the request of the Grants Management Officer, NCI. The NCI reserves the right to reanalyze, to publish, or to distribute its analyses of these data when it is in the interest of public health. Prior to release, publication or distribution of such analyses, the NCI will provide such analyses to the awardee. 14. Data Files Available to NCI Upon Request Upon the request of the Grants Management Officer, NCI, true copies of data files and supporting documentation for all NCI-supported protocols that have a major impact on patterns of care, as determined by the NCI, shall be made available to the NCI in a timely manner. 15. Notification of Patients by the Awardee During Patient's Lifetime In order for there to be an appropriate response in the event the NCI determines, either while a protocol is active or (if relevant) during the lifetime of the subjects following protocol closure, that a medically important toxicity or side effect is associated with protocol-directed treatment or that the medical care of one or more subjects may have been compromised by scientific misconduct or other finding affecting the integrity of the data or patient safety at the awardee institution or at a third-party institution, funded or unfunded, the awardee shall assure that the institution(s) responsible for these subject(s') accrual, whether funded or unfunded, will have procedures in place to: (i) contact each subject individually at his or her last known address on file with the institution and which give each subject contacted appropriate information and the right to communicate with an appropriate institutional representative and, in the event of misconduct, to meet with a physician not connected with the clinical trial or study in which the subject has participated; and (ii) encourage subjects to notify the institution of any changes of address. The procedure must provide for informing the subjects fully of: the consequences of the toxicity or misconduct for their care and well-being, if any, and the availability of follow-up; and their opportunity to examine any portion of their medical records relevant to the potential effect of the toxicity or side effect upon them or that may be affected by scientific misconduct or other findings affecting the quality or integrity of the data or patient safety. It is understood that under regulations at 45 CFR Section 74.53, NCI has a right of access to research records pertinent to the NCI funding. In exceptional circumstances, such as a public health emergency, the institutions will be required to provide subject names and treatments to the NCI in a format which allows direct notification of the patient by the NCI. 16. Progress Reporting Annual progress reports will be submitted to the NCI in accordance with the instructions in the CLINICAL TRIALS COOPERATIVE GROUP PROGRAM GUIDELINES. B. NCI Staff Responsibilities The role of the Cancer Therapy Evaluation Program (CTEP) staff as described throughout these terms and conditions of award is to assist and facilitate but not to direct research activities. This cooperative agreement is part of a larger program of investigational agent development in the NCI. Each of the CTEP staff listed below has very specific and well defined responsibilities in terms of investigational agent development and the role of DCT as a drug sponsor as defined in CFR 21 Part 312. 1. Scientific Resource for NCI-Supported Clinical Investigations The NCI Program Director, the Associate Director, CTEP (AD, CTEP), and staff of the Clinical Investigations Branch (CIB), the Investigational Drug Branch (IDB), the Biometric Research Branch (BRB), the Regulatory Affairs Branch (RAB), the Pharmaceutical Management Branch (PMB) and the Clinical Trials Monitoring Branch (CTMB) will serve as resources available to Cooperative Groups for specific scientific information with respect to treatment regimen, clinical trial design, investigational agent management and regulatory issues. The CIB Senior Investigator(s) designated by the NCI Program Director will assist the Group as appropriate in developing information concerning the scientific basis for specific trials and also will be responsible for advising the Group of the nature and results of relevant trials being carried out nationally or internationally. The CIB Senior Investigators and IDB Drug Monitors will also provide updated information on the efficacy and toxicity of investigational new agents supplied to Group members under an Investigational New Drug (IND) Application sponsored by the Division of Cancer Treatment (DCT). The CIB Senior Investigator will advise the Cooperative Groups of potential studies which will be relevant to new avenues of cancer therapy. 2. Protocol Development A protocol is the detailed written plan of a clinical experiment. The protocol must be mutually acceptable to the Group and to the CTEP Protocol Review Committee (PRC). Communication with CTEP staff at the various stages of protocol development is encouraged. The CIB Senior Investigator will assist the Group in protocol design as may be appropriate by providing information regarding: (a) the existence and nature of concurrent clinical trials in the area of research, pointing out possible duplication of effort, (b) information including relevant pharmacokinetic and pharmacodynamic data concerning investigational agents, and (c) availability of investigational agents, including biologic response modifiers. The CIB Senior Investigator will also comment on the scientific rationale and value of the proposed study, the design, the statistical requirements, and the implementation of the study, if indicated. CTEP staff will review and provide a Program response through the AD, CTEP, to Concepts for Phase III protocols and Letters of Intent for Phase II protocols, commenting on study originality and programmatic interest. These two mechanisms for preliminary review are required to expedite protocol development and implementation and to facilitate agreement on study priority and design (see the "INVESTIGATOR'S HANDBOOK," pp32-35, for further discussion of these mechanisms). 3. Review of Proposed Protocols Group protocols will be reviewed by the CTEP Protocol Review Committee (PRC) which will meet weekly. It will be chaired by the AD, CTEP or his/her designee. Ad hoc reviewers, external to NCI, will be utilized when deemed appropriate by the committee chairperson. Formal protocol review and CTEP approval prior to activation are required for the following types of studies: (a) all protocols utilizing DCT resources and investigational agents regardless of IND-sponsor; (b) all protocols that permit entry of one hundred or more patients; and (c) all phase III protocols. Other protocols will be filed with CTEP for information purposes but will not require CTEP approval. Advisory reviews of such protocols may be provided to the Group at CTEP's discretion. For all protocols that require review, the AD, CTEP will provide the Group with a consensus review that describes recommended modifications and other suggestions, as appropriate (see the Investigator's Handbook," pp 43-47, for further information regarding protocol review at CTEP). The major considerations relevant to Protocol Review by CTEP include: (a) the strength of the scientific rationale supporting the study, (b) the medical importance of the question being posed, (c) the avoidance of undesirable duplication with other ongoing studies, (d) the appropriateness of study design including interim monitoring plans, (e) a satisfactory projected accrual rate and follow-up period, (f) patient safety, (g) compliance with Federal regulatory requirements, (h) adequacy of data management, (i) appropriateness of patient selection, evaluation, assessment of toxicity, response to therapy and follow-up. If a proposed protocol is disapproved, the specific reasons will be communicated to the Group chairperson as a consensus review within 30 days of protocol receipt by the NCI. NCI will not provide investigational drugs or permit expenditure of NCI funds for a protocol that it has not approved. The CIB Senior Investigator will be available to assist the Group in developing a mutually acceptable protocol, consistent with the research interests, abilities and strategic plans of the Group and of the NCI. 4. Review of Quality Control and Study Monitoring The CTMB staff, will review and provide advice regarding mechanisms established by the Group for quality control of therapeutic and diagnostic modalities employed in its trials. The CTMB staff will review and approve the mechanisms established by the Group for study monitoring including the Group's on-site auditing program. CTEP and/or its contractor staff may attend, as observers, the on-site audits conducted by the Group. The frequency of participation by an NCI representative as observer will be determined by the NCI. 5. Review of Data Management and Analysis The BRB staff will review mechanisms established by the Group for data management and analysis. When deemed appropriate staff will make recommendations to ensure that data collection and management procedures are: (a) adequate for quality control and analysis; (b) as simple as appropriate in order to encourage maximum participation of physicians entering patients and to avoid unnecessary expense; and (c) sufficiently uniform across Groups. The NCI will have access to all data although they remain the property of the awardee institution. Data must also be available for external monitoring as required by NCI's agreement with the FDA relative to the NCI's responsibility as drug sponsor. 6. Data and Safety Monitoring Committees The NCI Program Director, assisted by the BRB staff will assess Group compliance with NCI established policies on Data and Safety Monitoring Committees (DSMCs) for Cooperative Group Phase III trials. One or more CTEP staff will serve as non-voting members on the DSMC. 7. Protocol Closure The AD, CTEP, may request that a Phase I or Phase II protocol study be closed to accrual for reasons including: (a) insufficient accrual rate; (b) poor protocol performance; (c) patient safety; (d) study results are already conclusive; and (e) emergence of new information which diminishes the scientific importance of the study question. The AD, CTEP, may request that the Group DSMC consider closing a Phase III protocol to accrual for reasons including: (a) insufficient accrual rate; (b) poor protocol performance; (c) patient safety; (d) study results are already conclusive; and (e) emergence of new information which diminishes the scientific importance of the study question. NCI will not provide investigational agents or permit expenditures of NCI funds for a Phase I or Phase II study after requesting closure (except for patients on treatment and follow-up). 8. Involvement in Investigational Drug Management The NCI will have the option to cross file or independently file an IND on investigational agents evaluated in trials supported under cooperative agreements. This would apply to drugs not developed in the NCI drug development program. The NCI Program Director, assisted by the RAB staff and the PMB staff will advise investigators of specific requirements and changes in requirements concerning investigational drug management that the Food and Drug Administration (FDA) may mandate. 9. Review of Compliance with Federally Mandated Regulatory Requirements The CTMB staff and the RAB staff will review and provide advice regarding mechanisms established by the Group to meet Food and Drug Administration (FDA) regulatory requirements for studies involving DCT-sponsored investigational agents and Office for Protection from Research Risks (OPRR) requirements for the protection of human subjects. 10. CTEP attendance at Cooperative Group Meetings CTEP staff, as designated by the NCI Program Director, will attend the semi-annual Group meetings and will be invited as a non-voting observer to Group Executive Committee Meetings. 11. Facilitate Completion Of Important Trials CTEP staff will take an active role in promoting the timely completion of important studies, for example by encouraging and facilitating Intergroup collaboration when appropriate, or by assisting in the mobilization of other available and required resources. C. Collaborative Responsibilities 1. Development of Intergroup Trials The CIB Senior Investigators will conduct disease or modality oriented strategy meetings for the purpose of jointly developing the DCT Clinical Trials Cooperative Group Program priorities for future protocol development. Group investigators, NCI staff and other extramural investigators will attend these meetings. The Groups and CTEP staff will work together to facilitate the timely development of protocols resulting from the consensus developed at such strategy meetings. 2. Investigational Drug Development When new avenues of cancer therapy involving investigational drugs are pursued, the clinical information should be acceptable to the FDA for inclusion in a New Drug Application (NDA). In collaboration with NCI staff, the Group will develop protocols to obtain such information as needed. 3. Data Safety and Monitoring Committees The appropriate conduct of the Group DSMC procedures are a collaborative responsibility of the Group and CTEP members. 4. Cooperative Group Chairpersons' Semi-Annual Meetings The Chairperson of each Cooperative Group, the NCI Program Director, the CIB Senior Staff, and other NCI personnel as indicated will meet semi-annually to discuss issues of relevance to the Clinical Trials Cooperative Group Program. 5. Cooperative Group Statisticians' Meeting Each Group's Chief Statistician, the NCI Program Director, the BRB staff, and other NCI personnel as indicated will meet together annually to discuss issues of relevance to the Clinical Trials Cooperative Group Program. D. 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 composed of one Group nominee, one NCI nominee, and a third member with clinical trials expertise chosen by the other two will be formed to review the CTEP decision and recommend an appropriate course of action to the Director, DCT. The arbitration procedures in no way affect the awardee's right to appeal an adverse determination under the terms of 42 CFR Part 50, Subpart D, and 45 CFR Part 16. The Group will not expend NCI funds to conduct any study disapproved by CTEP unless CTEP's disapproval has been modified by the arbitration process outlined above. INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of the NIH that women and members of minority groups and their subpopulations must be included in all NIH supported biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification is provided that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This new policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43) and supersedes and strengthens the previous policies (Concerning the Inclusion of Women in Study Populations, and Concerning the Inclusion of Minorities in Study Populations), which have been in effect since 1990. The new policy contains some provisions that are substantially different from the 1990 policies. All investigators proposing research involving human subjects should read the "NIH Guidelines For Inclusion of Women and Minorities as Subjects in Clinical Research," which was reprinted in the Federal Register of March 28, 1994 (59 FR 14508-14513) to correct typesetting errors in the earlier publication, and reprinted in the NIH Guide for Grants and Contracts, Volume 23, Number 11, March 18, 1994. Investigators also may obtain copies of the policy from the program staff listed under INQUIRIES. Program staff may also provide additional relevant information concerning the policy. LETTER OF INTENT Prospective applicants for this RFA are asked to submit, by June 23, 1995, a letter of intent that includes a descriptive title of the proposed research, the name, address, and telephone number of the Principal Investigator, the identities of other key personnel and participating institutions, and the number and title of the RFA in response to which the application may be submitted. Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows NCI staff to estimate the potential review workload and avoid conflict of interest in the review. The letter of intent is to be sent to: Richard S. Ungerleider, M.D. Division of Cancer Treatment National Cancer Institute Executive Plaza North, Room 741 Bethesda, MD 20892 Telephone: (301) 496-2522 FAX: (301) 402-0557 APPLICATION PROCEDURES The research grant application form PHS 398 (rev. 9/91) is to be used in applying for these grants. These forms are available at most institutional offices of sponsored research; from the Office of Grants Information, Division of Research Grants, National Institutes of Health, 6701 Rockledge Drive, Room 3032, MSC 7762, Bethesda, MD 20892- 7762, telephone 301/710-0267; and from the program administrator listed under INQUIRIES. The RFA label available in the PHS 398 (rev. 9/91) application form must be affixed to the bottom of the face page of the application. Failure to use this label could result in delayed processing of the application such that it may not reach the review committee in time for review. In addition, the RFA title and number must be typed on line 2a of the face page of the application form and the YES box must be marked. Submit a signed, typewritten original of the application, including the Checklist, and three signed, photocopies, in one package to: DIVISION OF RESEARCH GRANTS 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 and all appendix material must also be sent to: Ms. Toby Friedberg Division of Extramural Activities National Cancer Institute Executive Plaza North, Room 636 6130 Executive Boulevard Bethesda, MD 20892 Rockville, MD 20852 (for express mail) Applications must be received by August 25, 1995. If an application is received after that date, it will be returned to the applicant without review. The Division of Research Grants (DRG) 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 DRG will not accept any application that is essentially the same as one already reviewed. Applicants from institutions that have a General Clinical Research Center (GCRC) funded by the NIH National Center for Research Resources may wish to identify the GCRC as a resource for conducting the proposed research. If so, a letter of agreement from either the GCRC program director or principal investigator could be included with the application. SPECIAL INSTRUCTIONS FOR THE PREPARATION OF COOPERATIVE GROUP APPLICATIONS A. Inclusion of Women and Ethnic Minority Individuals in Leadership Positions The NCI encourages applicants for these cooperative agreements to include women and members of U.S. ethnic minority populations in positions of leadership in the Group structure. B. Application Preparation All applications must be submitted on the form PHS 398 (rev. 9/91). Successful applications for each Group component (Headquarters/Operations Office, Statistical and Data Management Center, and Main Member) will be awarded as separate cooperative agreements to the sponsoring institutions and will include the Terms and Conditions of Award specified in this RFA. Each individual application must contain a detailed budget for the first 12-month period and a budget for the entire proposed project period for direct costs. All applications, including that of the Headquarters/Operations Office, the Statistical and Data Management Center, and the Main Members should describe the scientific and administrative experience of key personnel and should include and follow the PHS Form 398 instructions for Biographical Sketches and Other Support information. On page 2 of the PHS 398 form, in the section entitled PERSONNEL ENGAGED ON PROJECT, it is imperative that all applicants list all individuals and their institutions participating in the scientific execution of the project in the format as specified including those with no requested salary support. All applicants must ensure that the list is complete using as many continuation pages as necessary. The key feature of this RFA is that it requires a Headquarters/Operations Office application to be submitted by a Group Chairperson that lists the Main Members and Statistical and Data Management Center as integral components of the Group. All Main Members seeking cooperative agreement funding must submit a separate application identifying the Group with which they are collaborating. The Statistical and Data Management Center application must be submitted separately, and must also identify the Headquarters/Operations Office with which it is affiliated. For each Cooperative Group being proposed, the specific application requirements are listed below: 1. Headquarters/Operations Office The essence of a Group's program of clinical trials should be described in the application for support of its Headquarters. The application should characterize the Group's mission, its plans to accomplish that mission, and present evidence of research accomplishments by the Group's scientific leadership. It should specify concrete research proposals in breast and bowel cancer. It should outline the Group's strategy for each disease or modality, including rationale and future plans; a clear sense of direction should be evident. In addition to its scientific proposals, the Headquarters application should also contain information describing the Group's organizational structure, and the operating procedures and policies to accomplish major Group objectives and responsibilities. a. Research Plan The following format is suggested for following items 1-4 of the "Research Plan" section of the standard PHS Form 398 instructions. 1) Major Research Objectives - This section should concisely describe the Group's several major research objectives. This section should include plans for the inclusion of women and minorities as research subjects in Group studies. 2) Group Organizational Structure - This should include a clear description of the formal organizational structure of the Group, including lines of authority and responsibility, with particular attention to the relationship of the organizational structure to the Group's major objectives. The organizational structure will usually include a number of disease, modality, and administrative committees, in addition to the three major functional components (Headquarters, Statistical/Data Management Office, and Main Member Institutions). The committees will have various research, quality control, and administrative mandates. Productive interaction of the organizational elements should be described and documented. The proposed members of the Group's executive committee should be named, along with their subspecialty affiliations. Procedures for the selection of Group leadership should be described. Procedures for credentialling members, for review of their performance, and for ranking member institutions in terms of contributions to the Group, should be described. 3) Research Strategies - It is essential for the Group and its research committees to develop and articulate comprehensive plans which summarize the Group's specific objectives and lines of investigation for each disease and modality chosen for study. For each DISEASE COMMITTEE, the application should: a) Briefly describe the major scientific goals and strategies of the committee. b) Identify potential protocols which exemplify how the committee plans to achieve its goals. c) Identify and discuss the major research questions relevant to the purview of the committee. 4) Quality Control and On-site Auditing - This section should describe the Group's plans for its programs of quality control and on-site auditing. This function will reside in the Statistical and Data Management Center but should be additionally described in the Headquarter's application. The budget request should be in the Statistical and Data Management Center application. 5) Group Administration - This section should address the major roles and responsibilities of the Group administrative staff together with other matters of relevance to the management of the Group. It should describe a system to ensure capable, efficient, and responsible management by the Group's leadership, as well as ways to identify problems and proposed solutions. Applications should clearly document that the proposed Group Chairperson is experienced in dealing with the problems of cooperative clinical cancer research and that s/he has appropriate experience to qualify him/her as the Group's leader. 6) Data and Safety Monitoring Committees - the application should describe the Group policies and procedures regarding DSMCs. It should include proposed membership rosters of the committee(s), and procedures for avoiding conflicts of interest, such as financial disclosure procedures. 7) Group Policies and Procedures - A copy of the proposed Group Constitution and Bylaws, and a copy of the Group Policies and Procedures, should be provided as an Appendix to the application. The application itself should specifically describe Group policies regarding conflict of interest issues, the training of Group investigators, nurses and data managers/clinical research associates regarding ethics in the conduct of clinical research, and procedures in the event of scientific misconduct. The application should document ongoing ethics training of Group participants, collection of conflict of interest statements from relevant members, and other efforts to employ these policies. At the time of the award, the Grants Management Specialist may request an additional copy of the Group's Constitution and Bylaws, and a copy of the Group Policies and Procedures. b. Budget The Headquarters/Operations Office budget should be presented in logical, discrete units, with specific budgets for each unit as well as the composite headquarters request. A separate budget page and item entitled "Developmental Fund" may be included. The purpose is to provide the Group leadership with resources to support new initiatives, special high-priority projects, and limited funding for candidate members. The first year's plans for this Developmental Fund must be carefully justified, and the Group's process for allocating the funds clearly described where relevant. The following budget guidelines apply specifically to the Headquarters/Operations Office and Statistical and Data Management Center budgets; the categories refer to the item entitled "Detailed Budget for Initial Budget Period" on (Form Page 4) of the PHS Form 398 grant application kit. 1) Personnel - Precise justification for the amount of effort requested for each position is essential. a) Scientific - research costs include the time and effort involved in developing the research agenda and repertoire of protocols for the Group, and analysis and publication of the results of Group research in peer reviewed journals in a timely manner. b) Data Management - research costs include the time and effort involved in the central collection, computerization and analysis of primary patient data; determination of eligibility; registration and randomization; forms development; etc. c) Laboratory Investigations - research costs include the time and effort related to additional laboratory investigations specific to the research goals of the project, i.e., not associated with conventional patient care (note: some Cooperative Groups recommend these activities be allocated by NCI directly, through institutional U10 awards; nevertheless, their description and justification should be included in the Headquarters/Operations Office application). d) Administrative - research costs include the time and effort involved in the overall management of the Group's resources, compliance with regulatory activities, quality assurance and study monitoring procedures. 2) Consultant Costs - Reasonable consultant costs are allowed, if the consultant is contributing directly to the conduct or development of Group research. Most of a Group's consultant costs should appear in the Headquarters budget. Clear and quantifiable justification is required. These costs include travel, per diem and consultant fees, if applicable and within institutional policy. 3) Equipment - Justification should include percent of time used for Group business as well as necessity for purchase. The amount of funds requested should be based on the percent of usage. Include only those equipment items that are required to conduct Group protocols. 4) Supplies - research costs include those related to communication and information dissemination among Group participants. Quantitative justifications based on actual use should be provided. 5) Travel - The importance of meetings to the accomplishments of the Group's research objectives is obvious, as is the necessity to maintain careful control of the size of this budget item. The budget for travel must be itemized and justified. It should include: o trips by the Group's leadership and investigators on behalf of the Group to the NCI and other national organizations where the results of the Group research must be represented or where Group research strategies are to be discussed; o travel for committee members to committee meetings held separately from the semi-annual Group meetings; o travel for persons on the Headquarters staff who must attend the Group's semi-annual meetings; o a reasonable number of carefully justified trips for provisional or otherwise unfunded Group members to attend the semi-annual meetings in order to encourage participation and assure input from all relevant modalities is also allowable (see above regarding Developmental Fund). 6) Alterations and renovations - These costs are not allowable in the Clinical Trials Cooperative Group Program. 7) Other expenses - research costs include those related to communication and information dissemination among Group members. Include here costs of equipment rental and maintenance (copiers, telephones, computers), postage, copying and printing, etc., justified quantitatively on the basis of previous experience, where relevant. 8) Consortium/contractual costs - research costs include support to Group members who are responsible for committees or laboratory investigations, for Group members whose institutions do not receive institutional U10 awards for the research costs related to approved clinical trials activities, or for patient accrual. These third party costs may be presented as consortium arrangements (for substantive programmatic work), as subcontracts, or as reimbursements based on formulas. If third party costs are requested for consortium/contractual participants, a separate detailed budget page, with appropriate justification, must be provided for each arrangement. Indirect costs to consortium/contractual participants are included in the direct cost level for the Headquarters. Groups are encouraged to structure their organization in a manner which minimizes the burden of indirect costs on the overall Group budget. Reimbursement for patient accrual is to be based on formulas that must relate to the institution's membership category, scientific and leadership contributions, and prior performance including accrual and assessment of data accuracy and timeliness. A description of how the formula was determined, including a line item budget breakdown of the research costs, must be included in the application. In addition, the application must include a plan for disbursement of funds that includes consideration of performance and quality factors including eligibility and evaluability rates; data accuracy and completeness; and quality of on-site audits, etc. The funds received by Affiliates for patient accrual should be subject to modification based on results of the Group's performance reviews. These costs should be included in the consortium/contractual costs category of the Headquarter's budget. Consortium arrangements and all other contractual arrangements, including all mechanisms for reimbursement for patient accrual, must be formalized in writing in accordance with applicable Public Health Service policy requirements (PHS Grants Policy Statement, revised 9/94, page 8-17). A statement that the applicant organization and the collaborating organization have established or are prepared to establish a formalized agreement that will ensure compliance with all pertinent Federal regulations and policies must be included in the application. Also include all pertinent biographical sketches and a list of all other support for all relevant consortium participants. 2. Statistical and Data Management Center Application The statistical and Data management center is funded via a separate cooperative agreement. Thus a separate application is required which should address operational roles and responsibilities discussed under RESEARCH OBJECTIVES, (B.) Organization. It should describe in detail the Group's data management practices and procedures, its quality control and study monitoring methodology, and its analytical techniques and resources. a. Research Plans The following format is suggested for following items 1-4 of the "Research Plan" section of PHS Form 398 instructions. Wherever appropriate, narrative should supplement (rather than duplicate or replace) standard manuals, which should be supplied. 1) Roles and Responsibilities - list the major objectives of the Group's statistical and central data management staff. 2) Organization and Facilities - describe the organization and facilities to accomplish the complex tasks of central data management, quality control, study monitoring, and data analysis. 3) Data Management Policies and Practices - describe the flow of data following submission from the individual investigator. 4) Quality Control - describe procedures for quality control and accuracy verification. 5) Study Monitoring Procedures - describe the Group's standard methods for ongoing study monitoring, including interactions with study chairs. 6) Study Design and Data Analysis - describe the Group's routine methodologic practices (e.g., methods of sample size calculations, choice of testing and estimation procedures, interim analysis policies, early stopping procedures, etc.) Include plans for the inclusion of women and minorities as research subjects in Group studies. 7) On-site Audit Program - describe the method by which the Group will structure, monitor, and regulate this program in conformance with the NCI-CTMB GUIDELINES FOR ON-SITE MONITORING OF CLINICAL TRIALS FOR COOPERATIVE GROUPS AND CCOP RESEARCH BASES. Also, describe the interactions that will occur with NCI. 8) Partnership in Group Research - describe the role and contributions of the Group's statisticians to Group research. The involvement of statisticians in designing studies should be documented. 9) Independent Research - described research being conducted by the statistical office of the Cooperative Group using Group resources, including the data base. b. Budget See budget guidelines in this RFA referring to the Headquarters/Operations Office. The statistical and data management center budget should be presented in logical, discrete units with specific budgets for each unit as well as the total Center's request. In accordance with the NCI-CTMB GUIDELINES FOR ON-SITE MONITORING OF CLINICAL TRIALS FOR COOPERATIVE GROUPS AND CCOP RESEARCH BASES, Groups are required to conduct routine on-site audits of Main Members/Affiliates that participate in NCI-supported clinical trials. Personnel, travel expenses, and computer systems to accomplish this task must be carefully and fully documented. Budgets shall include travel for protocol chairs and others who must perform quality control functions away from their home institution and travel for the on-site audit program. Because of the importance of the quality control and on-site audit program, a separate budget for each function should be prepared. 3. Main Member Applications Each Main Member application should concentrate on the contributions of the institution to the Group. Specifically, applications should focus on the roles and responsibilities defined in RESEARCH OBJECTIVES, (B.) Organization, Main Member Applications. The clinical trials and research strategies of the Group are described in the Headquarters application, and should not be repeated in the individual institution applications. Affiliate investigators associated with primary members must satisfy Group criteria for participation, and may request funds from only one source. Specific assets of the institution regarding access to particular patient populations should be included in the application. a. Research Plan The following format is suggested for following items 1-4 of the "Research Plan" section described in the standard form 398 instructions. Standardized reporting formats across the Group are strongly advised. 1) Summarize the institution's cancer research interest and capabilities. 2) Describe the potential scientific contributions of the institution's investigators to the Group, focusing on their roles in shaping the Group's research strategies and in scientific committee leadership. 3) Describe the role of the institution's investigators in chairing or otherwise managing protocols. 4) Describe potential institutional pilot studies and other clinical research contributions to the Group. 5) Identify core services provided by the institution, such as laboratory studies or assays for particular protocols, service on site-visit teams or audits, etc. 6) Describe the proposed participation by the institution's investigators in Group administrative committees (e.g., membership, audit, etc.) with attention to the particular expertise of the institution's investigators. 7) Describe institutional procedures for data management and data submission to the Group. Particular attention should be given to management of data from Affiliates. 8) Describe the organization employed for institutional Group participation. Document adequate participation from and interactions among all modalities and disciplines required for conduct of Group studies. Describe procedures for determining patients' protocol eligibility, and for their ongoing treatment once they are entered onto Group studies. Describe the process for determining intra-institutional protocol priorities. 9) Describe potential problems anticipated in achieving research goals together with concrete plans designed to address such problems. 10) If relevant, describe the existing Affiliate network, listing Affiliate sites; describe institutional procedures for processing Affiliate data and auditing Affiliate charts; describe communications systems between the Institution and its Affiliates. b. Budget Main members perform two specific activities - they contribute scientific expertise to the Group, and they accrue patients to Group clinical trials. Institutional budgets should request those costs necessary for conduct of Group studies at the institution and for attendance of a reasonable number of investigators at regular Group meetings. The budget of a typical primary member institution should be devoted largely to personnel, although some variation from this norm is permissible. Each institution must develop its request based upon its unique requirements. The importance of meticulous justification for all budget items should be apparent. The Group Chairperson should provide each institution with guidance in the preparation of a reasonable request, in the development of a consistent format for budget presentation, and in the use of consistent formulas for institutional travel budgets. The following budget guidelines apply specifically to Main member institution applications; the categories refer to the items entitled "Detailed Budget for Initial Budget Period" on (Form Page 4) of the PHS 398 grant application kit. 1) Personnel- Precise justification for the percent effort requested for each position is essential. a) Data Management - research costs include the time and effort involved in accurate data collection and submission. b) Other consultant costs (e.g., pathology, radiology), c) Intellectual - research costs include the time and effort involved in developing the research agenda and repertoire of protocols for the Group, and preparing the results of the Group's research for publication. d) Laboratory investigations - the time and effort related to additional laboratory investigations specific to the research goals of the project, i.e., not associated with conventional patient care (note: most Cooperative Groups place these activities in the Group Headquarters/Operations Office application.) e) Administrative - research costs include the time and effort involved in coordinating research activities at the institution, compliance with regulatory activities, quality assurance and study monitoring procedures and participation in the Group on-site audit program. 2) Consultant Costs- These are not usually appropriate in a primary member institution's budget. Requests should be justified in detail. These costs include travel, per diem and consultant fees, if applicable and within institutional policy. 3) Supplies/Equipment/Other - research costs include those associated with communication with the Group office and with Affiliate institutions, the costs of compiling and mailing data and the costs of mailing or handling patient-related specimens, forms, and materials (e.g., slides, X-ray films). Significant equipment costs are unusual; all must be carefully justified. The amount of funds requested should be based on the percent of usage. 4) Travel - Travel for a reasonable number of the institution's participating investigators, data managers and nurses to attend the regular Group meetings should be included in the institutional budgets. Attendance of investigators at meetings on behalf of the Group, or at special (i.e., non-routine) meetings of committees of the Group should generally be funded through the headquarters or statistical office award, rather than the institution award. 5) Consortium/Contractual Costs - Separate budget pages with detailed justification of all requested items should be submitted for each consortium agreement. Include applicable indirect costs. Reimbursement for affiliates accrual will be based on formulas that must relate to the institution's membership category, scientific and leadership contributions, and prior performance including accrual and assessment of data accuracy and timeliness. A description of how the formula was determined, including a line item budget breakdown of the research costs, must be included in the application. In addition, the application must include a plan for disbursement of funds that includes consideration of performance and quality factors including eligibility and evaluability rates; data accuracy and completeness; and quality of on-site audits, etc. The funds received by Affiliates for patient accrual should be subject to modification based on results of the Group's performance reviews. Consortium arrangements and all other contractual arrangements, including all mechanisms for reimbursement for patient accrual, must be formalized in writing in accordance with applicable Public Health Service policy requirements (PHS Grants Policy Statement, revised 9/94, page 8-17). A statement that the applicant organization and the collaborating organization have established or are prepared to establish a formalized agreement that will ensure compliance with all pertinent Federal regulations and policies must be included in the application. Also include all pertinent biographical sketches and a list of all other support for all relevant consortium participants. REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed for completeness by DRG and for responsiveness by the NCI. Incomplete and non-responsive applications will be returned to the applicant without further consideration. Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened by the NCI in accordance with the review criteria stated below. The initial peer review may be preceded by a site visit to the Group's statistical and data management facilities. The Scientific Review Administrator is responsible for all aspects of the peer review process, and will negotiate with the Group chairperson the date, duration and content of the site visit. The findings of the site visit team are provided to the parent review committee during its consideration of the application. Because of their interrelatedness, all applications from all components of a particular Group are reviewed simultaneously. The content of the Headquarters/Operations Office application is first evaluated; this review is an integral part of the review of each individual application of the Group, regardless of component. If the initial review committee recommends the Headquarters application for further consideration, the committee then assigns a priority score representing the overall peer review evaluation of the Group and recommends a period of award (generally three to five years). If the Headquarters application is scored, the committee evaluates the applications of the other individual components. The committee also develops budgetary recommendations for each scored application. If the Headquarters application is not recommended for further consideration (NRFC), the applications of the individual components are not reviewed and the application cannot be funded. Review Criteria The review criteria employed by the site visit team and the initial peer review committee for each of the three operational components are summarized below: A. Group Headquarters/Operations Office o Merit of Specific Research Plans - How meritorious are the research plans and strategies for each of the major areas of study? Are they appropriate in the context of national priorities? Are guidelines for the inclusion of women and minorities as research subjects being followed? Are there strategies outlined to increase accrual of women and minorities to clinical trials? o Key Personnel - Does the research experience and qualifications of the Principal Investigator demonstrate understanding of design, administration, and analysis of multi-institutional clinical trials in breast and bowel cancer and relevant laboratory studies? o Research Methodology - How well designed are the Group's planned clinical trials? Will their design allow clinically important conclusions to be drawn? o Patient Accrual - Is the membership of the Group adequate to mount multiple, concurrent, large-scale clinical trials in breast and bowel cancer? o Efficiency of Study Development - Will the process of study development proceed in an efficient and timely manner? Do mechanisms exist to ensure the rapid development and implementation of important studies? o Timeliness of Study Completion - Will the Group be able to carry out its planned studies in a reasonable period of time? Will Intergroup collaboration be utilized when necessary to satisfy the requirements for timely completion? o Overall Group Priorities - Are the overall priorities of the Group appropriate? Are its resources well directed? o Developmental Fund Plans - Are the specific plans for the developmental fund appropriate and consistent with the Group's overall goals and priorities? Will the fund be well managed with appropriate oversight? o Group Structure and Administration - Will the Group be well administered by the Chairperson and the Headquarters staff? Does its organization and infrastructure allow it to meet its major objectives and goals? o Publication Record - Has the Group developed plans that will encourage and permit timely publication of research in quality peer reviewed journals? o Group Cohesiveness - Will the Group function as a cohesive research team? o Interdisciplinary Coordination - Will there be adequate interdisciplinary participation in protocol development and design? Do protocol investigators reflect the modalities utilized? o Membership - Are the criteria for initial and continuing membership adequate? Does the Group's periodic evaluations of its members emphasize both high quality record-keeping and adequate patient accrual? o Companion Research - While not required, Group involvement in epidemiologic, diagnostic, cancer control, quality of life, cost- effectiveness, and prevention research, especially as it relates to or follows logically from the Group's prime therapeutic mission, is a strength. o Patient Advocate Participation - Are there defined plans and roles for patient advocates in the Group? Have they been included in the budget to attend Group meetings? o Translational Research - Is there a well defined and funded plan to develop a tumor banking system which facilitates correlative studies into the overall research effort? While not required, the capacity and expertise within the Group to develop innovative research ideas based on laboratory models and pilot these in limited institution trials with an eye to their potential use as experimental arms in phase III trials is a strength. o Adequacy of plans to include both genders and minorities and their subgroups as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. o Facilities - Are the offices, computer support systems, and overall parent facility commitment adequate to ensure a smoothly functioning Headquarters/Operations Office? Are there any problems with the structural layout that might serve as an impediment to a focused and well coordinated Operations Office? o Staff - Are the roles of the Headquarter's staff adequately defined to accomplish the goals of the Group? Is there an adequately defined staff to cover the multiple tasks which are the responsibility of the Operations Office. o Budget - Have costs for travel, office supplies, equipment and data management been adequately justified? Are detailed costs of Affiliate members provided? Are budgetary plans submitted for Group meetings and consultant fees? B. Statistical and Data Management Office This portion of the evaluation involves three facets: 1) the performance and capabilities of the statistical and data management office; 2) the Group's integration of the statistical and data management office's roles and responsibilities into the overall research program; and 3) the development and operation of a rigorous quality control program with on-site auditing. o Collaboration in Research - Will there be adequate statistical and data management collaboration in the development and conduct of the Group's research? o Adequacy of Study Design - Is there evidence that the protocols will be properly designed statistically? Will the sample sizes be adequate to detect realistic and medically important differences? Will the assumptions be adequately justified? Is the expected accrual rate carefully estimated? Are the designs used appropriate for the study questions? Are endpoint selections and sequential monitoring plans adequately described and justified? o Data Management - Are data management procedures adequate, appropriate, and consistent with accepted standards? Are procedures for the verification of data accuracy adequate? Is there clinical review of study data? Do quality assurance and quality control programs exist, including on-site audits that assure high-quality research and patient safety? o Statistical Analyses - Are analytical techniques, procedures, and policies adequate, appropriate, and consistent with accepted standards? Is there evidence that past publications of the Group Leadership demonstrate thorough and state-of-the-art methodology, awareness of problems of multiple analyses, and sufficient independence and lack of bias of statistical collaborators? o Key Personnel - Does the research experience and qualifications of the Principal Investigator demonstrate understanding of design, administration, and analysis of multi-institutional clinical trials in breast and bowel cancer and relevant laboratory studies? o Independent Research - While not required, involvement in research related to the design, conduct and analysis of cancer clinical trials is a strength. o Computing resources - Are computing resources adequate and appropriate to support Group activities as needed? o Facilities - Are the offices, computer hardware, and overall parent facility commitment adequate to assure smooth and efficient function? Are there deficiencies in the structural layout which might serve as an impediment to coordination of Group research efforts? o Staff - Are the roles of the staff adequately defined to accomplish the goals and meet the responsibilities? Is there an adequate number of personnel to meet the assigned tasks? o Budget - Have costs for the on-site audit plan been accurately detailed? Is there sufficient funding allotted to carry-out the multiple quality control tasks required? C. Main Members Both scientific and administrative contributions to the Group, and patient accrual and data quality enter into this evaluation. o Contributions to Group Science - What will be the contributions of the institution's investigators to the Group's research strategies and plans? Will the investigators chair research committees and studies? o Key Personnel - Does the research experience and qualifications of the Principal Investigator demonstrate understanding of design, administration, and analysis of multi-institutional clinical trials in breast and bowel cancer and relevant laboratory studies? o Participation in Group Activities and Administration - How will the institution's investigators participate in Group activities and meetings? o Interdisciplinary Coordination - To the extent required by the Group's research, is there adequate interdisciplinary cooperation and coordination? o Patient Accrual - Is the record of patient accrual appropriate in the context of Main Member/Affiliate accrual goals? Are projections for the future reasonable and adequate? Are women and minorities appropriately included as research subjects on Group trials? Are there strategies to increase accrual of women and minorities to clinical trials? o Data Quality - Is the recent data complete, accurate, and submitted in a timely fashion? o Protocol Compliance - What is the recent record of the quality of protocol participation? o Data Management - Are the institution's data management practices and procedures adequate and appropriate? o Publication - How will the institution's investigators contribute to publication of Group studies? o Translational Research - Although not required, the ability to conduct phase I and II pilot trials which can then serve to foster the Group's research goals is a strength. o Adequacy of plans to include both genders and minorities and their subgroups as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. o Facilities - Are the treatment facilities adequate to carry out clinical research? Does each Affiliate have a well organized central site which will coordinate the activities of its members? o Staff - Are there adequate data managers and nursing support to meet the patient care and data submission needs of clinical trials? Is the relationship between Affiliate and their Main Members carefully explained, including the responsibilities of the P.I. at each institution? o Budget - Have costs for on-site auditing of Affiliates been included (if this is the mechanism chosen by the Group for auditing of Affiliates)? Are travel and equipment costs adequately detailed? Is there adequate justification of personnel costs? AWARD CRITERIA Applications recommended by the National Cancer Advisory Board will be considered for award based upon (a) technical merit of the application as reflected in the priority score (b) availability of resources, and study population and (c) availability of funds. Furthermore, the applicant organization must indicate a commitment to accept provisions outlined under the SPECIAL REQUIREMENTS section, Terms and Conditions of Award. The anticipated date of award is March 1, 1996. INQUIRIES Written and telephone inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding scientific and/or administrative issues to: Richard S. Ungerleider, M.D. Division of Cancer Treatment National Cancer Institute Executive Plaza North, Room 741 6130 Executive Boulevard Bethesda, MD 20892 Rockville, MD 20852 (if using express mail) Telephone: (301) 496-6056 or (301) 496-2522 FAX: (301) 402-0557 Email: ungerler@dct.nci.nih.gov Direct inquiries regarding fiscal matters to: Ms. Crystal Wolfrey Grants Administration Branch National Cancer Institute Executive Plaza South, Room 243 6120 Executive Boulevard Bethesda, MD 20892 Rockville, MD 20852 (if using express mail) Telephone: (301) 496-7800, ext. 282 FAX: (301) 496-8601 Email: WOLFREYC@GAB.NCI.NIH.GOV AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.395, Cancer Treatment Research. Awards are made under authorization of the Public Health Service Act, Title IV, Part A (Public Law 78-410, as amended by Public Law 99-158, 42 USC 241 and 285) and administered under PHS grants policies and Federal Regulations 42 CFR 52 and 45 CFR Part 74. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. The PHS strongly encourages all grant and contract recipients to provide a smoke-free workplace and promote the non-use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routing 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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