Full Text CA-92-02 RADIOLOGIC DIAGNOSTIC ONCOLOGY GROUP IV: OVARIAN CANCER AND PEDIATRIC SOLID TUMORS NIH GUIDE, Vol. 21, No. 8, February 28, 1992 RFA: CA-92-02 P.T. 34 Keywords: Cancer/Carcinogenesis Diagnosis, Medical Medical/Diagnostic Imaging National Cancer Institute Letter of Intent Receipt Date: March 24, 1992 Application Receipt Date: May 26, 1992 PURPOSE The Radiation Research Program (RRP), Division of Cancer Treatment (DCT) of the National Cancer Institute (NCI), invites applications for cooperative agreements to establish a multi-institutional scientific group to optimize staging and follow up of pediatric solid tumors and ovarian cancer. HEALTHY PEOPLE 2000 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2000," a PHS-led national activity for setting priority areas. This RFA, Radiologic Diagnostic Oncology Group IV: Ovarian Cancer and Pediatric Solid Tumors, is related to the priority area of cancer. Potential applicants may obtain a copy of "Healthy People 2000" (Full Report: Stock No. 017- 001-00474-0) or "Healthy People 2000" (Summary Report: Stock No. 017-001-00473-1) through the Superintendent of Documents, Government Printing Office, Washington, DC 20402-9325 (telephone 202-783-3238). ELIGIBILITY REQUIREMENTS Non-profit and for-profit organizations and institutions, governments and their agencies, and foreign and domestic institutions are eligible to apply. Applications from minority individuals and women are encouraged. In order to participate in this program, applicant institutions must demonstrate, or meet the following requirements: A. Requirements for Participating Institutions 1. A commitment to participate in multi-institutional protocols and documentation of the facilities and professional personnel available to conduct cooperative imaging trials. This includes assignment of appropriate specialists required by each protocol including, but not limited to, radiologists, surgeons and pathologists, in order to ensure complete patient evaluation. 2. Individual applicant institutions must demonstrate the availability of state-of-the-art instrumentation and the capacity to perform various procedures. Specifically, this RFA solicits applications that compare various imaging techniques for the detection of ovarian cancer and pediatric solid tumors. Each member institution is not expected to participate in protocols in both pediatric solid tumors and ovarian cancer, but a given institution must possess equipment suitable for the developed protocol. In order to be qualified for these protocols, applicant institutions must have the instruments, facilities, and capabilities for performing the specified studies outlined below. a. The Ultrasound scanner should be 5 megahertz or larger. b. The magnetic resonance (MR) scanner field uniformity must be assured. Applicants must provide documentation, using data from phantoms or patients, of the signal-to-noise ratio, the contrast resolution, the spatial resolution, field uniformity and other pertinent information about the whole body MR scanners and surface coils (when applicable) intended to be used in this study. The study section will review and evaluate the technical quality of MR images in every application. c. The computer tomography (CT) scanners must be third or fourth generation high resolution units. d. Applicant institutions must be able to correlate imaging data with pathology and CT-directed biopsies as designed by the protocol. 3. The presence of expertise for review and evaluation of the quality of images and the existing procedures for quality control of imaging equipment, imaging technique, and image interpretation must be demonstrated. 4. The availability of qualified support personnel to ensure timely and accurate data retrieval and reporting is necessary. 5. The availability of sufficient expertise and the potential for adequate patient accrual must be demonstrated by the grantee institutions. Applicants must show the ability to organize, conduct, and monitor clinical trials in radiology. 6. The organizational plan must be presented for personnel and facilities capable of performing and supporting the administrative functions of a cooperative group member conducting imaging trials in cancer. B. Eligibility requirements for the Headquarters 1. Expertise in the design and coordination of multi-institutional cooperative clinical trials including interactions with participating institutions. 2. Capability to provide educational workshops and ongoing training for group participants in order to ensure the development of scientifically valid results in the most efficient manner. 3. Capacity to develop and implement an administrative and management structure for the RDOG IV including criteria for membership, an Executive Committee, a Quality Assurance Committee, a Protocol and a Research Strategy Committee that will assume responsibility for randomized studies and set the priorities for protocol development. 4. Capacity for monitoring performance of studies and producing timely reports on the quality of data for relevant diagnostic imaging modalities including, but not limited to, image interpretation and related information, sensitivity and specificity of imaging modalities. 5. Expertise in the development of experimental design for statistically valid multi-institutional imaging trials. 6. Availability of facilities and professional personnel with expertise in data management and analysis and the ability to participate in cooperative clinical trials to provide centralized statistical services. MECHANISM OF SUPPORT Support of this program will be through the cooperative agreement (UO1), an assistance mechanism in which substantial NCI programmatic involvement with the recipient during performance of the planned activity is anticipated. The nature of NCI staff involvement is described in the Section "Terms of Cooperation." Applicants will be responsible for the planning, direction, and execution of the proposed project. Except as otherwise stated in this RFA, awards will be administered under PHS grants policy as stated in the Public Health Service Grants Policy Statement, DHHS Publication No. (OASH) 90-50,000, revised October 1, 1990. This RFA is a one-time solicitation. Future unsolicited competitive continuation applications will compete as research project applications with all other investigator-initiated applications and be reviewed by the Division of Research Grants (DRG). If the NCI determine that there is a sufficient continuing program need, the NCI will invite recipients of awards under this RFA to submit competitive continuation cooperative agreement applications for review according to the procedures described in REVIEW CONSIDERATIONS below. FUNDS AVAILABLE Approximately $800,000 in total costs per year for three years will be committed to fund applications that are submitted in response to this RFA. It is anticipated that six to eight institutions plus the Headquarters component will be funded to establish the RDOG IV. This funding level is dependent on the receipt of a sufficient number of applications of high scientific merit. The total project period for applications submitted in response to the present RFA may not exceed three years. RESEARCH OBJECTIVES Background The Radiologic Diagnostic Oncology Group (RDOG) was formed in September 1987, in response to an RFA. The RDOG objective is timely evaluation of current and emerging imaging modalities in the management of patients with cancer. The development of multi-institutional clinical trial groups allows rapid patient accrual within a short period of time. This in turn assures rapid evaluation and optimization of imaging techniques for diagnosis, staging, and serial monitoring of cancer. Since the time of its establishment, RDOG clinical research has been important for the development of optimal imaging algorithms for prostate and lung cancer (RDOG I) and pancreatic and colon cancer (RDOG II). Four protocols are currently underway in ten academic centers in this country. Recently, an RFA (RDOG III) was issued to study musculoskeletal and head and neck tumor imaging, and seven new institutions have been funded. The results of each RDOG study should have a direct and immediate impact on patient care. Additionally, considerable health care cost saving is expected due to elimination of unnecessary diagnostic studies. The RDOG has had a significant impact on clinical research in Radiology. This is the first time that multi-institutional clinical trials in diagnostic imaging have been conducted in a centrally coordinated fashion with strict quality control and analysis of cost-effectiveness. Ultimately, RDOG study findings would be useful for the design of therapeutic protocols and formulation of clinical and medical insurance reimbursement policy. Moreover, the proposed clinical trials may stimulate spin-off projects addressing a number of questions that are not within the scope of the RDOG cooperative agreement. Indeed, potential research projects may involve detailed studies of MR tissue characterization, prognostic factors, and many other important areas in clinical radiology research. The specific focus of this solicitation is to expand the RDOG in order to include pediatric solid tumors and ovarian cancer, which have been recently identified as high priority research areas in clinical radiology. Ovarian Cancer Ovarian cancer is the leading cause of death among gynecologic malignancies in the United States (1). Significant improvement in patient survival requires optimization of diagnostic strategy for ovarian cancer detection and staging combined with more effective treatment regimens. The need for accurate staging of ovarian cancer for treatment planning is apparent. Non-radiologic methods for ovarian cancer diagnosis include pelvic examination and serum marker measurements. Pelvic examination, which has often been relied upon, is insensitive for small tumors (2). Although ovarian tumor markers, such as CA 125 antigen detected in about 80 percent of non-mucinous epithelial ovarian carcinomas, appear helpful as indicators of disease recurrence and progression, their diagnostic value has been limited (3). Indeed, targeting monoclonal antibodies to cell markers for ovarian cancer diagnosis has been problematic due to heterogeneous tumor antigen expression (4). While non-invasive radiologic procedures, such as ultrasound, x-ray computed tomography (CT) and MR imaging (MRI), have emerged as potentially important diagnostic tools, their role in staging of ovarian cancer has not been defined as yet. Intravaginal ultrasound has been reported to be useful for ovarian cancer screening by a number of investigators (5,6,7,8). However, one of the major problems of intravaginal ultrasound is the limited characterization of ovarian abnormalities, and the role of this technique in staging of ovarian cancer is unclear. Indeed, the main ultrasonographic criterion for the differentiation of benign from malignant ovarian lesions is the size of detected abnormality (with size greater than 10 cm indicating malignancy with higher degree of certainty) (6). More recently, flow imaging (color Doppler) has been reported to enhance ultrasonographic identification of potentially malignant ovarian masses through the assessment of the intraovarian vasculature (e.g., neovascularization) and blood flow impedance (9). The role of CT and MRI in ovarian cancer staging has been difficult to define due to rapid technologic and methodologic advances. Although introduction of CT has significantly improved the preoperative determination of disease extent in patients with ovarian cancer, some investigators reported that tumors smaller than 1 to 1.5 cm cannot be accurately visualized and about 40 percent of patients with negative CT scans have been found to have disease at the time of exploratory laparotomy (10,11). While MRI appears helpful for detection and characterization of pelvic diseases, its role in the evaluation of ovarian carcinoma has not been established (12). Patients with ovarian cancer frequently have "second look" laparotomy for accurate determination of the disease extent due to the critical role of this information in treatment planning. Thus, the RDOG IV imaging data can be readily compared to the "gold standard" of surgical and pathologic staging information. It is expected that RDOG IV studies will develop an optimal imaging strategy for ovarian cancer staging and will help to define the role of radiologic procedures with reference to surgical intervention in tumor staging. Pediatric Solid Tumors Non-central nervous system (CNS) pediatric solid tumors (e.g., neuroblastoma, Ewing's sarcoma, rhabdomyosarcoma) represent another high priority research area in clinical radiology. The difficulties with formulating an optimal approach to staging and follow-up of these tumors stem, at least in part, from the limited number of patients at a given institution. It is expected that the multi-institutional nature of RDOG IV studies would allow for enhanced patient accrual and development of the optimal approach to radiologic imaging of pediatric tumors. Neuroblastoma is the most common extracranial nonlymphomatous solid tumor in childhood (about 10 percent of all pediatric tumors) (13). Primary sites of neuroblastoma are abdomen, posterior mediastinum, and pelvis. About half of patients with neuroblastoma have metastases to bone marrow, liver, bone, or lymph nodes at the time of diagnosis. While children under 12 months of age have a favorable prognosis even when advanced disease is present, prognosis and treatment outcome in neuroblastoma in older children (>1 year of age) are dependent on extent of disease at the time of diagnosis (14). Indeed, metastatic disease is almost invariably fatal in older children. Treatment approach to neuroblastoma should optimize outcome and minimize treatment-induced morbidity. Patients with limited neuroblastoma usually have surgical resection. If there is no evidence of lymph node involvement or other evidence of residual regional disease, additional interventions are not usually warranted. Older children with unresectable localized tumors may benefit from combination chemotherapy, delayed surgical resection, and radiation therapy. Thus, accurate staging of neuroblastoma is important for management of these patients. It is expected that RDOG IV studies will develop the optimal imaging approach to determine the location and extent of the primary and metastatic neuroblastoma. Among other non-CNS pediatric solid tumors, Ewing's sarcoma and rhabdomyosarcoma have been identified as childhood malignancies requiring further studies for the development of optimal imaging strategy. Rhabdomyosarcoma accounts for about 5-10 percent of all pediatric solid tumors (13), with the primary sites of lesions as varied as head and neck (38 percent), genitourinary tract (21 percent), extremities (18 percent), trunk (7 percent) and retroperitoneum (7 percent). The extent of rhabdomyosarcoma at diagnosis is an important factor for treatment planning. Indeed, the role of surgery varies with the primary site, size, and extent of the disease at presentation. In early stages of the disease, if patients are rendered disease-free by surgery, radiation therapy is not required, while adjuvant chemotherapy improves survival. In more advanced disease, radiation therapy is usually necessary for local and regional control, and radiation fields depend on the local disease extent and regional lymph node involvement. The utility of systemic chemotherapy in patients treated with radiation depends on the residual disease. The relapse-free survival rates are 63-72 percent for patients with microscopic residual disease, 54-61 percent for patients with gross residual disease, and only 17-23 percent in patients with disseminated disease. Thus, accurate staging of the disease extent is critical for treatment planning and prognosis in children with rhabdomyosarcoma. Ewing's sarcoma is the second most common primary bone tumor of childhood. The characteristic feature of this tumor is the relatively high incidence of metastatic disease (14-50 percent) at the time of diagnosis. While surgical procedure alone results in less than 10 percent long-term survival rates, systemic adjuvant chemotherapy for preventing distant failure and radiation therapy for local control increase long-term survival rates. The choice between radiation treatment and surgical intervention for a primary lesion are guided by two major clinical end-points of therapy, tumor control and preservation of function. However, local control with primary radiation and chemotherapy appears to depend on tumor size. While radiation therapy is a primary mode of treatment for most local lesions, a very careful definition of irradiation fields is required in order to maintain function. Thus, the accurate determination of the local tumor extent on initial and follow-up radiologic images is essential for management of Ewing's sarcoma. It is expected that RDOG IV studies will evaluate relative accuracy of radiologic modalities, such as CT, MRI, and other techniques, in the determination of local and regional disease extent, and define the most effective approach to diagnosis of metastatic spread in children with neuroblastoma, rhabdomyosarcoma, and Ewing's sarcoma. Other The major thrust of this RFA is to develop the optimal imaging strategy for ovarian cancer and non-CNS pediatric solid tumors and to assess the impact of improved diagnosis on patient management and health care costs. It is expected that the following goals will be achieved: (1) Improved staging of ovarian cancer and pediatric solid tumors (2) Definition of the general role, indications, comparative accuracy, and proper sequence and timing of imaging procedures (3) Comparison of the role of radiologic procedures as compared to surgical exploration in the evaluation of disease extent (4) The impact of optimized imaging on treatment decisions, local disease control, and patient survival SPECIAL REQUIREMENTS Terms of Cooperation A. Nature of Participation by NCI Staff All RRP staff assistance, advice and support, as described throughout these Terms of Cooperation, will be communicated to awardees by the Associate Director, RRP (ADRRP), or designee. In all cases, the role of the NCI is to assist and facilitate but not to direct research activities. 1. RRP as a Scientific Resource for NCI-supported Clinical Investigations The ADRRP, or designee, will serve as a resource available to awardees for specific scientific information with respect to clinical trial design. The staff will assist the RDOG IV institutions as appropriate in developing information concerning the scientific basis for specific research protocols and also will be responsible for advising the group of the nature and results of relevant studies being carried out nationally or internationally. The ADRRP, or designee will participate in planning and strategy meetings, when indicated, of the RDOG IV institutions. At these meetings, RDOG IV institutions, assisted by the ADRRP, or designee, will review relevant information and establish and prioritize the outstanding research questions. 2. RRP Assistance in Protocol Development The protocol must be a study document mutually acceptable to the RDOG IV and to the ADRRP. Communication at the various stages of protocol development is encouraged. The ADRRP, or designee, 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. The ADRRP will assist the RDOG IV institutions in protocol design as may be appropriate by providing information regarding: (a) the existence and nature of concurrent clinical trials in the area of RDOG IV research, pointing out possible duplication of effort, and (b) relevant data concerning imaging research. The ADRRP, or designee, 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. All protocols for submission to NCI must be preceded by a letter from the RDOG IV Chairperson to the ADRRP describing the hypothesis investigated, the general design of the contemplated trial, and relevant information on accrual capabilities to document feasibility. The ADRRP will then formally review and provide a program response to these concepts, commenting on study originality and programmatic interest. This preliminary review will expedite protocol development and implementation and facilitate agreement on study priority and design. 3. RRP Review of Proposed Protocols All the RDOG IV scientific protocols will be reviewed by the ADRRP. Ad hoc reviewers, external to the NCI, will be utilized whenever the need for a specific additional expertise is identified by the ADRRP. For all protocols, the ADRRP, or designee, will provide the RDOG IV Chairperson with a written consensus review that describes recommended modifications and other suggestions as appropriate. The major considerations relevant to protocol review by the NCI 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, (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 and follow-up, evaluation, and assessment of complications/toxicity. If a proposed protocol is disapproved by the NCI, the specific reasons for lack of approval will be communicated by the ADRRP to the RDOG IV Chairperson as a consensus review within 45 days of receipt of the proposed protocol. Disagreements arising pursuant to protocol disapproval may be submitted to an arbitration panel. An arbitration panel composed of one RDOG IV nominee, one ADRRP nominee, and a third member with clinical trials expertise chosen by the other two will be formed to review the NCI decision and recommend an appropriate course of action to the ADRRP. These special arbitration procedures in no way affect the awardee's right to appeal an adverse determination in accordance with PHS regulations at 42 CFR Part 50, subpart D, and HHS regulations at 45 CFR Part 16. The RDOG IV will not expend NCI funds to conduct any study not approved by the NCI unless the disapproval has been modified by the arbitration process outlined above. 4. RRP Study Monitoring The ADRRP, or designee, will review RDOG IV mechanisms for study monitoring (see section Responsibilities of Awardees, RDOG IV Headquarters). 5. RRP Review of Data Management and Analysis The ADRRP, or designee, will review RDOG IV mechanisms established by the RDOG IV Headquarters for data management and analysis (see section Responsibilities of Awardees, RDOG IV Headquarters). The ADRRP, or designee, when deemed appropriate, will make recommendations to the RDOG IV Group Chairperson for assuring that data collection and management procedures are adequate for quality control and analysis and sufficiently uniform across the RDOG IV participating institutions. Any disagreements between NCI and RDOG IV members relating to data management and analysis that cannot be resolved by bilateral discussions will be submitted to the same arbitration process previously outlined. 6. Access to Data The NCI will have access to all data generated under this cooperative agreement and may periodically review the data. Data must also be available for external monitoring as required by agreement between the NCI and the FDA relative to the responsibility of the NCI as a study sponsor. The awardee will retain custody and primary rights to the data consistent with current HHS, PHS, and NIH policies. 7. RRP Involvement in Protocol Closure The ADRRP, or designee, will review RDOG IV mechanisms for interim monitoring of results and will monitor protocol progress. The ADRRP may request that a protocol study be closed to accrual for reasons including: (a) insufficient accrual rate; (b) achievement of the original accrual goal; (c) poor protocol performance; (d) patient safety; (e) conclusive study results; and (f) emergence of new information that diminishes the scientific importance of the study. The NCI will not permit expenditures of NCI funds for a study after requesting closure (except for patients already on-study). For any study closure, NCI will establish an arbitration process for institutions that wish to appeal protocol closure. This process will be identical to that described above for protocol disapproval. If the RDOG IV wishes to close accrual to a study prior to meeting the initially established accrual goal, the RDOG IV Chairperson must submit the interim results and written justification to NCI staff for review and approval. Unresolved disagreements between NCI staff and the RDOG IV institutions regarding the appropriateness of early study closure will be arbitrated by the process outlined above. 8. RRP Involvement in Investigational Device and Agent Management a. If applicable, RRP staff will advise the RDOG IV institutions of specific requirements and changes in requirements concerning investigational device and/or agent management that the FDA may mandate. Investigators performing trials under RDOG IV cooperative agreements will be expected, with RRP assistance, to comply with all FDA monitoring and reporting requirements for investigational devices, if applicable. b. Investigators performing NCI funded clinical trials will be advised by NCI staff of potential studies that will be relevant to new avenues of cancer diagnosis. When this involves an investigational device and/or agent, the clinical information must be acceptable to the FDA. With ADRRP assistance, the RDOG IV institutions will develop protocols to obtain such information needed, if applicable, for the projects. 9. RRP Review of Procedures for Compliance with Federally Mandated Regulations RRP staff will review procedures established by the RDOG IV Headquarters for monitoring of compliance and assurance to meet FDA regulatory requirements for studies involving investigational devices/agents, if applicable, and Office for Protection from Research Risks (OPRR) requirements for the protection of human subjects by all RDOG IV institutions (see section Responsibilities of Awardees, RDOG IV Headquarters). 10. RRP Review of Progress Performance of each RDOG IV member and affiliate will be reviewed annually by the ADRRP, or designee, on the basis of the information provided at the progress review meetings, annual and semi-annual reports. Each RDOG IV institution must submit an annual progress report. Annual and semi-annual reports submitted to the NCI shall contain highlights of progress made during that period and will include, at a minimum, summary data on protocol performance by each RDOG IV member and affiliate and other relevant data. In addition, periodic accrual information may be requested by the NCI for all active studies whenever deemed appropriate. A system for providing such information in a timely manner must be in place. Support recommended for the remainder of the project will be contingent upon favorable review by the ADRRP, or designee, of the progress of the project and sufficient patient accrual. Insufficient patient accrual, or noncompliance with the terms of award, including these Terms of Cooperation, may result in a reduction of budget, withholding of support, or termination of the award. B. Responsibilities of Awardees It is the responsibility of the awardee 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 awardee, with ADRRP or designee assistance, shall develop RDOG IV research goals, develop protocols for clinical cancer research in accord with the awardee's research interests, abilities and goals, and submit to the NCI for review and approval prior to implementation. 1. RDOG IV Headquarters The Principal Investigator of the Headquarters institution will serve as the RDOG IV Chairperson. The RDOG IV Headquarters, under the leadership of the RDOG IV Chairperson, will be responsible for the coordination of protocol development, quality control and study monitoring, data management and analysis, adherence to requirements regarding investigational device management (when applicable) and federally mandated regulations, protocol and performance reporting, and recommendations for resource adjustments. All the scientific and administrative decisions related to the RDOG IV-funded activities and made by the RDOG IV institutions or affiliates will be communicated to the ADRRP or designee by the RDOG IV Chairperson. The RDOG IV Chairperson will communicate the results of the NCI protocol reviews to the RDOG IV institutions. a. Study Monitoring The RDOG IV Headquarters, under the leadership of the RDOG IV Chairperson, is responsible for establishing a mechanism for study monitoring to assure accurate and timely knowledge of the progress of each study through: o tracking and reporting of patient accrual and adherence to defined accrual goals; o ongoing assessment of case eligibility and evaluability; o timely review and assessment of patient data; o if applicable, rapid reporting of procedure-related morbidity and measures to ensure communication of this information to all parties; o if applicable, interim evaluation and consideration of measures of outcome, as consistent with patient safety and good clinical trials practice; o timely communication of results of studies; and o a method of providing, upon NCI request, summary of the imaging methodology sensitivity/specificity and, when appropriate, morbidity data. b. Data Management and Analysis The RDOG IV Headquarters, under the leadership of the RDOG IV Chairperson, will develop procedures to ensure that data collection and management 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) standardized among the RDOG IV participating institutions. Any disagreements between RRP and RDOG IV members relating to data management and analysis that cannot be resolved by bilateral discussions will be submitted to the same arbitration process previously outlined. c. RDOG IV Compliance with Federally Mandated Regulations The RDOG IV Headquarters, under the leadership of the RDOG IV Chairperson, is responsible for establishing procedures for all RDOG IV institutions to comply with DHHS and FDA regulatory requirements for studies involving investigational devices/agents, if applicable, and the OPRR requirements for the protection of human subjects. These procedures include: o methods for assuring that each protocol is reviewed by the responsible Institutional Review Board (IRB) prior to patient entry, and that each protocol is reviewed at least annually by the IRB while the protocol is active in accordance with 45 CFR 46, Protection of Human Subjects. o if applicable, a system for assuring timely reporting of all serious and unexpected complications to the ADRRP, or designee. d. Progress Review The RDOG IV Headquarters, under the leadership of the RDOG IV Chairperson, will have a mechanism in place for assessing performance of its members, with particular attention to accrual of an adequate number of eligible patients onto group trials, timely submission of required data, conscientious observance of protocol requirements, authorship, and participation in group leadership. This mechanism will include a procedure for the RDOG IV Chairperson to recommend to the NCI an adjustment of funds within the group as appropriate for the level of participation in group activities including, but not limited to, accrual. Financial adjustments may be made by NCI at the time a non- competing continuation [Type 5] award is negotiated. The RDOG IV Chairperson, Principal Investigator from each RDOG IV institution and the ADRRP, or designee, shall meet twice a year to review RDOG IV progress, establish priorities, and plan future activities. The frequency of such meetings may be increased if it is deemed necessary. 2. Membership in RDOG IV NCI funding is contingent upon the institution remaining a member of the RDOG IV. 3. Planning Procedures It is anticipated that decisions on all RDOG IV activities will be reached by consensus of the group under the leadership of the RDOG IV Chairperson who will be responsible for communication with the ADRRP or designee. 4. Attendance Requirements It is required that a Principal Investigator, or designee, from all RDOG IV members participate at all meetings and workshops relevant to their protocol(s). 5. Protocol Development All RDOG IV institutions are expected to participate in the development of new and revised protocols under the leadership of the RDOG IV Chairperson. The RDOG IV Chairperson will submit such protocols in a timely fashion for review and approval by NCI. 6. Conduct of Research and Patient Accrual Awardees are expected to conduct pertinent clinical imaging studies consistent with approved applications and post-award procedures. Awardees also are expected to provide timely results from sufficient numbers of patients. All new and revised protocols must be submitted by the RDOG IV investigators to the appropriate IRB within 30 days of the date of the written approval from the RDOG IV Chairperson. patients may not be entered into new or revised protocols until the protocol has been reviewed and approved by the IRB in accordance with 45 CFR 46, Protection of Human Subjects. 7. Progress Review The RDOG IV Chairperson, the Principal Investigator from each RDOG IV institution and the ADRRP, or designee, shall meet twice a year to review RDOG IV progress, establish priorities, and plan future activities. The frequency of such meetings may be increased if it is deemed necessary. 8. Reporting Requirements Reporting requirements will be in agreement with NCI procedures. Annual progress reports will be submitted to the NCI and will include at a minimum summary data on protocol performance by each awardee. Interim reports of each activated and ongoing study shall appear in the minutes of each RDOG IV meeting and shall include specific data on patient accrual and, whenever appropriate, detailed reports of device/agent-associated morbidity. In addition, semi-annual accrual information may be requested by the ADRRP, or designee, for all active studies. A system for providing such information in a timely manner must be in place. In addition to the annual progress report and detailed final report currently required by research project grants and cooperative agreements, awardees shall provide a semi-annual interim report six months after the start date of each budget period. The report shall contain highlights of progress made during that period and will include at a minimum summary data on protocol performance by each RDOG IV member and other relevant data. 9. Publication of Data Timely publication of major findings is encouraged. Publication and oral presentation of work done under this agreement will require appropriate acknowledgement of NCI support. The NCI will have access to all data generated under this cooperative agreement and may periodically review the data. The awardee will retain custody of and primary rights to the data consistent with current DHHS, PHS, and NIH policies. C. These Terms of Cooperation are in addition to and not in lieu of otherwise applicable OMB administrative guidelines, HHS grant administration regulations at 45 CFR Part 74 and DHHS, PHS, and NIH grants administration policies. STUDY POPULATIONS SPECIAL INSTRUCTIONS TO APPLICANTS REGARDING IMPLEMENTATION OF NIH POLICIES CONCERNING INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH STUDY POPULATIONS NIH and ADAMHA policy is that applicants for NIH/ADAMHA clinical research grants and cooperative agreements will be required to include minorities and women in study populations so that research findings can be of benefit to all persons at risk of the disease, disorder or condition under study; special emphasis must be placed on the need for inclusion of minorities and women in studies of diseases, disorders and conditions which disproportionately affect them. This policy is intended to apply to males and females of all ages. If women or minorities are excluded or inadequately represented in clinical research, particularly in proposed population-based studies, a clear compelling rationale should be provided. The composition of the proposed study population must be described in terms of gender and racial/ethnic group, together with a rationale for its choice. In addition, gender and racial/ethnic issues should be addressed in developing a research design and sample size appropriate for the scientific objectives of the study. This information must be included in the form PHS 398 in Section 2, A-D of the Research Plan AND summarized in Section 2, E, Human Subjects. Applicants are urged to assess carefully the feasibility of including the broadest possible representation of minority groups. However, NIH recognizes that it may not be feasible or appropriate in all research projects to include representation of the full array of United States racial/ethnic minority populations (i.e., Native Americans [including American Indians or Alaskan Natives], Asian/Pacific Islanders, Blacks, Hispanics). The rationale for studies on single minority population groups should be provided. For the purpose of this policy, clinical research includes human biomedical and behavioral studies of etiology, epidemiology, prevention (and preventive strategies), diagnosis, or treatment of diseases, disorders or conditions, including not but limited to clinical trials. The usual NIH policies concerning research on human subjects also apply. Basic research or clinical studies in which human tissues cannot be identified or linked to individuals are excluded. However, every effort should be made to include human tissues from women and racial/ethnic minorities when it is important to apply the results of the study broadly, and this should be addressed by applicants. For foreign awards, the policy on inclusion of women applies fully; since the definition of minority differs in other countries, the applicant must discuss the relevance of research involving foreign population groups to the United States' populations, including minorities. If the required information is not contained within the application, the application will be returned. Peer reviewers will address specifically whether the research plan in the application conforms to these policies. If the representation of women or minorities in a study design is inadequate to answer the scientific question(s) addressed AND the justification for the selected study population is inadequate, it will be considered a scientific weakness or deficiency in the study design and will be reflected in assigning the priority score to the application. All applications for clinical research submitted to NIH are required to address these policies. NIH funding components will not award grants or cooperative agreements that do not comply with these policies. LETTER OF INTENT Prospective applicants are asked to submit, by March 24, 1992, a letter of intent that includes a descriptive title of the proposed research, the name and address of the Principal Investigator, the names of other key personnel, the participating institutions, and the number and title of the RFA in response to which the application is being submitted. Although a letter of intent is not required, is not binding, and does not enter into the review of subsequent applications, it is requested in order to provide an indication of the number and scope of applications to be reviewed. The letter of intent is to be sent to: Dr. Faina Shtern Chief, Diagnostic Imaging Research Branch Radiation Research Program National Cancer Institute Executive Plaza North, Suite 800 Bethesda, MD 20892 Telephone: (301) 496-9531 APPLICATION PROCEDURES The research grant application form PHS 398 (revised 9/91) is to be used in applying for cooperative agreements. These forms are available at most institutional business offices and from the Office of Grants Inquiries, Division of Research Grants, National Institutes of Health, Room 449, Westwood Building, 5333 Westbard Avenue, Bethesda, MD 20892, telephone (301) 496-7441, and from the NCI program director named below. The application must include a sample protocol for ovarian cancer and/or pediatric solid tumor diagnosis to illustrate the ability to perform clinical research. The RFA label available in the application form PHS 398 must be affixed to the bottom of the face page. Failure to use this label could result in delayed processing of the application such that it may not reach the review committee in time for review. In addition, the RFA number and title must be typed on line 2 of the face page of the application form. Submit a signed, typewritten original of the application, including the Checklist, and three signed, exact photocopies, in one package to the address below. The photocopies must be clear and single sided. DIVISION OF RESEARCH GRANTS National Institutes of Health Westwood Building, Room 240 Bethesda, MD 20892** At the time of submission, send two additional copies of the application to: REFERRAL OFFICER Division of Extramural Activities National Cancer Institute Westwood Building, Room 838 5333 Westbard Avenue Bethesda, MD 20892 Applications must be received by May 26, 1992. If an application is received after that date, it will be returned. If the application submitted in response to this RFA is substantially similar to a grant application already submitted to the NIH for review, but has not yet been reviewed, the applicant will be asked to withdraw either the pending application or the new one. Simultaneous submission of identical applications will not be allowed, nor will essentially identical applications be reviewed by different review committees. Therefore, an application cannot be submitted in response to this RFA that is essentially identical to one that has already been reviewed. This does not preclude the submission of substantial revisions of applications already reviewed, but such applications must include an introduction addressing the previous critique. Special Instructions for Preparation of Cooperative Agreement Applications General instructions for the preparation of the cooperative agreement application are contained in the grant application form PHS 398 (revised 9/91). Because the Terms of Cooperation, discussed above, will be included in all awards issued as a result of this RFA, it is critical that each applicant include specific plans for responding to these terms. Plans must describe how the applicant will comply with the program staff involvement and how all the Responsibilities of Awardees will be fulfilled. REVIEW CONSIDERATIONS A. Review Procedure Upon receipt, applications will be reviewed by the DRG for completeness. Incomplete applications will be returned to the applicant without further consideration. Evaluation for responsiveness to the program requirements and criteria stated in the RFA is an NCI program staff function. Applications that are judged non-responsive will be returned by the NCI, but may be submitted as investigator-initiated research grants at the next receipt date. Questions concerning the responsiveness of proposed research to the RFA may be directed to program staff listed under INQUIRIES. If the number of applications is large compared to the number of awards to be made, the NCI may conduct a preliminary scientific peer review to eliminate those that are clearly not competitive. The NCI will remove from competition those applications judged to be noncompetitive for award and notify the applicant and institutional business official. Those applications judged to be both competitive and responsive will be further evaluated according to the review criteria stated below for scientific and technical merit by an appropriate peer review group convened by the Division of Extramural Activities, NCI. The second level of review will be by the National Cancer Advisory Board. B. Review Criteria 1. Applications for the Headquarters will be reviewed on the basis of the following criteria: o Scientific merit and resources, appropriateness and adequacy of the proposed approach to experimental protocol development and biostatistical data processing. The proposed methodology must exhibit scientific soundness showing how the trials will be conducted to attain the objectives. o Qualifications and research experience of the Principal Investigator and staff including, but not limited to, previous experience with administration of multi-institutional clinical trials in imaging science. These should include the experience of the proposed personnel (statisticians, programmers, and data management staff) in the design, monitoring, analysis, and reporting of cooperative multi-center clinical trials. o Feasibility and merit of the proposed structure for RDOG IV administration and data management including, but not limited to, interactions with the RDOG IV participating institutions. 2. Applications for participating institutions will be reviewed on the basis of the following criteria: o The overall qualifications of applicant institutions to the requirement for membership in the collaborative group as stated in the eligibility requirement for participants (see Eligibility Requirements). o Adequacy of professional and support personnel. Record or evidence of willingness to work as a team with other group members and to participate in group-generated and program-monitored protocols according to their capacity. o Evidence of the ability to develop clinical trials in radiology. o Evidence of the ability of the applicant to complete imaging trials of substantial scientific merit. It is anticipated that different institutions will have varying patterns of patient referral and accession. Applicants must show that they have the potential to accomplish multi-center imaging trials of sound scientific quality in a reasonable period of time. o Evidence of the ability to accrue an adequate number of patients. o Availability of appropriate facilities, equipment, instrumentation, and other resources to ensure that each institution is capable of performing innovative cooperative trials in cancer diagnosis. o Appropriateness of the proposed budget and duration in relation to the proposed research. AWARD CRITERIA The earliest feasible start date for the initial awards will be December 1, 1992. In making funding decisions, the National Cancer Advisory Board considers the special needs of the NCI and the priorities of the National Cancer Program. Although this program is provided for in the financial plans of the NCI, the award of cooperative agreements pursuant to this RFA is also contingent upon the availability of funds for this purpose. INQUIRIES Written and telephone inquiries concerning the objectives and scope of this RFA and inquiries about whether or not specific proposed research would be responsive are encouraged and are to be directed to Dr. Shtern at the address below. Dr. Shtern welcomes the opportunity to clarify any issues or questions from potential applicants. Direct inquiries regarding programmatic issues to: Dr. Faina Shtern Chief, Diagnostic Imaging Research Branch Radiation Research Program National Cancer Institute Executive Plaza North, Suite 800 Bethesda, MD 20892 Telephone: (301) 496-9531 Direct inquiries regarding fiscal matters to: Ms. Sara Stone Grants Management Coordinator Grants Administration Branch National Cancer Institute Executive Plaza South, Suite 242 6120 Executive Boulevard Rockville, MD 20852 Telephone: (301) 496-7227, Extension 66 Facsimile: (301) 496-8601 AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance Number 93.395, Cancer Treatment Research. Awards are made under the authorization of the Public Health Service Act, Title IV, Part A (Public Law 78-410, as amended by Public Law 99-158, 42 USC 241 and 285) and administered under PHS grants policies and Federal Regulations 42 CFR Part 52 and 45 CFR Part 74. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. REFERENCES (1) American Cancer Society, Massachusetts Division, Cancer Manual, 7th Edition, 1986: 231-234 (2) American Cancer Society: Cancer Statistics, Reprinted from Ca-A Cancer Journal for Clinicians. Ca 1989; 3:39 (3) Gargano G, Correale M, Abbate I, Falco G, De Frenza N, Lorusso V, De Lena M, De Leonardis A. The role of tumor markers in ovarian cancer. Clin. Exp. Obst. Gyn. Vol. 17 (1): 23-29, 1990 (4) Averette, et al. Ovarian Cancer Diagnosis, Staging and Treatment. Cancer 65:703-708, 1990. (5) Schoenfeld et al. Surgery in post-menopausal women-the value of transvaginal sonography. Surgical Endoscopy, Springer-Verlag, 1990: pp. 108-113 (6) Rottem et al. Classification of ovarian lesions by high frequency transvaginal ultrasonography. J Clin Ultrasound. 18: 359-363, 1990. (7) Higgins et al. Transvaginal sonography as a screening tool for ovarian cancer. Gynecologic Oncology 34, 402-406, 1989. (8) Van Nagel et al. Transvaginal sonography as a screening method for ovarian cancer: a report of the first 1000 cases. Cancer, Vol 65: 573-577, 1990. (9) Bourne, T, Campbell S, Steer C, Whitehead MI, Collins WP. Transvaginal colour flow imaging: a possible new screening technique for ovarian cancer. BMJ 299, 1989: 1367-1370 (10) Sanders RC, McNeil BJ, Finberg HJ. A prospective study of computed tomography and ultrasound in the detection and staging of pelvic masses. Radiology 1983; 146: 447-452 (11) Calkins AR, Stehman FB, Wass JL, et al. Pitfalls in interpretation of computed tomography prior to second-look laparotomy in patients with ovarian cancer. Br. J. Radiology 1987; 60:975-979 (12) Chang YC, Hricak H. Current status of MR imaging of the female pelvis. Crit Rev Diagn Imaging 1989; 29 (4): 337-356 (13) Simone JV, Cassady JR, Filler RM. Cancers of childhood. In DeVita VT, Hellman S, Rosenberg SA (eds). Cancer: Principles and Practice of Oncology. Philadelphia, JB Lippincott Co, 1982: 1254-1330 (14) American Cancer Society Cancer Manual, Massachusetts Division, 7th Edition, 1986: 336-337 .
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Office of Extramural Research (OER) |
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Department of Health and Human Services (HHS) |
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