Full Text CA-96-012 MULTI-INSTITUTIONAL COOPERATIVE AGREEMENTS FOR CLINICAL EVALUATION OF MAGNETIC RESONANCE IMAGING IN BREAST CANCER NIH GUIDE, Volume 25, Number 12, April 19, 1996 RFA: CA-96-012 P.T. 34 Keywords: 0715036 Medical/Diagnostic Imaging Instrumentation, Medical National Cancer Institute Letter of Intent Receipt Date: May 15, 1996 Application Receipt Date: July 30, 1996 PURPOSE The Radiation Research Program (RRP) of the Division of Cancer Treatment, Diagnosis and Centers (DCTDC) of the National Cancer Institute (NCI), invites applications for cooperative agreements (U01) to study the sensitivity, specificity and local staging accuracy of breast MRI (BMRI) compared to conventional radiologic approaches in about 3,000 women with abnormal x-ray mammograms and/or abnormal physical examination (e.g., palpable mass). The NCI is seeking scientists from academic, non-profit and for-profit research organizations who will interact with other members in a Cooperative Consortium (called the Consortium throughout this Request for Applications (RFA)), and with the RRP in a concerted way to evaluate and optimize new approaches to breast cancer diagnosis. One Consortium, consisting of multiple collaborating institutions and called "Multi Institutional Consortium for Clinical Evaluation of MRI in Breast Cancer", will be funded by the NCI. The Consortium will consist of two separately funded organizational components (or awardees): (1) Headquarters institution, responsible for the identification and coordination of patient- accruing Clinical Sites; and (2) Data and Statistics Center. 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, Multi-Institutional Cooperative Agreements for Clinical Evaluation of Magnetic Resonance Imaging in Breast Cancer, is related to the priority area of cancer. Potential applicants may obtain a copy of "Healthy People 2000" (Full Report: Stock No. 017-001-00474-0 or Summary Report: Stock No. 017-001-00473-1) through the Superintendent of Documents, Government Printing Office, Washington, DC 20402-9325 (telephone 202-512-1800). ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic and foreign non-profit and for-profit organizations, public and private, such as universities, colleges, hospitals, laboratories, units of State and local governments, and eligible agencies of the Federal government. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as Principal Investigators. Each application package must be submitted from a single Consortium consisting of several participating institutions to ensure accrual of about 3,000 women over a period of four years (see APPLICATION PROCEDURES). Applications for the Headquarters and for the Data and Statistics Center should be submitted together but as separate applications; these two applications will be funded as separate awards. MECHANISM OF SUPPORT The administrative and funding instrument to be used for this program will be a cooperative agreement (U01), an "assistance" mechanism (rather than an "acquisition" mechanism) in which a substantial involvement between NCI program staff and the awardees is anticipated during performance of the activity. Under the cooperative agreement, the NCI purpose is to support and/or stimulate the recipient's activity by 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. Details of the responsibilities, relationships and governance of the study to be funded under cooperative agreement(s) are discussed later in this document under the section "Terms and Conditions of Award". The total project period for applications submitted in response to this RFA may not exceed four years. The anticipated award date is April 1, 1997. 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 will vary also. Award and level of support depend on receipt of applications of high scientific merit. This RFA is a one-time solicitation. If it is determined that there is a sufficient continuing program need, the NCI will invite recipients of awards under this RFA to submit competitive continuation cooperative agreement applications for review according to the procedures described in Review Considerations. Although this program is provided for in the financial plans of the NCI, the award of Cooperative Agreements pursuant to this RFA is contingent upon the availability of funds for this purpose. FUNDS AVAILABLE It is anticipated that two awards will be made at approximately $1,500,000 total costs per year for four years. The Consortium will consist of two organizational components (or awardees): (1) Headquarters institution, responsible for recruitment of patient-accruing Clinical Sites; and (2) Data and Statistics Center. The application for the Data and Statistics Center shall be separate from the application for the Headquarters component, but both applications should be planned and submitted together. RESEARCH OBJECTIVES Background Breast cancer is second only to lung cancer as the cause of cancer-related deaths in women in the United States. Conventional x-ray mammography has been shown to play an important role in detection and staging of breast cancer in women older than 50 years of age. However, younger women frequently have "radiodense" breast tissue, rendering breast cancer diagnosis with conventional mammography problematic. This scenario created a strong incentive to support development and evaluation of novel breast imaging technologies. Over the last few years, contrast-enhanced MRI of the breast (BMRI) has emerged as one of the most promising clinical tools for detection of early breast cancer and delineation of its anatomic local extent. Exploratory clinical trials indicate that BMRI may be more sensitive than conventional x-ray mammography in detecting small lesions. BMRI may be particularly useful for detection of breast cancer in women with essentially uninterpretable x-ray mammograms (e.g. when breast tissue is "radiodense" or "radio- opaque" due to silicon implants). Contrast-enhanced MRI is thus a promising adjunctive diagnostic tool and may be of particular value in the early detection of breast cancer in women with "radiodense" and "radio-opaque" breasts and, by virtue of its ability to improve local tumor anatomic delineation, in clinical staging of local disease in women with apparent early-stage breast cancer. Whereas current reported results appear promising, they are preliminary in nature and based on a limited patient sample in individual institutions. It is not known at this time what MRI technical approach is optimal (e.g. two- vs. three-dimensional acquisition, fat suppression vs. subtraction, trade-off between spatial and temporal resolution). However, it is expected that the applicants will present in their applications a specific range of standards for performing BMRI that will be accepted by all main member institutions. While the sensitivity of BMRI appears promising, specificity of this technology has been reported to be low. However, recent development of specialized imaging coils and MRI-guided biopsy is expected to have an important impact on tissue characterization of the MRI-detected lesions. The RRP, NCI, with the advice of experts from academia and industry in the fields of diagnostic imaging and breast cancer treatment, has determined that a clinical trial to evaluate the sensitivity, specificity and local staging accuracy of BMRI is, with the availability of breast-dedicated MR imaging coils and introduction of MRI-guided biopsy capability, both feasible and timely. A. Objectives and Scope The purpose of this RFA is to facilitate evaluation of sensitivity, specificity and local staging accuracy of BMRI compared to conventional imaging approaches in about 3,000 women with abnormal x-ray mammograms and/or abnormal physical examination. BMRI data in detection and staging of breast cancer may be compared to that of conventional x-ray mammography, ultrasound (US) and other imaging modalities. Histopathologic correlation of and/or follow up studies will be required for all patients. A sufficient number of patients must be available in each participating institution for successful completion of the proposed clinical trial. Each participating institution must demonstrate experience with clinical studies in BMRI (at least 100 previous examinations) and must adopt and participate in the Consortiums plan for histopathologic evaluation and/or follow up of MRI-detected lesions. In addition, it is expected that study participants will establish a database that would enable the Consortium to address vital questions such as: Can MRI reduce the number of diagnostic procedures, such as breast biopsies, in women with benign conditions? Can and/or should MRI data on local tumor staging make an impact on therapeutic decisions in women with early stage disease? It is anticipated that this non-randomized trial, focused on evaluation of diagnostic value of MRI and its role in optimization of breast cancer detection and staging, may, at its completion suggest the need for randomized clinical trials to validate: a) the impact of MRI data (e.g. improved staging accuracy through improved definition of local anatomic tumor extent) on therapeutic decisions in women with early-stage disease as well as, b) the role of MRI as a screening tool in reducing mortality of general (asymptomatic) population of women with "radiodense" breast tissue and patients at high genetic risk for breast cancer. Particular emphasis will be placed on the accrual of women younger than 50 years of age and minority women with "radiodense" breast tissue. B. Organization The Consortium will consist of two major operational components: 1) Headquarters institution, responsible for recruitment and performance of patient-accruing Clinical Sites; and 2) the Data and Statistics Center. Each component has general responsibilities in meeting the objectives outlined above or in completing tasks necessary to accomplish these goals. The Headquarters of the Consortium should describe membership criteria for inclusion and exclusion, procedures for selecting members of the Executive Committee and other details of governance, and will be led by a Chairperson who is ultimately responsible to NCI for the contents and conduct of the Consortium's research program. Beyond this requirement, the structure and management of the Consortium should be clearly described in the applications, including the identification of participating Clinical Sites and the criteria for their selection. The following sections describe the responsibilities and functions of two organizational components: 1. Headquarters and Chairperson. The Headquarters component of the Consortium is the direct responsibility of the Chairperson. It provides executive leadership and day-to-day administrative management of the Consortium. Through this office, the Chairperson implements Consortium's scientific and organizational policies. Specific roles and responsibilities include the following: a. Provide general scientific oversight, assuring development of a research plan and its priorities. b. Develop and provide to the Consortium membership and to NCI an administrative plan specifying Consortium structure and management, procedures and criteria for the selection of patient- accruing Clinical Sites, establishment of the Quality Assurance Committee and selecting its Coordinator, establishment and selection of the Executive Committee membership, and other details of governance. c. Foster and monitor the inclusion of women younger than 50 years of age, ethnic minorities and women with "radiodense" breast tissue in the Consortium's clinical trial. d. Verify that all Clinical Sites and other members have an approved Cooperative Project Assurance, or Multiple Project Assurance as required on file with the Office of Protection from Research Risks, Department of Health and Human Services. e. 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 Clinical Sites and other members of the Consortium. f. Subcontract and monitor performance of the leading investigators at patient-accruing Clinical Sites, including but not limited to the following: i. active participation in the Consortium's scientific and administrative committees and meetings; ii. contribution of their independent clinical and research experience to the Consortium; iii. patient accrual to the Consortium's protocol; iv. submission of accurate and timely patient data to the Data and Statistics Center; v. participation in the Consortium's on-site audit program; vi. assumption of responsibility for all Consortium activities conducted at their institutions. 2. Data and Statistics Center: The Data and Statistics Center has primary responsibilities for: Development and establishment methods for statistical data collection, management, analysis and monitoring, including on-site audits and audit reports. Audit reports should be submitted by the Director of the Data and Statistics Center to the Chairperson of the Consortium who will be responsible for the submission of the audit reports to the NCI Project Scientist within 10 weeks of their completion. The Director of the Data and Statistics Center will be the Principal Investigator (PI) of the data and statistical center component and an individual other than the Chairperson of the Consortium. Submission of the semiannual interim progress reports to the NCI Project Scientist, including as a minimum, summary data on protocol performance and accrual. Such reports are in addition to the annual progress report submitted in the non-competing continuation applications. SPECIAL REQUIREMENTS To promote the development of a collaborative program among the award participants, a number of issues need to be addressed in their applications as discussed below (See Application Procedures). Applicants should discuss the rationale for their choice of a standard imaging technique and plan for histopathologic correlation. They should document their ability to recruit a sufficient number of participants, should be able to develop a plan for effective administrative management, should discuss their capability to participate in clinical trials involving BMRI, conventional x-ray mammography and other technologies, and should state their willingness to follow the uniform protocol. DEFINITIONS The following definitions will be used throughout the enclosed Terms and Conditions of Award: AWARDEES - The organizations to which a cooperative agreement is awarded which are responsible and accountable to NCI for the use of funds provided and for performance of the cooperative agreement-supported project. CHAIRPERSON OF THE CONSORTIUM-- The person who submits the application for the Headquarters awardee institution as a Principal Investigator (PI) and who is responsible for the Consortium as a whole, including but not limited to: 1) selecting and coordinating activities of patient-accruing Clinical Sites; and 2) establishing the Quality Assurance Committee and selecting its Coordinator. The Chairperson is responsible for scientific and administrative operations of the Consortium. The participating institutions must agree to work together with the Chairperson of the Consortium. The Chairperson of the Consortium is a voting member and the Chair of the Executive Committee. COOPERATIVE AGREEMENT - An assistance mechanism in which substantial NCI programmatic involvement with the grant awardees is anticipated during performance of the planned activity. CONSORTIUM- The association of institutions who are submitting research grant applications together to conduct the planned clinical trial. DATA AND SAFETY MONITORING COMMITTEE (DSMC) - A NCI mandated committee with responsibilities described below (see DSMC, below) and geared towards protection of patient safety, ethics (e.g. conflict of interest)) and data impartiality. DATA AND STATISTICS CENTER -- The awardee institution responsible for development of procedures for statistical data collection, management, analysis and on-site monitoring, including audits and audit reports. The Director of the Data and Statistics Center is a person who submits a grant application on behalf of the Center as its Principal Investigator (PI). The Director of the Data and Statistics Center must be an individual other than the Chairperson of the Consortium. EXECUTIVE COMMITTEE - The committee chaired by the Chairperson of the Consortium and responsible for the main study oversight, including protocol development and progress monitoring. In addition to the Chairperson of the Consortium and the NCI Project Scientist, the Executive Committee will be composed at the minimum of the following voting members: Director of the Data and Statistics Center, Coordinator of the Quality Assurance Committee and one clinical investigator from each Clinical Site. The Chairperson may select other voting members of the Executive Committee deemed necessary for successful completion of the study. NCI PROJECT SCIENTIST - The staff member from the Radiation Research Program (RRP), Division of Cancer Treatment, Diagnosis and Centers (DCTDC) (cited in the INQUIRIES SECTION), who is the Associate Director of RRP or designatee to coordinate NCI interactions with the Consortium, administer and provide guidance for the overall program within the NCI. He/she is available for the duration of research conducted through this cooperative agreement and will be a voting member of the Executive Committee. QUALITY ASSURANCE (QA) COMMITTEE - The committee selected by the Chairperson of the Consortium from among the Consortium members and responsible for the development of procedures for centralized supply and quality control of instrumentation and approaches required by the experimental protocol. The Quality Assurance Committee is headed by its Coordinator, who is selected by the Chairperson of the Consortium. THE CANCER THERAPY EVALUATION PROGRAM (CTEP) PROTOCOL REVIEW COMMITTEE. The NCI committee that will review and approve the protocol and its amendments as proposed by the Consortium to ensure that they are within the scope of peer review and for safety considerations before implementation. TERMS AND CONDITIONS OF AWARD Applicability. These special Terms and Conditions of Award are in addition to and not in lieu of otherwise applicable OMB administrative guidelines, HHS grant administration regulations in 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, an "assistance" mechanism (rather than an "acquisition" mechanism) in which substantial NCI scientific and/or programmatic involvement with the awardees is anticipated during performance of the activity. Under the cooperative agreement, the NCI purpose is to support and/or stimulate the recipient's activity by 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 reside with the awardees 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. The NCI shall be represented in the Consortium by a Project Scientist selected from the Radiation Research Program. This representative will be referred to as the NCI Project Scientist. 1. Awardees' Rights and Responsibilities General The Awardees will have primary rights and responsibilities to define study objectives and approaches, and to plan, conduct, analyze and publish results, interpretations, and conclusions of their studies. The Awardees will have primary and lead responsibilities for the project as a whole, including research design and protocol development, participant recruitment and follow up, data collection, quality control, interim data and safety monitoring, final data analysis and interpretation, preparation of publications, with assistance from the NCI Project Scientist. Cooperation in the reporting of the study findings. The NCI will have access to and may periodically review all data generated under an award. Where warranted by appropriate participation, plans for joint publication with NCI of pooled data and conclusions are to be developed by the Principal Investigator or Executive Committee, as applicable. NIH policies governing possible co-authorship of publications with NCI staff will apply in all cases. In general, to warrant co-authorship, NCI staff must have contributed to the following: (a) significant intellectual contribution to the concept or experiments being tested; (b) performance of significant portions of the research activity; and (c) preparation of pertinent manuscripts. The awardees will retain custody of and the primary rights to the data developed under these awards, subject to Government rights to access consistent with current HHS, PHS, and NIH policies. Headquarters The Headquarters Awardees have primary responsibilities for: Establishment of procedures for all participating institutions to comply with FDA regulations for studies involving investigational drugs (e.g., contrast agents) or devices (e.g., MRI-guided biopsy equipment) and to comply with the requirements of 45 CFR Part 46 for the protection of human subjects. Establishment of the Executive Committee, chaired by the Chairperson of the Consortium and responsible for research design and protocol development, progress monitoring and project administrative oversight, including definition of objectives and approaches, planning, implementation, participant recruitment and follow-up, approval of procedures for data collection, analysis, interpretation, and publication of results, and approval of methods for instrumentation supply and quality assurance. The Executive Committee is responsible for ensuring accurate and timely assessment of the progress of each study, including establishment of procedures to ensure that data collection and management are: (l) adequate for quality control and analysis; (2) as simple as appropriate in order to encourage maximum participation of physicians and patients and to avoid unnecessary expense; and (3) sufficiently staffed across the participating institutions. Implementation of methods developed by the Data and Statistics Center and approved by the Executive Committee for statistical data collection, management, analysis and monitoring, including on-site audits and audit reports. Audit reports should be submitted by the Director of the Data and Statistics Center to the Chairperson of the Consortium who will be responsible for the submission of the audit reports to the NCI Project Scientist within 10 weeks of their completion. Implementation of mechanisms developed by the Quality Assurance Committee and approved by the Executive Committee for coordinated supply of contrast agents and instrumentation required by the experimental protocol, development of methods and protocols for acquisition and review of images, preparation of pathologic specimens, plan for histopathologic correlation and any other relevant correlative studies, and centralized standardization of instrumentation quality control, including technical requirements and performance standards for hardware and software instrumentation. Coordinator of the Quality Assurance Committee will be selected by the Chairperson of the Consortium from among the Consortium participants. Establishment of the DSMC that is independent of study leadership, is clearly free of conflict of interest, and have formally documented policies and procedures which are approved by NCI. The main objectives of the DSMC are to: i. Ensure that patients in the trial are protected and that their interests are not made secondary to the interests of scientific investigations. ii. 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. iii. Ensure that the credibility of trial reports and ethics of trial conduct are above reproach with no possible appearance of professional or financial conflicts of interest. iv. a. Enable physicians entering patients to remain free of knowledge of interim efficacy 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. b. Enable study leadership to remain free of knowledge of interim efficacy 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. The Chairperson The Chairperson of the Consortium is responsible for: The establishment of the Executive Committee. The definition of the final composition of the Executive Committee, with assistance from the NCI Project Scientist who will serve as a non-voting member. In addition to the Chairperson of the Consortium and the NCI Project Scientist, the Executive Committee will be composed at the minimum of the following voting members: The Director of the Data and Statistics Center, the Coordinator of the Quality Assurance Committee and one clinical investigator from each Clinical Site. The Chairperson of the Consortium may select other voting members of the Executive Committee deemed necessary for successful completion of the study. The scientific coordination for the protocol and the administrative operations of the Consortium. Under the leadership and coordination of the Chairperson, the investigators will be in charge of the development of a clinical protocol and of its modifications, if necessary, taking into account evolving scientific evidence related to the current state-of-the-art in BMRI and its new approaches not previously mentioned in the application. Under the leadership of the Chairperson of the Consortium and with assistance of the NCI Project Scientist, the Executive Committee will review the model clinical protocol proposed in the grant application, introduce modifications if necessary, finalize protocol development and monitor its implementation. The proposed protocol and all modifications will be submitted by the Chairperson of the Consortium to the NCI Project Scientist in compliance with the NCI protocol approval procedure that requires the review and approval of all protocols by the CTEP Protocol Review Committee. The accrual of patients. Although under the supervision of the Chairperson and Headquarters, it is the responsibility of individual Clinical Sites to accrue patients and to ensure that data will be submitted in a timely way to the central Data and Statistics Center. Data and Statistics Center The Data and Statistics Center staff are integral collaborators in all stages of study development, conduct, analysis, and reporting. In addition, the Data and Statistics Center funded by this RFA is responsible for data monitoring, including on-site audits. The general responsibilities assumed by this component will include: a. Ensure study feasibility and appropriateness of study design with respect to stated research objectives. b. Ensure that there are clear and consistent definitions of study objectives, eligibility criteria, primary analysis endpoints, evaluation criteria and guidelines for removal of patients from experimental protocol. c. Take primary responsibility for establishment and implementation of data monitoring, including on-site audits. d. Assume responsibility for planned interim analyses of clinical research and their timely reporting to DSMC. e. Prepare semi-annual progress reports, including patient accrual, eligibility, evaluability, and adverse effects (when applicable), in coordination with the Chairperson of the Consortium. f. Implement appropriate registration and accrual tracking procedures. g. Design, develop and implement forms required to collect Consortium data. h. Provide for all aspects of the collection and management of Consortium study data, especially timeliness and quality of data submission. i. Contribute to all decisions regarding the conduct of Consortium studies. j. Perform statistical analyses that use state-of-the-art methodology and provide unbiased results. 2. NCI Staff Responsibilities The NCI Project Scientist will have substantial scientific- programmatic involvement during conduct of this activity, through technical assistance, advice and coordination above and beyond normal program stewardship for grants, as described below. It is expected that the dominant role and prime responsibility for the activity will reside with the awardees for the project as a whole, although specific tasks and activities in carrying out the studies will be shared between the awardees and the NCI Project Scientist who will serve as the contact point for all facets of scientific interaction with the awardees. The NCI Project Scientist responsibilities will include: Interacting with the Chairperson of the Consortium on a regular basis to monitor study progress, to participate in the Executive Committee meetings and related activities. The NCI Project Scientist will be a non-voting member of the Executive Committee and, if applicable, subcommittees. The NCI retains, as an option, periodic external review of progress. Serving as a resource with respect to other ongoing NCI activities that may be relevant to the protocol to facilitate compatibility and avoid unnecessary duplication of effort. Being substantially involved in the design and coordination of research activities for awardees as elaborated below: a. Providing advice in the management and technical performance of the investigations, coordinating clearances for investigational drugs (e.g. contrast agents) and devices (e.g. MRI-guided biopsy equipment) to ensure that the proposed study is in accord with FDA requirements for investigational agent and device trials. b. Assisting, through participation in the Executive Committee, in the design, development, finalization, and coordination of a uniform standardized clinical protocol and statistical evaluations of data in the preparation of questionnaires and other data recording forms and in the publication of results. c. Submitting the experimental protocol and its revisions for review by the Protocol Review Committee of the CTEP that will review and approve the protocol and its amendments proposed by the Executive Committee of the Consortium to insure: i) That they are within the scope of peer reviewed research ii) That the plans to accrue sufficient women and/or minorities and are within regulations (see below under Inclusion of Women and minorities in Research Involving Human Subjects) iii) That there are sufficient safety considerations before implementation, as required by Federal regulations. The decision of the CTEP Protocol Review Committee will be communicated to the awardees by the NCI Project Scientist within 30 days of the Committee meeting. The NCI Project Scientist will monitor protocol progress, and may request that the Consortium DSMC consider closing a protocol to accrual for reasons including: (i) insufficient accrual rate; (ii) poor protocol performance; (iii) patient safety and regulatory concerns; (iv) study results that are conclusive before completion of full accrual; and, (v) emergence of new information that diminishes the scientific importance of the original study question. The NCI will not permit further expenditures of NCI funds for a study after requesting closure (except for patients already on study). If disagreements develop over recommended protocol closure for reasons other than patient safety or regulatory concerns NCI will establish an arbitration procedure to resolve differences between the awardees and the NCI as described below under Arbitration (Section 4). No expenditures of NCI funds will be allowed for protocols disapproved by NCI unless disapproval has been modified by arbitration panel. Reviewing and providing advice regarding methods established by the Consortium for statistical data collection, management, analysis and monitoring, including audits, in accordance with the procedures approved by the Executive Committee. Reviewing and providing advice regarding procedures established by the Consortium for coordinated supply and centralized quality control of contrast agents and instrumentation. Assessing Consortium compliance with the NCI established policies on DSMCs. NCI Project Scientist will serve as an observer during the DSMC meetings. 3. Collaborative Responsibilities In addition to the interactions defined above, NCI staff and the Consortium shall share responsibility for the following activities: a. The Chairperson of the Consortium functions as the scientific coordinator for the protocol and shall assume responsibility for administrative operations of the Consortium. The investigators will develop a clinical protocol and its modifications, if necessary, taking into account evolving scientific evidence related to the current state-of-the-art in BMRI and its new approaches not previously mentioned in the application. Under the leadership of the Chairperson of the Consortium and with assistance of the NCI staff, the Executive Committee will review the model clinical protocol proposed in the grant application, introduce modifications if necessary, finalize protocol development and monitor its implementation. The proposed protocol and all modifications will be submitted by the Chairperson of the Consortium to the NCI Project Scientist in compliance with the NCI protocol approval procedure that requires the review and approval of all protocols by the CTEP Protocol Review Committee. b. Executive Committee. An Executive Committee chaired by the Chairperson of the Consortium will be the main oversight body of the study. NCI Project Scientist will serve as a non-voting member of the Executive Committee. An initial meeting of the Executive Committee will be convened by the Principal Investigator early after the award in coordination with the NCI Project Scientist. In addition to the Chairperson of the Consortium and the NCI Project Scientist, as mentioned above, the Executive Committee will be composed at the minimum of the following voting members: Director of the Data and Statistics Center, Coordinator of the Quality Assurance Committee and one clinical investigator from each Clinical Site. Chairperson of the Consortium may select other voting members of the Executive Committee deemed necessary for successful completion of the study. The final structure and composition of the Executive Committee will be established at the first meeting by the Principal Investigator, with assistance from the NCI Project Scientist. With assistance of the NCI staff, the Executive Committee will finalize a model clinical protocol proposed in the grant application (and its modifications, if necessary), determine which correlative studies are appropriate and develop long term sequential planning, including prioritization of study goals. The Executive Committee will meet at least twice yearly under usual circumstances. Semiannual meetings of the Executive Committee will be convened by the Chairperson of the Consortium in coordination with the NCI Project Scientist. The Chairperson of the Consortium is responsible for coordinating the Executive Committee's activities, for preparing meeting agendas, and for scheduling and chairing meetings. The Executive Committee, under the leadership of the Chairperson of the Consortium, will document progress in written semiannual reports to the NCI Project Scientist, and will provide supplementary reports to designated NCI staff upon request. c. Data and Safety Monitoring Committee (DSMC). The DSMC is a NCI mandated committee with responsibilities described below (see DSMC, above) and geared towards protection of patient safety, ethics and data impartiality. The appropriate conduct of the Consortium DSMC procedures is a collaborative responsibility of the Consortium and the RRP/NCI program staff. 4. Arbitration Any disagreement that may arise on scientific/programmatic matters (within the scope of the award), between the awardees and the NCI may be brought to arbitration. An arbitration panel will be composed of three members -- one selected by the Consortium, a second member selected by the NCI, and the third member elected by the two prior selected members. This arbitration panel will review the RRP decision and recommend an appropriate course of action to the Director, Division of Cancer Diagnosis, Treatment and Centers. This special arbitration procedures in no way affect the awardees' right to appeal an adverse action that is otherwise appealable in accordance with PHS regulations at 42 CFR Part 5c, subpart D, and HHS regulations at 45 CFR Part 16. The Consortium will not expend NCI funds to conduct any study disapproved by RRP unless this disapproval has been modified by the arbitration process described 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 biochemical 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 Minorities in Study Populations, and Concerning the Inclusion of Women 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", reprinted in the NIH GUIDE FOR GRANTS AND CONTRACTS of March 18, 1994, Volume 23, Number 11. Investigators may also obtain copies of the policy from the program staff listed under Inquiries. Program staff may also provide additional relevant information concerning the policy. 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. For this study, all research subjects will be women, although a particular emphasis will be placed on recruitment of women younger than 50 years of age and minority women with "radiodense breast tissue". LETTER OF INTENT Prospective applicants are asked to submit, by May 15, 1996 a letter of intent that includes a descriptive title of the proposed research, 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 to avoid conflict of interest in the review. The letter of intent is to be sent to: Dr. Carl Mansfield Division of Cancer Treatment, Diagnosis, and Centers National Cancer Institute Executive Plaza North, Suite 800 6130 Executive Boulevard, MSC 7440 Bethesda, MD 20892-7440 Rockville, MD 20852 (for express/courier service) Telephone: (301) 496-6111 FAX: (301) 480-5785 Email: mansfieldc@dtpepn.nci.nih.gov APPLICATION PROCEDURES The research grant application form PHS 398 (revised 5/95) is to be used in applying for these grants. Applications kits are available at most institutional offices of sponsored research and may be obtained from the Grants Information Office, Office of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301/710-0267, email: ASKNIH@odrockm1.od.nih.gov; and from the program administrator listed under INQUIRIES. The RFA label available in the PHS 398 (rev. 5/95) 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 2 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, high quality/one sided photocopies, in one package to the address below. The photocopies must be clear and single sided. DIVISION OF RESEARCH GRANTS NATIONAL INSTITUTES OF HEALTH 6701 ROCKLEDGE DRIVE, ROOM 1040-MSC 7710 BETHESDA, MD 20892-7710 BETHESDA, MD 20817 (for courier/express service) At the time of submission, two additional copies of the application must also be sent to: Ms. Toby Friedberg Division of Extramural Activities National Cancer Institute (NCI) Executive Plaza North, Room 636 6130 Executive Boulevard Bethesda, MD 20892 USA Telephone: (301) 496-3428 Applications must be received by July 30, 1996. 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. This does not preclude the submission of a substantial revision of an application already reviewed, but such applications must include introduction addressing the previous critique. Special Instructions for the Preparation of Multiinstitutional Consortium Cooperative Agreements Applications Any special information should be provided which is required as a result of the use of the cooperative agreement mechanism, such as special meetings, budgetary requirements, special instructions for multi-center or multi-study projects, etc. Applicants must describe plans to accommodate stated program requests, criteria and staff involvement. It is critical that each applicant include specific plans for responding to these Terms and Conditions of Award. It is suggested that applicants be advised to include planned meetings in the budget requests. Plans must describe how the applicant will comply with the program staff involvement and how all the Awardees Responsibilities will be fulfilled. Application Preparation All applications must be submitted on the form PHS 398 (rev. 5/95). Successful applications for each of the two components of the Consortium (the Headquarters and the Data and Statistics Center) will be submitted in together and awarded separately to the sponsoring institutions. Each individual application must contain a detailed budget for the first 12 months period and a budget for the entire proposed project period for direct costs. The Headquarters and the Data and Statistics Center applications, should describe the scientific and administrative experience of key personnel and should include and follow the PHS 398 (rev. 5/95, Office of Grant Inquiries/Information Rockledge II/Rm. 6207 Bethesda, MD 20892 301-710-0267) instructions for Biographical Sketches and Other Support information. For each Consortium component, the specific application requirements are listed below: 1. Headquarters Application The Headquarters Application should contain a model experimental protocol for the multi-institutional evaluation of BMRI, which, in turn, should outline the Consortium's scientific strategy, including rationale and future plans; a clear sense of direction should be evident. In addition to its scientific proposal, the Headquarters application should also contain information describing the Consortium's organizational structure, including all the participating Clinical Sites and the plan for the establishment of the Quality Assurance Committee, and the operating procedures and policies to accomplish major objectives and responsibilities. The budget for the Headquarters should be presented in logical, discrete units. Separate budgets should be provided for the Executive Committee, Quality Assurance Committee, and each participating Clinical Site, with detailed justification of each item; a separate budget should be also prepared as a subcontract for each participating institution for which funds are requested, including applicable indirect costs (see NIH/DHHS Guidelines for Establishing and Operating Consortium Grants of January 1989). It is also suggested that applicants include plans for meetings in the budget requests. To promote the development of a collaborative program among the study participants, a number of issues need to be addressed by the applicants for the Headquarters as described below: i. Applicants should describe their rationale for their choice of the experimental protocol. The potential for the adequate patient accrual necessary for the achievement of the proposed study goals (and understanding of how the estimated ideal number is revised) should be demonstrated. ii. Applicants should present a plan for personnel and facilities capable of performing and supporting the administrative functions of a Consortium conducting imaging trials in cancer. Applicants must demonstrate the ability to organize, conduct, and monitor clinical trials in radiology. Applicants must describe a plan for qualified support personnel to ensure timely and accurate data retrieval and reporting. Applicants must describe procedures by which institutions participating in the Consortium would perform their functions, including protocols for accomplishing the clinical work and patient accrual and administrative project management. The application should include the proposed protocol for correlation of BMRI with conventional x-ray mammography and, if applicable, other technologies (e.g., US) with histopathologic findings. iii. The Chairperson of the Consortium should demonstrate expertise in the design and coordination of clinical trials, capability to provide educational workshops and ongoing training for Consortium participants, with special emphasis on MRI-guided biopsy, capacity to develop and implement an administrative and management structure for the Consortium, including an Executive Committee, a Quality Assurance committee, and Clinical Sites. The Chairperson will supervise the administrative and scientific aspects of the Consortium's function. iv. The Quality Assurance Committee Coordinator and staff should demonstrate experience in the development of review, evaluation and quality control procedures for contrast agents, imaging devices, imaging techniques, image interpretation and experimental approaches required by the protocol. v. Individual Clinical Sites in a Consortium should demonstrate commitment to participate in multi-institutional protocols, including their willingness to follow the uniform protocol, their ability to participate in the study and their documentation of the facilities and professional personnel available to conduct cooperative imaging trials. This includes assignment of appropriate specialists required by the experimental protocol including, but not limited to, radiologists, surgeons and pathologists, in order to ensure complete patient evaluation. Individual Clinical Sites in the Consortium should demonstrate the availability of the state-of-the-art instrumentation in BMRI, conventional x-ray mammography and other technologies required by the protocol. Each Clinical Site must have the instruments, facilities, and capabilities for the proposed experimental protocol. Clinical Sites must be able to interact effectively with the Executive Committee, Data and Statistics Center and Quality Assurance Committee. Clinical Sites must be able to correlate x-ray mammography imaging, BMRI, and US data with pathologic findings. Each Clinical Site must have the capability for performing biopsies of small lesions detectable only by MRI. This may consist of (but not limited to) the placement of appropriate markers with MRI guidance for surgical biopsy, or direct MRI-guided needle biopsy. 2. Data and Statistics Center Application The Data and Statistics Center Director and staff should demonstrate expertise in all areas of data collection, management and monitoring. The applicants should describe in detail the proposed plan for the management of data from multicenter clinical trials, including statistical data collection, management, analysis, monitoring and other related issues. They should describe in detail the Consortium's data management practices and procedures, its quality control and study monitoring methodology, and its analytical techniques and resources. The budget for the Data and Statistics Center application should be presented in logical, discrete units with specific budgets for each unit as well as the total Center's request. Personnel, travel expenses, and computer systems to accomplish the task of data management, including on-site audits, should be carefully and fully documented. REVIEW CONSIDERATIONS General Considerations All applications will be judged on the basis of the scientific and technical merit of the proposed project and the documented ability of the investigators to meet the RESEARCH OBJECTIVES of this RFA. Other considerations, such as the importance and timeliness of the proposed study, access to patients, and multidisciplinary nature of the studies, will be part of the evaluation criteria. Review Method Upon receipt, applications will be reviewed for completeness by DRG and for responsiveness by the NCI. Incomplete applications will be returned to the applicant without further consideration. If NCI staff find that the application is not responsive to the RFA, it will be returned to the applicant without further consideration. Applications that are complete and responsive to this Request for Applications will be reviewed for scientific and technical merit by an appropriate peer review committee convened by the NCI in accordance with the review criteria stated below. As part of the initial merit review, all applications will receive a written critique and may undergo a process in which only those applications deemed to have the highest scientific and technical merit will be discussed, assigned a priority score, and receive a second level review by the National Cancer Advisory Board (NCAB). Review Criteria Applicants are encouraged to submit and describe their own ideas about how best to meet the goals of the cooperative study and their specific protocols, and are expected to address issues identified under APPLICATION PROCEDURES of this RFA. The review committee will assess the scientific and technical merit of each of the two components of the Consortium, as summarized below: A. Consortium Headquarters -Scientific, technical, or medical significance and originality of proposed research plans; -Appropriateness and adequacy of the experimental approach and methodology proposed to carry out the research; -Qualifications and research experience of the Chairperson and key personnel, particularly, but not exclusively in the area of the proposed research; -Availability of appropriate facilities, equipment, instrumentation (including but not limited to the state-of-the-art conventional x-ray mammography, dedicated breast MR imaging coils, MRI-guided biopsy capability), and other resources to ensure that each institution participating in the Consortium is capable of performing innovative cooperative trials in breast cancer diagnosis; -Appropriateness of the proposed budget and project duration in relation to the proposed research; The initial review committee will also examine the provisions for the protection of human subjects, the safety of research environment, and conformance with the NIH Guidelines for the Inclusion of Women and Minorities as Subjects in Clinical Research: -Adequacy of plans to include minorities and their subgroups as appropriate for the scientific goals of the research. Plans for recruitment and retention of subjects will also be evaluated. A particular emphasis should be placed on the accrual of women younger than 50 years of age and minority women with radiodense breast tissue. Specific attention will be given to: -The overall qualifications of collaborating institutions in the Consortium as stated under the Application Procedures for participants (see Application Procedures); -A record or evidence of willingness of the professional and support personnel to work as a team with other Consortium members and with the NCI Project Scientist; -Evidence of the ability and /or the potential of the Chairperson to develop multicenter clinical trials of substantial scientific and technical merit in BMRI; -Evidence of the previous experience of the key professional personnel of Clinical Sites with clinical BMRI studies of sound scientific quality (at least 100 examinations) and their histopathologic correlation; -Evidence of the potential of Clinical Sites for reaching the adequate patient accrual necessary for the achievement of the proposed study goal in a reasonable period of time; -Evidence of the experience of the key personnel of the Quality Assurance Committee in the development of procedures for quality control of contrast agents and imaging devices, including standardization of instrumentation performance and technical requirements. B. Data and Statistics Center This portion of the evaluation involves multiple facets: -The performance and capabilities of the Data and Statistics Center; -The development and operation of the data quality control program with on-site monitoring, including auditing; -Evidence of the experience of the key personnel of the Data and Statistics Center in biostatistical study design and data collection, management, analysis and monitoring of multicenter clinical trials; -Adequacy of the facilities and computing resources to assure smooth and efficient function. AWARD CRITERIA Applications recommended by the National Cancer Advisory Board (NCAB) will be considered for award based upon (a) scientific and technical merit as reflected by the priority score; (b) availability of funds; and (c) programmatic priorities. Furthermore, the applicant organization must indicate a commitment to accept provisions outlined under the Terms and Conditions of Award in this RFA. Application Receipt Date: July 30, 1996 Review by the NCAB: February 25, 1997 Anticipated Award Date: April 1, 1997 INQUIRIES Inquiries concerning this RFA are encouraged. The opportunity to clarify issues or questions from potential applicants is welcome. Direct inquiries regarding scientific and programmatic issues to: Dr. Carl Mansfield Division of Cancer Treatment, Diagnosis and Centers National Cancer Institute Executive Plaza North, Suite 800 6130 Executive Boulevard, MSC7440 Bethesda, MD 20892-7440 Telephone: (301) 496-6111 FAX: (301) 480-5785 Email: mansfieldc@dtpepn.nci.nih.gov Direct inquiries regarding fiscal matters to: Ms. Eileen Natoli Grants Administration Branch National Cancer Institute Executive Plaza South, Suite 243 Bethesda, MD 20892 Telephone: (301) 496-7800, Extension 256 FAX: (301) 496-8601 Email: natolie@gab.nci.nih.gov 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 and 45 CFR Part 92. 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 recipients to provide a smoke-free workplace and promote the non-use of tobacco products. In addition, Public Law 103-227, The Pro- Children Act of 1994, prohibits smoking in certain facilities (or, in some cases, any portion of a facility) in which regular or routine education, library, day care, health care or early childhood development services are provided for 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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