Research (OER)
9000 Rockville Pike
Bethesda, Maryland 20892
and Human Services (HHS)
Full Text CA-97-020 COOPERATIVE TRIALS IN DIAGNOSTIC IMAGING NIH GUIDE, Volume 26, Number 28, August 22, 1997 RFA: CA-97-020 P.T. Keywords: National Cancer Institute Letter of Intent Receipt Date: November 18, 1997 Application Receipt Date: February 18, 1998 PURPOSE The Division of Cancer Treatment, Diagnosis and Centers (DCTDC), National Cancer Institute (NCI), invites applications for cooperative agreements to establish a single national Network of investigators that will perform multi-institutional clinical trials in diagnostic imaging related to cancer. The Network will have the capability to conduct a broad spectrum of clinical trials in imaging. Similar to the treatment cooperative groups supported by DCTDC, this Network will generate new trials in areas of high scientific opportunity. Unlike most other major National Institutes of Health (NIH) cooperative trials efforts, the structure and funding of this Network will not be linked to specific clinical trials. Because the Network's apparatus for conducting trials will be continually in place, this mechanism has considerable flexibility for allocating resources quickly to the testing of promising new imaging devices or agents, both in limited-institution pilot studies and in large multi-center settings. The initial focus of the Network will be cancer; once the Network is functioning productively, consideration will be given to broadening the agenda to include additional areas of medicine with the support of other institutes of the NIH. HEALTHY PEOPLE 2000 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2000," a PHS-led national activity for setting priority areas. This Request for Applications (RFA) is related to the priority area of cancer. Potential applicants may obtain a copy of "Healthy People 2000" (Full Report: Stock #017-001-00474-0 or Summary Report: Stock #017-001-00473-1), through the Superintendent of Documents, Government Printing Office, Washington, DC 20402- 9325 (telephone: 202-512-1800). ORGANIZATION The Network will consist of a Headquarters office that coordinates operations, a Biostatistics and Data Management Center (BDMC), and a number of participating institutions in which the studies are performed. Participating institutions will be selected by the Network's scientific leadership for their ability to contribute to the particular trials in the Network's research repertoire. Institutions will not be fixed "members" of the Network but will be selected for participation in particular studies. The Network will, therefore, have the flexibility to recruit institutions that best suit its scientific agenda, as this evolves over time. The scientific leadership of the Network will be organized in scientific committees covering high- priority topic areas in contemporary imaging. Membership in these committees will be drawn in flexible fashion from the entire community of expertise in imaging science in North America. Thus, both the committee structure of the Network and the membership in individual committees will change with time as scientific opportunity warrants. The Network shall be governed by a written constitution and bylaws, which should describe criteria for inclusion and exclusion of participants, procedures for selecting Network leadership and for adapting the composition of Network leadership to changes in scientific opportunity, and other details of governance. The Network shall be led by a Chair, who is ultimately responsible to the Network and to the NCI for the content and conduct of the Network's research program. Beyond these general requirements, the structure and management of the Network are the responsibility of the Network's leadership. The funding structure will consist of two cooperative agreements supporting a Headquarters and a Biostatistics and Data Management Center (BDMC). Participating sites, selected and credentialed by the Network leadership, will be reimbursed for accrual on a per capita basis by subcontracts from the Headquarters. In addition to accrual, Headquarters funds will support operations and coordinating functions, as well as the activities of the Network's scientific committees. A Developmental Fund may be requested to support new areas of particular opportunity. The BDMC award will support data management and analysis and related research on clinical trials methodology. The Network's quality assurance program may be supported from either the Headquarters or the BDMC award, at the discretion of the Network. ELIGIBILITY REQUIREMENTS Applications may be submitted by North American for-profit and non-profit organizations, public and private, such as universities, colleges, hospitals, laboratories, professional societies, units of state and local governments, and eligible agencies of the federal government. Foreign organizations outside North America are not eligible. Applications that include minority individuals and women as principal investigators are encouraged. Eligible organizations may apply for either a Headquarters award, a BDMC award, or both. Separate applications must be submitted for each type of award. Each Headquarters applicant must identify in both a cover letter and in the body of the application a single BDMC with which it is proposing to collaborate. Similarly, each applicant for a BDMC must identify both in a cover letter and in the body of the application the Headquarters with which it is proposing to collaborate. Potential applicants for the Headquarters and BDMC must, therefore, identify themselves to each other and establish affiliations both with each other and with the scientific leadership and participating institutional sites for the performance of the initial clinical trials that constitute the beginning research agenda of the Network. MECHANISM OF SUPPORT The administrative and funding instrument to be used for this RFA will be the cooperative agreement (U01), an assistance mechanism in which substantial NCI scientific and/or programmatic involvement with the awardee is anticipated during performance of the activity. Under the cooperative agreement, NCI's purpose is to support and stimulate the recipient's activity by working jointly with the recipient in a partner role. The NCI does not assume prime responsibility for or a dominant role in the activity, and the research conducted by the awardee is at all times investigator- initiated. Details of the responsibilities, relationships and governance of the studies to be funded under this cooperative agreement are discussed later in this RFA under the section "Terms and Conditions of Award." The total project period for applications submitted in response to this RFA may not exceed five years. The anticipated award date is December, 1998. Although this program is provided for in the financial plans of the NCI, awards pursuant to this RFA are contingent upon availability of funds for this purpose. This RFA is a one-time solicitation. If there is sufficient continuing program need, NCI will invite the recipients of awards under this RFA to submit competitive continuation cooperative agreement applications for review. FUNDS AVAILABLE Approximately $3 million total cost will be available in FY-1999 for the first year of support for awards made under this RFA; $4 million (total) for FY 00; and $5 million (total) for FY 01, 02, and 03. Each year following the first will have appropriate cost escalation in conformity with NIH grants policy. A single Network of national scope will be supported by the pair of awards made under this RFA. The level of support will be dependent upon the level of merit of the applications received and the availability of funds. Funding beyond the initial budget period will be contingent on the continued availability of funds for this purpose, the continued progress of the awardees, and the Network as a whole. RESEARCH OBJECTIVES Background For a number of years, the NCI has sponsored clinical trials in diagnostic imaging. The centerpiece of multi-center trials support has been the series of studies performed by the Radiologic Diagnostic Oncology Group (RDOG). Since 1987, this activity has conducted individual imaging studies in prostate, lung, colon, pancreatic, musculoskeletal, head and neck, ovarian, and pediatric tumors, as well as a comparison of image-guided stereotactic breast biopsy to an open surgical procedure. Except for the last study, the prevailing research agenda has involved comparisons between CT, MRI, and ultrasound, as appropriate, at the various anatomical sites. The focus of these studies has been on accuracy of assessment of extent of disease in patients presenting with newly diagnosed cancer. The RDOG activity was recompeted on five occasions with five separate RFAs; thus, a group was reconstituted anew for each research question in the RDOG series. The RDOG experience has been a very productive one for cancer imaging and for the clinical radiology community. It has been one of the very few sources worldwide of information from randomized comparisons of competing diagnostic modalities. For this reason, the RDOG studies have introduced rigorous methodology into the clinical testing of new imaging technologies. The RDOG activity was intended primarily to enable the comparison of already established imaging modalities and was not focused on the early evaluation of imaging techniques upon their introduction into the clinic. Nor did it begin to explore the full spectrum of promising diagnostic tools available to the contemporary investigative imager. The continued acceleration of the pace of technological and scientific progress is now no doubt faster than it has ever been. Existing imaging modalities undergo progressive technical improvement. The coupling of imaging with minimally invasive diagnostic and therapeutic procedures will make interventions better by limiting disfigurement, trauma, and expense. Further advances may make the assessment of extent of disease in oncology much simpler; for example, the availability of radionuclides attached to tumor-seeking ligands may greatly simplify imaging diagnosis, inasmuch as one injection of a suitable radiolabel might, in certain clinical situations, obviate the need for multiple independent imaging tests. The further development of techniques that mirror the functional or biochemical characteristics of tumors, rather than merely anatomic location and extent, is likely to illuminate major correlates of prognosis non-invasively and provide guidance in selecting appropriate therapy. Thus, the future development of imaging tools will proceed in parallel with an increasing understanding of tumor biology and a more detailed molecular understanding of the malignant state. Paradoxically, this scientific progress comes at a relatively difficult time for the introduction of innovative technologies into medical practice. Health care providers under increasing pressure to contain costs are reluctant to make large capital investments without the promise of significantly improved medical care and/or a reduction in the cost of care. More accurate images by themselves will not necessarily motivate new equipment purchases without evidence that the greater accuracy will translate into cost savings or better clinical results. These kinds of endpoints are most persuasively assessed using rigorous clinical trials methodology. The need for rigor in the generation of clinical evidence is also conditioned by the evolving domestic regulatory environment in the United States. Historically, the procedures governing FDA approval of devices have differed significantly from those relating to drugs, in that the role of formal clinical trials has been much more circumscribed for devices. As innovations in imaging depart increasingly from existing paradigms, and especially as imaging and intervention become much more closely linked, the need for formal clinical evidence of safety and effectiveness will assume overriding importance. Objectives and Scope The goal of this initiative is the creation of a Network that will serve as an instrument for the expert clinical evaluation of discoveries and technological innovations relevant to imaging. Its activities will result in the following: 1) the expeditious, reliable, and comprehensive clinical evaluation of new imaging modalities; 2) the facilitation of technology development and translational research relating to imaging in academia and in industry; 3) the development of improved clinical trials methodology specifically relevant to imaging and the early detection of cancer. These goals are closely interrelated. A Network of expert investigators should provide unbiased, reliable evidence on the relative merits of competing imaging methodologies for the staging of cancer. Where appropriate, this evaluation should include estimates of the relative cost-effectiveness of diagnostic interventions and of their impact on quality of life. Private industry should find collaboration with the Network a very appealing prospect for generating reliable evidence on the medical worth of its products, their safety and effectiveness, and their relative cost-effectiveness compared to conventional diagnostic approaches. This Network can also be expected to establish productive partnerships with the technology-assessment activities of third-party payers, whose quandaries about which medical interventions should and should not be reimbursed will be materially lessened by an increasingly firm base of evidence. In particular, having such information generated by a research group unconnected with particular commercial concerns will help payers with coverage decisions and providers with purchasing decisions. The development of improved clinical trials methodology for the evaluation of diagnostic devices will serve to expedite the often lengthy process and enrich the information yield in a manner that should benefit all constituencies - patients, sponsors, payers, and regulators. Scientific Agenda and the Need for Flexibility in Organization and Scientific Leadership The Network's scientific agenda will consist of a mix of limited- institution feasibility studies and large-scale, multi-center randomized trials. It is essential that the Network identify and concentrate its energies on the most promising scientific opportunities, that studies be completed within reasonable periods of time, and that the methodologies employed in studies be sound and, where appropriate, innovative. The Network's scientific committee structure should be organized around broad subject areas within the imaging field. As the Network gains experience and its scientific activities shift and broaden, the membership of committees and, indeed, the number and identity of the committees themselves should change in response to scientific opportunity. Individual committees may well come and go as the priorities of the Network evolve. Highly qualified scientists and physicians in imaging and related areas can be invited to assume committee membership in a flexible manner as the need arises. Neither the initial committee structure of the Network nor the membership of the several scientific communities should be regarded as fixed and unchanging in time. To ensure that the Network's scientific leadership and committee structure is adequately responsive to the most promising opportunties in the field, exhibits the desired degree of flexibility in composition and decision-making, and makes prioritization decisions free of conflicts of interest, the organizational structure should include an advisory panel of experts not directly involved in the research activities of the Network. Appointment to this advisory panel will be by mutual agreement between the Network Chair and the Associate Director, Diagnostic Imaging Program (DIP). Because imaging and treatment issues are often closely related and will become more so as technology evolves over the next few years, the Network will need meaningful participation from the radiotherapy, surgical and medical communities. In some of its activities, the Network may need to relate programmatically to the treatment cooperative groups supported by NCI. It may, in fact, turn out that certain kinds of trials, particularly those involving treatment, may work best as intergroup studies with one or more of the treatment-oriented cooperative groups. The need for such liaisons should be anticipated and provided for by the Network leadership. The Network and its scientific committees should develop, articulate and follow a research plan that summarizes the Network's thinking and anticipated lines of investigation for each area on which it chooses to focus. This plan should articulate both short-term and long-term goals and will aid the Network in prioritizing competing research ideas. The plan will include a balanced and interrelated program of small developmental and feasibility studies, larger pilot trials, and large-scale, multi-center efforts; all types of trials should take advantage of the Network's experience, expertise, and resources. The plans for each subject area will be a major focus of the peer-review process. Selection of Investigator-Participants and Study Sites - A Flexible Approach Investigators participating in Network research may come from either academic, community, or industry settings. For participation in a particular study, the Network leadership may solicit any site that has the necessary technical qualifications and accrual potential to contribute meaningfully to the study's execution and timely completion. Because the scientific agenda of the Network is expected to include a broad range of trials, a correspondingly broad spectrum of investigator specialty and expertise will be necessary. For example, three hypothetical trials focusing on image-guided, minimally invasive ablation of early prostate cancer, the staging of an intrathoracic carcinoma by PET, and a comparison of virtual colonoscopy to a fiber-optic procedure would likely require entirely different investigative groups, and perhaps even largely non-overlapping sets of institutions. The Network will be constructed in a flexible manner to permit the ad hoc affiliation of qualified groups to participate in high-priority research across the entire range of imaging studies relevant to cancer. Accrual from individual sites in the various trials will be reimbursed on a per- case basis; the appropriate rates of reimbursement will be set by the Network leadership. The Network will establish policies and procedures for credentialing participating sites and for conducting periodic review of the performance of all sites through its quality control and quality assurance procedures. The review will examine patient accrual, data accuracy and timeliness, protocol compliance, procedures for tracking and follow-up of patients, and audit results. Capabilities and Characteristics of the Network In order to accomplish its research objectives, the Network should have the following capabilities and characteristics: (1) dynamic and visionary scientific leadership at the forefront of research in imaging; (2) ability to accrue large numbers of patients with cancer to randomized clinical trials; (3) the capability to perform limited-institution pilot trials of new imaging modalities, devices, or agents, preparatory to multi-center randomized trials; (4) a statistical office led by individuals with experience in designing, conducting, and analyzing clinical trials; (5) the use of endpoints, in addition to those that directly measure diagnostic accuracy, that will enable an assessment of the broad impact of imaging innovations on the patient and on medical practice (these include, for example, cost-effectiveness and quality of life); (6) an internal performance review program that monitors the adequacy of accrual and the quality of record-keeping; (7) capability of dealing with regulatory responsibilities such as Investigational Device Exemptions (IDE) and Investigational New Drug (IND) applications to the Food and Drug Administration (FDA), and drug shipments and handling; (8) quality-assurance and quality-control programs that ensure both patient safety and high quality of research data; (9) methods and procedures for assuring inclusion in trials of adequate numbers of women and minority patients; (10) integration of members of the patient advocate community into appropriate Network committees and activities. Functions and Responsibilities The Network's two major organizational components have the following responsibilities: Headquarters The Headquarters is under the direct supervision of the Network's Chair, who serves as Principal Investigator of the Headquarter's award and implements the Network's scientific and organizational policies. The Headquarters provides executive leadership, scientific direction, and day-to-day administrative management of the Network. The Headquarters houses the scientific leadership and committee structure of the Network. Specific roles and responsibilities of the Headquarters include the following: a. develops the scientific agenda, specific research plans, and the Network's overall research priorities. This includes establishment of a process for soliciting the best ideas from the scientific community, for prioritizing them, and for assembling a roster of qualified participants. b. provides logistical and financial support to the Network scientific committees, monitors their productivity, and provides for the election or appointment of their leadership; c. oversees scientific and operational activities; d. develops a constitution and bylaws specifying Network structure and management, procedures for the selection of successor Chairs and other leadership, terms of office, criteria for participation, and other details of governance; e. serves as the center of information dissemination to the Network investigators and institutions, as well as to interested individuals and organizations outside the Network; f. provides overall management of Network resources, assuring allocation to priority projects and maintenance of a high degree of productivity from participants; g. develops policies and procedures for the selection and credentialing of participating sites and for all aspects of the conduct of Network activities; h. provides organizational and logistical support for Network meetings; i. conducts periodic review of the performance of participating sites according to criteria established by the Network; this review should focus on patient accrual and follow-up, data accuracy and timeliness, protocol compliance, results of audits, and adherence to regulatory requirements; j. establishes a Data and Safety Monitoring Committee (DSMC) for randomized clinical trials (and for any other trials that the Network leadership may deem appropriate) that is independent of study leadership, is clearly free of conflicts of interest, and has formally documented policies and procedures approved by NCI; provides organizational and logistical support to the DSMC; k. develops procedures for study monitoring to assure compliance with protocol design and protection of patients from research risks. This medical review should be coordinated with the quality assurance and quality control programs of the Network; l. encourages and provides financial support for the integration of community participation (patients and patient advocates) into Network activities by including them in Network meetings and on appropriate committees; m. fosters and monitors the inclusion of women and ethnic minorities in Network clinical trials; n. provides logistical and clerical support to the process of protocol development; develops and implements standards for protocol formatting; o. ensures internal Network and NCI review and approval of protocol concepts, final protocol documents, informed consents, and study amendments; advises NCI of changes in protocol status; p. produces and maintains current and accurate Network records; q. oversees Network compliance with regulatory requirements concerning the use of investigational devices and drugs, the reporting of adverse events, and the protection of human research subjects; r. provides guidance to the participants regarding clinical trials practices, including ethical issues involved in clinical research and conflict-of-interest considerations; s. tracks the progress of the Network's research and assures that the results of trials are published in appropriate peer-reviewed journals in a timely manner and in accordance with Network publication policies; t. verifies that all participating sites have a current approved Cooperative Project Assurance (CPA) or Multiple Project Assurance (MPA), as required on file with the Office for Protection from Research Risks (OPRR), NIH. Physicians in private practice must have an approved Non-institutional Investigator Agreement (NIA) on file with the Headquarters; u. monitors and maintains appropriate records for protocols, informed consents, assurances, and annual certifications of Institutional Review Board (IRB) review and approval (HHS Optional Form 310) for all participating sites; v. manages and allocates financial resources from the Headquarters budget and provides reimbursement for accrual to participating sites based on a predetermined per-case rate. Biostatistics and Data Management Center (BDMC) The Network's statistical and data management staff are integral collaborators in all stages of study development, conduct, analysis, and reporting. The responsibilities usually assumed by this component include: a. ensures study feasibility and appropriateness of study design with respect to stated study objectives; b. ensures that there are clear and consistent definitions of study objectives, eligibility criteria, primary analysis endpoints, and guidelines for removal of patients from study where necessary; c. develops appropriate designs to achieve specific study objectives; develops innovative designs and analytical techniques to maximize the information yield from trials of imaging devices; d. implements plans for monitoring of study data, including planned interim analyses of studies, where appropriate, and timely reporting to the DSMC of all adverse events. Interim study reports should be prepared according to Network policies. In general, reports of accrual, eligibility, evaluability, and adverse events should be made for each open study on at least a semi-annual basis; e. implements appropriate registration, randomization procedures, and accrual tracking procedures; f. designs, develops, and implements forms (paper or electronic) required to collect study data; g. provides for all aspects of the collection and management of Network study data, with due attention to quality and timeliness of data submission; h. contributes to all decisions regarding conduct of Network studies; i. performs statistical analyses that use state-of-the-art methodology and provides unbiased results; j. co-authors articles and abstracts based on protocol results and other Network data where appropriate; publishes on methodologic issues in interventional studies relating to diagnostics. Quality Control and Quality Assurance Program To ensure the correctness and integrity of its research database, the Network will establish quality-control and quality-assurance programs, including the development and implementation of an on- site audit program. According to the preference of the Network leadership, quality control and quality assurance activities may be located organizationally either in the Headquarters or the BDMC. The responsible organization will then provide the necessary logistical and financial support.The Network will take primary responsibility for its own on-site monitoring program and will be responsible for adherence to NCI's established procedures (these are described in a document entitled "NCI-CTMB Guidelines for On-Site Monitoring of Clinical Trials for Cooperative Groups and CCOP Research Bases" (hereafter "NCI-CTMB Guidelines") available from the Clinical Trials Monitoring Branch, CTEP, NCI). Assurance of Patient Safety and Study Quality The multi-center nature of many Network activities presents a variety of challenging methodologic problems regarding assurance of quality and consistency in study conduct. The need for formal mechanisms of medical review and quality control is clear. Other NCI-supported, multi-center organizations have developed a number of approaches to these matters. The following are examples of the kinds of considerations that will arise: 1. Imaging quality control includes, but is not limited to, the institution of suitable procedures to insure adequate control of image quality; standardization of techniques for image acquisition and processing across institutions, wherever appropriate; standardization of terminology regarding abnormalities and findings to be sought in images; quality-control measures to ensure accurate interpretation of images. 2. Radiation therapy quality control may involve, for teletherapy, either simultaneous (rapid turn-around) or retrospective review of port films and compliance with protocol-specified doses for individual patients. Minimal standards for acceptability of equipment may be required. Each radiation therapy facility that treats patients on Network studies will undergo periodic physics review and equipment calibration by the Radiologic Physics Center (RPC) in Houston, which has supplied each NCI cooperative group's radiation therapy quality-control office with the physics data necessary to conduct its case-level review. Analogous quality-control measures for image-guided brachytherapy should be developed as needed. 3. The quality control of drug administration (e.g., radiolabeled antibodies, investigational contrast agents, etc.) is usually carried out through retrospective review of submitted flow sheets, with determination of protocol compliance in dose administration and dose modification. The criteria vary considerably from study to study and from group to group and depend heavily on the specific research questions to be addressed. 4. Surgical quality control includes assessment by surgeons of the adequacy of protocol- specified surgical procedures through review of the operative notes, study specific surgical forms, and pathology reports. Standards of acceptability for specialized surgical equipment or requirements for participation in workshops may be necessary in some instances. Where appropriate, surgical modality committees may wish to draft handbooks of acceptable guidelines for surgical procedures used in studies. 5. Pathology review is usually retrospective and may be either by a committee within the Network or by an external reference panel. Pathology review is not required by NCI for all cases but should be employed when known variability in the accuracy of histologic diagnosis is a potentially serious problem or when pathology data may provide important prognostic information. 6. Appropriate quality control for other therapeutic or diagnostic modalities (for example, standardization of centralized laboratory procedures) is as essential to good data quality as those enumerated above. 7. Assuring the safety of individual patients participating in studies, maximizing the quality of their medical care, and ensuring that the interests of patient participants are not subsidiary to those of scientific investigation is critical to Network activities. All clinical treatment research carries with it the obligation to insure optimal therapy for participating patients. In this context, accurate and timely knowledge of the progress of each study is a critical Network responsibility and includes the following: a. Accurate tracking of patient accrual to individual studies at the participating sites and ensuring adherence to defined accrual goals. b. Ongoing assessment of patient eligibility and evaluability and correction of any specific problems that may occur. c. Adequate measures to ensure timely submission of protocol- required data for individual patients. d. Adequate measure to ensure timely medical review and assessment of the data from individual patients e. Rapid reporting of morbidity in individual patients related to diagnostic or therapeutic interventions, and measures to ensure communication of this information to all parties with the need to know, including the NCI and the Network's Data and Safety Monitoring Committees. f. Prompt assessment of the significance of such information in the context of the entire study's experience. g. Interim evaluation and consideration of measures of outcome, in a manner to be specified in advance for each study in accordance with established methodological procedures. 8. Quality Control and On-Site Auditing. A related need is for verification of the accuracy of data submitted from individual investigators to the Network. This need overlaps considerably with the obligation of DCTDC as a sponsor of investigational devices and agents. As a sponsor, DCTDC must provide for visits to each trials site for the purpose of: (a) auditing medical records to verify data accuracy, and (b) assuring compliance with the regulatory requirements of FDA, including appropriate storage and handling of investigational agents. The Network is, therefore, required to establish a system of periodic on-site audits of participating sites, with NCI oversight (see the "NCI-CTMB Guidelines"). Elements of the on-site audit program are as follows: a. Regulatory Obligation. As a sponsor of investigational agents and devices, the DCTDC is required by FDA regulations to maintain an on-site audit program. Through formal agreements with the FDA, DCTDC has delegated much of this responsibility to its investigative groups, with NCI overseeing the process. The specific purposes of the audit programs are to document the accuracy of data submitted to investigative groups and to verify investigator compliance with the regulatory requirements for all clinical investigations. b. Data Verification and Protocol Compliance. By comparison of submitted data with information contained in the patient's medical records, this component of the on-site audit program seeks to assure accuracy and completeness of research information integral to the assessment of: Patient eligibility Compliance with protocol-defined procedures End-point evaluation Intervention-related toxicity Protocol-required laboratory and diagnostic evaluations Overall quality of record-keeping Concomitant interventions or other information that might affect study results but is not recorded on submitted study forms c. Specific Regulatory Requirements. This component of the on-site audit program is intended to assess: Documentation of IRB approvals, reapprovals and protocol amendments Documentation of an IRB-approved properly signed and dated informed consent document for each case audited; these documents include an adequate description of the risks and benefits as contained in the model informed consent submitted to NCI at the time of protocol approval. Security of investigational drug handling Adequacy of NCI drug accountability records d. Procedures. The Network must establish and follow an on- site audit program and audit procedures in accordance with the "NCI-CTMB Guidelines". This requires that NCI be notified of all sites participating in each Network clinical trial. This notification will occur at the time of protocol submission to NCI either for protocol review or for informational purposes (see under NCI Staff Responsibilities, Section 3: Review of Proposed Protocols). Sites participating regularly in Network studies must be visited at least once every 36 months. All participants, however, are at yearly risk of an audit. Audits are conducted by peer investigators within the Network. A percentage of visits include NCI quality assurance staff or their agents. Protocols to be reviewed are selected by the Network in accordance with procedures outlined in the "NCI- CTMB Guidelines". A sample of studies involving investigational agents or devices is always included when the participating site has accrued patients to such studies. Individual cases are then randomly selected by the BDMC for review. A preliminary report must be faxed to CTMB within one working day of the audit. A final report of each audit is sent by the Network to CTMB within ten weeks of the audit. CTMB staff reviews the audit findings as well as the Network's evaluation and response to the results. e. Network Evaluation and Response. The discovery of actual fraud or other serious misconduct during cooperative group audits has been rare, but problems covering a wide spectrum of severity and type are often found. Most are appropriately dealt with by constructive suggestions and are usually remedied through education of investigators and data managers. Notification of NCI is required in the event of findings suggesting intentional misrepresentation of data or disregard for regulatory safeguards, as well as other matters of sufficient seriousness. In such instances, CTMB staff should be notified by telephone immediately, since other federal agencies may require notification. Procedures for immediate suspension of accrual at the participating site may be required. After reviewing the audit report and the Network's response, the CTMB staff may recommend further action to the Network or the NCI may take action independently. In cases of suspected fraud or other serious problems of compliance with regulatory requirements, the NCI may request formal investigation by the Office of Research Integrity, the Office for Protection from Research Risks, or the FDA. 9. Data and Safety Monitoring Committees. For randomized clinical trials, the NCI has required cooperative trials organizations to establish Data and Safety Monitoring Committees (DSMC) that are independent of study leadership, are clearly free of conflicts of interest, and have formally documented policies and procedures approved by NCI. The main objectives of the independent DSMC are to: Ensure that the patients in the trial are protected and that their interests are not made secondary to the interests of scientific investigation. 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. Ensure that the credibility of trial reports and ethics of trials conduct are above reproach with no actual or possible appearance of professional or financial conflicts of interest. Enable physicians entering patients to remain free of knowledge of interim efficacy and toxicity data. This permits physicians to continue to approach their patients honestly and avoids the need to modify informed consent based on statistically insignificant interim results. Enable study leadership to remain free of knowledge of (often unreliable) interim efficacy and toxicity data, so that they may deal honestly with their peers in encouraging them to enter patients in the study and so that they do not put themselves or the study at risk by inadvertently divulging interim results. SPECIAL REQUIREMENTS TERMS AND CONDITIONS OF AWARD These special Terms of Award are in addition to and not in lieu of otherwise applicable OMB administrative guidelines, HHS Grant Administration Regulations in CFR 45 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 (UO1), an "assistance" mechanism (rather than an "acquisition" mechanism) in which substantial NIH scientific and/or programmatic involvement with the awardee is anticipated during performance of the activity. Under the cooperative agreement, the NIH purpose is to support and/or stimulate the recipient's activity by involvement in and otherwise working jointly with the award recipient in a partner role, but it is not to assume direction, prime responsibility, or a dominant role in the activity. Consistent with this concept, the dominant role and prime responsibility for the activity resides with the awardee(s) for the project as a whole, although specific tasks and activities in carrying out the studies will be shared among the awardees and the NCI Program Staff. A. Awardee Rights and Responsibilities Certain of the awardee's generic programmatic responsibilities as an investigator for the conduct of the research supported by this RFA are described in two other NCI documents: (a) the Investigator's Handbook (a Manual for Participants in Clinical Trials of Investigational Agents Sponsored by the Division of Cancer Treatment, Diagnosis and Centers, National Cancer Institute); and (b) the "NCI-CTMB Guidelines." Specific portions of these documents, as enumerated in the following sections, are incorporated by reference as terms of award. These documents are available from the NCI upon request. Throughout these Terms and Conditions of Award "Participant" refers to all awardees as well as all institutions and/or individual investigators, both funded and unfunded, with whom they are participating or collaborating. 1. Development of Network Research Agenda and Protocols It is the responsibility of the Network to develop the details of the research design, including definition of objectives and approaches, the planning, implementation, and analysis of studies, and the publication of results, interpretations, and conclusions of studies. The Network shall, with NCI assistance, develop clinical protocols in accordance with the research interests, abilities, and goals of the Network. The Network leadership shall designate other Network investigators to serve as Protocol Chairperson for each proposed study. Protocols for DCTDC-sponsored investigational agents or devices will be developed in accordance with the instructions in the Investigator's Handbook. The Investigator's Handbook is a reference handbook for all investigators who use DCTDC- sponsored investigational agents in their clinical trials, irrespective of funding mechanism. The Investigator's Handbook describes, in accordance with NCI-FDA agreements: Requirements for Protocol Development and Submission Ordering Investigational Drugs from NCI Responsibility for Reporting of Results to NCI Adverse Event Procedures Accountability and Storage of Investigational Drugs Monitoring and Quality Assurance 2. Coordination and Internal Oversight of Network Activities In accordance with the Network constitution, bylaws, policies and procedures, the Network Headquarters (or BDMC as appropriate), under the leadership of the Network leadership and with NCI assistance, is responsible for coordinating protocol development, protocol submission, study conduct, quality control and study monitoring, drug ordering, data management, statistical analysis, protocol amendments/status changes, adherence to requirements regarding investigational drug management and federally mandated regulations, and protocol and performance reporting. All the scientific and administrative decisions related to the Network- funded activities will be coordinated by the Network leadership with the assistance of the staffs of the Headquarters and BDMC. The Network leadership or designee will be responsible for communication with the appropriate NCI staff. The Headquarters will establish policies and procedures for recruiting and credentialing participating sites. NCI will be notified of the sites participating in each protocol at the time of protocol submission to NCI either for review or for informational purposes (see under NCI Staff Responsibilities, Section 3: Review of Proposed Protocols). To ensure that the Network's scientific leadership and committee structure is adequately responsive to the most promising opportunties in the field, exhibits the desired degree of flexibility in composition and decision-making, and makes prioritization decisions free of conflicts of interest, the Network's organizational structure should include an advisory panel of experts not directly involved in the research activities of the Network. Appointment to this advisory panel will be by mutual agreement between the Network Chair and the Associate Director, DIP. 3. Protocol Submission Prior to protocol implementation, the Network Headquarters will submit protocols for review to the Protocol and Information Office, CTEP, NCI. Phase III protocols must be preceded by a concept- review letter describing the hypothesis to be investigated, the general design of the contemplated trial plus relevant information on accrual capabilities of the planned participating sites to document feasibility. For all non-Phase III trials that include a DCTDC investigational agent or device, a Letter of Intent (LOI) must be submitted to the Protocol and Information Office, CTEP. These two mechanisms for preliminary review are intended to expedite protocol development and implementation and to facilitate agreement on study priority and design (see Investigator's Handbook, pp. 32-35). The Network leadership, with the assistance of the Network Headquarters staff, will communicate the results of the NCI review of protocols to the participating investigators. 4. Network Compliance with Federally Mandated Regulatory Requirements The Network must be in compliance with all FDA regulatory requirements for studies involving investigational devices and agents and NIH policies applying to the conduct of research involving human subjects. These regulations include but are not limited to CFR 21 Parts 50, 56 and 312 and CFR 45 Part 46. Participants are required to follow established Network procedures for complying with the federally mandated regulations. a. The Network must be able to demonstrate that each participant has a current approved assurance number on file with OPRR. b. The Network must be able to demonstrate that each protocol, amendment, and informed consent document is approved by the responsible IRB prior to patient entry and at least annually thereafter, as appropriate for the degree of risk of the protocol, as stipulated by 45 CFR 46. Each investigator must have a current FDA Form 1572 and curriculum vitae on file with the Pharmaceutical Management Branch (PMB), CTEP. c. The Network must be able to demonstrate that each patient (or legal representative) gives written informed consent prior to entry on study. d. The Network must assure timely reporting of all serious and unexpected toxicities to NCI. e. The Network must establish and maintain an on-site audit program in compliance with the "NCI-CTMB Guidelines." f. The Network must have a method of providing, upon NCI request, summary efficacy and toxicity data to be included in DCTDC's Annual Report to the FDA for each investigational agent and device being developed under NCI sponsorship. g. The Network must implement NCI requirements for storage and accounting for investigational agents provided under DCTDC sponsorship. 5. Investigational Drug Management Investigators performing Network trials are expected, in cooperation with the NCI, to comply with all FDA monitoring and reporting requirements for investigational agents and devices. When new avenues of cancer diagnosis or therapy involving investigational drugs are pursued, the clinical information should be acceptable to the FDA for inclusion in an eventual licensing dossier for drugs, biologicals, or devices, as appropriate. 6. Quality Control and Study Monitoring a. The Network shall establish and implement mechanisms for quality control of therapeutic and diagnostic modalities employed in its trials. Participants are required to follow Network procedures for quality control. Quality control at a minimum should consist of: 1) Imaging Devices: Where appropriate, review (concurrent or retrospective) to assure accuracy of readings from the study sites; compliance with protocol-specified diagnostic parameters for individual patients; accuracy of device calibration across participating institutions. 2) Radiation therapy: Review (either concurrent or retrospective) of port films and compliance with protocol- specified doses for individual patients. Determination of adequacy of radiation delivery with assistance of the Radiological Physics Center (RPC), whose functions usually include equipment dosimetry, periodic institutional visits and other aspects of physics review. 3) Protocol-related Drug Administration: Review of flow sheets with determination of protocol compliance in dose administration and dosage modification. 4) Surgery: Assessment of adequacy of protocol-specified surgical procedures through review of operative notes and study-specific surgical forms. 5) Pathology: Verification of pathologic diagnosis in cases where known variability in the accuracy of histologic diagnosis is a potentially serious problem and where pathology data may provide important information relevant to the trial. b. The Network shall establish and implement mechanisms for study monitoring and quality assurance. Participants are required to follow Network procedures for study monitoring. The Network is responsible for assuring accurate and timely knowledge of the progress of each study through: 1) tracking and reporting of patient accrual and adherence to defined accrual goals; 2) ongoing assessment of case eligibility and evaluability; 3) timely medical review and assessment of patient data; 4) rapid reporting of treatment-related morbidity and measures to ensure communication of this information to all parties; 5) interim evaluation and consideration of measures of outcome as consistent with patient safety and good clinical trials practice; 6) timely communication of results of studies; and 7) an on-site monitoring program. The awardee is responsible for ensuring that all participating sites have routine audits in accordance with the "NCI-CTMB Guidelines" and that the results of audits are reported to the NCI in accordance with the guidelines. In the event that the NCI determines that the awardee failed to comply with these guidelines, the accrual of new patients to the Network's protocols at the affected site shall be suspended immediately upon notice of the NCI determination. The suspension will remain in effect until the awardee conducts the required audit and the audit report or remedial action is accepted by the NCI. The awardee will be responsible for notifying any affected site of the suspension. During the suspension period, no funds from this award may be provided to the site for new accruals, and no charges to the award for new accruals will be permitted. c. Quality Assurance and Quality Control of Data. The awardee must follow NCI-approved procedures developed by the Network for quality assurance of data collected by the Network and for the prevention and/or identification of false or otherwise unreliable data. The awardee must follow Network procedures for the assurance of data quality and quality control in accordance with Network guidelines and NCI policies. If there is any indication through the quality assurance and/or quality control programs, or through any other means, of a pattern of non-compliance with protocol or regulatory requirements or a finding of possible alteration of data, these findings must be reported in accordance with the "NCI-CTMB Guidelines." 7. Data Management The Network shall establish and implement mechanisms for data management that are: (a) adequate for quality control and analysis, and (b) as simple as possible in order to encourage maximum participation of physicians entering patients and to avoid unnecessary expenses. Participants are required to follow Network procedures for data management. 8. Data and Safety Monitoring Committees The Network must establish and maintain a Data and Safety Monitoring Committee (DSMC) for Phase III clinical trials. The policies and procedures of the DSMC must be approved by the Associate Director, DIP. The Network must comply with the approved policies and procedures of the DSMC. 9. Protocol Closure The Network shall establish and implement mechanisms for interim monitoring of results and monitoring protocol progress. If the Network wishes to close accrual to a study prior to meeting the initially established accrual goal, the interim results and other documentation should be made available to DIP staff for review and concurrence prior to implementation of the decision by the Network. It is recommended that statistical guidelines for early closure be presented as explicitly as possible in the protocol in order to facilitate these decisions. In the event that the DSMC has recommended early closure, DSMC procedures regarding notification of the Associate Director, DIP, must be followed. 10. Protocol Reporting Requirements Reporting requirements will be in agreement with FDA regulation and NCI procedures. NCI's procedures for data reporting from its clinical trials organizations are currently in evolution and will be provided to and discussed with the Network in detail at the inception of Network activities. Interim reports of each activated and ongoing study shall appear in the minutes of each Network meeting and shall include specific data on patient accrual as well as, when appropriate, detailed reports of treatment-associated morbidity. Quarterly accrual information must be provided by the Headquarters or BDMC as appropriate to the Program Director, DIP, for all active studies. A system for providing such information in a timely manner should be in place. Participants must provide accrual data to the Network in accordance with Network procedures. 11. Adverse Event Procedures In order to be in compliance with FDA regulations, all recipients of NCI support for clinical trials must promptly notify the NCI and any other sponsors of the trial of adverse events (i.e., adverse drug reactions) according to directions provided in the adverse event reporting section of the protocol. The awardee will notify all institutions/investigators participating in this project, funded or unfunded, about the above requirement and about the institutions'/ investigators' responsibility to report adverse events as specified in the protocol. The awardee will promptly notify the Program Director, DIP, of serious or life-threatening events, as instructed in the protocol. 12. Performance Review The Network shall establish and follow policies and procedures for credentialing participating institutions and conducting periodic review of the performance of each participating site. This review should examine patient accrual, data accuracy and timeliness, protocol compliance, long-term patient follow-up and audit results. The mechanism will include a procedure for the Network leadership to recommend an adjustment of funds within the Network as appropriate for the level of participation in Network activities, including (but not limited to) accrual. 13. Procedures in the Event of Scientific Misconduct If a duly authorized governmental or institutional body issues a final determination that scientific misconduct has occurred or if the awardee determines that other events have occurred which have significantly affected the quality or integrity of the Network data or patient safety, the awardee is responsible for notifying the Network's DSMC, the CTMB, the collaborating investigators, the appropriate IRBs, and other sponsors of the affected work. The awardee is also responsible, if the events described above have occurred, for ensuring that submitted but unpublished abstracts and manuscripts are corrected, if possible. If publication deadlines have passed or if abstracts and/or manuscripts containing the affected data have already been published, the awardee is responsible, within 90 days after learning of the event(s) significantly affecting the quality of the Network data or patient safety, for submitting to NCI a reanalysis of the results deleting the false or otherwise unreliable data, and disclosing within the text the reason(s) for the reanalysis. The awardee must submit the reanalysis for publication. The NCI may disseminate information about the reanalysis as broadly as it deems necessary. The awardee must use its best efforts to notify all scientists, research laboratories, and other organizations to which the awardee has sent research materials affected by false or otherwise unreliable data. True copies of data files and other supporting documentation from studies affected by scientific misconduct or other findings affecting the quality or integrity of data or patient safety shall be made available to the NCI in a timely manner upon the request of the Grants Management Officer, NCI. The NCI reserves the right to reanalyze, to publish, or to distribute its analyses of these data when it is in the interest of the public health. Prior to release, publication or distribution of such analyses, the NCI will provide such analyses to the awardee. 14. Data Files Available to NCI Upon Request Upon the request of the Grants Management Officer, NCI, true copies of data files and supporting documentation for all NCI- supported protocols that have a major impact on patterns of care, as determined by the NCI, shall be made available to the NCI in a timely manner. 15. Notification of Patients by the Awardee During Patient's Lifetime In order for there to be an appropriate response in the event the NCI determines, either while a protocol is active or (if relevant) during the lifetime of the subjects following protocol closure, that a medically important toxicity or side effect is associated with protocol-directed treatment or that the medical care of one or more subjects may have been compromised by scientific misconduct or other finding affecting the integrity of the data or patient safety at the awardee institution or at a third-party institution, funded or unfunded, the awardee shall assure that the institution(s) responsible for these subject(s') accrual, whether funded or unfunded, will have procedures in place to: a) contact each subject individually at his or her last known address on file with the institution and which give each subject contacted appropriate information and the right to communicate with an appropriate institutional representative and, in the event of misconduct, to meet with a physician not connected with the clinical trial or study in which the subject has participated, and b) encourage subjects to notify the institution of any changes of address. The procedure must provide for informing the subjects fully of the consequences of the toxicity or misconduct for their care and well-being, if any, and the availability of follow-up; and their opportunity to examine any portion of their medical records relevant to the potential effect of the toxicity or side effect upon them or that may be affected by scientific misconduct or other findings affecting the quality or integrity of the data or patient safety. Under regulations in CFR 45 Part 74.53, NCI has right of access to research records pertinent to studies conducted with NCI funding. In exceptional circumstances, such as a public health emergency, institutions may be required to provide subject names and treatments to the NCI in a format which allows direct notification of the patient by the NCI. 16. Collaboration with Device or Drug Manufacturers Joint projects and cost-sharing arrangements with industry are encouraged. Companies are expected to be a major source of technological innovation, and certain of its products are likely to be of great interest to the Network. These arrangements will be worked out on a case-by-case basis by the Network leadership and collaborating companies. The arrangement will in all cases conform to PHS regulations and any applicable NCI policies on interactions among industry, NCI-supported cooperative trials networks, and NCI. In all cases details of any financial or other arrangements between the Network and industrial companies will be available to NCI staff on request. 17. Progress Reporting Annual progress reports will be submitted to the DIP, NCI in accordance with guidelines provided by the NCI Program Director. B. NCI Staff Responsibilities The role of NCI staff as described throughout these terms and conditions of award is to assist and facilitate, but not to direct, research activities. This cooperative agreement is part of a larger program of cooperative clinical trials in the NCI. 1. NCI Staff Interactions. Because of the Network's diverse research agenda and the number of tasks that have to be accomplished for the Network to realize its goals, a number of NCI staff members from several organizational units must interact with the Network. The NCI Program Director (a staff member of the Diagnostic Imaging Program (DIP)), the Associate Director for the DIP, and staff members of the three branches of the DIP (the Functional Imaging Branch, the Image- Guided Diagnosis and Therapy Branch, and the Imaging Diagnosis Branch) will assist the Network as appropriate in developing information concerning the scientific basis for specific trials and also will be responsible for advising the Network of the nature and results of relevant trials being carried out by other organizations and potential studies relevant to new avenues of imaging diagnosis and image-guided therapy. From the Cancer Therapy Evaluation Program, DCTDC, the staff of the Pharmaceutical Management Branch will assist the Network in the ordering and management of investigational drugs; the Regulatory Affairs Branch will assist in assuring that Network activities are in conformity with federal regulations concerning the use of investigational devices and medicinal agents; the Biometric Research Branch will consult with the Network as needed in connection with biostatistics and issues of clinical trials design; staff of the Investigational Drug Branch (CTEP) and the Imaging Diagnosis Branch (DIP) will provide updated information on the efficacy and toxicity of investigational drugs or devices supplied to Network members under an Investigational New Drug (IND) Application or an Investigational Device Exemption (IDE) sponsored by DCTDC, NCI; staff of the Clinical Investigations Branch will assist the Network, as needed, in establishing liaisons with other clinical cooperative groups and in protocol-related and medical matters relating to the diseases under study. The Clinical Trials Monitoring Branch (CTMB) will oversee implementation of the Network's quality assurance and site visit monitoring program. The CTEP Protocol Review Committee, supplemented by members of the DIP, is the NCI body that will perform formal protocol reviews of submitted protocols of the Network. From the Radiation Research Program, staff will interact with the Network for studies involving image-guided delivery of therapeutic radiation. The DIP Program Director will provide the awardees with a comprehensive list of the NCI staff who will be involved, and the responsibilities of each NCI staff member. 2. Protocol Development A protocol is the detailed written plan of a clinical experiment. The protocol must be mutually acceptable to the Network and to the NCI. Communication with relevant NCI staff, as outlined in #1 above, at the various stages of protocol development is encouraged. NCI staff from the several organizational units outlined above will assist the Network in protocol design, as may be appropriate, by providing information regarding: (a) the existence and nature of concurrent clinical trials in the area of research, pointing out possible duplication of effort; (b) comments on proposed trial designs; and (c) relevant pharmacokinetic and pharmacodynamic data on investigational agents proposed for study. For proposed large multi-center trials, staff of the DIP and CTEP will provide the Network a formal review of concepts for protocols, commenting on study originality and scientific and medical impact. These two mechanisms for preliminary review are intended to expedite protocol development and implementation and to facilitate agreement on study priority and design (see the "Investigator's Handbook," pp 32-35). 3. Review of Proposed Protocols Network protocols will be reviewed by the CTEP Protocol Review Committee (PRC), augmented by staff of the Diagnostic Imaging Program, meeting at regular intervals for this purpose. Ad hocreviewers, external to NCI, will be utilized when deemed appropriate by the committee chairperson. Formal protocol review and NCI approval prior to activation are required for the following types of studies: (a) all protocols utilizing NCI resources and investigational agents regardless of IND or IDE sponsor; (b) all protocols that permit entry of 100 or more patients; and (c) all Phase III protocols. Other protocols will be filed with NCI for information purposes but will not require NCI approval. Advisory reviews of such protocols may be provided to the Network at NCI's discretion. For all protocols that require review, the Associate Director for the DIP will provide the Network with the Protocol Review Committee's consensus review that describes recommended modifications and other suggestions, as appropriate. The major considerations relevant to protocol review by the PRC include: (a) the strength of the scientific rationale supporting the study, (b) the medical importance of the question being posed, (c) the avoidance of undesirable duplication with other ongoing studies, (d) the appropriateness of study design including interim monitoring plans if appropriate, (e) a satisfactory projected accrual rate and follow-up period, (f) patient safety, (g) compliance with federal regulatory requirements, (h) adequacy of data management, (i) appropriateness of patient selection, evaluation, assessment of toxicity, response to therapy and follow-up. If a proposed protocol is disapproved, the specific reasons will be communicated to the Network chairperson as a consensus review within 30 days of protocol receipt by the Protocol and Information Office (PIO), CTEP. NCI will not provide investigational drugs or permit expenditure of NCI funds for a protocol that it has not approved. The Program Director and other DIP staff will be available to assist the Network in developing a mutually acceptable protocol, consistent with the research interests, abilities and strategic plans of the Network and of the NCI. 4. Review of Quality Control and Study Monitoring Staff of the Clinical Trials Monitoring Branch (CTMB) will review and provide advice regarding mechanisms established by the Network for quality control of therapeutic and diagnostic modalities employed in its trials. CTMB staff will review and approve the mechanisms established by the Network for study monitoring including the Network's on-site auditing program. Staff of CTMB, DIP, and/or the monitoring contractor may attend as observers the on-site audits conducted by the Network; the frequency of observer participation by NCI staff will be determined by the CTMB. 5. Review of Data Management Staff of the Biometric Research Branch (BRB) will review mechanisms established by the Network for data management. When deemed appropriate, staff will make recommendations to ensure that data collection and management procedures are: (a) adequate for quality control and analysis; (b) as simple as appropriate in order to encourage maximum participation of physicians entering patients and to avoid unnecessary expense; and (c) generally compatible with the standard formats for electronic data reporting to NCI. The NCI will have access to all data although they remain the property of the awardee institution. Data must also be available for external monitoring as required by NCI's agreement with the FDA relative to the NCI's responsibility as a sponsor of research with investigational drugs and devices. 6. Data and Safety Monitoring Committees The NCI Program Director, assisted by BRB staff, will assess Network compliance with NCI-established policies on Data and Safety Monitoring Committees (DSMCs) for multi-center Phase III trials. One or more NCI staff members will serve as non-voting members on the DSMC. 7. Protocol Closure The Associate Director, Diagnostic Imaging Program (DIP), may request that a Phase I or Phase II protocol study be closed to accrual for reasons including: (a) insufficient accrual rate; (b) poor protocol performance; (c) patient safety; (d) study results are already conclusive; and (e) emergence of new information that diminishes the scientific importance of the study question. The NCI will not provide investigational agents or permit expenditures of NCI funds for a Phase I or Phase II study after requesting closure, except for patients already on treatment and follow-up. The Associate Director, DIP, may request that the Network DSMC consider closing a Phase III protocol to accrual for reasons including: (a) insufficient accrual rate; (b) poor protocol performance: (c) patient safety; (d) study results are already conclusive; and (e) emergence of new information that diminishes the scientific importance of the study question. Any disagreement between NCI and the DSMC about protocol closure that cannot be resolved by discussion will be brought to Arbitration as outlined later under "Collaborative Responsibilities," except that the nominating parties will be the Associate Director, DIP, and the Chair of the DSMC. NCI will not provide investigational agents or permit expenditures of NCI funds for a Phase III study that has been closed, except for patients already on treatment or in follow- up. 8. Involvement in Investigational Drug and Device Management The NCI will have the option to cross file or independently file an IND on investigational agents evaluated in trials supported under cooperative agreements. This applies to drugs not developed in the NCI drug development program. In the case of investigational devices, the NCI, Network investigators, and the device supplier will decide collaboratively which organization will hold the IDE. The NCI Program Director, assisted by the staff of the Regulatory Affairs Branch (RAB) and the Pharmaceutical Management Branch (PMB), will advise investigators of specific requirements and changes in requirements concerning investigational drug or device management that the Food and Drug Administration (FDA) may mandate. 9. Review of Compliance with Federal Regulations CTMB and RAB staff will review and advise regarding mechanisms established by the Network to meet regulatory requirements of the FDA for studies involving NCI-sponsored investigational agents and devices, and those of the Office for Protection from Research Risks (OPRR) for the protection of human subjects. 10. NCI Attendance at Network Meetings NCI staff, as designated by the NCI Program Director, will attend the regular Network meetings and will be invited as a non-voting observer to Network leadership meetings. 11. Facilitating Collaboration with other Cooperative Groups NCI staff will take an active role in promoting the timely completion of important studies, for example by encouraging and facilitating intergroup collaboration when appropriate, or by assisting in the identification and mobilization of additional resources. C. Collaborative Responsibilities 1. Development of Intergroup Activities For certain types of scientific questions, particularly those involving the integration of imaging with therapeutic maneuvers, it may be desirable for the Network to seek collaboration with one or more of NCI's treatment cooperative groups. Establishment of these collaborations may be initiated by the investigators or NCI staff. From time to time the NCI holds disease- or modality- oriented strategy meetings for the purpose of jointly developing program priorities for future protocol development. Group investigators, NCI staff and other extramural investigators attend these meetings. The groups and NCI staff work together to facilitate the timely development of protocols resulting from the consensus developed at such strategy meetings. Investigators of the Imaging Network will be invited to attend these meetings as appropriate. 2. Investigational Drug and Device Development When trials of new imaging diagnostic or therapeutic approaches involving investigational drugs or devices are pursued, the clinical information resulting from them should be acceptable to the FDA for inclusion in a New Drug Application (NDA) or Product Manufacturing Application (PMA). In partnership with NCI staff and any collaborating drug or device company, the Network will develop protocols to obtain such information as needed. 3. Data and Safety Monitoring Committees (DSMC) Appropriate policies and procedures for the DSMC are a collaborative responsibility of the Network and NCI staff. 4. Cooperative Group Chairs' Semi-Annual Meetings The Chairs of each of NCI's treatment cooperative groups meet semi-annually to discuss issues of relevance to the clinical trials program. The Chair of the Network will be invited to attend this meeting, as many of the issues discussed are relevant to the activities of the Network. 5. Cooperative Group Statisticians' Meeting Similarly, the Network's Chief Statistician will be invited to attend the annual group statisticians' meeting to discuss issues of relevance to the clinical trials program. D. Arbitration Any disagreement that may arise on scientific/programmatic matters (within the scope of the award), between award recipients and the NCI may be brought to arbitration. An arbitration panel composed of one Network nominee, one NCI nominee, and a nominee 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 Director, DCTDC. The arbitration procedures in no way affect the awardee's right to appeal an adverse determination under the terms of 42 CFR Part 50, Subpart D, and 45 CFR Part 16. The Network will not expend NCI funds to conduct any study disapproved by NCI unless the disapproval has been overturned by the arbitration process outlined above. INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of the NIH that women and members of minority groups and their subpopulations must be included in all NIH- supported biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification are provided that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. The new policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43) and supersedes and strengthens the previous policies (Concerning the Inclusion of Women in Study Populations and Concerning the Inclusion of Minorities in Study Populations), which have been in effect since 1990. The new policy contains some provisions that are substantially different from the 1990 policies. All investigators proposing research involving human subjects should read the "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research," which was reprinted in the Federal Register of March 28, 1994 (59 FR 14508-14513) to correct typesetting errors in the earlier publication, and reprinted in the NIH Guide for Grants and Contracts, Volume 23, Number 11, March 18, 1994. Investigators also may obtain copies of the policy from the program staff listed under INQUIRIES. Program staff may also provide additional relevant information concerning the policy. LETTER OF INTENT Prospective applicants for this RFA are requested to submit by 11/18/97 a letter of intent that includes a descriptive title of the proposed research, the name, address, and telephone number of the Principal Investigator, the identities of other key personnel and participating institutions, and the number and title of the RFA in response to which the application may be submitted. Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows NCI staff to estimate the potential review workload and avoid conflict of interest in the review. The letter of intent is to be sent to: Anne Menkens, PhD Diagnostic Imaging Program National Cancer Institute Executive Plaza North, Room 800 6130 Executive Boulevard Bethesda, MD 20892 Rockville, MD 20852 (if using express mail) Telephone 301-496-9531 FAX 301-480-5785 e-mail [email protected] APPLICATION PROCEDURES The research grant application form PHS-398 (revised 5/95) is to be used in applying for these grants. These forms are available at most institutional offices of sponsored research; from the Grants Information Office, Extramural Outreach and Information Resources, NIH, 6701 Rockledge Drive, MSC-7910, Bethesda, MD 20892-7910. Telephone 301-710-0267. E-mail address is [email protected]. The RFA label available in the PHS-398 (revised 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 2a of the face page of the application form and the YES box must be marked. Submit a signed, typewritten original of the application, including the Checklist and three signed photocopies, in one package to: Division of Research Grants National Institutes of Health 6701 Rockledge Drive, MSC-7710 Bethesda, MD 20892-7710 Bethesda, MD 20817 (for express mail) At the time of submission, two additional copies and all appendix material must also be sent to: Ms. Toby Friedberg Division of Extramural Activities National Cancer Institute Executive Plaza North Building, Room 636 6130 Executive Boulevard Bethesda, MD 20892 Rockville, MD 20852 (for express mail) It is important to send these additional copies to NCI at the time of submission to DRG; otherwise the NCI cannot guarantee that the application will be reviewed in competition with the other applications received on or before the designated receipt dates. Applications must be received by 2/18/98. 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. SPECIAL INSTRUCTIONS FOR PREPARATION OF THE APPLICATION Application Preparation All applications must be submitted on the form PHS-398 (rev. 5/95). Successful applications for each Network component will be awarded as separate cooperative agreements to the sponsoring institutions and will include the Terms and Conditions of Award specified in this RFA. Each individual application must contain a detailed budget for the first 12-month period and a budget for the entire proposed project period for direct costs. All applications should describe the scientific and administrative experience of key personnel and should include and follow the PHS-398 form instructions for Biographical Sketches and Other Support information. On Page 2 of the PHS-398 form, in the section entitled "Personnel Engaged on Project," it is imperative that all applicants list all individuals and their institutions participating in the scientific execution of the project in the format as specified including those with no requested salary support. All applicants must ensure that the list is complete using as many continuation pages as necessary. A key feature of this RFA is that it requires the Headquarters application, submitted by the Network Chair, to list the BDMC with which it is affiliated. The BDMC application, submitted by the Chief Statistician, must also identify the Headquarters with which it is affiliated. The specific application requirements are listed below for each component: Headquarters The Network's proposed program of clinical trials should be described in the application for support of its Headquarters. The application should characterize the Network's mission, its plans to accomplish that mission, and present evidence of research accomplishments by the Network's scientific leadership. It should specify the concrete research proposals of the Network, including protocols for the initial studies the Network proposes to undertake. It should outline the Network's strategy for each class or category of investigation, including rationale and future plans; a clear sense of direction should be evident. In addition to its scientific proposals, the Headquarters application should contain a description of the Network's organizational structure, and the operational procedures and policies to accomplish major Network objectives and responsibilities. RESEARCH PLAN FOR HEADQUARTERS The following format is suggested for completing the "Research Plan" section (see pages 19 through 23 of the PHS 398 application brochure). The "Research Plan" section is not subject to the page limitations as stated in the form PHS 398. However, the suggested format and page recommendations are noted below. The application should be as concise as possible to ensure a thorough review. 1. Major Research Objectives (20 pages) This section should concisely describe the Network's several major research objectives. This section should include plans for the inclusion of women and minorities as research subjects in Network studies. 2. Organizational Structure (20 pages, including any organizational charts) This should include a clear description of the formal organizational structure of the Network, including lines of authority and responsibility, with particular attention to the relationship of the organizational structure to the Network's major objectives. The organizational structure will include a number of scientific and administrative committees, in addition to the two major functional components (Headquarters and BDMC). The committees will have various research, quality control, and administrative mandates. Plans for interaction of the organizational elements should be described clearly. The proposed members of the Network's leadership should be named, along with their subspecialty affiliations. Procedures for the selection of Network leadership, for selecting and credentialing participating sites, and for review of their performance should be described. 3. Research Strategies and the Scientific Committees (10 pages each) The Network's scientific leadership must articulate plans that summarize its specific objectives and lines of investigation in each area chosen for study. For each scientific committee, the application should: a. Briefly describe the major scientific goals, strategies, and broad research areas that the committee will be concerned with. b. Identify the specific research questions that the committee plans to address. Summaries of protocols representing the initial studies of each committee should be provided within the body of the application; samples of the full protocols are to be included as an "Appendix" 4. Developmental Fund (15 pages) Justification and plans for the use of Developmental Funds should be carefully described, including the procedures the Network will use for allocating these funds to areas of particular opportunity during the period of support. 5. Quality Control and On-Site Auditing (5 pages) If responsibility for quality control and on-site auditing will reside in the Headquarters, these functions should be described in detail here, along with the associated budget request. If they are to reside in the BDMC, they should be described in the BDMC application; in that case, the Headquarters application should indicate how the operational leadership of the Network, located in the Headquarters, plans to deal with results of audits that indicate the need for corrective action. There should be clear evidence of close collaboration between the two organizational units. 6. Network Administration (5 pages) This section should address the major roles and responsibilities of the Network administrative staff together with other matters of relevance to the management of the Network. It should describe a system to ensure capable, efficient, and responsible management by the Network's leadership, as well as ways to identify and solve problems. Applications should clearly document that the proposed Network Chair has the appropriate experience to qualify as the Network's leader. 7. Data and Safety Monitoring Committees (DSMC) (5 pages) The application should describe the Network policies and procedures regarding DSMCs. It should include proposed membership rosters of the committee(s), and procedures for avoiding conflicts of interest, such as financial disclosure. 8. Group Policies and Procedures (5 pages) The application should describe Network policies regarding conflict-of-interest issues, the training of the Network investigators, nurses and data managers/clinical research associates regarding ethics in the conduct of clinical research, and procedures in the event of scientific misconduct. The application should document any ongoing ethics training of Network participants, collection of conflict-of-interest statements from relevant members, and other efforts to employ these policies. BUDGET FOR HEADQUARTERS The Headquarters budget should be presented in logical, discrete units, with specific budgets for each unit as well as the composite Headquarters request. The standard PHS-398 form pages 4-5 are to be completed for each unit, with additional pages for budget justification to be used when necessary. A separate budget page and item entitled "Developmental Fund" may be included. The purpose is to provide the Network leadership with resources to support new initiatives and special high-priority projects. The first year's plans for this Developmental Fund must be carefully justified, and the Network's process for allocating the funds in subsequent years clearly described. The following budget guidelines apply specifically to the Headquarters and BDMC budgets; the categories refer to the item entitled "Detailed Budget for Initial Budget Period" on (Page 4) on the PHS Form 398 grant application kit. 1. Personnel Precise justification for the amount of effort requested for each position is essential. a. Scientific - research costs include the time and effort involved in developing the research agenda and repertoire of protocols for the Network, and analysis and publication of the results of Network research in peer-reviewed journals. Costs for the operation of scientific committees, where much of this work goes on, is permitted. These committees will be associated with specific areas of investigation described in the Headquarters application and will have responsibility for overseeing the development of research plans and specific studies for these areas. The budget justification in support of each scientific committee should be linked to their scientific activities. Peer review of the science of these committees will assist the Network leadership in prioritizing its research agenda and allocating its resouces. b. Data Management - research costs include the time and effort involved in the central collection, computerization and analysis of primary patient data; determination of eligibility; registration and randomization; forms development; etc. c. Laboratory Investigations - research costs include the time and effort related to additional laboratory investigations specific to the research goals of the project, i.e., not associated with conventional patient care. d. Administrative - research costs include the time and effort involved in the overall management of the Network's resources, compliance with regulatory activities, quality assurance and study monitoring procedures. 2. Consultant Costs Reasonable consultant costs are allowed, if the consultant is contributing directly to the conduct or development of Network research. Most of a Network's consultant costs should appear in the Headquarters budget. Clear and quantifiable justification is required. These costs include travel, per diem, and consultant fees, if applicable and within institutional policy. 3. Office Equipment Justification should include percent of time used for Network business as well as necessity for purchase. The amount of funds requested should be based on the percent of usage. Include only those equipment items that are required to conduct Network protocols. 4. Supplies Research costs include those related to communication and information dissemination among Network participants. Quantitative justifications based on actual use should be provided. 5. Travel The importance of meetings to the accomplishments of the Network's research objectives is obvious, as is the necessity to maintain careful control of the size of this budget item. The budget for travel must be itemized and justified. It should include: trips by the Network's leadership and investigators on behalf of the Network to the NCI and other national organizations where the results of the Network research must be represented or where Network research strategies are to be discussed; travel for committee members to committee meetings held separately from regular Network meetings; travel for persons on the Headquarters staff who must attend the Network's regular meetings; a reasonable number of carefully justified trips for potential Network participants to attend the semi-annual meetings, in order to encourage participation and assure input from important segments of the imaging research community and potential collaborators (see above regarding Developmental Fund). 6. Alterations and Renovations These costs are not allowable. 7. Other Expenses Research costs include those relating to communication and information dissemination among Network members. Include here costs of equipment rental and maintenance (copiers, telephones, computers), postage, copying and printing, etc., justified quantitatively on the basis of previous experience, where relevant. 8. Consortium/Contractual Costs Research costs include support to Network members who are responsible for committees or laboratory investigations, for the research costs related to approved clinical trials activities, or for patient accrual. These third-party costs may be presented as consortium arrangements (for substantive programmatic work), as subcontracts, or as reimbursements based on formulas. If third-party costs are requested for consortium/contractual participants, a separate detailed budget page, with appropriate justification, must be provided for each arrangement. Indirect costs to consortium/contractual participants are included in the direct-cost level for the Headquarters. Networks are encouraged to structure their organization in a manner which minimizes the burden of indirect costs on the overall Network budget. Reimbursement for patient accrual is to be based on formulas that should relate to reasonable average costs incurred by participant institutions, as well as prior performance, including accrual adequacy and assessment of data accuracy and timeliness. A description of how the formula was determined, including a line- item budget breakdown of the research costs, must be included in the application. In addition, the application should include a plan for disbursement of funds that includes consideration of performance and quality factors including eligibility and evaluability rates; data accuracy and completeness; and quality of on-site audits, etc. The funds received by participating sites for patient accrual should be subject to modification based on results of the Network's performance reviews. These costs should be included in the consortium/contractual costs category of the Headquarters budget. Consortium arrangements and all other contractual arrangements, including all mechanisms for reimbursement for patient accrual, must be formalized in writing in accordance with applicable Public Health Service policy requirements (PHS Grants Policy Statement, revised 9/94, Page 8-17). A statement that the applicant organization and the collaborating organization have established or are prepared to establish a formalized agreement that will ensure compliance with all pertinent federal regulations and policies must be included in the application. Also include all pertinent biographical sketches and a list of all other support for all relevant consortium participants. Biostatistics and Data Management Center The BDMC is funded through a separate cooperative agreement. Thus, a separate application is required which should address operational roles and responsibilities discussed under "Research Objectives," (B) Organization. It should describe in detail the Network's data management practices and procedures, its quality control and study monitoring methodology, and its analytical techniques and resources. RESEARCH PLAN FOR BDMC The following format is suggested for completing the "Research Plan" section (see pages 19 through 23 of the PHS 398 application brochure). The "Research Plan" section is not subject to the page limitations as stated in the form PHS 398, but is limited to 50 pages total. The application should be as concise as possible to ensure a thorough review. Wherever appropriate, narrative should supplement (rather than duplicate or replace) standard manuals, which should be supplied. 1. Roles and Responsibilities - List the major objectives of the Network's BDMC. 2. Organization and Facilities - Describe the organization and facilities to accomplish the complex tasks of central data management, quality control, study monitoring, and data analysis. 3. Data Management Policies and Practices - Describe the flow of data following submission from the individual investigators. 4. Quality Control - Describe procedures for quality control and accuracy verification. 5. Study Monitoring Procedures - Describe the Network's standard methods for ongoing study monitoring, including interactions with study chairs. 6. Study Design and Data Analysis - Describe the Network's routine methodologic practices (e.g., methods of sample size calculations, choice of testing and estimation procedures, interim analysis policies, early stopping procedures, etc.) Include plans for the inclusion of women and minorities as research subjects in Network studies. 7. Partnership in Network Research - Describe the role and contributions of the Network's statisticians to Network research. The involvement of statisticians in designing studies should be documented. 8. Independent Research - Describe research being conducted by the statistical office of the Network using Network resources, including the data base. BUDGET FOR BDMC See budget guidelines in this RFA referring to the Headquarters. The statistical and data management center budget should be presented in logical, discrete units with specific budgets for each unit as well as the total Center's request. The standard PHS-398 form pages 4-5 are to be completed for each unit, with additional pages for budget justification to be used when necessary. Quality Assurance and Quality Control Programs This section should be located within the Application of the organization (Headquarters or BDMC) that will bear responsibility for the function. The section (to be included in the "Research Plan", and limited to pages) should describe procedures for data verification. In accordance with the "NCI-CTMB Guidelines," the Network is required to conduct routine on-site audits of participants in NCI-supported clinical trials. Describe the method by which the Network will structure and execute this program in conformance with NCI's guidelines. Also, describe the interactions that will occur with NCI. As with other parts of the Applications, the Budget should be presented in logical, discrete units with specific budgets for each requested element. Personnel, travel expenses, and computer systems to accomplish these tasks must be carefully and fully documented. Budgets should include travel for protocol chairs and others who must perform quality control functions away from their home institution and travel for the on-site audit program. A separate budget for each function should be prepared. REVIEW CONSIDERATIONS AND CRITERIA Upon receipt, applications will be reviewed for completeness by DRG and for responsiveness by the NCI. Incomplete and non- responsive applications will be returned to the applicant without further consideration. Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer- review group convened by the NCI in accordance with the review criteria stated below. The peer review process may include a site visit to Network facilities. The Scientific Review Administrator is responsible for all aspects of the peer-review process, and, if a site visit is warranted, will negotiate with the Network chairperson the date, duration, and content of the site visit. Because of their interrelatedness, applications from both components of the Network are prepared and submitted simultaneously. For each pair of applications, the content of the Headquarters application is evaluated first. If the initial review committee recommends the Headquarters application for further consideration, the committee then assigns a priority score representing the overall peer-review evaluation of the Network and recommends a period of award (generally three to five years). The committee then evaluates the application of the corresponding BDMC. The committee also develops budgetary recommendations for each scored application. If a particular Headquarters application is not recommended for further consideration (NRFC), the application of the corresponding BDMC is not reviewed and that particular pair of applications cannot be funded. The review criteria employed by the site visit team and the initial peer-review committee for each operational component are summarized below. Headquarters 1. Merit of Specific Research Plans - How meritorious are the research plans, strategies, and protocols for each of the major areas of study? Do they take maximum advantage of contemporary scientific opportunities? Do they contain an appropriate balance of innovative pilot studies and larger multicenter comparative trials? Are there adequate plans in place for flexibly capitalizing on new scientific opportunities as they arise? 2. Overall Network Priorities - Does the Network have appropriate and effective processes in place for setting scientific priorities? Are the overall priorities of the Network appropriate? Are its resources well directed? 3. Key Personnel - Do the research experience and qualifications of the Principal Investigator demonstrate understanding of the imaging sciences, of the design, administration, and analysis of multi-institutional clinical trials, and of relevant laboratory studies? 4. Research Methodology - How well designed are the Network's planned clinical trials? Will their design allow clinically important conclusions to be drawn? 5. Patient Accrual - Is the participant membership of the Network adequate to support the carrying out of the Network's scientific agenda in a timely manner? 6.Timeliness of Study Completion - Will the Network be able to carry out its planned studies in a reasonable period of time? Will intergroup collaboration be utilized when necessary to satisfy the requirements for timely completion? 7. Efficiency of Study Development - Will the process of study development proceed in an efficient and timely manner? Do mechanisms exist to ensure the rapid development and implementation of important studies? 8. Developmental Fund Plans - Are plans for the use of any developmental funds appropriate and consistent with the Network's overall goals and priorities? Will the fund be well managed with appropriate oversight? 9. Network Structure and Administration - Will the Network be well administered by the Chair and the Headquarters staff? Do its organization and infrastructure allow it to meet its major objectives and goals? 10. Publication Plans - Has the Network developed plans that will encourage and permit timely publication of research in quality peer-reviewed journals? 11. Network Cohesion - Are the Network's organizational and administrative plans likely to lead to a well functioning, cohesive research group? Will the Network function as a cohesive research team? 12. Interdisciplinary Coordination and Collaboration - Will there be adequate interdisciplinary participation in protocol development and design? Do protocol investigators reflect the modalities utilized? Are there adequate plans for collaboration and interaction with other clinical trials organizations and with industrial sources of scientific and technological expertise? 13. Participants - Are the criteria for initial and continuing participation in Network studies adequate? Do the Network's periodic evaluations of its participants emphasize both high-quality recordkeeping and adequate patient accrual? 14. Patient Advocate Participation - Are there defined plans and roles for patient advocates in the Network? Have they been included in the budget to attend Network meetings? 15. Adequacy of Plans for Recruitment of Special Populations - Do plans include both genders and minorities and relevant subgroups as appropriate for the scientific goals of the research? Are federal guidelines for the inclusion of women and minorities as research subject being followed? Are there strategies outlined to increase accrual of women and minorities to clinical trials? Plans for the recruitment and retention of subjects will also be evaluated. 16. Facilities - Are the offices, computer support systems, and overall patient-facility commitments adequate to ensure a smoothly functioning Headquarters? Are there any problems with the structural layout that might serve as an impediment to a focused and well-coordinated Headquarters? 17. Staff - Are the roles of the Headquarters staff adequately defined to accomplish the goals of the Network? Is there an adequately committed staff to cover the multiple tasks of the Headquarters? 18. Budget - Have costs for travel, office supplies, equipment and data management been adequately justified? Are detailed costs of participants provided? Are budgetary plans submitted for Network meetings and consultant fees? 19. Advisory Panel - Are there processes or structures in place to ensure that the decision-making and priority-setting of the Network is likely to be flexible and free of conflicts of interest? 20. Protection of Human Subjects - Are suitable procedures in place to assure the protection of research subjects in accordance with applicable federal regulations? Biostatistics and Data Management Center This portion of the evaluation involves two facets: 1) the performance and capabilities of the BDMC; 2) the Network's integration of BDMC roles and responsibilities into the overall research program. 1. Collaboration in Research - Will there be adequate statistical and data management collaboration in the development and conduct of the Network's research? 2. Adequacy of Study Design - Is there evidence that the protocols will be properly designed statistically? Will the sample sizes be adequate to detect realistic and medically important differences? Will the assumptions be adequately justified? Is the expected accrual rate carefully estimated? Are the designs used appropriate for the study questions? Are endpoint selections and sequential monitoring plans adequately described and justified? 3. Data Management - Are data management procedures adequate, appropriate, and consistent with accepted standards? Are procedures for the verification of data accuracy adequate? Is there clinical review of study data? 4. Statistical Analyses - Are analytical techniques, procedures, and policies adequate, appropriate, and consistent with accepted standards? Is there evidence that past publications of the Network leadership demonstrate thorough and state-of-the-art methodology, awareness of problems of multiple analyses, and sufficient independence and lack of bias of statistical collaborators? 5. Key Personnel - Does the research experience and qualifications of the Principal Investigator demonstrate understanding of design, administration, and analysis of multi-institutional clinical trials in imaging? 6. Independent Research - Is there evidence of innovation in the development of novel designs and analytical approaches relevant to imaging studies? 7. Computing Resources - Are computing resources adequate and appropriate to support Network activities? 8. Facilities - Are the offices, computer hardware, and overall parent facility commitment adequate to assure smooth and efficient function? Are there deficiencies in the structural layout which might serve as an impediment to coordination of Network research efforts? 9. Staff - Are the roles of the staff adequately defined to accomplish the goals of the Network? Is there an adequate number of personnel to meet the assigned tasks? Quality Assurance and Quality Control Programs These criteria should be applied to the QA/QC section of whichever application (Headquarters or BDMC) it is included in. 1. Do appropriate quality-assurance and quality-control programs exist, including on-site audits that assure high-quality research and patient safety? 2. Have costs for the on-site audit plan been accurately detailed? Is there sufficient funding allotted to carry out the multiple quality- control tasks required? NETWORK CONSTITUTION AND BYLAWS The proposed Network Constitution and Bylaws and the Network's Policies and Procedures must be reviewed and approved by the Associate Director, DIP. This document is not to be submitted with the application, but must be submitted and approved before an award can be made by NCI. AWARD CRITERIA AND DATE Applications recommended by the National Cancer Advisory Board will be considered for award based upon (a) technical merit of the application as reflected in the priority score, (b) availability of resources and study population, and (c) availability of funds. Furthermore, the applicant organization must indicate a commitment to accept provisions outlined under the Terms and Conditions of Award. The anticipated date of award is December, 1998. EVALUATION OF THIS INITIATIVE The organizational structure and broad functional parameters stipulated for the Network by this RFA are certainly not the only ways to support a national clinical trials program in imaging. Before deciding whether this initiative should be reissued, therefore, the NCI wishes to have an assessment of the effectiveness of this mechanism over the first few years of its operation. Accordingly, approximately 3 1/2 years following the first-year award date (in the event of five-year awards), the leadership of the Network and the staff of NCI's Diagnostic Imaging Program will present an assessment of the Network's achievements to the NCI's Board of Scientific Advisors (BSA). The BSA will pay particular attention to the following aspects of Network functioning: Has the research agenda of of the Network taken appropriate advantage of available scientific opportunity? Are the Network's processes for decision-making, scientific prioritization, protocol generation, and study activation effective and efficient? Has the Network accrued to activated studies with appropriate speed? In comparison with the experience in past years, has there been a greater variety of clinical approaches tested and a more satisfactory translational research thrust in clinical imaging since the implementation of this initiative? Is the nature of the Network's scientific agenda and activities sufficiently productive to suggest that imaging technology assessment is best served by continuing an activity of this kind, or can the necessary work be accomplished better or more efficiently by other means? On the basis of its evaluation the BSA will advise the NCI on whether the initiative should be continued and recompeted after the first project period is completed. Note that this assessment is entirely separate from the formal peer-review process by which any applications in response to a reissued RFA will be evaluated. INQUIRIES Written and telephone inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding scientific and/or administrative issues to: Anne Menkens, PhD Diagnostic Imaging Program National Cancer Institute Executive Plaza North, Room 800 6130 Executive Boulevard Bethesda, MD 20892 Rockville, MD 20852 (if using express mail) Telephone FAX e-mail [email protected] Direct inquiries regarding fiscal matters to: Ms. Crystal Wolfrey Grants Administration Branch National Cancer Institute Executive Plaza South, Room 243 6120 Executive Boulevard Bethesda, MD 20892 Rockville, MD 20852 (if using express mail) Telephone: 301-496-7800 Ext. 282 FAX: 301-496-8601 Email: [email protected] AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.395, Cancer Treatment Research. Awards are made under authorization of the Public Health Service Act, Title IV, Part A (Public Law 78-410, as amended by Public Law 99-158, 42 USC 241 and 285) and administered under PHS grants policies and Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 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 and contract recipients to provide a smoke-free workplace and to promote the non-use of all tobacco products. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care, or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people. .
Return to NIH Guide Main Index
|
|
Office of Extramural Research (OER) |
|
National Institutes of Health (NIH) 9000 Rockville Pike Bethesda, Maryland 20892 |
|
Department of Health and Human Services (HHS) |
|
||||