Clinical Trials Cooperative Group Program Guidelines, August 1996 V. QUALITY CONTROL, STUDY MONITORING, INDEPENDENT DATA AND SAFETY MONITORING COMMITTEES AND ON-SITE AUDITS V.1. Background and Definitions V.2. Quality Control V.3. Study Monitoring V.4. Data and Safety Monitoring Committees On-Site Audit Program V.1. BACKGROUND AND DEFINITIONS The multi-center nature of Group trials presents a variety of challenging methodologic problems regarding assurance of quality and consistency in study conduct. The need for formal mechanisms of medical review and quality control is obvious and Groups have developed a number of approaches to these issues. In addition there are special problems in assuring the safety of individual patients participating in each study, in maximizing their likelihood of exposure to optimal treatment, and in general, ensuring that the interests of patient participants are not subsidiary to those of the scientific investigation. The continual assessment of the progress of studies necessary to achieve these ends is referred to in this document as study monitoring. A related need is for verification of the accuracy of data submitted from individual investigators to the Group. This need overlaps considerably with the obligation of the DCTD as a sponsor of investigational agents to visit each site where investigational agents are studied, for the specific purpose of: 1) auditing medical records, and 2) assuring compliance with regulatory requirements of the FDA, including appropriate storage and handling of investigational agents. Each Group is therefore required to establish a system of periodic on-site audits of each performance site, with CTEP oversight of the audit program. This dual responsibility of the Groups and the DCTD is referred to as the on-site audit program. (see the NCI­CTMB Guidelines for On­site Monitoring of Clinical Trials for Cooperative Groups and CCOP Research Bases.) V.2. QUALITY CONTROL Quality control is a complex topic spanning the entire range of diagnostic and therapeutic modalities employed by each Group. Generalization concerning optimal quality control is impossible. Cost and benefit are obviously important factors in this assessment. Examples of the kinds of considerations to be applied follow: Radiation therapy quality control may involve either simultaneous (rapid turnaround) or retrospective review of port films and compliance with protocol-specified doses for individual patients. Minimal standards for acceptability of equipment may be required. Each radiation therapy facility that treats patients on Group studies undergoes periodic physics review and equipment calibration by the Radiological Physics Center (RPC). The RPC in Houston, TX also supplies each Group's radiation therapy quality control office with the physics data necessary to conduct its case-level review. Chemotherapy quality control is usually carried out through retrospective review of submitted flow sheets, with determination of protocol compliance in dose administration and dosage modification. The criteria vary considerably from study to study and from Group to Group and depend heavily on the specific research questions addressed. 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. Pathology review is usually retrospective and may be either by a committee within the Group or by an external reference panel. Pathology review is not mandated by CTEP for all cases, but should be required by the Group when known variability in the accuracy of histologic diagnosis is a potentially serious problem or when pathology data may provide important prognostic information. Appropriate quality control for other therapeutic and diagnostic modalities is as essential to good data quality as those described above. Standardization of decentralized laboratory procedures (e.g., hormone receptor determinations) is an important case in point. V.3. STUDY MONITORING All clinical treatment research carries with it the obligation to ensure optimal therapy for participating patients, and optimal conduct of the research such that the patients' participation is meaningful. In this context accurate and timely knowledge of the progress of each study is a critical Group responsibility and includes the following: Precise tracking of patient accrual to individual studies and the mechanisms to ensure adherence to defined accrual goals; Ongoing assessment of patient eligibility and evaluability and correction of specific problems in this regard; Adequate measures to ensure timely submission of protocol-required data for individual patients; Adequate measures to ensure timely medical review and assessment of these individual patients' data; Rapid reporting of treatment-related morbidity in individual patients and measures to ensure communication of this information to all parties to whom it is important; Prompt assessment of the significance of such information in the context of the entire study's experience; Interim evaluation and consideration of measures of outcome (although to the extent consistent with patient safety and good clinical trials practice such interim analyses should be minimized in frequency; access by participating investigators to interim outcome data should be limited as much as possible; see V.4., Independent Data Monitoring Committees.) V.4. DATA AND SAFETY MONITORING COMMITTEES For Phase III trials, Groups are required to establish data and safety monitoring committees (DSMCs) that are independent of study leadership, are clearly free of conflicts of interest, and have formally documented policies and procedures which are approved by NCI. The main objectives of the DSMC are to: Ensure that patients in the trial are protected and that their interests are not made secondary to the interests of scientific investigations. 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 trial conduct are above reproach with no possible appearance of professional or financial conflicts of interest. a. Enable physicians entering patients to remain free of knowledge of interim efficacy data. This permits physicians to continue to approach their patients honestly and avoids the need to modify informed consent based on non-statistically-significant interim results. b. Enable study leadership to remain free of knowledge of interim efficacy data so that they may deal honestly with their peers in encouraging them to enter patients in the study and so that they do not put themselves, or the study, at risk by indirectly divulging interim results. V.5 ON-SITE AUDIT PROGRAM V.5.A. Purposes As a sponsor for investigational new agents, the DCTD is required by FDA regulations to maintain an on-site audit program. Through formal agreements with the FDA, the DCTD has delegated much of this responsibility to the Cooperative Groups, although CTEP oversees the program. The specific purposes of the audit programs are to document the accuracy of data submitted to the Cooperative Group, and to verify investigator compliance with protocol and regulatory requirements for all clinical investigations. V.5.B. Patient Case Reviews By comparison of submitted data with information contained in the patient's actual medical records, this component of the on-site audit program seeks to assure accuracy and completeness of Group information integral to the assessment of: a. Patient eligibility; b. Compliance with protocol-defined therapy; c. Tumor response; d. Treatment related toxicity; e. Protocol-required laboratory and diagnostic evaluations; f. Overall quality of record keeping; g. Concomitant therapy or other information which might affect study results but is not recorded on submitted study forms. V.5.C. Regulatory Requirements This component of the on-site audit program is intended to assess: a. Documentation of Institutional Review Board (IRB) approvals, reapprovals, and protocol amendments; b. Documentation of an IRB­approved, properly signed and dated informed consent document for each case audited, that includes an adequate description of the rules and benefits as contained in the model informed consent submitted to the NCI; c. Security of investigational drug handling; d. Adequacy of NCI drug accountability records (DAR). V.5.D. Procedures Each Cooperative Group must establish and follow an on-site audit program and audit procedures, in accordance with guidelines provided by and available from the Clinical Trials Monitoring Branch (CTMB), CTEP ("NCI-CTMB Guidelines for On-Site Monitoring of Clinical Trials for Cooperative Groups and CCOP Research Bases"). Each institution must be visited at least once every 36 months but remains at yearly risk of an audit. Audits are conducted by Group peers, but a percentage of institutions will be co-site visited by CTEP CTMB staff or their agents. Protocols to be reviewed are selected by the Group's Statistical and or Headquarters office in accordance with the above guidelines. A sample of investigational agent studies is always included when the performance site has accrued patients to such studies, as are intergroup studies. Individual cases are then randomly selected by the Statistical and/or Headquarters office for review. A preliminary audit report is to be FAXed to CTMB within one working day of the audit. A final report of each audit is sent by the Group to CTMB within ten weeks of the audit. CTMB staff review the audit findings as well as the Group's evaluation and response. V.5.E. Group Evaluation and Response The discovery of actual fraud or other serious research misconduct during a Group audit has been rare. On the other hand, problems covering a wide spectrum of severity and type are often found. Most are appropriately dealt with by constructive suggestions and are easily remedied through education of investigators and data managers. NCI follow-up is required in the event of findings suggestive of intentional misrepresentation of data and/or disregard for regulatory safeguards, as well as other matters of sufficient seriousness. In such instances, the NCI/CTMB staff should be notified by telephone immediately, since other Federal agencies may require notification. Procedures for immediate suspension of accrual at the performance site may be required. After reviewing the audit report and the Group's response, the CTMB staff may require further action such as a written corrective plan submitted by the institution or a repeat audit within a shorter interval than 36 months. In cases of suspected fraud or other serious problem of compliance with regulatory requirements, CTEP may request formal investigation by the US Public Health Service, the FDA, and/or the Justice Department. Back to Contents

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