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| Investigator's Handbook A Manual for Participants in Clinical Trials of Investigational Agents Sponsored by DCTD, NCI
Part D: The Organization of a Clinical Trial16. Monitoring and Quality Assurance
16. Monitoring and Quality Assurance 16.1 Introduction Sponsors and research bases must monitor their clinical trials. In assuring the quality of data, monitoring is a key component of any clinical trials program. Quality assurance and monitoring are concerned with the execution of a trial, rather than its conception, and with the quality of the data that support the scientific conclusions. Many individual activities are part of quality assurance, and investigators have recognized some of them as vital to the integrity of clinical trials for years. In particular, the quality control of pathology and radiotherapy has been part of the Cooperative Group program for a long time. More recently, investigators have increasingly recognized the importance of verifying the accuracy of other classes of data. We shall now discuss in more detail the items that form the major focus of the DCTD-sponsored quality assurance effort. Note that the first two classes of concern (protocol compliance and data accuracy) are really central problems in clinical trials methodology. The fact that they are assessed intensively by the on-site audit program should in no way divert attention from their essential importance to the scientific content of clinical trials.
16.2 Protocol Compliance 16.2.1 Cooperative Groups The groups have recognized the importance of assessing the extent of protocol compliance for many years. One of the first areas to receive attention was the confirmation of diagnosis. Today, virtually all groups have Pathology Committees or Reference Panels for selected studies; central pathology review reduces one important source of variability in trial results. Furthermore, most Cooperative Groups have quality control in radiotherapy, which consists at least of reviews of port films by group radiotherapists. These reviews are best done prospectively, so that errors can be detected in time to alter subsequent treatment. In the Cooperative Groups, the medical oncology committee or the protocol chair reviews case report forms to establish whether dose adjustments have followed protocol guidelines, and whether appropriate study tests have been obtained. In most Cooperative Groups, the protocol chair also reviews each case to determine eligibility, evaluability, and validity of response and adverse event assessment. In some cases, the statistical office accomplishes one or more of these tasks. All of these assessments are performed through review of submitted case report forms.
16.2.2 Cancer Centers The majority of Cancer Centers have organized procedures to assess protocol compliance centrally and systemically (Section 3, Research Bases). The CTEP on-site audit program evaluates protocol compliance as part of its monitoring visits. Indeed, this is a major focus of a monitoring visit to a Cancer Center, along with the administrative review for central data management, protocol development, and data collection.
16.2.3 CTEP Clinical Drug Development Contractors Protocol compliance is assessed by the Clinical Trials Monitoring Service (CTMS). Phase 1 and Phase 2/3 contractors submit raw data to CTMS, which reviews it carefully for extent of compliance with the protocol. Reports of these evaluations are provided to the investigator and to CTEP.
16.3 Data Accuracy The importance of verifying the accuracy of the basic data elements used in the analysis of study endpoints is obvious. Data accuracy is assessed during on-site audits by comparison of the research record (e.g., flow sheets) with the primary patient record. Response assessment may be evaluated by examination of radiographs or scintiscans, where relevant. In many of the early on-site audits performed, CTEP was concerned about the absence of formalized procedures at many centers for assessing these important issues internally. Many institutions lacked central registration mechanisms to enroll patients on trials. Centralized systems of data management were often not available. Some institutions lacked clear procedures for certifying the accuracy of research data. Formal procedures for evaluating the accuracy of response assessment, for example by second-party review, were commonly lacking. As institutions have recognized the importance of these tools for the conduct of clinical trials and have brought them "on-line," the quality of data has improved commensurately.
16.4 Procedural Requirements As an IND sponsor, the DCTD must verify that its investigators adhere to the various procedural requirements of investigational agent trials. The specific procedural activities checked at the time of the on-site audit are:
On-site auditors will also review the completeness of reporting adverse events and the quality of record keeping with particular reference to the completeness of the source documentation. Each of these areas is reviewed at the time of on-site audit. In addition, many Cooperative Groups and Cancer Centers maintain internal procedures to assure the quality of data on their trials and assure that regulatory requirements have been met.
16.5 Components of the Quality Assurance Program Implemented by CTEP 16.5.1 Monitoring Monitoring includes following the overall progress of the study to ensure that projected accrual goals are met in a timely fashion and excessive accrual is avoided; that eligibility and evaluability rates do not fall below acceptable standards; and that risks of the study do not outweigh benefits. Poor performance in any of these areas is cause for concern. Because these activities are performed during study execution, they may lead directly to improved conduct of the trial. The Cooperative Groups are performing these tasks according to systematic, formalized procedures. For Phase 1 studies, the CTMS performs these duties. Cancer Center studies are monitored by the CTMS with direct oversight from CTMB.
16.5.2 The On-Site Auditing Program 16.5.2.1 Purpose of Site Visit Audits
16.5.2.2 Outline of Audit Procedures
16.5.2.3 Adaptions of Basic Procedures to Specific Needs These basic procedures have been adapted to the several types of clinical trials organizations supported by NCI in the following way:
Relationship Between the Content of the Site Visit Audits and the Type of Clinical Trials Organization.
CTMS = Clinical Trials Monitoring Service (CTEP monitoring organization, which monitors Phase 1 and some Phase 2 trials, and coordinates On-Site Auditing Program)
Note 1:
Note 2:
16.6 Informed Consent and the Monitoring Program Many have asked about the legality of review of a patient's primary medical record by outside individuals. The answer is straightforward. No Federal law prohibits external review of a patient's medical record. The regulations of informed consent do require, however, that the patient be informed of "the extent to which confidentiality of records will be maintained." This means that there is no rule against chart review by outsiders, but that the patient must be told what will be done. For this reason, CTEP requires that each informed consent document for investigational agent trials it sponsors include a statement with the following language, "A qualified representative of FDA and NCI may review my medical records." CTEP may also suggest that the name of the manufacturer of the agent be included as having access to the records. This access may be necessary for the pharmaceutical company to prepare a New Drug Application (NDA) or Biologic License Application (BLA) for an agent. Also, please note that medical records are protected from inquiries under the Freedom of Information Act (FOIA). Even if the study is performed under Government sponsorship, any records on the premises of the investigator are not subject to FOIA requests. Furthermore, any patient-related records in Government files are protected from FOIA requests by the Privacy Act. As an additional measure of safeguarding, CTEP removes patient names from any documents in its possession.
16.7 Dealing with Problems Identified During On-Site Audits CTEP and the Cooperative Groups have a full range of options in dealing with problems identified at the on-site audit. In a great majority of cases, the measures are intended to be constructive, educational, and corrective rather than punitive. The actions that are taken vary with the individual case. All reports of on-site audits are sent to CTEP electronically. The reports are assessed by CTEP staff on a regular basis. When major problems are identified by a Cooperative Group audit, this information is immediately conveyed to the group chair and CTEP for further action and investigation. After requesting a written clarification, and following review of the case by the Cooperative Group and/or CTEP, appropriate measures will be applied if the original assessment is confirmed. The options for action include:
The following actions may be taken in instances of suspected data fabrication or falsification or other possible scientific misconduct:
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