Monitoring and Auditing

Monitoring and auditing are fundamental aspects of GCP. Although their purposes are similar (to assure appropriate trial conduct and data validity), the approaches differ. As stated in the ICH GCP document, monitoring is "the act of overseeing the progress of the clinical trial and ensuring that it is conducted, recorded, and reported in accordance with the protocol, standard operating procedures, GCP, and applicable regulatory requirements." Medical monitors, usually employees of the sponsor, perform on-site (and, if indicated, off-site) evaluations of trial-related activities. The extent and frequency of monitoring should be appropriate for the length, complexity, and other particulars of the trial. Among the functions of the monitor is identification of deviations in protocol conduct so that the sponsor may take appropriate corrective steps, e.g., retraining investigators, closing out certain sites, etc.

Auditing is defined in the ICH CGP document as "the systematic and independent examination of trial-related activities and documents." The audit is usually conducted at the conclusion of the trial. The sponsor may hire auditors who document findings in a written report to the sponsor. FDA field inspectors also conduct independent study audits. Traditionally, the purpose of the FDA audits has been to verify the data submitted to the FDA in support of a marketing application. However, the FDA and the sponsor may conduct "for cause" or directed audits at any stage of clinical investigation if there is reason to suspect a problem with trial conduct or data integrity.

The FDA has performed directed inspections at a few gene therapy clinical sites since 1999. The agency also audited approximately 70 gene transfer clinical sites selected at random to assess whether systemic problems with the conduct of such clinical studies existed. Inspectional findings will be discussed in more detail in section XVI.

An additional measure of human subject protection is use of a Data Monitoring Committee (DMC) to evaluate accumulating data from a clinical trial [22]. Generally, the sponsor establishes the DMC, including selecting the members and devising the charter. The DMC members should be independent of the sponsor and clinical investigators. The role of the DMC varies according to the charter and the nature of the study. The DMC is usually empowered to recommend study modifications to enhance safety of participants; in some cases, a DMC may recommend that a study be stopped if data indicate a major safety concern. Of note, DMCs review data submitted to them but do not visit sites to directly ensure that the data are accurate, the protocol is followed, consent is documented, etc. Thus, a DMC does not perform the functions of or obviate the need for study monitors. The FDA is in the process of developing guidance on DMCs.

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