(QA) efforts can be powerful and effective. Of note, there is substantial variation in the approach to data quality auditing within FDA, and factors such as deadlines, workloads, and competing priorities can significantly affect the nature and extent of auditing.

FDA clinical reviewers use four basic auditing tools: (1) checks for compliance with the protocol, (2) checks for data consistency, (3) checks of clinical judgment calls, and (4) interactions with field inspectors. Compliance with the protocol is a central part of both medical and statistical reviews and focuses on inclusion and exclusion criteria, blinding, randomization, treatment, assessment, and analysis. Consistency checks include comparisons among centers in multicenter trials, comparisons of data over time, especially in studies with multiyear accrual of subjects, and checks of the consistency of data in various formats (e.g., tables, summaries, listings, and labeling). Assessments that require clinical judgment—such as cause of death, the cause of an adverse event, or success versus failure—are often critically evaluated by clinical reviewers. The clinical reviewer interacts with the field auditor to help decide which sites will be visited, which data will receive the closest scrutiny on-site, and which documents, if any, will be retrieved from study sites for further scrutiny.

Specific elements that are checked include randomization, blinding and unblinding, inclusion and exclusion criteria, treatment of more sensitive populations, the level of drug compliance, and the manner in which efficacy and safety data are reported. Other data points examined on a patient-by-patient basis include death, adverse events that lead to withdrawal from the study, and other serious adverse events. Specific approaches are used for audits of the various trial elements and data types.

Paper audits represent a substantial investment of FDA resources. Frequently, half or more of the time spent by clinical and statistical reviewers reviewing a marketing application is spent on assessing data validity in the broad sense.

Clinical Site Review and Institutional Review Board Audits

Presented by David Lepay, M.D., Ph.D.

Director, Division of Scientific Investigations

Center for Drug Evaluation and Research, Food and Drug Administration

On-site inspections complement paper audits in the Food and Drug Administration's (FDA's) efforts to ensure data quality and integrity in clinical trials. The Bioresearch Monitoring Program, which was established in the late 1970s, seeks to detect sloppiness or misconduct that might affect human subject protection, data integrity, and sound decision making on applications. It also seeks to prevent data quality and integrity problems before they occur. Inspections are conducted in accordance with published standard operating procedures that are updated every 3

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