临床研究与生物伦理学杂志

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An Analysis of United States Food and Drug Administration Warning Letters Issued to Clinical Investigators from 1996 through 2011

Jessica A. Knowlton and Jim Y. Wan

The warning letter is a communication sent to sponsors, manufacturers and clinical investigators resulting from inconsistencies and inaccuracies found during FDA audits of clinical research-related activities. Warning letters to investigators can have a major impact on that physician’s practice and their affiliated institution. The objective of this research was to analyze the publicly available warning letters that were sent to clinical investigators during the years 1996 to 2011 to identify areas of deficiencies and educate current and future clinical investigators. The data was extracted from letters to Clinical Investigators published in the Electronic Reading Room on the FDA’s website.The specific regulationslisted in the letters that were deemed violated by the respective FDA auditor were used for data analysis and termed “infractions”.Between 1996 and 2011, 1,404 infractions were noted for 237 Clinical Investigators (mean = 5.14). The vast majority of these infractions occurred in 21 Code of Federal Regulation, parts 50, 312 and 812 (n= 215, 523 and 650 infractions, respectively) and reflected violations in the areas of informed consent, documentation and investigator responsibilities.During this timeframe, the average number of infractions per investigator per year did not decrease. Finally, the number of investigator warning letters that were issued was not correlated to the number of investigator audits. This data shows common deficiencies in clinical research programs and can assist investigators in developing preventative measures for future clinical research.