FDA Warning Letters: A 2011 Retrospective

The year just ended was a busy one for the US Food and Drug Administration (FDA), particularly with regard to inspections and enforcement activities. The FDAZilla blog predicted on November 30, 2011, that the number of 483 Forms issued for the year would exceed 10,000, or roughly one every 50 minutes.

If an FDA field investigator notes objectionable conditions or practices during an inspection of a regulated entity, Form FDA 483, “Notice of Inspectional Observations” will be issued at the conclusion of the inspection. The recipient of a 483 has no explicit regulatory obligation to respond but is strongly encouraged to do so, even if the 483 was issued with no action indicated (NAI) or voluntary action indicated (VAI). When a 483 is issued with official action indicated (OAI), the appropriate FDA district or regional office may choose to follow up with a warning letter, which usually signals that serious violations have been observed during one or more inspections. The recipient must take immediate corrective action and respond formally to FDA. If the response is incomplete or inadequate, FDA may initiate further enforcement actions up to and including suspension of some or all FDA-regulated activities.

FDA issued numerous warning letters related to clinical research activities during 2011. For clinical investigators, the most frequently cited violation was noncompliance with the protocol. Failure to maintain accurate case histories was a close second. Other recurring themes included supervision of research personnel, consent documentation, IRB approval and reporting, and drug accountability. IRBs were most cited for not following (and in some cases, not having) written procedures and for various review process issues such as late continuing reviews, improper use of expedited review, failure to ensure a quorum, and inadequate documentation of review activities.

The consequences of repeated violations and/or failure to implement effective measures for corrective and preventive action (CAPA) can be serious, as demonstrated by a letter that was highlighted in the ACRP Wire for January 5, 2012. FDA suspended the Bay Regional Medical Center IRB’s use of expedited review and halted enrollment in all ongoing trials overseen by the IRB, citing “a continuing pattern of deficiencies” and “[repeated failure] to meet the regulatory requirements of 21 CFR Part 56. The IRB had undergone three unsatisfactory inspections and had also received a warning letter in 2010.

Clinical trials, even simple ones, can generate large quantities of data that are challenging to manage. In the eyes of an auditor, failure to document compliance is essentially the same as actual noncompliance. The use of an electronic tracking system such as InfoEd can mitigate the risk that data or documents will go missing. Timely data entry, coupled with periodic review to identify and correct problems early, can significantly improve the quality of data. Continuous professional development for researchers and staff, supported by documentation of their training and qualifications, enhances the ability of the institution (or the investigator, or IRB) to conduct quality research.

Warning letters are publicly available online. Reviewing them on a regular basis can provide valuable insights into the appropriate conduct and oversight of research, as well as FDA’s current thinking on topics that have not yet been incorporated into regulations or formal guidance. The accreditation standards of the Association for the Advancement of Human Research Protection Programs (AHRPP) are also an excellent resource for both accredited and non-accredited institutions. Current InfoEd clients are invited to continue the discussion of this topic and share additional resources in the ICAG Forum.

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