Medical Device & Diagnostic Industry

Regulatory _Outlook
Gleaning Good Practices
from Warning Letters
Warning letter data provide an informative look at patterns in the device industry.
Michael Marcarelli
FDA Division of Bioresearch Monitoring

An FDA field investigator leaves your site after spending five days scrutinizing your device clinical trial records, interviewing study staff, asking pointed and open-ended questions, and reviewing your procedures.

About four months later, an overnight carrier delivers an envelope to you; it is from CDRH. You carefully open the envelope. It is a multi-page letter with the following words bolded across the top of the first page: “warning letter.”

But all is not lost. This article examines warning letter data from FY 2007 and discusses how device companies can learn from them.

Behind the Warning Letter

According to FDA’s Office of Enforcement, the agency issued 471 warning letters to regulated industry in FY 2007 (October 2006–September 2007).¹ Surprisingly, the CDRH Bioresearch Monitoring program (BIMO) issued 29, or 6%, of those letters in 2007 (in FY 2004, those numbers reached record highs of 44 and 9%, respectively). These BIMO warning letter percentages are significant considering that the CDRH BIMO program accounts for approximately 2% of the inspections conducted by FDA annually.

FDA’s Regulatory Procedures Manual indicates that a warning letter is

informal and advisory in nature. It communicates the agency’s position on a matter, but it does not commit FDA to taking enforcement action (e.g., civil money penalties). FDA’s practice is to give individuals and firms an opportunity to take voluntary and prompt corrective action before it initiates an enforcement action. The use of warning letters is based on the expectation that most individuals and firms will voluntarily comply with the law.²

CDRH BIMO looked at its FY 2007 warning letter data and wondered whether additional insights could be gleaned from mining and analyzing these data. The BIMO unit examined all 2007 warning letters to device clinical investigators (CI), sponsor/ monitors (S/M), and institutional review boards (IRBs) for information that could be useful to device companies as they develop risk assessment strategies for conducting clinical trials. BIMO rounded the percentages used in this article up or down to whole numbers.

CDRH BIMO issued 52% of its warning letters to clinical investigators (see Figure 1). This is not surprising considering that CDRH allocates almost 60% of its BIMO inspection resources to the oversight of clinical investigators. When we looked closer at the data, 60% of those investigators

were located in academic medical centers or local community hospitals and the remainder were in private practice. On the other hand, 31% of the CDRH BIMO warning letters went to device sponsors, to which 12% of BIMO inspectional resources are assigned. The majority of the sponsors were noncommercial or small businesses. Five warning letters (17%) also went to hospital IRBs, two of which were repeat offenders. CDRH BIMO inspected 323 regulated research entities in FY 2007, with the breakdown as follows: 183 clinical investigators, 92 IRBs, 40 sponsors, and 8 nonclinical laboratories, which must follow good laboratory practices (GLP). See Figure 2.

We also looked at the distribution of device good clinical practice (GCP) warning letters across the FDA district offices that conducted device GCP inspections. Interestingly, six firms under the regulatory umbrella of the Denver