Just the Stats, Ma’am: FDA Increases Inspections in Foreign Countries, Resulting in a Higher Rate of Enforcement Actions than Imposed on U.S. Facilities

The last time we blogged on news from a recent pharmaconference.com industry conference about current Good Manufacturing Practice (“GMP by the Sea,” agenda linked here), we provided some cute references to corn pudding recipes (blogpost linked here).  Despite universally positive feedback about those culinary diversions, this blogpost will simply report other Food and Drug Administration (FDA) compliance developments reported at the conference, supplemented by statistics identified by independent snooping.

On the drug side, FDA statistics shown at the GMP by the Sea conference indicate that the number of FDA inspections at drug manufacturing facilities outside the United States actually have dropped in recent months, although warning letters issued by FDA’s Center for Drug Evaluation and Research (CDER) have risen dramatically.  Specifically, FDA inspections of domestic drug establishments dropped slightly, from about 1,900 in fiscal year 2014 to about 1,800 in fiscal year 2018 (these numbers include more data than the inspection data in Chart 1 below).  At the GMP by the Sea Conference, data were only available for inspections of drug establishments in foreign countries through fiscal year 2017.  So we checked the publicly available database from FDA (which can be found here) and determined that, indeed, the number of foreign drug inspections peaked at 1,061 in fiscal year 2016, dropped to 981 in fiscal year 2017, and rose slightly to 991 in the last fiscal year.  (The total for fiscal year 2019 is incomplete, since that fiscal year doesn’t end until October 31, 2019.)

Chart 1: Drug inspections by FDA by Fiscal Year

FDA officials at the conference said that they believe that the reduced number of FDA foreign inspections is partially due to the government shutdown last year, but also increased FDA recognition of inspections performed by foreign inspectorates under the Mutual Recognition Agreement, the subject of many blogposts, the most recent being here.  Relying on inspections by European equivalents of FDA reduces the need for FDA to duplicate those inspections.

Even though the number of foreign and domestic inspections has dropped recently, the number of Warning Letters issued by CDER has increased, as discussed at GMP by the Sea in a presentation by Scott McIntire, Director of the Division of Enforcement for FDA’s Office of Regulatory Affairs.  The number of Warning Letters issued by CDER rose from about 80 in 2015 (not clear whether this is fiscal year or calendar year) to more than 150 in 2016 and a few more in both 2017 and 2018.

We have noticed that a lot of the GMP Warning Letters from CDER emanate from inspections FDA conducted in China and India, so we performed further analysis.  Over the last nine years, selected types of drug inspections in India and China showed a higher rate of classifications of Official Action Indicated (OAI; which result in enforcement actions) and Voluntary Action Indicated (VAI; meaning that there are significant corrections that inspected facilities are required to perform) than do FDA inspections of facilities in the United States.  Significantly, looking at the most serious classification of inspections (OAI), the percentage of inspections in China and in India over the last nine years that were classified OAI was 12%, whereas the comparable number in the United States was 8%.

Table 2 Classifications of Drug Inspections by Calendar Year

(looking at inspections relating to Drug Quality Assurance, Over-the-Counter Drug Evaluation, and Unapproved and Misbranded Drugs, CDER Projects ONLY)

2010

2011

2012

2013

2014

2015

2016

2017

2018

As for devices, the number of FDA inspections of medical device manufacturing facilities outside the United States increased by 243 percent from 2007 to 2017, according to Sean Boyd, Director of the Office of Regulatory Programs within the Office of Product Evaluation Quality at FDA’s Center for Devices and Radiological Health.  These figures are borne out by manipulating the publicly available inspection database from FDA which can be found here.  While the numbers don’t line up exactly with Capt. Boyd’s (some types of device inspections were not included on the database available on FDA’s website), the database shows 245 FDA foreign inspections of device establishments in fiscal year 2009 and 614 in fiscal year 2017.  The number of such inspections actually dropped off slightly in fiscal year 2018.  See chart below:

Chart 3 Device Inspections by Fiscal Year

Also on the device side, in response to a question, Capt. Boyd reported that he estimated that about 40% of the inspections that FDA conducts at medical device facilities result in delivery of an FDA Form 483 (Report of Observations) relating to Quality System Regulation deviations identified by FDA Investigators.

We could provide some analysis of these data by providing obvious advice to companies operating in India and China and subject to FDA regulation: you can expect increasing rates of FDA inspections and you need to be especially vigilant to avoid Warning Letters, which can lead to crippling Import Alerts.  We could also say that, while all OAI inspections are not created equal, the larger rate of OAI inspections in India and China is more damaging to the recipients of those inspections because it is very easy for FDA to impose Import Alerts on overseas manufacturers shipping drug products into the United States.  But to provide that level of analysis would violate Sgt. Joe Friday’s frequent admonition to provide, “Just the facts, ma’am,” or sir.

Young people who don’t listen to reruns of old radio programs can find further information about the fictional Sgt. Friday and the “Dragnet” radio program here.  He was notorious for, when interviewing women whose narratives began to stray, telling them, “Just the facts, ma’am.”

* Scott and Jasmin are legal assistants who provided research assistance for this blog post.