Subcommittees of the House Committee on Energy and Commerce heard testimony last week from the Government Accountability Office’s Mary Denigan-Macauley and from Janet Woodcock, Director of FDA’s Center of Drug Evaluation and Research, about the state of FDA’s foreign drug establishment inspection program.
FDA generally conducts three types of drug manufacturing establishment inspections: preapproval inspections; surveillance inspections; and, for-cause inspections. Both domestic and foreign establishments are subject to the same types of inspections and same manufacturing requirements.
By way of background, Dr. Denigan-Macauley noted that the GAO has had long-standing concerns about FDA’s ability to oversee the increasingly global drug supply chain. In written testimony, she said that in 2018 more than 60 percent of establishments manufacturing drugs for the U.S. market were located overseas, and as of March 2019, 40 percent of foreign establishments were located in India or China. In 2008, FDA inspected only about 8 percent of the foreign establishments eligible for inspection. In 2010 and 2016, GAO observed increases in foreign inspections, but reported that some foreign establishments had not ever been inspected.
Dr. Denigan-Macaulay described GAO’s preliminary observations from its ongoing work in three areas: the number of foreign inspections; inspection staffing levels; and, challenges unique to foreign inspections.
Based on its preliminary analysis of FDA data, GAO reports that the number of FDA inspections of foreign drug manufacturing establishments increased, and that in fiscal year 2015, the number of foreign inspections surpassed the number of domestic inspections. After 2016, however, the number began to decline, and from 2016-2018, both foreign and domestic inspections decreased – by approximately 10 and 13 percent respectively.
Dr. Woodcock noted in her testimony that prior to 2012, FDA was required to inspect domestic establishments every two years, but there was no similar requirement for foreign inspections. Passage of the Food and Drug Administration Safety and Innovation Act (FDASIA) in 2012 removed the requirement for the Agency to inspect domestic sites every two years and allowed FDA to use the risk-based approach it had developed to prioritize inspections of facilities according to risk. Dr. Woodcock also noted that the Generic Drug User Fee Act of 2012 and its reauthorization in 2017 (GDUFA) provided additional resources for inspections of foreign facilities.
Dr. Woodcock’s testimony on this subject provided additional details about the numbers. Specifically, she stated that CDER’s records showed that as of July 2016, 965 foreign manufacturing facilities had never been inspected by FDA. By the end of FY2019, 495 or 51% of these had been inspected, 359 or 37% had been removed from CDER’s list for a variety of reasons and were no longer part of FDA’s inspection obligation (e.g., they had gone out of business or were not serving the U.S. market). An additional 52 or 6% had refused inspection, 37 or 4% were “inaccessible” because FDA inspectors could not travel to the location (e.g., because of travel warnings), and 22 or 2% had no drug shipments.
Dr. Woodcock noted that although FDA’s inspections of foreign establishments, particularly those that had not been inspected as frequently as domestic facilities, had uncovered deficiencies, as of August 2019, 90 percent or more of the final outcomes of inspections were acceptable with either no action indicated (NAI) or voluntary action indicated (VAI) in all countries or regions except India. GAO’s written testimony noted that some investigators who conduct foreign inspections expressed concern that reviewers reclassify an inspector’s original classification recommendations of official action indicated OAI to VAI. GAO intends to look into this issue further as part of its ongoing work. Finally, Dr. Woodcock’s testimony states that concurrence rates on foreign drug inspections designated OAI went from 50% in 1998 to 73% in 2019.
GAO’s concerns about understaffing and high vacancy rates of foreign inspectors and translators were also described by Dr. Denigan-Macaulay. FDA relies on inspectors from three groups to perform foreign inspections: investigators based in the U.S. who perform domestic and occasional foreign inspections; investigators based in the U.S. who are dedicated to foreign inspections; and, investigators based in countries where FDA has foreign offices.
High vacancy rates in foreign offices are reported by both GAO and FDA. The number of qualified foreign office-based inspectors in FY2019 was 12. An additional 12 individuals are based in the U.S. and conduct exclusively foreign inspections. Among the challenges faced in recruiting for these positions are the fact that such investigators must already possess experience in conducting foreign inspections because the foreign offices do not have the ability to train new investigators. Consequently, recruitment is limited to FDA’s existing inspectors in the U.S. Dr. Woodcock also noted that it takes 1.5 to 2 years of training to bring a new hire to a fully proficient skill level. She also stated that beyond the usual challenges of achieving optimum staffing levels, the number of individuals who can be permanently attached to a foreign office is limited by some host countries. The GAO also stated that an FDA official had told them that it can take between one and over two years for a new investigator to receive the security training and complete the background check needed before they can begin a foreign-based assignment. These requirements are reported as being handled by the embassy and agencies other than FDA.
The language barrier and lack of FDA translators was identified as a potentially significant issue. GAO stated that FDA often relies on translators provided by the company being inspected or an external translator or consultant hired by the company. GAO stated that this practice adds time to inspections and raises questions about the information FDA receives. This, too, can be seen as an inequality between domestic and foreign inspections.
The third issue raised in the testimony was the amount of notice usually provided by FDA to foreign establishments prior to inspection. Specifically, the GAO written testimony states that although FDA is not required to provide advance notice of inspections, it generally provides 12 weeks’ notice. Some unannounced or short-notice inspections are performed by inspectors in China and India. GAO stated that the amount of notice provided foreign establishments raises questions about the equivalence of domestic and foreign inspections because the long lead time provides the facilities with the ability to address issues before the inspectors arrive. Among the reasons for the long lead time is that FDA reportedly wants to ensure that the establishment being inspected will be operational while they are there.
OTC monograph drugs and active pharmaceutical ingredients (APIs) used in compounding were called out in Dr. Woodcock’s testimony for being able to ship to the U.S. without their manufacturing facilities being inspected. She did not suggest how to bring these facilities under FDA’s inspection purview, but perhaps the groundwork is being laid.