The COVID-19 Inspection Backlog
In March 2020, FDA suspended in-person facility inspections for sites outside the U.S. and later paused domestic inspections in recognition of pandemic-related travel limitations and to safeguard the health and well-being of agency staff.2 In July 2020, FDA announced that it would prioritize certain domestic inspections using a risk-based approach, specifically those deemed “mission critical.”3 In tandem, FDA issued guidance on COVID-19 and inspections, in response to questions from industry regarding the impact of delays on pending applications and other issues.4
In FY2020, FDA inspectors were unable to complete more than 1,000 scheduled inspections.5 From March through September 2020, FDA conducted only three mission-critical foreign inspections (in Canada, Germany, and India) — far fewer than the roughly 600 foreign inspections FDA had conducted in each of the prior two years.6 During the same period, domestic inspections declined to 52.7
In March 2021, FDA’s Center for Drug Evaluation and Research (CDER) reported that 90-day facility inspection classification letters were down 49% and that 38% fewer drugs had been added to the inspection refusal import alert than in the prior fiscal year.
FDA Use of Alternative Tools
FDA has stated that during this period, it continues to expand its use of alternative tools to ensure the quality of imported drugs notwithstanding dramatic reductions in on-site inspection.8 These include
- physical examination of products at the U.S. borders or sampling and testing prior to interstate commerce
- use of information shared from foreign authorities through mutual recognition agreements and other confidentiality agreements9
- requesting information from applicants such as records and other information directly from facilities and other inspected entities “in advance of or in lieu of” certain drug inspections
FDA has also announced a pilot program to assess the use of video in remote inspections.10
“While these tools can provide useful information, most do not substitute for an inspection, and FDA will face a backlog as it was unable to complete more than 1,000 of its planned inspections for FY 2020,” a witness representing the Government Accountability Office (GAO) said in congressional testimony in March 2021.11 While FDA concurred with GAO’s recommendation to consider alternative tools, agency officials have also expressed reluctance as remote inspections could miss problems (e.g., falsification of records) — a particular concern with respect to facilities with past violations.12
In addition, legal questions remain as to FDA’s ability to rely on alternative methods. FDA has taken the position that only its own in-person inspections and European regulatory reports can satisfy statutory requirements for surveillance inspections.13 Likewise, FDA can substitute the review of records and other information for a preapproval inspection only in certain circumstances.14
Industry stakeholders have continued to raise concerns about the need for FDA to reach approval decisions on pending applications promptly, notwithstanding COVID-19-related inspection delays. FDA had asserted that postponed inspections generally were not interfering with timely approval decisions, but “unresolved facility inspection-related conditions” have been increasingly cited for delays in approval decisions.15 Accordingly, the agency’s reliance on alternative methods reportedly has become an issue in user-fee reauthorization discussions.16 Although mitigation measures such as travel restrictions are being relaxed in response to changing public health recommendations, there are indications that FDA officials are assuming that traditional on-site inspections will not return to prepandemic levels anytime soon.
In particular, a January 2021 report on FDA’s COVID-19 Pandemic Recovery and Preparedness Plan acknowledged that the uncertainty of the COVID-19 pandemic would continue to limit FDA’s ability to conduct onsite inspections.17 In light of this limitation, the report described a number of measures under consideration, using both existing legislative authority and potential statutory amendments, that would give FDA new flexibility to use alternative methods.
The report discussed three efforts currently underway to “clarify and expand the use of alternative inspectional approaches.” First, FDA may rely on Section 704(a)(4) of the Federal Food, Drug, and Cosmetic Act (FDCA) more frequently and more expansively.18 Second, FDA is assessing its inspectional operations across product areas, both domestically and internationally. FDA will consider “the risks and benefits of preannouncing inspections, risks and benefits of records review and remote assessments performed in advance or in lieu of inspection, and feedback from internal and external stakeholders.” The assessment will provide FDA with “a set of recommended solutions to further optimize its inspectional work” beyond the COVID-19 pandemic.19 Third, FDA will establish an Intra-Agency Inspectional Affairs Council (IIAC) for “tactical planning and coordination” of agencywide inspectional considerations.
The report also describes FDA’s plans to refine its inspectional practices for future emergency situations. According to the report, FDA plans to develop external “guidelines to designate work as mission-critical” by “finaliz[ing] the codification of criteria” used to designate an inspection as such. The report also discusses FDA’s development of a “comprehensive optimization roadmap” to enhance the effectiveness and efficiency of the Agency’s inspection program.20 As the roadmap is developed, FDA could also “systematically evaluate proposals for optimizing inspectional operations and related activities,” including modifications to current inspectional approaches. Changes would be implemented when they “would be feasible, advisable, defensible, and sustainable.” FDA’s “comprehensive optimization roadmap” would in turn “develop capabilities that would allow [the agency] to ‘convert’ to emergency approaches more quickly.”21
Maintaining Inspection Readiness
Maintaining inspection readiness remains vital as the intensity of inspections ramps up over the coming months. Manufacturers can be expected to be called on to address any differences in manufacturing methods implemented during COVID to ensure that any deviations are properly justified, documented, and consistent with applicable good manufacturing practice requirements.
In the meantime, remote evaluations conducted in lieu of in-person inspections present their own challenges and also require preparation. For example, employees communicating digitally may inadvertently create documents with risk implications for a company that are not an issue with in-person discussions. Remote evaluations also have inherent limitations that manufacturers could potentially address in advance — for example, it may be appropriate to consider, even before an inspection is scheduled, options to enable the agency’s alternative approach to achieve the same results as an in-person inspection. A manufacturer might, for example, seek to provide documents to FDA in advance to provide context for issues that might arise during the evaluation itself.
1GAO-12-409T, COVID-19: FDA’s Future Inspection Plans Need to Address Issues Presented by COVID-19 Backlog (March 4, 2021) (available at https://www.gao.gov/assets/gao-21-409t.pdf) [herein referred to GAO Report].
2See FDA Statement, Coronavirus Disease 2019 (COVID-19) Update: Foreign Inspections (March 10, 2020) (available at https://www.fda.gov/news-events/press-announcements/coronavirus-disease-2019-covid-19-update-foreign-inspections); see FDA Statement, Coronavirus (COVID-19) Update: FDA Focuses on Safety of Regulated Products While Scaling Back Domestic Inspections (March 18, 2020) (available at https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-focuses-safety-regulated-products-while-scaling-back-domestic).
3See FDA Statement, Coronavirus (COVID-19) Update: FDA prepares for resumption of domestic inspections with new risk assessment system (July 10, 2020) (available at https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-prepares-resumption-domestic-inspections-new-risk-assessment-system).
4FDA, Guidance for Industry: Manufacturing, Supply Chain, and Drug and Biological Product Inspections During COVID-19 Public Health Emergency Questions and Answers at 4 (updated January 29, 2021) (available at https://www.fda.gov/media/141312/download) [herein referred to COVID-19 Guidance].
5Id. at 11.
6See GAO Report at 7, 11.
8See COVID-19 Guidance at 4.
9Id.; see GAO Report at 9-10.
10See MedTech Insight, FDA Exploring Use Of Video – ‘Live Or Recorded’ – To Support Virtual Inspections During Pandemic (November 18, 2020) (available at https://medtech.pharmaintelligence.informa.com/MT143090/FDA-Exploring-Use-Of-Video--Live-Or-Recorded--To-Support-Virtual-Inspections-During-Pandemic) (citing Elizabeth Miller, Assistant Commissioner of Medical Products & Tobacco Operations, Office of Regulatory Affairs, Speaker, FDAnews’ 15th Annual Inspections Summit (November 17, 2020)).
11House Committee on Appropriations, FDA’s Foreign Drug Inspections Program, Witness – Dr. Mary Denigan-Macauley (March 9, 2021) (available at https://appropriations.house.gov/events/hearings/fdas-foreign-drug-inspections-program) [herein referred to House Testimony].
12See Politico, Drug industry pushes FDA to solve growing inspection backlog (March 2, 2021) (available at https://www.politico.com/news/2021/03/02/fda-pandemic-drug-inspection-471979) (citing Donald Ashley, Speaker, Food and Drug Law Institute Enforcement, Litigation, and Compliance Conference (December 2020)); see also New York Times, Pandemic Forces F.D.A. to Sharply Curtail Drug Company Inspections (March 9, 2021) (available at https://www.nytimes.com/2021/03/09/health/covid-fda-drug-inspections.html).
13See GAO-21-265, COVID-19: Critical Vaccine Distribution, Supply Chain, Program Integrity, and Other Challenges Require Focused Federal Attention (Jan. 28, 2021) (available at https://www.gao.gov/assets/gao-21-265.pdf); see also GAO Report at 13-14. FDA expanded the use of the mutual recognition agreement it has with the European Union to include inspections conducted outside of Europe by European regulators as a full substitute for FDA inspections. See GAO Report at 10.
14See 21 U.S.C. § 374(a)(4). See GAO Report at 10.
15See Pharmaceutical Technology, FDA Inspection Shutdown Increasingly Delays Approvals (February 2, 2021) (available at https://www.pharmtech.com/view/fda-inspection-shutdown-increasingly-delays-approvals); see also GAO Report at 13.
16See MedTech Insight, FDA Exploring Use Of Video – ‘Live Or Recorded’ – To Support Virtual Inspections During Pandemic (November 18, 2020) (available at https://medtech.pharmaintelligence.informa.com/MT143090/FDA-Exploring-Use-Of-Video--Live-Or-Recorded--To-Support-Virtual-Inspections-During-Pandemic).
17FDA, FDA COVID-19 Pandemic Recovery and Preparedness Plan (PREPP) Initiative Summary Report at 49 (January 2021) (available at https://www.fda.gov/media/145129/download).
18Id. at 50. FDCA Section 704(a)(4) allows the agency to request “any records or other information” from an “establishment engaged in the manufacture, preparation, propagation, compounding, or processing of a drug ... in advance or in lieu of an inspection.” FDCA § 704(a)(4)(A), 21 U.S.C. § 374(a)(4)(A). According to the report, FDA had already used Section 704(a)(4) to make more than 400 record requests since January 2020 “in advance or in lieu of an inspection.” PREPP Report, supra note 17, at 49.
19Id. at 50. FDA expects this assessment to be completed by the end of 2021.
20Id. at 51. The agency explained that the optimization roadmap may include scaling the use of virtual tools, such as read-only access to sponsor databases; increased bandwidth and streaming capabilities in facility assessments; a more consistent and advanced approach to assess risk-based resource allocation to inspections; a transition to a more continuous, stakeholder-centric engagement model with industry; and accelerated efforts to align efforts with international regulatory authorities.
21Id. at 51-52.
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