By Kalah Auchincloss, SVP & deputy general counsel, Greenleaf Health, Inc.
Almost exactly one year ago, in March 2020, the U.S. FDA announced that it was suspending all foreign and domestic inspections except those it deemed “mission critical.” This unusual move was a response to the then-emerging COVID-19 pandemic—an attempt to reduce transmission of the virus and protect both FDA personnel and industry employees.
Even as it suspended inspections, the agency assured the public that it had “full confidence in the safety and quality of the products we all use every day and that the FDA will continue to leverage all available authorities to continue to ensure the integrity of the products we regulate.” A year into the pandemic, the FDA is still conducting only limited inspections in the U.S. and evidence has emerged of a significant inspection backlog that could compromise the safety and quality of the U.S. drug supply.
This article provides a brief timeline of inspection-related events over the last year (see Figure 1). It then discusses the impact of a year of limited inspections and the changes that we might expect as the FDA begins to shift back to more normal operations.
Where Are We Today?
The press releases in March 2020 referred to “alternative tools” the FDA would use in lieu of inspections to continue to approve new medical products and keep existing products safe. The FDA has described these authorities in numerous speeches and presentations, as well as in guidance, including: requesting and reviewing records “in advance of or in lieu of” an inspection under section 704(a)(4) of the Federal Food Drug and Cosmetic Act (FD&C Act); examining the previous inspection and compliance history of a facility; leveraging inspection reports from recognized foreign authorities under the Mutual Recognition Agreement (MRA) or from capable authorities that are members of the Pharmaceutical Inspection Co-operation Scheme (PIC/S); and employing import controls at the border to prevent unsafe products from entering the U.S.
In particular, the FDA has frequently used its authority to request records under section 704(a)(4) of the FD&C Act and its ability to rely on foreign inspection reports under the MRA. For example, in a speech from September 2020, an FDA representative indicated that it had requested records under section 704(a)(4) more than 500 times since the start of the pandemic, and that more than 100 of those requests were part of the review of medical product applications, supporting decisions on whether or not to approve a product. Further, the Office of Pharmaceutical Quality (OPQ) 2020 Annual Report stated that reliance on alternative tools avoided the need to conduct 153 on-site facility inspections prior to application approval. The Pandemic Recovery and Preparedness Plan (PREPP) Initiative Report confirms the FDA’s increasingly frequent use of these alternative authorities, noting that the use of the MRA with the European Union increased by close to 35% between March and October 2020 compared to the same time frame in 2019. (For a closer look at the PREPP report, see “FDA's COVID-19 PREPP Initiative Summary Report — Key Takeaways For Manufacturers.”)
As a result of its switch to alternative tools, the agency has done a remarkable job of continuing to meet user fee goal dates. An FDA website indicates that for drug and biological products (except biosimilars), the FDA met application user fee goal dates at least 90% of the time in 2020; this is in keeping with the FDA’s commitments to industry in the user fee letters. The website also states that by relying on alternative tools to complete facility assessments, CDER reduced the need to conduct preapproval inspections about 50% of the time over the last year.
By my own independent research, I can find only 11 instances since March 2020 in which the FDA has issued a complete response letter or missed a decision date solely as a result of an inability to conduct an on-site inspection. This is in comparison to more than 50 novel drug approvals and more than 900 generic drug application approvals in 2020. All in all, the data indicate that the FDA has successfully continued to meet user fee dates to bring critical drugs to patients.
Unfortunately, routine surveillance inspections have not fared so well. A GAO report on the COVID-19 response painted a disturbing picture of a significant inspection backlog, finding that the FDA conducted only about 500 of the approximately 1,500 anticipated surveillance inspections in FY2020. From March to October 2020—the first six months of the pandemic—the FDA conducted only 52 domestic and three foreign inspections, compared to about 400 domestic and 600 foreign inspections in the same time frame in each of the previous two years. The inability to conduct inspections is not surprising—until recently the COVID-19 case rate was too high in most U.S. counties to safely send FDA investigators on-site. It is, however, disappointing that the FDA has not managed to utilize its “alternative tools” as effectively for surveillance inspections as it has in the preapproval arena.
It is also notable that remote or virtual inspections have been absent from the FDA’s toolbox. The agency has been clear that section 704(a)(4) records requests and reliance on foreign inspection reports and other “alternative tools” are not the same as an inspection. These tools may provide data that can inform the need for an inspection, but they do not start with a Form-482, the traditional opening of an on-site inspection, nor do they result in a Form-483 list of observations. In short, these tools are “assessments” that may supplement inspections, but they are not equivalent. The FDA has also refused to consider the use of video technology to conduct a virtual inspection, and until recently it has been reluctant even to use technology to add virtual components to its remote assessments.
While the FDA has largely managed to meet user fee goal dates, it clearly has not been as successful in mitigating the impact of suspending other types of inspections. Although an understandable immediate response to a public health emergency, continuing along this path will have significant consequences for the future. For example, companies classified as Official Action Indicated (OAI) will continue to linger in that status (preventing approval of new drugs made at those facilities), drug shortages may worsen, and the current risk-based inspection model will prove inadequate to properly prioritize the highest-risk facilities.
GAO recognized the need for the FDA to shift its thinking from short-term emergency response to longer-term strategic planning. The report noted that the inspection backlog could jeopardize the agency’s goal of risk-based inspections and recommended that the FDA ensure inspection plans for future fiscal years “identify, analyze, and respond” to those issues. Both GAO and the PREPP Initiative Report also recognized the need for a better set of tools for the FDA, including virtual components. For example, GAO’s second recommendation in its report is that the FDA:
“fully assess the agency’s alternative inspection tools and consider whether these tools or others could provide the information needed to supplement regular inspection activities or help meet the agency’s drug oversight objectives when inspections are not possible in the future.”
The PREPP Initiative Report proposed similar action items, including that the FDA: improve its communications regarding its approach to inspections; develop a comprehensive “inspection optimization roadmap” that could include the scale up and use of virtual tools; and create a framework to define and measure the effectiveness of inspectional approaches. Industry trade associations and other stakeholders have also submitted proposals suggesting similar next steps.
Fortunately, these recommendations have not fallen on deaf ears. In the weeks since the two reports were released, the FDA has indicated its willingness to conduct “remote interactive evaluations” of facilities, potentially incorporating some level of virtual technology—e.g., video conferences or virtual site walk-throughs as part of a 704(a)(4) records request. The FDA is still unwilling to move to true virtual inspections or to label its alternative tools an inspectional equivalent, but this is a big step in the right direction. The FDA has also begun to conduct more on-site inspections as vaccination rates increase and COVID-19 case rates decrease.
Nonetheless, the pandemic has wreaked havoc with the agency’s traditional inspectional model. The FDA will need to consider serious changes in the future, including consistent use of technology to enhance the use of alternative tools, and perhaps even a move toward virtual inspections, in addition to an altered risk-based model to more effectively prioritize facilities for physical inspection in light of the current backlog. An on-site physical inspection can no longer be the gold standard for all facilities; continued reliance on the current set of “alternative tools,” with additional tools and technology added, must be part of the solution, in addition to on-site inspections.
Figure 1. Timeline of Key Inspection-Related Events March 2020 – March 2021
- FDA announces suspension of most foreign and domestic inspections with the exception of “mission critical” inspections.
- Statement from FDA continuing to postpone inspections except those that are "mission critical."
- FDA announces it will resume domestic inspections on July 20 based on the COVID-19 Advisory Level (a safety assessment by county).
- OPQ’s 2020 Annual Report mentions inspections, particularly focused on preapproval inspections (PAI) and the use of alternative tools.
 This provision explicitly applies to drugs and biologics, but not to medical devices. The FDA also believes section 704(a)(4) does not apply to BIMO inspections. However, the FDA has been successfully relying on voluntary records requests for BIMO inspections and devices. SMG 9004.1 outlines the process for 704(a)(4) records requests, https://www.fda.gov/media/124338/download.
 See e.g., Guidance for Industry, Manufacturing, Supply Chain, and Drug and Biological Product Inspections During COVID-19 Public Health Emergency Questions and Answers, August 2020 https://www.fda.gov/media/142051/download.
 Data from Elizabeth Miller (FDA ORA) presented at the PDA/FDA Joint Regulatory Conference, September 2020; see also Preparing for the Return of FDA inspections, Bowman Cox, Pink Sheet, February 3, 2021.
 PREPP Initiative Report, p. 49, https://www.fda.gov/media/145129/download. The PREPP Initiative was launched in August 2020 to “Identify opportunities that strengthen [FDA’s] on-going COVID-19 response and build the Agency’s resilience to respond to future public health emergencies.” The initiative involved agency interviews, and external listening sessions hosted by third parties, among other things.
 FDA does not make CRL letters public, but companies often announce that they have received a CRL after the goal date passes. From publicly available documents I found CRLs sent to CorMedix, Novartis, Liquidia, Alkermes, Sanofi, Zosano, and Nabriva for inability to conduct an inspection, and delayed goal dates for Mallinckrodt, Revance, BMS, and Spectrum.
 See e.g., FDA presentation at PDA Webinar, June 2020.
 Presentation by Doug Throckmorton, CDER Deputy Director, FDA/Xavier PharmaLink Conference, March 11, 2021, https://www.xavierhealth.org/events/pharmalink-2021.
About The Author:
Kalah Auchincloss, J.D., M.P.H., is SVP of regulatory compliance and deputy general counsel for Greenleaf Health. She has more than a decade of food and drug legal, policy, and regulatory experience at the FDA, on Capitol Hill, and in the private sector. At Greenleaf, Auchincloss advises pharmaceutical and medical device companies on compliance, policy, and other issues. Before moving to Greenleaf, Auchincloss spent six years at the FDA, most recently as deputy chief of staff, but also serving in CDER’s Office of Compliance and Office of Regulatory Policy. You can contact her at email@example.com.