Kalah Auchincloss, senior vice-president and deputy general counsel, Greenleaf Health, Inc.

Kalah Auchincloss

In December 2019, the world changed when China identified a novel, highly infectious and deadly coronavirus, SARS-CoV-2, also referred to as COVID-19. By January 2020 (if not earlier), the virus had spread to the United States, and on Jan. 31, 2020, the then-Secretary of Health and Human Services (HHS), Alex Azar, declared a public health emergency (1).

The virus has had far-reaching, previously unimaginable consequences for daily life. In addition to the more visible day-to-day changes experienced, regulatory agencies have also had to significantly adjust their operations as a result of SARS-CoV-2. For example, FDA suspended domestic and foreign on-site inspections of facilities that manufacture FDA-regulated products early in the pandemic.

This article explores the evolution of FDA’s approach to inspections of drug and biologics manufacturing facilities over the past year. This review includes a description of the actions FDA has taken with respect to inspections in response to the COVID-19 pandemic and then moves to lessons learned, including a discussion of what the future might hold.

Timeline of FDA inspectional activities and policies during COVID-19

Secretary Azar’s declaration of a public health emergency under the Public Health Services Act allowed national, state, and local governments additional flexibility and funding to respond to COVID-19 (1). FDA itself has taken a number of actions to protect the safety of its employees and the employees of regulated industry, and to most efficiently and effectively use its resources. The following timeline of FDA activities related to inspections provides context for the environment in which both FDA and the pharmaceutical industry are operating in 2021.

March 2020: suspension of most on-site inspections. 

To protect the health and safety of its workforce, on March 10 and March 18, 2020, FDA suspended all foreign and domestic surveillance inspections, respectively, except those deemed “mission critical” (2, 3). In its announcements, FDA reassured the public that the Agency had “full confidence in the safety and quality of the products we all use every day” and that it was “evaluating additional ways to conduct our inspectional work…include[ing], among other things, evaluating records in lieu of conducting an onsite inspection” (3). It also noted that “mission critical” inspections, including for-cause inspections, would continue, on a case-by-case basis, although it did not further elaborate on the criteria for “mission critical.”

FDA extended the suspension of inspections in a May 2020 announcement, reiterating that it would “continue to utilize and implement additional alternative inspection tools and approaches while postponing domestic and foreign routine surveillance inspections” (4). The May announcement also reemphasized that “mission critical” inspections were being identified on a case-by-case basis and alluded to a collaboration with the Centers for Disease Control & Prevention (CDC) to develop a process that would govern when, how, and where to reinstate on-site facility inspections (4).

Throughout the spring and early summer, FDA continued its “mission critical” only policy, focusing on the use of “alternative tools” to achieve its mission when inspections were not possible, and repeatedly reassuring the public about the safety and quality of medical products, even without FDA’s presence on site (5).

Perhaps most importantly, in the absence of on-site inspections, FDA has dramatically increased its records requests under section 704(a)(4) of the Federal Food, Drug & Cosmetic Act (FD&C Act). More specifically, section 704(a)(4) provides FDA with authority to request, “in advance of or in lieu of an inspection”, records or information FDA may otherwise request upon (physical) inspection under section 704(a) of the FD&C Act.Note that this provision applies only to drugs and biologics, not to medical devices.FDA also believes section 704(a)(4) does not apply to bioresearch monitoring (BIMO) inspections of clinical trial sites. However, FDA has been relying on voluntary records requests for both BIMO sites and device facilities and encourages all facilities to follow the records request procedures laid out in a staff manual guide (6).

In addition to records requests, FDA may also rely on information from inspections by regulatory authorities in the European Union under the Mutual Recognition Agreement (MRA) (7) and from capable authorities in certain countries that participate in the Pharmaceutical Inspection Co-operation Scheme (PIC/S) (8).PIC/S is an informal cooperation between over 50 countries with comparable inspection standards intent on harmonizing international good manufacturing practice (GMP) standards (8). Inspections of facilities manufacturing vaccines (and plasma derived products) are not immediately included within the scope of the MRA, although there is a provision to evaluate the possibility of their inclusion no later than 2022. In addition, preapproval inspections are within scope, but require additional coordination because they are application specific. Thus, at this point, FDA and the EU have focused largely on routine GMP inspections (9). The Agency may also review a facility’s past FDA compliance history and inspectional outcomes or employ tools at the border under 21 U.S.C. § 381 to sample foreign pharmaceutical products or detain and refuse entry to products that appear to be adulterated or misbranded (see 

Table I. Alternative tools. [Click to Enlarge]

July 2020: “Prioritized” domestic inspections resume

. On July 10, FDA announced that it would resume domestic inspections on July 20, 2020 (10). The announcement indicated that FDA would use a COVID-19 Advisory Rating System to assess whether inspections could safely be conducted, applied at the county level. FDA also stated that all inspections would be preannounced to allow for safety planning, which is a significant, but necessary change from prior policy for domestic inspections (10).

August 2020: FDA releases guidance on inspections.

 Almost a month after FDA planned to resume domestic inspections, the Agency released a guidance on inspections in August 2020 (11).In a frequently asked questions format, the guidance provided some useful insights, including: reiterating that FDA would resume “prioritized domestic inspections, which generally include pre-approval and surveillance inspections based on the COVID-19 Advisory Rating System”; an expanded definition of “mission critical” inspections, to include new factors such as breakthrough or Regenerative Medicine Advanced Therapy (RMAT) designation as well as products used to diagnose, treat, or prevent a serious disease or medical condition for which there is no other appropriate substitute; and an explanation of when FDA would issue a complete response letter (CRL) for inspection-related issues versus when it would simply defer the goal date on an application (11).

The guidance also made very clear that given the state of the pandemic and the ongoing limited ability to conduct inspections, FDA would continue to use the “alternative tools” described above to inform regulatory decisions on an application. More specifically, the guidance states that “CDER [Center for Drug Evaluation and Research] and CBER [Center for Biologics Evaluation and Research] are continuing to evaluate applications, strategically applying a holistic approach in the decision-making process to determine if an inspection is warranted or if an inspection is no longer needed due to information gained through the use of the additional tools mentioned above” (11). Notably, the guidance focused largely on pre-approval inspections necessary to make a decision on a pending application. It did not address follow-up inspections to close out a warning letter at facilities that have implemented corrective actions, or who are otherwise seeking reclassification out of “official action indicated” (OAI) status. It also mentioned, but did not directly address, routine surveillance inspections (11).

In response to significant external pressures to improve transparency around section 704(a)(4) records requests, FDA updated the guidance document in January 2021 to reflect a new process for communicating with industry about such records requests. Although slim on details, the guidance now states the following in response to Question 5:

“FDA is also working directly with facilities to communicate any issues identified through a review of records or other information requested. For example, for both CDER- and CBER-regulated products, interim processes have been implemented to communicate with manufacturing facilities regarding issues identified following a review of records or other information requested in advance of or in lieu of a pre-approval or pre-license inspection. Responses from the facility regarding these issues will, as feasible, be considered before taking an action on a pending application.” 

Fall 2020: data about inspections and alternative tools begins to emerge

. After the August guidance, FDA did resume expanded domestic inspections, although foreign inspections were still limited only to those deemed “mission critical.” In October, for example, Judy McMeekin, Associate Commissioner for Regulatory Affairs at FDA, indicated in a speech that FDA had conducted more than 200 “mission critical inspections” (both foreign and domestic) during the pandemic, which included “inspections of facilities for which there may be a drug shortage, or inspections needed for approval of a novel drug or drugs related to the treatment of COVID-19” (12).

The Agency also spoke at several conferences in the fourth quarter of 2020, providing the public with limited data on the frequency with which FDA was employing the “alternative tools” discussed above (see 

). At those conferences, senior agency personnel reassured participants that decisions on applications would not encounter inspection-related delays and that the Agency was prioritizing inspections with pending user goal dates “using a benefit versus risk calculation that will factor public health and access to critical therapies”and had also been able to make judgments on the quality of “hundreds” of drug manufacturing facilities without actually visiting them (13, 14).

Table II. Data on FDA 704(a)(4) Records Requests through August 2020 (Reference 14). [Click to enlarge]

Agency staff also hinted at additional alternative tools in the pipeline, suggesting the possibility that video and other technology could be employed to supplement or enhance inspections. One CDER employee even suggested that a guidance on “remote evaluations using interactive video or other types of interactive tools and techniques” would be forthcoming (15), while another referred to a more formalized process for communicating outcomes from a 704(a)(4) records request and officially closing it out (16), and a third referred to testing the use of live video during inspections of two produce farms and requesting feedback on remote inspections for the drug industry (12). Late in December, an Office of Regulatory Affairs official reiterated that the agency was “working aggressively” to develop a more formal 704(a)(4) process and that there was also a “working group” considering the use of virtual technologies (16).

Early 2021: the data begin to tell a different story.

 In January, February, and early March of 2021, even more data began to emerge about the impact of a year of limited inspections. On the one hand, FDA continued to tout its successes with alternative tools and emphasize that the Agency was continuing to consider how to improve those tools, including with virtual components. On the other hand, industry and other third parties, including the Government Accountability Office (GAO), painted a different picture of a growing backlog of inspections, a lack of transparency and consistent processes around the use of alternative tools, and a desperate need for FDA to shift from emergency mode to long-term thinking and planning about the conduct of inspections.

CDER’s Work to Meet User Fee Goals During the Pandemic

, included a wealth of data on the Agency’s successful use of alternative tools (17). Notably the website states that: CDER completed facility assessments to meet goal dates by reducing the need to conduct pre-approval inspections 48% of the time in the third quarter of Fiscal Year (FY) 2020, 60% of the time in the fourth quarter of FY2020, and 51% of the time in the first quarter of FY2021 (17); and with the exception of biosimilar applications, FDA met CDER and CBER goal dates more than 90% of the time in the third and fourth quarters of FY2020 and the first quarter of FY2021, consistent with its goal letter commitments (17).

The Agency also issued the first warning letter on the basis of a records request alone (with no onsite inspection) to a Chinese company manufacturing an adulterated hand sanitizer product (18); issued a guidance on review timelines after a complete response letter was sent (19); updated the August manufacturing guidance to include a new process for communication regarding 704(a)(4) records requests (as discussed earlier); continued PDUFA VII and GDUFA III negotiations, including discussions about alternative tools and future inspection options (20, 21); and issued its Office of Pharmaceutical Quality (OPQ) Annual Report for 2020, which emphasized OPQ’s ability to pivot to alternative tools during the pandemic once inspections shut down, and its commitment to “develop[ing] new approaches and explore[ing] new technologies and processes to conduct facility assessments under our current authorities” (22). According to the report, with the use of alternative tools, OPQ avoided the need to conduct 153 on-site facility inspections prior to application approval, and averted 293 potential drug shortages (22).

GAO, however, provided a grimmer outlook. In an extensive report published in January

 GAO found that from March to October 2020:

Fifty-two domestic surveillance inspections were conducted compared to approximately 400 during the same time frame in each of the previous two years

Three mission critical foreign inspections were conducted (only one was non-COVID related) compared to more than 600 in the same time frame in each of the previous two years

More than 1000 of the 1500 planned surveillance inspections were 

GAO strongly encouraged FDA to “ensure that inspection plans for future fiscal years identify, analyze, and respond to the issues presented by the backlog of inspections that could jeopardize its goal of risk-driven inspections”, and “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” (23).

The COVID-19 Pandemic Recovery and Preparedness Plan (PREPP) initiative report supported GAO’s recommendations. The PREPP initiative was created 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” (24). The initiative relied on support from external third parties, including through agency interviews, external listening sessions, and facilitated implementation of certain initiatives. The PREPP initiative report released in January 2021 included a section with three recommendations for improving FDA inspections: implement better communication regarding FDA’s approach to inspections during COVID-19 (including guidelines to designate work as mission critical); develop a comprehensive inspection optimization roadmap, such as scaling up the use of virtual tools, better allocation of resources toward risk-based inspections, improved global harmonization, and enhanced stakeholder engagement; and define and measure the effectiveness of inspectional approaches (24).

With this context in mind, there are five key takeaways from the past year that are important to consider as the pandemic progresses, and possibly comes to a close.

Alternative tools are critical as inspections are still limited.

 Even with the resumption of certain domestic inspections, and the possibility of foreign inspections also resuming (inspections have started back up in China and India as of January), it is clear from the limited data presented in August 2020 and from FDA statements over the past several months, that the Agency is still relying heavily on the use of alternative tools to inform the need for on-site inspections and, in some cases, avoid them altogether. This is particularly true with current case rates severely truncating the ability travel to on-site locations. At the end of December 2020, FDA was blunt that it has curtailed domestic inspections back to “mission critical” only, and that even those were limited, given the uptick in cases (16).

Within those alternative tools, records requests under section 704(a)(4) appear to be the primary tool in lieu of an inspection, used to help determine whether an on-site inspection is needed or may be waived. FDA is liberally using this authority to request records from drug manufacturers, but also considering its use on a voluntary basis for programs to which the statutory authority does not explicitly apply (devices and BIMO inspections) (14). FDA has also listened to requests from industry to refine the records request process and provide transparency regarding the outcomes of such a request by updating the manufacturing Q&A guidance. As we emerge from what appears to be the worst phase of the pandemic to date, there is every reason to believe that FDA will continue to heavily rely on records requests, and perhaps expand its use.

. Despite its increasing reliance on records requests, FDA has been clear that requests made under section 704(a)(4) are not the equivalent of an inspection (16). Even if virtual technology is used as part of a records request to provide pictures or video feed of a facility, FDA has held fast to its view that an inspection—which begins with the presentation of FDA credentials and FDA Form-482 and often ends with an FDA Form 483 listing concerning observations—is on-site only. At this point there is no such thing as a “virtual” or “remote” inspection by FDA (16). The result is that FDA has focused its attention on records requests as a tool to determine whether or not an on-site, preapproval inspection is needed to make a decision about an application, or whether the inspection may be waived. It has not expanded its use to reclassify a facility or close-out a warning letter, which FDA believes still requires a physical, on-site review of corrective actions (16). It also appears, from the GAO report, that routine surveillance inspections are suffering (23).

Despite best efforts, there are regulatory and real-world consequences.

 The reality of living in a world with limited inspections and no “remote” FDA inspections is that if “alternative tools” are inadequate, not appropriate, or otherwise signal a need for an on-site visit that cannot be safely conducted, FDA is stuck with the difficult decision of delaying goal dates, issuing a CRL, and/or letting facilities remain in OAI status (therefore barring approval of products manufactured at those sites). This situation can lead to drug shortages and significant access problems for patients.

FDA has done its absolute best to mitigate these consequences—it approved 53 novel drugs in 2020, six more than it approved in 2019 (25)—but it cannot avoid them altogether. It has deferred PDUFA dates at least five times during the pandemic because of an inability to conduct a necessary on-site PAI and issued a CRL seven times for the same reason (one CRL was issued after major deficiencies were found during an inspection) (See 

). FDA does not make CRLs public, but from publicly available information, it seems as if FDA has reserved CRLs or delays in PDUFA dates for situations in which questions raised are significant enough that FDA requires an on-site inspection; and/or the Agency estimates that it will take the facility significant time to resolve the deficiencies, thus the review clock needs to be restarted (See 

Table III. Complete response letters (CRLs) and delayed goal dates as a result of inability to conduct inspection. NDA is new drug application. BLA is biologics license application. PAI is preapproval inspection.

[Note: references in table] [Click to enlarge]

Compared to the more than 500 records requests made (which led to decisions on more than 100 applications, including 77 approvals), it appears that a CRL or delayed PDUFA date is not a first-choice option. Nonetheless, CRLs and missed dates are happening, and may begin to happen with more frequency as inspections are further cut back. Moreover, companies are increasingly frustrated at FDA’s refusal to use alternative tools to review corrective actions at sites that have received a warning letter or are in OAI status, and, as GAO found, routine surveillance inspections have been severely curtailed.

. Although it has done its best in a difficult situation, as the pandemic drags on it becomes more clear that FDA cannot continue to miss goal dates and let OAI status linger. Moreover, the GAO report points to an enormous backlog of routine surveillance inspections that simply were not conducted in FY20. As the backlog piles up, public pressure mounts, and patient access to medications is compromised, FDA will need to reevaluate its inspection policies. For example, the agency could explore whether a true “virtual” inspection of a facility is possible, which would include issuing a Form-482 and closing it out with a Form-483 and would result in the same regulatory consequences as an on-site inspection (e.g., a warning letter, classification or reclassification of the site, approval/withhold decision on an application). At a minimum, FDA will need to consider whether virtual tools can be used to supplement a 704(a)(4) records request to enhance facility “assessments” or “evaluations” that, even if not legally an inspection, could lead to the same outcome as an inspection (including reclassification of an OAI site). Dr. Throckmorton alluded to this idea of “remote interactive evaluations” of facilities at a conference in March 2021, which is encouraging, noting that the Agency has had useful experiences with the limited number of such evaluations it has conducted to date (39). There will always be circumstances which necessitate a physical, on-site review of a facility, but if nothing else, the pandemic has shown us that flexibility and adaptability are critical.

Alternative tools likely to stick around. 

Once the pandemic is over, and FDA resumes a more normal schedule of for-cause, surveillance, and pre-approval inspections, it is still highly likely that it will continue to use its alternative tools far more liberally than in pre-pandemic times. In particular, the reliance on 704(a)(4) records requests has enabled the Agency to more efficiently deploy inspection resources and to more effectively conduct those inspections that are necessary. This is extremely valuable to FDA and will not be forgotten post-pandemic. Moreover, given the backlog of surveillance inspections, and the external pressures from GAO, industry, and other stakeholders, as the emergency response calms down, FDA will have to grapple with its risk-based inspections model. Serious re-thinking of how, when, and under what framework FDA conducts inspections will be needed as FDA begins to think about its long-term inspectional plan.

FDA’s conduct of inspections has significantly changed over the past year. As we wait for the vaccines to be administered and life to return to a more normal cadence, I hope we can expect further changes in inspection policy from FDA, including guidance on the use of virtual tools and/or “remote interactive evaluations”, more formal processes for 704(a)(4) records requests, and even true remote inspections. As part of these new policies, FDA will need to clearly define terminology, paying particular attention to use of the terms “inspection”, “evaluation”, “assessment”, “remote”, and “virtual”, all of which have been thrown about over the past year, but inconsistently used.

For industry’s part, if we assume that records requests are here to stay and that there may be a virtual component to those requests not too far in the future, industry should consider continuing to engage with FDA on the processes and policies the Agency is developing—there is an opportunity now to provide feedback to FDA and to have opinions heard—and begin to prepare for the new realities of the inspection process. For example, become familiar with FDA Staff Manual Guide 9004.1, ensure the necessary infrastructure and training are in place to handle records requests (including virtual components), recognize the difference between an inspection and a records request and the different regulatory outcomes, and consider developing internal policies and procedures to respond to records requests before one is received. And, we all need to consider the GAO and PREPP initiative reports, and begin to think long-term about a revised inspectional framework.

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27. CorMedix, “CorMedix Receives Complete Response Letter From Fda For Defencath™ Catheter Lock Solution,” Press Release, March 1, 2021.
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, Jan. 20, 2021.
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32. Liquidia, “Liquidia Receives Complete Response Letter from FDA for LIQ861 (Treprostinil) Inhalation Powder for the Treatment of Pulmonary Arterial Hypertension,” Press Release, Nov. 25, 2020.
33. Alkermes, “Alkermes Receives FDA Complete Response Letter Related to ALKS 3831 Manufacturing Records Review,” Press Release, Nov. 17, 2020.
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, Nov. 16, 2021. 
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36. Spectrum, “FDA Delays Approval for Hanmi’s Neutropenia Drug Rolontis,” Press Release, Oct. 27, 2020. 
37. Zosana, “Zosano Pharma Receives Complete Response Letter from FDA for Qtrypta,” Press Release, Oct. 21, 2020.
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39. D Throckmorton, Deputy Director of CDER, FDA/Xavier PharmaLink Conference, March 12, 2021.

Kalah Auchincloss is senior vice-president and deputy general counsel, Greenleaf Health, Inc.

Articles

This article explores the evolution of FDA’s approach to inspections of drug and biologics manufacturing facilities during the COVID-19 pandemic.