Podcast: Non-binding Guidance: Recent Developments in FDA Inspection Policy and Implications for Drug and Device Manufacturers
This installation of Ropes & Gray’s podcast series Non-binding Guidance focuses on recent developments in FDA inspection policy, including implications of the pandemic-related slowdown on product quality and approval delays as well as progress FDA has been making in clearing the inspection backlog. In March 2020, many routine inspections, such as foreign pre-approval and for-cause inspection assignments not deemed “mission-critical,” were temporarily postponed, but FDA has recently restarted some inspections. In this episode, Ropes & Gray life sciences regulatory & compliance practice group leader, Greg Levine, and Ropes & Gray counsel and former FDA Office of Chief Counsel attorney, Beth Weinman, discuss the significance of these developments and what FDA-regulated entities can expect when thinking about and preparing for FDA inspections in 2022.
Note: On December 29, 2021, following the recording of this podcast, FDA announced that, through January 19, 2022, it would conduct only mission critical foreign and domestic onsite inspections and would temporarily postpone certain other inspectional activities due to the spread of the Omicron variant. The agency also postponed the planning of prioritized surveillance foreign inspection assignments scheduled to begin in February 2022. These actions are likely to affect some FDA approval decisions and the agency’s attempt to clear its inspections backlog. The extent of the impact will depend on how quickly FDA can resume its previously planned on-site activities. (https://www.fda.gov/news-events/press-announcements/fda-roundup-january-4-2022)
Greg Levine: Welcome to Non-binding Guidance, a podcast series from Ropes & Gray focused on current trends in FDA regulatory law, as well as other important developments affecting the life sciences industry. I'm Greg Levine, a partner in the firm based in Washington, D.C., and head of Ropes & Gray's life sciences regulatory and compliance practice group. I'm joined by my colleague, Beth Weinman, counsel on our life sciences regulatory and compliance team and a former enforcement litigator for FDA’s Office of Chief Counsel, also based in Washington, D.C. Today, we will focus on recent developments in FDA inspection policy. We'll discuss implications of the pandemic-related slowdown in inspections, progress FDA has been making in resuming inspections and catching up on the inspection backlog, and what FDA-regulated entities can expect when thinking about and preparing for FDA inspections in 2022.
Beth, why don't we start by talking about FDA's inspection slowdown, and how the Agency has been prioritizing inspection since then. Will you walk us through that?
Beth Weinman: In March 2020, FDA temporary postponed most foreign routine surveillance facility inspections, and significantly scaled back domestic inspections. The Agency said at the time that it would use “alternative tools” to inspect when possible, but it wasn't totally clear what that meant at the time.
In May 2020, FDA announced that it would conduct certain “mission-critical” for-cause and pre-approval inspections. FDA announced that inspections it considered “mission-critical” would be inspections where the product to be inspected either required follow-up due to recall or a serious adverse event; was used to treat a serious condition and there wasn't any substitute; was related to FDA's COVID-19 response (including drug shortages); or had received breakthrough therapy or an RMAT [Regenerative Medicine Advanced Therapy] designation.
In July 2020, FDA announced it would resume prioritized domestic inspections, using what it called a “COVID-19 Advisory Rating” system, and that system was supposed to help the Agency identify when and where it would be safest to conduct inspections. Prioritized domestic inspections would be pre-announced, and would include pre-approval, surveillance, and for-cause inspections. Inspections would be prioritized according to factors such as whether the inspection is intended to follow-up on a previous violative inspection; if the inspection was needed to support a product approval decision where no other application deficiencies were known that would preclude approval; whether the inspection would be considered high-risk under statutory inspection frequency mandates; or otherwise had maximized the use of limited inspection resources to achieve the greatest public health impact during the pandemic.
In August 2020, FDA confirmed that foreign pre-approval and for-cause inspection assignments not deemed “mission-critical” would remain temporarily postponed.
Greg, you and I have been working on some challenging foreign inspection issues recently. Can you talk a bit about what has been going on with foreign inspections in the aftermath of that August 2020 announcement that foreign pre-approval and for-cause inspections that were not deemed “mission-critical” would remain temporarily postponed?
Greg Levine: The short answer is that FDA's been ramping up its foreign inspection activity over time. In our legal practice, we've been seeing more and more of the foreign inspections conducted, and I think it would be fair to say that so far these inspections have been of the “mission-critical” type, and not the routine surveillance type of inspections. But beginning in late 2020, FDA’s China office resumed doing limited pre-approval inspections, and then in the beginning of 2021 had resumed similar pre-approval inspections from its India office.
Most recently, in December 2021 during an FDLI Enforcement Conference, Elizabeth Miller, FDA Assistant Commissioner of Medical Products and Tobacco Operations in the Office of Regulatory Affairs, announced that the Agency will be resuming a pilot program it had previously initiated to perform unannounced and short-notice inspections in India, and that they would be expanding that program into China. That program responds to long-standing concerns that have been expressed by members of Congress and others about the perceived uneven playing field between domestic and foreign establishments, where only the foreign establishments would receive prior notice of FDA inspections. There's been a longstanding issue with FDA's ability to conduct unannounced foreign inspections for various reasons—there’s legal questions about their legal authority to do so, or to require such inspections, and then there's more practical reasons like the need to coordinate logistics with the establishment before putting people on a plane, for example, to fly to a foreign country. Of course, where FDA has people on the ground now in certain countries like India and China, that potentially addresses that latter issue, at least to some extent.
In any event, there are some interesting questions about how well that program's going to work, and in our practice, we've already seen some serious challenges with FDA trying to initiate inspections on 10 days’ notice. It's going to be interesting to see how well that program succeeds—but in any event, that's kind of where we are with the foreign inspections. We are seeing these inspections again, pre-approval and BIMO [Bioresearch Monitoring] inspections, not so much the routine surveillance inspections.
Beth, why don't we turn to the implications of FDA's inspection slowdown, what it has meant for industry, and could you talk about what it's meant for the public more generally as well?
Beth Weinman: First of all, reduced inspections have meant reduced oversight of drug manufacturing and many have been concerned that that could lead to higher risk or less safe products. Another implication that has industry worried is the potential inability of FDA to approve certain drugs or devices on expected timelines. The GAO reported on these issues in March of 2021 when it released its report called "FDA's Future Inspection Plans Need to Address Issues Presented by COVID-19 Backlog."
In that report, the GAO found that the total number of foreign and domestic drug inspections that had been conducted by FDA from March 2020 through October 1, 2020 had plummeted. FDA had conducted only three foreign drug inspections in that 2020 time frame. In comparison, in fiscal year 2019, FDA had conducted 694 domestic, and 977 foreign drug inspections. The limited number of foreign inspections is particularly significant as the report noted that 74% of establishments manufacturing active pharmaceutical ingredients, and 54% of establishments manufacturing finished drugs for the U.S. market, were located overseas as of May 2020.
The GAO report also noted that FDA had been unable to complete more than 1,000 of its planned fiscal year 2020 surveillance drug inspections. The significant reduction in inspections has impacted the timing of product approvals. From March 2020 to March 2021, FDA received over 13,500 applications for medical product approval and was forced to delay 68 application decisions for drugs, devices, and biologics, due to its inability to conduct pre-approval, pre-market, or pre-license inspections, which is about 5% of the total applications. I'll note that 61 of those 68 applications that were delayed were not considered to be “mission-critical.” FDA also experienced minor delays in conducting follow-up compliance inspections for facilities with “official action indicated” status, completing 90% of its follow-up activities in fiscal year 2020.
We don't have statistics to back up concerns that have been articulated about product quality due to limited inspections. But GAO's report, and FDA's response, which came in the form of a May 2021 document titled, "Resiliency Roadmap for FDA Inspectional Oversight," has led to congressional concern. On July 22, 2021, the House of Representatives' Committee on Energy and Commerce wrote to acting Commissioner Woodcock to ask for more information about FDA's efforts to mitigate its backlog of manufacturing facility inspections, and drug approval delays, stemming from this backlog. The letter asked a series of questions about FDA's anticipated return to standard operations for both domestic and foreign inspections, and also asked for detailed information about drug approval delays. The Committee also asked for more information about how FDA can use alternative tools—whether they be foreign body inspections, record requests, or remote interactions—to help ameliorate the inspection backlog.
Greg, FDA keeps talking about using alternative tools to maintain oversight while it can't get to all the sites it wants to. What do those tools look like, and will remote evaluations ever be able to replace inspections?
Greg Levine: Well, I don't think anyone thinks the remote evaluations will replace inspections. In fact, this seems to be a consensus of international regulatory agencies. There was a report recently by the International Coalition of Medicines Regulatory Authorities—a grouping of regulatory agencies globally—and while they all seem to use these various kinds of alternative tools, nobody seems to think it's a replacement, particularly if you have issues like data integrity issues that you'd be concerned about at a site. There are certain things that are just hard to do remotely; you can't really replace being in front of someone and seeing them, and asking questions in person firsthand.
But as for FDA, to help maintain oversight of manufacturing quality while the inspections were paused, the Agency leveraged certain alternative inspection tools. These included relying to some extent on inspections conducted by foreign regulators, requesting and reviewing records and other information offsite, and sampling and testing products. With regard to the foreign regulators, FDA has determined that inspections conducted by certain European countries are considered equivalent to FDA inspections, so they will just accept those as a substitute for FDA inspections. In the drug area, with regard to requesting records, FDA has legal authority under Section 704(a)(4) of the Federal Food, Drug, and Cosmetic Act to request records and receive records in advance of, or even in lieu of, a facility inspection—so, FDA uses that tool. Outside the drug area, it doesn't have that legal authority, but it can still request records, and in many cases, there's going to be an incentive for the entity that would be the subject of the request to cooperate with the FDA. And then to some extent, sampling and testing of product can help protect against problematic products, but I don't think anyone considers that to be a failsafe method, and certainly they can't do that with most products coming in to the country or being distributed domestically.
The alternative tools have allowed FDA to take some regulatory actions against foreign drug manufacturing establishments with manufacturing deficiencies during the inspection pause. And so again, going back to that concern about the foreign product, in particular, where FDA's inspections have been fewer than domestic, from March 1 to December 1, 2020, the FDA placed 64 foreign establishments on import alert for a variety of reasons. One was because of an inspection report from a foreign regulatory authority. Another nine were for refusing FDA record requests. There were more than 50 issues identified with product sampling.
With regard to some of the specific areas where remote tools may not be as effective, according to that ICRMA report that I mentioned, as I said, it's harder to conduct effective interviews. Face-to-face you can assess body language, nervous behaviors, and so forth. The dynamics of the meetings can impede free-flow of information, and I think we've all dealt with that with our Zoom meetings, and Teams meetings, and these kinds of things—it can sometimes be less than smooth in how the meeting proceeds. There can be delays in availability of personnel or documents that might raise uncertainties about whether there's been some kind of interference, or the authenticity of documents. If you're dealing with really large records, that can be sometimes impractical to transfer and view remotely. You can, of course, see in person the physical layout of a site, so there might be design features that are missed. You can't replicate sensory perceptions like hearing things, and smelling things, and so on, which might suggest some risk to an investigator. And in the Good Clinical Practices area, it can be hard to do remote inspections in some cases of investigator sites where it might be a very large burden on investigators to provide access to paper records, and then the inspection of source documents sometimes can be impossible due to local legal requirements.
FDA has also published guidance on what it calls “remote interactive evaluations.” Beth, why don't you explain those, and how they are similar or different from ordinary inspections?
Beth Weinman: FDA responded to this question exactly in a final guidance that it issued in April 2021. That guidance was called "Remote Interactive Evaluations of Drug Manufacturing and Bioresearch Monitoring Facilities During the COVID Public Health Emergency." FDA made clear in the guidance, first of all, that we're dealing with drug evaluations, and that remote interactive evaluations are not and would not be a replacement for surveillance inspections. But as for process, FDA noted that generally, it will request records and other information under Section 704(a)(4) of the FDCA before initiating a remote interactive evaluation. Then as part of that evaluation, FDA might request and review documents, records, and other information in electronic systems. It might use live stream or pre-recorded video to examine facilities, operations, and data or other information—and I noted that there is concern about how good that type of video is in examining the facility like an inspector would be able to do live, but it gives at least some insight. FDA noted that through the facility's point of contact, it would schedule interviews and meetings to address any questions or concerns it had. It would evaluate a facility's corrective actions—for example, in response to a previous inspection or evaluation, or in response to issues identified in the ongoing remote interactive evaluation. FDA said that it would provide verbal updates to the facility on all observations and outstanding issues whenever feasible. And upon completion of the remote interactive evaluation, FDA would have a closeout meeting with facility management. If the remote interactive evaluation was intended to supplement a scheduled inspection, FDA would issue an FDA Form 483 at the close of the inspection. Otherwise, FDA would present a list of written observations, but would not issue a 483. In either case, however, FDA encourages a response to those written observations within 15 days.
A remote interactive evaluation could be used to support FDA's assessment of pending applications, to preclude the need for an inspection and a follow-up to report a concern. However, if issues are identified during a remote interactive evaluation, the evaluation might support a regulatory meeting, a warning letter, an import alert, recall activities, or other enforcement actions that might cause FDA to prioritize the facility for an inspection, or justify follow-up or compliance inspections, or any other surveillance activity.
The guidance also describes how the Agency would request and conduct voluntary remote interactive evaluations at drug manufacturing facilities as part of the BIMO program, and also with respect to outsourcing facilities. FDA might request remote interactive evaluation for inspections that are not deemed “mission-critical” or prioritized, or that otherwise have been impacted by travel restrictions, and would use a risk-based methodology to decide when to perform remote evaluations. Although remote evaluations are voluntary, declining an FDA request for such an evaluation could impede the Agency's ability to make a timely regulatory decision—for example, regarding the adequacy of a clinical trial used in support of a pending application, or the adequacy of a drug manufacturing operation that's described in an application.
Greg, so we know that FDA has various alternative tools at its disposal, but they're not a substitute for inspections, and we also know that FDA continues to have a sizable backlog. How does FDA expect to catch up and get back on track? What is its plan?
Greg Levine: In response to the GAO report that you mentioned earlier, FDA released a document, a plan, what they called a “Resiliency Roadmap for FDA Inspectional Oversight” in May of 2021. In that document, they outlined best-case, base-case, and worst-case possible scenarios. In July of 2021, FDA transitioned to the base-case scenario, and that means under that scenario the FDA would move to standard operational levels for domestic surveillance inspections. So, domestic surveillance inspections only would move to standard operational levels, and the foreign inspections would remain in the “mission-critical” prioritization or “mission-critical” inspection focus. In November, FDA published an update on its resiliency roadmap and it announced that it actually had exceeded all of its targets under the base-case—so actually, it was doing better than it had planned to, or expected to, under that base-case scenario. But of course, that's addressing only the domestic inspections.
The other thing in that report that FDA reported on is where they are on inspections for pending applications, and there, the FDA had made progress from the prior report in May to November in getting cleared some of the pending applications that were delayed because of inspectional delays from the earlier report, but of course, they not surprisingly had received more applications in the interim. So, as of November, there were still 60 applications that were delayed due to the inspectional delays. I think what we'll expect to see going forward is FDA under its plan is going to continue to operate under the base-case. We hope that the Omicron variant won't make them go backwards, but if they can continue to do that, they'll try to clear some of the backlog. For the international inspections, they're still going to be somewhat limited in the way they have been, and so we think we'll still continue to use some of the alternative tools that we've talking about, the interactive evaluations and so on. And then product approvals, we'll hopefully get closer to being back on track soon, but there's still a backlog that's going have to be worked through for some time.
Beth, one last question for today and I think we're going to be out of time, but from the perspective of regulated entities, manufacturers, what should they be thinking about as FDA works on its plan to eliminate the backlog and get back to more normal inspectional operations?
Beth Weinman: Manufacturers are going to have to make sure their facilities are inspection-ready, with the expectation that FDA is going to be coming back to inspect, though it's hard to say exactly what that schedule's going to look like. Over the course of the pandemic there have been stops and starts in terms of FDA activity, but FDA has issued a number of pandemic-related guidances to help companies and facilities prepare for future inspections whenever they would get started. For example, in September 2020, FDA published a guidance on “Resuming Normal Drug and Biologic Manufacturing Operations During the COVID Pandemic,” and that sets out a roadmap for the ways that companies can approach getting their house in order prior to an FDA inspection. Similarly, in May 2020, FDA revised its guidance on “Postmarketing Adverse Events Reporting for Medical Products and Dietary Supplements During a Pandemic,” wherein FDA had permitted certain delayed adverse event reporting due potentially to pandemic-related employee absenteeism as long as certain documentation was maintained. FDA is going to be looking at that documentation and making sure that reports are timely submitted, or else if they were not, that the appropriate documentation was maintained.
Outside of specific concerns that are highlighted in FDA guidances, disruptions caused by the pandemic and manufacturing operations, or employee attendance, may have impacted broader quality initiatives. For example, there may have been delays in quality audits, or in procedure reviews, employee trainings, or CAPA activities. FDA frequently cites manufacturers for failing to implement appropriate policies and procedures, but also for failing to adhere to policies and procedures as they're written, and manufacturers will need to make sure they are prepared to account for any deviations, and document what was done in connection with those deviations.
Greg Levine: Thank you, Beth. I think we probably would have hoped that, by now, some of those FDA guidance documents for the pandemic would no longer be relevant, but as things have gone it seems they still may be for some time. Beth, thank you for joining me today, and thank you to our listeners. For more information on this topic or others, please visit our website at www.ropesgray.com, and of course, if we can help you navigate any of the topics we've discussed, please don't hesitate to get in touch. You can also subscribe to this series wherever you regularly listen to podcasts, including on Apple, Google or Spotify. Thank you for listening.