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September 9, 2020

Key FDA Drug Inspection Challenges Amid COVID-19

Compliance Law360, Life Sciences Law360, Public Policy Law360

The COVID-19 pandemic has created challenges not only for businesses, but for regulators, as well.

Like many agencies, the U.S. Food and Drug Administration is able to perform much of its work remotely, However, in evaluating whether to approve products or whether products on the market are meeting the FDA's standards, the agency typically relies on physical inspections.

Because of COVID-19 travel restrictions, the FDA has curtailed its inspection program. The agency has recently announced an interim policy for drug and biological product inspections during the COVID-19 emergency, but the policy leaves many questions unanswered and puts the onus on drug and biologics companies to be proactive in providing the FDA with information that the agency needs.

The FDA's pre-COVID-19 policies recognize that inspections play an important but not always essential role in approvals and post-market oversight for drugs and biologics. In order to approve a drug or biologic, the FDA must find that the product is safe and effective.

As part of this analysis, the FDA has often conducted an inspection of relevant manufacturing facilities, both for the finished product and for active pharmaceutical ingredients. The agency has set forth several nonbinding factors for determining whether an inspection is necessary, such as the compliance history of the facility, the difficulty in manufacturing the product, and whether the product contains a new molecular entity.1

The FDA also performs surveillance inspections, which examine manufacturing practices for approved products. These inspections are risk-based, and the FDA has discretion to choose which sites to inspect.2 Finally, the FDA usually performs on-site inspections to verify that a firm has taken corrective action following the issuance of a warning letter.3

These warning-letter follow-up inspections are important because the FDA will generally deny applications for products made from facilities that have received warning letters until the agency decides that the facility has corrected problems cited in the warning letter.

In August, the agency issued a guidance regarding manufacturing, supply chain, and drug and biological product inspections during the COVID-19 public health emergency. The guidance summarizes the current status of inspections – that because of COVID-19, the FDA can perform some prioritized domestic inspections, but continues to be unable to conduct most foreign inspections.

The agency stated that it would attempt to perform mission critical inspections, such as those for applications for important therapies, but even if the FDA wished to send its investigators overseas for these inspections, some foreign governments would not allow travel from the U.S. or would impose a quarantine on U.S. travelers.

The FDA is thus faced with a dilemma – if it cannot perform an inspection, does the FDA deny an application (in agency lingo, issue a complete response letter) for an important new therapy that could save lives or for a drug that could alleviate a shortage?

At the same time, the FDA must be certain that all drugs and biologics it approves are safe and effective. In its guidance, the agency seeks to resolve the dilemma by stating that it would sometimes use noninspection tools to evaluate whether an application may be approved. These tools include information from trusted regulatory partners, a firm's compliance history, or obtaining records from a firm in advance of or in lieu of an inspection.4

The FDA's approach makes sense, as far as it goes, but leaves some issues unresolved. The tools the FDA identifies are ones the agency used prior to COVID-19. The agency, of course, evaluates compliance history when making decisions. In its 2017 mutual recognition agreement with the European Union, the FDA found that European regulators were proficient in evaluating manufacturing facilities, and agreed with the EU that each regulator would rely on the other's surveillance inspections in their geographic jurisdictions.

Although the agreement did not require reliance on preapproval inspections and only applied to facilities in the U.S. and Europe, it is natural to extend it to these other forms of inspections. If a European regulator finds that a facility can manufacture a product in accordance with current good manufacturing practices, which are largely harmonized standards and approaches that apply in Europe as they do in the U.S., then FDA should rely on that result.

The ability to obtain records remotely is a power the FDA sought and got in Section 706 of the FDA Safety and Innovation Act. Prior to COVID-19, the FDA had sporadically used this records authority, but its widespread use is sensible. Much of an on site inspection involves investigators examining records. And the FDA official can examine them in his or her office as they would in a facility.

The guidance is, however, silent on three important issues. One is the use of virtual or video assessments. During an on-site inspection, the FDA often observes how a product is made and how a facility is designed. The FDA investigators also typically interview plant personnel.

Although the FDA cannot perform these tasks by just reviewing records, it can do so through live video feeds.

If the FDA cannot be satisfied about a plant's current good manufacturing practices compliance without a visual observation, rather than delay an approval of an important therapy, it would make sense for the agency to conduct a virtual assessment.

The second issue is whether companies can retain independent auditors who can travel to sites and prepare reports for the FDA. The agency has a long history of relying on impartial reports of this nature.

Finally, the guidance does not resolve how the FDA will use noninspection tools to confirm that a site has resolved issues in a prior FDA warning letter and can be removed from official-action-indicated status, which often blocks new approvals. If the issue in a warning letter relates to facts that can be confirmed with a review of records, a video assessment, or by a European regulator, logically, the FDA should be able to decide whether to change the status of the affected facility.

To be sure, there are warning letters in which the FDA will want a physical inspection to verify remedial action. But leaving firms on official-action-indicated status longer than is necessary can delay approvals of new therapies or of generics that introduce competition or alleviate possible drug shortages. Of course, the FDA should never clear a warning letter if there remains a question of current good manufacturing practices compliance, but delaying access to new products is a cost that should be considered.

If the COVID-19 travel restrictions continue for a while, these unanswered questions will become more pressing, as the FDA is confronted with more product application and warning letter decisions.

It is important that, however the agency resolves these issues, it does so consistently and transparently, so that companies can plan and try to meet the FDA's expectations. In the interim, companies should proactively ask the agency how they can supply it with information to evaluate an application or the remediation of a warning letter. Companies should also offer alternatives, such as video assessments.

In performing its core role of ensuring access to safe and effective therapies, the FDA has a history of being flexible while protecting patients. COVID-19 presents an unprecedented challenge for the FDA, but the agency has the tools to perform its important mission.

  1. See generally FDA CPGM 7346.832.

  2. FDASIA Section 705 (risk-based inspection criteria) and CDER MAPP 5014.1.

  3. RPM Section 4-1-8 ("Usually the standard for verifying that corrections have been implemented will be a follow-up inspection").

  4. Section 704(a)(4) of the Federal Food, Drug, and Cosmetic Act.