(Insight Biologics)Being Prepared for FDA Virtual Inspections
Health and safety measures adopted by the FDA as a result of the COVID-19 pandemic have sharply reduced the number of physical inspections conducted by FDA. Since March 2020, FDA has limited travel by FDA staff, which has stopped most physical inspections both in the U.S. and abroad. We expect the growing use of virtual inspections by FDA and recommend that clients make modifications to their usual preparedness planning to be ready for virtual inspections. This memo provides our current thinking on many common client questions and is being shared to help you in your internal planning. Keep in mind that FDA’s experience in using virtual inspections is still early, and we would expect that practices would evolve over time. Ultimately, we would look to the FDA to potentially issue guidance about virtual inspections to provide more clarity and transparency on these topics, particularly if virtual inspections become a more routine part of FDA’s approach to compliance.
Are physical (in-person) inspections still occurring?
Most physical inspections are not occurring at this time. This includes inspections conducted by other health regulators in Europe which FDA can rely on through the Mutual Recognition Agreement. In some very limited areas, physical inspections are still occurring, such as “for cause” inspections, and pre-approval inspections for critical therapies or to address shortages. But in general, physical inspections have been halted.
What are FDA’s options other than conducting physical inspections?
It has long been a challenge for FDA to strike the right balance on how many inspections it conducts and how detailed those inspections will be. The staff and travel restrictions arising from the pandemic put even more strain on this issue. That said, FDA has the following general tools at its disposal in inspection situations:
• Physical inspection
• Virtual inspection
• Records request
• Inspection by another body (e.g. another regulator)
• Special case techniques (e.g., sampling or import alerts)
• Waive inspection
What criteria would FDA use to determine whether to waive an inspection? Or to prioritize inspections that need to happen?
During this period where restrictions are imposed by the COVID-19 pandemic, the general approach that FDA would take in making decisions regarding prioritization and timing of inspections or waiving inspections can be inferred from existing approaches on inspections in other situations. For example, under the Compliance Program Guidance Manual, for pre-approval inspections, FDA has adopted a risk-based approach that considers the risks related to the specific product, facility and process. It would also be reasonable to expect that specific risks relating to the company’s profile would be considered, such as companies with a history of compliance issues. However, beyond our assumption that a similar general framework would be adopted, it is not known how FDA would ultimately apply such criteria in the current environment.
Can a sponsor be negatively impacted by the suspension of physical inspections?
Yes. FDA will generally not be under any obligation to provide relief to the sponsor due to the unavailability of physical inspection capacity. It will be at FDA’s discretion and decided on a caseby-case basis, but undoubtedly some sponsors will be negatively impacted. In one recent example, Nabriva Therapeutics announced that they received a Complete Response Letter from FDA on their NDA resubmission due in part to the FDA’s inability to conduct onsite inspections.
What is a virtual inspection?
Virtual inspection is a catch-all term to describe an inspection conducted by FDA without a physical visit. It could include any of the following, alone or in combination - records requests by email, telephone interviews and video conference meetings - to satisfy an inspection requirement. Although a virtual inspection uses a different format, the decisions and outcomes which result are the same as for physical inspections. For example, a Form 483 can be issued at the conclusion of a virtual inspection; FDA can use virtual inspections to close out a Warning Letter.
What should a sponsor consider given the virtual format of an inspection?
While in some ways virtual inspections can be more convenient for both the sponsor and FDA, virtual inspections present new risks for sponsors that should be understood in advance. For example, unlike physical inspections, virtual inspections can be called at any time. Because FDA staff do not need to travel to an inspection site, scheduling and potentially conduct of a virtual inspection could occur later in a review cycle. Also, virtual inspections will generally result in fewer opportunities for sponsors to explain context of their information, and less time in live conversation with FDA staff to be able to advocate the sponsor’s position. Where a sponsor anticipates that it will need to engage in a lot of discussion to provide FDA staff with context and rationale of a situation, virtual inspections would create new risks compared to handling the same issue in a physical inspection. As such, it is critical that a sponsor be proactive - think about the areas of particular interest to FDA and ensure that the associated records can stand on their own to the extent possible.
How should a sponsor prepare for a virtual inspection?
Companies that have a well-developed practice of preparedness for physical inspections will generally be well-prepared for virtual inspections, but it is important to note that virtual inspections require their own special preparations. Just as companies would plan and practice for physical inspections, they should evaluate all of the demands of a virtual inspection. For example, IT requirements for video and telephone communications need to be determined and tested. Ensure digital copies of records that would typically be inspected in-person can be quickly presented. Consider time zone differences and whether all necessary facility staff can be available within U.S. business hours. As each company plans for virtual inspections, they will identify their own areas of need beyond what is already in place as part of physical inspection preparations.
Would a sponsor receive advance notice of a virtual inspection?
In general, we would expect FDA to be guided by its past practice in giving advance notice. However, it is worth pointing out some differences. As FDA has broad discretion in how it conducts its inspections, it has occurred that FDA has initiated virtual inspection activity without prior notice. Also, FDA has also initiated requests without an accompanying Notice of Inspection (Form 482), so in those cases it is not always immediately clear whether the request is part of a formal inspection. These examples illustrate the importance of advance preparations for the company even though in typical situations, we would expect advance notice.
When will physical inspections resume?
We expect FDA to resume physical inspections gradually and in stages. It will ramp up domestically more quickly than internationally. And the resumption process is likely to depend on the degree of COVID-19 containment in each individual state or country as a key factor, so it may not be predictable since COVID-19 conditions can change quickly. Further complicating the situation, some countries may ban travel from the U.S. for an extended period of time due to the size of the outbreak in the U.S. In those cases, there may or may not be exemptions for this type of government travel, so even if the FDA is ready to travel internationally, they may not be permitted to enter certain countries.
Will virtual inspections be used as a stop gap measure or a permanent tool of the FDA?
The physical inspection is obviously not going away. But because FDA has always faced challenges in using its limited inspection resources, it seems inevitable that virtual inspections will be here to stay even after the pandemic has passed. It would be a complement to FDA’s other inspection tools, but one that could gain quicker acceptance since FDA would have a significant sample of virtual inspections from the pandemic period to use in determining the most effective ways to use virtual inspections in the future.
We recommend that all clients ensure that their compliance teams have adequately prepared for
the possibility of virtual inspections. It is important to note that there is very little public
information from the FDA on the topic of virtual inspections. Clients are advised to consider this
bulletin as just one tool to help their teams in thinking through how to be ready for virtual
inspections, but to also be prepared for possibilities that this bulletin does not consider. It is still
early in this process and we expect new developments to come as FDA gains more experience
with its use of virtual inspections.