Lots of FDA Guidance, But Few Drug Manufacturing “Remote Interactive Evaluations” (We Would Call Them “Virtual Inspections”)

We were preparing this blogpost about FDA’s draft guidance on “Remote Interactive Evaluations” when we learned something.  A phone call to FDA requested information about the number of Remote Interactive Evaluations (RIEs) that FDA has performed at drug manufacturing facilities since it announced in April 2021 that it would start using them as an alternative to on-site inspections.  In response, we learned that only about seven – and certainly less than 10 – RIEs for manufacturing compliance have been performed at drug facilities in the last 30 months.  This stands in stark contrast to FDA on-site drug manufacturing inspections, which have resumed in the wake of the easing of COVID-related restrictions, totaling more than 1,800 during the same period.  To accomplish so few RIEs, especially when on-site inspections dropped off dramatically about three and a half years ago, is certainly a missed opportunity, in our view.  The number of RIEs also stands in stark contrast to the number of RIEs – more than 100 – that the Bioresearch Monitoring (BiMo) Program has performed.  Admittedly, BiMo inspections (into items like adequacy of bioequivalence data, consistency of clinical trial data with medical records, and compliance with clinical trial protocols) lend themselves better to an RIE than assessing manufacturing compliance with regulatory requirements.

Not having much more to say about the paucity of the use of this alternative method of reviewing a manufacturing site’s regulatory compliance, let us turn to the recent draft guidance about RIEs.  Compared with the COVID-centered version of the document released in April 2021, there is very little that is new or different.

We should explain what RIEs are.  Early in the COVID epidemic, many other regulatory agencies worldwide – but not FDA – launched virtual inspections (also referred to as “remote inspections”) of drug and medical device manufacturing facilities when COVID restricted travel and on-site inspections.  FDA, late to the game, published a guidance about its substitute for virtual inspections, making clear it doesn’t want to call RIEs “inspections,” for reasons that are somewhat obscure but are discussed in the guidances.  Significantly, FDA agrees that the RIEs may be conducted in lieu of an inspection.

Under the new guidance, many of the same conditions apply as under the one that was issued 30 months ago:

• The guidance notes that requests for documents under the governing statutes and virtual inspections (inspectors are in a remote location, and tour the facility using equipment that can furnish an audio and video feed, with the inspectors directing where the video camera should venture and asking the questions) are both considered “Remote Regulatory Assessments.”
• The guidance states that FDA does “not intend to accept requests from applicants or facilities for FDA to perform a remote interactive evaluation,” because decisions to perform an RIE “depend on many factors and information not always known to applicants or facilities, and it would be unduly burdensome on all parties to establish a request-based program.” Raising the question: how does FDA define “all parties?”  Many of our clients wouldn’t consider it a burden to request an RIE to try to resolve a Warning Letter, an Import Alert, or a suspension of review of a new drug application because an earlier inspection resulted in a manufacturing facility being classified as Official Action Indicated.  Contrariwise, FDA states in the draft guidance that RIEs may be used to “rank or prioritize a facility for an inspection, particularly a surveillance CGMP inspection.”  This implies that FDA may engage with companies on a more frequent basis than the standard (although unobserved, in practice) 2-year cycle.
• FDA specifically states that RIEs may be utilized to conduct Preapproval Inspections, which are conducted at manufacturing facilities prior to approval of a new drug application.
• RIEs will require the facility to accommodate the “use of teleconference, livestream video, and screen sharing of data and documents.”
• The guidance applies to facilities manufacturing human drugs, biologics, and veterinary medications, and to clinical trial sites for drugs.
• Responses to written observations made as a result of an RIE will not be made in a Form 483 (issued at the conclusion of about half of FDA’s on-site drug inspections), but facilities are still “encouraged” to file responses within 15 business days.

What was added in the new draft guidance?

• Facilities where FDA requests that an RIE be performed will need to consent, in writing, to the performance of the RIE (the earlier guidance did not require consent in writing). It is unclear what would happen if the facility refuses: probably, a refusal would be foolhardy, for a number of reasons. The current and earlier guidances note that declining an RIE may delay regulatory decisions, such as approvals of applications for marketing authorization.  Likewise, a refusal to permit an RIE may well trigger an on-site inspection.  The answer to which type of inspection industry would prefer is probably self-evident.
• Comments on the guidance are invited. In contrast, the April 2021 guidance noted that it was being “implemented immediately,” without “public participation” in the drafting of a final guidance.