FDA Announces Implementation of "Remote Interactive Evaluations" of Drug Manufacturing Establishments and Biomedical Research
In March 2020, because of COVID-19 health risks and travel restrictions, the Food and Drug Administration (FDA) suspended most of its inspection program, both in the United States and abroad. The agency limited inspections to those that were priority or mission critical, including some pre-approval inspections for important new therapies and some for-cause inspections. During the pandemic, FDA also increased its use of some alternatives to in-person inspections, such as relying on inspections by foreign regulators and requesting records in lieu of inspection.1 To this point, FDA had not embraced real-time video assessments, in which FDA investigators would examine facilities and interview employees using a live video feed.
On April 14, FDA changed course and published guidance that established a new policy for the use of "remote interactive evaluations." In Remote Interactive Evaluations of Drug Manufacturing and Bioresearch Monitoring Facilities During the COVID-19 Public Health Emergency: Guidance for Industry (Guidance), FDA discussed how sites would be chosen for these evaluations, how evaluations would be conducted and concluded, and what use FDA would make from the information it obtained in evaluations.
Summary of the Guidance
The Guidance is co-authored by the Center for Drug Evaluation and Research, Center for Biologics Evaluation and Research, Center for Veterinary Medicine, and the Office of Regulatory Affairs. It covers many types of manufacturing and biomedical research inspections for biologics and human and animal drugs: pre-approval; pre-license; post-approval; surveillance; and follow-up and compliance. For the latter type of inspection, although FDA may use remote evaluations to verify some corrective actions, it will continue to require in-person inspections to evaluate remediation following a warning letter, regulatory meeting, or enforcement action. The Guidance does not affect food, tobacco, or medical device inspections and remains in effect only during the COVID-19 emergency.
FDA will apply risk management tools to determine which sites are eligible for remote evaluations. Perhaps in response to the requests it has received from some companies for remote evaluations, FDA explicitly states that it will no longer accept such requests. Instead, FDA will contact companies that the agency decides are appropriate for remote evaluation and secure the company's agreement to proceed. In deciding whether a remote evaluation is appropriate, FDA will consider whether the specific purpose of the inspection can be served (for example, whether FDA can evaluate the suitability of a facility for manufacturing the drug in a pending application), compliance history, and whether there are any data integrity issues.
If FDA decides that a remote evaluation is appropriate, the agency and the company will have a videoconference to discuss logistics, responsibilities and expectations. Topics will include: identity of the FDA team; scope of the evaluation; information technology requirements; methods for sharing documents; and timing.
Remote evaluations will be comprehensive and will require significant preparation from companies. FDA will generally ask for some documents prior to the remote evaluation. Companies will have to scan sometimes voluminous paper documents to make them available to FDA. The agency may also ask for video recordings during the evaluations. FDA is clear about its expectations: "Documents and other information requested during a remote interactive evaluation are expected to be provided within a reasonable timeframe, similar to requests for documents or other information made during an inspection."2 Evaluations will include spontaneous discussions with employees. They will occur during the business hours of the facility. For security reasons, FDA will use its own conferencing platforms, which are FDA versions of Microsoft Teams, Zoom and Adobe connect.
FDA points out that remote interactive evaluations are not technically "inspections, " as set forth in Sections 510(h)(3) or 704(a)(1) of the Federal Food, Drug, and Cosmetic Act (FDCA). Nor are they record requests under Section 704(a)(4) of the FDCA. This means that a failure to agree to a remote evaluation would not render the relevant products adulterated under Section 501(j). As a practical matter, this legal distinction makes little difference, particularly to those companies with pending applications. FDA states, "[d]eclining FDA's request to perform a remote interactive evaluation could impede our ability to make a timely regulatory decision (e.g., regarding adequacy of a clinical trial used in support of a pending application or adequacy of a drug manufacturing operation described in the application)."3 Thus, failure to agree to a remote evaluation would, at a minimum, likely lead to a delay in approval. In the context of surveillance inspections, it could also cause FDA to conduct an in-person inspection, as soon as it is able.
Upon completion of a remote evaluation, FDA investigators will have a close-out meeting similar to those for in-person inspections. At the meeting, the agency will not issue an FDA Form 483, but will issue a list of written observations that will be quite similar. As with a Form 483, companies will have 15 working days to respond to FDA's observations.
The agency will use the information obtained in a remote evaluation in much the same way that it uses information obtained in an in-person inspection. FDA states that it will use the information collected: to decide whether to approve an application; to decide whether a physical inspection is needed; and to support an import alert, warning letter, recall request or other compliance or enforcement action. The agency also states that it will use information from evaluations to meet its user fee timeframes and that it “generally intends to use existing timelines established for reporting on and evaluating the outcome of an inspection for the remote interactive evaluation.”4
Implications and Questions
The Guidance will help FDA avoid or minimize delays in evaluating pending drug and biologic applications, and will generally be helpful to both industry and patients. However, it is important for companies to recognize that a remote interactive evaluation will require the same or even more preparation than would an in-person inspection. Companies may have to scan and perhaps translate large volumes of paper documents. They may be unaccustomed to answering questions from a regulator remotely and will need to rehearse, using technology similar to that employed by FDA. In the virtual meeting with FDA that will precede a remote evaluation, companies should ask FDA not only about logistics, but about any documents that the company can compile prior to the evaluation. Although the agency will expect some technical glitches, it will expect companies to be able to respond to its queries promptly and to be able to locate documents and information. Thus, as with in-person inspections, companies should designate a point person for the evaluation, choose someone to take notes, assemble an off camera team to locate documents, and follow other inspection best practices.
Although the Guidance provides a lot of information about how the agency will conduct a remote evaluation, it does leave open some questions:
- Will the use of remote evaluations continue after the COVID-19 emergency? Although the Guidance will lapse with the emergency, it is quite possible that the agency may find these evaluations to be a useful and efficient tool and decide to continue them.
- Will FDA offer additional guidance on how it will prioritize which facilities it will remotely evaluate? The Guidance provides a general outline, but industry may ask for more clarity.
- Will FDA classify remote evaluations using the Official/Voluntary/No Action Indicated framework? The Guidance states that FDA may use evaluations as a basis for warning letters and decisions to issue complete response letters, which usually accompany Official Action Indicated classification. The Guidance does not clearly state, however, that FDA will apply the framework.
- If FDA classifies remote evaluations using the using the Official/Voluntary/No Action Indicated framework, will it post those results on the FDA Inspection Classification Database on the agency’s website? The Guidance states that FDA will use “existing timelines established for reporting on” inspections, but it is unclear whether the agency is referring to public reporting, rather than just notification to firms.
- Will remote interactive evaluations be used in the medical device, food, or tobacco areas? The Guidance does not apply to these products and inspections of different FDA-regulated products vary significantly, but it is possible that FDA may expand the use of this tool in the future.
However FDA addresses these questions, for some time, remote interactive evaluations will play an important part in the approval process and post-market assessment of biologics and human and animal drugs.
© Arnold & Porter Kaye Scholer LLP 2021 All Rights Reserved. This Advisory is intended to be a general summary of the law and does not constitute legal advice. You should consult with counsel to determine applicable legal requirements in a specific fact situation.