Signaling again its intent to continue the use of remote interactive evaluations (RIEs) in its surveillance of the facilities it regulates, the FDA in new draft guidance describes how it conducts RIEs at drug manufacturing sites, facilities subject to oversight through the agency’s bioresearch monitoring (BIMO) program, and registered outsourcing facilities.

The agency may use various alternative oversight tools, such as remote regulatory assessments (RRAs), “in advance or in lieu of an inspection or to support an inspection of a facility and assess compliance with applicable laws and regulations,” the FDA said in the new draft guidance, “Remote Interactive Evaluations of Drug Manufacturing and Bioresearch Monitoring Facilities,” which was posted Oct. 25.

An RRA is an option when an FDA program office determines that an inspection is not necessary, feasible or practical, and the assessment may consist of or include a request to conduct a voluntary RIE.

Types of Drug Inspections

Under the agency’s current policy, all the FDA’s drug inspection programs are possible candidates for RIEs, including:

• Preapproval inspections (PAIs) and prelicense inspections (PLIs), which are conducted to assess drug and biological product marketing applications. PAIs and PLIs are conducted to ensure that a manufacturing facility can conform with current good manufacturing practice (cGMP) requirements, verify conformance with the application, and confirm that the data in the application are accurate and complete.
• Postapproval inspections (PoAIs), which focus on a specific drug and changes to its manufacturing operations, process validations, changes to the applicable application, and any supporting activities according to cGMP requirements and commitments made in the application.
• Surveillance inspections, which examine drug quality operations and controls and cGMP compliance at drug manufacturing facilities and outsourcing facilities.
• Follow-up and compliance inspections, initiated in response to a specific drug quality problem or facility issue to investigate, for example, product safety, effectiveness or quality concerns arising from defect reports; information about a facility provided by an informant; violative activities discovered during the inspection of another facility; or corrective actions undertaken in response to, for example, a Warning Letter or regulatory meeting.
• BIMO inspections, comprehensive inspections of all aspects of the conduct and reporting of FDA-regulated research, including the rights, safety and welfare of research subjects; the accuracy, reliability and integrity of clinical and nonclinical data transmitted to the agency; and compliance with FDA regulations governing the conduct of clinical and nonclinical trials, including the regulations for informed consent and ethical review.

FDA Still Not Taking Requests

As in the past, the FDA said that it does not intend to accept requests from applicants or facilities for the agency to perform an RIE.

“Such decisions depend on many factors and information not always known to applicants or facilities,” the agency said, “and it would be unduly burdensome on all parties to establish a request-based program.”

Notifying a Facility

When the FDA determines that an RIE is appropriate for a particular facility or drug, it notifies the facility and applicant by email or phone using the facility registration or application information. The agency will request confirmation of a facility’s willingness and ability to participate in the RIE, including the use of teleconferencing, livestream video, and screen-sharing of data and documents.

Once the FDA has the facility’s agreement to the RIE, it will identify the agency lead for the evaluation and work with the facility to plan and coordinate activities for the evaluation.

“Declining FDA’s request to perform [an RIE] 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),” the agency stated in the draft guidance.

Special Considerations for Various Inspection Types

The draft guidance included special considerations for each inspection type, including the following:

PAIs and PLIs: The FDA may request a RIE if the agency determines that:

• remote interaction with the facility will help the FDA assess risks identified during preapplication review; and
• there are no data integrity issues that in the agency’s view require an inspection.

PoAIs: The FDA may request a RIE when:

• a facility has an acceptable inspection history with no data integrity or other concerns that the agency determines require an inspection; and
• specific application considerations and cGMP manufacturing risks that warrant a PoAI can be sufficiently assessed through an RIE.

Surveillance inspections: The FDA will follow the risk-based approach used for surveillance inspections when it prioritizes domestic and foreign facilities for RIEs. The agency will use information gathered through an RIE to determine the scope, depth and timing of a future inspection.

Follow-up and compliance inspections: After pursuing an advisory action such as issuing a Warning Letter or conducting a regulatory meeting, the FDA generally will conduct an inspection to confirm that corrective actions have been implemented. To evaluate defect reports such as Field Alert Reports or Biological Product Deviation Reports, the agency may request an RIE and/or make a Section 704(a)(4) records request.

BIMO inspections: The FDA will consider BIMO facilities for RIEs “according to existing risk-based facility selection methodologies when there are no data integrity or other concerns that FDA determines require an inspection, and information to be evaluated can be accessed remotely.” Information from an RIE can be used to access a facility’s conduct, including the reliability of its data and its human subject protections, to determine the acceptability of BIMO studies for the agency’s application decision-making.

Preparing for an RIE

Before an RIE, the FDA will schedule a brief virtual meeting to discuss “logistics, responsibilities and expectations.”

Among the possible discussion topics for the virtual meeting are:

• the schedule of the virtual interactions and the anticipated duration of the RIE;
• the agency’s expectations during livestreaming walkthroughs of the facility;
• video streaming technology and other methods for sharing requested information;
• technological limitations that could impair or prevent the RIE; and
• a check of the internet connection throughout the facility to verify that the signal strength will support livestreaming video and audio during the RIE.

Conducting the RIE

The FDA said that it expects facilities “to cooperate with the same level of transparency as they would during an FDA inspection." The facility is expected to be “operational to the extent possible for FDA to evaluate areas and operations of interest.”

If the facility cannot support video or other virtual interactions, or if the agency determines that video and other virtual interaction during the RIE “does not permit a sufficient examination of the facility or of a corrective action,” the FDA may terminate the RIE and instead perform an inspection “or use other available tools.”

The FDA will not issue a Form FDA 482 Notice of Inspection to announce or open an RIE.

The agency uses its own IT platforms and equipment to host virtual interactions during RIEs. Currently the agency uses three conferencing platforms: FDA Microsoft Teams, FDA Zoom for Government, and FDA Adobe Connect.

Usually the FDA will request and review documents and other information before an RIE “to ensure the livestream interactions are as efficient as possible.” However, the agency may request additional documents and other information at any time during the RIE.

“FDA expects all documents provided during the [RIE] in response to FDA’s request to be provided in electronic format or accessible by screen-sharing during a live interaction so that the documents can be assessed efficiently,” the agency stated in the draft guidance.

If a facility that maintains documents in paper format requests an RIE, the FDA added, it “should consider taking steps to enable FDA’s remote viewing and verification of the facility’s documents, procedures and electronic systems.” Requested documents maintained in paper format should be scanned as searchable PDF files when possible.

Concluding the RIE

The RIE will conclude with a closeout meeting between the FDA and the facility’s management. The agency may present a written list of observations. The FDA does not consider the list to constitute a final agency action or decision, and it will not issue Form FDA 483 inspectional observations.

Facility Responses

“As with an inspection,” the agency said, “FDA encourages facilities to respond during the discussion and/or provide responses in writing to the observations within 15 U.S. business days.”

The FDA also encouraged responses to RIEs in support of PAI and PLI programs to be submitted within 15 U.S. business days.

Uses of Information From RIEs

Among other regulatory purposes, the FDA said that information and documentation collected during an RIE may be used:

• to support the agency’s assessment of pending applications, including whether to approve an application;
• to preclude the need for an inspection to follow-up on a reported concern or defect;
• to support a regulatory meeting, Warning Letter, import alert, recall or other enforcement action;
• to rank or prioritize a facility for an inspection, “particularly a surveillance cGMP inspection”; or
• to justify a follow-up or compliance inspection or any other surveillance activity.

Withdrawal of COVID-19 PHE Guidance

With the publication of the new draft guidance, the FDA has withdrawn its April 2021 COVID-19 PHE guidance document “Remote Interactive Evaluations of Drug Manufacturing and Bioresearch Monitoring Facilities During the COVID-19 Public Health Emergency.”

In its notice of the availability of the October 2023 draft guidance, published in the Federal Register on Oct. 26 (88 Fed. Reg. 73602), the FDA said that the COVID-19 PHE guidance was no longer needed because the recommendations in the new draft guidance, when finalized, will be applicable outside the context of the PHE.

Comments on the draft guidance are due by Dec. 26 and may be submitted online (Docket No. FDA-2023-D-4416).