Remote Reviews Lead to Regulatory Action as FDA Expands Oversight Toolbox

As we predicted, the U.S. Food and Drug Administration (FDA) has permanently adopted many of the remote evaluation tools it piloted during the COVID-19 pandemic as the agency seeks to increase its oversight of manufacturers and the global supply chain. FDA continues to expand guidance in this area, including a July 2022 draft guidance titled “Conducting Remote Regulatory Assessments” — revised and expanded in a Q&A-style draft guidance published on January 25, 2024 — and an October 2023 draft guidance on remote interactive requests. Further, FDA recently stated that a forthcoming proposed rule amending 21 C.F.R. Part 1271, applicable to human cells, tissues, and cellular and tissue-based products (HCT/Ps), will establish requirements for the submission of records or other information in advance of or in lieu of an inspection and require participation in a remote interactive evaluation, if requested.

But some manufacturers continue to struggle with these newer remote evaluation tools even as FDA has used these tools to support regulatory action. For example, FDA’s website includes over 30 warning letters issued in 2023 that resulted at least in part from evidence collected through Federal Food, Drug, and Cosmetic Act (FD&C Act) Section 704(a)(4) remote records requests. These remote record requests have also resulted in a number of import alerts due to the identification of good manufacturing practice (GMP) issues or refusals, including at least 15 import alerts issued in 2023 alone. These regulatory actions span FDA’s portfolio of regulated products, including drugs and foods.

The Expanding Remote Oversight Toolbox

With FDA relying on remote evaluation tools to collect evidence to support regulatory actions, it is more important than ever for manufacturers to understand these tools and how to respond when a remote request is received. Below we provide an overview of FDA’s growing remote oversight toolbox and some recommendations based on our experience supporting manufacturers around the globe.

One of the remote evaluation tools that FDA implemented during the pandemic is Remote Interactive Evaluations or RIEs. FDA recently issued draft guidance providing additional information on the agency’s current thinking with respect to RIEs. Specifically, on October 23, 2023, FDA released its draft guidance for industry, “Remote Interactive Evaluations of Drug Manufacturing and Bioresearch Monitoring Facilities.”¹  The purpose of this guidance is to explain how FDA requests and conducts voluntary RIEs at drug manufacturing facilities and drug facilities that are covered under the Bioresearch Monitoring (BIMO) program.

Notably, the RIE guidance explains that even through the initiation of an RIE is not preceded by the issuance of a Form FDA 483, Notice of Inspection, FDA will apply the RIE policy to all drug inspection programs: Preapproval Inspections/Pre-Licensing Inspections (PAIs/PLIs), Postapproval Inspections, Surveillance Inspections, Follow-Up/Compliance Inspections, and BIMO inspections. The RIE guidance also states that FDA intends to use risk management methods/tools to select facilities for RIEs. FDA states that it will not accept RIE requests from applicants, nor will it establish a request-based program.

The guidance lists specific considerations for different types of RIEs:

• Preapproval Inspections and Pre-license Inspections — The RIE would support an application action under the conditions that the RIE would help assess risks identified during application review and there are no data integrity or other issues that require an on-site inspection. The RIE guidance also states that RIEs to support PAIs or PLIs may be accompanied by a records request under FD&C Act Section 704(a)(4). Unlike RIEs, records requests under FD&C Act Section 704(a)(4) are mandatory and require a facility’s response to FDA.
• Postapproval Inspections — RIEs would be an option when a facility has an acceptable inspection history with no data integrity or other issues that require an on-site inspection, and the RIE would be sufficient to assess any application considerations and current GMP (CGMP) risks.
• Surveillance Inspections — FDA states that prioritizing domestic and foreign facilities in this category would use the same risk-based approach currently used for selecting facilities for on-site inspections. The guidance explains that the RIE does not constitute an inspection but that the information collected from the RIE would be used to determine scope, depth, and timing of a future inspection.
• Follow-Up/Compliance Inspections — The RIE could be appropriate when an inspection cannot be conducted because of travel restrictions or to supplement a planned inspection. FDA states that after advisory actions (warning letter, regulatory meeting), an inspection is usually conducted so FDA can confirm corrective actions at the facility. Regarding Field Alert Reports and Biological Product Deviation Reports, FDA may request records under Section 704(a)(4) of the FD&C Act.
• BIMO Inspections — FDA will use a risk-based approach to select BIMO facilities for RIEs. Conditions include when there are no data integrity or other concerns that would require an on-site inspection and when information can be evaluated and accessed remotely. FDA would use a BIMO RIE to assess the facility’s study conduct, data reliability, and human subject protections to determine the acceptability of the BIMO studies under drug product applications.

Possible requests and activities that would occur during a RIE:

• requests and reviews of documents, records, and information
• use of livestream and/or prerecorded video to demonstrate facilities, operations, and other data and information to FDA
• interviews with site personnel
• evaluation of corrective actions and verbal updates related to previous observations

In each case, manufacturers should treat the RIE with the same level of preparation as an FDA inspection, including carefully evaluating each request, closely reviewing documents before providing them to FDA to ensure the documents are responsive and do not contain errors, and preparing subject matter experts before they speak to FDA.

The RIE guidance also explains FDA’s RIE closeout procedures. FDA will conduct a closeout meeting with facility management and present a list of observations, with details. FDA does not issue a Form FDA 483, List of Inspectional Observations; however, FDA encourages facilities to respond to RIE observations in writing within 15 business days. Importantly, information collected during RIEs can be used to support pending applications (including approvals); preclude the need for followup inspections; support advisory and enforcement actions; rank/prioritize facilities for surveillance CGMP inspections; and justify a followup/compliance inspection or surveillance activity.

Concluding Thoughts

We recommend that drug manufacturing and BIMO facilities evaluate their IT platforms and assess their site readiness for a RIE request from FDA. Although voluntary, RIEs may provide an opportunity to strategically demonstrate sustainable cGMP compliance to the agency without requiring an on-site inspection, and declining to participate can delay FDA’s assessment of a facility, including pending applications and other agency actions.

As evidenced by recent enforcement activity, FDA will continue to use remote oversight tools to collect information relevant to its mission. Companies should acknowledge this growing trend and develop processes to enable effective management of FDA’s evolving inspection techniques. In particular, consider incorporating remote sessions and record requests into existing internal audit programs and regulatory inspection management procedures.

¹ Remote Interactive Evaluations of Drug Manufacturing and Bioresearch Monitoring Facilities, FDA Guidance for Industry, October 2023.