Lessons from the Pandemic: FDA Proposes Permanently Adopting Alternative Tools for Drug Facility Inspections

I. Introduction

On September 22, 2023, FDA issued a new draft guidance titled Alternative Tools: Assessing Drug Manufacturing Facilities Identified in Pending Applications (the “Alternative Tools in Pending Applications Draft Guidance”). The draft guidance describes alternative regulatory tools FDA used widely during the COVID-19 pandemic and now plans to adopt as regular practices for assessing good manufacturing practice (“GMP”) compliance at drug manufacturing facilities identified in new drug and biologic applications. These tools include remote document assessments, remote interactive evaluations, and reliance on foreign regulatory agency inspection reports.

On October 26th, FDA published a related but separate draft guidance titled Remote Interactive Evaluations of Drug Manufacturing and Bioresearch Monitoring Facilities (the “RIE Draft Guidance”). As the title suggests, this draft guidance addresses remote interactive evaluations in more detail than the draft guidance on use of alternative tools in pending applications. It describes the criteria FDA plans to use to determine when to propose use of a remote interactive evaluation (“RIE”) in lieu of or as a supplement to all categories of on-site inspections. This draft guidance also discusses the process by which FDA will request and conduct RIEs, what an RIE virtual planning meeting will look like, and FDA expectations during and following an RIE.

These draft guidance documents reflect FDA’s intention to make permanent the use of certain inspectional assessment tools that FDA applied broadly in response to the COVID-19 pandemic. In both documents, FDA distinguishes between mandatory written record requests the agency makes pursuant to its statutory authority in 21 U.S.C. §374(a)(4) and voluntary agency requests to use other alternative tools.

Industry has much to gain by ensuring that facilities have the necessary technology and are otherwise prepared to cooperate with FDA requests to use alternative inspection tools, though consenting to agency use of those tools that are not legally mandated is not without risk. Firms should therefore make sure they are familiar with the benefits and risks associated with the use of such tools so that they can make informed decisions regarding whether to consent to their use.

II. Use of Alternative/Remote Tools During the Pandemic

During the COVID-19 public health emergency, FDA used several tools to assess and oversee drug manufacturing facilities when on-site inspections were not possible due to travel or quarantine restrictions. Such tools allowed FDA to evaluate facilities and approve some new drug and biological license applications that would otherwise have been delayed for lack of a pre-approval inspection.

According to a January 2022 GAO Report, alternative tools reduced FDA’s need to conduct its own preapproval inspection about 50 to 60% of the time from mid-fiscal year 2020 through mid-fiscal year 2021.¹ Further, use of alternative tools allowed FDA to review at least 90 percent of brand and generic drug applications and supplements on or before their user fee goal dates as of Q2 2021.² Between April 2021 and November 2021, FDA conducted more than 600 domestic and more than 200 foreign remote regulatory assessments.³

FDA’s goal in using these alternative tools is to maximize operational flexibility and efficiency when use of these tools can allow the agency to obtain needed information without causing unnecessary risk. The recent draft guidance documents make clear that industry can expect to see continued use of such tools as alternatives or supplements to typical FDA inspectional activities.

III. Remote Regulatory Assessment (RRA)

An RRA is an examination of an FDA-regulated drug establishment or its records, conducted entirely remotely, to evaluate compliance with applicable FDA requirements. An RRA can take different forms. For example, FDA may make a formal request for copies of equipment records, process validation records and reports, test results, deviations and associated reports, complaints, or other information related to compliance with cGMP and other applicable FDA requirements, pursuant to its authority under section 704(a)(4) (21 U.S.C. 374(a)(4) of the Federal Food, Drug and Cosmetic Act (“FDCA”). The Agency may also seek a teleconference or a virtual meeting for clarification of the records requested.

An RIE is another category of RRA. An RIE typically involves remote visual observation of a product, facility, manufacturing operations and records, whether through livestreaming of video or screen sharing. The agency may make informal requests to view or receive records as part of an RIE. Generally, any interaction between facility staff and FDA will be virtual, through video or telephone conferencing.

Both draft guidance documents emphasize the mandatory nature of responding to records “requests” under 21 U.S.C. § 374(a). Refusing to respond is a violation of 21 U.S.C. § 331(e), which explicitly prohibits refusing access to or the copying of any record required by 21 U.S.C. § 374(a) and is punishable as a criminal offense. While a manufacturer must respond to a records request under section 21 U.S.C. § 374(a)(4), it is not legally bound to agree to an RRA that takes the form of a virtual meeting to discuss the records or to share documents in response to an informal record request. However, an insufficient response to a mandatory records request can lead to delayed action on an approval application or a complete response letter if FDA reviewers lack sufficient information to make a regulatory determination or confirm that application deficiencies have been satisfactorily addressed. Participation in an RIE  is also voluntary. A facility may decline to participate in an RIE, though doing so may similarly prolong a decision on an application or necessitate an in-person inspection to address a compliance concern.

The RIE Draft Guidance notes that in some cases, the agency may request records or request participation in an RIE prior to an on-site inspection.

A. Considerations for When an RIE May Be Appropriate

The RIE Draft Guidance outlines specific considerations relevant to whether an RIE would be appropriate. According to FDA:

• Pre-approval/Pre-license inspections: FDA may request an RIE to assist in the evaluation of a drug pre-approval or biologic pre-license inspection if (1) such a remote interaction is likely to help the agency assess risks identified in the application review, and (2) there are no data integrity or other issues that in FDA’s view would require an on-site inspection.
• Post-approval inspections: FDA may request an RIE when (1) a facility has an acceptable inspection history with no data integrity or other concerns that would warrant an on-site inspection; and (2) specific application issues and manufacturing risks that warrant a post-approval inspection can be sufficiently assessed through an RIE.
• Surveillance inspections: FDA will follow the same risk-based approach it uses for surveillance inspections when prioritizing facilities for RIEs. While an RIE does not constitute an inspection as contemplated by the statutory provisions establishing FDA’s mandatory inspection authority, FDA can use information gathered via RIE to determine the scope, depth and timing of a future statutorily authorized and required inspection.
• Follow-Up and Compliance Inspections: FDA asserts that the appropriateness of an RIE for follow-up or compliance inspections will depend on the nature of the facility and the reason for the inspection, including the facility’s inspection history and any data integrity concerns. The draft guidance notes that following a Warning Letter, regulatory meeting, or similar advisory action, FDA will generally conduct an inspection to confirm the implementation of corrective actions. In contrast, to evaluate reports of product defects such as Field Alert Reports or Biological Product Deviation Reports, FDA may request an RIE or make a mandatory request for records.
• Bioresearch Monitoring (BIMO) Inspections: FDA says that it will not consider use of RIEs for BIMO inspections if there are data integrity or other concerns that require on-site assessment or if the information that needs to be evaluated cannot be evaluated remotely. When FDA determines that an RIE would be appropriate, the information obtained, including information regarding data reliability and human subject protection, will be used to determine whether the BIMO studies assessed are acceptable to support drug and biologic applications.

B. Preparation and Coordination for RIE

Once the agency determines that an RIE is appropriate for a particular facility, it will notify the facility by electronic mail or a phone call and will request confirmation, in writing, when possible, that the facility is willing and able to participate in the RIE. The RIE request will typically identify the name and address of the facility to be evaluated, the reason for the evaluation, and the names of planned FDA participants, if known in advance. If the facility agrees to the RIE, FDA will reach out to confirm a point of contact, to facilitate planning, and to determine the facility’s ability to transfer records and interact remotely with FDA staff. The RIE Draft Guidance advises timely responses to FDA requests for information and timely communication regarding any challenges the facility might have in meeting FDA’s requests.

FDA will schedule a brief virtual meeting to discuss RIE logistics, responsibilities, and expectations. This pre-RIE virtual meeting may address topics such as the objectives and scope of the RIE, the FDA and facility participants, the anticipated length of the RIE and schedule, FDA’s expectations during livestreamed walkthroughs of the facility, and other logistical issues. FDA may also check the facility’s internet connection or seek to otherwise confirm that the facility’s technological capabilities are sufficient to allow the virtual assessment to be productive. The RIE Draft Guidance notes that for security reasons, FDA will use its own IT platforms and equipment to facilitate the remote interactive evaluations, like videoconferences and livestreaming of video.

FDA advises referencing its July 2022 Draft Guidance, titled Conducting Remote Regulatory Assessments Questions and Answers, for information on how best to prepare for an RRA. This draft guidance describes the various categories of activities that are considered to be types of RRAs, including an RIE, and what establishments should expect when participating in an RRA.

C. FDA Expectations for an RIE

At the outset of an official FDA inspection, the Agency issues the site a notice called a Form “482.” By contrast, FDA does not issue a 482 at the beginning of an RIE. FDA nevertheless states in the RIE Draft Guidance that it expects participants to cooperate with the same level of transparency as in an FDA inspection. FDA expects appropriate facility staff to be available at scheduled times for interviews or other interactions and that the facility is operational to the extent possible, enabling FDA to evaluate areas or operations of interest. During the RIE, FDA may request and review records, use livestream or recorded video to examine facilities, operations, and other information, conduct interviews, and request meetings to address questions or concerns. If a facility is unable to support the remote interaction, or FDA is unable to conduct a sufficient examination of a facility or corrective action using the available remote tools, FDA may terminate the RIE and follow up with an inspection or use of other available tools.

Assuming the RIE proceeds as planned, FDA will provide verbal updates to the facility regarding observations and outstanding issues whenever feasible. When the RIE is complete, FDA will conduct a closeout meeting with facility management and present a written list of observations, if any are made. The agency will discuss the observations in enough detail to ensure the facility understands them and can respond to them. Like FDA’s expectation that firms will respond to a Form “483” issued at the close of an inspection, FDA encourages facilities to respond to any written RIE observations, either during the closeout meeting or in written responses submitted within 15 business days of the closeout.

IV. Other Alternative Tools that May Be Used in Preapproval and Prelicense Inspections

A. Assessment of Inspections Conducted by Trusted Foreign Regulatory Partners

In addition to the potential use of records requests or RIEs, the Alternative Tools in Pending Applications Draft Guidance contemplates collaboration with foreign regulatory partners and assessment of inspection information collected by those partners as an alternative tool that may be used in connection with a product application decision. FDA will look to such information for a description of the facility’s current state of cGMP control and to determine whether a prior inspection covered the manufacturing operations described in an application. If a facility lacks a robust prior FDA inspection history, foreign reports can help FDA determine whether a preapproval or prelicense inspection is necessary or whether additional information obtained through an RRA or inspection is needed to assess the facility.

FDA’s draft guidance notes that the agency is currently evaluating the utility of collaborative assessments with regulatory partners for preapproval and prelicense inspections. A collaborative assessment may include a combination of an on-site lead inspectorate and one or more participating remote regulatory authorities connecting through virtual interactive technologies. A pilot project on this approach is ongoing, and FDA says it will use its learning from that project to inform whether to pursue hybrid FDA/foreign assessments in the future.

FDA does not need a facility’s consent to request records or reports from a foreign regulatory partner or to rely on a foreign inspection when FDA has an agreement with such partners. However, a firm would have to agree for FDA to participate remotely during a foreign inspection.

B. Use of Remote Subject Matter Experts to Supplement Inspection Teams

A final alternative tool FDA intends to employ when evaluating pending applications involves remote involvement of FDA subject matter experts to supplement an inspection team when (1) the expertise and input of the subject matter expert is determined to be necessary for an adequate assessment of an application product, manufacturing process, or a facility, and to verify conformance to the application and cGMP compliance, and (2) the physical, on-site participation of such an individual is not feasible.

When FDA anticipates using remote resources during an inspection, the agency intends to notify the facility by electronic correspondence or by telephone call and include a written request for confirmation of the facility’s willingness and ability to interact with remote FDA personnel using virtual technology, including the use of a livestreaming video, screen sharing, and teleconference.

C. Factors FDA Will Consider When Evaluating Appropriate Use of Alternative Tools in Preapproval and Prelicense Inspections

In the Alternative Tools in Pending Applications Draft Guidance, FDA provides a non-exclusive list of factors it says it will consider in determining whether and when use of alternative tools may be appropriate in lieu of an inspection or otherwise to support an application decision. Such factors include whether:

• The manufacturing operations proposed in the application are the same as or sufficiently related to operations covered in previous inspections of the facility by FDA or a trusted foreign regulatory partner.
• The application-specific risks or applicable facility operations can be adequately assessed through alternative tools.
• The product addresses an urgent need (e.g., a critical public health need, a pervasive drug shortage, or other unforeseen situations).
• An inspection is not feasible because of travel limitations (e.g., pandemics, natural disasters, other unstable situations preventing travel).

FDA has made it clear that NDA and BLA sponsors or facilities may not request an alternative assessment and should be ready for a regular pre-approval inspection.

V. Weighing the Risks Associated with Use of Alternative Inspection Tools

FDA has credited its use of alternative inspection tools for enabling the agency to move its application decision-making forward during the pandemic even when traditional on-site inspections were difficult or impossible to conduct. When facing the possibility of a delay in product approval or closure of a compliance issue due to FDA’s inability to conduct an in-person inspection, FDA’s use of alternative tools that facilitate timely agency access to desired information may work to the manufacturer’s benefit.

For remote assessments to work, facilities will have to use technologies like video conferencing, video streaming and document sharing. Facilities will be well advised to establish procedures and implement best practice training for personnel involved in responding to remote document requests and for participating in remote assessments. For example, failing to properly end a video conference or press mute when side conversations are ongoing can result in others on the line listening in to conversations that site personnel believe to be strictly internal. Similarly, lack of care in use of a video conferencing, screen sharing, or chat function might enable third parties to see information the site did not intend to share. Facilities should therefore update their inspection readiness training programs to account for these new tools, technologies, and procedures.

Industry should carefully consider all risks that may arise due to use of alternative tools, including those that go beyond potential snafus with technology. For example, should FDA move forward with its proposal on collaborative assessments and participate remotely in an inspection conducted by a foreign regulatory partner, FDA may push the foreign investigator to scrutinize areas that the foreign partner would not otherwise have examined. Or, if FDA raises concerns or seeks answers to questions from the foreign investigator, misunderstandings could arise from language or cultural barriers. Similarly, an FDA subject matter expert participating remotely might not get a full or clear picture of a process of interest or part of the site, causing the expert’s assessment to be less favorable than it would be if the expert had been on-site. Other concerns include the potential for FDA to record streamed video or audio, or a witness interview, during a remote assessment,  that technology used to show manufacturing processes and site locations may not provide needed context that would show the site in a better light, and that in-person meetings and discussion may provide a more effective way to respond to and alleviate agency questions and concerns given the potential for miscommunication when only remote means are employed.

Sites should be aware of the possibility that a remote assessment can lead to judgments based on incomplete information or miscommunications between FDA remote participants and those on-site. Additionally, ensuring information security can be critical. Careless use of technology in remote evaluations could lead to leaks of confidential, privileged, or even protected patient information.

While companies will not be able to refuse appropriate record requests made pursuant 21 U.S.C. 374(a), or reliance on foreign records and inspections, they should think strategically about whether the benefits of potentially expedited decision-making outweigh risks associated with voluntary alternative tools, before consenting to FDA requests to use such tools.

VI. Conclusion

The COVID-19 pandemic required significant agency flexibility and ingenuity to address the risks of the novel coronavirus while also keeping ordinary regulatory oversight programs moving forward. The use of remote inspectional tools proved largely successful in enabling FDA to gain visibility inside manufacturing facilities and to conduct critical risk assessments. One of the lessons learned from the COVID-19 pandemic was that these novel methods for evaluation and assessment work and can improve agency efficiency and resource management. FDA plans to use these alternative inspectional tools to replace or supplement pre-approval inspections when appropriate in light of product quality and manufacturing process risks. Further, it appears the agency is poised to use RIEs when appropriate to confirm facility compliance in post-approval, surveillance, follow-up compliance and BIMO inspections. Industry may stand to benefit from use of these new tools to the extent they facilitate more efficient inspections and timely decision making. However, companies should also evaluate potential risks before agreeing to voluntary remote assessments in lieu of or as a supplement to in-person inspections.

The deadline for comments on the Alternative Tools in Pending Applications Draft Guidance is November 21, 2023. The comment period for the RIE Draft Guidance ends on December 26, 2023. Ropes & Gray will continue to monitor developments in this area. If you have any questions about this Alert, or would like assistance in submitting comments to FDA, please contact any member of our FDA regulatory practice or your usual Ropes & Gray advisor.