Houston, We Have A Problem: FDA Confirms That It Will Only Conduct Mission-Critical Inspections and Prioritized Domestic Inspections of Drug and Biological Product Manufacturers During the COVID-19 Pandemic

It has been almost seven months since the Secretary of the Department of Health and Human Services (HHS) declared a public health emergency on January 31, 2020 due to the Coronavirus Disease 2019 (COVID-19).  The Food and Drug Administration has described this time as an “evolving and dynamic situation,” and has continued to provide critical guidance to industry to help respond to the pandemic.¹ 

In August 2020, FDA issued a temporary guidance for industry entitled, “Manufacturing, Supply Chain, and Drug and Biological Product Inspections During COVID-19 Public Health Emergency Questions and Answers.” ²   The guidance provides answers to “frequently asked questions about regulatory and policy issues related to inspections, pending drug applications, and changes in manufacturing facilities for approved pharmaceutical products.”  FDA also emphasizes that the Center for Drug Evaluation and Research (CDER), the Center for Biologics Evaluation and Research (CBER), and the Office of Regulatory Affairs (ORA) “remain fully capable” of continuing daily activities, such as application assessments, facility evaluations during the pandemic.³ 

In March 2020, FDA temporarily postponed all domestic and foreign routine surveillance facility inspections, as well as surveillance inspections in support of the Bioresearch Monitoring (BIMO) program.⁴   Four months later, in July 2020, the agency announced that it was beginning to work toward resuming “prioritized domestic inspections” using its COVID-19 Advisory Rating system to determine the types of regulatory activity that could take place in a given geographic region.⁵   FDA determined that it would continue, on a “case-by-case basis, to conduct only “mission-critical” inspections or where possible to do so safely, resuming prioritized domestic inspections, which generally include pre-approval and surveillance inspections.”⁶   FDA also announced that prioritized domestic inspections would be pre-announced to FDA-regulated businesses for the foreseeable future.  According to FDA, this was the agency’s attempt to ensure the safety of the investigators and firm employees, as well as to make sure that the appropriate staff are on-site to assist FDA staff with inspection activities.

Similar to other guidance documents, this guidance was implemented without prior public comment because of the COVID-19 pandemic.  However, the guidance remains subject to comments in accordance with the agency’s good guidance practices and may be submitted at any time.  We provide some highlights below.

Mission-Critical Inspections

FDA considers many factors in determining whether an inspection is mission-critical.  These factors include, but are not limited to, “whether the products have received breakthrough therapy designation or regenerative medicine advanced therapy designation, or are products used to diagnose, treat, or prevent a serious disease or medical condition for which there is no other appropriate substitute.”   Both for-cause and pre-approval inspections can be deemed mission-critical.  In addition, in determining whether to conduct a mission-critical inspection, the agency will also take into account the safety of its investigators, employees at a site or facility, and where applicable, clinical trial participants and other patients at investigator sites.

Regardless of whether the manufacturing site is domestic or foreign, the agency considers the same factors to determine whether an inspection is mission-critical.  Currently, any foreign pre-approval and for-cause inspections that are not deemed to be mission-critical remain temporarily postponed.  With respect to pre-approval inspections, FDA intends to continue to use other tools, such as inspection reports from other trusted foreign regulatory partners, requesting information from applicants, and requesting records and other information directly from facilities and other inspected entities.⁷   Foreign inspections deemed mission-critical will still be considered on a case-by-case basis.

Safety of Imports During the COVID-19 Pandemic

While FDA is not conducting routine foreign facility inspections, FDA is expanding the use of other tools, when possible, to ensure the quality and safety of products being imported into the United States.  These include physical examinations of products arriving at the U.S. border or product sampling and testing before release into commerce, review of facilities compliance histories, shared information from trusted foreign regulatory partners and requesting records in “advance of or in lieu of” certain drug inspections.⁸   If a product appears not to meet the applicable requirements for safety, effectiveness, or quality, FDA has the authority to refuse admission of the product into the United States.⁹

FDA continues to work closely with U.S. Customs and Border protection to stop the importation of violative products into the country.

Effect of Limited Inspections on Pending Applications

According to the guidance, applications will not automatically receive a Complete Response Letter if FDA cannot conduct an inspection.  If, based on a benefit-risk assessment of the product and based on available information about the facility or the site, the agency determines that an inspection is needed before approval of the application, FDA will communicate this to the applicant.  FDA will follow one of two pathways:

• If FDA determines that an inspection is necessary for approval because available information raises concerns about the adequacy of the facility or site, and the inspection cannot be completed during the review cycle, FDA intends to inform the applicant of this issue as soon as possible during the review cycle. Specifically, FDA intends to inform the applicant that an inspection will be needed before the application can be approved, but, due to travel, the inspection may not be conducted before the action date.  If the inspection of a facility that raises such concerns has not been completed by the action date, FDA generally intends to issue a complete response.

• If there is inadequate information to make a determination on the acceptability of a facility, FDA may defer action on the application until an inspection can be completed. In such cases, the project manager will contact the applicant.¹⁰

Manufacturing and Supply Chain Change Requests

The guidance provides information about changes to approved applications during COVID-19, such as adding or changing facilities, as well as manufacturing process changes.  With regard to manufacturing changes to an approved product that are needed during the pandemic, FDA is using multiple tools, including risk-based reduction in supplement reporting categories and flexible assessment practices.  Specifically, FDA is willing to consider requests from applicants to submit certain changes using a lower reporting category based on risk mitigation information for New Drug Applications or Biologics License Applications related to the treatment or prevention of COVID-19 or drugs/biologics in shortage.  Any applicant wishing to request a lower supplement reporting category should clearly provide “(1) their rationale, (2) supporting information, and (3) risk-mitigation approaches, because this information is needed to consider a reduction in reporting category.”¹¹

AGG Observations

• Given that the pandemic is still ongoing, foreign firms should factor in potential delays in the approvals of their drug or biological product applications. While a Complete Response Letter is not automatic, because of the numerous travel restrictions for U.S. travelers, there is a high likelihood that FDA may not be able to travel to complete inspections for the foreseeable future.

• Another key takeaway from this guidance is the importance of keeping accurate and complete records because, as noted above, FDA may request company records in assessing an application instead of a facility inspection. Thus, FDA may be able to complete the review of an application, assuming there are no major safety concerns, if the firm, in addition to meeting other requirements, is able to answer FDA’s questions and provide appropriate records.

• While FDA is offering some flexibility with regard to changes to approved applications, the agency is not lowering the standards for the type of information needed to support the approval of changes to marketed drugs or biologics applications. However, the agency appears committed to working with sponsors during the pandemic to expedite the assessments of any such supplements.

[1] See HHS’ Determination that a Public Health Emergency Exists (January 31, 2020, renewed April 21, 2020, and July 23, 2020), available at https://www.phe.gov/emergency/news/healthactions/phe/Pages/default.aspx.

[2] Available at https://www.fda.gov/media/141312/download.

[3] Id. at 2.

[4] See FDA Statement, Coronavirus (COVID-19) Update:  FDA Focuses on Safety of Regulated Products While Scaling Back Domestic Inspections, available at https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-focuses-safety-regulated-products-while-scaling-back-domestic.  The COVID-19 Advisory Rating system (COVID-19 Advisory Level) “uses real-time data to qualitatively assess the number of COVID-19 cases in a local area based on state and national data. We are also making the Advisory Level data available to our state partners who carry out inspections of FDA-regulated entities on the agency’s behalf under contract.”  Thus, “resuming prioritized domestic inspections will depend on the data about the virus’ trajectory in a given state and locality and the rules and guidelines that are put in place by state and local governments.”

[5] https://www.fda.gov/news-events/press-announcements/coranavirus-covid-19-update-fda-prepares-resumption-domestic-inspections-new-risk-assessment-system.  

[6] See Guidance at 3.

[7] Id. at 3.

[8] Id. at 4, citing to section 704(a)(4) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. § 374(a)(4)).

[9] Id.

[10]  Id. at 3.

[11] Id. at 7.