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Applications put on hold as agency limits alternative oversight methods.
Last March, FDA halted most field inspections of biopharmaceutical facilities and clinical research sites due to travel and contact restrictions imposed by the COVID-19 pandemic. Agency officials said they would rely more on the past compliance history of a production site, quality control documents requested from the manufacturer and inspection reports and other information from other trusted regulatory authorities to determine whether an inspection was needed to approve a new or changed product from that facility. The agency also has weighed the viability of conducting virtual inspections, with limited success. More commonly, FDA has expanded product inspections in its labs or import control facilities to assure quality.
The inspection hiatus did not delay most new product approvals for much of the past year, as many drugs came from facilities that had been inspected recently or had a sufficiently strong compliance record to support a regulatory decision. But now inspection issues are delaying more new product approvals. In December 2020, FDA postponed approval of an important new cholesterol therapy inclisiran from Novartis due to concerns about the European contract manufacturer producing the new product. FDA sent Novartis a Complete Response Letter (CRL) Dec. 18, 2020, explaining that it could not approve the drug by its user fee action date due to “unresolved facility inspection-related conditions” that could not be overcome due to foreign travel restrictions.1
FDA also delayed approval in November of a CAR-T liso-cel therapy to treat adults with large B-cell lymphoma from Bristol Myers Squibb when travel restrictions prevented an inspection of the Lonza production facility in Texas. Also in November, Revance Therapeutics acknowledged it would not be able to market a new injectable anti-wrinkle skin treatment because FDA was unable to inspect the company’s California manufacturing facility on time. FDA similarly delayed the review of Spectrum’s neutropenia drug Rolontis, which the company licensed from a South Korean firm that FDA was unable to inspect. And Alkermes said it received a CRL for its new treatment for schizophrenia and bipolar disorder when a remote records review done in place of a preapproval inspection found issues related to a tablet coating process at its Ohio facility.2 Alkermes resubmitted its application in late December and now expects an approval decision by mid-year.
Although agency officials indicated in July they might start conducting some critical domestic site visits, few occurred as infection rates accelerated again. FDA issued guidance in August addressing a range of questions related to the inspection situation to help manufacturers cope.3 The agency further acknowledged the growing difficulties created by the inspection hiatus in guidance posted Dec. 21, 2020 to clarify how quickly (or slowly) it would act following a manufacturer’s response to a CRL when a facility assessment remains necessary before FDA can approve an original drug application or important supplement.4 The advisory states that reviews of resubmitted applications for products that require an inspection may take four or six months or more.
The December guidance notes the difficulties in conducting necessary facility assessments and acknowledges that it often is not feasible to rely on alternative tools, such as records requests or review of inspection reports from trusted foreign regulators, and that such strategies “can be as resource intensive as inspections.” Analysts note, moreover, that some FDA requests for GMP-related documents have been extensive, involving line listings, lab reports, adverse event notices, requiring multiple data submissions that raise concerns about data security.
The agency’s distrust of alternative oversight methods applies particularly to production sites with past compliance problems, observed Don Ashley, director of Office of Compliance at the Center for Drug Evaluation and Research (CDER). He reported that the agency is doing more product sampling this past year, relative to site inspections, in weighing the need to issue warning letters or import alerts, at a December 2020 FDA enforcement conference sponsored by the Food & Drug Law Institute (FDLI).
Ashley further expressed skepticism about utilizing alternative oversight strategies for follow-up inspections of companies looking to remedy issues raised in earlier Official Action Indicated (OAI) citations. He noted that most follow-up inspections of such sites in prior years revealed that earlier problems had not been corrected, giving him “reason for pause” in relying closely on company reports on resolving serious issues.
An interesting point is that an FDA prior-approval inspection is not required to authorize an Emergency Use Authorization (EUA) for a drug or biologic. FDA officials emphasized that they were not cutting corners in moving quickly to approve EUAs for critical vaccines to counter COVID-19 based on accelerated clinical testing, and that companies had to submit full information on manufacturing processes and to establish quality control operations. But actual site inspections are not required until the manufacturer files a biologics licensing application (BLA) for its vaccine, although enforcement officials may take other steps to ensure quality production. In granting an EUA in November 2020 to Eli Lilly for a monoclonal antibody (bamlanivimab) to treat moderate COVID-19 infections on an outpatient basis, FDA directed Lilly to retain an independent third party to review batch records for discrepancies in drugs made at a New Jersey facility that had been cited for quality control issues at previous inspections.5