Inspections: GAO calls on FDA to plan for backlog, review alternatives

Regulatory NewsRegulatory News | 01 February 2021 |  By 

In a nearly 350-page report to Congress on the federal government’s COVID-19 response, the Government Accountability Office (GAO) calls on the US Food and Drug Administration (FDA) to review its inspections approach and come up with a plan to address its looming backlog.
Pandemic inspection alternatives
In the early days of the pandemic, FDA halted non-mission-critical foreign and domestic inspections and relied on alternative tools, such as inspection reports from foreign regulators, records requests and product sampling, to complement its oversight activities. The agency has since resumed some prioritized domestic inspections based on a rating system and, according to Acting Center for Drug Evaluation and Research Director Patrizia Cavazzoni’s recent Twitter post, “FDA has begun conducting prioritized inspections by investigator staff in China and is planning to initiate prioritized inspections in India shortly.”
Unsurprisingly, the pandemic has taken its toll on FDA’s inspections program, cutting the number of drug establishment inspections the agency carried out in FY2020 to less than half of what it had done in the previous two fiscal years. GAO says the drop in inspections has added to its “long-standing concerns about FDA’s ability to oversee drugs manufactured overseas.” (RELATED: Do FDA’s foreign offices help keep US drugs safe? GAO says answer is unknown, Regulatory Focus 18 January 2017; FDA defends its oversight of foreign drugs amid Senate, GAO criticism, Regulatory Focus 3 June 2020).
“Prior to COVID-19, FDA typically conducted more than 1,600 inspections of foreign and domestic drug manufacturing establishments each year, but inspections have been reduced significantly. Alternative tools have helped FDA continue its oversight, but are not a comprehensive or long-term substitute for FDA inspections,” GAO writes.
More than half of facilities that manufacture drugs for the US are located in other countries, with India and China being home to about a third of foreign drug establishments.
GAO found that from March, when FDA halted most foreign inspections, to September, the agency conducted just three “mission critical” foreign inspections: two for-cause inspections involving a Canadian hand sanitizer manufacturer and a German active pharmaceutical ingredient (API) maker, and one pre-approval inspection related to an Indian drugmaker’s application for chloroquine phosphate tablets. In FY2018 and FY2019, FDA carried out more than 600 foreign inspections in the same span of time.
FDA also conducted just 52 domestic inspections from March to September, compared to about 400 in that time in each of the prior two years.
In FY2020, GAO found that FDA substituted inspection reports from European regulators for more than 160 inspection in Europe and asked for 30 reports from European regulators or Pharmaceutical Inspection Co-operation Scheme (PIC/S) members pertaining to establishments in China, India, Korea, Japan and elsewhere.
The extent that FDA can rely on inspections carried out by other regulators varies. “According to FDA officials, as of November 2020, FDA deemed that inspections conducted outside of Europe from 19 of 28 European regulators can be substituted for an FDA inspection. However, reports for inspections from the other 9 European regulators conducted outside of Europe and by PIC/S members can only be used to help obtain ‘surveillance-level oversight’ while inspections are paused and are not full substitutes for an FDA inspection,” GAO writes.
The report points out that FDA’s ability to rely on inspections carried out by its overseas counterparts may be limited going forward, as other regulators have also postponed inspections during the pandemic.
Foreign regulators may not be able to fill in the gap for inspections in two of the largest pharmaceutical export markets, India and China, where FDA typically conducts more foreign inspections than other regulators.
“Thus, there may not always be a foreign regulator report to rely on while FDA inspections are paused,” GAO states, adding that in FY2019, FDA conducted nearly 1000 inspections in India and China.
FDA has also relied on alternative tools to compensate for its inability to conduct most preapproval inspections amid the pandemic. According to GAO, in FY2020 FDA made “over 130 requests for records and other information to support preapproval applications listing establishments in at least 27 countries.”
Similarly, FDA made more than 310 requests for records and other information in lieu of surveillance inspections for establishments in 36 countries.
Recommendations and a new backlog
Based on its findings, GAO makes two recommendations to FDA related to inspections during and beyond the pandemic.
First, GAO calls on FDA to fully assess its alternative inspection tools and “consider whether these tools or others could provide the information needed to supplement regular inspection activities or help meet its drug oversight objectives when inspections are not possible in the future.”
Second, GAO frets that a looming backlog of inspections could jeopardize the agency’s strategic goal of shifting more of its inspections to a risk-based model and instructs the agency to assess its inspectionplans for the coming years.
According to GAO, FDA has not fully assessed its alternative tools beyond reliance on European regulator inspection reports. “FDA has not assessed whether inspections conducted by PIC/S members are equivalent to FDA inspections. Thus, any establishments for which FDA uses PIC/S member reports for surveillance-level oversight during the COVID-19 inspection pause will still require an FDA inspection in the near future.” But FDA officials told GAO there are limits to what it can use such alternative tools for. “For example, FDA officials told us that only FDA in-person inspections and European regulator reports can satisfy its statutory requirements for risk-based surveillance inspections.”
Such an assessment could also inform whether any statutory changes “would allow [FDA] to more fully utilize alternative tools to meet its inspection responsibilities [and] increase the resilience of its drug manufacturing oversight going forward.”
While FDA’s new and generic drug approvals have continued apace during the pandemic and the agency has been able to meet its user fee agreement performance goals, there have been instances where the agency’s inability to conduct an inspection has delayed decisions on products. (RELATED: FDA details review timelines as facility assessment-related CRLs pile up, Regulatory Focus 22 December 2020; FDA approves fewer generics in FY2020, ending record streak, Regulatory Focus 21 October 2020; FDA sped progress for most of 2020's novel drugs, Regulatory Focus 14 January 2021).
GAO and drug industry representatives interviewed for the report warn that a continued pause in preapproval inspections could lead to future delays in drug approvals.
GAO also expressed concern that the postponements could create a backlog of inspections of facilities that have never been inspected or that have not been inspected within five years. FDA considers such inspections to be mandatory and prioritizes the remainder of the inspections it carries out each year based on risk.
“The backlog of mandatory inspections this will create if inspections continue to be postponed could both extend the maximum interval between FDA inspections beyond FDA’s 5-year policy and reduce the resources available in fiscal year 2022 for inspecting the other highest priority establishments identified by its model,” GAO writes, noting that the agency has not yet finalized its surveillance inspection approach for FY2022, giving it an opportunity to assess its approach.
Drug industry representatives suggested to GAO that FDA could also add remote inspection capabilities to its arsenal of alternative inspection tools. FDA confirmed to GAO that it is looking into the possibility of using “other tools to serve as supplements to FDA inspections, including using remote video and other remote and live interactions with establishment staff and records to evaluate drug manufacturing operations.”


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