The FDA accrued a massive backlog of inspections in 2020 as a result of suspensions due to the COVID-19 pandemic.
They are now laying the groundwork to get site reviews back on track.
How Did the Backlog Happen?
Last March, because of the pandemic, the FDA decided to temporarily pause foreign and domestic inspections, except for those they deemed “mission critical.” This included, “COVID-19-related products, breakthrough therapies, products used to treat serious diseases where there’s no substitute, and products that require a follow-up because of recalls or other safety issues,” the regulator said.
However, the FDA faced problems with its foreign inspections even before the spread of COVID-19. Between 2016 and 2018, both foreign and domestic inspections slumped, partially due to staffing issues, with language barriers presenting another problem as well.
According to a U.S. Government Accountability Office (GAO) report, as early as December of 2016, there were still 963 foreign manufacturing facilities that had never been inspected. By the end of 2019, the FDA said it had inspected 496, or around 52% of the previously uninspected facilities outlined by GAO, as well as permanently removing an additional 361 of those facilities. Despite an upturn in foreign inspections in 2019, the COVID-19 pandemic disrupted the progress, carrying out only three foreign inspections total in the 2020 fiscal year following the pause in March.
What is the FDA’s Plan Moving Forward?
The FDA acknowledges the pandemic could still disrupt its plans and the work will be largely dependent on the course of the COVID-19 pandemic. If the pandemic continues to create barriers, the FDA says it “would focus on oversight work most critical to its mission and limit inspection activities.” In that scenario, they would continue to use alternative methods such as remote inspections and document requests rather than inspecting the facilities in person with the hope that some accountability and oversight are better than none.
“FDA has begun to assess how its alternative tools can be used to supplement its regular inspection activities or substitute for them when inspections are not possible, but needs to complete this assessment,” Mary Denigan-Macauley, Ph.D.
Director of GAO’s health care team (via email)
According to the Acting Commissioner of the FDA, Janet Woodcock, M.D., between March 2020 and March 2021, the FDA conducted a total of 821 “mission-critical” inspections and 777 priority domestic inspections. If they want to catch up on last year’s backlog, the FDA says it needs to complete 26,250 site inspections in the fiscal year(which ends September 30) where more than 15,500 of the outstanding site inspections are for food producers.
Of those 26,250 inspections needed for 2021, the FDA reported it has completed nearly 3,000 of that total as of March 2021. For those remaining six months of the fiscal year, the agency plans to look to international partners for help, but “if the agency’s partners are unable to conduct these inspections, FDA will be responsible for carrying them out.”
The GAO States That New FDA Measures are “Useful” But Not Equivalent to Full Inspections
The FDA has also turned to alternate inspection tools for its foreign drug oversight. They are relying on ex-U.S. regulators, reviewing records, and testing drugs manufactured overseas in lieu of full visits. These measures are “useful,” but “not equivalent” to a full inspection, according to the GAO. The GAO also took issue with the FDA’s practice of announcing foreign visits up to 12 weeks in advance, giving manufacturers a chance to rectify problems ahead of the inspection.
This raises the question of whether the FDA’s foreign and domestic inspections are equivalent when it comes to advance notice, processes, and requirements. However, due to COVID-19 protocol, the FDA is now announcing domestic inspections ahead of time as well in a bid to protect its staff and the manufacturers.
U.S. Reliance on Foreign Drug Manufacturers Highlighted by COVID-19 Pandemic
As of May 2020, the FDA reported that 74% of drug manufacturers producing active ingredients and 54% of those turning out finished meds for the U.S. market were located overseas. According to the GAO, the fiscal year 2015 marked the first time the FDA carried out more foreign manufacturing inspections than domestic, with most of those occurring in China and India.
During a Senate Finance Committee hearing in early June, CEO David Light of independent testing lab Valisure warned that a slowdown in on-site inspections strained regulators’ ability to ensure the quality of U.S. medicines.
“Manufacturing problems that arise from the escalated production of drugs [tied to COVID-19] and a lack of FDA inspectors on the ground at foreign plants could produce a domino effect for years to come,” Light said. “The lifecycle of a drug in the supply chain is many years, and it could be many more before significant and serious issues are found, let alone addressed.”
David Light, CEO of Valisure
Foreign manufacturers have previously asked the FDA to consider alternative measures to inspect their facilities. In mid-April, major Indian pharmaceutical companies pleaded with the FDA to conduct “desk reviews” or virtual facility inspections during the pandemic in order to “ensure the continuous supply of much-needed drugs in the United States.”
The Indian Pharmaceutical Alliance asked for virtual reviews of facilities that are new, are slated to produce a new class of drugs, or have completed a corrective action plan following a previous inspection failure. Among the alliance’s members are India’s largest drug manufacturers, including Cipla, Cadila, Dr. Reddy’s Laboratories, and Abbott India.
The group also requested the FDA consider recognizing inspections by foreign regulators and temporarily waiving on-site inspections “based on past inspection history and the critical nature of products, such as drug shortages or products that do not currently have generic alternatives.” The FDA at the time said it had not conducted any virtual inspections but indicated “these alternative approaches to on-site inspection have provided FDA with useful information.”
Inspection Backlog Hinders Drug Manufacturers
The FDA’s inspection backlog hamstrung approval hopes for a few drug manufacturers last year. In late November, the FDA delayed action on Revance’s frown-line injection daxibotulinumtoxinA, because it couldn’t make it out to the company’s manufacturing facility (located in Newark, California) on time, which the regulator blamed on COVID-19 restrictions. That same month, the FDA was unable to conduct an inspection of a Lonza facility in Texas slated to produce the viral vector for Bristol Myers Squibb’s liso-cel, now known as Breyanzi.
Additionally, the FDA delayed its review of Spectrum’s neutropenia candidate Rolontis after officials twice delayed a plant inspection. Likewise, Mallinckrodt revealed it would have to wait a bit longer for an FDA decision on its regenerative skin tissue therapy StrataGraft, after COVID-19 travel restrictions delays derailed the timeline for a manufacturing plant inspection.
FDA is Ready to Resume its Usual Operations But Are Far From a Full-Scale Restart
The FDA will draft its own risk criteria, based on local and state infection data, to pick and choose those facilities and would need to see a major shift in new COVID-19 cases before resuming operations fully.
“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.”
FDA Commissioner Stephen Hahn, M.D.
As a safety measure for employees, investigators would pre-announce their visits rather than making unplanned inspections. That said, the rise of the Delta variant throughout the country and the world could further disrupt inspections and its processes, so ultimately it’ll be yet another waiting game to see how to move forward.