FDA Inspections of Foreign Drug Manufacturers Are CollapsingIn 2022, the FDA only inspected 6% of the overseas plants where drugs and their ingredients are produced.
This story was originally published by ProPublica.
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For years, U.S. pharmaceutical companies have relied on drugs produced overseas to meet Americans’ medical needs. And for years, it’s been clear that federal drug regulators couldn’t keep up with inspections of the plants that made those drugs.
But a series of recent deaths linked to eyedrops produced overseas that were tainted with bacteria points to just how seriously behind the Food and Drug Administration is. Three people died and eight others were blinded in the United States from the drops, which were made in a plant in the Indian state of Tamil Nadu that the agency had never inspected prior to the outbreak. Worse, public health officials say they have detected the drug-resistant bacterial strain, which had never been seen in the U.S., among patients who never used the eyedrops, meaning it has likely achieved community spread.
A ProPublica analysis of FDA inspection data as of April shows that the agency’s inspections of overseas drug manufacturers, located mostly in India and China, has dropped precipitously even as the number of manufacturers has remained relatively steady. In fiscal year 2019, the year before the COVID-19 pandemic limited travel and movement, the FDA inspected 37% of the nearly 2,500 overseas manufacturers; in 2022, the agency only inspected 6% of around 2,800. And in India, where the contaminated eyedrops originated, the FDA inspected only 3% of manufacturers in 2022—significantly less than in 2019, when 45% of plants were inspected.
The FDA, which is tasked with ensuring the safety and efficacy of both prescription and over-the-counter drugs, has acknowledged that limited resources make it impossible to inspect every plant, whether in the U.S. or not, that makes drugs or their ingredients. But the agency has been slow to make improvements.
This is not the first time that American consumers have been injured or killed as a result of contaminated drugs produced overseas. In the 1980s, drugs manufactured in Italy intended to prevent seizures resulted in epileptic seizures and two deaths. In 2007 and 2008, hundreds had allergic reactions, some fatal, to a commonly used blood thinner, prompting an FDA investigation. Some of the cases were later linked to an ingredient produced in a facility in China that had never been inspected by the FDA.
The Government Accountability Office, a federal watchdog agency, has warned for decades that the number of overseas inspections was worryingly low. Just weeks before the first cluster of COVID-19 patients was reported in China at the end of 2019, the GAO reported that despite some improvements in how the FDA tracked and prioritized its efforts, inspections of both foreign and domestic drug plants were on the decline, due in large part to challenges retaining staff and filling vacancies.
“While our drug supply is generally safe, problems do occur, as evidenced by contaminated eye drops in the last few months,” said Mary Denigan-Macauley, director of public health at the GAO. “No one wants to lose their vision or an eye simply from taking eyedrops to alleviate dry eyes.”
Without a doubt, the COVID-19 pandemic slowed inspections to a trickle—in fiscal year 2021, according to the data, the agency inspected a mere 99 overseas sites, less than 4% of eligible foreign manufacturers. By comparison, 15% of domestic manufacturers were inspected that year. (Nearly three-quarters of manufacturers of U.S. drug ingredients, and more than half of producers of finished drugs, are located overseas.)
During the pandemic, the FDA began announcing domestic visits beforehand and paused surveillance visits overseas except for those deemed “mission critical,” conducting most preapprovals of new drugs without visiting foreign manufacturing sites.
The FDA defended this decision in an email statement to ProPublica, saying it used “alternative inspectional tools such as remote interactive evaluations, record requests, and leveraging information from trusted regulatory partners.”
Both the GAO and Rep. Sanford J. Bishop, a Georgia Democrat, say these remote interactions do not offer the same insight that in-person, unannounced inspections do. The FDA itself affirmed the utility of inspections in its latest annual report on pharmaceutical quality: “In the absence of inspections, many of these situations” that could result in defective products, “and possible public harm, could have gone undetected.”
But three years after the pandemic started, the FDA has been slow to return to pre-pandemic inspection rates. The pandemic heightened the urgency surrounding the FDA’s drug inspection process, as the need for more equipment, vaccines and antiviral medications, many of which are produced overseas, increased. Though routine domestic surveillance inspections resumed in July 2021, routine foreign inspections remained on hold until February 2022.
In December, President Joe Biden signed a year-end spending package that allocated $10 million for a pilot program to “increase unannounced foreign inspections” of drug makers. But that was just a tiny fraction of the $3.5 billion earmarked for all FDA drug quality oversight programs.
“We have got to be protective of the health, safety and welfare of the American people,” said Bishop, who pushed for funding for overseas inspections in the House. “That is the job of the FDA.”
Experts hope the pilot program will address standards surrounding those visits, which have drawn criticism for being too permissive. Unlike domestic inspections, foreign manufacturers were routinely given a heads-up before an inspection and allowed to provide their own translators, practices that FDA inspectors have admitted could make information gathered unreliable. The FDA said that it planned to use the additional $10 million to increase staffing for foreign inspections and to work on prioritizing inspections that the agency was unable to perform during the pandemic.
Among the foreign establishments never inspected was a Global Pharma Healthcare factory in Tamil Nadu that produced artificial tears sold by U.S. companies EzriCare and Delsam Pharma. As an over-the-counter product that does not require FDA approval, the eyedrops fell into another FDA regulatory blind spot. Though the FDA has the authority to inspect manufacturers of over-the-counter products before they are sold to consumers, there is no requirement that an inspection must occur prior to the sale — unlike for prescription drugs.
The FDA is asking Congress to require that manufacturers notify the FDA of their intent to distribute over-the-counter drugs well in advance of selling them, potentially providing the FDA a “feasible opportunity” to conduct inspections.
But even that requirement might not have made much of a difference. According to the GAO’s 2022 report on FDA foreign inspections, a growing backlog of manufacturers slated for routine surveillance inspections is skewing in a concerning direction. The percentage of overseas manufacturers that hadn’t been inspected within five years, or which have never once been inspected, has grown from 30% in 2020 to more than 80% in 2022. And if the FDA prioritizes sites that have not been inspected recently, that might come at the expense of inspecting sites identified by the FDA as posing the highest public health risk.
Preventing future public health risks, like the ongoing eyedrop outbreak, has to be a priority, said Denigan-Macauley of the GAO.
“These problems are not hypothetical. They are real,” she said.
In the case of the imported tainted eyedrops, in January, the FDA and the Centers for Disease Control and Prevention traced back the Pseudomonas aeruginosa outbreak to the Global Pharma Healthcare-produced EzriCare Artificial Tears. That same month, the FDA requested records from the manufacturer regarding an unrelated issue and, concerned by Global Pharma’s “inadequate response,” placed it on an import alert, preventing its products, including the eyedrops, from entering the U.S. In early February, the FDA recommended a recall of the EzriCare and Delsam Pharma eyedrops, though it waited weeks to finally conduct an on-site inspection, only to find multiple sanitary and safety issues. The companies did not respond to a request for comment, though in a February press release EzriCare said that it was cooperating with the CDC and FDA. Global Pharma has said to The New York Times it is “fully cooperating with U.S. federal authorities.”Wait, before you go…
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