The Food and Drug Administration’s (FDA) foreign inspection program was heavily criticized in a House Energy and Commerce Subcommittee hearing this week titled “Protecting American Health Security: Oversight and Shortcomings in the FDA’s Foreign Drug Inspection Program.” The expert witness testimony made it clear that U.S. labs were treated differently than foreign ones, and despite increases in hiring at the FDA over the years, lawmakers have a lot to be concerned about when it comes to the FDA conducting proper oversight of foreign manufacturing facilities.
This most important, perhaps, is the increasing problem with drug shortages, and how recalls of products from dirty labs, primarily in India, have led to drug shortages.
Similar to the Ways & Means Committee hearing on drug shortages on Tuesday, Energy and Commerce Committee members and witnesses said that voluntary recalls by overseas labs lead to drug shortages. The FDA has repeatedly said that when balancing drug safety with drug supply it tips the scales to favor supply. But that means allowing for imports from labs that repeatedly get poor grades after inspections.
“The FDA has some statutory tools to deal with critical shortages, but it has, on occasion, allowed foreign drugs to supply the market in order to resolve them,” John W.M. Claud, counsel for Hyman, Phelps & McNamara said. He was one of the three witnesses.
Well known healthcare advocate, Dinesh Thakur of the Thakur Family Foundation – a grant giving organization that does a lot of work with Indian labs, discussed what some of these inspections find.
“Let me start with cisplatin, a cancer drug that was in shortage all of last year. This company in India that makes generic cisplatin for oncology patients here had in one of their FDA observations in a 2023 inspection, investigators saying they saw plastic bags of torn and discarded documents in their quality controls scrap area under a stairwell and on a truck outside its facility,” he said about India pharmaceutical producer Strides Pharma Science in 2019. “The FDA also said that an analyst observed in reporting acetic acid in a trash bin and accused the employee in charge, stating that the FDA observed the analyst destroying other information as well. How is this acceptable?”
Strides was given a warning letter, but they were not banned from selling to the U.S.
Almost half the warning letters for manufacturing violations issued that year were for Indian drug makers, the FDA said.
The trend continued. In 2019, Indian pharmaceutical giant Aurobindo was given a warning letter. Aurobindo’s New Jersey facility was inspected in 2020 and got bad grades. There, the agency found many issues, including water leaks in packaging and encapsulation rooms as well as impurity concerns. Ceiling leaks were a persistent issue for the facility; the FDA pointed out four instances in 2018 where leaks caused drug contamination. The facility is closed.
Aurobindo’s plant in Hyderabad India was rebuked by the FDA in January 2022, and was given yet another warning letter for “failing to adequately investigate batch failures of active pharmaceutical ingredients (API) and not evaluating the possible effect of changes on the intermediates and APIs manufactured at the site.” According to the FDA, these citations were “significant deviations from current good manufacturing practices” for active ingredients.
Full Committee Chair Cathy McMorris Rodgers (R-WA-5) mentioned the Aurobindo study by CPA during the hearing.
That report revealed that at least two Aurobindo suppliers have a documented history of producing drugs that may fall below quality standards required by the FDA. and that 13 of their key starting material and API sources in China are controlled by state entities. Some 21 of Aurobindo’s China suppliers are run by the provincial governments, which make them subservient to CCP politics in Beijing.
Sen. Marco Rubio (R-FL) said of the report: “America and its allies’ reliance on Communist China is deeper and more dangerous than most people realize. This report serves as yet another reminder of the critical need for the U.S. to reshore and nearshore pharmaceutical manufacturing.”
Rodgers submitted the CPA Aurobindo report for the record.
“It was in China where a whistleblower warned despite FDA resistance that a commonly used blood pressure medication was contaminated, leading to a wide scale recall in 2018,” Chairwoman Rodgers said. “What makes all this more disturbing is that we hold domestic manufacturers to a much higher standard than we do foreign manufacturers. We need a level-playing field that encourages domestic manufacturing. These issues with the FDA’s foreign inspection program go back decades.” Aurobindo never faced an import alert following those warning letters.
The majority of establishments manufacturing drugs destined for the United States are located overseas. India and China are two of the biggest players, with China being an integral part of the India pharmaceutical supply chain. They supply the chemical and organic compounds used in the lab to make API, and also can supply API for use in making finished drugs like pills and tablets, for instance.
The brand name and generic drugs, as well as those sold over the counter are made at more than 2,000 facilities in the United States, and nearly 2,800 labs in countries across the globe, Mary Denigan-Macauley, director of public health at GAO told the Committee.
“We continue to have concerns that inspections conducted overseas are not equivalent to those in the United States,” she said. “Specifically, FDA’s practice of relying on interpreters provided by the foreign establishment being inspected raises serious concerns about the accuracy of information being gathered.”
Rep. Gary Palmer (R-AL-6) said the inspection regime “creates an unlevel playing field for domestic versus foreign.”
Palmer said he liked unannounced inspections of American labs. “I think that ought to be the case for the foreign facilities as well,” he said. It is not and barring the hiring of hundreds of inspectors overseas, that is not going to happen anytime soon.
Rep. Neal Dunn (R-FL-2) also cited the CPA report on Aurobindo, saying the United States and the rest of the world “are completely reliant on Chinese manufacturing to meet our generic drug needs due to their dominance in API. India, the second largest supplier of pharmaceuticals to the U.S. also sources 70 percent of its API from China. Unreliable inspection practices leave us vulnerable to the risk of tainted medications, and the lack of accountability to meet FDA standards demonstrates a weakness in the supply chain,” he said.
When asked by the Committee what type of information the FDA inspectors have on where the drug ingredients are sourced from, Enigan-Macauley said they have some visibility, but not all.
“They have to get information about where the API may come from,” she said. “It’s not definitive as to where it all comes from.”
FDA’s Foreign Inspection Program Has Long History of Failure
In 1998, the Government Accountability Office (GAO) reported the FDA had problems with the timeliness with which investigators submitted inspection reports, their frequency of routine inspections, and delays in taking prompt enforcement action against foreign drug manufacturers. In 2007, the GAO highlighted the FDA didn’t know how many foreign manufacturers were subject to inspection, that the agency inspected relatively few foreign manufacturers, and the agency could not provide the exact number of uninspected foreign establishments. And as recent as 2022, another GAO report found the FDA was still struggling to hold foreign drug manufacturers accountable.
Last year, a ProPublica investigation revealed that the FDA’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.
American pharmaceutical companies are subject to unannounced inspections. Foreign ones are announced weeks in advance.
“It’s alarming to me that given this advanced warning, the FDA still found deficiencies during — deficiencies during 66 percent of the foreign inspections. And that includes serious deficiencies in 16 percent of those inspections,” said Subcommittee Chairman Morgan Griffith (R-VA-9). “According to the FDA, there’s only one investigator based in China and only five FDA staff based in India. Without a functioning foreign inspection program, one with unannounced inspections that imposes real consequences for failing to maintain good manufacturing practices like American labs have to deal with, then we have lost the ability to deter negligent actors, putting Americans at risk.”
The FDA is not a shrinking enterprise. While it could use more support for inspections abroad, immediate remedies are required. The FDA’s task of weighing supply over safety is a difficult balancing act, but one that has favored supply to avoid shortages over issuing import alerts.
The FDA has also been given the authority to inspect more labs both here and abroad. In 2011, Congress passed the Food Safety Modernization Act, which directed the FDA to inspect so-called high-risk facilities at least once every three years. These would be facilities that received action alerts, warning letters or import alerts.
The Environmental Working Group, a non profit in Washington D.C., said in 2022 that stateside inspections fell, according to the Association of Food and Drug Officials. The total number of inspections by state officials on behalf of the FDA fell from 7,391 in 2019 to 6,131 in 2022, according to the Association. And the number of FDA inspections of foreign facilities increased slightly between 2011 and 2019, from 992 to 1,751, before plummeting during the pandemic.
The full-time employee headcount at the FDA’s Center for Drug Evaluation and Research went from 5,203 in 2018 during the Trump administration to 5,624 in his last year in office. Overall, the FDA hired roughly 800 new staffers in that period.