The nationwide recall of the fourth-most prescribed drug in the U.S. is expanding, with Teva Pharmaceutical Industries Ltd. and Marksans Pharma Ltd. being the latest manufacturers to announce voluntary recalls of metformin hydrochloride extended-release tablets due to the possibility of excessive levels of N-nitrosodimethylamine (NDMA).

The U.S. recall, which began May 29, with Apotex Inc.’s 500-mg extended-release tablets, comes six months after regulators in Singapore and Switzerland initiated recalls – and more than three months after the FDA sounded the all-clear when it released findings of its investigation showing no unacceptable levels of the probable carcinogen in 16 batches of metformin from seven companies. However, an independent analysis of 38 batches from 22 companies raised questions about the adequacy of the FDA’s sampling, as it found that 42% of the tested batches exceeded the agency’s acceptable daily intake limit for NDMA. New Haven, Conn.-based Valisure, an online pharmacy that batch validates every drug it dispenses, found that some of the samples it tested had 16 times the permissible limit of NDMA.

“This means millions of Americans are taking a drug every day that contains a carcinogen that absolutely should not be there,” Valisure founder and CEO David Light told the Senate Finance Committee last week during an oversight hearing focusing on the FDA’s inspections of foreign drug manufacturing facilities.

Before it filed the citizen petition in March that prompted the current recalls, Valisure asked Emery Pharma, an FDA-registered analytical laboratory, to independently verify its results. Emery’s results showed even higher NDMA levels in the metformin samples.

As a next step, Valisure conducted a direct-to-consumer crowdsourcing study in which it asked individuals throughout the U.S. to send it samples of their metformin for free analysis. The pharmacy, which has an attached analytical lab, received 128 samples from people in 30 states. Again, 42% of the samples had detectable levels of NDMA and, when scaled to the maximum daily tablet dose, 36% of the samples contained levels exceeding FDA limits. The highest level detected was 65 times the FDA’s acceptable daily limit, according to written testimony Light submitted to the committee.

“We have very serious problems in the drug supply chain that are caused by a very complex set of factors, all of which are made worse by COVID-19,” Light told the senators, adding that Valisure rejects more than 10% of all drugs it receives due to various quality issues.

Sampling concerns

Light noted that the metformin samples the FDA analyzed may have been acquired through voluntary submissions direct from manufacturers, “which can introduce significant sampling bias and would not be an independent measure of quality.” Those samples aren’t comparable with the tablets a patient receives. By time an individual fills a prescription at the pharmacy, the drug is already a year or two old and has passed through many hands, Light explained.

Those factors were an issue when the FDA called for a separate NDMA-related recall in April. The agency asked manufacturers to immediately withdraw all prescription and over-the-counter ranitidine (Zantac) products from the U.S. market after finding that NDMA impurities in some of the heartburn drugs increases when stored at higher than room temperature, including temperatures the drugs may be exposed to during distribution and handling by consumers. Independent testing by Valisure and other third parties also showed that the older a ranitidine product was, the greater the level of NDMA.

“We didn't observe unacceptable levels of NDMA in many of the [ranitidine] samples that we tested,” the FDA’s Janet Woodcock said at the time. “However, since we don't know how or for how long the product might have been stored, we decided that it should not be available to consumers and patients unless its quality can be assured.”

Scientists had been sounding the alarm about the chemical instability of ranitidine and similar drugs for years, even before the FDA approved it in 1983, Light told the Finance Committee last week. Because of that instability, the drug can form NDMA over time. But despite those warnings and numerous studies linking the use of ranitidine during pregnancy to childhood tumors and birth defects, “ranitidine became one of the best-selling drugs in history and among the most commonly prescribed drugs to treat acid reflux in pregnant women and infants,” Light said.

Then last year, Valisure tested a bottle of generic Zantac syrup prescribed to the infant daughter of one of the company’s co-founders. “The results were so dramatic that we immediately took the drug off our formulary and tasked our full scientific staff to investigate,” Light said. Recognizing the magnitude of the problem, Valisure filed a citizen petition requesting the FDA remove ranitidine from the market.

Since Valisure is not part of the “regulatory pharmaceutical bubble,” Light told the senators that filing a citizen petition is all it can do when it finds serious drug quality issues. When the company has tried to discuss problems with the FDA outside the citizen petition process, it’s been told to take them up with the manufacturers, Light said. But the manufacturers don’t have to act on the information.

While the FDA has responded to Valisure’s latest petition by requesting a recall of several extended-release formulations of metformin, which account for about one-fourth of the prescriptions of the diabetes drug, the company said the recall should be extended to immediate-release formulations, as Valisure’s testing showed they also can contain unacceptable levels of NDMA.

In explaining its recall, the FDA said its findings of NDMA in metformin were generally lower than what Valisure reported.

Light explained that the likely cause of the discrepancies is that the agency’s published method for its metformin analysis didn’t include an internal control. “Internal controls are considered scientific best practice by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use … and are industry standard for the analysis of NDMA in complex samples like drinking water, wastewater, soil, food and beverages, biological samples, and pharmaceutical products,” Light said.

Solutions

Drug quality problems go well beyond metformin, ranitidine and NDMA. Light’s written testimony noted that there are about three drug recalls in the U.S. every day, with about 100 recalls a year considered potentially life-threatening.

“These recalls can be attributed, at least in part, to the fact that the chemical quality of medications is primarily checked by manufacturers, which self-report the results,” according to the testimony. “Most manufacturers are located overseas, where oversight by the FDA is difficult and fraud is commonplace.”

Light’s testimony cited a 2015 white paper in which the FDA acknowledged that it “has no formal means for quality surveillance, except through inspections” and conceded that “inspection findings have not been a reliable predictor of the state of quality.”

In addition, the FDA recognized that “product recall and defect reporting data demonstrate unacceptably high occurrences of problems attributed to inherent defects in product and process design; these data further indicate failures in the implementation of manufacturing process scale-up as well as routine production.”

Besides putting the lives of patients at risk, drug quality problems also account for the majority of drug shortages and generate fear and mistrust that contribute to medication nonadherence, Light said.

So what’s the solution? Light suggested two options – data-driven, color-coded drug quality scores that would bring transparency and give buyers a choice based on quality and, for a handful of critical drugs such as metformin, a certification program based on independent testing at the manufacturer level.

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