An FDA official said an antihypertensive investigation would uncover more contaminated pills

One of the most important prescription drug recalls of recent years is endless. The US Food and Drug Administration is continuing the investigation and recall of a class of drugs used by millions of people that began last summer, but there is still "a lot to find," said a director. from this agency.

Starting in July, separate lots of blood pressure medications from different companies were removed from the pharmacy shelves. They are known as angiotensin II or ARA receptor inhibitors and contain either valsartan, losartan or irbesartan. The reason? These blood pressure medications contained impurities posing a cancer risk to users.

"The investigation is not over," Dr. Janet Woodcock, director of the FDA's Center for Drug Evaluation and Research, told CNN this week. Working with regulators around the world, she said that she was anticipating the discovery of new batches of contaminated drugs.

When did the contamination start?

Woodcock said the problem seemed to arise after 2010, when a Chinese manufacturer had modified its synthetic processes.

An agency spokeswoman later said that according to the information available in this ongoing investigation, the FDA believed that the first possible appearance of NDMA would have occurred in 2014.

However, the FDA only started recalling the drug on July 13, a week after 22 other countries have already stopped researching specific manufacturers of valsartan tablets to protect patients. In fact, two months earlier, regulators in the European Union had begun a review following reports that drugs containing valsartan imported from Zhejiang Huahai Pharmaceuticals were contaminated with an impurity known as NDMA (N-nitrosodimethylamine).

Used to make liquid fuel for rockets, NDMA is a by-product of the manufacture of certain pesticides, but it can also be introduced unintentionally during certain chemical reactions.

Nitrosamines are genotoxic, which means that they affect the replication of DNA and can eventually cause cancer, Woodcock explained. By testing various BRA-based drugs, the FDA has discovered additional batches made by several manufacturers that are contaminated with NDMA and, in some cases, another nitrosamine known as NDEA (N-Nitrosodiethylamine).

Why have the drugs been contaminated?

The search for a cause suggests that these impurities were generated by specific chemical reactions in the manufacturing process of the active pharmaceutical ingredient, Woodcock said. The FDA believes that the contamination may have been caused in part by the reuse of materials, such as solvents, during the process.

It is also possible "that part of the original material contains some of that amount," Woodcock said, adding that "it's not something that would be easy to find," because the impurities of low concentration are measured in parts per million. . When the problem was discovered, the FDA had to develop a test that could identify nitrosamine in drugs that widen the blood vessels.

The FDA has put in place protective mechanisms against drug contamination, said Maisha Kelly Freeman, professor and director of the Center for Health Innovation and Results Research for Patients at the University of Samford. Manufacturers are obliged to report impurities, for example, and the agency inspects factories according to the risks. However, there is a problem.

"Of course, if they do not look for it, they do not really know it's happening," Freeman said. And that's what happened with contaminated ARAs. "Before discovering this compound, they did not even know that a chemical reaction could produce the compound," she said.

How many people use these drugs?

"The importance of this recall is that it is one of the best-selling drugs in American pharmacies," Freeman said.

Losartan was the 9th most dispensed drug in the country, according to 2016 data. Valsartan was No. 92 and irbesartan No. 171. In a single year, 49 million patients were dispensed losartan, 8 million valsartan and 3 million irbesartan, said Freeman, pointing out that the total of 60 million US patients does not include hospitals and VA systems, only patients who buy community pharmacies. These are physical operations supervised by pharmacists and include chain stores but not hospital or online pharmacies.

In short, the risk of cancer in these patients seems low. "If 8,000 patients take a contaminated product over a four-year period, only one will develop cancer," said Freeman. "This is the worst case scenario if a person takes the product each time they fill it."

Patients involved in the recall may not have taken a contaminated product continuously, as pharmacies often purchase the same drug from different manufacturers.

"The impact is supposed to be relatively small," Freeman said. Of course, if a patient is your loved one and that he or she has developed cancer, you might not think so, she said.

How does the FDA control the manufacture of drugs in the world?

Woodcock said the FDA oversees manufacturing processes in facilities around the world and said the agency finds that some manufacturers "take shortcuts".

"We know everyone is not on top," she said, adding that "the vast majority of places we inspect are rated satisfactory." The agency is taking a range of measures, including warning letters and consent decrees. , to make the manufacturers "again compliant".

Some manufacturers who fail inspections voluntarily take steps to improve their operations, while others need "official action," such as the FDA's refusal to grant new approvals to the plant "until it will be repaired, "said Woodcock. Some domestic factories were ordered to clean up their acts under the supervision of a judge.

"For foreign sites, we are able to create import alerts and they can not import anything into the United States," she said. "So we have very good hammers for foreign sites if they do something wrong."

Why do factories fail inspections?

In a study published in 2016, Freeman evaluated the FDA's recalls over a 30-month period ending December 31, 2014.

"There are so many recalls from the FDA over the course of a year, it's pretty hard to really understand why they happen," she said.

During the study period, approximately 3,000 recalled products were analyzed by Freeman and his colleagues. They found that a total of 348 manufacturers were associated with the recalled drug products, while the most common reasons for recall were contamination, mislabeling, adverse reactions, defective product and the correct potency .

"Obviously, there are so many manufacturers on the market, it would be difficult for the FDA to visit each site at regular intervals to be able to ensure that this sort of thing does not happen," said Freeman.

How often does the FDA inspect factories?

The FDA conducts an inspection before the start of production, and then, once the cycles are running, it conducts an inspection based on a "risk-based prioritization," Woodcock said. The time that a plant has been inspected is taken into account and helps guide the FDA.

Nathan Cortez, Professor and Associate Dean of Research at SMU Dedman Law School, wrote in an e-mail, "These supply chain issues occur periodically for products imported from China – sometimes for pharmaceuticals, sometimes for food products. "

Cortez said that with so many US imports from China, "it is difficult to say if periodic problems are inevitable or if they are lax on the part of the national authorities. Whatever the case may be, the FDA occasionally conducts inspections abroad with the permission of the Chinese government. "

Woodcock said, "We are not alone in this game. The European Union has inspectors, South Korea inspectors, Japan inspectors, Australia, and so on. So, there are many people who come and watch these [facilities]. "

The Chinese government is collaborating and wants to work with the FDA, said the agency. Difficulties accessing a facility in China or elsewhere are usually caused by the specific company involved, but those who refuse an FDA inspection are subject to an import alert.

What some people do not understand is that if manufacturers fail an inspection or have a problem, it does not always mean that "the product is bad," said Woodcock. "What this means is that their practices are not optimal for maintaining the mass production of this product. It's a high bar.

How did the recall affect patients and pharmacists?

"Most patients have to go in and get their medications changed" to a lot of drugs that have not been affected, Freeman said. Other people see their prescriptions changed.

From the point of view of community pharmacies, this recall was difficult because many pharmacies do not keep the number of batches of drugs after dispensing. Freeman said, "This information is not being tracked effectively." She hopes that in the coming years, technologies such as barcodes will be in place to help identify affected patients.

Freeman belongs to several Facebook groups where pharmacists have complained that ARB's "numerous recalls" in the past year "only increased patient distrust of the FDA and pharmacists."

After contacting people and stating, in essence, "your valsartan is fine," this information was changed shortly after, when a new FDA recall list was expanded to include the patient's batch of products . Another pharmacist wrote to Freeman: "Tell patients not to come here angry. We try to help. "

Have there been additional benefits?

Cortez has not heard of the lawsuits related to the recall – although that may of course be the case, he said. But "manufacturing claims are relatively rare and hard to prove," he said. And suing foreign manufacturers can be difficult because it can be more difficult, although not impossible, to enforce judgments.

Whether lawsuits are forthcoming or forthcoming, the House of Representatives Committee on Energy and Trade sent a letter to FDA Commissioner Scott Fottlieb last week asking him to keep abreast of the current situation. ARA.

"The roots of this ever-expanding series of recalls seem to be related to at least two foreign drug manufacturing plants: Zhejiang Huahai Pharmaceutical in China and Hetero Labs in India," according to the letter. "The inspection reports of these two plants report serious problems in both plants, even before the detection of carcinogens."

Woodcock said, "Once this whole investigation is closed, it will probably mean creating more international standards so that this incident can not happen again. But it's ultimately.

How can the FDA improve?

"We have ideas on how things could be improved," said Woodcock, adding that the FDA had already approved changes to some manufacturing operations.

Pharmaceutical manufacturers would do better with "closed systems, much more automation, computer control", which we do not often see in today 's industry, has she said. More advanced manufacturing would be "greener" and involve fewer, although more skilled employees, including chemical engineers, Woodcock said.

"We believe that the business case will ultimately be convincing", which means that manufacturing costs will be lower, even with initial investments in new machines and others, "but we are in a transition phase", she said.