There is no end in sight for one of the biggest drug prescriptions lately. The US Food and Drug Administration is investigating and recalling a class of drugs used by millions of people last summer, but there is still "more to find," says an agency director.
A lot of blood is excreted from July Pressure medicaments from various companies were withdrawn from the pharmacy shelves. They are known as angiotensin II receptor blockers or ARBs and contain either valsartan, losartan or irbesartan. The reason? These blood pressure medicines contained contaminants that pose a risk of cancer to users.
"The investigation is ongoing," Dr. Janet Woodcock, director of the FDA's Center for Drug Evaluation and Research, told CNN this week. She said she works with regulators from around the world and expects that more spoiled drug batches will be found.
When did the contamination begin?
Woodcock said the problem occurred sometime after 2010, when a Chinese manufacturer made changes to its synthetic processes.
A spokeswoman for the agency later said that the FDA estimated the first possible appearance of NDMA in 2014 based on the information available in this ongoing investigation.
However, the FDA did not begin recalling the drug until July 13, a week after 22 other nations had already pulled plugs from certain valsartan pills manufacturers to protect patients. Two months earlier, European Union regulators had initiated a review after reports that valsartan-containing drugs imported from Zhejiang Huahai Pharmaceuticals were reported to be contaminated with NDMA (N-nitrosodimethylamine).
Used for the production of rocket fuel. NDMA is a byproduct in the production of some pesticides, but it can also be inadvertently introduced by certain chemical reactions.
Nitrosamines are genotoxic, which means that they affect DNA replication and may cause cancer, explains Woodcock. In a series of ARB drugs, the FDA tested more batches from various manufacturers contaminated by NDMA, and in some cases another nitrosamine called NDEA (N-nitrosodiethylamine).
Why were the drugs contaminated?
19659007] The search for a cause suggests that these contaminants were generated by specific chemical reactions in the pharmaceutical drug manufacturing process, Woodcock said. The FDA believes that the contamination could result in part from the reuse of materials such as solvents during the process.
It's also possible that "some of the raw material had some of that," Woodcock added, "It's not something that's easy to find," because the low-content impurities are measured in parts per million. When the problem was discovered, the FDA had to develop a test to identify nitrosamine in the blood vessel elevation drugs.
There are FDA safety precautions to prevent drug contamination, said Maisha Kelly Freeman, Professor and Director of Samford University Center for Health Innovation and Patient Outcome Research. For example, manufacturers have to report impurities, and the agency checks the factories in terms of risk. However, there is a catch.
"If they're not looking for it, they do not really know it's going to happen," Freeman said. And that's what happened to corrupt ARBs. "Before they found this particular connection, they did not even know that there could be a chemical reaction that could produce the compound," she said.
How many people are taking these medications?
"The importance of this recall is It is one of the major medications that are dispensed in US pharmacies," Freeman said.
Losartan was the nation's # 9 drug donated most frequently based on 2016 data. Valsartan was No. 92 and Irbesartan was No. 171. In a single year, 49 million patients were given to losartan, 8 million valsartan and 3 million irbesartan. Freeman said that the total of 60 million American patients do not include hospitals and the VA systems, only patients who buy from pharmacies in the community. These are inpatient surgeries supervised by pharmacists and include outlets, but not hospital or online pharmacies.
At a glance, the risk of these patients developing cancer seems to be low. "If 8,000 patients take a contaminated product over a four-year period, only one will contract cancer," Freeman said. "That's the worst case if someone took the affected product every time it was filled."
Patients affected by the recall may not have constantly taken a spoiled product because pharmacies often buy the same drug from different manufacturers.
"The impact should be relatively small," said Freeman. Of course, if a patient is your own beloved person and he has cancer, you do not think so, she said.
How does FDA drug delivery work worldwide?
Woodcock said FDA oversees the manufacturing processes of facilities around the world, noting that the agency is "beating down" some manufacturers.
"We are aware that not all are up-to-date," she said, adding, "The vast majority of places we inspect have proven to be satisfactory. "The Agency has taken a number of measures, including warning letters and declarations of consent, to bring manufacturers back into compliance.
Some manufacturers who do not contest their inspections take steps to improve their operations while others require "official measures", such as: For example, the FDA refuses to grant new approvals for the plant "until it is resolved," Woodcock said. Some domestic factories have been asked to clean up their actions under the supervision of a judge.
"We can set up import alerts for foreign locations and they can not import anything to the US," she said. "So we have pretty good hammers for the overseas sites if they do something wrong."
Why do factories fail inspections?
In a study published in 2016, Freeman evaluated the FDA over a 30-month period, December 31, 2014.
"There are so many FDA recalls over the course of a year that it's difficult to really describe why they occur, "she said.
Around 3,000 products recalled during the investigation period were analyzed by Freeman and her colleagues. A total of 348 manufacturers were associated with recalled drugs, they found, while the most common reasons for callbacks were contamination, incorrect labeling, adverse reactions, defective product and correct efficacy.
"Obviously, there are so many manufacturers that do not exist There, it would be difficult for the FDA to visit each site on a regular basis to make sure it does not happen," said Freeman.
How often inspected The FDA Factories Before the production starts, and once the runs are in full swing, it checks for "risk-based prioritization," Woodcock said, "How long has a factory been investigated is going into risk."
Nathan Cortez, a professor and Associate Dean of Research at the SMU Dedman School of Law, wrote in an email: "These supply chain problems Prices for products imported from China 'are regularly increased – sometimes for medicines, sometimes for food.'
Cortez said, with so many US imports from China 'it's hard to tell if periodic problems are unavoidable Likely or the result of negligence, home supervisors are there. In any case, the FDA occasionally performs foreign inspections with the permission of the Chinese government. "
Woodcock said," We are not the only ones in this game. The European Union has inspectors, South Korea inspectors, Japan inspectors, Australia, etc. So there are many people coming in and overcoming [facilities].
The Chinese government is working together to work with the FDA, the agency said. Challenges in accessing a facility in China or elsewhere are usually caused by the company, but those who refuse to inspect the FDA are subject to an import warning.
What some people do not understand is that manufacturers do not pass the inspection or have some problems, it does not always mean that "the product is bad," Woodcock said. "What it means is that these practices are not optimal to sustain the mass production of this product. It is a stretch.
How has the recall affected patients and pharmacists?
"Most patients have to come in and have their medications exchanged" on many medications that were not affected, Freeman said. For others, the recipe is changed.
From a communist point of view, this recall is difficult, as many pharmacies are not taking much medication after dispensing, Freeman said: "This information is not being effectively tracked. It hopes that in the next few years, technologies such as barcodes will help identify patients Will be available.
Freeman belongs to several Facebook groups in which pharmacists have complained that the ARBs have often withdrawn in the past year "increased the patients' distrust of the FDA and the pharmacists." A pharmacist told Freeman that the recall was "embarrassing".
After contacting individuals and saying, "Your valsartan is fine," this information was changed shortly after a new FDA recall list was added to the patient's product batch. Another pharmacist wrote to Freeman: "Tell the patient that you do not come here angry. We try to help.
Have there been any other failures?
Cortez has not heard any recourse-related litigation – although of course that would be possible, he said, but "manufacturing claims are relatively uncommon and difficult to prove," he said It's difficult to sue foreign manufacturers because it's harder, but not impossible, to enforce judgments.
Whether or not legal action has been taken, the House Committee on Energy and Trade last week sent a letter to FDA Commissioner Dr. Scott Gottlieb He called for a briefing on the situation of the ARB.
"The roots of this ever-growing series of recalls seem to be related to at least two foreign drug manufacturing facilities: Zhejiang Huahai Pharmaceuticals in China and Hetero Labs in India," he said the letter. "Inspection reports from these two factories point to serious problems in Be factories even before the carcinogens were discovered. "
Woodcock said," If this entire investigation is completed, it probably means that more international standards will be created so that this particular incident will not happen again. But that's down the line.
How can the FDA improve?
"We have ideas on how things could be better," said Woodcock, adding that the FDA has already approved changes to some manufacturing processes.
Pharmaceutical manufacturers would With "closed systems, far more automation and computer control" better than what's common in the industry today, the more advanced manufacturing would be "greener" and would involve fewer, albeit more highly skilled, employees, including chemical engineers, Woodcock said.
"We believe that ultimately the business case will be compelling" – which means lower manufacturing costs even with initial investment in new machines and the like – "but we are in a transitional phase," she said.