. The US Food and Drug Administration continues to investigate and recall a class of drugs used by millions of people who began last summer, but there is still "more to find," says the agency director.
Beginning in July, separating a lot of blood from pharmacy shelves took drugs from the pressure of various companies. They are known as angiotensin II receptor blockers or ARVs and either contain valsartan, or losartan, or irbesartan. Reason? These Blood Pressure Drugs contain impurities that pose a risk to cancer users.
"The study is not concluded," said Dr Janet Woodcock, director of the FDA's Center for FDA Evaluation and Research, told CNN this week. Working with regulators from all over the world, she said she expects a lot of contaminated drugs to be found.
When was pollution started?
Woodcock stated that this problem arose after 2010, when the Chinese manufacturer made changes
The spokesman for the agency later stated that, based on available information in this investigation, the FDA evaluates the first possible appearance of NDMA in 2014.
However, the FDA did not initiate a recall of the drug until July 13, one week after 22 other countries have already pulled a stomp on the specific formulators of valsartan tablets to protect patients. In fact, two months earlier, the regulators of the European Union initiated a review of the following reports that drugs containing valsartan imported from Zhejiang Huahi Pharmaceuticals were contaminated with an admixture known as NDMA (N-nitrosodimethylamine). NDMA is a byproduct in the production of pesticides, but it can also be unintentionally introduced due to certain chemical reactions.
Nitroamines are genotoxic, that is, they affect DNA replication and may cause cancer, explained Woodcock. When testing various ARBs, the FDA identified additional batches made by several manufacturers that were contaminated with NDMA and, in some cases, other nitrosamines, known as NDEA (N-nitrosodiethylamine)
. 19659007] Search for the cause indicates that these impurities are generated by specific chemical reactions in the process of producing an active pharmaceutical ingredient, says Woodcock. The FDA believes that contamination may have resulted, in part, in the reuse of materials such as solvents during the process.
It is also possible that some of the source materials may have had some part of it, said Woodcock. that "this is not something that would be easy to find", because the low-level impurities are measured in parts per million. When this issue was detected, the FDA was to develop a test that could identify nitrosamines in dilated blood vessels.
There are FDA preventive measures to prevent drug contamination, says Macy Kelly Freeman, professor and director of Samford University's Center for Healthcare Innovation and Patient Survey. Manufacturers, for example, are forced to report impurities, and the agency checks the factories on a priority basis. But there is a catch.
"Obviously, if they do not look for it, they do not really know what is happening," Freeman said. And this is exactly the case in the case of spoiled ARVs. "Before they found this particular compound, they did not even know that there could be a chemical reaction that could have been made out of a connection," she said.
How many people are using these drugs?
Losartan was the 9th most widespread drug in the country based on data for 2016. Valsartan was No. 92, and irbesartan was No. 171. For one year, 49 million patients were then distributed with losartan, 8 million valsartan, and 3 million irbesartan, said Freeman, noting that a total of 60 million American patients do not include hospitals. VA systems, only patients buy from public pharmacies. These are bricks and mortars that are controlled by pharmacists and include a chain of stores, but not hospitals or online pharmacies.
At first glance, the risk of developing these cancers is low. "If 8,000 patients take the contaminated product within four years, only one of them will develop cancer," Freeman explained. "This is the worst scenario if someone takes the affected product every time they fill it."
Patients who suffer from recurrence may not permanently take the spoiled product because pharmacies often buy the same drug from various
"The effect should be relatively small," Freeman said. Of course, if the patient is your own beloved person and he or she has developed cancer, you may not think about it, she said.
How is the FDA Police engaged in the production of drugs?
Woodcock said that the FDA controls production processes around the world and noted that the agency believes that some manufacturers "cut corners".
"We are well aware that not everyone is up," she said, adding that "the overwhelming majority of the sites we are inspecting is satisfactory. "The agency has a number of actions, including written reservations and approvals, to bring manufacturers in compliance.
Some non-verifiable manufacturers voluntarily take steps to improve their operations, while others require "official actions" such as the FDA refuses to grant new approvals to the plant "until it is fixed," said Woodcock Some domestic factories were ordered to clear their actions under the supervision of a judge.
"For foreign sites, we can enter import notifications, and they can not import anything to the US," she said.
Why do not the factories check?
In a study published in 2016, Freeman evaluated the FDA's recall within a 30-month period. December 31, 2014.
"It's a reminder to the FDA throughout the year, it's very difficult to characterize why they are happening," she said.
During the research period, about 3,000 products were reviewed by Freeman and colleagues. In total, 348 were related to medicinal products withdrawn, but the most common reasons for the recall were pollution, false labeling, adverse reaction, defective product, and correct potency.
"Obviously, there are so many manufacturers out there, it would be difficult for the FDA to visit each site on a regular basis to be able to make sure that such kind of thing does not happen," said Freeman.
How often do FDA check factories? 19659007] The FDA checks before the production begins, and then, after launch in full swing, it checks on the basis of "priority risk" basis, said Woodcock. How long has the plant been inspected, it takes into account the risk and helps the FDA management.
Nathan Cortez, a professor and deputy dean on research at the law school of DMDU, wrote in an e-mail message: periodically for products imported from China – sometimes for medicines, sometimes for food products.
Cortez said that with so much US imports coming from China, "it is difficult to say whether periodic problems are inevitable or because of the weakness of internal control. In any case, the FDA carries out foreign audits sometimes with the permission of the Chinese government. "
Woodcock said: "We are not the only one in this game. The European Union has inspectors, South Korea has inspectors, Japan has inspectors, Australia, and so on. So, many people come and explore these [facilities].
The Chinese government is cooperating and wants to work with the FDA, the agency reports. Issues associated with gaining access to an item in China or elsewhere, usually caused by a specific participating company, but those who refuse to verify the FDA are subject to an import warning. or there are some problems, it does not always mean that "the product is bad," said Woodcock. "This means that they are doing practices that are not optimal for maintaining mass production of this product.
How are patients and pharmacists reminded?
"Most patients should come and get their medications to change them" on many medicines that were not affected, said Freeman. Other people get changes in their recipes.
From the pharmacy network point of view, this challenge was complicated, since many pharmacies do not store prescription numbers after they are issued, Freeman said: "This information is not monitored effectively. She hopes that technologies such as barcode scanners will be introduced in the next few years. codes that will help identify suffered patients.
Freeman belongs to several Facebook groups, in which pharmacists complained that "many references" to ARB over the past few years. One pharmacist told Freeman that it was "awkward" to recall.
After contacting some individuals and saying in essence that "your valsartan is OK," this information was changed shortly after the new FDA recall list expanded to include the patient's product batch. Another pharmacist wrote Freeman: "Tell the patients that they do not come here to be angry. We are trying to help.
Have there been any additional effects?
Cortez has not heard of any litigation related to the recall – although, of course, maybe he said. But "production claims are relatively rare and difficult to prove," he said. And it may be difficult to sue foreign manufacturers, because it may be harder, if not impossible, to enforce decisions.
"The roots of this constantly expanding series of reminders seem to relate to at least two foreign manufacturing institutions: Zhejiang Huahai Pharmaceutical in China and Hetero Labs in India." "The inspection reports from these two plants indicate serious problems at both plants, before carcinogens were detected."
Woodcock said: "As soon as this investigation is over, it probably means creating more international standards so that this particular incident could not be repeated.
How to improve the FDA?
" We have ideas about how as everything could be better, "said Woodcock, adding that the FDA had already approved changes to some manufacturing operations.
Pharmaceutical manufacturers work better with" closed systems, much more automation, computer management, "which today is not often is found in the industry, she said.
"We believe that in the end "The business case will be convincing," which means that production costs will be lower even with initial investments in new machines and such "but we are in the transition phase," she said.