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(Bloomberg) – Last year, US regulators issued a stern warning to US consumers that a heart medicine made in China and taken by millions of people was contaminated with a potentially carcinogenic chemical.
The Food and Drug Administration has overseen the recall of the contaminated pills. But even in this case, the agency that helps safeguard a global drug supply chain was doing fewer inspections in the drug factories in the country of origin of the problem.
Treatments by Chinese companies now account for nearly one in every 10 generic medicines authorized by the FDA to be sold. However, agency inspections to ensure that approved drugs met US standards dropped by nearly 11%, reaching 125 in China for the fiscal year ended Sept. 30, compared to the previous year. , according to data obtained by Bloomberg through requests for public registries. .
Using hundreds of pages of US government documents, Bloomberg spent last year reporting on a supply chain that is expanding around the world and ending in American medicine cabinets. . Although overall inspections of this network are declining, records show that those being carried out, from West Virginia to China through India, raise doubts about the data supposed to prove that the drugs are safe and effective.
These doubts are sometimes dismissed by the FDA management. According to an inspection report obtained by Bloomberg, an FDA inspector had determined in May 2017 that some of the medications that she was providing in the US market could be of substandard quality. the plant that had triggered the recall of heart medications in July of last year.
The FDA inspector's visit in 2017 had raised a number of issues. The Chinese drug manufacturer, Zhejiang Huahai Pharmaceutical Co. Ltd., had omitted from official records the results of quality tests showing that the unnamed drugs did not meet US standards, but had instead obtained satisfactory grades. writes the FDA inspector in his report. The inspector recommended that the agency send a warning letter to Zhejiang Huahai, one of China's largest exporters of pharmaceuticals, that would have meant that he could not obtain permission to manufacture new generic drugs in this plant before the list of problems is resolved.
But four months later, FDA officials at the agency's headquarters in Silver Spring, Maryland, dismissed the inspector. Zhejiang Huahai Pharmaceutical was allowed to avoid these penalties and solve the problem itself – perhaps missing an opportunity to detect the contaminant causing cancer more than a year ago.
"It's not normal to tell the truth," said Kevin Schug, a professor of badytical chemistry at the University of Texas at Arlington, after reading Bloomberg's demand-driven inspection report. Schug specializes in the type of testing that pharmaceutical companies use to perform quality controls. "I certainly would not want to take [any] drug had gone through this process. "
An FDA spokesperson, Sarah Peddicord, said patient safety dictates the agency's response. After the 2017 inspection, the problem of impurities was discovered, "the FDA reviewed the results of the inspection and took into account the corrective measures proposed by the company to decide what action to take."
More and more drugs consumed by Americans come from China, where the costs of production are lower. The drugs manufactured in China accounted for 8% of the FDA's generic approvals from 2018 to October 30, up from 1% in 2015, according to Morris Borenstein, senior badyst at Moody's.
Yet, inspections of generic manufacturers in China have dropped. The recent downturn has pushed the number of FDA inspections in the country to a level below what it was a few years ago when the agency had pledged to strengthen its capabilities at the US Food and Drug Administration. # 39; abroad. FDA Commissioner Donald Trump, Scott Gottlieb, has made marketing more generic drugs on the market a priority as part of the president's efforts to drive down prices.
In his defense of his agency's approach, Gottlieb stated that he uses a formula that weighs the risk factors, including the date a plant was inspected and what the inspection revealed – not the geography .
"If you look at it from a risk perspective – on the part of the people who do the intelligence work and who know where the risks are – it's not just that we've done x number of times." inspections on x number of years of x number of institutions, "Gottlieb said in an interview." The risk points are changing with the nature of the supply chain. "
The so-called surveillance inspections conducted in FY17, which included Gottlieb's first few months in office, totaled 140 in China, 14% less than the 163 FDA inspections that had been conducted during the year. Fiscal year 2016. The agency uses surveillance inspections to ensure that companies comply with US standards. manufacturing standards and check the accuracy of the internal quality tests performed by the companies.
In a Friday update on the heart medication recall, the FDA said that any additional inspections should not focus on a particular country, but on the facilities that perform the treatment, which is called valsartan. "We remain confident in the use of the current risk-based FDA approach, which does not include geographic location as a risk factor, and in our continued ability to protect patients against potentially harmful products, "said the agency.
Zhejiang Huahai did not answer the question whether he could have found a potential carcinogen, a chemical called NDMA, earlier. Jun Du, chairman and CEO of Prinston Pharmaceutical Inc., a subsidiary of Zhejiang Huahai, said in an email that the FDA had completed its 2017 inspection of the Chinese plant after the company had submitted detailed responses to the sightings from the inspector.
"Since the start of the recall, we have been in close contact with the FDA and have collaborated throughout the project with agency staff, our clients and our patients," Du said.
Zhejiang Huahai provided valsartan, the active ingredient – a widely used treatment for high blood pressure, taken alone and sold in combination with other cardiovascular drugs – on behalf of large companies such as Teva Pharmaceutical Industries Ltd., the largest manufacturer of generic drugs in Europe. the world. After the FDA reported the problem of contamination, Teva began recalling valsartan and valsartan from other drugs in July. Since then, other companies have also recalled, including some companies that did not buy valsartan in Zhejiang Huahai, such as Mylan NV, the second largest generic company, for using a similar carcinogenic ingredient , the NDEA.
Zhejiang Huahai has already had problems with his data. In 2016, Chinese regulators asked pharmaceutical manufacturers to withdraw their requests to sell new medicines that may contain false or incomplete data. Zhejiang Huahai withdrew its claims for generics for epilepsy, blood pressure and depression, claiming at the time that the problems related to faulty tests conducted by a Chinese contract research organization, affiliated with a large hospital in China.
The growing number of companies buying their ingredients from China is raising concerns about the generalization of these problems, said Randall Zusman, director of the Division of Hypertension at the Mbadachusetts Heart Center Hospital Center.
"I found it surprising that Teva, which owns its own manufacturing plants, is buying Chinese Valsartan for its products," Zusman said. "They found that it was economically appropriate to buy from this Chinese supplier, which shows how much this could extend if this continues to be the case."
Zusman said that one of his colleagues had consulted him about a patient who had developed bladder cancer while he was taking valsartan. It's unclear whether valsartan has contributed to cancer, said Zusman, but that's a concern. "Obviously, this is very scary to the patient," he said. "And it's a disappointment for me to think that I might have prescribed a drug that could have caused a malignant tumor."
He is not currently starting any of his patients under valsartan. Although there are alternatives, the recall raised doubts in his mind about the drug.
"I think back every time I prescribe one of these medications," Zusman said of valsartan products.
The FDA inspector who went to the Zhejiang Huahai factory in Linhai City wrote in his inspection report that the company's practice was to record pbad marks for drugs that , originally, did not meet US standards for routine quality testing. He stated that his findings cast a "cloud of uncertainty over the accuracy of the test results" used to obtain authorization to sell drugs in the United States, according to the documents from the public registry application.
Quality tests, which are a common practice in the manufacture of pharmaceutical products, make it possible to check the quantity of active ingredient contained in a medicine and to search for a possible contamination. The FDA's inspector has recommended the company to receive a warning letter, one of the most severe reprimands from the FDA: it may impose restrictions on the ability for a company to sell products in the United States. Companies that receive a warning letter must also undergo a rigorous evaluation of their tests. methods.
According to a memo obtained through public registration applications, FDA officials who overcame the inspector's concerns about Zhejiang Huahai decided to let the company solve the problem, choosing not to impose drug manufacturer restrictions. FDA officials said the agency had found no violations during the 2010 and 2014 inspections and that the test results in question had not affected the finished products.
About a year after the inspector's concerns were dismissed, a company that buys valsartan from Zhejiang Huahai found an impurity in the Chinese company's active ingredient, discovered as the potentially carcinogenic chemical, NDMA. Zhejiang Huahai's valsartan manufacturing plant was subsequently banned from sending drugs to the United States (the FDA did not identify the customer who discovered the impurity.)
The FDA inspector who originally went to the factory had written in his report that the failed quality tests that the company had omitted from the official records included those that detected impurities in anonymous drugs that the company did not seek to identify.
Zhejiang Huahai was supposed to find a way to identify impurities or get rid of them, said Schug, a professor of badytical chemistry. If NDMA was introduced or created during the manufacturing process, tests would probably identify it, he said.
"They certainly should have caught it, and they should have changed the procedure to fix it," Schug said.
Zhejiang Huahai did not comment on specific questions about the failure of the tests. The inspectors visited the Linhai factory in July and August, after the start of the Valsartan recall. The FDA again found that Zhejiang Huahai had omitted tests indicating unknown impurities, according to a warning letter sent by this agency to the company on Nov. 29.
The letter said that if Zhejiang Huahai "had conducted further investigation", the workers might have found indicators "alerting you to the presence of NDMA". impurities in all pharmaceutical ingredients manufactured by Zhejiang Huahai, not only in valsartan.
Zhejiang Huahai has been cooperating with the FDA throughout its investigation, said Du, chief executive of Prinston. "In detailed badyzes and corrective action plans, the company took into account each of the FDA's observations in 2018, as well as the elements mentioned more recently by the FDA in its warning letter," he said. -he declares.
Since the revelation of NDMA in Zhejiang Huahai Valsartan, the FDA has periodically updated the recall notification because new samples of valsartan – and even similar drugs called losartan and irbesartan – were contaminated. The agency is trying to determine how the chemical gets into the products and is currently reviewing the manufacturing processes of the companies to determine if they are likely to form an NDMA or an NDEA.
Companies who recalled the drug did not receive it from Zhejiang Huahai, but manufacturers of the recalled products of Valsartan used a similar process to make the tablets. This process is different from the branded version of valsartan called Diovan, manufactured by the Swiss drug manufacturer Novartis AG. Diovan does not contain NDMA or NDEA and has not been recalled.
Zhejiang Huahai's valsartan contained "significantly higher" NDMA levels than those of other recalled versions of the drug, the FDA announced in its November warning letter.
US regulators expect companies to control themselves. "The review of records by the FDA relies on the fact that manufacturers perform appropriate tests capable of detecting impurities," said Peddicord, spokesman for the agency. "It is the responsibility of the manufacturer to ensure that these tests are based on an adequate badessment of the impurities that may form during the manufacturing process."
The agency said it was working with valsartan manufacturers concerned with the recall "to minimize or eliminate" the risk of likely formation of carcinogenic impurities.
In the case of Zhejiang Huahai, the company had last modified its processes in 2011, according to the FDA. And the agency said the carcinogenic potential could have been in valsartan for as long as four years.
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