Former FDA inspector warns of dangers of US drugs manufactured in China and India

May 10, 2019, 17:01 UTC

By Didi Martinez, Brenda Breslauer and Stephanie Gosk

The notice arrived at Denise Schreck, a New Jersey woman with hypertension, last July.

"URGENT PRODUCT RECALL", launched the word at the top of the pharmacy's letter.

The blood pressure medications used by Schreck and millions of other Americans were contaminated. Guilty party? A chemical that can cause cancer.

Schreck went online to learn more and discovered that the generic drug, valsartan, actually contained a contaminant formerly used in the production of rocket fuel, according to a government fact sheet.

"I was really blown away," 51-year-old Schreck told NBC News. "It's shocking to know that you're taking a probable carcinogen for four years."

For more information, log in to NBC Nightly News with Lester Holt tonight at 6:30 pm ET / 5:30 pm CT

The recall of Valsartan was hardly a surprise for Massoud Motamed, former inspector of the US Food and Drug Administration (FDA). More than a year before the notice was issued, Motamed had attempted to sound the alarm on systemic issues that he considered to be of concern in two institutions in China and India producing the active ingredients of the company. Generic valsartan and other drugs for hypertension.

Speaking publicly for the first time, Motamed told NBC News that the FDA had finally rejected his recommendation to crack down on one of the factories. Perhaps more alarmingly, he says that the problems encountered in the two overseas drug production facilities are not unique.

"That's only the tip of the iceberg," said Motamed in an exclusive interview.

The Valsartan case highlights a new reality in the pharmaceutical industry: a growing reliance on foreign manufacturers to provide raw ingredients for drugs sold in the United States. According to FDA data, about 85% of facilities manufacturing US drug ingredients are located abroad, many come from China and India, where production costs are low and experts say that the supervision local authorities is less strict.

This change has contributed to a flood of recent recalls and growing concern over the safety of drugs consumed in the United States.

Since last summer, pharmaceutical companies have announced a total of 45 generic drug reminders to help save blood pressure. They include some versions of valsartan and two other drugs for hypertension, losartan and irbesartan, as well as other drugs for hypertension that contain the drugs recalled in their formulation. The raw ingredients were all found at overseas manufacturing sites where drugs can be processed at a lower cost than US facilities.

"Growing up, we had this sentence:" You get what you pay for, "said Motamed." We have this conviction for everything but pharmaceuticals. If we want to stimulate competition and lower prices, it is at the expense of quality. "

For Motamed, reminders tell only part of the story. According to him, a more systemic problem is largely ignored: FDA inspectors are struggling to keep up with the pace of foreign drug manufacturers who may bury or conceal production problems.

According to the agency's data, last year the FDA inspected only one in five human drug manufacturing facilities.

As US inspectors strive to review an extensive network of drug production plants abroad, the FDA is often forced to rely on the words of the facility's managers, Motamed said. .

"I believe Americans would be surprised at how much we rely on the manufacturer and what they tell us to say that a drug is good or bad," said the former inspector. at NBC News.

According to agency data, the FDA has also inspected only about one in five drug manufacturing facilities in the country. But unlike inspections in US factories, where investigators can come forward without warning and ask for more time to review conditions if they detect potential problems, Motamed explained that revisions to foreign sites are often hampered by language barriers. and time constraints.

"Let's say I'm in a home facility and I tell my supervisors that I find all these problems and that I need more time to inspect.This happens – no problem," Motamed said.

"This is not the case of a foreign facility." I had inspections where I could have really enjoyed the extra time and I knew that there were problems to discover, but I had to leave the country. "

Motamed spent three years as an investigator with the FDA, working primarily overseas to inspect manufacturing facilities overseas. A native of Texas with a Ph.D. In biochemistry, Motamed, 34, joined the agency driven by the desire to contribute to the field of public health.

He had held this position for more than two years when he went to inspect the Zhejiang Huahai Pharmaceutical Factory in Linhai, China – the company that produced the contaminated ingredients in Schreck's recalled drug – in May 2017.

Motamed's four-day inspection revealed a series of alarming problems that he later described in official reports. Facilities and equipment not maintained. Anomalies in the tests are not the subject of an investigation. And "unknown impurities" are considered a laboratory error.

After his visit, and as reported by Bloomberg for the first time, Motamed recommended sending a warning letter to the company, an official action barring the company from obtaining the Authorization to produce new drugs in the United States until the problem is solved.

But three months later, he was rejected by the FDA management. The FDA has decided to allow Zhejiang Huahai to fix the problems itself, the agency said in an official document obtained by NBC News, citing the firm's compliance history and its "answers". adequate "to the impurities of their tests.

"Many factors influence FDA decisions at some point regarding action to be taken as a result of an inspection," the FDA said in a statement to NBC News. "We make these decisions in the interest of patient safety based on all the information we have, including the evidence gathered during an FDA inspection and the corrective measures proposed by the manufacturer."

After being criticized for dealing with the case, the FDA said it would have been "unlikely" to capture the impurities at the source of the recall during a routine inspection.

"Nevertheless, our inspections revealed systemic problems of supervision that could have created conditions conducive to the emergence of quality problems," reads in an FDA press release of January 2019.

In a statement to NBC News, Zhejiang Huahai said "working closely with regulators from here and elsewhere to assess the source of the impurities behind the recall" and determine if "any modification of its manufacturing processes is necessary ".

The problems were not limited to installations in China. In investigating a drug manufacturing plant in India, Hetero Labs Limited, in December 2016, Motamed discovered what appeared to be a shameless attempt to conceal problems in the factory.

"I used to go to the bathroom and I always saw people going into an archive room, and that's not typical," Motamed said.

He decided to review the company's closed circuit television images. What the inspector saw then shocked him.

The inspection report indicates that Motamed has viewed images of individuals shredding company documents four days before his arrival.

"They were awake all night destroying considerable amounts of documents just before our audit," said Motamed. "… It means that there are systemic problems."

"It's one of the most disturbing findings I've had over the years," added the former inspector.

The FDA finally sent a warning letter to Hetero in August 2017, citing "serious violations of current good manufacturing practices". Some 19 months after Motamed first reported suspicious activity in the plant, it turned out that Hetero was one of the sources of contaminated drug ingredients for sale in the United States.

Hetero has not responded to several requests for comments from NBC News.

In the case of valsartan products, the FDA announced last August that more than half of all drugs sold in the United States were removed from store shelves.

Although it is not known exactly how many people have been affected by the recalls, the simple demand for drugs suggests that these drugs could reach millions of people. In 2016, 1.6 million people purchased valsartan and 9.2 million losartan, according to data provided by the US Department of Health and Human Services.

The recalls create a thorny challenge for consumers such as Don Grybb, who said he was struggling to find an alternative after discovering that his drug, valsartan, had been removed from store shelves.

"Almost from one prescription to the other, I would see significant changes in my blood pressure," said Grybb, 68, of Michigan.

The FDA and external health professionals warned consumers of the abrupt cessation of their medications because of the recall, saying the short-term risks outweighed the potential consequences of the consumption of the drug. recalled medicine.

Uncertainties surrounding drugs also pose problems for physicians.

"It's hard to know what to prescribe to patients," said Dr. Randall Zusman, a cardiologist at the Massachusetts General Hospital Cardiology Center in Boston. "You want to assume that it's safe and effective.You do not want to have the impression of prescribing something that is causing harm."

The FDA states that the overall risk posed by impurities is low. For valsartan, FDA tests revealed that the pills contained 3 to 210 times the level acceptable by the agency for NDMA, the potentially carcinogenic substance at the center of the recall. According to the FDA, if 8,000 people took the highest daily dose of the contaminated medicine for four years, there could be another case of cancer in their lifetime.

"This worries us and we know that it worries the public," the FDA said in a statement. "The problem is appropriate."

Experts said contaminants are still potent at low levels. "This goes far beyond the risk that government agencies generally find acceptable," said Lisa Lefferts, a senior scientist at the Center for Science in the Public Interest. "Although most people do not contract cancer because of the contaminants contained in these pills, it is an unacceptable and preventable risk."

The FDA has published a list of drugs that are free of potentially carcinogenic substances and has indicated that it is working to mitigate and prevent shortages.

"Our first action was to immediately undertake a major operation to research and identify the root causes of the presence of these impurities and to collaborate with companies to reduce the risks that these impurities posed to patients," he said. FDA Director Dr. Janet Woodcock. for the Center for Evaluation and Drug Research, said in a statement to NBC News.

Dozens of consumers have now gathered to sue almost every company involved in the recall, as part of a consolidated multi-party litigation in New Jersey.

"There are a lot of things that could have been done to prevent something like that," Daniel Nigh, counsel for the plaintiffs, told NBC News.

The Association for Accessible Medicines, the generic drug trade group, said its "member companies active in the field of the affected products had voluntarily recalled their drugs containing valsartan and had worked closely" with the FDA.

"Patients in the United States can be sure that the drugs they take are safe and effective," the group added. "Generic drug companies and the Food and Drug Administration are ensuring that prescription drugs meet the same high quality standards, regardless of where they are made."

Motamed left the FDA in 2017, disappointed with his experience trying to control a sprawling industry in what he described as a "cat and mouse" game in which companies do what they do can to conceal their problems at the FDA. He believes that the agency needs to hire more qualified investigators and must conduct more inspections at foreign facilities producing pharmaceutical ingredients.

Now working for the private pharmaceutical sector in India, Motamed said he was speaking out to raise public awareness of the risk of contaminated drugs.

"I think there is an important part that, if we test it here in the United States, would not pass," said Motamed.

As for Schreck, concern over valsartan reminders prompted him to tidy up his bottle of pills in a small brown cupboard over his kitchen sink.

Why? She sees evidence that could be used in court if a cancer were to infect her body one day.

"I hate to think that, for this reason, I run an additional risk of developing cancer," said Schreck. "But that's my proof."