IN LATE 2013, pharmacists at the Cleveland Clinic made a striking decision: The health system would no longer stock a generic version of an immunosuppressant drug, tacrolimus, made by the Indian company Dr. Reddy’s Laboratories.
The internal announcement surprised Dr. Randall Starling, a Cleveland Clinic heart failure specialist. Starling regularly treated patients who received heart transplants; immunosuppressant drugs were critical to the success of these procedures.
The Dr. Reddy’s version of the immunosuppressant on which his patients’ lives depended was by far the cheapest, priced far below the $3,000 per month price tag of the brand name drug, Prograf, made by Astellas. But the Cleveland Clinic’s pharmacists — who did wide-ranging research to determine which drugs the hospital should or shouldn’t use — were growing uncomfortable with the number of recalls of Dr. Reddy’s drugs.
The generic drug became a variable in a treatment plan with no room for error. “If we’re giving a patient inert medication,” that is, medication that doesn’t work, “it’s a huge failure of the system,” said Starling. “An organ has been wasted potentially,” and so has money: The average cost of transplanting a heart is well over $1 million.
Over the next six months, the physician worked with his staff to make sure that none of their patients was taking the Dr. Reddy’s tacrolimus and that the hospital’s inpatient and outpatient pharmacies no longer carried it. But he couldn’t control what his patients took once they left the clinic’s grounds.
Soon enough, his worst fears were realized.
In October 2014, Cedric Brown, a 48 year-old patient who’d undergone a successful heart transplant 18 months earlier, was admitted to the hospital with symptoms of acute organ rejection. Despite Brown’s successful transplant and recovery, by the time he landed back in the hospital’s intensive care unit, he had gained 50 pounds and felt terrible.
On a Monday morning, Starling arrived in Brown’s hospital room to consult on his case. Standing by Brown’s bedside, he asked, “Did you get a new prescription?”
Brown said yes — the pill was a different size and color than Prograf.
With permission, Starling fished in the patient’s bag and found the tacrolimus made by Dr. Reddy’s.
Starling told his patient, “You are never going to take this one again.”
Brown’s pharmacy had given him a generic, which wasn’t surprising. Driven by America’s need to keep down pharmaceutical costs, the US drug supply is now 90 percent generic.
The majority of generics bought in the US are made overseas: Roughly 40 percent are manufactured in India; 80 percent of the active ingredients in all of our drugs, whether brand-name or generic, are made in India and China. As one drug-ingredient importer put it, “Without products from overseas, not a single drug could be made.”
The vast amount of overseas manufacturing presents an enormous challenge for the Food and Drug Administration (FDA), which must safeguard thousands of drugs manufactured abroad by foreign companies.
The FDA contends that it has a reliable review system for all approved drugs. “The FDA inspects all brand-name and generic manufacturing facilities around the world which manufacture product for the US market to confirm they meet FDA’s requirements for manufacturing process,” the agency said recently. It asserts that all the generics it approves are bioequivalent to the brand (meaning, they reach the same level of absorption in the blood).
But American physicians — particularly those who prescribe drugs that require precise dosing — are questioning the FDA’s ability to police overseas manufacturing. Are all those drugs clinically equivalent? And do the generic drugs that the agency approves actually meet the FDA’s standards, since the agency’s own investigators have discovered staggering fraud in a number of overseas drug plants?
CLEVELAND CLINIC’S CONCERNS about generics began in 2007 when cardiologist Dr. Harry Lever heard a radio broadcast about the FDA’s struggle to inspect adulterated food and ingredients imported from China. Stories of so-called “filthy” food, like fish bred in polluted waters and fed banned veterinary drugs, made him think about the medicines being imported from overseas.
Lever had one of the nation’s biggest practices in treating hypertrophic cardiomyopathy (HCM), a condition in which the heart’s muscle tissue thickens and potentially restricts blood flow. For years, the beta blockers and calcium channel blockers that he prescribed would reliably ease his patients’ irregular heartbeats or help lower their blood pressure. But increasingly, he noticed that some of the patients he’d stabilized on brand-name drugs developed symptoms again when they switched to certain generics.
One of his patients, Karen Wilmering, had obstructive HCM, which blocked the blood flow out of her heart’s left ventricle. For years, she’d taken brand-name Pravachol, made by Bristol-Myers Squibb, to control her cholesterol. One day, her pharmacy switched her to the generic. When Lever ran another test, Wilmering’s cholesterol results were alarmingly high.
Lever asked Wilmering which company made her cholesterol drug. When she told him it was Glenmark, Lever “almost jumped out of the chair, because Glenmark is from India,” Wilmering recalled.
Whenever drugs had roused Lever’s suspicion, he had researched the drug maker and the locations of its plants — basic information absent from the drug’s packaging or product label. He also enlisted Cleveland Clinic’s pharmacists, who routinely gathered data from manufacturers and the FDA as part of their research into which drugs the hospital should use.
Lever and the pharmacists had discovered that a complex supply chain made it extremely difficult to know where drugs had been made, who made them, and which ones worked best.
But it was becoming clear that a preponderance of problematic drugs had been manufactured in India.
Lever dialed Wilmering’s pharmacist and insisted that she be switched to Teva’s version, which he believed would work better. In less than a month, her cholesterol dropped back to the normal range. Even Lever was stunned by the new numbers.
The following year, Glenmark recalled thousands of bottles of its pravastatin sodium, due to patient complaints that the medicine gave off a strong fishy odor. A Glenmark spokesperson said the recall was “voluntary, proactively initiated by Glenmark, and not related to product efficacy.”
LEVER GREW INCREASINGLY concerned about the FDA’s ability to oversee drug manufacturing abroad. In December 2012, he sent a detailed letter to Dr. Janet Woodcock, director of the FDA’s Center for Drug Evaluation and Research, specifically flagging the metoprolol succinate formulation made by the Indian generic-drug company, Wockhardt. In his letter, he noted that he could not properly control his patients’ chest pain, heart rate, or blood pressure when they took Wockhardt’s drug, but their symptoms abated if he switched them back to the brand-name version.
“While I have no data to back up my concerns, I have a significant amount of experience with this disease and see a large number of patients,” he wrote. “It is absolutely clear to me that there are differences that are clinically significant.”
Within two days, Lever received a detailed response from the FDA’s Office of Pharmaceutical Quality, pledging to conduct a comparative study of the brand and generic metoprolol products.
Seven months later, three FDA inspectors arrived at the Wockhardt plant in the Chikalthana area of Aurangabad, in western India. They searched through the plant’s computer systems and discovered that its technicians had been conducting unofficial pretests of its drugs to evaluate the results, then deleting evidence of those tests from the plant’s hard drives and retesting the drugs in the official computer system.
The evidence suggested the plant was manipulating its quality tests to ensure that its drugs — even those that didn’t meet specifications — got passing results.
Shockingly, eight months after the Wockhardt inspection, a senior FDA official contacted Lever at the Cleveland Clinic to explain that an “extensive multidisciplinary investigation” had determined that Wockhardt’s metoprolol succinate was bioequivalent to the brand. The FDA had reached this conclusion, in part, by reviewing the company’s own initial data, which the FDA inspectors had flagged as suspicious.
In the end, it was Wockhardt itself, followed by Dr. Reddy’s, that recalled their metoprolol succinate from the market, with the admission that the drugs were not bioequivalent. Lever had been correct all along.
AS LEVER LOST confidence in the FDA, Cleveland Clinic pharmacists developed a confidential black list of drugs it would no longer buy, dominated by generic drugs manufactured in India.
The Dr. Reddy’s tacrolimus went on that black list.
Tacrolimus was a so-called narrow therapeutic index drug that required precise dosing; minor variations could lead to life-threatening complications.
The Cleveland Clinic’s doctors were not alone in their concerns about Dr. Reddy’s tacrolimus. In October 2013, a pharmacist at the Loma Linda University Medical Center in California reported to the FDA, through its online complaint database Medwatch, that “multiple patients” who used the Dr. Reddy’s tacrolimus had “unpredictable levels leading to inadequate immunosuppression and subsequent transplant failure.” The report from Loma Linda noted, “This has only been seen with the Dr. Reddy’s brand of Prograf.”
In 2017, a study commissioned by the FDA found Dr. Reddy’s tacrolimus to be bioequivalent to the brand and interchangeable with it.
Regardless, months after Cedric Brown’s admission to the intensive care unit, it happened again — another heart-transplant patient suffering from organ rejection who had taken the Dr. Reddy’s formulation was admitted to the hospital. Several more followed.
In June 2018, Kristy Jordan, 35, arrived at Cleveland Clinic’s emergency room, suffering from chest pain and shortness of breath. She’d had a successful heart transplant three years earlier and had taken Prograf daily to prevent organ rejection. But six months before, a CVS pharmacy refilled her prescription with the Dr. Reddy’s tacrolimus. In the emergency room, tests showed that she had lower-than-expected levels of tacrolimus in her blood and was suffering from organ rejection. Doctors stabilized her.
Jordan continued to feel sluggish and never fully recovered. Last September, she died of a heart attack. Starling said that there was no way to know whether the tacrolimus made by Dr. Reddy’s contributed to her death. But he pointed out that hospitals are now required to pay penalties to Medicare when their patients are readmitted. “If we learn that part of our efforts to prevent readmissions are thwarted by bad drugs,” he noted, “it’s going to be a very important discovery.”
OVER THE PAST two decades, US pharmaceutical companies have been moving their manufacturing to China, India, and other foreign markets to slash labor and production costs. Foreign drug manufacturers, in turn, have been seeking approvals from the FDA to gain entry to our pharmaceutical market — the world’s largest and most lucrative. By 2005, the Food and Drug Administration had more drug plants to inspect overseas than it did within US borders.
While the agency has struggled to police a global drug supply, US patients have faced a perfect storm of consequences. The ever-climbing prices of brand-name drugs have led to our reliance on the lowest-cost manufacturers overseas.
Recently, dozens of versions of the generic blood pressure medicines — valsartan and losartan — have been recalled, due to ingredients manufactured in China that contained a carcinogen that had gone undetected for years.
Recalls due to flawed manufacturing have contributed to chronic drug shortages.
The US makes almost none of its own antibiotics anymore, leaving us in a perilous state of pharmaceutical dependence on other countries, a situation that has become a national security risk.
Solving these problems requires a multi-pronged solution to reduce brand-name drug prices, overhaul the FDA’s foreign inspection program and revamp a system in which regulators rely on company-submitted data to verify drug quality. But along with these efforts must come a rethink of who makes our drugs where. Shouldn’t some percentage of our essential drugs be made on US soil?
Senator Elizabeth Warren, now running for president, has proposed that the US government get into the business of manufacturing generic drugs as a way to address the public health crisis of unaffordable medicine. A newly launched non-profit drug manufacturer, Civica Rx, headquartered in Utah, aims to manufacture drugs in short supply within the US, and disclose its manufacturing locations on patient dispensing labels.
If these efforts gain traction, they could help to remove the question marks currently hovering over the low cost generics that doctors and patients rely on: Where were these manufactured, under what conditions, and will they really be as clinically effective as the brand-name drugs?
Katherine Eban, an investigative journalist, is the author of “Bottle of Lies: The Inside Story of the Generic Drug Boom.”