Knut Royce is a veteran investigative reporter who has won numerous journalism awards and contributed to three Pulitzer Prize–winning stories. He contributed to the Worldfocus signature story: Contaminated drug imports threaten Americans.
Since the 1930s, heparin — a cheap and widely-administered blood thinner derived from pig guts — has helped save the lives of millions of dialysis and surgery patients. Then, in 2006, Chinese suppliers of the drug’s basic material contaminated it with a mysterious ingredient. Patients began to die.
For more than a year, the Food and Drug Administration, America’s pharmaceutical watchdog, was oblivious to the silent killer lurking inside heparin, a Worldfocus investigation has learned.
How many died will never be known. Thousands suffered immediate reactions, ranging from facial swelling to nausea, diarrhea and dangerous drops in blood pressure. Others developed potentially lethal symptoms that are not immediately visible but can last for months and FDA officials worry about yet-unknown reactions.
Our investigation uncovered flaws in the FDA’s voluntary system that relies on timely notification by health providers of unusual serious reactions to drugs. Most reports are late, incomplete and represented only a fraction of patients suffering side-effects. And the investigation found that patients continued to be exposed to the tainted heparin long after recalls were issued.
China is rapidly becoming one of the world’s leading suppliers of the chemicals that make drugs work— the active pharmaceutical ingredient, or API. But it also has a problematic record of cutting costs by substituting approved ingredients with cheaper products that fool quality control tests — and kill patients. “One of the scary things is that the FDA leadership tells me that they believe the number of Chinese drug manufacturers will soar in the future,” said William Hubbard, a former FDA associate commissioner. “So not only is there an immediate problem but the problem is going to get worse.”
The contamination of heparin is but the latest scandal involving Chinese drugs. Raw ingredient producers in China had contaminated the drug’s active ingredient by adding a much cheaper synthetic chemical that mimicked the behavior of heparin and fooled testing by the ingredient’s wholesale purchasers, including pharmaceutical giant Baxter Healthcare Corp. The synthetic fraud is 100 times cheaper to produce than untainted raw heparin, according to congressional testimony.
The Worldfocus investigation has learned that the contaminant, oversulfated chondroitin sulfate (OSCS), was invented in a laboratory by a team of University of Iowa and Japanese scientists who wanted to create synthetic heparin. They published a paper on their findings in 1998. After publication, they tested the product on mice. The mice died. Unfortunately no paper was published disclosing the alarming result of the in vivo experiment, since it was deemed to be unsuccessful and unworthy of peer review.
Not knowing that the material was lethal, Shandong University in China filed a patent for the chemical on Dec. 20, 2005, believing that it could provide a cheap substitute for heparin. “It was our material,” recalls Robert J. Linhardt, a world-renowned heparin specialist who led the Iowa team and is now a professor at the Rensselaer Polytechnic Institute. “Based on our paper, I guess they believed it could have been useful in vivo.”
Within weeks of the patent’s filing, Chinese chemists working for raw material processors in unregulated workshops, or middlemen called consolidators, created batches of the OSCS. The deadly concoction was chemically altered from its raw source — animal cartilage, sharkskin or crustaceans — and then blended with crude heparin. The mixture was further refined in Chinese plants into heparin’s key “active pharmaceutical ingredient,” the API, and shipped to drug manufacturers around the world for final processing, packaging and distribution. The FDA has identified 12 different Chinese firms involved in the distribution, but refuses to name them. One of them was Changzhou SPL, an API factory whose majority stakeholder is Scientific Protein Laboratories of Waunakee, Wis. Changzhou SPL was a direct supplier to Baxter.
Until now, only the Changzhou SPL plant has been identified as the supplier of contaminated API to the United States, all to Baxter. But SPL’s factory in Wisconsin also produced tainted heparin API from crude material bought from Chinese consolidators, according to documents obtained by Worldfocus.
The Chinese counterfeiters, who have not been identified, apparently tested the American and European detection systems by initially producing a relatively small amount of contaminated heparin crude. Sandoz, a German subsidiary of Novartis, the large Swiss pharmaceutical firm, detected the tainted ingredient.
But SPL’s testing, based on accepted U.S. and European pharmacopeia screening methods of the time, did not catch two corrupted shipments of crude heparin that had arrived at its Wisconsin factory in the spring of 2006. The factory processed the material in early July and began shipping it to clients almost immediately, according to SPL internal records obtained by Worldfocus. It unknowingly sold the contaminated API to eight pharmaceutical and medical device firms, including Baxter, B. Braun and Covidien. SPL discovered that those early shipments had been corrupted after a team of FDA, Baxter and outside researchers cracked the OSCS code in March 2008 and devised new testing methods. SPL did not respond to several requests for an interview with CEO David Strunce or another company spokesperson.
Sandoz, which also received contaminated shipments early in 2006, detected it — though not through the accepted testing standard for heparin, which would have allowed the OSCS to slip through. It caught the OSCS through a test it had devised years earlier to catch another, much less dangerous contaminant often found in heparin, dermatan sulfate, according to a presentation the firm made at a conference on heparin held this June in Strasbourg, France. Sandoz did not learn until later that the unwanted ingredient was OSCS, but it was sufficiently alarmed that it returned the shipment to its Chinese suppliers, together with their testing method to ensure that future lots would arrive uncontaminated.
“The hypothesis about [the early lots] was that it was kind of a test case. [The Chinese] were sort of probing the system” to see if the product could fool the testing for contaminants, Rensselaer’s Linhardt said the FDA privately told him.
This was not the first time that skilled Chinese chemists were able to replace an ingredient with a cheap substitute that escaped detection by American and global testing standards. Thousands of victims (humans, cats and dogs) fell ill or were killed by the chemical melamine, inserted in substandard milk products and pet food to artificially raise their protein level and fool the existing tests.
Satisfied after their test shipment passed through the supply line, the Chinese producers began to increase the percentage of the cheap substitute. By the summer of 2007, they flooded the market with the corrupted product through Changzhou SPL, Baxter’s supplier, and a number of other Chinese API firms supplying China and the rest of the world. In all, 11 countries have detected OSCS in their heparin, but only one, Germany, has reported reactions similar to those in the U.S. Its tainted drug was produced by Rotexmedica, not Sandoz, according to the FDA. In an e-mail exchange, Baxter told us that it started to receive bad lots from Changzhou in the summer of 2007, and processed the API into finished product from “late summer through fall” of that year. Company spokesperson Erin Gardiner told us that only 1 percent of the company’s API for all its drugs comes from China, though the proportion is likely to increase over the next few years. At the same time, she said, “We have learned lessons from this that are now woven into the very fabric of our company, like identifying new and emerging risks.”
Ram Sasisekharan, a professor of biological engineering at the Massachusetts Institute of Technology who led teams of researchers in March that helped unravel what was poisoning the heparin supply and how it could be detected, said that clinical samples provided by the FDA showed a clear pattern. “You can plot out the amounts (of OSCS) in the months beginning earlier in (2007) and it just goes up every month in our samples,” peaking at about 35 percent late in 2007, he told us.
Telltale clues about contaminated heparin supplies didn’t reach the FDA until 2008. Dr. Ali al-Hakim, a heparin expert at the FDA, told officials at the Strasbourg conference in June that deaths “related to allergic or hypotensive (drop in blood pressure) reactions with the contamination had been noted as early as 2006,” according to a summary of conference workshops obtained by Worldfocus. A study published earlier this month suggests that thousands of patients suffered immediate, though mostly non-lethal, drops in blood pressure, nausea and shortness of breath, symptoms similar to those described by Dr. al-Hakim. There also was a spike in the number of patients whose platelet count became dangerously low, according to research results published in 2008. Only by studying these side effects long after the fact did a handful of doctors and researchers realize that the clues had been missed.
Under a voluntary system, medical practitioners are asked to report to the FDA or, more commonly, to the drug manufacturer, unusual reactions — or “adverse events” — to drugs. By the fall of 2007, the OSCS content was so high in Baxter doses and was being injected in so many patients that side-effects became epidemic. Yet very few adverse event reports were filed. FDA’s adverse event report shows that there were 246 death reports from Jan. 1, 2007 to June 2008. But only 8 of them were filed in 2007.
The first alert came to the Centers for Disease Control and Prevention, best known for detecting and controlling contagious diseases, and not to the FDA, which monitors the efficacy of drugs. The St. Louis (Mo.) Children’s Hospital became alarmed after several young patients suffered acute allergic reactions during dialysis beginning on Nov. 17, 2007. Acute allergic reactions and drops in blood pressure are a known, but extremely rare, side effect of untainted heparin. This was a cluster of cases. The hospital notified the Missouri Department of Health, which in turn alerted the CDC on Jan. 7, 2008.
The CDC contacted several dialysis facilities around the country and was told that they, too, had noticed clusters of patients coming down with multiple reactions. On Jan. 9, the CDC notified the FDA that something was wrong.
By the end of January 2008, the CDC had gathered information from 21 hospitals and dialysis clinics using Baxter heparin showing that 113 of their patients had suffered unusual reactions within an hour of injection. The CDC then obtained the cooperation of 23 facilities that had reported no heparin reaction. They had relied on heparin manufactured by APP Pharmaceuticals, which at the time split the U.S. intravenous heparin market 50-50 with Baxter but imported no Chinese API. The 23 became the control group. The data was provided to a team of researchers led by Sasisekharan. In a Dec. 2008 paper published in the New England Journal of Medicine by Sasisekharan’s team and the CDC, the researchers concluded that indeed there was a causal relation between the OSCS and the outbreak of severe reactions.
The research team’s conclusions were based on CDC’s small sample of facilities and patients, and covered episodes from late November 2007 through January 2008. There are more than 5,000 dialysis centers and almost 6,000 hospitals in the United States. More than 10 million patients receive heparin each year, so the number of cases of allergic reactions over the past couple of years likely reached into the thousands.
Meanwhile, by the end of December 2007, Baxter was also learning from a handful of early reports that there was an unexplained increase in allergic reactions. This was more than three months after Baxter unwittingly released its first lot of contaminated heparin for public consumption. On Jan. 9, 2008, the same day the CDC had alerted the FDA that there was a problem, Baxter placed some of its heparin lots on hold. Two days later it contacted the FDA and disclosed to the agency the increase in reports of allergic reactions, according to a March 5 Baxter report. On Jan. 17, 2008, after consulting with the FDA, Baxter recalled nine lots of heparin. The lots had been produced between September and November. The following month Baxter recalled virtually all of its heparin products.
Most of the attention to date has focused on Baxter because it produced intravenous, multi-dose high heparin concentration vials that prompted the immediate adverse reactions. The API SPL produced in Wisconsin was sold mostly to pharmaceutical equipment firms, which coat catheters, pumps, stents and other devices with small amounts of heparin, or produce low-concentration heparin lock flushes to clear IV lines and catheters. Yet experts believe that these, too, can cause adverse reactions if contaminated by the OSCS, and the 2006 deaths reported by Dr. al-Hakim appear linked to these products, since Baxter had yet to receive the contaminated API it used for intravenous injections.
SPL reacted with urgency once it learned from new testing in March that it had shipped to eight pharmaceutical firms the two lots of contaminated API its Wisconsin plant processed in 2006, according to SPL correspondence with its clients. “Stop using these lots immediately!” SPI’s Strunce pleaded in a March 17 letter to a top Covidien official. Similar alerts went to the seven other clients who had purchased the API from those two lots. They immediately recalled their products.
For many patients, it was too late. By June 3, 2008, the FDA received 97 reports of adverse reactions to the medical devices and lock-flush solutions, including 11 deaths. Dr. Janet Woodcock, director of the FDA’s Center for Drug Evaluation, co-authored a letter in the September 2008 issue of the New England Journal of Medicine warning of yet-unknown side-effects. “We assert that there is no acceptable level of OSCS in any heparin-based product,” she concluded.
The FDA had been blindsided. The public recalls — and the accompanying media attention — prompted a number of health care providers to review their patient history and resulted in the filing of hundreds of adverse event reports, including dozens of deaths, they now believed were linked to the tainted heparin. Some of those events had occurred more than a year earlier.
The FDA’s most recent data on adverse events for heparin shows that health practitioners linked heparin to 246 patient deaths in 2007. Yet all but eight of the events weren’t reported until 2008. Of the 149 deaths in 2007 more demonstrably linked to tainted heparin (where patients suffered allergic reactions or sudden drops in blood pressure), all but three were reported in 2008.
It is nearly impossible to establish an absolute link between the administration of a drug and the death of a patient. Many of the patients are severely ill, some terminally, or may have had other problems that contributed to the death. When the FDA earlier in 2008 analyzed 93 deaths from January through March, when reports peaked, it found that in half of the cases so little information was provided in the reports that it couldn’t establish cause of death. It eliminated heparin as the cause of death altogether in only 23 of the cases.
Nevertheless, the FDA’s heparin adverse reaction numbers mask the true extent of the devastation. Only a fraction of severe and unusual drug reactions are ever reported. “Numerous published scientific reports include a statement that no more than 10 percent and in some cases as little as 1-2 percent of (adverse) events occurring are reported to the FDA,” according to a recent report by the Institute for Safe Medication Practices, a non-profit organization that monitors safety in drugs.
Hubbard, the former FDA associate commissioner, told us that the adverse reaction reporting system is enormously flawed. “When the FDA gets the reports it never gets to fully analyze them and react to them,” he said, in part because the small number of analysts has remained constant over the past decade while the number of reports has grown ten-fold. “The system isn’t very rigorous to begin with…It’s basically a voluntary system, where people (medical practitioners) aren’t attentive…Once publicity occurs people go back and say, ‘Uh oh, we had a case here and we should have reported it.’”
Reports also are not filed because health providers fear involvement in costly wrongful death litigation. The heparin disaster has already prompted the filing of dozens of suits around the country. David Zoll, who represents 63 heparin plaintiffs in a consolidated federal suit in Toledo, Ohio, says that the FDA has been “unable to protect the public from unsafe drugs from overseas.”
The adverse event reports focused largely on allergic reactions and drops in blood pressure, the extremely rare side-effects of heparin.
But a spike in a much more common side-effect was not registered at all in the adverse event reports. Uncontaminated heparin is known to occasionally trigger a reaction called heparin-induced thrombocytopenia (HIT), a potentially deadly drop in the platelet count, which rarely exhibits visible symptoms. It can linger in the body for months. The doses contaminated with OSCS appear to have significantly increased the incidence of that reaction. But because HIT is a known reaction to untainted heparin, those episodes, when discovered, were seldom reported to the FDA and an opportunity for early discovery of the killer drug was missed.
In an e-mail exchange, Karen Riley, an FDA spokesperson, said that the adverse event report data was “inconclusive for unusual spikes in reporting for heparin-induced thrombocytopenia.” She said that none of the HIT reports disclosed which heparin lots had been used, so analysts were unable to link the reactions to contaminated or uncontaminated heparin.
It was after the recalls in January and February 2008 and the related publicity that some medical experts, reviewing patient data, learned what had happened. Two heparin researchers, one in Canada, which experienced minor OSCS contamination, and the other in Germany, which was more severely afflicted by the bad drug, compared notes of heparin reaction from patients at their clinics this winter, when adverse events spiked, and last winter. HIT reactions remained stable in Canada but doubled at the German clinic, the researchers reported in a letter to the New England Journal of Medicine this fall. Doctors in some U.S. hospitals supplied by Baxter heparin vials also reviewed patient cases “and saw a before and after reaction,” Rensselaer’s Leonhardt said. “They could see a jump in HIT in that patient population that had been exposed to contaminated heparin.” And earlier this month a team of six researchers presented a paper at the annual meeting of the American Society of Hematology disclosing that patients subjected to OSCS had four times the amount of HIT antibodies in their blood than control groups.
Unfortunately, recalls earlier in 2008 didn’t rid all hospital and clinic shelves of dangerous drugs. Numerous adverse reactions to the contaminated heparin were recorded months after the recalls. The FDA’s most recent published summary of adverse reaction reports on heparin includes data only through May, when the last of the recalls were issued. But in an Oct. 23, 2008 letter to Rep. Joe Barton (R-Tex.), the FDA said that 13 new deaths had been reported to the agency from June 1 to Sept. 22, 2008.
The most disturbing evidence that medical practitioners don’t always react to recalls comes from the California Health Department and the state’s pharmacy board. After a total of five recalls of most heparin products the pharmacy board and health department sent inspectors in May to 533 hospitals and clinics. They found that 93 of them still had the recalled heparin on site. Worse, they found evidence that in 29 of them the heparin was still being administered to patients. In late May, the FDA issued a nationwide alert disclosing California’s findings. Even after the alert, California inspectors continued to find tainted heparin in some hospitals. “We suspect that the same problem could be occurring in other states as well,” said health department spokesman Ken August.
– Knut Royce