When Heparin Ingredient Price Increased, Trouble Began
Monday, April 14, 2008
In 2007, four months prior to hundreds of Americans experiencing severe and on occasion fatal allergic reactions to the widely prescribed blood thinner drug, Heparin, the price of the Chinese-produced main ingredient used to make the medicine doubled in price. This finding was provided by a report from an authoritative drug information company in China.The highly unusual increase of the price within a quarter of a year should have been a red flag to drug makers that something significant and perhaps dangerous was happening to the ingredient of a medication widely used in life-threatening situations, industry experts said. Heparin contains a substance that is extracted from the intestines of pigs and is collected in slaughterhouses and on farms.
Between November 2006 and February 2007, hundreds of Americans suffered serious allergic reactions after taking Chinese-made Heparin, and 62 died, the FDA reported. Some patients always respond poorly to Heparin, but FDA statistics show three fatal allergic reactions in 2006.
In March 2008, the agency discovered through chemical testing that Heparin made in China and distributed in the United States by Baxter International had been contaminated with inexpensive over-sulfated chondroitin, an altered version of a widely used dietary supplement.
The company that bought the Chinese raw material and began processing the drug; Scientific Protein Laboratories (SPL) of Waunakee, Wis., and Changzhou, China acknowledged this week that the price of unprocessed Heparin doubled in China in the last half of 2007 and said the company passed on some of the increase to its customers. Baxter spokeswoman Erin Gardiner said that the company faced "modest" price increases in 2007 because it had long-term contracts, but that it saw a "substantial" rise this year.
Wayne Pines, an SPL spokesman, attributed the price spike to a supply shortage caused by an epidemic of "blue ear" disease in Chinese pigs and by decisions of Chinese villages and companies to get out of pig farming and shift to more lucrative businesses. Pines said the price doubling did not raise any safety concerns.
But some businesspeople that deal in pharmaceuticals said the sudden increase in the long-stable price of an important ingredient should have raised concern among purchasing agents.
"This price increase should be, has to be, seen as a signal to purchasing managers," said Guy Villax, chief executive of the European drug company Hovione and a board member of the European trade association for drug ingredient makers.
"You have a situation here where the supply chain begins in slaughterhouses and villagers' homes, and a sudden disruption of that supply doesn't raise safety questions? I don't know whether anyone could have detected the contaminant early on, but at least they should have been looking," he said.
Villax added that the supply shortage and the steep price increase offered an obvious opportunity for individuals "who don't play by the rules" to make windfall profits by adding cheaper materials to the raw Heparin as a way to meet the demand.
The FDA has not said whether it thinks the contaminant was intentionally added to the drug, but officials described it as a Heparin-like compound that appeared to have been formulated so that standard quality-control tests could not detect it.
Although officials have not conclusively linked the contaminant to the allergic reactions and deaths, they have said there is clearly an overlap between the two. Chondroitin sulfate does not occur naturally but can be made from pig cartilage.
FDA spokeswoman Karen Riley said Friday that the agency was aware that the price of raw Heparin increased dramatically last year but did not necessarily see it as a signal of potential quality problems. The rise was apparently the result of the blue ear disease outbreak, she said, but the agency is looking at other possibilities.
"We are aware that with other products in other years, ingredients that look like the approved drug have been added for economic advantage, to make a quick buck," she said.
The price increase is detailed in a report by the Chinese drug information company Oriental Health E-Commerce Business (Beijing), recently renamed Healthoo.com. The company collects data on drug sales and prices from Chinese customs offices and is considered authoritative by Western businesspeople. The Heparin report, made public only recently, contains statistics but no commentary.
The Healthoo report shows that the price of crude Heparin exported from China went from $629 per kilogram in January 2007 to $1,507 per kilogram in December. The report also shows that more than 50 percent of the crude Heparin went to the United States, 37 percent to Germany and the rest to other nations.
The report shows that the cost of refined Heparin exported by China rose at about the same rate as that of raw Heparin strongly suggesting that the increase was driven by the price of the raw material, rather than by processing problems.
In recent years, China has been the world's primary source for the active ingredient in Heparin, but in e-mail on April 11, 2008, Healthoo said that significantly less Heparin is being exported from China now because of the supply problems.
No Heparin deaths have been documented in other countries, but the contamination was detected and allergic reactions were reported in France, Germany, Italy and elsewhere. It is unclear whether the lack of reported deaths outside the United States is because of differences in the sources of Heparin or of a more aggressive U.S. system of reporting adverse events.
Heparin, which is used as a blood thinner during surgery and dialysis, has been on the market since the 1930s. Like many pharmaceuticals especially inexpensive generic drugs it is now largely made abroad, increasingly in lightly regulated nations such as China and India. The FDA's ability to oversee the supply chains has become a much-discussed issue on Capitol Hill.
Brant Zell is past chairman of the Bulk Pharmaceuticals Task Force, a group within a larger American organic-chemicals trade association that deals with drug ingredients. He said unusual price spikes, such as the one involving Heparin, have buyers "asking questions like, "Is something unethical going on here?"
He said the case highlights a new reality that when a problem arises with an American-manufactured drug, the FDA usually addresses it quickly and can take action promptly. But when a problem surfaces in China or India, where regulation and oversight are far less strict, it inevitably takes officials longer to determine what is happening and why.
"The truth is that there's not a level playing field here when it comes to regulation in the United States versus a place like China," Zell said. "And since many Chinese are quite a few years behind us in understanding quality control and good manufacturing, problems like with Heparin will be hard to avoid because it's just harder to pick up the early warning signals."
Jon Martino, a specialist in tracking and detecting counterfeit drugs and a former global investigations manager for Amgen, a major biotech company, said that U.S. firms that get their unprocessed Heparin from China are to some extent "at the mercy" of their suppliers.
"Baxter is dependent on getting" that active pharmaceutical ingredient and "would drop to their knees to get it for their patients," he said. "Maybe they thought it was a temporary glitch in price, maybe they didn't do their due diligence as well as they could have. But the basic point is that they need to get those ingredients, because they have so many customers to supply."
Posted in Dangerous Drugs