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Apr-25-2008US researchers confirm heparin contaminant(topic overview)
CONTENTS:
- The U.S. Food and Drug Administration (FDA) said yesterday, Monday 21st April, that contamination of the blood thinner heparin, used in surgical and dialysis procedures to stop blood clots, is a worldwide problem. (More...)
- Under the cloud of contaminated heparin deaths, Food and Drug Administration Commissioner Andrew von Eschenbach received a rude welcome from Congress Tuesday, accused by Rep. John Dingell, D-Mich., of "carrying the water" for the Bush administration, "toe-dancing around the hard facts," and making promises that turn out to be nothing more than "hooey." (More...)
- "Our findings suggest that a simple bioassay" -- a chemical test -- "could help protect the global supply chain of heparin," Sasisekharan said. (More...)
- New Zealand is one of 11 countries supplied with the drug Heparin. (More...)
- Heparin is made from pig intestines that are often collected from small, mostly unregulated farms in China. (More...)
- U.S. health officials says as many as 81 patients in the U.S. died soon after taking the tainted heparin. (More...)
- The emerging consensus, voiced yesterday at a House subcommittee hearing, comes a day after the FDA said as many as 81 Americans died after taking a popular blood-thinning drug tainted somewhere in China with an unapproved chemical. (More...)
- The raw material for all of the contaminated heparin worldwide can be traced to China, Woodcock said. (More...)
- Dr. Sasisekharan and colleagues said, none of the pigs given control heparin had any substantive changes in blood pressure. (More...)
- The FDA has given Changzhou SPL 30 days to respond to the charges in the letter.'' (More...)
- U.S. companies already import 40 percent of API from India and China, a number that is expected to double within a decade. (More...)
- Neither the Chinese nor Baxter will comment on the inspection. (More...)
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The U.S. Food and Drug Administration (FDA) said yesterday, Monday 21st April, that contamination of the blood thinner heparin, used in surgical and dialysis procedures to stop blood clots, is a worldwide problem. The agency stressed while there is still no scientific evidence of a direct link between the contaminant, and dozens of deaths and hundreds of severe allergic reactions in the U.S., they have established a credible route through which such a link might be possible. Earlier this year, there was a significant increase in reported deaths and adverse reactions in the U.S. following use of batches of heparin product made by Baxter International. Baxter implemented a phased recall of its heparin products, and lab tests by the FDA and others showed that the products linked to the adverse reactions and deaths contained a contaminant, a form of chondroitin sulfate, derived from animal cartilage. [1] "Sophisticated analytical techniques enabled complete characterization of the contaminant present in heparin. This study also provides the scientific groundwork for critical improvements in screening practices that can now be applied to monitor heparin, thus ensuring patient safety," Ram Sasisekharan, senior author of the papers and the Underwood Prescott Professor of Biological Engineering and Health Sciences and Technology at Massachusetts Institute of Technology, said in a prepared statement. U.S. health officials said they believed that oversulfated chondroitin sulfate (OSCS) might be responsible for the dozens of deaths and hundreds of adverse reactions in the United States that have been linked with contaminated heparin between roughly last November and February. That belief was bolstered by the fact that the U.S. Food and Drug Administration said it had identified a likely "biological mechanism" by which the oversulfated chondroitin sulfate leads to the adverse reactions seen so far, Dr. Janet Woodcock, director of the FDA's Center for Drug Evaluation and Research, said at a Monday news conference. Those reactions include difficulty breathing, nausea or vomiting, excessive sweating and falling blood pressure, and life-threatening shock.[2]
The contaminant is oversulfated chondroitin sulfate, the researchers said, confirming earlier U.S. Food and Drug Administration findings. It appears to activate two inflammatory pathways, causing severe allergic reactions and low blood pressure, Ram Sasisekharan of the Massachusetts Institute of Technology and colleagues reported in the New England Journal of Medicine. "These results provide a potential link between the presence of chemical contaminant in heparin and the clinical symptoms observed in affected patients," Sasisekharan said in a statement.[3]
Chinese officials, however, disputed the finding and said the compound over-sulfated chondroitin sulfate could not be "the root cause" of the adverse reactions. Speaking Monday at the Chinese Embassy here, Jin Shaohong, a top official with the Chinese National Institute for the Control of Pharmaceutical and Biological Products, said some of the batches of heparin associated with severe allergic reactions and distributed by Baxter International did not have the synthetic chondroitin in them. He also said that heparin with the contaminant has been found in many nations, but that none has reported a similar spike in harmful reactions as in the United States. Jin said the Chinese government was conducting its own investigation of the heparin issue, which would include a visit today to Baxter's New Jersey processing plant, where officials hoped to collect additional samples of the tainted drug. He said the allergic reactions could have been created by impurities introduced when the imported raw heparin was refined by Scientific Protein Laboratories of Wisconsin and then prepared for distribution in New Jersey.[4] Jin said that "the results of our recent investigation and other available evidence do not support the theory that the root cause" of the adverse reactions to heparin was the over-sulfated chondroitin that the FDA identified as the likely culprit. FDA officials have raised the possibility that the contaminant was intentionally added to the heparin, but have said they still don't know for sure how it got into the supply. Baxter spokeswoman Erin Gardiner said her company disagreed with the Chinese conclusions, adding that the evidence is now strong that the over-sulfated chondroitin caused the problem. She also said the Chinese were incorrect when they said some batches of heparin that caused severe reactions did not contain chondroitin. Woodcock said that Chinese officials had tested batches of heparin with methods less sensitive than those used in the United States and elsewhere and had missed the presence of the contaminant. She said FDA scientists now believe the adverse reactions were most pronounced when large doses of the drug were administered quickly, and the contaminant acted as a "mediator" that caused a response similar to an allergic reaction.[4]
Many predict that it won't be long before gasoline costs more than $4 a gallon in many parts of the country and a barrel of oil reaches $125. Before the FDA made its announcement about Heparin, the Chinese government began what the WSJ characterizes as a "pushback" against the conclusions. At a press conference, Chinese officials said they want to look into whether the problem was caused in the end stage of the production process. The FDA disputes the Chinese assertion that severe adverse reactions have not been observed in any other countries, although it's unclear whether contaminated heparin is linked to deaths anywhere else. The NYT and WSJ highlight how this is the latest example of the growing rift between the United States and China over safety issues. It's becoming clearer just how little oversight there is of imported products.[5] Chinese officials disputed FDA's conclusions. Although Chinese officials agree that OSCS is in heparin sourced from their country, they question whether it is the cause of adverse reactions, said Jin Shaohong, deputy director-general for the Chinese National Institute for the Control of Pharmaceutical & Biological Products, at a press conference in Washington, D.C. He said Chinese scientists had found no OSCS in batches of heparin associated with adverse reactions. Tests in the U.S. do show OSCS in those troublesome lots, said Janet Woodcock, director of FDA's Center for Drug Evaluation & Research. She also noted that reactions to the contaminated drug appear to depend on the dose a person received and how quickly it was administered, and she said treatment standards can vary between countries. "Even in the U.S., the adverse events did not occur in every individual who was exposed to contaminated heparin, so there's some biologic variation," she added.[6]
In a media briefing, director of the FDA's CDER Janet Woodcock said that the agency has both in vitro and animal data displaying a " solid mechanistic link " between the contaminant found in various lots of heparin that originated in China, and the series of serious adverse events and deaths that have been reported after patients were administered the contaminated product. This data confirms that the contaminant, which was earlier identified as over-sulfated chondroitin sulfate, can cause events that would lead to adverse reactions in patients given the drug.[7] The 11 countries are: Australia, Canada, China, Denmark, France, Germany, Italy, Japan, The Netherlands, New Zealand and the USA. Another FDA CDER document posted yesterday updates the U.S. figures on the adverse events and deaths linked to the drug. This details the adverse event reports, including deaths, reported to the FDA between 1st January 2007 to 13th April 2008 (note this is according to date of report and not date of event; some reports came in later, once awareness of the situation increased). Altogether there have been 131 reports of deaths in the U.S. (from any cause, that is with or without allergic reaction) following use of heparin since 1st January 2007, with 123 of them reported on or after 1st January 2008. The FDA stressed that the fact allergic reaction or high blood pressure were reported does not mean these caused the deaths. A third document posted on the FDA CDER website yesterday was a letter to Changzhou SPL, stating that a recent inspection by U.S. FDA officials had found significant deviations between procedures at the plant and U.S. practice in the manufacture of active pharmaceutical ingredients (APIs).[1] The Food & Drug Administration (FDA) informed the plant in a warning letter that all future shipments from the Changzhou SPL facility will be refused entry to the U.S. until the factory makes required corrections and the FDA is able to confirm that it is in compliance with Current Good Manufacturing Practice standards. Baxter International recalled nearly all its heparin injections in the U.S. after some patients experienced extreme - and in some cases fatal - allergic reactions, including difficulty breathing, nausea, vomiting, excessive sweating, and rapidly falling blood pressure that was life threatening after being administered the products.''[8] While more than 80 percent of active drug ingredients are produced abroad, the U.S. Food and Drug Administration inspects few foreign plants and does not have adequate plans to increase them, said members of a U.S. House of Representatives panel. "I believe FDA is not up to the task, as it cannot or will not undertake the reforms needed to protect Americans from this threat from abroad," said House Energy and Commerce Committee Chairman John Dingell, a Michigan Democrat. The scrutiny of the FDA's foreign drug oversight intensified after Baxter International Inc (BAX.N: Quote, Profile, Research ) recalled most of its heparin products in February because of a spike in reports of sometimes-fatal allergic reactions.[9] The U.S. Food and Drug Administration Monday sent a warning letter to Changzhou SPL, the Chinese plant identified as the source of contaminated heparin sold by Baxter International in the United States, the Times said. In its letter the FDA said the plant used unclean tanks to make heparin, accepted raw materials from an unacceptable vendor and had no way to remove impurities, according to the Times.[10] The New York Times leads with the Food and Drug Administration announcing that contaminated heparin from 12 Chinese companies has been found in 11 countries and is linked to 81 deaths in the United States. Chinese Embassy officials strongly disputed the claims, saying that the man-made contaminant can't be the real cause of the deaths and suggested the problem may have originated in the United States. USA Today leads with Pentagon records showing that the Army has increased the use of involuntary extensions to maintain troop levels despite the fact that Defense Secretary Robert Gates said last year that they should be kept to a minimum.[5]
FDA officials said Monday that as many as 81 deaths and hundreds of severe reactions among patients taking the blood thinner heparin have been traced to a man-made contaminant from China. Chinese officials disputed these claims, saying the contaminant is not the cause of the problems. In light of the heparin situation, von Eschenbach told lawmakers at Tuesday's hearing of his plans to improve the FDA's system that currently inspects only about 10 to 20 of China's 700 registered drug firms per year. He said the agency's response to growing challenges in a "rapidly and radically changing world" has not been adequate.[11] The commissioner still has not provided specifics. Dingell and other lawmakers said the FDA must conduct more inspections of companies sending drugs to the U.S. to ensure they are safe, citing deaths and allergic reactions linked to contaminated versions of the blood-thinner heparin from China as well as a host of other tainted products, including toothpaste, that were shipped to the U.S. '''You cannot do your job, you are not doing your job,'' Dingell told von Eschenbach, who was a witness at the hearing before the energy and commerce panel's investigations subcommittee.'' Earlier this year, Representative Bart Stupak said that if Americans "knew how little the FDA did to assure the food and drug supply, if the truth ever came outpeople would be marching in the street."'' Stupak'''an eight-term Democratic congressman and chairman of the Subcommittee on Oversight and Investigations of the House's powerful Energy and Commerce panel, which has jurisdiction over the FDA'''is at the center of an aggressive effort by congressional Democrats to spotlight what they say are problems with the Bush administration's position on consumer-safety issues.''[12] 81 deaths in the U.S. have been attributed to reactions from contaminated heparin that came from a factory in China that had never been inspected. FDA Commissioner Andrew C. von Eschenback responded that he agreed more foreign inspections need to be made, but not every two years like the House Energy and Commerce Commission was suggesting. Rep. John Shimkus, R-Illinois, answered back that he felt the balance of inspections in the U.S. to those of foreign companies did not match the "risk priorities."[13]
U.S. recalls of Chinese heparin ingredients began in February. Chinese officials don't agree that the deaths were caused by contamination that may have occurred in their country. They say that the problem could stem from manufacturing of the finished drug at a plant in New Jersey. At a House hearing Tuesday, lawmakers chastised the FDA for not increasing its focus on foreign drug makers after the heparin crisis and other contamination scares. The FDA inspects domestic drug plants every 2.7 years, on average, they noted. "It's clear the FDA needs some new thinking on how to deal with the 21st century," said Rep. Joe Barton (R) of Texas.[14] The FDA can't say for sure what caused the reactions, but the chief suspect is a contaminant that the agency discovered in supplies of raw heparin coming from China. On Monday Chinese officials raised the possibility that the problems started in the U.S., and said they plan to visit a Baxter International (OTCBB:BXTRR) (NYSE:BAX) plant in New Jersey to get a better picture of how the finished product is developed.[15] Oversulfated chondroitin sulfate is derived from a popular supplement used to treat arthritis, among other things. It can resemble heparin's active ingredient but is much cheaper, leading some experts to suspect it was added deliberately. "This study also provides a set of screening methods that could be used to monitor the heparin supply and ensure the absence of oversulfated chondroitin sulfate contamination," they wrote. In February Baxter International Inc (BAX.N: Quote, Profile, Research ) recalled most of its heparin products, made with ingredients from China. Chinese officials said on Monday they had tested batches of heparin used by patients who reported health problems and only some of these batches contained the contaminant. They said other contaminants, problems with the device used to inject the drug or health factors with the patients who used the drug could be to blame.[16] Jin Shaohong, deputy director-general of the China National Institute for the Control of Pharmaceutical and Biological Products, said that Chinese investigators tested batches of heparin used by patients who reported health problems, and only some contained chondroitin sulfate. He also said that heparin with the contaminant has been found in many nations, but that none has reported a similar spike in harmful reactions as in the United States.[17]
Researchers have identified the chemical in the contaminated blood thinner Heparin that killed 81 people in the U.S. and made patients here and in Europe sick: The researchers freeze-dried the heparin and used a combination of nuclear magnetic resonance imaging and liquid chromatography-mass spectrometry to analyze its structure. In addition to a known impurity of heparin called dermatan sulfate, they found that contaminated lots contain a molecule that looks similar to heparin and showed it was almost certainly oversulfated chondroitin sulfate. China says their tests show that only some of the Heparin that caused the problems contained the contaminants, so it therefore must be something else: They said other contaminants, problems with the device used to inject the drug or health factors with the patients who used the drug could be to blame.[18] Earlier yesterday, a senior Chinese health official, Jin Shaohong, said that the contaminant that had been found in batches of the Baxter's blood thinner, thought to be an oversulfated form of chondroitin sulfate, was not to blame for the deaths, because according to China's own investigations, some of the adverse events followed use of heparin that did not contain the contaminant. Woodcock disputed this assertion, and told the press that the Chinese tests "did not find contamination, but we are fairly certain because of multiple labs doing the testing that this lot contains contaminants".[1]
A Chinese official disputed the assertion the blood thinner has caused death, but conceded that heparin produced in China contained a contaminant. "We don't have a strong evidence to show that it is heparin or its contaminant that caused the problem," Ning Chen, second secretary of the Chinese embassy, told the Times. He said the illnesses associated with heparin had occurred only in the United States, and insisted Chinese inspectors should be allowed to inspect the U.S. plant where the final stage of the drug's production took place.[10] The company said there were five deaths in which a reaction from the company's brand of heparin may have contributed. Chinese officials say the illnesses associated with heparin have occurred only in the United States, and they want their people to inspect the U.S. plant where the final stage of the drug's production took place. Baxter maintains the contamination occurred before the product reached Baxter or its raw ingredient supplier.[19]
Baxter's heparin was the first to be found to contain the contaminant in February after the FDA received hundreds of reports of serious injuries and/or deaths in patients who had been administered heparin made by the company. Baxter subsequently pulled its product from the market while an investigation ensued. This week the agency issued a warning letter to the Chinese firm that supplied the heparin active pharmaceutical ingredient (API) to Baxter along with some other companies - Changzhou SPL, a subsidiary of U.S. firm Scientific Protein Laboratories (SPL) - after an inspection of its facility revealed " significant deviations " from current good manufacturing practice (GMP).[7] The FDA has linked tainted heparin with 81 deaths in the U.S., and hundreds of adverse reactions. Baxter International recalled nearly all its heparin injections in the U.S. after some patients experienced extreme - and in some cases fatal - allergic reactions, including difficulty breathing, nausea, vomiting, excessive sweating, and rapidly falling blood pressure that was life threatening after being administered the products.[17] Eighty-one deaths following allergic reactions have been reported to the FDA in patients treated with some brand of heparin since January 2007. The FDA did not inspect Baxter's Chinese supplier before approving its version. At the hearing, lawmakers said they feared other patients could be harmed as the FDA inspects foreign drug plants at the rate of only once every 13 years.[9] Von Eschenbach told the House Subcommittee on Oversight and Investigations that in heparin's case, even if the Chinese plant had been inspected years ago, "we would not have detected that contamination" because the test to detect it was just developed. The GAO also reported to Congress that "as early as 1998, the FDA needed to improve its foreign drug inspection program," and that "one database showed 3,000 registered makers and another revealed that 6,800 makers actually shipped their drugs into the country last year."[18] The FDA had never inspected the plant where the suspected heparin contamination occurred. Resources say that the agency plans on stepping up their inspections this year to total 50. This is simply an unacceptable in my opinion. We are talking about the health and safety of drugs taken by millions of American citizens with virtually no federal safeguards to ensure their safety. FDA commissioner Andrew von Eschenbach agreed that more inspections are needed and requested more money for these inspections, but did not elaborate to what extent the inspections would be expanded.[20] " The permanent overseas offices in China will also allow greater access for inspections and greater interactions with manufacturers to help assure that products that are shipped to the U.S. meet standards for safety and manufacturing quality," said Murray Lumpkin, deputy commissioner for International and Special Programs, FDA. Establishing a presence on the ground in China in particular has become crucial for the agency, as the country has been at the centre of a string of numerous consumer safety breaches of late and has been criticised over its lack of oversight over the quality of the escalating number of food and drug imports reaching U.S. shores, the latest being a health scare involving contaminated lots of heparin. The DIA has announced the recent opening of its first office in India, in Mumbai, along with the creation of a Provisional Advisory Council of India (ACI).[21] The unfolding scandal of contaminated blood thinner from China is the latest in a string of revelations about dangerous imports from a country that has risen to become manufacturer to the world. U.S. lawmakers now are pushing for more protection for American consumers, as hearings in Congress this week have made clear. Even the head of the Food and Drug Administration (FDA) says he needs more money ''' and a new approach ''' to try and ensure that products entering the country are safe. Other countries may well follow suit.[14] WASHINGTON Food and Drug Administration officials said Monday they have new evidence that links hundreds of serious adverse reactions and scores of deaths among patients given the blood thinner heparin to a man-made contaminant introduced during production in China.[4] U.S. officials said an altered form of chondroitin sulfate was to blame, but on Monday a Chinese health official said something else must have caused the reactions. Leavitt said he was confident Chinese officials would deal with the matter. "The 'Made in China' brand gets hurt and China knows that," Leavitt said, adding that he expects Chinese officials to take strong action when they track down the source of the heparin contamination. "They've taken strong action in the past," he noted. In July, China executed the former head of the State Food and Drug Administration for taking bribes to let medicine companies slip past his regulatory net. Leavitt said he was concerned when he saw how little regulation China has of drug and device manufacturing. "We are concerned that there is a gap, that some of their companies refer to themselves as chemical companies," he said.[22] The scientists, led by MIT professor Ram Sasisekharan, identified the contaminant, and have shown how it triggered deadly allergic reactions that left at least 81 dead in the United States alone. "There was an absolute imperative to solve this health crisis as quickly as possible," Sasisekharan, who coordinated both studies, told AFP by email. Based on their findings, the U.S. Food and Drug Administration (FDA) identified the toxic substance earlier this week as a synthetic compound called oversulfated chondroitin sulfate (OSCS).[23] Scientists at MIT say their tests have identified the contaminate in the blood thinning drug heparin, which has caused a fatal allergic reaction in some people who took it. They identify the chemical as oversulfated chondroitin. Earlier, the U.S. Food and Drug Administration came to the same conclusion, but their finding was disputed by China, which produces the drug.[24] WASHINGTON, April 23 (Reuters) - Researchers said they had identified a chemical contaminating the blood-thinner heparin from China, confirming U.S. Food and Drug Administration findings that it was oversulfated chondroitin sulfate. They said they had used a standard analytical method to find the contamination, which had been difficult to pinpoint before, and said it might be used to screen other batches.[16]
The U.S. Food and Drug Administration (FDA) says a contaminant sourced to a Chinese factory has been found in heparin supplies in 11 countries.[25] The contaminant in the batches of blood-thinning drug heparin linked to 81 patient deaths in the U.S. has been identified, according to the Food and Drug Administration (FDA).[26]
Dr. Janet Woodcock, director of the Food and Drug Administration's drug center, said Chinese officials had agreed contaminated heparin had originated in China. Woodcock said the agency was "fairly confident ''' that this contaminant is capable of triggering these adverse reactions."[27] Baxter International, the maker of troubled heparin, disputed the Chinese officials' statement and claimed that evidence is strong that the contaminant is the cause. The company recognized though that only four deaths were associated with its heparin and is now considering discontinuation of its heparin business. Although the current studies suggested a possibility, direct evidence is lacking to say oversulfated chondroitin sulfate is the cause for human allergic reactions because the contaminant could not be tested for its safety in humans. At least, the U.S. regulators and others now may a tool in hands to distinguish the contaminated heparin from the uncontaminated.[28] Chinese officials early on Monday disputed the FDA speculation and claimed that the oversulfated chondroitin sulfate is not the root cause for the allergic reactions patients who used heparin experienced because the same adverse effects were also observed in patients who used heparin without the contaminant.[28] The FDA released a warning letter to Changzhou SPL Co., hours after Chinese officials voiced doubts that a contaminant identified in the blood thinner heparin caused severe allergic reactions in hundreds of U.S. patients.[29] Eighty-one people in the U.S. given heparin died since January 2007 after suffering allergic reactions, according to the FDA. The contaminant can lead to allergic reactions and deaths, the agency said, although Chinese officials have challenged that contention.[30]
The tainted heparin had been used by at least 81 U.S. patients who died soon afterwards. They had classic allergic reactions, with plummeting blood pressure, swelling of the larynx and other severe symptoms. Their cases forced manufacturer Baxter International (BAX.N: Quote, Profile, Research ) to recall the commonly used blood-thinner and caused a diplomatic squabble between U.S. and Chinese officials.[3] Chinese officials said Monday that the problems could have occurred in the United States, or that chronic conditions in some patients led to severe reactions in hundreds of U.S. patients. They plan to visit a Baxter International plant in Cherry Hill, N.J., to get a better picture of heparin's development.[31] At an embassy news conference, Chinese officials said the problems linked to heparin could have occurred in the United States, or that chronic conditions in some patients led to severe reactions. They plan to visit a Baxter International plant in Cherry Hill, N.J., to get a better picture of heparin's development. They also hope to take back some samples for their investigation.[29]
A Chinese official asked that China be allowed to inspect drug plants in the United States and denied the links between the deaths or illnesses. "We don't have a strong evidence to show that it is heparin or its contaminant that caused the problem," said Ning Chen, second secretary at the Chinese Embassy.[27]
Shaohong also said Chinese officials are focusing on the whole product, and speculated that other contaminants, problems with the device used to inject the heparin, or health factors with the patients who used the drug could also be causing the reactions.[17]
China and the United States have tangled over a series of health-related scandals - first the discovery of high levels of lead in toys, and, most lately, contaminated heparin. Baxter International Inc recalled most of its heparin products in February after at least 62 reported deaths and other severe reactions among patients treated with the blood thinner, which is used to prevent blood clots.[22] In the U.S., people worried about the safety of Chinese-made toys, food, and other products have been focusing on pharmaceutical company Baxter International ( BAX ), which has recalled much of its blood thinner heparin after suspicions that a tainted ingredient in the drug from China caused illness and deaths among some patients.[32]
The contaminant is oversulfated chondroitin sulfate, a "cheap fake additive" that can be detected only through sophisticated testing. In February drug company Baxter International Inc recalled most of its heparin products, made with ingredients from China.[19]
The FDA on March 5 said it had detected an unidentified contaminant in heparin injections sold by Baxter International. It was determined that most of the active ingredients in the drug came from a plant in Changzhou, eastern China working with Wisconsin-based Scientific Protein Laboratories, which supplies Baxter.[10] The FDA and the affected companies appear to have managed the incident well, minimizing American exposure to suspect heparin. Baxter International voluntarily recalled nine lots of its multi-dose vials of the drug in January, and the next month expanded the recall. The FDA investigated SPL facilities in China and Wisconsin ' as well as a plant in New Jersey, determining whether the heparin could have been contaminated by its packaging.[33] FDA officials say the contaminated heparin came from factories in China that manufacture the drug for Baxter International. The tainted heparin has been blamed for 81 U.S. deaths so far, and earlier this week, the FDA announced that contaminated batches were also found in 10 other countries.[34] After announcing mid-March that it had found a contaminant in heparin, the FDA said Monday that it now believes there's "a very solid mechanistic link" between the contaminated heparin and bad reactions associated with the medication. The FDA said it has gathered information from 11 other countries that also found a contaminant in their heparin supply and traced the contaminant to just one country. "The one thing they have in common is China," said Deborah Autor, director of the FDA's Center for Drug Evaluation and Research's office of compliance.[35]
Scientists now have identified the contaminant that the FDA believes led to 81 deaths in the U.S. The contaminant was found in the common blood thinner heparin. It appears to have been intentionally substituted to make the drug more cheaply.[36] The assurance follows a warning from the U.S. Food and Drug Administration in New York that contaminated blood thinner from China linked to 81 deaths in the United States is present in drug supplies in 11 countries, including New Zealand.[37] The Food and Drug Administration Monday said blood thinner containing oversulfated chondroitin sulfate had been discovered in Australia, Canada, China, Denmark, France, Germany, Italy, Japan, the Netherlands, New Zealand and Italy, The New York Times reported Tuesday.[27]
With dozens of people dead after receiving infusions of the contaminated blood thinner heparin, the head of the Food and Drug Administration faced withering scrutiny from a congressional subcommittee, countering accusations he has willfully underfunded inspections and also left the U.S. market vulnerable to a potential terrorist attack in the form of tainted food or medicine.[38] Changzhou SPL Co., the Chinese maker of an ingredient in the blood thinner drug heparin, does not have adequate systems for ensuring the materials it uses are safe, the Food and Drug Administration told the company Monday.[31] The Chinese manufacturer of a heparin ingredient does not have adequate systems for ensuring that the raw materials it uses are safe and that any impurities are removed, the Food and Drug Administration told the company Monday.[29]
The article states that the Chinese supplier of heparin escaped oversight by China's state food and drug agency, as well as by the U.S. Food and Drug Administration, because it registered itself as a chemical manufacturer rather than a drug supplier.[39] WASHINGTON (AP) — The Food and Drug Administration is making progress in conducting more inspections of foreign drug manufacturers, but still inspects relatively few facilities. The agency conducted 30 such inspections in the last fiscal year and plans to conduct at least 50 this year, according to government auditors. The FDA is responsible for overseeing the safety and effectiveness of drugs marketed in the United States regardless of where they are manufactured.[40] Representative John D. Dingell, Democrat-Michigan and chairman of the House Energy and Commerce Committee, has long been unhappy with the U.S. Food and Drug Administration (FDA) and its commissioner, Andrew von Eschenbach.'' Dingell recently accused von Eschenbach of not doing his job in regards to drug safety, and has repeatedly asked the FDA chief how much it would cost to do more inspections of foreign drug makers.''[12] April 22 (Bloomberg) -- Andrew von Eschenbach, the commissioner of the U.S. Food and Drug Administration, isn't doing his job and hasn't asked for enough money to inspect overseas drugmakers, a senior lawmaker said today at a hearing. Representative John D. Dingell, a Democrat from Michigan who is chairman of the House Energy and Commerce Committee, pointed his finger at von Eschenbach and repeatedly asked the FDA chief how much it would cost to do more inspections.[30]
The blood-thinning drug has been cited by the U.S. Food and Drug Administration (FDA) as causing 81 deaths as of Wednesday.[41]
The Food Drug Administration (FDA) has said that the heparin from that plant was contaminated with a counterfeit ingredient from China.[17] The FDA has said it didn't inspect a plant in China that made the main ingredient in Baxter International Inc.' s heparin, which was found to be contaminated.[30] In March, the FDA confirmed that it had found a counterfeit ingredient, oversulfated chondroitin sulfate, in samples of the active ingredient used in Baxter heparin. That ingredient was supplied to Baxter by Changzhou SPL, a Chinese plant partially owned by Wisconsin-based Scientific Protein Laboratories.''[8] The raw ingredient for Baxter's recalled heparin came from Wisconsin-based Scientific Protein Laboratories, which in turn owns a Chinese factory -- Changzhou SPL -- and buys additional raw heparin from other Chinese suppliers. FDA Commissioner Andrew von Eschenbach is expected to highlight the agency's plans to open a new office in China next month during Tuesday's hearing, which begins at 10 a.m. EDT. Lawmakers will also hear from FDA's science advisers, who recently said the agency needs at least $375 million in new funding next year to repair its understaffed, outdated inspection program.[15] Chinese scientists yesterday visited the Baxter plant in Cherry Hill for the samples. "This is basically a courtesy we extended to host them since they were in the states attending an FDA regulators' meeting," said Baxter spokeswoman Erin Gardiner. "We are evaluating their request" to take heparin samples to China. "I'm not going into any more detail," she added. Baxter said it investigated on its own and confirmed that Cherry Hill was "not the root" of the contaminant. It contends the contaminant was introduced earlier in the supply chain - in China - before reaching Baxter's Wisconsin supplier, Scientific Protein Laboratories L.L.C. Changzhou SPL, the focus of the FDA warning letter, is a joint venture with Scientific Protein Labs.[42]
The suspicious material may have been introduced intentionally before the product reached Baxter's U.S. factory in New Jersey, the FDA said. Baxter got its heparin from a plant in Changzhou, China, which was sourced by village workshops and rural pig lots.[43]
Eschenbach addressed differences with China over a U.S. finding that problems with the drug heparin were caused by what the FDA calls significant deviations from good manufacturing processes by a Chinese company, saying U.S. analysis methods are more accurate. Where heparin is concerned, he says the FDA has ensured the safety of future supplies, and he had this response to a question from Louisiana Congressman Charles Melancon.[44] Could this kind of problem be stopped at the supplier level? A General Accounting Office report estimated that it would cost $67 million per year to inspect the 3,000-plus plants worldwide that supply drugs to the U.S. the FDA has $11 million budgeted for this purpose. Can inspection and oversight systems be trusted, even if more money was spent? According to The Washington Post, "The FDA acknowledged last month that it had never inspected the plant because it confused it with another facility with a similar name, and Chinese officials said they did not inspect it because it was listed as a plant producing chemicals rather than pharmaceuticals." These facts make Woodcock's assurances of safety a bit harder to trust.[45] Domestic firms are inspected an average of once every 2.7 years. At least 80 percent of all active ingredients used by U.S. manufacturers to produce drugs are imported, according to lawmakers. The FDA has 3,249 overseas drug manufacturers on a list that it uses to plan its inspections, according to the GAO, the investigative arm of Congress. Inspecting those plants every two years would cost the agency at least $67 million annually, according to the GAO. The FDA plans to spend about $11 million this year for all overseas pharmaceutical inspections.[30] '''In addition to addressing the need to increase our inspections we also need to overhaul the entire system,'' von Eschenbach said.'' The FDA is trying to improve the safety of drug imports by increasing collaboration with regulators overseas and stationing agency employees in China and other countries, he said. The FDA conducts annual inspections of about seven percent of overseas drug makers that ship to the U.S., which means, at this rate, it will take 13 years to visit them all, according to the Government Accountability Office (GAO)'''the investigative arm of Congress.''[12] FDA commissioner Andrew von Eschenbach says steps are under way to establish offices in China and elsewhere to prevent dangerous products from entering the U.S. "The increasing global nature of product development and production requires our continuous and intensive interaction beyond our border. This plan includes the establishment of FDA offices in China, India, Latin America Europe and the Middle East," he said. While agreeing that the low inspection rate is unacceptable, he asserts that merely increasing the number of inspections would be insufficient. He was confronted by an angry Democratic Congressman John Dingell, who noted that the FDA budget for all inspections totaled just $11 million, and questioned the Bush administration's commitment to correcting the problem. "You are not soliciting the resources that you need to do your job to protect the American people the way the law says you should, and that you are tolerating an administration which is allowing this kind of situation to obtain because they are too damn tight to see to it that the American people have the funds that are necessary to protect them against wrongdoing in foreign countries."[44]
According to the U.S. Government Accountability Office, which is the investigative arm of Congress, the FDA has made some progress in increasing inspections, but only 10 to 20 of more than 700 Chinese companies shipping drug products to the U.S. are inspected each year.[44] About 80% of active ingredients used in drugs sold in the U.S. come from overseas, a figure that has increased significantly in recent years. In November, the Government Accountability Office found that the FDA could inspect about 7% of foreign companies annually, and on average inspected such facilities at a rate of once every 13 years.[46] Now Congress is calling on the FDA to better monitor foreign manufacturers of drug ingredients used by U.S. companies.[36]
In the U.S. heparin case, FDA scientists determined that suspicious lots of API used to make the drug were imported from China and appeared to contain 5 to 20 percent of a heparin-like compound which mimicked heparin activity so closely that it was not recognized during routine testing.[33]
"Our analysis suggests effective screening methods that can be used to determine whether or not heparin lots contain the contaminant reported here," Sasisekharan and colleagues wrote in the journal Nature Biotechnology. They tested oversulfated chondroitin sulfate taken from FDA samples and found it directly activated an extreme allergic reaction, called anaphylaxis, in pigs. They also freeze-dried the heparin and used a combination of nuclear magnetic resonance imaging and liquid chromatography-mass spectrometry to analyze its structure.[3] Many patients in the United States and Europe who got the contaminated heparin suffered immediate allergic reactions, with plummeting blood pressure, swelling of the larynx and other severe symptoms. The researchers freeze-dried the heparin and used a combination of nuclear magnetic resonance imaging and liquid chromatography-mass spectrometry to analyze its structure. In addition to a known impurity of heparin called dermatan sulfate, they found that contaminated lots contain a molecule that looks similar to heparin and showed it was almost certainly oversulfated chondroitin sulfate.[16] The procedure was detailed in the NEJM and is ready to be used to detect oversulfated chondroitin sulfate. In the study, heparin contaminated with OSCS and synthesized OSCS were tested and found they caused allergic reactions in pigs similar to those observed in patients.[28]
The researchers analyzed six heparin preparations linked with adverse reactions in patients and four preparations that had not been associated with adverse events. They found all the heparin preparations linked with allergic reactions contained a contaminant similar chemically to synthesized OSCS. "This study also provides the scientific groundwork for critical improvements in screening practices that can now be applied to monitor heparin, thus ensuring patient safety," Ram Sasisekharan, senior author of the study said in a statement. In another paper simultaneously published in the New England Journal of Medicine, the researchers states in their report that the regulators now have a validated procedure to detect contaminated heparin.[28] Because OSCS closely resembles heparin, less sensitive tests had not detected the compound. Another study published yesterday in the New England Journal of Medicine shows that OSCS causes inflammation, allergic reaction and high blood pressure, a likely explanation for patient deaths. To determine how OSCS might affect humans, Sasisekarahen's team treated blood with the contaminated heparin or OSCS. In both cases, the contaminant evoked molecular signs of allergy and inflammation.[26] The researchers found that the contaminated heparin activates two inflammatory pathways, causing severe allergic reactions and low blood pressure. "These results provide a potential link between the presence of chemical contaminant in heparin and the clinical symptoms observed in affected patients.[34]
"Heparin should not be contaminated, regardless of whether or not that contamination causes acute adverse events," Woodcock was quoted as saying. "We are fairly confident based on the biological information that we have had that this contaminant is capable of triggering these adverse reactions." These include allergic or hypersensitivity-type reactions, with symptoms including low blood pressure, shortness of breath, nausea, vomiting, diarrhea, and abdominal pain, according to the FDA's website.[10] OSCS causes allergic reactions and raises blood pressure, which might explain some of the patient deaths. "These contaminants cause the biological symptom associated with the adverse events," says Moheb Nasr, a chemist at the FDA.[26]
Woodcock also revealed that in vitro and animal tests now demonstrate a clear causal link between OSCS and adverse events, probably by triggering chemical mediators in the blood that produce allergic reactions, including anaphylaxis and hypotension. She said that the data need to be peer reviewed and that FDA will try to publish the results expeditiously, as well as discuss them with Chinese officials. Dermatan sulfate is not known to be harmful but nonetheless should be kept to a low level, she said.[6] Laboratory tests have revealed a clear link between a heparin contaminant--oversulfated chondroitin sulfate (OSCS)--and severe allergic reactions in humans that may have resulted in some deaths, FDA officials said at an April 21 press briefing.[6]
The FDA said the chondroitin sulfate was molecularly changed to mimic heparin'''s blood-clotting properties. At a news conference earlier this week, a Chinese official disputed that the heparin problems occurred in that country.[17]
Chinese officials said some batches that did not contain the contaminant, known as over-sulfated chondroitin sulfate, made people sick. They also said that more than 10 countries used the contaminated ingredient, but have not reported adverse reactions.[35] "We have seen adverse event reports on batches where the contaminant has been confirmed to be present." Baxter was considering the Chinese officials' request for additional heparin samples for their own further testing, Gardiner said. The Chinese officials also said that aside from the U.S. and Germany, more than 10 other countries used heparin containing the contaminant to produce their final injection but reported no side effects.[29] The tainted heparin killed at least 81 patients and forced a widespread recall of the commonly used blood-thinner. It also caused a diplomatic squabble between U.S. and Chinese officials. "Given the nature of this contaminant, traditional screening tests cannot differentiate between affected and unaffected lots," Ram Sasisekharan of the Massachusetts Institute of Technology and colleagues wrote in the journal Nature Biotechnology.[16]
According to U.S. figures, 62 people died from allergic reactions associated with batches of heparin that were recalled. Eschenbach declined during testimony to make a specific request for funds required to increase foreign inspections, although he agreed with lawmaker's rough estimates of 60 to 70 million dollars. Chinese government officials this week requested additional samples of heparin from the U.S. for further testing, and asserted that besides the United States and Germany, heparin doses used in 10 other countries had caused no side effects.[44] Jin Shaohong, deputy director of the National Institute for the Control of Pharmaceutical and Biological Products in China, said officials had analyzed several batches of heparin ingredients and concluded that some batches causing allergic reactions in the United States did not contain the suspected contaminant. Shaohong said one heparin batch that generated 100 reaction reports - 25 of them serious - did not contain the contaminant.[42]
Jin Shaohong, a top official with the Chinese National institute for the Control of Pharmaceutical and Biological Products, also claimed that a key ingredient with the contaminant was also used by other countries to make other brands of heparin, but no adverse effects were reported.[28]
Heparin is used clinically as a blood thinner and is commonly given to patients undergoing heart surgery or dialysis ( C&EN, March 24, page 46 ). A spike in reported adverse reactions to the drug prompted heparin manufacturers to recall products earlier this year.[6] Reports about contaminated supplies of the blood thinner heparin raise a number of big, unsettling questions about the global economy, the FDA's ability to police imports of drug ingredients and patient vulnerability.[45] FDA Commissioner Andrew von Eschenbach faces tough questions from Rep. John Dingell, D-Mich., in wake of 81 deaths associated with contaminated blood thinner, heparin.[11]
CHERRY HILL, N.J. - A delegation of Chinese officials have completed their tour of a New Jersey plant that makes heparin, a blood thinner with a contaminant linked to as many as 81 deaths.[47] A Chinese official cited by the New York Times on Tuesday disputed the assertion that the blood thinner has caused deaths, but conceded that heparin produced in China contained a contaminant.[23]
NEW YORK (AFP) — A contaminated blood thinner from China linked to 81 deaths in the United States is present in drug supplies in 11 countries, the New York Times said Tuesday, citing federal regulators.[10] Apr 23, 2008 10:31 AM Medsafe is confident that the New Zealand batches of the blood thinner drug Heparin are not contaminated, despite being linked to deaths in the United States.[19]
The FDA has identified 12 Chinese companies that have supplied contaminated heparin to Australia, Canada, China, Denmark, France, Germany, Italy, Japan, the Netherlands, New Zealand and the United States, the report said. It does not know the original source of the contamination or where it entered the supply chain, the Times said.[10] According to the FDA, contaminated heparin has now been linked to as many as 81 deaths and hundreds of injuries in United States.[2]
"We haven't made a decision whether or not we are going to re-enter with heparin," Parkinson told analysts. "Our priority continues to be understanding the issues that got us to this point," he added. "We need to ensure that that supply chain is controlled as effectively as possible and that we really, truly understand the root cause of this. Those are the necessary things we need to assess before we would decide to re-enter." While the FDA has not determined how the contaminated heparin entered the supply chain, the agency on Monday provided its most definitive link between the foreign substance and the allergic reactions.[43] The hearing comes just as scientists, drug makers and foreign investigators get closer to figuring out what caused a recent spike in severe allergic reactions and as many as 81 deaths that may be associated with the blood thinner heparin.[35] The issue of foreign-drug facility inspections was the subject of a House Energy and Commerce Oversight and Investigations Subcommittee hearing in the wake of contamination problems with Baxter International Inc.' s (BAX) blood- thinner heparin, which has been linked to hundreds of serious allergic reactions and as many as 81 deaths.[46]
WASHINGTON (AP) - On Monday, Chinese and U.S. officials butted heads over whether a contaminated blood thinner caused severe allergic reactions linked to dozens of deaths. Lawmakers will investigate whether U.S. inspectors would have even spotted such contaminants at the source.[15] WASHINGTON, April 22 (UPI) -- U.S. regulators said contaminated blood thinner from China, linked to 81 deaths in the United States, has been found in several countries.[27]
The hearing comes less than a month after FDA revealed that more than 60 people have died of side effects seen with a contaminated batch of the blood thinner heparin that was manufactured in China.[15] Yesterday a House panel reprimanded the FDA for their poor performance when inspecting foreign-made medications, in the aftermath of the recall of contaminated batches of the blood thinner heparin.[20]
Concerns about the inspection program were recently highlighted, auditors said, when the agency learned that contaminated doses of the blood thinner heparin had probably come through a Chinese plant that the agency had never inspected.[40] The officials also said contaminated lots of the blood thinner have been traced to 12 different Chinese companies that were somehow involved in heparin manufacture.[2]
WEDNESDAY, April 23 (HealthDay News) -- U.S. researchers say they've confirmed that lots of the blood thinner heparin pulled from the market are contaminated with a man-made chemical called oversulfated chondroitin sulfate.[2] Since Baxter's heparin was recalled, the primary distributor of heparin vials has become Schaumburg-based APP Pharmaceuticals Inc., which said it has been able to provide adequate supplies and not had contamination issues. Earlier this week, the FDA said heparin from several manufacturers, including Baxter, has been contaminated with oversulfated chondroitin sulfate, a chemically modified dietary supplement derived from animal cartilage. Such contaminated heparin has been found in 11 countries, the FDA said.[43] In March, the FDA confirmed that it had found oversulfated chondroitin sulfate in samples of the active ingredient used in Baxter heparin.[48]
The FDA is looking at a contaminant, oversulfated chondroitin sulfate, that the agency discovered in material supplies of heparin coming from China.[42] The FDA can't say for sure what caused the reactions, but the chief suspect is a contaminant that the agency discovered in supplies of raw heparin coming from China a compound derived from animal cartilage that so closely mimics heparin that routine purity tests can't detect it.[29] FDA officials said new evidence linked a contaminant in heparin made in China to the reactions.[9]
FDA spokeswoman Karen Riley responded that the FDA tested from the same heparin lot "and we have found contaminant." "They have used a different test, not the one the international community is using to screen for contaminants. It has less sensitivity and specificity, and it is especially not as good when you have a smaller percentage of contaminant in the drug. Riley said, "We are convinced that this particular lot did have contaminant, based on our testing."[42] Medsafe spokesman Dr Stewart Jessamine said the agency was first told of the problem in January and has been in close contact with the FDA since. He said Medsafe's American counterpart had released test methods to check the purity of heparin. "We in turn have required manufacturers selling this product in New Zealand to test it," he told Radio New Zealand. No contamination was found in products currently on the market, he said.[37] The letter said the company had not adequately evaluated the suppliers of the crude materials, and the crude material itself, and that the manufacturing equipment was not suitable for purpose. It said that tanks to make the API were certified as clean, but "unidentified material" was found clinging to their inside surfaces. Woodcock told the press she would not comment on the details of evidence collected so far because the better thing to do is wait until it is published in scientific literature when other scientists have had a chance to review it. She also said the agency was not "able to rule out the fact that there could be other problems leading to these adverse events", reported CNN. This has also been the position maintained by Baxter, which to a certain extent reflects what the Chinese authorities said yesterday, where the possibility that manufacturing problems after the raw ingredient has left China, and the condition of the patients themeselves, could be contributing factors. Woodcock said she hoped that scientific dialogue will help to overcome some of the skepticism about the FDA suggestions.[1] When the FDA did investigate, it found significant amounts of a contaminant in the active ingredient used by Baxter, which originated in the China joint venture, Changzhou SPL. It was horrible when pets died due to food contaminated with melamine; it was worse when toys we give to our children were contaminated with lead.[39] Yesterday the FDA CDER website posted a number of documents updating the heparin situation. One is a world map highlighting 11 countries where heparin containing the contaminated active ingredient from China has been found.[1]
The FDA identified the Changzhou SPL plant as the source of the contaminated heparin. U.S. officials have reportedly written to the plant warning that it lacks the means to remove impurities, does not adequately clean its tanks and purchases raw materials from unregulated vendors. Bahrain relies on international regulatory bodies such as the FDA for information concerning its imports.[41] The Times also said officials have discovered heparin lots that included the cheap fake additive manufactured as early as early as 2006, although a spike in illnesses associated with contaminated heparin began in November and persisted through February. The Chinese inspectors finished their tour of Baxter's plant yesterday.[17] Baxter spokeswoman Erin Gardiner says a group of Chinese officials who were in the United States toured the plant on Tuesday and met with Baxter representatives to discuss heparin.[47] Chinese officials have suggested that the problem comes from the manufacturing of the finished drug at the Cherry Hill, N.J., plant of Baxter International.[47]
In January, Baxter began getting increased reports of severe patient reactions - shortness of breath, low blood pressure, nausea and abdominal pain. In February, the Deerfield, Ill., drugmaker voluntarily recalled all its heparin doses and temporarily stopped manufacturing the drug at its Cherry Hill plant.[42] The blood-thinning drug Heparin, made by Baxter, is at the center of safety concerns. At its best, it's a global drug market that helps patients in all corners of the world get the medications they need. At worst, it's a supply chain that's exceedingly difficult to unravel when those drugs are associated with making people sick. Just how difficult it is to ensure the safety of a final product made with ingredients coming from abroad was glaringly apparent this week in Washington.[35] The U.S. Food and Drug Administration is investigating Baxter's China-based supply chain, where the product's active ingredient originates.[43] The U.S. Food & Drug Administration on Apr. 21 announced that the Chinese factory producing the ingredient continued to have problems meeting safety standards.[32]
Everyone seems to be picking on the poor Food and Drug Administration (FDA) these days, but for vastly different reasons. To the hundreds of thousands of victims (including dead ones) of adverse prescription drug reactions each year, and their families, the FDA is failing to protect the public. These people believe the agency should spend more time and effort making sure drugs are safe and effective before approval.[49] FDA Condemned for Lack of Inspections Food and Drug Administration (FDA) officials were raked over the coals this week for the administration's lack of inspections of foreign drug manufacturing plants. Both Republicans and Democrats.[13] At the current pace, "the F.D.A. would need at least 27 years to inspect every foreign medical device plant that exports to the United States, 13 years to check every foreign drug plant and 1,900 years to examine every foreign food plant," reports the NYT.[5] Each year, the FDA inspects 8 percent of the 3,000 foreign firms shipping drugs to the United States, the Government Accountability Office said in a new report. Von Eschenbach emphasized that increased funding and staffing wasn't the entire solution, and he highlighted several agency initiatives to improve foreign drug inspections, such as relying on outside firms to certify facilities and targeting the riskiest imports for scrutiny.[50]
"If we don't make some rapid progress on fixing the foreign drug inspection program, the next melamine or heparin tragedy will soon be upon us," said Stupak, a Michigan Democrat. FDA Commissioner Andrew von Eschenbach said increasing globalization of manufacturing and a growing market "has placed tremendous strains on our import safety system" and that he had "consistently endorsed the fact that this will require additional resources."[9] Crosse said some of the steps the FDA is proposing address "some of the concerns" the GAO raised about the foreign-drug inspection program in November. "Given the growth in foreign drug manufacturing for the U.S. market and the current large gaps in FDA's foreign drug inspections, FDA will need to devote considerable resources to this area if it is to increase the rate of inspections," the GAO said in a new report issued Tuesday. "However FDA's plans currently call for incremental increases that will have little impact in the near future to reduce the interval between inspections for these establishments."[46] In total, the agency has been granted approval from the U.S. State Department to establish eight full-time, permanent FDA positions at U.S. diplomatic posts in China over the next 18 months, pending authorisation from the Chinese government. In addition to this, the watchdog has indicated that it will also be hiring five local Chinese nationals to work with the new FDA staff at the U.S. Embassy in Beijing and the U.S. Consulates General in Shanghai and Guangzhou. The move is part of its " Beyond our Borders " initiative, which aims to build stronger cooperative relationships with the FDA's counterpart agencies around the world and enhanced technical cooperation with foreign regulators, as the globalisation trend intensifies.[21] Giving an update on its China plans, Mike Leavitt, secretary of the FDA's Health and Human Services (HHS) advised the media that although the agency's new office in Beijing will be officially opened in October following final approval from the Chinese government, it expects to have staff already operating in the country in May. It has been announced that the new China office will be lead by Christopher Hickey, who will move from his present role as director of the HHS' Asia and Pacific offices.[21]
Apr 22, 2008 4:46 PM Simply sending inspectors to China and other countries will not be enough to make sure food and drugs are safe and independent certification may be the best solution, U.S. Health and Human Services Secretary Michael Leavitt said on Monday. He said Christopher Hickey, the U.S. agency's Asia and Pacific director, was preparing to set up an office to strengthen oversight of food, drugs and devices imported from China. Ultimately, Leavitt said, regulation is not the answer and he called for a new industry of global independent certification of farms, factories and other producers. Leavitt, just back from a trip to Indonesia, Singapore and Vietnam, said he believes U.S. officials need to set up shop in several regions. "I believe there is a need for us to be in India," he said, naming Central America and Vietnam as well. "We are beginning to lay the groundwork for our presence in those countries," Leavitt said, saying he would visit China in May, and Central America and Mexico in June.[22] Chinese officials deny that the problem originated in China. The heparin scare may be dominating the health news in the U.S. media, but that's not stopping multinationals from boosting their ties with the Chinese medical industry. Dutch conglomerate Philips ( PHG ), which is switching its focus away from electronics and semiconductors and toward higher-growth areas like medical equipment, is boosting its alliances with manufacturers, universities, and hospitals in China.[32]
Chinese officials have rejected claims by U.S. authorities that Chinese imports are to blame for deaths among users of the blood-thinning drug heparin.[25]
BAHRAIN is not at risk from allegedly contaminated Chinese drugs said to have killed more than 80 people in the U.S. An investigation had found no stocks of the allegedly contaminated brand of the drug heparin in Bahrain, says Health Ministry drug control director Dr Mohammed Nasser.[41] Janet Woodcock, director of the agency's Center for Drug Evaluation and Research, said the contaminant has been traced to 12 different Chinese companies and has been found in heparin batches shipped to 11 nations, all of it from China.[4] At a press conference convened at the Chinese embassy in Washington, Professor Jin Shoahong of China's pharmaceuticals standards agency was quick to dispute the claims. He said there was no evidence that the contaminant - a chemical called oversulphated chondroitin sulphate - was to blame for the deaths. "In addition to the USA and Germany, more than 10 other countries also use the heparin ingredient that contained oversulphated chondroitin sulphate to produce final heparin injection," he said. "But there are no reports of problems from these countries."[25] Now there comes the claim that China is to blame for a contaminant in heparin which it holds responsible for up as many as 81 deaths. It has accused a Chinese factory of using unclean tanks to make heparin ingredients, and of buying raw materials from disreputable sellers.[25]
THURSDAY April 24, 2008 (foodconsumer.org) -- Now there is some scientific evidence to prove that the contaminant found in heparin associated with hundreds of allergic reasons and up to 81 deaths is a man-made chemical known as oversulfated chondroitin sulfate, according to a new study.[28] Raw heparin is normally sourced from the intestines of pigs or the lungs of cows, while the contaminant ' oversulfated chondroitin sulfate ' comes from animal cartilage. It is more abundant (and so cheaper) than raw heparin, and not registered for medical use because it causes severe allergic reactions.[33]
Writing in the New England Journal of Medicine, Ram Sasisekharan and his colleagues at MIT said the chemical in heparin appears to cause severe allergic reactions and abnormally low blood pressure. "These results provide a potential link between the presence of chemical contaminant in heparin and the clinical symptoms observed in affected patients," Sasisekharan said.[24] Sasisekharan's team found the contaminant in six lots of heparin linked to patient deaths or allergic reaction by using two extremely sensitive analytic methods ' nuclear magnetic resonance and liquid chromatography.[26] A team of scientists led by MIT professor Ram Sasisekharan has identified the contaminant present in Baxter'''s heparin and has also found the mechanism by which it causes the allergic reactions, if injected in the body.[51]
Heparin associated with allergic reactions and deaths was made of a key ingredient prepared by a Chinese company that is solely controlled by a Wisconsin company.[28] From January 2007 to the present, 131 deaths were reported, including 81 involving allergic reactions or hypotension, prompting a heparin recall and the investigation.[10]
A South Jersey manufacturing plant has found itself at the center of an international imbroglio over contamination in a blood-thinning drug linked to severe allergic reactions and as many as 81 deaths.[42]
The FDA has cleared Baxter Internationals Cherry Hill plant, which makes heparin, of any role in contamination of the drug.[42] In it the FDA said the plant used unclean tanks to make heparin, accepted raw materials from an unacceptable vendor and had no way to remove impurities, The New York Times reported. It does not know the original source of the contamination or where it entered the supply chain, the Times said.[37]
Marcia Crosse: Director of health care for the Government Accountability Office (GAO). The GAO this week released a report on the FDA's foreign drug inspection program that said it would take nearly two decades for the federal agency to inspect all plants overseas.[36] The Government Accountability Office, an investigative arm of Congress, estimated it would cost between $67 million and $71 million to inspect the 3,200-plus foreign drug plants registered with the FDA every two years.[9] GAO analysis said it would cost the FDA $67 to $71 million each year to inspect the thousands of foreign plants on the agency's priority list.[18]
A new government audit says the FDA would have to invest an additional $56 million next year simply to begin full inspections of foreign plants.[5]
When asked by lawmakers how much money the FDA needed to conduct additional inspections, von Eschenbach declined to give a specific figure, saying GAO's estimates were in the ballpark. Rep. Michael Burgess, R-Texas, predicted the FDA wouldn't get any additional money in this election year. He added Congress probably wouldn't be able to agree on a budget and would need to approve what is known as a continuing resolution, which keeps the agency funded at current levels until a new budget is put in place.[46] First authorized in 2003, ADUFA created a framework by which drug manufacturers pay fees that supplement the agency's appropriations and animal drug reviewers meet demanding performance deadlines. The ADUFA program, which must be reauthorized by Congress every five years, has enabled the FDA to dramatically reduce its review time of new animal drugs, bringing medications to the market more quickly while maintaining high standards for safety and efficacy.[52] Gee, did someone forget to tell the president that the experts over at the FDA have already given notice that the agency is completely incompetent? The FDA's science board spent a year studying problems at the agency, and concluded that a lack of resources and personnel "is imposing a significant risk to the integrity of the food, drug, cosmetic and device regulatory system, and hence the safety of the public."[49]
The Partnership for Safe Medicines applauds the Committee for recognizing that the FDA's ability to safeguard America's food and drug supplies is being compromised by numerous challenges and obstacles. Unfortunately, this recent case of heparin contamination is just one example of the increasingly global problem of counterfeit drugs sold to an unsuspecting public.[53] The Partnership for Safe Medicines, a group of organizations and individuals dedicated to protect consumers from counterfeit medicines, issued the following statement regarding today's hearing on the Food and Drug Administration's (FDA) ability to enforce safety regulations held by the Senate Committee on Health, Education, Labor, and Pensions.[53] NewswireToday - /newswire/ - Washington, DC, United States, 04/24/2008 - The Partnership for Safe Medicines issued a statement regarding today's hearing on the Food and Drug Administration's ability to enforce safety regulations held by the Senate Committee on Health, Education, Labor, and Pensions.[53]
Under the cloud of contaminated heparin deaths, Food and Drug Administration Commissioner Andrew von Eschenbach received a rude welcome from Congress Tuesday, accused by Rep. John Dingell, D-Mich., of "carrying the water" for the Bush administration, "toe-dancing around the hard facts," and making promises that turn out to be nothing more than "hooey." [11] Dr. Andrew C. von Eschenbach, commissioner of the Food and Drug Administration, agreed that the agency needs more resources and for the first time accepted estimates, albeit tentatively, that an additional 500 inspectors and $70 million in funding was required to bolster foreign drug inspections.[50] Members of Congress have sharply criticized the U.S. Food and Drug Administration, saying underfunding and a failure to act aggressively to increase foreign inspections is putting Americans at risk from dangerous drug and food imports.[44] VOA's Dan Robinson reports from Capitol Hill. For the fiscal year beginning in October, the Food and Drug Administration requested a $130 million budget increase, with the intention of improving its capabilities to inspect foreign companies manufacturing drugs for the U.S. market.[44] The House Energy and Commerce subcommittee is examining how thoroughly the Food and Drug Administration inspects overseas manufacturing plants where nearly 40 percent of the medicines sold in the U.S. are made.[15] The Food and Drug Administration inspected the Cherry Hill plant in February and gave it a clean bill of health.[42]
The Food and Drug Administration says the raw materials for heparin, which come from pig intestines harvested in China, are responsible for the contamination.[47] Use of Heparin Concerns the Food and Drug Administration The Food and Drug Administration recently asked the makers of many kinds of medical devices that contain the drug Heparin to test their supplies.[54]
The U.S. Food and Drug Administration today delivered recommendations to Congress for two programs that provide funding for the review of pioneer and generic animal drugs.[52] A hearing on Capitol Hill today will examine the Food and Drug Administration's foreign drug inspection program.[35]
If we don'''t make some rapid progress on fixing the foreign drug inspection program, the next melamine or heparin tragedy will soon be upon us.''' In order to solve these types of problems the severely under funded agency is going to need Congress to put their money where their mouth is.[20] Among the most controversial problems are inspections in China, where U.S. and European test results identified contamination in ingredients used to manufacture the blood thinning medicine heparin.[44] An inspection by U.S. regulators of the Chinese factory that supplied tainted heparin ingredients to Baxter International revealed significant deviations from U.S. Current Good Manufacturing Practice standards.''[8] The raw ingredient for Baxter International's recalled heparin came from Wisconsin-based Scientific Protein Laboratories, which in turn owns a Chinese factory Changzhou SPL and buys additional raw heparin from other Chinese suppliers.[29]
One batch of heparin injections free of the contaminants has resulted in about a hundred adverse events, of which 25 were serious. The officials also noted that the implicated Chinese factory Changzhou SPL was managed and overseen by a manager from its U.S. headquarters.[29] Wang added: "The adverse effects might be the result of a contaminant in a heparin product that came from a Chinese factory. It might, and it might not. The problem might be at any place along the way," he said. "It's not the intention of the Chinese to exchange charges with the U.S., but to share with the media their impression - it's still open as to the root cause of this heparin problem."[42]
Last week an official of the Chinese National Institute for the Control of Pharmaceutical and Biological Products said the substance identified as a contaminate could not be the cause of the adverse reactions reported among heparin users.[24] FDA officials said 12 Chinese companies manufactured the heparin, but when the cheaper additive was introduced to the products is still in question.[27]
The FDA says the drug, sourced to a Chinese factory, had been found in heparin supplies in 11 countries.[41] The Chinese subsidiary is called Changzhou SPL. Dr Janet Woodcock, Director of the FDA's Center for Drug Evaluation and Research, told the press yesterday that the agency had now "established a mechanism by which we think this contaminant could cause these adverse events", reported CNN, but she did not go so far as to say there was certain proof, only that the route was possible.[1] FDA previously identified a contaminant in lots of heparin associated with adverse reactions as OSCS ( C&EN, March 24, page 13 ).[6] For theNature Biotechnologypaper, researchers from MIT, the FDA, and elsewhere analyzed six heparin preparations that had been linked with adverse reactions in patients, as well as four "control" preparations not associated with adverse events.[2] The FDA countered, saying a cluster of adverse reactions to heparin has been reported in Germany.[17]
Ten countries in addition to the U.S. have now found OSCS in heparin, although only the U.S. and Germany have seen an increase in adverse reactions to the drug.[6] Contaminated batches of the drug have been found in 10 countries and the U.S. Eighty-one deaths and perhaps hundreds of adverse reactions in the U.S. may be linked to the drug (although it hasn't been firmly established that the drug caused the deaths).[45]
U.S. officials also announced Monday that contaminated heparin products have now been found in at least 10 countries, in addition to the United States.[2] The kinin-kallikrein pathway can lead to the generation of bradykinin, a powerful vasoactive mediator, Dr. Sasisekharan and colleagues said. To test the possible effects in vivo, they gave pigs intravenous injections (at 5 mg/kg) of heparin, contaminated heparin, synthetic oversulfated chondroitin sulfate, or chondroitin sulfate A. Two of the six animals treated with contaminated heparin suffered at least a 30% drop in blood pressure over the first 30 minutes after infusion, they found, while those treated with synthetic oversulfated chondroitin sulfate had even more profound drops in blood pressure.[55] Note that these studies confirm that the heparin was contaminated with oversulfated chondroitin sulfate, as previously indicated by the FDA, and offer an explanation of the biological effects of the compound.[55] The FDA said the chondroitin sulfate was molecularly changed to mimic heparin'''s blood-clotting properties.[48]
Oversulfated chondroitin sulfate, which is derived from animal cartilage, has a structure very similar to that of heparin and thus cannot be identified with the tests normally used to inspect batches of heparin. Traditional heparin safety screens test only for contaminants such as protein, lipids or DNA, and thus would not detect the presence of sugar chains that do not belong.[48] Oversulfated chondroitin sulfate, derived from animal cartilage, is a long sugar molecule that is structurally similar to heparin and thus was not detected, the researchers said. To tease out the nature of the contaminant, the researchers used nuclear magnetic resonance techniques to determine its characteristics, which they described as "highly unusual" owing to the presence of both a 3-O-sulfated glucuronic acid and a tetrasulfated disaccharide repeat unit. They compared the NMR spectrum of the contaminant, derived from studying tainted samples, to that of freshly synthesized oversulfated chondroitin sulfate and found the two spectra matched. It is "highly unlikely that the contaminant reported here is produced naturally," they said in Nature Biotechnology.[55] Top image depicts the chemical structure of chondroitin sulfate, the contaminant found in batches of heparin.[34]
Guerrini M, et al "Oversulfated chondroitin sulfate is a contaminant in heparin associated with adverse clinical events" Nature Biotech 2008; DOI:10.1038/nbt1407.[55]
"Our findings suggest that a simple bioassay" -- a chemical test -- "could help protect the global supply chain of heparin," Sasisekharan said. Neither of the studies, however, address the question of exactly where or at what stage of production the contaminant was introduced, he added. More than one million multi-dose vials of heparin are sold per month in the United States, according to the FDA. Half of them are manufactured by Baxter. [23] The FDA said Baxter's supply may have been intentionally contaminated with an animal-like substance similar to heparin that was put into the product to increase certain suppliers' profits.[43] The pharmaceutical companies feel the FDA is a nuisance, way too fussy about drug safety details and terribly slow with approval. This, they say, deprives consumers of the latest drugs, not to mention delaying company profits. Drug companies have long insisted that going to all the trouble and expense of obtaining FDA approval for their drugs and medical devices should entitle them to complete immunity from all product liability lawsuits.[49] Before being pulled from the market, Merck & Company's drug Vioxx, a pain medication described as no more effective than over-the-counter pain relievers, caused more than 100,000 heart attacks and at least 50,000 deaths in the United States, according to senior FDA researcher Dr. David Graham. The public did not learn details about Merck"s massive data doctoring until forced to open up its cooked books in courtroom proceedings. Even when lawsuits force some companies to come clean on their dirty secrets, we must remember that the gold standard of clinical science itself, the placebo-controlled randomized trial, has been downgraded to a fool's gold standard.[49] As any first year student of science can tell you, a scientifically valid clinical trial demands the use of a control group receiving a placebo with zero active ingredients, without exception. In any other industry, these kinds of creative "improvements" to established scientific protocol would be called "cheating." Drug companies have their own word for drug safety trials that violate basic rules of science, "profitable." Lawsuits have traditionally served as the only check and balance available to shore up the shortcomings of the FDA. As things stand, if preemption wins the day and lawsuits are forbidden, the drug companies will be free to get away with murder more than ever because they will never be forced to disclose exactly how the numbers were fudged or what data was withheld to gain approval.[49] Perhaps Congress shouldn't have cut so much of the FDA's funding. It's funny that Baxter in Illinois buys their active ingredient in China from a firm that's owned by a company in Maryland. Why do we allow these companies to outsource to nations with no or substandard safety protocols and good practice guidelines--Chinese FDA has a long way to go and their government will never look out for the working conditions of their citizens the way we do. Sure, this translates into cheaper production for Pharms but this has never translates into cheaper prices at the consumer level. These companies are just resorting to another cost-cutting measure to increase profits--especially when many large blockbusters are ready to go off patent. In this increasingly globalizing marketplace where we devalue domestic craftsmanship in favor of the value of the foreign bottom-line, we need to hold someone liable for cases like this.[18] Republicans voiced support for some of the ideas. In November, the Bush administration issued its own import safety plan, which emphasizes working with foreign governments and U.S. manufacturers to assure the quality of supplies and production. Health and Human Services Secretary Michael O. Leavitt said in an interview that his trips abroad to advance import safety showed the best approach to safeguarding imports wasn't necessarily more FDA requirements or inspections.[50]
"You simply are absolutely incapable of addressing your responsibilities.'' Von Eschenbach said the FDA is doing more overseas inspections than ever before, although he agreed with lawmakers that still more are needed. He repeatedly said the U.S. must take other actions as well, adding that more frequent inspections wouldn't have detected the tainted heparin.[30] Von Eschenbach, who was confirmed to lead the FDA in late 2006 argued that the FDA is doing more overseas inspections than ever before and acknowledge that more is needed and the U.S. must take other actions, adding that more frequent inspections wouldn't have detected the tainted heparin'''in which 81 died and hundreds more were sickened'''because even if an inspection had taken place, the contaminant wouldn't have been found because conventional tests couldn't have detected it.[12]
Grilling: FDA Commissioner Andrew von Eschenbach testified at a congressional hearing on the contaminated pharmaceutical drug heparin Tuesday.[14] The FDA plans to station employees in three Chinese cities - - Beijing, Guangzhou and Shanghai -- to inspect food and drug facilities and assist the country's regulators, von Eschenbach said at the hearing.[30]
The FDA has linked hundreds of allergic reactions to contaminated doses of the drug.[47] China had been making claims that the contaminant can'''t be the reason behind the allergic reactions. Now, these findings provide a proof in FDA'''s hands and it can strongly put its point forward.[51] The FDA has established, through animal tests, a biologic link between the contaminant and allergic reactions.[42]
A variety of underlying medical conditions were involved, and only three of the deaths listed allergic reactions or low blood pressure among the medical events preceding death, the FDA said.[10]
The FDA has counted 62 deaths from allergic-style reactions that were associated with recalled heparin batches.[29] From January 2007 through March 2008, the FDA had received 131 reports of deaths associated with heparin made by Baxter and other companies.[51] The FDA launched an investigation after seeing a spike in deaths reported after heparin administered between November and February.[10] German regulators have also reported a rash of illnesses in patients using heparin, FDA official Janet Woodcock said.[10]
The agency inspection concluded that there is "no assurance" that processing steps Changzhou used to manufacture heparin sodium, USP are capable of effectively removing impurities. The FDA said that the firm "fails to have adequate systems" for evaluating the suppliers of heparin crude materials, and the crude materials themselves, to ensure that these materials are acceptable for use.[7] The test methods performed by Changzhou for heparin sodium USP "have not been verified to ensure suitability" under actual conditions of use, the FDA wrote. The equipment used to manufacture heparin sodium USP " is unsuitable for its intended use ", the agency said.[7]
The letter also stated that Changzhou had acknowledged to the FDA that it received and used heparin crude materials from a workshop that Changzhou itself had deemed as "unacceptable" in a "pre-audit". The FDA warning letter to Changzhou SPL said that the testing methods employed by the facility were'' not " verified to ensure suitability under actual conditions of use," and that equipment used at the factory to make heparin ingredients was "unsuitable for its intended use".[8]
For the study published on Wednesday in Nature Biotechnology, researchers at Massachusetts Institute of Technology, the FDA and other organizations used sophisticated analytical techniques to completely characterize the contaminant present in tainted heparin.[28] The FDA has identified the contaminant as a modified form of a common nutritional supplement. That substance is cheaper to produce than Heparin; leading to suspicions that it may have been intentionally added somewhere along a complex and lightly regulated supply chain in China.[54] According to the FDA, as many as 81 Americans may have died after taking heparin, a blood thinning agent, tainted in China via the addition of a poisonous chemical.[14] The FDA say a compound called oversulphated chondroitin sulphate (OSCS) in the tainted heparin, which was imported from China, is probably responsible.[26]
Dingell said the FDA had failed to ask Congress for sufficient funding to protect the public from unsafe drugs. "You presided over this (heparin contamination) because you do not have the resources to do the job you need.[9] Auditors estimate the FDA would need far more resources to inspect, every two years, each of the 3,249 foreign drug establishments listed by the agency.[40] Last year the FDA conducted only 30 inspections of the more than 3,200 foreign drug facilities.[20] The FDA has budgeted about $11 million in the current fiscal year for foreign- facility inspections. FDA Commissioner Andrew von Eschenbach said the agency hopes to inspect about 500 foreign facilities this year after conducting 332 last year.[46] Dr. Andrew C. von Eschenbach, commissioner of the FDA, acknowledged that inspection of 500 foreign facilities each year, a minimum number laid out by several lawmakers, would cost around $20 million a year.[38]
Congress went after FDA Commissioner Andrew von Eschenbach for the FDA's lax inspection protocols, particularly with regard to foreign factories.[18]
Dingell objected when the commissioner didn't provide specifics. Dingell and other lawmakers said the FDA must conduct more inspections of companies sending drugs to the U.S. to ensure they are safe.[30] Apparently it has also become normal to delete negative drug reactions from safety reports submitted to the FDA, and lie about who wrote the reports, as we discovered with the Vioxx debacle. Since the FDA does not carry out drug safety research itself, its decisions are based on whatever selective and biased reporting the companies decide to hand in.[49] One scientist within Johnson and Johnson urged the company to conduct a formal evidence-based review following FDA approval because of "an abnormally high number of'spontaneous cases' of clotting disorders, as well as death," associated with the patch. The company never performed such a study. To its credit, Johnson and Johnson does admit that initial drug safety data on the patch was altered using a "correction factor." This is another way of saying "we made up the numbers." J&J; lawyers swear this kind of monkey business is normal and standard procedure for safety trials, and I believe them.[49] All three presidential candidates support making drug importation easier to combat the "high cost of health care." They seldom acknowledge the inherent risk ' and associated external costs ' in such importation. According to the FDA, over half of the drugs Americans buy over the Internet don't work ' and at least one North American death has been officially linked to drugs purchased this way.[33] We need to give the FDA all the tools it truly needs to fix the problems, including a dramatic, and sustained, funding increase. We need to work with governments around the world to adopt a tougher stand against the perpetrators of counterfeit medicines that reflects the gravity of their offenses. We need to send a message to these criminals that we will not tolerate activities to compromise public health. The Partnership encourages everyone to learn how they can take steps to protect themselves from contraband and potentially counterfeit medicines'because counterfeit drugs are unsafe at any cost.[53]
In fiscal year 2004, FDA reviewed 90 percent of all new animal drug applications within 295 days.[52] In fiscal year 2008, FDA reduced review time for 90 percent of new animal drug applications to 180 days. If reauthorized, ADUFA is expected to generate $98 million in user fees over the next five years to support FDA review of these new animal drug applications.[52]
New Zealand is one of 11 countries supplied with the drug Heparin. Medsafe spokesman Doctor Stewart Jessamine says they have known about the problem since January and have been keeping a close eye on those using it. Jessamine says so far no-one has reported any illnesses involving Heparin, meaning it's unlikely the contaminant has made it to New Zealand. [19] "There was one batch of product of low molecular weight heparin, which internationally was found to contain that contaminant, and that product hadn't yet made it out to patients." It was quarantined and withdrawn, he said. "We're confident that the product that is available in New Zealand for use in patients through hospitals and doctors, is not at risk through contamination," he said.[37] The heparin is made from the lining of the pig's stomachs. Being unable to meet the contracted demand, they found a substitute. This follows the same pattern as the pet food poisoning of several years ago, and is, unfortunately, typical in other industrial products from China.[26]
Last year consumers saw millions of Chinese-made toys recalled for violations of lead paint standards among other defects, contaminated Chinese-made pet foods, and now contaminated heparin has been linked to 81 deaths in the U.S. alone.[20] Baxter International Inc.' s Cherry Hill plant - a complex of one-story buildings near Springdale Road and surrounded by a black metal security fence - turns out 35 million vials of injectable heparin a year, or about half the U.S. supply for hospitals and medical centers.[42] Later, two Baxter security guards asked several photographers to move away from the plant's main gate, on Olney Avenue, which led into a massive parking area. The other major U.S. supplier of injectable heparin, APP Pharmaceuticals Inc., of Schaumburg, Ill., is continuing to manufacture heparin and screening its supplies for contaminants.[42]
Chinese inspectors have visited the Baxter International plant in New Jersey where the final processing of tainted heparin took place.[17] Tainted heparin has been traced to a Chinese plant operated by Baxter supplier Scientific Protein Laboratories of Wisconsin.[38]
Chinese officials allege the contamination could have occurred in the U.S. and have demanded access to the U.S. plant where the vials for the drug are made.[41] The entire U.S. budget for inspecting overseas drug makers is not large enough to check all of the plants in China'''which has the largest number of plants registered to send drugs to the U.S.'''every two years, according to an analysis released today by the GAO. This entry was posted on Wednesday, April 23rd, 2008 at 9:33 am and is filed under Legal News, Pharmaceuticals.[12] According to ABC News, Estimates suggest more than 80 percent of all active ingredients used by U.S. drug manufacturers come from abroad.[18] No less that 80 percent of all active ingredients used by U.S. manufacturers to produce drugs are imported.''[12]
WASHINGTON, April 22 (Reuters) - Lax U.S. oversight of drug ingredient makers in China and other countries is putting Americans at risk of exposure to more dangerous medicines like the tainted blood-thinner heparin, lawmakers said on Tuesday.[9] Drugs like the blood thinner heparin face a long and winding road as they're transformed from raw ingredients into sophisticated medications.[35] New Zealand's supply of blood thinner heparin has been tested and is not contaminated, the medicine safety agency Medsafe says.[37] PARIS (AFP) — An international team of researchers racing against the clock have figured out how tainted batches of the blood thinner heparin slipped past safety screens to kill dozens of patients in the United States and Germany, according to a pair of studies released Thursday.[23] ScienceDaily (Apr. 24, 2008) - An international team of researchers led by MIT has explained how contaminated batches of the blood-thinner heparin were able to slip past traditional safety screens and kill dozens of patients recently in the United States and Germany.[34]
The findings were published online Wednesday inNature Biotechnology. And, according to a paper published online simultaneously in theNew England Journal of Medicine, the same researchers state that regulators now have at their disposal a test to detect contaminated heparin. Regulators have said they have been hampered in their efforts to safeguard the public from contaminated heparin because of an uncertainty over exactly what the contaminant is and the lack of a test to spot such a contaminant.[2] There is disagreement between U.S. and Chinese regulators about whether the contaminant found in supplies of heparin is responsible. To view the full text of this article, you must be logged in as a registered member.[56] The contaminant was found in the heparin raw ingredient made by a Chinese subsidiary owned by the Wisconsin based company Scientific Protein Laboratories (SPL).[1]
Heparin is made from pig intestines that are often collected from small, mostly unregulated farms in China. Baxter maintains the contamination occurred before the product reached Baxter or its raw ingredient supplier. [16] France, Italy, and Denmark, the U.S., Germany, Switzerland and Japan are among the countries to recall heparin products after a heparin contamination scare over product materials linked to China.[7] Customers with questions about Baxter's U.S. vial-based heparin product recall may call the Center for One Baxter at 1-800-4-BAXTER (1-800-422-9837).[18]
Deerfield-based Baxter International Inc. supplied roughly half the heparin used in the U.S. market at the time.[38] Dr. Jeremy Berg, director of the National Institute of General Medical Science, said that in addition to being vital for public health, identifying the recent impurity in heparin was a chemical triumph. The researchers used a unique combination of scientific techniques to accomplish this complex task, which can also be of use to detect other impurities in pharmaceutical materials, he added. In January, Baxter had voluntarily recalled nine lots of its heparin sodium injection in 1,000-unit vials, after reports of adverse reactions.[51] More than 100 patients have experienced adverse reactions after receiving the tainted heparin.[34]
Scientist now know why contaminated heparin caused serious and sometimes fatal reactions in hundreds of patients. In a study published in the "New England Journal of Medicine", researchers say that pigs treated with tainted heparin have exhibited side effects similar to those seen in humans.[48] The Times also said officials have discovered tainted heparin lots that were manufactured as early as early as 2006, although a spike in illnesses associated with contaminated heparin began in November and persisted through February. This entry was posted on Thursday, April 24th, 2008 at 5:53 am and is filed under Legal News, Pharmaceuticals.[48] "The FDA has already moved to put screening methods in place to detect contaminated heparin," said Sasisekharan.[23] The FDA has determined that the heparin was contaminated by a foreign substance.[38]
"The current regulatory system is woefully insufficient, a fact that has been proven by the tragedies caused by unsafe heparin," said Rep. John D. Dingell, D-Mich., in a statement Monday. "It's clear that FDA does not have the ability to protect the American people from unsafe food and drugs."[35]
Changzhou was told by the FDA to respond to the agency in writing with a corrective action plan. In response to the warning letter, Changzhou has stated that it " does not reflect its actual state of compliance with GMP " and insisted that it is cooperating with the FDA on the matter and will soon provide a comprehensive response to the letter as instructed. In the meantime, shipments to the U.S. of products manufactured by Changzhou are currently being refused admission into the country because " the methods and controls used in their manufacture do not appear to conform to cGMP, " the FDA said.[7] As if things weren"t bad enough already, the U.S. Supreme Court is poised to rule in favor of drug-maker Wyeth in a case that will likely usher in total preemption of lawsuits for all products approved by the FDA.[49]
The funding is tied to meeting specific performance goals that will ensure efficient scientific evaluation of the safety and effectiveness of animal drugs. "We are pleased to provide our recommendations to Congress today, as they are important components of our desire to provide the best products possible for animal care," said Bernadette Dunham, D.V.M., Ph.D., director of the FDA's Center for Veterinary Medicine.[52] While it is not possible to trace a direct link to the adverse events and deaths, since the product recall, the number of deaths and adverse events reported to the FDA has returned to the previous level.[1] The FDA's statistics showed 62 deaths associated with the severe reaction in the 15 months from January 2007 through last month -- an increase from the agency's previous count. Of these reported deaths, 47 came in the four-month period from November, 2007 to February, 2008.[54]
The Government Accountability Office's report will be part of a hearing Tuesday by a House oversight and investigations subcommittee. The auditors said it's just too early to determine the effectiveness of the FDA's plans for improved oversight of foreign facilities. The agency has said it's exploring the creation of a cadre of investigators who would conduct foreign inspections, but it has not provided any additional details or time frames.[40] Experts estimate that for the FDA to inspect all foreign facilities at the same rate as domestic facilities, the current $10 million foreign inspection budget would need to be increased by seven fold. Without the funds to perform the inspections the agency has no chance at drastically improving performance in this area.[20] Later, a panel that included two former senior FDA enforcement officials and the head of the GAO's health-care division criticized the FDA on several fronts. The agency has failed to keep its computer systems up to date, does not adequately track foreign manufacturing operations and needs to more effectively coordinate regulatory efforts with foreign agencies, panelists said.[38]
"Foreign inspections are unfortunately the neglected stepchild of the FDA's drug inspection program and that simply cannot continue," said Rep. Joe L. Barton, a Texas Republican.[50] "If we don't make some rapid progress on fixing the foreign drug inspection program, the next 'melamine' or 'heparin' tragedy will soon be upon us," said Rep. Bart Stupak, a Michigan Democrat.[50]
U.S. health officials says as many as 81 patients in the U.S. died soon after taking the tainted heparin. Their symptoms included swelling of the larynx and low blood pressure. [24] Heparin is commonly used in dialysis to prevent clotting of the blood when it circulates in a dialysis machine. It makes the blood thinner and thus reduces the loss of the blood during dialysis. Anemic patients can'''t afford this blood loss as it could prove fatal for them.[51] Heparin is a blood thinner, often used on patients undergoing cardiac surgery or kidney dialysis.[33] Heparin, a blood thinner used by millions of patients during kidney dialysis and heart surgery to prevent blood clots, is normally produced from pig intestines.[23]
China is the world's leading supplier of heparin, a blood thinner often made from a substance in the intestines of pigs.[54]
Heparin is an anticoagulant for patients undergoing surgery, blood transfusions, and other treatments requiring a blood-clotting inhibitor. It is derived from pig intestines and processed by unregistered workshops and consolidators in China.[42] BOSTON, April 24 -- Researchers here revealed today how the adulterated heparin from China evaded detection at the U.S. border and how it killed scores of patients.[55]
WASHINGTON, April 23 (Reuters) - Researchers said they had identified a chemical contaminating the blood-thinner heparin from China and also shown how it could cause a sometimes fatal allergic reaction in people.[3] The concerns came after a number of serious allergic reactions were linked to medical devices which contained Heparin.[54]
The official said the same batch of the drug had been distributed in ten other countries, but there had been no reports of similar allergic reactions.[24] The company recalled vials of the popular blood thinner two months ago following reports of potentially deadly allergic reactions.[43] The first leads to a dangerous decrease in blood pressure, the second a serious allergic reaction.[48]
Difficulty in breathing, nausea, vomiting, excessive sweating and rapidly falling blood pressure are few reactions that are developed in people who have been injected with contaminated drug.[51] Serious reactions to the drug have included difficulty breathing, nausea, vomiting, excessive sweating, and rapidly falling blood pressure that can lead to life-threatening shock.[24]
When the researchers gave either tainted heparin or OSCS to pigs, the animal's blood pressure plummeted, echoing the symptoms in humans. The study "establishes a mechanistic link between oversulphated chondroitin sulphate and the symptoms that are associated with the adverse events, such as the lowering of blood pressure," Nasr says.[26] "The oversulfated chondroitin can therefore not be a suspected root cause of heparin adverse events as reported in U.S. media previously," Shaohong said.[29]
The chondroitin contaminant has a structure very similar to that of heparin. It thus cannot be identified with the tests normally used to inspect batches of heparin.[51] The chondroitin contaminant, derived from animal cartilage, has a structure very similar to that of heparin, taken from pig intestines. It thus cannot be identified with the tests normally used to inspect batches of heparin.[3]
The contaminant, which is derived from animal cartilage, has a structure very similar to that of heparin and thus cannot be identified with the tests normally used to inspect batches of heparin. It is unclear whether the contaminant got into the heparin during the manufacturing process, or how and where contamination could have occurred during the process. More investigations are needed to address this issue. Traditional heparin safety screens test only for contaminants such as protein, lipids or DNA, and thus would not detect the presence of sugar chains that do not belong.[34] The researchers showed how the compound killed by activating two separate inflammatory pathways. They suggested that the methods they used to identify the compound might be employed by regulators to prevent a repetition. The tainted heparin slipped past regulators because current tests look for contaminants such as protein, lipids, or DNA, Dr. Sasisekharan and colleagues said.[55]
A study published in the British journal Nature shows why the deadly chemical was so hard to detect. "Traditional safety screens for heparin only test for contaminants such as protein, lipids or DNA," explained Sasisekharan.[23] "Sophisticated analytical techniques enabled complete characterization of the contaminant present in heparin. This study also provides the scientific groundwork for critical improvements in screening practices that can now be applied to monitor heparin, thus ensuring patient safety," said Sasisekharan, senior author of the papers and the Underwood Prescott Professor of Biological Engineering and Health Sciences and Technology at MIT.[34] Germany also discovered the contaminant and recalled batches of heparin after some patient illnesses.[29]
Woodcock did point out that although identifying the mechanism by which the contaminant could cause the reactions strengthens the association considerably, not every patient who received the contaminated product was adversely affected.[7] Baxter bought the chemical grade heparin from SPL to make the injectable forms for clinical use. The responsibility really belongs to Baxter to ensure that their final products are not contaminated.[26] I am writing to express my concern regarding the lack of oversight of China-based companies that supply heparin, a product used in some surgical procedures, and that the lack of surveillance may cause an outbreak of transmissible spongiform encephalopathies, or TSEs, the human form of this being Creuztfeldt-Jakob, or variant C-J disease. The fact that a local woman died of this disease should initiate a full investigation to try to determine when she got it and how ("Portsmouth woman's death under investigation," April 11).[39] To the drug lords hiding in the boardrooms of the pharmaceutical houses, I say if you are afraid to stand up for the integrity of your products and face your victims in the courtroom, then switch to the pesticide business where chemicals for sale are fully intended to cause death and disability.[49] Over the past two years, the agency has already started running conferences on drug discovery and clinical development in India, pertaining to the global development of biopharma products.[21] The agency is required to inspect domestic companies every two years and to inspect foreign facilities before the agency approves a new drug or medical device made in that facility.[46] There isn't a requirement for foreign reinspections. Dingell and other lawmakers said they would soon introduce legislation that would require the agency to inspect foreign drug companies every two years.[46]
Marcia Crosse, GAO's health-care director, said the agency would need about $70 million to inspect the more than 3,000 foreign drug facilities every two years.[46]
I wish the mainstream media would bring this up and demand an answer out of the FDA how they could get all freaked out about the Canadian drug issue but let this practice slide by. I guess they assume all of us have such short memories that we won't remember something they did five years ago.[18] The FDA has since asked drug makers to use a test that can pick up the contaminant.''[12] The FDA has identified the contaminant as oversulfated chondroitin sulfate, a "cheap fake additive" that can be detected only through sophisticated testing, the paper said.[10] The team, led by Professor Ram Sasisekharan of MIT, identified the chemical structure of the contaminant, known as oversulfated chondroitin sulfate (OSCS). The researchers present their findings and offer new approaches to detecting the contaminant in a report appearing April 23 in the online edition of Nature Biotechnology. Another team led by Sasisekharan has shown exactly how OSCS can kill-specifically by setting off an allergy-like reaction.[34]
Woodcock's announcement seemed to conflict with statements made earlier Monday by Chinese health officials who said oversulfated chondroitin sulfate was not responsible for the reported injuries and deaths.[2] Chinese officials said the chemical, an altered form of chondroitin sulfate, was not to blame.[9]
The Chinese officials contended Monday that batches not containing the contaminant called oversulfated chondroitin also have been associated with side effects.[29] The dispute reached a crescendo Monday after a briefing at the Chinese Embassy in Washington, where a Chinese official disputed that oversulfated chondroitin was the cause of the reactions.[42]
Chinese scientists and medical experts on Monday disagreed, saying the contaminant is not to blame for the adverse reactions.[35] All the preparations linked with adverse reactions contained a contaminant similar to chemically synthesized OSCS, the researchers said.[2]
Obviously, if the "placebo" causes adverse reactions similar to the tested drug, the drug looks much better.[49]
The emerging consensus, voiced yesterday at a House subcommittee hearing, comes a day after the FDA said as many as 81 Americans died after taking a popular blood-thinning drug tainted somewhere in China with an unapproved chemical. [50] The FDA was careful to avoid using the word "counterfeit" when discussing the incident - but when pressed by reporters, Center for Drug Evaluation and Research director Dr. Janet Woodcock, admitted that the agency was "99 percent sure is not a natural component that got in there as part of the purification process."[33] I digress. President Bush has long pushed for preemption of lawsuits for drug companies, arguing that the expert doctors at the FDA are the only people in the country smart enough to understand these complicated matters, and the courts should not try and second-guess the all-wise FDA.[49] Over recent decades, drug companies have "streamlined" standard clinical procedures to improve chances for FDA approval.[49]
The ADUFA recommendations include an "end review amendment" process which will enable the FDA to work with a drug manufacturer at the end of a review to make corrections to an application, resulting in reduced review time.[52] Most incidents occurred at blood dialysis centres with patients taking a high dose administered over a short period of time, the FDA reported.[23] The Times said regulators in Germany have reported several illnesses among dialysis patients who used the drug.[27]
The Reason Is Likely Simply. This case showed us a glimpse of the biggest loop hole in the drug safety. This chinese factory is actually owned by SPL based in Minesota and is registered as a chemical company. It avoided the regulation because it does not manufacture drugs for patients, only chemicals.[26] We bring together industry, academia, regulators and patient organisations to provide ongoing training for professionals on regulations, clinical practices and safety standards that will impact the approval of drugs developed in India for the global market[21]
The larger question--can the safety of U.S. drugs be guaranteed in an expanding global economy?--is likely to be with us for some time.[45]
China has disputed the allegation, claiming no countries other than the U.S. have experienced problems with the drug.[41] The Chinese government suggested that the problem may have been at the U.S. end, and the FDA quickly responded issuing a warning to SPL (and Beijing) citing "significant deviations" from good manufacturing processes and recommending disapproval of future applications to manufacture APIs.[33] The FDA released a "warning" letter Monday to a Chinese material supplier, Changzhou SPL, citing "significant deviations" from good manufacturing practices. The Chinese said they wanted to get some samples from the Cherry Hill plant to conduct their own investigation.[42] The FDA has sent a warning letter to Changzhou SPL, the Chinese plant identified as the source of the contamination.[37]
"In addition to addressing the need to increase our inspections, we also need to overhaul the entire system," von Eschenbach said. Republicans on the committee agreed the FDA needed to improve its record of checking overseas plants.[9] More foreign plant inspections than ever were conducted by the FDA in 2007, dedicating about $10 million to the process.[18]
The FDA has proposed spending about $11 million on foreign inspections in fiscal 2008, the GAO said.[9] Rep. John D. Dingell said the initiatives weren't enough. Dingell raised his voice, pounded his desk and pointed at the commissioner to pressure him for an estimate on how much more funding the FDA needed for foreign inspections.[50]
FDA inspections of the Changzou, China facility of Scientific Protein Labora tories (SPL), the company responsible for producing the suspect API, revealed insufficient standard-setting and poor record keeping.[33] Simply increasing inspections would be insufficient, Von Eschenbach said. The FDA is implementing a broad plan that included opening an office in China, upgrading computer systems and working with authorities in other countries, he said.[9]
ESCHENBACH: Well, the FDA is working very directly with our counterparts in China. They are engaged I think in a very conscientious effort to improve their entire system within the country. I have met with their minister of health who believes this is as important to the health and welfare of Chinese people as it is to the rest of the world."[44] Philips recently formed a research alliance with a hospital and university in the western Chinese city of Chengdu and announced the acquisition of a company making patient-monitoring equipment in the southern city of Shenzhen. The industry "will start to see more companies moving their manufacturing to China," predicts David Jin, chief executive for Greater China for Philips Health Care, which also operates a joint venture with a Chinese company in northeastern China, the Neusoft Group, making MRI, CT scan, ultrasound, and X-ray equipment. Other companies are paying attention to China, too. Siemens last September opened a medical research and development, manufacturing, service, sales, and marketing center in Shanghai that the German conglomerate expects to employ 1,000 people this year. It's the largest facility of its kind for Siemens in Asia, the company boasts. General Electric's ( GE ) health-care division last August announced a plan to work with Premier Diagnostic Health Services, a Vancouver company with a Hong Kong subsidiary, to sell and operate positron emission tomography (PET) scans to Chinese health providers such as the People's Liberation Army 101 Hospital in the eastern city of Wuxi.[32]
The pharmaceutical manufacturer's that are buying the raw drugs are the ones who are responsible for making sure the drug they are buying is safe for human use. Pharmaceutical manufacturers are supposed to fully test raw drugs to meet USP standards, but nowadays, a lot of them "qualify" their vendor and then only perform identification tests upon receipt of the drug. The problem is, the way the pharmaceutical manufacturers qualify their vendors. They basically full test the first few lots of drug received and audit the vendor by sending them a survey to fill out, without anyone from the company ever visiting the site of manufacture of the drug so these companies can easily be manufacturing in deplorable conditions, without the company knowing. I think we need to be more like the European model and hold these companies and their executives accountable for cutting corners that endanger human life.[18]
Sasisekharan emphasized the remarkable willingness of dozens of scientists across the globe to work together to rapidly resolve what might otherwise have left people with serious uncertainties about drug safety. "The generosity and willingness of people to do whatever they could to help solve this problem was unlike anything I'd experienced before. It is extremely satisfying to see how teamwork has resulted in the application of rigorous, peer-reviewed science that helps to keep our medicines safe," he said. Sasisekharan expressed his hope that such effective teamwork will extend to other dimensions of public health, in which rigorous team-based science leads not only toward safer drugs, but also toward safer foods and a safer environment.[34] WASHINGTON - Citing contamination of drugs, pet food and toothpaste from China, members of Congress have endorsed funding for more federal safety inspectors and to police overseas suppliers.[50]
Rep. Bart Stupak, chairman of the panel's oversight subcommittee, also pointed out that pet food from China was contaminated last year with the chemical melamine and killed scores of U.S. dogs and cats.[9] The entire U.S. budget for inspecting overseas drugmakers isn't even large enough to check all of the plants in China every two years, according to an analysis released today by the GAO.[30] The GAO finds that China's drug plants are inspected once every 30 to 40 years.[18]
The raw material for all of the contaminated heparin worldwide can be traced to China, Woodcock said. [6] In blinded laboratory tests, the contaminated heparin activated the biological pathways, while normal heparin did not.[48] In vitro tests showed that the contaminated heparin activated kallikrein amidolytic activity in human plasma, while control samples did not.[55]
The scientists also wrote that a test has been developed that can determine if heparin has been contaminated with the chemical causing the side effects.[48]
To understand the biological effects of the contaminant, the researchers studied 29 clinical lots of heparin, including 13 associated with adverse events. In blinded tests, the 13 associated with adverse events were shown to contain the contaminant, compared with none of the control lots, they said in the NEJM.[55] "Our analysis suggests effective screening methods that can be used to determine whether or not heparin lots contain the contaminant reported here."[16] Baxter's heparin was used by millions of people to prevent blood clots during kidney dialysis and other medical procedures.[43] Heparin is commonly used before certain types of surgery to prevent dangerous blood clots.[29]
The agency said that the Changzhou provided no assurance that processing steps used to manufacture heparin ingredients were capable of effectively removing impurities.''[8] The heparin ]] heparin problems have been reported and studied since 2006, and safeguards have been put in place in the meantime, the agency says.[45] Dao Dong Wang, spokesman for the Chinese Embassy, said that Chinese authorities had not excluded "any possibilities as to the cause of the problem related to heparin. It's still an open question."[42] Is there anything you can do? If you're on heparin, you can consult with your doctor. This particular problem has been the focus of attention for quite some time, and there is no red-light panic in the medical community.[45] The heparin recall has made it easier to get our insurance company to agree to pay for the more expensive alternative. They plan to transition her to heparin for the final four weeks of pregnancy (since it metabolises in half the time that enoxaparin does).[18]
A March 10 article in the Wall Street Journal concerned the recall of heparin sold by Baxter Pharmaceuticals because it had been associated in the deaths of several people.[39] Heparin is generic. If Baxter wants to compete with other companies selling it, they have to keep costs as low as they can. That competition does lower costs for consumers. I've seen my cost for a med I take drop by 90 percent as more companies brought out their generic versions.[18] In February, Baxter International stopped manufacturing multiple-dose vials of heparin.[24]
In companion papers published online in Nature Biotechnology and the New England Journal of Medicine, Ram Sasisekharan, Ph.D., of the Massachusetts Institute of Technology, and colleagues in the U.S. and elsewhere also explained why the tainted heparin originally passed muster.[55] The FDA has also been talking to governments in China and India about placing U.S. inspectors there.[50] FDA had traced the source of the active ingredient to be Scientific Protein Laboratories LLC of Waunakee, Wis., which has a facility in China known as Changzhou SPL.[51] One FDA employee will begin a temporary assignment in China next month, according to the agency.[30] In the past 20 years, the FDA has lost more than $300 million in funding to inflation despite the responsibility of putting into effect 123 new laws, the agency's Science Board said.[50] The new protocol for public safety seems pretty obvious: Avoid taking anything approved by the FDA.[49] "Bahrain is in constant contact with the FDA to ensure that it remains unaffected by quality control problems," said Health Ministry chief of food safety Dr Abdulla Hammed.[41]
Currently the FDA can only stop products at the border after a problem has been found.[46] The FDA plans to establish permanent overseas offices in numerous countries, including China, to help address the problem.[18] Von Eschenbach said the FDA is doing what it can to make strategic changes designed to address an increasingly complex workload. "I believe we are making progress, but the problems are substantial, and they require substantial effort," he said.[38] During von Eschenbach's appearance, some Republicans questioned whether the FDA is paying enough attention to possible tampering. "You do have to wonder, is this an unscrupulous merchant with his thumb on the scale? Or is it someone who is intent on doing us harm?" asked Rep. Michael Burgess (R- Texas ). Burgess said companies sometimes hesitate to point out troubles in their supply chain for fear of putting themselves at a competitive disadvantage. "The FDA needs to make a requirement that they be forthcoming, lest we get a bucket of chicken wings with plutonium in them, which no one wants to see," he said.[38]
The FDA says the contaminant in the herparin is a chemical called over-sulphated chondroitin sulphate.[41] The FDA has since asked drugmakers to use a test that can pick up the contaminant.[30]
Providing details of the episode that were previously disclosed by the FDA only in sweeping statements, the researchers confirmed that oversulfated chondroitin sulfate was the deadly culprit.[55] The researchers found that the chondroitin sulfate activates two inflammatory pathways: one that initiates blood clotting and dilation of the blood vessels, and one that produces anaphylactic toxins.[48]
Dr. Sasisekharan and colleagues said, none of the pigs given control heparin had any substantive changes in blood pressure. The physiological changes were mirrored by rapid induction of the amidolytic activity of kallikrein, they said. [55] The study "provides the scientific groundwork for critical improvements in screening practices that can now be applied to monitor heparin, thus ensuring patient safety," Dr. Sasisekharan said in a statement.[55] T ainted heparin in 11 countries has caused the deaths of 81 patients, highlighting the potential danger of cheaply produced ' sometimes counterfeit ' imported medicines. Congress is holding multiple hearings on the tragedy, but it's unlikely that they'll draw the appropriate conclusion.[33] German regulators have also reported a rash of illnesses in patients using heparin.[19]
About 350 adverse events associated with Baxter products have been reported since the beginning of the year, compared to less than 100 for all of 2007.[23] The agency said it confused records on that facility and another with a similar name. Baxter and its supplier say the contaminant must have been added earlier in the supply chain, before the products reached their factories.[30]
The chief suspect is a contaminant that the agency found in supplies coming from China.[31] Von Eschenbach told lawmakers that even if an inspection had taken place, the contaminant wouldn't have been found because conventional tests couldn't have detected it.[30]
Von Eschenbach acknowledged that the agency has not kept up with the rapid increase in drug imports.[50]
The drug is used in kidney dialysis and during some types of surgery to prevent blood clots.[25] "In addition to being vital for public health, identifying the recent impurity in heparin was a chemical triumph," said Dr. Jeremy Berg, director of the National Institute of General Medical Science, which helped pay for the study. "The research team accomplished this difficult task by using a unique combination of scientific techniques that might in the future be used to detect other impurities in pharmaceutical materials."[3] Kishimoto TK, et al "Contaminated heparin associated with adverse clinical events and activation of the contact system" N Engl J Med 2008; 358: DOI: 10.1056/NEJMoa0803200.[55] Contaminated heparin became the latest flash point after recalls began in February.[50]
The FDA has given Changzhou SPL 30 days to respond to the charges in the letter.'' This entry was posted on Thursday, April 24th, 2008 at 7:06 am and is filed under Legal News, Pharmaceuticals. [8] The company said it regretted FDA's decision and that it did not believe the warning letter reflected Changzhou SPL's actual state of compliance with good manufacturing practices.[29] Until it complies, the FDA will recommend denial of any applications listing the company as the manufacturer of any pharmaceutical ingredient.[31]
Woodcock added, "it is very important that we all be confident that we understand the link, to ensure that the testing that FDA and others have put in place will prevent further adverse events."[2]
U.S. companies already import 40 percent of API from India and China, a number that is expected to double within a decade. While a few companies in both countries have the technical capacity to make good products, regulatory structures are weak there, and their markets are plagued by counterfeit and substandard medicines which annually kill tens of thousands ' maybe hundreds of thousands ' of their citizens. [33] Both Republicans and Democrats expressed their concern that U.S. plants are inspected every two years, while some foreign manufacturers haven't seen a U.S. inspector for up to 10 years, and some maybe never.[13]
If adopted by Congress, the Animal Drug User Fee Act (ADUFA) reauthorization would provide funding for the review of new animal drug applications for the next five years.[52] A few years ago Dr. Allen Roses, an executive vice president with drug maker GlaxoSmithKline admitted in an interview that prescription drugs are irrelevant to the health of most people, most of the time. "The vast majority of drugs - more than 90 per cent - only work in 30 or 50 percent of the people," he said.[49] Johnson and Johnson is only one of the drug giants salivating at the enormous windfall in store once the courtroom doors are locked to drug-injured parties. J&J; lawyers are already using the preemption argument to defend the company from 3,000 women suing for serious health problems caused by its birth control patch.[49]
We have seen time and time again that unscrupulous suppliers will not hesitate to use foreign, even toxic, materials in a drug's raw materials if it means more money.[53] Randomization of patient selection has been replaced with "run-up" and "pre-trial adjustment" periods, in which test subjects are removed from the study whose responses make placebos look too good or the drug too toxic. This prevents the data from being "skewed" by real-world responses.[49]
Neither the Chinese nor Baxter will comment on the inspection. This entry was posted on Wednesday, April 23rd, 2008 at 5:55 am and is filed under Legal News, Pharmaceuticals. [17] The New England Journal of Medicine study offers the first potential link between the contaminant and the reported deaths.[34]
SOURCES
1. FDA Says Heparin Contamination Is A Worldwide Problem
2. Researchers Identify Contaminant in Tainted Heparin - washingtonpost.com
3. US researchers confirm heparin contaminant | Reuters
4. Health | FDA says new evidence links heparin problems to China | Seattle Times Newspaper
5. The FDA says tainted heparin has been found in 11 countries. - By Daniel Politi - Slate Magazine
6. Chemical & Engineering News: Latest News - Impurity Linked To Adverse Events
7. FDA links contaminant to adverse events: issues warning to China facility
8. FDA Issues Chinese Heparin Supplier Warning Letter After Finding Conditions Unsuitable
9. US Lawmakers: FDA fails on foreign drug oversight | Reuters
10. AFP: Contaminated blood thinner from China is in 11 countries: report
11. ABC News: FDA Chief Faces Wrath of Congress
12. Lawmaker Chides FDA Head on Drug Oversight
13. FDA Condemned for Lack of Inspections
14. Tainted Chinese imports spur calls to protect consumer | csmonitor.com
15. Ahead of the Bell: FDA drug inspections under review
16. US researchers confirm heparin contaminant | Reuters
17. Chinese Complete Inspection of Baxter Heparin Plant
18. Health: Recalled Heparin Contaminant Confirmed, And Congress Grills FDA On Inspections
19. Medsafe's confident that blood thinner is safe | HEALTH | NEWS | tvnz.co.nz
20. FDA Criticized for Foreign Inspection Problems
21. FDA China presence imminent; DIA sets up in India
22. US safety inspector to start role in China | WORLD | NEWS | tvnz.co.nz
23. AFP: Scientists show how tainted blood thinner turned deadly
24. MIT Researchers Confirm Contamination in Heparin
25. BBC NEWS | Asia-Pacific | US row over China-made blood drug
26. 'Unnatural' contaminant to blame for heparin deaths - health - 24 April 2008 - New Scientist
27. Tainted heparin found overseas - UPI.com
28. Contaminant in heparin identified scientifically
29. FOXNews.com - FDA Says Heparin Manufacturer Does Not Have Adequate Safety Measures - Health News | Current Health News | Medical News
30. Bloomberg.com: Science
31. Across the nation | Freep.com | Detroit Free Press
32. Chinese MRIs, Coming to Your Hospital
33. Roger Bate on Cheaper Drugs? on National Review Online
34. Scientists Unravel Heparin Death Mystery
35. ABC News: Who's Safeguarding the Drug Supply?
36. MPR: Heparin contamination and the FDA
37. Blood thinner not contaminated - Medsafe - New Zealand news on Stuff.co.nz
38. FDA commissioner grilled on drug oversight lapses -- chicagotribune.com
39. Chinese products -- dailypress.com
40. The Associated Press: Auditors: FDA has long way to go on foreign inspections
41. Untitled
42. Cherry Hill manufacturer caught in drug flap | Philadelphia Inquirer | 04/23/2008
43. Baxter weighs whether to sell heparin vials again in U.S. market -- chicagotribune.com
44. VOA News - US Congress Rebukes US Agency Over Inspections of Food and Drug Imports
45. Heart Disease - Heparin Contamination: What You Need to Know
46. Lawmakers See Big Gaps In FDAs Foreign-Drug Inspections
47. Chinese officials tour drug plant where heparin is made -- Newsday.com
48. Scientists Show Chemical in Tainted Heparin Caused Illnesses
49. FDA-approved Lawsuit Preemption
50. Better foreign drug oversight is sought -- baltimoresun.com
51. Heparin containment confirmed by U.S. researchers - The Money Times
52. FDA Proposes Recommendations for Two Animal Drug Funding Programs
53. Newswire / Press Release: Consumer Protection Group Issues Statement About FDA's Ability to Enforce Safety Regulations - Pharma/BioTech/Nutrition - Jones Public Affairs, Inc. | NewswireToday
54. Use of Heparin Concerns the Food and Drug Administration
55. Medical News: How Tainted Heparin Slipped Through U.S. Safety Net - in Nephrology, ESRD from MedPage Today
56. Possible mechanism behind heparin adverse events identified
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