Evelyn Pringle November 2006
In October 2006, the German-based drug maker, Bayer AG, said it was a "mistake" to withhold a study from the FDA that showed the drug, Trasylol, can cause lethal side effects and that the company had suspended two employees involved in the fiasco.
Critics say that's not good enough.
An October 4, 2006 editorial, titled, "Bayer’s Duplicity on Drug Safety," in the New York Times said: "Bayer A.G.’s limp excuse for withholding data suggesting that a heart-surgery drug is dangerous won’t wash."
"The failure by the German pharmaceutical giant," it states, "to inform the Food and Drug Administration of the disquieting results of a large observational study cannot be sloughed off as a mere 'mistake on the company’s part.'"
In a paper titled, "Dangerous Deception - Hiding the Evidence of Adverse Drug Effects," in the November 23, 2006, New England Journal of Medicine, Dr Jerry Avorn, a professor of medicine at Harvard Medical School, points out that:
"Many aspects of the aprotinin saga are familiar to observers of the drug-evaluation process: a product is approved because it is more effective than placebo, worries emerge about its safety, few or no adequately powered controlled trials are conducted to address these issues, and payers spend huge sums on the drug, despite the dearth of evidence that it is better than older, cheaper agents."
"The health care system," Dr Avorn says, "has a hard time performing drug-safety analyses, in large part because it relies on the pharmaceutical industry to conduct most research on the risks and benefits of medications."
He says it is naive to think that drug companies will voluntarily fund studies that could sink lucrative products, and that the FDA lacks the regulatory clout to require them.
Aprotinin was approved by the FDA in 1993, for reducing blood loss and the need for blood transfusion in patients undergoing coronary-artery bypass surgery.
By the time the news of the hidden Bayer study was made public in late September 2006, the FDA had been reassessing the safety of Trasylol for 9 months, following the publication of two studies that linked the drug to heart attack, stroke and kidney disease.
The agency began its reassessment of Trasylol after a paper titled, "The Risk Associated with Aprotinin in Cardiac Surgery," by Mangano et al, was published in the New England Journal of Medicine and described a study of 4,374 patients scheduled for coronary artery bypass graft surgery in multiple centers in multiple countries in which patients received either no medication, or one of 3 drugs intended to reduce blood loss, including aprotinin, aminocaproic acid, tranexamic acid.
The study reported an association of Trasylol with an increased risk of cardiovascular events such as myocardial infarction or heart failure, and cerebrovascular events such as stroke, encephalopathy or coma, and renal dysfunction or failure.
The researchers reported that patients taking Trasylol experienced a 2-fold increase in kidney failure, as well a 48% higher chance of heart attack and 181% increase in stroke. They also pointed out that Trasylol is 10 times more expensive than the 2 generic drugs used in the study.
The study was the first comprehensive, non-industry sponsored analysis of Trasylol’s safety, and was based on a systematic sampling scheme at 69 of the world’s leading cardiac centers in North and South America, Europe, the Middle East and Asia.
Dr Dennis Mangano, of the non-profit Ischemia Research and Education Foundation, who led the study, told the Senior Journal on January 26, 2006, "Unfortunately, comprehensive observational studies also are very costly, and given that there truly is no mandate or incentive for the pharmaceutical industry to aggressively find safety problems once a drug is marketed, it is up to society to find creative ways to independently assess safety."
"Otherwise," he stated, "the Vioxx—and now Aprotinin—sagas will only be but the first of a series of public health drug-safety failures.”
The Ischemia Foundation provided all of the funding for the Mangano study, totaling more than $35 million, including site grants, central analysis and data disposition and manuscript grants.
At the very least, doctors should be informing their patients about the risks posed by Trasylol and the fact that safer generic alternatives are available, Dr Mangano told Reuters on January 25, 2006.
Neither aminocaproic or tranexamic acid was found to be associated with an increased risk of renal, cardiac or cerebral events and both are much cheaper, at $11 and $44 per dose respectively, compared to up to $1,400 a dose for Trasylol.
The researchers concluded that stopping the use of Trasylol could prevent more than 11,000 cases of kidney failure annually, and save more than $1 billion in dialysis costs each year, as well as nearly $250 million spent on Trasylol itself.
The second Trasylol study titled, "A propensity score case-control comparison of aprotinin and tranexamic acid in high-transfusion-risk cardiac surgery," by Karkouti et al was published in the journal, Transfusion, in January 2006.
This study used a statistical methodology to compare outcomes from patients undergoing CABG who received either Trasylol or another drug intended to decrease the risk of bleeding and found that Trasylol increased the risk for renal dysfunction or failure.
The study that Bayer withheld also found that Trasylol increased the risk of death, kidney damage, heart failure and stroke, but the results were not disclosed at a September 21, 2006, meeting of an FDA Advisory Committee, held to assess the safety of the drug.
Bayer scientists even appeared at the meeting to discuss the possibility that Trasylol, might have serious risks and never mentioned a word about their newest study. Bayer was forced to make the results public a week later after Dr Alexander Walker, a professor at Harvard's School of Public Health, who was involved in the study informed the FDA of the study's existence.
In a statement at the time, Bayer claimed that it "mistakenly" did not tell the FDA about a study that included the evaluation of roughly 67,000 hospital records saying:
“This. . . was not shared immediately with the agency because it was preliminary in nature and raised significant questions on the study population, outcomes, and methodology. Bayer believes that despite the highly preliminary nature of data, the information should have been shared with the FDA prior to the September 21 advisory-committee meeting held to assess the safety and efficacy of Trasylol. This was a mistake on the company’s part.”
The study withheld, was a review of a large database of patients, comparing the side effects of several drugs including Trasylol, used to control excess bleeding, Bayer told Bloomberg News on October 6, 2006.
A company spokeswoman said that Bayer contracted Ingenix, a company that specializes in data-mining hospital databases, to conduct the analysis in the first half of 2006, according to Forbes.com on September 29, 2006.
In a Public Health Advisory issued when the research became known, the FDA said that the study linked Trasylol to increased risk of death, serious kidney damage, congestive heart failure and strokes.
Without seeing the results of the study commissioned by Bayer, a week earlier, the FDA advisory panel voted against strengthening the warning label on Trasylol.
A statement in an email from Bayer quoted by Bloomberg News on November 22, 2006, now claims: "Bayer is committed to sharing all safety information with relevant regulatory agencies."
However, following the publication of the two studies in January 2006, back in February, 2006, Thomas Segerson, MD, Vice President, Medical & Scientific Affairs at Bayer, sent out a "Dear Health Care Professional," letter in Canada saying the same thing and stating in part: "We have been working and will continue to work closely with regulatory authorities in countries where Trasylol is marketed to address questions regarding product safety."
"We share the company's data on Trasylol," Dr Segerson stated, "with regulatory authorities on an ongoing basis and welcome their evaluation of these published reports."
So what is the public to believe since those statements were obviously false when made. The truth is that Bayer tried to hide the results of the study until it could figure out some way to discount them and only came clean after Dr Walker blew the whistle.
On December 15, 2006, the FDA issued a press release addressing the hidden study that said in part, "The preliminary results from that study suggest that in addition to serous kidney damage, Trasylol may increase the chance for death, congestive heart failure (a weakening of the heart), and strokes."
"The FDA review of this additional Trasylol safety information," the agency said, "is continuing and it may result in other actions, including additional changes to the labeling."
Critics say that's not good enough; that its time for drug makers who conceal studies to be held criminally responsible for the injuries and deaths associated with their products.