The New York Times, September 30, 2006
Bayer failed to report risks of drug
By Gardiner Harris
WASHINGTON Bayer, the German pharmaceutical giant, failed to reveal to U.S. regulators the results of a large study suggesting that a widely used heart-surgery medicine might increase the risks of death and stroke, the U.S. Food and Drug Administration has announced.
Bayer scientists even appeared at a public meeting called by the agency on Sept. 21 to discuss the possibility that the drug, Trasylol, might have serious risks. But they did not mention the study or its worrisome results.
In a highly unusual move, the FDA on Friday released a public health advisory saying it had learned of the study's existence only on Wednesday.
Preliminary results of the study demonstrate "that use of Trasylol may increase the chance for death, serious kidney damage, congestive heart failure and strokes," the advisory said.
Nevertheless, the agency did not change its advice about whether patients should be given the drug. Instead, it reiterated previous warnings that Trasylol's use should be limited to patients in whom the risks of blood loss outweigh the drug's risks.
The disclosure comes exactly two years after Merck announced that it was withdrawing its arthritis drug, Vioxx, after a study showed that it doubled the risks of heart attacks. Since then, members of the U.S. Congress and even top scientific advisers have concluded that the food and drug agency lacks the regulatory authority and the money needed to detect and protect against drug dangers.
Drug companies have also been sharply criticized for failing to make public the results of some tests of their drugs on people that suggest that the drugs are either ineffective or dangerous. Some members of Congress have proposed legislation that would require that nearly all human drug trials be announced and their results disclosed publicly.
A top Food and Drug Administration official said the agency learned of the Trasylol study on Wednesday only after receiving a tip from a researcher involved in it. The official insisted on anonymity because of the sensitive nature of the information.
In a written statement, Bayer said "that it mistakenly did not inform" the agency of the study and added, "This data was not shared immediately with the agency because it was preliminary in nature."
Staci Gouveia, a Bayer spokeswoman, said the company nonetheless stood behind the safety of Trasylol, which has become one of Bayer's fastest sellers. Sales last year were $200 million and were expected to nearly triple this year.
Several members of the advisory committee that met last week said they were shocked that Bayer failed to inform them of the study.
"For them not to mention that it was under way, that it was being analyzed or that results were available is appalling and will do significant harm to their reputation for transparency," said Dr. John Teerlink, an associate professor of medicine at the University of California at San Francisco, and a member of the advisory committee.
Steven Findlay, a health care analyst at Consumers Union and another committee member, said the agency needed to investigate whether Bayer knowingly withheld the information from the advisory committee.
"The safety of this drug is called into further question now," Findlay said.
Doctors give Trasylol to patients before surgery to reduce the risks of blood loss, and it is needed for transfusions in patients undergoing heart bypass surgery. Trasylol, also known as aprotinin, has been on the market for 13 years.
But two recent studies suggested that the drug might have serious risks. One of the articles, published in January in The New England Journal of Medicine, found that the drug increases the risks of kidney failure, heart attack and stroke. The study concluded that halting the drug's use would prevent 10,000 to 11,000 cases of kidney failure a year and save more than $1 billion a year in dialysis costs, as well as nearly $250 million spent on the drug itself.
There are other, less-expensive drugs that can be used in Trasylol's place.
Still, the advisory panel concluded that Trasylol's risks are worth taking for some patients. Despite the results of the new study, Teerlink said that might still be true.
October 2, 2006 Sue Hughes (Heart Wire)
Aprotinin safety again in spotlight as new study suggests increased cardiac events
West Haven, CT - Just days after an FDA advisory committee effectively endorsed the safety of aprotinin (Trasylol, Bayer), a new study conducted for Bayer has come to light that suggests that there could be an increased risk of cardiovascular events with the drug after all.
A front-page story in the New York Times, headlined "FDA says Bayer failed to reveal drug risk study," reports that the FDA only learned of the study because of a tip from a researcher involved in it.
That Bayer chose not to reveal these results before or at the advisory-committee meeting has angered some of the panel members. The company has now acknowledged that not sharing the data before the meeting was a "mistake."
The FDA's cardiovascular and renal advisory committee met on September 21 to discuss two observational studies published earlier this year questioning the safety of aprotinin, an antifibrinolytic drug used to reduce bleeding risk in CABG patients. One study, by Mangano et al , suggested an increased risk of cardiovascular events and renal insufficiency with aprotinin; the other study, by Karkouti et al , suggested some renal toxicity but did not show any increased cardiovascular risk.
Because of concerns about methodology in the Mangano study, because Mangano did not allow independent analysis of his data by the FDA, and because this was the only study that suggested an increased cardiovascular risk with the drug, the advisory committee concluded that there was not enough evidence to support changing the cardiovascular-safety labeling of the drug.
But just six days later, Bayer admitted to the FDA that it had commissioned an observational study of its own to investigate the cardiovascular safety of aprotinin and that preliminary results of that study suggested that the use of aprotinin increases the chance of death, serious kidney damage, congestive heart failure, and stroke.
FDA issues new safety warning
On September 29, the FDA issued a statement saying that it was not aware of these new data when the advisory-committee meeting was held and that it is now evaluating the new study and its implications for appropriate use of the drug .
In the meantime, the FDA offers the following advice:
· Physicians who use aprotinin should carefully monitor patients for the occurrence of toxicity, particularly to the kidneys, heart, and brain, and promptly report observed adverse-event information to Bayer or to the FDA MedWatch program.
· Physicians should consider limiting aprotinin use to situations in which the clinical benefit of reduced blood loss is essential to the medical management of the patient and in which its benefits outweigh potential risks.
These recommendations are similar to those provided in a February 8, 2006 FDA Public Health Advisory, which was issued after the publication of the initial studies.
The FDA statement notes that, in the new Bayer study, which was conducted by a contract research organization, hospital data from 67 000 CABG patients were examined. Of these, 30 000 patients were treated with aprotinin and 37 000 were treated with other products. The report, which used complex epidemiological and statistical methods, suggested that patients receiving aprotinin were at increased risk for death, kidney failure, congestive heart failure, and stroke.
Advisory committee angry
Members of the cardiorenal advisory committee were understandably angry that Bayer had not revealed this information before the meeting.
Dr Robert Harrington (Duke University, Durham, NC) commented to heartwire: "Bayer's failure to even disclose that these data were available and under preliminary analysis is very disturbing to me. The process of evaluation, comment, and the provision of advice on important drug efficacy and safety data only works when all of the involved parties are open and honest about their data. It is ironic that we spent part of the panel meeting criticizing Dr Mangano for failing to allow the FDA to perform an independent review of his database, yet Bayer failed to even acknowledge the existence of these data. It is especially troubling when several panel members, including me, commented that more data and more analyses were needed to fully understand the risks and benefits of the drug. I'd like to know if the Bayer team. . . present that day had knowledge of the existence of the data and why they chose not to even mention it."
Dr Michael Lincoff (Cleveland Clinic, OH), also a member of the advisory panel, had similar views. "It was astounding to me that they did not disclose the information that the study had been conducted, even if the findings were considered preliminary. They were in the midst of an entire day's discussions at the FDA on that precise topic, where there was substantial comment regarding the desirability of more contemporary data than their older trials. It is inconceivable that the representatives from Bayer did not know about the existence of the study or its potential relevance to the committee," he told heartwire.
The chair of the committee, Dr William Hiatt (University of Colorado Health Sciences Center, Denver), confirmed that he was unaware of these new data at the September 21 meeting. "While the new study does not change things at the moment, after full review by the FDA, it possibly could change our impression of the safety of aprotinin," he said.
Another advisory-committee member, Dr John Teerlink (University of California, San Francisco), is quoted in the New York Times as saying of Bayer: "For them not to mention that it was under way, that it was being analyzed, or that results were available is appalling and will do significant harm to their reputation for transparency."
Bayer acknowledges "mistake"
Bayer issued a statement saying it was a mistake not to have informed the FDA about the study before the advisory-committee meeting. "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 these 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 statement reads. It adds that the company will work with the investigators and other experts to examine the underlying source data and fully understand the results.
Comment by Vera Hassner Sharav
ALLIANCE FOR HUMAN RESEARCH PROTECTION (AHRP), www.ahrp.org
Failure to disclose study findings to the FDA is a federal crime.
So what is preventing the U.S. Department of Justice from prosecuting Bayer for manslaughter?
Executives of Enron, WorldCom (MCI), Global Crossing, Adelphia, Tyco et al were prosecuted and sentenced to prison.
Why are pharmaceutical giants whose repetitive crimes of concealment have resulted in hundreds of thousands of preventable deaths-allowed to continue to use their government license to engage in business as usual?
One primary reason-as confirmed in the scathing report by the Institute of Medicine-safety is not a priority for the FDA which consistently shields those whom FDA officials perceive as the agency's paying "clients." Whereas taxpayers are treated with lethal drugs bearing FDA's seal of approval, pharmaceutical and biotech companies receive the red carpet treatmenteven when they are caught selling lethal drugs without warning.
The Times reports that despite Bayer's failure to reveal the results: "Nevertheless, the agency did not change its advice about whether patients should be given the drug. Instead, it restated previous warnings that Trasylol's use should be limited to patients in whom the risks of blood loss outweighed the drug's risks."
The Times also reports: "Several members of the advisory committee that met last week said they were shocked that Bayer failed to inform them of the study."
About as "shocked" as Claude Reins was when told there was gambling in Casablanca!