By Marc Greilsamer
Suppressed data? Secret informants? Fall guys? Welcome to the pharmaceutical industry, which is filled with enough mystery and intrigue to satisfy even the most demanding crime-drama aficionado. Yet, the issues that come into play in this gigantic, lucrative industry are quite real–and are certainly matters of life or death.
Questions and accusations are swirling around the German drug maker Bayer A.G., their heart-surgery drug, <"http://www.yourlawyer.com/topics/overview/trasylol">Trasylol (aprotinin), and the risk of potentially fatal side effects. But what distinguishes this case from most run-of-the-mill drug-safety controversies is the fact that Bayer may have withheld, either intentionally or errantly, pertinent information about Trasylol from the U.S. Food and Drug Administration.
On September 21, the FDA held a meeting of their Cardiovascular and Renal Drugs Advisory Committee specifically to discuss the safety of aprotinin injection, which is sold by Bayer under the trade name Trasylol. (Trasylol is used to reduce blood loss, prevent low blood pressure, and limit the need for transfusions in patients undergoing major heart surgery.) The main question at hand at the meeting: Is Trasylol usage associated with elevated risk of renal failure, myocardial infarction, heart failure, or stroke?
Present at that meeting were two Bayer executives: Michael Rozycki, Ph.D., director of U.S. regulatory affairs, and Pamela Cyrus, M.D., vice president of U.S. medical affairs. Joined by two outside professors, the Bayer group made a presentation to the committee that included an overview of the subject, a risk-benefit assessment, a review of clinical data, and a discussion of the methodology of two independent studies published in 2006–one in Transfusion and one in the New England Journal of Medicine–that called into question the safety of Trasylol. They were also asked to provide their own “recent safety and efficacy data” to the committee.
According to the FDAÃ¢â‚¬â„¢s official minutes of the meeting, committee members were then asked to vote on the following: “Based upon the presentations today, do you regard the totality of clinical data as supporting acceptable safety and efficacy for Trasylol usage among certain Ã¢â‚¬Â¦ patients?” Eighteen members voted yes, one abstained. There was some talk of changing the label warning language–from “increased risk” to “high risk”–but no changes were approved.
All things considered, there was nothing out of the ordinary to be found here. But on September 29, about a week after that meeting took place, the FDA made a rather unusual statement regarding Trasylol and its safety:
“Since January, 2006, the Food and Drug Administration (FDA) has been conducting a safety review of Trasylol (aprotinin injection). The review was triggered by the results of two published research studies: one that reported an increase in the chance of kidney failure, heart attack, and stroke in patients treated with Trasylol compared to those treated with other similar drugs, and the other that reported an increase in kidney dysfunction compared to another drug. On September 21, 2006, FDA held a public meeting of the Cardiovascular and Renal Drugs Advisory Committee to discuss the safety and overall risk-benefit profile for Trasylol. At that meeting, the committee discussed the findings from the two published observational studies, the Bayer worldwide safety review, and the FDA review of its own post-marketing database.
“On September 27, 2006, Bayer Pharmaceuticals told FDA that it had conducted an additional <"http://www.yourlawyer.com/topics/overview/trasylol">safety study of Trasylol. The preliminary findings from this new observational study of patients from a hospital database reported that use of Trasylol may increase the chance for death, serious kidney damage, congestive heart failure, and strokes. FDA was not aware of these new data when it held the September 21, 2006, Advisory Committee meeting on Trasylol safety. FDA is actively evaluating these new data and their implications for appropriate use of the drug.”
While the FDA was “not aware of these new data” at the time of its meeting, BayerÃ¢â‚¬â„¢s Global Drug Safety Group certainly was–and yet the company failed to share these new findings with committee members at the September 21 meeting. So far, Bayer has not been punished in any way for what they officially called an “error.” Yet, the question remains: Was Bayer engaged in any criminal wrongdoing and should they be subject to criminal charges?
“The FDA ought to be investigating whether there was a willful attempt to withhold relevant information at this hearing,” says Steven Findlay, a health care analyst at Consumers Union and managing editor of Consumer Reports Best Buy Drugs. Findlay is the “consumer representative” of the Cardiovascular and Renal Drugs Advisory Committee and a voting member who was present at the meeting. If Bayer representatives at the meeting “knew of the existence of the study and consciously, with conspiracy, withheld the results,” Findlay says, they may be vulnerable to criminal proceedings by the Justice Department.
Another voting committee member present at the meeting, John R. Teerlink, M.D., associate professor of medicine at the University of California, San Francisco, claims that Bayer did not provide sufficient and accurate data on which to base his decisions. “I believe that there should be consequences for Bayer in withholding this information,” Teerlink says. “If possible, the punishment should be severe enough to provide a deterrent for future such actions.”
It is quite possible that the FDA would not have known of the existence of BayerÃ¢â‚¬â„¢s most recent data had it not been for a whistleblower who forced Bayer to disclose the information following the September 21 meeting. Apparently, that whistleblower was Alexander Walker, a professor at Harvard and a researcher at Ingenix, the research group that was contracted to do the study and analyze the data. Bayer subsequently notified the FDA of its internal study on September 27.
In that internal study, the contractor examined 67,000 hospital patient records and found an elevated risk of death, serious kidney damage, congestive heart failure, and stroke in Trasylol patients. According to the company, the results were originally withheld because they considered the data preliminary and questioned the validity of the methodology. But at the September 21 meeting, they failed to even acknowledge the studyÃ¢â‚¬â„¢s existence.
In a late-September statement, the company acknowledged its failure to provide the results of their study to the FDA advisory committee, saying, “Bayer believes that despite the highly preliminary nature of this data, the information should have been shared with the FDA prior to the September 21st Advisory Committee meeting held to assess the safety and efficacy of Trasylol. This was a mistake on the companyÃ¢â‚¬â„¢s part.”
The consequences of BayerÃ¢â‚¬â„¢s dubious decision to withhold the data remain unclear, but the company will likely face legal and financial ramifications, not to mention a damaging blow to their public image. In an October 4 editorial, the New York Times said, “Bayer A.G.Ã¢â‚¬â„¢s limp excuse for withholding data suggesting that a heart-surgery drug is dangerous won’t wash. The failure by the German pharmaceutical giant to inform the Food and Drug Administration of the disquieting results of a large observational study cannot be sloughed off as a mere Ã¢â‚¬Ëœmistake on the company’s part.Ã¢â‚¬â„¢”
Even before this latest controversy, Trasylol was not having a huge impact on BayerÃ¢â‚¬â„¢s bottom line. It accounted for merely 3 percent of their overall drug sales in the first half of 2006, and sales had decreased more than 25 percent compared to the first half of 2005. ItÃ¢â‚¬â„¢s uncertain why the company would jeopardize its public reputation, its ethical standing, and its stock price–and incur a risk of lawsuits and criminal proceedings–to protect a product that had already faced significant safety challenges. It is believed by many that Bayer had been interested in expanding the FDA-approved usage of the drug to include other types of surgery–a prospect that seems unlikely now.
So what should be the next steps for all parties concerned? For their part, the company announced in October that theyÃ¢â‚¬â„¢d hired an independent counsel, Fred F. Fielding Esq., from Wiley Rein & Fielding LLP, and “charged him with conducting a complete and thorough investigation into the matter.” They also suspended two anonymous senior employees from their Global Drug Safety Group, saying that “based on our investigation so far, we believe this was a serious error in judgment by two individuals.” TheyÃ¢â‚¬â„¢ve also “submitted a copy of the preliminary report to the FDA and notified other regulatory authorities.”
An FDA spokesperson declined to comment for this report, and it is not clear what actions the agency is taking at this point, if any, other than examining the data that Bayer belatedly provided. According to committee member Findlay, “The FDA appears to be very concerned about this sequence of events and is taking an appropriately deliberative look at the facts and the evidence, and who at Bayer knew what and when Ã¢â‚¬Â¦ for the purposes of resolving issues within the scope of their regulatory jurisdiction. We would urge them to do this in timely manner and refer for legal review anything that needs to be.”
“The most important thing that needs to be known,” he adds, “is whether the Bayer representatives at the meeting that day knew of this study and its importance and whether there was an agreement to withhold or hide that information. And if so, why?”
Both Findlay and Teerlink believe that the FDA should have access to and fully analyze all of the data from the Bayer-sponsored study. However, they both stress that the FDA should also review the complete data from the original New England Journal of Medicine study published in January–a study whose methodology has also come into question. “The irony of this process is that it is quite possible that the committee would have had the same criticisms of the large [Bayer-sponsored] administrative registry, which was not presented, as the other observational data which was presented, and arrived at a similar conclusion,” Teerlink says. “Hopefully, the FDA will have a chance to critically review and interpret the data from this survey.”
That January study, spearheaded by Dr. Dennis T. Mangano of the Ischemia Research and Education Foundation (IREF), set the wheels in motion. Titled “The Risk Associated with Aprotinin in Cardiac Surgery,” that study concluded, “The association between aprotinin and serious end-organ damage indicates that continued use is not prudent. In contrast, the less expensive generic medications aminocaproic acid and tranexamic acid are safe alternatives.” In their observational study, IREF looked at 4374 patients undergoing revascularization.
“Among the 3013 patients undergoing primary surgery,” the study found, “aprotinin, but not aminocaproic acid or tranexamic acid, was associated with an increased risk of death (2.8 percent vs. 1.3 percent), cardiovascular events (20.4 percent vs. 13.2 percent), cerebrovascular events (4.5 percent vs. 1.6 percent), and renal events (5.5 percent vs. 1.8 percent). Specifically, with regard to cardiovascular events, aprotinin was associated with a 48 percent increase in the risk of myocardial infarction and a 109 percent increase in the risk of heart failure.”
The whole unseemly episode may send shockwaves throughout the entire pharmaceutical industry. The FDA has already come under considerable fire for what many politicians and medical professionals believe to be an ineffective and lax drug-approval system. A controversy such as this one will only serve to fuel the fire. As usual, the FDA will face mounting pressure on all sides. How they decide to handle this affair may have larger implications for both the drug-approval process itself and the regulatory systems in place to support FDA rules and guidelines.
“Drug companies and the FDA are supposed to share a common objective–patient safety,” says Jason Mark, an attorney at Parker & Waichman, LLP, a victimsÃ¢â‚¬â„¢-rights law firm. “It is all too common in the current race for new drugs and greater profits for drug companies to distort or withhold data–and for the FDA to subsequently turn its cheek. There needs to be greater accountability. If the FDAÃ¢â‚¬â„¢s intention is to accept at face value BayerÃ¢â‚¬â„¢s statement that the failure to disclose relevant safety information was a “mistake,” without any further inquiry or investigation, then why have the agency at all? The involved FDA employees should simply go onto the payroll of Bayer so that their allegiance to the company is open and transparent.”
In 2004, the Justice Department handed down an eight-count indictment against San Diego-based corporation Metabolife International, Inc., and its founder, Michael J. Ellis. The indictment charged both defendants with “six counts of making false, fictitious, and fraudulent representations to the Food and Drug Administration and two counts of corruptly endeavoring to influence, obstruct, and impede proceedings concerning the regulation of dietary supplements containing ephedra being conducted by the FDA.”
In announcing the indictment, U.S. Attorney Carol Lam said, “It is never acceptable for corporations to lie to regulatory agencies, but it is particularly egregious when those lies threaten the public health.” Dr. Lester M. Crawford, acting FDA commissioner at the time, added, “One of FDA’s highest priorities involves our responsibility to ensure that information about products we regulate is truthful and not misleading, because people depend on that information to make informed choices. We will pursue to the full extent of the law those who would seek to mislead consumers by providing false information or impeding investigations of risky products.”
Of course, the particulars of the Bayer case are quite different in many ways. In BayerÃ¢â‚¬â„¢s case, if there were any “lies,” they were most likely “lies of omission,” which, if nothing else, are much more difficult to prove in court. (Neither Findlay or Teerlink recall any false or fraudulent statements being made at the September 21 meeting.) Yet, the legal barometer may be whether or not Bayer intentionally and purposefully misled the FDA in a way that compromised the agencyÃ¢â‚¬â„¢s ability to make accurate judgments.
Certainly, Bayer will be subject to a range of civil lawsuits, and their handling of the situation may very well work against them when they go to trial. Still, it remains to be seen if the federal government will take any punitive action in the way of fines or criminal charges. The answer to that question will be watched closely.