The crux of the argument that FDA approval of a drug should preempt state lawsuits over that drug is that it should be experts at the FDA who decide whether a drug is safe and what warnings that drug’s label should carry. Implicit in this argument are the assumptions that the FDA has access to the information it needs to make expert decisions and that it will make its decisions quickly when lives are at risk. The Trasylol story proves these assumptions to be false.
Aprotinin is a naturally-occurring enzyme produced by cows. It was first discovered in the 1930′s, and brought to market under the name Trasylol by Bayer in 1959. Trasylol increases the rate at which blood clots, and Bayer sought FDA approval to use the drug during Coronary Artery Bypass Graft (CABG, pronounced cabbage) surgery to reduce blood loss and minimize the need for blood transfusion.
The FDA mistakenly approved the usage of Trasylol in 1993, and it rescinded that approval in 2007 after mounting evidence showed the drug was causing patients to suffer from renal failure, have strokes and heart attacks, and even die within thirty days of using the drug. The total number of lives lost to Trasylol will never be known, but at least one researcher has pegged the death toll at 1,000 lives per month during 2006/2007.
Bayer Ignored Evidence That Trasylol Caused Renal Failure
Trasylol had been available in Germany (Bayer is a German company) since 1959, and a number of prominent German researchers began to suspect that Trasylol caused kidney problems as early as the 1970′s. One such researcher was Dr. Juergen Fischer, the Director of the Institute for Experimental Medicine at the University of Cologne. In the early 1980′s, he went to Bayer with evidence of Trasylol’s kidney toxicity. 60 Minutes interviewed him about his experience with Bayer and he stated that “I felt that Bayer wasn’t interested to examine these side effects” of Trasylol. This is actually an understatement.
It appears that Bayer actually tried to hide information about those side effects. In 1984, Bayer held a symposium in Luxembourg entitled “New aspects of the TRASYLOL therapy.” Dr. Fischer attended and presented his findings. Here’s what Dr. Fischer had to say about the symposium:
What were the reactions to your talk?
[Dr. Fischer] It turned out that this would remain the only critical contribution. Within the session attended by all participants great interest was shown in my presentation, so I believed to have given good reasons for clinical studies to be initiated. Later I spoke on different occasions to colleagues working at clinics, but the further development is well known: German clinics predominantly issued publications in favour of TRASYLOL, sometimes with a small remark that nothing significant was found concerning the kidneys. And in the publication of all the lectures of the symposium almost every evaluation and warning of my lecture had been deleted. (Emphasis added.)
In spite of this, the publication includes your conclusion “when using high dosages of Aprotinin with already damaged kidneys and particularly when reducing the temperature, the renal function should be closely supervised”. Hence the dangers of TRASYLOL (active substance: Aprotinin) for the renal function was already known and published for a long time?
Contrary to the allegations of the BAYER company, at least since 1984 many German heart surgeons as well as those responsible for this drug were aware that studies on animals published by various authors from 1970 to 1984 had shown massive side effects of TRASYLOL upon kidneys. What could be a better proof than a conference book published by BAYER itself?
To be fair, just because a drug causes kidney problems in lab rats doesn’t necessarily mean it will do so in humans. But Bayer had every incentive not to study the problem further. Evidence produced during a lawsuit against Bayer over the drug Baycol illustrates Bayer’s apparently longstanding philosophy regarding drug side effects: A note written by a Bayer official read, ”If the F.D.A. asks for bad news, we have to give, but if we don’t have it, then we can’t give it to them.” Remember that it is the pharmaceuticals, and not the FDA that conducts studies to determine whether a drug is safe and effective. How can we count on the FDA to make the right choice if pharmaceuticals can simply bury their heads in the sand to avoid learning about drug side effects?
The FDA Mistakenly Approves Trasylol
In 1993, the FDA clearly made the wrong decision when it approved Trasylol for use on patients undergoing CABG surgeries at “high risk” of blood loss. To their credit, the FDA noted the drug carried a risk of kidney toxicity, but their decision that the benefits of Trasylol outweighed those risks was incorrect because there were already two other drugs on the market that were just as effective as Trasylol and that carried none of the side effects. Perhaps even more importantly, those other drugs cost about 1/10th of what Trasylol cost.
Unfortunately for patients everywhere, Bayer hoped to turn their bovine drug into a cash cow, and pressured the FDA into approving the usage of Trasylol for all patients undergoing CABG surgery. In 1998, the FDA did and Bayer began heavily marketing the expensive drug. By 2005, the drug was used in 1/3rd of all CABG surgeries, and Bayer estimated the drug’s sales would hit $600 million by 2006. 2006 didn’t turn out quite as Bayer planned.
More Evidence of Renal Failure
In January of 2006, the highly-respected Dr. Dennis Mangano (M.D. and Ph.D. in Math/Physics) published the results of a 10-year, $45-million dollar study in the New England Journal of Medicine. Dr. Mangano, like Dr. Fischer, found that Trasylol increased the risk of renal failure:
Given our findings, especially with regard to serious renalevents among patients undergoing either primary or complex surgery,and given the cost of aprotinin therapy, which is at least 10times that of aminocaproic or tranexamic acid, we estimate thatconsiderable global health care savings would accrue if aprotininwere replaced by either aminocaproic acid or tranexamic acid.Specifically, extrapolating international-use patterns, we estimatethat for renal complications alone, the replacement of aprotininwith aminocaproic acid would prevent renal failure requiringdialysis in 11,050 patients per year, yielding an indirect savings(from the saved cost of dialysis) of more than $1 billion peryear, in addition to direct savings (from reduced drug costs)of nearly $250 million per year. Replacement of aprotinin withtranexamic acid would prevent 9790 complications necessitatingdialysis each year, yielding similar direct and indirect savings. [Considering that the majority of patients who undergo CABG surgery are eligible for Medicare or Medicaid, that means the taxpayers paid the majority of this $1.25 billion dollar expense. - JCL]
In conclusion, the observed association between aprotinin andserious end-organ damage indicates that continued use is notprudent, whereas the less expensive generic medications aminocaproicacid and tranexamic acid are safe alternatives.
What did the FDA do when confronted with this data? It moved at its typical glacial pace. Eight months after receiving it, the FDA convened a meeting to discuss Dr. Mangano’s study and to allow Bayer to respond. Here’s what Dr. Mangano had to say about the meeting:
“The whole thing was a set-up,” he said. “We did not have anything to gain financially by this. We were making an observation about safety.”
Mangano noted that the chairman of the panel, Dr. William R. Hiatt, has written papers underwritten by Bayer, and that three committee members received waivers to vote because of financial interests in drug companies.
“The system is ridiculous,” he said. “It’s all pro-industry. Who’s protecting the patient?” [The court system... until preemption eliminates an injured patient's right to sue. - JCL]
Predictably, the FDA caved into Bayer once again, and the committee voted 18-0 to approve the continued use of Trasylol, but only for “high risk” patients. In other words, the FDA admitted its 1998 decision to approve the drug Trasylol for all patients was a mistake. And who paid for that mistake? The thousands of people who died or suffered health problems because of Trasylol, and the taxpayers whose tax dollars paid for Trasylol and Trasylol-related medical expenses.
While the FDA panel voted to restrict the usage of Trasylol to “high risk” patients, it might have voted to withdraw the drug entirely if Bayer hadn’t suppressed important information from the panel. Bayer had commissioned its own study of the effects of Trasylol, and the results of the study it paid for were the same as Dr. Mangano’s: The study found that Trasylol was causing renal failure and killing patients. But rather than disclose the existence of the study to the FDA, all of the Bayer representatives kept quiet. Unfortunately for Bayer, the FDA learned about the study:
Days after the advisory meeting, the FDA was contacted by a researcher who said Bayer had hidden important evidence from regulators.
When contacted by the FDA, Bayer said it had “mistakenly” neglected to mention the giant study. The company said the data was “preliminary in nature and raised significant questions on the study population, outcomes and methodology.”
That response sounds hollow to several advisory committee members still stung by Bayer’s behavior. Dr. Michael Lincoff, vice chairman of cardiovascular research at Cleveland Clinic in Ohio, said that several panelists had commented during the meeting on the need for more data.
“At no point did the Bayer folks say, ‘It’s on its way,’” he said.
Steve Findlay, a panel member and health care analyst with Consumers Union, said Bayer’s actions were “intentional and very disingenuous.”
Committee members were understandably upset at Bayer’s deception, but corporate apologist and preemption-promoter Ted Frank downplayed Bayer’s failure to disclose the existence of the study:
But 60 Minutes reports that Dr. Alexander Walker “bl[e]w the whistle,” when in fact, Bayer self-reported the existence of the i3 study on September 27—only six days late.
Alanis Morissette might compare Bayer’s “six-day-late” disclosure to a “death row pardon, two minutes too late.”
Bayer’s late disclosure was not ironic. It was another instance of a pharmaceutical company withholding data from the FDA in order to keep a profitable drug on the market. If the FDA had the same subpoena power that trial lawyers have (and that preemption will take away from them) the FDA would likely have known about this study in time for the September 2006 meeting. Instead, it would be an entire year before the FDA would meet again to discuss Bayer’s study.
Trasylol is Killing Patients
Just four months after the September 2006 meeting, the Journal of the American Medical Association (JAMA) published another study by Dr. Mangano, this time about the long-term risks of using Trasylol. Analyzing his previous data again, Dr. Mangano now found that Trasylol was literally killing patients:
We estimate that over the past year, aprotinin was prescribedworldwide to at least 200 000 cardiac surgery patientshaving a profile similar to patients in our study. For suchpatients, our study found a 5% absolute increase in 5-year mortality(1% per year for 5 years) associated with aprotinin use, comparedwith either aminocaproic or tranexamic acid use. Thus, in 2006alone, had aprotinin been replaced with either of these genericagents, we estimate that approximately 2000 deaths per yearfor the next 5 years (or 10 000 total deaths) might havebeen avoided.
The association between aprotinin and long-term mortality indicatesthat serious safety concerns extend beyond the perioperativeperiod. Therefore, continued use of aprotinin in this populationdoes not appear prudent, given that safer alternatives—aminocaproicacid and tranexamic acid—are available.
The two alternative drugs mentioned cost about ten times less than Trasylol, by the way; about $150 dollars vs. about $1,500 dollars.
The FDA: Hurry Up and Wait
Let’s put this in perspective. The FDA is tasked with protecting the public from dangerous drugs. A week after reviewing a study from a highly respected researcher that showed Trasylol was causing renal failure, the FDA learned that the drug’s own manufacturer had concealed a study with similar results. Four months later another prestigious medical journal concludes Trasylol is killing patients. Instead of immediately convening an emergency meeting to determine once and for all whether Trasylol should stay on the market, it waited another eight months to meet. When thousands of lives are at stake, it’s simply unacceptable for the FDA to wait eight months before acting. Dr. Mangano would later state that the FDA’s delay in acting was responsible for the deaths of 1,000 patients per month.
By the time the FDA met in September of 2007, there was a mountain of evidence that the risks of Trasylol outweighed the benefits of the drug. There were Dr. Fischer’s studies from the 1980′s, there were of course Dr. Mangano’s two studies, and Bayer’s own study – all of which showed drastic increases in mortality and renal failure associated with the use of Trasylol. Faced with all of this evidence, the FDA nevertheless voted 16-1 to ke
ep Trasylol on the market. How did it justify that decision? By criticizing the methodology of the various studies.
The studies were what is known as observational studies in which researchers examine medical records of thousands of patients and draw conclusions. For example, if one conducted an observational study of victims of people who ingested cyanide, one would likely conclude cyanide to be dangerous. The FDA prefers to make decisions based on clinical studies. To continue the analogy, a similar clinical study would give some patients cyanide and others a placebo. There is no question that clinical studies are less subject to bias, but shouldn’t the FDA err on the side of caution when faced with this type of evidence?
Americans Are Safe Because of Canada
The very next month after the FDA’s decision that Trasylol was safe, a clinical study of Trasylol was halted in Canada because of patient safety. The study was conducted in order to compare the effectiveness of drugs in the same class as Trasylol. The researchers conducting the study were ethically obligated to end the study when they discovered that patients using Trasylol died 50% more often than those on competing drugs. As a result of the Canadian study, the FDA finally – finally - corrected its 1993 error and revoked its approval of Trasylol. Put another way, if it weren’t for the Canadian study, thousands more patients might have died because of an FDA error.
Even when it has all of the necessary information, the FDA may still make an error that results in the loss of lives and taxpayer dollars. When that happens – especially if a pharmaceutical hid or misrepresented data – it’s important for injured patients to be able to seek appropriate compensation from the pharmaceutical that made the drug. Preemption will force innocent patients to bear all the costs – human and financial – of FDA mistakes and pharmaceutical deceit. Unless and until the entire FDA pre and post drug approval process is reformed to put patients first, preemption is bad public policy.