Parker Waichman LLP Injury Alerts
AVANDIA: Another Diabetes Drug That May Have Potentially Deadly Side Effects.May 1, 2007
In order to understand how Avandia became the latest “blockbuster” prescription drug to fall from grace and be labled as a potential health risk, you must go back over seven years to March 2000. It was at that time that REZULIN was removed from the market by the FDA as a result of having been linked to a mounting number of cases of serious liver damage and death. The drug had already been removed from the market in England in December of 1997 where officials refused to allow its reintroduction. The Merck Manual recognized troglitazone (in 200-800 mg doses once a day) as capable of causing "serious hepatotoxicity."
REZULIN was approved in 1997 to treat Type 2 diabetes which usually comes on in adulthood and is the most common form of the disease. REZULIN, known generically as TROGLITAZONE, was manufactured and marketed by Parke-Davis.
REZULIN (troglitazone) was one of several anti-hyperglycemic drugs or "glitazones" which are known as thiazolidinediones. These drugs are insulin-sensitizers that improve insulin sensitivity in skeletal muscle and suppress hepatic glucose output. The only thiazolidinedione available in the United States is troglitazone of which REZULIN was one. The medical literature, however, clearly recognized that troglitazone "has potentially idiosyncratic hepatotoxicity." (Merck Manual, 17th Edition p. 176).
Only eight months after REZULIN was marketed in the United States, the Food and Drug Administration (FDA) announced that the drug had been linked to illness and death from liver failure. For this reason, the FDA recommended frequent monitoring of liver function in patients taking REZULIN.
Significantly, these problems had been apparent while the drug was being tested according to Dr. Anne Peters, then an endocrinologist at the University of California at Los Angeles. Dr. Peters noted that the abnormal test results were so extreme they should have been regarded as a "red flag." Dr. Peters, and others, believed that REZULIN should have been marketed from the beginning with strong warnings and the requirement that those taking the drug have frequent tests of liver function. Instead, the drug was marketed without any recommendation for liver monitoring.
As with later drug “disasters,” such as Vioxx, the FDA (for a multitude of reasons ranging from incompetence to undue influence by the pharmaceutical industry) has regularly approved powerful prescription drugs without initial warnings that, in hindsight, were certainly justifiable or, at the very least, would have represented a “better safe than sorry” approach that no one could have criticized later on.
Unfortunately, the injuries and deaths continued. Surveys showed that few patients were being properly monitored. Labeling changes ordered by the FDA did nothing to remedy the situation and soon, serious divisions developed within the agency itself. By the beginning of this year, four senior FDA physicians as well as Dr. Robert I. Mishbin, the FDA Medical Officer most closely involved with the government's approval and continued support of REZULIN, were strongly urging its withdrawal from the market. In fact, in a January 24, 2000 E-Mail to his superiors, Dr Mishbin stated: "I see no reason why any well-informed physician would continue to prescribe [REZULIN]." In warning that "additional cases of preventable liver failure" may occur, Dr. Mishbin also stated that he did not see "any reason why FDA should delay in taking steps to remove [REZULIN] from the market." The FDA's response was to threaten Dr. Mishbin with disciplinary action or dismissal from federal service.
Although the director of the FDA's drug review center, Dr. Janet Woodcock claimed in a March, 2000 prepared statement that the FDA still believed the benefits of REZULIN to outweigh its risks, a member of the FDA Advisory Committee stated that he was "not surprised" to hear of the dramatic increase of reported liver-failure cases associated with the drug. Moreover, even long before Dr. Mishbin's change of position, two other FDA physicians had raised serious questions concerning REZULIN.
In October, 1996, FDA Medical Officer, Dr. John L. Gueriguian recommended REZULIN not be approved because of potential liver and heart toxicity. That same month, Dr. Gueriguian was stripped of further involvement in reviewing REZULIN and his negative review purged from agency files. In 1999, Dr. David J. Graham, a senior FDA epidemiologist, publicly warned the agency's Advisory Committee that every REZULIN user was at risk for sudden liver failure. In fact, Dr. Graham presented data indicating that, even with monthly monitoring, REZULIN patients still ran the risk of spiraling into sudden liver failure.
Interestingly, the withdrawal of REZULIN in Britain in 1997 was set in motion by GlaxoWellcome, the very company with rights to market the drug in Europe. As a result of the deaths and liver injuries in the United States and Japan, Glaxo officials concluded that they no longer believed the benefits of REZULIN outweighed the risks associated with its use. Glaxo took this position because there was no way to predict which REZULIN patients would be harmed and because the incidence of liver injuries and death, by that time, was unacceptably high.
Due to the rapidly increasing evidence that REZULIN posed a very real risk of serious liver injury and death, REZULIN labeling in the United States was changed four times between November, 1997 and June, 1999. Each change called for more frequent liver function testing, yet each change was followed by an increase in the total number of REZULIN patients suffering liver failure and death. Despite its very questionable history, REZULIN generated sales of over $1.8 billion up to January 2000 and, at its peak, was prescribed 488,000 times in January of 1999.
At the time REZULIN was being thoroughly discredited as a safe treatment for diabetes, two relatively new alternatives to REZULIN were being marketed. Avandia, known generically as rosiglitazone, (originally manufactured by SmithKline Beecham PLC, now GlaxoSmithKline “GSK”) was approved in May, 1999 and Actos (Eli Lilly & Co. and Takeda Chemical Industries, now sold by Takeda Phamaceuticals) was approved in July, 1999.
Although both drugs are chemically similar to REZULIN, they were not believed to pose similar risks of liver damage and death. Nonetheless, careful medical monitoring of these new drugs was strongly recommended. Long-term (longitudinal) testing was far from complete.
Whether REZULIN could have been marketed in a way that maximized its benefits while minimizing the risk to those taking the drug will never be known. What we do know is that the poorly monitored and highly suspect way in which REZULIN was rushed to market has left in its wake an unacceptably large number of catastrophically injured and dead people whose only mistake was to believe REZULIN represented a safe and effective way to control their diabetes. Clearly, the "hype" was nothing but that.
It was into the void created by the abrupt withrawal of REZULIN from the market that Avandia was welcomed by the FDA, the medical profession, and diabetics seeking an immediate alternative to REZULINin order to continue their treatment. Of course, this also occurred at a time when the FDA was in the midst of being labeled everything from a “leaderless and rudderless” agency to a “paper tiger” in terms of its ability to safeguard the public.
To be sure, the FDA is still in disarray and remains under fire from public watchdog groups, internal whistleblowers, medical experts, and Congressional critics. In fact, many detractors continue to see the FDA as a mere tool or rubber stamp of the pharmaceutical industry.
Once REZULIN was eliminated as a competitor, Avandia became the biggest-selling diabetes drug in the world. Sales to millions of diabetics (13 million prescriptions annually in the U.S. alone) now bring in some $3 billion in annual sales to GSK. Yet, there has always been a nagging question among experts concerning the drug’s safety profile.
Nine months ago, GSK posted a study on a rather obscure company website. That study indicated Avandia increased patients' heart disease risk by 30%. GSK officials claim they told the FDA about this data at about the same time. The FDA, however, has confirmed that GSK had warned the agency of a potential safety problem some two years ago. Amazingly (or, maybe not so amazingly) neither GSK nor the FDA took any additional steps to warn the public until this month.
What prompted GSK to make this sudden revelation was the release of a fast-tracked study by The New England Journal of Medicine on the Internet. The FDA was also forced to issue a Safety Alert warning of a "potentially significant" excess risk of heart attack and heart-related deaths.
The charmed life that Avandia had led since the catastrophic demise of REZULIN was immediately called into question. Rep. Henry Waxman, D-Calif., promptly called a June 6 hearing of the House Oversight and Government Reform Committee to examine the FDA's supervision of Avandia. The FDA has again had its function as a public watchdog agency thrown into serious question. Sen. Charles Grassley, R-Iowa, an outspoken critic of the FDA asked: "Do we have another Vioxx on our hands?"
The study in question links Avandia to a 43% increase in the risk of heart attack and a 64% increase in the risk of death from all cardiovascular causes. Notably, the bulk of the data were GSK's own, gathered from 42 other studies of all sizes. Several of those studies had even been posted on the GSK website.
What makes this finding so significant is that cardiovascular disease is the leading cause of death in diabetes and is responsible for between 65% and 80% of all deaths in diabetics, according to Dr. Steven Nissen of the Cleveland Clinic, lead author of the study.
"The reasons we give drugs to lower blood sugar is to prevent the complications of diabetes, the most important of which is heart disease. When a drug increases that risk, it can have profound public health consequences," said Dr. Nissen.
When the studies were analyzed together (involving over 27,000 patients), there were 86 heart attacks and 39 deaths from heart disease among Avandia patients; there were 72 heart attacks and 22 deaths among patients not taking the drug.
GSK has challenged the study claiming that there are a number of weaknesses in Nissen’s analysis including the fact that the data from the 42 studies were never designed to be examined together. A spokesperson for the company maintained that previous clinical trials, including data from an ongoing European trial and an analysis of 30,000 patients in a managed-care database presented no indication that Avandia was dangerous.
While Dr. Nissen acknowledged the “weaknesses” in the study, he nevertheless believes “the results will stand up over time."
A real concern among medical experts as well as other critics of FDA oversight is: "What did the FDA know and when?" says Yale cardiologist Dr. Harlan Krumholz. "That's an open question. Here, somebody's gone through data that's existed for some time. What's going on at FDA? What's going on at the company?"
Dr. Stuart Seides of Washington Hospital Center is also alarmed by the fact that: "One has to wonder why the FDA was sitting on this information" that "an excess incidence of cardiac events had been sitting out there for the better part of a year and has not been brought to our attention."
As usual, the FDA has taken anything but an aggressive (pro-public) stand declaring that it has not completed its review of the data posted on the GSK website in August 2006 and that it wants to complete its analysis and then hold “a public discussion at an advisory committee meeting as soon as possible." Unfortunately, the opinions of FDA advisory committees are not binding and it could be months before such a meeting could be held.
The new findings are significant because Avandia and Actos, a similar compound, have become so widely used as a major form of diabetes treatment. The belief has been that cardiovascular events should decrease as insulin sensitivity is increased. Avandia and Actos enable the body to make the most of the insulin it produces.
Avandia and Actos can cause weight gain and swelling because they prompt the kidneys to retain water. For this reason, they are used with caution in patients with congestive heart failure. Moreover, even though Avandia was approved in 1999 and reduces blood sugar by about 60%, there is no clinical evidence to prove that the drug actually prevents heart attacks and strokes.
One study involving Actos (PROactive) appears to indicate the drug may protect the heart and may actually prevent heart attacks. Testing at Yale is being done to see whether Actos can prevent strokes and the Cleveland Clinic is conducting a trial to determine if the drug can reduce artery blockages.
Because of the Avandia revelations, however, the FDA has asked Takeda to conduct its own analysis similar to the one performed by Dr. Nissen and his team.
Patients taking Avandia are being warned not to stop taking the drug without talking to their doctors since the incidence of heart-related problems and deaths is a small one and discontinuing the drug abruptly may be dangerous in that it can cause a sudden increase in blood sugar.
If Avandia is found to present heart-related risks, there may be even greater scrutiny of the FDA. Currently, the House and Senate are considering bills to reform the agency. If not passed by September, the FDA will not be adequately funded. These bills would give the FDA more money to conduct the type of analyses done by Dr. Nissen. The Senate bill would also compel companies to make all study results public thereby making it easier for independent researchers to conduct their own analyses.
Thus, the story of Avandia truly revolves around the rise and fall of REZULIN. Pfizer was able to beat SmithKiline Beecham to market in 1997 with a product from the same class of drugs. By 1999, however, the FDA found itself in a growing controversy involving serious side effects linked to REZULIN. This may very well have pressured the FDA into a premature approval of Avandia followed by less than diligent monitoring of the drug’s post-approval clinical tests, which were always available to the agency had it taken the time to conduct its own analysis of the results.
In any event, what the public now faces is the potential for another Vioxx debacle and one more example of an FDA that is mired in bureaucratic quicksand and undue influence from the pharmaceutical industry.
If you or a loved one has suffered an injury that you suspect is associated with Avandia or any other prescription (or over-the-counter) medication, please contact the attorneys at Parker Waichman LLP at www.yourlawyer.com for a free consultation and analysis of your particular situation.