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AVANDIA A Testament to Why Rushing Drugs to Market Is A Bonanza for the Pharmaceutical Industry and a Death Sentence for the PublicOct 1, 2008 Introduction
In what many experts and consumer advocates view as a terribly misguided effort to speed new drugs to market, the FDA has employed the “fast track” approval process for several years. For the pharmaceutical industry, the reward has been billions of dollars in profit from a multitude of unsafe, prematurely-approved drugs. The public’s reward has been widespread injury and death from the 24 drugs pulled from the market since 1997.
One in five new drugs has serious side effects that do not show up until well after FDA approval. This often results from two serious flaws in the current “fast track” or “accelerated” approval process, namely, the lack of longitudinal (long-term) testing and the use of test groups which are far too small to represent an accurate sampling of the true range of patients who are likely to take the drugs being tested.
Significantly, in a high percentage of situations, problems develop either; (1) after patients have taken a drug for greater periods of time than the test groups, or (2) in segments of the population which were never included in the test groups at all or, at least not in a sufficient representative sample size.
This is precisely why the consumer watchdog organization, Public Citizen, strongly suggests that consumers follow its “Seven Year Rule” by not taking any potentially dangerous prescription drug until it has been safely marketed for 7 years. Many of the recalled drugs did not survive for 5 years. In fact, 7 of them failed before being on the market 2 years.
An analysis of 548 drugs approved from 1975 through 1999 revealed that 56 (slightly more than 10 percent) were later given a serious side-effect warning or taken off the market entirely. In 2004, Merck’s voluntary withdrawal of Vioxx represented the largest prescription drug recall in history. That recall, however, was, by no means, the whole story with respect to problematic drugs that were either close to approval or already o the market.
While one would hope that manufacturers do not intend for their drugs to create such widespread problems for patients, their rush to gain FDA approval results (time and time again) in insufficient (or non-existent) long-term testing and the use of inadequate test groups, which (by accident or design) exclude patients with many conditions produce thereby producing distorted results and insufficient data to infer what some of the effects of the drug will be when it is prescribed to a large group of people with varying conditions or levels of illness. In addition, companies may fail to conduct adequate longitudinal studies to determine the long-term effects of the drug and it may be years after the drug’s approval before patients start to exhibit serious and potentially fatal reactions.
The removal of a drug from the market is based on the level of risks associated with the drug, the availability of alternative treatments, and the nature of the illness that the drug is intended to treat. Robert Temple, director of the office of medical policy in the FDA’s drug center says the FDA tolerates “gross toxicities for cancer and AIDS drugs that [they] wouldn’t tolerate for an antihistamine.”
Avandia steps into the void left when
Rezulin was pulled from the market
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, is made and marketed by Parke-Davis, a division of Warner-Lambert Company of Morris Plains, New Jersey.
REZULIN was removed from the market by the FDA in March of 2000 as a result of having been linked to a mounting number of cases of serious liver damage and death. At that time two new alternatives to REZULIN were being marketed. AVANDIA, known generically as rosiglitazone, (SmithKline Beecham PLC) was approved in May, 1999 and ACTOS (Eli Lilly & Co. and Takeda Chemical Industries) 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.
Since the goal of every pharmaceutical company is to get their drug to market before the competition is able to market a similar drug, for about two years, REZULIN was extremely successful because it was the newest drug of its particular type on the market. AVANDIA and ACTOS, both marketed in 1999, were well behind REZULIN and hardly household names until REZULIN was withdrawn from the market. Almost overnight, SmithKline Beecham began to flood the airwaves with advertisements for AVANDIA hoping to capture as many REZULIN users as possible before Eli Lilly & Company (makers of ACTOS) also took advantage of the REZULIN debacle.
Once REZULIN was eliminated as a competitor, Avandia became the biggest-selling diabetes drug in the world. In 2006, sales to millions of diabetics (13 million prescriptions annually in the U.S. alone) brought 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.
At one point GSK posted a study on a rather obscure company website. That study indicated Avandia increased patients' heart disease risk by 30%. GSK officials claimed they told the FDA about this data at about the same time. The FDA, however, confirmed that GSK had warned the agency of a potential safety problem some two years before that. Amazingly (or, maybe not so amazingly) neither GSK nor the FDA took any additional steps to warn the public until this years later.
What prompted GSK to make that 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 hearing of the House Oversight and Government Reform Committee to examine the FDA's supervision of Avandia. The FDA 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 linked 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 made that finding so significant was 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 challenged the study claiming that there were 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 believed “the results will stand up over time."
A real concern among medical experts as well as other critics of FDA oversight was: "What did the FDA know and when?" said 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 was 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 took 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 wanted 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 usually takes months before such meetings are held.
Those findings in 2005 and 2006 were significant because Avandia and Actos, a similar compound, had already 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.
Patients taking Avandia are warned not to stop taking the drug without talking to their doctors since discontinuing the drug abruptly may be dangerous in that it can cause a sudden increase in blood sugar.
Thus, the story of Avandia truly revolves around the rise and fall of REZULIN. Pfizer was able to beat SmithKline 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-like debacle and one more example of an FDA that is mired in bureaucratic quicksand and undue influence from the pharmaceutical industry.
The current Avandia controversy
Many experts now believe Avandia should be pulled from the market immediately. Public Citizen, the consumer watchdog organization, has notified its subscribers by email that, “The Food and Drug Administration (FDA) should immediately ban the dangerous diabetes drug Avandia (rosiglitazone) because it can cause death from liver failure and has many other life-threatening risks that far outweigh its benefits, Public Citizen said in a petition filed Oct. 30, 2008, with the agency.”
“New research released by Public Citizen about the drug, used to treat Type 2 diabetes, comes as a working group with representatives from the American Diabetes Association (ADA), together with the European Association for the Study of Diabetes, unanimously advised against using Avandia, whose generic name is rosiglitazone, because of their concerns about the drug's risks. This statement appears in the newly published issue of Diabetes Care, the ADA's peer-reviewed medical journal. Despite a significant decrease in its use since publication of a study linking it to increased risk of heart attacks, approximately 10,000 prescriptions a day are still filled for this unacceptably dangerous drug, which is sold by GlaxoSmithKline.”
“Public Citizen has identified 14 cases of Avandia-induced liver failure, including 12 deaths. These cases were derived from the FDA Adverse Event Reporting System after careful review of the agency's MedWatch forms, which are submitted to the agency when adverse drug reactions are suspected.”
“Liver toxicity is only the most recently noted danger of Avandia; Public Citizen has encouraged diabetes sufferers to avoid taking the drug because it increases the risk of heart attack approximately 40 percent, doubles the risk of heart failure and bone fractures, and increases the risk of anemia and vision loss from macular edema, a swelling of the retina caused by fluids accumulating in the eye. There were 39 times more reports of macular edema per million prescriptions filled for Avandia than for an older diabetes drug, glipizide.”
“Avandia prescriptions fell sharply following a May 2007 study published in The New England Journal of Medicine connecting the drug with increased heart attack risk. In 2006, the number of people taking the drug peaked at 13.2 million. Since then, that number has dropped to 4.6 million. This means that about 10,000 prescriptions a day are filled for this dangerous drug.”
"The scientific consensus against Avandia is overwhelming," said Dr. Sidney Wolfe, director of Public Citizen's Health Research Group. "The timing of these findings should give the FDA the momentum it needs to act swiftly to prevent further needless deaths and health damage by banning this drug."
“Safer, more effective drugs for Type 2 diabetes include metformin (brand name Glucophage) and glipizide (brand name Glucotrol). Pioglitazone (sold as Actos), a drug in the same family as the dangerous Avandia, is not recommended, as it shares most of Avandia's toxicities - except for the risk of heart attack - and the ADA does not number it among the preferred therapies for most diabetics.”
The following are excerpts from Public Citizen’s petition to the FDA to ban Avandia (test data, tables, charts, and graphs have been omitted):
Andrew Von Eschenbach, M.D., Commissioner
U.S. Food and Drug Administration
5600 Fishers Lane
Rockville, MD 20857
Dear Dr. Von Eschenbach:
Public Citizen, representing more than 80,000 consumers nationwide, hereby petitions the Food and Drug Administration (FDA) pursuant to the Federal Food, Drug and Cosmetic Act 21 U.S.C. Section 355(e)(3), and 21 C.F.R. 10.30, to immediately ban the diabetes drug, Avandia (rosiglitazone; GlaxoSmithKline). Our petition is based on rosiglitazone’s multiple, serious risks, including one just documented by our new analysis of 14 cases of liver failure, of which 12 resulted in death. In addition there is clear previous evidence of increased risk of heart attacks, heart failure, bone fractures, anemia and macular (retinal) edema with vision loss. The evidence for this unique combination of toxicities is compounded by the accompanying lack of evidence of any clinical benefit, compared to other approved drugs for diabetes, such as metformin, insulin and sulfonylureas. Because of a lack of evidence that benefits are outweighed by risks, both the American Diabetes Association and the European Association for the Study of Diabetes, in a statement submerged in a pre-publication consensus article on treatment of diabetes released last week, concluded that for the treatment of diabetes, “given that other [treatment] options are now recommended, the consensus group members unanimously advised against using rosiglitazone.”
As evidence of the multiple serious side effects of rosiglitazone has mounted, there has been a sharp decrease in prescriptions for the drug, as shown on page 2 of this document. The peak number of prescriptions was in 2006, with 13.2 million prescriptions filled in the U.S. In the past full year (July 2007-June 2008), there were still 4.6 million prescriptions filled, thus exposing hundreds of thousands of people with diabetes to a drug that is clearly doing more harm than good. This means that each day, approximately 10,000 prescriptions for rosiglitazone are still being filled. Thus, it is urgent for the FDA to immediately ban rosiglitazone.
History of Public Citizen Health Research Group Actions on Avandia
March 2000. Public Citizen petitioned FDA to revise the labeling for rosiglitazone and pioglitazone due to multiple safety issues including cardiac toxicity, liver toxicity, weight gain, edema, anemia, low blood pressure, elevated lipid levels and possible changes in progesterone levels.
January 2005. In the fourth edition of our book, Worst Pills, Best Pills, and on our web site www.worstpills.org we urged readers not to use rosiglitazone.
July 2007. At an FDA hearing on the safety of rosiglitazone, we testified that the risks clearly outweighed the benefits and advocated removing the drug from the market.
Summary of Efficacy and Safety Data (more details and references in the latter part of the petition)
Our review of the published and unpublished (FDA) data revealed the following efficacy concerns:
When studied head-to-head with metformin and glyburide, rosiglitazone is not as effective in reducing blood sugar and hemoglobin A1c.
Both hemoglobin A1c (HbA1c) and blood sugar levels deteriorate when patients on other types of oral anti-diabetic drugs are switched to rosiglitazone.
For metformin, sulfonylureas and insulin, long-term data now show a reduction in myocardial infarction and all-cause mortality. No such data exist for rosiglitazone. Rather, it is likely that rosiglitazone increases the risk of myocardial ischemia.
Our review of the data revealed the following safety concerns:
Liver Failure: Severe hepatotoxicity ultimately led to withdrawal of troglitazone from the market, first in Great Britain, then in the United States. Acute liver failure has also been reported in relation to rosiglitazone use. We have identified 14 cases of rosiglitazone-induced acute liver failure, including 12 deaths, from the FDA Adverse Event Reporting System (AERS) after careful review of MedWatch forms. Most of these cases have not been reported in the literature.
Myocardial Ischemia: Three recent meta-analyses have demonstrated an increased risk of myocardial ischemia or myocardial infarction with rosiglitazone. The approximate increase in the risk of heart attacks is 40%.
Congestive Heart Failure: Rosiglitazone was associated with fluid overload and heart failure in early clinical trials, and several large randomized controlled trials (RCTs) have confirmed this toxicity, which likely occurs through PPAR-mediated sodium retention. Several meta-analyses estimate the increased risk to be approximately two-fold.
Macular Edema: Rosiglitazone causes a generalized edema in many patients as a result of leakage of plasma from blood into tissues. When this leakage occurs in the eye, there is damage to the retina, including the vision-critical macular portion, often causing a decrease in vision. The rate of reports to the FDA of macular edema with rosiglitazone, adjusted for the relative amounts of prescriptions, was 39 times higher than with the older diabetes drug, glipizide.
Anemia: Rosiglitazone has been consistently associated with decreased hematocrit and hemoglobin in a clear, dose-related fashion, as well as with more severe cases of anemia. This is not due simply to increased plasma volume, as was proposed by the manufacturer, but likely reflects direct hematologic toxicity.
Fractures: Peroxisome proliferator-activated receptor (PPAR gamma), the receptor which rosiglitazone acts upon (see below), is also expressed in bone along with many other tissues. Animal studies have shown that rosiglitazone decreases bone formation; human studies have confirmed this finding and also shown that rosiglitazone results in decreased bone mineral density as well as a doubling in the risk of bone fractures.
Description, indications, and mechanism of action
The glitazones are agonists of a member of the peroxisome proliferator-activated receptor (PPAR) family of nuclear transcription factors, particularly the gamma isoform, PPAR gamma. PPAR gamma receptors are expressed in many tissues and thus are responsible for a multitude of responses, the effects varying depending on the target tissue. When rosiglitazone binds to these receptors, they react in turn by binding to DNA, initiating gene expression. The effect exploited for diabetes treatment is to lower plasma glucose which it does, in part, by converting glucose into fat.
I. EFFICACY CONCERNS
IA. ROSIGLITAZONE IS NOT AS EFFECTIVE AS GLYBURIDE OR METFORMIN IN REDUCING HbA1c
IB. UNLIKE OTHER EXISTING ORAL THERAPIES, ROSIGLITAZONE HAS NOT BEEN SHOWN TO REDUCE COMPLICATIONS OR MORTALITY FROM TYPE 2 DIABETES MELLITUS
II. SAFETY CONCERNS
IIA. LIVER TOXICITY (Human Data)
LIVER TOXICITY (Animal Data)
IIB. CARDIAC TOXICITY: MYOCARDIAL INFARCTION (Human Data)
IIC. CARDIAC TOXICITY: HEART FAILURE (Human Data)
IID. MACULAR EDEMA (Human Data)
IIE. ANEMIA (Human Data)
IIF. FRACTURES (Human Data)
The FDA is in possession of clear, unequivocal evidence that rosiglitazone causes a wide variety of toxicities. Many of these are life-threatening, such as heart attacks, heart failure, liver failure and, in addition, there are other toxicities which greatly harm the health of diabetics using this drug. These other toxicities include increased bone fractures, impairment of vision, anemia and edema.
Unlike older treatments for diabetes which actually lessen the risk of heart attacks and all-cause mortality, such as metformin, the sulfonylurea drugs (such as glipizide) and insulin, rosiglitazone increases cardiovascular outcomes such as heart attacks and heart failure.
The recent decrease in prescribing of rosiglitazone still leaves hundreds of thousands of people using this dangerous drug, thereby harming their health and increasing their risk of dying prematurely.
In an unusual move, the American Diabetes Association and the European Association for the Study of Diabetes have concluded that for the treatment of diabetes, “given that other [treatment] options are now recommended, the consensus group members unanimously advised against using rosiglitazone.”
The FDA has more than adequate legal authority to immediately start the process of removing this drug from the market in the U.S. Failure to do so will represent a dangerous dereliction of the agency’s responsibility as part of the Public Health Service.
Elizabeth Barbehenn, Ph.D., Pharmacologist
James Floyd, M.D., Staff Researcher
Sidney Wolfe M.D., Director, Public Citizen’s Health Research Group
It is clear from the above that the ill-advised rush to approve Rezulin, and then unwisely keep it on the market, lead directly to thousands of injuries and many deaths, while making Parke-Davis billions of dollars in profit. When Rezulin suffered its disastrous withdrawal, there was a rush to fill the void with the inadequately tested and highly suspect Avandia. The decision has made GSK billions, while leaving more injury and death in its wake. Public safety simply cannot be continued to be sacrificed in order to line the pockets of the pharmaceutical giants.
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.