Pfizer Legal Win Might BlockSome Lawsuits Over Celebrex
By NATHAN KOPPEL and HEATHER WON TESORIERONovember 20, 2007; Page A13
Pfizer Inc. scored a victory yesterday through a federal ruling that might wipe out some lawsuits alleging that the drug maker's painkiller Celebrex caused heart attacks and strokes.
U.S. District Judge Charles R. Breyer of San Francisco ruled that plaintiffs in the litigation haven't presented scientifically reliable evidence that Celebrex caused heart attacks or strokes when taken at a daily dosage of 200 milligrams. That is the most common dosage, according to Pfizer.
Celebrex is the last drug in the COX-2 inhibitor class that is sold in the U.S. Merck & Co.'s Vioxx and Pfizer's other COX-2 painkiller, Bextra, were withdrawn from the market amid safety concerns.
There are more than 3,000 Celebrex plaintiffs, according to the ruling, but it isn't clear how many the ruling will affect. Paul Sizemore, a plaintiffs' attorney with Girardi & Keese in Los Angeles, estimates that about 900 Celebrex cases involve plaintiffs who were prescribed the 200-milligram dose. However, he says, many of the plaintiffs took the drug twice a day.
"When does a 200-milligram case become a 400-milligram case?" he says. "We are going to have to review medical records and contact the clients to see what the actual usage was."
New York plaintiffs' lawyer Paul Pennock of Weitz & Luxenberg, which also handles Celebrex cases, estimates about two-thirds of the Celebrex cases will be unaffected by the ruling. But those involving 200-milligram dosages will be eliminated, he says.
"We are pleased with the decision of the federal court, which recognizes the lack of any credible evidence linking Celebrex, at its most common dosage form, with heart attacks or strokes," Pfizer General Counsel Allen Waxman said.
Write to Nathan Koppel at nathan.koppel@wsj.com and Heather Won Tesoriero at heather.tesoriero@wsj.com
1 comentario:
The scientific and legal approach to evaluating a COX-2 inhibitor is flawed or misleading. They key is understanding fatty acid metabolism, clinical trials, and body’s regulatory goals. The body is constantly seeking to achieve optimal balance among conflicting goals (bleed vs coagulate, inflammation to contain undesirable infections, cancer, etc. vs. no inflammation to reduce pain, etc.). Although ideally the body makes the best decision most of the time, we have managed to change that. Because of highly inappropriate eating (being overweight, drastic changes in fatty acid metabolism), environmental factors (zillions of pollutants, toxic chemicals, etc.), the body faces extreme needs and cannot make optimal decisions. It can overshoot, becoming too coagulable (making unnecessary clots) or causing too much pain, or be unable to fight infections or cancer or bleeding. We seek to help the body with drugs. As a side effect, we can make matters worse. A powerful drug such as a COX-2 inhibitor can, even in small doses, trigger severe cardiovascular disease within a very short time period. As a general rule, a dose effective enough to reduce pain or cause other desirable effects is large enough to cause undesirable effects.
Fatty acid biochemistry is extremely complex. Due to similarities in their biochemical structure, I predicted that numerous fatty acids can produce eicosanoid-like substances such as prostaglandins and leukotrienes. Eicosanoids (see wikipedia, but beware I do not consider it accurate, for example the 20 carbon fatty acids are not essential fatty acids) are primarily made from 20 carbon fatty acids of the omega-3 and omega-6 family (what I named essential fats). Key enzymes in this process are COX-1 and COX-2. Different body cells have different quantities or variations of COX-1 and COX-2. They also have different quantities and types of the precursors 20 carbon fatty acids. Depending on a variety of stimuli and substances present (vitamins, pH, proteins, etc.), the body “decides” what is considers the optimal mixture to make of fatty acids and fatty acid derivatives for each cell. It decides on this optimal mixture so that platelets (and the blood) neither coagulate too easily (leading to clots) or too poorly (leading to bleeding). But Americans now have managed to shift the balance of fatty acids far out from the reasonable ranges expected by evolution. Americans have huge ranges of blood levels of critical precursors for COX enzymes/inhibitors, far outside reasonable limits (a consequence of diets low in fat, high in calories, etc.). The results can be short term adverse effects such as heart attacks, or undesirable very long term effects such as kidney disease or decreased brain function. Drugs can accelerate these undesirable effects by making the body’s regulatory (healing) process more difficult. But drugs may be needed when people are unwilling to change lifestyles.
Until I implemented methods to accurately measure over 50 fatty acids in blood (about 1980s), researchers inaccurately measured key fatty acids (such as EPA, 20:3w9) and others. The result was a belief that Americans ate plenty of fat and essential fats. I proved that Americans had substantial deficiencies and imbalances of the w3 and w6 families, particularly of the 20 carbon precursors to eicosanoids. The key words are deficiencies and imbalances, concepts frequently overlooked. Based on my analysis of blood samples from the Framingham Heart Study, other studies and patient samples, I projected that more than 30% of adult Americans have deficiencies of w6, more than 50% have deficiencies of w3s, and probably more than 70% have undesirable imbalances (where the mixtures of w3s and w6s are far outside desirable ranges). These imbalances alter production of eicosanoids. Humans were also producing large quantities of unusual fatty acids such as 20:3w9. Based on biochemical principles, I predicted that many unusual fatty acids now produced by humans in substantial quantities were precursors to a wide range of eicosanoid-like substances that had pathological (undesirable consequences). See www.essentialfats.com.
An enzyme inhibitor usually causes the body to change production of many other substances. If we inhibit some substances formed from a specific 20 carbon fatty acid, the body is likely to make more of that 20 carbon fatty acid and more of its other derivatives. So, if we inhibit the formation of a fatty acid derivative that causes pain, we may increase the formation of a fatty acid derivative that causes platelet aggregation (thrombosis, clots). In general, the greater the inhitition, the greater the body’s response to it. Comparing two drugs or doses, the one with the greatest inhibition of pain-producing eicosanoids would induce more clots. Thus, the more selective the drug in its inhibition, the more complex its side effects. In practice, this is not that simple. There are numerous factors at play and the end result is very difficult to predict, particularly because doctors rarely order the blood tests that will provide the data to make predictions, such as a fatty acid profile, and patients rarely take the steps that would help them with the least risk, such as losing weight, eating healthier, etc.
Putting it all together, a drug that inhibits COX-2, when taken in a dose sufficient to produce desirable effects, is likely to produce undesirable effects. The time it takes to produce undesirable effects should be comparable to the time it takes to produce desirable effects, namely hours. Over a period of days the body begins to adjust to the drug by overproducing other substances. Eventually it reaches a new “equilibrium.” People may feel less pain, but are at much higher risk of adverse cardiovascular effects. Then a minor event that would not have triggered a heart attack before is enough to cause a heart attack now. This is a simple physics-chemistry problem. If we place over a supporting bean enough weight to almost break it, the extra weight of a bird may break it. What causes it to break? The bird or the undesirable load? I submit that taking COX-2 inhibitors shifts the body to a highly unstable state. The time it takes for an undesirable effect (i.e., a heart attack) to occur depends on many individual factors. Patients are unaware of high close they are to the cliff, and what things they do that can move them over the cliff. Almost certainly, the COX-2 inhibitors move patients closer to the cliff of cardiovascular events. Whether they fall or not, and when they fall depends on lifestyle, environmental factors, weather, exercise, other stressors, etc.
In a clinical trial, it could take months or years before the undesirable effects become “statistically significant.” Patients ought to be better informed about the likely side effects, provided with measures of the likelihood of side effects, and informed about other steps to take.
Clinical trials frequently compare Drug ZX vs. placebo, usually lack of treatment. Instead, trials should compare Drug ZX vs. current state of the art treatment (such as weight loss, optimal diet, very low dose drugs such as 30 mg aspirin, etc.). We may find that optimal treatment for most people is quite different from current recommendations.
Society is already penalizing certain drug users that chose to take drugs even if they have adverse consequences (i.e., heroin). Perhaps insurers have a duty not to pay for drugs for patients when the drugs are more likely to hurt than help, although in a free society, under ideal conditions of informed consent, individuals could chose to take drugs anyway. Perhaps drug manufacturers have a duty to provide more information that is relevant to making an informed decision. Perhaps doctors ought to spend more time diagnosing expected problems and explaining them to patients. Perhaps patients should change their lifestyles to prevent disease. Perhaps . . . perhaps.
Edward Siguel, MD, PhD.
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