American Journal of Law & Medicine

The Vioxx story: would it have ended differently in the European Union?(Globalization of Pharmaceuticals: International Regulatory Issues)

I. INTRODUCTION

The rise and fall of the pain-killer Vioxx is one of the most remarkable marketing stories in pharmaceutical history. A true riches to rags tale, its events unfolded with lightning speed in an industry defined by lethargy.

On May 20, 1999, the Merck Company secured FDA approval of Vioxx for the management of acute pain in adults and for relief of the signs and symptoms of osteoarthritis. (2) From that date through August 2004, 105 million Vioxx prescriptions were filled in the US (3) and an undetermined number were filled outside the US. (4) In 2003 alone, Merck's worldwide Vioxx sales totaled $2.5 billion. (5)

The fall happened even more quickly than the rise. In March 2000, Merck published a study raising the specter of cardiovascular problems associated with taking Vioxx. (6) In November 2000, The New England Journal of Medicine published a study raising similar concerns. (7) In February 2001, an FDA advisory panel became sufficiently concerned about the association of Vioxx and cardiovascular events that it advised the FDA to require a label warning about the possible link. (8) Merck continued, however, with an aggressive marketing campaign to physicians that minimized any link between Vioxx and cardiovascular events. (9) Then, in September of 2001, the FDA warned Merck to cease misleading physicians and in April 2002 ordered Merck to add label warning about cardiovascular risk. (10) Finally, on September 30, 2004, Merck withdrew Vioxx from the market in the U.S. and over 80 other countries as concerns about the risks of using Vioxx mounted. (11)

Of course, Merck suffered economic fallout over the withdrawal of Vioxx. Merck's stock has plunged by thirty percent since the withdrawal (12) and it recently announced that it was closing five manufacturing plants and laying off approximately seven thousand workers---eleven percent of its workforce. (13) Moreover, in the midst of this woeful news, Merck's CEO announced that he will step down. (14)

There is litigation fallout, too. To date, Vioxx patients and their survivors have filed more than 6,000 lawsuits against Merck. (15) That number is growing exponentially and is expected to swell to more than ten thousand. (16)

So far, the scorecard is inconclusive. Merck and the plaintiffs each have a victory and a third case ended in a mistrial. (17) While estimates on eventual total liability vary wildly from $12 billion to $50 billion, (18) no one doubts that Merck's losses will be substantial. (19)

The mis-tried case may hold the key to the resolution of future litigation. The judge in the case ordered a re-trial. (20) On retrial, a new piece of evidence will likely find its way to the jury. The New England Journal of Medicine recently re-examined a manuscript it published in 2000. (21) The Journal concluded that the Merck-employed authors of the article edited the manuscript to delete data revealing heart attacks in three of the study participants. (22) One of the authors served as Merck's lead scientific witness in the first three trials. (23) On retrial of the third case and in all subsequent cases, analysts expect plaintiffs' lawyers to use the Journal's revelation to cross-examine that witness and to cast doubt on the company's credibility. (24)

This tale certainly has the ingredients to brand it as a distinctly US phenomenon. It features a pharmaceutical industry with extraordinary political influence over a solitary regulatory agency, US-style marketing to physicians and patients, and an unpredictable litigation system. But, could this story have also unfolded in the European Union?

Can the regulated influence the regulators in the EU in the same way that Merck has been able to influence the FDA in the US? Could a once decentralized pharmaceutical regulatory system that is moving toward centralization have spawned a similar outcome? Are EU regulators sufficiently strong enough to resist financial and political influences? Is a regulatory process that is a compromise between multi-national and national power more or less subject to the process corruption that may have occurred in the Vioxx story?

This essay will consider whether the Vioxx story would have ended differently if its central acts had transpired in the European Union. Part II provides a background to the chemical compound that is Vioxx. Part III presents an abridged, annotated timeline of the rise and fall of Vioxx. Part IV outlines the US regulatory process. Part V outlines the EU Regulatory process. Part VI and VII close this essay with commentary on whether the EU regulatory model provides a recipe for a similar disaster or a prescription for Detoxx. They will consider the influence of the regulated on the regulators, structural differences between the U.S. and E.U. regulatory systems, the relative strengths of the regulatory bodies, and the direction (or lack of direction) of the two regulatory systems.

II. VIOXX: OF GAIN WITHOUT PAIN?

Vioxx is one of the pharmaceutical industry's first-generation COX-2 inhibitors. (25) The human body produces two COX enzymes. (26) COX-1 protects the stomach lining. (27) COX-2 is released at the site of an injury. (28) COX-2 releases prostaglandins, which are hormone-like substances that inhibit inflammation. (29) Aspirin and most non-steroidal pain killers inhibit both COX enzymes. (30) Use of those pain killers may relieve pain, but, at the same time, damage the stomach lining, (31) causing stomach pain and/or gastric bleeding. (32)

COX-2 inhibitors inhibit COX-2 enzymes, but do not inhibit COX-1 enzymes. As a result, they reduce the pain at the site of an injury or inflammation, but do not damage the stomach lining. The patient gets the benefit of pain relief without the side effect of an upset stomach or, even, an ulcer.

There is, however, a potential hazard that accompanies the use of COX-2 inhibitors. COX-2 enzymes produce prostacyclin. (33) Prostacyclin, in turn, produces a prostaglandin protein that opens blood vessels and prevents platelets from clumping. (34) COX-2 inhibitors may suppress prostacyclin. (35) The result can lead to the clumping of platelets, which produces a stroke, or the constriction of blood vessels, which leads to a heart attack. (36)

So, the "designer drug" (37) invented to do the work of aspirin without ripping through the stomach lining, may also have a significant downside. While designing away one health issue, researchers may have designed in another. What is striking about the Vioxx story is that Merck's designers may have anticipated the designed-in side effect.

III. TIMELINE: OF FACT OR FICTION?

Several points along the path of Vioxx's meteoric rise and fall indicate the extent of Merck's knowledge regarding the possibility of an inadvertently designed-in defect. The first occurred well before the FDA's 1999 approval of Vioxx. In November 1996, Merck considered the possibility of conducting a clinical trial study to prove that Vioxx is gentler on the stomach than aspirin and other non-steroidal older painkillers. (38) The Vioxx patients were not able to take any aspirin in order to show the difference most clearly. A Merck internal memo warned that in such a clinical trial "there is a substantial chance that significantly higher rates" of cardiovascular problems would be seen in the Vioxx group. (39)

Several months later, in February 1997, another internal memo presented an even more pessimistic view of the consequence of a comparative study: if the study is carried out "you will get more thrombotic events"--more blood clots--"and kill [the] drug." (40) In response, Alise Reicin, Merck's vice president for clinical research (and whom Merck has called as its scientific witness in all three products liability trials to date) proposed in an e-mail message that people with high risk of cardiovascular problems be kept out of the study so that the difference in the rate of cardiovascular problems between the Vioxx patients and the others "would not be evident. …

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