Vioxx-type danger and legal frivolity

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Last week, a Texas jury found Merck was liable for the death of a man, Robert Ernst, who took Vioxx, the company's painkiller. While the company will appeal an award of over $250 million to the Ernst widow, claiming that the jury did not find that Vioxx caused his death, the jury punished Merck for failing to change its marketing practice after its own study identified a small group of patients that had more heart problems after taking Vioxx. It's message was, in the word of the words of one juror: "Stop doing the minimum to put your drugs on the market."

Vioxx likely did not cause Mr. Ernst's death. But the jury made it clear that causation is not the issue. Rather it believed that Merck was irresponsible for not doing a better job in making people aware of the real risks and benefits of Vioxx. While Merck may ultimately win its appeal on the merits, the fact is, if it has determined who would benefit from Vioxx and who is at risk, Merck could have avoided its current problems.

Ironically, it was Merck's biggest critics in the medical community who wanted to provide the firm with the tools for doing so largely because they believe Vioxx is a good drug for most people. In particular, scientists and physicians pointed to the fact that there is tremendous genetic variability in how people respond or react to Vioxx as well as all other drugs. Merck and other companies must tailor drug development and promote prescribing to smaller groups of patients based on these genetic differences. And specifically it must invest more money in developing diagnostics that tell who will respond to drug and how.

Genetic variations explain up to 90 percent of the difference in response and reaction to drugs. The study of the drug-gene connection, called pharmacogenomics, led first to the discovery of two genes that determine whether we metabolize medicines quickly, slowly or in a timely fashion. They also determine how a drug is absorbed and how fast it leaves our bodies. As a result, these genes can explain why one drug works perfectly for one person and can trigger a fatal event in another. Genetic tests are now available to help doctors screen patients and adjust dosages to improve prescribing for a wide variety of drugs.

Is it or was it possible to tailor pain killers and their uses to avoid triggering heart problems? Merck's studies excluded people prone to heart problems by not studying the effect of Vioxx on people taking medicines to control high blood pressure or prevent heart attacks. In particular, even after excluding these people from a large study, called VIGOR, comparing the impact of Vioxx to an older painkiller on stomach ulcers, Merck's research showed that its drug was causing more high blood pressure and heart attacks. Merck did not research why that might be the case. Rather, it chalked up the difference to a hypothetical assertion that the older painkiller — naproxen — acted more like aspirin to thin blood. Merck did not consider the alternative possibility — also theoretical at the time — that Vioxx promotes the production of prostacyclin, another protein that causes blood to coagulate.

After the VIGOR study, Merck did look at the impact of Vioxx on the heart in a study of patients taking the drug to prevent colon cancer. Patients on Vioxx had twice as many heart problems (1.4 percent to .75 percent of patients on a sugar pill) regardless of whether someone was at risk for heart disease. The company withdrew the drug after that finding since it had not established a link between Vioxx, biology and genetics.

If Merck had pursued the path of personalized medicine, it would not be facing massive lawsuits. In 1998, Garret Fitzgerald, a professor of clinical pharmacology at the University of Pennsylvania, conducted research suggesting that the cardiovascular problems with Vioxx were linked to a genetic variation that increased prostacyclin production significantly than those without the mutation. He asked Merck to conduct small studies with animals and small groups of patients to determine if this were the case and what mutations were involved.

Such research could have been used to develop diagnostics to discover who will benefit most from Vioxx. Ironically, even as Merck is fighting 4,000 wrongful death lawsuits, it wants to bring Vioxx back for a smaller group of patients using such molecular tools.

Better science, not big damage awards, are the way to safer and more effective drugs. Litigation will discourage companies from pursuing research on drugs for incurable illnesses that, even with genetic testing, will have serious side effects. The only way out of this mess is for companies to personalize the development and prescribing of drugs. Merck's learned the lesson of not targeting treatments the hard way. Let's hope other companies are more proactive. Personalized medicine will make Vioxx-type lawsuits a rare effect of our legal system instead of the disease it is today.

Robert Goldberg is director of the Manhattan Institute's Center for Medical Progress.