Listening to Vioxx: FDA Must Focus on Clinical Research, Not Misleading Animal Tests
By John J. Pippin, M.D., F.A.C.C.

To some arthritis sufferers, the yellow pill seemed like a miracle. But then came the alarming truth. On September 30, the pharmaceutical giant Merck announced that long-term use of Vioxx, an anti-inflammatory medication taken by 20 million Americans since 1999, could double the risk of heart attack or stroke.

So Vioxx was yanked off the market, leaving puzzled consumers to wonder how this dangerous drug ever reached the pharmacy. That question also troubles Congress, which recently began investigating how the Food and Drug Administration handles drug safety concerns.

But one key problem may go unrecognized. Unsafe drugs reach the market partly because the FDA focuses more on misleading animal tests than on reliable clinical trials like the one that just unmasked the dangers of Vioxx.

Every drug approved for human use by the FDA was shown to be safe in animal studies. But as a cardiologist, I can tell you that animal testing never revealed the cardiovascular risk posed by Vioxx. Indeed, some animal experiments actually led researchers to believe the drug could protect the cardiovascular system.

For example, a 2002 experiment on mice found that Vioxx and another related drug significantly reduced atherosclerosis in the animals. The researchers, who published their results in Current Opinions in Lipidology, concluded that such drugs could be a potential therapy for the prevention of atherosclerosis.

Meanwhile, clinical research was uncovering the truth. In 2001, Cleveland Clinic researchers found that Vioxx posed a significantly greater heart attack risk than naproxen, an over-the-counter anti-inflammatory.

Unfortunately, the FDA didn’t take such concerns seriously enough. The agency asked Merck to add warning language to the drug’s label, but Vioxx stayed on the market until Merck voluntarily recalled it. As a result, tens of thousands of people may have suffered related heart attacks or strokes.

That’s shocking, but similar episodes abound. In the mid-1990s, doctors began noticing that many people taking the weight-loss drugs fenfluramine and phentermine, used in the fen-phen combination, developed a dangerous thickening of their heart valves. Fenfluramine appeared safe in animal tests but proved dangerous to humans.

Even basic toxicology tests on animals aren’t serving us well. The Multicenter Evaluation of In-Vitro Cytotoxicity program found that rat and mouse tests were only about 65 percent accurate in predicting lethal blood concentrations of chemicals in humans. But a combination of human-cell tests and computer modeling predicted toxicity with 80 percent precision.

Why does animal testing fail? One reason is basic biology. Physiological differences between species can make animals like rats a poor model for how a drug will work in a human.

That’s why, historically, animal tests have been a boon to companies making unsafe products. The classic example is the tobacco industry, which defended the healthfulness of cigarettes for years by pointing to inconclusive animal experiments.

Drug companies shouldn’t be allowed to use the same crutch. As a first step to keeping consumers safe, the FDA must stop pretending that animal tests accurately predict results in humans.

Some superior alternatives already exist, and the development of others must be a priority. The government must also improve its monitoring of drugs that have already been approved. For example, the FDA should require all medical personnel to report potential adverse drug reactions, instead of relying on voluntary reporting by perceptive physicians.

Celebrex and Bextra, two potentially dangerous drugs in the same class as Vioxx that may be chosen as alternatives, deserve particularly close examination.

Good science could save consumers from the next Vioxx--but that won’t happen unless the government stops relying on antiquated animal tests.

Cardiologist John J. Pippin, M.D., F.A.C.C., is a member of the Physicians Committee for Responsible Medicine.

Posted Nov. 1, 2004

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