Commentary: Rezulin: The Fda Made The Right Call

When a promising new diabetes drug, troglitazone, was associated with liver injuries in 150 patients and four deaths, many thought the appropriate response was obvious. Sure enough, on Dec. 1, Glaxo Wellcome, distributor of troglitazone under the name Romozin in Great Britain, decided to pull the drug after consultation with British regulators.

Many applaud that decision. "The British authorities determined that the risks outweigh the benefits," explains pharmacist Larry D. Sasich of the Public Citizen Health Research Group. "They made the right decision." London-based Lehman Brothers drug analyst Johanna Walton agrees. "If the U.S. had known what it knows now, it may never have approved the drug," she says.

But the Food & Drug Administration had a different reaction, and so did Warner-Lambert, the maker of the drug, marketed as Rezulin in the U.S. That same day, the FDA reaffirmed Rezulin's worth, while adding new safeguards it believes will prevent further tragedies.

Who was right? There won't be final proof of that until physicians learn whether the new safeguards do the trick. But an analysis of the evidence to date suggests the U.S. made the correct call.

"TOTALLY ILLOGICAL." Prominent diabetes experts in the U.S. side firmly with the FDA. Gerald Bernstein of the Albert Einstein College of Medicine and incoming president of the American Diabetes Assn., for instance, calls the British decision "totally illogical," given the prevalence of the disease and the value of the drug. Some 15 million Americans have Type II diabetes, in which they slowly lose the ability to make insulin, and thus can't regulate their levels of blood sugar. The result may be blindness, kidney failure, and the loss of limbs. The total cost of Type II diabetes in the U.S. alone: $92 billion per year.

Bernstein and others argue that troglitazone offers a promising new approach to controlling the disease. True, in many cases, diabetes can be kept in check by diet and exercise and there are also existing drugs that lower blood sugar. If those fail, patients can inject insulin. Troglitazone, however, offers a new biochemical mechanism. That not only means freedom from the side effects of the existing drugs, but also the possibility of improving quality of life for many diabetes sufferers by eliminating or reducing their need for insulin.

That's why the FDA gave the drug top priority and approved it in only six months, compared with an average of 14 months. Even then, the agency knew that the drug caused some worrisome liver changes in about 2% of patients enrolled in Warner-Lambert's clinical trials. So the agency warned doctors to look out for liver problems. "The reality is that we don't know everything when any drug is approved," says Murray Lumpkin, deputy drug chief at the FDA. "That's why we have a system of post-marketing surveillance."

In retrospect, the agency should have given doctors more specific orders on how to monitor patients. "Their mistake is that they left it up to us to determine what to do," says one physician. In fact, the data suggest that in cases of serious liver injury or death, regular liver monitoring likely would have revealed signs of stress before extensive damage occurred.

The new FDA-mandated label on Rezulin leaves less room for error. It requires doctors to measure liver enzyme levels--a key sign of stress--every month. Both U.S. and British authorities "agree there is a very troublesome liver toxicity," explains FDA's Lumpkin. "But we believe there is a way to manage the risks by informing people and doing very comprehensive monitoring."

The British fret that the risks may be greater than the FDA and Warner-Lambert realize. What's more, some critics question whether the benefits offered by troglitazone are as great as Warner-Lambert claims. Given the existence of alternative proven treatments, there may be little point in adding a potentially dangerous new drug, they say. "That argument has some merit, especially in a public health system with controlled expenditures," says Mayer B. Davidson, current president of the American Diabetes Assn.

But the Americans have the stronger argument. The reality is that all drugs come with risks. It's a testament to our medical system that we usually manage to discover and minimize these risks so patients can realize the benefits many drugs offer.