Rezulin Recall: Fast-Moving FDA Hits a New Speed Bump

From the WebMD Archives

March 22, 2000 (Washington) -- As the dust begins to settle around the latest drug to get withdrawn from the market, experts are raising new questions about the merits of the system that brought the drug to the public in the first place. In the span of just two years, the antihistamine Seldane (terfenadine), the obesity drugs Ponidimin (fenfluramine) and Redux (dexfenfluramine), the prescription painkiller Duract (bromfenac sodium), and now the diabetes drug Rezulin (troglitazone) -- all have been withdrawn from the market. And all were among the several "fast track" drugs approved by the FDA.

It all began when acting FDA Commissioner Michael Friedman, MD, got a letter from Congress reminding him that recent amendments to the FDA's regulations were passed to ease the approval of drugs that "address an unmet medical need." In other words, accelerate the process of drug review by the FDA to bring some new drugs to the market faster. But now, in light of the voluntary withdrawal of Rezulin from shelves on Tuesday, which was linked to about 63 deaths from liver damage, that process, once heralded for modernizing an aging agency, quickly is becoming a major point of contention.

Critics of the accelerated process argue that though "fast track" approvals may serve an important purpose in terms of life-threatening conditions such as HIV, the withdrawal of Rezulin, a diabetes drug, demonstrates that the system is being abused. The fast track process played an instrumental role in getting Rezulin on the market, although, according to Sidney Wolfe, MD, director of the consumer watchdog group Public Citizen, that drug should have never been approved.

"Much of the problem lies with the FDA having lowered its safety standards, but [the] fast track [process] is being abused," Wolfe tells WebMD. His organization played a large role in Rezulin's eventual withdrawal from the market. "This drug wasn't a breakthrough."

Rezulin was approved in 1997 under accelerated review process because health care professionals argued that the drug represented a new treatment option for patients whose diabetes could not be controlled using older medications.

"As a new modality, it really established a new important treatment for controlling blood sugars," Barry Goldstein, MD, PhD, director of endocrinology at Jefferson Medical College in Philadelphia, tells WebMD.

Supporters of the "fast track" process also point out that this recent spate of drug withdrawals are in part due to the misuse of prescription drugs by both doctors and patients. Asked whether Rezulin's liver damage ever concerned him, Goldstein says "No. This came up in the very beginning, and it was predictable."

In 1999, Goldstein switched the majority of his patients to Avandia (rosiglitazone) which, along with Actos (pioglitazone), is in the same class as Rezulin but believed to be safer. But he still believes that Rezulin's withdrawal was "unwarranted." His present concern is that pressure may now be put on the FDA to relabel or withdraw other drugs in this class, although bowing to this outside pressure "would not in the best interests of patients."

"I think many people are now confused by the way the FDA makes decisions," he tells WebMD.

In an earlier interview with WebMD, the FDA's chief reviewer for this class of drugs, David Orloff, MD, said the agency's preference is to change a drug's label rather than withdraw it. Side effects can be limited if the doctor knows what to expect, he told WebMD.

John Jenkins, MD, a deputy director at the FDA's Center for Drug Evaluation, tells WebMD, "We don't know everything about a drug when it is approved. These rare Rezulin-related liver failures are a demonstration that no drug is without risk, and that those risks constantly must be re-evaluated."

Jenkins also argues that Rezulin was not approved under the "fast track" process. That process, he tells WebMD, did not even exist when the agency received the approval application for Rezulin. However, he says, the agency did give the drug a priority review because it believed at that time that this drug represented an important advance.

The agency has made significant strides in cutting down its overall approval times for all drugs. The average approval time in 1988 was almost 30 months for the approval of 68 new products. In 1999, the agency approved 77 products in an average of about 13 months.

That acceleration has a number of people worried. There are other questionable drugs besides Rezulin that also benefited from this rapid approval process, Wolfe tells WebMD. He would not elaborate because Public Citizen is still "looking into these issues." But future petitions could be filed, he says.

So, the question remains, do these faster approval times represent a lowering of the agency's safety standards? No, says Jenkins. A review of the FDA's overall performance would show that there actually are fewer product withdrawals today than in the past, when the agency was taking a longer time to review drug applications, he tells WebMD.

But the agency might still have a hard time convincing people that it does have their best interests in mind. On one hand, supporters of Rezulin say the withdrawal clearly reflects that the agency is open to outside pressures, meaning that any drug could become a target. And on the other hand, critics of Rezulin say that the agency's approval of that drug and its subsequent withdrawal proves that the FDA failed to do its job because signals for liver damage existed in the early human studies.

Ironically, they both have something in common. They are latest generation of the FDA's critics, a group that at one time simply wanted the FDA to speed things along.