Rezulin Proves the System Works
By Gilbert L. Ross
Copyright 2000 Wall Street Journal
March 29, 2000
Last week's withdrawal of Warner-Lambert's diabetes drug Rezulin has
provoked a predictable outcry from self-styled consumer groups charging
that the Food and Drug Administration's laxity and haste permits unsafe
drugs into the marketplace. Actually, Rezulin's withdrawal shows that the
FDA approval process works exactly as it should. Just because a drug is
withdrawn does not mean it should not have been approved in the first
place.
When it was initially approved in 1997, Rezulin was viewed by regulators
and physicians alike as a blockbuster drug important enough to be
approved under the FDA's newly instituted "fast track" protocol. Some
liver abnormalities were apparently detected during Rezulin's
pre-marketing testing, but not in sufficient frequency to halt its approval
and release.
The disease Rezulin treats, type 2 diabetes (the form most common in
adults), is both dangerous and often refractory to usual remedies. Diabetes
is the most common cause of blindness and kidney failure in adults; it is a
major risk factor for heart disease and stroke; and it is now being
diagnosed more commonly in children as well. It affects 15 million
Americans. It is estimated that in the short time since Rezulin's introduction,
it has been used to treat 1.9 million people. About 750,000 were still on it
-- until last week.
Rezulin was popular because it was the first in a new class of diabetes
treatments known as glitazones, which have a unique mode of action:
enhancing the body's sensitivity to its own insulin and reducing the amount
of sugar produced in the liver. Unlike many other diabetes drugs, Rezulin
doesn't lower blood sugar to dangerously low levels.
Diabetes specialists found Rezulin to be an effective addition to their
treatment regimen for many diabetics. But over the course of the past three
years, more liver abnormalities were noted. Warnings to physicians were
added to the package label at the behest of the FDA on two separate
occasions, first advising physicians to use more frequent blood testing, and
then restricting its use to those who did not benefit from other medications.
Some doctors, however, failed to follow these directions assiduously.
In 1999 two similar agents for diabetes treatment were approved and
marketed: SmithKline Beecham's Avandia and Eli Lilly & Co.'s Actos.
Thus far, the liver toxicity that led to 63 deaths among patients on Rezulin
has not been found with these drugs.
Last week, as a result of standard postmarketing surveillance, the FDA
sensibly asked Warner-Lambert to withdraw Rezulin, given the availability
of the newer, safer agents. But this remedial action came too late to suit
Sidney Wolfe of the Naderite group Public Citizen. He immediately
criticized the FDA for having approved the drug in the first place. He
argued that since FDA's fast-track procedure was initiated, dangerous
drugs have been unleashed on the American public. He went on to note
that if the agency had acted earlier, as had authorities in Britain, some
patients would still be alive.
But many diabetics would be sicker, or dead, without Rezulin, given that its
two alternatives were not available in 1997 and 1998. That's the real
lesson: Rezulin's unique benefits justified its risks. The risk/benefit ratio is as
paramount when the FDA evaluates a medicine as when a physician
prescribes one. The enviable health and longevity of the American people
is in large measure attributable to the professionalism and responsibility of
the FDA in evaluating our pharmaceuticals. Of more than 500 drugs
approved since 1980, only 15 -- slightly more than 2% -- have been
withdrawn.
The FDA rightly stands by its approval process on Rezulin. In its own
defense, the agency makes an obvious but important point: The small-scale
clinical trials that precede mass-marketing of a drug cannot possibly detect
all side effects. Rezulin was tested on 2,500 patients before release, and
none suffered severe liver damage. Officials of the FDA's Clinical Drug
Evaluation Center point out that Rezulin would not have been withdrawn
even now were it not for the availability of newer, safer insulin-sensitizer
drugs. But even the most thorough regulatory process will fail if the
appropriate safeguards are ignored when a drug is mass-marketed. This is
the responsibility of the treating physician.
All drugs have risks, especially new drugs, and we often need the data
from postmarketing surveillance to detect them. To shy away from
releasing breakthrough drugs because of fear of unpredictable side effects
would cripple a system that has saved countless lives.
Gilbert L. Ross is the medical director of the American Council on Science
and Health in New York.
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