THALIDOMIDE GETS STRICT FDA APPROVAL

Risky drug offers promise for variety of ills

WASHINGTON -- Thalidomide, a sedative whose use produced thousands of babies
with flipperlike limbs and other deformities, was approved for use in the
United States for the first time Thursday, nearly four decades after it was
stripped from pharmacy shelves around the globe.

The decision by the Food and Drug Administration marked a major reversal for
the agency, which rejected thalidomide in 1960 as it was being promoted
worldwide as a harmless cure for morning sickness. That initial rejection
spared countless American infants and sealed the FDA's reputation as the
finest consumer-safety authority in the world.

Today, thalidomide is showing promise for treating maladies as diverse as
AIDS, blindness, cancer and autoimmune disease. Technically, the FDA has
approved it to treat a complication of leprosy, but the majority of
prescriptions are expected to be written for ``off-label'' uses,
particularly the severe mouth ulcers and wasting that occur in the late
stages of AIDS.

``This is monumental,'' said Dr. Norman Fost, professor of pediatrics at the
University of Wisconsin who has been a close observer of the thalidomide
controversy. ``It is one of the most interesting and important drugs that
the FDA has ever and will ever be asked to approve.''

The FDA first announced its intention to approve thalidomide in September.
But it took 10 months for the government -- working with drug manufacturer
Celgene Corp. of Warren, N.J. -- to iron out a complex distribution plan
that is intended to prevent birth defects.

The resulting system will make thalidomide the most strictly regulated
medicine in the nation's history. Pharmacists will be required to register
with Celgene to dispense the drug, and doctors must register to prescribe
it. Patients must fill out detailed surveys that will be submitted to a team
of Boston University researchers, who will track the use of thalidomide.

Women of childbearing age who want to take thalidomide will be required to
use two forms of birth control. They will undergo weekly pregnancy tests in
the first month, during which time prescriptions will be filled for seven
days at a time. In subsequent months, pregnancy tests will be conducted and
prescriptions filled every 30 days.

``This is more rigorous than anything I am aware of in the world,'' said Dr.
Allen Mitchell, director of the Slone Epidemiology Unit at the Boston
University School of Public Health, which will run the
thalidomide-monitoring system.

For Celgene, a tiny biotechnology company that has never before brought a
drug to market, the FDA's approval was the culmination of five years of
work. Bruce Williams, the company's director of marketing, said the drug
could reach pharmacy shelves in four to six weeks. The drug will not be
cheap; Williams estimated it would cost patients an average of $12 a day,
but said it would probably be used for only several months at a time.

``We are somewhat sobered by the fact that now, all the responsibility that
we know we are taking on is real,'' Williams said. ``Even with that, this
feels great. It's been a long haul.''

But for the original victims of thalidomide, Thursday's approval was no
cause for celebration. Of the estimated 12,000 thalidomide babies, about
5,000 survive.

``We're somber,'' said Randy Warren, the founder of the Thalidomide Victims
Association of Canada. Warren, 36, was born with deformed hands and stumps
for legs after his mother took just two teaspoons of the drug early in her
pregnancy. ``We remember all the people that were lost.''

Warren's group helped design the safety rules, reasoning that FDA-regulated
thalidomide was preferable to no oversight. ``We hope that history won't
repeat itself, but it will,'' he said with a sigh.

In designing the plan to prevent birth defects, FDA officials had to strike
a delicate balance that would weigh safety against the prospect that severe
restrictions would drive the drug underground. It was the black-market trade
in thalidomide, which was being imported from Brazil and sold over the
Internet several years ago, that prompted the FDA to consider approving the
drug in the first place.

``We need to strike a balance between regulation and overregulation,'' said
Dr. Debra Birnkrant, deputy director of the FDA's Division of Antiviral
Products. ``We do this feeling comfortable that we have a strong
safety-monitoring program and that the data support the safety and efficacy
of this product.''

The issue of whether, or if, more deformed babies will be born has been a
contentious one. While both Celgene and FDA officials say they believe they
can achieve their goal of no new birth defects, others, including Warren and
Fost, are skeptical.

``It is certainly not achievable,'' Fost said. ``There is nothing in the
world that has zero risk. Not water, not air, not cars, not anything. The
question is what are reasonable measures to come as close to that goal as
possible.''

Should birth defects -- the agency calls them ``adverse events'' -- occur,
Birnkrant said, the FDA and Celgene would investigate. If it turns out that
a doctor or pharmacist is refusing to comply with the rules of the
distribution system, privileges to prescribe or dispense the drug might be
revoked.

Most experts expect doctors to react cautiously to the drug's approval, in
part because they fear lawsuits and in part because of the cumbersome
bureaucracy that goes along with prescribing it. Celgene's Williams
predicted that fewer than 10,000 patients would use thalidomide in its first
year on the market.

Originally manufactured by a German company, thalidomide was banned from
drugstores in 1962 but never disappeared from use. In the mid-1960s, an
Israeli doctor gave it to leprosy patients who had trouble sleeping. To his
surprise, their skin lesions cleared up almost overnight.

By 1975, the U.S. Public Health Service had set up a special ``compassionate
use'' program to distribute thalidomide to patients with erythema nodosum
leprosum, or ENL, a complication of leprosy that causes skin lesions, fever
and other symptoms. By the late 1980s, Brazil and Mexico had approved
thalidomide for sale.

Then, in 1991, Gilla Kaplan, a scientist at Rockefeller University,
discovered that thalidomide helps regulate the immune response by
suppressing a crucial protein called tumor necrosis factor alpha. She teamed
up with Celgene, whose scientists began investigating the drug's use for
AIDS. Other companies began investigating thalidomide for other ailments,
including brain cancer and macular degeneration, which causes blindness.

Three years ago, after reports that drug buyers' clubs in New York and San
Francisco had been purchasing thalidomide illegally in Brazil and
distributing it to AIDS patients, the FDA issued invitations to Celgene and
the other companies to submit applications to market thalidomide.

Checked-by: Melodi Cornett