http://www.latimes.com/news/nation/reports/fda/lat_thal001220.htm
Wednesday, December 20, 2000
A Long-Feared Drug Gets the Green Light
Thalidomide: Approved to treat just leprosy, its alleged promotion
as treatment for cancer draws sharp criticism.
By DAVID WILLMAN, Times Staff Writer
WASHINGTON--On Sept. 5, 1997, a Food and Drug Administration
panel met to ponder the once-imponderable: Should thalidomide be
approved in the United States?
Decades earlier, the pill's use abroad as a nighttime sedative
by expectant mothers had resulted in the gruesome disfiguring of
thousands of newborns. The FDA medical officer responsible for
keeping thalidomide off the U.S. market, Dr. Frances O. Kelsey, was
honored as a national hero in 1962 by President Kennedy.
Thirty-five years later, the Celgene Corp. was seeking FDA
approval of thalidomide, ostensibly for an extremely narrow use:
treating the complications of leprosy.
The agency already allowed experimental use of the drug for
leprosy and AIDS, and some of these patients saw improvements in skin
growths or sores. But the drug's effectiveness remained unproven. A
study published by the New England Journal of Medicine in May 1997
found that some AIDS patients' underlying disease worsened on
thalidomide, compared with those who took a placebo.
Unlike at most advisory meetings, the top administrators at the
FDA's drug-review center--Dr. Janet Woodcock and her deputy, Dr.
Murray M. "Mac" Lumpkin, took seats at the U-shaped conference table.
Agency administrators had encouraged Celgene in 1995 to test
thalidomide's potential, following interest and illicit distribution
of the drug among AIDS patients.
None of the three FDA medical officers who reviewed thalidomide
supported approval. Drs. Kathryn O'Connell and Brenda Vaughan and
their boss, Dr. Jonathan Wilkin, found that the studies submitted by
Celgene failed to establish effectiveness or safety.
Wilkin, director of the dermatology drugs division, worried that
Celgene would seek a far broader market for thalidomide. Once a
company wins approval for a new drug, the compound may be prescribed
lawfully for any medical purpose.
"If there are two dozen new patients a year that are going to be
using thalidomide for [leprosy], then that hardly seems to me to be a
profitable market," Wilkin told the FDA's Dermatologic and Ophthalmic
Drugs Advisory Committee. "So, the question is where is this really
leading? I think that off-label use is where the vast majority of the
use would occur. It would dwarf actually the use for" leprosy.
Wilkin decried the absence of any scientifically acceptable
study supporting Celgene's application. He warned of the drug's
capacity to severely damage white blood cells and the central nervous
system, including among AIDS patients. Wilkin flatly told the
advisory committee that thalidomide was "not approvable."
Just as Wilkin finished speaking, Lumpkin raised his left hand
to be recognized.
"I just don't want there to be any misunderstanding within the
public that what you've heard is, quote unquote, the agency's
recommendation," he said, adding: "What the primary reviewer, what
the secondary reviewer, what the division director have done is given
us their opinions and that's part of the equation. . . . They are not
the deciding officials."
The advisory committee voted 8 to 1 that the benefits of
thalidomide outweighed the risks. On July 16, 1998, the agency
approved thalidomide, declaring it "will be among the most tightly
restricted drugs ever marketed."
At Celgene, the top executive credited Woodcock and Lumpkin for
trumping the presentations of division director Wilkin, and medical
officers O'Connell and Vaughan.
"Certainly there was a lot of concern on our part that in the
end the FDA would decide not to approve thalidomide based on some of
those presentations," said John W. Jackson, company chairman and
chief executive officer. "However, we were confident that the senior
people at the FDA had encouraged us. . . . They felt that it should
get approved and be on the market."
Jackson added: "They felt . . . there was a need for this drug
in the AIDS community."
Celgene from the outset promoted thalidomide for purposes having
nothing to do with leprosy, including the treatment of various
cancers, officials later alleged. On July 30, 1998--just two weeks
after thalidomide had been approved--officials working in the FDA's
drug-marketing office contacted Celgene and expressed concern about
the company's promotion of thalidomide for uses "other than" the
narrow, approved treatment of leprosy.
On April 21, 2000, the director of the marketing office, Thomas
W. Abrams, wrote to Celgene's Jackson, alleging that the company "is
demonstrating a continuing pattern and practice of violative
behavior." Abrams added: "Celgene's actions are particularly
troublesome. . . . Perhaps more than for any other available drug,
the need to provide and distribute thalidomide responsibly is
essential to the public health."
Jackson said in an interview that Celgene "has never advocated
any off-label promotion [for thalidomide]. Our objective was and
always has been to comply fully with the rules and regulations of the
FDA."
After the FDA's approval of thalidomide, the drug gained
virtually no popularity in treating AIDS patients. Jackson said that
thalidomide is now being used "almost entirely" for treating various
cancers.
Reports filed with the FDA since the drug's approval cited
thalidomide as a suspect in 16 deaths from the July 1998 approval
through June 2000. Three of those who died, women ages 56, 59 and 63,
had a white blood cell disorder, neutropenia, about which Wilkin had
warned the advisory committee.
Jackson said the deaths were unsurprising because thalidomide is
used to treat extremely sick patients. He said that special controls
for dispensing the drug have proven a success and that no birth
defects have emerged. Doctors and pharmacies must register with
Celgene before dispensing thalidomide, and each new patient is
supposed to view a video showing the flipper-like limbs that can
result from use during pregnancy.
Agency officials declined to allow Wilkin, O'Connell or Vaughan
to grant interviews for this article. The FDA also has declined for
more than a year to provide their medical reviews, requested under
the Freedom of Information Act.
Said a specialist familiar with those documents, who spoke on
condition of anonymity: "The reviewers looked at the data set,
considered the public health and did what they thought best. . . . If
you're looking for differences between upper management and the
reviewers--read the reviews."
An FDA spokeswoman, Rae Jones, said the prospect of off-label
use "had no bearing" on the agency's decision to approve thalidomide.
When thalidomide was approved, securities analysts predicted
that it could generate annual sales of $300 million by 2004.
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