http://www.latimes.com/news/nation/reports/fda/lat_relenza001220.htm
Wednesday, December 20, 2000
RELENZA:
Official Asks If One Day Less of Flu Is Worth It
Still on the market, the drug has been linked to 22 deaths so far.
By DAVID WILLMAN, Times Staff Writer
Glaxo executives were steaming in early 1999 over the work of
biostatistician Michael Elsahoff and other FDA reviewers who had
examined the company's new flu drug, Relenza.
The reviewers found that Relenza was no more effective than a
placebo in treating common flu symptoms among American patients. The
drug showed better results in foreign studies. But the reviewers also
found that Relenza, a powdery inhalant, was potentially unsafe for
flu patients with asthma or other respiratory disease.
Relenza is not a vaccine. It is designed to be taken within two
days of the onset of flu-like symptoms such as fever, cough, sore
throat or headache. Relenza may reduce by about one day a patient's
symptoms.
The drug underwhelmed members of the FDA's Antiviral Drugs
Advisory Committee. It voted, 13 to 4, on Feb. 24, 1999, to reject it.
"There isn't sufficient efficacy to warrant me recommending this
drug for my family or myself," said Dr. John D. Hamilton, a professor
of medicine at Duke University. Said another committee member, Dr.
Sharilyn Stanley of the Texas Health Department: "I have significant
concerns."
Glaxo reacted quickly.
Dr. James Palmer, the company's director of medical, regulatory
and product strategy, told an FDA administrator in a March 2, 1999,
letter that the staff's position on Relenza "is completely at odds
with the will of Congress that drug development and approval proceed
swiftly and surely." The letter was addressed to Dr. Heidi M. Jolson,
director of the FDA's antiviral drugs division.
The Glaxo executive accused the reviewers of "blindsiding" the
company. He said one FDA medical officer "exerted considerable and,
we believe, misguided and inappropriate influence on the review." He
decried the "total silence" at the advisory meeting of another agency
physician. He termed Elashoff's analysis "extreme." He said the
"advisory process was distinctly biased against fair and open
consideration of [Relenza]." A copy of the letter was obtained by The
Times.
Elashoff said his superiors told him he would no longer make
presentations to the advisory committee. He said he was asked at
least five times to delete the anti-Relenza recommendation from his
review. He refused. The FDA declined to comment on these matters.
The agency approved Relenza on July 26, 1999. In a memo dated
that same day, Jolson provided a mixed assessment.
Relenza, she said, had not been shown effective for patients
over 65 or those "with a variety of respiratory, cardiovascular and
other medical conditions." She said "special precautions are
warranted" if Relenza is used by patients with respiratory disease.
These groups would encompass patients most vulnerable to death from
the flu. On the other hand, Jolson said, "the totality of the data"
suggested that some Relenza patients could expect modest benefit and
that their influenza A or B symptoms might improve an average of one
day sooner by taking the drug.
The FDA medical officer first assigned to review Relenza, Dr.
Barbara Styrt, wrote that "a rationale can be constructed either for
non-approval or for approval." She ultimately backed approval, saying
that concerns could be addressed through "label language" and later
studies. Analysts at Merrill Lynch & Co. predicted the drug would
generate sales topping $400 million within four years.
Glaxo, aiming for customers as widespread as the flu itself,
last fall placed ads for Relenza on network television. The
lighthearted spots featured an actor from the "Seinfeld" sitcom.
Problems emerged quickly.
Following the voluntarily reported deaths of seven Relenza
patients, the FDA issued an unusual "public health advisory" to
doctors on Jan. 12, 2000, warning of the limited role of Relenza and
another recently approved flu-symptom drug. Two of the dead had
bacterial infections and should have been treated with antibiotics.
The agency said it had received "several reports of
deterioration of respiratory function following inhalation of Relenza
in patients with underlying asthma" or another breathing problem.
Reports filed through June show that Relenza was cited as a suspect
in 22 deaths.
In July, Glaxo issued a warning letter to health professionals,
noting "reports of serious respiratory adverse events when Relenza
was used in patients with known airways disease." The letter also
said that patients with no history of such disease had suffered
"decline in respiratory function."
The company added: "Some adverse events have required immediate
treatment or hospitalization, and some patients . . . have had fatal
outcomes." The Glaxo letter said it was "difficult to determine"
whether Relenza caused the deaths.
None of which has surprised Elashoff.
"Even if you accept the company line, that it knocks a day off
the flu, a day is not much when you compare it to your life," he
said, adding that the approval "was certainly a top-down decision."
Woodcock said the FDA's actions reflect a balancing of risks and
benefits. She noted that "strengthened" warning language was added to
the product label in April and that a newer study had shown the drug
to be effective and safe for children age 7 and older.
Glaxo spokeswoman Ramona DuBose said Relenza "is an important
tool for physicians to have to reduce the risk of the disease."
She said the drug can reduce symptoms from both A and B flu
strains "by at least a day."
The Glaxo executive wrote the letter in March 1999, DuBose said,
to "vehemently protest" the FDA staff's performance at the advisory
committee meeting. "We weren't given the opportunity to fully prepare
our responses to the FDA's questions."
DuBose said Glaxo would not comment on the volume of reported
deaths, adding: "No causal relationship has ever been established
between Relenza and any death, anywhere in the world."
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