http://www.latimes.com/news/nation/reports/fda/lat_lotronex001220.htm
Wednesday, December 20, 2000
LOTRONEX:
Officer Foresaw Deadly Effects
"Irritable bowel" remedy pulled after reports of serious injuries.
By DAVID WILLMAN, Times Staff Writer
Agency officials agreed in July 1999 to conduct a fast-track
medical review of Lotronex, a pill from Glaxo Wellcome Inc. intended
to treat irritable bowel syndrome in women. To justify such
accelerated review, the FDA must find that the targeted disease is
"serious."
Irritable bowel syndrome can result in abdominal pain and
frequent trips to the bathroom. But it neither maims nor kills people.
An FDA medical officer, Dr. John R. Senior, discovered during
the review that four Lotronex patients in clinical studies suffered a
potentially life-threatening complication called ischemic colitis,
which results from inadequate blood flow to the colon.
Senior, a former pharmaceutical industry executive and a
gastrointestinal specialist, knew the rarity of ischemic colitis:
Some physicians can practice for decades without treating a single
case.
While some cases would be mild and reversible, Senior wrote,
ischemic colitis "can be catastrophic."
Senior found other troubling results. He warned that 27% of the
patients who took Lotronex in Glaxo's studies experienced
constipation. He noted that not a single patient who took a placebo
pill developed ischemic colitis and that only 5% of the placebo
patients got constipated.
Glaxo representatives denied that Lotronex had caused the cases
of ischemic colitis and said any risks could be adequately managed.
But Senior warned of the potential for Lotronex patients to suffer
debilitating bowel injuries or death.
If these were the risks, what were the potential benefits?
FDA reviewers found that Lotronex improved symptoms in only 10%
to 20% of the patients. Still, an FDA advisory committee, whose
participants included a paid consultant to Glaxo, unanimously
recommended approval. (The yes vote voiced by the Glaxo consultant,
Dr. Arnold Wald of Pittsburgh, was invalid, agency officials say,
because of his status as a temporary appointee.)
The FDA had a choice: Withhold approval of Lotronex until Glaxo
undertook a major safety study to assess the drug's link to ischemic
colitis or approve the drug conditioned on a pledge by Glaxo to
perform the study in the following year.
Top FDA officials chose not wait. They approved Lotronex on Feb.
9, 2000. The original labeling said that ischemic colitis had
occurred "infrequently" in the clinical studies and that there was no
way to predict which patient was at highest risk.
It was Lotronex's first approval worldwide. Securities analysts
estimated it would generate sales of up to $2 billion within five
years.
A spate of bowel injuries emerged quickly--consistent with Senior's fears.
In June, the FDA's Woodcock embraced the crafting of a
"medication guide" aimed at advising patients of Lotronex's risks.
But the leaflets were not delivered to pharmacies until late
September. Meanwhile, Woodcock's staff proposed a black box warning
for Lotronex's label but retreated when Glaxo publicly opposed the
idea.
By October, 49 cases of ischemic colitis in Lotronex
patients--including five deaths--had been reported to the FDA.
Records show that no fewer than 91 patients were hospitalized, many
with severe constipation. Several bowel surgeries, including the
removal of a patient's colon, were performed.
FDA officials who had backed the approval of Lotronex maintained
their support for the drug into November, but staff epidemiologists
pointed to the surgeries and deaths and the likelihood that those
voluntarily reported events were a small fraction of the true scope
of harm.
They urged withdrawal.
Glaxo and the FDA announced on Nov. 28 that Lotronex would be
pulled from the U.S. market. At that point, Glaxo's promised study of
the drug's link to ischemic colitis still had not enrolled a single
patient.
Asked why the FDA approved Lotronex, given the ischemic colitis
risk, Woodcock indicated that her aides had believed Glaxo's view of
the risk more than Senior's.
"At the [November 1999] advisory committee, the company proposed
that these were [unsurprising] incidences of ischemic colitis, not
causally related to drug," Woodcock said, adding: "We can't not
approve drugs because they have certain side effects; they're all
going to have side effects. We have to determine, are they going to
be adequately managed?"
In subsequent written comments, Woodcock noted that some
patients complain when a drug they believe helps them is withdrawn.
"People who suffer from serious, life-limiting, or
life-threatening illnesses have repeatedly and forcefully told the
FDA that they are willing to take greater risks because of the nature
of their illnesses," Woodcock told The Times.
A Glaxo executive, Dr. Richard S. Kent, said the company
continued to believe that the risks could be satisfactorily managed
through labeling and related measures.
During the nine months that Lotronex was on the U.S. market,
sales exceeded $56 million through October, according to the research
firm IMS Health. The drug was never sold in any other nation.
_______________________________________________
Biofuel mailing list
Biofuel@sustainablelists.org
http://sustainablelists.org/mailman/listinfo/biofuel_sustainablelists.org
Biofuel at Journey to Forever:
http://journeytoforever.org/biofuel.html
Search the combined Biofuel and Biofuels-biz list archives (50,000 messages):
http://www.mail-archive.com/biofuel@sustainablelists.org/
