By Richard Woodman

May 18, 2001 ? LONDON (Reuters Health) - Patients taking a controversial
new drug for irritable bowel syndrome may have died because the US cooking.net">food
and Drug Administration (FDA) has become a "servant of [the drug]
industry," the editor of The Lancet medical journal claimed in the May
19th issue.

In a devastating editorial, Richard Horton said that although
GlaxoSmithKline (GSK) voluntarily withdrew Lotronex (alosetron) from the
US market last November after the deaths of five patients, senior FDA
officials were now seeking to reintroduce it.

"This story reveals not only dangerous failings in a single drug's
approval and review process but also the extent to which the FDA, its
Center for Drug Evaluation and Research (CDER) in particular, has become
the servant of industry," he said.

The two-page editorial, entitled "Lotronex and the FDA: a fatal erosion of
integrity," accuses the FDA of receiving hundreds of millions of dollars
funding from industry.

It claims the views of FDA scientists who raised safety questions about
the drug were dismissed by FDA officials and that the scientists were
excluded from further discussion about the drug's future.

And it alleges that negotiations between the FDA and GSK on the drug's
future involved a "two-track process, one official and transparent, one
unofficial and covert."

Lotronex was licensed by the FDA in February 2000 but was never approved
by the European Medicines Evaluation Agency.

The company withdrew the product in the US on November 28 after 49 cases
of ischaemic colitis and 21 of severe constipation, including instances of
obstructed and ruptured bowel. In addition to five deaths, 34 patients had
required admission to hospital and 10 needed surgery.

The Lancet says that as early as July, it was known that seven patients
had developed serious complications. The clinical data confirmed
"substantial and potentially life-threatening risks" but instead of
withdrawing Lotronex the FDA issued a medication guide. "This decision was
to prove fatal."

The editorial says FDA scientists knew that the medication guide advising
patients to stop taking Lotronex if they felt "increasing abdominal
discomfort" was impractical since abdominal pain is also a cardinal
symptom of an irritable bowel.

FDA scientists argued that it was unreasonable to expect either patients
or their physicians to judge pain as an early warning of possibly fatal
ischaemic colitis. This view was dismissed by FDA officials.

"The scientists who raised these issues felt intimidated by senior
colleagues and were excluded from further discussions about Lotronex's
future."

The journal says that in a memorandum dated November 16, FDA scientists
said, "Early warning of the dire side effects of this drug is clearly not
feasible" and added a "risk management plan cannot be successful."

However, this conclusion was blurred by the time of the key November 28th
meeting between GSK and FDA officials. Rather than reject the company's
risk management proposal and withdraw Lotronex, the FDA offered several
conciliatory options including voluntarily withdrawal pending further
discussion.

The editorial claims "many within the FDA's leadership now want to bring
Lotronex back. An advisory committee meeting set up to do so is being
planned for June or July."

In April, GSK chief executive Jean-Pierre Garnier said he believed the
odds were low that Lotronex would be relaunched because of the difficulty
of predicting which patients might be at risk of severe side effects. But
industry analysts who have met R&D head Tachi Yamada more recently told
Reuters the company now appeared to be more optimistic about a Lotronex
relaunch.

GSK spokesman Martin Sutton told Reuters, "We regard the editorial as
misleading. There have been discussions between FDA and GlaxoSmithKline
officials. These meetings have all been conducted according to usual
regulatory and industry practices. Both the FDA and ourselves are trying
to find a resolution that will benefit and protect patients."

He added that the timing of any advisory committee meetings was a matter
for the FDA.

An FDA spokesperson said the agency is still formulating its response to
the editorial.

Horton told Reuters Health he became interested in Lotronex because The
Lancet published some of the trial data that led to the FDA approving the
drug. "As the year went on, we noticed that there were increasing reports
of adverse events.

"Then as I got more intrigued about what was happening, it opened up into
an issue of how science is dealt with by the FDA and how, because of
industry funding, it has fatally compromised its independence.

"The scientists within the FDA who analyze and interpret adverse drug
reactions have been largely ignored after the drug was approved and
marketed. That is where there has been a terrible failure in evaluating
the safety of this drug.

"The FDA is not only compromised because it receives so much funding from
industry but because it comes under incredible Congressional pressure to
be favourable to industry. That has led to deaths."

Horton pointed out that irritable bowel syndrome may be extremely
unpleasant but is not life-threatening. To approve a drug that can lead to
ruptured bowel and death was at odds with the normal balance between risk
and benefit, he said.

"This is a drug whose application was approved for full unrestricted
marketing within 7 months. That is insufficient to gather safety data.
Pushing through an application so quickly is irresponsible."

Horton said that GlaxoSmithKline "has failed to gather sufficient evidence
to justify the safety of this product." He added that the company had
applied pressure through private communication to senior FDA officials.
"Instead of an accountable review process, one has a covert, unofficial
process."

This is not Horton's first attack on the drug industry. In recent
editorials he has criticised the "tightening grip of big pharma" over what
researchers can publish in medical journals.

His latest editorial demands that:

*  Lotronex should be reclassified as an investigational new drug, thus
limiting its use to experimental settings only.
*  Covert private communications between FDA officials and industry must stop.
*  Drug approvals and safety reviews should take place through accountable
procedures.
*  Greater weight should be given to the epidemiologic advice provided to
advisory committees.
*  There should be an independent congressional audit of the FDA's drug
approval processes.
*  Oversight of the pharmaceutical industry should be removed from CDER's
control because safety cannot be overseen by a centre that received
industry funding.
*  FDA should welcome, not censure, differences of opinion within the
organisation.
*  The FDA's new commissioner should be an epidemiologically trained
physician experienced in conducting clinical trials and independent of
industry.

SOURCE: The Lancet 2001;357:1544-1545.

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