LANCET QUESTIONS FDA INTEGRITY, CLAIMING DRUG INDUSTRY INFLUENCE

LONDON (Reuters Health) May 17 - Patients taking a controversial new drug
for irritable bowel syndrome may have died because the US Food and Drug
Administration has become the "servant of the drug industry," the editor of
The Lancet claimed on Thursday.

In a devastating editorial, Richard Horton said that although
GlaxoSmithKline voluntarily withdrew alosetron (Lotronex) 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," Horton said.

The 2-page editorial, entitled "Lotronex and the FDA: a fatal erosion of
integrity," accuses the FDA of receiving hundreds of millions of dollars in
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.

The editorial also alleges that negotiations between the FDA and
GlaxoSmithKline on Lotronex's future involved a "two-track process, one
official and transparent, one unofficial and covert."

Lotronex, a new 5-HT antagonist class of drug for irritable bowel syndrome,
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 cases of severe constipation, including instances
of obstructed and ruptured bowel, were reported. In addition to 5 deaths,
34 patients required admission to hospital and 10 needed surgery.

Horton writes 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 editorialist also points out that FDA scientists knew that the
medication guide, which advised 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," he continues. "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."

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 28
meeting between GlaxoSmithKline and FDA officials. Rather than reject the
company's risk management proposal and withdraw Lotronex, the FDA offered
several conciliatory options including voluntary withdrawal pending further
discussion.

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

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 analyse 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 an extremely
unpleasant condition, but is not life-threatening. To approve a drug that
can lead to ruptured bowel and death is 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.

In his current Lancet editorial Horton recommends that:

Lotronex should be reclassified as an investigational new drug, 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 epidemiological advice provided to
advisory committees.

There should be an independent congressional audit of the FDA's drug
approval processes.

Pharmacovigilance should be removed from CDER's control because safety
cannot be overseen by a center that receives industry funding.

FDA should welcome, not censure, differences of opinion within the
organization.

The FDA's new commissioner should be an epidemiologically trained physician
experienced in conducting clinical trials and independent of industry.

GlaxoSmithKline 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." Sutton
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.

GlaxoSmithKline chief executive Jean-Pierre Garnier said in April 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.

However, industry analysts who have met R&D head Tachi Yamada more recently
told Reuters that the company now appeared to be more optimistic about a
Lotronex relaunch.