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Patients taking a controversial new drug
for irritable bowel syndrome may have died because the US
Food and Drug Administration (FDA) has become a "servant
of [the drug] industry."
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.
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 ischemic 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 ischemic 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.
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 favorable
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 criticized 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.
The Lancet
May 19, 2001;357:1544-1545
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