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 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.