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