Agency officials agreed in July 1999 to conduct a fast-track medical review of Lotronex, a pill from Glaxo Wellcome Inc. intended to treat irritable bowel syndrome in women. To justify such accelerated review, the FDA must find that the targeted disease is “serious.”
Irritable bowel syndrome can result in abdominal pain and frequent trips to the bathroom. But it neither maims nor kills people.
An FDA medical officer, Dr. John R. Senior, discovered during the review that four Lotronex patients in clinical studies suffered a potentially life-threatening complication called ischemic colitis, which results from inadequate blood flow to the colon.
Senior, a former pharmaceutical industry executive and a gastrointestinal specialist, knew the rarity of ischemic colitis: Some physicians can practice for decades without treating a single case.
While some cases would be mild and reversible, Senior wrote, ischemic colitis “can be catastrophic.”
Senior found other troubling results. He warned that 27% of the patients who took Lotronex in Glaxo’s studies experienced constipation. He noted that not a single patient who took a placebo pill developed ischemic colitis and that only 5% of the placebo patients got constipated.
Glaxo representatives denied that Lotronex had caused the cases of ischemic colitis and said any risks could be adequately managed. But Senior warned of the potential for Lotronex patients to suffer debilitating bowel injuries or death.
If these were the risks, what were the potential benefits?
FDA reviewers found that Lotronex improved symptoms in only 10% to 20% of the patients. Still, an FDA advisory committee, whose participants included a paid consultant to Glaxo, unanimously recommended approval. (The yes vote voiced by the Glaxo consultant, Dr. Arnold Wald of Pittsburgh, was invalid, agency officials say, because of his status as a temporary appointee.)
The FDA had a choice: Withhold approval of Lotronex until Glaxo undertook a major safety study to assess the drug’s link to ischemic colitis or approve the drug conditioned on a pledge by Glaxo to perform the study in the following year.
Top FDA officials chose not wait. They approved Lotronex on Feb. 9, 2000. The original labeling said that ischemic colitis had occurred “infrequently” in the clinical studies and that there was no way to predict which patient was at highest risk.
It was Lotronex’s first approval worldwide. Securities analysts estimated it would generate sales of up to $2 billion within five years.
A spate of bowel injuries emerged quickly--consistent with Senior’s fears.
In June, the FDA’s Woodcock embraced the crafting of a “medication guide” aimed at advising patients of Lotronex’s risks. But the leaflets were not delivered to pharmacies until late September. Meanwhile, Woodcock’s staff proposed a black box warning for Lotronex’s label but retreated when Glaxo publicly opposed the idea.
By October, 49 cases of ischemic colitis in Lotronex patients--including five deaths--had been reported to the FDA. Records show that no fewer than 91 patients were hospitalized, many with severe constipation. Several bowel surgeries, including the removal of a patient’s colon, were performed.
FDA officials who had backed the approval of Lotronex maintained their support for the drug into November, but staff epidemiologists pointed to the surgeries and deaths and the likelihood that those voluntarily reported events were a small fraction of the true scope of harm.
They urged withdrawal.
Glaxo and the FDA announced on Nov. 28 that Lotronex would be pulled from the U.S. market. At that point, Glaxo’s promised study of the drug’s link to ischemic colitis still had not enrolled a single patient.
Asked why the FDA approved Lotronex, given the ischemic colitis risk, Woodcock indicated that her aides had believed Glaxo’s view of the risk more than Senior’s.
“At the [November 1999] advisory committee, the company proposed that these were [unsurprising] incidences of ischemic colitis, not causally related to drug,” Woodcock said, adding: “We can’t not approve drugs because they have certain side effects; they’re all going to have side effects. We have to determine, are they going to be adequately managed?”
In subsequent written comments, Woodcock noted that some patients complain when a drug they believe helps them is withdrawn.
“People who suffer from serious, life-limiting, or life-threatening illnesses have repeatedly and forcefully told the FDA that they are willing to take greater risks because of the nature of their illnesses,” Woodcock told The Times.
A Glaxo executive, Dr. Richard S. Kent, said the company continued to believe that the risks could be satisfactorily managed through labeling and related measures.
During the nine months that Lotronex was on the U.S. market, sales exceeded $56 million through October, according to the research firm IMS Health. The drug was never sold in any other nation.