LOTRONEX: Study Finds FDA Conflict of Interest

After eight months on the market, the irritable bowel syndrome drug Lotronex has been cited as the cause for a number of bowel surgeries, deaths and disorders, prompting a Los Angeles Times investigation that found FDA officials had "repeatedly played down questions about the drug's safety while siding with the manufacturer, Glaxo Wellcome Inc., in important regulatory decisions." The FDA on Feb. 9 formally approved Lotronex, a drug intended to treat women with irritable bowel syndrome, a "nonfatal" disorder causing diarrhea and constipation. From that point through Oct. 30, the FDA received 93 reports of patients being hospitalized after taking Lotronex, and 49 reports of patients developing ischemic colitis, a potentially lethal complication stemming from inadequate blood flow to the colon. Through August, 334,000 prescriptions were written for Lotronex, which generated $42.1 million in sales in that time period. While the FDA now is taking steps to reevaluate Lotronex's safety, the Times reports that during the drug's approval process, FDA officials "disregarded the significance of concerns raised by an agency medical officer" and elected a paid Glaxo consultant to serve on the advisory committee responsible for recommending approval of Lotronex. In addition, despite warnings that the drug was linked to ischemic colitis, the FDA approved Lotronex "on a condition that the study would take place after the drug entered the market," instead of delaying the drug's approval, the Times reports. That study has yet to take place. In approving the drug, FDA officials also agreed not to enforce a "black-box" warning on the medication's label that would alert patients and physicians to its potential side effects.

The FDA's dealing with Lotronex is "the latest example of how the pressure to get new drugs to the market can clash with the agency's mandate to protect public health and safety," the Times reports. Despite the fact that five other irritable bowel syndrome treatments were already on the market and that the syndrome is considered "nonfatal," the FDA had agreed to conduct a "fast-track" review of Lotronex on the basis that it would treat a "serious" disease. The fast track process hindered FDA medical officer John Senior's efforts to "sound an alarm about Lotronex" last November. Senior, an intestinal specialist, wrote in his review, "It is very disturbing that [Glaxo] has chosen to downplay so strongly the important issue of constipation, induced commonly and predictably by (Lotronex), and has totally ignored the (problems) of ischemic colitis." In a review of Glaxo's clinical studies, Senior found that four patients had developed ischemic colitis and 27% had experienced constipation. In light of these findings, FDA administrator Dr. Florence Houn in November called a meeting with the Gastrointestinal Drugs Advisory Committee to determine whether additional safety studies "should be performed prior to approval or after approval." Dr. Arnold Wald, an intestinal specialist at the University of Pittsburgh who the Times reports had ties to Lotronex and Glaxo, was the only member to respond "directly" to Houn's question. Knowing that additional studies performed prior to approval would have "knocked Lotronex off the fast track and delayed, if not dimmed, sales," Wald advised, "I think we could approve the drug with the caveat that we monitor it very carefully. ... So I would not hold up the approval pending that data." The Times reports that at the time of the meeting, Wald held a grant from Glaxo "on a matter unrelated" to Lotronex and had assisted Glaxo on early studies of Lotronex. Along with several colleagues, Wald also had begun teaching a series of courses for Glaxo's sales representatives to hone "their familiarity with irritable bowel syndrome." But Wald said his financial ties to Glaxo "did not taint the advice he gave to the FDA." Admitting that his relationship with Glaxo was "a potential conflict," Wald added, "But personally, it wouldn't be enough to misrepresent the drug in terms of my professional reputation."

Glaxo also challenged an FDA proposal to put a black-box warning on Lotronex labels -- a "black-bordered feature [that] signifies pronounced risk and is more noticeable to patients and their physicians." Glaxo Chief Medical Officer and Vice President Dr. Richard Kent had said, "We don't feel ... that this drug is a dangerous drug and merits a black box ... patients and physicians may end up making inappropriate decisions around whether to use this drug. It think there is a duty to warn that we all have; I think there is a great duty not to over-warn. We have put the risks and benefits of all these products in proper perspective." Glaxo representatives also suggested that "preexisting medical complications or patients' use of other drugs may have caused some of the hospitalizations" associated with Lotronex use. The FDA originally dropped its proposal for a black-box warning, but announced a "safety-labeling change" on Aug. 24 after the first Lotronex-related fatality was reported on July 17. Kent sent a letter to doctors and pharmacists, reporting "serious complications of constipation, including obstruction, perforation, impaction, toxic megacolon and secondary ischemia, in patients treated with Lotronex."

There have been five deaths among Lotronex users, but Glaxo said that three of those deaths were not caused by the drug. The pharmaceutical company has yet to launch a "major new study" on Lotronex and ischemic colitis, but Glaxo representative Allen Mangel said that the company "'will absolutely want to meet with the FDA very soon' to discuss the drug's future." Company spokesperson Ramona Dubose added, "We have complete confidence in the safety profile of this drug. We believe that any risks can be managed." The FDA also stands behind its decision to approve the drug. FDA drug center Director Dr. Janet Woodcock said in an interview, "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?" But Houn said the FDA "is concerned about the serious adverse event reports of ischemic colitis and severe constipation associated with Lotronex" (Willman, Los Angeles Times, 11/2).