FDA Minimized Issue of Lotronex’s Safety
In the drug’s first eight months on the market, five people who took it died. Several others underwent bowel surgeries--one had a colon removed. A total of 49 patients developed ischemic colitis, a potentially life-threatening complication.
As a result, the Food and Drug Administration is now “reevaluating” the safety of Lotronex, a drug intended to treat women with a nonfatal disorder, irritable bowel syndrome. But a Los Angeles Times investigation of the FDA’s handling of Lotronex found that over the last year agency officials repeatedly played down questions about the drug’s safety while siding with the manufacturer, Glaxo Wellcome Inc., in important regulatory decisions.
The FDA officials disregarded the significance of concerns raised by an agency medical officer who examined the drug before its approval. They chose a paid consultant to Glaxo to serve with an advisory committee that recommended approval of the drug. They agreed with Glaxo not to place a highly visible “black-box” warning on the label of Lotronex. Rather than wait for Glaxo to conduct a major new study of the drug’s link to ischemic colitis, the agency approved the pill on a condition that the study would take place after the drug entered the market. The study has yet to begin.
And for the last several months, the officials have declined, in the face of data gathered by FDA epidemiologists, to seek withdrawal of the drug.
The FDA’s handling of Lotronex is the latest example of how the pressure to get new drugs to market can clash with the agency’s mandate to protect public health and safety. Since 1993, the agency has dramatically stepped up approvals of new drugs submitted by the $100-billion pharmaceutical industry, with fortunes rising or falling on sales of a single medication.
In the last three years, the FDA has been forced to withdraw nine drugs from the market after reports of deaths and injuries linked to the compounds.
An FDA administrator, Dr. Florence Houn, on Wednesday defended the agency’s decisions on Lotronex but added, “FDA is concerned about the serious adverse event reports of ischemic colitis and severe constipation associated with Lotronex.” When the agency approved Lotronex, Houn said, officials suspected that the ischemic colitis seen with the drug was nonfatal and reversible.
3 Deaths Not Linked to Drug, Firm Says
A representative of Glaxo, Dr. Allen Mangel, said the company has investigated three of the five deaths and believes those events were not caused by Lotronex. Mangel said Glaxo has not been able to adequately probe the remaining two deaths. He said the company “will absolutely want to meet with the FDA very soon” to discuss the drug’s future.
As for Glaxo’s pledge to launch the major new study regarding ischemic colitis and Lotronex, Mangel said the company and the FDA are still negotiating details of how to conduct the research. A spokeswoman for Glaxo, Ramona Dubose, said the company stands behind Lotronex.
“We have complete confidence in the safety profile of this drug,” Dubose said. “We believe that any risks can be managed.”
The FDA takes into account whether other treatments are available when deciding whether to approve or withdraw drugs. For irritable bowel, there are five drugs on the U.S. market, including Lotronex. Doctors say that none is effective at easing all symptoms of the disorder, which can include abdominal pain, diarrhea and constipation. However, a search by The Times of records maintained by the FDA since 1993 found that only Lotronex has been cited as the “suspect” in a case of ischemic colitis.
It was last November when an FDA medical officer named John Senior tried to sound an alarm about Lotronex. Time was short. The FDA had agreed to conduct a “fast-track” review of Lotronex, on the basis that it would treat a “serious” disease. Dr. Senior, while stopping short of recommending rejection or approval of Lotronex, deplored Glaxo’s approach to the safety concerns surrounding the drug.
“It is very disturbing that the applicant 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,” Senior, a bowel specialist, wrote in his review.
Senior identified four cases within Glaxo’s clinical studies of ischemic colitis--the potentially lethal complication that results from inadequate blood flow to the colon. He noted that no patient taking a placebo had developed it.
“This finding represents a signal of a potentially serious problem,” Senior warned in his review, adding that drug-induced ischemic colitis can be “mild and transient” but can also result in gangrene of the bowel and death.
He found that 27% of the patients taking Lotronex experienced constipation.
Improvement in Patients Cited
As for the drug’s potential benefits, the FDA medical-review staff concluded that 10% to 20% of patients in Glaxo’s clinical studies gained improvement in their symptoms that could be attributed to Lotronex. The drug is intended for women whose predominant irritable-bowel symptom is diarrhea. Once a drug is approved by the FDA, doctors can prescribe it for anyone or any purpose they deem appropriate.
After Senior apprised the Gastrointestinal Drugs Advisory Committee of patients’ risk for ischemic colitis, Dr. Houn asked panelists whether more safety studies “should be performed prior to approval, or after approval?”
The question was crucial to Glaxo because withholding approval until more safety data could be examined would have knocked Lotronex off the fast track and delayed, if not dimmed, sales. Only one committee participant, Dr. Arnold Wald of Pittsburgh, responded directly to Houn’s question:
“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,” said Wald, who recalled that he participated at the meeting as a temporary special government employee paid by the FDA.
Wald, it turns out, was no stranger to Lotronex or Glaxo, according to FDA records and interviews.
Wald at the time of the meeting had a grant from Glaxo, the panel’s secretary announced, “on a matter unrelated” to Lotronex. He also had helped conduct one of the early studies of Lotronex on Glaxo’s behalf, as an intestinal specialist at the University of Pittsburgh.
In an interview, Wald acknowledged that it was also around November 1999--the same month as the FDA advisory meeting--that he and several faculty colleagues began teaching a series of courses for Glaxo’s sales representatives, honing their familiarity with irritable bowel syndrome.
The Gastrointestinal Drugs Advisory Committee voted unanimously to recommend prompt approval. The FDA formally approved Lotronex on Feb. 9, completing a review that took seven months. Securities analysts predicted Lotronex would generate sales for Glaxo of up to $2 billion within five years.
When the FDA approved Lotronex, Glaxo retained Wald to make presentations to physicians who might prescribe the drug. Wald said that his financial ties to Glaxo did not taint the advice he gave to the FDA.
“We do have that relationship,” Wald said of his work with Glaxo. “That’s a potential conflict. But personally, it wouldn’t be enough to misrepresent the drug in terms of my professional reputation.”
Wald said that he holds no regret about advising the FDA to approve Lotronex quickly--instead of waiting for additional safety data concerning the drug’s capacity to induce ischemic colitis.
“They proved their efficacy; it seemed to be safe,” Wald said, adding: “I don’t really have any concerns about the drug.”
Lotronex began arriving on pharmacy shelves in March. And in April, the FDA received the first voluntarily filed reports of serious side effects among the new patients, according to records reviewed under the Freedom of Information Act. In one case, a 59-year-old woman was hospitalized and the health professional who filed the report listed Lotronex as the “primary suspect” drug.
By early June, a total of eight new ischemic colitis cases had emerged. Six other Lotronex patients were hospitalized with constipation-related complications, and three of them required surgery.
On June 27--less than five months after the FDA approved Lotronex--the agency convened a special meeting of the advisory committee.
Another FDA medical officer, Dr. Hugo Gallo-Torres, told the advisory committee that “there is a causal relationship” between Lotronex and both ischemic colitis and constipation. Gallo-Torres a few months earlier had recommended approval of Lotronex, despite saying it was “a hard to explain/accept coincidence” that no patient taking placebos in the clinical studies suffered ischemic colitis.
‘Black-Box’ Warning Opposed by Glaxo
Glaxo representatives suggested that preexisting medical complications or patients’ use of other drugs may have caused some of the hospitalizations. A company executive, citing competitive considerations, said Glaxo opposed the FDA staff’s proposal to place a “black-box” warning in the drug’s labeling. This black-bordered feature signifies pronounced risk and is more noticeable to patients and their physicians.
“We don’t feel . . . that this drug is a dangerous drug and merits a black box,” said Dr. Richard S. Kent, Glaxo’s chief medical officer and vice president.
With a black box, Kent said, “patients and physicians may end up making inappropriate decisions around whether to use this drug. I think there is a duty to warn that we all have; I think there is a great duty not to over-warn. We have to put the risks and benefits of all these products in proper perspective.”
The FDA dropped the proposal for a black-box warning.
The first fatality of a Lotronex patient was reported to the FDA on July 17, a 50-year-old woman who suffered “mesenteric occlusion,” a severe blockage of blood to the colon. This report, filed voluntarily by a health professional, identified Lotronex as the “primary suspect” drug in the death. Glaxo denies that Lotronex caused this death.
On Aug. 24, the FDA and the company announced a safety-labeling change.
In a letter to doctors and pharmacists, Kent acknowledged reports “of serious complications of constipation, including obstruction, perforation, impaction, toxic megacolon, and secondary ischemia, in patients treated with Lotronex. In some cases these complications have required intestinal surgery, including colectomy,” the removal of the patient’s colon.
Records kept by the FDA show that, through Oct. 30, the agency had received 93 reports of patients being hospitalized after taking Lotronex. In each of the reports, the doctor or other party cited Lotronex as the “primary suspect” drug in the event.
In an interview on June 30, the FDA’s drug center director, Dr. Janet Woodcock, cited Lotronex as an example of what she termed a fresh commitment to pro-actively monitor the risks of newly approved drugs. She praised a leaflet, called a “medication guide,” that the FDA and Glaxo had agreed to develop for Lotronex patients.
Why, given the warnings of potentially fatal ischemic colitis for a drug that is not lifesaving itself, did the FDA approve Lotronex?
“We can’t not approve drugs because they have certain side effects,” Woodcock said. “They’re all going to have side effects. We have to determine, are they going to be adequately managed?”
Lotronex generated $42.1 million in sales through August for Glaxo, according to IMS Health, an information-services firm. During this period 334,000 prescriptions were written, some to the same patients.
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Times researchers Janet Lundblad in Los Angeles and Sunny Kaplan in Washington contributed to this story.
