>Date: Mon, 13 Nov 2000 22:19:20 -0600 (CST) >From: Circare <[email protected]> > >From: Vera Hassner Sharav, President >CIRCARE: Citizens for Responsible Care & Research, > A Human Rights Organization > Tel. 212-595-8974 FAX: 212-595-9086 > [email protected] > >FYI > >"Why, given the warnings of potentially fatal ischemic colitis for a drug >that is not lifesaving itself, did the FDA approve Lotronex?" > > >From the number of deadly drugs approved by the FDA, one wonders whether >making them affordable is in the public interest??? > >The Los Angeles Times reports that within the last 3 years, the FDA has >struck out 9 times by approving deadly drugs in an approval process that is >corrupted by industry affiliated FDA advisory panels. > >" 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." > > If the FDA relies the advice of drug company representatives who want their >company's drugs approved--and ignores warnings from its own unbiased >experts--WHY DO WE NEED THE FDA? > >~~~~~~~~~~~~~~~~~~~~~~~ > ><http://www.latimes.com/RealMedia/ads/click_lx.ads/www.latimes.com/ne ws/nati >on/updates2/lat_lotronex001102.htm > >LOS ANGELES TIMES >Thursday, November 2, 2000 | > >FDA Minimized Issue of Lotronex's Safety > > Health: Times study finds officials sided with drug maker on regulatory >concerns. Agency reevaluation is underway. > >By DAVID WILLMAN, Times Staff Writer > > WASHINGTON--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. > >--- > Times researchers Janet Lundblad in Los Angeles and Sunny Kaplan in >Washington contributed to this story. > >Copyright 2000 Los Angeles Times > >Kid Fever ><http://www.latimes.com/RealMedia/ads/click_lx.ads/www.latimes.com/ne ws/nati >on/updates2/lat_lotronex001102.htm/29623/Bottom/IH-KidFever001/kf_Ban ner_468 >.gif/63306138643531333339626363653030>
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