# U.S. News: A pill turned bitter



## Jeffrey Roberts (Apr 15, 1987)

http://www.usnews.com/usnews/issue/001211/drug.htm Business & Technology 12/11/00 A pill turned bitter How a quest for a blockbuster drug went fatally wrong By Joseph P. Shapiro It's a baby-blue pill, smaller than a button on a blouse. But big hopes rode on the medication called Lotronex, whose brief career on the market ended last week after it was blamed for three deaths. For patients like Cynthia Huschle, a 36-year-old Connecticut woman who struggles with a  debilitating digestive disease, the oval tablet has allowed her, for the first time, to do simple things taken for granted by every other mom, like going trick-or-treating with her kids on Halloween. For pharmaceutical giant Glaxo Wellcome, it promised to be one of those rare drugs that millions of patients would rely onï¿½a billion-dollar-a-year blockbuster. But neither the patients, nor the manufacturer, nor the Food and Drug Administration fully reckoned with the drug's dark side. Since Lotronex first went on sale in March, some 300,000 women have taken it, trying to find relief from a disorder called irritable bowel syndrome. And while the drug brought life-changing benefits to patients like Huschle, it has also been linked to at least 70 cases of severe side effects resulting in hospitalizations, surgeries, and deaths. For the past year, U.S. News has followed Lotronex through its fight for government approval and its battle to stay on the market, which ended last week when it was withdrawn. Both Glaxo and the FDA are on the defensive about their roles in the debacle. For the FDA, Lotronex was yet another embarrassing about-faceï¿½the third drug since March to be pulled off the market because of unanticipated side effects. For Glaxo, which marshaled patients as well as its own experts to push for approval with the mildest possible safety warnings, the episode plays into the hands of critics who believe the drug industry puts profits ahead of public safety. "Using this drug was like playing Russian roulette," says Larry Sasich of Public Citizen's Health Research Group, a consumer advocacy organization that had called for Lotronex's withdrawal. FDA officials say they did their best to weigh the risks while giving the drug a fair shake. And Richard Kent, Glaxo's chief medical officer, insists Lotronex is safe and says even drugs like aspirinï¿½to which hundreds of deaths are attributed each yearï¿½could not meet the safety standard applied to Lotronex. One clear lesson is that ensuring public safety is harder than ever as pharmaceutical companies come up with record numbers of new drugs and aggressively promote them to eager patients. For decades, drug companies had tried to develop a drug to serve a vast untapped market of people struggling with IBS. A poorly understood ailment that causes painful stomach cramps and either extreme constipation or chronic diarrhea, IBS by some estimates affects 15 percent of the U.S. population, mostly women. For some of them, it can be crippling. Huschle suffers from a severe form of diarrheal IBS, which began eight years ago following gall-bladder surgery, and quickly circumscribed her life. She gave up classroom teaching to become a reading specialistï¿½simply so that she had the flexibility to run to a bathroom on a second's notice. She left ordinary chores, like shopping, to her husband, she says, because "I never knew if I had time to go down one aisle and up the other before I had to run to the bathroom." A Glaxo researcher's epiphany in the early 1990s had raised hopes for a treatment. The researcher, Patrick Humphrey, was  already legendary for discovering the anti-migraine drug Imitrex. Like migraines, he realized, IBS involved pain and mostly affected women. And like migraines, he suspected, IBS was caused by the loss of a body chemical, serotonin. That led him to a key insight: "I believed IBS is a migraine of the gut." The next step was to test the hundreds of compounds left over from the development of Imitrex. One, GR68755, worked to replace serotonin in the gut. But it would take years of testingï¿½first on animals and then in human clinical trialsï¿½to ensure that GR68755, later renamed Lotronex, was safe and effective. And it took plenty of lobbying by Glaxo and by patients to get the drug approved. Balancing safety with the potential benefits of Lotronex was tricky from the start. About 20 to 30 percent of women with IBS experience diarrhea and fecal incontinence. Another 20 to 30 percent get extreme constipation. Others move from one category to the other. Clinical trials showed that while Lotronex relieved the diarrhea, it could exacerbate constipation. Alarmingly, 27 percent of those who used it became so severely constipated that they had to drop out of the trials. Approval with reservations. As hundreds of pages of FDA and Glaxo company documents obtained by U.S. News through a Freedom of Information Act request show, Glaxo fought to market the drug broadly and downplayed the likelihood that Lotronex could cause dangerous constipation. Constipation was an infrequent side effect, Glaxo wrote in a proposed warning label. That stirred a withering critique from John Senior, an FDA medical reviewer. "This is inappropriate," he warned in an October 1999 memo. "Constipation was NOT infrequent, but occurred in more than a quarter of the patients; it was COMMON, and almost to be expected." Senior also complained that Glaxo had "buried in the fine print" a rarer but even more serious side effect: four cases of a potentially deadly ulceration of the intestines called ischemic colitis. Approval of the drug was delayed while the FDA investigated these cases. But by February of this year, FDA officials felt reassured that the complications could be controlled when caught quickly by careful doctors and patients. The agency approved Lotronexï¿½but only for women with no recent history of constipation.  Despite the setback, Glaxo Wellcome expected its new drug to be a blockbuster. As Glaxo's Allen Mangel, who oversaw the international development of Lotronex, puts it: "Functional bowel disease represents the next frontier of disease with huge unmet medical needs." Some analysts predicted worldwide sales of Lotronex would reach $1 billion a year, the heady level of a handful of drugs, like the anti-arthritis pill Celebrex, with 1999 sales of $1.3 billion. Misunderstood. Even before the drug was approved, Glaxo had begun laying the groundwork for this kind of success. One challenge was consciousness-raising. IBS was a "hidden disease," too embarrassing for many sufferers to discuss, and dismissed by many doctors as psychosomatic. So while Glaxo was spending millions of dollars on clinical trials and research, it began an expensive campaign to make the world aware of IBS. The company helped underwrite an international meeting where doctors agreed on protocols for diagnosing IBS. It also paid for an extensive survey that found IBS was a large and misunderstood medical problem. In trying to make it okay to talk about IBS, Glaxo got crucial help from an IBS patient named Nancy Norton. Nine years ago, this textile conservator and contractor's wife had started a national support group for people with IBS from her kitchen table in suburban Milwaukee. Over the years, her group, the International Foundation for Functional Gastrointestinal Disorders, had become a reliable source of information for thousands of members. But she wanted to expand it and get more attention for IBS. Norton's desire for growth meshed with Glaxo's desire to sell Lotronex. Contributions to IFFGD soared to $606,657 in 1998, doubling its assets in just one year. A significant amount came from Glaxo, although neither it nor Norton will say how much. By last year, Norton and Glaxo were working together on a wide range of efforts to publicize IBS, even briefly sharing the same public relations firm. Norton flew to three FDA approval hearings on Lotronex, sometimes with other IBS patients. Working with Glaxo, she says, was a matter of "building bridges" to get the medical industry to help people with IBS. To market. As the expected approval date drew near, Glaxo's marketing force swung into action. In focus groups across the  country last winter and spring, Glaxo sales representatives listened to women tell heart-rending tales of how IBS had limited their lives. The stories would help them make a compelling case to doctors for prescribing the drug. They also helped shape Glaxo's marketing strategy: For one thing, the women in these focus groups made it clear that they would pay a steep price for the drug, as much as $2.50 per pill, even if insurance didn't cover it. That's what Glaxo charged when Lotronex finally went on sale, in mid-March. Even then, Glaxo had to overcome skepticism by many doctors. Some, like Pennsylvania gastroenterologist William Mahood, worried that patients would view Lotronex as a quick fix and stop doing other things to control IBS, like moderating their diet or using a bulking agent. To win over doctors, Glaxo helped underwrite continuing medical education conferences and even set up an Internet seminar that doctors could attend from their home computers. But shortly after the first prescriptions were written, the FDA got more reports of dangerous ischemic colitis. This time, unlike in the clinical trials, the complication didn't simply go away when a woman stopped using the drug. That set off alarms for Victor Raczkowski, a physician and 10-year veteran of the FDA who helps run the office that reviews gastrointestinal drugs. The agency had just ordered the widely used diabetes pill Rezulin pulled from pharmacy shelves after more than 60 deaths, and it faced heavy criticism for not moving fast enough. The risks had looked manageable in the clinical trials; not until Rezulin was in the medicine cabinets of hundreds of thousands of people did the magnitude of the dangers become clear. Now Raczkowski feared there might be a similar problem with Lotronex. On June 27, the FDA advisory panel that had approved Lotronex reconvened for an extraordinary reconsideration of a recently approved drug. As FDA officials have learned to their dismay, doctors are overwhelmed trying to keep current on new drugs and their side effects and often don't read warning labels. So Raczkowski and his staff urged something that seemed certain to grab doctors' attention: a warning displayed in a black border, like the one on a package of cigarettes. But Glaxo officials feared that a black-box warning would frighten doctors and patients away from Lotronex. So they counterattacked aggressively, bringing company doctors and even IBS patients to the meeting. Glaxo's Kent argued that the FDA had not required a black box warning for Viagra, which had been linked to numerous deaths. In at least half of the adverse reactions to Lotronex, Glaxo officials said, doctors incorrectly prescribed the drug to people who suffered from constipation. In some cases it was even being given to men. Glaxo proposed undertaking its own extensive effort to inform doctors about the side effects. The FDA relented, announcing in late August that it would require pharmacists filling a prescription for Lotronex to include the first-ever "medical guide"ï¿½printed and paid for by Glaxoï¿½that explained the side effects in lay language. In effect, the FDA was counting on patients to read the guide and be more vigilant about monitoring their own symptoms. In the weeks that followed, a spike in the reported complications, including the first deaths, suggested that the extra warning would not be enough. In some cases, Raczkowski noticed, women had no warning symptoms before they became seriously ill. At a tense meeting around an FDA conference table last Tuesday, the FDA demanded that Glaxo accept controls as tight as those on dangerous drugs like Thalidomide. To get Lotronex, patients would go to doctors specially registered with the FDA. Glaxo would then monitor each case and expel doctors who did not follow strict prescribing procedures. Kent complained that such a step would put the drug company in the extraordinary position of "policing doctors." Instead, Glaxo announced that afternoon that it would withdraw Lotronex from the U.S. market. At home that evening, Cynthia Huschle was "shocked" when she heard of Glaxo's decision on the news. The next morning she bought her last refill of Lotronexï¿½enough, if she cuts her daily dosage in half, to last another three months. She mourns her short-lived freedom from IBS. In the balancing act between safety and access, she says she can make her own assessment of risk. Says Huschle, "I had begun to dream again." ï¿½ U.S.News & World Report Inc. All rights


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## Jeffrey Roberts (Apr 15, 1987)

Letter to the EditorRe: A pill turned bitter by Joseph P. ShapiroMany former Lotronex users have been driven to dispair as a result ofGlaxo Wellcome's decision to withdraw Lotronex. Even with the knowledgeof the "drug's dark side" users maintain that they would gladly take therisk in order to free themselves from the daily grinds of living withIrritable Bowel Syndrome. The withdrawal is a regrettable situation andone which questions why dollars and cents seem to continue to controlthe quality of life for sufferers so dependent on the pharmaceuticalsdevelopment of new drugs.Jeffrey RobertsPresident & FounderIBS Self Help Groupibs###ibsgroup.org http://www.ibsgroup.org


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## Guest (Dec 13, 2000)

Thank you for including the article. It was a big leap for me. It has been helpful for me to know that I am not alone with this problem. My intent was to bring more awareness to everyone else about our plight. I just hope we can get Lotronex back or new options.Thank youCynthia Huschle


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## JeanG (Oct 20, 1999)

Thanks for posting this Jeff. Your letter to them was very good. Let's hope that something gets resolved soon.JeanG


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## Guest (Dec 15, 2000)

Great post Jeff. This article lays out the whole story. Thanks again.Brian


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## Jeffrey Roberts (Apr 15, 1987)

I was just informed that my Letter to the Editor (above) will be in the January 15, 2001 edition.Look for it on newstands starting Monday January 8 ,2001.Jeff


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## LindaR322 (Aug 21, 2000)

Hi Jeff, Congrats to getting the letter published! Just curious though, was there a response? Linda


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## Jeffrey Roberts (Apr 15, 1987)

I picked up a copy of the magazine today and confirmed that the letter is in there on the top of page 2.It's on-line here: http://www.usnews.com/usnews/issue/010115/15lett.htm No direct response as of yet.Thanks,Jeff[This message has been edited by Jeffrey Roberts (edited 01-08-2001).]


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