# NY Times: F.D.A. Pulls a Drug, and Patients Despair



## Jeffrey Roberts (Apr 15, 1987)

F.D.A. Pulls a Drug, and Patients DespairJanuary 30, 2001By DENISE GRADYIn November, as soon as he learned that the drug Lotronex was beingwithdrawn from the market, Corey Miller, who had been taking it forabout eight months, began stockpiling it. He persuaded a doctor towrite an extra prescription, and went to 20 drugstores in search ofthe recalled pills. Mr. Miller, a 30-year-old architect in Atlanta, knew that Lotronexhad caused serious side effects in some patients and had beenlinked to several deaths. But he had suffered no ill effects. Onthe contrary, Lotronex was the only drug that had ever helped him,stopping the severe abdominal pain and diarrhea caused by anillness called irritable bowel syndrome. "It was a miracle medicine for me," he said.Lotronex was takenoff the market on Nov. 28, less than 10 months after being approvedby the Food and Drug Administration. About 300,000 people had takenit. It was withdrawn because about 70 patients had developed severeconstipation or ischemic colitis, a lack of blood flow to thecolon. Some needed surgery, including one woman who had to have herentire colon removed. There were five deaths, including threepossibly linked to the drug. Nonetheless, several thousand patientshave contacted the F.D.A. since the recall, wanting Lotronex back.A spokesman for the agency said that the demand for Lotronex washigher than that for any other recalled drug, and that officialswere willing to consider bringing the drug back, though in alimited way. On Jan. 23, officials from the F.D.A. and the drug'smanufacturer, GlaxoSmithKline, met to discuss Lotronex, but neitherside would disclose what took place. The rise and fall ^W and possible resurrection ^W of Lotronexhighlights a longstanding problem facing the F.D.A. andpharmaceutical companies: what to do when a useful drug turns outto have significant side effects, particularly when the problems donot become apparent until after the drug is approved.The problem has intensified in recent years because the F.D.A.,given increased financing and ordered by Congress in 1992 to speedup the evaluation process, is approving new drugs faster than inthe past. The number of withdrawals has grown, in part because moredrugs are being approved. Three drugs were taken off the market in1999, and 10 have been withdrawn since 1997. Critics of the industry and the F.D.A. say the agency has actedhastily and approved too many unsafe drugs that have injured orkilled patients. But the agency says the percentage of drugsrecalled has been relatively steady for the past 20 years,averaging under 3 percent of the drugs approved. Once a drug reaches the market, aggressive promotion to doctorsand advertising to consumers often lead to rapid growth in sales,so that, as in the case of Lotronex, hundreds of thousands ofpeople are taking a new drug just months after its approval.When serious side effects occur, especially with drugs being usedon such an enormous scale, consumer advocates like Dr. SidneyWolfe, who directs the Public Citizen Health Research Group inWashington, say that the only way to prevent further harm topatients is to get the drug off the market as quickly as possible.The group sought to have Lotronex banned, arguing that it made nosense to use a drug with potentially life-threatening side effectsfor a disease like irritable bowel syndrome, which is debilitatingbut does not kill people. But pulling a product off the market may in effect punish patientswho were helped by the drug. And since pharmaceutical companiesspend hundreds of millions of dollars to bring a drug to market,withdrawals have a harsh financial impact as well.The patient uprising over Lotronex is an odd turnabout. Usually,if the F.D.A. comes under fire from consumers, it is for havingapproved problematic drugs in the first place, not for taking themaway. But Lotronex was the first drug made specifically to treatchronic diarrhea caused by irritable bowel syndrome, and thesepatients and their doctors say there is no other drug for them toswitch to, no other effective treatment for their condition. Whilethe illness is not fatal, many patients say the sudden attacks ofdiarrhea ruin their lives, and they want to take their chances withthe drug. A spokesman for the F.D.A. said the appeals from patients seemedto be personal rather than form letters or scripted phone calls. "People are talking about serious life issues such as being ableto keep a job and function on a daily basis, or just go out oftheir house," said Jason Brodsky, a spokesman for the agency."Their lives were changed by the medication."Dr. Victor Raczkowski, as deputy director of the F.D.A. officethat evaluates gastrointestinal drugs, was involved in bothapproving Lotronex and withdrawing it. "The pharmaceutical industryand the F.D.A. need better sets of tools to handle safety issuesthat might come up once a drug is approved," he said. "This isrelatively new territory for the industry and the F.D.A." When a new drug is marketed, side effects are virtuallyinevitable, and they are sometimes more severe or more common thanwhen the drug was being tested. An F.D.A. report in 1999 said sideeffects can emerge after marketing because far more people use thedrug than in preliminary studies, enough to let uncommon problemsshow up. They often take the drug for longer periods than those instudies as well. Some researchers have urged that new drugs be phased in moreslowly, prescribed at first only by specialists and only forcertain types of patients, to allow time for side effects to bedetected and changes made before the drug is in the hands ofhundreds of thousands of people.The F.D.A. report noted that side effects also crop up aftermarketing because patients in the real world are different fromthose in studies: they may include children, who in the past wererarely studied, or they may be older and sicker, sometimes withmultiple illnesses being treated by different drugs, which mayinteract with the new medication. Older people are also moresensitive to drugs than younger ones, and standard doses may be toohigh for them. In addition, doctors in private practice and their patients maynot stick as closely to directions as those participating instudies. As a result, people who should not take a new drug may getit anyway. The F.D.A. report stated that more than half of all sideeffects could be avoided if drugs were used properly. Doctors' and patients' failure to follow directions may havecontributed to problems in recent withdrawals like those of thediabetes drug Rezulin and the painkiller Duract. Rezulin waswithdrawn because it caused liver failure in some patients. Thepotential for liver trouble emerged after the drug was marketed,and its labeling was changed to instruct patients and doctors thatregular blood tests were needed to monitor their liver function, sothat patients could stop the drug if abnormalities occurred.Surveys showed that few got the tests.Duract, which also caused liver failure, was not supposed to betaken for more than 10 days, but some patients did take it for alonger time, including those whose livers failed. In the case of Lotronex, Dr. Raczkowski said that while manypatients with complications had used the drug incorrectly, manyothers and their doctors had followed directions to the letter.And, he said, the existence of severe side effects even in patientswho used the drug properly convinced the F.D.A. that it had to act. Whatever the cause, serious side effects cannot be ignored,especially in a drug being taken by hundreds of thousands ofpeople. "It's hard to work through that in a crisis situation," Dr.Raczkowski said. Lotronex was approved in February 2000 for women with chronicdiarrhea caused by irritable bowel syndrome. The bowel disorder canalso cause constipation, but Lotronex was not supposed to beprescribed for patients with that form of the disease. The drugeases abdominal pain and diarrhea by acting on nerves in thegastrointestinal tract. The approval was limited to women becausepreliminary studies had not found a benefit in men. Nonetheless,doctors were free to prescribe the drug "off-label" to men, andmany did. The potential market for Lotronex was enormous: about 15percent of Americans have irritable bowel syndrome. When problems were reported within a few months, the F.D.A.responded in August by requiring that the manufacturer attach toeach bottle of pills a pamphlet describing the risks, and warningpatients of danger signs to watch out for. But labeling changes may not work. A report published in Decemberin the Journal of the American Medical Association about anotherdrug with serious side effects noted that changing the directionsor warnings did no good. Doctors went on prescribing it incorrectlyanyway. As reports of side effects from Lotronex mounted, Public Citizenembarked on a campaign against the drug and petitioned the F.D.A.to ban it. The group insisted that irritable bowel syndrome was nota serious enough disease to warrant the risks posed by Lotronex.Many patients were incensed, and they blame Public Citizen for thedrug's ultimate withdrawal. Richard Fireman, a Lotronex user in Chicago who communicates withother patients via the Internet, said: "Somebody online said theywished they could give Dr. Wolfe irritable bowel syndrome, so he'dknow what he was talking about. I feel the same way. I've neverbeen so angry." But Dr. Wolfe said: "I've been contacted by relatives of peoplewho died or people who had emergency surgery and had big chunks oftheir intestines removed, and who said thank you for getting thisoff the market." At meetings with Glaxo Wellcome in the fall, (the company becameGlaxoSmithKline in December, after a merger), F.D.A. officialssuggested ways to keep the drug on the market, but limit access toit to minimize risks and track problems more effectively. But thecompany rejected the suggestions.Ramona Dubose, a spokeswoman for GlaxoSmithKline, said: "What theywere proposing was that Lotronex would only be available throughgastroenterologists who had been certified by Glaxo to prescribethe drug. Then, we as a company were responsible for monitoringevery prescription written, and if any physician wrote off-label,they would be kicked out of the program, which put us in theuntenable position of policing physicians. We would have to supplythe drug. It would no longer go through pharmacies." The ban on off-label prescribing, Ms. Dubose pointed out, wouldmake it impossible for men to get Lotronex. "Look at the safety profile of Lotronex," she said. "It doesn'tmake any sense to us to put it under such restrictions. We feltlike we had no option but to withdraw the drug." But Dr. Raczkowski said there were still other options, via twomain routes. The one that he called the most expedient, with thepotential to restore the drug to some patients within weeks, wouldbe to classify it as an investigational new drug, the categorygiven to drugs that are experimental and still under study.Patients could then get the drug by meeting certain medicalcriteria and signing up for programs that would be run like studiesand would provide data to the F.D.A. Lotronex might be reserved forpatients with the severest symptoms, who had already been helped bythe drug, because in them the benefits would most likely outweighthe risks, Dr. Raczkowski said. The programs would have to includesafety monitoring and reporting, and be approved by the F.D.A. andby ethics panels at hospitals or clinics. Patients would have tosign consent forms that explained the risks and benefits. Another drug taken off the market last year, Propulsid, is beingprovided to some patients in this kind of program, Dr. Raczkowskisaid. That drug, used to treat gastroesophageal reflux, waswithdrawn because it caused heart problems in some patients. Butmany people took it without ill effect, and for some, it was theonly thing that worked, and those patients are being allowed tocontinue using it. But the investigational status has serious drawbacks, Dr.Raczkowski said. The monitoring and reporting are cumbersome. Moreimportant, drug companies must provide investigational drugs forfree, or in some cases at cost. "In terms of longer term access, probably the better solution iscontinued marketing under conditions that both the drug company andthe F.D.A. would agree to," he said. But he declined to reveal what those conditions might be, saying,"It's for the F.D.A. and the company to sit down and discuss,outside of the public eye." http://www.nytimes.com/2001/01/ 30/health/30DRUG.html?pagewanted=all?ex=981871275&ei=1&en=320d2a28f850ccf6?ex=981871605&ei=1&en=f4d4f6f3517c4cf4[/URL]Copyright 2001 The New York Times Company[This message has been edited by Jeffrey Roberts (edited 01-30-2001).]


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## Jeffrey Roberts (Apr 15, 1987)

http://www.nytimes.com/2001/02/06/science/06LETT.html February 6, 2001 Letters: Deprived of a Drug o the Editor: I am a 49-year-old man who had irritable bowel syndrome for more than 40 years, until Lotronex came along ("F.D.A. Pulls a Drug, and Patients Despair," Jan. 30). I have a daughter, 15, I could finally take to the movies, and she even talked me into going to Times Square from our home in Brooklyn. It was one of the best days of my life. Now, I'm afraid I'm going to go back to the way I was before: often overcome with feelings of terror and dread as I dealt with my I.B.S. I have about a two-week supply of Lotronex left, and I am taking it sparingly. For me, Lotronex was a miracle. I need it back. WILLIAM GALLO New York To the Editor: I have had irritable bowel syndrome for more than 25 years and Lotronex was the only thing that ever gave me my life back ("F.D.A. Pulls a Drug"). I feel bad for those who had serious side effects from it, but every prescription I've ever taken lists side effects. I was skeptical about taking a new drug. In fact, when my doctor first told me about Lotronex, I said, "I do not want to take something that will end up being pulled off the market and possibly kill people." But after hearing Lotronex users discuss their improved quality of life, I changed my mind. I had a wonderful summer. I could bicycle with family and friends. My husband and I went on a wonderful vacation. I could not believe how nice it was to live without looking for toilets. Now, with the drug withdrawn, I am one of the fortunate people able to get enough Lotronex to last this entire year. I hope the F.D.A. and Glaxo agree to put Lotronex back on the market or someone discovers another answer. It seems so unfair that everyone has to suffer because some people had problems after taking Lotronex. JAN HAMILTON Oak Lawn, Ill.


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