In his bathroom medicine cabinet, Jeffrey Roberts is hoarding 14 precious pills -- all he has left of his supply of Lotronex, a prescription drug for irritable bowel syndrome (IBS). He hasn't touched the vial in weeks even though that makes him vulnerable, he says, to diarrhea, abdominal pain and spasms severe enough to keep him confined to his house for days.
But next week Roberts, the president and founder of the IBS Self-Help Group and coordinator of the Lotronex Action Group, plans to start taking the pills again in preparation for a special occasion. The event is an April 23 meeting at the U.S. Food and Drug Administration (FDA) where government officials, consumers, physicians and health advocates will consider the safety and feasibility of reintroducing the controversial drug, unavailable since November 2000. That's when its manufacturer, Glaxo Wellcome (now Glaxo SmithKline) pulled it from the market after it was linked to at least 49 cases of ischemic colitis -- the blocking of blood flow to the colon -- and at least five deaths.
But more than the renewed availability of Lotronex will be at stake in next week's meeting. The debate over the drug will be a test case for an issue that has been dogging the FDA for years: how and when to restrict availability of market-approved drugs shown to help some patients after evidence appears that they can also cause serious side effects and even death. Similar scrutiny of other drugs is sure to follow.
Since November 2000, Roberts and fellow IBS patients have bombarded Glaxo and the FDA with calls for the drug's return to pharmacy shelves. Public Citizen's Health Research Group has been equally vociferous in demanding that the drug stay off the market or, at the very least, not be sold without stringent safeguards and strict distribution limits.
Next week's meeting is unusual for two reasons: Very few drugs withdrawn because of side effect concerns have been allowed back on the market. And the decision makers will come not only from the Gastrointestinal Drug Advisory Committee, a long-standing FDA advisory committee, but also from the FDA's new Subcommittee on Drug Safety and Risk Management.
The new group (which will shortly gain full committee status, according to the FDA) is expected to deal largely with safety issues that arise after a drug has been approved by the FDA.
Why not just get all the kinks out before approving a drug? Often, all the kinks aren't known then. Before approval, drugs are generally tested in thousands of people, sometimes even tens of thousands. But often rare side effects don't show up until a drug is being used in hundreds of thousands of people. And while glaring side effects often show up during clinical trials, rare risks may not be apparent for four to five years after approval, says George Bakris, professor of preventive medicine at St. Luke's Rush Presbyterian Medical Center in Chicago and president of the American College of Clinical Pharmacology.
A General Accounting Office report found that 51 percent of drugs cause serious side effects that aren't detected until after they're on the market. Pulling drugs off the market could end the side effect problem -- but it would also eliminate some effective drugs that could be used safely by some or even most users.
That, in fact, has been one course of action, when warnings aren't deemed sufficient. Since 1980, 14 drugs besides Lotronex -- including the diabetes drug Rezulin and the antibiotic Duract -- have been withdrawn because of serious side effects. Such withdrawals remove a source of treatment for many patients who don't experience the problem side effects.
For example, the 2000 withdrawal of Propulsid, which relieved nighttime heartburn caused by gastroesophageal reflux disease but was linked to irregular heartbeats in a small number of users, drew protests from many patients. Propulsid maker Janssen Pharmaceutica, in consultation with the FDA, resolved the matter by making the drug available only to those few who could prove through their doctor that no other drug was effective for their condition. Propulsid patients worry that the FDA could still decide that the drug should be banned entirely at some point.
For deadlier safety issues that affect more patients, the debate grows more complex. Even if your symptoms are so distressing that you're willing to risk your life to take a drug, is the government justified in letting you take that risk? In the case of non-life-threatening conditions like IBS, says Larry Sasich, a pharmacist and policy analyst with Public Citizen, the answer is: maybe, but only if the drug is restricted to the neediest patients and these patients give their informed consent.
In strictly clinical terms, IBS is more of a nuisance than a serious illness, say experts. According to the American Gastroenterological Association (AGA), it affects up to 11 percent of the U.S. population. In these people, an apparent problem in neural communication between the brain and the gut allows mild stimuli, such as gas or stress, to produce diarrhea, constipation, spasm and pain, says Ray Clouse, a professor of medicine at Washington University in St. Louis who is a former co-chair of the AGA's educational campaign on functional digestive disorders. What seems to have made Lotronex so appealing to patients, says Clouse, is that, unlike other drugs available, it helped control multiple symptoms.
While Public Citizen has questioned the drug's effectiveness, noting that clinical trials compared it only with a placebo and not other IBS drugs, Clouse says other products have not tested as well against a placebo.
But Roberts says the FDA and others underestimate the condition's devastating personal impact.
That is what the committee will have to weigh in considering what restrictions to apply should the drug be reintroduced. Almost inevitably, the committee's recommendations will involve some consumer inconvenience. Restrictions that took effect last week on the acne drug Accutane, which is known to cause birth defects, might serve as example. After reports showed that thousands of pregnancies were still occurring in women using Accutane despite stern warnings on the need for birth control while taking the drug, the FDA added safeguards. These mandate, among other things, monthly doctor visits, repeated pregnancy tests, informed consent and a sticker from the doctor that must be presented to the pharmacist before the drug can be dispensed.
Predictably, IBS sufferers want the fewest restrictions possible on Lotronex. In a survey, members of Roberts's group said they want prescriptions to cover a 90-day supply and prescribing authority accorded to all doctors -- not just gastroenterologists -- and they don't want to have to waive their legal rights in the event of serious side effects.
Public Citizen has said that the drug should be restricted to previous users -- primarily women -- who took it with no ill effects. (The original approval was only for women, who are more likely than men to have the condition). The group also wants: a patient consent form, which would note that ischemic colitis occurs in as many as one in 300 users of the drug; FDA guidelines on when patients who are concerned about the effects of the drug should contact their physician; and a list from Glaxo of all drug users and their physicians to allow periodic monitoring, assessment and data collection by the FDA. Neither the FDA nor Glaxo has yet made public their recommendations for a return of Lotronex.
The diverging pressures show why the new safety subcommittee is desperately needed, say drug experts.
Subcommittee members, announced several months ago, include such experts as Michael Cohen, director of the Institute for Safe Medication Practices, a nonprofit based outside Philadelphia that deals with medication error issues, and Ruth Day, a Stanford University psychologist who has worked on improving patient package inserts to communicate medication risk and safety. Ray Woosley, a consultant to the committee, is a former chairman of the department of clinical pharmacology at Georgetown University Medical Center who is now vice president for health affairs at the University of Arizona.
Future subcommittee tasks may include recommendations on how best to communicate drug safety information to patients and physicians. A 1998 article in the Journal of the American Medical Association, co-authored by Curt Furberg, a member of the new group, decried the lack of any FDA mechanism for ensuring that its warnings are followed. For example, the article noted, the FDA's post-approval warnings about the addictive nature of a narcotic drug, propoxyphene, did not reduce the number of prescriptions written for the drug or the overdose deaths associated with it.
After next week's meeting, the subcommittee is scheduled to meet twice more this year. While the FDA has not yet announced the agendas for those meetings, if Public Citizen's activity is any indication, they're likely to be full. Just in the last few weeks, the advocacy group has called for the banning of two medications that appear to cause serious side effects in some patients -- Meridia, a weight loss drug, and Arava, a drug to treat arthritis.
Francesca Lunzer Kritz is a regular contributor to the Health section.