Testimony of Sidney M. Wolfe M.D., Director, Public Citizen’s Health Research Group
Drug Safety Advisory Committee
Hearing Concerning Alosetron (Lotronex)
In August, 2000, almost four years ago, we petitioned the FDA to ban alosetron because, in our view, its serious, life-threatening adverse effects outweighed the marginally better-than-placebo effectiveness. At the time of our petition, the FDA was aware of 26 cases of ischemic colitis in people using alosetron. In the major randomized, placebo-controlled clinical trials prior to approval there had been three cases of ischemic colitis in 832 patients (1/277) on alosetron, but none in 700 placebo patients. According to an FDA memo, in one large trial with adequate ascertainment of ischemic colitis, 10 out of 1819 women being treated with alosetron for diarrhea-predominant irritable bowel syndrome (IBS) developed ischemic colitis over the 24-week duration of the trial (S3B30020). There were no cases in the 899 patients in that trial treated with traditional therapy. By the time marketing was stopped in November, 2000, there had been 85 cases of ischemic colitis reported to the FDA among the estimated 275,000 patients who had used the drug.
Since drug safety must always be viewed in the context of drug benefit, a review of the evidence of benefit for alosetron in the treatment of diarrhea-predominant irritable bowel syndrome is appropriate. In an analysis we published in the Lancet of data from one of the clinical trials,a so-called statistically significant effect has little clinical relevance. As seen in the figure on the next page from the Lancet article, on a scale of 0 to 4 for abdominal pain/discomfort, alosetron relieved their symptoms barely more than a placebo. The dose used in that trial was 2 milligrams per day, twice the starting dose in the current phase of marketing alosetron.
This excellent, hard to exceed, placebo response rate is consistent with the findings from a review of 27 randomized placebo-controlled studies testing various treatments for irritable bowel syndrome. The median placebo response rate was 47% (measured as % improved) with rates as high as 84%, and 11 studies had placebo response rates of 60% or greater. Unlike alosetron, placebos do not cause ischemic colitis.
Because IBS is a poorly defined disease, which, although capable of causing significant distress in some individuals, is neither progressive nor life-threatening, the occurrence of serious adverse reactions to alosetron, such as ischemic colitis sometimes requiring surgery, tips the risk-benefit equation against using the drug.
Lotronex Risk Management Program (RMP)
The experience during the first 1+ years of the alosetron risk management plan has hardly, as GlaxoSmithKline (GSK) has stated, “been successful.” Among the problems, somewhat predictable because of the lack of the kinds of controls that could realistically be taken only under an IND, were the following:
- 20% of the patients getting the drug did not have all of the three criteria specified for getting a drug; frequent/severe abdominal pain; frequent bowel urgency/fecal incontinence; and disability/restriction of daily activities
- only 42% of patients with a Lotronex prescription pre-enrolled in the Survey Program and only 36% completed a baseline questionnaire
- 20% of prescribing doctors not enrolled in the prescribing program for Lotronex
The most alarming finding during this period was the reporting of eight cases of ischemic colitis and, according to the manufacturer, eight additional cases of “complications of constipation.” The latter included a case of partial intestinal obstruction, one in which there was exploratory surgery for small intestinal obstruction, and a patient with diarrhea and intestinal obstruction.
Assuming the accuracy of the GSK estimate of 9,365 patients getting alosetron during the RMP, the rate of ischemic colitis reports (8/10,000 patients or 0.85 per 1,000) is actually higher than the rate of spontaneous reports during the earlier 2,000 marketing, before market withdrawal (85/275,000 patients or 0.31 per 1,000).
There are differences in the conditions for reporting that might explain some of this discrepancy but not all of it. Enrolled physicians agreed to report all serious adverse events as a condition of participation. However, four of the eight cases of ischemic colitis were reported by patients, not physicians. Similarly, none of the eight cases of serious complications of constipation were reported by the prescribing physician (one was reported by a nurse). Either the patients did not tell the physicians who prescribed the drug that they had gotten ischemic colitis or physicians violated their agreement to report such cases.
The fact that 11 of the 16 cases of ischemic colitis or complications of constipation were reported by patients as part of the Lotronex Patient Follow-Up Survey Program may compensate for some, but not all, of the serious reporting deficiencies by the participating physicians. There is little question that just as the 85 cases of ischemic colitis reported during 2000 were but a fraction of the actual cases, so too are these recent RMP ischemic colitis cases.
For effective, life-saving drugs, such as some cancer therapies or the anti-psychotic drug, clozapine, risk management is a critical part of their use and we support such efforts. But alosetron joins an increasing number of other drugs, none with unique, clinically significant benefits, that have been the subject of ultimately failed FDA-approved risk management programs (the diabetes drug Rezulin, the pain-killer Duract, the gastrointestinal drug Cisapride, the blood pressure drug Posicor) and were taken off the market.
When I testified before this committee in 2002, I stated that “The reintroduction of Lotronex into the market, even with the restrictions proposed by Glaxo, would be a serious public health mistake, likely, if not certain, to result in the need to ban the drug again.” It is time to end this failed effort to resuscitate marketing, and to take alosetron off the market again. As we suggested in 2002, there is no reason why, under a carefully controlled IND, the drug could not be made available to the several thousands of people who might still choose to use it. This has previously been done for the diabetes drug phenformin and the gastrointestinal drug cisapride after their marketing we terminated.
Given the marginal evidence of effectiveness and the continuing serious risks of the drug, Glaxo’s suggestion to relax the restrictions on availability of alosetron to increase its use is nothing but ghoulish:
The primary concern at present relates to the low rate of product prescribing given our understanding of the target population size. This may reflect unintended barriers to prescription to the extent that appropriate and needy patients are being underserved. Alternatives designed to redirect or remove some of the unintended barriers from the physician and from the patient are required if Lotronex is to address the significant unmet medical need of appropriate women with severe diarrhea predominant IBS. Our goal is to work with the FDA to modify the RMP for Lotronex to improve product access for appropriate physicians and patients while continuing to effectively manage risk. (from page 87, GSK Briefing Document)
 Memo from Zili Li, MD, MPH, FDA, 3/15/02, Reevaluating the risk of ischemic colitis and its association with alosetron among female IBS patients in the United States.
 Barbehenn E, Lurie P, Wolfe SM. Alosetron for irritable bowel syndrome. Lancet 2000; 356(9246):2009-10.
 Spiller RC. Problems and challenges in the design of irritable bowel syndrome clinical trials: experience from published trials. Am J Med 1999; 107:91s-97s.
 These results of the program are from the GlaxoSmithKline briefing document for this hearing.