Letter in the Lancet on Alosetron (Lotronex)
This letter, by Health Research Group Researcher Elizabeth Barbehenn, Ph.D., Deputy Director Peter Lurie, M.D., MPH and Director Sidney Wolfe, M.D., appeared in Lancet on December 9, 2000.
Alosetron for irritable bowel syndrome
Sir – Michael Camilleri and colleagues (March 25, p 1035)[1] report that alosetron is an effective treatment for irritable bowel syndrome (IBS). However, the US Food and Drug Administration (FDA) Medical Officer’s Review (now available at www.fda.gov/cder/approval/index.htm accessed on Nov 12, 2000), which we originally obtained through the US Freedom of Information Act, has led us to question some of the analyses presented in the article.
The graphic techniques used by Camilleri and colleagues greatly exaggerate alosetron’s efficacy. Their figure 3 presents the relative difference in pain and discomfort scores from baseline on a 0-4 scale for the treated and placebo groups. Presented this way, the drug seems effective. However, when we plotted the absolute data contained in the Medical Officer’s Review, the data points are almost superimposable (figure). The exclusion of the baseline data from Camilleri and colleagues’ figure 3, unusual in a graph of this type, has the additional effect of enlarging the Y axis, and creating an apparent greater benefit for the drug.
Trend in absolute pain and discomfort scores
The important finding that efficacy was confined to diarrhoea-predominant patients and was not evident among patients who alternated between diarrhoea and constipation (alternators) is relegated to a single sentence in the results. The FDA used this subgroup analysis as the basis for denying approval of the drug for use in alternators. Instead, Camilleri and colleagues concentrate overwhelmingly on the marginal benefits of the drug in the full study population, which they describe in their report’s title as IBS patients, obscuring the fact that they provide no evidence of benefit on the primary outcome variable in constipation-predominant patients (who were excluded) or alternators. This form of data presentation could lead to overprescribing.
Moreover, whether the diarrhoea-predominant patients even had diarrhoea is unclear. The medical officer reviewing the study stated: “Patients considered by investigators to fit the diarrhea-predominant subtype had at baseline … stool consistency values that were neither loose nor watery.”
The Medical Officer’s Review is dated Nov 4, 1999, well before Camilleri and colleagues’ report went to press. Since five of the six investigators are employees of the pharmaceutical company that generated these data, the Medical Officer’s Review should have come to their attention in time to be incorporated into the final draft of the report. These discrepancies raise important questions about data presentation in studies sponsored by pharmaceutical companies.
References
[1] Camilleri M, Northcutt AR, Kong S, Dukes GE, McSorley D, Mangel AW. Efficacy and safety of alosetron in women with irritable bowel syndrome: a randomised, placebo-controlled trial. Lancet 2000; 355: 1035-40.