Janet Woodcock, M.D.
Director, Center for Drug Evaluation and Research
Food and Drug Administration
5600 Fishers Lane
Rockville MD, 20857
Dear Dr. Woodcock:
Zelmac, Zelnorm (tegaserod) is a drug for constipation-predominant Irritable Bowel Syndrome (IBS) for which FDA issued an “approvable” letter in August 2000 pending the submission of further clinical data. We presume that an important reason for the request for more data was related to tegaserod’s being implicated in the production of ovarian cysts since that was a major cause for concern in the Medical Officer’s Review and the FDA Advisory Committee discussion.
According to information presented to the Zelmac Advisory Committee meeting, tegaserod was associated with nine cases of ovarian cysts in women in clinical trials, eight of whom were taking tegaserod, all on the highest dose of this drug. All eight developed symptoms and five underwent hospitalization and surgery (one placebo patient had polycystic ovarian disease that did not require surgery). FDA reviewers estimated that the risk of ovarian cysts was three times higher in tegaserod than in placebo recipients. The presence of ovarian cysts was not surprising since, in animal studies, tegaserod caused a statistically significant, dose-related increase in their incidence and the receptor for tegaserod is present in human ovaries.
The FDA obviously remains concerned about the safety of tegaserod as evidenced by the recent non-approvable letter (June 18, 2001) requesting additional data on causes of the increased amount of abdominal surgery in women using this drug. However, to our knowledge, no clinical trials conducted thus far have used ultrasound monitoring (which would detect ovarian cysts even if they were not yet symptomatic); such trials have the potential of providing a definitive answer as to the role of tegaserod in ovarian cyst formation. The requested trial presents an obvious opportunity to obtain ultrasound data that would help answer the question of tegaserod’s role.
Yet, this trial using ultrasound may not happen: we have obtained an internal Novartis document dated July 3, 2001 that is especially disturbing since it indicates that Novartis is planning to perform still another clinical trial with tegaserod that will, again, not incorporate ultrasound monitoring. Rather than do the study in a way that would address legitimate safety concerns, they have hired an “external expert” to rationalize away the problem of ovarian cysts and concluded: “Novartis therefore does not feel [it] necessary to conduct special gynecological investigations (e.g. ultrasound) in the planned study with tegaserod in female patients with chronic constipation.”
Thus, in spite of 1) clinical trials that indicate a 3-fold increase in ovarian cysts, many of which required surgery, 2) the presence of receptors for tegaserod in human ovaries which makes them a potential target for the drug, and 3) a dose-related increase in incidence of ovarian cysts in animal studies, Novartis continues to insist there is no problem. The company knows that if they have to use ultrasound to monitor women, evidence might accumulate that tegaserod does indeed induce ovarian cysts, and this they do not want to happen as it might doom their drug. Therefore, they insist that there is no problem and that they should not be required to monitor for ovarian cysts in their next clinical trial.
Ultrasound monitoring in a properly designed clinical trial setting, however, is the only way to settle this important issue. Tegaserod is a drug that is, at best, minimally effective and that may be causing substantial harm. We urge the FDA to insist that ultrasound is utilized in any future trials, both before and after treatment, and in sufficient numbers of women to answer this vital question.
Elizabeth Barbehenn, Ph.D.
Sidney M. Wolfe, M.D.
Public Citizen’s Health Research Group
 FDA Preliminary Medical/Statistical Review for Zelmac; June 26, 2000.
 Dr. Raymond Joseph, FDA; Advisory Committee Transcript for Zelmac; June 26, 2000; p.154.
 FDA Preliminary Medical/Statistical Review; June 26, 2000, p.16.
 FDA Preliminary Medical/Statistical Review; June 26, 2000, p.17.
 Bach T, Syversveen T, Kvingedal AM, et al. 5-HT4(a) and 5-HT4(b) receptors have nearly identical pharmacology and are both expressed in human atrium and ventricle. Naunyn-Schmiedeberg’s Arch Pharmacol 2001;363:146-160.