NEW YORK, Mar 22 (Reuters Health) - Consumer advocacy group Public Citizen has petitioned the US Food and Drug Administration (FDA) not to approve Novartis Pharmaceuticals' Zelmac (tegaserod) as a treatment for irritable bowel syndrome (IBS), citing the drug's "questionable" effectiveness and "serious safety concerns."
IBS is a collection of gastrointestinal symptoms including bloating, severe abdominal pain, and cycles of constipation and diarrhea that do not fit into known disease categories. Novartis aims to have its drug candidate Zelmac approved to treat the constipation-predominant form of IBS, a nonfatal condition usually diagnosed in women.
Public Citizen's concerns about Zelmac stem from safety data that it received from the FDA this summer. Those clinical trial results showed that there were eight cases of ovarian cysts in women, who were all receiving the highest dose of the compound, the group said.
"All eight (study participants) developed symptoms in association with the use of Zelmac and five underwent hospitalization and surgery," the group said in its March 22 open letter to Dr. Janet Woodcock, director of the FDA's Center for Drug Evaluation and Research.
FDA reviewers have estimated that Zelmac recipients were three times more likely to develop cysts than placebo recipients were, Public Citizen asserts in the letter. The incidence of cyst development may be even higher, the group suggested.
Further, the development of cysts in Zelmac patients could have been anticipated, Public Citizen alleges. It noted that in animal trials the compound "caused a statistically significant, dose-related increase in their incidence."
In addition, the drug has not even been proven effective, Public Citizen maintains. "Only a minority of patients 'respond' to the drug and the absolute benefits conferred (compared to placebo) are not clinically significant," it said.
In only one of the key trials was effectiveness demonstrated, and even then the benefit "is very modest," Dr. Peter Lurie, deputy director of Public Citizen's health research group told Reuters Health. "Most people who are on this drug and who appear to get better are getting better because of a placebo effect, not because of the drug."
When Novartis Pharmaceuticals' first-completed pivotal study failed to achieve significant results for its two effectiveness endpoints--study participants' ability to relieve themselves and a decrease in abdominal discomfort/pain--the firm dropped the criterion of discomfort/pain, Public Citizen said.
Response to Zelmac was measured instead by participants' global assessment. By lowering the threshold of what it defined as relief, Novartis manipulated its results, Public Citizen said. Still, this tack "produced only one pivotal trial with a statistically significant result," the consumer group said.
"I can't tell you with certainty" that the FDA will indicate Zelmac to treat IBS, but "we're worried they will, because they seemed less concerned than we are about the ovarian cysts," Lurie said.
His discontent with Zelmac stems from his view that a toxic, yet ineffective drug, is being aimed at a non-life-threatening condition. Constipation-predominant IBS sufferers could be better served by the use of laxatives or a change in diet.
Novartis' Dr. Sam Sue, vice president of research and development for gastroenterology, said on Thursday that Novartis Pharmaceuticals Corp. "stands behind and affirms the safety and efficacy of Zelmac, and strongly refutes the claims made by Public Citizen."
The Swiss firm said that it would put together a more detailed and focused statement on the issue later in the day, he noted. As for Public Citizen's specific allegation that Novartis manipulated its Zelmac data by changing the discomfort/pain endpoint during its pivotal trials, Sue had "no comment on that at this time." |
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