Rimonabant, R.I.P.

Sanofi's drug had seemed simple enough: It was designed to flip a common experience of cannabis smokers on its head. When cannabinoids bind to the CB1 receptors in the brain, the user experiences a sudden burst in appetite—commonly called "the munchies." By blocking the receptors' ability to bind the body's internal cannabinoids, known as endocannabinoids, the drug would reduce hunger and help obese people resist the temptation to overeat. Sanofi's new medication did meet its weight-loss end points; according to Chang, rimonabant trial subjects lost an average of 4.5 percent and 4.7 percent (according to dosage) compared to placebo in different Phase III trials,

The drug was launched in 18 EU countries, beginning with the UK in June 2006, under EMEA's conditional approval. But reports of psychiatric side effects limited its use, excluding patients with major depression. According to Wolters Kluwer, in May 2008, as adverse-events reports piled up, the European agency updated the label to indicate that depression may occur as a side effect in patients with no symptoms other than obesity. And more trouble surfaced in the US. After FDA issued an approvable letter in February 2006, the agency's advisory board voted 14-0 against recommending approval just four months later, stating that Sanofi had failed to provide sufficient safety data to demonstrate that rimonabant's benefits outweighed its risks. "The potential market for this drug and the continued uncertainty about its risks, both known and unknown, lead to our concern about the use of this drug in the general population," FDA staff medical reviewer Amy Egan told The New York Times. Egan's analysis indicated that the drug doubled a patient's risk of problems like anxiety, depression, aggression, and psychosis, while other data showed a rise in suicidality, including three suicides during clinical studies, according to the Times.

FDA is all but certain to maintain its careful monitoring of safety signals for obesity drugs. Cuttler, for one, expects the agency to extend the tighter cardiovascular standards for diabetes drugs to obesity therapies as well. But the agency's new Risk Evaluation and Mitigation Strategy (REMS) framework promises to enable drugmakers to begin working with national health authorities to develop strategies to report and control risk as they seek NDAs.

For CNS drugs being tested in obesity trials, new methods of identifying suicidality and other psychiatric risks may provide not only more accurate safety data, but also a better shot at approval. "Whether or not these drugs cause a risk is the critical question we have to answer," says Kelly Posner, a child psychologist and research scientist at Columbia University, who helped develop the new data-collection tools. "But up until now, none of the studies were set up to answer that question."

According to Posner, who helped FDA classify the suicide signals that sunk rimonabant, the data were troubling. Based on retrospective adverse-event reporting, they were not only inconsistent and poorly defined but tended to inflate the incidence in the drug group, because patients on a drug typically have more side effects and therefore more opportunity to talk to doctors about suicidality. This unbalanced counting problem is called "ascertainment bias."

The new methods correct this problem by prospectively monitoring a trial's participants—asking every patient across drug and placebo the same pre-determined questions on every visit. "We have obesity studies where, when we relied on spontaneously generated adverse events, there were approximately 450 [suicidality] hits," Posner says. "When we relied on prospective monitoring, there were about 12." (See "Should Rimonabant Get a Second Chance?").

The Five Percent Solution

FDA requires that an obesity drug to meet either one of two efficacy requirements. The top-ranked criterion is that patients on treatment lose an average of five percent more body weight than patients on placebo. Failing that, an NDA can win approval if it achieves what is referred to as "categorical efficacy," requiring that at least 35 percent of subjects in the drug group lose more than five percent of their body weight; this percentage must then be at least twice the percentage of those who lose more than 5 percent in the placebo group. In other words, if the drug does not work for everyone, it at least works well enough for a sizeable population.

While a 5 percent loss of body weight may not make a cosmetic difference for most obese people, it can provide significant health benefits, particularly by improving blood pressure, cholesterol, and blood glucose levels. Yet what's sufficient for FDA approval may not win over large numbers of doctors. "We've done some work surveying physicians, and they really want a drug to be in the double-digit weight-loss range," Wong says. Still, some prescribers are likely to take the chance that a patient may respond very well to a specific drug. Others may prescribe a drug for the metabolic benefits of modest weight loss.