FDA Likely to Approve Antipsychotic To Prevent Suicidal Behavior

Novartis Pharmaceuticals last month won the influential support of the Food and Drug Administration’s Psychopharmacological Drugs Advisory Committee (PDAC) for the company’s application to label Clozaril (clozapine) “for the treatment of emergent suicidal behavior in patients with schizophrenia or schizoaffective disorder.”

The PDAC’s vote was 8 to 0 in favor of the indication, with one abstention. Although the FDA is not bound by the vote—final approval rests with agency regulators, not the advisory committee—the agency only rarely disagrees with committee recommendations.

If the FDA does grant final approval, which according to FDA documents is highly likely, the drug will become the first medication to be indicated for suicidal behavior.

The PDAC meeting, held November 4, was unusual in that the committee was asked to consider an application for marketing of a drug that the agency had already deemed approvable. More commonly, the committees are asked to weigh in on a drug application prior to any official action by the agency. However, according to Thomas Laughren, M.D., the FDA’s team leader for psychiatric drug products, the agency had reached a preliminary conclusion that the drug was approvable, yet questions remained.

“There are questions and issues of sufficient importance,” Laughren told committee members, “that we felt it would be useful to bring this application to the PDAC for independent feedback prior to our taking a final action.”

The FDA first asked the committee to consider whether the agency’s concerns about the methodology of the primary clinical trial submitted to support the application were sufficient enough to block approval. Second, the agency asked the committee to determine whether the single trial was sufficient to prove the medication safe and effective.

“Ordinarily, of course,” Laughren said, “at least two adequate, well-controlled trials are required. However, effectiveness can also be established on the basis of a single well-controlled trial and ‘confirmatory evidence.’ ”

Third, Laughren noted, the agency was seeking input on the new claim itself, a drug to be used specifically to treat suicidal behavior.

The single clinical trial submitted by Novartis was the International Suicide Prevention Trial (InterSePT). The study involved 980 patients with schizophrenia or schizoaffective disorder in 11 countries.

The investigators sought to study the comparative rates of hospitalization for imminent risk of suicide and significant suicide attempts in high-risk patients randomly assigned to receive either clozapine (300 mg to 900 mg a day) or olanzapine (Zyprexa) 10 mg to 20 mg a day).

The study was an open-label design with blinded raters, and treating psychiatrists were free to use any interventions, including additional pharmacotherapy, as needed, based on their clinical judgment. This was a significant concern for the FDA. The agency questioned whether the study results were biased by treating psychiatrists knowing which study drug each patient was on and whether the data were further confounded by use of multiple other psychiatric drugs in most subjects.

Documents pertaining to the application and pending approval of Clozaril to treat suicidal behavior, including proposed final labeling, are posted on the FDA’s Web site at www.fda.gov/ohrms/dockets/ac/cder02.htm. ▪