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.
The study outcomes were significant. Over the two-year study period, the probability of a significant suicide attempt or hospitalization to prevent suicide was lower with Clozaril (24 percent) than olanzapine (32 percent). Those findings translate into patients being treated with Clozaril having a 24 percent lower risk of suicide attempt or hospitalization to prevent suicide compared with olanzapine-treated patients.
During the PDAC’s discussion, some members felt that the agency’s methodological concerns were "appropriate and valid."
Yet members noted that one of the most "startling findings" of the study was that Clozaril’s effect on suicidal behaviors appears to be independent of the overall severity of the patient’s symptoms. Ratings scores on the PANSS and CGI as well as other measures were not significantly different between the patients taking Clozaril and those taking olanzapine. PDAC members said that indicates that the reduction in suicide is independent of the patient’s general improvement.
"Given the seriousness of such behavior, we clearly need specific treatments," noted Dilip V. Jeste, M.D., the Estelle and Edgar Levi Chair in Aging and a professor of psychiatry and neurosciences at the University of California at San Diego.
"While drugs alone will not treat suicidal behavior," Jeste told Psychiatric News, "and must be combined with psychosocial interventions, there is growing evidence to suggest some biological basis for suicidal behavior."
Steven Potkin, M.D., a professor of psychiatry at the University of California, Irvine, and a clinical investigator in the study, hailed the committee’s vote. "The InterSePT study suggests that clozapine should be a first-line treatment consideration in acutely suicidal patients with schizophrenia regardless of their stage of illness and should not be limited to treatment of refractory patients. Its conclusions should offer new hope to suicidal schizophrenia patients."
Potkin said the results are especially significant because the study’s methods closely mirrored real-world conditions of treatment for patients with schizophrenia. "Given the nearly 3 million patients in the United States with schizophrenia and schizoaffective disorder, and a 9 percent suicide rate, as many as 60,000 lives may be saved by treatment with clozapine," Potkin told Psychiatric News.
An FDA spokesperson indicated no clear timetable for final approval of the application; however, a Novartis spokesperson noted that the company is hopeful that an approval letter would be received in the first quarter of 2003.
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. ▪