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CIBA-GEIGY's ANAFRANIL (CLOMIPRAMINE) UNANIMOUSLY RECOMMENDED FOR APPROVAL BY ADVISORY COMMITTEE; REVIEW COMES 4-1/2 MONTHS AFTER NDA FILING

Executive Summary

Ciba-Geigy's Anafranil is safe and effective in the treatment of obsessive compulsive disorder (OCD) and should be approved for the indication, FDA's Psychopharmacological Drugs Advisory Committee unanimously agreed at its Dec. 1 meeting. The approval recommendation comes just four-and-a-half months after Ciba-Geigy submitted its NDA for the tricyclic antidepressant. Designated as a "1A" drug (a new molecular entity with significant therapeutic advantage over existing therapies), the agent has been on a fast-track review at FDA. Ciba-Geigy met with FDA in May 1986 to design Phase III studies for Anafranil (clomipramine), and the drug was made available to patients under a Treatment IND in August 1988. The development history behind clomipramine, however, is somewhat more extensive. Ciba-Geigy originally sought approval for use of the drug as an antidepressant in July 1975. That application was turned down the following year. The firm then began a clinical program for OCD in 1979, which it subsequently abandoned because of complications in sorting out the antidepressant effects of the drug. Clomipramine is currently marketed in approximately 70 countries for depression and/or OCD and has been available in some of those countries for over 20 years. The panel was quick to agree that clomipramine is effective in OCD, and instead focused most of its attention on safety issues related to dosing and pediatric use. The biggest safety concern with clomipramine is seizures, which occurred in 0.7% of the approximately 3,500 patients studied in the U.S., with a cumulative rate of 1.5% at one year. That rate is approximately five times the rate seen with most antidepressants. The two pivotal trials presented to the committee evaluated improvement in OCD symptoms from baseline in patients treated for 10 weeks with either clomipramine or placebo. In order to qualify for the trial, patients had to meet DMS III-R (Diagnostic and Statistical Manual) criteria for the disease, have a score of at least 16 on the Yale-Brown OCD Scale (ranges from 0 to 40, 40 being the most severe), and have a score of at least seven on the NIMH OCD scale (ranges from 1-15, 15 being the most severe). Patients with depression were only allowed in the trial if their primary diagnosis was for OCD. Both trials had a two week lead-in phase, followed by four weeks of titration. By week five, patients were all receiving 200 mg/day. Dosage in week five and six was in the 200 mg/day-250 mg/day range, and at week seven patients were allowed to be dosed up to 300 mg. * Both trials showed statistically superior results at week 10 compared to placebo and found patient improvement in the clomipramine-treated group beginning at week one. In one of the trials, the 118 clomipramine-treated patients dropped from a baseline Yale-Brown OCD Scale (Y-BOCS) score of 26 by approximately one point each week, ending the 10-week period with a score of 16. The 121 placebo patients remained essentially the same, dropping from 26 to 25 after 10 weeks. Clomipramine patients' scores on the NIMH rating scale dropped an average of roughly 3.5 points from their baseline score of 10, while placebo patients exhibited no change. Results in the second trial were almost identical, with the exception of the third efficacy variable -- the percentage of patients achieving at least a 35% drop in Y-BOCS scores from baseline. At week 10, 46% of clomipramine patients in the first trial achieved the 35% goal, while 63% of the 142 clomipramine-treated patients did in the second trial. Commenting on the efficacy data, FDA clinical reviewer Karin Kook, who presented the trial results, said: "The efficacy of clomipramine in doses of up to 250 mg/day has been demonstrated in two studies of adults who met DSM III-R criteria for obsessive compulsive disorder." Although she did not present pediatric study results, Kook noted that "efficacy has also been demonstrated in adolescents, aged 10 to 17 years of age, who were dosed at dosages up to 3 mg/kg/day." The adolescent study was of a similar design as the adult trials and found similar results, Kook said. The committee agreed that because few patients were treated at the 300 mg dose, and only for a limited time period, labeling should state that safety and efficacy of doses above 250 mg/day is unknown. Committee members had different views on the dosing issue. Several committee members pointed out that doses of greater than 250 mg might be associated with a greater incidence of side effects, while others argued for more flexible labeling, noting that nonresponders in the trials might benefit from higher doses. Committee member Markku Linnoila, MD, National Institute for Alcohol Abuse and Alcoholism, for example, said that certain patients may metabolize the drug at such a fast rate that 250 mg does not provide a therapeutic dose. Commenting on the dosing issue, Division of Neuropharmacological Drug Products Director Paul Leber, MD, said: "When you don't know much, my reaction is to take the posture that one should be fairly conservative . . . What I still don't know is if there's a residual of patients that will not respond no matter what dose you put them on. Without fixed dose studies that examine these things systematically, we're all flying by the seat of our pants . . . I think Markku is [probably correct], but what if he's not. Then we could be faced by an epidemic of seizures." The committee was also concerned about the limited amount of data in children and the absence of any information about the long-term effects on children. To address the shortage of data on long-term effects, the committee considered the possibility of asking Ciba-Geigy to do a post-marketing study. Linnoila, however, pointed out that once the drug is approved, it will be difficult to get a comparison group of untreated OCD children, making results hard to interpret. The committee unanimously agreed that it would not want to see clomipramine contraindicated in children/adolescents, and recommended instead that labeling include the number and ages of children treated with the drug in clinical trials. * Besides the seizure rate, the only adverse reaction identified by FDA as being beyond normal expectations for a tricyclic antidepressant was a 16% incidence of ejaculation failure and other less pronounced effects on sexual function, including changes in libido and orgasm.

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