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Executive Summary

Pfizer's sertraline approval is contingent on the completion of several pending studies requested by FDA on drug dissolution, food effects, and morning versus evening dosing. Based on submitted data, FDA's Psychopharmacological Drugs Advisory Committee recommended approval of the drug for the treatment of depression on Nov. 19. The advisory committee voted six-to-one (with two abstentions) that Pfizer's clinical data supported the drug's efficacy for the treatment of depression. The panel unanimously agreed to the drug's safety for that use. FDA Neuropharmacological Drug Products Group Leader Thomas Loughren, MD, reported to the committee that there are several areas in the Pfizer NDA "where we need a little bit more work." Putting the additional studies in perspective, Loughren pointed out that the chemistry and pharmacology data have been looked at "very carefully." Although not "finalized," Loughren said those reviews have found "no problems in either of these areas that would preclude approval of this product." FDA is requesting at least three types of studies, Loughren observed: "We still need to have dissolution studies. We still require additional food effects studies. We are going to want an additional study comparing the pharmacokinetics comparing morning dosing and evening dosing." FDA has determined that the product has "a very prominent food effect," Loughren noted. The availability of the drug "is increased roughly 40% when it is given with food compared to a fasting state." He further noted that the "clearance of the drug is diminished somewhat [approximately 40%] in the elderly compared to younger individuals." Loughren pointed out that that might have implications on dosing. On the dosing schedule, Loughren said that FDA does not know the lowest effective dose or dosing interval. He complimented Pfizer on conducting maintenance dosing studies. "We rarely have any direct data on continuation or maintenance efficacy in NDAs for depression even though this is an important clinical issue." Noting that the design of those studies "could have been improved," Loughren said Pfizer "ought to be commended for doing it." Loughren pointed out that Pfizer may do further Phase IV work following approval. "There are some clinical questions that remain," Loughren said. The company "has committed to doing an additional trial to try and address some of these clinical issues. The proposal would be to do this on a postmarketing basis." Sertraline is the second serotonin reuptake inhibitor for depression to be recommended for approval by the committee. Lilly's Prozac (fluoxetine) was approved by FDA in December 1987, two years after the drug cleared the advisory committee. Since its approval, Prozac has become the top-selling antidepressant agent and analysts expect worldwide sales of the drug to top $700 mil. this year. Pfizer's NDA for sertraline included data from six double-blind placebo-controlled trials in patients with major depressive disorder. Two of the trials were considered pivotal by FDA in demonstrating efficacy of the drug. Pfizer also presented a 44-week maintenance dose study, which FDA felt supported the drug's efficacy. Another trial comparing sertraline with amitriptyline found that amitriptyline was superior to placebo but showed no difference between sertraline and placebo. "The sponsor has provided two studies -- one of which is more consistent than the other -- that demonstrate the effectiveness of sertraline," FDA Neuropharmacological Drug Products Division Clinical Reviewer Hillary Lee, PhD, concluded. The more definitive study, an eight-week trial of 427 depressed patients from eight centers, compared a daily dose range of 50 to 200 mg sertraline to placebo and to amitriptyline 50-150 mg daily. Both sertraline and amitriptyline were statistically superior to placebo in their reductions of the Hamilton Rating Scale for Depression (HAM-D) total score and for depression item. Like amitriptyline, sertraline also statistically reduced the Clinical Global Impressions (CGI) severity item and Symptom Check List (SCL) depression factor and improved the overall CGI score. However, amitriptyline efficacy scores were generally higher than those for sertraline in the trial. "Results for amitriptyline are consistently numerically superior to those for sertraline," remarked FDA statistical reviewer Japobrata Choudhury, PhD. The results of a second pivotal study of 347 patients, conducted at eight centers over six weeks, were somewhat less consistent, FDA said, although most results were in the positive direction. Because patients received fixed doses of 50 mg, 100 mg or 200 mg sertraline, FDA's Lee said, they did not have time to adjust to the higher doses, leading to a high early dropout rate. "The high dose sertraline group has the smallest number of completers," Lee noted. "Only 42% completed the trial." Out of five efficacy variables, only two were statistically significant in the second trial, the HAM-D depression item and the Profile of Mood States (POMS) depression factor. The Hamilton Rating Scale for Depression total score for sertraline did not demonstrate consistent statistical significance over placebo. The HAM-D total score covers the widest range of clinical symptoms and includes side effects frequently experienced with sertraline, Lee said. Advisory committee member Robert Prien, PhD, branch chief of affective and anxiety disorders in the National Institute of Mental Health's Somatic Treatments Program, said that while he agreed that the first pivotal study showed a clear drug effect. From the second study, however, "the differences in mean scores between drug and placebo are marginal at best," Prien said. FDA Neuropharmacological Drug Products Division Director Paul Leber, MD, concurred that the two studies showed no more than "modest to minimal treatment effect." However, he added that the drug could be approved if the committee thought there was a enough of a difference between sertraline and placebo. "They are not big treatment effects, make no 'ands,' 'ifs,' or 'buts' about it," Leber said. The long-term maintenance dose study was deemed inconclusive by FDA because of the large number of investigators involved in the study, the inadequate definition of major efficacy variables, and various protocol violations. While data from the study could not be considered definitive because of the "serious protocol deficiencies," Lee noted that "the idea of including maintenance studies in an NDA for depression is one which the FDA would like to foster, because such studies more closely approximate the way antidepressants are used." Several advisory committee members criticized the design of five of the six studies Pfizer submitted in the NDA. "I think there is sufficient evidence for efficacy, though I hope that the lesson from today is that additional work will be well rewarded when it is put into the front end of studies," committee chairman Daniel Casey, MD, Veteran Affairs Medical Center Psychiatry Service, stated. The most skeptical remarks came from Makku Linnoila, MD, clinical director of intramural research at the National Institute of Alcohol Abuse and Alcoholism, who called the studies "deplorable." Linnoila commented: "One sees a premiere American pharmaceutical company bringing forward data from clinical studies where experienced academic clinical psychopharmacologists can pretty much a priori say that there are going to be difficulties." The committee also looked at two in-patient studies, which showed no superior treatment benefit with sertraline over placebo. Some committee members expressed concern that sertraline may not work as effectively in severely ill patients who are hospitalized. FDA argued that the studies lacked assay sensitivity and, therefore, no conclusions could be drawn from the in-patient data. "We had a very similar problem in making the decision about Prozac," FDA's Loughren noted. The problem was solved, he said, by including a statement in Prozac labeling, noting that "the antidepressant action of Prozac in hospitalized depressed patients has not been adequately studied." He said: "I think we are basically in the same situation here." One issue that has put Prozac in the spotlight recently has been reports of an increased incidence of attempted suicide among patients on the antidepressant. FDA presented results from the sertraline safety database of over 2,500 patients that showed no disproportionate number of suicide attempts among patients taking the drug. The committee agreed that there is no evidence to conclude that sertraline may increase suicide attempts in depressed patients. Pfizer has claimed that sertraline has lower central nervous system effects, like nervousness, agitation, anxiety and insomia, than Prozac. However, those comparisons may have to wait for the results of a head-to-head study with the two antidepressants that is now underway. Pfizer has said that study would be completed by early 1991 ("The Pink Sheet" Jan. 29, p. 15).



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