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Executive Summary

Burroughs Wellcome's antiepileptic drug Lamictal reduces seizure frequency as an adjunctive therapy for partial epilepsy in refractory adults, FDA's Peripheral and Central Nervous System Drugs Advisory Committee agreed at its March 20 meeting. The committee voted unanimously that the drug is safe and effective as an add-on therapy in adults with partial epilepsy. FDA Medical Reviewer John Feeney, MD, presented the committee with the efficacy data from three trials submitted by Burroughs Wellcome of Lamictal (lamotrigine). Four other controlled trials conducted by the company and reported in the NDA were not presented. Feeney said those studies all showed placebo to be worse than Lamictal with varying statistical significance. The three multi-center, double-blind, placebo-controlled trials presented to the committee enrolled a total of 355 patients with partial epilepsy. Inclusion criteria for the two U.S. studies (US 05 and US 06) required enrollees to be between 18 and 65 years of age, have at least four partial seizures per month, take no more than two concurrent anti-epileptic drugs (AEDs), have stable plasma levels of concurrent AEDs and no valproic acid, and have no progressive neurologic condition. The U.K. study (UK 35) allowed valproic acid, but only if the patient were taking a concomitant enzyme-inducing AED, and required the patient to have been on a stable dosage of any AEDs for the previous three months. Outcome variables for the three studies varied slightly, but all looked at total seizure frequency, number of seizure days per week, and a physician's global evaluation. The median seizure frequency at baseline of all patients enrolled in the efficacy studies was 3.0/week; the mean was 6.6/week. US 05 was the only parallel study conducted; US 06 and UK 35 were crossover designs. The 216 patients enrolled in US 05 received Lamictal 300 mg/day, 500 mg/day or placebo. A 12-week baseline phase was followed by 24 weeks of treatment and a subsequent taper phase. The treatment phase included about five weeks of dose titration and was split into two 12-week time frames. The "Sponsor's Preferred Analysis" of US 05, which only analyzed those patients who had completed each phase of treatment, found the median change in seizure frequency compared to baseline for weeks one through 12 to be approximately 20% for the 300 mg group and 31% for the 500 mg group, compared to about 11% for placebo. The median change compared to baseline for weeks 13-24 was roughly 23% for the 300 mg group, 32% for 500 mg and 14% for placebo. After 24 weeks of treatment, 191 of the original 216 patients in US 05 remained. Thirteen of the non-completers were in the 500 mg group and six in the 300 mg group, with most failing to complete the first 12 treatment weeks. Across all controlled U.S. studies, 8% of Lamictal patients dropped out due to adverse experiences and 1% for lack of effect. Among the placebo group, those figures were 4% and 1%, respectively. No deaths occurred in the U.S. studies. Across the entire database of 2,621 patients, 9.1% of Lamictal patients were discontinued due to adverse events, with rash accounting for 2.9% of discontinuations. Feeney noted that Burroughs Wellcome performed a parametric analysis on US 05 of the change in log-transformed seizure counts which found that in both times frames, the 300 mg group was not statistically significantly different from placebo, and that for the 500 mg group the difference from placebo was significant for weeks one through 12, but did not quite meet statistical significance for week 13-24. The US 06 crossover study consisted of an eight-week baseline period followed by two treatment periods of 14 weeks, including a two-week taper at the end of each, separated by a four-week washout. The median percentage change in raw seizure frequency between drug and placebo for 12 weeks of treatment was 20% under both the Sponsor's Preferred Analysis and FDA's intent-to-treat analysis. For UK 35, the median change in all partial seizures between drug and placebo was 22.9%, and the change in seizure days was 22.3%. All 41 patients enrolled in UK 35 completed the study and were included in the nonparametric analysis. The interaction of Lamictal with other AEDs elicited a series of questions by committee members. While Burroughs Wellcome indicated that measurements of plasma- levels of other AEDs in US 06 were found to be essentially unchanged throughout the 14-week Lamictal treatment period, committee member Antonio Delgado-Escueta, MD, Veterans Administration Medical Center, Los Angeles, noted that there was a higher frequency of certain adverse events, including dizziness and diplopia, in patients concomitantly treated with Lamictal and carbamazepine. Burroughs Wellcome's Nancy Earl responded that other AEDs have their own safety profiles but noted that the difference between the placebo and Lamictal groups in this respect indicated that "it could be an add-on effect." To address some of the committee's concerns about drug-drug interaction and the group's interest in establishing whether Lamictal exerts its effect through another drug or by itself, Burroughs Wellcome presented the information it had available regarding monotherapy with Lamictal. In open-label, uncontrolled studies, 69 patients have been converted to Lamictal monotherapy in the U.S. and 50 remain on treatment. Thirty percent of those 50 patients became and have remained seizure-free through an average of 19 months monotherapy. All but two of those who are seizure-free became so while still on polytherapy. At the time of NDA submission in January 1992, FDA's Feeney noted, there was some concern regarding the incidence of sudden unexplained deaths in epilepsy (SUDs) associated with Lamictal therapy. At that time, there were eight incidence of SUD. Feeney noted that the November 1992 expansion of the database improved the figures somewhat, but that FDA was "still concerned." Burroughs Wellcome convened a panel in Seattle on December 9, 1992, which did a blind analysis of all cases and established categories to aid in the definition of SUD: definite, probably or questionable, definitely not, and insufficient data. The group identified 16 definite and six possible SUDs in the 4,841 patients who had been exposed to Lamictal worldwide as of November 1992. The incidence density calculated was one per 262 patient years. The panel concluded that that was in the range expected, Feeney explained. While published studies generally have found an incidence rate between one in 370 patient-years and one in 2,000 patient-years, Feeney pointed out, the demographics are not available for a lot of those studies. In the last few months, Feeney said, reports from Europe have found higher rates of SUD in refractory patients, those who make up the Lamictal population. Feeney explained that it was "somewhat reassuring to us that perhaps the nature of the databases would explain the observed incidence of SUDs in this {Lamictal] population." In the absence of any data from controlled studies in children, the committee unanimously voted that the sponsor had not shown Lamictal to be safe and effective in the treatment of children with partial epilepsy. The group agreed that the results for adult patients could not be extrapolated to the pediatric group without information showing that the disease process and response to treatment is the same in the two populations. Burroughs Wellcome reported that it is planning controlled studies in the pediatric age group and in young adults. The experience the company has with patients under 12 years of age in open, uncontrolled foreign studies showed 46% of 285 patients withdrawn from treatment, 13% for adverse experiences and 24% for lack of effect. Lamictal is approved in 10 countries. Burroughs Wellcome submitted an application in Canada last summer that is under review.

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