NDA 20-358

Page 3

 

Study Results

 

Before commenting on the findings for these 3 studies, we thought it would be useful to provide our summary of the data, which we have done in Enclosures 2-5.  Enclosures 2-4 (Tables 1-3) summarize the 2-sided significance levels, by week, for pairwise comparisons of bupropion SR with placebo in the 3 studies (203, 205, and 212, respectively).  These are the results of analyses done on intent-to-treat samples and include the results of both LOCF and OC analyses.  Enclosure 5 (Table 4-6) summarizes treatment effect size data for these 3 studies, defined here as the difference between bupropion SR and placebo in mean change from baseline for HAMD-17 or –21 Total Score at week 8, for LOCF analyses.

 

Comments on Efficacy Data for Individual Studies

 

Our comments will focus on “positive findings,” i.e., p-values of ≤0.05, 2-sided, for either LOCF or OC analyses, favoring bupropion SR over placebo in pairwise comparisons for any of the 8 weeks of each study.

 

Study 203

 

(1)                 Unadjusted Results

 

The results in Table 1 were unadjusted for multiple comparisons, and even without such adjustment, these data did not suggest a consistent superiority for bupropion SR, at either dose, over placebo.

 

The results were strongest for the 150 mg/day dose group, in particular for CGI Severity and Improvement.  However, even for those variables, there was a loss of significance in the OC analyses beyond 5 weeks.  There was less consistent support for this dose on the HAMD-17 total score, i.e., positive findings at weeks 3, 4, 7, and 8, but only for the LOCF analysis.  There was very little support on either the HAMD-28 total score or the HAMD Item 1.

 

The results were weaker for the 300 mg/day dose group, with the most positive findings for CGI improvement on the LOCF analysis.  For 3 of the remaining 4 variables, there were positive findings only for week 8 in the LOCF analyses, except for an additional positive results for week 6 LOCF on CGI severity.  There were no positive findings for HAMD-28 total score.

 

(2)                 Adjusted Results

 

Given the two dose groups in this study, it was necessary to make an adjustment for multiple comparisons.  One approach was to use Dunnett’s test, which yielded a critical p-value of 0.025 for declaring any particular finding positive.  Using this criterion p-value, the positive findings on the CGI severity and improvement scores for the 150 mg dose group generally prevailed, however, there were virtually no positive findings on the 3 HAMD variables for the 150 mg/day dose group or for any of the 5 variables for the 300 mg/day dose group.

 

 

 

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