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NDA 20-358 |
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Since a second goal of your program, beyond
developing a sustained release formulation that you hoped would be associated
with a lower seizure risk, was to support a change in the recommended dose
range from the currently recommended range of 300-450 mg/day to a lower range,
i.e., 150-300 mg/day, you launched a series of clinical trials. While you recognized the need for clinical
efficacy trials to support such a chance, you unfortunately, embarked on this
program without sufficiently alerting us to your intentions and without seeking
our input.
A third goal of your program, and a corollary to
your primary motivation of developing a less seizurogenic formulation, was to
provide the support needed to modify labeling with regard to seizure risk. Your large open study designed to provide an
estimate of seizure risk with the new formulation, although described as a study
of the new formulation, was importantly also an examination of seizure risk
associated with a lower dose range.
We consider your bioequivalence program to have been
successful in achieving the goals stated above for that program. In fact, under steady state conditions at
the 300 mg/day dose, we believe that you have shown equivalence for parent drug
with regard to both rate and extent of absorption (i.e., for bupropion SR 150-
mg bid vs bupropion IR 100 mg tid). For
that major metabolites, which appear to be the predominant active species of
this drug, there is no question about your having met the test of equivalence
with regard to both rate and extent of absorption under steady state conditions
at the 300 mg/day dose. Although the IR
and SR products are not bioequivalent during the interval prior to attainment
of steady state, we do not believe this would bar a conclusion of overall
bioequivalence for a chronically administered product, such as an
antidepressant. We would therefore be
prepared to approve the sustained release tablets at a dose of 300-400 per day.
In absence of additional studies that demonstrate
the effectiveness of bupropion SR in the 150-300 mg/day dose range, it would
not be possible to approve the SR formulation in the proposed dose range. For the reasons detailed below, we do not
believe you have shown bupropion sustained release tablets to be effective at
these doses.
Deficiencies in the Efficacy Data
We examined studies 203, 205, and 212, i.e., your
randomized, placebo-controlled trials in depressed outpatients utilizing
bupropion SR doses ranging from 100 to 400 mg/day, focusing on the following
variables as key measures of an antidepressant effect: HAMD-17, HAMD-21, and
HAMD-28 Total Scores; MADRS Total Score; HAMD Depressed Mood Item (Item 1):
CGI-Severity; and CGI-Improvement. We
considered both last-observation-carried-forward (LOCF) or observed-cases (OC)
analyses.
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