data
for establishing an effectiveness link between the IR effectiveness data and
the SR formulation.
There
was also the question of whether or not the sponsor would need to conduct an
additional bioequivalence study at the maximum recommended dose, since equivalence
for the IR and SR formulations had been established only at 300 mg/day. However, given the linear kinetics for the
IR formulation between 300 and 450 mg/day, there was an internal consensus that
no additional biopharmaceutics studies would be needed to support this
approval.
Two
chemistry deficiencies were noted in our 5-25-05 non-approvable letter, i.e.,
regarding stability data and environmental assessment, and these issues have
been adequately addressed in the 9-22-95 re-submission.
To
my knowledge, there are no other outstanding issues that would preclude the
approvability of this NDA.
2.0
LABELING REVISION
The
draft labeling included in the 9-22-95 resubmission of this NDA was
substantially deficient, primarily regarding the clinical sections. The major difficulty in my view was the
failure in the revised labeling to adequately emphasize the dose-relatedness
for certain important adverse events and to include in labeling incidence data for these events at bupropion
doses that are being recommended. It is
again important to note that the SR program failed to demonstrate the
effectiveness of bupropion SR, and consequently, we are relying on the IR data,
generally at higher doses than those used in the SR program, for our judgement [judgment]
about the effectiveness of the SR formulation.
In
the draft of labeling accompanying the approvable letter, I have substantially
re-written much of the clinical sections, and in other cases, I have embedded
requests for the sponsor to make revisions on the basis of data that they can
readily access. The draft labeling
contains numerous embedded comments explaining in detail why we are proposing
changes in their labeling, and I will comment more briefly here on some of the
key issues that were subject to revision.
CLINICAL
PHARMACOLOGY
Pharmacodynamics
The
sponsor added language suggesting a mechanism for the antidepressant action of
bupropion. Such language is not present
in currently approved labeling and its addition is contrary to what has in
recent years been our general approach in this section, namely, to neutrally
describe the pharmacology of a drug and simply
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