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NDA 20-825 for ziprasidone in the treatment of schizophrenia
was originally submitted March 18, 1997. A not-approvable
letter was issued to Pfizer for this NDA on June 17, 1998,
based on “the judgement that ziprasidone prolongs the QTc
and that this represents a risk of potentially fatal ventricular
arrhythmias that is not outweighed by a demonstrated and
sufficient advantage of ziprasidone over already marketed
antipsychotic drug products.” This judgement was based on
a finding in the short-term, fixed dose, placebo-controlled
phase 2/3 studies of a dose-related tendency for ziprasidone
to increase the QTc. The size of the QTc increase compared
to placebo was about
: 10 msec at the 160 mg/day dose. In addition, we raised
the concern that the 10 msec increase observed may have
represented an underestimate, given the fact that most ECGs
were likely obtained at trough ziprasidone plasma levels,
and Cmax plasma levels might be expected to be at least
double those seen at trough. The June 17, 1998 letter expressed
the view that the size of the QTc increase
is a factor in determining the degree of risk of ventricular
arrhythmias, and further, suggested that “we would find
QTc prolongation at maximum blood levels in the 5- 10 msec
range, with adequate assurances that there are very few
outliers and that there are no factors that lead to substantially
greater values in individuals (such as drug-drug interactions)
sufficiently reassuring, in the absence of contrary evidence,
to. support approval of a new antipsychotic such as ziprasidone.”
The letter recommended further study to determine the QTc
effect of ziprasidone at peak plasma concentrations, in
comparison with other atypical antipsychotics and with several
standard antipsychotics.
Pfizer has since conducted Study 054, a head-to-head safety
comparison of ziprasidone at its optimal dose with several
other antypsychotics at their optimal doses (haloperidol,
thioridazine, olanzapine, risperidone, and quetiapine),
with ECGs obtained at estimated Tmax for each of these drugs.
This study also included a phase adding a metabolic inhibitor
for each of these drugs to determine the additive effects
on QTc of what would be expected to be maximal inhibition
of the clearance of each of these drugs.
In summarizing the results of study 054, Pfizer has stated
that this study reveals an effect on QTc prolongation approximately
10 msec greater than that observed with 4 of the comparision
drugs (i.e., haloperidol, olanzapine, risperidone, and quetiapine),
and an effect on QTc prolongation .approximately 10 msec
less than that observed with thioridazine. We are in agreement
with Pfizer on this finding of,the relative placement of
ziprasidone vs the other drugs in this study, i.e., a QTc
prolongation 10 msec greater for ziprasidone compared to
these 4 drugs and a 10 msec lesser effect compared to thioridazine.
Regarding the increases from baseline observed for the other
drugs in study 054, it is not clear, in our view, whether
the observed QTc increases represent actual drug-related
effects or represent placebo effect, since we have an abundance
of data from multiple independent development programs showing
no difference between haloperidol (at the oral dose used
in study 0’54) and placebo on QTc.
We are also in general agreement with Pfizer on the antipsychotic
efficacy of ziprasidone based on the short-term, fixed dose,
placebo-controlled phase 2/3 studies. Of note, however,
we are not aware of any evidence from these or any other
studies of any superior antipsychotic efficacy for ziprasidone
compared to any other antipsychotic drugs, either in typical
schizophrenic patients or in those shown refractory to standard
antipsychotic therapy. The planned program for the July
19th meeting will begin with presentations by Pfizer of
the overall antipsychotic efficacy and safety of ziprasidone,
with a particular emphasis on the findings pertinent to
QTc prolongation. FDA presentations will follow, and will
also focus on the issue of QTc prolongation and risk of
ventricular arrhythmias. These presentations will include
data and discussions regarding other drugs with findings
pertinent to the issue of QTc prolongation, such as terfenadine,
sertindole, thioridazine, and the quinolones. An update
will be provided on a labeling change recently implemented
for the drug thioridazine.
The general questions for the committee will focus on the
s.afety and efficacy of ziprasidone for the treatment of
schizophrenia. In particular, the critical safety question
will be the relevance of the 10 msec prolongation of the
QTc observed for ziprasidone, and not for several other
antipsychotic drugs included in study 054, for the approvability
of this drug. Besides this memo, FDA’s package for this
meeting includes a draft review of study 054 from the Division
of Cardio-Renal Drug Products. This draft review reaches
a conclusion that ziprasidone’s greater QTc prolongation
effect than observed with a number of other antipsychotic
drugs is predictive of a greater risk of potentially fatal
ventricular arrhythmias for ziprasidone compared to these
other drugs, and that this greater risk should, in the absence
of a demonstration of some other greater benefit of ziprasidone
compared to. these other drugs, lead to either the non-approval
of ziprasidone or a second line status for this drug. It
is important to note that the Divisiion of Neuropharmacological
Drug Products and ODE-I have not yet reached a conclusion
on this important question, and it is primarily for this
reason that we have scheduled this meeting.
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