DEPARTMENT OF HEALTH AND HUMAN SERVICES Public
Health Service Food
and Drug Administration Cardio-Renal
Advisory Committee Questions Pravastatin/Aspirin 18
January 2002
_________________________________________________________________
The
Cardio-Renal Advisory Committee is asked to opine on the benefits and risks of
a fixed-dose combination product consisting of pravastatin and aspirin for use
in patients who are prescribed these two products as individual entities. It is common knowledge that FDA will accept
applications for fixed-dose combination products when 2 (or more) approved
drugs are commonly prescribed together, for convenience (and perhaps for better
compliance).
In
discussions of such products, we have said that availability of such
convenience formulations should not alter health care provider’s prescribing
practices (e.g. by not providing a
full range of useful doses). Generally
that means that a full range of dosing strengths of each individual entity
should be available for the combination product, thereby providing convenience
but not influencing selection of doses or dosing regimens of individual
entities.
Further,
the Division has asserted that it should be well established that both entities
should be taken concomitantly, since the existence of a fixed-dose combination
product implies that they should be
taken together not just that they can
be taken together. Generally speaking,
the Division has required for fixed dose combination antihypertensive products
that the effects of the combination (A + B) be greater than the effects of
either one alone (A or B). Moreover,
the effects of several doses of A in combination with several doses B be
evaluated (often in a factorial trial) so that some description of the use of
A+B can be compared with either A or B alone.
The
sponsor has chosen a single dose of pravastatin (40 mg) and two doses of
buffered aspirin (81 and 325 mg) to combine.
Thus there will be two formulations of the fixed-dose combination
marketed, 40 mg pravastatin/81 mg buffered aspirin and 40 mg pravastatin/325 mg
buffered aspirin. Although initial
marketing will be accomplished by co-packaging, formulations of fixed-dose
combinations have been prepared and are awaiting completion of stability
studies. The fixed-dose combinations
will be marketed as soon as data are available. Although the application is for a co-packaged product, the
Advisory Committee is asked to consider the issue the same as that of marketing
of a fixed-dose combination product.
Pravastatin is approved for use in a) Primary
Prevention in those individuals at increased risk for atherosclerosis-related
clinical events as a function of cholesterol level, the presence or absence of
coronary heart disease, and other risk factors, b) Secondary Prevention of
cardiovascular events, total mortality and stroke, and c) for the treatment of
Hyperlipidemia.
Aspirin is for use in the following patient
populations: a) Secondary Prevention of
death and stroke in patients who have had Transient Ischemic Attacks, or stroke
(all CNS indications related to thrombotic events), b) Secondary Prevention in
patients who have survived a myocardial infarction, and c) patients who are
suspected of having an acute myocardial infarction, patients with unstable
angina, and patients who are having revascularization procedures (coronary or
carotid) who have underlying occlusive vascular disease. Aspirin is given for life, according to the
dosing and administration section for patients who have had unstable angina or
PTCA.
1.0
Can you
define a patient population for whom pravastatin plus buffered aspirin would be
indicated?
1.1
If yes,
please define the population; this would be the population named in the indications
section for the combination product.
1.2
Are there
patient populations where there might be net harm from giving both pravastatin
and buffered aspirin together?
1.2.1
If so,
please define some of these populations.
2.0
There are
no data from any trial prospectively-designed to test the hypothesis that
pravastatin (at any dose) plus
buffered aspirin (at any dose) produced a better clinical outcome (measured by
any clinical end-point) than either pravastatin or buffered aspirin alone.
2.1
Is that
sufficient reason to cease
consideration of approval of the fixed dose combination product? In other words, is it necessary to have the
results of specifically designed controlled clinical trials to consider
approval of this fixed dose combination product?
2.2
If not,
what might be sufficient?
3.0
One could argue that, for the patient
population you have defined, since the purported mechanisms of action for the
demonstrated clinical benefit of each agent are very different (something to do
with lipids for pravastatin and something to do with platelets for aspirin),
showing that there were no important pharmacokinetic or pharmacodynamic
interactions (using surrogates) would be an adequate basis for approval of the
fixed dose combination product.
3.1
Do you
agree with this? If so,
3.1.1
Are there
sufficient data present to support the presence of or lack of significant
pharmacokinetic interaction?
3.1.2
Are there
sufficient data present to support the presence of or lack of significant
pharmacodynamic drug interaction?
4.0
The
sponsor has provided 3 different meta-analyses (data from 5 placebo-controlled
trials, the total number of randomized patients being 14,617) that address
whether or not administration of pravastatin plus buffered aspirin has a greater effect than either buffered
aspirin or pravastatin alone. Some of
the selected trials required that patients have greater than normal levels of
serum cholesterol; others did not.
4.1
Do these
14,617 randomized patients represent a reasonable approximation of the patients
for whom this combination product would be indicated?
4.2
From the
results of the meta-analyses, do you conclude that the data show that
pravastatin plus buffered aspirin
has a greater effect than either buffered aspirin or pravastatin alone;
4.2.1
Using as
a standard of 2 trials at a p< 0.05, is the strength of evidence from the
meta-analyis as strong as this standard?
4.2.2
Using as
a standard of one trial at a p< 0.05, is the strength of evidence from the
meta-analysis as strong as this standard?
4.3
Which of
the models offered by the sponsor (Cox Proportional Hazard, Bayesian
hierarchical Cox proportional hazards, or Model 3) is most supportive, are they
all equally supportive, or are they equally non-supportive?
5.0
Upon what
basis was the dose of buffered aspirin chosen, for use in the fixed-dose combination
product?
5.1
Do you
consider this reasonable?
5.2
What
alternative doses can you recommend?
5.3
Should
one wait, prior to approval, on settling the question of buffered aspirin dose?
6.0
Upon what
basis was the dose of pravastatin chosen, for use in the fixed-dose combination
product?
6.1
Do you
consider this reasonable?
6.2
What
alternatives can you recommend?
6.3
Should
one wait, prior to approval, on settling the question of pravastatin dose?
7.0
Assuming
that you have concluded something about the strength of evidence that pravastatin
and buffered aspirin should be taken together and that the doses to be
available in the fixed- dose combination product are appropriate, what is the
strength of evidence that a fixed-dose combination product (taking a single
pill), has increased clinical benefit with respect to taking two pills (not
necessarily together)?
7.1
Should we
require better demonstration of additional benefit provided by “convenience”?
7.2
What kind
of demonstration would be better?
8.0
How
likely is it that the availability of the fixed dose combination product would
encourage:
8.1
Inappropriate
use of buffered aspirin for primary prevention?
8.2
Inappropriate
use of a dose of 40 mg pravastatin?
8.3
Inappropriate
use of a dose of 325 mg buffered aspirin?
8.4
Inappropriate
use of a dose of 81 mg buffered aspirin?
9.0
Do you
recommend approval of the fixed-dose combination of product of pravastatin plus
buffered aspirin?