DEPARTMENT OF HEALTH AND HUMAN SERVICES
and Drug Administration
18 July , 2002
Advisory Committee is asked
to opine on the relative efficacy of
a n antihypertensive regimen containing
candesartan compared with a regimen containing
losartan at a dose of 100 mg per day .
Specific guidance is sought on the adequacy of the
current program to support a claim of superior efficacy for candesartan when
compared with losartan, as well as guidance on how to describe any
relevant differences in labelling. Specific
guidance is also sought on the adequacy of the
advice we have given sponsors , intended to
guide future development programs.
In the past, the Agency
has told sponsors that demonstrating superiority to another antihypertensive
medication was a
relevant clinical benefit, and that such a claim required the following data:
1) Evaluation of the
antihypertensive effects of the respective drugs at the highest approved doses.
comparison is not done with the approved product, bioequivalence of the study
formulation and the approved product must be demonstrated. Our
recommendation has been that this evaluation should include at least two
forced-titration trials to adequately assess the drug’s relative
antihypertensive effects. We have also said that unless a placebo group is
included in the trials no information about absolute antihypertensive efficacy
can be inferred ; only comparative
2) Data comparing the
safety of the two agents, providing evidence that they do
not significantly differ with regard to adverse effects not captured by changes
in blood pressure.
The present sponsor has
provided data from three randomized trials, including two forced-titration
trials. These were conducted comparing candesartan force-titrated to a dose of
32 mg per day and losartan force-titrated to a dose of 100 mg per day. The
Agency and the sponsor have agreement with
regard to the numerical results of the efficacy analyses for
the three trials.
the candesartan development program:
sponsor compared once per day dosing for both products, although the labeling
for both includes the possibility that twice per day dosing may be more
1.1.1. Did the
program compare the highest labeled dose of candesartan with the highest
labeled dose of losartan?
was no significant change in mean BP when patients were titrated from 16 to 32
mg of candesartan and from 50 to 100 mg of losartan.
1.1.1. How do
you explain this?
1.1.1. Is this
observation relevant for the relative efficacy of these two products?
relative antihypertensive efficacy, compare the benefits of being ‘superior’ in
lowering BP compared with another approved antihypertensive drug to lowering BP
compared with placebo:
beneficial than lowering BP to an equal degree with compared with placebo.
to being superior in lowering BP to an equal degree when compared with placebo.
beneficial than lowering BP to an equal degree when compared with placebo.
candesartan reduced diastolic BP by around 3 mm Hg at the trough measurement
relative to losaratan in the two forced-titration studies. Are these
differences in BP lowering reported in these trials for candesartan and
losartan clinically meaningful?
The sponsor has
summarized the available safety data from the submitted trials in your briefing
book. Consider the importance of relative safety in assessing superiority
claims for antihypertensives with extensive post-marketing safety databases.
Are the submitted data
adequate to compare the safety of losartan and candesartan?
If not, what additional
information is needed?
Would your answer change
if the comparator was from a different drug class ( e.g. ,
If so, are there safety
concerns that undermine or enhance the relative risk/benefit ratio for
candesartan when compared with losartan?
Do you recommend approval
of candesartan as having demonstrated
superior antihypertensive efficacy when compared with losartan?
how should the findings of these trials be included in the approved labeling :
1.1.1. F or Candesartan ?
should the potential use of losartan 50 mg BID be reflected in the label?
1.1.1. For L osartan?
advice given to sponsors seeking to assess relative antihypertensive efficacy
is summarized above.
should the relative antihypertensive effect of two drugs be made: trough DBP, 24-hour ABPM, other method?
there additional requirements you would recommend?