Transcript Non-Inferiority Trials and Equivalence Trials

Understanding the Concept of Equivalence and
Non-Inferiority Trials
CM Gibson, 2000
Terminology
• The term active-control trial refers to all studies in which the
control treatment is an active one.
– If the intent is to show that the differences between
control and study treatments are not large in either
direction the study is called an equivalence trial.
– If the intent of a study is to demonstrate that the study
treatment is not substantially worse than than the control
treatment the study is called a non-inferiority trial.
• Both types of trials seek to reject the possibility that
differences in treatment effects equal or exceed a preset
limit or margin.
Jay P. Siegel, American Heart Journal April 2000:S166-S170
Equivalency & Non Inferiority in Plain English
• Goal of an Equivalency Study: “With 95% certainty can I say
that the mortality rates lie within 1% of each other for these
two drugs”?
• Goal of a Non-Inferiority Study: “With 95% certainty can I
say that drug A is no worse than 1% than drug B”?
CM Gibson, 2000
Understanding Equivalence
Superiority: Does the 95% CI contain zero?
1%
0%
+1%
Equivalence: Does the 95% CI lie between 1% and +1%?
1%
To left of 1%
is clinically
meaningful
CM Gibson, 2000
0%
Between 1% and +1%
is not clinically
meaningful
+1%
To right of 1%
is clinically
meaningful
Terminology
• An alternative term for a non-inferiority trial is sufficiency
trial.
– This designation implies simply that the trial is designed to
demonstrate that the activity of the study drug is, compared
with the active control, sufficient to meet the trial’s purpose (eg,
to support an expert recommendation or a regulatory
approval).
Jay P. Siegel, American Heart Journal April 2000:S166-S170
Background
• Prior to undertaking the trial, the degree of inferiority (or
difference) that is clinically relevant must first be established
• A trial is then designed and to reject the hypothesis that a
difference of that size or larger exists1.
• The efficacy of a new therapeutic agent would be established
if its treatment effects are proven to be at least equivalent to
those observed from a standard-of-care regimen, which itself
has a well established and substantial level of efficacy2.
• If a new agent not only demonstrates its equivalence with
standard therapy, but also offers advantages in terms of
either toxicity, ease of administration, or cost, the new agent
may provide an important advance in clinical care2.
1. Jay P. Siegel, American Heart Journal April 2000:S166-S170
2. Thomas R. Fleming, American Heart Journal April 2000:S171-S176
The Choice of Active Control
• If efficacy is to be established through comparison with an
active control, it is essential that the active control have a
well established, predictable, quantifiable effect at a dose
and regimen that has been well studied.
• This effect is best established by multiple randomized
controlled trials, comparing the active control with placebo.
Jay P. Siegel, American Heart Journal April 2000:S166-S170
Setting the Value of the Margin
• Establishing a margin - the smallest unacceptable degree of clinical
inferiority (and of superiority in an equivalence trial) of the new
treatment must be prospectively defined
• In acute MI studies, this has traditionally been a 1% difference in
mortality, a difference which resulted in changes in practice
patterns following GUSTO 1. This is an approximate 15% relative
reduction in mortality.
• An estimate of the efficacy of the active control group is then made
based upon event rates prior trials.
• Based upon the projected efficacy of the active control, the trial is
then appropriately powered to determine if the two drugs lie within
this margin.
Jay P. Siegel, American Heart Journal April 2000:S166-S170
Parameters of Comparison
• Patient population, concomitant therapies and
endpoints are important both for estimating activecontrol effect size and for ensuring a fair
comparison between study drug and active control.
Jay P. Siegel, American Heart Journal April 2000:S166-S170
Non-Inferiority Trial Example
Window of Non-Inferiority Margin
Superior
5.1
Inferior
5.5
6.0
6.5
6.9
Hypothetical Control
Treatment Event Rate
•If the experimental treatment event rate is < 5.1, then the experimental treatment would be superior
to the active control.
•If the experimental treatment event rate falls between the 5.1 and 6.9 range, then the experimental
treatment is non-inferior to the active control.
•If the experimental treatment event rate is > 6.9, then the experimental treatment is inferior to the
active control.
Equivalence Trial Example
Equivalence Established
Equivalence not established
5.1
Equivalence not established
6.0
6.9
Hypothetical Control
Treatment Event Rate
•In an equivalence trial, if the experimental treatment event rate falls between 5.1 and 6.9, the study
would establish equivalence between the experimental therapy and the active control.
•If the experimental treatment event rate falls outside the 5.1 to 6.9 range, the study would fail to
establish equivalence between the experimental treatment and the active control.
Differences Between Equivalency and
Non-Inferiority Trials
• What if there is superiority in an equivalency trial? If a
strategy proves be to superior, (I.e. the event rate is below
5.1% in the previous trials), this would be viewed as an
equivalent result in an equivalency study.
• What if there is superiority in a non-inferiority trial?
Superiority can be claimed.
• Conclusion: Non-inferiority trial design retains the ability to
show superiority
CM Gibson 2000
Examples of Equivalency Studies in Thrombolysis Trials
Mortality
(%)
InTIME-2
ASSENT-2
GUSTO-III
n-PA
t-PA
6.77
6.60
TNK-tPA
t-PA
6.16
6.18
r-PA
t-PA
7.47
7.24
Absolute
Difference
(95% CI)
Other
Better
t-PA
Better
P Value for
Equivalence
0.17
(1.0, 0.68)
0.02
(0.59, 0.62)
0.047
0.006
0.23
(1.11, 0.66)
NS
-1
0
+1
ASSENT-2 Investigators. Lancet. 1999;354:716-722; Adapted from GUSTO-III Investigators. N Engl J Med.
1997;337:1118-1123. Adapted from Giugliano RP, et al. Circulation. 1999;100:I-651.