Non Inferiority Trial
0%
event rate
100%
superiority study
control - placebo
experiment - drug
experiment better
-∞
0%
experiment worse
+∞
0
ARR=EER-CER
EER
CER
event rate
100%
superiority study
control - placebo
experiment - drug
presumption that experiment may be worse
than control! But does it matter? is it clinically
significant?
0%
100%
non inferiority study
control - drug A
experiment - drug B
a positive non inferiority trial result
supports the statement that the
experimental treatment is
no worse than the standard
✱
treatment
✱within
a predetermined acceptable margin of equivalence
margin of equivalence
“how much worse than the active
control you’re willing to accept”
ok if not worse than X%
0%
100%
non inferiority study
control - drug A
experiment - drug B
non inferior
experiment better
-∞
experiment worse
inconclusiv
e
+∞
X%
0
if upper CI is less than X, non inferior!
0%
100%
non inferiority study
control - drug A
experiment - drug B
the margin of equivalence is determined by
•what is deemed to be a clinically significant difference,
•the expected event rates,
•regulatory requirements,
•the known effect of the standard treatment over placebo,
•severity of the disease,
•toxicity,
•inconvenience, or cost of the standard treatment,
adherence and
•the primary endpoint.
Superiority Trial
•type I error is falsely finding a treatment effect when there is
none
•type II error is failing to detect a treatment effect when truly one
exists.
Non inferiority Trial
• the null and alternative hypotheses are reversed;
•type I error is the erroneous acceptance of an inferior new
treatment,
•type II error is the erroneous ejection of a truly non inferior
treatment
non inferior
experiment better
-∞
0%
experiment worse
inconclusiv
e
7%
0
3.3%
+∞
100%
treatment failure at day 10
control - Abx
experiment - No Abx
non inferior
experiment better
experiment worse
1.2%
-∞
0%
6.8%
7%
0
4.1%
inconclusiv
e
5.3%
+∞
100%
treatment failure at day 10
control - Abx
experiment - No Abx
non inferior
experiment better
experiment worse
inconclusiv
e
13.5%
24.3%
-∞
0%
7%
0
12.9%
26.4%
+∞
100%
new lesions at day 10
control - Abx
experiment - No Abx
want to
prove
superiority
trial
equivalence
null
threshold
hypothesis
experiment is
experiment falsely finding
superior to
and placebo
treatment
placebo or not applicable
are equally
effect when
other
effective
there is none
treatment
experiment is
non inferior to
active control
(no placebo)
acceptable
“worst”
treatment
effect
experiment is
equally
equivalence
effective to
trial
active control
(no placebo)
acceptable
“worst” and
“best”
treatment
effect
non
inferiority
trial
type I error type II error ITT analysis
failing to
detect a
treatment
effect when
there is one
good
falsely finding
falsely
experiment is non inferiority rejecting the
may increase
inferior to
when the
experiment
type I error
active control experiment is when it is non
inferior
inferior
experiment
and active
control are
not equally
effective
falsely finding
equivalence
falsely
rejecting
equivalence
may increase
type I error
commonalit
y
very common
increasing
rare