Non Inferiority Trial

0% 100%

experiment - drug control - placebo

event rate

superiority study

0% 100%event rate

0ARR=EER-CER

-∞ +∞

experiment better experiment worse

experiment - drug control - placebosuperiority study

EER CER

0% 100%

experiment - drug B control - drug Anon inferiority study

presumption that experiment may be worse than control! But does it matter?

is it clinically significant?

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”

0% 100%

ok if not worse than X%

experiment - drug B control - drug Anon inferiority study

0% 100%

X%

experiment - drug B control - drug Anon inferiority study

0-∞ +∞

experiment better experiment worse

if upper CI is less than X, non inferior!

non inferior inconclusive

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

0% 100%3.3%

7%

experiment - No Abxcontrol - Abx

0-∞ +∞

experiment better experiment worsenon inferior inconclusi

ve

treatment failure at day 10

0% 100%

7%

experiment - No Abxcontrol - Abx

0-∞ +∞

experiment better experiment worse

4.1% 5.3%

1.2% 6.8%

non inferior inconclusive

treatment failure at day 10

0% 100%

7%

experiment - No Abxcontrol - Abx

0-∞ +∞

experiment better experiment worse

12.9% 26.4%

13.5%24.3%

non inferior inconclusive

new lesions at day 10

want to prove

equivalence

thresholdnull

hypothesistype I error

type II error

ITT analysis

commonality

superiority trial

experiment is superior to placebo or other

treatment

not applicable

experiment and placebo are equally effective

falsely finding

treatment effect when

there is none

failing to detect a

treatment effect when there is one

good very common

non inferiority

trial

experiment is non

inferior to active

control (no placebo)

acceptable “worst”

treatment effect

experiment is inferior to

active control

falsely finding non inferiority when the

experiment is inferior

falsely rejecting

the experiment when it is

non inferior

may increase

type I errorincreasing

equivalence trial

experiment is equally

effective to active

control (no placebo)

acceptable “worst” and

“best” treatment

effect

experiment and active control are not equally effective

falsely finding

equivalence

falsely rejecting

equivalence

may increase

type I errorrare