Non Inferiority Trial

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Non Inferiority Trial
2
event rate
0
100
superiority study
experiment - drug
control - placebo
3
experiment better
experiment worse
-8
8
0
ARREER-CER
CER
EER
0
100
event rate
superiority study
experiment - drug
control - placebo
4
presumption that experiment may be worse than
control! But does it matter? is it clinically
significant?
0
100
non inferiority study
experiment - drug B
control - drug A
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• 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

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margin of equivalencehow much worse than the
active control youre willing to accept
ok if not worse than X
0
100
non inferiority study
experiment - drug B
control - drug A
7
non inferior
inconclusive
experiment better
experiment worse
8
-8
X
0
if upper CI is less than X, non inferior!
0
100
non inferiority study
experiment - drug B
control - drug A
8

• 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.

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• 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

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non inferior
inconclusive
experiment better
experiment worse
8
-8
7
0
0
100
3.3
treatment failure at day 10
experiment - No Abx
control - Abx
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non inferior
inconclusive
experiment better
experiment worse
1.2
6.8
8
-8
7
0
0
100
4.1
5.3
treatment failure at day 10
experiment - No Abx
control - Abx
12
non inferior
inconclusive
experiment better
experiment worse
13.5
24.3
8
-8
7
0
0
100
12.9
26.4
new lesions at day 10
experiment - No Abx
control - Abx
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want to prove equivalence threshold null hypothesis type 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 error increasing
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 error rare
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