Perspectives on Non-Inferiority Clinical Trials
– based on draft FDA guidance doc
DSBS 20 May 2010
H. Lundbeck A/S
7-Apr-15
1
Key contents in FDA draft guidance
• Margins
– M1 = effect of active control
– M2 = ”clinical” margin (fraction of M1)
• Analysis methods
– Fixed Margin method
– Synthesis method
H. Lundbeck A/S
7-Apr-15
2
Notation
• δCP = effect of active control vs placebo
• δTC = effect of test drug vs active control
• δTP = effect of test drug vs placebo = δTC + δCP
NB: A positive figure indicates ”better”
H. Lundbeck A/S
7-Apr-15
3
Base logic of NI test
• If δCP = M1, then showing that δTC > -M1
amounts to showing that δTP > 0, since δTP =
δTC + δCP
• Showing that δTC is greater than some fraction
f of M1, δTC > -fM1 (=M2), amounts to
showing that δTC + fδCP > 0 or δTC + δCP = δTP
> (1-f)δCP , i.e. that a fraction (1-f) of the
effect of C has been preserved
H. Lundbeck A/S
7-Apr-15
4
Inferences based on 95% CI for δTC
T superior to P
demonstrated
M1(δTP=0)
Preserved:p=0%
H. Lundbeck A/S
Preservation of
p % benefit
demonstrated
M2
0%<p<100%
7-Apr-15
δTC=0
p=100%
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T superior to C
demonstrated
Analysis methods
• Fixed Margin
– Use historical estimate of δCP and its SE to derive a
fixed margin for the test (typically lower limit of 2sided 95% CI)
• Synthesis
– Treat historical estimate of δCP as a random variable
– Assume independence between historical data and
NI trial and use as analysis basis
• δTP = δTC + δCP
• V(δTP) = V(δTC)+ V(δCP)
H. Lundbeck A/S
7-Apr-15
6
Fixed Margin versus Synthesis criteria
Fixed margin method:
δˆTC  f  δˆCP
 1.96
SETC  f  SECP
Synthesismethod:
δˆ  f  δˆ
CP
TC
SE  f  SE
2
TC
H. Lundbeck A/S
7-Apr-15
2
2
CP
 1.96
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Fixed Margin versus Synthesis criteria
• Fixed margin method inefficient and overly
conservative (Rothmann et al., Stats in Med
22: 239-264, 2003)
• Synthesis method more efficient and takes the
variability of both historical data and NI trial
data into account in a natural way
H. Lundbeck A/S
7-Apr-15
8
More conservative method
FDA position on margins and methods
Fixed Margin
M1
Fixed Margin
M2
Synthesis
M1
Synthesis
M2
Preferred option
H. Lundbeck A/S
7-Apr-15
More conservative margin
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The case for ”One Standard of Evidence”
(PhRMA PISC Expert Team White Paper, BASS XV, 2008)
• The traditional standard of evidence for efficacy of a
new treatment T is statistically significant evidence that
δTP > 0
• Why should an arbitrarily higher standard of evidence
(δTP > δ > 0) be used when an active-controlled (AC)
trial has been used?
• Preservation margin is arbitrary
– Preserving less than p% does not imply ineffectiveness of
T
– In contrast, δTP = 0 has a definite objective clinical
meaning
• Requiring a higher standard of evidence for AC trials
institutes a regulatory bias in favor of the first drug to
be approved (requiring preservation of p% may lead to
rejection of T even thought T is better than C)
H. Lundbeck A/S
7-Apr-15
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Hypothetical example: 95% CIs relative to P
T and C are both superior to P
and data suggests that T might be
better than C but because C was
approved first and T does not
meet the p% margin T can’t be
approved
C vs P
T vs P
δTP=0
H. Lundbeck A/S
p % margin
7-Apr-15
11
Example: Metastatic Bladder Cancer
• Randomized trial* of Gemzar + cisplatin
compared to MVA + cisplatin
• An earlier randomized trial** showed
superioty of MVA + cisplatin to cisplatin
• In our notation T=Gemzar, C=MVA,
P=cisplatin
– δTC = log hazard ratio (MVA over Gemzar)
– δCP = log hazard ratio (”no treatment” over MVA)
– δTP = log hazard ratio (”no treatment” over Gemzar)
* Von der Masse et al.: JCO, 18:3068-3077
** Loehrer et al.: JCO, 10:1066-1073
H. Lundbeck A/S
7-Apr-15
12
Metastatic Bladder Cancer cont’d
• Point estimates
ˆCP  0.421(variance0.0181)
ˆTC  0.039(variance0.0147)
ˆTP  0.382(variance0.0328) fromsynthesisanalysis
• Synthesis method estimated 90.7% preservation of
benefit but lower 95% bound was only 11.7%
• So ”preservation of 50% benefit” criterion was not met
but Gemzar+cisplatin was statistically superior to
cisplatin alone (2-sided pvalue=0.035)
H. Lundbeck A/S
7-Apr-15
13
Metastatic Bladder Cancer cont’d
• Assuming constancy of δCP across trials
– Gemzar improves survival when added to cisplatin
(p=0.035)
– Gemzar+cisplatin was estimated to have similar
efficacy as MVA+cisplatin (estimated HR=0.96)
• Why do a test for preservation of effect?
H. Lundbeck A/S
7-Apr-15
14
Conclusions
• One standard of evidence for efficacy should
be used – superiority to placebo – regardless
of the design used (placebo- or activecontrolled)
• The synthesis method should be used rather
than the fixed margin method for better
efficiency
H. Lundbeck A/S
7-Apr-15
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