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![Page 1: 2006, Tianjin, China 071201sf.ppt - Faragalli 1 Statistical Hypotheses and Methods in Clinical Trials with Active Control Non-inferiority Design Yong-Cheng.](https://reader035.fdocuments.us/reader035/viewer/2022062423/5697bf7d1a28abf838c84cf7/html5/thumbnails/1.jpg)
071201sf.ppt - Faragalli 1
2006, Tianjin, China2006, Tianjin, China
Statistical Hypotheses and Methods in Clinical Trials with Active Control Non-inferiority Design
Statistical Hypotheses and Methods in Clinical Trials with Active Control Non-inferiority Design
Yong-Cheng Wang
Centocor, Inc., Johnson & Johnson Pharmaceutical Companies, PA, USA
2006 International Conference on Design of Experiments and Its Applications
July 9-13, 2006, Tianjin, P. R. China
Yong-Cheng Wang
Centocor, Inc., Johnson & Johnson Pharmaceutical Companies, PA, USA
2006 International Conference on Design of Experiments and Its Applications
July 9-13, 2006, Tianjin, P. R. China
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2006, Tianjin, China2006, Tianjin, China
OutlineOutline
Introduction– Notations & Definitions– Objectives of non-inferiority (NI) trials
Non-inferiority Hypotheses – Fixed margin– Fraction retention
Non-inferiority Analysis Methods– Fixed margin– Fraction retention– Two CI procedure– Bayesian
Summary
Introduction– Notations & Definitions– Objectives of non-inferiority (NI) trials
Non-inferiority Hypotheses – Fixed margin– Fraction retention
Non-inferiority Analysis Methods– Fixed margin– Fraction retention– Two CI procedure– Bayesian
Summary
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Yong-Cheng Wang
IntroductionIntroduction
Notations, Definitions, NI objectivesNotations, Definitions, NI objectives
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071201sf.ppt - Faragalli 4
2006, Tianjin, China2006, Tianjin, China
Notations & Definitions Notations & Definitions
Endpoint: time to event (e.g., survival, TTP)
Hazard ratios: HR(T/C) and HR(P/C)
Treatment effect: 1 = HR(T/C) -1
Control effect: 2 = HR(P/C) -1
Fraction retention of control effect: = 1 – {1 / 2}, or
Fraction loss of control effect: 1 - = 1 / 2,
where, T, C and P are treatment, control and placebo, respectively, and are under the constancy assumption:
C = C1 (active control) = C2 (historical control)
Endpoint: time to event (e.g., survival, TTP)
Hazard ratios: HR(T/C) and HR(P/C)
Treatment effect: 1 = HR(T/C) -1
Control effect: 2 = HR(P/C) -1
Fraction retention of control effect: = 1 – {1 / 2}, or
Fraction loss of control effect: 1 - = 1 / 2,
where, T, C and P are treatment, control and placebo, respectively, and are under the constancy assumption:
C = C1 (active control) = C2 (historical control)
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2006, Tianjin, China2006, Tianjin, China
Objectives of NI TrialsObjectives of NI Trials
To demonstrate new treatment effect by showing:
Not worse than a given _margin:Test Drug > Active Control - _margin
Retain a fraction of control effect: to test if new treatment preserves a fraction of control effect:
Test Drug > % Active Control
To demonstrate new treatment effect by showing:
Not worse than a given _margin:Test Drug > Active Control - _margin
Retain a fraction of control effect: to test if new treatment preserves a fraction of control effect:
Test Drug > % Active Control
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Yong-Cheng Wang
NI HypothesesNI Hypotheses
Fraction retention / Fixed marginFraction retention / Fixed margin
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2006, Tianjin, China2006, Tianjin, China
NI Hypotheses – Fraction RetentionNI Hypotheses – Fraction Retention
Fraction retention NI hypotheses:
H0: ≤ 0 vs. Ha: > 0
or, if 2 = HR(P/C) - 1 > 0,
H0: 1 (1- 0 ) 2 vs. Ha: 1 < (1 - 0 ) 2
Fraction retention NI hypotheses:
H0: ≤ 0 vs. Ha: > 0
or, if 2 = HR(P/C) - 1 > 0,
H0: 1 (1- 0 ) 2 vs. Ha: 1 < (1 - 0 ) 2
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2006, Tianjin, China2006, Tianjin, China
Selection of Fraction RetentionSelection of Fraction Retention
The selection of depends on several factors:
objective of active control trial– claim non-inferiority or equivalence– claim efficacy
clinical judgment
statistical judgment– distributional properties of the ratio of treatment effect vs.
active control effect– mean effect size of active control– variability of active control effect
The selection of depends on several factors:
objective of active control trial– claim non-inferiority or equivalence– claim efficacy
clinical judgment
statistical judgment– distributional properties of the ratio of treatment effect vs.
active control effect– mean effect size of active control– variability of active control effect
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2006, Tianjin, China2006, Tianjin, China
NI Hypotheses – Fixed Margin NI Hypotheses – Fixed Margin
If fix control effect 2 = M1 > 0, and define margin M = 0* M1, where 0 is a fixed level of fraction retention, then NI hypotheses become:
H0: 1/M1 0 vs. Ha: 1/M1 < 0 , or
H0: HR(T/C) 1+M vs. Ha: HR(T/C) < 1+M
If fix control effect 2 = M1 > 0, and define margin M = 0* M1, where 0 is a fixed level of fraction retention, then NI hypotheses become:
H0: 1/M1 0 vs. Ha: 1/M1 < 0 , or
H0: HR(T/C) 1+M vs. Ha: HR(T/C) < 1+M
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2006, Tianjin, China2006, Tianjin, China
Selection of Fixed MarginSelection of Fixed Margin
Arbitrary margin: questionable
Margin based on control effect ~ two CI method: Based on the lower limit (LL) of % CI for HR(P/C), i.e.
Margin = 0*[LL of % CI for HR(P/C) -1]
e.g., 0 = 0.5, LL of % CI = 1.2, then margin = 0.1
If the 95% CI for HR(T/C) lies entirely beneath 1 + margin (NI cutoff), “non-inferiority” is concluded.
Arbitrary margin: questionable
Margin based on control effect ~ two CI method: Based on the lower limit (LL) of % CI for HR(P/C), i.e.
Margin = 0*[LL of % CI for HR(P/C) -1]
e.g., 0 = 0.5, LL of % CI = 1.2, then margin = 0.1
If the 95% CI for HR(T/C) lies entirely beneath 1 + margin (NI cutoff), “non-inferiority” is concluded.
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Yong-Cheng Wang
NI Analysis MethodsNI Analysis Methods
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071201sf.ppt - Faragalli 12
2006, Tianjin, China2006, Tianjin, China
NI Statistical TestsNI Statistical Tests
Linearization method (Mark Rothmann)
Ratio test (Yong-Cheng Wang)
Two 90% (or 95%) CI procedure (CBER/FDA/US)
CI for the ratio (Hasselblad & Kong)
Bayesian (Richard Simon)
Linearization method (Mark Rothmann)
Ratio test (Yong-Cheng Wang)
Two 90% (or 95%) CI procedure (CBER/FDA/US)
CI for the ratio (Hasselblad & Kong)
Bayesian (Richard Simon)
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2006, Tianjin, China2006, Tianjin, China
NI Tests – Linearization Method (Rothmann)NI Tests – Linearization Method (Rothmann)
NI hypotheses: Assuming HR(P/C) > 1
H0(1): logHR(T/C) (1-0)logHR(P/C) vs.
Ha(1): logHR(T/C) < (1-0)logHR(P/C)
Test statistic for H0(1) vs. Ha
(1):
NI hypotheses: Assuming HR(P/C) > 1
H0(1): logHR(T/C) (1-0)logHR(P/C) vs.
Ha(1): logHR(T/C) < (1-0)logHR(P/C)
Test statistic for H0(1) vs. Ha
(1):
0(1)
2 2 20
ˆ ˆlogHR(T/C)-(1-δ )logHR(P/C)
ˆ ˆse (logHR(T/C))+(1-δ ) se (logHR(P/C))Z
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2006, Tianjin, China2006, Tianjin, China
NI Tests – Ratio Test (Wang)NI Tests – Ratio Test (Wang)
Estimate of :
where and are estimates of hazard ratios.
Estimate of :
where and are estimates of hazard ratios.ˆHR(P/C)
ˆ ˆ ˆ[HR(P/C)-1]-[HR(T/C)-1] HR(T/C)-1ˆ 1ˆ ˆHR(P/C)-1 HR(P/C)-1
ˆHR(T/C)
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2006, Tianjin, China2006, Tianjin, China
NI Tests – Ratio Test (Wang)NI Tests – Ratio Test (Wang)
NI hypothesis:
H0: 0 vs. Ha: > 0
Test statistic:
Concern: Is Z* normal?
NI hypothesis:
H0: 0 vs. Ha: > 0
Test statistic:
Concern: Is Z* normal?
0ˆ-δˆs.e.( )
Z
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2006, Tianjin, China2006, Tianjin, China
NI Tests – Ratio Test (Wang)Asymptotic Normality of Z*
NI Tests – Ratio Test (Wang)Asymptotic Normality of Z*
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071201sf.ppt - Faragalli 17
2006, Tianjin, China2006, Tianjin, China
NI Tests – Ratio Test (Wang)Asymptotic Normality of Z*
NI Tests – Ratio Test (Wang)Asymptotic Normality of Z*
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2006, Tianjin, China2006, Tianjin, China
NI Tests – Ratio Test (Wang)NI Tests – Ratio Test (Wang)
Interim statistic:
Zk* is approximately normally distributed, and
Interim statistic:
Zk* is approximately normally distributed, and
2 20
2
ˆlog( ) -log(δ +k)ˆs.e.(log( ) )
kk
Zk
* * N(0, 1) (when )kZ Z k
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2006, Tianjin, China2006, Tianjin, China
NI Tests – Ratio Test (Wang)NI Tests – Ratio Test (Wang)
Normality of Z* (Xeloda trials, simulation runs=100,000)Normality of Z* (Xeloda trials, simulation runs=100,000)
Number of Events
600 800 1000 1200 1400 1600 1800
p 68.2% 80.9% 88.9% 93.8% 96.6% 98.2% 99.1%
where p = proportion of simulation runs passed Shapiro-Wilk test.
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2006, Tianjin, China2006, Tianjin, China
NI Tests – Two 95% CI Method (FDA/US)NI Tests – Two 95% CI Method (FDA/US)
Two 95% CI method:
Define the non-inferiority cutoff (1+margin) as
+ 0.5*LL of 95% CI for HR(P/C) - 1)
If the 95% CI for HR(T/C) lies entirely beneath this cutoff, non-inferiority is concluded.
Two 95% CI method:
Define the non-inferiority cutoff (1+margin) as
+ 0.5*LL of 95% CI for HR(P/C) - 1)
If the 95% CI for HR(T/C) lies entirely beneath this cutoff, non-inferiority is concluded.
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2006, Tianjin, China2006, Tianjin, China
NI Tests – CI of Ratio Method (H & K)NI Tests – CI of Ratio Method (H & K)
A “95%” confidence interval is calculated using a normal distribution with standard error
A “95%” confidence interval is calculated using a normal distribution with standard error
1 1 2
1 1
ˆ ˆlog ( / ) log ( / )ˆˆlog ( / )
HR P C HR T C
HR P C
2
2 2 1 12 2
1 1 2 1 1
ˆ ˆ ˆlog ( / ) (log ( / )) (log ( / ))ˆ ˆ ˆlog ( / ) log ( / ) log ( / )
HR T C Var HR T C Var HR P C
HR P C HR T C HR P C
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2006, Tianjin, China2006, Tianjin, China
NI Tests – Bayesian Method (Simon)NI Tests – Bayesian Method (Simon)
The posterior density for 1=logHR(T/C) is normal with mean (1+2) and variance (1+ 2).
1: log HR(T/C) 2: logHR(C/P)
1: var(log HR(T/C)) 2 : var(logHR(C/P))
The posterior prob (T is superior to C):
P(<0)=1-[(1+2)/sqrt(1+ 2)]
The prob (1-k)100% of the effect of C to P is not lost with T is
Pr(-k<0, <0).
The posterior density for 1=logHR(T/C) is normal with mean (1+2) and variance (1+ 2).
1: log HR(T/C) 2: logHR(C/P)
1: var(log HR(T/C)) 2 : var(logHR(C/P))
The posterior prob (T is superior to C):
P(<0)=1-[(1+2)/sqrt(1+ 2)]
The prob (1-k)100% of the effect of C to P is not lost with T is
Pr(-k<0, <0).
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Yong-Cheng Wang
SummarySummary
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2006, Tianjin, China2006, Tianjin, China
Summary of Active Control NI TrialsSummary of Active Control NI Trials
If control effect is small, active control trial should be a “superiority” trial, not a “non-inferiority” trial.
Appropriate assessment of the control effect based on historical data may be difficult when
– few trials, especially only one trial– changing the population– changing the standard care
Selection of the fraction retention should be based on both clinical and statistical judgments.
Interpretation of results needs to be with caution.
If control effect is small, active control trial should be a “superiority” trial, not a “non-inferiority” trial.
Appropriate assessment of the control effect based on historical data may be difficult when
– few trials, especially only one trial– changing the population– changing the standard care
Selection of the fraction retention should be based on both clinical and statistical judgments.
Interpretation of results needs to be with caution.
![Page 25: 2006, Tianjin, China 071201sf.ppt - Faragalli 1 Statistical Hypotheses and Methods in Clinical Trials with Active Control Non-inferiority Design Yong-Cheng.](https://reader035.fdocuments.us/reader035/viewer/2022062423/5697bf7d1a28abf838c84cf7/html5/thumbnails/25.jpg)
Yong-Cheng Wang
ENDEND
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