Académique Documents
Professionnel Documents
Culture Documents
Biostatistics
Sample Size Estimation
for BE Studies
Helmut Schtz
BEBAC
Workshop | Bucarest, 19 March 2013
1 59
To bear in Remembrance...
Whenever a theory appears to you
as the only possible one, take this as
a sign that you have neither understood the theory nor the problem
which it was intended to solve. Karl R. Popper
Even though its applied science
were dealin with, it still is science!
Leslie Z. Benet
Workshop | Bucarest, 19 March 2013
2 59
Overview
zClassical
Patients
zRecent
analysis
developments
Review
of guidelines
Workshop | Bucarest, 19 March 2013
3 59
and
zAll
Defendant innocent
Defendant guilty
Error type I
Correct
Correct
Error type II
4 59
and
zOr
Error type I
Correct (Ha)
Correct (H0)
Error type II
zIn
Patients risk
Correct (BE)
Producers risk
5 59
zPatients
0.5
0.6
0.8
1.25
1.67
95% one-sided CI
0.5
0.6
5% patients <0.8
0.8
1.25
5% patients >1.25
1.67
0.5
0.6
0.8
1.25
1.67
6 59
and
zProducers
Set
If
power is set to 80 %,
one out of five studies will fail just by chance!
0.05
BE
not BE
0.20
0.20 = 1/5
7 59
Power Curves
Power to show BE
with 12 36
subjects for
CVintra 20%
36
24
1
0.9
16
0.8
0.7
Power
n
24
16:
power 0.896 0.735
22 Cross-over
12
0.6
0.5
20% CV
0.4
0.3
0.2
T/R
1.05 1.10:
power 0.903 0.700
0.1
0
0.8
0.85
0.9
0.95
1.05
1.1
1.15
1.2
1.25
T/R
Workshop | Bucarest, 19 March 2013
8 59
n
16
17
18
19
20
power
73.54%
76.51%
79.12%
81.43%
83.47%
9 59
power
40
95%
24
90%
16
power
sample size
32
85%
8
0
5%
10%
15%
20%
25%
80%
30%
CVintra
Workshop | Bucarest, 19 March 2013
10 59
Background
zReminder:
Exact
11 59
Background
zPower
estimations
Brute
12 59
minimum
12
13 59
14 59
15 59
Approaches to Establishing
Bioequivalence (2001)
Based
GL (2010)*
Consider
potency differences.
Sample size based on 80 90% power.
Do not interpolate linear between CVs (as stated in
the GL)!
* All points removed in current (2012) GL.
Workshop | Bucarest, 19 March 2013
16 59
EU
zEMEA
Detailed
zEMA
GL on BE (2010)
Batches
17 59
Hierarchy of Designs
zThe
Information
Hierarchy
of designs:
Parallel:
22 Xover:
Partial replicate:
Full replicate:
18 59
Coefficient(s) of Variation
zFrom
CV% (between)
Total CV% (pooled)
CVinter % = 100 e
CVtotal % = 100 e
MSE B + MSEW
2
MSEB MSEW
2
1
19 59
Coefficient(s) of Variation
zCVs
If
drug, formulation
design
methylphenidate MR
SD
12 AUCt
paroxetine MR
MD
32 AUC
lansoprazole DR
SD
47 Cmax
CVtotal
19.1
20.4
25.2
55.1
62.1
47.0
25.1
54.6
7.00
Pilot
20 59
CVs have a high degree of uncertainty (in the pivotal study it is more likely that
you will be able to reproduce the PE, than the
CV)
The
21 59
Are
25
28
36
1.286
30
40
52
1.300
35
52
68
1.308
40
66
86
1.303
If pilot n=24:
n=72, ratio 1.091
22 59
23 59
24 59
Hints
zLiterature
Preferably
25 59
Algebra
zCalculation
Point
of CVintra from CI
PE = CLlo CLhi
Estimate
n1 = n2 = N
If
Difference
CL = ln PE ln CLlo
Workshop | Bucarest, 19 March 2013
or
CL = ln CLhi ln PE
26 59
Algebra
zCalculation
Calculate
CL
MSE = 2
1 1
t
+
n1 n2 12 ,n1 + n2 2
CVintra from
MSE as usual
27 59
Algebra
zCalculation of CVintra from CI (contd)
Example: 90% CI [0.91 1.15], N 21 (n1 = 11, n2 = 10)
0.11702
= 0.04798
MSE = 2
1 1
+ 1.729
11 10
28 59
Algebra
zProof: CI from calculated values
Example: 90% CI [0.91 1.15], N 21 (n1 = 11, n2 = 10)
2 MSE
2 0.04798
SE =
=
= 0.067598
N
21
CI = eln PE tSE = e0.022741.7290.067598
CI lo = e0.022741.7290.067598 = 0.91
CI hi = e0.02274+1.7290.067598 = 1.15
9
29 59
Sensitivity to Imbalance
zIf
Balanced Sequences
assumed
Sequences
in study
n1
n2
CV%
12
12
26.29
13
11
26.20
14
10
25.91
15
25.43
16
24.74
30 59
No Algebra
in R-package PowerTOST,
function CVfromCI (not only 22 cross-over,
but also parallel groups, higher order crossovers, replicate designs). Example:
zImplemented
library(PowerTOST)
CVfromCI(lower=0.91, upper=1.15, n=21, design="2x2", alpha=0.05)
[1] 0.2219886
31 59
Literature data
12
10
frequency
8
6
4
2
to ta l
0
100 m g
10
15
20
CVs
25
stu d ie s
200 m g
30
32 59
Pooling of CV%
zIntra-subject
33 59
Pooling of CV%
zIntra-subject
Calculate
W df
Calculate the pooled CV from total variance
W2 df df
CV = e
1
calculate an upper (1) % confidence
limit on the pooled CV (recommended = 0.25)
W2 df 2 ,df
CL = e
1
Optionally
CV
34 59
Pooling of CV%
zDegrees
Name in PowerTOST
n2
2x2
33 Latin Squares
2n 4
3x3
2n 4
3x6x3
3n 6
4x4
2n 3
2x2x3
3n 4
2x2x4
3n 4
2x4x4
3n 4
2x3x2
Name
35 59
Pooling of CV%
zExample:
CVintra
15%
25%
20%
N
n seq. df W
W W df
2.1566 56
12 6 20 0.149 0.0223 0.4450
16 2 14 0.246 0.0606 0.8487
24 2 22 0.198 0.0392 0.8629 pooled pooled
52
56
2.1566 0.196 0.0385
n- 2
2n- 4
0.0385
100 e
0.25
1
0.75
-1
CVpooled CVg.mean
19.81% 19.57%
( ,df)
48.546 21.31% +7.6%
36 59
Pooling of CV%
package PowerTost function CVpooled,
examples data.
zR
library(PowerTOST)
CVs <- ("
PKmetric | CV | n | design | source
AUC
| 0.15 | 12 | 3x6x3 | study 1
AUC
| 0.25 | 16 | 2x2
| study 2
AUC
| 0.20 | 24 | 2x2
| study 3
")
txtcon <- textConnection(CVs)
CVdata <- read.table(txtcon, header=TRUE, sep="|",
strip.white=TRUE, as.is=TRUE)
close(txtcon)
CVsAUC <- subset(CVdata,PKmetric=="AUC")
print(CVpooled(CVsAUC, alpha=0.25), digits=4, verbose=TRUE)
Pooled CV = 0.1981 with 56 degrees of freedom
Upper 75% confidence limit of CV = 0.2131
Workshop | Bucarest, 19 March 2013
37 59
Pooling of CV%
zOr
38 59
Pooling of CV%
library(PowerTOST)
expsampleN.TOST(alpha=0.05,
targetpower=0.8, theta0=0.95,
CV=c(0.15,0.25,0.2),
dfCV=c(20,14,22),
alpha2=0.25, design="2x2",
print=TRUE, details=TRUE)
39 59
Pooling of CV%
zDoing
Does
40 59
Tools
zSample
41 59
Approximations obsolete
zExact
z Approximations
based on
noncentral t (FARTSSIE17)
alpha
<- 0.05
# alpha
CV
<- 0.30
# intra-subject CV
theta1 <- 0.80
# lower acceptance limit
theta2 <- 1/theta1 # upper acceptance limit
theta0 <- 0.95
# expected ratio T/R
PwrNeed <- 0.80
# minimum power
Limit
<- 1000
# Upper Limit for Search
n
<- 4
# start value of sample size search
s
<- sqrt(2)*sqrt(log(CV^2+1))
repeat{
t
<- qt(1-alpha,n-2)
http://individual.utoronto.ca/ddubins/FARTSSIE17.xls
nc1
<- sqrt(n)*(log(theta0)-log(theta1))/s
nc2
<- sqrt(n)*(log(theta0)-log(theta2))/s
prob1 <- pt(+t,n-2,nc1); prob2 <- pt(-t,n-2,nc2)
power <- prob2-prob1
n
<- n+2
# increment sample size
if(power >= PwrNeed | (n-2) >= Limit) break }
Total
<- n-2
if(Total == Limit){
cat('Search stopped at Limit', Limit,
http://cran.r-project.org/web/packages/PowerTOST/
' obtained Power', power*100, '%\n')
} else
require(PowerTOST)
cat('Sample Size', Total, '(Power', power*100, '%)\n')
sampleN.TOST(alpha=0.05,
targetpower=0.80, theta0=0.95,
CV=0.30, design='2x2')
or
/ S+
z Exact method (Owen) in
R-package PowerTOST
42 59
Comparison
CV%
original values
Method Algorithm 5 7.5 10 12 12.5
Owens Q 4 6
PowerTOST 1.1-02 (2013) exact
8
8
10
Patterson & Jones (2006) noncentr. t AS 243
4 5
7
8
9
et
al.
t
Diletti
(1991)
noncentr. Owens Q 4 5
7 NA
9
t
noncentr.
nQuery Advisor 7 (2007)
AS 184
4 6
8
8
10
noncentr. t AS 243
FARTSSIE 1.7 (2010)
4 5
7
8
9
noncentr. t AS 243
4 5
7
8
9
EFG 2.01 (2009)
brute force ElMaestro 4 5
7
8
9
central t
?
NA 5
StudySize 2.0.1 (2006)
7
8
9
Hauschke et al. (1992)
approx. t
NA NA
8
8
10
t
approx.
Chow & Wang (2001)
NA 6
6
8
8
Kieser & Hauschke (1999) approx. t
2 NA
6
8 NA
CV%
original values
Method Algorithm 22.5 24 25 26 27.5
Owens Q
PowerTOST 1.1-02 (2013) exact
24 26 28 30 34
Patterson & Jones (2006) noncentr. t AS 243
23 26 28 30 33
Diletti et al. (1991)
noncentr. t Owens Q
23 NA 28 NA
33
t
noncentr.
nQuery Advisor 7 (2007)
AS 184
24 26 28 30 34
noncentr. t AS 243
FARTSSIE 1.7 (2010)
23 26 28 30 33
noncentr. t AS 243
23 26 28 30 33
EFG 2.01 (2009)
brute force ElMaestro 23 26 28 30 33
central t
?
StudySize 2.0.1 (2006)
23 26 28 30 33
Hauschke et al. (1992)
approx. t
24 26 28 30 34
t
approx.
Chow & Wang (2001)
24 26 28 30 34
NA 28 30 32 NA
Kieser & Hauschke (1999) approx. t
Workshop | Bucarest, 19 March 2013
14
12
11
NA
12
11
11
11
11
12
10
10
28
34
34
NA
34
34
34
34
34
36
34
38
15
12
12
12
12
12
12
12
12
12
12
12
30
40
39
39
40
39
39
39
39
40
38
42
16 17.5
14
16
13
15
NA
15
14
16
13
15
13
15
13
15
13
15
14
16
12
14
14 NA
32
44
44
NA
44
44
44
44
44
46
44
48
34
50
49
NA
50
49
49
49
49
50
50
54
18
16
16
NA
16
16
16
16
16
16
16
16
20
20
19
19
20
19
19
19
19
20
18
20
22
22
22
NA
22
22
22
22
22
22
22
24
36
54
54
NA
54
54
54
54
54
56
56
60
38
60
60
NA
60
60
60
60
60
64
62
66
40
66
66
NA
66
66
66
66
66
70
68
74
43 59
0.85 0.90
11
5
21
7
35 11
54 16
77 22
103 29
134 37
168 46
206 56
247 67
292 79
PE (GMR, T/R)
0.95 1.00 1.05 1.10
4
4
4
5
5
5
5
7
7
6
7 10
9
8
9 14
12 10 12 19
15 13 15 25
19 16 18 32
23 19 23 39
28 23 27 48
33 27 33 57
39 32 38 67
1.15
7
12
20
30
41
56
72
90
110
132
155
CV%
5.0
7.5
10.0
12.5
15.0
17.5
20.0
22.5
25.0
27.5
30.0
0.85 0.90
14
6
28
9
48 14
74 21
106 29
142 39
185 50
232 63
284 77
342 92
403 108
PE (GMR, T/R)
0.95 1.00 1.05 1.10
4
4
4
5
6
5
6
8
8
7
8 13
11
9 11 18
15 12 15 25
20 15 19 34
26 19 24 43
31 23 30 54
37 28 36 65
44 34 43 78
52 39 51 92
1.15
8
16
26
40
57
75
99
124
151
181
214
1.20
28
60
104
161
231
312
405
509
625
751
888
44 59
L and L Endrnyi
Sample Sizes for Designing Bioequivalene Studies for Highly Variable Drugs
J Pharm Pharmaceut Sci 15/1, 7384 (2011)
0.85 0.90
194 53
127 51
90 44
77 40
75 40
81 42
88 46
99 53
109 58
136 67
144 72
PE (GMR, T/R)
0.95 1.00 1.05 1.10 1.15 1.20
27 22 26 45 104 >201
29 25 29 45 84 >201
29 27 30 42 68 139
29 27 29 37 57 124
30 28 30 37 53 133
32 30 32 40 56 172
36 33 36 44 63 >201
40 37 40 50 71 >201
45 41 45 56 80 >201
50 46 50 62 89 >201
54 51 55 68 97 >201
Workshop | Bucarest, 19 March 2013
0.85 0.90
145 45
74 37
60 33
59 31
66 30
80 30
88 31
98 32
106 35
136 38
144 40
PE (GMR, T/R)
0.95 1.00 1.05 1.10 1.15 1.20
24 21 24 39 82 >201
24 22 25 34 54 109
24 22 24 31 47 104
23 22 24 29 43 116
24 22 23 28 41 133
24 22 24 28 44 172
24 23 24 30 50 >201
25 24 25 31 53 >201
26 25 26 31 62 >201
27 26 27 34 70 >201
40 27 29 37 76 >201
45 59
interpolate!
zUse the most conservative cell entry
(higher CV, PE away from 1)
Example: Sample size for CV 18%, PE 0.92, 80% power?
PE (GMR, T/R)
CV%
0.90 0.95 1.00
17.5 29 15 13
20.0 37 19 16
PE (GMR, T/R)
CV%
0.90 0.95 1.00
17.5 29 15 13
20.0 37 19 16
Round up to next
even number (38)
46 59
n = 38
z Approximations
z Hauschke et al. 1992:
n = 24
z Chow and Wang 2001: n = 22
z FARTSSIE.xls:
n = 22
z Exact: n = 22
Workshop | Bucarest, 19 March 2013
47 59
48 59
library(PowerTOST)
sampleN.RSABE(CV=0.40, details=F)
Sample size
n
power
30
0.827170
Workshop | Bucarest, 19 March 2013
49 59
Sensitivity Analysis
zICH
E9 (1998)
Section
50 59
Sensitivity Analysis
zExample
2
+ 1); ln(0.22 + 1) = 0.198042
nQuery Advisor: w = ln(CVintra
20% CV:
n=26
25% CV:
power 90% 78%
Sensitivity Analysis
zExample
52 59
Sensitivity Analysis
zTo
library(PowerTOST)
power.TOST(alpha=0.05, theta0=0.95, CV=0.25, n=26, design="2x2")
[1] 0.7760553
power.TOST(alpha=0.05, theta0=0.95, CV=0.20, n=22, design="2x2")
[1] 0.8688866
power.TOST(alpha=0.05, theta0=0.95, CV=0.25, n=22, design="2x2")
[1] 0.6953401
power.TOST(alpha=0.05, theta0=0.90, CV=0.20, n=26, design="2x2")
[1] 0.6694514
power.TOST(alpha=0.05, theta0=0.90, CV=0.25, n=22, design="2x2")
[1] 0.4509864
53 59
Sensitivity Analysis
zMust
54 59
Thank You!
55 59
To bear in Remembrance...
Power. That which statisticians are always calculating
but never have.
Power: That which is wielded by the priesthood of
clinical trials, the statisticians, and a stick which they
use to beta their colleagues.
Power Calculation A guess masquerading as mathematics.
Stephen Senn
You should treat as many patients as possible with the
new drugs while they still have the power to heal.
Armand Trousseau
56 59
57 59
References
zCollection
http://bebac.at/Guidelines.htm
zICH
References
LA Gould
Group Sequential Extension of a Standard Bioequivalence
Testing Procedure
J Pharmacokin Biopharm 23/1, 5786 (1995)
DOI: 10.1007/BF02353786
Jones B and MG Kenward
Design and Analysis of Cross-Over Trials
Chapman & Hall/CRC, Boca Raton (2nd Edition 2000)
Hoenig JM and DM Heisey
The Abuse of Power: The Pervasive Fallacy of Power
Calculations for Data Analysis
The American Statistician 55/1, 1924 (2001)
http://www.vims.edu/people/hoenig_jm/pubs/hoenig2.pdf
SA Julious
Tutorial in Biostatistics. Sample sizes for clinical trials with
Normal data
Statistics in Medicine 23/12, 1921-1986 (2004)
Julious SA and RJ Owen
Sample size calculations for clinical studies allowing for
uncertainty about the variance
Pharmaceutical Statistics 5/1, 29-37 (2006)
Patterson S and B Jones
Determining Sample Size, in:
Bioequivalence and Statistics in Clinical Pharmacology
Chapman & Hall/CRC, Boca Raton (2006)
Workshop | Bucarest, 19 March 2013