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Power TOST

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22 views132 pages

Power TOST

Uploaded by

Akbar Hachiken

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Available Formats

Download as PDF, TXT or read online on Scribd

Package ‘PowerTOST’

January 18, 2021

Encoding UTF-8
Type Package
Title Power and Sample Size for (Bio)Equivalence Studies
Version 1.5-3
Date 2021-01-18
Description Contains functions to calculate power and sample size for
various study designs used in bioequivalence studies. Use known.designs() to
see the designs supported. Power and sample size can be obtained based on
different methods, amongst them prominently the TOST procedure (two one-sided t-tests).
See README and NEWS for further information.
Imports mvtnorm, stats, utils, graphics, grDevices, cubature (>=
1.3-6), TeachingDemos
Suggests crossdes, knitr, rmarkdown, devtools, tufte, emmeans
ByteCompile yes
LazyData true
VignetteBuilder knitr

URL https://github.com/Detlew/PowerTOST

BugReports https://github.com/Detlew/PowerTOST/issues
License GPL (>= 2)
NeedsCompilation no
Author Detlew Labes [aut, cre] (<https://orcid.org/0000-0003-2169-426X>),
Helmut Schütz [aut] (<https://orcid.org/0000-0002-1167-7880>),
Benjamin Lang [aut]
Maintainer Detlew Labes <[email protected]>
Repository CRAN
Date/Publication 2021-01-18 16:20:16 UTC

1
2 R topics documented:

R topics documented:
bib.CL . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
CI.BE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
CI.RatioF . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
ct5.1+ct5.2+ct5.3+ct5.4.1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
ct9.6.2+ct9.6.6 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
ct9.6.4+ct9.6.8 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
ctSJ.VIII.10+ctSJ.VIII.20+ctCW.III . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
CV2se+se2CV+CV2mse+mse2CV . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
CVCL . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
CVfromCI . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
CVp2CV . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
CVpooled . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
CVwRfromU . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
exppower.noninf . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
exppower.TOST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
expsampleN.noninf . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
expsampleN.TOST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
known.designs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
OwensQ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
OwensQOwen . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
OwensT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
pa.ABE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
pa.NTIDFDA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44
pa.scABE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46
power.2TOST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49
power.dp . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51
power.HVNTID . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53
power.noninf . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55
power.NTIDFDA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58
power.RatioF . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60
power.RSABE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62
power.RSABE2L.sdsims . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65
power.scABEL . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69
power.scABEL.sds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73
power.TOST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76
power.TOST.sds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79
power.TOST.sim . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81
pvalue.TOST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84
reg_const . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86
sampleN.2TOST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88
sampleN.dp . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90
sampleN.HVNTID . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93
sampleN.noninf . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95
sampleN.NTIDFDA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98
sampleN.RatioF . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101
sampleN.RSABE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103
bib.CL 3

sampleN.RSABE2L.sdsims . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106
sampleN.scABEL . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110
sampleN.scABEL.ad . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113
sampleN.scABEL.sdsims . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117
sampleN.TOST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120
scABEL . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124
scABEL.ad . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126
type1error.2TOST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 130

Index 131

bib.CL Design matrices of period balanced incomplete block designs

Description

This function returns the ‘design’ matrix of incomplete block designs described by Chow & Liu.
The design matrices were recoded 1=R, 2=T1, 3=T2, . . .

Usage

bib.CL(trt, p)

Arguments

trt Number of treatments (3 to 5).

p Number of periods (2 to trt-1).

Value

Matrix containing the sequences in rows and periods in columns.

The entry (i, j) of the matrix corresponds to the treatment or dose (index) a subject within i-th
sequence gets in the j-th period.

Author(s)

D. Labes

References

Chow SC, Liu JP. Design and Analysis of Bioavailability and Bioequivalence Studies. Boca Raton:
CRC Press; 3rd edition 2009. Chapter 2.6.
4 CI.BE

Examples
# 4 treatments/doses, 3 periods
bib.CL(4, 3)
# gives 4 sequences
# to see this in Chow & Liu's coding
tmt <- c("R", "T1", "T2", "T3")
matrix(tmt[bib.CL(4, 3)], ncol=3)

CI.BE 1–2*alpha confidence interval given point estimate, CV, and n

Description

Utility function to calculate the 1 − 2α CI given point estimate, CV, and n for the various designs
covered in this package.

Usage

CI.BE(alpha = 0.05, pe, CV, n, design = "2x2", robust = FALSE)

Arguments

alpha Type I error probability, significance level. Defaults to 0.05.

pe Point estimate (GMR).
CV Coefficient of variation as ratio (not percent).
n Total number of subjects if a scalar is given.
Number of subjects in (sequence) groups if given as vector.
design Character string describing the study’s design.
See known.designs() for designs covered in this package.
robust Defaults to FALSE.
Setting to TRUE will use the degrees of freedom according to the ‘robust’ evalu-
ation (aka Senn’s basic estimator). These degrees of freedom are calculated as
n-seq.
See known.designs()$df2 for designs covered in this package.

Value

Returns the 1 − 2α confidence interval.

Returns a vector with named elements lower, upper if arguments pe and CV are scalars, else a
matrix with columns lower, upper is returned.
CI.RatioF 5

Note
The function assumes an evaluation using log-transformed data.
The function assumes equal variances in case of design="parallel" and the higher order crossover
designs.
The implemented formula covers balanced and unbalanced designs.

Whether the function vectorizes properly is not thoroughly tested.

Author(s)
D. Labes

Examples
# 90% confidence interval for the 2x2 crossover
# n(total) = 24
CI.BE(pe = 0.95, CV = 0.3, n = 24)
# should give
# lower upper
# 0.8213465 1.0988055
# same total number but unequal sequences
CI.BE(pe = 0.95, CV = 0.3, n = c(13, 11))
# lower upper
# 0.8209294 1.0993637

CI.RatioF 1–2*alpha Fieller CI given point estimate, CV (, CVb) and n

Description
Utility function to calculate the 1 − 2α Fieller confidence interval given the point estimate, CV (,
CVb), and n for the parallel group and 2 × 2 crossover.

Usage
CI.RatioF(alpha = 0.025, pe, CV, CVb, n, design = c("2x2", "parallel"))

Arguments
alpha Type I error probability, aka significance level.
Defaults here to 0.025 because this function is intended for studies with clinical
endpoints.
pe Point estimate of T/R ratio.
CV Coefficient of variation as ratio (not percent). In case of design="parallel"
this is the CV of the total variability, in case of design="2x2" the intra-subject
CV.
CVb CV of the between-subject variability. Only necessary for design="2x2".
6 CI.RatioF

n Total number of subjects if a scalar is given.

Number of subjects in (sequence) groups if given as vector.
design A character string describing the study design.
design="parallel" or design="2x2" allowed for a parallel two-group design
or a classical TR|RT crossover design.

Details

The CV(within) and CVb(etween) in case of design="2x2" are obtainedvia an appropriate ANOVA
from the error term and from the difference (MS(subject within sequence)-MS(error))/2.

Value

Returns the 1 − 2α confidence interval.

Note

The function assumes an evaluation using un-transformed data.

The function assumes equal variances in case of design="parallel".
The formula implemented covers balanced and unbalanced designs.

Note that when the mean of the denominator of the ratio is close to zero, confidence intervals
might be degenerated and are returned as NA. In such a case a warning is issued.

Whether the function vectorizes properly is not thoroughly tested.

This function is intended for studies with clinical endpoints. In such studies the 95% confidence
intervals are usually used for equivalence testing. Therefore, alpha defaults here to 0.025 (see EMA
2000).

Author(s)

D. Labes

References

Locke CS. An exact confidence interval from untransformed data for the ratio of two formulation
means. J Pharmacokin Biopharm. 1984;12(6):649–55. doi: 10.1007/BF01059558
Hauschke D, Steinijans VW, Pigeot I. Bioequivalence Studies in Drug Development. Chichester:
John Wiley; 2007. Chapter 10. doi: 10.1002/9780470094778.fmatter
European Medicines Agency, Committee for Proprietary Medicinal Products. Points to consider on
switching between superiority and non-inferiority. London, 27 July 2000. CPMP/EWP/482/99

See Also

CI.BE, power.RatioF
ct5.1+ct5.2+ct5.3+ct5.4.1 7

Examples
# 95% Fieller CI for the 2x2 crossover
CI.RatioF(pe = 0.95, CV = 0.3, CVb = 0.6, n = 32)

ct5.1+ct5.2+ct5.3+ct5.4.1
Sample Size Tables for the Classical 2x2 Crossover Design

Description
These data.frames give sample size tables calculated with sampleN.TOST() for the 2×2 design.

Details
The data.frames can be accessed by their names.

data.frame Description
ct5.1 Multiplicative model, theta1=0.8, theta2=1.25 (1/theta1), exact
ct5.2 Multiplicative model, theta1=0.75, theta2=1.3333 (1/theta1), exact
ct5.3 Multiplicative model, theta1=0.9, theta2=1.1111 (1/theta1), exact
ct5.4.1 Additive model, theta1=–0.2, theta2=+0.2 (BE limits 0.80 – 1.20), exact

Note
Scripts for creation of these data.frames can be found in the /test sub-directory of the package.
Comparing the results of these scripts to the corresponding data.frames can be used for validation
purposes.

Author(s)
PowerTOST

Source

data.frame Origin Details

ct5.1 Hauschke et al. Table 5.1 (p 113–114)
ct5.2 Hauschke et al. Table 5.2 (p 115–116)
ct5.3 Hauschke et al. Table 5.3 (p 118)
ct5.4.1 Chow & Liu Table 5.4.1 (p 158)
8 ct9.6.2+ct9.6.6

References
Hauschke D, Steinijans VW, Pigeot I. Bioequivalence Studies in Drug Development. Chichester:
John Wiley; 2007.
Chow SC, Liu JP. Design and Analysis of Bioavailability and Bioequivalence Studies. Boca Raton:
CRC Press; 3rd edition 2009.

Examples
ct5.1
ct5.2
ct5.3
ct5.4.1

ct9.6.2+ct9.6.6 Sample Size Tables for the 2x2x3 Replicate Crossover Design

Description
These data.frames give sample size tables calculated with sampleN.TOST() for the 2×2×3 replicate
crossover design (2-treatment 2-sequence 3-period design.

Details
The data.frames can be accessed by their names.

data.frame Description
ct9.6.2 Additive model, theta1=–0.2, theta2=+0.2 (BE limits 0.80 – 1.20)
approximate power via shifted non-central t-distribution
ct9.6.6 Multiplicative model, theta1=0.8, theta2=1.25 (1/theta1)
approximate power via shifted non-central t-distribution

Attention! CV is se (standard error) of residuals.

Author(s)
PowerTOST

Source

data.frame Origin Details

ct9.6.4+ct9.6.8 9

ct9.6.2 Chow & Liu Table 9.6.2 (p 292)

ct9.6.6 Chow & Liu Table 9.6.6 (p 293)

References
Chow SC, Liu JP. Design and Analysis of Bioavailability and Bioequivalence Studies. Boca Raton:
CRC Press; 3rd edition 2009.

Examples
ct9.6.2
ct9.6.6

ct9.6.4+ct9.6.8 Sample Size Tables for the 2x4x4 Replicate Crossover Design

Description
These data.frames give sample size tables calculated with sampleN.TOST() for the 2×4×4 replicate
crossover design (2-treatment 4-sequence 4-period design).

Details
The data.frames can be accessed by their names.

data.frame Description
ct9.6.4 Additive model, theta1=–0.2, theta2=+0.2 (BE limits 0.80 – 1.20)
approximate power via shifted non-central t-distribution
ct9.6.8 Multiplicative model, theta1=0.8, theta2=1.25 (1/theta1)
approximate power via shifted non-central t-distribution

Attention! CV is se (standard error) of residuals.

Note

Scripts for creation of these data.frames can be found in the /test sub-directory of the package.
Comparing the results of these scripts to the corresponding data.frames can be used for validation
purposes.

Author(s)

PowerTOST
10 ct9.6.4+ct9.6.8

Source
ctSJ.VIII.10+ctSJ.VIII.20+ctCW.III 11

data.frame Origin Details

ct9.6.4 Chow & Liu Table 9.6.4 (p 294)
ct9.6.8 Chow & Liu Table 9.6.8 (p 298)

References
Chow SC, Liu JP. Design and Analysis of Bioavailability and Bioequivalence Studies. Boca Raton:
CRC Press; 3rd edition 2009.

Examples
ct9.6.4
ct9.6.8

ctSJ.VIII.10+ctSJ.VIII.20+ctCW.III
Sample Size Tables for the Parallel Group Design

Description
These data.frames give sample size tables calculated with sampleN.TOST() for the parallel group
design (2 groups).

Details
The data.frames can be accessed by their names.

data.frame Description
ctSJ.VIII.10 Multiplicative model, theta1=0.9, theta2=1.1111 (1/theta1), target power=90%
approximate power via non-central t-distribution
ctSJ.VIII.20 Multiplicative model, theta1=0.8, theta2=1.25 (1/theta1), target power=90%
approximate power via non-central t-distribution
ctCW.III Additive model, theta1=–0.2, theta2=+0.2 (BE limits 0.80 – 1.20), exact

Attention! Julious gives sample size per group.

Note

Author(s)
PowerTOST

Source

data.frame Origin Details

ctSJ.VIII.10 Julious Table VIII (p. 1972), column ‘Level of bioequivalence 10%’
ctSJ.VIII.20 Julious Table VIII (p. 1972), column ‘Level of bioequivalence 20%’
ctCW.III Chow & Wang Table III (p. 164)

Seems the last reference is not very reliable (compare to the table in the paper).

References
Julious SA. Tutorial in Biostatistics. Sample sizes for clinical trials with Normal data. Stat Med.
2004;23(12):1921–86. doi: 10.1002/sim.1783
Chow SC, Wang H. On Sample Size Calculation in Bioequivalence Trials. J Pharmacokinet Phar-
macodyn. 2001;28(2):155–69. doi: 10.1023/A:1011503032353

Examples
ctSJ.VIII.10
ctSJ.VIII.20
ctCW.III

CV2se+se2CV+CV2mse+mse2CV
Helper functions

Description
Calculates the standard error or the mean squared error from a given CV and vice versa for log-
normal data.

Usage
CV2se(CV)
se2CV(se)
CV2mse(CV)
mse2CV(mse)

Arguments
CV coefficient of variatio as ratio (not percent)
se standard error
mse mean squared error (aka residual variance)
CVCL 13

Value
Returns
se = sqrt(log(CV^2+1))
CV = sqrt(exp(se^2)-1)
mse = log(CV^2+1)
CV = sqrt(exp(mse)-1)

Note
These functions were originally intended for internal use only but may be useful for others.

Author(s)
D. Labes

Examples
# these functions are one liners:
CV2se <- function(CV) return(sqrt(log(1.0 + CV^2)))
se2CV <- function(se) return(sqrt(exp(se^2)-1))

CV2se(0.3)
# should give:
# [1] 0.2935604

se2CV(0.2935604)
# [1] 0.3

CVCL Confidence limits of a CV for log-normal data

Description
The function calculates the 1−α confidence limits (either 1-sided or 2-sided) via the χ2 distribution
of the error variance the CV is based on.

Usage
CVCL(CV, df, side = c("upper", "lower", "2-sided"), alpha = 0.05)

Arguments
CV Coefficient of variation as ratio (not percent)
df degrees of freedom of the CV (error variance)
side Side(s) to calculate the confidence limits for, defaults to upper
alpha Type I error probability, aka significance level
14 CVfromCI

Value
Numeric vector of the confidence limits named as lower CL and upper CL.
In case of the one-sided upper confidence limit the lower CL is = 0.
In case of the one-sided lower confidence limit the upper CL is = Inf.

Author(s)
D. Labes

Examples
# upper one-sided 95% CL of a CV=0.3
# from a study with df=22 (f.i. a 2x2 crossover with n=24)
# default side="upper" since not explicitly given
CVCL(0.3, df = 22)
# should give:
# lower CL upper CL
# 0.0000000 0.4075525

CVfromCI CV from a given Confidence interval

Description
Calculates the CV (coefficient of variation) from a known confidence interval of a BE study.
Useful if no CV but the 90% CI was given in literature.

Usage
CVfromCI(pe, lower, upper, n, design = "2x2", alpha = 0.05, robust = FALSE)
CI2CV(pe, lower, upper, n, design = "2x2", alpha = 0.05, robust = FALSE)

Arguments
pe Point estimate of the T/R ratio.
The pe may be missing. In that case it will be calculated as geometric mean
of lower and upper.
lower Lower confidence limit of the BE ratio.
upper Upper confidence limit of the BE ratio.
n Total number of subjects under study if given as scalar.
Number of subjects in (sequence) groups if given as vector.
design Character string describing the study design.
See known.designs() for designs covered in this package.
alpha Error probability. Set it to (1-confidence)/2 (i.e. to 0.05 for the usual 90%
confidence intervals).
CVfromCI 15

robust With robust=FALSE (the default) usual degrees of freedom of the designs are
used.
With robust=TRUE the degrees of freedom for the so-called robust evaluation
(df2 in known.designs()) will be used. This may be helpful if the CI was evalu-
ated via a mixed model or via intra-subject contrasts (aka Senn’s basic estima-
tor).

Details
See Helmut Schütz’ presentation for the algebra underlying this function.

Value
Numeric value of the CV as ratio.

Note
The calculations are based on the assumption of evaluation via log-transformed values.
The calculations are further based on a common variance of Test and Reference treatments in repli-
cate crossover studies or parallel group study, respectively.

In case of argument n given as n(total) and is not divisible by the number of (sequence) groups
the total sample size is partitioned to the (sequence) groups to have small imbalance only. A mes-
sage is given in such cases.
The estimated CV is conservative (i.e., higher than actually observed) in case of unbalancedness.

CI2CV() is simply an alias to CVfromCI().

Author(s)
Original by D. Labes with suggestions by H. Schütz.
Reworked and adapted to unbalanced studies by B. Lang.

References
Yuan J, Tong T, Tang M-L. Sample Size Calculation for Bioequivalence Studies Assessing Drug Ef-
fect and Food Effect at the Same Time With a 3-Treatment Williams Design. Regul Sci. 2013;47(2):242–
7. doi: 10.1177/2168479012474273

Examples
# Given a 90% confidence interval (without point estimate)
# from a classical 2x2 crossover with 22 subjects
CVfromCI(lower=0.91, upper=1.15, n=22, design="2x2")
# will give [1] 0.2279405, i.e a CV ~ 23%
#
# unbalanced 2x2 crossover study, but not reported as such
CI2CV(lower=0.89, upper=1.15, n=24)
# will give a CV ~ 26.3%
# unbalancedness accounted for
CI2CV(lower=0.89, upper=1.15, n=c(16,8))
16 CVp2CV

# should give CV ~ 24.7%

CVp2CV Decompose CV(T) and CV(R) from ’pooled’ CV of T/R

Description

Helper function to calculate CV(T) and CV(R) from a pooled CV(T/R) assuming a ratio of the
intra-subject variances.

Usage

CVp2CV(CV, ratio = 1.5)

Arguments

CV ‘pooled’ CV of T and R (as ratio, not percent).

ratio Ratio of the intra-subject variances s^2(T)/s^2(R).
May be a vector.

Details

In case of knowing only the CV(T/R) f.i. from an ordinary cross-over you can calculate the compo-
nents CV(T) and CV(R) assuming a ratio of the intra-subject variances.
The formula the function is based on:
log(1.0 + CV^2) = (sWT^2 + sWR^2)/2
Insert sWT^2 = ratio * sWR^2 and solve for sWR^2.

Value

Returns a numeric vector of the CV values for Test and Reference if only one ratio is given.
Returns a matrix with named columns CVwT and CVwR if ratio is given as vector.

Author(s)

D. Labes

Examples
CVp2CV(0.4, ratio=2)
# gives
# [1] 0.4677952 0.3225018
CVpooled 17

CVpooled Pooled CV from several studies

Description
This function pools CVs of several studies.

Usage
CVpooled(CVdata, alpha = 0.2, logscale = TRUE, robust = FALSE)
## S3 method for class 'CVp'
print(x, digits = 4, verbose = FALSE, ...)

Arguments
CVdata A data.frame that must contain the columns CV, n and design where CV are the
error CVs from the studies, n the number of subjects and design is a character
string describing the study design.
See known.designs() for designs covered in this package.
If the design column is missing the classical 2×2 crossover is assumed for each
study. A message is displayed under that circumstances.

A data.frame that contains the columns CV and giving the degrees of freedom
df directly is also accepted as CVdata.
alpha Error probability for calculating an upper confidence limit of the pooled CV.
Recommended 0.2–0.25 for use in subsequent sample size estimation.
See f.i one of H. Schütz’ presentations.
logscale Should the calculations be done for log-transformed data? Defaults to TRUE.
robust Defaults to FALSE.
Set to TRUE will use the degrees of freedom according to the ‘robust’ evaluation
(aka Senn’ basic estimator). These dfs are calculated as n-seq.
They are also often more appropriate if the CV comes from a ‘true’ mixed effects
model evaluation (FDA model for average bioequivalence).
See known.designs()$df2 for the designs covered in this package.
x An object of class "CVp".
digits Number of significant digits for the CV and the CL.
verbose Defaults to FALSE. Prints only the pooled CV and df.
If set to TRUE the upper confidence limit is also printed.
... More args to print(). None used.

Details
The pooled CV is obtained from the weighted average of the error variances obtained from the CVs
of the single studies, weights are the degrees of freedom df.
If only n is given in the input CVdata, the dfs are calculated via the formulas given in known.designs().
18 CVpooled

If both n and df are given the df column precedes.

If logscale=TRUE the error variances are obtained via function CV2se(). Otherwise the pooled
CV is obtained via pooling the CV^2.

Value
A list of class "CVp" with components

CV value of the pooled CV

df pooled degrees of freedom
CVupper upper confidence interval of the pooled CV
alpha input value

The class "CVp" has a S3 methods print.CVp.

Warning
Pooling of CVs from parallel group and crossover designs does not make any sense.
Also the function does not throw an error if you do so.

Note
The calculations for logscale=FALSE are not described in the references. They are implemented
by analogy to the case via log-transformed data.
The calculations are based on a common variance of Test and Reference formulations in replicate
crossover studies or a parallel group study, respectively.

Author(s)
D. Labes

References
H. Schütz’ presentations about sample size challenges.
Patterson S, Jones B. Bioequivalence and Statistics in Clinical Pharmacology. Boca Raton: Chap-
man & Hall / CRC Press; 2nd edition 2017. Chapter 5.7 “Determining Trial Size”.

AUC | 0.30 | 12 | 2x2 | study 2

Cmax | 0.31 | 12 | 2x2 | study 2
AUC | 0.25 | 12 | 2x2x4| study 3 (full replicate)
")
txtcon <- textConnection(CVs)
CVdata <- read.table(txtcon, header = TRUE, sep = "|",
strip.white = TRUE, as.is = TRUE)
close(txtcon)

# evaluation of the AUC CVs

CVsAUC <- subset(CVdata, PKmetric == "AUC")
CVpooled(CVsAUC, alpha = 0.2, logscale = TRUE)
# df of the 'robust' evaluation
CVpooled(CVsAUC, alpha = 0.2, logscale = TRUE, robust = TRUE)
# print also the upper CL, data example 3
CVsAUC3 <- subset(CVsAUC,design != "2x2x4")
print(CVpooled(CVsAUC3, alpha = 0.2, robust = TRUE), digits = 3, verbose = TRUE)
# will give the output:
# Pooled CV = 0.235 with 32 degrees of freedom (robust dfs)
# Upper 80% confidence limit of CV = 0.266
#
# Combining CVs from studies evaluated by ANOVA (robust=FALSE) and
# by a mixed effects model (robust=TRUE). dfs have to be provided!
CVs <- ("
CV | n |design| source | model | df
0.212 | 24 | 2x2 | study 1 | fixed | 22
0.157 | 27 | 3x3 | study 2 | fixed | 50
0.148 | 27 | 3x3 | study 3 | mixed | 24
")
txtcon <- textConnection(CVs)
CVdata <- read.table(txtcon, header = TRUE, sep = "|",
strip.white = TRUE, as.is = TRUE)
close(txtcon)
print(CVpooled(CVdata, alpha = 0.2), digits = 3, verbose = TRUE)
# will give the output:
# Pooled CV = 0.169 with 96 degrees of freedom
# Upper 80% confidence limit of CV = 0.181

CVwRfromU CVwR from the upper expanded limit (ABEL)

Description
Calculates the intra-subject CV (coefficient of variation) of the reference from the upper expanded
limit of a BE study (replicate design for ABEL). Useful if no CVwR but the expanded limits were
given.

Usage
CVwRfromU(U, regulator = "EMA")
U2CVwR(U, regulator = "EMA")
20 exppower.noninf

Arguments
U Upper expanded limit.
Must be within {1.2500, 1.4319} if regulator="EMA" and within {1.2500,
1.5000} if regulator="HC".
regulator Regulatory body’s settings for expanding the BE acceptance limits, given as a
string from the choices "EMA" or "HC". Defaults to regulator="EMA".

Details
Only the upper expanded limit is supported since it offers one more significant digit than the lower
expanded limit.

Value
Numeric value of the CVwR as ratio, where CVwR = sqrt(exp((log(U)/r_const)^2)-1).

Note
U2CVwR() is simply an alias to CVwRfromU().

Author(s)
H. Schütz

Examples
# Given the upper expanded limit and using the defaults
CVwRfromU(U = 1.38)
# should give [1] 0.44355, i.e., a CVwR ~ 44%
# Upper limit from a study according the Health Canada’s rules
CVwRfromU(U = 1.48, regulator = "HC")
# should give [1] 0.55214

exppower.noninf Expected power of the non-inferiority test

Description
Calculates the so-called expected, i.e., unconditional, power for a variety of study designs used in
bioequivalence studies.

Usage
exppower.noninf(alpha = 0.025, logscale = TRUE, theta0, margin, CV, n,
design = "2x2", robust = FALSE,
prior.type = c("CV", "theta0", "both"), prior.parm = list(),
method = c("exact", "approx"))
exppower.noninf 21

Arguments
alpha Significance level (one-sided). Defaults here to 0.025.
logscale Should the data be used on log-transformed or on original scale? TRUE (default)
or FALSE.
theta0 Assumed ‘true’ (or ‘observed’ in case of prior.type != "CV") ratio or differ-
ence.
In case of logscale=TRUE it must be given as ratio T/R.
If logscale=FALSE, the difference in means. In this case, the difference may be
expressed in two ways: relative to the same (underlying) reference mean, i.e. as
(T-R)/R = T/R - 1; or as difference in means T-R. Note that in the former case
the units of margin and CV need also be given relative to the reference mean
(specified as ratio).
Defaults to 0.95 if logscale=TRUE or to -0.05 if logscale=FALSE
margin Non-inferiority margin.
In case of logscale=TRUE it is given as ratio.
If logscale=FALSE, the limit may be expressed in two ways: difference of
means relative to the same (underlying) reference mean or in units of the dif-
ference of means. Note that in the former case the units of CV and theta0 need
also be given relative to the reference mean (specified as ratio).
Defaults to 0.8 if logscale=TRUE or to -0.2 if logscale=FALSE.
CV In case of logscale=TRUE the (geometric) coefficient of variation given as ratio.
If logscale=FALSE the argument refers to (residual) standard deviation of the
response. In this case, standard deviation may be expressed two ways: relative
to a reference mean (specified as ratio sigma/muR), i.e. again as a coefficient of
variation; or untransformed, i.e. as standard deviation of the response. Note that
in the former case the units of theta0, theta1 and theta2 need also be given
relative to the reference mean (specified as ratio).

In case of cross-over studies this is the within-subject CV, in case of a parallel-

group design the CV of the total variability.
n Number of subjects under study.
Is total number if given as scalar, else number of subjects in the (sequence)
groups. In the latter case the length of n has to be equal to the number of (se-
quence) groups.
design Character string describing the study design. See known.designs() for designs
covered in this package.
robust Defaults to FALSE. Set to TRUE will use the degrees of freedom according to the
‘robust’ evaluation (aka Senn’s basic estimator). These degrees of freedom are
calculated as n-seq.
See known.designs()$df2 for designs covered in this package.
prior.type Specifies which parameter uncertainty should be accounted for. In case of
prior.type = "CV" (the default), only the uncertainty with respect to the CV
will be considered (i.e. the given treatment effect is assumed to be fix). In case
of prior.type = "theta0" only uncertainty with respect to the treatment ra-
tio/difference will be accounted for (i.e. the given CV is assumed to be fix).
22 exppower.noninf

In case of prior.type = "both" the power value will be unconditional with

respect to both the CV and theta0.
prior.parm A list of parameters expressing the prior information about the variability and/or
treatment effect. Possible components are df, SEM, m and design.
For prior.type = "CV" the degrees of freedom from the prior trial are required.
This information can be provided by specifying the single component df or the
combination consisting of m and design.
For prior.type = "theta0" the standard error of the treatment difference from
the prior trial is required. This information can be provided by specifying the
single component SEM or the combination consisting of m and design.
For prior.type = "both" the degrees of freedom and the standard error of the
treatment difference are required. This information can be provided by speci-
fying the combination consisting of df and SEM or via the combination m and
design.
See ’Details’ for a technical description on each component.
method Defaults to method="exact". In that case the expected power will be calculated
as expected value of the power with respect to the (prior) distribution of the re-
spective parameter(s).
Set to method="approx" the expected power according to the approximate for-
mulas given in the book from Julious or in the Julious/Owen paper will be cal-
culated (using non-central t); this only affects prior.type = "CV".

The prior.parm argument is a list that can supply any of the following components:

df Error degrees of freedom from the prior trial (>4, maybe non-integer). df = Inf is allowed and
for method = "exact" the result will then coincide with power.noninf(...).
Note: This corresponds to the df of both the CV and the difference of means.
SEM Standard error of the difference of means from the prior trial; must always be on additive scale
(i.e., usually log-scale).
m Number of subjects from prior trial. Specification is analogous to the main argument n.
design Study design of prior trial. Specification is analogous to the main argument design.

For prior.parm, the combination consisting of df and SEM requires a somewhat advanced knowl-
edge of the prior trial (provided in the raw output from for example the software SAS, or may be
obtained via emmeans of package emmeans. However, it has the advantage that if there were miss-
ing data the exact degrees of freedom and standard error of the difference can be used, the former
possibly being non-integer valued (e.g. if the Kenward-Roger method was used).
Details on argument prior.type:

CV The expectation is calculated with respect to the Inverse-gamma distribution.

exppower.noninf 23

theta0 The expectation is calculated with respect to the conditional distribution theta0 | σ 2 = s^2
of the posteriori distribution of (theta0, σ 2 ) from the prior trial.
both The expectation is calculated with respect to the posteriori distribution of (theta0, σ 2 ) from the
prior trial. Numerical calculation of the two-dimensional integral is performed via cubature::hcubature.
Notes on the underlying hypotheses
If the supplied margin is < 0 (logscale=FALSE) or < 1 (logscale=TRUE), then it is assumed higher
response values are better. The hypotheses are
H0: theta0 <= margin vs. H1: theta0 > margin
where theta0 = mean(test)-mean(reference) if logscale=FALSE
or
H0: log(theta0) <= log(margin) vs. H1: log(theta0) > log(margin)
where theta0 = mean(test)/mean(reference) if logscale=TRUE.

If the supplied margin is > 0 (logscale=FALSE) or > 1 (logscale=TRUE), then it is assumed lower
response values are better. The hypotheses are
H0: theta0 >= margin vs. H1: theta0 < margin
where theta0 = mean(test)-mean(reference) if logscale=FALSE
or
H0: log(theta0) >= log(margin) vs. H1: log(theta0) < log(margin)
where theta0 = mean(test)/mean(reference) if logscale=TRUE.
This latter case may also be considered as ‘non-superiority’.

Value
Value of expected power according to the input.

Author(s)
B. Lang, D. Labes

References
Grieve AP. Confidence Intervals and Sample Sizes. Biometrics. 1991;47:1597–603. doi: 10.2307/
2532411
O’Hagan, Stevens, JW, Campell MJ. Assurance in Clinical Trial Design. Pharm Stat. 2005;4:187–
201. doi: 10.1002/pst.175
Julious SA, Owen RJ. Sample size calculations for clinical studies allowing for uncertainty in
variance. Pharm Stat. 2006;5:29–37. doi: 10.1002/pst.197
Julious SA. Sample sizes for Clinical Trials. Boca Raton: CRC Press / Chapman & Hall; 2010.
Bertsche A, Nehmitz G, Beyersmann J, Grieve AP. The predictive distribution of the residual vari-
ability in the linear-fixed effects model for clinical cross-over trials. Biom J. 2016;58(4):797–809.
doi: 10.1002/bimj.201500245
Box GEP, Tiao GC. Bayesian Inference in Statistical Analysis. Boston: Addison-Wesley; 1992.
Held L, Sabanes Bove D. Applied Statistical Inference. Likelihood and Bayes. Berlin, Heidelberg:
Springer; 2014. doi: 10.1007/9783642378874
Senn S. Cross-over Trials in Clinical Research. Chichester: John Wiley & Sons; 2nd edition 2002.
24 exppower.TOST

Zierhut ML, Bycott P, Gibbs MA, Smith BP, Vicini P. Ignorance is not bliss: Statistical power is
not probability of trial success. Clin Pharmacol Ther. 2015;99:356–9. doi: 10.1002/cpt.257

See Also

expsampleN.noninf,power.noninf

Examples
# Expected power for non-inferiority test for a 2x2 crossover
# with 40 subjects. CV 30% known from a pilot 2x2 study with
# 12 subjects
# using all the defaults for other parameters (theta0 carved in stone)
# should give: [1] 0.6761068
exppower.noninf(CV = 0.3, n = 40, prior.parm = list(df = 12-2))
# or equivalently
exppower.noninf(CV = 0.3, n = 40, prior.parm = list(m = 12, design = "2x2"))

# May be also calculated via exppower.TOST() after setting upper acceptance limit
# to Inf and alpha=0.025
exppower.TOST(CV = 0.3, n = 40, prior.parm = list(df = 10), theta2 = Inf, alpha=0.025)

# In contrast: Julious approximation

exppower.noninf(CV = 0.3, n = 40, prior.parm = list(df = 10), method = "approx")
# should give: [1] 0.6751358

# Compare this to the usual (conditional) power (CV known, "carved in stone")
power.noninf(CV = 0.3, n = 40)
# should give: [1] 0.7228685
# same as if setting df = Inf in function exppower.noninf()
exppower.noninf(CV = 0.3, n = 40, prior.parm = list(df = Inf))

# Expected power for a 2x2 crossover with 40 subjects

# CV 30% and theta0 = 0.95 known from a pilot 2x2 study with 12 subjects
# using uncertainty with respect to both CV and theta0
exppower.noninf(CV = 0.3, theta0 = 0.95, n = 40,
prior.parm = list(m = 12, design = "2x2"), prior.type = "both")
# should give a decrease of expected power to 0.5982852

exppower.TOST Expected power of the TOST procedure

Description

Calculates the so-called expected, i.e., unconditional, power for a variety of study designs used in
bioequivalence studies.
exppower.TOST 25

Usage
exppower.TOST(alpha = 0.05, logscale = TRUE, theta0, theta1, theta2,
CV, n, design = "2x2", robust = FALSE,
prior.type = c("CV", "theta0", "both"), prior.parm = list(),
method = c("exact", "approx"))

Arguments
alpha Significance level (one-sided). Commonly set to 0.05.
logscale Should the data be used on log-transformed or on original scale? TRUE (default)
or FALSE.
theta0 Assumed ‘true’ (or ‘observed’ in case of prior.type != "CV") ratio or differ-
ence.
In case of logscale=TRUE it must be given as ratio T/R.
If logscale=FALSE, the difference in means. In this case, the difference may be
expressed in two ways: relative to the same (underlying) reference mean, i.e. as
(T-R)/R = T/R - 1; or as difference in means T-R. Note that in the former case
the units of CV, theta1 and theta2 need also be given relative to the reference
mean (specified as ratio).
Defaults to 0.95 if logscale=TRUE or to 0.05 if logscale=FALSE
theta1 Lower (bio-)equivalence limit.
In case of logscale=TRUE it is given as ratio.
If logscale=FALSE, the limit may be expressed in two ways: difference of
means relative to the same (underlying) reference mean or in units of the dif-
ference of means. Note that in the former case the units of CV, theta0 and
theta2 need also be given relative to the reference mean (specified as ratio).
Defaults to 0.8 if logscale=TRUE or to -0.2 if logscale=FALSE.
theta2 Upper (bio-)equivalence limit.
In case of logscale=TRUE it is given as ratio. If logscale=FALSE, the limit may
be expressed in two ways: difference of means relative to the same (underlying)
reference mean or in units of the difference of means. Note that in the former
case the units of CV, theta0 and theta1 need also be given relative to the refer-
ence mean (specified as ratio).
If not given, theta2 will be calculated as 1/theta1 if logscale=TRUE or as
-theta1 if logscale=FALSE.
CV In case of logscale=TRUE the (geometric) coefficient of variation given as ratio.
If logscale=FALSE the argument refers to (residual) standard deviation of the
response. In this case, standard deviation may be expressed two ways: relative
to a reference mean (specified as ratio sigma/muR), i.e. again as a coefficient of
variation; or untransformed, i.e. as standard deviation of the response. Note that
in the former case the units of theta0, theta1 and theta2 need also be given
relative to the reference mean (specified as ratio).

In case of cross-over studies this is the within-subject CV, in case of a parallel-

group design the CV of the total variability.
n Number of subjects under study.
Is total number if given as scalar, else number of subjects in the (sequence)
26 exppower.TOST

groups. In the latter case the length of n has to be equal to the number of (se-
quence) groups.
design Character string describing the study design. See known.designs for designs
covered in this package.
robust Defaults to FALSE. Set to TRUE will use the degrees of freedom according to
the ‘robust’ evaluation (aka Senn’s basic estimator). These df are calculated as
n-seq.
See known.designs()$df2 for designs covered in this package.
prior.type Specifies which parameter uncertainty should be accounted for. In case of
prior.type = "CV" (the default), only the uncertainty with respect to the CV
will be considered (i.e. the given treatment effect is assumed to be fix). In case
of prior.type = "theta0" only uncertainty with respect to the treatment ra-
tio/difference will be accounted for (i.e. the given CV is assumed to be fix).
In case of prior.type = "both" the power value will be unconditional with
respect to both the CV and theta0.
prior.parm A list of parameters expressing the prior information about the variability and/or
treatment effect. Possible components are df, SEM, m and design.
For prior.type = "CV" the degrees of freedom from the prior trial are required.
This information can be provided by specifying the single component df or the
combination consisting of m and design.
For prior.type = "theta0" the standard error of the treatment difference from
the prior trial is required. This information can be provided by specifying the
single component SEM or the combination consisting of m and design.
For prior.type = "both" the degrees of freedom and the standard error of the
treatment difference are required. This information can be provided by speci-
fying the combination consisting of df and SEM or via the combination m and
design.
See ’Details’ for a technical description on each component.
method Defaults to method="exact". In that case the expected power will be calculated
as expected value of the power with respect to the (prior) distribution of the re-
spective parameter(s).
Set to method="approx" the expected power according to the approximate for-
mulas given in the book from Julious or in the Julious/Owen paper will be cal-
culated (using non-central t); this only affects prior.type = "CV".

Details
This function calculates the so-called expected power taking into account that usually the parame-
ters (CV and/or theta0) are not known but estimated from a prior study with some uncertainty. The
expected power is an unconditional power and can therefore be seen as probability for success. See
references for further details.
The prior.parm argument is a list that can supply any of the following components:
df Error degrees of freedom from the prior trial (>4, maybe non-integer). df = Inf is allowed and
for method = "exact" the result will then coincide with power.TOST(...).
Note: This corresponds to the df of both the CV and the difference of means.
SEM Standard error of the difference of means from the prior trial; must always be on additive scale
(i.e., usually log-scale).
exppower.TOST 27

m Number of subjects from prior trial. Specification is analogous to the main argument n.
design Study design of prior trial. Specification is analogous to the main argument design.

For prior.parm, the combination consisting of df and SEM requires a somewhat advanced knowl-
edge of the prior trial (provided in the raw output from for example the software SAS, or may be
obtained via emmeans of package emmeans. However, it has the advantage that if there were miss-
ing data the exact degrees of freedom and standard error of the difference can be used, the former
possibly being non-integer valued (e.g., if the Kenward-Roger method was used).
Details on argument prior.type:

CV The expectation is calculated with respect to the Inverse-gamma distribution.

Value
Value of expected power according to the input.

Author(s)
B. Lang (thanks to G. Nehmiz for the helpful discussions), D. Labes

See Also
expsampleN.TOST,power.TOST
28 expsampleN.noninf

Examples
# Expected power for a 2x2 crossover with 40 subjects
# CV 30% known from a pilot 2x2 study with 12 subjects
# using all the defaults for other parameters (theta0 carved in stone)
exppower.TOST(CV = 0.3, n = 40, prior.parm = list(df = 12-2))
# should give: [1] 0.7365519
# or equivalently
exppower.TOST(CV = 0.3, n = 40, prior.parm = list(m = 12, design = "2x2"))

# In contrast: Julious approximation

exppower.TOST(CV = 0.3, n = 40, prior.parm = list(df = 10), method = "approx")
# should give: [1] 0.7359771

# Compare this to the usual (conditional) power (CV known, "carved in stone")
power.TOST(CV = 0.3, n = 40)
# should give: [1] 0.8158453
# same as if setting df = Inf in function exppower.TOST()
exppower.TOST(CV = 0.3, n = 40, prior.parm = list(df = Inf))

# Expected power for a 2x2 crossover with 40 subjects

# CV 30% and theta0 = 0.95 known from a pilot 2x2 study with 12 subjects
# using uncertainty with respect to both CV and theta0
exppower.TOST(CV = 0.3, theta0 = 0.95, n = 40,
prior.parm = list(m = 12, design = "2x2"), prior.type = "both")
# should give [1] 0.5114685

expsampleN.noninf Sample size based on expected power for the non-inferiority test

Description
Estimates the sample size based on the expected power for a variety of designs used in bioequiva-
lence studies. See known.designs for the study designs covered.

Usage
expsampleN.noninf(alpha = 0.025, targetpower = 0.8, logscale = TRUE,
theta0, margin, CV, design = "2x2", robust = FALSE,
prior.type = c("CV", "theta0", "both"), prior.parm = list(),
method = c("exact", "approx"), print = TRUE, details)

Arguments
alpha Significance level (one-sided). Defaults here to 0.025.
targetpower Power to achieve at least. Must be >0 and <1. Typical values are 0.8 or 0.9.
logscale Should the data used on log-transformed or on original scale? TRUE or FALSE.
Defaults to TRUE.
expsampleN.noninf 29

theta0 Assumed ‘true’ (or ‘observed’ in case of prior.type != "CV") ratio or differ-
ence.
In case of logscale=TRUE it must be given as ratio T/R.
If logscale=FALSE, the difference in means. In this case, the difference may be
expressed in two ways: relative to the same (underlying) reference mean, i.e. as
(T-R)/R = T/R - 1; or as difference in means T-R. Note that in the former case
the units of margin and CV need also be given relative to the reference mean
(specified as ratio).
Defaults to 0.95 if logscale=TRUE or to -0.05 if logscale=FALSE
margin Non-inferiority margin.
In case of logscale=TRUE it is given as ratio.
If logscale=FALSE, the limit may be expressed in two ways: difference of
means relative to the same (underlying) reference mean or in units of the dif-
ference of means. Note that in the former case the units of CV and theta0 need
also be given relative to the reference mean (specified as ratio).
Defaults to 0.8 if logscale=TRUE or to -0.2 if logscale=FALSE.
CV In case of logscale=TRUE the (geometric) coefficient of variation given as ratio.
If logscale=FALSE the argument refers to (residual) standard deviation of the
response. In this case, standard deviation may be expressed two ways: relative
to a reference mean (specified as ratio sigma/muR), i.e. again as a coefficient of
variation; or untransformed, i.e. as standard deviation of the response. Note that
in the former case the units of theta0, theta1 and theta2 need also be given
relative to the reference mean (specified as ratio).

If prior.type="CV" may be given as vector: The CVs are then pooled (as a
weighted mean with their degrees of freedoms as weights).

In case of cross-over studies this is the within-subject CV, in case of a parallel-

group design the CV of the total variability.
design Character string describing the study design.
See known.designs() for designs covered in this package.
robust Defaults to FALSE. With that value the usual degrees of freedom will be used.
Setting to TRUE will use the degrees of freedom according to the ‘robust’ evalu-
ation (aka Senn’s basic estimator). These df are calculated as n-seq.
See known.designs() for designs covered in this package.
prior.type Specifies which parameter uncertainty should be accounted for. In case of
prior.type="CV" (the default), only the uncertainty with respect to the CV
will be considered (i.e., the given treatment effect is assumed to be fix). In
case of prior.type="theta0" only uncertainty with respect to the treatment
ratio/difference will be accounted for (i.e., the given CV is assumed to be fix).
In case of prior.type="both" the power value will be unconditional with re-
spect to both the CV and theta0.
prior.parm A list of parameters expressing the prior information about the variability and/or
treatment effect. Possible components are df, SEM, m, design.
For prior.type="CV" the degrees of freedom from the prior trial are required.
This information can be provided by specifying the single componentdf or the
combination consisting of m and design.
30 expsampleN.noninf

For prior.type = "theta0" the standard error of the treatment difference from
the prior trial is required. This information can be provided by specifying the
single component SEM or the combination consisting of m and design.
For prior.type = "both" the degrees of freedom and the standard error of the
treatment difference are required. This information can be provided by speci-
fying the combination consisting of df and SEM or via the combination m and
design.
See section ‘Details’ for a technical description of each component.
method Defaults to method="exact". In that case the expected power will be calculated
as expected value of the power with respect to the (prior) distribution of the re-
spective parameter(s).
Set to method="approx" the expected power according to the approximate for-
mulas given by Julious or Julious & Owen will be calculated (using the non-
central t); this only affects prior.type = "CV".
print If TRUE (default) the function prints its results.
If FALSE only a data.frame with the results will be returned.
details If TRUE the design characteristics and the steps during sample size calculations
will be shown.
If not specified, the default value is FALSE for prior.type != "both" and TRUE
otherwise.

Details
The sample size is estimated based on iterative evaluation of expected power. The starting value of
the sample size search is taken from a large sample approximation if prior.type="CV". Else an
empirical start value is obtained. Note that in case of prior.type="both" the calculation may still
take several seconds.
Note also that the expected power is always bounded above by the so-called probability of technical
success (PTS) which may be a value less than 1.Therefore, it may be possible that it is either not
possible to calculate the required sample size at all or that the sample size gets very large if the
given targetpower is less but close to the PTS.

Notes on the underlying hypotheses

If the supplied margin is < 0 (logscale=FALSE) or < 1 (logscale=TRUE), then it is assumed higher
response values are better. The hypotheses are
H0: theta0 <= margin
H1: theta0 > margin
where theta0 = mean(test)-mean(reference) if logscale=FALSE
or
H0: log(theta0) <= log(margin)
H1: log(theta0) > log(margin)
where theta0 = mean(test)/mean(reference) if logscale=TRUE.

If the supplied margin is > 0 (logscale=FALSE) or > 1 (logscale=TRUE), then it is assumed lower
response values are better. The hypotheses are
H0: theta0 >= margin
H1: theta0 < margin
expsampleN.noninf 31

where theta0 = mean(test)-mean(reference) if logscale=FALSE

or
H0: log(theta0) >= log(margin)
H1: log(theta0) < log(margin)
where theta0 = mean(test)/mean(reference) if logscale=TRUE.
This latter case may also be considered as ‘non-superiority’.

Value
A data.frame with the input values and the result of the sample size estimation.
The Sample size column contains the total sample size in case of all designs implemented.

Author(s)
B. Lang, D. Labes

References
Grieve AP. Confidence Intervals and Sample Sizes. Biometrics. 1991;47:1597–603. doi: 10.2307/
2532411
O’Hagan, Stevens, JW, Campell MJ. Assurance in Clinical Trial Design. Pharm Stat. 2005;4:187–
201. doi: 10.1002/pst.175
Julious SA, Owen RJ. Sample size calculations for clinical studies allowing for uncertainty in
variance. Pharm Stat. 2006;5:29–37. doi: 10.1002/pst.197
Julious SA. Sample sizes for Clinical Trials. Boca Raton: CRC Press; 2010.
Bertsche A, Nehmitz G, Beyersmann J, Grieve AP. The predictive distribution of the residual vari-
ability in the linear-fixed effects model for clinical cross-over trials. Biom J. 2016;58(4):797–809.
doi: 10.1002/bimj.201500245
Box GEP, Tiao GC. Bayesian Inference in Statistical Analysis. Boston: Addison-Wesley; 1992.
Held L, Sabanes Bove D. Applied Statistical Inference. Likelihood and Bayes. Berlin, Heidelberg:
Springer; 2014. doi: 10.1007/9783642378874
Senn S. Cross-over Trials in Clinical Research. Chichester: John Wiley & Sons; 2nd edition 2002.
Zierhut ML, Bycott P, Gibbs MA, Smith BP, Vicini P. Ignorance is not bliss: Statistical power is
not probability of trial success. Clin Pharmacol Ther. 2015;99:356–9. doi: 10.1002/cpt.257

See Also
exppower.noninf,known.designs,sampleN.noninf

Examples
# Classical 2x2 cross-over, target power = 80%,
# assumed true ratio = 95%, margin = 0.8,
# intra-subject CV=30% estimated from prior 2x2 trial
# with m = 12 subjects
expsampleN.noninf(theta0 = 0.95, margin = 0.8, CV = 0.3, design = "2x2",
prior.parm = list(m = 12, design = "2x2"))
# gives n = 58 with achieved expected power 0.809148
32 expsampleN.TOST

# Compare this to the usual sample size with CV assumed

# as 'carved in stone'
sampleN.noninf(theta0 = 0.95, margin = 0.8, CV = 0.3)

# Perform 'non-superiority' (lower is better) with assumed

# true ratio = 105% and margin 125%
expsampleN.noninf(theta0 = 1.05, margin = 1.25, CV = 0.3, design = "2x2",
prior.parm = list(m = 12, design = "2x2"))
# should give n = 56 with achieved expected power 0.806862

# More than one CV with corresponding degrees of freedom

# other settings as above in first example
CVs <- c(0.25, 0.3)
dfs <- c(22, 10)
expsampleN.noninf(theta0 = 0.95, margin = 0.8, CV = CVs,
prior.parm = list(df = dfs))
# should give a pooled CV=0.2664927 with 32 df and a sample
# size n=42 with achieved expected power 0.814073 exact
# achieved expected power 0.816163 approximate acc. to Julious

# Uncertainty is accounted for CV and theta0

expsampleN.noninf(CV = 0.3, prior.type = "both",

prior.parm = list(m = 12, design = "2x2"))
# gives a dramatic increase in sample size (n = 194)
# due to small pilot trial

expsampleN.TOST Sample size based on expected power

Description
Estimates the sample size based on the expected power for a variety of study designs used in bioe-
quivalence studies. See known.designs for the study designs covered.

Usage
expsampleN.TOST(alpha = 0.05, targetpower = 0.8, logscale=TRUE, theta0,
theta1, theta2, CV, design = "2x2", robust = FALSE,
prior.type = c("CV", "theta0", "both"), prior.parm = list(),
method = c("exact", "approx"), print = TRUE, details)

Arguments
alpha Significance level (one-sided). Commonly set to 0.05.
targetpower Power to achieve at least. Must be >0 and <1. Typical values are 0.8 or 0.9.
logscale Should the data used on log-transformed or on original scale? TRUE (default) or
FALSE.
expsampleN.TOST 33

theta0 Assumed ‘true’ (or ‘observed’ in case of prior.type != "CV") bioequivalence

ratio or difference.
In case of logscale=TRUE it must be given as ratio T/R.
If logscale=FALSE, the difference in means. In this case, the difference may be
expressed in two ways: relative to the same (underlying) reference mean, i.e. as
(T-R)/R = T/R - 1; or as difference in means T-R. Note that in the former case
the units of CV, theta1 and theta2 need also be given relative to the reference
mean (specified as ratio).
Defaults to 0.95 if logscale=TRUE or to 0.05 if logscale=FALSE
theta1 Lower (bio-)equivalence limit.
In case of logscale=TRUE it is given as ratio.
If logscale=FALSE, the limit may be expressed in two ways: difference of
means relative to the same (underlying) reference mean or in units of the dif-
ference of means. Note that in the former case the units of CV, theta0 and
theta2 need also be given relative to the reference mean (specified as ratio).
Defaults to 0.8 if logscale=TRUE or to -0.2 if logscale=FALSE.
theta2 Upper (bio-)equivalence limit.
In case of logscale=TRUE it is given as ratio. If logscale=FALSE, the limit may
be expressed in two ways: difference of means relative to the same (underlying)
reference mean or in units of the difference of means. Note that in the former
case the units of CV, theta0 and theta1 need also be given relative to the refer-
ence mean (specified as ratio).
If not given, theta2 will be calculated as 1/theta1 if logscale=TRUE or as
-theta1 if logscale=FALSE.
CV In case of logscale=TRUE the (geometric) coefficient of variation given as ratio.
If logscale=FALSE the argument refers to (residual) standard deviation of the
response. In this case, standard deviation may be expressed two ways: relative
to a reference mean (specified as ratio sigma/muR), i.e. again as a coefficient of
variation; or untransformed, i.e. as standard deviation of the response. Note that
in the former case the units of theta0, theta1 and theta2 need also be given
relative to the reference mean (specified as ratio).

If prior.type="CV" may be given as vector: The CVs are then pooled (as a
weighted mean with their degrees of freedoms as weights).

In case of cross-over studies this is the within-subject CV, in case of a parallel-

group design the CV of the total variability.
design Character string describing the study design.
See known.designs for designs covered in this package.
robust Defaults to FALSE. With that value the usual degrees of freedom will be used.
Set to TRUE will use the degrees of freedom according to the ‘robust’ evaluation
(aka Senn’s basic estimator). These df are calculated as n-seq.
See known.designs()$df2 for designs covered in this package.
prior.type Specifies which parameter uncertainty should be accounted for. In case of
prior.type = "CV" (the default), only the uncertainty with respect to the CV
will be considered (i.e., the given treatment effect is assumed to be fix). In case
34 expsampleN.TOST

of prior.type = "theta0" only uncertainty with respect to the treatment ra-

tio/difference will be accounted for (i.e., the given CV is assumed to be fix).
In case of prior.type = "both" the power value will be unconditional with
respect to both the CV and theta0.
prior.parm A list of parameters expressing the prior information about the variability and/or
treatment effect. Possible components are df, SEM, m, design.
For prior.type = "CV" the degrees of freedom from the prior trial are required.
This information can be provided by specifying the single component df or the
combination consisting of m and design.
For prior.type = "theta0" the standard error of the treatment difference from
the prior trial is required. This information can be provided by specifying the
single component SEM or the combination consisting of m and design.
For prior.type = "both" the degrees of freedom and the standard error of the
treatment difference are required. This information can be provided by speci-
fying the combination consisting of df and SEM or via the combination m and
design.
See ’Details’ for a technical description on each component.
method Defaults to method="exact". In that case the expected power will be calculated
as expected value of the power with respect to the (prior) distribution of the re-
spective parameter(s).
Set to method="approx" the expected power according to the approximate for-
mulas given in the book from Julious or in the Julious/Owen paper will be cal-
culated (using non-central t); this only affects prior.type = "CV".
print If TRUE (default) the function prints its results. If FALSE only a data.frame with
the results will be returned.
details If TRUE the design characteristics and the steps during sample size calculations
will be shown.
If not specified, the default value is FALSE for prior.type != "both" and TRUE
otherwise.

Details
The sample size is calculated based on iterative evaluation of expected power. The starting value of
the sample size search is taken from a large sample approximation if prior.type = "CV". Other-
wise, an empirical start value is obtained. Note that in case of prior.type = "both" the calculation
may still take several seconds.
Note also that the expected power is always bounded above by the so-called probability of technical
success (PTS) which may be a value less than 1. Therefore, it may be possible that it is either not
possible to calculate the required sample size at all or that the sample size gets very large if the
given targetpower is less but close to the PTS.

The estimated sample size gives always the total number of subjects (not subject/sequence in
crossovers or subjects/group in parallel designs – like in some other software packages).

Value
A data.frame with the input values and the result of the sample size estimation.
The Sample size column contains the total sample size in case of all designs implemented.
expsampleN.TOST 35

Author(s)
B. Lang, D. Labes

See Also
exppower.TOST,known.designs,sampleN.TOST

Examples
# Classical 2x2 cross-over, target power = 80%,
# BE limits 80 ... 125%, assumed true BE ratio = 95%,
# intra-subject CV=30% estimated from prior 2x2 trial
# with m = 30 subjects
expsampleN.TOST(CV=0.3, prior.parm = list(m = 30, design = "2x2"))
# -> gives n = 42 with achieved expected power 0.806262
# Compare this to the usual sample size with CV assumed known ('carved in stone')
sampleN.TOST(CV=0.3)
# -> gives n = 40 subjects
# Compare this to the case where uncertainty is accounted for CV and theta0
# Not run due to timing policy of CRAN - may run several seconds

expsampleN.TOST(CV=0.3, prior.parm = list(m = 30, design = "2x2"),

prior.type = "both")
# -> gives n = 72 subjects

# More than one CV with corresponding degrees of freedom

# other settings as above in first example
CVs <- c(0.25, 0.3)
dfs <- c(22, 10)
36 known.designs

expsampleN.TOST(CV=CVs, prior.parm = list(df = dfs))

# -> gives a pooled CV=0.2664927 with df=32
# and a sample size n=34 with achieved expected power 0.812653 exact
# achieved expected power 0.815019 approximate acc. Julious

known.designs Show the ’known’ designs

Description
Returns the known study designs for which power and sample size can be calculated within this
package.

Usage
known.designs()

Details
This function is for informal purposes and used internally for obtaining characteristics of the designs
used in calculation formulas.

Value
Returns a data.frame with

no number of the design

design character string for identifying the design
df degrees of freedom of the design
df2 ‘robust’ degrees of freedom of the design
steps step width in the iterative sample size estimation
bk so-called design constant in terms of total n
bkni design constant in terms of number of subjects in (sequence) groups
The design character string has to be used in the functions calls for power and sample size.

Note
The design string for higher order crossover designs is named as:
treatments x sequences x periods in case of replicate designs and
treatments x periods in case of crossover designs for more then 2 treatments with number of
sequences equal number of treatments.

The df for the replicate crossover designs are those without carry-over in the model.
Chen et al. used models with carry-over, i.e., one df lower than here.
OwensQ 37

The design constant bk in case of design 2x2x4 is here bk=1.

Chen et al. used bk=1.1 due to carry-over in the model.

n is the total number of subjects for all designs implemented.

df2 = degrees of freedom for the so-called ‘robust’ analysis (aka Senn’s basic estimator).
These degrees of freedom are often also more appropriate in case of evaluation via a ‘true’ mixed
model (e.g. the FDA’ for replicate designs).

The design 2x2x2r is the 2-treatment-2-sequence-2-period design with 2 repeated targets deter-
mined in each period (sequences TT|RR or RR|TT) described by Liu. Implemented are the charac-
teristics of this design for the evaluation via assuming no S×F interaction and equal variabilities of
Test and Reference.

Author(s)

D. Labes

References

Chen KW, Chow SC, Liu G. A Note on Sample Size Determination for Bioequivalence Studies with
Higher-order Crossover Designs. J Pharmacokin Biopharm. 1997;25(6):753–65.
Senn S. Cross-over Trials in Clinical Research. Chichester: John Wiley & Sons; 2nd edition 2002.
U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug
Evaluation and Research (CDER). Guidance for Industry. Statistical Approaches to Establishing
Bioequivalence. January 2001. download
Liu J-p. Use of the Repeated Crossover design in Assessing Bioequivalence. Stat Med. 1995;14(9-
10):1067–78.

Examples
known.designs()

OwensQ Owen’s Q-function

Description

Calculates Owen’s Q function.

Usage

OwensQ(nu, t, delta, a=0, b)

38 OwensQ

Arguments

nu degree of Owen’s Q
t parameter t
delta parameter delta
a lower integration limit, only a=0 implemented
b upper integration limit

Details

Uses the relationship to non-central t-distribution (see Chou)

OwensQ = pt(t, df=nu, ncp=delta) - Integal_b_Inf(Q_integrand)

The definite integral is numerically evaluated using integrate after a variables transformation
resulting in the integration range from 0 to 1 instead of the semi-infinite original range. This may
result in higher precision and better numerical stability.

The arguments to the function must be scalars. No vectors allowed.

Value

Numeric value of Owen’s Q-function at given input arguments.

Note

This function is intended for internal use in the power calculations.

But may be useful for others.

Author(s)

D. Labes

References

Owen DB. A special case of a bivariate non-central t-distribution. Biometrika. 1965;52(3/4):437–

46. doi: 10.2307/2333696
Chou YM. A bivariate noncentral T-distibution with applications. Commun Stat Theory Methods.
1992;21(12):3427–62. doi: 10.1080/03610929208830988

See Also

OwensQOwen
OwensQOwen 39

Examples
# This function is mainly intended for internal use.
OwensQ(10, 2.5, 5, 0, 2)
#should give [1] 9.388137e-06
OwensQ(10, -2.5, -5, 0, 2)
#should give [1] 0.05264363

OwensQOwen Owen’s Q-function via repeated integration by parts

Description
This is an implementation of the algorithm given by Owen via repeated integration by parts.

Usage
OwensQOwen(nu, t, delta, a=0, b)

Arguments
nu degree of Owen’s Q
t parameter t
delta parameter delta
a lower integration limit.
Only a=0 implemented, other values give an error.
b upper integration limit

Value
Numeric value of Owen’s Q function.

Note
The argument a=0 could be dropped but is retained for sake of completeness.

Note
This function is mainly for comparative / validation purposes.
The function requireds OwensT function.

Author(s)
D. Labes

References
Owen DB. A special case of a bivariate non-central t-distribution. Biometrika. 1965;52(3/4):437–
46. doi: 10.2307/2333696
40 OwensT

OwensT Owen’s T-function

Description
Calculates the definite integral from 0 to a of
exp(-0.5*h^2*(1+x^2))/(1+x^2)/(2*pi).

Usage
OwensT(h, a)

Arguments
h parameter h
a upper limit of integration

Details
The function is an R port of FORTRAN code given in the references and MATLAB code given by
John Burkardt under the GNU LGPL license.

The arguments of OwensT() have to be scalars because the implementation doesn’t vectorize.

Value
Numerical value of the definite integral.

Note
This function is only needed as auxiliary in OwensQOwen.
But may be useful for others.

Author(s)
MATLAB code by J. Burkardt, R port by D. Labes
pa.ABE 41

References
Goedhart PW, Jansen MJW. Remark AS R89: A Remark on Algorithm AS 76: An Integral Useful in
Calculating Central t and Bivariate Normal Probabilities. J Royal Stat Soc C. 1992;41(2):496–7.
doi: 10.2307/2347586
Boys R. Algorithm AS R80: A Remark on Algorithm AS 76: An Integral Useful in Calculating Non-
central t and Bivariate Normal Probabilities. J Royal Stat Soc C. 1989;38(3):580–2. doi: 10.2307/
2347755
Thomas GE. Remark ASR 65: A Remark on Algorithm AS76: An Integral Useful in Calculat-
ing Non-Central t and Bivariate Normal Probabilities. J Royal Stat Soc C. 1986;35(3):310–2.
doi: 10.2307/2348031
Chou Y-M. Remark AS R55: A Remark on Algorithm AS 76: An Integral Useful in Calculating Non-
central T and Bivariate Normal Probabilities. J Royal Stat Soc C. 1985;34(1):100–1. doi: 10.2307/
2347894
Thomas GE. Remark AS R30: A Remark on Algorithm AS 76: An Integral Useful in Calcu-
lating Non-Central t and Bivariate Normal Probabilities. J Royal Stat Soc C. 1979;28(1):113.
doi: 10.2307/2346833
Young JC, Minder C. Algorithm AS 76: An Integral Useful in Calculating Non-Central t and Bi-
variate Normal Probabilities. J Royal Stat Soc C. 1974;23(3):455–7. doi: 10.2307/2347148
Burkardt J. ASA076. Owen’s T Function. Last revised 25 November 2018. https://people.sc.
fsu.edu/~jburkardt/m_src/asa076/asa076.html
Owen DB. Tables for Computing Bivariate Normal Probabilities. Ann Math Stat. 1956;27(4):1075–
90. doi: 10.1214/aoms/1177728074

pa.ABE Power analysis for average bioequivalence (ABE)

Description
An analysis tool for exploration/visualization of the impact of expected values (CV, theta0, reduced
sample size due to drop-outs) on power of BE decision via ABE if these values deviate from the
ones assumed in planning the sample size of the study.
42 pa.ABE

Usage

pa.ABE(CV, theta0 = 0.95, targetpower = 0.8, minpower = 0.7, design = "2x2", ...)
## S3 method for class 'pwrA'
print(x, digits = 4, plotit = TRUE, ...)
## S3 method for class 'pwrA'
plot(x, pct = TRUE, ratiolabel = "theta0", cols = c("blue", "red"), ...)

Arguments

CV Coefficient of variation as ratio (not percent).

In case of cross-over studies this is the within-subject CV.

theta0 ‘True’ or assumed T/R ratio. Often named GMR.

Must be given as ratio.
targetpower Power to achieve at least in sample size estimation. Must be >0 and <1.
Typical values are 0.8 or 0.9. Defaults to 0.8.
Note that targetpower < 0.5 doesn’t make much sense.
minpower Minimum acceptable power to have if deviating from assumptions for sample
size plan.
Has to be lower than targetpower. Defaults to 0.7.
minpower < 0.5 doesn’t make much sense.
design Character string describing the study design.
See known.designs() for designs covered in this package.
... More arguments to pass to power.TOST().
F.i. alpha, theta1, theta2 or robust if other values then the defaults for these
arguments are needed.
See man page of power.TOST().

More arguments passed to the S3 methods. Here currently ignored.

Additional arguments of the S3 methods:
x Object of class 'pwrA'.
digits Digits for rounding power in printing. The ’. . . ’ argument is currently ignored
in print().
plotit If set to TRUE, the default, the print method calls plot(x) if R is running inter-
actively.
pct If set to TRUE (the default) scales CV, theta0, and power in percent in plot().
Else they will be given as ratios, the usual standard in PowerTOST.
ratiolabel Label of the T/R-ratio. Can be set to any string, e.g. to "GMR". Defaults to
"theta0", the usual standard in PowerTOST.
cols Colors for the plots. cols[1] gives the color for plotting points with power>targetpower.
From targetpower toward minpower the color changes gradually to cols[2].
pa.ABE 43

Details

Power calculations are done via power.TOST() and calculations of CV and theta0 which gave a
power=minpower are derived via R base uniroot. While one of the parameters (CV, theta0, N)
is varied, the respective two others are kept constant. The tool shows the relative impact of single
parameters on power.
The tool takes a minimum of 12 subjects as required in most BE guidances into account.

It should be kept in mind that this is not a substitute for the “Sensitivity Analysis” recommended in
ICH-E9. In a real study a combination of all effects occurs simultaneously. It is up to you to decide
on reasonable combinations and analyze their respective power.

Value

Returns a list with class "pwrA" with the components

plan A data.frame with the result of the sample size estimation. See output of sampleN.TOST().
paCV A data.frame with value pairs CV, pwr for impact of deviations from CV.
paGMR A data.frame with value pairs theta0, pwr for impact of deviations from theta0
(GMR).
paN A data.frame with value pairs N, pwr for impact of deviations from planned N
(dropouts).
method Method of BE decision. Here fix = "ABE".
minpower Minimum acceptable power.

The class 'pwrA' has the S3 methods print() and plot(). See pa.scABE for usage.

Note

The code of deviations from planned sample size tries to keep the degree of imbalance as low as
possible between (sequence) groups. This results in a lesser decrease of power than more extreme
dropout-patterns.

Author(s)

Idea and original code by H. Schütz with modifications by D. Labes to use PowerTOST infrastruc-
ture.

References

Schütz H. Deviating from assumptions. August 08, 2014. BEBA Forum

See Also

power.TOST,known.designs,pa.scABE,pa.NTIDFDA
44 pa.NTIDFDA

Examples
# using the defaults
# design="2x2", targetpower=0.8, minpower=0.7, theta0/GMR=0.95
# BE margins from defaults of sampleN.TOST() 0.8 ... 1.25
# print & plot implicitly
pa.ABE(CV = 0.2)
# print & plot

res <- pa.ABE(CV = 0.2)

print(res, plotit = FALSE) # print only
plot(res, pct = FALSE, ratiolabel = "GMR") # changed from defaults

pa.NTIDFDA Power analysis for scaled ABE for NTIDs according to FDA

Description
An analysis tool for exploration/visualization of the impact of expected values (CV, theta0, reduced
sample size due to drop-outs) on power of BE decision via scABE for narrow therapeutic drugs
(NTIDs) if these values deviate from the ones assumed in planning the sample size of the study.
The only implemented design is the full replicate design "2x2x4" according to the FDA Warfarin
guidance.

Usage
pa.NTIDFDA(CV, theta0 = 0.975, targetpower = 0.8, minpower = 0.7, ...)

Arguments
CV Coefficient of variation of the intra-subject variabilities of Test and Reference as
ratio (not percent).
Here only the case CVwT=CVwR is implemented, i.e., CV has to be a scalar.
theta0 ‘True’ or assumed T/R ratio. Often named GMR.
Must be given as ratio. Defaults here to 0.975.
targetpower Power to achieve at least in sample size estimation. Must be >0 and <1.
Typical values are 0.8 or 0.9. Defaults to 0.8.
Note that targetpower < 0.5 doesn’t make much sense.
minpower Minimum acceptable power to have if deviating from assumptions for sample
size plan.
Has to be lower than targetpower. Defaults to 0.7.
minpower < 0.5 doesn’t make much sense.
... More arguments to pass to power.NTIDFDA().
F.i., alpha, theta1, theta2 or nsims if other values than the defaults for these
arguments are needed.
See man page of power.NTIDFDA().
pa.NTIDFDA 45

Details

Power calculations are done via power.NTIDFDA() and calculations of CV and theta0 which result
in minpower are derived via uniroot().
While one of the parameters (CV, theta0, n) is varied, the respective two others are kept constant.
The tool shows the relative impact of single parameters on power.
The tool takes a minimum of 12 subjects into account as demanded in most BE guidances. How-
ever, it should be kept in mind that the FDA requires at least 24 subjects to be enrolled in studies
intended for reference-scaling.

Value

Returns a list with class 'pwrA' with the components

plan A data.frame with the result of the sample size estimation. See output of sampleN.NTIDFDA().
paCV A data.frame with value pairs CV, pwr for impact of deviations from CV.
paGMR A data.frame with value pairs theta0, pwr for impact of deviations from theta0
(GMR).
paN A data.frame with value pairs N, pwr for impact of deviations from planned N
(dropouts).
method Method of BE decision. Here fix = "NTID FDA".
regulator Here fix = "FDA".
minpower Minimum acceptable power from the call of the function.

The class 'pwrA' has the S3 methods print() and plot(). See pa.ABE for usage.

Warning

Be extremly carefull if your sample size plan has extremly small CV near or below 0.05 (5%).
Adapt in that case your expected true ratio (theta0) to values nearer to 1 to not run into errors
and/or long execution times.

Note

The code for impact of deviations from planned sample size tries to keep the degree of imbalance
as low as possible between (sequence) groups. This results in a lesser decrease of power than more
extreme dropout-patterns.

Author(s)

D. Labes according to code by H. Schütz for pa.ABE() and pa.scABE().

46 pa.scABE

References

Food and Drug Administration, Office of Generic Drugs (OGD). Draft Guidance on Warfarin
Sodium. Recommended Dec 2012. download
Yu LX, Jiang W, Zhang X, Lionberger R, Makhlouf F, Schuirmann DJ, Muldowney L, Chen ML,
Davit B, Conner D, Woodcock J. Novel bioequivalence approach for narrow therapeutic index
drugs. Clin Pharmacol Ther. 2015;97(3):286–91. doi: 10.1002/cpt.28
Jiang W, Makhlouf F, Schuirmann DJ, Zhang X, Zheng N, Conner D, Yu LX, Lionberger R. A Bioe-
quivalence Approach for Generic Narrow Therapeutic Index Drugs: Evaluation of the Reference-
Scaled Approach and Variability Comparison Criterion. AAPS J. 2015;17(4):891–901. doi: 10.1208/
s1224801597535
Endrényi L, Tóthfalusi L. Determination of Bioequivalence for Drugs with Narrow Therapeutic
Index: Reduction of the Regulatory Burden. J Pharm Pharm Sci. 2013;16(5):676–82. open access

See Also

power.NTIDFDA,print.pwrA,plot.pwrA,pa.ABE,pa.scABE

Examples
# using the defaults:
# targetpower=0.8, minpower=0.7, theta0/GMR=0.975
# BE margins from defaults of sampleN.NTIDFDA() 0.9002 ... 1.1108
# 1E5 sims in power.NTIDFDA()
# not run due to timing policy of CRAN for examples
# may run some ten seconds or more

plot(pa.NTIDFDA(CV=0.1))

pa.scABE Power analysis for scaled average bioequivalence (scABE)

Description

An analysis tool for exploration/visualization of the impact of expected values (CV, theta0, reduced
sample size due to drop-outs) on power of BE decision via scABE (for highly variable drugs) if
these values deviate from the ones assumed in planning the sample size of the study.

Usage

pa.scABE(CV, theta0 = 0.9, targetpower = 0.8, minpower = 0.7,

design = c("2x3x3", "2x2x4", "2x2x3"),
regulator = c("EMA", "HC", "FDA", "GCC"), ...)
pa.scABE 47

Arguments
CV Coefficient of variation of the intra-subject variability as ratio (not percent).
Here only the case CVwT=CVwR is implemented, i.e., CV has to be a scalar.
theta0 ‘True’ or assumed T/R ratio. Often named GMR.
Must be given as ratio. Defaults to 0.9 here since HVD have a greater scatter in
point estimates of T/R.
targetpower Power to achieve at least in sample size estimation. Must be >0 and <1.
Typical values are 0.8 or 0.9. Defaults to 0.8.
Note that targetpower < 0.5 doesn’t make much sense.
minpower Minimum acceptable power to have if deviating from assumptions for sample
size plan.
Has to lower than targetpower. Defaults to 0.7.
minpower < 0.5 doesn’t make much sense.
design Character string describing the study design.
Defaults to 2x3x3, the partial replicate design (TRR|RTR|RRT).
regulator Character string describing the scaled ABE method recommended by the regu-
latory bodies "EMA", "HC", "FDA" or "GCC".
Defaults to "EMA", method of scaled (expanded) bioequivalence limits.
... More arguments to pass to power.scABEL() or power.RSABE().
F.i., alpha, theta1, theta2 or nsims if other values than the defaults for these
arguments are needed.
See man pages of power.scABEL() or power.RSABE().

Details
Power calculations are done via power.scABEL() or power.RSABE() and calculations of CV and
theta0 which result in minpower derived via R base uniroot.
While one of the parameters (CV, GMR, N) is varied, the respective two others are kept constant.
The tool shows the relative impact of single parameters on power.

The tool takes a minimum of 12 subjects as required in most BE guidances into account. How-
ever, the sample size will be increased from the estimated one if one of the following conditions is
applicable:
• The FDA requires at least 24 subjects enrolled in studies intended for reference-scaling.
• The EMA requires at least 12 eligible subjects in the sequence RTR of the TRT|RTR-design
(hence the minimum sample size is 24).
You should be aware that this is not a substitute for the “Sensitivity Analysis” recommended in
ICH-E9. In a real study a combination of all effects occurs simultaneously. It is up to you to decide
on reasonable combinations and analyze their respective power.

Value
Returns a list with class 'pwrA' with the components
plan A data.frame with the result of the sample size estimation.
See output of sampleN.scABEL() or sampleN.RSABE().
48 pa.scABE

paCV A data.frame with value pairs CV, pwr for impact of deviations from CV.
paGMR A data.frame with value pairs theta0, pwr for impact of deviations from theta0
(GMR).
paN A data.frame with value pairs N, pwr for impact of deviations from planned N
(dropouts).
method Method of BE decision. Here fix = "scABE".
regulator "EMA", "HC", or "FDA".
minpower Minimum acceptable power from the call of the function.

The class 'pwrA' has the S3 methods print() and plot(). See pa.ABE for usage.

Note

Author(s)

Idea and original code by H. Schütz with modifications by D. Labes to use PowerTOST infrastruc-
ture.

References

Schütz H. Deviating from assumptions. August 08, 2014. BEBA Forum

See Also

power.scABEL,power.RSABE,known.designs,print.pwrA,plot.pwrA,pa.ABE,pa.NTIDFDA

Examples

# Implicitely using the defaults:

# design = "2x3x3", targetpower = 0.8, minpower = 0.7,
# theta0 = 0.9, GMR = 0.90, regulator = "EMA"
# widened BE margins from defaults of sampleN.scABEL() 0.7462 ... 1.3402
# 1E5 sims in power.scABEL()
# not run due to timing policy of CRAN, may run some ten seconds

# Implicit print & plot

pa.scABE(CV = 0.4)
power.2TOST 49

power.2TOST Power for two simultaneous TOST procedures

Description
Calculates the exact power of two simultaneous TOST procedures (where the two parameters of the
two TOSTs are correlated with some correlation) for various study designs used in BE studies

Usage
power.2TOST(alpha = c(0.05, 0.05), logscale = TRUE, theta0, theta1, theta2,
CV, n, rho, design = "2x2", robust = FALSE, nsims, setseed = TRUE,
details = FALSE)

Arguments
alpha Vector; contains one-sided significance level for each of the two TOSTs.
For one TOST, by convention mostly set to 0.05.
logscale Should the data used on log-transformed (TRUE, default) or on original scale
(FALSE)?
theta1 Vector; contains lower bioequivalence limit for each of the two TOSTs.
In case of logscale=TRUE it is given as ratio, otherwise as diff. to 1.
Defaults to c(0.8,0.8) if logscale=TRUE or to c(-0.2,-0.2) if logscale=FALSE.
theta2 Vector; contains upper bioequivalence limit for each of the two TOSTS.
If not given theta2 will be calculated as 1/theta1 if logscale=TRUE
or as -theta1 if logscale=FALSE.
theta0 Vector; contains ‘true’ assumed bioequivalence ratio for each of the two TOSTs.
In case of logscale=TRUE each element must be given as ratio,
otherwise as difference to 1. See examples.
Defaults to c(0.95,0.95) if logscale=TRUE or to c(0.05,0.05) if logscale=FALSE.
CV Vector of coefficient of variations (given as as ratio, e.g., 0.2 for 20%).
In case of cross-over studies this is the within-subject CV,
in case of a parallel-group design the CV of the total variability.
In case of logscale=FALSE CV is assumed to be the respective standard devia-
tion.
n Number of subjects under study.
Is total number if given as scalar, else number of subjects in the (sequence)
groups. In the latter case the length of n vector has to be equal to the number of
(sequence) groups.
rho Correlation between the two PK metrics (e.g., AUC and Cmax) under consid-
eration. This is defined as correlation between the estimator of the treatment
difference of PK metric one and the estimator of the treatment difference of PK
metric two. Has to be within {–1, +1}.
design Character string describing the study design.
See known.designs() for designs covered in this package.
50 power.2TOST

robust Defaults to FALSE. With that value the usual degrees of freedom will be used.
Setting to TRUE will use the degrees of freedom according to the ‘robust’ evalu-
ation (aka Senn’s basic estimator). These degrees of freedom are calculated as
n-seq.
See known.designs()$df2 for designs covered in this package.
Has only effect for higher-order crossover designs.
nsims Number of studies to simulate. Defaults to 1E5.
setseed Logical; if TRUE, the default, a seed of 1234567 is set.
details Logical; if TRUE, run time will be printed. Defaults to FALSE.

Details
Calculations are based on simulations and follow the distributional properties as described in Phillips.
This is in contrast to the calculations via the 4-dimensional non-central t-distribution as described
in Hua et al. which was implemented in versions up to 1.4-6.

The formulas cover balanced and unbalanced studies w.r.t (sequence) groups.

In case of parallel group design and higher order crossover designs (replicate crossover or crossover
with more than two treatments) the calculations are based on the assumption of equal variances for
Test and Reference products under consideration.

The formulas for the paired means ’design’ do not take an additional correlation parameter into
account. They are solely based on the paired t-test (TOST of differences = zero).

Value
Value of power.

Note
If n is given as scalar (total sample size) and this number is not divisible by the number of (sequence)
groups of the design an unbalanced design with small imbalance is assumed. A corresponding mes-
sage is thrown showing the assumed numbers of subjects in (sequence) groups.
The function does not vectorize properly if design is a vector. Moreover, theta0 and CV must be of
length two, thus further vectorizing is not possible.
Other vector input is not tested yet.

Author(s)
B. Lang, D. Labes

References
Phillips KF. Power for Testing Multiple Instances of the Two One-Sided Tests Procedure. Int J
Biostat. 2009;5(1):Article 15.
power.dp 51

Hua SY, Xu S, D’Agostino RB Sr. Multiplicity adjustments in testing for bioequivalence. Stat Med.
2015;34(2):215–31. doi: 10.1002/sim.6247
Lang B, Fleischer F. Letter to the Editor: Comments on ‘Multiplicity adjustments in testing for
bioequivalence.’ Stat Med. 2016;35(14):2479–80. doi: 10.1002/sim.6488

# Setting as before but use rho 1 and high number of simulations

# to reproduce result of power.TOST()
p1 <- power.2TOST(theta0 = rep(1.05, 2), CV = rep(se2CV(0.3), 2),
n = 24, rho = 1, nsims=1E7)
p2 <- power.TOST(theta0 = 1.05, CV = se2CV(0.3), n = 24)
all.equal(p1, p2, tolerance = 1e-04)

power.dp Power of dose-proportionality studies evaluated via Power model

Description
Calculates the power of dose-proportionality studies using the power model for crossover (Latin
square) or parallel group designs via a confidence interval equivalence criterion.

Usage
power.dp(alpha = 0.05, CV, doses, n, beta0, theta1 = 0.8, theta2 = 1/theta1,
design = c("crossover", "parallel", "IBD"), dm = NULL, CVb)

Arguments
alpha Type 1 error. Commonly set to 0.05.
CV Coefficient of variation for intra-subject variability if design="crossover" or
CV of total variability in case of design="parallel".
doses Vector of dose levels. At least two doses have to be given.
52 power.dp

n Number of subjects. Is total number if given as scalar, else number of subjects

in the (sequence) groups. In the latter case the length of n vector has to be the
same as length of vector doses.
n has to be >2.
beta0 ‘True’ slope of power model. If missing defaults to 1+log(0.95)/log(rd)
where rd is the ratio of highest to lowest dose.
theta1 Lower acceptance limit for the ratio of dose normalized means (Rdmn).
Transformes into slope acceptance range as described under item beta0.
theta2 Upper acceptance limit for the ratio of dose normalized means (Rdmn).
design Crossover design (default), parallel group design or incomplete block design
(IBD).
Crossover design means Latin square design with number of doses as dimension.
dm ’Design matrix’ of the incomplete block design (IBD) if design="IBD".
This matrix contains the sequences in rows and periods in columns. The entry
(i, j) of the design matrix corresponds to the dose (index) a subject with i-th
sequence gets in the j-th period. Can be obtained f.i. via functions of package
crossdes or via function bib.CL().
CVb Coefficient of variation of the between-subject variability.
Only necessary if design="IBD". Will be set to 2*CV if missing. This is only a
crude rule of thumb. Better obtain an estimate of CVb from a previous crossover
study.

Set CVb=0 if an all-effects-fixed model shall be used. This model gives higher
power than the random subject effects model.

Details

The power calculations are based on TOST for testing equivalence of the slope of the power model
with alternativ hypothesis slope = 1.
Power is calculated via non-central t-approximation only.
The calculations are based on mixed effects model (random intercept aka random subject effect).
For design="cossover" or design="parallel" the results coincide with all-effects-fixed model.

Value

Value of power according to the input arguments.

Warning

This function is ‘experimental’ only since it is not thorougly tested yet. Especially for design="IBD"
reliable test cases are missing.

Author(s)

D. Labes
power.HVNTID 53

References
Patterson S, Jones B. Bioequivalence and Statistics in Clinical Pharmacology. Boca Raton: Chap-
man & Hall/CRC: 2006. p. 239.
(contains presumably a bug)
Sethuraman VS, Leonov S, Squassante L, Mitchell TR, Hale MD. Sample size calculation for the
Power Model for dose proportionality studies. Pharm Stat. 2007;6(1):35–41. doi: 10.1002/pst.241
Hummel J, McKendrick S, Brindley C, French R. Exploratory assessment of dose proportionality:
review of current approaches and proposal for a practical criterion. Pharm. Stat. 2009;8(1):38–49.
doi: 10.1002/pst.326

theta2 Conventional upper ABE limit to be applied in the FDA procedure.

Defaults to 1.25 if not given explicitly.
theta0 ‘True’ or assumed T/R ratio.
Defaults to 0.95 if not given explicitly.
CV Intra-subject coefficient(s) of variation as ratio (not percent).
• If given as a scalar (length(CV)==1) the same CV of Test and Reference is
assumed (homoscedasticity, CVwT==CVwR).
• If given as a vector (length(CV)==2), i.e., assuming heteroscedasticity, the
CV of the Test must be given in CV[1] and the one of the Reference in the
CV[2].
n Number of subjects under study.
May be given as vector. In that case it is assumed that n contains the number of
subjects per sequence groups.
Attention! In case of the "2x2x3" (TRT|RTR) design the order of sample sizes
is important if given as vector. n[1] is for sequence group ’TRT’ and n[2] is
for sequence group ’RTR’.
If n is given as single number (total sample size) and this number is not divisible
by the number of sequences of the design an unbalanced design is assumed.
A corresponding message is thrown showing the numbers of subjects in the
sequence groups.
design Design of the study to be planned.
"2x2x4" is the full replicate design with 2 sequences and 4 periods (TRTR|RTRT).
"2x2x3" is the 3-period ful replicate design with sequences TRT|RTR.
Defaults to design="2x2x4".
nsims Number of simulations to be performed to obtain the empirical power. Defaults
to 100,000 = 1e+5.
details If set to TRUE the computational time is shown as well as the components for the
BE decision.
p(BE-ABE) is the simulated probability for the conventional ABE test. p(BE-
sratio) is the probability that the upper 90% confidence limit of the ratio of
sWT/sWR is < 2.5.
setseed Simulations are dependent on the starting point of the (pseudo) random number
generator. To avoid differences in power for different runs a set.seed(123456)
is issued if setseed=TRUE, the default.

Details

For deciding BE the study must pass the conventional ABE test (90% CI within the acceptance
range) and additional the test that the ratio of sWT/sWR is < 2.5.

The simulations are done via the distributional properties of the statistical quantities necessary for
deciding BE based on this method.
Details can be found in a document Implementation_scaledABE_sims located in the /doc sub-
directory of the package.
power.noninf 55

Value
Returns the value of the (empirical) power if argument details=FALSE.
Returns a named vector if argument details=TRUE.
p(BE) is the power, p(BE-ABE) is the power of the ABE test alone and p(BE-sratio) is the power
of the criterion ’ratio of sWT/sWR is <= 2.5’ alone.

Note
The FD’s guidances recommend only the full replicate design "2x2x4" (TRTR|RTRT). The results
for the design "2x2x3" (TRT|RTR) are to be considered as experimental since at present not thor-
ougly tested.

Author(s)
D. Labes

References
Food and Drug Administration, Office of Generic Drugs (OGD). Draft Guidance on Dabigatran
Etexilate Mesylate. Recommended Jun 2012; Revised Sep 2015, Jul 2017. download
Food and Drug Administration, Office of Generic Drugs (OGD). Draft Guidance on Rivaroxaban.
Recommended Sep 2015. download

See Also
sampleN.HVNTID and power.NTIDFDA, sampleN.NTIDFDA for NTIDs with low variability

Examples
# using the defaults:
# GMR=0.95, theta1=0.8, theta2=1.25, full replicate design 2x2x4, 100,000 simulations
# and a CV of 0.3 (=30%) for both Reference and Test, with 24 subjects, balanced
power.HVNTID(CV = 0.3, n = 24)
# should give a power of 0.86354

power.noninf Power of the one-sided non-inferiority t-test

Description
Function calculates of the power of the one-sided non-inferiority t-test for normal or log-normal
distributed data.

Usage
power.noninf(alpha = 0.025, logscale = TRUE, margin, theta0, CV, n,
design = "2x2", robust = FALSE)
56 power.noninf

Arguments
alpha Significance level (one-sided). Defaults here to 0.025.
logscale Should the data used on log-transformed or on original scale? TRUE (default) or
FALSE.
theta0 ‘True’ or assumed T/R ratio or difference.
In case of logscale=TRUE it must be given as ratio T/R.
If logscale=FALSE, the difference in means. In this case, the difference may be
expressed in two ways: relative to the same (underlying) reference mean, i.e. as
(T-R)/R = T/R - 1; or as difference in means T-R. Note that in the former case
the units of margin and CV need also be given relative to the reference mean
(specified as ratio).
Defaults to 0.95 if logscale=TRUE or to -0.05 if logscale=FALSE
margin Non-inferiority margin.
In case of logscale=TRUE it is given as ratio.
If logscale=FALSE, the limit may be expressed in two ways: difference of
means relative to the same (underlying) reference mean or in units of the dif-
ference of means. Note that in the former case the units of CV and theta0 need
also be given relative to the reference mean (specified as ratio).
Defaults to 0.8 if logscale=TRUE or to -0.2 if logscale=FALSE.
CV In case of logscale=TRUE the (geometric) coefficient of variation given as ratio.
If logscale=FALSE the argument refers to (residual) standard deviation of the
response. In this case, standard deviation may be expressed two ways: relative
to a reference mean (specified as ratio sigma/muR), i.e. again as a coefficient of
variation; or untransformed, i.e. as standard deviation of the response. Note that
in the former case the units of theta0, theta1 and theta2 need also be given
relative to the reference mean (specified as ratio).

In case of cross-over studies this is the within-subject CV, in case of a parallel-

Details
The power is calculated exact via non-central t-distribution.
power.noninf 57

Notes on the underlying hypotheses

If the supplied margin is < 0 (logscale=FALSE) or < 1 (logscale=TRUE), then it is assumed higher
response values are better. The hypotheses are
H0: theta0 <= margin vs. H1: theta0 > margin
where theta0 = mean(test)-mean(reference) if logscale=FALSE
or
H0: log(theta0) <= log(margin) vs. H1: log(theta0) > log(margin)
where theta0 = mean(test)/mean(reference) if logscale=TRUE.

Value

Value of power according to the input arguments.

Warning

The function does not vectorize if design is a vector.

The function vectorize properly if CV or theta0 are vectors.
Other vector input is not tested yet.

Note

This function does not rely on TOST but may be useful in planning BE studies if the question is not
equivalence but ‘non-superiority’.
Hint: Evaluation of Fluctuation in the EMEA’s Note for Guidance between a modified release
formulation and an immediate release product.

Author(s)

D. Labes

References

Julious SA. Sample sizes for clinical trials with Normal data. Stat Med. 2004;23(12):1921–86.
doi: 10.1002/sim.1783

See Also

known.designs,sampleN.noninf
58 power.NTIDFDA

Examples
# using all the defaults: margin=0.8, theta0=0.95, alpha=0.025
# log-transformed, design="2x2"
# should give: 0.4916748
power.noninf(CV=0.3, n=24)

power.NTIDFDA (Empirical) Power for BE decision via FDA method for NTIDs

Description
This function performs the power calculation of the BE decision via the FDA’s method for narrow
therapeutic index drugs (NTIDs) by simulations. The study design could be the full replicate design
2x2x4 with 4-periods (TRTR|RTRT) or the 2x2x3 replicate design with sequences TRT|RTR.

Usage
power.NTIDFDA(alpha = 0.05, theta1, theta2, theta0, CV, n, design=c("2x2x4", "2x2x3"),
nsims = 1e+05, details = FALSE, setseed = TRUE)

Arguments
alpha Type I error probability, significance level. Conventionally mostly set to 0.05.
theta1 Conventional lower ABE limit to be applied in the FDA procedure.
Defaults to 0.8 if not given explicitly.
theta2 Conventional upper ABE limit to be applied in the FDA procedure.
Defaults to 1.25 if not given explicitly.
theta0 ‘True’ or assumed T/R ratio.
Attention! Defaults here to 0.975 if not given explicitly. The value was chosen
closer to 1 because the potency (contents) settings for NTIDs are tightened by
the FDA.
CV Intra-subject coefficient(s) of variation as ratio (not percent).
• If given as a scalar (length(CV)==1) the same CV of Test and Reference is
assumed (homoscedasticity, CVwT==CVwR).
• If given as a vector (length(CV)==2), i.e., assuming heteroscedasticity, the
CV of the Test must be given in CV[1] and the one of the Reference in the
CV[2].
n Number of subjects under study.
May be given as vector. In that case it is assumed that n contains the number of
subjects per sequence groups.
Attention! In case of the "2x2x3" (TRT|RTR) design the order of sample sizes
important if given as vector. n[1] is for sequence group ’TRT’ and n[2] is for
sequence group ’RTR’.
power.NTIDFDA 59

If n is given as single number (total sample size) and this number is not divisi-
ble by the number of sequences of the design an unbalanced design is assumed.
A corresponding message is thrown showing the numbers of subjects in the se-
quence groups.
design Design of the study to be planned.
"2x2x4" is the full replicate design with 2 sequences and 4 periods (TRTR|RTRT).
"2x2x3" is the full replicate design with 2 sequences and 3 periods (TRT|RTR).
Defaults to design="2x2x4".
nsims Number of simulations to be performed to obtain the empirical power. Defaults
to 100,000 = 1e+5.
details If set to TRUE the computational time is shown as well as the components for the
BE decision.
p(BE-ABE) is the simulated probability for the conventional ABE test. p(BE-
sABEc) is the probability that the 95% CI of the ABE criterion is <0.
p(BE-sratio) is the probability that the ratio of sWT/sWR is <= 2.5.

setseed Simulations are dependent on the starting point of the (pseudo) random number
generator. To avoid differences in power for different runs a set.seed(123456)
is issued if setseed=TRUE, the default.

Details

The linearized scaled ABE criterion is calculated according to the SAS code given in the FDA War-
farin guidance. For deciding BE the study must pass that criterion, the conventional ABE test and
additional the test that the ratio of sWT/sWR is <= 2.5.

The simulations are done via the distributional properties of the statistical quantities necessary for
deciding BE based on these method.
Details can be found in a document Implementation_scaledABE_sims located in the /doc sub-
directory of the package.

Value

Returns the value of the (empirical) power if argument details=FALSE.

Returns a named vector if argument details=TRUE.
p(BE) is the power, p(BE-sABEc) is the power of the BE test via scaled ABE criterion alone, p(BE-
ABE) is the power of the conventional ABE test alone and p(BE-sratio) is the power of the criterion
’ratio of sWT/sWR is <= 2.5’ alone.

Note

The FDA’s method is described for the ABE limits 0.8 ... 1.25 only. Setting theta1, theta2 to other
values may not be reasonable and is not tested.

The results for the design "2x2x3" are to be considered as experimental since at present not thor-
ougly tested.
60 power.RatioF

Author(s)
D. Labes

References
Food and Drug Administration, Office of Generic Drugs (OGD). Draft Guidance on Warfarin
Sodium. Recommended Dec 2012. download
Yu LX, Jiang W, Zhang X, Lionberger R, Makhlouf F, Schuirmann DJ, Muldowney L, Chen ML,
Davit B, Conner D, Woodcock J. Novel bioequivalence approach for narrow therapeutic index
drugs. Clin Pharmacol Ther. 2015;97(3):286–91. doi: 10.1002/cpt.28
Jiang W, Makhlouf F, Schuirmann DJ, Zhang X, Zheng N, Conner D, Yu LX, Lionberger R. A Bioe-
quivalence Approach for Generic Narrow Therapeutic Index Drugs: Evaluation of the Reference-
Scaled Approach and Variability Comparison Criterion. AAPS J. 2015;17(4):891–901. doi: 10.1208/
s1224801597535
Endrényi L, Tóthfalusi L. Determination of Bioequivalence for Drugs with Narrow Therapeutic
Index: Reduction of the Regulatory Burden. J Pharm Pharm Sci. 2013;16(5):676–82. open access

See Also
sampleN.NTIDFDA
and power.HVNTID, sampleN.HVNTID for NTIDs with high variability

Examples
# using the all defaults:
# GMR=0.975, theta1=0.8, theta2=1.25, 100,000 simulations
# and a CV of 0.1 (= 10%) with 12 subjects, balanced
power.NTIDFDA(CV = 0.1, n = 12)
# should give a power of 0.62553

power.RatioF Power for equivalence of the ratio of two means with normality on
original scale

Description
Calculates the power of the test of equivalence of the ratio of two means with normality on original
scale.
This test is based on Fieller’s confidence (‘fiducial’) interval and Sasabuchi’s test (a TOST proce-
dure as well).

Usage
power.RatioF(alpha = 0.025, theta1 = 0.8, theta2, theta0 = 0.95,
CV, CVb, n, design = "2x2", setseed=TRUE)
power.RatioF 61

Arguments
alpha Type I error probability, aka significance level.
Defaults here to 0.025 because this function is intended for studies with clinical
endpoints.
theta1 Lower bioequivalence limit. Typically 0.8 (default).
theta2 Upper bioequivalence limit. Typically 1.25.
Is set to 1/theta1 if missing.
theta0 ‘True’ or assumed T/R ratio. Typically set to 0.95 for planning.
CV Coefficient of variation as ratio. In case of design="parallel" this is the CV
of the total variability, in case of design="2x2" the intra-subject CV (CVw in
the reference).
CVb CV of the between-subject variability. Only necessary for design="2x2".
n Number of subjects to be planned.
n is for both designs implemented the total number of subjects.

design A character string describing the study design.

design="parallel" or design="2x2" allowed for a two-parallel group design
or a classical TR|RT crossover design.
setseed If set to TRUE the dependence of the power from the state of the random number
generator is avoided. With setseed = FALSE you may see the dependence from
the state of the random number generator.

Details
The power is calculated exact using the bivariate non-central t-distribution via function pmvt of the
package mvtnorm.
Due to the calculation method of the used package mvtnorm – randomized Quasi-Monte-Carlo –
these probabilities are dependent from the state of the random number generator within the precision
of the power. See argument setseed.

Value
Value of power according to the input.

Note
This function is intended for studies with clinical endpoints where the 95% confidence intervals are
usually used for equivalence testing.
Therefore, alpha defaults here to 0.025 (see EMEA 2000).

The formulas given in the references rely on the assumption of equal variances in the two treat-
ment groups for the parallel group design or on assuming equal within-subject and between-subject
variabilities for the 2×2 crossover design.

Author(s)
D. Labes
62 power.RSABE

References
Fieller EC. Some Problems in Interval Estimation. J Royal Stat Soc B. 1954;16(2):175–85. doi: 10.1111/
j.25176161.1954.tb00159.x
Sasabuchi S. A test of a multivariate normal mean with composite hypotheses determined by linear
inequalities. Biometrika. 1980;67(2):429–39. doi: 10.1093/biomet/67.2.429
Hauschke D, Kieser M, Diletti E, Burke M. Sample size determination for proving equivalence
based on the ratio of two means for normally distributed data. Stat Med. 1999;18(1):93–105.
Hauschke D, Steinijans V, Pigeot I. Bioequivalence Studies in Drug Development. Chichester:
Wiley; 2007. Chapter 10.
European Agency for the Evaluation of Medicinal Products, CPMP. Points to Consider on Switching
between Superiority and Non-Inferiority. London, 27 July 2000. CPMP/EWP/482/99

"2x2x4" TRTR | RTRT

Warning

In case of the design "2x2x3"" heteroscedasticity (i.e., CVwT != CVwR) may lead to poor agree-
ment of the power values compared to those calculated via the ‘classical’ way of subject data sim-
ulations if the design is unbalanced in respect to the number of subjects in the sequence groups.
Therefore, the function issues a warning for that cases.

Author(s)

D. Labes
power.RSABE2L.sdsims 65

References
Food and Drug Administration, Office of Generic Drugs (OGD). Draft Guidance on Progesterone.
Recommended Apr 2010. Revised Feb 2011. download
Tóthfalusi, L, Endrényi, L. Sample Sizes for Designing Bioequivalence Studies for Highly Variable
Drugs. J Pharm Pharmaceut Sci. 2011;15(1):73–84. open access
Tóthfalusi L, Endrényi L, García Arieta A. Evaluation of Bioequivalence for Highly Variable Drugs
with Scaled Average Bioequivalence. Clin Pharmacokin. 2009;48(11):725–43. doi: 10.2165/
1131804000000000000000
Muñoz J, Alcaide D, Ocaña J. Consumer’s risk in the EMA and FDA regulatory approaches for
bioequivalence in highly variable drugs. Stat Med. 2015;35(12):1933–43. doi: 10.1002/sim.6834

power.RSABE2L.sdsims (Empirical) Power of BE Decision via Reference Scaled ABE

Description
These function performs the power calculation of the BE decision via the reference scaled ABE
based on subject data simulations. Implemented are the methods ABEL, Hyslop and ‘exact’ as
described in the references.
The estimation method of the key statistics needed to perform the RSABE decision is the usual
ANOVA .
66 power.RSABE2L.sdsims

Usage
power.RSABE2L.sdsims(alpha = 0.05, theta1, theta2, theta0, CV, n,
design = c("2x3x3", "2x2x4", "2x2x3"), design_dta = NULL,
SABE_test = "exact", regulator, nsims = 1e+05,
details = FALSE, setseed = TRUE, progress)

Arguments
alpha Type I error probability, significance level. Conventionally mostly set to 0.05.
theta1 Conventional lower ABE (Average Bioequivalence) limit to be applied in the
mixed procedure if CVsWR <= CVswitch. Also lower limit for the point estimate
constraint.
Defaults to 0.8 if not given explicitly.
theta2 Conventional upper ABE limit to be applied in the mixed procedure if CVsWR <=
CVswitch. Also upper limit for the point estimate constraint.
Defaults to 1.25 if not given explicitly.
theta0 ‘True’ or assumed T/R ratio.
Defaults to 0.90 according to the two Lászlós if not given explicitly.
CV Intra-subject coefficient(s) of variation as ratio (not percent).
• If given as a scalar (length(CV)==1) the same CV of Test and Reference is
assumed (homoscedasticity, CVwT==CVwR).
• If given as a vector (length(CV)==2), i.e., assuming heteroscedasticity, the
CV of the Test must be given in CV[1] and the one of the Reference in the
CV[2].
n Number of subjects under study.
May be given as vector. In that case it is assumed that n contains the number of
subjects in the sequence groups.
If n is given as single number (total sample size) and this number is not divisible
by the number of sequences of the design an unbalanced design is assumed. A
corresponding message is thrown (showing the numbers of subjects in sequence
groups).
Attention! In case of the "2x2x3" (TRT|RTR) design the order of sample sizes
per sequence is important if given as vector. n[1] is for sequence group ’TRT’
and n[2] is for sequence group ’RTR’.
design Design of the study.
"2x3x3" is the partial replicate design.
"2x2x4" is a full replicate design with 2 sequences and 4 periods.
"2x2x3" is a full replicate design with 2 sequences and 3 periods.
Defaults to design="2x3x3". Details are given the section about Designs.
design_dta Alternatively to using the arguments design and n the design may be defined via
a data.frame with columns subject,sequence,period and tmt. This feature is
experimental in the sense that the data.frame is not checked for complying with
the assumed structure.
If you use the argument design_dta you don’t need to specify the arguments
design and n.
power.RSABE2L.sdsims 67

The default design_dta=NULL means that design and n are used for the internal
construction of the design data.frame.
SABE_test This argument specifies the test method to be used for the reference scaled ABE
decision.
Default is the "exact" ‘ncTOST’ method of the two Laszlós. Other choices are
"ABEL", "hyslop" and "fda". See Details.
regulator Regulatory settings for the widening of the BE acceptance limits.
May be given as character "EMA" or as an object of class ’regSet’ (see reg_const).
Defaults to regulator="EMA" if missing.
This argument may be given also in lower case if given as character.

If given as object of class ’regSet’ the component est_method can not be "ISC".
nsims Number of simulations to be performed to obtain the empirical power. Defaults
to 100,000 = 1e+05.
If simulations are aimed for empirical alpha nsims=1e+06 is recommended.
details If set to TRUE the computational time is shown as well as the components for
the BE decision.
p(BE-RSABE) is the probability of a positive outcome of the SABE test.
p(BE-PE) is the probability that the point estimate is within theta1 ... theta2.
p(BE-ABE) is the simulated probability for the conventional ABE test.
setseed Simulations are dependent on the starting point of the (pseudo) random number
generator. To avoid differences in power for different runs a set.seed() is
issued if setseed=TRUE, the default.
progress Should a progressbar be shown? Defaults to TRUE if missing and nsims >5e5.

Details
The methods rely on the analysis of log-transformed data, i.e., assumes a log-normal distribution
on the original scale.

The data.frame with columns subject,sequence,period and tmt necessary for evalution of sim-
ulated subject data is constructed internally from the arguments design and n or may be given user
defined via the argument design_dta. The last option is usefull if missing data have to be consid-
ered or if designs have to be evaluated which are not in the list of argument design.

The estimation method for obtaining the statistics necessary to perform the reference scaled ABE
decision is the usual ANOVA with effects treatment, period, sequence and subject within sequence
for the evaluation of all data and period, sequence and subject within sequence for the evaluation of
the Reference formulation data only.

The SABE tests implemented are:

"exact" ‘exact’ based method of the two Laszlós (see references, called there ‘ncTOST’)
"ABEL" Average bioequivalence with expanding limits
"hyslop" BE decision via the linearized RSABE criterion and its upper 95% CI
"fda" Hyslop with an additional bias correction term as implemented in the SAS code of the
FDA ’s Guidance on Progesterone.
68 power.RSABE2L.sdsims

Value
Returns the value of the (empirical) power if argument details=FALSE.

Returns a named vector if argument details=TRUE.

p(BE) is the power, p(BE-RSABE) is the power of using the reference scaled ABE alone, and p(BE-
pe) is the power of the criterion ‘point estimate within acceptance range’ alone. p(BE-ABE) is the
power of the conventional ABE test given for comparative purposes.

Designs
Although some designs are more ‘popular’ than others, power calculations are valid for all of the
following designs:

"2x2x4" TRTR | RTRT

Note
The function is relatively slow. The run-time for 1 Mio. simulations is between ~ 1 up to 6 minutes
for n=12 or n=120 and 1 Mio. sim’s (see the call under examples) on a machine with an Intel core
i7 processor.
Thus be patient and go for a cup of coffee if you use this function with higher sample sizes and aim
for estimating the type 1 error!

Author(s)
D. Labes

References
Food and Drug Administration, Office of Generic Drugs (OGD). Draft Guidance on Progesterone.
Recommended Apr 2010. Revised Feb 2011. download
Tóthfalusi L, Endrényi L. An Exact Procedure for the Evaluation of Reference-Scaled Average
Bioequivalence. AAPS J. 2016;18(2):476–89. doi: 10.1208/s1224801698736.
Tóthfalusi L, Endrényi L. Algorithms for evaluating reference scaled average bioequivalence: power,
bias, and consumer risk. Stat Med. 2017;36(27):4378–4390. doi: 10.1002/sim.7440

power.scABEL (Empirical) Power of BE decision via scaled (widened) BE acceptance

limits

Description
These function performs the power calculation of the BE decision via scaled (widened) BE accep-
tance limits by simulations.

Usage
power.scABEL(alpha = 0.05, theta1, theta2, theta0, CV, n,
design = c("2x3x3", "2x2x4", "2x2x3"), regulator,
nsims, details = FALSE, setseed = TRUE)

n Number of subjects under study.

May be given as vector. In that case it is assumed that n contains the number of
subjects in the sequence groups.
If n is given as single number (total sample size) and this number is not divisible
by the number of sequences of the design an unbalanced design is assumed. A
corresponding message is thrown showing the numbers of subjects in sequence
groups.
Attention! In case of the "2x2x3" (TRT|RTR) design the order of sample sizes
is important if given as vector. n[1] is for sequence group ’TRT’ and n[2] is
for sequence group ’RTR’.
design Design of the study.
"2x3x3" is the partial replicate design.
"2x2x4" is a full replicate design with 2 sequences and 4 periods.
"2x2x3" is a full replicate design with 2 sequences and 3 periods.
Defaults to "2x3x3". Details are given the section about Designs.
regulator Regulatory settings for the widening of the BE acceptance limits.
May be given as character from the choices "EMA", "HC", "FDA", "GCC" or as an
object of class ’regSet’ (see reg_const).
Defaults to regulator="EMA" if missing.
This argument may be given also in lower case if given as character.

nsims Number of simulations to be performed to obtain the empirical power. Defaults

to 100,000 = 1e+05.
If not given and theta0 equals one of the expanded limits (i.e., simulating em-
pirical alpha), defaults to 1e+06.
details If set to TRUE the computational time is shown as well as the components for the
BE decision.
p(BE-wABEL) is the probability that the CI is within (widened) limits.
p(BE-PE) is the probability that the point estimate is within theta1 ... theta2.
p(BE-ABE) is the simulated probability for the conventional ABE test.
setseed Simulations are dependent on the starting point of the (pseudo) random number
generator. To avoid differences in power for different runs a set.seed() is
issued if setseed=TRUE, the default.

Details
The methods rely on the analysis of log-transformed data, i.e., assume a log-normal distribution on
the original scale.

The widened BE acceptance limits will be calculated by the formula

[L, U] = exp(-/+ r_const * sWR)
with r_const the regulatory constant and sWR the standard deviation of the within subjects variabil-
ity of the Reference. r_const = 0.76 (~log(1.25)/0.29356) is used in case of regulator="EMA" or
regulator="HC" and in case of regulator="FDA" r_const = 0.89257... (log(1.25)/0.25). If the
CVwR of the Reference is < CVswitch=0.3 the conventional ABE limits apply (mixed procedure).

In case of regulator="EMA" a cap is placed on the widened limits if CVwR>0.5, i.e., the widened
power.scABEL 71

limits are held at value calculated for CVwR=0.5. In case of regulator="HC" the capping is done
such that the acceptance limits are 0.6666 ... 1.5 at maximum.

The case of regulator="GCC" is treatd as special case of ABEL with CVswitch = CVcap = 0.3.
The r_const = log(1.25)/CV2se(0.3) assures that for CV>0.3 the widened BE limits of 0.7 ... 1.3333
are used.

The simulations are done via the distributional properties of the statistical quantities necessary for
deciding BE based on widened ABEL.
For more details see the document Implementation_scaledABE_simsVx.yy.pdf in the /doc sub-
directory of the package.

Function power.scABEL() implements the simulation via distributional characteristics of the ‘key’
statistics obtained from the EMA recommended evaluation via ANOVA if regulator="EMA" or if
the regulator component est_method is set to "ANOVA" if regulator is an object of class ’regSet’.
Otherwise the simulations are based on the distributional characteristis of the ‘key’ statistics ob-
tained from evaluation via intra-subject contrasts (ISC), as recommended by the FDA.

Value
Returns the value of the (empirical) power if argument details=FALSE.

Returns a named vector if argument details=TRUE.

p(BE) is the power, p(BE-ABEL) is the power of the widened ABEL criterion alone and p(BE-pe) is
the power of the criterion ‘point estimate within acceptance range’ alone. p(BE-ABE) is the power
of the conventional ABE test given for comparative purposes.

Designs
Although some designs are more ‘popular’ than others, power calculations are valid for all of the
following designs:

"2x2x4" TRTR | RTRT

Warning

Cross-validation of the simulations as implemented here and via the ‘classical’ subject data simu-
lation have shown somewhat unsatisfactory results for the 2x3x3 design if the variabilities for Test
and Reference are different and/or sequences exteremly unbalanced.
The function power.scABEL() therefore gives a warning if calculations with different CVwT and
CVwR are requested for the 2x3x3 partial replicate design. For "EMA" subject simulations are
provided in power.scABEL.sdsims. For more details see the above mentioned document Imple-
mentation_scaledABE_simsVy.xx.pdf.
72 power.scABEL

Note
In case of regulator="FDA" the (empirical) power is only approximate since the BE decision
method is not exactly what is expected by the FDA. But the “Two Laszlós” state that the scABEL
method should be ‘operational equivalent’ to the FDA method.
To get the power for the FDA favored method via linearized scaled ABE criterion use function
power.RSABE.

In case of regulator="HC" (based on ISC), power is also only approximative since Health Canada
recommends an evaluation via mixed model approach. This could only implemented via subject
data simulations which are very time consuming. But ISC may be a good substitute.

Author(s)
D. Labes

References
Tóthfalusi L, Endrényi L. Sample Sizes for Designing Bioequivalence Studies for Highly Variable
Drugs. J Pharm Pharmaceut Sci. 2011;15(1):73–84. open source

See Also
sampleN.scABEL,power.RSABE,reg_const

Examples
# using all the defaults:
# design="2x3x3", EMA regulatory settings
# PE constraint 0.8-1.25, cap on widening if CV>0.5
# true ratio=0.90, 1E+6 simulations
power.scABEL(CV = 0.4, n = 29)
# should give:
# Unbalanced design. n(i)=10/10/9 assumed.
# [1] 0.66113
#
# with details=TRUE to view the computational time and components
power.scABEL(CV = 0.5, n = 54, theta0 = 1.15, details = TRUE)
# should give (times may differ depending on your machine):
# 1e+05sims. Time elapsed (sec): 0.07
#
# p(BE) p(BE-wABEL) p(BE-pe) p(BE-ABE)
# 0.81727 0.82078 0.85385 0.27542
#
# exploring 'pure ABEL' with the EMA regulatory constant
# (without mixed method, without capping, without pe constraint)
rs <- reg_const("EMA")
rs$CVswitch <- 0
rs$CVcap <- Inf
rs$pe_constr <- FALSE
power.scABEL(CV = 0.5, n = 54, theta0 = 1.15, regulator = rs)
# should give
power.scABEL.sds 73

# [1] 0.8519

power.scABEL.sds (Empirical) Power of BE decision via scaled (widened) BE acceptance

limits

Description
These function performs the power calculation of the BE decision via scaled (widened) BE accep-
tance limits based on subject data simulations.
This function has an alias power.scABEL.sds().

Usage
power.scABEL.sdsims(alpha = 0.05, theta1, theta2, theta0, CV, n,
design = c("2x3x3", "2x2x4", "2x2x3"), design_dta=NULL,
regulator, nsims = 1e+05, details = FALSE, setseed = TRUE,
progress)

Arguments
alpha Type I error probability, significance level. Conventionally mostly set to 0.05.
theta1 Conventional lower ABE limit to be applied in the mixed procedure if CVsWR <=
CVswitch. Also lower limit for the point estimate constraint.
Defaults to 0.8 if not given explicitly.
theta2 Conventional upper ABE limit to be applied in the mixed procedure if CVsWR <=
CVswitch. Also upper limit for the point estimate constraint.
Defaults to 1.25 if not given explicitly.
theta0 ‘True’ or assumed T/R ratio.
Defaults to 0.90 according to the two Lászlós if not given explicitly.
CV Intra-subject coefficient(s) of variation as ratio (not percent).
• If given as a scalar (length(CV)==1) the same CV of Test and Reference is
assumed (homoscedasticity, CVwT==CVwR).
• If given as a vector (length(CV)==2), i.e., assuming heteroscedasticity, the
CV of the Test must be given in CV[1] and the one of the Reference in the
CV[2].
n Number of subjects under study.
May be given as vector. In that case it is assumed that n contains the number of
subjects in the sequence groups.
If n is given as single number (total sample size) and this number is not divisible
by the number of sequences of the design an unbalanced design is assumed. A
corresponding message is thrown showing the numbers of subjects in sequence
groups.
Attention! In case of the "2x2x3" (TRT|RTR) design the order of sample sizes
is important if given as vector. n[1] is for sequence group ’TRT’ and n[2] is
for sequence group ’RTR’.
74 power.scABEL.sds

design Design of the study to be planned.

"2x3x3" is the partial replicate design (TRR|RTR|RRT).
"2x2x4" is the full replicate design with 2 sequences and 4 periods.
"2x2x3" is the 3-period design with sequences TRT|RTR.
Defaults to design="2x3x3".
design_dta Alternatively to using the arguments design and n the design may be defined via
a data.frame with columns subject,sequence,period and tmt. This feature is
experimental in the sense that the data.frame is not checked for complying with
the assumed structure.
If you use the argument design_dta you don’t need to specify the arguments
design and n.
The default design_dta = NULL means that design and n are used for the inter-
nal construction of the design data.frame.
regulator Regulatory settings for the widening of the BE acceptance limits.
May be given as "EMA" or as an object of class ’regSet’ (see reg_const).
Defaults to regulator="EMA" if missing.
This argument may be given also in lower case if given as character.

If given as object of class ’regSet’ the component est_method must not be

"ISC".
nsims Number of simulations to be performed to obtain the empirical power. Defaults
to 100,000 = 1e+05.
If simulations are aimed for empirical alpha nsims=1e+06 is recommended.
details If set to TRUE the computational time is shown as well as the components for the
BE decision.
p(BE-wABEL) is the probability that the CI is within (widened) limits.
p(BE-PE) is the probability that the point estimate is within theta1 ... theta2.
p(BE-ABE) is the simulated probability for the conventional ABE test.
setseed Simulations are dependent on the starting point of the (pseudo) random number
generator. To avoid differences in power for different runs a set.seed() is
issued if setseed=TRUE, the default.
progress Should a progressbar be shown? Defaults to TRUE if missing and nsims >5E5.

Details
The methods rely on the analysis of log-transformed data, i.e., assume a log-normal distribution on
the original scale.

The widened BE acceptance limits will be calculated by the formula

[L, U] = exp(± r_const * sWR)
with r_const the regulatory constant and sWR the standard deviation of the within subjects variabil-
ity of the Reference. r_const = 0.76 (~log(1.25)/0.29356) is used in case of regulator="EMA". If
the CVwR of the Reference is < CVswitch=0.3 the conventional ABE limits apply (mixed proce-
dure).
In case of regulator="EMA" a cap is placed on the widened limits if CVwr>0.5, i.e., the widened
limits are held at value calculated for CVwR=0.5.
power.scABEL.sds 75

The simulations are done by simulating subject data (all effects fixed except the residuals) and
evaluating these data via ANOVA of all data to get the point estimate of T vs. R along with its 90%
CI and an ANOVA of the data under R(eference) only to get an estimate of s2wR.
The data.frame with columns subject,sequence,period and tmt necessary for evalution of sim-
ulated subject data is constructed internally from the arguments design and n or may be given user
defined via the argument design_dta. The last option is usefull if missing data have to be consid-
ered or if designs have to be evaluated which are not in the list of argument design.
This feature is experimental in the sense that the data.frame is not checked for complying with the
assumed structure.

Value
Returns the value of the (empirical) power if argument details=FALSE.

Returns a named vector if argument details=TRUE.

p(BE) is the power, p(BE-wABEL) is the power of the widened ABEL criterion alone and p(BE-pe)
is the power of the criterion ’point estimat within acceptance range’ alone. p(BE-ABE) is the power
of the conventional ABE test given for comparative purposes.

Note
The function is mainly intended for crosscheck of power.scABEL() results.
But may be mandatory for cases where power.scABEL() results are inaccurate (low sample sizes
and/or heteroscedasticity).
It is relatively slow. The run-time of this function doing 1 Mio sims is between ~ 7-8 sec for n=12
and ~ 3-4 min for n=120 on a machine with an Intel core i7 processor.
Thus be patient and go for a cup of coffee if you use this function with high sample sizes!

Author(s)
D. Labes, B. Lang

References
Tóthfalusi L, Endrényi L. Sample Sizes for Designing Bioequivalence Studies for Highly Variable
Drugs. J Pharm Pharmaceut Sci. 2011;15(1):73–84. open source

power.TOST Power of the classical TOST procedure

Description
Calculates the exact or approximate power of the two-one-sided t-tests (TOST) procedure for vari-
ous study designs used in BE studies.

Usage
power.TOST(alpha = 0.05, logscale = TRUE, theta1, theta2, theta0, CV, n,
design = "2x2", method="exact", robust=FALSE)

Arguments
alpha Significance level (one-sided). Commonly set to 0.05.
logscale Should the data used on log-transformed or on original scale? TRUE (default) or
FALSE.
theta0 ‘True’ or assumed T/R ratio or difference.
In case of logscale=TRUE it must be given as ratio T/R.
If logscale=FALSE, the difference in means. In this case, the difference may be
expressed in two ways: relative to the same (underlying) reference mean, i.e. as
(T-R)/R = T/R - 1; or as difference in means T-R. Note that in the former case
the units of CV, theta1 and theta2 need also be given relative to the reference
mean (specified as ratio).
Defaults to 0.95 if logscale=TRUE or to 0.05 if logscale=FALSE
theta1 Lower (bio-)equivalence limit.
In case of logscale=TRUE it is given as ratio.
If logscale=FALSE, the limit may be expressed in two ways: difference of
means relative to the same (underlying) reference mean or in units of the dif-
ference of means. Note that in the former case the units of CV, theta0 and
theta2 need also be given relative to the reference mean (specified as ratio).
Defaults to 0.8 if logscale=TRUE or to -0.2 if logscale=FALSE.
theta2 Upper (bio-)equivalence limit.
In case of logscale=TRUE it is given as ratio. If logscale=FALSE, the limit may
be expressed in two ways: difference of means relative to the same (underlying)
reference mean or in units of the difference of means. Note that in the former
case the units of CV, theta0 and theta1 need also be given relative to the refer-
ence mean (specified as ratio).
If not given, theta2 will be calculated as 1/theta1 if logscale=TRUE or as
-theta1 if logscale=FALSE.
CV In case of logscale=TRUE the (geometric) coefficient of variation given as ratio.
If logscale=FALSE the argument refers to (residual) standard deviation of the
response. In this case, standard deviation may be expressed two ways: relative
to a reference mean (specified as ratio sigma/muR), i.e. again as a coefficient of
power.TOST 77

variation; or untransformed, i.e. as standard deviation of the response. Note that

in the former case the units of theta0, theta1 and theta2 need also be given
relative to the reference mean (specified as ratio).

In case of cross-over studies this is the within-subject CV, in case of a parallel-

group design the CV of the total variability.
n Number of subjects under study.
Is total number if given as scalar, else number of subjects in the (sequence)
groups. In the latter case the length of n vector has to be equal to the number of
(sequence) groups.
design Character string describing the study design.
See known.designs() for designs covered in this package.
method Method for calculation of the power.
Defaults to "exact" in which case the calculation is done based on formu-
las with Owen’s Q. The calculation via Owen’s Q can also be choosen with
method="owenq".
Another exact method via direct integration of the bivariate non-central t-distribution
may be chosen with method="mvt". This may have somewhat lower precision
compared to Owen’s Q and longer run-time.
Approximate calculations can be choosen via method="noncentral" or method="nct"
for the approximation using the non-central t-distribution. With method="central"
or method="shifted" the relative crude approximation via ‘shifted’ central t-
distribution is chosen.
The strings for method may be abbreviated.
robust Defaults to FALSE. With that value the usual degrees of freedom will be used.
Set to TRUE will use the degrees of freedom according to the ‘robust’ evaluation
(aka Senn’s basic estimator). These degrees of freedom are calculated as n-seq.
See known.designs()$df2 for designs covered in this package.
Has only effect for higher-order crossover designs.

Details

The exact calculations of power are based on Owen’s Q-function or by direct integration of the
bivariate non-central t-distribution via function pmvt of package mvtnorm.
Approximate power is implemented via the non-central t-distribution or the ‘shifted’ central t-
distribution.

The formulas cover balanced and unbalanced studies w.r.t (sequence) groups.

The formulas for the paired means ’design’ do not take a correlation parameter into account. They
are solely based on the paired t-test (TOST of differences = zero).
78 power.TOST

Value
Value of power according to the input arguments.

Note
Of course it is highly recommended to use the default method="exact" :-).
There is no reason beside testing and for comparative purposes to use an approximation if the exact
method is available.

If n is given as scalar (total sample size) and this number is not divisible by the number of (sequence)
groups of the design an unbalanced design with small imbalance is assumed. A corresponding mes-
sage is thrown showing the assumed numbers of subjects in (sequence) groups.
The function does not vectorize properly if design is a vector.
The function vectorizes properly if CV or theta0 are vectors.
Other vector input is not tested yet.

The former function power2.TOST() designd to handle unbalanced studies is defunct since power.TOST()
handles balanced as well as unbalanced designs.

Author(s)
D. Labes, direct integration of bivariate non-central t-distribution by B. Lang

References
Phillips KF. Power of the Two One-Sided Tests Procedure in Bioequivalence. J Pharmacokin Bio-
pharm. 1990;18(2):137–44. doi: 10.1007/BF01063556
Diletti D, Hauschke D, Steinijans VW. Sample Size Determination for Bioequivalence Assessment
by Means of Confidence Intervals. Int J Clin Pharmacol Ther Toxicol. 1991;29(1):1–8.

# power for the 2x2 cross-over study with 24 subjects, CV 25%

# and 2 drop-outs in the same sequence group (unbalanced study)
power.TOST(CV=0.25, n=c(10,12))
power.TOST.sds 79

# should give: [1] 0.6912935

# not the same compared to the balanced setting
power.TOST(CV=0.25, n=22)
# should give: [1] 0.6953401

power.TOST.sds Power calculation of the BE decision with models incorporating

groups

Description
The power is obtained via subject data simulations.
Three models are implemented:

• gmodel==1 is full FDA model for testing group-by-treatment interaction followed by gmodel==2
or gmodel==3 with data of the biggest group depending on the test of the treatment by group
interaction
• gmodel==2 is full FDA model but without group-by-treatment interaction
• gmodel==3 is model with pooled groups, i.e. without any group term

Usage
power.TOST.sds(alpha = 0.05, theta1, theta2, theta0, CV, n,
design = c("2x2", "2x2x2", "2x3x3", "2x2x4", "2x2x3"),
design_dta = NULL, grps = 2, ngrp = NULL, gmodel = 2,
nsims = 1e+05, details = FALSE, setseed = TRUE, progress)

Arguments
alpha Type I error probability, significance level. Conventionally mostly set to 0.05.
theta1 Lower BE limit. Defaults to 0.8 if not given explicitely.
theta2 Upper BE limit. Defaults to 1.25 if not given explicitely.
theta0 ‘True’ or assumed T/R ratio.
Defaults to 0.95 if not given explicitly.
CV Intra-subject coefficient(s) of variation as ratio (not percent).
• If given as a scalar (length(CV)==1) the same CV of Test and Reference is
assumed (homoscedasticity, CVwT==CVwR).
• If given as a vector (length(CV)==2), i.e., assuming heteroscedasticity, the
CV of the Test must be given in CV[1] and the one of the Reference in the
CV[2].
n Number of subjects under study.
May be given as vector. In that case it is assumed that n contains the number of
subjects in the sequence groups.
If n is given as single number (total sample size) and this number is not divisible
by the number of sequences of the design an unbalanced design is assumed. A
80 power.TOST.sds

corresponding message is thrown showing the numbers of subjects in sequence

groups.
Attention! In case of the "2x2x3" (TRT|RTR) design the order of sample sizes
is important if given as vector. n[1] is for sequence group ’TRT’ and n[2] is
for sequence group ’RTR’.
design Design of the study to be planned.
"2x2" or "2x2x2" is the conventional cross-over design.
"2x3x3" is the partial replicate design (TRR|RTR|RRT).
"2x2x4" is the full replicate design with 2 sequences and 4 periods.
"2x2x3" is the 3-period design with sequences TRT|RTR.
Defaults to design="2x2".
design_dta Alternatively to using the arguments design and n the design may be defined via
a data.frame with columns subject,sequence,period and tmt. This feature is
experimental in the sense that the data.frame is not checked for complying with
the assumed structure.
If you use the argument design_dta you don’t need to specify the arguments
design and n.
The default design_dta = NULL means that design and n are used for the inter-
nal construction of the design data.frame.
grps Number of (logistical) groups. Defaults to 2.
ngrp Vector of number of subjects in groups.
gmodel Number describing the model incorporating group effects
• gmodel=1 is full FDA model for testing group-by-treatment interaction fol-
lowed by gmodel=2 or gmodel=3 with data of the biggest group depending
on the test of the treatment by group interaction
• gmodel=2 is full FDA model but without group-by-treatment interaction
• gmodel=3 is model with pooled groups, i.e. without any group term
Defaults to gmodel=2.
nsims Number of simulations to be performed to obtain the empirical power. Defaults
to 100,000 = 1e+05.
If simulations are aimed for empirical alpha nsims=1e+06 is recommended.
details If set to TRUE the computational time is shown.
setseed Simulations are dependent on the starting point of the (pseudo) random number
generator. To avoid differences in power for different runs a set.seed(123456)
is issued if setseed=TRUE, the default.
progress Should a progressbar be shown? Defaults to TRUE if missing and nsims >5E5.

Details
The power is calculated via subject data sims.
The evaluation of BE is done via 1-2*alpha confidence interval using classical ANOVA for the
models with group effects.
The data.frame with columns subject,sequence,period and tmt necessary for evalution of sim-
ulated subject data is constructed internally from the arguments design and n or may be given user
power.TOST.sim 81

defined via the argument design_dta. The last option is usefull if missing data have to be consid-
ered or if designs have to be evaluated which are not in the list of argument design.
This feature is experimental in the sense that the data.frame is not checked for complying with the
assumed structure.

Value
Returns the value of the (empirical) power

Note
The run time of the function may be relatively long.
Take a cup of coffee and be patient.

Author(s)
D. Labes

References
Schütz H.
Multi-Group Studies in Bioequivalence. To pool or not to pool?
Presentation at BioBriges 2018, Prague. https://bebac.at/lectures/Prague2018.pdf

Examples
# power for gmodel=2, 2x2 crossover, grps=3 with even number of subjects
power.TOST.sds(CV=0.2, n=18, grps=3)
# gives [1] 0.78404
# without considering groups
power.TOST.sds(CV=0.2, n=18, gmodel=3)
# gives [1] 0.7887

power.TOST.sim Power of the TOST procedure obtained via simulations

Description
Power is calculated by simulations of studies (PE via its normal distribution, MSE via its associated
χ2 distribution) and application of the two one-sided t-tests. Power is obtained via ratio of studies
found BE to the number of simulated studies.

Usage
power.TOST.sim(alpha = 0.05, logscale = TRUE, theta1, theta2, theta0, CV, n,
design = "2x2", robust = FALSE, setseed = TRUE, nsims = 1e+05)
82 power.TOST.sim

In case of cross-over studies this is the within-subject CV, in case of a parallel-

(aka Senn’s basic estimator). These degrees of freedom are calculated as n-seq.
See known.designs()$df2 for designs covered in this package.
Has only effect for higher-order crossover designs.
setseed Simulations are dependent on the starting point of the (pseudo) random number
generator. To avoid differences in power for different runs a set.seed(1234567)
is issued if setseed=TRUE, the default.
Set this argument to FALSE to view the variation in power between different runs.
nsims Number of studies to simulate. Defaults to 100,000 = 1E5.

Value

Value of power according to the input arguments.

Note

This function was intended for internal check of the analytical power calculation methods. Use of
the analytical power calculation methods (power.TOST()) for real problems is recommended.
For sufficient precision nsims > 1E5 (default) may be necessary. Be patient if using nsims=1E6.
May take some seconds.

Author(s)

D. Labes

See Also

power.TOST,

Examples
# using the default design 2x2, BE range 0.8 ... 1.25, logscale, theta0=0.95
power.TOST.sim(alpha = 0.05, CV = 0.3, n = 12)
# should give 0.15054, with nsims=1E6 it will be 0.148533
# exact analytical is
power.TOST(alpha = 0.05, CV = 0.3, n = 12)
# should give 0.1484695

# very unusual alpha setting

power.TOST.sim(alpha = 0.9, CV = 0.3, n = 12)
# should give the same (within certain precision) as
power.TOST(alpha = 0.95, CV = 0.3, n = 12)
# or also within certain precision equal to
power.TOST(alpha = 0.95, CV = 0.3, n = 12, method = "mvt")
# SAS Proc Power gives here the incorrect value 0.60525
84 pvalue.TOST

pvalue.TOST p-value(s) of the TOST procedure

Description
Calculates the p-value(s) of the TOST procedure via students t-distribution given pe, CV and n.

Usage
pvalue.TOST(pe, CV, n, logscale = TRUE, theta1, theta2, design = "2x2",
robust = FALSE, both = FALSE)
pvalues.TOST(pe, CV, n, logscale = TRUE, theta1, theta2, design = "2x2",
robust = FALSE, both = TRUE)

Arguments
pe Observed point estimate of the T/R ratio or difference.
In case of logscale=TRUE it must be given as ratio T/R.
If logscale=FALSE, the observed difference in means. In this case, the differ-
ence may be expressed in two ways: relative to the same (underlying) reference
mean, i.e. as (T-R)/R = T/R - 1; or as difference in means T-R. Note that in the
former case the units of CV, theta1 and theta2 need also be given relative to
the reference mean (specified as ratio).

CV In case of logscale=TRUE the observed (geometric) coefficient of variation

given as ratio.
If logscale=FALSE the argument refers to the observed (residual) standard de-
viation of the response. In this case, standard deviation may be expressed two
ways: relative to a reference mean (specified as ratio sigma/muR), i.e. again
as a coefficient of variation; or untransformed, i.e. as standard deviation of the
response. Note that in the former case the units of pe, theta1 and theta2 need
also be given relative to the reference mean (specified as ratio).

In case of cross-over studies this is the within-subject CV, in case of a parallel-

group design the CV of the total variability.
n Total number of subjects if given as scalar.
Number of subjects in (sequence) groups if given as vector.
logscale Should the data be used after log-transformation or on original scale?
TRUE or FALSE. Defaults to TRUE.
theta1 Lower (bio-)equivalence limit.
In case of logscale=TRUE it is given as ratio.
If logscale=FALSE, the limit may be expressed in two ways: difference of
means relative to the same (underlying) reference mean or in units of the dif-
ference of means. Note that in the former case the units of CV, pe and theta2
need also be given relative to the reference mean (specified as ratio).
Defaults to 0.8 if logscale=TRUE or to -0.2 if logscale=FALSE.
pvalue.TOST 85

theta2 Upper (bio-)equivalence limit.

In case of logscale=TRUE it is given as ratio. If logscale=FALSE, the limit may
be expressed in two ways: difference of means relative to the same (underlying)
reference mean or in units of the difference of means. Note that in the former
case the units of CV, theta0 and theta1 need also be given relative to the refer-
ence mean (specified as ratio).
If not given, theta2 will be calculated as 1/theta1 if logscale=TRUE or as
-theta1 if logscale=FALSE.
design Character string describing the study design.
See known.designs() for designs covered in this package.
robust If set to TRUE triggers the use of degrees of freedom according to the ‘robust’
evaluation (aka Senn’s basic estimator). These degrees of freedom are calculated
as n-seq.
See known.designs()$df2. Has only effect for higher-order crossover designs.
Defaults to FALSE. With that value the usual degrees of freedom will be used.
both Indicates if both p-values (t-tests of pe >= theta1 and pe <= theta2) shall be given
back or only the maximum.
Defaults to FALSE for the function pvalue.TOST() and to TRUE for the function
pvalues.TOST().

Value

Returns the p-value(s).

Returns a vector with named elements p.left, p.right if arguments pe and CV are scalars, else a
matrix with columns p.left, p.right.
p.left gives the p-value of testing
HA1: theta >= theta1
and p.right the p-value of testing
HA2: theta <= theta2
against their respective Nulls.

Note

The formulas implemented cover balanced and unbalanced designs.

SAS procedure TTEST with the TOST option names p.left = Upper, p.right= Lower according
to the tail of the t-distribution to be used for obtaining the p-values.

Author(s)

B. Lang, man page by D. Labes

86 reg_const

References
Schuirmann DJ. A comparison of the two one-sided tests procedure and the power approach for
assessing the equivalence of average bioavailability. J Pharmacokin Biopharm. 1987;15:657–80.
doi: 10.1007/BF01068419
Hauschke D, Steinijans V, Pigeot I. Bioequivalence Studies in Drug Development. Chichester:
Wiley; 2007.

# max. p-value only as 'overall' pvalue, preferred by Benjamin

pvalue.TOST(pe = 0.912, CV = 0.333, n = 24)
# should give 0.08777621, i.e., inequivalence can't be rejected
# this is operationally identical to
CI.BE(pe = 0.912, CV = .333, n = 24)
# lower limit = 0.7766 outside 0.8 ... 1.25, i.e., inequivalence can't be rejected

reg_const Constructor of an object with class ’regSet’ containing the regulatory

settings for ABEL

Description
This function may be used to define regulatory settings not implemented yet in PowerTOST.

Usage
reg_const(regulator, r_const, CVswitch, CVcap, pe_constr)

Arguments
regulator Name of the regulatory body as a string. Implemented settings are for "EMA",
"FDA", "HC", and "GCC".
The former (inofficial) settings for "ANVISA" are covered by the EMA settings.
In case of regulator="USER" the other arguments must be given. Otherwise,
they may be missing.
reg_const 87

r_const Regulatory constant.

CVswitch CV to switch to the widened acceptance limits.
CVcap CV for capping the widening of the acceptance limits.
pe_constr Logical. Shall pe constraint be applied? Defaults to TRUE.

Value

Returns an object of class ’regSet’, a list with components

name Name of the settings

CVswitch see arguments
r_const Regulatory constant
CVcap see arguments
pe_constr see arguments
est_method "ANOVA" or "ISC"

Class ’regSet’ has a S3 print method.

The component est_method is automatically set to "ANOVA", except for regulator="FDA" or regulator="HC"
where "ISC" is used.

Note

The former inofficial regulatory settings for regulator="ANVISA" are covered by regulator="EMA"
(see the BEBA Forum, May 2016).

The settings for CVcap of Health Canada (regulator="HC") were chosen in such a way that the
limits of the acceptance range are capped nearly exact to 1/1.5 up to 1.5. Literally it is given rounded
to 3 significant digits (Health Canada, April 18, 2016).

Author(s)

D. Labes

Examples
# to retrieve the EMA settings
reg_const("EMA")
# to define the old ANVISA settings
reg <- reg_const("USER", r_const = 0.76, CVswitch = 0.4, CVcap = 0.5)
reg$name <- "Old ANVISA"
# Use reg as argument in the scaled ABEL power / sample size functions for
88 sampleN.2TOST

sampleN.2TOST Sample size based on power of two TOSTs

Description
Estimates the necessary sample size to have at least a given power when two parameters are tested
simultaneously.

Usage
sampleN.2TOST(alpha = c(0.05, 0.05), targetpower = 0.8, logscale = TRUE,
theta0, theta1, theta2, CV, rho, design = "2x2", setseed = TRUE,
robust = FALSE, print = TRUE, details = FALSE, imax = 100,
nsims = 1e+05)

Arguments
alpha Vector; contains one-sided significance level for each of the two TOSTs.
For one TOST, by convention mostly set to 0.05.
targetpower Power to achieve at least. Must be >0 and <1.
Typical values are 0.8 or 0.9.
logscale Should the data used on log-transformed or on original scale? TRUE (default)
or FALSE.
theta0 Vector; contains ‘true’ assumed T/R ratio for each of the two TOSTs.
In case of logscale=TRUE each element must be given as ratio,
otherwise as difference to 1. See examples.
Defaults to c(0.95,0.95) if logscale=TRUE or to c(0.05,0.05) if logscale=FALSE.
theta1 Vector; contains lower bioequivalence limit for each of the two TOSTs.
In case of logscale=TRUE it is given as ratio, otherwise as diff. to 1.
Defaults to c(0.8,0.8) if logscale=TRUE or to c(-0.2,-0.2) if logscale=FALSE.
theta2 Vector; contains upper bioequivalence limit for each of the two TOSTs.
If not given theta2 will be calculated as 1/theta1 if logscale=TRUE
or as -theta1 if logscale=FALSE.
CV Vector of coefficient of variations (given as as ratio, e.g., 0.2 for 20%).
In case of cross-over studies this is the within-subject CV,
in case of a parallel-group design the CV of the total variability.
In case of logscale=FALSE CV is assumed to be the respective standard devia-
tion.
rho Correlation between the two PK metrics (e.g., AUC and Cmax) under consid-
eration. This is defined as correlation between the estimator of the treatment
difference of PK metric one and the estimator of the treatment difference of PK
metric two. Has to be within {–1, +1}.
design Character string describing the study design.
See known.designs() for designs covered in this package.
sampleN.2TOST 89

setseed Logical; if TRUE, the default, a seed of 1234567 is set.

robust Defaults to FALSE. With that value the usual degrees of freedom will be used.
Set to TRUE will use the degrees of freedom according to the ‘robust’ evaluation
(aka Senn’s basic estimator). These degrees of freedom are calculated as n-seq.
See known.designs()$df2 for designs covered in this package.
Has only effect for higher-order crossover designs.
print If TRUE (default) the function prints its results.
If FALSE only the result list will be returned.
details If TRUE the design characteristics and the steps during sample size calculations
will be shown.
Defaults to FALSE.
imax Maximum number of steps in sample size search.
Defaults to 100.
nsims Number of studies to simulate. Defaults to 100,000 = 1E5.

Details
The sample size is estimated via iterative evaluation of power of the two TOSTs.
Start value for the sample size search is taken from a large sample approximation (one TOST) ac-
cording to Zhang, modified.
The sample size is bound to 4 as minimum.

The estimated sample size gives always the total number of subjects (not subject/sequence in
crossovers or subjects/group in parallel designs – like in some other software packages).

Value
A list with the input and results will be returned.
The element name "Sample size" contains the total sample size.

Warning
The function does not vectorize properly.
If you need sample sizes with varying CVs, use f.i. for-loops or the apply-family.

Note
If both theta0 are near the acceptance limits then the starting value may not be a good approxima-
tion resulting in a lot of iteration steps; imax may need to be increased to obtain the required sample
size.

Author(s)
B. Lang, D. Labes
90 sampleN.dp

References
Phillips KF. Power for Testing Multiple Instances of the Two One-Sided Tests Procedure. Int J
Biostat. 2009;5(1):Article 15.
Hua SY, Xu S, D’Agostino RB Sr. Multiplicity adjustments in testing for bioequivalence. Stat Med.
2015;34(2):215–31. doi: 10.1002/sim.6247
Lang B, Fleischer F. Letter to the Editor: Comments on ‘Multiplicity adjustments in testing for
bioequivalence’. Stat Med. 2016;35(14):2479–80. doi: 10.1002/sim.6488
Zhang P. A Simple Formula for Sample Size Calculation in Equivalence Studies. J Biopharm Stat.
2003;13(3):529–538. doi: 10.1081/BIP120022772

# Sample size for a parallel group design,

# evaluation on the original (untransformed) scale
# BE limits 80 ... 120% = -20% ... +20% of reference,
# assumed true BE ratio 0.95% = -5% to reference mean for both parameters,
# total CV=20% for both parameters, and correlation 0.9 between parameters
# should give n=54 with power=0.8149
sampleN.2TOST(logscale=FALSE, theta0 = rep(-0.05, 2), CV = c(0.2, 0.2),
rho = 0.9, design = "parallel")

sampleN.dp Sample size estimation of dose-proportionality studies evaluated via

the power model

Description
Performes a sample size estimation for dose-proportionality studies using the power model for
cossover (Latin square), parallel group designs or incomplete block designs via a confidence interval
equivalence criterion.

Usage
sampleN.dp(alpha = 0.05, CV, doses, targetpower = 0.8, beta0, theta1 = 0.8,
theta2 = 1/theta1, design = c("crossover", "parallel", "IBD"),
dm=NULL, CVb, print = TRUE, details = FALSE, imax = 100)
sampleN.dp 91

Arguments
alpha Type 1 error. Usually set to 0.05.
CV Coefficient of variation. Is intra-subject CV for design="crossover" and CV
of total variability in case of design="parallel"
doses Vector of dose values under study. At least two doses have to be given.
targetpower Power to achieve at least. Must be >0 and <1.
Typical values are 0.8 or 0.9.
beta0 ‘True’ or assumed slope of the power model. If missing defaults to 1+log(0.95)/log(rd)
where rd is the ratio is the ratio of the highest to the lowest dose.
Has to be within slope acceptance range according to 1+log(theta1)/log(rd)
and 1+log(theta2)/log(rd). Otherwise, the function issues an error.
theta1 Lower acceptance limit for the ratio of dose normalized means (Rdmn).
Transformes into slope acceptance range as described under item beta0.
theta2 Upper acceptance limit for the ratio of dose normalized means (Rdmn).
design Crossover design (default), parallel group design or incomplete block design
(IBD).
Crossover design means Latin square design with number of doses as dimension.
dm ’Design matrix’ of the incomplete block design (IBD) if design="IBD".
This matrix contains the sequences in rows and periods in columns. The entry
(i, j) of the design matrix corresponds to the dose (index) a subject with i-th
sequence gets in the j-th period. Can be obtained f.i. via functions of package
crossdes. See examples.
Function bib.CL returns some IBDs described by Chow & Liu.
CVb Coefficient of variation of the between-subject variability.
Only necessary if design="IBD". Will be set to 2*CV if missing. This is only a
crude rule of thumb. Better obtain an estimate of CVb from a previous crossover
study.

Set CVb=0 if all-effects-fixed model shall be used. This model gives lower sam-
ple sizes than the mixed model with random subject effects (random intercept).
print If TRUE (default) the function prints its results.
If set to FALSE only the data.frame with the results will be returned.
details If details=TRUE the steps during sample size search will be shown. Defaults to
FALSE.
imax Maximum number of steps in sample size search.
Defaults to 100. Adaption only in rare cases needed, if any.

Details
The sample size is estimated via iterative evaluation of power.dp().
Start value for the sample size search is taken from a large sample approximation.
The sample size is bound to number of dose or sequence groups as minimum.
Balanced designs are used although this is not absolutely necessary.

The estimated sample size gives always the total number of subjects (not subject/sequence in
crossovers or subjects/group in parallel designs – like in some other software packages).
92 sampleN.dp

Value
A data.frame with the input and results will be returned.
The Sample size column contains the total sample size.

Warning
This function is ‘experimental’ only, since it is not thorougly tested yet. Especially for design="IBD"
reliable test cases are missing.

Author(s)
D. Labes

References
Chow SC, Liu JP. Design and Analysis of Bioavailability and Bioequivalence Studies. Boca Raton:
CRC Press; 3rd edition 2009.
Patterson S, Jones B. Bioequivalence and Statistics in Clinical Pharmacology. Boca Raton: Chap-
man & Hall/CRC: 2006. p. 239.
(contains presumably a bug)
Sethuraman VS, Leonov S, Squassante L, Mitchell TR, Hale MD. Sample size calculation for the
Power Model for dose proportionality studies. Pharm Stat. 2007;6(1):35–41. doi: 10.1002/pst.241
Hummel J, McKendrick S, Brindley C, French R. Exploratory assessment of dose proportionality:
review of current approaches and proposal for a practical criterion. Pharm. Stat. 2009;8(1):38–49.
doi: 10.1002/pst.326

# incomplete block design with 5 doses, 3 periods

# from library(crossdes)
doses <- c(5, 25, 50, 100, 200)
CVb <- mse2CV(0.8)
levels <- length(doses)
per <- 3
block <- levels*(levels-1)/(per-1)
# IBD based on balanced minimal repeated measurements design
# gives n=30 and 10 sequences
ibd <- crossdes::balmin.RMD(levels, block, per)
sampleN.dp(CV = 0.2, doses = doses, beta0 = 1, design = "IBD", dm = ibd,
CVb = CVb, targetpower=0.9)
sampleN.HVNTID 93

sampleN.HVNTID Sample size estimation for BE decision via FDA method for highly
variable (HV) narrow therapeutic index drugs (NTIDs)

Description
This function performs the sample size estimation for the BE decision via the FDA’s method for
highly variable NTIDs as described in respective guidances based on simulations.
The study designs may be the full replicate design 2x2x4 with 4 periods (TRTR|RTRT) and the
3-period replicate design 2x2x3 with sequences RTR|TRT.

Usage
sampleN.HVNTID(alpha = 0.05, targetpower = 0.8, theta0, theta1, theta2, CV,
design = c("2x2x4", "2x2x3"), nsims = 1e+05, nstart, imax = 100,
print = TRUE, details = TRUE, setseed = TRUE)

print If TRUE (default) the function prints its results. If FALSE only the resulting
dataframe will be returned.
details If set to TRUE, the default, the steps during sample size search are shown. More-
over the details of the method settings are printed.
setseed Simulations are dependent on the starting point of the (pseudo) random number
generator. To avoid differences in power values for different runs a set.seed(123456)
is issued if setseed=TRUE, the default.

Details

For deciding BE the study must pass the conventional ABE test and additionally the test that the
ratio of sWT/sWR is <= 2.5.

The estimated sample size gives always the total number of subjects (not subject/sequence – like in
some other software packages).

Value

Returns a data.frame with the input and sample size results.

The Sample size column contains the total sample size.
The nlast column contains the last n value. May be useful for re-starting.

Warning

For some input constellations the sample size search may be very time consuming and will eventu-
ally also fail since the start values chosen may not really reasonable for them.
In case of a failed sample size search you may restart with setting the argument nstart.

Note

The design recommended by the FDA is the full replicate design "2x2x4".
The sample size estimation is done only for balanced studies since the break down of the total
subject number in case of unbalanced sequence groups is not unique. Moreover the formulas used
are only valid for balanced designs.
The FDA method is described for the ABE limits 0.8 ... 1.25 only. Setting theta1, theta2 to other
values may not be reasonable and is not tested.
The minimum sample size is 6, even if the power is higher than the intended targetpower.

Author(s)

D. Labes
sampleN.noninf 95

See Also
power.HVNTID
and power.NTIDFDA, sampleN.NTIDFDA for NTIDs with low variability

Examples
# using all defaults but CV
sampleN.HVNTID(CV = 0.3)
# should give
# n=22 with an (empirical) power of 0.829700

# Test formulation with lower variability but same pooled CV

CVs <- CVp2CV(0.3, ratio = 0.25)
sampleN.HVNTID(CV = CVs)
# should give (no distinct difference to example above)
# n=22 with an (empirical) power of 0.837520

sampleN.noninf Sample size for the non-inferiority t-test

Description
Function for estimating the sample size needed to have a pre-specified power for the one-sided
non-inferiority t-test for normal or log-normal distributed data.

Usage
sampleN.noninf(alpha = 0.025, targetpower = 0.8, logscale = TRUE,
margin,theta0, CV, design = "2x2", robust = FALSE,
details = FALSE, print = TRUE, imax=100)

Arguments
alpha Significance level (one-sided). Defaults here to 0.025.
targetpower Power to achieve at least. Must be >0 and <1.
Typical values are 0.8 or 0.9.
logscale Should the data used on log-transformed or on original scale? TRUE (default) or
FALSE.
96 sampleN.noninf

theta0 ‘True’ or assumed T/R ratio or difference.

In case of logscale=TRUE it must be given as ratio T/R.
If logscale=FALSE, the difference in means. In this case, the difference may be
expressed in two ways: relative to the same (underlying) reference mean, i.e. as
(T-R)/R = T/R - 1; or as difference in means T-R. Note that in the former case
the units of margin and CV need also be given relative to the reference mean
(specified as ratio).
Defaults to 0.95 if logscale=TRUE or to -0.05 if logscale=FALSE
margin Non-inferiority margin.
In case of logscale=TRUE it is given as ratio.
If logscale=FALSE, the limit may be expressed in two ways: difference of
means relative to the same (underlying) reference mean or in units of the dif-
ference of means. Note that in the former case the units of CV and theta0 need
also be given relative to the reference mean (specified as ratio).
Defaults to 0.8 if logscale=TRUE or to -0.2 if logscale=FALSE.
CV In case of logscale=TRUE the (geometric) coefficient of variation given as ratio.
If logscale=FALSE the argument refers to (residual) standard deviation of the
response. In this case, standard deviation may be expressed two ways: relative
to a reference mean (specified as ratio sigma/muR), i.e. again as a coefficient of
variation; or untransformed, i.e. as standard deviation of the response. Note that
in the former case the units of theta0, theta1 and theta2 need also be given
relative to the reference mean (specified as ratio).

In case of cross-over studies this is the within-subject CV, in case of a parallel-

group design the CV of the total variability.
design Character string describing the study design.
See known.designs for designs covered in this package.
robust Defaults to FALSE. With that value the usual degrees of freedom will be used.
Set to TRUE will use the degrees of freedom according to the ‘robust’ evaluation
(aka Senn’s basic estimator). These df are calculated as n-seq.
See known.designs()$df2 for designs covered in this package.
Has only effect for higher-order crossover designs.
details If TRUE the design characteristics and the steps during sample size calculations
will be shown.
Defaults to FALSE.
print If TRUE (default) the function prints its results.
If FALSE only the data.frame with the results will be returned.
imax Maximum number of steps in sample size search.
Defaults to 100. Adaption only in rare cases needed.

Details
The sample size is calculated via iterative evaluation of power.noninf().
Start value for the sample size search is taken from a large sample approximation.
The sample size is bound to 4 as minimum.

The estimated sample size gives always the total number of subjects (not subject/sequence in
sampleN.noninf 97

crossovers or subjects/group in parallel designs – like in some other software packages).

Notes on the underlying hypotheses

If the supplied margin is < 0 (logscale=FALSE) or < 1 (logscale=TRUE), then it is assumed higher
response values are better. The hypotheses are
H0: theta0 <= margin vs. H1: theta0 > margin,
where theta0 = mean(test)-mean(reference) if logscale=FALSE
or
H0: log(theta0) <= log(margin) vs. H1: log(theta0) > log(margin),
where theta0 = mean(test)/mean(reference) if logscale=TRUE.

Value
A data.frame with the input settings and results will be returned.
Explore it with str(sampleN.noninf(...)

Warning
The function does not vectorize properly.
If you need sample sizes with varying CVs, use f.i. for-loops or the apply-family.

Author(s)
D. Labes

References
Julious SA. Sample sizes for clinical trials with Normal data. Stat Med. 2004;23(12):1921–86.
doi: 10.1002/sim.1783

# 'non-superiority' case, log-transformed data

# with assumed 'true' ratio somewhat above 1
sampleN.noninf(CV = 0.3, targetpower = 0.9,
margin = 1.25, theta0 = 1.05)
# should give n=62

sampleN.NTIDFDA Sample size estimation for BE decision via the FDA’s method for nar-
row therapeutic index drugs (NTIDs)

Description
This function performs the sample size estimation for the BE decision for the FDA’s method for
NTIDs based on simulations. The study design is the full replicate design 2x2x4 (TRTR|RTRT) or
the 3-period replicate design with sequences TRT|RTR.

Usage
sampleN.NTIDFDA(alpha = 0.05, targetpower = 0.8, theta0, theta1, theta2, CV,
design = c("2x2x4", "2x2x3"), nsims = 1e+05, nstart, imax = 100,
print = TRUE, details = TRUE, setseed = TRUE)

Arguments
alpha Type I error probability. Per convention mostly set to 0.05.
targetpower Power to achieve at least. Must be >0 and <1.
Typical values are 0.8 or 0.9.
theta0 ‘True’ or assumed T/R ratio.
Attention! Defaults here to 0.975 if not given explicitly. The value was chosen
closer to 1 because the potency (contents) settings for NTIDs are tightened by
the FDA.
theta1 Conventional lower ABE limit to be applied in the FDA procedure.
Defaults to 0.8 if not given explicitly.
theta2 Conventional upper ABE limit to be applied in the FDA procedure.
Defaults to 1.25 if not given explicitly.
CV Intra-subject coefficient(s) of variation as ratio (not percent).
• If given as a scalar (length(CV)==1) the same CV of Test and Reference is
assumed (homoscedasticity, CVwT==CVwR).
• If given as a vector (length(CV)==2), i.e., assuming heteroscedasticity, the
CV of the Test must be given in CV[1] and the one of the Reference in the
CV[2].
design Design of the study to be planned.
"2x2x4" is the full replicate with 2 sequences and 4 periods (TRTR|RTRT).
"2x2x3" is the full replicate with 2 sequences and 3 periods (TRT|RTR).
Defaults to design="2x2x4".
sampleN.NTIDFDA 99

nsims Number of simulations to be performed to obtain the empirical power. Defaults

to 100,000 = 1e+5.
nstart Set this to a start value for the sample size if a previous run failed.
May be missing.
imax Maximum number of steps in sample size search. Defaults to 100.
print If TRUE (default) the function prints its results. If FALSE only the resulting
dataframe will be returned.
details If set to TRUE, the default, the steps during sample size search are shown. More-
over the details of the method settings are printed.
setseed Simulations are dependent on the starting point of the (pseudo) random number
generator. To avoid differences in power values for different runs a set.seed(123456)
is issued if setseed=TRUE, the default.

Details
The linearized scaled ABE criterion is calculated according to the SAS code given in the FDA War-
farine guidance. For deciding BE the study must pass that criterion, the conventional ABE test and
additional the test that the ratio of sWT/sWR <= 2.5.

The estimated sample size gives always the total number of subjects (not subject/sequence – like in
some other software packages).

Value
Returns a data.frame with the input settings and sample size results.
The Sample size column contains the total sample size.
The nlast column contains the last n value. May be useful for re-starting.

Warning
For some input constellations the sample size search may be very time consuming and will even-
tually also fail since the start values chosen may not really reasonable for them. This applies es-
pecially for theta0 values near to the implied scaled (tightened/widened) ABE limits according to
exp(±1.053605*swR).
In case of a failed sample size search you may restart with setting the argument nstart.
In case of theta0 values outside the implied scaled (tightened/widened) ABE limits no sample size
estimation is possible and the function throws an error (f.i. CV=0.04, theta0=0.95).

Note
The design recommended by the FDA is the full replicate design "2x2x4".
The sample size estimation is done only for balanced studies since the break down of the total sub-
ject number in case of unbalanced sequence groups is not unique. Moreover the formulas used are
100 sampleN.NTIDFDA

only valid for balanced designs.

The FDA method is described for the ABE limits 0.8 ... 1.25 only. Setting theta1, theta2 to other
values may not be reasonable and is not tested.

The results for the design "2x2x3" are to be considered as experimental since at present not thor-
ougly tested.
The minimum sample size is 6, even if the power is higher than the intended targetpower.

Author(s)

D. Labes

References

See Also

power.NTIDFDA and power.HVNTID, sampleN.HVNTID for NTIDs with high variability

Examples
sampleN.NTIDFDA(CV = 0.04,theta0 = 0.975)
# should give
# n=54 with an (empirical) power of 0.809590
#
# Test formulation with lower variability
sampleN.NTIDFDA(CV = c(0.04,0.06),theta0 = 0.975)
# should give
# n=20 with an (empirical) power of 0.0.814610
#
# alternative 3-period design
sampleN.NTIDFDA(CV = 0.04,theta0 = 0.975, design="2x2x3")
# should give
# n=86 with power = 0.80364
sampleN.RatioF 101

sampleN.RatioF Sample size for equivalence of the ratio of two means with normality
on original scale

Description

Estimates the necessary sample size to have at least a given power based on Fieller’s confidence
(‘fiducial’) interval.

Usage

sampleN.RatioF(alpha = 0.025, targetpower = 0.8, theta1 = 0.8, theta2,

theta0 = 0.95, CV, CVb, design = "2x2", print = TRUE,
details = FALSE, imax=100, setseed=TRUE)

Arguments

alpha Type I error probability.

Defaults here to 0.025 because this function is intended for studies with clinical
endpoints.
targetpower Power to achieve at least. Must be >0 and <1. Typical values are 0.8 or 0.9.
theta1 Lower bioequivalence limit. Typically 0.8 (default).
theta2 Upper bioequivalence limit. Typically 1.25.
Is set to 1/theta1 if missing.
theta0 ‘True’ or assumed T/R ratio. Typically set to 0.95.
CV Coefficient of variation as ratio. In case of design="parallel" this is the CV
of the total variability, in case of design="2x2" the intra-subject CV (CVw in
the reference).
CVb CV of the between-subject variability. Only necessary for design="2x2".
design A character string describing the study design.
design="parallel" or design="2x2" allowed for a two-parallel group design
or a classical TR|RT crossover design.
print If TRUE (default) the function prints its results. If FALSE only a data.frame with
the results will be returned.
details If TRUE the steps during sample size calculations will be shown.
Defaults to FALSE.
imax Maximum number of steps in sample size search.
Defaults to 100. Adaption only in rare cases needed.
setseed If set to TRUE the dependence of the power from the state of the random number
generator is avoided.
102 sampleN.RatioF

Details

The sample size is based on exact power calculated using the bivariate non-central t-distribution via
function pmvt of the package mvtnorm.
Due to the calculation method used in package mvtnorm these probabilities are dependent from the
state of the random number generator within the precision of the power.

The CV(within) and CVb(etween) in case of design="2x2" are obtained via an appropriate ANOVA
from the error term and from the difference (MS(subject within sequence)-MS(error))/2.

The estimated sample size gives always the total number of subjects (not subject/sequence in
crossovers or subjects/group in parallel designs – like in some other software packages).

Value

A data.frame with the input values and results will be returned.

The sample size n returned is the total sample size for both designs.

Note

This function is intended for studies with clinical endpoints.

In such studies the 95% confidence intervals are usually used for equivalence testing.
Therefore, alpha defaults here to 0.025 (see EMEA 2000).

Author(s)

D. Labes

References

Fieller EC. Some Problems in Interval Estimation. J Royal Stat Soc B. 1954;16(2):175–85. doi: 10.1111/
j.25176161.1954.tb00159.x
Sasabuchi S. A test of a multivariate normal mean with composite hypotheses determined by linear
inequalities. Biometrika. 1980;67(2):429–39. doi: 10.1093/biomet/67.2.429
Hauschke D, Kieser M, Diletti E, Burke M. Sample size determination for proving equivalence
based on the ratio of two means for normally distributed data. Stat Med. 1999;18(1):93–105.
Hauschke D, Steinijans V, Pigeot I. Bioequivalence Studies in Drug Development. Chichester:
Wiley; 2007. Chapter 10.
European Agency for the Evaluation of Medicinal Products, CPMP. Points to Consider on Switching
between Superiority and Non-Inferiority. London, 27 July 2000. CPMP/EWP/482/99

See Also

power.RatioF
sampleN.RSABE 103

Examples
# sample size for a 2x2 cross-over study
# with CVw=0.2, CVb=0.4
# alpha=0.025 (95% CIs), target power = 80%
# 'true' ratio = 95%, BE acceptance limits 80-125%
# using all the defaults:
sampleN.RatioF(CV = 0.2, CVb = 0.4)
# gives n=28 with an achieved power of 0.807774
# see Hauschke et.al. (2007) Table 10.3a

# sample size for a 2-group parallel study

# with CV=0.4 (total variability)
# alpha=0.025 (95% CIs), target power = 90%
# 'true' ratio = 90%, BE acceptance limits 75-133.33%
sampleN.RatioF(targetpower = 0.9, theta1 = 0.75,
theta0 = 0.90, CV = 0.4, design = "parallel")
# gives n=236 with an achieved power of 0.900685
# see Hauschke et.al. (2007) Table 10.2

# a rather strange setting of ratio0! have a look at n.

# it would be better this is not the sample size but your account balance ;-).
sampleN.RatioF(theta0 = 0.801, CV = 0.2, CVb = 0.4)

sampleN.RSABE Sample size estimation for BE decision via linearized scaled ABE cri-
terion

Description
This function performs the sample size estimation for the BE decision via linearized scaled ABE
criterion based on simulations.

Usage
sampleN.RSABE(alpha = 0.05, targetpower = 0.8, theta0, theta1, theta2, CV,
design = c("2x3x3", "2x2x4", "2x2x3"), regulator = c("FDA", "EMA"),
nsims = 1e+05, nstart, imax=100, print = TRUE,
details = TRUE, setseed=TRUE)

theta1 Conventional lower ABE limit to be applied in the mixed procedure if CVsWR <=
CVswitch.
Also Lower limit for the point estimate constraint.
Defaults to 0.8 if not given explicitly.
theta2 Conventional upper ABE limit to be applied in the mixed procedure if CVsWR <=
CVswitch. Also upper limit for the point estimate constraint.
Defaults to 1.25 if not given explicitly.
CV Intra-subject coefficient(s) of variation as ratio (not percent).
• If given as a scalar (length(CV)==1) the same CV of Test and Reference is
assumed (homoscedasticity, CVwT==CVwR).
• If given as a vector (length(CV)==2), i.e., assuming heteroscedasticity, the
CV of the Test must be given in CV[1] and the one of the Reference in the
CV[2].
design Design of the study to be planned.
"2x3x3" is the partial replicate design.
"2x2x4" is a full replicate design with 2 sequences and 4 periods.
"2x2x3" is a full replicate design with 2 sequences and 3 periods.
Defaults to design="2x3x3". Details are given the section about Designs.
regulator Regulatory body settings for the scaled ABE criterion.
Defaults to design="FDA".
Also the scaled ABE criterion is usually calculated with the FDA constant
r_const=log(1.25)/0.25 you can override this behavior to use the EMA set-
ting r_const=0.76 to avoid the discontinuity at CV=30% and be more stringent.
nsims Number of simulations to be performed to obtain the (empirical) power.
nstart Set this to a start for the sample size search if a previous run failed.
After reworking the start n in version 1.1-05 rarely needed.
imax Maximum number of steps in sample size search. Defaults to 100.
print If TRUE (default) the function prints its results. If FALSE only the result data.frame
will be returned.
details If set to TRUE, the default, the steps during sample size search are shown.
setseed Simulations are dependent on the starting point of the (pseudo) random number
generator. To avoid differences in power for different runs a set.seed(123456)
is issued if setseed=TRUE, the default.

Details
The linearized scaled ABE criterion is calculated according to the SAS code given in the FDA pro-
gesterone guidance.

The simulations are done via the distributional properties of the statistical quantities necessary for
deciding BE based on scaled ABE.
For more details see a document Implementation_scaledABE_simsVx.yy.pdf in the /doc sub-directory
of the package.

If a CVcap is defined for the regulator, the BE decision is based on the inclusion of the CI in
sampleN.RSABE 105

the capped widened acceptance limits in case of CVwR > CVcap. This resembles method ‘Howe-
EMA’ in Muñoz et al. and is the standard behavior now if regulator="EMA" is choosen.

The estimated sample size gives always the total number of subjects (not subject/sequence – like in
some other software packages).

Value
Returns a data.frame with the input and sample size results.
The Sample size column contains the total sample size.
The nlast column contains the last n value. May be useful for restarting.

Designs
Although some designs are more ‘popular’ than others, sample size estimations are valid for all of
the following designs:

"2x2x4" TRTR | RTRT

Warning
The sample size estimation for theta0 >1.2 and <0.85 may be very time consuming and will eventu-
ally also fail since the start values chosen are not really reasonable in that ranges. This is especially
true in the range about CV = 0.3 and regulatory constant according to FDA.
If you really need sample sizes in that range be prepared to restart the sample size estimation via
the argument nstart.
Since the dependence of power from n is very flat in the mentioned region you may also consider
to adapt the number of simulations not to tap in the simulation error trap.

Note
The sample size estimation is done only for balanced designs since the break down of the total
subject number in case of unbalanced sequence groups is not unique. Moreover the formulas used
are only for balanced designs.
The minimum sample size is n=6, even if the power is higher than the intended targetpower.

Author(s)
D. Labes

References
Food and Drug Administration, Office of Generic Drugs (OGD). Draft Guidance on Progesterone.
Recommended Apr 2010. Revised Feb 2011. download
106 sampleN.RSABE2L.sdsims

Tóthfalusi, L, Endrényi, L. Sample Sizes for Designing Bioequivalence Studies for Highly Variable
Drugs. J Pharm Pharmaceut Sci. 2011;15(1):73–84. open access
Tóthfalusi L, Endrényi L, García Arieta A. Evaluation of Bioequivalence for Highly Variable Drugs
with Scaled Average Bioequivalence. Clin Pharmacokin. 2009;48(11):725–43. doi: 10.2165/
1131804000000000000000
Muñoz J, Alcaide D, Ocaña J. Consumer’s risk in the EMA and FDA regulatory approaches for
bioequivalence in highly variable drugs. Stat Med. 2015;35(12):1933–43. doi: 10.1002/sim.6834

See Also

power.RSABE, power.scABEL

Examples
# using all the defaults:
# design=2x3x3 (partial replicate design), theta0=0.90,
# ABE limits, PE constraint 0.8 - 1.25
# targetpower=80%, alpha=0.05, 1E5 simulations
sampleN.RSABE(CV = 0.3)
# should result in a sample size n=45, power=0.80344

sampleN.RSABE2L.sdsims
Sample size estimation for BE Decision via Reference Scaled ABE

Description

These functions performs the sample size estimation of the BE decision via the reference scaled
ABE based on subject data simulations. Implemented are the methods ABEL, Hyslop and ‘exact’
(see the References in power.RSABE2L.sdsims).
The estimation method of the key statistics needed to perform the RSABE decision is the usual
ANOVA .
This function has an alias sampleN.RSABE2L.sds().

Usage

sampleN.RSABE2L.sdsims(alpha = 0.05, targetpower = 0.8, theta0,

theta1, theta2, CV,
design = c("2x3x3", "2x2x4", "2x2x3"),
SABE_test = "exact", regulator, nsims=1e5,
nstart, imax = 100, print = TRUE,
details = TRUE, setseed = TRUE, progress)
sampleN.RSABE2L.sdsims 107

Arguments
alpha Type I error probability. Per convention mostly set to 0.05.
targetpower Power to achieve at least. Must be >0 and <1.
Typical values are 0.8 or 0.9.
theta0 ‘True’ or assumed T/R ratio.
Defaults to 0.90 according to the two Lászlós if not given explicitly.
theta1 Conventional lower ABE limit to be applied in the mixed procedure if CVsWR <=
CVswitch.
Also Lower limit for the point estimate constraint.
Defaults to 0.8 if not given explicitly.
theta2 Conventional upper ABE limit to be applied in the mixed procedure if CVsWR <=
CVswitch. Also upper limit for the point estimate constraint.
Defaults to 1.25 if not given explicitly.
CV Intra-subject coefficient(s) of variation as ratio (not percent).
• If given as a scalar (length(CV)==1) the same CV of Test and Reference is
assumed (homoscedasticity, CVwT==CVwR).
• If given as a vector (length(CV)==2), i.e., assuming heteroscedasticity, the
CV of the Test must be given in CV[1] and the one of the Reference in the
CV[2].
design Design of the study to be planned.
"2x3x3" is the partial replicate design.
"2x2x4" is a full replicate design with 2 sequences and 4 periods.
"2x2x3" is a full replicate design with 2 sequences and 3 periods.
Defaults to design="2x3x3". Details are given the section about Designs.
SABE_test This argument specifies the test method to be used for the reference scaled ABE
decision.
Default is the "exact" ‘ncTOST’ method of the two Laszlós. Other choices are
"ABEL", "Hyslop" and "FDA". See Details.
This argument may be given also in lower case.
regulator Regulatory settings for the widening of the BE acceptance limits.
May be given as character "EMA" or as an object of class ’regSet’ (see reg_const).
Defaults to regulator="EMA" if missing.
This argument may be given also in lower case if given as character.
If given as object of class ’regSet’ the component est_method can not be "ISC".
nsims Number of simulations to be performed to obtain the (empirical) power. The
default value 100,000 = 1e+5 is usually sufficient. Consider to rise this value if
theta0<=0.85 or >=1.25. But see the warning section.
nstart Set this to a start for the sample size search if a previous run failed.
After reworking the start n in version 1.1-05 rarely needed.
imax Maximum number of steps in sample size search. Defaults to 100.
print If TRUE (default) the function prints its results. If FALSE only the result
data.frame will be returned.
details If set to TRUE (default), the steps during sample size search are shown.
108 sampleN.RSABE2L.sdsims

Details
The methods rely on the analysis of log-transformed data, i.e., assume a log-normal distribution on
the original scale.

The widened BE acceptance limits will be calculated by the formula

The estimated sample size gives always the total number of subjects (not subject/sequence – like in
some other software packages).

Designs
Although some designs are more ‘popular’ than others, sample size estimations are valid for all of
the following designs:

"2x2x4" TRTR | RTRT

the argument nstart.

Since the dependence of power from n is very flat in the mentioned region you may also consider
to adapt the number of simulations not to tap in the simulation error trap.

Note

We are doing the sample size estimation only for balanced designs since the break down of the total
subject number in case of unbalanced sequence groups is not unique. Moreover the formulas used
are only for balanced designs.
The minimum sample size is 6, even if the power is higher than the intended targetpower.

Subject simulations are relatively slow. Thus be patient and go for a cup of coffee if you use
this function with high sample sizes!

Author(s)

H. Schütz

See Also

power.RSABE2L.sdsims, sampleN.scABEL, reg_const

Examples

# using the defaults:

# partial replicate design, targetpower=80%,
# true assumed ratio = 0.90, 1E+5 simulated studies
# ABE limits, PE constraint 0.8 - 1.25
# EMA regulatory settings
# compare results

CV <- 0.4
method <- c("exact", "abel", "hyslop", "fda")
res <- data.frame(SABE_test = c("ncTOST", "ABEL",
"Hyslop", "FDA"),
n = NA, power = NA)
for (i in 1:nrow(res)) {
res[i, 2:3] <- sampleN.RSABE2L.sdsims(CV = CV,
SABE_test = method[i],
details = FALSE,
print = FALSE)[8:9]
}
print(res, digits = 4, row.names = FALSE)
# should result in a sample size n=48 with all methods,
# power=0.8197 (ncTOST), 0.8411 (ABEL), 0.8089 (Hyslop), 0.8113 (FDA)
110 sampleN.scABEL

sampleN.scABEL Sample size estimation for BE decision via scaled (expanded) BE ac-
ceptance limits

Description
This function performs the sample size estimation via power calculations of the BE decision via
scaled (expanded) BE acceptance limits, based on simulations.

Usage
sampleN.scABEL(alpha = 0.05, targetpower = 0.8, theta0, theta1, theta2, CV,
design = c("2x3x3", "2x2x4", "2x2x3"), regulator,
nsims = 1e+05, nstart, imax = 100, print = TRUE, details = TRUE,
setseed = TRUE)

Defaults to regulator="EMA" if missing.

This argument may be given also in lower case if given as character.

nsims Number of simulations to be performed to obtain the (empirical) power. The

default value 100,000 = 1e+5 is usually sufficient. Consider to rise this value if
theta0 <=0.85 or >=1.20. But see the warning section.
nstart Set this to a start for the sample size search if a previous run failed.
After reworking the start n in version 1.1-05 rarely needed.
imax Maximum number of steps in sample size search. Defaults to 100.
print If TRUE (default) the function prints its results. If FALSE only the result
data.frame will be returned.
details If set to TRUE (default), the steps during sample size search are shown.
setseed Simulations are dependent on the starting point of the (pseudo) random number
generator. To avoid differences in power for different runs a set.seed(123456)
is issued if setseed=TRUE, the default.

Details
The simulations are done via the distributional properties of the statistical quantities necessary for
deciding BE based on ABEL (‘Average Bioequivalence with Expanded Limits’). For more details
see a description in the /doc sub-directory of the package.

Function sampleN.scABEL() is based on power calculations via simulations using the distribu-
tional characteristics of the ‘key’ statistics obtained from the EMA recommended evaluation via
ANOVA if regulator="EMA" or if the regulator component est_method is set to "ANOVA" if regu-
lator is an object of class ’regSet’.
Otherwise, the simulations are based on the distributional characteristis of the ‘key’ statistics ob-
tained from evaluation via intra-subject contrasts (ISC), as recommended by the FDA.

The estimated sample size gives always the total number of subjects (not subject/sequence – like in
some other software packages).

Function sampleN.scABEL2() is solely based on power calculations via simulation using the dis-
tributional characteristics of the ‘key’ statistics obtained from evaluation via intra-subject contrasts
(ISC). This function is deprecated.

Designs
Although some designs are more ‘popular’ than others, sample size estimations are valid for all of
the following designs:
112 sampleN.scABEL

"2x2x4" TRTR | RTRT

Warning
The sample size estimation for extreme theta0 (<0.83 or >1.21) may be very time consuming and
will eventually also fail since the start values chosen are not really reasonable in that ranges. This
is especially true in the range around CV = 0.3 and regulatory constant according to FDA.
If you really need sample sizes in that range be prepared to restart the sample size estimation via
the argument nstart.
Since the dependence of power from n is very flat in the mentioned region you may also consider
to adapt the number of simulations not to get caught in the simulation error trap.

If results of power.scABEL are expected to be inaccurate (partial replicate design with unbalanced
sequences and/or heteroscedasticity in the case of CVwT > CVwR , subject data via sampleN.scABEL.sdsims
should be simulated instead. Very time consuming (easily 100times slower)! Subject data simula-
tions are only supported for regulator="EMA" and regulator="GCC".

In case of regulator="FDA" the sample size is only approximate since the BE decision method
is not exactly what is expected by the FDA. But the two Lászlós state that the scABEL method
should be ‘operationally’ equivalent to the FDA method. Thus the sample size should be compara-
ble.
Consider in case of regulator="FDA" to use the function sampleN.RSABE() instead.

In case of regulator="HC" the underlying power is only approximative since the Health Canada
recommends evaluation by a mixed model approach. But this could only implemented via subject
data simulations which are very time consuming.

The minimum sample size is 6, even if the power is higher than the intended targetpower.

Author(s)
D. Labes

References
Tóthfalusi L, Endrényi L. Sample Sizes for Designing Bioequivalence Studies for Highly Variable
Drugs. J Pharm Pharmaceut Sci. 2011;15(1):73–84. open access
sampleN.scABEL.ad 113

See Also
power.scABEL, sampleN.scABEL.sdsims, sampleN.RSABE, reg_const

Examples
# using all the defaults:
# partial replicate design, targetpower=80%,
# true assumed ratio = 0.90, 1E+5 simulated studies
# ABE limits, PE constraint 0.8 - 1.25
# EMA regulatory settings
sampleN.scABEL(CV = 0.3)
# should result in a sample size n=54, power=0.8159

# Now with former (inofficial) ANVISA settings, CVswitch=40%

# (since 2016 ANVISA uses the same settings as EMA)
reg <- reg_const("USER", r_const = 0.76, CVswitch = 0.4, CVcap = 0.5)
reg$name <- "Old ANVISA"
sampleN.scABEL(CV = 0.3, regulator = reg)
# should result in a sample size n=60, power=0.8101

# For the full replicate design, target power = 90%

# true assumed ratio = 0.9, FDA regulatory settings
# sims based on evalaution via ISC
sampleN.scABEL(CV = 0.4, targetpower = 0.9, design = "2x2x4",
regulator = "FDA")
# should result in a sample size n=32, power=0.9125

# Fixed wider limits (0.7500 - 1.3333) for the GCC

sampleN.scABEL(CV = 0.4, targetpower = 0.9, design = "2x2x4",
regulator = "GCC")
# should result in a sample size n=40, power=0.9039

sampleN.scABEL.ad Sample size estimation for ABEL and iteratively adjusted alpha

Description
This function performs a sample size estimation for the BE decision via Average Bioequivalenc
with Expanding Limits (ABEL) based on simulations. Simultaneously alpha is iteratively adjusted
in order to maintain the consumer risk at the nominal level.

Usage
sampleN.scABEL.ad(alpha = 0.05, targetpower = 0.8, theta0, theta1, theta2,
CV, design = c("2x3x3", "2x2x4", "2x2x3"), regulator,
nstart = NA, nsims = 1e+06, imax = 100, tol, print = TRUE,
details = FALSE, alpha.pre = 0.05, setseed = TRUE,
sdsims = FALSE, progress)
114 sampleN.scABEL.ad

Arguments
alpha Type I error (TIE) probability (nominal level of the test). Per convention com-
monly set to 0.05.
targetpower Power to achieve at least. Must be >0 and <1. Typical values are 0.80 to 0.90
(i.e., 80% to 90%). Defaults to 0.80 if not given explicitly.
theta0 ‘True’ or assumed T/R ratio. Defaults to 0.90 according to the two Lászlós if
not given explicitly.
theta1 Conventional lower ABE limit to be applied in the mixed procedure if CVwR==CVswitch.
Also lower limit for the point estimate constraint. Defaults to 0.80 if not given
explicitly.
theta2 Conventional upper ABE limit to be applied in the mixed procedure if CVwR==CVswitch.
Also upper limit for the point estimate constraint. Defaults to 1.25 if not given
explicitly.
CV Intra-subject coefficient(s) of variation as ratio (not percent).
• If given as a scalar (length(CV)==1) the same CV of Test and Reference
is assumed (homoscedasticity: CVwT = CVwR ).
• If given as a vector (length(CV)==2) – assuming heteroscedasticity –
the CV of Test must be given in the first element and the one of Reference
in the second.
design Design of the study to be planned.
"2x3x3" is the partial replicate design.
"2x2x4" is a full replicate design with 2 sequences and 4 periods.
"2x2x3" is a full replicate design with 2 sequences and 3 periods.
Defaults to "2x3x3". Details are given the section about Designs.
regulator Regulatory settings for the widening of the BE acceptance limits. Choose from
"EMA" (default), "HC", or "GCC". This argument may be given also in lower case.
nstart Best “guess” sample size. If not given (default), simulations start with the sam-
ple size estimated for alpha (or alpha.pre, if given), theta0, and targetpower.
Can also be set to start the sample size search if a previous run failed.
According to regulatory requirements must be >=12 for the EMA and >=24 for
ANVISA .

nsims Number of simulations to be performed to estimate the (empirical) TIE and in

each iteration of adjusting alpha. The default value 1,000,000 = 1E+6 should
not be lowered.
imax Maximum number of steps in sample size search. Defaults to 100.
tol Desired accuracy (convergence tolerance). Defaults to 1E-6.
print If TRUE (default), the function sends its results to the console.
details If TRUE (default), the steps during sample size search are shown. Additionally
information about the impact on power by adjusting alpha and change of study
costs due to the increased sample size is given.
alpha.pre Pre-specified alpha (optional). Must be <=alpha. ABEL will be performed at
level alpha.pre and the TIE assessed at level alpha.
Less powerful than adjusting alpha but an alternative in the critical region of
sampleN.scABEL.ad 115

maximum inflation of the TIE. In certain scenarios Bonferroni’s 0.025 is not

sufficient to preserve the Type I Error.
Not recommended if CVwR ≥ 0.45 due to poor power characteristics.
setseed Simulations are dependent on the starting point of the (pseudo) random number
generator. To avoid differences in power for different runs set.seed(123456)
is issued if setseed=TRUE (default).
sdsims If FALSE (default) power is estimated by the respective ‘key’ statistics. Recom-
mended for speed reasons.
Set to TRUE if results of power.scABEL are expected to be inaccurate (par-
tial replicate design with unbalanced sequences and/or heteroscedasticity where
CVwT > CVwR ) and subject data via power.scABEL.sdsims should be sim-
ulated instead. Very time consuming (easily 100times slower)! Subject data
simulations are only supported for regulator="EMA" and regulator="GCC".
progress Set to TRUE if a progress bar should be displayed. Defaults to FALSE.
Ignored if sdsims=FALSE.

Details
The simulations are done via the distributional properties of the statistical quantities necessary for
assessing BE based on ABEL. Simulations of the TIE are performed at the upper (expanded) limit U
of the acceptance range. Due to the symmetry around 1 results are valid for the lower (expanded)
limit L as well.
U at the EMA’s and Health Canada’s CVcap, the GCC’s for any CVwR > 0.30:

scABEL(CV=0.5, reg="EMA")[["upper"]]
[1] 1.43191
scABEL(CV=0.57382, reg="HC")[["upper"]]
[1] 1.5
scABEL(CV=0.31, reg="GCC")[["upper"]]
[1] 1.333333

Simulated studies are evaluated by ANOVA (Method A) as recommended in the EMA’s Q&A-
document and by intra-subject contrasts if regulator="HC". Health Canada requires a mixed ef-
fects model which cannot be implemented in R. However, intra-subjects contrasts are a sufficiently
close approximation.

If an inflation of the TIE is expected (i.e., >alpha), alpha is iteratively adjusted until at least the
target power is reached and the consumer risk is maintained (<=alpha). For details about the algo-
rithm see the respective section of scABEL.ad.

The estimated sample size gives always the total number of subjects (not subject/sequence – like in
some other software packages).

Value
Returns a data.frame with the input and results for adjusted alpha, type I error, sample size, and
achieved power.
The Sample size column contains the total sample size. If no adjustment is necessary, NA will be re-
turned in the alpha.adj column and other results are identical to the ones obtained by sampleN.scABEL.
116 sampleN.scABEL.ad

Designs
Although some designs are more ‘popular’ than others, sample size estimations are valid for all of
the following designs:

"2x2x4" TRTR | RTRT

Warning

The sample size estimation for extreme theta0 (<0.83 or >1.21) may be time consuming and will
eventually also fail since the start values chosen are not really reasonable in that ranges.
If you really need sample sizes in that range be prepared to restart the sample size estimation with
nstart above the last one before failure.
Since the dependence of power from n is very flat in the mentioned region you may also consider
to adapt the number of simulations not to tap in the simulation error trap.

See also the Warning section of the function power.scABEL concerning the power value agree-
ment to those obtained from simulations via subject data.

For the GCC and CVwR ≤ 0.30

Note

We are doing the sample size estimation only for balanced designs since the break down of the total
subject number in case of unbalanced sequences is not unique. Moreover the formulas used are
only for balanced designs.

Author(s)

H. Schütz

References

Tóthfalusi L, Endrényi L. Sample Sizes for Designing Bioequivalence Studies for Highly Variable
Drugs. J Pharm Pharmaceut Sci. 2011;15(1):73–84. open access
Wonnemann M, Frömke C, Koch A. Inflation of the Type I Error: Investigations on Regulatory
Recommendations for Bioequivalence of Highly Variable Drugs. Pharm Res. 2015;32(1):135–43.
doi: 10.1007/s110950141450z
Muñoz J, Alcaide D, Ocaña J. Consumer’s risk in the EMA and FDA regulatory approaches for
bioequivalence in highly variable drugs. Stat Med. 2015;35(12):1933–43. doi: 10.1002/sim.6834
Labes D, Schütz H. Inflation of Type I Error in the Evaluation of Scaled Average Bioequivalence,
and a Method for its Control. Pharm Res. 2016;33(11):2805–14. doi: 10.1007/s1109501620061
sampleN.scABEL.sdsims 117

See Also
scABEL.ad, sampleN.scABEL, power.scABEL, scABEL

Examples
# --- Not run due to timing policy of CRAN for examples
# each may run some ten seconds or more
# using all the defaults:
# TRR|RTR|RRT, target power 80%, assumed ratio 0.90, 1E+6 simulated studies,
# EMA regulatory settings (ABE limits, PE constraint 0.8 - 1.25)

sampleN.scABEL.ad(CV = 0.3)
# should result in n 60, power 0.8022.
# Note: Without adjustment by sampleN.scABEL(): n 54, power 0.8159
# Easier to show the details:

sampleN.scABEL.ad(CV = 0.3, details = TRUE)

#
# TRTR|RTRT, target power 90%, pre-specified alpha 0.025

sampleN.scABEL.ad(CV = 0.3, targetpower = 0.9, design = "2x2x4", alpha.pre = 0.025)

# should result in n 60, power 0.9021; pre-specified alpha justified.

sampleN.scABEL.sdsims Sample size estimation for BE decision via scaled (expanded) BE ac-
ceptance limits

Description
These functions performs the sample size estimation via power calculations of the BE decision via
scaled (expanded) BE acceptance limits, based on subject data simulations.
This function has an alias sampleN.scABEL.sds().

Usage
sampleN.scABEL.sdsims(alpha = 0.05, targetpower = 0.8, theta0, theta1, theta2, CV,
design = c("2x3x3", "2x2x4", "2x2x3"), regulator, nsims = 1e5,
nstart, imax = 100, print = TRUE, details = TRUE,
setseed = TRUE, progress)

theta1 Conventional lower ABE limit to be applied in the mixed procedure if CVsWR <=
CVswitch.
Also Lower limit for the point estimate constraint.
Defaults to 0.8 if not given explicitly.
theta2 Conventional upper ABE limit to be applied in the mixed procedure if CVsWR <=
CVswitch. Also upper limit for the point estimate constraint.
Defaults to 1.25 if not given explicitly.
CV Intra-subject coefficient(s) of variation as ratio (not percent).
• If given as a scalar (length(CV)==1) the same CV of Test and Reference
is assumed (homoscedasticity, CVwT = CVwR ).
• If given as a vector (length(CV)==2), i.e., assuming heteroscedasticity, the
CV of the Test must be given in CV[1] and the one of the Reference in the
CV[2].
design Design of the study to be planned.
"2x3x3" is the partial replicate design.
"2x2x4" is a full replicate design with 2 sequences and 4 periods.
"2x2x3" is a full replicate design with 2 sequences and 3 periods.
Defaults to design="2x3x3". Details are given the section about Designs.
regulator Regulatory settings for the widening of the BE acceptance limits.
May be given as "EMA", "GCC", or as an object of class ’regSet’ (see reg_const).
Defaults to regulator="EMA" if missing.
This argument may be given also in lower case if given as character.
If given as object of class ’regSet’ the component est_method must not be
"ISC".
nsims Number of simulations to be performed to obtain the (empirical) power. The
default value 100,000 = 1e+5 is usually sufficient. Consider to rise this value if
theta0 <=0.85 or >=1.20. But see the warning section.
nstart Set this to a start for the sample size search if a previous run failed.
After reworking the start n in version 1.1-05 rarely needed.
imax Maximum number of steps in sample size search. Defaults to 100.
print If TRUE (default) the function prints its results. If FALSE only the result
data.frame will be returned.
details If set to TRUE (default), the steps during sample size search are shown.
setseed Simulations are dependent on the starting point of the (pseudo) random number
generator. To avoid differences in power for different runs a set.seed(123456)
is issued if setseed=TRUE, the default.
progress Should a progressbar be shown? Defaults to TRUE if missing and nsims >5E5.

Details
The methods rely on the analysis of log-transformed data, i.e., assume a log-normal distribution on
the original scale.

The expanded BE acceptance limits will be calculated by the formula

[L, U] = exp(± r_const * sWR)
sampleN.scABEL.sdsims 119

with r_const the regulatory constant and sWR the standard deviation of the within subjects variabil-
ity of the Reference. r_const = 0.76 (~log(1.25)/0.29356) is used in case of regulator="EMA". If
the CVwR is < CVswitch=0.3 the conventional ABE limits apply (mixed procedure).
In case of regulator="EMA" a cap is placed on the widened limits if CVwR > 0.50, i.e., the
widened limits are held at value calculated for CVwR = 0.50.
In case of regulator="GCC" fixed wider limits of 0.7500 – 1.3333 for CVwR > 0.30 are applied
and the conventional limits otherwise.

The estimated sample size gives always the total number of subjects (not subject/sequence – like in
some other software packages).

Designs
Although some designs are more ‘popular’ than others, sample size estimations are valid for all of
the following designs:

"2x2x4" TRTR | RTRT

Warning
The sample size estimation for very extreme theta0 (<0.83 or >1.21) may be very time consuming
and will eventually also fail since the start values chosen are not really reasonable in that ranges.
If you really need sample sizes in that range be prepared to restart the sample size estimation via
the argument nstart.
Since the dependence of power from n is very flat in the mentioned region you may also consider
to adapt the number of simulations not to get caught in the simulation error trap.

Note
We are doing the sample size estimation only for balanced designs since the break down of the total
subject number in case of unbalanced sequence groups is not unique. Moreover the formulas used
are only for balanced designs.
The minimum sample size is 6, even if the power is higher than the intended targetpower.
120 sampleN.TOST

Subject simulations are easily more than 100times slower than simulations based on the ‘key’ statis-
tics. We recommend this function only for the partial replicate design (TRR|RTR|RRT) assuming
heteroscedasticity in the case of CVwT > CVwR .
Thus be patient and go for a cup of coffee if you use this function with high sample sizes!

Author(s)
H. Schütz

References
Tóthfalusi L, Endrényi L. Sample Sizes for Designing Bioequivalence Studies for Highly Variable
Drugs. J Pharm Pharmaceut Sci. 2011;15(1):73–84. open access

See Also
power.scABEL.sdsims, sampleN.scABEL, reg_const

Examples
# using the defaults:
# partial replicate design, targetpower=80%,
# true assumed ratio = 0.90, 1E+5 simulated studies
# ABE limits, PE constraint 0.8 - 1.25
# EMA regulatory settings
# Heteroscedasticity (CVwT 0.4, CVwR 0.3)
# compare results and run times

CV <- c(0.4, 0.3)

expl <- data.frame(method = c("subject simulations", "\'key\' statistics"),
n = NA, power = NA, seconds = NA)
start <- proc.time()[[3]]
expl[1, 2:3] <- sampleN.scABEL.sdsims(CV = CV, print = FALSE,
details = FALSE)[8:9]
expl[1, 4] <- proc.time()[[3]] - start
start <- proc.time()[[3]]
expl[2, 2:3] <- sampleN.scABEL(CV = CV, print = FALSE,
details = FALSE)[8:9]
expl[2, 4] <- proc.time()[[3]] - start
print(expl, row.names = FALSE)
# should result in a sample size n=69, power=0.80198 for
# the subject simulations and n=66, power=0.80775 for the
# 'key' statistics

sampleN.TOST Sample size based on power of TOST

Description
Estimates the necessary sample size to have at least a given power.
sampleN.TOST 121

Usage

sampleN.TOST(alpha = 0.05, targetpower = 0.8, logscale = TRUE,

theta0, theta1, theta2, CV, design = "2x2", method="exact",
robust=FALSE, print = TRUE, details = FALSE, imax=100)

Arguments

alpha Significance level (one-sided). Commonly set to 0.05.

targetpower Power to achieve at least. Must be >0 and <1.
Typical values are 0.8 or 0.9.
logscale Should the data used on log-transformed (TRUE) or on original scale (FALSE)?
Defaults to TRUE.
theta0 ‘True’ or assumed T/R ratio or difference.
In case of logscale=TRUE it must be given as ratio T/R.
If logscale=FALSE, the difference in means. In this case, the difference may be
expressed in two ways: relative to the same (underlying) reference mean, i.e. as
(T-R)/R = T/R - 1; or as difference in means T-R. Note that in the former case
the units of CV, theta1 and theta2 need also be given relative to the reference
mean (specified as ratio).
Defaults to 0.95 if logscale=TRUE or to 0.05 if logscale=FALSE
theta1 Lower (bio-)equivalence limit.
In case of logscale=TRUE it is given as ratio.
If logscale=FALSE, the limit may be expressed in two ways: difference of
means relative to the same (underlying) reference mean or in units of the dif-
ference of means. Note that in the former case the units of CV, theta0 and
theta2 need also be given relative to the reference mean (specified as ratio).
Defaults to 0.8 if logscale=TRUE or to -0.2 if logscale=FALSE.
theta2 Upper (bio-)equivalence limit.
In case of logscale=TRUE it is given as ratio. If logscale=FALSE, the limit may
be expressed in two ways: difference of means relative to the same (underlying)
reference mean or in units of the difference of means. Note that in the former
case the units of CV, theta0 and theta1 need also be given relative to the refer-
ence mean (specified as ratio).
If not given, theta2 will be calculated as 1/theta1 if logscale=TRUE or as
-theta1 if logscale=FALSE.
CV In case of logscale=TRUE the (geometric) coefficient of variation given as ratio.
If logscale=FALSE the argument refers to (residual) standard deviation of the
response. In this case, standard deviation may be expressed two ways: relative
to a reference mean (specified as ratio sigma/muR), i.e. again as a coefficient of
variation; or untransformed, i.e. as standard deviation of the response. Note that
in the former case the units of theta0, theta1 and theta2 need also be given
relative to the reference mean (specified as ratio).

In case of cross-over studies this is the within-subject CV, in case of a parallel-

group design the CV of the total variability.
122 sampleN.TOST

design Character string describing the study design.

See known.designs() for designs covered in this package.
method Method for calculation of the power.
Defaults to "exact" in which case the calculation is done based on formu-
las with Owen’s Q. The calculation via Owen’s Q can also be choosen with
method="owenq".
Another exact method via direct use of the bivariate non-central t-distribution
may be chosen with method="mvt". This may have somewhat lower precision
compared to Owen’s Q and has a much longer run-time.
Approximate calculations can be choosen via method="noncentral" or method="nct"
for the approximation using the non-central t-distribution. With method="central"
or method="shifted" the relatively crude approximation via the ‘shifted’ central
t-distribution is chosen.
The strings for method may be abbreviated.
robust Defaults to FALSE. With that value the usual degrees of freedom will be used.
Set to TRUE will use the degrees of freedom according to the ‘robust’ evaluation
(aka Senn’s basic estimator). These df are calculated as n-seq.
See known.designs()$df2 for designs covered in this package.
Has only effect for higher-order crossover designs.
print If TRUE (default) the function prints its results. If FALSE only the data.frame with
the results will be returned.
details If TRUE the design characteristics and the steps during sample size calculations
will be shown. Defaults to FALSE.
imax Maximum number of steps in sample size search.
Defaults to 100. Adaption only in rare cases needed.

Details

The sample size is estimated via iterative evaluation of power of the TOST procedure.
Start value for the sample size search is taken from a large sample approximation according to
Zhang, modified.
The sample size is bound to 4 as minimum.

The estimated sample size gives always the total number of subjects (not subject/sequence in
crossovers or subjects/group in parallel designs – like in some other software packages).

Value

A data.frame with the input and results will be returned.

The Sample size column contains the total sample size.

Warning

The function does not vectorize properly.

If you need sample sizes with varying CVs, use f.i. for-loops or the apply-family.
sampleN.TOST 123

Note
Of course it is highly recommended to use the default method="exact". :-)
There is no reason besides testing and for comparative purposes to use an approximation if the exact
method is available at no extra costs.

Author(s)
D. Labes

References
Phillips KF. Power of the Two One-Sided Tests Procedure in Bioequivalence. J Pharmacokin Bio-
pharm. 1990;18:137–44. doi: 10.1007/BF01063556
Diletti D, Hauschke D, Steinijans VW. Sample Size Determination for Bioequivalence Assessment
by Means of Confidence Intervals. Int J Clin Pharmacol Ther Toxicol. 1991;29(1):1–8.

Diletti D, Hauschke D, Steinijans VW. Sample size determination: Extended tables for the multi-
plicative model and bioequivalence ranges of 0.9 to 1.11 and 0.7 to 1.43. Int J Clin Pharmacol Ther
Toxicol. 1992;30(Suppl 1):S59–62.
Zhang P. A Simple Formula for Sample Size Calculation in Equivalence Studies. J Biopharm Stat.
2003;13(3):529–538. doi: 10.1081/BIP120022772

# Exact calculation for a parallel group design

# evaluation on the original (untransformed) scale
# BE limits 80 ... 120% = -20% ... +20% of reference,
# assumed true BE ratio 0.95% = -5% to reference mean,
# total CV=20%
# should give n=48 (total) power=0.815435
sampleN.TOST(logscale = FALSE, theta1 = -0.2, theta0 = -0.05,
CV = 0.2, design = "parallel")

# A rather strange setting of theta0! Have a look at n.

# It would be better this is not the sample size but the running total
# of my bank account. But the first million is the hardest. ;-)
sampleN.TOST(CV = 0.2, theta0 = 0.8005, theta1 = 0.8)
124 scABEL

scABEL Scaled (widened) BE Acceptance Limits

Description
The (widened) scaled BE acceptance limits are calculated according to the regulatory settings of
EMA, HC, FDA or via user defined regulatory settings.

Usage
scABEL(CV, regulator)

Arguments
CV Coefficient of variation (of the Reference) as ratio.
regulator Regulatory body settings for the widening of the BE acceptance limits.
May be given as character from the choices "EMA", "HC" (Health Canada),
"GCC" (Gulf Cooperation Council), "FDA" or as an object of class ’regSet’ (see
reg_const).
Defaults to regulator="EMA" if missing.
The former regulator="ANVISA" is no longer allowed. The ANVISA recom-
mends since 2016 the EMA’s regulatory settings.
The former regulator="USER" is no longer accepted but can be handled now
via function reg_const() to define an object with class ’regSet’.

Details
The widened BE acceptance limits are calculated by the formula
[L, U] = exp(-/+ r_const * sWR)
with r_const the regulatory constant and sWR the standard deviation of the within subjects variabil-
ity of the Reference.

• regulator="EMA" or regulator="HC"
r_const = 0.76 (~ log(1.25)/sqrt(log(0.30^2+1)))
• regulator="GCC"
r_const = 0.97997... (= log(1/0.75)/sqrt(log(0.30^2+1)))
• regulator="FDA"
r_const = 0.89257... (= log(1.25)/0.25)
If the CVwR of the Reference is < CVswitch=0.3 the conventional ABE limits apply (mixed proce-
dure).

In case of regulator="EMA" a cap is placed on the widened limits if CVwR>0.5, i.e., the widened
limits are held at the value calculated for CVwR=0.5.
In case of regulator="HC" the capping is done such that the acceptance limits are 0.6666 . . . 1.5 at
maximum, i.e., CVcap=0.57382. Literally it is given by Health Canada rounded to three significant
digits as 57.4%.
scABEL 125

Value
Returns a vector of lenghth 2 if one CV is given or a matrix if CV is given as vector with named
components lower and upper of the scaled acceptance limits.

Note
The scaled acceptance limits (coined ‘implied limits’ by Davit et al.) are not directly used in the
BE evaluation for HVDP(s) recommended by the FDA. They are included here for comparative
purposes. Moreover, there are controversies where to locate the ‘implied limits’ and whether the
so-called ‘desired consumer-risk model’ should be used.

Author(s)
D. Labes

References
Davit BM, Chen ML, Conner DP, Haidar SH, Kim S, Lee CH, Lionberger RA, Makhlouf FT,
Nwakama PE, Patel DT, Schuirmann DJ, Yu LX. Implementation of a Reference-Scaled Average
Bioequivalence Approach for Highly Variable Generic Drug Products by the US Food and Drug
Administration. AAPS J. 2012;14(4):915–24. doi: 10.1208/s122480129406x
Health Canada, Therapeutic Products Directorate. Guidance Document. Comparative Bioavailabil-
ity Standards: Formulations Used for Systemic Effects. 2018/06/08. ISBN: 978-0-660-25514-9

See Also
power.scABEL,sampleN.scABEL,reg_const

Examples
scABEL(CV = 0.3, regulator = "EMA")
# should give the conventional (unscaled) BE limits:
# lower upper
# 0.80 1.25

scABEL(CV = 0.5, regulator = "EMA")

# should give the (maximum) expanded limits:
# lower upper
# 0.6983678 1.4319102

# define old ANVISA settings via reg_const()

rc <- reg_const("USER", r_const = 0.76,
CVswitch = 0.4, CVcap = 0.5)
rc$name <- "ANVISAold"
scABEL(CV = 0.4, regulator = rc)
# should give the conventional (not expanded) limits:
# lower upper
# 0.80 1.25

scABEL(CV = 0.55, regulator = "HC")

126 scABEL.ad

# should give the widened limits:

# lower upper
# 0.6765789 1.4780241

scABEL(CV = 0.55, regulator = "GCC")

# should give the widened limits:
# lower upper
# 0.750000 1.333333

scABEL(CV = 0.55, regulator = "FDA")

# should give the 'implied' limits:
# lower upper
# 0.6320032 1.5822705

scABEL.ad Iteratively adjusted alpha for ABEL

Description
This function iteratively adjusts alpha for the BE decision via Average Bioequivalence with Ex-
panding Limits (ABEL) based on simulations in order to maintain the consumer risk at the nominal
level.

Usage
scABEL.ad(alpha = 0.05, theta0, theta1, theta2, CV,
design = c("2x3x3", "2x2x4", "2x2x3"), regulator,
n, alpha.pre = 0.05, imax = 100, tol, print = TRUE,
details = FALSE, setseed = TRUE, nsims = 1e+06,
sdsims = FALSE, progress)

Arguments
alpha Type I Error (TIE) probability (nominal level of the test). Per convention com-
monly set to 0.05.
theta0 ‘True’ or assumed T/R ratio. Defaults to 0.90 according to the two Lászlós if
not given explicitly.
theta1 Conventional lower ABE limit to be applied in the mixed procedure if CVwR==CVswitch.
Also lower limit for the point estimate constraint. Defaults to 0.80 if not given
explicitly.
theta2 Conventional upper ABE limit to be applied in the mixed procedure if CVwR==CVswitch.
Also upper limit for the point estimate constraint. Defaults to 1.25 if not given
explicitly.
CV Intra-subject coefficient(s) of variation as ratio (not percent).
• If given as a scalar (length(CV)==1) the same CV of Test and Reference is
assumed (homoscedasticity, CVwT==CVwR).
scABEL.ad 127

• If given as a vector (length(CV)==2), i.e., assuming heteroscedasticity, the

CV of the Test must be given in CV[1] and the one of the Reference in the
CV[2].
design Design of the study.
"2x3x3" is the partial replicate design.
"2x2x4" is a full replicate design with 2 sequences and 4 periods.
"2x2x3" is a full replicate design with 2 sequences and 3 periods.
Defaults to "2x3x3". Details are given the section about Designs.
regulator Regulatory settings for the expanding of the BE acceptance limits. Choose from
"EMA" (default), "HC", "GCC", or "FDA". This argument may also be given in
lower case.
n Total sample size of the study or a vector of sample size / sequences. If n leads
to an unbalanced design (i.e., is not a multiple of two in the full replicate designs
or not a multiple of three in the partial replicate), the code tries to keep subjects
/ sequence as balanced as possible.
In evaluating a particular unbalanced study always give n as a vector.
Only if design="2x2x3" (TRT|RTR) the order of sample sizes is important.
n[1] is for sequence TRT and n[2] for sequence RTR.
If n is missing, a sample size is estimated with target power 0.80 and pre-
specified alpha if defined. Otherwise, alpha is used.
alpha.pre Pre-specified alpha (optional). Must be <=alpha. ABEL will be performed at
level alpha.pre and the TIE assessed at level alpha.
Less powerful than adjusting alpha but an alternative in the critical region of
maximum inflation of the TIE. In certain scenarios Bonferroni’s 0.025 is not
sufficient to preserve the Type I Error (e.g., the third example).
Not recommended if CVwR >= 0.45 due to poor power characteristics.
imax Maximum number of steps in sample size search. Defaults to 100.
tol Desired accuracy (convergence tolerance). Defaults to 1E-6.
print If TRUE (default), the function sends its results to the console.
details If TRUE, the relative change of the consumer risk in percent is shown. Addi-
tionally information about the impact on power (for specified theta0 and target
power 0.80), runtime, and number of simulations (iterations) are given. Defaults
to FALSE.
setseed Simulations are dependent on the starting point of the (pseudo) random number
generator. To avoid differences in power for different runs set.seed(123456)
is issued if setseed=TRUE (default).
nsims Number of simulations to be performed to estimate the (empirical) TIE error and
in each iteration of adjusting alpha. The default value 1,000,000 = 1E+6 should
not be lowered.
sdsims If FALSE (default) power is estimated by the respective ‘key’ statistics. Recom-
mended for speed reasons.
Set to TRUE if results of power.scABEL are expected to be inaccurate (par-
tial replicate design with unbalanced sequences and/or heteroscedasticity where
CVwT > CVwR) and subject data via power.scABEL.sdsims should be sim-
ulated instead. Very time consuming (easily 100times slower)! Subject data
simulations are only supported for regulator="EMA" and regulator="GCC".
128 scABEL.ad

progress Set to TRUE if a progress bar should be displayed. Ignored if sdsims=FALSE.

Details
The simulations are done via the distributional properties of the statistical quantities necessary for
assessing BE based on ABEL. Simulations for the TIE are performed at the upper (expanded) limit
U of the acceptance range. Due to the symmetry around 1 results are valid for the lower (expanded)
limit L as well.
U at the EMA’s and Health Canada’s CVcap, the GCC’s for any CVwR > 0.3:

scABEL(CV=0.5, reg="EMA")[["upper"]]
[1] 1.43191
scABEL(CV=0.57382, reg="HC")[["upper"]]
[1] 1.5
scABEL(CV=0.5, reg="GCC")[["upper"]]
[1] 1.333333

Simulated studies are evaluated by ANOVA (Method A) as recommended in the EMA’ Q&A-
document and by intra-subject contrasts if regulator="HC". Health Canada requires a mixed-
effects model which cannot be implemented in R. However, intra-subjects contrasts are a suffi-
ciently close approximation.
The Type I Error in ABEL depends only on CVwR and – to a minor degree – the sample size. Algo-
rithm:

1. The TIE is assessed based on alpha (or alpha.pre) and compared to the nominal level of the
test alpha.
2. If no inflation of the TIE is found, the algorithm stops.
3. Otherwise, alpha is iteratively adjusted (i.e., alpha.adj <alpha) until no more relevant infla-
tion of the TIE is detected (i.e., abs(TIE -alpha) <= tol).

Value
Sends results to the console if argument print=TRUE (default).
Returns a list with the input, adjusted alpha, and Type I Error (for nominal and adjusted alpha) if
argument print=FALSE.
If no adjustment is necessary, NAs will be returned for the respective variables (alpha.adj, TIE.adj,
rel.change, pwr.adj, rel.loss).

Designs
Although some designs are more ‘popular’ than others, power calculations are valid for all of the
following designs:

"2x2x4" TRTR | RTRT

Warning
See the Warning section of the function power.scABEL concerning the power value agreement to
the one obtained by simulations via subject data.

Note
Specifying theta0 is not necessary.
If theta0 is not given, achievable power for the common target of 0.80 (both for alpha and adjusted
alpha) will be estimated. If theta0 is specified, its value will be used; again for target power 0.80.
If you are interested in other levels of power, use sampleN.scABEL.ad.
The EMA’s method is currently recommended in other jurisdictions as well (e.g., by the WHO; in
ASEAN States, Australia, Brazil, Egypt, the Eurasian Economic Union, New Zealand, the Russian
Federation, and the East African Community).
If CVwR > 30%, fixed wider limits of 0.7500–1.3333 are recommended by the Gulf Cooperation
Council (Bahrain, Kuwait, Oman, Qatar, Saudi Arabia, United Arab Emirates).

Author(s)
H. Schütz

References
Wonnemann M, Frömke C, Koch A. Inflation of the Type I Error: Investigations on Regulatory
Recommendations for Bioequivalence of Highly Variable Drugs. Pharm Res. 2015;32(1):135–43.
doi: 10.1007/s110950141450z
Muñoz J, Alcaide D, Ocaña J. Consumer’s risk in the EMA and FDA regulatory approaches for
bioequivalence in highly variable drugs. Stat Med. 2015;35(12):1933–43. doi: 10.1002/sim.6834
Labes D, Schütz H. Inflation of Type I Error in the Evaluation of Scaled Average Bioequivalence,
and a Method for its Control. Pharm Res. 2016;33(11):2805–14. doi: 10.1007/s1109501620061
Tóthfalusi L, Endrényi L. Algorithms for Evaluating Reference Scaled Average Bioequivalence:
Power, Bias, and Consumer Risk. Stat Med. 2017;36(27):4378–90. doi: 10.1002/sim.7440
Molins E, Cobo E, Ocaña J. Two-Stage Designs Versus European Scaled Average Designs in Bioe-
quivalence Studies for Highly Variable Drugs: Which to Choose? Stat Med. 2017;36(30):4777–88.
doi: 10.1002/sim.7452
European Medicines Agency, Committee for Medicinal Products for Human Use. Guideline on the
Investigation of Bioequivalence. London, 20 January 2010. CPMP/EWP/QWP/1401/98 Rev. 1/
Corr **
European Medicines Agency, Committee for Medicinal Products for Human Use. Questions & An-
swers: positions on specific questions addressed to the Pharmacokinetics Working Party (PKWP).
London, 19 November 2015. EMA/618604/2008 Rev. 13
Health Canada, Therapeutic Products Directorate. Policy on Bioequivalence Standards for Highly
Variable Drug Products. Ottawa, 18 April 2016. 16-104293-140
Executive Board of the Health Ministers’ Council for GCC States. The GCC Guidelines for Bioe-
quivalence. 30 March 2016. Version 2.4
130 type1error.2TOST

See Also
sampleN.scABEL.ad, power.scABEL, power.scABEL.sdsims, scABEL

Examples
# Using all defaults:
# TRR|RTR|RRT, target power 80% for assumed ratio 0.90 (estimated sample size 54),
# EMA regulatory settings (ABE limits and PE constraint 0.80 - 1.25),
# 1E+6 simulated studies.
# Not run: due to timing policy of CRAN for examples

scABEL.ad(CV = 0.3)
# Should result in adjusted alpha 0.03389 (TIE 0.5000, TIE for nominal alpha 0.07189).
#
# As above but subject data simulations.

scABEL.ad(CV = 0.3, sdsims = TRUE)

# Should result in adjusted alpha 0.03336 (TIE 0.5000, TIE for nominal alpha 0.07237).
#
# TRT|RTR, heteroscedasticity, sample size 48 (unbalanced), subject data simulations.

scABEL.ad(CV = c(0.25, 0.3), design = "2x2x3", n = c(23, 25), sdsims = TRUE)

# Should result in adjusted alpha 0.02465 (TIE 0.5000, TIE for nominal alpha 0.09050).
#
# TRTR|RTRT, CV 0.35, sample size 33 (unbalanced).

scABEL.ad(CV = 0.35, design = "2x2x4", n = c(16, 17))

# Should result in adjusted alpha 0.03632 (TIE 0.5000, TIE for nominal alpha 0.06544).

type1error.2TOST Type I error rate for two simultaneous TOST procedures

Description
Was designed to calculate the type I error rate of two simultaneous TOST procedures (where the
two parameters of the two TOSTs are correlated with some correlation) for various study designs
used in BE studies.
Is defunct now since it suffers from insufficient precision to obtain the type 1 error (TIE) via simu-
lations.
Due to the intersection-union principle the TIE is always upper bounded to alpha by theory.
Index

bib.CL, 3, 53, 91, 92 11

CI.BE, 4, 6, 86 emmeans, 22, 27

CI.RatioF, 5 exppower.noninf, 20, 31
CI2CV (CVfromCI), 14 exppower.TOST, 24, 35
ct5.1 (ct5.1+ct5.2+ct5.3+ct5.4.1), 7 expsampleN.noninf, 24, 28
ct5.1+ct5.2+ct5.3+ct5.4.1, 7 expsampleN.TOST, 27, 32
ct5.2 (ct5.1+ct5.2+ct5.3+ct5.4.1), 7
ct5.3 (ct5.1+ct5.2+ct5.3+ct5.4.1), 7 hcubature, 27
ct5.4.1 (ct5.1+ct5.2+ct5.3+ct5.4.1), 7
ct9.6.2 (ct9.6.2+ct9.6.6), 8 integrate, 38
ct9.6.2+ct9.6.6, 8
ct9.6.4 (ct9.6.4+ct9.6.8), 9 known.designs, 18, 26, 28, 31–33, 35, 36, 43,
ct9.6.4+ct9.6.8, 9 48, 51, 56, 57, 78, 90, 96, 97, 123
ct9.6.6 (ct9.6.2+ct9.6.6), 8
ct9.6.8 (ct9.6.4+ct9.6.8), 9 mse2CV (CV2se+se2CV+CV2mse+mse2CV), 12
ctCW.III
(ctSJ.VIII.10+ctSJ.VIII.20+ctCW.III), OwensQ, 37, 40, 41
11 OwensQOwen, 38, 39, 40, 41
ctSJ.VIII.10 OwensT, 39, 40, 40
(ctSJ.VIII.10+ctSJ.VIII.20+ctCW.III),
11 pa.ABE, 41, 45, 46, 48
ctSJ.VIII.10+ctSJ.VIII.20+ctCW.III, 11 pa.NTIDFDA, 43, 44, 48
ctSJ.VIII.20 pa.scABE, 43, 46, 46
(ctSJ.VIII.10+ctSJ.VIII.20+ctCW.III),plot.pwrA, 46, 48
11 plot.pwrA (pa.ABE), 41
CV2mse (CV2se+se2CV+CV2mse+mse2CV), 12 pmvt, 61, 77, 102
CV2se (CV2se+se2CV+CV2mse+mse2CV), 12 power.2TOST, 49, 90
CV2se+se2CV+CV2mse+mse2CV, 12 power.dp, 51, 92
CVCL, 13 power.HVNTID, 53, 60, 95, 100
CVfromCI, 14, 18 power.noninf, 24, 55, 97
CVp2CV, 16 power.NTIDFDA, 46, 55, 58, 95, 100
CVpooled, 17 power.RatioF, 6, 60, 102
CVwRfromU, 19 power.RSABE, 48, 62, 68, 72, 106
power.RSABE2L.sds
data2x2 (ct5.1+ct5.2+ct5.3+ct5.4.1), 7 (power.RSABE2L.sdsims), 65
data2x2x3 (ct9.6.2+ct9.6.6), 8 power.RSABE2L.sdsims, 65, 106, 109
data2x4x4 (ct9.6.4+ct9.6.8), 9 power.scABEL, 48, 65, 69, 75, 106, 112, 113,
data_parallel 115–117, 125, 127, 129, 130
(ctSJ.VIII.10+ctSJ.VIII.20+ctCW.III), power.scABEL.sds, 73

131
132 INDEX

power.scABEL.sdsims, 71, 115, 120, 127,

130
power.scABEL.sdsims (power.scABEL.sds),
73
power.TOST, 27, 43, 76, 83, 123
power.TOST.sds, 79
power.TOST.sim, 81
print.CVp (CVpooled), 17
print.pwrA, 46, 48
print.pwrA (pa.ABE), 41
pvalue.TOST, 84
pvalues.TOST (pvalue.TOST), 84

reg_const, 63, 67, 68, 70, 72, 74, 75, 86, 107,
109, 110, 113, 118, 120, 124, 125

sampleN.2TOST, 51, 88
sampleN.dp, 53, 90
sampleN.HVNTID, 55, 60, 93, 100
sampleN.noninf, 31, 57, 95
sampleN.NTIDFDA, 55, 60, 95, 98
sampleN.RatioF, 62, 101
sampleN.RSABE, 65, 103, 113
sampleN.RSABE2L.sds
(sampleN.RSABE2L.sdsims), 106
sampleN.RSABE2L.sdsims, 106
sampleN.scABEL, 72, 109, 110, 115, 117, 120,
125
sampleN.scABEL.ad, 113, 129, 130
sampleN.scABEL.sds
(sampleN.scABEL.sdsims), 117
sampleN.scABEL.sdsims, 112, 113, 117
sampleN.TOST, 35, 78, 120
scABEL, 117, 124, 130
scABEL.ad, 115, 117, 126
se2CV (CV2se+se2CV+CV2mse+mse2CV), 12

type1error.2TOST, 130

U2CVwR (CVwRfromU), 19
uniroot, 43, 47

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