power.HVNTID {PowerTOST}

(Empirical) Power for BE decision via FDA method for highly variable NTIDs

Description

This function performs the power calculation of the BE decision via the FDA’s method for highly variable narrow therapeutic index drugs (NTIDs) as described in respective guidances based on simulations. The study design could be the full replicate design 2x2x4 with 4-periods (TRTR|RTRT) or the 2x2x3 replicate design with 3-periods and sequences TRT|RTR.

Usage

power.HVNTID(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. Commonly 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.
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.

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 thorougly tested.

The method is also required by China’s Center of Drug Evaluation.

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

Food and Drug Administration, Office of Generic Drugs (OGD). Draft Guidance on Edoxaban Tosylate. Recommended May 2017; Revised Mar 2020. 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