Helmut
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2019-06-14 18:01

Posting: # 20326
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 package replicateBE on CRAN [R for BE/BA]

Dear all,

package replicateBE is on CRAN. Background information in its Vignette.

Data can be imported from CSV- or XLS(X)-files. Following ten designs are covered:
  • Four period full replicates
    • TRTR | RTRT
    • TRRT | RTTR
    • TTRR | RRTT
    • TRTR | RTRT | TRRT | RTTR 1
    • TRRT | RTTR | TTRR | RRTT 1
  • Two period full replicate
    • TR | RT | TT | RR 2
  • Three period full replicates
    • TRT | RTR
    • TRR | RTT
  • Three period partial replicates
    • TRR | RTR | RRT
    • TRR | RTR 3
Implemented:
  • Estimation of CVwR (and CVwT in full replicates)
    A linear model of log-transformed PK responses and effects sequence, subject(sequence), period of the reference (and test, if possible) treatment – where all effects are fixed (i.e., ANOVA).
    Estimated via function lm() of library stats.
    In full replicate designs assessment of \(s_{wT}/s_{wR}\) and the upper confidence limit of \(\sigma_{wT}/\sigma_{wR}\) for the WHO’s reference-scaling of AUC.

  • Method A
    A linear model of log-transformed PK responses and effects sequence, subject(sequence), period, treatment – where all effects are fixed (i.e., ANOVA).
    Estimated via function lm() of library stats.

  • Method B
    A linear mixed model of log-transformed PK responses and effects sequence, subject(sequence), period, treatment – where subject(sequence) is a random effect and all others are fixed.

    Two options
    1. Estimated via function lmer() of library lmerTest. Uses Satterthwaite’s degrees of freedom equivalent to SAS’ DDFM=SATTERTHWAITE and Phoenix/WinNonlin’s DF Satterthwaite. Potentially better for highly incomplete data.
    2. Estimated via function lme() of library nlme. Uses degrees of freedom equivalent to SAS’ DDFM=CONTAIN and Phoenix/WinNonlin’s DF Residual. Implicitly preferred according to the EMA’s Q&A document and hence, the default.
  • ABE
    Conventional Average Bioequivalence. Optionally with tighter (EMA: NTIDs) or wider limits (GCC: Cmax).
Assessment of potential outliers in the ABEL-methods is done by box plots of studentized model residuals.

Enjoy!

Bug reports to GitHub or the maintainer.


  1. Confounded effects (design not recommended).
  2. Balaam’s design (not recommended due to poor power characteristics).
  3. Extra-reference design; biased in the presence of period effects (design not recommended).

Cheers,
Helmut Schütz
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