TRR.RTR.RRT {replicateBE}

Reference Datasets for TRR|RTR|RRT (partial) Replicate Designs

Description

Datasets from the public domain or simulated to be evaluated by method.A(), method.B(), or ABE().

Format

• Reference Dataset 02
  24 subjects.
  Balanced (eight subjects in each of the three sequences) and complete (no missing data). No outliers.
  A data frame with 72 observations on the following 6 variables:

  rds02

  subject	a factor with 24 levels: 1, 2, ..., 24
  period	a factor with 3 levels: 1, 2, 3
  sequence	a factor with 3 levels: TRR, RTR, RRT
  treatment	a factor with 2 levels: T, R
  PK	a numeric vector of pharmacokinetic responses acceptable for reference-scaling (generally Cmax)
  logPK	a numeric vector of the natural logarithms of PK

  In the source evaluated by SAS v9.1 for ABEL. Reported results:

  SAS Proc GLM

  CVwR	11.2%
  PE	102.26% (Method A and B)
  90% CI	97.32% – 107.46% (Method A and B)

• Reference Dataset 04
  Data set of Table II given by Patterson & Jones. 51 subjects.
  Balanced (17 subjects in each of the three sequences) and complete. No outliers.
  A data frame with 153 observations on the following 5 variables:

  rds04

  subject	a factor with 51 levels: 1, 2, ..., 56
  period	a factor with 3 levels: 1, 2, 3
  sequence	a factor with 3 levels: TRR, RTR, RRT
  treatment	a factor with 2 levels: T, R
  PK	a numeric vector of pharmacokinetic responses (here Cmax)

  In the source evaluated by SAS with the FDA’s mixed effects model (termed ‘Method C’ by the EMA; not compatible with the guideline). Reported results:

  SAS Proc MIXED

  CVwR	61%
  PE	137%
  90% CI	119% – 159%

• Reference Dataset 07
  Simulated with CV_wT = CV_wR = 35%, GMR 0.90. 360 subjects.
  Balanced (120 subjects in each of the three sequences) and complete. No outliers.
  A data frame with 1,080 observations on the following 5 variables:

  rds07

  subject	a factor with 360 levels: 1, 2, ..., 360
  period	a factor with 3 levels: 1, 2, 3
  sequence	a factor with 3 levels: TRR, RTR, RRT
  treatment	a factor with 2 levels: T, R
  PK	a numeric vector of pharmacokinetic responses (generally Cmax)

• Reference Dataset 30
  Simulated with heteroscedasticity (CV_wT = 14%, CV_wR = 28%, CV_bT = 28%, CV_bR = 56%), GMR = 0.90. 12 subjects. 14 subjects.
  Imbalanced (six subjects in sequence TRR, five in RTR, and three RRT) and incomplete (two missings in sequences TRR and RTR and three in sequence RRT). Missings / period: 0/1, 0/2, 7/3. No outliers.
  A data frame with 35 observations on the following 5 variables:

  rds30

  subject	a factor with 14 levels: 1, 2, ..., 39
  period	a factor with 3 levels: 1, 2, 3
  sequence	a factor with 3 levels: TRR, RTR, RRT
  treatment	a factor with 2 levels: T, R
  PK	a numeric vector of pharmacokinetic responses (generally Cmax)

Details

Dataset	N	CVwR (%)	Evaluation
rds02	24	<30	method.A(), method.B(), ABE()
rds04	51	>30	method.A(), method.B()
rds07	360	>30	method.A(), method.B()
rds30	14	<30	method.A(), method.B(), ABE()

Note

In software sequences and treatments are ranked in lexical order. Hence, executing str() or summary() will show sequence as "RRT", "RTR", "TRR" and treatment as "R", "T". In BE – by convention – sequences are ordered with T first. The package follows this convention.

Author(s)

Helmut Schütz (R-code for simulations by Detlew Labes)

Source

Dataset	Origin	Description
rds02	EMA	Annex III.
rds04	Patterson & Jones	Cmax data of Table II.
rds07	R	Large simulated data set with homoscedasticity.
rds30	R	Simulated with heteroscedasticity; imbalanced and incomplete.

References

European Medicines Agency. London, 21 September 2016. Annex I, Annex III.

Patterson SD, Jones B. Viewpoint: observations on scaled average bioequivalence. Pharm Stat. 2012; 11(1): 1–7. doi:10.1002/pst.498

Examples

str(rds02)
row <- c(10:12, 1:3, 16:18)
rds02[row, ]
summary(rds02[2:6])