Bioequivalence and Bioavailability Forum

Dear all,

Michael (aka “mittyri” here and “mittyright” at Certara’s forum) and I updated the Phoenix WinNonlin template for the EMA’s ABEL ( free download).

New
• Works in Phoenix 6.4 and 7.0 (previously there were two versions of the template in order to deal with the different graphics engines).
  
• 4-period 2-sequence design
  • TTRR | RRTT
  Useful for steady state studies.
• 4-period 4-sequence designs
  • TRTR | RTRT | TRRT | RTTR
    
  • TRTR | RTRT | TTRR | RRTT
• 3-period 2-sequence (partial) replicate design
  • TRR | RTR (aka “extra reference design”)
  Not recommended since lacking period effects have to be assumed. Since the test is not admini­stered in the third period, the treat­ment comparison will be biased in the presence of true period effects. This design should be avoided and is included only for completeness.
  
• Plots of standardized residual vs. subject and vs. model predictions.
  
• Comparison of within-subject variabilities of test and reference (full replicate designs only).
  • Based on s_wT∕s_wR-ratio (like in PBE and IBE).
    
  • Based on the upper confidence limit of the σ_wT∕σ_wR-ratio (like in the FDA’s warfarin guidance).
• Documents folder
  • Q&A-document of the EGA/EMA joint workshop.
    
  • Instructions.

Changed
• The name of both treatments can be specified (previously only the one of the reference).

Experimental (not officially supported)
• TR | RT | TT | RR (aka Balaam’s design)¹
  Not recommended due to its very poor power characteristics and included only for completeness. Cross-validated only against R v3.4.1 with one data set.

The template was developed in PHX 6.4.0.768 and tested in PHX 7.0.0.2535. The template was cross-validated with 26 data sets (all designs, up to 360 subjects) against SAS v9.4 (Methods A, B, C), R v3.4.1 (A, B), STATISTICA (A, B), and partly (Q&A data sets I and II; Methods A, B) against STaTa v14, SPSS v22, and JMP v10.² As usual, use at your own risk.

In your project delete all PDFs in the Documents folder in order to reduce its size. The run-time is slightly better than in previous versions but needs patience. Since Phoenix swaps inter­mediate results to the system drive, it will take a while to complete. On my machine (with fast solid-state drives) execution of the Q&A’s data set I takes 2:15 minutes (Phoenix 6.4) and 1:50 minutes (Phoenix 7.0). If you have a hard drive, it may take substantially (?) longer.

Reports of defects and especially experiences with Windows installed on a hard drive are welcome at the
Certara Forum (registration necessary).

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1. Balaam LN. A Two-Period Design with t² Experimental Units. Biometrics 1968; 24(1): 61–73. doi:10.2307/2528460.
   
2. Schütz H, Labes D, Tomashevskiy M, González de la Parra M, Shitova A, Fuglsang A. Reference Datasets for Studies in a Replicate Design Intended for Average Bioequivalence with Expanding Limits. AAPS J. 2020; 22: 44. doi:10.1208/s12248-020-0427-6.