Bioequivalence and Bioavailability Forum

Dear all,

I try to figure out when – and hopefully why – the partial replicate design TRR|RTR|RRT entered the scene.

I must confess that I never heard about it till I was asked at a workshop in Ahmedabad in 2008. I knew only another partial replicate, the so-called extra-reference design TRR|RTR ¹ (which should be avoided since it is biased in the presence of period effects).
The first paper ² of the ‘Two Lászlós’ dealt solely with the two-sequence, three-period full replicate design TRT|RTR. It laid the foundations of reference-scaled ABE.
The FDA’s guidance of 2001 stated in Appendix B.2.:

… the two-sequence, three-period design TRR|RTT is thought
to be optimal among three-period replicated crossover designs.

Fine with me. Same design characteristics, balanced like the TRT|RTR. Not a single word about the partial replicate.

The partial replicate is given in the FDA’s progesterone guidance of April 2010 and by the EMA in Annex I of September 2016 (appeared first in Rev. 3 of the Q&A document in January 2011) though regulatory documents ≠ scientific justification.

If you know any publication (preferrably prior to 2010), please let me know.

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1. Chen KW, Chow SC, Li G. A Note on Sample Size Determination for Bioequivalence Studies with Higher-order Crossover Designs. J Pharmacokin Biopharm. 1997;25(6):753–65. doi:10.1023/a:1025738019069.
   
2. Endrényi L, Tóthfalusi L. Regulatory Conditions for the Determination of Bioequivalence of Highly Variable Drugs. J. Pharm Pharmaceut Sci. 2009;12(1):138–49. Open access.