3 period full replicate [RSABE / ABEL]

posted by Helmut Homepage – Vienna, Austria, 2015-06-24 20:25 (3222 d 11:57 ago) – Posting: # 14981
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Ahoy!

❝ I was too fast,


A privilege of the youth. :-D

Note that the BE-GL does not state a specific design, only:

If an applicant suspects that a drug product can be considered as highly variable […], a replicate cross-over design study can be carried out.
For the acceptance interval to be widened the bioequivalence study must be of a repli­cate design where it has been demonstrated that the within-subject variability for Cmax of the reference com­pound in the study is >30%.
It is acceptable to apply either a 3-period or a 4-period crossover scheme in the repli­cate design study.


❝ Who's got some publications about the performance of RTR / TRT? Do they exist?


See the ones mentioned above. AFAIK, the last one was the basis for EMA’s approach; the paper introduced the term “ABEL” = Average Bioequivalence with Expanding Limits. All (!) simu­­la­tions were performed for TRT|RTR (for an example plot see this post). The TRT|RTR is also mentioned in FDA’s Guidance (Appendix C, Table 3) in the context of IBE. Write a letter to László Endrényi asking him what he thinks about the partial replicate. :pirate:
Honestly, I don’t know why the partial replicate entered the European scene. Just because it was examined by the FDA before?

Edit: After the concept paper on HVDs/HVDPs* was published in 2006, I suggested at con­fe­ren­ces that agencies should collect real data and explore the performance of different me­thods. The data exist, since the pre-specied widening of the acceptance range for Cmax to 0.75–1.3333 also required a replicate design. Reaction: Nada, Zero, Τίποτα. The same people don’t get­ting tired to say “I don’t believe in simulations”, in the case of refe­rence-scaling do exactly this – rely entirely on them. OK, fine with me. But the sim’s were done for 3- and 4-period fully repli­cated designs!

@Dan: Ask the agency for the background of their statement.

‘Who controls the past,’ ran the Party slogan,
‘controls the future: who controls the present controls the past.’
George Orwell (Nineteen Eighty-Four, 1949; Chapter 3)

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