Bioequivalence and Bioavailability Forum

3 period full replicate [RSABE / ABEL]

posted by Helmut  – Vienna, Austria, 2015-06-24 20:25 (3458 d 16:46 ago) – Posting: # 14981
Views: 31,329

Ahoy!

❝ I was too fast,

A privilege of the youth.

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 C_max 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.
Honestly, I don’t know why the partial replicate entered the European scene. Just because it was examined by the FDA before?

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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 C_max 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.

• If they carried out simulations with the partial replicate demonstrating that it performs “better” than the 3-period full replicate (ha-ha!), they should publish these results.
  
• If this completely unjustified statement is the agency’s policy, don’t select it as a RMS. What about choosing Spain or Hungary?

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• See its discussion points. One of them:
  • Decide what to do if the within-subject variance ratio shows that the test product is more variable than the reference product.
  Only possible in a full replicate design, right?
  The concept paper was more or less written single-handed by László Tóth­falusi and the only one ever (in an Orwellian manner) deleted in October 2007 from EMA’s website.

‘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)

—
Dif-tor heh smusma 🖖🏼 Довге життя Україна! 
Helmut Schütz


The quality of responses received is directly proportional to the quality of the question asked. 🚮
Science Quotes

Complete thread:

• 3 period full repli­cate Dr_Dan 2015-06-24 13:55 [RSABE / ABEL] 
  • 3 period full replicate ElMaestro 2015-06-24 14:11
  • 3 period full replicate Helmut 2015-06-24 14:29
  • 3 period full replicate d_labes 2015-06-24 14:38
    • 3 period full replicate Dr_Dan 2015-06-24 16:43
      • 3 period full replicate Helmut 2015-06-24 18:00
        • 3 period full replicate ElMaestro 2015-06-24 18:11
          • 3 period full replicateHelmut 2015-06-24 18:25
            • 3 period full replicate d_labes 2015-06-25 08:52
              • 3 period full replicate ElMaestro 2015-06-25 10:37
                • OT d_labes 2015-06-25 11:20
                  • OT ElMaestro 2015-06-25 11:54
                    • OT d_labes 2015-06-25 13:51
      • CVs (borderline OT) Helmut 2015-06-26 13:51
        • CVs (R, T) from pooled CV d_labes 2015-07-02 09:09
          • Answering an un­asked ques­tion Helmut 2015-07-02 13:03
            • Answer to an un­asked answer d_labes 2015-07-02 14:21
              • Bloody typo! Helmut 2015-07-02 14:33
        • CVs (borderline OT) zizou 2015-07-05 19:20
          • Degrees of freedom 3-period full replicate d_labes 2015-07-06 11:10
            • Degrees of freedom 3-period full replicate ElMaestro 2015-07-06 11:59
              • Degrees of freedom 3-period full replicate d_labes 2015-07-06 13:53
            • Degrees of freedom 3-period full replicate zizou 2015-07-06 17:25
  • The almighty oracle has spoken! Helmut 2015-07-23 23:54
    • Almighty oracle's mysterious saying d_labes 2015-07-24 08:23