heaven sent

2017-12-29 17:24

Posting: # 18128
Views: 1,684

 Partial replicate or Reference scaling [RSABE / ABEL]

Do I understand correctly that Reference scaling is the same design as Partial Replicate:

Edit: Category changed; see also this post #1. Please follow the Forum’s Policy. [Helmut]
Vienna, Austria,
2017-12-29 18:36

@ heaven sent
Posting: # 18129
Views: 1,556

 Partial replicate ≠ Reference scaling

Hi heaven sent,

interesting nick. ;-)

» Do I understand correctly that Reference scaling is the same design as Partial Replicate:

No, you don’t.
  • Reference-scaling is a method assessing bioequivalence.
  • The partial replicate is a design for it.
Though you need a replicate design for reference-scaling, this partial replicate is only one of them. In general I don’t recommend partial replicates since the statistical model behind is tricky (especially in the case of heteroscedasticity: CVwT ≠ CVwR). Better to opt for one of the fully replicate designs. Most commonly used are TRTR | RTRT (4 periods) and TRT | RTR (3 periods).
  • 4 period (full) replicates
    • TRTR | RTRT
    • TRRT | RTTR
    • TTRR | RRTT
    • TRTR | RTRT | TRRT | RTTR 1
    • TRRT | RTTR | TTRR | RRTT 1
  • 2 period (full) replicate
    • TR | RT | TT | RR 2
  • 3 period (full) replicates
    • TRT | RTR
    • TRR | RTT
  • 3 period (partial) replicates
    • TRR | RTR | RRT
    • TRR | RTR 3
  • The FDA requires at least 24 dosed subjects if the study is intended for reference-scaling.
    The EMA requires at least 12 eligible subjects in the sequence repeating R of the 3 period full replicate designs.
  • In any of the designs conventional (unscaled) average bioequivalence ABE can be evaluated as well (e.g., if CVwR <30% or reference-scaling for a particular PK metric is not acceptable).
  • The statistical models differ between regulations.
    • FDA (model RSABE: reference-scaled average bioequivalence).
    • EMA (model ABEL: average bioequivalence with expanding limits) – also adopted by the WHO, Eurasian Economic Union, Australia, New Zealand, Brazil, Egypt, South Africa, ASEAN States.
      Cmax and some PK metrics of MR-products. WHO: pilot phase for AUC; full replicate design mandatory.
    • Health Canada (ABEL but potentially wider limits). Only AUC.
    • Gulf States, Mexico: ABE but wider acceptance limits for Cmax (75–133%).
  • Only for jurisdictions which have adopted ABEL and the Gulf States / Mexico you have to provide a clinical justification that expanding the acceptance limits imposes no risk (safety/efficacy) on patients.
  • Conventional sample size estimation is not possible – you need to perform simulations. I recommend the package PowerTOST for the statistical software R (open-source and free of costs).

  1. Confounded effects (design not recommended).
  2. Balaam’s design (not recommended due to poor power characteristics).
  3. Extra-reference design (biased in the presence of period effects; design not recommended).

Helmut Schütz

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