Bioequivalence and Bioavailability Forum

Main page Policy/Terms of Use Abbreviations Latest Posts

 Log-in |  Register |  Search

Back to the forum  Query: 2018-05-21 11:15 CEST (UTC+2h)
heaven sent

2017-12-29 17:24

Posting: # 18128
Views: 822

 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: 750

 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 

The quality of responses received is directly proportional to the quality of the question asked. ☼
Science Quotes
Back to the forum Activity
 Thread view
Bioequivalence and Bioavailability Forum | Admin contact
18,269 posts in 3,882 threads, 1,161 registered users;
19 users online (1 registered, 18 guests).

Science is wonderfully equipped to answer the question “How?”
but it gets terribly confused when you ask the question “Why?”    Erwin Chargaff

BEBAC Ing. Helmut Schütz