Hi heaven sent,
» Do I understand correctly that Reference scaling is the same design as Partial Replicate:
» RRT, RTR, TRR ?
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
). Better to opt for one of the fully replicate designs. Most commonly used are TRTR | RTRT (4 periods) and TRT | RTR (3 periods).
2 period (full) replicate3 period (full) replicates3 period (partial) replicates
- 4 period (full) replicates
- TRTR | RTRT
- TRRT | RTTR
- TTRR | RRTT
- TRTR | RTRT | TRRT | RTTR 1
- TRRT | RTTR | TTRR | RRTT 1
- TRR | RTR | RRT
- TRR | RTR 3
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.
- 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%).
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).
- Confounded effects (design not recommended).
- Balaam’s design (not recommended due to poor power characteristics).
- Extra-reference design (biased in the presence of period effects; design not recommended).