Bioequivalence and Bioavailability Forum

Hi heaven sent,

interesting nick.

❝ 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: CV_wT ≠ CV_wR). 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

Notes:

• 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 CV_wR <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.
    C_max 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 C_max (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).

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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).