Bioequivalence and Bioavailability Forum

Dear ElMaestro & Skar,

❝ ❝ Normally we use Expected deviation of 5% or 7.5% in sample size calculation for bioequivalence study.

❝ I am not aware of any other strict rule regarding the maximum expected deviation, but of course some..... erm hehe.... common sense (sorry HS, I couldn't think of any other term) is needed here.

I love common sense. Maximum ±5% in EMA’s GL targets measured content of test and reference – not the expected ∆. We shouldn’t forget

• content uniformity,
  
• random error in drawing the sample for measuring content (how representative are a few units of a formulation for the batch?), and
  
• variability of the analytical method.

In other words it might well be that a measured difference within ±5 % is too optimistic in sample size estimation. The ‘old’ NfG (Section 3.1) stated:

The number of subjects required is determined by

1. the error variance associated with the primary characteristic to be studied as estimated from a pilot experiment, from previous studies or from published data,
   
2. the significance level desired,
   
3. the expected deviation from the reference product compatible with bioequivalence (∆) and
   
4. the required power.

This section was boiled down (cookbook!) in the recent GL’s Section 4.1.3 to:

The number of subjects to be included in the study should be based on an appropriate sample size calculation.

If you take the points mentioned on top into account, it might be reasonable to expect a larger ∆ even for measured ±≤5 %. I’m happy with Skar’s 7.5%.

❝ If you have a good method in vitro for your expected T/R and it turns out the expected T/R is 0.85 then it might be a good idea to reformulate rather than initiate a study. From an ethics perspective I do see a bit of reason in doing so.

Supported.