Bioequivalence and Bioavailability Forum

Hi martin,

❝ My interpretation of regulatoy guidelines: adding additional fixed effect factors to the factors mentioned in the guidelines is typically considered as not acceptable by regulators.

There was not a lot of concrete info in your post, but in my humble experience you are totally right where ordinary BA/BE is concerned: regulators rarely allow deviations in pivotal trials.

However, milder winds are blowing when we talk BE for biologics in EU. Here covariates found their way into the melée because many companies suggested it (and they did so because FDA wanted covariates).

I don't from the top of my head remember a case where an applicant wanted a "less obvious" fixed effect in the proposed model and was outright successful.
The new/creative/funky/funny fixed factors I have come across recently were in crossovers where we always have subjects fit as fixed. In such cases, when the proposed new fixed factors are subject-specific they don't really do anything in terms of the residual or its df's. For example, if we specify CYP phenotype as fixed factor, columns for phenotype in the model matrix would add up exactly to an intercept, so we wouldn't be going anywhere.

Welcome to the home of funky and funny pharmacokinetics where "Garbage in Gospel out" is day of life.

1. allowing long washout periods have seen studies with 4 -5 months washout.
2. other choice we can imagine is Two stage adaptive study design and including ANCOA in place of ANOVA...

want to know what other experts think?

❝ In short:

• pretty long half-life
  

• huge total variablity (i.e. within + between variability)
  
• total variability is expected to be explained to some degree by some covariates