Bioequivalence and Bioavailability Forum

Dear Helmut!

❝ The following code removes all the test data from the data-set and then fits a model where the residual variance corresponds to the within subject variance for the test product.

Thanks for pointing me to this Gem I had read over up to now!


Concerning your bonus questions:
No distinct answer from my side.

For our ongoing studies we have decided to go with the FDA model (both 90% CI and sigma_wR) because

• we have written it down in the study protocols
  
• We are convinced that it is the correct model, if not partial replicate
  

as the primary analysis and the EMA model as further analysis.

Lets see what our sponsors will do.

I am seeking for a compilation of arguments why the EMA model is inferior, which I will write down in my SAP.
Here my two cents:

• The assumptions of the EMA recommended evaluation can not a-priori justified. Especially the evaluation of the average BE via a model assuming equal intra-subject variabilities of the Test and reference formulations (model A - Proc GLM evaluation same as for a 2x2 crossover) is contradictory to the reasons of use of a replicate crossover, namely the possibility to estimate separate intra-subject variabilities.
  
• As the EMA Q&A already states "...This model (Model C - FDA model) will provide the same point estimate as methods A and B if all subjects provide data for all treatment periods. However it will generally give wider confidence intervals than those produced by methods A and B..."
  This may lead to anticonservative behaviour with an inflation of the patients risk above 5%.
  As Willavize and Morgenthien have shown by simulations¹⁾ especially the neglection of the subject-by-treatment interaction may result in a type I error inflation up to 17%.
  
• It is well known that the least square estimates of the treatment effects are only unbiased if there are no missings in the data. From the dataset I of the EMA Q&A it is nevertheless obvious that these estimates should be used in case of missings.
  
• The estimation of the intra-subject variance of the Reference formulation with a model neglecting the data for the Test formulation bears the danger of bias in the estimates of the period effects and presumable also the estimates of s²_wR.
  

¹⁾ Willavize, Morgenthien
"Comparision of models for average bioequivalence in replicated crossover designs"
Pharm. Stat. 2006 Jul-Sep;5(3):201-11.

Dear all! You are invited to contribute to this list and qualify it, preferably with literature, if you are also convinced that the FDA model is superior.

BTW: The Morrisk dance plays a prominent role in some of Terry Pratchett's "Discworld" novels. This Literature is highly recommended for people having contact with institutions like EMA for their mental health .