Evaluation of Reference variability [Design Issues]

posted by ElMaestro  – Belgium?, 2010-03-16 17:13  – Posting: # 4922
Views: 1,860

Dear Marcel and HS,

» I would say there are two reasons.
  • The general reason, that no
    » reference to previous studies is allowed when it comes to widening of the
    » acceptance range. CVintra,ref >30% must be demonstrated within
    » the submitted study.
  • There is also a pharmacokinetic reason. Drugs with nonlinear PK may
    » show different variability throughout the dose range. Think about
    » e.g., saturation effects. Example: ASS -> salicylic acid.

Warning: This post is not fully thought through yet.
The comment from HS implies we would no longer be able to talk about highly variable drugs per se; we would have to think along the lines of "drug X is a highly variable drug at dose Y" etc. Perhaps we could not even talk about highly variable drugs, but about highly variable drug doses.
I am not sure this is fully in line with current thinking; in the PK-subgroup's earlier definition of a highly variable drug there was no mention of such considerations. Granted, this does not mean that they don't exist.

A further implication: Let's say we want to develop a generic of Schützomycin. The product is available in one strength, posology is 1 tablet daily. Now we also have an LC/MS/MS assay we cannot improve further upon and which has a pretty high LLOQ so we decide to do a BE study in healthy volunteers each being dosed 2 tablets. The ethics board accepts it, because Schützomycin is a nice drug with little safety concern.
So we do our study and find high variability for the product (haha, if a statistical menthod was only available nnwwsnm), and blah blah we end up with equivalence. We submit the dossier and we feel good. On Day 70 we get a short message from CA: "Potential serious risk to public health: Because high variability may be a dose dependent phenomenon, the applicant should provide evidence that the drug is not only highly variable at double the recommended dose."

This would be quite an evil one to deal with. Again, I have not thought it through, I am just relaying my initial thoughts to HS' post.


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