Some desultory thoughts [Design Issues]

posted by Helmut Homepage – Vienna, Austria, 2010-03-16 18:59  – Posting: # 4923
Views: 1,930

Hi ElMaestro!

» Warning: This post is not fully thought through yet.

Warning: So is my reply.

» ... we would no longer be able to talk about highly variable drugs per se;

It was always important to make a distinction between HVDs (Highly variable Drugs) and HVDPs (Highly variable Drug Products).

» ... 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.

Yes, probably.

» I am not sure this is fully in line with current thinking;

Both the Q&A-document (2006) and the new BE-GL talk about HVDs/HVDPs. And CV>30% has to demonstrated in a replicate design study. If we want to claim a wider acceptance range, for some drugs/formulations IMHO a historical justification would also do the job. After so many studies we all know that PPIs - especially in fed state - are HVDPs. But we need the replicate design anyhow to perform the scaling (theoretically, because we don't have a statistical method :angry:).
Marcel's question dealt with a historical reference (CV>30% after another dose). My two answers were based on:
- no historical reference anyway
- a worst case scenario (well, I still think that may be possible)

» 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 [...] decide to do a BE study in healthy volunteers each being dosed 2 tablets. The ethics board accepts it, because Schützomycinis a nice drug with little safety concern.

Fine to hear that Schützomycin is a nice drug. When I read the GL, I was wondering how anyone can take the responsibility of dosing more than the approved daily dose for analytical reasons. 'Anyone' in that case = sponsor + investigator + IEC. The drug was shown to be nice at the registered strength and OAD. No data for doubled dose. There are some anecdotal reports that Schützomycin if administered off-label is toxic to the sensory cells of the ear, sometimes causing complete hearing loss.

» [...] 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.

This would be the absolute show-stopper.

Helmut Schütz

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