Posting: # 17488
The WHO is apparently opening a pilot phase to allow scaling for AUC on a case-by-case basis. Protocols and justifications are to be submitted in advance to the WHO PQP team.
Posting: # 17490
» The WHO is apparently opening a pilot phase to allow scaling for AUC on a case-by-case basis. Protocols and justifications are to be submitted in advance to the WHO PQP team.
THX at lot for this gem! Obviously people at the WHO are more clever than the EMA’s – by avoiding this IMHO, undesired – side effect. Kudos!
Something puzzles me when reading the respective section of TRS 992, Annex 7, Section 7.9.3 “Highly variable active pharmaceutical ingredients” again…
A “highly variable API” has been defined as an API with an intrasubject variability of > 30% in terms of the ANOVA-CV (14). Proving the bioequivalence of FPPs containing highly variable APIs can be problematic because the higher the ANOVA-CV, the wider the 90% confidence interval. Thus large numbers of subjects must be enrolled in studies involving highly variable APIs to achieve adequate statistical power.
Neither in (14) nor in any of all the other Bio-International conference I attended, 30% was set as the limit for the API. The respective section of (14) reads:
In some cases, however, it has been difficult to meet these criteria in experiments with a reasonable number of subjects. This may be, at least in part, a function of high intrasubject variability of the drug itself and/or the drug product. […]
The distinction between HVDs (highly variable if administered IV or as a solution) and HVDPs (highly variable if administered as a pharmaceutical product) was first made by Midha a couple of years later. Whether we have to deal with a HVD or a HVDP is of academic interest only. If reference-scaling would be only acceptable for HVDs (highly variable APIs!) many HVDPs would fall through the cracks. Example: CVintra of IV diclofenac <10% but CVintra of enteric coated diclofenac ~40%. At last the last paragraph of the WHO’s GL talks about “highly variable FPPs”. Confused? So am I.
The quality of responses received is directly proportional to the quality of the question asked. ☼
Posting: # 17491
» THX at lot for this gem! Obviously people at the WHO are more clever than the EMA’s
In actuality, they are for many practical purposes exactly the same people.
» Confused? So am I.
There is no point is asking why, I think. They need 4 periods? They specifically seem to want to compare variability for Ref and Test. Are we back to the all the stuff that didn't work 10-20 years ago, population BE and individual BE and such. Obviously not the case. So it is anyones guess what the intent is given the wording.
However, there is plenty useful info in the guidance. Don't let a few inconsistencies spoil the party. Let the scaling for AUCt commence...
It of course comes at a handy time when WHO are opening up for biologics. This isn't a co-incidence .
"(...) targeted cancer therapies will benefit fewer than 2 percent of the cancer patients they’re aimed at. That reality is often lost on consumers, who are being fed a steady diet of winning anecdotes about miracle cures." New York Times (ed.), June 9, 2018.
Posting: # 17492
» It of course comes at a handy time when WHO are opening up for biologics. This isn't a co-incidence .
Didn't have a look at PARs, but EMA has a high number of biosimilars approved (compared to e.g. FDA), is the variability in AUC really an issue and how did the applicants account for, if EMA allows no scaling for AUC?
Kindest regards, nobody