The standard approach for the approval of generic drugs is to run a bioequivalence study to demonstrate that said product is comparable to an approved (i.e. reference) drug in its rate and extent of absorption.
These data points are determined from the pharmacokinetic parameters, and for ‘standard’ drugs the AUC and Cmax must fall between preset regulatory bioequivalence limits from 80% to 125%.
But what about those drugs which don’t match those limits?
Labeled as Highly Variable Drugs (HVD), these are the drugs whose within-subject variance is larger than 30%. In other words, while most drugs have a predictable pharmacokinetic profile within a particular subject, these drugs have a pharmacokinetic profile that may differ from each other, even while being administered to the same subject.
Despite their high variability they are believed to have a wide therapeutic window, and even allowing for their less than standard characteristics, can be both safe and effective. Given the higher uncertainty around their pharmacokinetics and their efficacy, the chance of a spurious result increases, and it's therefore critical to take additional measures to take this into account during the testing phase.
The typical solution is simply to scale the average bioequivalence with intrasubject variation. Usually, this is done in three or more period crossover studies, where at least one formulation is administered twice. The intrasubject variation of one or both formulations can then be directly estimated. Using a similar model to average bioequivalence, the interpretation is a scaled confidence interval which is widened based on the calculated intra-subject variation. Needless to say, the guidelines for such testing are very specific and have to meet the exacting limits prescribed by the regulatory bodies.
With vast experience in both partial and fully replicated studies, including the statistical evaluation of results in accordance with both EMA and FDA rules in order to cater for regional differences, QUINTA-ANALYTICA should be your first point of call when even contemplating taking a new drug to market.
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October 28, 2021