Variability and impact on design of bioequivalence studies.

In 2008, the European Agency for the Evaluation of Medicinal Products released a draft guidance on the investigation of bioequivalence for immediate release dosage forms with systemic action to replace the former guidance of a decade ago. Revisions of the regulatory guidance are based upon many questions over the past years and sometimes continuing scientific discussions on the use of the most suitable statistical analysis methods and study designs, particularly for drugs and drug products with high within-subject variability. Although high within-subject variability is usually associated with a coefficient of variation of 30% or more, new approaches are available in the literature to allow a gradual increase and a levelling off of the bioequivalence limits to some maximum wider values (e.g. 75-133%), dependent on the increase in the within-subject variability. The two-way, cross-over single dose study measuring parent drug is still the design of first choice. A partial replicate design with repeating the reference product and scaling the bioequivalence for the reference variability are proposed for drugs with high within-subject variability. In case of high variability, more regulatory authorities may accept a two-stage or group-sequential bioequivalence design using appropriately adjusted statistical analysis. This review also considers the mechanisms why drugs and drug products may exhibit large variability. The physiological complexity of the gastrointestinal tract and the interaction with the physicochemical properties of drug substances may contribute to the variation in plasma drug concentration-time profiles of drugs and drug products and to variability between and within subjects. A review of submitted bioequivalence studies at the Food and Drug Administration's Office of Generic Drugs over the period 2003-2005 indicated that extensive pre-systemic metabolism of the drug substance was the most important explanation for consistently high variability drugs, rather than a formulation factor. These scientific efforts are expected to further lead to revisions of earlier regulatory guidance in other regions as is the current situation in Europe.