New Approach for Evaluating Highly Variable Drugs Based on EMEA Bioequivalence Guideline 2010

Highly variable drugs or drug products (HVDP) issue is one of frequent asked question raised from many pharmaceutical industries. Conducting the BE study for HVDP usually needs a lot number of subjects. The large variability in Cmax will result to unacceptable range of Cmax which is out of the standard bioequivalent acceptance criteria 80.00 – 125.00%. To discuss further about aforementioned case, Committee for Medicinal Products for Human Use (CHMP) of European Medicines Agency (EMEA) has stated this matter on the updated revision of “Guideline on The Investigation of Bioequivalence” issued on 20 January 2010.

What is a highly variable drug or drug product and what is the bioequivalence acceptance criteria for this product?

Highly variable drugs products (HVDP) are those whose intra-subject variability for a parameter is larger than 30%. For HVDP the acceptance interval for Cmax may in certain cases be widened to a maximum of 69.84 – 143.19%. For the acceptance interval to be widened the bioequivalence study must be of a replicate design where it has been demonstrated that the within-subject variability for Cmax of the reference compound in the study is >30%. The applicant should justify that the calculated intra-subject variability is a reliable estimate and that it is not the result of outliers.

The request for widened interval must be prospectively specified in the protocol and have to be supported by risk assessment on the safety of drugs. On the other side, the acceptance range of AUC should remain at 80.00 – 125.00% regardless of variability.

The extent of the widening is defined based upon the within-subject variability seen in the bioequivalence study using scaled-average-bioequivalence according to [U, L] = exp [±k·sWR]. Using this methodology, the table below gives examples of how different levels of variability lead to different acceptance limit.