If two medicines are bioequivalent there is no clinically significant difference in their bioavailability.
Although bioequivalence is most commonly discussed in relation to generic medicines, it is important to note that bioequivalence
studies are also performed for innovator medicines in some situations such as:
- between early and late clinical trial formulations or between the formulations used in clinical trials and the product
to be marketed for new medicines
- when changes in formulation have occurred after an innovator product has been approved, for example a change in one
or more excipients (inactive ingredients)
Bioequivalence studies are a surrogate marker for clinical effectiveness and safety data as it would not normally be
practical to repeat clinical studies for generic products. It is accepted that if plasma concentrations of the active
ingredient of the generic and innovator medicines are the same, then their concentration at the site of action and therefore
their safety and effectiveness will be the same. In addition to being bioequivalent, a generic medicine must conform to
high quality standards in terms of the method of manufacture and the purity of the final pharmaceutical form.
There are internationally agreed standards for measuring and assessing bioequivalence (see Appendix).
Acceptance Criteria for Bioequivalence
Bioequivalence is determined based on the relative bioavailability of the innovator medicine versus the generic medicine.
It is measured by comparing the ratio of the pharmacokinetic variables for the innovator versus the generic medicine where
equality is 1.
The acceptance criteria are such that to be classified as bioequivalent, plasma concentrations of the generic medicine
will not differ significantly compared with the innovator medicine. Studies have demonstrated that actual differences
between observed mean plasma concentrations of generic and innovator medicines were no greater than 5%.
In order to determine that two medicines are bioequivalent there must be no more than a 20% difference between the AUC
and Cmax. This is based on international consensus that differences less than this are not clinically significant.
In order to establish this, the AUC and Cmax for the generic medicine are compared to that for the innovator
medicine (Figure 1).
Bioequivalence is based on a comparison of ratios where the ratio of generic to innovator for each pharmacokinetic variable
does not differ by more than 8:10, this is how the range for the confidence intervals is defined:
- 8/10 = 0.80 gives the lower limit
- 10/8 = 1.25 gives the upper limit
The 90% confidence intervals for the ratios of both Cmax and AUC should be contained within the limits 0.80–1.25
(see Figure 2). Thus bioequivalence is based on ratios where the nominal equality is 1. It is not based on differences
in absolute values.
In practice, the generic product should have a ratio of mean values (AUC and Cmax generic: innovator) close
to 1, indicating equality. If the observed ratio is closer to 0.8 or 1.25, then the data would have to contain little
or no variation from the mean for the 90% confidence intervals of the ratio to lie in the 0.8 to 1.25 range that is necessary
to demonstrate bioequivalence.2