Where Did the 80-125% Bioequivalence Criteria Come From?

Most drug developers involved in clinical pharmacokinetics are familiar with the 80-125% bioequivalence criteria. This criterion is used to compare two drug treatments with the purpose of evaluating if they are bioequivalent.

Before we explain where 80-125% bioequivalence range came from, let me explain the specifics of the criterion. Often, we would like to know if two treatments (e.g. 2 formulations, male vs. female, hepatic impaired vs non-impaired, etc.) differ in systemic exposure. The currently accepted test is the “bioequivalence test.”

This test states that two treatments are not different from one another if the 90% confidence interval of the ratio of a log-transformed exposure measure (AUC and/or C_max) falls completely within the range 80-125%. AUC stands for area under the curve for the concentration-time curve. C_max is the maximum concentration on the concentration-time curve.

Note that we only conclude that the two treatments are “not different” from one another. We don’t conclude that they’re the “same.” However, if the 90% confidence interval falls outside the 80-125% range, we conclude that the two treatments differ significantly.

The basis for the 80-125% range is arbitrary … sort of. The FDA (and other regulatory bodies) decided that differences in systemic drug exposure up to 20% are not clinically significant. Now, that may lead you to believe that the appropriate range should be 80-120% (100% ± 20%) … but that isn’t the range.

This is because the pharmacokinetic parameters for exposure (AUC and/or C_max) are log-normally distributed. If you transform these exposure parameters by taking the logarithm, you will get a normal distribution.

Normal distributions are generally required for specific statistical tests. Thus, the symmetrical ± 20% must be in the log-transformed space so that the statistical test of bioequivalence is valid. The following table illustrates the different ratios, and the log-transformed difference.

Starting at the lower limit (80%), we calculate the natural log of the ratio as -0.223. The natural log of the ratio of 100% is 0. Therefore, a symmetrical distribution around 100% on the natural log transformed ratio would be ± 0.223. As shown in the table above, this corresponds to 125% at the upper limit. That’s how we get 80-125% as the target range that represents ± 20% systemic exposure.

This same principle can be used for comparing 2 treatments where a wider range is acceptable.

When conducting a study to compare two treatments, make sure you pick the correct range for the statistical test. Regulators generally accept all these ranges shown in the above table. If you need a custom range (e.g.  ± 25%), calculate it by determining the ln(ratio) of the lower limit. Then create the symmetrical ln(ratio) for the upper limit and back-calculating the untransformed upper limit.