Bioavailability and bioequivalence studies are crucial for every phase of drug discovery and development. Bioavailability is the extent to which an active ingredient reaches the systemic circulation and becomes available at the site of drug action. On the other hand, bioequivalence studies show that the bioavailability of two drug products does not differ significantly.
Bioequivalence studies for generic drugs are commonly discussed and debated. However, bioequivalence studies are also conducted for innovator drugs. These cases include:
- Testing drug formulations between clinical trials and marketed drugs or early and late clinical trial formulations
- Testing drug formulations when sponsors make changes to an approved drug product, for instance, changes in inactive ingredients
Bioequivalent drug products are crucial for the drug discovery cycle of generic products. Bioequivalence studies ensure that effectiveness and safety data are derived for generic drugs without repeating extensive clinical trials. The baseline assumption for bioequivalence studies is that if the plasma concentration of two drug products is the same, their concentration will be the same at the site of action. And hence their effectiveness and safety will also be the same. However, manufacturing generic drug products should conform to high-quality standards. Let us now understand measuring bioequivalence for generic drug products.
Generally, bioequivalence studies are conducted in healthy populations to reduce any associated variability between different drug products. Bioequivalence studies are in vivo assessments conducted through cross-over studies. In these studies, each subject acts as a control and is considered adequate for bioequivalence testing. The generated results allow interpretation of the data to respective patient populations such as children, elderly, or organ-impaired patients.
Bioequivalence is measured by comparing the PK parameters of the innovator and the generic drug product. The ratio between these parameters is 1. The acceptance criteria for bioequivalent drug products is that the plasma concentration of the two drugs will not differ significantly. Studies have shown that the mean plasma concentration difference between two bioequivalent drug products is less than 5%. An international consensus has determined a limit of 20% difference between the Cmax and AUC values of two drug products. The difference in AUC and Cmax values must not exceed 20%. Hence, sponsors compare the AUC and Cmax of the innovator and generic drug in bioequivalence studies for generic drugs.
The ratio between the innovator and generic drug must not differ by more than 8:10. This ratio determines the confidence interval for bioequivalence studies. Hence, 8/10 gives 0.80, the lower limit, while 10/8 gives 1.25, the upper limit of the confidence interval. The 90% confidence intervals should thus remain within the upper limit of 1.25 and lower limit of 0.80.
A ratio of mean AUC and Cmax values of the generic and innovator drug close to 1 indicates equality. If the ratio is near the extreme values of 1.25 or 0.8, then the data must not contain variation from the mean values so that the confidence interval of 90% lies within the 0.8 to 1.25 range.