Studies measuring bioavailability and bioequivalence (BA/BE) are vital for NDA, IND, and ANDA submissions. Bioavailability refers to the rate and extent to which a drug product becomes available at the site of drug action. Bioavailability studies provide drug absorption data and information related to drug pharmacokinetics, making them crucial in the early drug discovery phases.
Two drug products are bioequivalent when the rate and extent of drug absorption and availability at the site of drug action do not differ significantly. Bioequivalence studies are necessary for generic formulations where a test drug is compared to a reference-listed drug. Bioequivalence analysis involves testing the exposure profile of a reference drug and a test drug product. The current article is a quick guide to BE study guidelines.
Guidelines for bioequivalence studies
As both BA/BE studies focus on drug absorption and its distribution in the systemic circulation, FDA recommends similar approaches for BA/BE analysis. However, BE studies have a more formal process consisting of predetermined BE limits and specific references.
During IND submissions, BE documents can help compare product strength equivalence, early and late clinical trial formulations, clinical trial and stability study formulations, and to-be-marketed drug and clinical trial formulations. For each of the above comparisons, the new strength or new method drug is the test drug, and the prior formulation is the reference product. However, the extent of BE documentation depends on relevant guidelines that may define the proportion of changes and suggestions required through subsequent in vivo and in vitro studies.
For significant post-approval changes, FDA recommends conducting in vivo BE studies to demonstrate bioequivalence between the modified drug and the prior drug before changes. Besides, the regulatory guidance suggests supplementing completion studies for specific post-approval changes before the drug is marketed to the target population. Moreover, the FDA has provided the SUPAC-MR and SUPAC-IR guidelines for in vivo and in vitro BE studies for modified-release and immediate-release drug products.
Generally, scientists perform BE studies using a crossover study design. Determining the sample size for a crossover study design requires demonstrating intrasubject variability. A parallel design may often be necessary for BE analysis. However, researchers must consider both intra-subject and inter-subject variability for parallel studies.
When BE data is unavailable for a drug product, sponsors must prove that the absorption rate does not affect the efficacy and safety of the test drug product. This evidence is usually demonstrated through concentration-response data or dose-response data. However, without this data, sponsors must reformulate the drug product, conduct additional safety or efficacy studies or change the manufacturing method.
Sometimes, the Cmax and AUC data can be insufficient to exhibit similarity in efficacy and safety data. This inadequacy is particularly evident when the reference product and test drug product profiles differ in systemic concentration. Such differences in systemic concentration profile may suggest different clinical responses between the test and reference drug. During such cases, the FDA recommends additional data analysis, clinical studies, or exposure-response assessment for evaluating BE between two drug products.