Bioavailability/Bioequivalence (BA/BE) Studies

A common design to compare two formulations is a randomized, two-period, two-sequence single-dose crossover design. A sufficient length of washout period of at least five half-lives (the time it takes for the drug to be eliminated from the body) between dosing periods is necessary to prevent a possible carry-over effect of the previous dose to the next dosing period. Sometimes, a higher-order crossover design (Balaam’s design, two-sequence three-period dual design, four-period design with two sequences, four-period design with four sequences) may be needed to estimate intra-subject variability between formulations.

For the renewal or extension of product registrations of generic medicines, the test product used in bioequivalence studies should be compared with a corresponding dosage form of the comparator or innovator product. The test product should be representative of the actual marketed product.

An appropriate sample size calculation should be done to determine the number of participants included in the study. It is also imperative to control factors that may result in variations unrelated to the differences between drug products. For this reason, studies are normally performed on healthy volunteers. The suitability of volunteers should be based on clinical laboratory tests, a medical history, and a physical examination. Participants are preferably nonsmokers and without a history of alcohol or drug abuse. Additional medical investigations and precautions may have to be carried out before, during, and after the completion of the study depending on the drug’s therapeutic class and safety profile.

Other than the characteristics of participants, diet, fluid intake, and physical activity are also standardized. There may be certain food and drinks that should be abstained from which may interact with circulatory, gastrointestinal, hepatic, or renal function (e.g. alcoholic drinks, caffeine, grapefruit, citrus fruits, or other food and beverages containing xanthines) during a suitable period before and during the study. Participants should also not take any other concomitant medication (including herbal remedies) for an appropriate interval before as well as during the study. In case unavoidable, such as in the instances of treatment of adverse events, the use of concomitant medication should be reported indicating its purpose and dose and time of administration.

Administration of drug products or formulations to the participants should be based on the randomization plan. Generally, a single dose study should be conducted after fasting for a specified number of hours as stated in the study protocol, and subsequent fasting usually four hours after administration dosing. A standardized volume of fluid intake should be administered with the test and comparator products as fluid intake may influence gastric passage for oral administration forms. After the administration, blood samples are withdrawn from the participants at specified time intervals. Each collected sample is analyzed to determine drug concentration at a specific time point. Drug concentrations are analyzed over time to determine the rate and extent of absorption of the drug products under study.