Bioavailability and bioequivalence (BABE) studies are necessary components of IND and NDA applications. Bioavailability studies the rate and extent to which a drug is absorbed and becomes available at the site of action. Bioavailability testing helps sponsors determine the amount of drug absorbed and understand the pharmacokinetic properties of the drug product.
BA/BE in clinical trials has become a routine analysis. Bioequivalence testing demonstrates that the rate and extent of drug absorption and its availability at the site of action are not significantly different when administered at the same doses under similar conditions. Sponsors conduct in vivo and in vitro bioequivalence studies to assess drug exposure between a test and a reference drug product. Moreover, BE studies are critical for specific drug formulations or changes in the manufacturing process during different drug development stages. Hence, in today’s article, we provide you with five expert tips while designing bioequivalence studies.
Designing a BE study
Sponsors generally conduct BE studies using a crossover study design. Moreover, sponsors should consider intrasubject variability while determining the sample size. Sometimes a parallel study design is necessary for evaluating BE. In these cases, sponsors should consider the total variability, including both intra subject and intersubject variability.
Ensuring stable rate and extent of absorption
Sponsors should ideally meet the rate and extent of absorption limits in BE studies. If the rate and/or extent of absorption of a test product is outside the acceptable limits compared to the reference drug, the drug product might fail in BE testing. For instance, if the systemic exposure of a test product is significantly higher, the results typically demonstrate safety concerns at higher systemic concentrations.
Avoiding lower systemic exposure
If the test product has a significantly lower systemic exposure than the reference drug, the test product potentially lacks therapeutic efficacy. On the other hand, higher systemic exposure indicates concern for both efficacy and safety. This concern suggests that the test and reference products are not comparable and may produce variability in clinical use.
Considerations in the absence of BE testing
When a BE study is not demonstrated, researchers must show that the test drug does not significantly differ in the rate and extent of absorption. They must demonstrate the efficacy and safety of the test drug based on the concentration-response or dose-response data. If sponsors fail to provide this evidence, they should reformulate the product, change the manufacturing process or provide additional efficacy and safety data for a successful drug development campaign.
Understanding when additional data will be needed for BE studies
Sometimes, Cmax and AUC-based conclusions are insufficient to demonstrate efficacy and safety data between a test and a reference drug product. This inefficiency is likely when systemic concentration-time profiles are different for the test and reference drug product. For instance, the difference in systemic concentration profile suggests that the test drug and the reference drug will have different clinical responses. Hence, in these conditions, sponsors may need additional data analysis, clinical studies, or exposure-response evaluations to study BE between two drug products.
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