The FDA has provided draft guidance for the industry entitled “Bioavailability and Bioequivalence Studies Submitted in NDAs or INDs—General Considerations.” This document includes systematic guidance on how to conduct bioequivalence and bioavailability (BABE) clinical trials for submission of INDs and NDAs.
Regulatory bodies define bioavailability as the rate and extent to which an active ingredient is absorbed from a given drug product and becomes available at the site of action. BA data provides an estimate of the fraction of the drug absorbed and information related to the pharmacokinetics of a drug.
Bioequivalence is defined as the absence of a significant difference in the rate and extent to which the active ingredient in pharmaceutical formulation becomes available at the site of drug action when administered or given at the same molar dose under similar conditions.
BE studies compare the exposure profile of a test drug product to that of a reference drug product. If two drug products are shown to be bioequivalent, they are assumed to reach the same therapeutic effect and they are therapeutically equivalent.
A BABE study should be crossover in design unless a parallel or another design option is more suitable. Researchers often consider a standard 2-sequence, 2-period (or 2×2) crossover design for a bioequivalence study.
Conduct of BABE clinical trial:
- The BA or BE study should be conducted under fasting conditions (after an overnight fast of at least 10 hours). If the BA or BE study needs to be undertaken with food, separate FDA guidance is available to assist sponsors.
- The test and reference products must be administered with about 8 ounces (240 milliliters) of water to an appropriate number of subjects.
- Usually, the highest marketed strength should be administered as a single unit. If warranted, multiple units of the highest strength can be administered, provided the total single dose remains within the labeled dose range, and the total dosage is safe for administration to the study subjects.
- An adequate washout period should separate each treatment, with 5.5 half-lives for immediate-release products and 8.5 half-lives for controlled release products.
- The lot numbers of both the test and reference listed products and the expiration date for the reference product should be stated. FDA recommends that the assayed drug content of the test product batch should not differ from the reference product by more than +/- 5 percent.
Blood sample collection and sampling times
Blood sampling should continue for at least three or more terminal elimination half-lives of the drug to capture 90% of the relevant AUC. It is undesirable to draw too much blood too frequently from subjects under study. The sample collection should be spaced in such a way that the maximum concentration (Cmax) of the drug in the blood and terminal elimination rate constant (λz) can be estimated accurately.
Data submission and analysis
For IR products, FDA indicates that a single dose fasting study in bioanalytical laboratory is required, while a limited food effect study may be required when needed. For CR products, FDA recommends single-dose non-replicate fasting and food-effect studies to be conducted. Multiple-dose experiments are generally not expected. Average bioequivalence is claimed if the geometric means ratio (GMR) of average bioavailability between the test and reference products is within the BE limit of the following (80%, 125%) with 90% assurance based on log-transformed data.
USFDA has provided guidance on the conduct of bioequivalence and bioavailability studies, and this article mentions the vital steps for conducting BABE trials that include specifications for study design, data handling, sample collection, data submission, and analysis.