Drug Research & Development Overview: Understanding In-vivo And In-vitro Approach In Bioequivalence Testing. Bioavailability and bioequivalence (BA/BE) studies are crucial drug research and development components. BA/BE studies in clinical research provide critical data about the rate and extent of drug absorption and its availability at the site of drug action. Bioequivalence testing is crucial in demonstrating bioequivalence between a test and a reference drug product.
By definition, bioequivalence analysis demonstrates that test product and reference product do not significantly differ in the rate and extent of drug absorption and its availability at the site of drug action when administered at the same doses and under similar study conditions. Sponsors may demonstrate bioequivalence by using in vitro and in vivo studies such as pharmacodynamic, pharmacokinetic, and clinical studies. In certain justifiable cases, sponsors can establish bioequivalence by in vitro studies alone. The following overview will help understand the in vivo and in vitro approaches in bioequivalence testing.
In vivo bioequivalence testing
In vivo bioequivalence testing begins with the Fundamental Bioequivalence Assumption, which states that if two drug products are bioequivalent, then it can be assumed that they are therapeutically equivalent. The next step is to conduct bioequivalence testing under a valid study design with appropriate statistical assessment and submission.
However, in practice, bioequivalence is demonstrated by showing that the confidence interval of drug absorption is within the predetermined bioequivalence limits. A bioavailability or bioequivalence analysis should be a crossover study unless another study design is more valid for scientific reasons. Hence, generally, bioequivalence study has a standard two-sequence, two-period crossover design.
For analyzing bioequivalence testing, sponsors try to achieve average bioequivalence for the test drug. Average bioequivalence means that the average bioavailability of the test and reference drug product lies within the BE limit of 80%-125%. method of Interval hypothesis testing and confidence interval approach is commonly employed statistical methods in in-vivo bioequivalence testing.
In vitro bioequivalence testing
The US FDA recommends seven in vitro tests for assessing single actuation content uniformity for in vitro bioequivalence between a test and reference drug product. These seven tests include plume geometry, cascade impaction, laser diffraction, droplet size distribution, spray pattern, emitted-dose uniformity, priming/repriming, and tail-off profile.
Concerning study design for in vitro bioequivalence studies, FDA recommends testing three products from each lot and sub-lots. Moreover, ten samples should be randomly drawn for each in vitro test. Sponsors randomize study samples for in vitro bioequivalence tests. However, the study analyst will not have the randomization access codes. In addition, sponsors may use an automated actuation station having fixed settings such as dose time, actuation force, return time, and hold time for in vitro tests.Drug Research & Development Overview: Understanding In-vivo And In-vitro Approach In Bioequivalence Testing
As in vivo and in vitro bioequivalence studies are vital components for generic product testing, biological and pharmaceutical companies are more interested in bioequivalence testing. Although in vivo bioequivalence assessments have some pre-defined criteria, in vitro assessments are still not complete and lack clarity in data analysis and study design. Hence, successful bioequivalence testing will need adequate focus on in vitro studies.