Bioequivalence Studies

Bioequivalence (BE) studies are necessary for generic drug products. They help demonstrate bioequivalence between a reference-listed drug and a brand-name drug. Hence, similar to bioavailability studies for the new drug development process, BE studies are crucial for generic drug products. The current article highlights seven common myths of BE studies observed at different phases of a drug development project.

1. Bioequivalence studies are performed on the patient population.

Although any clinical trial must include the patient population, bioequivalence trials are conducted with healthy individuals. Bioequivalence testing aims at comparing the bioavailability of two drug products. Hence, these two drug products must not be significantly different. All studies inherently have background noise. This noise is generally due to random fluctuations in biological measurements.  This background noise may mask potential differences observed between the two drug formulations. Due to dynamic differences in comorbidities, constitution, and co-medication in the patient population, researchers use healthy individuals to assess any minute differences observed among formulations.

2. All bioequivalence trials use a two-way crossover design.

A two-way crossover study design is commonly used in bioequivalence testing. However, more complex BE designs such as fully-replicated designs are necessary under certain circumstances. For example, while evaluating intra-individual variability, scientists can employ a double crossover approach. These study designs are necessary for highly variable drug products. Highly variable drug products have an intra-individual variance of more than 30% and require more broadened bioequivalence testing criteria.

3. Misunderstanding failed bioequivalence, passing bioequivalence, and inconclusive outcome.

A bioequivalence trial will either generate a single outcome, bioequivalence or bioinequivalence. However, sometimes bioequivalence studies may generate inconclusive outcomes. There are several reasons for inconclusive outcomes, though the inadequate sample size is the most common ., Researchers can design a second sample study to reassess assay variability on such occasions. Alternatively, researchers can plan a 2-stage bioequivalence study to assess sample variability.

4. Highly variable drugs need BE studies with a larger subject population.

It is common to assume that a highly variable drug will need a larger sample size. Though this necessarily need not be the case. Highly variable drugs have intra-subject variability higher than 30%. Regulatory agencies consider variability effects based on confidence intervals. So if a highly variable drug has a wide therapeutic window, the study may not require stringent bioequivalence criteria.

5. Test and reference products for BE testing must have identical doses.

 The above statement does sound accurate. But it is debatable because the identical dose used can be either the dosage form, for example, 100 mg capsule, or the bioavailable dose at the site of action.

6. In the case of a fixed-dose combination product having a new molecule and an already approved drug product, sponsors who conduct  BE studiesin the US, can use the data for worldwide registration.

An innovator drug with a single global compositional image dosage form will not require individual BE studies for regional markets. However,  generic components,  will depend on the regional market image and associated reference listed drug in that particular market.

7. For a marketed dose of 1000 mg, with intended five doses of 200 mg each, researchers have to use the clinical doses for BE testing.

BE studies need testing at the highest strength of a drug product. BE focuses on assessing the drug performance and not the drug doses. So for this example, the BE strength will be 200 mg.