Bioequivalence and bioavailability studies (BA/BE studies) are crucial components of the drug development process. Early BA/BE studies in clinical research pave the way to subsequent complex studies. For generic drug products, bioequivalence testing forms the basis for demonstrating biological equivalence between a test drug and its corresponding reference listed drug. Usually, both in vivo and in vitro bioequivalence studies (BE) are needed to submit ANDA applications.
In bioequivalence analysis, highly variable drugs are drugs that exhibit variability in Cmax and AUC parameters. Generally, highly variable drugs have an intra-subject variability of 30%. Data suggests that around 10% of ANDA applications have some degree of high variability in BE studies. In the present article, we will discuss the strategy for designing in vitro BE studies and the testing methodology for highly variable drugs.
Design of in vitro bioequivalence studies and testing methodology
FDA guidance recommends performing in vitro BE studies through seven in vitro tests. The seven in vitro tests are droplet size distribution, emitted dose uniformity, plume geometry, spray pattern, tail-off profile, and priming/re-priming studies. Each of these seven tests should demonstrate comparable characteristics between a test and a reference-listed drug.
Three products from each lot are needed for these in vitro tests. Researchers randomly select ten samples from each lot and randomly assign them for in vitro tests. Moreover, researchers don’t have access codes for randomization. An automated actuation station is generally employed for in vitro BE studies. Furthermore, these tests can be assessed through profile analysis or non-profiled analysis.
Issues about bioequivalence analysis for highly variable drugs
At first, the issues surrounding highly variable drugs don’t seem serious. Most of the applications for ANDA clear the requirement of 0.80-1.25 regulatory levels. However, this data does not reflect the true nature of all parties concerned with generic drug development. Studies show that the drug failure rate because of being a highly variable drug goes up to 54%. The data states that only the drugs passing the regulatory criterion are submitted to the FDA, and hence the regulatory bodies usually underestimate the financial consequences of highly variable drugs.
Over the years, various attempts have been made to uplift some of the challenges faced during in vivo bioequivalence testing of highly variable drugs. Some of the recommendations are as follows.
- Relaxation of regulatory requirements
- Widening of BE limits based on reference variability
- Direct expansion of BE limits
- Expansion of BE limits based on scaling and sample size
- Expansion of BE limits based on a Fixed sample size
Noteworthy, scaled average bioequivalence is a promising approach with which regulatory bodies are moving forward.
The assessment of in vitro bioequivalence studies for highly variable drugs has increasingly garnered attention from several players in the drug development space. In vivo BE studies have some statistical criteria, but for in-vitro BE studies, statistical criteria, clinical trial designs, and data analysis still have gaps. Hence, drug development companies and regulatory bodies must work together to bridge these gaps in in-vitro bioequivalence studies.