Bioequivalence and biocomparability testing
BioPharm: Have you seen a rise in projects for bioequivalence or biosimilar comparability testing? If so, what unique challenges does
that process present?
Gillett (Charles River): Changes in biologics manufacturing or the development of biosimilars can trigger a regulatory focus on bioequivalence. We
support comparability assessment of many types starting in early in discovery, which can include comparison of drug biochemistry,
binding and potency curves, and toxicology assessments. These are all used along with clinical data to support a sponsor's
claim to comparability and to support international approvals. We expect a rise in these projects as the biosimilars market
Kauffman (Lancaster Labs): Lancaster Laboratories has seen a rise in requests for bioequivalence or biosimilar studies from sponsors in Asia and the
US. A key objective is to identify a few crucial tests that can be applied early in product development and performed to demonstrate
comparability with the innovator product. At later stages of clinical development, full characterization is performed in
accordance with GMPs.
Breau (MPI): Biosimilars are becoming attractive because, with many key biological drugs set to come off patent protection within the
next three years, they provide an entry to a lucrative market with minimal risk. Similarly, biosimilars are attractive to
consumers and insurance providers because of the potential cost reduction without sacrificing efficacy. However, biologics
are, by their nature, more complex than small molecules as noted above, and current technology does not permit complete analysis
of biologics to prove identity of the biosimilar, as is the case for small molecules.
Thus, the development of biosimilars may require the successful execution of bioequivalence studies that assess pharmacokinetics
parameters, as well as clinical endpoints, and not just plasma pharmacokinetics parameters.
In addition, bioequivalence studies for biologics are executed as parallel studies, rather than crossover studies, due to
their long pharmacokinetics half-lives and washout periods. This requires that the clinical studies be sufficiently powered
to ensure that bioequivalence is achieved; inter–individual variation is more crucial than in a classic crossover design.
The development of biosimilars is further complicated by the selection of the bioanalytical method used to assess bioequivalence.
Antibodies are the major reagents used to develop immunoassays to quantitate biologics. Because the biosimilar is not identical
to the innovator's product, it is possible to develop antibodies selective for the biosimilar that bind differently to the
originator compound. Although this would appear to be the ideal choice with respect to selectivity, the introduction of additional
variables to the development process can lead to failure by not demonstrating bioequivalence, due to change in the bioanalytical
Greer (SGS): Biosimilar comparability testing is a major growth area being driven by legal and regulatory requirements. A main challenge
is to assess the various international regulatory guidelines that have been established to ascertain what type of testing
program would be appropriate for a particular molecule. Although guidances exist—including the recently released ones by FDA—it
is clear that authorities examine every submission on a case-by-case basis. In practice, it is important to work in-step with
the authorities, providing projected proposals and preliminary data at a much earlier point in the timeline than usual.
At the analytical level, there are a plethora of challenges related to the choice of originator product to be used in the
comparison studies, together with the fact that the clinical studies cannot be run in the usual way. Additionally, focus should
be directed to choosing the right and sensitive patient population. Similar clinical efficacy should be demonstrated in adequately
powered, randomized, parallel group comparative clinical trial(s), preferably double-blind in the most sensitive patient population.
Thus preclinical data are key in setting up the best study design and meeting the regulatory requirements with the right justifications.