Preclinical CMC studies are crucial for achieving an abbreviated approval pathway for a biosimilar. GMP batch release assays
should be supplemented by additional characterization studies to enhance the claim of similarity, for example with GMP/GLP
cell-based and in vitro assays. Because innovator companies do not publish detailed CMC results, this information must be produced independently
using results from clone selection, media and feed development, purification and formulation.
Biosimilar developers may improve on the innovator molecule through modern manufacturing and analytics, but this improvement
may trigger designation by regulatory authorities as a "biobetter," or even an innovator drug, resulting in a more extensive
development pathway. Biobetters are considered new molecular entities and usually require a full development process.
Analytical methods for developing biosimilars are similar to those used for developing innovator drugs. However, because the
goal with biosimilars is comparability, the approaches and issues associated with the analytical methods are somewhat different,
as explained below. For a biosimilar erythropoietin (EPO), for example, the sponsor must use the same EPO brand as the comparator.
The sponsor must purchase several lots and either aim for properties somewhere in the middle of the range shown by the innovator
drug or demonstrate the same level of variability. The same approach applies to stability, accelerated stability, and shelf
Comparative in vivo animal efficacy studies are useful in demonstrating nonclinical similarity. Some models, however, are proprietary, and others
may have become redundant since the innovator drug was introduced. By contrast, comparative in vivo animal safety studies can be less valuable. EMA product specific guidelines, for example, suggest that the rodent is the
species of choice wherever possible for biosimilar testing (3). This type of testing is possible with compounds such as EPO,
but less so with monoclonal antibodies, where nonhuman primates are frequently the only relevant species. Animal safety studies
may be complemented by an assessment of pharmacodynamic responses in some cases, but this is not always possible with highly
Predicting human immunogenicity and pharmacokinetics from primate studies can be similarly challenging. Antidrug antibodies
(ADAs), which occur regularly in test animals, may often confound pharmacokinetic studies. Primate toxicology studies lack
sufficient statistical power, and immunogenicity is generally poorly predictive of clinical immunogenicity.
The majority of biologics do not show true toxicity, but rather exaggerated pharmacology. Hence, toxicology studies may add
limited value for these molecules if not carefully designed.
Early discussions with regulators regarding clinical studies of biosimilars are highly recommended to confirm that the preclinical
package will adequately support clinical development. These discussions also are essential if the sponsor plans to extrapolate
efficacy and safety data across different indications.
Certain clinical study design issues are specific to biosimilars. Comparability must be shown in a step-wise fashion in both
the pharmacokinetic and pharmacodynamic settings. Immunogenicty assessment is also required to show correlation to clinical
efficacy and safety. Sponsors need to evaluate immunogenicity in all individuals in the clinical trial, not only those who
are symptomatic. Sponsors must demonstrate clinical efficacy and safety through clearly defined comparability margins. Equivalence
studies are required under the current European guidance, but noninferiority designs may be acceptable.
To streamline patient recruitment, sponsors may petition to combine Phases I and III, a strategy that EMA is currently considering.
Securing patients and investigator sites is yet another reason to perform preliminary clinical feasibility studies well ahead
of Phase III, preferably during preclinical work. An important consideration of clinical feasibility assessment/site identification
is that some sites motivated by innovative or novel studies may not wish to participate in biosimilar studies.
Drug supply can affect how the sponsor chooses to test a drug. Studies conducted in the European Union, for example, must
employ reference material registered in Europe. In the US, FDA is likely to require US-registered material (2). Regulators
in both regions are in discussion and considering ways to relax origination rules, perhaps by allowing for a future single
source option for reference material.