Biosimilar mAb development clarified
The mAb guideline's overall aim is to lay down general principles for nonclinical and clinical studies on any potential differences
between a biosimilar mAb and a reference mAb and how much these differences may amount to a dissimilarity between the two
products. The guideline recommends a step-wise approach, with both in vitro and in vivo studies being conducted on a case-by-case basis. For example, comparative in vitro studies would be conducted first to assess differences in binding or function, with the necessity for additional steps involving
in vivo work being determined by the need for additional information.
Extrapolation of clinical efficacy and safety data to other indications of the biosimilar, based on the overall evidence from
the comparability exercise, would be acceptable, according to the guideline.
In its draft guideline on quality of biosimilars, EMA states that, "it is not expected that all quality attributes (between
the biosimilar and the reference product) will be identical and minor differences may be acceptable, if appropriately justified"
(2). In the mAb guideline, the agency points out that assays have been developed in recent years allowing more in-depth characterization
of complex proteins both at the physicochemical and functional levels. These assays have enabled more effective assessment
of minor quality differences in manufacturing processes for mAbs. Nonetheless, EMA warns that "in the current state of knowledge
it may be difficult to interpret the relevance of minor quality differences" when comparing a biosimilar with a reference
mAb (1) .
Regulators expect that during the postauthorization pharmacovigilance stage, unpredicted adverse results from differences
in manufacturing process could be detected. Incorrect extrapolations from nonclinical or clinical data during comparability
assessments could also be revealed.
The EU's pharmacovigilance legislation, approved in 2010, simplifies reporting of adverse drug reactions and the submission
of periodic safety update reports (PSURs), data from both of which will be held centrally.
Postauthorization safety and efficacy studies can be requested from drug-licence holders by the authorities. Applicants for
marketing approvals of medicines will have to submit postauthorization risk-management plans.
For biosimilars, particularly mAbs, pharmacovigilance requirements will be tougher than for conventional medicines. "The pharmacovigilance
system is an essential part of monitoring biosimilars after approval," says Morrison. "[The legislation] provides for additional
monitoring for biological products, including biosimilars."
The mAb guideline states that applicants for marketing authorization of their mAbs or other biosimilars will have to provide
a "comprehensive concept" of how further postauthorization safety studies will be carried out. The safety plan will cover
safety claims based on extrapolations of efficacy and safety data during the comparability exercise and occurrences of rare
and particularly serious adverse effects. In addition, because adverse reactions to biosimilars could be due to defects in
manufacturing processes, the products should be clearly identifiable by name and batch number, according to the mAb guideline.