To supplement an eight-year-old basic regulation laying down the general principles behind the introduction of biosimilars, EMA has issued a series of product-specific guidelines. These cover biosimilars for insulins, somatropins, granulocyte-colony stimulating factor (G-CSF), epoetins, low-molecular weight heparin, and interferon-α (3). However, the guideline on mAbs is seen as technically the most challenging because of the complexity of the drugs in terms of their biological structure, range of clinical indications, and potential for unwelcome adverse effects, particularly immunogenicity.
The mAb guideline was published at the same time as a separate one on immunogenicity in mAbs, which the EMA points out are associated with unwanted immunogenicity (4). Because the mAb guideline concentrates primarily on safety and efficacy, quality matters are being covered by the general quality guideline for biosimilars, currently in the consultation stage."The finalization of the EU mAbs guideline can be regarded as another major milestone in the scientific framework for biosimilars," says Suzanne Kox, senior director of scientific affairs, at the European Generic Medicines Association (EGA), which is in Brussels.
THE HIGH COST OF DEVELOPMENT
The EMA, unlike with nationally-approved generic drugs, is responsible for licensing biosimilars and has so far authorized 14—two somatropins, five epoetins, and seven G-CSF filgrastims. The publication of the mAb guideline is expected to trigger a sizeable number of mAb biosimilars applications. As with previous guidelines, however, the one on mAbs confirms the expectation that biosimilars production and development will be an expensive business because of the high cost of manufacturing facilities and of conducting nonclinical and clinical trials.
"To get started in the biosimilars business, a lot of investment is required in biopharmaceutical production facilities—probably around €300–400 million ($390–520 million)," said Andreas Barner, chairman of Boehringer Ingelheim, at an R&D conference at Ludwigshafen, Germany, earlier this year. "Even more important will be the high cost of developing biosimilars because, for the first time, nonoriginal medicines will have to be supported by large-scale clinical trials," he continued. "The sector will suit companies which already have biopharmaceutical plants and have experience of bringing original compounds to the market."
In the EU, the cost of regulatory compliance for biosimilars will be pushed up even further by the implementation of the EU's new rules on pharmacovigilance, which stipulate additional postlaunch monitoring of biological drugs, particularly biosimilars, and mAbs.
"[Pharmacovigilance] is particularly important with monoclonal antibodies as these are complex molecules with complex safety profiles," says Alan Morrison, chairman of the regulatory affairs advisor committee of the UK Bioindustry Association (BIA).
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) .