The European Union has reached an important stage in its efforts to make the region a biosimilars production center. The London-based
European Medicines Agency (EMA), which licenses EU pharmaceuticals, has finalized a guideline on biosimilar monoclonal antibodies
(mAbs) and is drafting another one on the key issue of quality of biosimilars (1, 2).
Cover courtesy: Photodisc/Thinkstock
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
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
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,
"[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) .