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 specifically on immunogenicity in mAbs, which the EMA points out are known to be 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).