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).
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.
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, non-original 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 post-launch 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) .
Regulators expect that during the post-authorization 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, par ticularly 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 post-authorization 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.
A global enterprise
Because of the high expenditure necessary on manufacturing facilities, development, and pharmacovigilance activities, biosimilar producers are looking for ways of curbing costs. Merck Serono and Dr. Reddy’s are among pharmaceutical companies that have formed an alliance in the production and development of biosimilars, mainly mAbs, to spread the risk. DSM of the Netherlands and Crucell, a Dutch subsidiary of Johnson & Johnson, have reduced the scope of Percivia, their US-based joint venture in biosimilars by ending in-house product development. “In order to reduce the overall development costs, we need in the EU and in the US a scientific framework which allows global development,” says Kox.
The European Commission has appeared to be acknowledging the need for global development of biosimilars when it recently announced it would accept applications for approvals of biosimilars containing data from reference products that come from outside the EU. “[With this announcement] a new regulatory paradigm is born, which is a great achievement after years of discussion,” says Kox. “The issue of the reference product is not the only one to achieve global development. But for companies to be able to use data from tests from reference products that are not sourced from the EU constitutes a major and far-reaching regulatory breakthrough.”
The European Commission has yet to finalize details on how a comparability exercise with a reference product outside the EU would work. But the decision does seem to show that the EU is intent on continuing to take a lead on biosimilar regulatory matters without waiting for US guidance on the development of biosimilars to be formally adopted. FDA issued three draft guidance documents earlier this year to assist companies in developing biosimilars for the US market (5–7). Under the Patient Protection and Affordable Care Act of 2010, biosimilars are due to be allowed to be marketed in the country by 2014.
1. EMA, Guideline on Similar Biological Medicinal Products Containing Monoclonal Antibodies—Non-Clinical and Clinical Issues (London, June, 2012).
2. EMA, Guideline on Similar Biological Medicinal Products Containing Biotechnology-Derived Proteins as Active Substance: Quality Issues, revision 1 (London, May 2012).
3. EMA, “Multidisciplinary: Biosimilar,” www.ema.europa.eu/ema/indexjsp?curl=pages/regulation/
accessed Oct. 13, 2012.
4. EMA, Guideline on Immunogenicity Assessment
of Monoclonal Antibodies Intended for In Vivo Clinical Use (London, June, 2012).
5. FDA, Guidance for Industry: Q & As Regarding Implementation of the BPCI Act of 2009 (Rockville, MD, Feb. 2012).
6. FDA, Scientific Considerations in Demonstrating Biosimilarity to a Reference Product (Rockville, MD, Feb. 2012).
7. FDA, Quality Considerations in Demonstrating Biosimilarity to a Reference Protein Product (Rockville,
MD, Feb. 2012).