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For global markets, there is a need to balance the imperative to get to market quickly against the evolving regulatory landscape
Despite the controversy surrounding the thicket of regulatory requirements for approval of biosimilars in various markets, regulatory agencies and governments around the world are pushing for these products’ availability as part of their efforts to reduce healthcare costs. The advent of biosimilars thus appears to be inevitable. The only questions are when that occurs, and what the process will be for biosimilar drug developers to get their products to market. At Catalent, our experience and continued involvement with biosimilar drug developers give us a valuable perspective on what that process will be in the United States, Europe, and other key markets, including those where biosimilars have been commercially sold for a number of years.
The situation in the EU
Let’s first look at the European Union (EU), which of all the world’s more regulated markets is perhaps furthest along in terms of paving the way for approval and marketing of biosimilars. In 2005, the European Medicines Agency (EMA) became the world’s first regulatory body to draft guidelines on biosimilar products.  Those guidelines were followed by complementary guidelines on quality issues and nonclinical and clinical issues (2006) [2,3], immunogenicity assessment (2007) , and specific guidelines for several types of medications.  The EMA is currently revising the 2006 nonclinical/clinical issues guideline; the first draft revision of the 2006 guideline on quality issues is now available.  Additionally, in 2012, the EMA published a guideline on nonclinical and clinical issues pertaining to monoclonal antibodies. 
More recently, the EMA published a draft guidance outlining general principles for developing biosimilars in the EU. Under the guidance, biosimilar sponsors who use a reference product approved outside the EU must provide data from analytical studies demonstrating an “acceptable bridge” between the biosimilar, the non-EU reference product, and the EU-approved innovator reference product. The guidance, which is to replace the 2005 general guidance on biosimilars, does not define what EMA considers “similarity,” nor does it specify what constitutes a “significant difference” between a biosimilar and an innovator product. 
Although the EMA has approved 14 biosimilars (mostly recombinant proteins) for marketing (see Table), and the first biosimilar antibodies are poised to enter the market, biosimilars have had only partial success thus far in the EU, due to lingering questions over “meaningful differences in efficacy” between biosimilar and reference biopharmaceutical drugs (aka “innovator products”); a lack of demand-side incentives to prescribe or dispense biosimilars; a limited number of companies with the expertise and financial wherewithal to bring biosimilars to market; physician brand-loyalty to innovator products; application of rebate contracts to innovator products following expiry of patent protection; and life-cycle management strategies of innovator product marketers. 
The situation in the US
In the US, the Patient Protection and Affordable Care Act of 2010, through section 7002 of the Biologics Price Competition and Innovation (BPCI) Act of 2009, created an abbreviated approval pathway for evaluation of biosimilars. [10,11] The abbreviated pathway was further spelled out in FDA’s 2012 draft guidance for the industry on implementation of the BPCI Act approval process for biosimilars, in which the agency stated a “totality-of-the-evidence” approach would be used to review scientific and quality considerations in demonstrating biosimilarity to a reference protein product. [11,12] For a would-be biosimilar developer, the FDA’s approach leaves ample room for interpretation. The guidance included a requirement for “a clinical study or studies (including assessment of immunogenicity and pharmacokinetics or pharmacodynamics) sufficient to demonstrate safety, purity, and potency in one or more appropriate conditions of use for which the reference product is licensed.” 
As these regulations undergo further review and revision, the US remains behind Europe, Latin America, and Asia in terms of biosimilar drug development and commercialization. Although the US market for biosimilars is slowly growing, with more companies expressing interest in biosimilars (and a handful of US-based companies evaluating and/or using Catalent cell lines for possible biosimilar development), uptake is not as broad as in Europe or Asia.
In the last six years, 10 Latin American countries have published regulations concerning approval of biosimilars. Most of these countries follow and/or consider international standards such as those issued by the EMA, FDA, and World Health Organization (WHO), though some (e.g., Mexico, Cuba, Venezuela, Brazil) have regulations that consider international standards as well as local market aspects.  Biosimilar products are already available in some Latin American countries, and biosimilar drug development activity tends to be more robust in this region than in the US. Given that the regulatory framework for biosimilars is more advanced in Europe than in other regions, the model for biosimilars development in Latin America will probably more closely resemble that of Europe than that of the US.
For an outsourcing partner such as Catalent, Asia-based drug companies—especially those based in India—constitute a growing proportion of our biosimilar customer base. Among Asian nations, India has made the most headway in terms of bringing biosimilars to market. Many biosimilar developers are taking advantage of India’s comparatively short regulatory pathway to bring products to market faster, and using their commercial experience in India to expand into regulated markets, such as the EU. Some Indian drug companies are leveraging their commercial exposure in India to collaborate with EU-based companies to take their biosimilar compounds to EU clinical trials.
In Japan, where biologics are relatively new, interest in biosimilars is just starting to heat up. Establishment of contract manufacturing partnerships with Japanese companies specializing in biologics is a recent phenomenon.
How outsourcing partners are advancing biosimilars
One of the key issues facing biosimilar developers is that innovator companies can retain their proprietary process knowledge, even if they lose control of the composition of the biologic compound. Consequently, biosimilar developers must develop processes that result in proteins that are as similar as possible to innovator biologic molecules. Partners are therefore providing important process development services (in addition to manufacturing services) to ensure such similarity. These services include evaluation for activity, antibody-dependent cell-mediated cytotoxicity (ADCC), glycosylation, pharmacokinetics (PK), pharmacodynamics (PD), and other factors.
Having knowledge of the process development the innovator used can not only help attain similarity needed, but also significantly shorten the development time. Not surprisingly, innovator companies are very protective of this information, and some have tried to prevent release of PD data from FDA documentation to potential competitors. Outsourcing partners are thus playing an important role in terms of helping biosimilar developers control such factors as media conditions, pH, and temperature shifts, any of which can potentially affect yield or glycosylation.
Some partners are also developing biosimilar cell lines for sale to companies for further development and manufacturing. Those partners with dedicated analytical services and regulatory groups, such as Catalent’s, can also provide data on key attributes that can help a biosimilar developer determine if its product meets requirements for biosimilarity.
Additionally, some partners are providing customers with protein material for evaluation to determine if it is “similar” enough to take the cell line for development and manufacturing. Catalent can provide data on multiple clones to help companies determine which cell lines to target for development, whether in-house or by Catalent. We can also develop proprietary sequences for biosimilars that customers bring to us.
Providing crucial regulatory support can be an important service to companies operating in markets with a more advanced regulatory framework (e.g., US and EU). Such companies may need more data than companies in less-regulated countries (e.g., India), and therefore will probably become more involved in analytics. With our Regulatory Affairs group, Catalent can also advise customers on regulatory issues they are likely to face in the markets in which they hope to introduce biosimilars. Catalent can thus provide an integrated offering of development, analytical and regulatory support.
Table: EMA-approved biosimilars 
Where biosimilars are headed: challenges and opportunities
Patent-life extensions of innovator products suggest that development of biosimilars will not go unchallenged. Indeed, Amgen’s 2011 extension of the Enbrel® patent  has left many would-be developers of biosimilars uncertain of how—and whether—to move forward. Where there is momentum is in applying the commercial experience of generic products in India and other less-regulated markets to biosimilars, starting in Europe (where Biocon and Mylan are collaborating to start biosimilar clinical trials) and possibly extending to the US.
Another area of uncertainty is interchangeability, not only in terms of the ability to exchange from one molecule to the next at the pharmacy level, but also from one indication to another. In the US, Virginia recently enacted the first state law allowing pharmacists to dispense biosimilars, provided FDA has licensed the biosimilar product as interchangeable with the prescribed biologic product.  The procedural requirements attached to the Virginia law (e.g., requiring pharmacists to inform patients of the substitution prior to dispensing the product, and to record the brand name or product name, along with the name of the biosimilar manufacturer, on the dispensing record and prescription label) will make potential use of biosimilars more difficult.
Furthermore, unlike generics, biosimilars will probably require additional studies and post-marketing data to alleviate consumer and physician concerns about safety, although FDA probably will not rely very much on data from other countries. From a marketing perspective, innovator companies will probably exploit such safety concerns while reinforcing their own safety track records.
Additionally, biosimilar marketers will need sizeable sales forces due to the smaller cost differential vis-à-vis innovator products (i.e., compared to generics), as well as to reassure their customers about safety. Many smaller companies may therefore seek partnerships with larger companies as a means to deploy an adequate sales force.
Innovator companies may respond to the entry of biosimilars by positioning their products as “biobetters.” Some innovator companies may make minor modifications to their products to add value, extend patents, or enhance market share. Such improvements or changes may be a new route of administration, improved bioavailability (e.g., longer half-life), or conversion from vial to prefilled syringe (i.e., to reduce the risk of contamination and for patient convenience). Innovator companies may thus promote “biobetters” for their potential to improve compliance, especially if these products can be administered at home, which may help increase market share and revenue.
Despite the challenges facing biosimilar developers, and the efforts of some innovator companies to delay biosimilars’ arrival, it is only a matter of time before a viable market emerges for biosimilars. The rising interest in biosimilars, as reflected in the increasing demand for biosimilar proteins and cell lines for potential development, suggests that the market for biosimilars will be robust. As governments around the world have stated their commitment to lowering healthcare costs, interest in biosimilars is likely to intensify. At the same time, innovator companies may try to stem the tide by launching their own biosimilar development efforts, securing patent extensions for their original molecules, or supporting laws that may make it more difficult to bring biosimilars to market. Such developments will bear watching as biosimilar developers strive to develop a vibrant market for their products.
ABOUT THE AUTHOR
Sven Lee is global vice president, biologics at Catalent Pharma Solutions