Companies developing biosimilars face a challenge of adopting the right commercial and regulatory strategy, as the regulatory environment is not yet harmonized across the major markets. Draft guidelines for Japanese biosimilars were published by its regulatory agency in September 2008.
By 2010 biologics are expected to constitute more than 15% of the global pharmaceutical market1, with some products worth around $18 billion expected to go off patent by 2011. Most first wave biologics are already off patent and the first few biosimilars or follow-on biologics, have been approved in Europe. The first wave of biosimilars includes products such as EPO, growth hormones, cytokines and insulin. These products are relatively small molecules and are either not glycosylated or only glycosylated to a small extent.
Antibodies on the other hand are much larger molecules and more extensively glycosylated. However, antibodies are also the best selling biologics with Roche?s Avastin having annual sales of US$9.2billion and Abbott and Eisai?s Humira (adalimumab) US$9.1billion. The key patent for Avastin expires in 2016, and that for Humira expires in 2017. Other large sellers will be coming off patent in the nearer future, for instance the US Patent for Enbrel (etanercept) expires in 2012 and that for Remicade (infliximab) will be expiring in 2013. The blockbuster biologics coming off patent in the next few years look attractive to companies who wish to enter the biosimilar development space and secure a share of the market, but will present additional development and marketing challenges because of their greater complexity. As expected much of the reviewers focus is on Quality and the potential of biosimilars for immunogenicity, which is already impacting the approval of biosimilars and is likely to be even more important for the more complex and heavily glycosylated products in development.
Companies developing biosimilars face a challenge of adopting the right commercial and regulatory strategy, as the regulatory environment is not yet harmonized across the major markets. Draft guidelines for Japanese biosimilars were published by its regulatory agency in September 2008. Whilst the EMEA has had biosimilar guidelines in place since 2004, those in the USA are still subject of intense discussion. President Obama is committed to getting legislation on the US statute books and it seems more likely then that it will be „when? biosimilar guidelines will be in place in the USA, rather than „if?. The American Bio Industry Association (BIO) have spent large amounts of money in lobbying and the US Senate and House have not agreed to support 12 months patent exclusivity. With the increased activity stimulated by the new administration?s commitment to act upon, many companies are now developing products to ensure that they have them in place, when innovator products come off patent and the FDA guidelines are in place. Whilst the details of the FDA guidelines are not clearly defined yet, many expect them to follow the EMEA?s lead and are using the EMEA guidelines to outline their development strategy.
In addition to the ICH and EMEA guidelines on developing biological medicinal products there are also several EMEA guidelines specifically covering the development of biosimilars.
The „overarching? EMEA Guideline on similar biological medicinal products (EMEA/CHMP/437/04)2 introduces the concept of biosimilarity. It outlines the principles and acts as a „user guide? to help the sponsor find and understand guidelines of relevance. It sets out the requirements for the „comparator? or „reference? product which should be used throughout the development and suggests different approaches for different product types. Finally, the guideline indicates the 10 year data exclusivity for branded biologicals.
Perhaps the most important is the guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: quality issues (EMEA/CHMP/49348/05)3. Products need to have similar molecular structural properties, robust comparative physico-chemical and biological characterization is required to confirm this. The guidelines make it clear that biosimilars should comply with the same quality standards as for innovative products. In practice it may be felt that, as technology advances the biosimilar products are required to comply with higher standards, afforded by new technology introduced since the original product approval. For monoclonal antibodies, the EMEA draft guideline on production and quality control of monoclonal antibodies and related substances (EMEA/CHMP/BWP/157653/2007)4, should also be consulted. Finally, the ICH Q5E Note for guidance on biotechnological/biological products subject to changes in their manufacturing process (EMEA/CPMP/ICH/5721/03)5 , provides good general guidance and is useful as it not only reflects European thinking, but also that of the other OECD countries.
The third EMEA guideline specific to biosimilars, is the guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues (EMEA/CHMP/BMWP/42832/2005)6. Before initiating clinical development, non-clinical studies should be performed and these should be comparative and powered to detect differences between the biosimilar and reference product. The testing strategy will typically include in vitro binding assays and cell-based functional assays, however interpretation of the guidelines can be difficult for such studies. The guidelines indicate that a comparator product should be included in such studies. However, reference drug substance is normally not available requiring isolation of drug substance from commercially available drug product and demonstration of comparability. This adds to the complexity of such studies and substantially to the costs of proving comparability in in vitro ligand binding or cell-based assays. Whilst routine toxicity & safety pharmacology studies are not required the sponsor should investigate specific safety concerns. Typically (but not always), this means a repeat dose toxicity study in primates which includes toxicokinetics and should examine binding antibodies raised against the biological and determine whether they are neutralizing. The purpose of this is not primarily for direct assessment of safety, although this can be useful in limited cases, but is aimed at understanding their effect on kinetics and pharmacological action of the drug.
The same guidance also addresses clinical development needs. The exact clinical study requirements depend on “existing knowledge about the reference biological medicinal product and the claimed therapeutic indication(s)” and some more specific guidelines are in place for particular products as detailed later. The general non-clinical and clinical issues guideline details some important general clinical study design requirements. The test product should be manufactured by the final manufacturing process to ensure that the product tested reflects what the sponsor intends to market. This rationale should also be extended backwards as far as possible with pre-clinical testing conducted on a product which physically and chemically resembles the final product. This relates not only to the primary structure, but also to post-translational modification. The clinical program must include comparative PK with the reference product and comparative PD with the reference product in a relevant population. Comparative combined PK/PD trials may be sufficient in some circumstances. Clinical efficacy should be assessed in the intended patient population. Clinical safety assessment post-approval is always required for biosimilars and in particular immunogenicity is specifically mentioned and critical to the risk assessment.
Finally, the EMEA also has draft guidelines outlining clinical and non-clinical data requirements for four specific product types: Recombinant insulin, human growth factor, erythropoietin and Colony Stimulating Factors. Specific guidance documents on pre-clinical and clinical studies to be conducted for the development of other biosimilar product classes are expected to become available as activity in particular classes increases.
Whilst the market for biosimilars is large those developing them face high market entry costs. The regulatory pathway in Europe is relatively clear and there is now the political will in the USA to ensure that pathways will be defined in the not too distant future. The next challenge for the industry will be to balance the high set-up and development costs for more complex products against the potentially larger market for monoclonal antibody and fusion protein products. To do this, where the complexity of manufacture is high and demonstration of physical and functional similarity difficult, will be a challenge which we are striving to address.
Finally, a challenge will remain for „Biogeneric companies? to persuade clinicians that they can safely and effectively replace branded monoclonal antibodies or fusion protein originator product with a biosimilar. Whilst the complexity of the second wave of products will make this more difficult the positive experience of clinicians with less complex biosimilars (especially in Europe and Asia), and further squeezing of healthcare budgets is likely to make this task easier.
Clearly, despite the difficulties, the potential rewards are attractive as evidenced by the large number of companies currently developing biosimilars.