This is an exciting time for biosimilars. Based on a recent MarketsandMarkets report, the global biosimilars market is expected to be worth $19.4 billion by 2014, growing at a CAGR of 89.1% from 2009 to 2014.
While the opportunity is immense, the risk involved with biosimilar development is still high with large up-front investment required and possible failure of the drug during development stages. Given the nature of biosimilars development, choosing the right CRO with capabilities across the drug development spectrum is critical to market success.
Biosimilars are molecules manufactured to emulate a marketed biologic drug in chemical composition and structure, and possess comparable pharmacologic activity, safety, and efficacy. Unlike generic small molecule drugs, however, creating an exact copy of a therapeutic protein is impossible, as the manufacturing process is integral to the final drug product composition and by its nature can never be identical. As a result, regulatory agencies evaluate this category of biologics based on their level of similarity to, rather than the exact replication of, the innovator drug.
Biosimilars allow the creation of high-value medicines with lower regulatory and clinical testing requirements than those for new biological entities (NBEs), but require the demonstration of robust chemical comparability to the innovator compound. The depth and breadth of required testing depends on how well sponsors demonstrate comparability to the innovator molecule. Those with compelling comparability data observe a reduced regulatory burden.
In February 2012, the FDA issued formal draft guidance on biosimilars titled "Scientific Considerations in Demonstrating Biosimilarity to a Reference Product," defining biosimilars as molecules that are "highly similar" to a reference product, with "no clinically meaningful differences."
The draft warns of significant differences between approval mechanisms for small molecule and biologic follow-on products, specifically that a one-size-fits-all pathway would not be possible. The FDA says it will instead "consider the totality of the evidence" when assessing follow-on products.
Specifically, the FDA will consider the product's complexity, formulation, stability, and available analytics, and then apply a risk-based approach relying heavily on pharmacovigilance. The draft FDA guidance is modeled on the European Medicines Agency (EMA) 2004 biosimilars guidance document, which is currently undergoing an update. Other jurisdictions that have borrowed heavily from the EMA guidance include the World Health Organization,Japan,Korea,Canada, and South American countries.
Biosimilar approvals have thus far been limited to follow-on versions of granulocyte colony-stimulating factor (G-CSF), human growth hormone, and erythropoietin. Within a few years, however, patent expirations and emerging regulatory guidances are expected to drive rapid growth. Patents for cytokines, human growth hormone, and insulin expired long ago, which explains why these molecules comprise most of the marketed biosimilars.
The need for increased analytics and the desire for compressed timelines in biosimilars development demands expertise across all phases of development. Selecting a contract research organization (CRO) with proven expertise and broad capabilities in biosimilar development is critical to market success.
Unlike small molecule generics, biosimilars present significant analytical challenges at every stage of development. Developers must invest early in Chemistry, Manufacturing, and Controls (CMC)-type analysis to demonstrate comparability to the reference molecule at every stage, particularly during manufacturing. During nonclinical testing, considerations include assays for in vitro pharmacology, in vivo efficacy, pharmacokinetics, and toxicology. Immunogenicity testing during the clinical phases of development is critical and requires anti-drug antibody assays, as well as assays to assess the neutralizing potential of the immune response, if any.
While analytical and assay considerations do not disappear during human testing, other significant factors, such as review board approvals, ethics, study center availability, and subject recruitment come to the forefront. Similarly, post-approval considerations include initiating a drug registry and accurately tracking the molecule's usage despite a strong tendency by caregivers to ignore brand distinctions between versions of the same molecule.
Market access is another area where an experienced CRO can reduce time to market, for example by creating a strong analysis-based similarity package, and supporting price discounting essential for favorable coverage status. As with innovator drugs, the commercial success of biosimilars depends on the three main stakeholders of market access: payers, providers, and patients. Although the potential cost savings that biosimilars offer may be attractive to payers, some may be reluctant to steer utilization towards these agents without compelling safety, efficacy, and comparability data. Similarly, prescribers and patients may prefer proven treatments over somewhat less-expensive products that may not have a track record. All these activities, from preclinical to market access, demand a high-level regulatory skill set as well.
Most CROs specialize in either preclinical or clinical development. As with innovator molecule development projects, the technology transfer required to hand-off a development project from one CRO to the next can create disconnects between phases leading to costly project delays. This is magnified with biosimilars, which generally do not undergo Phase II human testing. Planning for Phase III, which relies on early-stage analytical, process and formulation data, must begin concurrently with Phase I, and sometimes even during the preclinical stage. This development compression is unheard of with innovator molecules, and demands strong communication and cooperation across preclinical and clinical competencies.
Biosimilars have emerged as one of the fastest-growing development opportunities in the biopharmaceutical sector. However, biosimilar development presents challenges at every level, from selection of a manufacturing platform, to analytical assays, demonstrating comparability, to in vivo testing, clinical testing, market access, and post-marketing surveillance.
Sponsors can minimize roadblocks while streamlining biosimilar development by front-loading analytical methods that demonstrate comparability with the reference molecule, selecting animal studies judiciously, and preparing to maintain a Phase IV drug registry. Companies that navigate these activities successfully may be rewarded with an expedited regulatory review.
Since development timelines are compressed for biosimilars, good planning and communication among technical and regulatory competencies becomes a powerful ally. This can be achieved by working with a CRO capable of providing and executing an integrated development plan from early to late development in order to meet each regulatory milestone for a client's biosimilar needs with their endpoint in mind.
Raymond Donninger, MBChB, MBA, is a senior program manager in Early Development at Covance. In 2008, Raymond joined Covance's Program Management group with particular experience in large molecule development. He has been responsible for the provision of expert advice to clients in the design and execution of effective strategies for biotherapeutic development through pre-clinical and early clinical studies. Raymond also has specific expertise in the field of biosimilar drug development and has been responsible for the successful design, execution, and management of early biosimilar drug development projects for both therapeutic proteins and monoclonal antibodies. Raymond obtained his Bachelor of Medicine and Bachelor of Surgery degree from the University of Cape Town (South Africa) and his MBA from the Gordon Institute of Business Science (South Africa).