Biosimilars, also known as 'biogenerics', 'follow-on proteins' or 'follow-on biologics', are approved new versions of innovator biopharmaceutical products developed following patent expiry. They are distinct from generic drugs, defined by the FDA as drugs that are identical or within an acceptable bioequivalent range to the small molecule innovator drug with equal dose, strength, safety, efficacy, intended use and method of administration. Unlike the more widespread generic small molecule drugs, biosimilars are large molecules that are produced by living organisms and exhibit highmolecular complexity. In contrast to small molecule generics produced by chemical synthesis offering high levels of stability, biosimilar molecules are very sensitive to the slightest manufacturing process changes.
As new manufacturers of biosimilars cannot access the cell bank, molecular clone or the exact fermentation and purification process used to develop the original innovator product, this cannot be identically replicated. To ensure complete confidence in biosimilars, regulations are needed to eliminate concerns that biosimilars may perform differently to the original product. Unlike in the case of generics, clinical trials must generally be undertaken for each new biosimilar, as even miniscule variations in impurities, breakdown products or molecular conformation can result in serious implications for patient health.Regulatory landscape in Europe and the US
The European Medicines Agency (EMA) has implemented an approval scheme that specifically distinguishes between biosimilars and generic drugs in recognition that the generic approach is not scientifically appropriate for these products. 2006 saw the EMA become the world's first regulatory body to legalise a pathway for biosimilar approval, providing 10 years of data exclusivity for innovator drugs and biologics against biosimilar products. The need to minimise the risk to the patient and to protect their safety is recognised in the EMA guidelines by establishing a regulatory framework that requires extensive testing before approval.
The EU guidelines acknowledge that biosimilars are different from the original product in terms of their raw materials and manufacturing processes, and that even slight differences can significantly alter a biosimilar therapy's safety and effectiveness.1 Therefore, the EMA is using a case-by-case approach, which requires comparability between the biosimilar and the innovator product to be justified by appropriate studies, such as clinical trials. However, although the European requirements for biosimilars are extensive when compared with small-molecule generics, they do not necessarily include full Phase III clinical trials in all cases and therefore can often provide for an abbreviated pathway for approval.
In July 2009, two US healthcare bills, the Biologics Price Competition and Innovation Act of 2007 and the Pathway for Biosimilars Act were proposed to create an approval pathway for biosimilars. The two bills survived committee votes in US Congress and the Senate respectively before being reconciled and passed by the House of Representatives in March 2010 as part of the Healthcare Reform legislation. The legislation now stipulates that biosimilars must be subject to at least one clinical trial to demonstrate their safety and efficacy.
The introduction of the new law also guarantees manufacturers a period of 12 years' exclusive market access for innovator biologics before competitors can produce the corresponding biosimilars. This 12-year protection for the original biological compares with only five years of protection for conventional drugs before generic versions appear. In addition, this legislation establishes a regulatory framework by which the manufacturers of biosimilars can gain marketing approval from the FDA. On considering similar biological legislation in 2008, the Congressional Budget Office estimated that over 10 years, as much as $25 billion could be saved through its provisions for FDA approval of biosimilars by significantly driving reductions in the prices of biological drugs.2
However, when discussing the clear benefits of this 12 year data exclusivity to innovator biologics manufacturers, the World Generic Medicines Congress, which took place in London (UK) in February 2010, concluded that the extended exclusivity period has significant implications in delaying the development of biosimilars. As a consequence, the provision is facing fierce opposition from generics manufacturers and some politicians who argue that a shorter exclusivity period is necessary to make the development of biosimilars financially viable. On the other hand, drug innovators contend that the 12-year exclusivity period is vital to recoup the massive research investment they put into the discovery and development of new biologicals.
The first biosimilar medicines were approved by the European Commission in 2006.3 However, despite biosimilars now being a reality across the EU, the future of biosimilars in the US market is dependent upon the application of the regulatory framework, facilitated by the Congressional enactment of legislation. Interested observers will be keen to see how the new US legislative pathway for biosimilars works out in practice when the first applications are filed and the FDA applies the new regulatory framework to those applications.