Following a surge in the use of biologics in hard-to-treat disease areas, such as rheumatology, oncology and other chronic
diseases, reflected in an industry prediction that biopharmaceuticals will soon make up 50% of new drug approvals, there has
been a significant rise in interest in the field of biosimilars. The possibility of marketing new versions of existing biopharmaceuticals
whose patents have expired is becoming increasingly attractive to manufacturers, particularly as more innovator products come
off patent over the coming years.
Dr Pablo Fernandez
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.