Dr Pablo Fernandez is Senior Vice President, Medical Affairs, PharmaNet.

Pablo Fernandez

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.   

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.

  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

 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.

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.

  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.  

Across the globe, pharmaceutical companies are making headway in the field of biosimilars. However, although a number of countries have, for the last few years, approved the marketing of biosimilars through their general existing regulatory requirements, the US, Europe, Japan and Canada are the only regions to have established specific regulatory approval systems for biosimilars. In Japan, Sandoz, a generic drug company and subsidiary of Swiss innovator Novartis, has gained marketing approval of Japan's first therapeutic biosimilar, Somatropin BD, the recombinant human growth hormone somatropin. In Canada, Sandoz has also received market authorisation for Omnitrope, where it is the first biosimilar of a previously approved recombinant drug to achieve approval from Health Canada under 'Information and Submission Requirements for Subsequent Entry Biologics'. Sandoz believes that the European provision of 10 years of data exclusivity, plus two or three years of market exclusivity, offers a valuable guideline for the US. 

Following Sandoz's move into the biosimilars market several years ago, the industry has seen regulators becoming more familiar with the process. Over the next few years a number of other generic companies are expected to attempt to enter Western markets with biosimilars. Indian manufacturers including Ranbaxy, Dr Reddy's Laboratories and Biocon, are aiming to gain approval for their biosimilars in Europe in the near future as well as eventually in the US. Despite these ambitious plans, there are still considerable barriers, including regulatory hurdles, patent litigation and marketing issues, which will continue to restrict companies' attempts to enter the field.   

In light of the uncertain global regulatory environment and as the worldwide market for biosimilars continues to grow, mounting pressure will be placed on biopharmaceutical manufacturers as they jockey for position within the newly competitive marketplace. In spite of the uncertainties, one certainty remains: the need for significant R&D investment to get a biosimilar to market. 

The manufacture of biosimilar drugs requires specialised capabilities, meticulous planning, highly skilled staff and significant financial investment. This investment could, however, place strain upon a company, draining its resources and diluting its overall success.  

To ensure that the approval process for a new biosimilar is efficient with reduced timetomarket, manufacturers are starting to outsource to CROs that provide a full spectrum of services encompassing drug discovery, development, preclinical and clinical trial processes, and the accompany data and risk management. Aside from having access to the appropriate technology and equipment, CROs can offer a wide breadth of expertise, having in some cases been involved in the development of the original biological products, which can prove extremely helpful for manufacturers that are new to biosimilars development and when technical issues arise. 

Some CROs are also highly specialised in applying analytical techniques, such as mass spectrometry to characterise and profile biologics, and Enzyme-Linked Immuno-Sorbent Assays (ELISAs), Radio-Immuno Assays (RIAs) and multiplexed Meso Scale assays to conduct comparative immunoassay analyses with the reference product.  

There are clear market opportunities and challenges for biopharmaceutical companies engaging in the development of biosimilars. Outsourcing to CROs may accelerate the time to market; a fundamental benefit being the reduction of pressure on companies to invest in new technology and personnel, and the ability to free up capacities for innovative or high margin products. As such, the use of CROs for such projects is expected to continue to rise as the market for biosimilars experiences growth. 

The biosimilars field is a rapidly growing segment of the pharmaceutical market. US market research firm Decision Resources has found that nearly one-quarter of the top 100 drugs in 2007 were biologicals and 13 of them achieved worldwide revenues of more than $2 billion dollars. Further interest in biosimilars will also no doubt be driven by the fact that many of these drugs will reach their patent expiry within the next 5–10 years.  

As the industry moves forward, global development is essential to enable pharmaceutical companies to remain competitive and financially viable. It is also the only feasible way to improve worldwide availability, affordability and access to biologicals. The European Generics Medicines Association (EGA) suggests that in pursuing these goals, a sciencebased approach towards global development should be adopted to achieve regulatory approval in the main markets.  

				Looking at the medium-term prospects, it is unlikely that a high number of newcomers will enter the Western marketplace and only those who are able to cost-effectively develop high-quality molecules that meet EMA and FDA standards, are likely to remain in it.

 is Senior Vice President, Medical Affairs, PharmaNet. 

1. EMEA Guideline on Similar Biological Products, October 2005.

2. S. 1695 Biologics Price Competition and Innovation Act of 2007

 (Congressional Budget Office, Washington DC, US, June 2008). 

3. Biosimilar Medicines FAQ, European Generic Medicines Association. 

Articles

As biopharmaceuticals will soon make up 50% of new drug approvals there has been a significant rise in interest in the field of biosimilars.