Need and Growth of Biosimilars

Last week the US Senate held a hearing to discuss the rising cost of insulin; the prices of insulin have trebled in the last few years and one of the factors that were reported was the need for more inexpensive " generic" versions of Insulin or biosimilars that could help in providing affordable insulin. In India, the first long-acting basal insulin glargine biosimilar was approved in 2009, while the first insulin glargine biosimilar to be approved in the EU and USA was in 2014.

The market for generic versions of biologics drugs is growing both in the developed and developing countries.  As more drugs come off patent, pharmaceutical companies are investing more money into creating biologics as the cost of introducing the drug into the market is significantly lower and the time to market is also shorter compared to an entirely new drug which can take anywhere between 10-15 years.   Biosimilars also provide a more affordable option in developing countries where the originator drugs are prohibitively expensive due to the royalties collected on them and the majority of the population is uninsured severely limiting treatment options.  

Generics versus Biosimilars 

A generic version of a drug like aspirin is manufactured using chemical methods.  These chemical compounds are exact replicas of the originator drug.  They share the same physicochemical, pharmacokinetic and pharmacodynamic properties as the original molecule.  While generics are synthetic chemical compounds, biosimilars are derived from a biological source or manufactured using living cells,  and these molecules are never exact replicas of the originator drug and therefore referred to as biosimilars.  Consider an antibody, a protein that has a molecular weight of 150 kDa  - almost three orders of magnitude larger than aspirin (molecular weight 180.158) that is made up of twenty different amino acids strung together which is folded over itself in a very specific way to generate a molecule that has a three-dimensional structure.  In addition, in an antibody, some of the amino acids are glycosylated and the different protein subunits are linked through covalent bonds.  These post-translation modifications add an additional layer of complexity to the protein.

Why is it difficult to manufacture a generic version of a biological drug?

The challenge in manufacturing a biosimilar antibody or protein is to make sure every amino acid in the protein sequence is identical to the original molecule and the biosimilar carries the same post-translational modifications.  A lot easier said than done.  Biosimilars may or may not be manufactured using the exact method used for the original drug as this information is not freely available as it is often protected by patents.  As a result, different cells may be used for manufacture using different media, growth conditions which all result in minor differences in the protein that is synthesized by these cells.  Differences in post-translational modification could arise generating different isoform ratios, which may affect its efficacy. Downstream processing can also influence isoform ratios.  Finally, the type of excipients added and the formulation of the product can affect its stability, structure, and function.   

Comparability Studies

The purpose of the comparability studies is to address similarities and differences in a biosimilar in relation to the originator drug and any impact it may have on a patient treated with a biosimilar.  Though the development cycle is shorter for biosimilars the companies still have go through the rigor and quality checks required by the FDA to get approval to market the biosimilar within the USA and these requirements vary depending on the country.  For example in India, as of 2016, CDSCO, the regulatory authority responsible for approving clinical trials and drugs has put forth a guideline for marketing biosimilars in India.  The guideline states that a similar biologic can be developed provided the originator drug has been approved for use in India or licenses/ marketed or approved in any ICH country.  The comparability studies should demonstrate comparable quality, safety and efficacy data between the biosimilar and the originator biologic drug.

Development of a biosimilar involves executing a number of analytical and bioanalytical tests that are used for characterizing the molecules and these results are compared with the originator drug.  Differences in structure, post-translational modifications, impurity levels, isoform ratios, function, immunogenicity, pharmacokinetic and pharmacodynamic studies are collected and are required to be reported to the regulatory agencies in EU and the USA before the drug can be approved in the clinic.  In fact, a glargine insulin biosimilar was approved in the US through a “new drug application” and not via a “biosimilar” approval route.

Use of biosimilars in the Clinic

Physicians are often faced with substituting a biosimilar for the originator drug due to price and in countries like India where there are multiple biosimilars available for the same originator the switching decision can be tricky.  Typically, biosimilars are prescribed for new cases rather than switching someone already taking the originator drug. The cost of a biosimilar, though lower than that of the originator drug can still be expensive for several sections of society.  For example, there are 114 brands of erythropoietin sold in India and a vial of erythropoietin from Johnson & Johnson marketed under the name of Eprex sells for ~ Rs 2010 ($29.68) for a vial of 4000iu while Ranbaxy’s erythropoietin for ~Rs 1500 ($22.15) for a vial of same strength, while Epofit manufactured by Intas Pharmaceuticals is sold at ~ Rs 785 ($11.59).  More awareness and education regarding biosimilars is necessary for both patients and physicians to allow them to take an informed decision regarding the use of a biosimilar.  

These questions become extremely important in countries like India where there are insufficient quality measures and regulatory checks in place for manufacturing drugs.  In order to complicate matters further, many versions of erythropoietin sold in India are considered as non-innovator drugs and not biosimilars.  These drugs though based on the originator drug may contain different sequences or impurities.   Both biosimilars / non-innovator drugs become a bane to society if introduced into the market without adequate clinical data to support their use.  Hence, having strict quality measures that are continuously enforced, preclinical studies and clinical studies to support each drug that is marketed, and clear labeling requirements becomes essential.  With proper systems and processes in place, biosimilars will prove to be a blessing even for developing countries.