term "Biosimilar" is used to refer to a biological product
that resembles a biological product approved by the Food and Drug
Administration. In true sense, biosimilars are cost-effective
imitations of FDA approved biologicals that are used to treat
different kinds of pathological conditions and they come with
identical levels of efficacy and safety standards. The FDA approved
biological products on which the biosimilars are based are called
reference products and the Biologics Price Competition and Innovation
Act of 2009 states that a product can only be termed as biosimilar
when credible laboratory data exist to substantiate the claims of
high biological similarity. Since biosimilars are not quite the exact
copies of biologicals it becomes necessary that they clear more
rigorous tests to be accepted as replacements. An FDA approved
biosimilar can be dispensed by a pharmacist in place of the reference
product if the need arises without the need for any intervention from
the prescribing doctor and needless to say, all biosimilars fulfil
the same rigorous safety and efficacy requirements recommended by FDA
While biosimilar research and development is still at a very nascent stage in the United States, the scene is very different across the Atlantic in Europe. For the year 2015, trade analysts have predicted business in excess of $4 billion in the European biosimilar industry and the forecasts for the coming years are even more encouraging. The trend however has not gone unnoticed and the promising market forecasts are good enough reasons for pharma giants such as Pfizer to invest $17 billion in Hospira acquisition, a pharma company with a very robust presence in the biosimilar sector. FDA has also already taken the first steps to bring biosimilars to the United States by allowing a biosimilar for a drug called filgrastim that is used to boost the immune system of patients receiving treatment for cancer (Lorenzetti 2015).
How are biosimilars created:
It is already known that the production of biologicals is an extremely complex process and as a molecule, biologicals are also highly complex compared to the generic drugs. With regards to biosimilars, the manufacturing process is equally complex if not less and it becomes critically important that they are able to guarantee the same levels of efficacy and quality as that of the reference biological product. The creation of biosimilars involves development of proprietary cell lines and this is precisely the reason why their manufacturing process is very different from that of the reference biological (Mellstedt, Niederwieser and Ludwig, 2007).
In the biosimilar development and manufacturing process, the first step is to thoroughly understand the molecular characteristics and the structure of the reference biological product. This step should be able to clearly identify all the biological, chemical, clinical and structural attributes of the reference product and the most ideal approach is to analyze the product at different time point along its lifeline. The information gathered from this step can be used by the biosimilar manufacturer to create a roadmap for the development of their product with same levels of efficacy and safety (Sandoz-biosimilars.com, 2016).
In the next step, the production and testing of the biosimilars can be carried out using highly sophisticated biotechnology protocols and bio-analytical tools in a manner that they perfectly satisfy all the milestones defined in the roadmap developed in the first stage. The production steps will have to optimized multiple times to ensure that the biosimilar molecule produced have the same structural, chemical and clinical properties as that of the reference product. Because of the multiple optimization cycles the biosimilar manufacturing and development process takes far longer time compared to the reference biological product. After the product is ready it becomes necessary for the manufacturer to liaison with the drug regulatory authorities to draw up plans to carry out clinical trials so that the product can be released into the market for use. Figure 1 below presents an overview of the biosimilar development and manufacturing process (Sandoz-biosimilars.com, 2016).
Fig 1: An overview of the biosimilar development process (Sandoz-biosimilars.com, 2016)
Biosimilar manufacturers do not have access to the production protocols of reference products
(Schellekens and Ryff, 2002). Also since there are no definitive ways to predict how a particular protein molecule will behave clinically, the differences between a biosimilar product and the reference product can easily go unnoticed. For this reason, the need to enforce strict guidelines becomes very critical to ensure that the difference in the protein characteristics, if any, will not put users to any harm and will have the same level of efficacy that is expected from the reference biological. Figure 2 below shows an overview of the European Medicines Agency guidelines for biosimilars (Mellstedt, Niederwieser and Ludwig, 2007).
Fig 2: European Medicines Agency guidelines for biosimilars (Mellstedt, Niederwieser and Ludwig, 2007)
Uneasiness with biosimilars:
While biosimilars can be highly beneficial for the healthcare industry there are issues that need to addressed to alleviate the fear surrounding their use. As already stated, biosimilar manufacturers have no access to the manufacturing protocols of the reference product because of proprietary issues. For this reason the development process of a biosimilar molecule is blind in nature, thanks to the lack of knowledge and information. Once the final product is ready, the biosimilar manufacturers are required to reverse engineer the process to ensure that the manufactured biosimilar is identical to the reference in terms of the clinical and biological attributes. This is a highly complex and time consuming process that requires high levels of sophistication, monitoring and pharmacovigilance. Given these complexities, the European Medicines Agency guidelines state that a biosimilar must clear clinical studies to demonstrate their similarity with the reference product before being considered for approval by the regulatory body. Needless to say, these are stringent regulations but there are instances where biosimilars that have cleared all the tests during their manufacturing and development stages have exhibited variations from their reference products (Miletich et al., 2011).
Another potential concern surrounding not just biosimilars but biologicals in general is immunogenicity. Even Though biosimilars share structural, clinical and biological attributes with their reference product, the immunogenic reactions that they may elicit could vary significantly. For this reason the data on immunogenicity concerning the reference product can never be directly applied to the related biosimilar product. There could also be instances when a particular drug elicits an adverse reaction when administered to a particular individual. In such cases the information on the label of the medicine is referenced to see if any contraindication is mentioned or if the reaction elicited is unique. This is followed by the execution of the safety protocols mentioned in the label to offset the adverse reaction. However, when a biosimilar shows any adverse reaction in a patient, the information on the label of the reference product could be rendered meaningless (Sharma, 2015).
While the issues and the concerns mentioned in the earlier section are justified there are ways to deal with them and offset all the risks. Some of them could be rigorous surveillance of the biosimilars after being released into the market to detect any adverse immunogenic reaction and proper independent evaluation of all biosimilar adverse reactions and their notification in the biosimilar labels.
In the recent years, phenomenal progress in medical research have led to the development of biologics that are providing new hope to patients suffering from cancer and autoimmune diseases. Market analysts have predicted that by the year 2020 a range of biological products with sales in the excess of $67 billion will lose their patents and the biologic market share as a whole will touch yearly turnover of over $250 billion (Zwebb, 2016). Biosimilars will constitute 4-10% of this market share and given the fact that they are low-priced by up to 30% compared to their reference product, the cost benefit to the healthcare industry and eventually to the patients is self-evident (Rovira et al., 2011).
In spite of the initial promise of massive cost benefits the development of biosimilars is not moving at a very fast pace. In the markets trend, even though encouraging, is still at an evolutionary stage. People have also expressed concerns surrounding the stability and the usability of biosimilars as when it comes to the health and safety of patients, there is no scope for complacency. In this context, it can be anticipated that the development of the biosimilar market in a large scale will face barriers and hurdles and it will be prudent for the biosimilar manufacturers to thoroughly understand the risks and properly evaluate if it could be a trade-off with the cost benefits to the healthcare industry across the globe. Without doubt, biosimilars come with their own benefits and with it the responsibility of all the players in the healthcare industry to collaborate closely and develop products that are safe and can increase the outreach of good healthcare to the underprivileged sections of the planet.
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