Biosimilars - The generic biopharma therapeutic drugs

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What are biosimilars?

By definition a biosimilar is 'a biological medicinal product referring to an existing one and submitted to regulatory authorities for marketing authorization by an independent application after the time of the protection of the data has expired for the original product' [6]

In simpler terms, biosimilars are biotechnological drugs that have very similar quality, safety and efficiency of other drugs on the market but are dispensed at substantially lower prices to the original drugs are non-proprietary generic equivalents and are made by different sponsors and produced at a much lower cost due to less research and production costs which we will explain later.

Biosimilars have an extensive amount of uses in our modern world and are essential in the future of pharmaceuticals. Patents on certain biopharmaceuticals have expired or expiring soon will allow unrelated companies to produce generic copies of these drugs to patients. These drugs however differ from ordinary generic drugs we see on the current market, for example: the size and extreme complexity of the product makes it very difficult to produce these biosimilars. This difference in drug types means that they cannot be governed and regulated in the same way as ordinary generic drugs that are relatively simple in chemical and production terms.

Biosimilars will also have a significant effect on world economies. In the US alone, sales of biopharmaceuticals amount to more than $30 billion and in Europe, over €60 billion. With cheaper pharmaceuticals such as biosimilars, lowered costs of drugs will benefit everybody, including healthcare costs and patients. [1]

Marketing History

The marketing of biotechnological drugs began at the beginning of the 80's and the property rights and patents from then have since now expired or will be expired soon. Regulatory authorities must find the issues of concern with these new drugs including the laws and regulations for the commercialization of non-proprietary or "generic" biotechnology drugs. Guidelines will need to be implemented and future predictions predict they will have a significant effect on the biosimilars market.

There is a lot of controversy over the naming of biosimilars such as "biogeneric", "second entry biologic", "subsequent entry biologic", "unpatented biologic product", "multi-source product" and the name given by the US FDA: "follow on biological". In the science community, it is felt that the term "biogeneric" should be avoided as the name implies that concepts relative to traditional generic products may be produced into biopharmaceuticals, as we know this is not true. The term biosimilars will be used in this assignment. [4]

Production Considerations

Producing biopharmaceuticals is a very long and complex process; they are often large recombinant proteins that undergo drastic post-translational modifications and are usually produced by living cells and tissues. The molecular size and complexity of biopharmaceuticals and their production in living cells makes the final product very sensitive to changes in production conditions. Every step of production of a biosimilar will affect the end product significantly. Changes may occur to the expression systems used for production, culture conditions (e.g. temperature and nutrients), purification and processing, formulation, storage and packaging stages. These small changes in manufacturing processes may have a significant impact on the quality, purity, biological characteristics and clinical activity of the final product.

Even when these biosimilars are cultivated from the same genetic material, doing everything precisely the same, same formulation and the same manufacturing steps, this does not guarantee the two products will be the same. This can be down to a number of reasons such as oligomerization, modification of the protein primary sequence and different glycosylation patterns. This demonstrates the complexity of the job at hand. [7]

Producing biopharmaceuticals and the way in which they are made are property of their respective companies. Therefore biosimilar companies cannot directly copy or clone bio pharmaceutical processes. When biosimilars are made, the manufacturers must show that their products have similar likeness and effects of the originator drugs, they must also show that there is direct consistency between production runs to avoid patients over or under dosing on the drug.

The products must be thoroughly tested via many methods before being granted as being safe. Such tests are in-vitro tests which compare biosimilars to originator products. The product's characteristics that are compared are higher-order protein structure, polar charge and hydrophobic properties, isoforms and aggregates, receptor/target binding, bioactivity and prediction of immunoreactivity with assays based on conformation-dependent antibodies. [3]

The Approval of Biosimilars

For biosimilars, clinical trials are not just the verification and registration of a generic small molecule drug product; they are required rather than just bioequivalence studies. They are treated as directed by the EU Directive 2001/83/EC which states "that where a biological medicinal product which is similar to a reference biological product, does not meet the conditions in the definition of generic medicinal products, the results of appropriate pre-clinical tests or clinical trials relating to these conditions must be provided."

The biggest challenge is to find the exact nature and behavior of the non-clinical and clinical program required to gain regulatory approval. The producer is advised to provide a detailed description of the nature of the product and the strategy used to demonstrate the biosimilar relative to the originators products' profile in terms of quality, safety and efficiency.

How the product does in these quality tests in terms of proven comparability will have a significant impact on the number the clinical and non-clinical studies the biosimilar will need to be subjected to. The official dossier should be submitted by the applicant to the EMEA and contain data on possible unwanted immune reactions to the therapeutic protein. Post-marketing pharmacovigilance plans are also expected to be included in the biosimilar dossier.

Generic pharmaceuticals contain efficient, safe and well established active substances. These drugs must be proven to show bio equivalence with the reference product. Generally speaking, this means that the producers must show that the same dose of the generic and reference product behave in the organism in the same way. They must also be at the same quality standard. This means, consequently, that the generic drug must be interchangeable with the reference product and available as an option to the original treatment.

The marketing application for biosimilars requires the results of toxilogical and pharmacological trials to proceed to manufacturing. This is due to the complex development processes of these bio-products. Every stage in production of these products requires absolute quality control, "the process is the product".

A different approach is required as opposed to the generic approach. It must follow the EU Directive 2003/63/EC (Annex I, Part II, section 4) states that:

"…the information to be supplied shall not be limited to pharmaceutical, chemical and biological data, supplemented with bio-equivalence and bio-availability data. The type and amount of additional data (i.e. toxicological and other non-clinical and appropriate clinical data) shall be determined on a case by case basis in accordance with relevant scientific guidelines published by EMEA (Directive 2003/63/EC)."

There are different requirements to prove safety and efficiency and these are product specific. The most significant question to be answered by any bio-similar applicant is how much testing is required to demonstrate how their product is similar to the reference product and the type of data they will include in their biosimilar marketing authorisation application. [5]

Comparability Studies

The European Directive 2004/27/EC notes the biosimilar medicines subject as follows:

"Where a biological medicinal product which is similar to a reference biological product does not meet the conditions in the definition of generic medicinal products, owing to, in particular, differences relating to raw materials or differences in manufacturing processes of the biological medicinal product and the reference biological medicinal product, the results of appropriate pre-clinical tests or clinical trials relating to these conditions must be provided. The type and quantity of supplementary data to be provided must comply with the relevant criteria stated in Annex I and the related detailed guidelines. The results of other tests and trials from the reference medicinal product's dossier shall not be provided (Directive 2004/27/EC)."

The basic outline of this directive indicates that comparability studies between a similar biological product and its originating product must be performed, however it does not suggest how they must be performed. As mentioned earlier, tests for these biosimilars can be very different from each other as production processes are complex and vary from one case to another.


Physico-chemical comparability

Biological comparability

Pre-clinical comparability

Clinical comparability

The reference medicinal product must be authorized in the Community on the basis of a complete dossier in accordance with the provision of Article 8 of Directive 2001/83/EC, as amended (Directive 2001/83/EC). The data and criteria extracted from the tests must demonstrate the similarities of the products in terms of quality, safety and efficiency.


Immunogenicity is the ability of a particular substance to provoke an immune response from the body. This is another factor that distinguishes biosimilars from generic drugs. Changed immunogenicity is a very significant safety consideration in biosimilars' studies. The immunogenicity profile can have a devastating effect on the products safety. It must be thoroughly tested on a considerate number of patients to compare the hostile event profile between the biosimilar and the reference product. [5] For example: Antibodies induced against a biopharmaceutical may interact with the corresponding endogenously produced protein and cause severe side effects e.g. pure red cell aplasia with erythropoietin biosimilars. Even though these effects might only be seen in a small minority of patients, on a large scale however, this can be catastrophic. [6]

Another example of this is when biopharmaceuticals are used to replace endogenous proteins, which may be present in different concentrations (e.g. the use of ESAs in CKD patients with anaemia). This protein carries the serious risk of stimulating the immune system to develop anti-product anti-bodies that may cross react with the endogenous protein. This gives the biosimilar the potential to induce an undesired immune response. [7]

Differences between biological protein products claiming to be biosimilars to approved and regulated biopharmaceuticals already on the market are a main concern to the pharmaceutical industry and regulatory agencies around the world. The intristic structural and physicochemical heterogeneity of biopharmaceuticals and the extraordinarily complex manufacturing process has the potential to affect their safety and efficacy. This means that these biosimilars that manufacturers claim to work are very difficult to test and approve which, in turn means that there is a risk to patients that use these therapeutics. [7]

The extent of data available after medicinal trials may be limited depending on the aggressiveness, rarity and immunogenic potential of the therapeutic protein. However, predicted immune reactions are required to be tested before marketing authorization. Even after the marketing authorization, further trials may be conducted which may be included in the biosimilar application's risk management plan. In Europe, immunogenicity data is kept for 1 year and should normally be available pre authorization. [5]

Biosimilars in Oncology

Through the use of recombinant technologies, a variety of therapeutic proteins have allowed the use of biopharmaceuticals to become significant players in the ongoing battle against cancer. As we learned earlier, a lot of the patents on these pharmaceuticals have expired or are expiring soon. This has driven the development of alternative therapeutics we know as biosimilars.

The primary and secondary structures and biological functions in a biosimilars protein should be an exact copy of the reference products. This is to ensure the similar effect and functions within a body. However, the tertiary structure within the biosimilar may be completely different from the reference product. This change, however, is hard to determine and difficult to prove in tests. This is the main problem occurring with regard to immunogenicity, the difference in the tertiary structures may affect the immune response of patients in different ways.

Early trials of new biosimilars such as the erythropoietin biosimilar had very successful results. The erythropoietin biosimilar has been shown to have the same effect on hemoglobin concentration in chronic renal failure and chemotherapy-induced anemia as the reference product. These trials, however, were performed on a small number of patients and with short observation periods. [6]


Price competition in the UK generics market is very intense, this means that the biosimilar market will more than likely follow suit when biosimilars are finally introduced to primary healthcare. I believe this will be accomplished when they release the insulin biosimilar. It may revolutionize the pharmaceutical market and open people up to the possibility of follow on biologics.

The competition is especially relevant to the biopharmaceuticals markets which carry a higher price tag then generic drugs and conventional pharmaceuticals. Regulatory authorities will need to address certain discordances and work to meet the requirements to aid the development of biosimilars. This, however is easier said than done as there is always a pressure on the government for the healthcare budgets and they cannot wait until biosimilars turn a profit.

Instead they must develop interim mechanisms that allow the HTA (Health Technology Assessment) organizations to assess biosimilars demonstrating comparable pharmacological and biological activity to reference as we talked about earlier in the comparability section. Scientists believe the HTA organizations should lead the way of the EMEA (European Medicines Agency) and accept pharmacokinetic and pharmacodynamics equivalence as a proxy of biosimilarity. After these reasons and in the absence of persuasive reasons in specific cases, the HTA bodies should accept the CMA as the basis of the cost effectiveness deliberations.

When comparability studies are not available, the HTA bodies should accept efficacy, utility and costs derived from the studies of the originator product based on a meta-analysis. This model and other models need to remain dynamic. Biosimilar manufacturers and producers and regulators are advised to remain rigorous pharmocovigilance for immunoreactivity or other rare cases.



[1] Ira S. Krull, Anurag S. Rathore. (2010). Biosimilars: introduction, concerns, and opportunities... BIOTECHNOLOGY TODAY. 28 (1), p 598.

[2]Roger, Simon D. (2010). Biosimilars: current status and future directions. Expert opinion on biological therapy. 10 (7), p1011.

[3] Roger, Simon. (2010). Biosimilars: current status and future directions. Expert Opinion on biological therapy. 10 (3), p 1011-1018.

[4] Genazzani, Armando A. Biggio, Giovanni Caputi, Achille Patrizio Del Tacca, Mario Drago, Filippo Fantozzi, Roberto Canonico, Pier Luigi. (2007). Biosimilar Drugs: Concerns and Opportunities... Current Opinion. 21 (6), p 351-356.

[5] Leyre Zuñigaa and Begoña Calvo. (2010). Biosimilars approval process. Regulatory Toxicology and Pharmacology. 56 (3), p374-377.

[6] Håkan Mellstedt. (2010). Implications of the development of biosimilars for cancer treatment. Future Oncology. 6 (7), p1065-1067.

[7] Huub Schellekens. (2009). Biosimilar therapeutics-what do we need to consider? Nephrology Dialysis Transplantation Plus. 2 (1), i27-36.

[8] Alan Stewart. (2009). Addressing the Health Technology Assessment of Biosimilar Molecules. Current Medical Research and Opinion. 26 (9), p2119-2126.