Biosimilars: from the poor relations of generics to the nouveau riche of 2020
With marketed products in just three rather minor therapy areas and global sales in 2010 estimated at around $250m,1 biosimilars may have barely registered on pharmacists’ radars. But the rapidly expanding market for branded biological products — already worth $120bn of the near $900bn global pharmaceutical market — is resulting in some eye-watering predictions for biosimilars in the next five to 10 years. Add to that the growing interest of “big pharma”, with its serious research and development and marketing spend, and biosimilars could soon be transformed from the poor relations of traditional generics into the next generation nouveau riche.
“When some of today’s big biotech products come off patent in the next few years, it will be a major opportunity for biosimilars to compete. But a lot will depend on whether the current generation of biosimilars have proved they are as safe and effective as the original biological products, so that clinicians become confident about using them,” explains Jorge Mestre-Ferrandiz, senior economist at the Office of Health Economics (OHE).
He points out that some of the more extravagant predictions for the first generation of biosimilars — erythropoietin, granulocyte colony stimulating factor and growth hormone — were based on extrapolating from experience of growth in the more conventional chemical generics market. But that was a mistake.
“Chemical generics can typically offer up to an 80–90 per cent price discount and take most of the market for the original product within two to three years after a patent is lost. But biosimilars aren’t like generics — they are similar, not identical. The regulatory hurdles are different and this is having a major impact on the price that can be charged for a biosimilar and the proportion of the market that is likely to be achieved. So we are starting to see a reality check on how the biosimilar market is likely to develop and how it might progress to ‘biogenerics’, if at all,” Dr Mestre-Ferrandiz said.
Similar, not identical
The Medicines and Healthcare products Regulatory Agency requires that, unlike chemical generics, biosimilar products have their own evidence of comparative safety and efficacy before they receive marketing approval. This is because they are likely to have a similar but not identical structure to the reference biological product with which they will compete.
The MHRA advises that, unlike chemical generics, biosimilars should be prescribed by brand name to avoid any possibility of substitution when they are dispensed.2 Similarly, adverse drug reporting should always use the brand name of the product, rather than the generic name.
EU regulatory framework
The has established a regulatory framework for approval of biosimilars on a case-by-case basis. The agency defines a biosimilar as a biological medicine that is similar to another biological medicine that has already been authorised for use.4 In turn, biological medicines are defined as medicines that are made by a living organism, such as a bacterium or yeast. These can consist of relatively small molecules, such as human growth hormone or human insulin, or complex molecules such as monoclonal antibodies.
The EMA states that biosimilars can only be authorised for use once the period of data exclusivity on the original “reference” biological medicine has expired — generally after a period of at least 10 years. It requires a company to show that a biosimilar is similar to the reference medicine and does not have any meaningful differences in terms of quality, safety or efficacy.
Although the amount of information needed to support a biosimilar licence application is less than for a new biological product, it is much more than the evidence of clinical pharmacokinetic bioequivalence that can usually get a chemical generic product onto the market. Requirements include preclinical evidence of comparable pharmacodynamics and toxicity with the reference biological, and clinical trial evidence of comparable efficacy and safety in appropriate patient populations.
In a recent review of regulatory hurdles in a report published by the OHE, Gopalan Narayanan, manager and head, biologicals and biotechnology unit of the MHRA, pointed out that clinical trial endpoints for biosimilars do not necessarily have to be those required of a new drug, but they do need to be sensitive enough to reveal any differences compared with the reference product.5 Trials have to be large enough to show true differences and long enough — six to 12 months — to demonstrate safety. There is also a requirement for a risk management programme or pharmacovigilance plan for post-marketing surveillance, and all biosimilars should carry a black triangle on their packaging.
“A good post-approval plan is an important complement to a robust pre-approval assessment. It assures regulators that safety issues will be monitored and addressed if they arise. This is far better than being surprised by a rash of adverse reports,” concluded Dr Narayanan.
Biosimilars: what’s available in the uk
In the UK, three biological products are currently available as biosimilars;
• Filgrastim (Neupogen) is also available as Tevagrastim, Ratiograstim, Zarzio and Nivestim
• Somatropin (Genotropin) is also available as Omnitrope
Last year, the National Institute for Health and Clinical Excellence recommended a biosimilar for the first time in any of its guidance.3 It included Omnitrope as one of seven somatropin products for the treatment of child growth deficiencies. Marketed by Sandoz, Omnitrope was the first biosimilar to be licensed in the EU in 2006.
The EMA has published general guidelines on the regulation of biosimilars and more specific concept papers, and draft and finalised guidelines on the testing requirements for different types of product. These currentlycover erythropoietin biosimilars, interferon alpha and beta biosimilars, low molecular weight heparin biosimilars, follicle-stimulation hormone biosimilars and, most recently, monoclonal antibody (MAb) biosimilars. Released at the same time as the draft MAb biosimilar guidance was an additional guideline on immunogenicity assessment for MAbs intended for in vivo use.
All the additional regulatory testing required for biosimilars is reflected in the increased cost of their development compared with generics — currently estimated at $75–250m per licensed biosimilar, compared with only $2–3m for a licensed generic. This is still considerably less than the approximately $800m to get an original biological product on the market, but the biosimilar arena is clearly no place for the faint-hearted. Although the EMA has approved biosimilars for erythropoietins, somatotropin and G-CSFs, applications for biosimilar insulin and interferon have failed.
The major players
Sandoz — once a stand-alone pharmaceutical company but, since 2003, the global generics arm of Novartis — claims an almost 50 per cent share of the global regulated market for biosimilars. It markets three biosimilar products in the UK:Binocrit, Zarzio and Omnitrope.
Sandoz recently announced that it had begun a phase II clinical trial of biosimilar rituximab. This anti-CD20 MAb will be a major prize for any biosimilar company when it comes off patent in 2015. The reference biological product, MabThera, marketed by Roche, ranks among the top three biologic drugs worldwide, with 2009 sales of $5.6bn. Sandoz’s phase II study in rheumatoid arthritis patients aims to demonstrate bioequivalence to MabThera, and will collect pharmacokinetic, pharmacodynamic, efficacy and safety data. Preclinical studies have already shown sufficient similarity of biosimilar rituximab with Mabthera.
US-based company Hospira specialises in generic injectable pharmaceuticals and markets Retacrit and Nivestim in the UK, and claims one of the largest biosimilar pipelines. In 2009, it announced a distribution agreement with Korean contract manufacturers Celltrion, which boasts biosimilar MAbs in development for breast and colon cancers, Crohn’s disease, rheumatoid arthritis and Hodgkin’s lymphoma.
Two other companies have biosimilars on the market in the UK. Teva, the Israeli firm specialising in generics, markets Tevagrastim and, in 2009, it announced a partnership with Swiss producer of pharmaceutical ingredients Lonza to develop, manufacture and market a biosimilar portfolio. Ratiopharm, the German generics manufacturer, markets Ratiograstim in the UK, but was recently bought by Teva.
Outside the UK, other generics specialists are marketing their own versions of the first-generation biosimilars erythropoietins, filgrastim and somatropin and, in emerging markets, already dipping their toes in the potentially more lucrative MAb biosimilar market before patents on reference products have expired in Europe and the US. One of the best known of these companies, Dr Reddy’s, launched Reditux (rituximab) for the treatment of Hodgkin’s lymphoma as long ago as 2007 and has eight biosimilars in development, two of them in clinical trials.
“Big pharma” fights back
With its Herceptin (trastuzumab), MabThera (rituximab) and Avastin (bevacizumab) providing juicy targets for biosimilar companies in the next few years, Roche has already outlined its strategy to deal with interlopers by developing “biobetters”. It defines these as new biological compounds designed to be better or superior to the reference product, with marked differences in clinical efficacy, safety and convenience.
Last December, the company announced promising efficacy in phase II studies for GA101, the first type II, glycoengineered anti-CD20 MAb, which was used in hard-to-treat patients with non-Hodgkin’s lymphoma, some of whom had failed on rituximab. Already in phase III clinical trials is Roche’s pertuzumab, an anti-HER2 MAb that appears to act synergistically with the company’s established HER2 blocker, trastuzumab. As “biobetters” for bevacizumab, Roche has a range of MAbs in development that target tumour angiogenesis.
Given the need to put “biobetters” through the more rigorous and more expensive testing procedures for new biological molecules — with no guarantee that they will actually prove better than the primary brands — some major pharmaceutical companies have put aside decades of antipathy to generics and are pursuing biosimilars of their own.
Merck established its BioVentures arm in 2008, with the intention of developing a portfolio of both novel biologics and biosimilars and, last year, announced that it had five new biologics and two biosimilar candidates in clinical development, with plans for five biosimilar programmes in phase III development by 2012.
Pfizer, too, is endeavouring to straddle the “biobetter” and biosimilar platforms. Last year, it announced a deal to market biosimilar versions of recombinant human insulin and the insulin analogues glargine, aspart and lispro, produced by Indian biotech company Biocon.
From biosimilars to biogenerics?
Estimates of how much of the biologicals market will be captured by biosimilars vary wildly — from a fairly conservative 5 per cent in the next few years to an optimistic 60 per cent in the largest markets over the longer term. Clearly, it is far too early for accurate predictions. With only a dozen or so biosimilars having run the gauntlet of the European licensing system and US regulations still in development, it is difficult to know how worthwhile even “big pharma” will find it to focus on biosimilars. The few who have bulging pipelines of future biological blockbusters may feel justified in sticking to their heritage of innovation. But others with more modest offerings may feel that there are rich pickings to be made from biosimilars, despite the more stringent testing required than for chemical generics.
Economists are predicting that price reductions for biosimilars will not reach the dizzy levels achieved with traditional generics — good news for pharmaceutical companies taking the biosimilar route, if not for the NHS. Dr Mestre-Ferrandiz explains that the driving force for a successful transition from a biosimilar to a biogeneric market is the accumulation of solid post-marketing safety data.
“The critical point may be two or three years after a biosimilar is licensed, when there is enough data to encourage clinicians to consider it as interchangeable with the original product. At that point, competition on price, and perhaps the reputation of the manufacturer, may start to play a part. Physicians may feel more confident using biosimilars from major pharmaceutical companies whose other products they have prescribed over many years.”
Against such a background, what savings can the NHS realistically expect from the rapidly evolving biosimilars market, and how will pharmacists be involved in ensuring value for money?
Next month, we will examine whether biosimilars can save the NHS money.
1 Datamonitor. Pharmaceutical key trends 2011 — biosimilar market overview and generics market outlook: 2015.
2 Medicines and Healthcare products Regulatory Agency (MHRA), 2008, Drug Safety Update, 1(7):8.
3 National Institute for Health and Clinical Excellence. Human growth hormone (somatropin) for the treatment of growth failure in children. Review of NICE technology appraisal guidance 42, 2010.
4 European Medicines Agency. Biosimilar medicines. Available at: (accessed 15 April 2011).
5 Office of Health Economics. Biosimilars: how much entry and price competition will result? 2010. Available at: (accessed 15 April 2011).
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