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About Biosimilars

Biosimilars are successors to biologic drugs whose patents have expired, offering the potential for cost savings and improved patient access worldwide

Biosimilars are highly similar – but more affordable – successors to biologic drugs whose patents have expired. Unlike generic versions of chemical drugs, biosimilars are not exact copies of originators because the manufacturing process of these large, complex molecules is too difficult to replicate precisely. For this reason, biosimilars require rigorous assessment, including head-to-head clinical trials compared to their originators, to gain regulatory approval.

Once licensed, biosimilars have the potential to achieve significant cost savings and greater global patient access to biologic treatment in areas like oncology, rheumatology and diabetes.

What is a biosimilar?   +

Aspirin molecule and mAbBiologic medicines are large, complex molecules produced by living organisms, and used for the prevention, treatment, or cure of a disease. The illustration below contrasts the molecular size and complexity of a typical biologic (here a monoclonal antibody) with that of a typical chemical drug (aspirin), which is more than 800 times smaller than the biologic.1

Biosimilars are closely matched successors to biologics whose patents have expired. They always have the same primary amino acid sequence as the originator biologic, but are not structurally identical. Because the manufacture of biologics involves a sophisticated and proprietary process based on the culture of living cells, these molecules are very difficult to replicate precisely. Thus, biosimilars are developed with the intention to be as ‘similar’ to the originator biologic as possible. To win regulatory approval, this close similarity has to be demonstrated not only in the laboratory but also in head-to-head clinical trials, which compare prospective biosimilars directly with their originator biologics in terms of efficacy, safety, and immunogenicity.  

Note: A recent study showed that neutralizing antibodies to an originator biologic may cross-react with a biosimilar version, potentially rendering the biosimilar clinically ineffective.2 Such findings demonstrate the very close match between some biosimilars and their originators.


Regulatory definitions of a biosimilar vary by agency:

EMA
European Medicines Agency

A biological medicinal product that contains a version of the active substance of an already authorised original biological medicinal product (reference medicinal product). A biosimilar demonstrates similarity to the references medicinal product in terms of quality characteristics, biological activity, safety and efficacy based on a comprehensive comparability exercise.3
FDA
US Food and Drug Administration

A biological product that (a) is highly similar to the reference product notwithstanding minor differences in clinically inactive components and for which (b) there are no clinically meaningful differences between the biological product and the reference product in terms of safety, purity, and potency of the product.4
WHO
World Health Organization

"A biotherapeutic product which is similar in terms of quality, safety, and efficacy to an already licensed reference biotherapeutic product.5

Learn more about Regulatory Requirements >>

How do biosimilars differ from generics?   +

While designed to be more cost-effective versions of biologics in the same way as the generic versions of branded chemical drugs, biosimilars are not the same as generics because they are not identical copies of their originators.

Characteristics Generics Biosimilars
Manufacturing Chemical synthesis Derived from living cells
Active ingredient Identical to originator Same primary amino acid sequence as originator but 'similar' 3D structure6,7
Ease of reproduction Relatively easy to 'reverse engineer' an identical copy Manufacturing process very difficult to replicate so an identical copy is not possible8
How do biosimilars differ from biobetters?   +

What is a biobetter?  Biobetters (also known as ‘biosuperiors’) are essentially new products.  They have the same molecular target and mechanism of action as a previously developed biologic but have been structurally modified or re-formulated to offer improved safety, better efficacy or greater convenience in terms of dosing frequency, route of administration or storage requirements.  An example of a biobetter is pegfilgrastim, a pegylated version of filgrastim with the benefit of a longer half-life. The biobetter concept is in fact far from new, even if the term was only introduced in 2007. Drugs described today as ‘biobetters’ were previously described simply as ‘next generation products’, implying that they offer an incremental benefit compared with the predecessor product.  There is no standard definition of a biobetter and, in contrast to biosimilars, the term is used rather loosely.

How is biobetter development regulated?   A biobetter is a new originator product and is viewed as such by regulators. It must therefore undergo conventional pre-clinical and clinical development, including placebo-controlled Phase III studies.  Some ‘short cuts’ might be available for biobetter developers (e.g. knowledge of the earlier product may reduce R&D costs and help with selecting biomarkers and with safety monitoring) but it is important to bear in mind that biobetters cannot exploit the abbreviated development pathways open to biosimilars and are usually as expensive as their predecessors, if not more so.

How can biologic products vary and why might this be important?   +

Minor variations occur naturally between batches of biologics because these medicines are produced by living organisms which are inherently variable (a phenomenon known as ‘microheterogeneity’).9 In addition, minor modifications to inactive ingredients, culture media or primary packaging materials may all slightly alter the molecular structure of biologics. Such changes have the potential to affect efficacy, safety, and immunogenicity – which has been observed with originator biologics that have undergone seemingly innocent alterations to their production methods. This is why any known and potential differences between a candidate biosimilar and its originator must be proven to be clinically insignificant for the biosimilar to obtain regulatory approval.10
Why do we need biosimilars?   +

Biologics have transformed the therapeutic landscape in many areas of medicine, but their costs can exceed those of small-molecule chemical drugs by many orders of magnitude. As a result, it is widely believed the expenditure required for modern biologics is unsustainable.11,12



In oncology, biologics have increased patients’ survival and reduced disease recurrence but treatment costs have soared.
  • In the United States, spending for cancer has risen 222% over the past 20 years13 and many new generation oncology biologics carry price tags of $100,000 per patient per year.14
  • In the United Kingdom, no fewer than eight breast cancer biologics with proven overall survival benefit have been rejected by the National Institute for Health and Care Excellence (NICE) since 2011 because of their cost.1
In diabetes, insulin is on the WHO’s Essential Medicines list, yet access is limited worldwide.
  • More than 80% of the world’s diabetes population live in low- and middle-income countries, but 70% of insulin is used in the developed world.15
  • In Latin America, patients have to self-fund a high proportion of the cost of their insulin – up to 40–60%.15
  • In Malawi, the cost of 1 month’s supply of intermediate-acting insulin is equivalent to approximately 20 days’ wages.16
In rheumatoid arthritis (RA), biologics have reduced deformity and made remission a realistic goal, but are limited to the few who can afford them.17,18
  • In more than 50% of European countries, one year’s treatment for RA with a biologic DMARD (disease-modifying anti-rheumatic drug) exceeds the per capita gross domestic product (GDP) by as much as 11 times,19 suggesting that almost 40% of the European population (~320 million people) has severely restricted access to biologic DMARDs.19
  • In developing nations, where healthcare focuses on fatal diseases, access to biologic DMARDs can be almost unheard of.20


The sobering reality is that all over the world, patients diagnosed with life-threatening and debilitating illnesses are faced with the added trauma of a substantial financial burden. They are often forced to make agonizing choices between the treatment most likely to help them and other fundamental priorities for themselves and their families. Meanwhile the clinical freedom of doctors specializing in fields like oncology and rheumatology is significantly restricted by cost constraints.
What cost savings can we expect from biosimilars?   +

While discounts on biosimilars cannot match those of chemical generics because of the level of investment required for their development, regulatory approval and manufacturing, they are still expected to generate significant savings owing to the high unit costs of their originators.

  • In Europe, discounts of up to 35%21 have been achieved with biosimilars. However, headlines were made in mid-2015 when a discount of 45% for a biosimilar version of infliximab was negotiated by a major French hospital group.22 Even greater discounts have been secured in Norway and Denmark where clinicians can now treat a patient for 3 years with biosimilar infliximab for the same price as 1 year with the originator.23,24
  • In the United States, the first licensed US biosimilar, Zarxio, was launched in September 2015 at a relatively modest discount of 15% compared with the originator. However a well-publicized forecast from CVS Health Corp (a major US pharmacy benefit manager) has predicted that discounts of 40–50% are likely to be forthcoming.25 
  • Research published in April 2016 by the IMS Institute of Healthcare Informatics predicted that savings from biosimilars in the US and top 5 EU markets could range from $56 to $110 billion (€49–98 billion) by 2020. The estimates are based upon the fact that, by 2020, eight major biologics are expected to lose exclusivity protection, including treatments for autoimmune disorders and diabetes. If the average discount offered with a biosimilar of each product is 20%, the total saving is predicted to be $56 billion, projected to rise to $110 billion if average discounts of 40% are secured. The report points out that savings will also depend on policy decisions made and actions taken around incentives and stakeholder education.26
What impact could biosimilars ultimately have on healthcare?   +

Lower costs could:

  • save €1.6 billion/year across Europe, based on a 20% discount on the top five off-patent biologics27
  • free up healthcare budgets to allow funding for innovative products.

Learn more about Market uptake and impact of biosimilars in Europe >>

Increased competition has the potential to:  

  • drive down the costs of originators24,25
  • motivate originator companies to invest in new innovation.25
Greater affordability could improve clinical practice by:

  • placing biologics within reach of a greater proportion of the eligible patient population18,24,28
  • allowing previously restricted products to become standard of care.29
Use of technology that has evolved since the launch of the originator product may offer additional conveniences to patients and healthcare providers, including:

  • longer out-of-fridge stability
  • pre-filled syringes with adaptors to enable needleless injection into an intravenous line
  • integrated needle-safe devices to make disposal safer.
References   +

1. Kozlowski S, Woodcock J, Midthun K and Berhman Sherman R. Developing the nation’s biosimilars program. N Engl J Med (2011) 365:385–388.
2. The Rheumatologist, 6 April 2016. Remicade antibodies cross-react to biosimilars. http://www.the-rheumatologist.org/article/remicade-antibodies-cross-react-biosimilars/. Accessed 30 May 2016.
3. Guideline on Similar Biological Medicinal Products. CHMP/437/04 Rev 1. European Medicines Agency (EMA) 2005. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2013/05/WC500142978.pdf. Accessed 16 September 2014.
4. Guidance for Industry: Scientific Considerations in Demonstrating Biosimilarity to a Reference Product. US Food and Drug Administration (FDA) 2012.
5. Guidelines on Evaluation of Similar Biotherapeutic Products (SBPs). World Health Organization (WHO) 2009.
6. Tsiftsoglou AS, Ruiz S and Schneider CK. Development and regulation of biosimilars: current status and future challenges. BioDrugs (2013) 27:203–211.
7. Kay J. Biosimilars: a regulatory perspective from America. Arth Res Ther (2011) 13:112.
8. Schellekens H. Biosimilar therapeutics—what do we need to consider? NDT Plus (2009) 2(Suppl 1): i27–i36.
9. Schneider CK. Biosimilars in rheumatology: the wind of change. Ann Rheum Dis (2013): 72:315–318.
10. Guidance for Industry: Scientific Considerations in Demonstrating Biosimilarity to a Reference Product. US Food and Drug Administration (FDA) 2012.
11. Reuters, 26 September 2011. Cancer cost "becoming unsustainable" in rich nations. http://uk.reuters.com/article/2011/09/26/uk-cancer-costs-idUKTRE78P25420110926?feedType=RSS&feedName=topNews. Accessed 20 November 2014.
12. Battley JE, Connell LC, Graham DM and O’Reilly S. Cost effectiveness and cancer drugs. J Clin Oncol (2014) 32:1091–1092.
13. Cornes P. The economic pressures for biosimilar drug use in cancer medicine. Targ Oncol (2012) 7(Suppl 1):S57–S67.
14. FiercePharma, 23 April 2014. NICE rejects Roche's hot new breast cancer drug Kadcyla, then invites negotiations. http://www.fiercepharma.com/story/nice-rejects-roches-hot-new-breast-cancer-drug-kadcyla-then-invites-negotia/2014-04-23. Accessed 19 November 2014.
15. International Diabetes Federation. Global access to and availability of insulin. Diabetes Voice (2006) 51: Special Issue. http://www.idf.org/sites/default/files/attachments/article_464_en.pdf. Accessed 19 November 2014.
16. Mendis S, Fukino K, Cameron A et al. The availability and affordability of selected essential medicines for chronic diseases in six low- and middle-income countries. Bull World Health Organ (2007) 85:279–288.
17. Horton SC and Emery P. Biological therapy for rheumatoid arthritis: where are we now? Br J Hosp Med (2012) 73:1;12–18.
18. Scheinberg MA and Kay J. The advent of biosimilar therapies in rheumatology—“O Brave New World”. Nat Rev Rheumatol (2012) 8:430–436.
19. Putrik P, Ramiro S, Kvien TK et al. Inequities in access to biologic and synthetic DMARDs across 46 European countries. Ann Rheum Dis (2014) 73:198–206.
20. Osiri M & Maetzel A. The economic burden of rheumatoid arthritis: Asia/Thailand perspective. In: Handbook of Disease Burdens and Quality of Life Measures (2010) 1733–1750.
21. Rovira J, Espín J, García L and Olry de Labry A. The impact of biosimilars’ entry in the EU market. European Commission 2011.
22. Biosimilar News, 9 July 2015. Hospira wins French tender with biosimilar infliximab. http://www.biosimilarnews.com/hospira-wins-french-tender-with-biosimilar-infliximab. Accessed 15 October 2015.
23. GaBi Online, 13 March 2015. Huge discounts on biosimilar infliximab in Norway. 
http://www.gabionline.net/Biosimilars/General/Huge-discount-on-biosimilar-infliximab-in-NorwayAccessed 15 October 2015.
24. Firstword Pharma, 12 June 2015. Denmark joins Norway in securing a 60 percent-plus discount for biosimilar Remicade – what impact on the rest of Europe? http://www.firstwordpharma.com/footer/benefits#axzz3l88RqYe3. Accessed 15 October 2015. [Subscription required]
25. Reuters, 11 March 2015. CVS says biotech drug copies may bring savings of 40–50 percent. http://www.reuters.com/article/us-cvs-health-biosimilars-idUSKBN0M72GK20150311. Accessed 30 May 2016.
26. IMS Health, 28 March 2016. IMS Health: Surge in biosimilars to drive significant change in health system costs, patient access and competition by 2020. https://www.imshealth.com/en/about-us/news/ims-health-surge-in-biosimilars-to-drive-change-in-health-system-costs. Accessed 30 May 2016.

27. Haustein R, de Millas C, Höer A and Häussler B. Saving money in the European healthcare systems with biosimilars. GaBi Journal (2012) 1(3-4):120–126.
28. Strober BE, Armour K, Romiti R et al. Biopharmaceuticals and biosimilars in psoriasis. What the dermatologist needs to know. J Am Acad Dermatol (2012) 66:317–322.
29. McCamish M and Woollett G. The state of the art in the development of biosimilars. Clin Pharmacol Ther (2012) 91:405–417.

Video Spotlights
Industry perspective: How can biosimilars influence access to care?
Industry perspective: How can biosimilars influence access to care?
Quintiles perspective: How can biosimilars influence standard of care?
Quintiles perspective: How can biosimilars influence standard of care?
Investigator perspective: Rheumatoid Arthritis: Improving access to biologics
Investigator perspective: Rheumatoid Arthritis: Improving access to biologics
Investigator perspective: Oncology: Improving access to biologics
Investigator perspective: Oncology: Improving access to biologics