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.
Biologic 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:
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
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
World Health Organization
|"A biotherapeutic product which is similar in terms of quality, safety, and efficacy to an already licensed reference biotherapeutic product.5
|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|
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.
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 diabetes, insulin is on the WHO’s Essential Medicines list, yet access is limited worldwide.
|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
Lower costs could:
Increased competition has the potential to:
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.