What is a biosimilar?
A biosimilar is a medicinal product that is similar to a biological medicinal product that has already been authorised (the ’biological reference medicinal product’).
It is a version of an already licensed drug for which similarity has been proven in an extensive comparability exercise, encompassing physical, chemical, biological and pharmacological properties, including efficacy and safety.
This excludes products in other regions of the world that have not been endorsed via the WHO pathway as a biosimilar.
References:
- Vulto AG and Jaquez OA. Rheumatology (Oxford) 2017;56:iv14–iv29;
- WHO Expert Committee on Biological Standardization - 72nd and 73rd report 2021. Available from : https://www.who.int/publications/i/item/9789240024373. Accessed July 2021
Biosimilarity is a key regulatory and development concept
A biosimilar is a biological medicinal product that contains a version of the active substance of an already authorized original biological medicinal product.
A biosimilar demonstrates similarity to the reference medicinal product in terms of quality characteristics, biological activity, safety and efficacy based on a comprehensive comparability exercise.1
A biological product that is highly similar to the reference product notwithstanding minor differences in clinically inactive components and there are no clinically meaningful differences between biosimilar product and the reference product in terms of safety, purity, and potency of the product2.
References:
- Guideline on similar biological medicinal products. Available from: www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2014/10/WC500176768.pdf. Accessed November 2020
- Biosimilar product regulatory review and approval. Available from: https://www.fda.gov/files/drugs/published/Biosimilar-Product-Regulatory-Review-and-Approval.pdf. Accessed November 2020
The basics of biosimilars
A biosimilar is a version of an already licensed drug for which similarity has been proven in an extensive comparability exercise, encompassing physical, chemical, biological, and pharmacological properties, including efficacy and safety.1
Size matters: Biologics are complex
Unlike small-molecule drugs, biologics are large, complex structures that are manufactured in living cells and have significant natural variability.
References:
- Adapted from Kozlowski S, Woodcock J, et al. New Engl J Med 2011;365:385–388;
- Abraham J, Semin Oncol 2013;40:S5–S24
Based on their nature and manufacture, heterogeneity is commonplace in biologicals.
The focus of biosimilars development is not to establish benefit:risk but to demonstrate similarity to reference product.
References:
Wolff-Holz E, Burgos G, et al. ESMO Open 2018;3:e000420
Biosimilars may differ in terms of device/formulation
To read more about how advanced technologies have led to improved characterisation of complex biologicals allowing development of high-quality biosimilars, please click here
Manufacturing biosimilars
Totality of evidence
Biosimilarity is demonstrated through extensive structural and functional comparability studies and a tailored clinical program
A new drug development paradigm, based on an all-encompassing comparability exercise
References:
Wolff-Holz E, Burgos G, et al. ESMO Open 2018; 3.e000420
Similarity needs to be demonstrated across a multiplicity of attributes using different methods
References:
- Adapted from Cho I, Lee N, et al. mAbs 2016;8:1136–1155;
- Ramanan S and Grampp G. BioDrugs 2014;28:363–37
The real challenge for regulators is knowing which differences matter: critical quality attributes
Physicochemical characteristics
Variable region
- Deamidation
- Oxidation
- N-terminal pyroglutamate
- Glycosylation
- Glycation
Constant region
- Deamidation
- Oxidation
- Acetylation
- Glycosylation
- C-terminal lysis
- Di-sulfate bond shuffling
- Fragmentation/clipping
Biological characteristics
Binding
- Affinity
- Activity
- Cross-reactivity
- Unintentional reactivity
Effector function
- Complementary interaction
- FcRn, FcγR interaction
- Mannan binding ligand interaction
- Mannose receptor interaction
Other biologic properties
- PK properties
- Epitope/immunogenicity
- Modulatory region (tregitope)
References:
Adapted from: Declerck P and Farouk Rezk M. Rheumatology (Oxford) 2017;56:iv4–13
Reference biologics versus biosimilars: how similar are they?
Hypothetical
example of quality
attributes of a biosimilar
monoclonal antibody candidate
Reference product
Biosimilar
References:
Adapted from: Schiestl M, Li J, et al. Biologicals 2014;42:128–132
Stepwise assessment for totality of evidence
Each step should rely on the most advanced state-of-the-art capabilities
No step can refute/ overcome significant differences in preceding steps
All three steps must be satisfied to demonstrate biosimilarity
Analytics are much more sensitive at detecting small differences
References:
Consensus Information Paper 2019. Biosimilars in the EU. Information guide for healthcare professionals.
Available from https://www.ema.europa.eu/en/documents/leaflet/biosimilars-eu-information-guide-healthcare-professionals_en.pdf
Clinical studies comparing a biosimilar to its reference product should be performed in sensitive indications
“The study population should generally be representative of approved therapeutic indication(s) of the reference product and be sensitive for detecting potential differences between the biosimilar and the reference”
References:
Adapted from EMA Guidelines on similar biologic medicinal products, Dec 2014
EMA. Guideline on similar biological medicinal products. 18 December 2014. Available from: https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-similar-biological-medicinal-products-containing-biotechnology-derived-proteins-active_en-2.pdf, accessed 15 March 2021
Extrapolation
What is extrapolation of indications
The regulatory process of granting a clinical indication to a medicine without own/new clinical efficacy and safety data to support that indication
When biosimilar comparability has been demonstrated in one indication, extrapolation of clinical data to other indications of the reference product could be acceptable, but needs to be scientifically justified1
If the “total evidence” in the biosimilar application supports a demonstration of the biosimilarity for at least one of the reference product’s indications, then it is possible for the biosimilar manufacturer to use data and information to scientifically justify approval for other indications that were not directly studied by the biosimilar manufacturer2
References:
- EMA. Guideline on similar biological medicinal products containing monoclonal antibodies – non-clinical and clinical issues. Available from: https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-similar-biological-medicinal-products-containing-monoclonal-antibodies-non-clinical_en.pdf, accessed July 2021
- FDA. Biosimilar product: regulatory review and approval. Available from: https://www.fda.gov/files/drugs/published/Biosimilar-Product-Regulatory-Review-and-Approval.pdf, accessed 15 March 2021
Extrapolation is a well-established regulatory and scientific principle
- Extrapolation has been applied following major changes in the manufacturing process of originator biologicals
- The manufacturer follows regulatory guidance to conduct a comprehensive comparability program to establish that any pre- and post-manufacturing changes are sufficiently similar to allow continued authorisation
- Once approved, the new version is expected to have the same efficacy and safety in all therapeutic indications
References:
Weise M, Kurki P, et al. Blood 2014;124:3191–6