Jeannette Y. Wick, RPh, MBA, FASCP

This article was originally published in 

The variety of biologic medicines now available has helped countless patients deal with diseases for which traditional treatments were unsatisfactory. Individuals who have autoimmune diseases, cancer, and diabetes have benefited, as have those with previously untreatable genetic diseases. The most complex biologics first entered the market in the 1980s and 1990s, and for this reason, many of their patents are expiring.

 The concept of biosimilars was a rational idea that loosely mimicked the idea of generic drugs.

 However, because biologics are large, 3-dimensional, complex molecules, it took some time for regulatory agencies around the world to develop appropriate regulations.

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Most clinicians now understand that biosimilars, although not identical to the innovator biologic, create greater patient access to therapies much like generic drugs have done for decades.

 Biologics and biosimilars are, as the terminology suggests, similar. Both are produced from living cells using biotechnology rather than chemical synthesis.

We now classify biologics into 3 categories, as follows

Some biologics correlate closely to endogenous enzymes, hormones, antibodies, or other substances. Using them substitutes for deficiencies in those substances.

Monoclonal antibodies bind to soluble or cell surface targets and interrupt signaling pathways and the body’s aberrant responses to those pathways.

Engineered proteins mimic fusible proteins, receptor antagonists, and soluble receptors.

In addition, medicine has used many less complex biologics, such as blood products, enzymes, hormones, and vaccines.

 is the director of the Office of Pharmacy Professional Development at the University of Connecticut at Storrs.

The European Medicines Agency (EMA) developed its biosimilar regulations more quickly than the FDA did, approving the recombinant human growth hormone somatropin (Valtropin; BioPartners) in 2006.

 In the US, by 2022, the FDA had licensed 1775 biologics, with 82 of those products being biosimilars.

As all stakeholders in the biosimilar process have become more comfortable with the terminology, the language of biosimilars has, in turn, evolved. Some researchers talk about intended copies, biobetters, and stand-alone products. These biologics are different from either the innovator biologic or the biosimilar. 

The EMA and the FDA have similar approaches to establishing biosimilarity.

 For both the EMA and the FDA, the sponsoring manufacturer needs to study biological and physiochemical comparability to the innovator biologic. They also need to conduct at least 1 clinical trial to look at efficacy and tolerability. Manufacturers must use analytical characterization, receptor binding studies, and bioassays. Using additional laboratory and clinical assessments, companies must demonstrate that their biosimilar’s mechanism of action, functional activity, and basic characteristics are similar to those of the innovator’s product.

Despite the rigorous review process that precedes licensing of a biosimilar, controversies persist. Some experts worry about immunogenicity.

 Biologics, primarily because of their high molecular weight and complex composition, can produce unexpected or undesirable immune responses. Patients may develop antidrug antibodies that may result in rare hypersensitivity and anaphylaxis, or decrease the biosimilar’s effectiveness.

 Using extrapolation, manufacturers can sometimes demonstrate that their product will address the desired clinical indication without conducting an actual trial. However, any data that they use must emanate from very sensitive clinical models. Many stakeholders in the process are highly critical of any extrapolation when it comes to biosimilars.

Finally, a concern of great interest to pharmacists is interchangeability and substitution.

 Interchangeability is a question that prescribers often have when they start a patient on a biologic; they wonder whether the biosimilar will be as safe and effective as the innovator product, and they have other questions when they need or want to switch a patient from an originator product to a biosimilar. Substitution is familiar to pharmacists as the ability to dispense a biosimilar without the prescriber’s consent or the patient’s approval. In most cases, substitution is not allowed for biosimilars.

Pharmacists will encounter unfamiliar situations as the number of biosimilars grows. The first is probably the need to conduct an economic analysis before deciding to use a biosimilar. Biosimilars can reduce health care costs and improve access for patients. Pharmacists will understandably field questions from patients and prescribers and should be prepared to answer intelligently.

1. Mascarenhas-Melo F, Diaz M, Gonçalves MBS, et al. An overview of biosimilars—development, quality, regulatory issues, and management in healthcare. 

2. Declerck P, Rezk MF. The road from development to approval: evaluating the body of evidence to confirm biosimilarity. 

 2017;56(suppl 4):iv4-iv13. doi:10.1093/rheumatology/kex279

3. Gámez-Belmonte R, Hernández-Chirlaque C, Arredondo-Amador M, et al. Biosimilars: concepts and controversies. 

. 2018;133:251-264. doi:10.1016/j.phrs.2018.01.024

4. Agbogbo FK, Ecker DM, Farrand A, et al. Current perspectives on biosimilars. 

. 2019;46(9-10):1297-1311. doi:10.1007/s10295-019-02216-z

5. Kim H, Alten R, Avedano L, et al. The future of biosimilars: maximizing benefits across immune-mediated inflammatory diseases. 

. 2020;80(2):99-113. doi:10.1007/s40265-020-01256-5

6. Konstantinidou S, Papaspiliou A, Kokkotou E. Current and future roles of biosimilars in oncology practice. 

. 2020;19(1):45-51. doi:10.3892/ol.2019.11105

7. Millán-Martín S, Zaborowska I, Jakes C, Carillo S, Bones J. Comparability study for the determination of post-translational modifications of biotherapeutic drug products and biosimilars by automated peptide mapping analysis. ThermoFisher Scientific. 2018. Accessed June 19, 2024. 

https://assets.thermofisher.com/TFS-Assets/CMD/Application-Notes/an-21850-lc-ms-comparability-biosimilars-an21850-en.pdf

8. Ismail S, Abu Esba L, Khan M, Al-Abdulkarim H, Modimagh H, Yousef C. An institutional guide for formulary decisions of biosimilars. 

. 2023;58(1):38-48. doi:10.1177/00185787221138007

9. Schreitmüller T, Barton B, Zharkov A, Bakalos G. Comparative immunogenicity assessment of biosimilars. 

. 2019;15(3):319-329. doi:10.2217/fon-2018-0553

10. Socinski MA, Curigliano G, Jacobs I, Gumbiner B, MacDonald J, Thomas D. Clinical considerations for the development of biosimilars in oncology. 

. 2015;7(2):286-293. doi:10.1080/19420862.2015.1008346

11. Kabir ER, Moreino SS, Sharif Siam MK. The breakthrough of biosimilars: a twist in the narrative of biological therapy. 

12. Ascef BO, Lopes ACF, de Soárez PC. Health technology assessment of biosimilars worldwide: a scoping review. 

. 2020;18(1):95. doi:10.1186/s12961-020-00611-y

13.Lyman GH, Balaban E, Diaz M, et al. American Society of Clinical Oncology statement: biosimilars in oncology. 

. 2018;36(12):1260-1265. doi:10.1200/JCO.2017.77.4893

14. Rugo HS, Linton KM, Cervi P, Rosenberg JA, Jacobs I. A clinician’s guide to biosimilars in oncology. 

. 2016;46:73-79. doi:10.1016/j.ctrv.2016.04.003

15. Rodriguez G, Mancuso J, Lyman GH, et al. ASCO policy statement on biosimilar and interchangeable products in oncology. 

. 2023;19(7):411-419. doi:10.1200/OP.22.00783

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