Biosimilars: What are they? How are they tested? Why do we need them?

By Prof Richard Gale

Consultant Medical Ophthalmologist
York Teaching Hospital NHS Foundation Trust, York, UK

What are they?

Biologics are not generic medications. Generic drugs are small, chemically synthesized molecules identical to the corresponding branded product. Biosimilars are purified from products made in living cells.

Because the manufacturing process for each branded (reference) product is proprietary, the biosimilar always differs slightly in structure from the reference product.1

Biologics are a diverse group of generally large, complex molecules that are produced in living organisms.2,3 Most biologic medicines contain active substances that vary greatly in size and molecular complexity (Figure 1).3

A biosimilar is a biologic product that is highly similar to and has no clinically meaningful differences from an existing approved reference or innovator product (i.e., the single biologic product, already approved, against which a biosimilar product is compared).3,4

Highly similar: What does it mean?
Regulatory bodies, including the United States Food and Drug Administration (FDA) and the European Medications Agency (EMA) have very similar and specific definitions for biosimilars and tightly controlled processes for approving them.4,5

How are they tested?
Establishing biosimilarity relies on in-depth analytical studies comparing the physicochemical and functional characteristics of the biosimilar vs the reference product (Figure 2).6,7

Evaluation of regulatory frameworks supports the conclusion that these regulations are robust and adaptable, and that they strike an appropriate balance between patient safety and feasibility of biosimilar development.8,9

All biologics are subject to variability

The manufacture of a biologic depends on actions within living cells. No two batches of a biologic agent are identical. This is referred to as microheterogeneity.10

In addition, manufacturers continually refine their production processes (Figure 3), and this introduces small changes in the molecules produced.11

Manufacturers must carry out assessments to demonstrate that the actions of their biologics have not changed with evolution in manufacturing processes,11,12 much in the way that a biosimilar must be compared with the reference product.

Why do we need them?
In most countries, biologic medications have become a burden on health- care system budgets. The main benefit of biosimilars is reduced drug acquisition costs.14-16

Biosimilars are less costly than originator biologics primarily because biosimilars do not have to undergo the intensive clinical development associated with approval of an originator.

Furthermore, biosimilars do not incur high costs for marketing, market access, and postmarketing research and development.

The potential cost savings associated with switching from a reference product to a biosimilar have been modeled and these studies consistently predicted reductions in drug acquisition cost.15-17

Another analysis focused on rheumatologic disease and cost savings that could be achieved by substituting biosimilars for two reference tumor necrosis factor inhibitors.

This simulation included France, Italy, and Sweden and had a 3-year time horizon. Analysis of the etanercept biosimilar indicated cost savings ranging from €15 to €63 million depending on the speed of biosimilar uptake and the country evaluated.

Most importantly, switching to the biosimilar would result in the potential to treat an additional 3,850–7,676 patients in France, 4,420–8,840 in Italy, and 2,050–4,080 in Sweden over 3 years with budgetary restrictions in place at the time when the study was carried out.18

The lower price and similar effectiveness of biosimilars vs reference products (i.e., increased cost-effectiveness) may support reimbursement to a larger number of patients and might also permit the product to be advanced to an earlier line of treatment.

Cost savings might also be used to support increased staffing at healthcare facilities.

Competition between biologics that have reached the end of their patent life and biosimilars may stimulate innovations in formulations for existing agents and next-generation products (Figure 4).19,20

Are biosimilars changing practice and the cost of care?

The first biosimilar was approved in the European Union in 2006 and since then many more have been approved by the FDA and/or EMA (Figure 5).21

Perhaps more important than the number of biosimilars approved is the extent to which they can be used in place of reference products in clinical practice. This varies with both the therapeutic area and region.22-24

Perceived limitations of biosimilars
One limitation of biosimilars is the nocebo effect which is defined as negative expectations that lead to negative consequences following an inert exposure.

It is possible that some adverse events observed after switch- ing to biosimilars from reference biologics result from this effect.25

It has also been suggested that greater pharmacovigilance is needed for biosimilars vs reference agents.26

Clinical trials for biosimilars generally have equivalence designs that require smaller sample sizes than those required for approval of reference products and thus more limited safety assessments.26

It has also been noted that the risk for development of anti-drug antibodies may not be sufficiently studied for biosimilars.27 These issues have prompted suggestions for more long-term studies of the safety of these products.27

Many biosimilars are being developed worldwide. However, their full clinical and economic value will only be realized as their use increases in clinical practice.28

Providing education and encouraging the use of biosimilars that have been repeatedly shown to have similar efficacy and safety to reference products in clinical trials and routine clinical practice20,29-31 are important goals.32

A particularly important point for any educational initiatives is the fact that safety analyses for all biosimilars studied have not indicated any unexpected clinical important adverse events not already observed with the reference agents.33

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Date of preparation: October 2021



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