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Optimising anti-TNF treatment using biosimilars

Biosimilars in clinical practice

Last updated: 25th Jul 2023
Published: 6th Aug 2020
Declaration of sponsorship:
Anti-TNF Treatment Using Biosimilars – Overview
In this section

Biosimilars in clinical practice - what are biosimilars?

Learn about biosimilar medicines, and how they can benefit the clinical management of diseases and conditions

  • Compare similarities and differences in the development processes for originator biologics versus biosimilars
  • Review anti-tumour necrosis factor (anti-TNF) health economic data for gastroenterology, rheumatology, and dermatology diseases
  • Learn the scientific evidence behind biosimilar development and the biosimilar regulatory approval pathway

What are biosimilars?

Biological medicines have revolutionised healthcare since their development in the 1980s. Recently, biosimilars have established their place in the clinic, benefitting almost every stakeholder in the healthcare system. So, what are biosimilars and how could they be important to your practice?

A biosimilar is a medicine containing a version of the active substance of an approved biological medicine whose patent has expired (known as a reference product). A biosimilar is approved once it has been shown not to have any clinically meaningful differences in terms of quality, safety and efficacy from the reference product1,2.

As of 1 September 2022, 86 biosimilars have been approved by the European Medicines Agency (EMA)1 and 38 by the US Food and Drug Administration (FDA)3. Biosimilars based on tumour necrosis factor alpha inhibitors (anti-TNFs), such as adalimumab, etanercept, infliximab and rituximab, have been approved for the treatment of gastrointestinal, rheumatological, and dermatological diseases1,3. Anti-TNF biosimilars offer a lower cost treatment option and can potentially improve patient outcomes by providing more treatment options4.  The arrival of biosimilars has led to cost reductions that allow earlier access to effective treatments, leading to improved patient outcomes and quality of life (QoL)4. For example, the development of biosimilars to anti-TNFs such as etanercept and adalimumab for the treatment of psoriasis has led to significant improvements in health-related quality of life in patients5.

As biologic medicines, biosimilars differ from generics in their molecular size, structure and the complexity of their development1,6. Also, biosimilars are more costly and difficult to produce than generic versions of small-molecule drugs (Figure 1). It can take 5–10 years and an investment of $100–250 million to bring a biosimilar to market, compared with about two years and $1–10 million to develop a conventional generic6.

Biological molecules have more complex structures than small molecule medicines

Figure 1. Biological molecules have more complex structures than small molecule medicines. Mab, monoclonal antibody.

The manufacturer of an original biological medicine must demonstrate its safety and efficacy in clinical trials. Biosimilar development focuses on in-depth analyses to confirm that the biosimilar is highly similar to its reference product in terms of structure, composition, and in vitro activity1. At least one clinical study is required to compare the pharmacokinetics of the reference product and biosimilar, and at least one randomised trial is required to demonstrate clinical equivalence (Figure 2)1,7.

 

Drug development comparison. The development processes for biologics and biosimilars are considerably more rigorous than the development process for small molecule generics

Figure 2. Drug development comparison. The development processes for biologics and biosimilars are considerably more rigorous than the development process for small molecule generics (Adapted8). PD, pharmacodynamics; PK, pharmacokinetics.

If a biosimilar has comparable safety and efficacy in one therapeutic indication to a reference product, then the data may be extrapolated to other indications already approved for the reference medicine7,9. Consequently, a biosimilar may be approved in all indications for which the reference product has been approved without multiple clinical trials7. Safety data are monitored and reported on a continuous basis according to rigorous pharmacovigilance regulations outlined by the EMA and US FDA1,9.12,13

Interchangeability can have a scientific or legal meaning10:

  • In the EU, interchangeability is a scientific term meaning that a product can be safely switched 
  • In the US, it is a legal term which allows automatic substitution at the pharmacy level 

Interchangeability is slightly different to 'switching', which refers to the treatment decision made by a physician to switch patients treated with a reference product to a biosimilar. Substitution refers to a pharmacist substituting one prescribed reference product for a biosimilar without the need to consult a physician1.

It is estimated that in the UK, the healthcare system can make substantial savings of £200–300 million per year if patients are initiated on or switched to biosimilars11. These savings can then be reinvested into other aspects of patient care to increase the number of health service staff, to increase funding for nurses and to maintain the quality of the social care system11. As the number of treatment options increases, manufacturers reduce the prices of their products to increase market share and this in turn increases patient access to biologic medicines (Figure 3)12,13.

Estimated cost savings by biologic class over a ten-year period from 2017 to 2026

Figure 3. Estimated cost savings in the US by biologic class, 2017–2026 (Adapted12). Anti-TNF, anti-tumour necrosis factor; COPD, chronic obstructive pulmonary disease.

The health economic perspective

In this short video, Professor Thomas Dörner (Charité University Hospitals, Berlin, Germany) describes how the arrival of anti-tumour necrosis factor (TNF) biosimilars has affected access to biologic treatment options, the initiation of treatment, and how various countries, including South Korea, Australia and European nations, have expanded their use of anti-TNF biosimilars.


Professor Thomas Dörner (Charité University Hospitals, Berlin, Germany) asks if the use of biosimilars is associated with stigma. Learn about the need for greater education in biologics and biosimilars, such as their validation processes and biomarkers.

Biosimilars provide benefits from a health economics perspective11,13. But do anti-TNF biosimilars offer value across gastrointestinal, rheumatological, and dermatological diseases?

Inflammatory bowel disease

Inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, are chronic inflammatory disorders that impose substantial health and economic burdens worldwide14. Globally, the number of people with IBS increased from 3.7 million in 1990 to 6.8 million in 201714.

Increasing confidence in biosimilars is reflected in clinical practice toward early implementation and treatment with biosimilars in patients at risk of early disease progression15

The introduction of biosimilars for infliximab, for example, is expected to have a major impact on the cost profile of gastrointestinal immune-mediated inflammatory disease16. A Dutch study reported that cost savings over five years could yield €493 million in total, predominantly determined by price reduction of anti-TNF therapy with physicians switching patients towards biosimilars16.

There are a high number of comorbidities linked to inflammatory conditions, including osteoporosis, cardiovascular disease, neuropsychological disorders and metabolic syndrome17. Biosimilars offer patients greater access to treatment at an earlier stage, which may prevent the emergence of comorbidities17.

Rheumatological disorders

Rheumatoid arthritis is a systemic autoimmune disorder that causes pain and swelling in multiple joints of the body. The global age-standardised prevalence of rheumatoid arthritis in 2017 was estimated at 246.6 per 100,000, which is a 7.4% increase from the prevalence in 199018; however the burden of rheumatoid arthritis varies geographically18. Other rheumatological disorders including ankylosing spondylitis and psoriatic arthritis have a global prevalence of 0.2–1.6% and 0.01–0.19%, respectively19.

Compared with 2016, the year before any etanercept or infliximab biosimilars were available, the price per treatment day across overall anti-TNF inhibitor use decreased by 13% in the European Union, and volume per treatment day increased by 19%. Biosimilars are available at a lower cost and are increasing the access to therapies for more patients11.

The introduction of biosimilars may widen access to biologic therapy and improve overall patient outcomes

Guidelines do not prioritise the use of any particular biosimilar and so the choice of biosimilar for any particular patient may come down to physician-patient judgement and should involve an informed decision-making process20. There are a number of comorbidities linked to rheumatological diseases, including cardiovascular disease, infections and osteoporosis, which affect a high proportion of patients21,22. Careful management of rheumatological diseases is important for the prevention of comorbidities particularly among an ageing patient population21,22. 

Providing patients with affordable treatment can improve their access to medicines that can be started earlier and maintained longer, which can prevent comorbidities1

Dermatological disorders

Plaque psoriasis and hidradenitis suppurativa are chronic dermatological inflammatory diseases with a high prevalence globally, affecting up to 0.9–8.5% and 0.03–4% of the population, respectively23,24. Recent estimates of the annual total and direct healthcare costs of moderate-to-severe psoriasis were US$22,713 per patient and US$13,731, respectively, and €1,617–13,343 and €1,314–8,966 per patient-year, respectively, across France, Germany, Italy, and Spain25.

Dermatological diseases have been shown to have an adverse effect on the mental health of patients, particularly those with plaque psoriasis and hidradenitis suppurativa26,27. Comorbidities include depression, anxiety, and suicidal thoughts or behaviour26,27.

Treating dermatological diseases at an early stage can significantly increase the quality of life of the patient, biosimilars can provide this opportunity to patients26

How can biosimilars be used in patients, and what evidence supports their use?

In this short video, Professor Joao Gonclaves (Director, iMed-Research Institute for Medicines; Professor of Immunology and Pharmacology, University of Lisbon, Portugal) introduces the assessment of biosimilars, and biosimilar safety, efficacy, and tolerability data.

Professor Joao Goncalves (Director, iMed-Research Institute for Medicines; Professor of Immunology and Pharmacology, University of Lisbon, Portugal ) outlines how education on biosimilars should include the mechanisms of action of biologics, how to mitigate the nocebo effect, and the need for support programs for patients and healthcare professionals.

Recently the concept of the nocebo effect has gained renewed interest as a result of introducing biosimilars in therapy. Nocebo effects are negative responses to a therapeutic agent that cannot be explained by the pharmacological properties of the agent28. Various factors that give rise to negative expectations of a treatment, including psychological, physiological and neurobiological factors, can contribute to nocebo effects28,29. In the case of biosimilars, gaps in patient and healthcare professional (HCP) awareness, understanding and perception may contribute to the nocebo effect, reducing the clinical benefit of biosimilars28.  In some cases, patients have discontinued biosimilars, despite having no worsening of disease, after switching from reference products28. 

Given the crucial contribution of the nocebo effect to clinical outcomes, it is important that HCPs understand the scientific evidence behind biosimilar development and the biosimilar regulatory approval pathway29,30. It is widely acknowledged that provider education and acceptance of biosimilars is one of the factors critical to increasing uptake of biosimilars28. When HCPs are confident in their biosimilar knowledge, they can help reduce the risk of nocebo effects and improve patient adherence28.

A systematic literature review identified an extensive body of evidence from retrospective and cohort studies evaluating the impact of switching from reference to biosimilars for a variety of disorders31. This review found no significant difference in efficacy, safety or immunogenicity when patients were switched from reference products to biosimilars31.

Data from randomised controlled trials (RCT) and recent real-world evidence (RWE) across gastroenterology, rheumatology and dermatology therapy areas shows that HCPs can be confident that there are no differences in safety and efficacy when they prescribe biosimilars as an alternative to reference medicine (Table 1)30. In addition to RWE and RCTs, pharmacovigilance of biosimilars should also increase confidence of HCPs prescribing anti-tumour necrosis factor (anti-TNF) biosimilars31.

Summary of randomized controlled switching studies (including open-label extensions)

Table 1. Summary of randomised controlled switching studies (including open-label extensions) (Adapted30). ACR, American College of Rheumatology; AS, ankylosing spondylitis; DB, double-blind; IBD, inflammatory bowel disease; OL, open-label; OLE, open-label extension; PsA, psoriatic arthritis; PsO, psoriasis; pts, patients; RA, rheumatoid arthritis; RCT, randomised controlled trial; RP, reference product; w, weeks. 

The infliximab biosimilars CT-P13 and SB2 have been studied extensively to determine their safety and efficacy in the treatment of inflammatory conditions. For example, a nationwide, observational study to evaluate the efficacy, safety, and immunogenicity of CT-P13 in the treatment of IBD, compared with reference infliximab, demonstrated that the efficacy and safety of CT-P13 were in line with reference infliximab after a total of 195 patient years of follow-up32. The efficacy of the biosimilar was evaluated in 434 patients who received treatment for at least eight weeks, using time-to-event methods for censored observations: 35 patients were primary failures (8.1%)32. After further 8, 16, and 24 weeks, the efficacy estimations were 95.7%, 86.4%, and 73.7% for naive, 97.2%, 85.2%, and 62.2% for pre-exposed, and 94.5%, 90.8%, and 78.9% for switch, respectively (log-rank P=0.64)32.

Two RCTs in patients with rheumatoid arthritis33 and ankylosing spondylitis34 provided support for regulatory approval of CT-P13, a biosimilar of the reference drug inflimab.  Each trial incorporated a switching event and at least 1-year follow-up. Each trial was also followed by an open-label extension where patients receiving reference infliximab were transitioned to CT-P13. Both studies demonstrated no clinically meaningful differences in safety and efficacy of CT-P13, compared to reference product33,34.

Similarly, SB2, another biosimilar of infliximab, received regulatory approval after an RCT in patients with moderate-to-severe rheumatoid arthritis confirmed safety and efficacy of SB2 was comparable to infliximab35.

Phase III confirmatory studies were conducted to support approval of GP2015 (biosimilar etanercept) and ABP-501 (biosimilar adalimumab) in patients with psoriasis. For both studies the safety and efficacy of the switched and non-switched arms were similar36,37.

Intravenous therapy in rheumatoid arthritis

As of June 2021, 15 biosimilars have been approved by the FDA for rheumatic diseases, and an additional 16 by the EMA38. They are administered either intravenously (IV) or subcutaneously (SC), as with their reference medicinal products (RMPs)38.

View the educational content in this section to learn more about the economic burden, safety, and patient preferences of IV therapy for rheumatoid arthritis (RA). Download an infographic, including potential very common side effects of IV therapy for RA, and special considerations for women.

Economic burden and considerations

RA has both direct and indirect costs. It has a huge indirect cost on employment. With RA, people are 53% more likely to be unemployed39.

Overall indirect costs of RA have been estimated to be $10.9 billion (in 2005 dollars) in the US39

Direct costs of RA vary between countries; however, the largest cost tends to be on new drugs for treatment. Biosimilars are lower in price than their RMP, while still offering similar efficacy and safety, therefore providing a cost-effective option39.

A budget impact analysis of intravenous (IV) biosimilars of rituximab and trastuzumab in five European country markets (UK, France, Germany, Spain and Italy) found there could be a net budget saving of €4.05 million to 303.86 million for rituximab (See Figure 4) and €19 million to 172 million for trastuzumab40. This could create substantial savings to health services41 and could be redirected into other areas of RA management39.

A summary of the net budget impact results for rituximab: base-case and scenario 1-3 for the U.K.

Figure 4: A summary of the net budget impact results for rituximab: base-case and scenario 1-3 for the U.K.

Safety of IV therapies

A study presented at ACR 2022, analysed 24,919 real-world adverse events (AEs) of IV infliximab and SC infliximab therapy42. It showed there were no significant differences between AEs and serious AEs in the two types of therapy administration42.

Patient preferences

One study investigating SC versus IV CT-P13 in 375 RA patients found that SC was non-inferior to RA and suggested the convenience of SC could be an advantage to patients43.

A study on adherence to treatment with IV biological agents in RA found, that on average, patients lost three infusions annually44. It found the only independent predictor of good adherence, as measured by median infusions/year, was having health coverage (8.5±2.5 vs 10.7±1.5, P<0.001)44.

In the RIVERIA study, IV and subcutaneous (IV) anti-TNF therapies for people with RA were compared45. It was found both IV and SC therapies were well accepted, with 50.2% preferring IV therapy, and 49.8% preferring SC therapy45. People chose IV therapy due to the safety felt by having the treatment in the hospital and the reassurance from a present physician45. Therefore, treatment choice needs to consider an individual’s preferences and attitudes.

Intravenous therapy for rheumatoid arthritis infographic

Download this two-page infographic covering: IV treatments for RA; benefits of IV therapy for RA; potential side effects, and considerations for pregnancy and fertility.

Intravenous therapy for rheumatoid arthritis

Download infographic here

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References - Biosimilars in Clinical Practice

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  2. European Medicines Agency and the European Commission. Biosimilars in the EU - Information guide for healthcare professionals. 2019. Available at: https://www.ema.europa.eu/en/documents/leaflet/biosimilars-eu-information-guide-healthcare-professionals_en.pdf. Accessed 19 April 2022.
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