Tore K Kvien & Guro L Goll argue that biosimilars are an opportunity for improving access to treatment & reducing cost and provide comment on the NOR-SWITCH study
Biological drugs are complex molecules which have improved the treatment of patients with rheumatological, gastroenterological and dermatological diseases during the last 20 years. Within these disease groups, many patients suffer from inflammation that leads to pain, disability and organ damage. Biological drugs target substances that enhance inflammation, and hence they hinder the disease process. The most widely used biologics have been the monoclonal antibodies infliximab and adalimumab and the fusion protein etanercept, all called tumour necrosis factor inhibitors (TNFi) because they neutralise the proinflammatory signalling substance (cytokine) TNFα.
TNFi have revolutionised the treatment of patients with rheumatoid arthritis and related rheumatic diseases (spondyloarthritis, psoriatic arthritis) as well as inflammatory bowel diseases (Crohn’s disease, ulcerative colitis) and psoriasis because they are effective also in patients who have failed conventional treatments like the cytotoxic drug methotrexate. These drugs improve the health status and quality of life as well as workability in patients with these diseases. However, access to these treatments has been limited by their cost which has usually been about €10-15,000 per treatment year from their launch around the year 2000. The recent availability of competitive biosimilars has dramatically altered pricing and patient access in many countries.
Patents for originator biological drugs
The manufacturing and marketing of originator biological drugs have been protected by patents. The patent for infliximab expired in EU in 2015 (the year before in some European countries like Norway), for etanercept in 2016 and for adalimumab in 2018. Importantly, there are differences across countries regarding patent expirations – for example, etanercept and adalimumab still have patent protection in the United States for some additional years.
When a patent expires, there is an opportunity for other manufacturers to produce copies of the originator product which are called biosimilars, since they are reproductions of the original, but not completely identical. We are all familiar with generic drugs, which are identical and less expensive copies of chemical substances (drugs). Biological drugs are large, complex molecules produced by living cells; hence, a perfect copy is impossible to make. The main idea is that the biosimilar should be comparable to the reference product – it should be neither better nor worse – but it should be less expensive.
The European Medicines Agency (EMA) has paved the way to develop guidelines for the approval of biosimilars. This comparability exercise to show similarity between the candidate biosimilar and the reference product includes a comprehensive preclinical testing, examination of pharmacokinetic properties and at least one phase 3 clinical trial in one of the approved indications of the reference product. When approval is granted by the regulatory agency, the biosimilar will usually be approved for all indications for the reference product in a regulatory process termed extrapolation of indication.
Biosimilars certainly have some medical issues, but their use is also very much related to health policy because they may reduce costs and provide opportunities for better access to good therapies for more patients in need.
Challenges for acceptance and prescription of biosimilars
First, we think most clinicians have confidence in the quality of the regulatory approval process by EMA. The first biosimilar monoclonal antibody infliximab was CT-P13, developed and manufactured by Celltrion in South Korea, and approved by EMA in 2013. It was marketed in Norway from the beginning of 2014 (under two different brand names, Remsima and Inflectra, which actually competed with each other). Later, other biosimilar products for infliximab, etanercept and adalimumab have been approved by EMA and have become available for patients.
From a clinical perspective, biosimilars present two main questions:
Can biosimilars be considered on equal footing with the reference product when starting or changing therapy for medical reasons? We think that the majority of European rheumatologists will answer yes to this question – an answer “no” would mean that the regulatory approval process by the EMA is not trusted.
The other main question is whether a patient on stable and successful treatment on a biologic agent can transition or switch their therapy to a biosimilar of the reference product for economic reasons alone. There are more diverse opinions about this question in some countries, partly because this question is not directly addressed by the approval process of EMA. However, switching data from originator to biosimilar in extension studies as well as multiple switching including back and forth switching in randomised phase 3 clinical studies have not raised any concerns.
Important real-life data from the DANBIO registry have shown that switching mandated by the Danish health authorities (switching from originator to biosimilar infliximab or from originator to biosimilar etanercept) has not raised any concerns. However, switch studies from the Netherlands (BIO-SWITCH and BIO-SPAN) have indicated that communication from healthcare providers to patients is important to reduce the nocebo effect and improve drug adherence.
The NOR-SWITCH study, published in the Lancet in 2017 (Jørgensen KK et al. Lancet 2017; 389(10086):2304-16), was financed by the Norwegian government with an amount of about €2500 in the governmental budget for 2014. Pharma companies had no involvement in the planning or conduct of the study. This was a randomised double-blind, non-inferiority trial in 482 adult patients on stable treatment with infliximab for at least six months to examine whether switching from the reference infliximab to the biosimilar CT-P13 was non-inferior to continued treatment with the originator product.
Patients were followed for 12 months with disease worsening as the primary endpoint. The study confirmed that switching to the biosimilar CT-P13 was not inferior to continued treatment with the originator product and the robustness of this main finding was supported by results from several secondary endpoints including disease activity scores, remission, health-related quality of life, adverse events and – importantly – drug levels and anti-drug antibody formation reflecting immunogenicity. Further, a 6-month extension study published in J Intern Med in 2019 (Goll GL et al. J Intern Med 2019; 285(6):653-69) supported the results from the main study.
The impact of the results from NOR-SWITCH and other switch studies have been tremendous in Norway regarding access to biological agents. Norway has a national tender system where companies offer an annual price for their product. Since various biological agents, as well as JAK-inhibitors, have similar efficacy and safety at a group level, the drug with the lowest cost will be ranked first in the tender and becomes the drug of choice for all new patients starting biologic treatment.
Switching from an originator to a biosimilar product is recommended when the biosimilar is less expensive than the reference product. The overall result of this competitive pricing system has, for example, been a fourfold increase in the use of infliximab since 2015, a threefold increase in the use of adalimumab and 50% increase in the use of etanercept – even though Norway also had liberal access to biological agents before 2015. Importantly, with the cost reductions due to the tender system, the total spending of money on biological agents is about 25% lower even with the increased use.
We think the Norwegian model is an excellent example of how countries by good government organisation and conscious effort can increase competition by using tender systems and help bring down costs while improving access to expensive drugs.
*Please note: this is a commercial profile