Written by: Rebecca Parkin, AnneMarie DeFrein and Patricia Heckmann, National Cancer Control Programme
Cancer is recognised as a major health concern. The number of cancers diagnosed annually in Ireland is rising and the significant cost of new drug treatments for cancer, including biological medicines (or biologicals), has been cited as an ongoing challenge.1, 2 In recent years, in addition to their increased use in other diseases, biologicals have become a vital part of treatment for cancer, as both therapeutic and supportive care agents.3, 4 However, the high cost of these treatments places a significant burden on healthcare systems. The expiration of patents for biologicals has allowed the development of biosimilar medicines (biosimilars). A regulatory framework for the approval of biosimilars was established in Europe in 2003, with the USA implementing a framework in 2009.3 Since the introduction of the first biosimilar by the European Medicines Agency (EMA) in 2006, a number of biosimilars have been approved and safely used in the treatment of cancer.5 Their approval has led to increased market competition, resulting in a reduced cost burden and enabling accessibility of treatments to patients with cancer.5 As such, biosimilars represent one of the ways to obtain sustainability of systemic anti-cancer therapy (SACT ) and maximise funding for new medicines. The introduction of biosimilars for the treatment of cancer into the healthcare market in Ireland is welcomed by the National Cancer Control Programme (NCCP). In 2017, the NCCP convened a multidisciplinary working group, involving key stakeholders, to develop and agree a national guidance document on the use of biosimilars in the treatment of cancer.6
This article aims to outline the background to the development and approval of biosimilars, with a focus on their role in the treatment of cancer.
What are biological medicines and biosimilars?
A biological medicine (or biological) is a medicine that contains an active substance made by a biological process or derived from a biological source.7 Biologicals include proteins such as hormones (erythropoietins, insulins and growth hormones) or enzymes that are naturally produced in the human body, and monoclonal antibodies. They may also be blood products, immunological medicinal products and advanced technology products such as gene and cell therapies.8 They vary in size and structural complexity, from simple proteins such as insulin or growth hormone to more complex ones such as coagulation factors or monoclonal antibodies (see Figure 1).
A biosimilar is a biological medicine that is highly similar to another biological (also known as a reference biological medicine) in terms of its quality, safety and efficacy.6, 7 A reference biological medicine is one which already has a marketing authorisation and has been approved for use in patients. Biosimilars contain a version of the active substance of an approved reference biological and should be used in the same way as the reference biological and in accordance with its Summary of Product Characteristics (SmPC).6, 7
All biologicals have an inherent degree of natural variability due to their biological nature, i.e. no two batches of a product will be the exact same. This is also true for biosimilars, which will never be an exact copy of their biological counterparts because of the complex process needed for their production.5 EMA approval indicates that any differences between a biosimilar and its reference biological will have been shown not to affect safety or effectiveness,5 through a rigorous comparability exercise which is carried out at quality, nonclinical and clinical levels.
Are biosimilars the same as generic medicines?
No, they are not the same. Generics are smallmolecule drugs made from a fixed chemical structure that can be easily replicated, e.g. methotrexate, whereas biosimilars of advanced biologicals are much larger, complex molecules derived from living cells with inherent natural variability, e.g. monoclonal antibodies such as rituximab (see Figure 2). Because of their biological and variable nature, biosimilars cannot be regarded as generic medicines. As such, it should be remembered that “biosimilar” is a regulatory term, not a scientific one.6
Figure 1: Examples of different protein types in biologicals approved in the EU Adapted from5
How are biosimilars approved?
Biosimilars are reviewed by the EMA through a centralised procedure, following an application from the pharmaceutical company. The EMA provide a scientific opinion to the European Commission who approve the biosimilar medicine and grant it an EU-wide marketing authorisation. The legal framework and regulatory pathway agreed in the EU outlines that biosimilars must be manufactured to the same quality standards as the reference biological medicine.5, 6 Since 2006, biosimilar versions of several reference biologicals have been approved in the EU and many are available in Ireland. In the Irish setting, after a biosimilar has gained EU approval, the company may submit a reimbursement application to the HSE, in line with the criteria outlined in the Framework Agreement on the Supply and Pricing of Generic, Biosimilar and Hybrid Medicines (2021).10
Extrapolation of indications
For the approval of biosimilars, a process called extrapolation of indications is used. This is where a biosimilar is approved for use in the same indication held by the reference biological medicine, even though it has not been directly studied in a comparative clinical trial.11 For a biosimilar to gain approval, it needs to demonstrate that there are no clinically meaningful differences relative to the reference medicine, in a sensitive patient population. Once comparability has been demonstrated in one indication (i.e. the most sensitive), confirmative clinical studies are not required for all other approved indications.
This extrapolation of indications, versus a clinical trial, may have led to some initial hesitancy in the adoption of biosimilars. Research in the US has shown that uptake can be slow initially due to challenges such as policy change and lack of patient and provider education.12 An Irish study carried out in 2017 highlighted concerns held by medical specialists in relation to biosimilars and emphasised the need for educational initiatives.13 However, there is a growing body of evidence to support their effectiveness, with uptake in some countries near 100%.14 Increased uptake may be driven by financial incentives offered to encourage biosimilar prescribing.15
Figure 2 Molecular weight comparisons: small-molecule drugs versus larger biologicals. Not drawn to scale. Ave: Average; Da: Daltons; EPO: Erythropoietin; mAbs: Monoclonal antibodies. Adapted from9
Interchangeability and substitution
In the context of biosimilars and reference biological medicines, it is important to be aware of the terminology for interchangeability and substitution practices in the EU.5
Interchangeability
The EMA defines interchangeability as ‘the possibility of exchanging one medicine for another medicine that is expected to have the same clinical effect. This could mean replacing a reference biological medicine with a biosimilar (or vice versa) or replacing one biosimilar with another’.5 This process must be carried out under the supervision of a physician. Hospital biosimilar policy should detail the process to be followed when changing a patient from one biological medicine to another.6, 7 This may include supplying the patient with dedicated patient information on the use of biosimilars and / or a discussion between the patient and prescribing physician.7
In September 2022, the EMA and the Heads of Medicines Agencies (HMA) issued a joint statement confirming that biosimilars approved in the EU are interchangeable (at prescriber level) with their reference medicine or with an equivalent biosimilar. While already practised in many Member States, this joint position on interchangeability harmonises the EU approach. Decisions regarding substitution at pharmacy-level, however, are managed by individual Member States.16
Substitution (at pharmacy level)
Unlike small-molecule drugs , biological medicines cannot be substituted at pharmacy level. The Health (Pricing and Supply of Medical Goods) Act 2013 specifically excludes biological medicines (including biosimilars) from being substituted at pharmacy level.17
Biosimilars in Ireland
In January 2016, the HSE Medicines Management Programme (HSE-MMP) highlighted the potential for biosimilars to significantly reduce drug expenditure and facilitate greater access to such treatments.18 On the introduction of a biosimilar to the Irish market, the 2021 Framework Agreement on the Supply and Pricing of Medicines provides for an automatic price reduction of 37.14% for patent-expired, non-exclusive biologicals in addition to the agreed rebates.10, 19 Since 2016, the HSE-MMP has supported the appropriate introduction of biosimilars into clinical use in Ireland, including implementing a prescribing initiative, which has resulted in a significant increase in biosimilar uptake in Ireland since 2019.18, 19
In 2018, the MMP commenced the best-value biological (BVB) medicine initiative to evaluate therapeutic areas where there is potential for biosimilars to be introduced. The initiative aims to realise potential efficiencies from the availability of biosimilars, and to work with the HSE and clinicians to increase uptake of identified BVB medicines in Ireland. To date, the MMP has identified BVB medicines for TNF-α inhibitors (adalimumab and etanercept) under the High Tech Arrangement. They have recently initiated a BVB process for granulocyte stimulating factors (G-CSFs) which are used as supportive agents in the treatment of cancer.
Biosimilars for the treatment of cancer in Ireland
Biologicals and their biosimilar counterparts have been used in the treatment of cancer for many years and this use will grow as more patents expire. Biosimilars approved for the treatment of cancer are licensed by the EMA for all indications held by the reference product, based on extrapolation of efficacy and safety data.20 There are a number of biosimilars available in Ireland used in the treatment of cancer. These include the supportive care agents G-CSFs, used for the prevention and treatment of chemotherapy-induced neutropenia and epoetins, which can be used for the treatment of chemotherapy-induced anaemia,3 see Table 1 above. Additionally, there are biosimilars of therapeutic agents including monoclonal antibodies (mAbs), see Table 2 above. The availability of different formulations has been a particular challenge to the uptake of some biosimilars used in the treatment of cancer. For example, rituximab and trastuzumab have both intravenous and subcutaneous formulations available for administration but a biosimilar is only available in intravenous form.
Conclusion and future directions
Cancer prevalence and the cost of cancer treatment continue to increase globally.
The high costs, particularly of biologicals, may present a challenge in ensuring access for patients to optimal treatment. Cost and accessibility barriers can create disparities in treatment for cancer and resulting clinical outcomes.21 Biologicals and their biosimilar counterparts have an integral role to play in the treatment of cancer. As biologicals are high-cost components of cancer care, the availability of safe and effective biosimilars has huge potential to reduce cancer care costs and enable access to biologicals and other expensive cancer treatments for patients with cancer.22 The implementation of biosimilars should follow a methodical, staged approach with engagement of all relevant stakeholders.6, 7, 23
Several additional biosimilar candidate drugs / medicines are being globally investigated and are at various stages of clinical development and regulatory approval.4 More than 10 years of research has shown that biosimilars are safe and effective.3 There has been a significant increase in the utilisation of biosimilars in Ireland since 2019,19 with a growing body of evidence and experience supporting broader uptake.
The continued development and utilisation of biosimilars is welcomed by the NCCP, the broader HSE and a number of other Irish and European bodies. Optimising the use of biosimilars will facilitate access for patients and support health services to deal with the rising cost of new medicines.
For additional information, please refer to the NCCP Guidance on the use of Biosimilar Medicines in Cancer Treatment document (available on the NCCP website) or email oncologydrugs@cancercontrol.ie.
References available on request
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