Switching patients from an originator biologic (the reference product) to a biosimilar version has been a topic of keen interest in recent years, both in Australia and globally, as more biosimilars have emerged onto the market. This trend has flowed from the expiration of data exclusivity and patent protection for a number of important originator biologics. While biosimilar medicines have been available in Australia for over a decade, biosimilars to the disease‐modifying antirheumatic drugs (DMARDs) (e.g. infliximab, rituximab, etanercept and adalimumab biosimilar products) have only come onto the market in the last 2-5 years. As at February 2020, the Schedule to Australia’s Pharmaceutical Benefits Scheme (PBS) listed 86 originator biologics, with 17 of these biologics having one or more biosimilar brands.
Despite more biosimilars becoming available as alternatives to established biologics, and initiatives by the Australian Government to reduce the administrative burden of switching for prescribers and to enhance consumer confidence in biosimilars, the uptake of biosimilar products has remained limited in Australia.
There are strong financial incentives for the Australian Government to seek to increase the uptake of biosimilars and thus drive competition and lower prices for biological medicines in Australia. In the 2018-2019 financial year, biologics accounted for 8 of the top 10 PBS-subsidised drugs by expenditure. Further, the majority of blockbuster biologics are intended for long-term use in chronic diseases, adding significantly to the cost of subsidising their supply.
In this article, we examine some concerns that have been raised in relation to the practice of biosimilar substitution by pharmacists, and review the current medical consensus on substitution and interchangeability. We also consider Australia’s regulatory arrangements for biosimilar approval and substitution, which present some unique opportunities for promoting wider biosimilar adoption.
Concerns related to switching
Unlike generic versions of small molecule medicines, which are assumed to be identical (in relevant respects) to the originator drug, biosimilars are highly similar, but not identical, to their reference biologic, which has raised concerns about their substitutability. When biosimilars first emerged, interchangeability was an issue of considerable controversy, with concerns expressed about:
- whether efficacy and safety would be compromised when patients were switched between a biologic and biosimilar product or from one biosimilar to another, and in particular when multiple switching occurs;
- whether switch-related immunogenicity (neutralising antibodies against the biosimilar product and/or any naturally occurring counterpart protein) may be triggered when switching from a biologic to a biosimilar (or between biosimilars); and
- whether it is desirable for biosimilar sponsors to be permitted to seek marketing approval for multiple additional indications by extrapolation from the reference biologic’s data, once biosimilarity has been established for a single indication.
These concerns have in some respects remained, despite evidence and better understanding concerning the safety and efficacy of individual biosimilars, as discussed in further detail below.
Terminology – interchangeability and substitutability
The use of terminology in this area varies between jurisdictions, and has been the source of some confusion. In Australia and Europe, interchangeability generally refers to the practice of changing one medicine for another equivalent medicine by the treating physician, with the clinical decision to exchange one medicine for another medicine (with the same therapeutic intent in a given patient by the prescribing doctor) referred to as switching.
The term substitution, as used in Australia, refers to the practice of dispensing one medicine instead of another equivalent and interchangeable medicine by a pharmacist, without requiring consultation or approval from the prescriber.
By contrast to Australian usage, in the United States the term ‘interchangeable biosimilar’ refers to a regulatory standard, whereby a pharmacist is permitted to substitute an interchangeable product for the reference product without consulting the prescriber, subject to individual state regulations. The United States’ ‘interchangeable biosimilar’ designation is roughly equivalent to Australia’s substitution practices, although no biosimilar to date has obtained interchangeable status in the United States.
The issue of structural variability
Much of the concern about switching patients from biologics to biosimilars arises from the inherent structural variability of biologic molecules. Biologics are pharmaceutical products that contain one or more active substances that are derived from living cells or organisms. A common form of a biologic medicine currently in use is a monoclonal antibody. A biosimilar is a version of a reference (approved) biologic that has established similarity to its reference product in terms of quality, safety and efficacy.
Biologics and biosimilars differ from traditional small-molecule drugs, with the latter being structurally simple, chemically synthesised and easily characterised. Biologics, on the other hand, are large, highly complex molecules that are not easily characterised. Biologics are also sensitive to manufacturing process conditions, particularly in relation to post-translational modifications, such as glycosylation patterns. This can lead to variability in the final structure of individual molecules, referred to as micro-heterogeneity, which can lead to a risk of product divergence. Slight variation may also occur between each batch of a biologic manufactured, referred to as batch-to-batch variation.
Is switching considered safe?
The propensity for minor structural variability in biologics, as described above, has given rise to concerns that biologics and biosimilars may be less suitable for pharmacy-level substitution than traditional, small-molecule medicines. On the other hand, there has now been over 10 years of real-world clinical experience with switching involving biosimilars that have been launched, as well as a growing number of studies regarding the safety and efficacy of switching, such as between certain erythropoietin-stimulating agents, filgrastim, insulin, adalimumab, rituximab, infliximab and etanercept, and their corresponding biosimilars.
Australia’s biosimilars regulatory scheme
In Australia, the Therapeutic Good Administration (TGA) has responsibility for registration and marketing authorisation of medicines (focusing on safety, efficacy and manufacturing quality) while the Pharmaceutical Benefit Advisory Committee (PBAC) advises the Australian Government on whether supply of a medicine should be subsidised (focusing on cost-benefit analysis) as well as advising on brand substitutability and other matters relating to the PBS.
Due to the complexity of biologic molecules and their propensity for structural variation, establishing biosimilarity requires more rigorous regulatory processes than those applied to establishing bioequivalence of generic medicines. The TGA assesses each biosimilar based on the totality of available data, comparing it to the reference product in terms of its physicochemical structure, biological activity, preclinical data (pharmacokinetic and pharmacodynamic data) and clinical trials data (efficacy, safety and immunogenicity). Regulatory approval for a biosimilar requires that no clinically meaningful differences exist and that the biosimilar molecule is therapeutically equivalent to the reference medicine.
In general, a Phase III clinical trial for a single indication will be sufficient to confirm biosimilarity (together with preclinical and physiochemical data). Once biosimilarity is established, it may be possible for a biosimilar to be approved for other indications by so-called ‘indication extrapolation’ from the reference product’s data. An Australian consensus statement on the use of biosimilars in haematological conditions published by an expert panel in April 2020 reported that post-approval experience has confirmed that extrapolation of indications is a safe practice.
Australia’s approach to substitutability
The Australian Government has taken a relatively pro-substitution approach to biosimilars, with substitutable biosimilars denoted in the Schedule of Pharmaceutical Benefits with an ‘a’ superscript (a-flagged). However, the prescribing physician can prevent pharmacy-level brand substitution by ticking the “brand substitution not permitted” box on the prescription form. Where a prescription indicates that no substitution is allowed, it is an offence under section 103(2) of the National Health Act 1953 for a pharmacist to dispense a brand other than that specified on the prescription. Where brand substitution is permitted, good pharmacy practice further requires that the pharmacist consult with the patient before substituting another brand. These safeguards are intended to ensure that no uncontrolled substitution occurs in practice in Australia.
As noted previously, the PBS (as at February 2020) lists 86 originator biologics, with 17 reference biologics having one or more biosimilar products, with all but a few biosimilars being ‘a’ flagged to their reference product.
PBAC assessment of biosimilar substitutability
The PBAC first announced in April 2015 that biosimilar products would be ‘a’ flagged to their reference product as a default position in Australia. However following consumer consultation, this position was revised in July 2015, with the PBAC instead stating that recommendations for ‘a’ flagged status would be made on a case-by-case basis. This change in stance, the Committee indicated, was meant to reassure consumers that biosimilars would not, simply by virtue of being a biosimilar, be provided with automatic substitutability. The PBAC further advised that the following matters would be relevant considerations in support of ‘a’ flagged PBS listing status:
- TGA determination of biosimilarity to the reference biologic;
- absence of any evidence to suggest significant differences in clinical effectiveness or safety compared with the reference product;
- absence of any evidence identifying patient populations where the risks of using the biosimilar product are disproportionately high;
- availability of data that the biosimilar was safe and effective in treatment-naïve patients initiated on the biosimilar product; and
- availability of data to support equivalent safety and effectiveness when switching between the reference product and the biosimilar.
In March 2018, the PBAC once again revised its position on the assessment of brand equivalence and substitution for biosimilars, this time noting that the TGA’s determination of biosimilarity adequately covered matters of safety and efficacy. The PBAC’s simplified criteria now includes only the following matters:
- TGA determination of biosimilarity;
- availability of supportive data relating to the effects of switching between the reference product and the biosimilar product(s); and
- practical considerations relating to substitution by the pharmacist at the point of dispensing (e.g., strength of formulation and number of units per pack).
The PBAC indicated that where there is insufficient data to support ‘a’ flagging, additional data should be collected to facilitate future reconsideration. The Committee has also made clear that its preference is to extrapolate biosimilarity across all indications proposed for subsidy rather than requiring indication-specific data.
The United States’ ‘interchangeability’ designation
By contrast, in the United States interchangeability is a regulatory standard with a higher bar in terms of the clinical data required. The Food and Drug Administration (FDA) released updated guidance for biosimilar interchangeability in May 2019, which contemplates two categories of licensed biosimilars – ‘biosimilars’ and ‘interchangeable biosimilars’. However, to date, no biosimilar products approved for marketing in the United States have been designated as ‘interchangeable’ by the FDA.
The United States is currently the only country that requires a biosimilar sponsor to submit additional clinical trials data to obtain an interchangeability designation. Qualifying ‘interchangeable’ products must demonstrate to the FDA’s satisfaction that they may be expected to produce the same clinical result as the reference product in any given patient. The FDA requires sponsors to conduct switching studies for any biosimilar that is administered more than once. Such studies must incorporate at least two separate exposure periods for each of the products tested (i.e. at least three switches between reference biologic and biosimilar). In order to produce this data, biosimilar sponsors must expend significant resources to conduct clinical switching studies satisfying these requirements. Once the product meets the requirements of an interchangeable biosimilar for at least one indication, the sponsor may seek to be licensed for additional indications for which the reference product is licensed by extrapolation.
Does substitution occur in Europe?
Unlike the FDA, the European Medicines Agency (EMA) has not adopted a stance on interchangeability and does not regulate interchangeability, nor substitution practices, which fall under the authority of individual European Union (EU) member states. In this regard, it is reported that no pharmacy-level substitution occurs in the EU, and moreover no EU member has deemed that switching studies are a necessary requirement for biosimilar substitutability.
By way of example, the United Kingdom does not permit pharmacy-level substitution and instead leaves this to the prescribing physician’s discretion. France went as far as introducing laws granting pharmacy-level substitution of biosimilars for treatment-naïve patients only, but it is yet to put this into practice as a result of opposition to the implementation of substitution practices.
‘a’ flagging and skinny-labelling strategies
Sponsors of both biologics and biosimilars should take note of the interplay between ‘a’ flagging and so-called ‘skinny-labelling’ strategies aimed at carving out patent-protected indications to allow a biosimilar supplier to potentially avoid patent infringement by arguing that it does not have reason to believe its product would be put to an infringing use. The PBAC is only permitted to list a product on the PBS in respect of indications for which the product has been granted marketing approval by the TGA. Thus one potential approach for biosimilar sponsors is to limit their application for marketing approval to only those indications for which patent protection has expired or is unlikely to withstand a validity challenge. However, it is not clear that such an approach will avoid patent infringement in respect of a non-indicated use. Australian courts have grappled with these indirect infringement issues in recent years, which are legally complex and highly dependent on the specific facts attending the products, patent and market relevant to the innovator and generic/biosimilar products in question.
The way forward?
The slow market uptake of biosimilars in Australia has generally been attributed to the understandable lack of familiarity and comfort with biosimilar products by treating physicians, pharmacists and patients alike.
It is to be expected that confidence in biosimilars will increase with time. It is also likely to be enhanced through substitution policies and initiatives (such as Australia’s practice of ‘a’ flagging biosimilars on a case-by-case basis), clearer guidelines on interchangeability and substitutability designations, expert medical consensus statements on biosimilar use, as well as pricing incentives. In this regard, it will be of interest to see how the market uptake of biosimilars develops over this decade.
 PBS. ‘Biological Drugs and Brands listed on the Pharmaceutical Benefits Scheme’. http://www.pbs.gov.au/info/browse/biological-medicines-currently-listed-on-the-pbs#P. Accessed 23 May 2020.
 PBS. ‘PBS Expenditure and Prescriptions Report 1 July 2018 to 30 June 2019’. http://www.pbs.gov.au/statistics/expenditure-prescriptions/2018-2019/PBS_Expenditure_and_Prescriptions_Report_1-July-2018_to_30-June-2019.pdf. Accessed 23 May 2020.
 Gregory G.P. et al. ‘A consensus statement on the use of biosimilar medicines in hematology in Australia’. Asia-Pacific Journal of Clinical Oncology. April 2020. https://doi.org/10.1111/ajco.13337; Weise M et al. ‘Biosimilars: what clinicians should know’. Blood. 2012;120:5111‐5117.
 Ramanan S and Grampp G. ‘Drift, evolution, and divergence in biologics and biosimilars manufacturing’. BioDrugs. 2014;28(4):363–72.
 Ibid; La Noce A. and Ernst M. ‘Switching from reference to biosimilar products: an overview of the European approach and real-world experience so far’. European Medical Journal. September 2018. https://emj.europeanmedical-group.com/wp-content/uploads/sites/2/2018/09/Switching-from-Reference….pdf. Accessed 23 May 2020.
 TGA. ‘Biosimilar medicines regulation – Version 2.2’. https://www.tga.gov.au/sites/default/files/biosimilar-medicines-regulation.pdf. Accessed 23 May 2020.
 As above note 3
 As above note 3, Table 2 – Table of Recommendations.
 Department of Health. ‘Biosimilar medicines: the basics for health care professionals’. March 2017. https://www1.health.gov.au/internet/main/publishing.nsf/content/biosimilar-awareness-initiative/$File/Biosimilar-medicines-the-basics-for-healthcare-professionals-Brochure.pdf. Accessed 23 May 2020.
 As above note 1.
 PBAC. ‘Reimbursement of Biosimilar Medicines’. PBAC Special Meeting April 2015. http://www.pbs.gov.au/industry/listing/elements/pbac-meetings/pbac-outcomes/2015-04/2015-04-biosimilars.pdf. Accessed 23 May 2020.
 PBAC. ‘Consumer Hearing on Biosimilars’. PBAC Meeting July 2015. http://www.pbs.gov.au/industry/listing/elements/pbac-meetings/pbac-outcomes/2015-07/consumer-hearing-record-on-biosimilars-2015-07.pdf. Accessed 23 May 2020.
 PBAC. ‘Public summary document – Considering brand equivalence/substitution for biosimilar medicines’. PBAC meeting March 2018. http://www.pbs.gov.au/info/industry/listing/elements/pbac-meetings/psd/2018-03/Biosimilar%20medicines-psd-march-2018. Accessed 23 May 2020.
 FDA. ‘Considerations in demonstrating interchangeability with a reference product: guidance for industry’. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM537135.pdfAccessed 23 May 2020.
 Centre for Biosimilars. ‘Boehringer Ingelheim Policy Chief Discusses Biosimilar Outlook’. 8 May 2020. https://www.centerforbiosimilars.com/conferences/festival-of-biologics-2020/boehringer-ingelheim-policy-chief-discusses-biosimilar-outlook. Accessed 23 May 2020.
 Welch A. R. 2017. ‘What Systems Are Needed to Create a Viable Biosimilar Market?’ Biosimilar Development. https://www.biosimilardevelopment.com/doc/what-systems-are-needed-to-create-a-viable-biosimilar-market-0001
 Ibid; Murphy A. et al. ‘New FDA Guidance on Biosimilar Interchangeability’. Life Science Leader, July 2019. https://www.lifescienceleader.com/doc/new-fda-guidance-on-biosimilar-interchangeability-0001. Accessed 23 May 2020.
 La Noce A and Ernst M. ‘Switching from reference to biosimilar products: an overview of the European approach and real-world experience so far’. European Medical Journal. 2018;3:74-81.
 As above note 17.
 As above note 19.
 As above note 17.