Author byline as per print journal: Andriy Krendyukov, MD, PhD; Marta Bakowska, BA (Hon), MPH; Dirk Schiller, PhD; Sanjay Singhvi, BSc (Hon), MBBS, MBA

Submitted: 2 May 2023; Revised: 14 January 2024; Accepted: 19 January 2024; Published online first: 26 January 2024

Introduction

Biological therapies have revolutionized care for many patients with chronic conditions, including cancers [1]. However, as the largest driver of rising prices for therapeutic agents [2], they put a financial strain on healthcare systems, limiting patients’ access to required medication [3]. With the expiration of patents for biological medicines, the opportunity to develop and market biosimilar medications arises, promising to make the treatment benefits of biological drugs more accessible. While the cost of developing and manufacturing biosimilars remains high compared with generics, they still offer savings to healthcare systems by delivering the same quality, efficacy, and safety. According to a recent report from the Association for Accessible Medicine, the biosimilar sale price was, on average, 50% less than the reference brand biological price [4]. Furthermore, competition from biosimilars has reduced the sales price of their corresponding reference biological by an average of 25%. Biosimilars bear no significant clinical differences from their reference medicinal product and face rigorous approval pathways. Although biosimilar manufacturing and its corresponding regulations have become more established, resulting in an increased number of approvals, healthcare providers and patients might often lack confidence in their use, despite the potential for reducing treatment costs and improving patient access. In this opinion paper, the authors assess factors that may impede the acceptance of biosimilars in the medical community and explore measures to enhance confidence.

Failure to understand the logic of biosimilar development

The first consideration is that the regulatory requirements for the approval of a conventional biological and a biosimilar differ. The manufacture of the biological follows the established product development pathway, in which clinical trials have a significant role. These trials range from phase I clinical pharmacology studies to extensive phase II and III efficacy and safety trials, confirming therapeutic benefit without excess toxicity.

For a biosimilar, therapeutic benefit is derived from data obtained from the reference medicine. The objective of a biosimilar development programme is therefore not to demonstrate efficacy and safety per se, but rather to establish high similarity with the reference biological based on totality of evidence, including comparability in i) analytic features; ii) pharmacokinetics; iii) pharmacodynamics; and iv) immunogenicity. In this approach, analytic studies and in vitro functional tests are the foundation of the development pathway. They use extensive structural and functional assays to compare the candidate biosimilar with the reference biological for relevant features such as primary amino acid sequence, tertiary conformational structure, post-translational modifications, e.g. glycosylation, and assess any impurities and degradation products both upon release and during shelf life. This is followed by non-clinical in vitro and, exceptionally, in vivo testing, and subsequent clinical evaluation, including a comparative pharmacokinetics/pharmacodynamics (PK/PD) study that is usually conducted in healthy volunteers. The reasoning is that if a biosimilar passes these tests, then it must be as effective and safe as the reference product in the clinical setting. The development programme may culminate in a confirmatory comparative clinical study.

Biologicals are produced in biological systems with proprietary, specialized manufacturing processes, in which small variations can influence the final structure and, thus, the function of a medicine [5]. Such variations may also occur in biosimilar development. The risks of such variations are controlled by comparability studies, as described in the ICH Q5E guideline and relevant biosimilar guidelines. The biosimilar development pathway is very rigorous, as demonstrated by long-term follow up [6, 7].

The lack of familiarity and knowledge surrounding the development process continues to lead to confusion and decreased confidence in the safety and effectiveness of approved biosimilars by prescribers [8]. Indeed, healthcare providers, particularly in fields where biosimilars have been more recently adopted, often do not realize the strength of data that is required for their approval and evaluate their efficacy and safety solely on the basis of clinical data [5, 9–15].

The unpublished preliminary results of an online survey conducted by the authors amongst physicians across different specialities revealed that when asked to rate the importance of evidence supporting a biosimilar, ‘clinical data’ rated highest, with around 85% of respondents stating that this evidence was of high to very high importance (Supplementary data). This was followed by clinical phase II/III data and immunogenicity data, both rated as of high to very high importance by 76% of respondents. The proportion of respondents giving other evidence the same level of importance was lower: 53% for PK and PD data, 45% for in vitro and in vivo data, and 40% for physicochemical data.

In vivo animal studies and confirmatory efficacy and safety studies – unnecessary regulatory burdens?

In the rapidly developing field of biosimilars, guidelines and legislation are continually evolving in response to accumulating evidence from analytical, non-clinical and clinical evidence, along with real-world clinical data from approved biosimilars.

It is clear that standard animal toxicology studies cannot provide meaningful data on the potential differences in safety between biosimilars and their reference products [16].

In 2019, the World Health Organization (WHO) Expert Committee on Biological Standardization noted that a more tailored and reduced clinical data package for biosimilars may be acceptable in certain cases. A recently published conceptual paper explored the possibilities for updating the WHO guidelines and streamlining the clinical development of biosimilars. The paper suggests that state-of-the-art analytical and functional testing, as well as robust PK and PD studies, are essential elements for biosimilar development. In contrast, in vivo animal studies and large confirmatory efficacy and safety studies are generally not needed to prove the equivalence of a biosimilar to the originator [6]. This is reflected in the updated WHO guidelines published in 2022 [17].

Following suit, the UK Medicines and Healthcare products Regulatory Agency (MHRA) guidance on the licensing of biosimilars noted that in most cases, a comparative confirmatory efficacy trial may not be necessary [18], stating that if the analytical and purity profile of the candidate biosimilar is highly similar to that of the reference product, there is no scientific reason for its PKs, efficacy, safety, and immunogenicity to be different. A recent study analysed marketing authorization applications for 33 monoclonal antibodies and three fusion proteins and determined whether a negative application outcome could have been predicted based on the evidence in the submission package, regardless of clinical trial data [19]. The results showed that a robust analytical/functional similarity package, together with a PK trial capturing data on safety and immunogenicity was appropriate even for the approval of very complex biosimilars.

Terms used by regulators may cause confusion among healthcare providers

The biosimilar field is characterized by several terms and concepts including extrapolation, switching, substitution, and interchangeability, which continue to cause confusion and misinformation. For instance, in mathematical terminology, extrapolation refers to projecting unknown values from trends in known data. However, when applied to biosimilars, extrapolation can only happen when the biosimilar matches the reference biological on all critical quality attributes [20], supported by a scientific justification. Extrapolation of the biosimilar can then be made from biosimilar molecule to reference molecule for use in all approved indications held by the reference biological therapy, but not directly studied in a comparative clinical trial with the biosimilar. Thus, clinical studies supporting the authorization of biosimilar filgrastim were performed in patients with breast cancer undergoing myelosuppressive chemotherapy. Other indications, including stem cell mobilization and severe chronic neutropenia, were approved on the basis of extrapolation with no clinical data available at the time of market authorization. More than a decade of clinical experience for filgrastim is now available to reassure physicians concerning the efficacy and safety of biosimilar filgrastim in all its indications [21, 22]. In the online survey, only a third of respondents could correctly define extrapolation as it related to authorization of a biosimilar, and only 15.8% were aware that the most appropriate indication for a confirmatory study for extrapolation is the most sensitive patient population for detecting any potential difference between the products. Other research has shown that acceptance of extrapolation may be less likely across disease entities: e.g. extrapolating data from rheumatoid arthritis to Crohn’s disease (although both are inflammatory diseases), and across different phases of the same disease (from palliative to curative), i.e. the efficacy of a biosimilar trastuzumab in metastatic disease extrapolated to its use in early breast cancer [5]. To date, extrapolation has not resulted in any safety or efficacy problems.

Interchangeability – disharmony of terminology creates problems

Uncertainty also surrounds whether the evidence of safety and efficacy is sufficient to support interchangeability with reference biologicals. Additionally, the complexity and dynamic nature of reverse and multiple switches, along with potential patient acceptance of using a biosimilar and associated nocebo effects, contribute to the uncertainty. For instance, if patients are satisfied with their current medication, they might be reluctant to accept the change. This reluctance poses a risk of them experiencing the nocebo effect and perceiving a loss of efficacy or even the onset of adverse events, which they may then attribute to the biosimilar [23]. These concerns are based on theoretical considerations and perceptions.

EMA does not formally regulate the substitution process (the practice of dispensing one medicine instead of another medicine without consulting the prescriber). This responsibility falls within the remit of individual EU Member States. Analysis of data from switching studies provided in EU regulatory submissions has shown that single or multiple switches between the reference biological and its biosimilar versions had no negative impact on efficacy, safety or immunogenicity [7]. It therefore appears that concerns regarding immunogenicity following switching are unfounded. Switching from one biosimilar to another biosimilar of the same reference product is common in clinical practice in the EU and has also been documented in the published literature [24, 25].

There are differences in the definitions and approaches to interchangeability between countries and regions. In the EU, interchangeability is defined as ‘the possibility to use a medicinal product instead of another one without any changes in its clinical effect [26].’ The Heads of Medicines Agencies (HMA) and EMA consider that once a biosimilar is authorized in the EU, it is interchangeable. This means: (i) a biosimilar can be used instead of its reference product (or vice versa); or (ii) one biosimilar can be replaced with another biosimilar of the same reference product. In Denmark and Norway, the interchangeability of certain biologicals is automatic without consultation with prescribers or patients.

In Canada and the US, interchangeability refers to automatic substitution, wherein the biosimilar ‘may be substituted for the reference product without the intervention of the healthcare provider who prescribed the reference product’. According to the Food and Drug Administration (FDA), a biosimilar needs further clinical switch studies to become ‘an interchangeable’ that can be substituted at the pharmacy level. This concept is problematic from an international harmonization point of view. The scientific value of switch studies is being questioned, and the different approaches in the EU and US cause further confusion to healthcare providers.

Discussion and conclusions

As patents for high-cost reference biologicals come to an end, competition from biosimilars is increasing. By 2023, patents on nearly 20 oncology biologicals will expire [27], and the expansion of biosimilars will reach new therapeutic areas including neurology, cardiology and ophthalmology. The availability of biosimilars can potentially result in substantial cost savings for patients and healthcare providers, and consequently, greater and earlier patient access to effective therapies. Biosimilars are an important part of the solution to support more sustainable healthcare systems worldwide and increase patients’ access to innovative biologicals.

In the authors’ opinion, education will be key to enhancing the acceptance of biosimilars. The misconceptions concerning biosimilars are deeply rooted. There is a tendency for physicians to believe that the abbreviated clinical development and the biosimilar-specific flexible approval process suggest reduced product quality and safety. Consequently, many are hesitant to switch patients from originator products to biosimilars without evidence from switching studies. Physicians are accustomed to evidence from animal studies, safety studies and clinical trials, but they are not familiar with the specific approval track for biosimilars. This track involves assessing the totality of evidence, with a strong emphasis on comprehensive analytic data. The scientific foundation of biosimilars is solid. Medical societies and other relevant learned societies, as well as payers, need to invest resources in educating physicians and other stakeholders about the rigorous approval process for biosimilars. As this is an evolving field, training should be continuous, with regular updates as guidelines and legislation change. Training will also be required on specific terms, such as extrapolation, if physicians are to embrace the approval of biosimilars for applications beyond the initial approved setting.

There has been a long reliance on randomized-controlled trials for regulatory decision-making, which are laborious, costly, and produce data that can have limited applicability in real-world clinical practice. To support biosimilar acceptance, there is a need for high-quality information communicated in an ongoing manner on biosimilar safety, efficacy, and comparability to the reference biological. To avoid unequal competition between existing biosimilars (approved with a data package that included clinical phase III trials) and future biosimilars that may be approved without the necessity for clinical comparative data, education must continue to focus on evolving regulatory pathways and knowledge. If not, physicians may incorrectly assume that future biosimilars have inferior supporting data and may be less likely to use them.

Publishing post-marketing surveillance and other observational studies of real-world data offers an important opportunity for marketing authorisation holders of biosimilars to provide additional evidence in areas where physicians may have particular concerns, such as effectiveness and safety, immunogenicity, long-­­­­term safety, efficacy in extrapolated ­indications, and the effects of switching. Considering the limited number of patients studied during the registration process of biosimilars, it is crucial to place a strong emphasis on pharmacovigilance. This can be achieved through collaboration with patient registries established in several countries.

Should physicians be gatekeepers for the use of biosimilars?

Finally, while physicians currently serve as the main gatekeepers in determining whether patients receive a reference biological or a biosimilar, the choice is also influenced by regulatory frameworks, economic incentives, clinical evidence, and patients’ preferences. More and more countries will introduce automatic substitution or other types of mandatory switches; however, this does not diminish the importance of information. Physicians, pharmaceutical companies, regulatory agencies, and health authorities should collaborate closely to demonstrate the equal efficacy and safety of both the original biologicals and their biosimilars, enabling more patients to have greater access to these medicines.

Funding sources

This paper was not funded.

Competing interests: Beyond employment, the authors report no conflicts of interest.

Andriy Krendyukov is an employee of Aspire Pharma (UK) and Mannheim University (Germany). Marta Bakowska and Sanjay Singhvi are employees of VML Health, UK. Dirk Schiller is an employee of both STADA Arzneimittel AG and Schiller BioPharma Consulting, both based in Germany.

Provenance and peer review: Not commissioned; externally peer reviewed.

Authors

Andriy Krendyukov, MD, PhD
Aspire Pharma Ltd, UK

Marta Bakowska, BA (Hon), MPH
VML Health, UK

Dirk Schiller, PhD
Schiller Biopharma Consulting, Germany

Sanjay Singhvi, BSc (Hon), MBBS, MBA
Director, VML Health, UK

The supplementary data that support the findings of this study are available from the editorial office upon reasonable request.

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