Biosimilars are biological drugs that are similar to, and cheaper than other biological drugs (called “reference originator biologics”) that are already in use. They share an identical amino-acid sequence but, given the inherent variability of biological molecules, not full “sameness”. Biosimilar registration follows a strictly regulated pathway based on a totality-of-evidence approach. This article critically discusses the particulars of biosimilar development, including the continuous development of regulatory guidelines, familiarises readers with biosimilar-specific terminology, addresses the typical challenges of writing biosimilar dossiers, and summarises future directions in biosimilar development in the context of a changing competitive landscape. After reading this article, medical writers with diﬀerent backgrounds, including those previously unfamiliar with key aspects of biosimilar development, should be able to better understand and apply these guidelines in their daily biosimilar work.
WHAT ARE BIOSIMILARS? WHAT ARE THEY NOT?
Biologics or biological drugs are products created from living organisms or that contain components of living organisms. Biosimilars are biological drugs that are similar to, and cheaper than, other biological drugs (called “reference originator biologics”) that have already been approved for use on the market. Since biologics and biosimilars are created in living cells, they cannot be chemically synthesised like conventional drugs and their generics.
While a biosimilar candidate and an originator biologic share the same amino-acid sequence, they can never be identical, due to the inherent variability of complex biological molecules. In other words, a biosimilar and its reference biologic share a similar (but never exactly the same) functional version of the active substance. Examples of biosimilars (and biologics) include monoclonal antibodies, hormones, small proteins, vaccines, and fusion proteins.1 Biosimilars (and biologics) that are monoclonal antibodies or derivatives thereof target pro-inflammatory cytokines, most commonly tumour necrosis factor alpha.
In the EU, a biosimilar is defined as a biological medicine highly similar to another biological medicine already approved in the EU, for which there are no clinically meaningful diﬀerences to the reference medicine in terms of safety, quality and eﬃcacy.2 In the US, a biosimilar product is defined as a biologic product approved based on demonstrating that it is highly similar to an US FDA-approved biologic product that has no clinically relevant diﬀerences in terms of safety and eﬀectiveness compared with the reference product; only minor diﬀerences in clinically inactive components are allowed for a product to be deemed biosimilar.3 Other terms used to describe biosimilars are: follow-on biologic, follow-on protein, and subsequent entry biologic.4 An essential aspect to keep in mind is that the EU-approved and US-approved reference products are not considered equivalent by default.
Biological medicines (originator biologics and biosimilars) oﬀer treatment options for patients with chronic and often disabling conditions such as diabetes, autoimmune disease, and cancer.2 Biologics have a 12-year exclusivity in the US5 and an 11-year exclusivity in the EU, comprising 10 years for new biologics (eight-year data exclusivity and two-year market exclusivity) and a one-year extension for a new indication.6
A biosimilar candidate can be manufactured and (once biosimilarity to an originator has been shown) sold at a lower cost than the originator biologic, as the clinical development programme for a biosimilar is lean and relies heavily on the eﬃcacy and safety experience previously established with the originator. Thus, it can be beneficial for patients with chronic conditions to gain access to biosimilar medicines at prices more accessible than those of their originator biologics, and profitable for companies to specialise in biosimilar development. Biosimilars have been on the market for 13 years in the EU (the first approval of a biosimilar product in the EU was in 2006)2 and for 4 years in the US (the first approval by the US FDA was in 2015).7
REGULATORY ASPECTS OF BIOSIMILAR DEVELOPMENT
Since variability (be it qualitative or quantitative) may result not only in a loss of biological function, but also in severe and potentially unknown adverse events, biosimilars need to follow a highly regulated regulatory pathway. This pathway diﬀers between the EU and the US.
Historically, regulatory requirements in the EU and US have developed in parallel with the development of biosimilars. The regulatory framework for biosimilars was established in the EU in 2003. The Committee for Medicinal Products for Human Use (CHMP) overarching guideline on biosimilars came into force in 2005 and a revised version came into eﬀect in 2015.8 In recent years, both the overarching guideline and its sister guidelines (that focus on quality, non-clinical, and clinical issues) have been updated, reflecting the growing experience with biosimilars. In recent years, the US FDA has also been heavily engaged in developing guidelines for biosimilar development9 and providing advice to stakeholders. In 2010, the World Health Organization published a “similar biotherapeutic products” guideline.10 Eﬀorts towards global guidelines are however still in a very early stage. See Table 1 for further details.
Table 1. Biosimilars in the EU and in the US – a selection of key diﬀerences
Additionally, diﬀerent health authorities currently prefer and use slightly diﬀerent terminology. It is thus up to pharmaceutical companies to develop internal best practices with input from their regulatory aﬀairs departments regarding terms acceptable for use in the EU, US, and the rest of the world.
Interestingly, because of the inherent variability of biologics, an originator manufacturer of biological products also faces challenges when introducing changes in the manufacturing process, and needs to demonstrate equivalence, for example, for diﬀerent formulations of the same medicinal product. Changes in the regulatory requirements intended primarily to support and facilitate changes to biologics’ manufacturing processes triggered the evolution of the concept of the biochemical bridge, whereby a comprehensive analytical (biochemical and biophysical) comparative testing programme could be used as part of the justification for demonstration of equivalence or similarity.4 The biochemical bridge easily lent itself to the analysis of candidate biosimilars and played an important role in starting to define diﬀerences and their correlations to physiological and clinical eﬀects (see section The world upside down below).
The EU-approved and US-approved reference products are not considered, by default, similar to each other and thus it is essential that studies aiming to establish similarity use the reference biologic matching the intended target region. In practice, in a lean development programme, this often means that both reference products will be included in the same clinical study, and the equivalence of the biosimilar candidate will be tested against both.
Regulatory requirements for paediatric biosimilar development diﬀer between the EU and the US. In the EU, Regulation (EC) No 1901/ 200 exempts manufacturers of candidate biosimilars from providing a paediatric investigational plan (PIP).11 In contrast, according to the 2016 revised US FDA draft guidance on PSPs,12 a paediatric study plan (PSP) is needed for candidate biosimilars in the US.13
THE WORLD UPSIDE DOWN
Biosimilarity to a reference product (biologic originator) is established based on a so-called totality-of-evidence approach. The bulk of a biosimilar development programme is made of comprehensive analytical (biochemical and biophysical) comparative testing as part of the justification for demonstration of equivalence or similarity, while the clinical part is – especially when looking at it with an originator mindset – very lean (see Figure 1). Residual uncertainties need to be addressed.
Biosimilars follow a step-wise development, with the risk of failure decreasing at each step:
- quality comparability is essential and involves comprehensive characterisation and comparison of physicochemical and biological properties; the degree of similarity demonstrated at this level might determine the amount of additional evidence that needs to be generated at later stages; for further information on quality attributes requirements by region,14,15 see Table 1.
- pre-clinical (functional) comparability oﬀers reassurance on similar eﬀects and involves functional in vitro assays to define and compare the mode(s) of action:
- in vitro studies are always required and normally cover most functional aspects.
- it is essential to determine the level of concern depending on quantitative/ qualitative diﬀerences in critical quality attributes.
- in vivo PK (pharmacokinetics)/ PD (pharmacodynamics) and/or safety studies may be necessary in case of e.g., a new expression system; see Table 1 for details by region
- clinical comparability involves testing in a sensitive population and dose at a sensitive time point using an appropriate statistical model and testing approach; usually the details for phase III conduct are agreed upfront with the health authority of the region intended for registration.
Figure 1. Biosimilar vs. originator development – the world upside down
CLINICAL BIOSIMILAR DEVELOPMENT
Unlike in originator drug development, clinical programmes for biosimilar candidates are lean and rely on the clinical experience with the originator biologic. Most of these programmes only comprise:
- one phase I PK/PD bridging study in healthy volunteers.
- one phase III confirmatory eﬃcacy and eﬃcacy study in patients with the most sensitive indication; switching treatment groups is usually included in the study design.
The objective of both types of studies is to show equivalence between the proposed biosimilar and its corresponding originator product, for which a solid justification for the applied equivalence margins is required. For generics studies, a 90% confidence interval within 80% – 125% equivalence margins is acceptable for demonstrating bioequivalence, on the assumption that the generic and originator medicines will have the same behaviour in the body once absorbed. For biosimilarity, however, a diﬀerent confidence interval may be needed to demonstrate similarity in exposure; this needs to be discussed and justified. For generics, the focus is on comparing the absorption of the test and reference products, while for biosimilars it is of interest to determine a potential diﬀerence both in the absorption and the elimination phase.
As already mentioned, when running global development programmes and designing clinical studies, it is to be kept in mind that the EU-approved product and the US-approved product are not by default equivalent, and that the equivalence margins and confidence interval requirements may diﬀer between regions. In addition, what is considered the most sensitive indication (to show diﬀerences) and the most sensitive population within this indication is usually agreed upon upfront with the respective health authorities before running a comparative clinical eﬃcacy and safety study.
Biosimilar studies do not test for superiority. An equivalence design at the 90% or 95% confidence interval is used in phase III comparative trials (generally preferred to a non-inferiority design) and establishes that the biosimilar is neither superior nor inferior to the reference product.16 For detailed statistical considerations in biosimilar development, see Balfour and Schmitt in this issue.17
Dose-ranging studies are not conducted in biosimilar development, as a biosimilar candidate will be approved for the specific approved dose(s) of the originator once biosimilarity has been shown and extrapolation has been scientifically justified (see below for further details). Additionally, in the case of manufacturing changes during the course of development of the biosimilar candidate, bridging studies between formulations are needed to establish their equivalence (just as they are needed for biological originator manufacturers in such situations) to ensure function preservation given the inherent biological variability of biologics.
Immunogenicity is a major safety concern (manifesting as hyper sensitivity reactions) not only for biosimilars, but for the development of biologics in general. The development of antidrug-antibodies (in particular neutralising antibodies) could also impact eﬃcacy (potentially resulting in a decrease or loss of eﬃcacy), therefore clinical design and corresponding documents need to address such concerns. Antibody formation takes time, thus one-year immunogenicity data are required for most monoclonal antibody applications in the EU.
Previous knowledge about the immunogenicity of the originator biologic is valuable, nonetheless the immunogenic potential of small diﬀerences in quality attributes of the biosimilar candidate may not be easy to predict or understand. Methods for antibody detection are becoming increasingly sensitive, thus it is often challenging to meaningfully compare data with the candidate biosimilar with historical data provided in the label of the originator biologic.
Overall, the biosimilar candidate should have the same safety profile as the originator biologic. Lower immunogenicity (and thus improved safety) could be accepted, whereas higher immunogenicity cannot. In cases of lower immunogenicity, however, eﬃcacy could look artificially higher due to lower levels of neutralising antibodies and entail higher rates of other adverse events. This could nonetheless be accepted, provided that patients without antidrug-anti bodies show comparable eﬃcacy.
An essential concept for biosimilar development is the extrapolation to other indications. Once biosimilarity has been established based on the totality-of-evidence, extrapolation from the studied indication to all indications approved for the reference biologic is possible based on solid scientific justification.
In other words, extrapolation is the term used to describe the use of a biosimilar for an indication approved for the originator that was not directly tested in the development programme of the biosimilar.4 Eﬃcacy and safety do not need to be established de novo in each indication of the originator biologic, but a solid rationale is needed and extrapolation is granted on a case-by-case decision for each biosimilar. Key factors for the scientific rationale are usually a shared clinically relevant mode of action across indications, and the sensitivity of the studied indication and its relevance for other indications.
INTERCHANGEABILITY, SUBSTITUTION, AND SWITCHING
Following the approval of a small molecule pharmaceutical product, being able to switch (or substitute) between pharmaceutical drug products (from originator to generic) is a well-established and extensively used practice and is typically implemented at the pharmacy level. However, in addition to restrictions against biosimilar extrapolation, this type of switching (between originator and biosimilar) and interchangeability requires approval at the national level in the EU. The terms “interchangeability”, “substitution”, and “switching” all refer to the practice of treating patients with the originator biologic and then changing treatment to an approved biosimilar, or changing from one approved biosimilar to another approved biosimilar.4,18 There are a number of diﬀerences with which the EMA and the US FDA regard the interchangeability of biologics and biosimilars, as detailed in Table 2.
Table 2. Interchangeability and substitution in the EU and in the US – key diﬀerences18
WHAT WRITERS WORKING ON BIOSIMILAR DOCUMENTS NEED TO KNOW
When working on biosimilar documents, writers should pay particular attention to the major key challenges described in Table 3.
For further relevant details and practical tips for the daily work of medical writers, see Brauburger and Heisel-Stöhr (focus: clinical study reports [CSRs] and common technical documents [CTDs]);19 Prechtel et al. (focus: pharmacovigilance documents),20 and McMinn et al. (focus: lay summaries)21 in this issue of Medical Writing.
Table 3. Key challenges in writing biosimilar clinical documents and how to address them
BIOSIMILAR DEVELOPMENT – WHAT’S NEXT?
“First wave” biosimilars (growth hormones and monoclonal antibodies) were vastly more complex than pharmaceutical preparations, yet relatively simple biological molecules. Biosimilars with more complex structures are currently under development, with multi-subunit, extensively post-translationally modified, and lipid-containing products; such products may raise new complications and concerns.4
In addition, the competitive biosimilar land scape is changing. A number of new companies have recently entered the biosimilar development scene and they are making fast progress. With speed-to-market being an essential factor for profitable biosimilar development, traditional key players/pharma giants that were once pioneers in the field may strategically opt out from pursuing certain biosimilar development programmes,22 as their new competitors cut their way forward. With most monoclonal antibodies coming oﬀ patent by 2020 and given the introduction of biosimilars, existence of their originator biologics, and creation of biobetters (improved versions of the originator biologics), the oncology landscape and its key stakeholders (prescribers, pharmacists, nurses, patients, reimbursing bodies, and manufacturers) will be facing many challenges.1 Several older challenges remain: the acceptance of biosimilars by the general public and their ample use in health care; a better understanding of the impact of diﬀerences in quality attributes on clinical eﬃcacy and safety;14,15 a meaningful approach to collecting post-marketing safety data from biosimilars and their reference biologics; and eﬀorts to globally converge regulatory requirements, including the potential use of a global reference product.
The world of biosimilars brings exciting opportunities for professional medical writers. As a new wave of biosimilars is currently under development, and regulations in the EU and the US are simultaneously becoming increasingly more complex, teams working on biosimilar development will need increasing guidance. Medical writers can play an important role in the eﬃcient development of biosimilar documents that are fit-for-purpose, both by proactively helping establish best practices for the writing of such documents and by generally driving the shift from an originator to a biosimilar mindset.
I would like to thank Lisa Chamberlain James for her comments on an earlier version of this article.
- Tabernero J, Vyas M, Giualini R, et al. Biosimilars: a position paper of the European Society for Medical Oncology, with particular reference to oncology prescribers. ESMO Open. 2016. 1: 1–5.
- European Medicines Agency. Biosimilar medicines – overview [cited 2019 Mar 06] https://www.ema.europa.eu/en/human-regulatory/overview/biosimilar-medicines-overview.
- Pfizer Biosimilars [cited 2019 Mar 05] Available from: https://www.pfizerbiosimilars.com/characteristics-of-biosimilars.
- Ramzan A. The future of biosimilars – monoclonal antibodies and beyond. Regulatory Rapporteur. 2015;12(9):5–9.
- FDA Draft Guidance for Industry Reference Product Exclusivity for Biological Products Filed Under Section 351(a) of the PHS Act [cited 2019 Mar 06] Available from: https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM407844.pdf.
- GABI Report. Biosimilars Marketed in Europe [cited 2019 Mar 06] Available from: http://www.gabionline.net/Reports/Biosimilars-marketed-in-Europe.
- First Biosimilar Approved in the United Stated [cited 2019 Mar 06] Available from: https://www.pharmacytimes.com/product-news/first-biosimilar-approved-in-united-states.
- EMEA/CHMP/BMWP/42832/2005 Rev1 Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues [cited 2019 Mar 06] Available from: https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-similar-biological-medicinal-products-containing-biotechnology-derived-proteins-active_en-2.pdf.
- FDA Listing of Biosimilar Guidances [cited 2019 Mar 06]. Available from: https://www.fda.gov/drugs/guidancecomplianceregulatoryinformation/guidances/ucm290967.htm.
- World Health Organization. Biologicals – Similar Biotherapeutic Products [cited 2019 Mar 06]. Available from: https://www.who.int/biologicals/biotherapeutics/similar_biotherapeutic_products/en/.
- Regulation (EC) No 1901/2006 of the European Parliament and of the Council of 12 December 2006 on medicinal products for paediatric use and amending Regulation (EEC) No 1768/92, Directive 2001/20/EC, Directive 2001/83/EC and Regulation (EC) No 726/2004. Oﬃcial Journal of the European Union L 378/1.
- US Food and Drug Administration. Pediatric Study Plans: Content of and Process for Submitting Initial Pediatric Study Plans and Amended Initial Pediatric Study Plans Guidance for Industry. Draft Guidance. Revision 1; March 2016. [cited 2019 Mar 06]. Available from: https://www.fda.gov/downloads/drugs/guidances/ucm360507.pdf.
- Radovan B, Beeby B. Writing pediatric study plans (PSPs) – the impact of the revised 2016 FDA draft guidance. J Clin Stud. 2018;10(4):20–5.
- EMA/CHMP/138502/2017 Draft reflection paper on statistical methodology for the comparative assessment of quality attributes in drug development [cited 2019 Mar 06]. Available from: https://www.ema.europa.eu/en/statistical-methodology-comparative-assessment-quality-attributes-drug-development.
- FDA Guidance for Industry: Quality Considerations in Demonstrating Biosimilarity of a Therapeutic Protein Product to a Reference Product [cited 2019 Mar 06]. Available from: https://www.fda.gov/downloads/drugs/guidances/ucm291134.pdf.
- Alten R, Cronstein BN. Clinical trial development for biosimilars. Semin Arthritis Rheum. 2015;44(6):S2–S8.
- Balfour A, Schmitt S. Statistical principles in biosimilar development. Med Writ. 2019;28(2):28–32.
- GABI Journal Editor. USA and Europe diﬀer in interchangeability of biosimilars. GABI J. 2017;6(4):183–4.
- Brauburger K, Heisel-Stöhr S. Writing biosimilar clinical study reports and submission documents – what to expect and what to consider. Med Writ. 2019;28(2):33–8.
- von Bruchausen T , Prechtel K, Rechsteiner S. Same but diﬀerent: Basic tools for biosimilar and generic pharmacovigilance writing. Med Writ. 2019;28(2):45-52.
- McMinn D, Scott C, Jeﬀs B. Layperson materials in the sphere of biosimilars and generic medicines. Med Writ. 2019;28(2):53–6.
- GABI Online – Generics and biosimilars initiative. Pfizer drops five preclinical biosimilar programmes [cited 2019 Mar 06]. Available from: http://www.gabionline.net/Biosimilars/ General/Pfizer-drops-five-preclinical-biosimilar-programmes.