Interchangeability of biosimilars: a global perspective for pharmacists

Introduction

The first innovator biologic drug was introduced around 40 years ago in the early 1980s, while the first biosimilar medicine was introduced in the EU in 2006 and the United States in 2015^[1],[2],[3]
. The use of innovator biologics and biosimilars in contemporary pharmacotherapy is increasing exponentially, and they are now the fastest growing market sector of the pharmaceutical industry^[4]
.

Biologics are used in the management of several long-term conditions, including rheumatoid arthritis, Crohn’s disease, psoriasis and ankylosing spondylitis, and are often required when other chemical small-molecule therapies have been trialled and are ineffective, or do not generate sufficient response^{[5],[6],[7],[8]}
.

Owing to patent expiry of several innovator biologics, a series of highly similar biologics (i.e. biosimilars) are becoming available. This is encouraged in the UK as switching patients to biosimilars is estimated to save the NHS millions of pounds^[8]
.

Although there is a benefit in terms of cost saving, pharmacists need to be aware of other considerations related to the use of biosimilars in practice. This article provides pharmacists with an overview of the pivotal concepts of biosimilar interchangeability with innovator biologics.

Sources and selection criteria

The information discussed in this review was identified via a literature search using EMBASE, PubMed/MEDLINE and the Cochrane Library. Searches for journal articles and conference abstracts were run from 1 January 1980 to 6 March 2019 using the search terms: “biologic medicines”, “biosimilars” or “biobetters”. The only inclusion criteria was that the journal papers and conference abstracts were in English; no additional inclusion or exclusion criteria were applied.

The search yielded around 4,000 publications. Another important resource was the Australian government-commissioned literature review on these medicines from 2004 to 2018^[9]
.

Nomenclature and definitions

There are many terms, definitions and abbreviations used in this field internationally, owing to differences between countries and regulatory frameworks; however, the following descriptions help to succinctly and accurately describe these.

Biologic medicine

This is an active substance or substances made by or derived from a biological source, rather than a chemical source or being synthesised chemically. Biologic medicines are either relatively small molecules (e.g. human insulin) or large and complex molecules (e.g. monoclonal antibodies). Typically, these are proteins or protein-containing agents produced using biotechnology (e.g. recombinant DNA techniques) and manufactured in cell culture or in living organisms, including humans, animals or microorganisms (e.g. yeast)^[10]
.

Biosimilars

A non-innovator biologic is known as a biosimilar. It is a product that is highly similar to — and has no clinically meaningful differences from — an approved innovator product^[11]
. The similarity is determined by comparability studies and the generation of confirmatory data and evidence^[12]
. These are also known interchangeably as ‘follow-on biologics’ and ‘subsequent-entry biologics’.

The structure and function of the innovator and the proposed biosimilar product — including chemical identity, purity and bioactivity — are compared to demonstrate that the biosimilar is highly similar to the innovator product^[13]
. Minor differences between clinically inactive components of the innovator product and the proposed biosimilar product are acceptable^[13]
. 

A biosimilar has no clinically meaningful difference in safety and efficacy from the innovator biologic (i.e. critical quality attributes [CQAs] are similar). CQAs are divided into four categories:

• Content-related attributes (e.g. protein content);
• Structural attributes;
• Isoform profile;
• Impurities and biological activity^[14]
  .

Biosimilars are not replicas of innovator biologics and cannot be regarded as (or be confused with) small-molecule drug (SMD) generics (i.e. they are not biogenerics). Other terms used for biosimilars include ‘similar biotherapeutic products’ (SBPs), ‘subsequent-entry biologics’ (SEBs) or ‘non-original biologics’ (NOBs). The term ‘biomimic’ is also used, but production of exact molecular copies of biologics (‘biocopies’) are almost impossible. Universally accepted international terminology is important for biosimilars as different countries use different definitions and regulatory requirements^[15]
.

Biobetters

As this review focuses on biosimilars, a definition of biobetters is provided only to explicitly highlight how they differ from biosimilars. Biobetters, also known as second-generation biologics, are related to existing biologics by target of action, but have been intentionally modified to have a different disposition, efficacy, safety or stability^[16],[17]
. They build on the success of an approved biologic, but present a lower commercial risk for biotechnology companies than a novel class of biologic.

Interchangeability

This is generally defined as the medical practice of changing one medicine for another to achieve the same clinical effect in each clinical setting and patient, on the initiative of, or with, the prescriber’s agreement^[18]
. However, the demonstration of interchangeability can pose challenges with respect to clinical similarity in efficacy and safety of a biosimilar compared to its innovator biologic^[19],[20]
. As such, an interchangeable biologic product is a biosimilar that produces the same clinical outcome in any given patient.

Switching

This is a decision to exchange one medicine for another with the same therapeutic intent. Another term used in this context is ‘non-medical switching’, which is when a patient whose current therapy (e.g. an innovator biologic) is effective and well tolerated, but is switched to another product (such as a biosimilar) for a reason that is not medically necessary (i.e. to save money)^[21]
.

Shared decision making between doctors, pharmacists and patients is critical for successful switching^[22]
. Patients’ attitudes and levels of satisfaction with being switched to a biosimilar are related to being given sufficient necessary information concerning their health^[23]
. Evidence from EU rheumatic disease experience involving a single switch concluded that biosimilars can be used for all registered indications as safely as their originators with no negative impact on efficacy^[24]
.

Similarly, in 2018, a systematic literature review on the clinical outcomes of switching from innovator biologics to biosimilars concluded that clinical outcomes were unaltered^[25]
. However, another comprehensive review of the clinical outcomes of switching concluded that there are important evidence gaps around the safety of switching, and that sufficiently powered clinical trials and pharmacovigilance studies are still required^[26]
.

Substitution

This refers to dispensing one medicine instead of another equivalent/interchangeable medicine by the pharmacist without consulting the prescriber^[27]
. Interchangeability and switching are only permitted or recommended in some patients or conditions, or at different treatment periods (e.g. continuation of therapy vs. initiating therapy).

Making a switch comes with challenges; therefore, there needs to be clear local and national biosimilar substitution and switching policies and switch management strategies^[28]
. Pharmacists play a pivotal role in raising awareness of biosimilars among doctors and patients, and minimising scepticism about biosimilar quality and safety.

Challenges for biosimilar use

One of the hurdles in the adoption of biosimilars is the lack of interchangeability with reference biologics^[29]
. Biosimilars can be used instead of innovator biologics, but additional studies and registries may enhance switching^[15]
. While interchangeability is an important issue for pharmacists and doctors, different definitions and regulatory frameworks that exist in the United States, Europe and other jurisdictions add to the complexity.

In the EU, the European Medicines Agency does not assess or make recommendations on interchangeability; therefore, interchangeability does not mean substitution. However, this is generally physician-led or driven by national policy. Some member states, for example, Finland, the Netherlands, Germany and Norway, have signalled that biosimilars licensed in the EU are interchangeable^[30]
.

There are also different perceptions of biosimilar interchangeability and substitution across different healthcare professional groups in different countries. In Europe, for example, rheumatologists have expressed the greatest awareness of biosimilars, but gastroenterologists have the highest confidence in their safety and efficacy^[31]
. There is a relationship between the duration of rheumatology practice experience and the likelihood of use and perception towards biosimilars^[32]
. By contrast, most Canadian rheumatologists feel concerned or very concerned about whether a pharmacist has the ability to substitute an innovator biologic with a biosimilar without a physician’s approval^[33]
. In an Australian tertiary setting, a biosimilar was deemed acceptable to patients if recommended by a rheumatologist^[34]
.

Research has suggested that pharmacist substitution should only be considered in well-defined circumstances (i.e. the prescriber approves which product is dispensed, pharmacists provide unbiased information and patients are informed and agree with substitution), motivated by specific needs and informed by high-quality evidence^[35]
. This suggests that individually tailored educational programmes may be needed for different medical specialties.

Classes of biologics

A wide variety of innovator biologics and biosimilars exist and are used in different clinical indications, medical specialities and by specialist physician groups (e.g. rheumatologists, gastroenterologists and dermatologists). Innovator biologics and biosimilars include:

• Allergenics (e.g. allergen extracts, allergen patch tests and antigen skin tests);
• Biological disease-modifying anti-rheumatic drugs;
• Blood or blood components for haemophilia;
• Cytokines (e.g. interferons);
• Growth factors (e.g. human epithelial growth factor);
• Hormones (e.g. insulin);
• Monoclonal antibodies;
• Vaccines
  ^[36]
  .

Biosimilars are not available for all innovator biologics that are registered/marketed. Of the about 300 innovator biologics that are currently registered globally, 64 biosimilars are registered in the EU and only 27 are registered in the United States^[37],[38]
.

Differences between biologics and small-molecule drugs

Innovator biologics and biosimilars are very different from their SMD chemical predecessors in terms of molecular complexity and natural variability. Many factors that hinder the full acceptance and adoption of biosimilars arise from important differences in the properties of innovator biologic/biosimilars and SMDs (see Table)^[39]
.

Pharmacovigilance plans

The risk profile of a biosimilar is expected to be similar to its innovator product. However, an additional theoretical risk exists that a similarity exercise may fail to detect differences in safety and efficacy, which are only revealed at a later stage^[40]
. There is a need for stringent post-marketing pharmacovigilance measures to detect any safety signals between biosimilars and their innovator products^[41],[42]
. For example, the EMA mandates the implementation of a risk management plan as a condition of marketing approval^[43]
.

In addition, partnerships between regulatory agencies and the biosimilar companies are needed to implement both active and passive post-marketing surveillance plans to gather real-world data once the biosimilar has started to be prescribed^[44]
. Pharmacist-reported adverse events, via the Medicines and Healthcare products Regulatory Agency’s (MHRA’s) Yellow Card scheme or other reporting systems, may also contribute to expedited post-marketing data for biosimilars provided the brand name and batch number are captured^[45]
.

Pharmacovigilance is a challenge in a multi-source procurement environment, as is the traceability of the specific biosimilar. Documentation of the specific biosimilar product used by each patient is important and is a challenge within some pharmacovigilance databases. For instance, spontaneous reporting systems are most vulnerable owing to the manual nature of data transfer and when naming conventions differ across different jurisdictions^{[46],[47],[48]}
. In the UK, biosimilars are prescribed by their brand name, so this issue is less critical. However, there is an urgent need to globally harmonise nomenclature for biosimilars to realise the full benefits of pharmacovigilance plans^[49]
.

Regulatory and policy frameworks and other issues

The unique development and manufacturing processes that are involved in the creation of biosimilars pose distinct regulatory challenges compared with SMD generic medicines. The regulatory framework for biosimilars is based almost universally on demonstrating similarity to innovator biologics^[50]
.

Indication extrapolation, defined as approval of biosimilars for all indications of the innovator product, raises further questions of how harms and benefits can be confirmed even though the specific indications may not have been studied^[51]
. The similarity to the innovator biologic is the guiding principle for extrapolation to multiple indications, and extrapolation of clinical data from other indications is an important concept in the development of biosimilars and is permitted by major regulatory agencies, as long as it is scientifically justified^{[52],[53],[54]}
. Most regulatory agencies are pragmatic in aligning regulatory approval frameworks for biosimilars to keep up with scientific evidence, while balancing the need for early availability of these agents.

Pharmacists can be proactive in ensuring that their national medicines policy accommodates new classes of therapy and should question whether there is a national policy on adoption of biosimilars. For example, NHS England has been promoting adoption of biosimilars for several years^[55]
. There may also be hospital/health district or NHS trust policies on biosimilars or use of specific innovator biologics and, if this is the case, this provides additional opportunities for pharmacists on pharmacy and therapeutics committees to influence biosimilar uptake.

Pharmacoeconomic and pricing considerations

Expenditure on all medicines is an important element of health service costs. Specialty high-cost innovator biologics hinder the benefits of these drugs and to curb such runaway drug costs, many countries have implemented biosimilar policies to provide full benefits of innovator biologics, incluing England via its framework for biosimilars^[55]
.

Providing affordable treatment is the ultimate promise of biosimilars; however, budget savings cannot be placed above patient safety. Striking the right balance between medicines budget requirements and patient outcomes is not easy.

Biosimilars generally offer smaller price reductions and have a reduced competitive edge compared with their generic equivalents owing to barriers to biosimilar market entry, for example:

• High capital costs of manufacturing;
• Special requirements for pharmacovigilance;
• Lack of automatic switching or substitution;
• Patent issues^[56],[57]
  .

Biosimilar price discounts alone have little impact, and supply and demand-side incentive policies remain important drivers of biosimilar uptake^[58]
.

Pharmacists — especially those providing biosimilar procurement advice — must understand the complex drivers outlined above of biosimilar pricing. Many UK pharmacists, who are involved in procurement coordinated via regional medicines optimisation committees, are already familiar with these issues. Ultimately, the slow adoption of biosimilars is costly, not only in terms of total health budgets, but also for patient outcomes^[59]
.

Manufacturing and post-translational modifications

Biosimilars, like innovator biologics, raise challenges compared with SMDs owing to the complexity of manufacture and production. For example, they may be minor natural variations in the molecular structure (collectively known as microheterogeneity) and post-manufacturing (post-translational) modifications^[60],[61]
. The production process for innovator biologics and biosimilars determines their protein properties^[62],[63]
. Minuscule differences in the product may result in different clinical outcomes; therefore, consistent drug discovery and manufacturing is likely to minimise variations. In addition, with innovator biologics and biosimilars there is:

• Drift (i.e. unintended/unexplained deviations in manufacturing);
• Evolution (shift in quality attributes outside of established acceptable ranges);
• Divergence (different patterns of product drift and evolution over time leading to clinically meaningful differences)^[64]
  .

These can collectively lead to product variability and diverse product attributes.

However, biotechnology processes and manufacturing innovations that are needed for a number of reasons (e.g. regulatory requirements, production scale-up, change in facility or raw materials, improving quality/consistency or optimising production efficiency) may lead to higher-quality innovator biologics and biosimilars^[65],[66]
.

Demonstrating biosimilarity includes analytical characterisation for similarity in primary amino acid and higher-order structures, post-translational modifications (PTMs), assessment of optimal target binding, and testing for impurities and optimal potency^[67]
. Bioanalytical challenges to support biosimilar development, assessment of PTMs, 3D structures and protein aggregation, and overall analytical characterisation of biosimilars are available^{[68],[69],[70]}
.

Examples of changes that can occur during the manufacturing process include:

• Aggregation;
• Misfolding;
• Chemical degradation of specific amino acids;
• Other chemical degradation pathways (e.g. sialylation, carboxylation and sulphation);
• Glycosylation heterogeneity^[71],[72]
  .

There is need for more specific and sensitive analytical techniques for biosimilar characterisation and for monitoring manufacturing processes, product variations and PTMs.

Quality use of medicines concepts

Quality use of medicines concepts (i.e. the suitable selection of health management options and choice of medicine if necessary and its safe and effective use) are now firmly embedded for SMDs. The challenge is to refine these for innovator biologics and biosimilars in line with national and international medicine policies and regulatory frameworks.

Issues for patients and their carers should be considered, and all healthcare professionals should also be aware of the benefits and harms of these high-cost, beneficial medicines. In addition, policies and implementation plans need to be in place to ensure sustainable and affordable access to biosimilars across the continuum of patient care.

The nocebo effect, a negative effect of a medical treatment that is induced by patients’ expectations, but is unrelated to the physiologic/pharmacologic actions of the treatment, can affect patient acceptance of biosimilars^{[73],[74],[75]}
. While current evidence is insufficient to confirm a biosimilar nocebo effect, it influences patient acceptance of biosimilars and the attitude of doctors, patients and payers, which will be critical to the adoption of biosimilars^[76],[77]
.

Another consideration is unwanted immune response (i.e. immunogenicity). Innovator therapeutic proteins, as well as biosimilars, are manufactured in living cells. The immunogenic profile of therapeutic proteins and the ensuing risk to patients is determined by a multiplicity of product-, process- and patient-related factors that need to be systematically evaluated during clinical development to ensure appropriate benefit/risk assessment^[78]
. Protein heterogeneity generated during protein production, formulation and/or delivery may also affect immunogenicity^[79]
. Clinical consequences of immunogenicity include:

• No effect;
• Acute consequences (e.g. anaphylaxis);
• Non-acute consequences (e.g. a reduction or loss of efficacy);
• Severe complications owing to neutralisation of the natural counterpart, or general immune system reactions and delayed hypersensitivity^[80]
  .

These immunogenicity reactions generally occur in <1% of patients and become obvious at late stages of phase III trials or after approval^[80]
.

The main question is whether the immunogenicity profile of the biosimilar resembles that of the innovator biologic. Regulatory frameworks are designed to ensure this similarity and to optimise detection of immunogenicity reactions.

Devices (e.g. pre-filled syringes, pens or pumps) used for biosimilar administration may have critical practical implications for patients and are important for dosing accuracy and reproducibility, as well as long-term patient compliance and adherence
^[81]
. As a minimum from a patient perspective, one would envisage that the device through which a biosimilar is administered must at least be able to match the innovator biologic’s device for convenience and comfort. Inferior usability may also reduce treatment adherence and product uptake by patients.

Enhancing biosimilars use

Pharmacists can help ensure biosimilars are prescribed appropriately (e.g. through direct substitution by independent pharmacist prescribers or by influencing others); however, full adoption of biosimilars is yet to be realised in some hospitals or hospital trusts. Barriers to this include:

• Hospital or payer financing system that discourage their use;
• Lack of confidence in biosimilars and unfounded distrust of biosimilar biotech companies by stakeholders, including certain sections of the medical community, patients and patient groups;
• Uncertainty about the interchangeability and substitution of biosimilars^[82]
  .

One way to overcome these barriers is through education of doctors, patients and patient advocacy groups with clinical guidelines and the evidence base^{[83],[84],[85]}
.

Hospital pharmacists should outline considerations (e.g. clinical parameters, product characteristics and institutional guidelines) for formulary inclusion of biosimilars^[86],[87]
. They should advocate for their institution’s position on biosimilars and ensure that it is evidence-based^[88]
.

Pharmacists should assist other healthcare professionals through the decision-making process on biosimilars by ensuring they can explain the following:

• Availability and labelling requirements;
• Comparative effectiveness;
• Cost;
• National and local guidelines;
• Long-term safety;
• Patient preferences;
• Route and method of administration^[89]
  .

It is important for pharmacists to remember that strong action on their part means strong outcomes for adoption of biosimilars^[90]
. They can also play a role in changing beliefs (e.g. that switching to a biosimilar and indication extrapolation respectively are safe and effective) and behaviours (e.g. positive framing of biosimilar conversations with patients), and are pivotal to bringing the multitude of stakeholders together to enhance the uptake of biosimilars^[91]
.

Conclusion

The science behind biosimilars is complex and the international published literature is changing faster than regulatory and policy frameworks. Therefore, it is imperative that pharmacists keep abreast of such rapid changes in the evidence base because they will be expected to lead discussions with doctors and patients on the interchangeability of innovator biologics with biosimilars.