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Biosimilars

Introduction

While biological agents have transformed care of patients with rheumatic diseases, access to these agents remains an unmet need in many parts of the world, largely due to their high costs. Biosimilars are biological agents that have been shown to have equivalent safety and efficacy to an already authorized original biopharmaceutical agent. They are associated with reduced costs and have the potential to substantially improve patient access to healthcare. However, unlike generics, these drugs are not exact copies, and due to the complex nature of these molecules, several important issues must be considered by regulators and drug manufacturers. One important consideration is that of switching between originators and biosimilars, which must be shown to be safe. Additionally, nomenclature for biosimilars must be precise enough to enable the biosimilar and originator products to be differentiated, particularly for the purposes of monitoring and pharmacovigilance. In terms of pharmacoeconomics, budget impact analyses suggest that biosimilar agents will be associated with significant direct cost savings and additional patients being treated, potentially translating into earlier therapy escalation, increased patient access and improved long-term outcomes.

medwireNews features

Biosimilars: The story so far

medwireNews provides an overview of the evidence supporting the equivalence of biosimilar drugs and their reference products, and answers some questions about the use of biosimilars in rheumatology.

Talking to patients about biosimilar drugs

In this medwireNews podcast, Editorial Board member Victoria Ruffing discusses how to talk to patients about biosimilar drugs, and outlines questions and concerns they may have.

Overview of biosimilars

Biosimilars in rheumatology: current perspectives and lessons learnt

This review updates previous discussions of biosimilars and aspects of biosimilar development, with a focus on the regulatory environment and the latest data on biosimilar tumor necrosis factor (TNF) inhibitors.

Summary
  • Biosimilars are biological agents that have been assessed by regulatory authorities as having efficacy and safety similar to an already authorized original biopharmaceutical (reference product).
  • There are several biosimilar monoclonal antibodies available, although not all have been approved by all regulatory authorities for use in all therapeutic indications that the reference products are approved for. Currently available biosimilars approved for treatment of rheumatic diseases include:
    • CT-P13 –infliximab biosimilar, the first monoclonal antibody biosimilar approved;
    • BOW015 – infliximab biosimilar;
    • HD203 – etanercept biosimilar;
    • ZRC-3197 – adalimumab biosimilar.
  • All biological agents are associated with the development of a high rate of antidrug antibodies and biosimilars and reference products have similar immunogenicity
  • The presence of antidrug antibodies has been shown to correlate with reduced therapeutic response compared with patients who do not develop these antibodies. As such these antibodies should be considered as important biomarkers of response to both biosimilars and reference drugs.
  • Issues to consider with the use of biosimilars are:
    • Switching – therapeutic transition from a reference product to a biosimilar (or vice versa) at the instigation of the prescriber;
    • Substitution –replacement of a biosimilar with its reference product by someone other than the prescriber;
    • Interchangeability – designation that allows a biosimilar to be substituted for its reference product without prescriber input.
  • It is important that each biosimilar is named in such a way as to allow them to be distinguished from their reference product during pharmacovigilance.

Dӧrner T, Kay J. Nat Rev Rheumatol. 2015;11:713–724. doi:10.1038/nrrheum.2015.110.

Switching biosimilars

Switching from originator infliximab to biosimilar CT-P13 compared with maintained treatment with originator infliximab (NOR-SWITCH): a 52-week, randomised, double-blind, non-inferiority trial

This paper reports the results of the NOR-SWITCH study, which was conducted to examine switching from originator infliximab to biosimilar CT-P13 across six different indications in terms of efficacy, safety and immunogenicity.

Summary
  • The NOR-SWITCH study was a 52-week, multicenter, randomized, double-blind, parallel-group, phase 4 trial conducted to determine if CT-P13 was non-inferior to infliximab originator among patients with Crohn’s disease, ulcerative colitis, spondyloarthritis, rheumatoid arthritis, psoriatic arthritis or chronic plaque psoriasis, who had been stable on infliximab originator for at least 6 months.
  • Of 498 patients recruited, 482 were randomized: 241 to receive continued infliximab treatment and 241 to switch to CT-P13.
  • Overall, mean patient age was 47.9 years, 39% of patients were female and mean duration of infliximab originator treatment duration prior to randomization was 6.8 years. Patients were receiving treatment for Crohn’s disease (32%), ulcerative colitis (19%), spondyloarthritis (19%), rheumatoid arthritis (16%), psoriatic arthritis (6%) or chronic plaque psoriasis (7%).
  • Disease worsening (primary endpoint) occurred in 26% of patients in the infliximab originator group and 30% in the CT-P13 group, with an adjusted risk difference of –4.4% (95% confidence interval [CI], –12.7% to 3.9%; within the prespecified noninferiority margin of 15%).
  • Similar numbers of patients experienced at least one treatment-emergent adverse event (AE), in both groups (70% in the infliximab originator group, and 68% in the CT-P13 group, with the most frequent treatment-emergent AEs being related to infections.
  • For serious treatment-emergent AEs, the numbers were again similar between the infliximab originator and CT-P13 groups (10% vs 9%, respectively).
  • Anti-drug antibodies were observed at any time point in 11% of patients in the infliximab originator group and 13% in the CT-P13 group.
  • Overall, the NOR-SWITCH study demonstrated that switching from originator to biosimilar infliximab CT-P13 was non-inferior to continued treatment with originator infliximab.

Jørgensen KK, Olsen IC, Goll GL et al. Lancet. 2017;389: 2304–2316. doi:10.1016/S0140-6736(17)30068-5.

Therapeutic drug monitoring (TDM) as a tool in the switch from infliximab innovator to biosimilar in rheumatic patients: results of a 12-month observational prospective cohort study

This study was conducted to assess the utility of therapeutic drug monitoring in patients undergoing a switch from innovator infliximab to biosimilar infliximab for various rheumatic diseases.

Summary
  • All rheumatic patients at one medical center in the Netherlands aged ≥18 years who were receiving innovator infliximab (Remicade®) (n=27) were switched to the biosimilar infliximab Inflectra® as part of routine care
  • Patients were receiving treatment for various rheumatic conditions and half of the patients were also receiving immunosuppressant drugs.
  • Prior to the switch, only 56% of patients had infliximab concentrations within the suggested therapeutic range, and infliximab concentrations ranged from very low to very high. One patient with very low infliximab concentrations had very high levels of antibodies to infliximab and two had low levels of such antibodies.
  • After the switch, therapy was discontinued in seven patients, mostly during the first 6 months after switching; one of these patients developed high levels of antibodies to infliximab and two experienced high disease activity after switching.
  • Infliximab concentrations prior to switching did not predict subsequent failure of switching; both patients with low levels of antibodies to infliximab successfully continued biosimilar therapy.
  • Neither C-reactive protein nor disease activity scores were significantly different before or at three time points after switching (just after, at 6 months, and at 12 months).
  • The authors note that therapeutic drug monitoring is a useful tool in monitoring patients switching from innovator infliximab to biosimilars, and suggest that it should be used to further optimize infliximab therapy.

Schmitz, EMH, Benoy-De Keuster S, Meier AJL et al. Clin Rheumatol. 2017;36:2129–2134. doi:10.1007/s10067-017-3686-6.

Switching between reference biologics and biosimilars for the treatment of rheumatology, gastroenterology, and dermatology inflammatory conditions: considerations for the clinician

This paper provides a review of available data regarding switching from reference biological agents (i.e. infliximab, etanercept, adalimumab and rituximab) to their respective biosimilar agents.

Summary
  • An important question that remains to be answered for healthcare professionals considering biosimilars, is “should the biosimilar immediately replace the reference product currently in use by the stable patient?”
  • A literature search was conducted to identify studies involving a switch between reference and biosimilar infliximab, etanercept, adalimumab or rituximab, with 53 studies selected for analysis.
  • Trial designs for switching studies should include the following six elements;
    • A randomized design with appropriate control arms;
    • At least 1-way switch from originator to biosimilar;
    • Assessment of immunogenicity;
    • Sufficient washout between treatments (multiple switching);
    • Sufficient power to assess efficacy and safety (equivalence);
    • Sufficient follow-up period.
  • Regarding switching between reference and biosimilar infliximab:
    • Data from 26 studies of switching between infliximab and CT-P13, in patients with rheumatic disease, inflammatory bowel disease (IBD) and psoriasis, suggest that such a switch is well tolerated and effective.
      • Immunogenicity data from 12 studies show no difference in the incidence of anti-drug antibodies between reference infliximab and CT-P13.
    • Currently there are limited data on switching between reference infliximab and the biosimilars SB2 or NK (each of which has a single study), and further studies are required to demonstrate the safety of switching between these products.
  • There are six different biosimilars/proposed biosimilars to etanercept; data showing the safety of switching to biosimilar etanercept is only available for SB4 and GP2015.
    • There is currently no evidence to support switching between reference etanercept and the proposed biosimilars HD203, CHS-0214, LBEC0101 or TuNEX.
  • There is only one European Medicines Agency (EMA)/US Food and Drug Administration (FDA)-approved adalimumab biosimilar (ABP 501), however there are two proposed adalimumab biosimilars, SB5 and M923, in phase III studies.
  • There are no approved rituximab biosimilars, although there are two proposed rituximab biosimilars, CT-P10 and GP2013.
    • Data for switching from adalimumab or rituximab reference products and their biosimilars are limited and thus the safety of such switching has not been demonstrated.
  • The authors propose the following recommendations regarding switching between reference and biosimilar treatments:
    • The decision to switch should be based on scientifically sound data;
    • Switching should be a clinical decision made by the treating physician on an individual, case-by-case basis;
    • Switching data from one biological agent should not be used to inform switching decisions for others;
    • Automatic pharmacy substitution should not occur;
    • Patients should be closely followed post-switching for adverse events.

Moots R, Azevedo V, Coindreau JL et al. Curr Rheumatol Rep. 2017;19:37. doi:10.1007/s11926-017-0658-4.

Efficacy and safety of switching from innovator rituximab to biosimilar CT-P10 compared with continued treatment with CT-P10: results of a 56-week open-label study in patients with rheumatoid arthritis

This paper reports the results of an open-label extension of a phase I randomized, controlled trial in patients with rheumatoid arthritis, to compare efficacy and safety between patients who continued to receive CT-P10 and those who received rituximab in the clinical trial who were switched to CT-P10.

Summary
  • An important question regarding biosimilars is whether patients can be switched from an innovator biological agent to a less expensive biosimilar without adverse impact on efficacy and safety.
  • To address this question, researchers conducted a multicenter, single-arm, open-label extension study enrolling patients with rheumatoid arthritis who had completed a phase I randomized-controlled trial of CT-P10 versus innovator rituximab.
  • A total of 87 patients who completed the randomized-controlled trial to 72 weeks entered this extension, of whom 58 had been in the CT-P10 group and 29 in the rituximab innovator group; 38 patients from the CT-P10 group and 20 from the rituximab innovator group met predefined disease activity and safety criteria to receive CT-P10 in this extension.
  • Efficacy, as measured by Disease Activity Score using 28 joints (DAS28) scores and European League Against Rheumatism (EULAR) responses, was comparable between patients who continued CT-P10 and those who switched from innovator rituximab, with no significant differences in any efficacy endpoint.
  • At least one adverse event was reported in 23.7% of patients in the maintenance group and in 20.0% of patients in the switch group; infections occurred in three and two patients in the maintenance and switch groups, respectively.
  • This study found that switching from innovator rituximab to biosimilar CT-P10 did not adversely affect efficacy or safety in patients with rheumatoid arthritis over 56 weeks’ follow-up after switching.

Park W, Suh CH, Shim SC et al. BioDrugs. 2017;31:369–377. doi:10.1007/s40259-017-0233-6.

Regulatory requirements

Clinical trial development for biosimilars

This paper provides an overview of the current regulatory framework in Europe and the US regarding the development and approval process of biosimilars, with a focus on the clinical phase of development of monoclonal antibodies for the treatment of inflammatory conditions.

Summary
  • Due to the complex nature of biological agents, it is not possible to manufacture identical molecules or generics, as is done with small molecule agents.
  • Currently, both the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) guidelines for the development of biosimilars involve a rigorous stepwise process, with the primary goal of demonstrating that purity, potency and safety of the biosimilar are similar to the reference product, rather than independently establishing the efficacy and safety of the biosimilar.
  • Early clinical studies are conducted to demonstrate similarities of the pharmacodynamics (PD) and pharmacokinetics (PK) of the biosimilar and the reference product, with the results of these studies providing a scientific basis for a selective and targeted approach to further clinical testing.
  • Phase 3 trials should have an equivalence design at the 90% or 95% confidence interval (CI) (preferable over a non-inferiority design), with a sample size and duration to allow sufficient exposure to the biosimilar and reference product, and allow for detection of clinically relevant differences in safety (including immunogenicity) or efficacy.
  • It is important when comparing a biosimilar and a reference product to select relevant endpoints, with those chosen generally being those used during clinical trials of the reference product.
  • Biological agents play an important role in the treatment of inflammatory conditions, and the development of biosimilars aims to increase patient access to biological agents.

Alten R, Cronstein BN. Semin Arthritis Rheum. 2015;44(6 suppl):S2–S8. doi:10.1016/j.semarthrit.2015.04.002.

Clinical and regulatory perspectives on biosimilar therapies and intended copies of biologics in rheumatology

This paper outlines important differences between biosimilars and intended copies, and reviews the manufacturing process for biosimilars as well as the regulatory framework for these agents in various regions of the world.

Summary
  • Access to biologics for the treatment of rheumatic diseases remains an unmet need in many parts of the world, largely due to their high costs. Biosimilars are highly similar copies of these agents that are associated with reduced costs, with the potential to substantially improve access to these medicines.
  • The term biosimilar is a regulatory definition, defined by the World Health Organization (WHO) as a “biotherapeutic product which is similar in terms of quality, safety and efficacy to an already licensed reference biotherapeutic product”. These products should not be viewed as generics, as they cannot be manufactured to be identical to the originator.
  • Intended copies are non-comparable biotherapeutic products, where the manufacturer has copied an already licensed biological agent but not followed a comparative development pathway, and clear evidence of similarity is lacking.
  • There are numerous important differences in the molecular complexity and manufacturing processes between small molecules and biological agents. Biological agents are proteins, usually manufactured using living systems, and are much larger and more complex than small molecules.
  • The manufacturing process for the originator biological agent is proprietary, and thus biosimilar manufacturers need to reverse engineer the reference product to produce a highly similar product.
  • With advances in technology, characterization of biological agents has become increasingly precise, with biosimilars able to be specifically engineered to very closely resemble the originator product.
  • Clinical development of a biosimilar requires rigorous head-to-head comparison with the originator, to demonstrate that any difference in efficacy or safety is within a prespecified non-inferiority margin.
  • Regulatory requirements for biosimilar approval are largely consistent across major regulators, and an increasing number of Asian countries are also establishing regulatory pathways for biological agents. However, in some parts of the world the regulatory landscape is still evolving, with intended copies of biological agents still available, despite a lack of quality clinical trials or adequate evaluation.

Mysler E, Pineda C, Horiuchi T et al. Rheumatol Int. 2016;36:613–625. doi: 10.1007/s00296-016-3444-0.

A ‘global reference’ comparator for biosimilar development

The authors of this paper provide a proposal for selecting a reference comparator for biosimilars, without the need for bridging studies to confirm the comparability of a local reference product to products licensed outside of a regulatory jurisdiction.

Summary
  • In many jurisdictions around the world, bridging studies are required to demonstrate comparability between local and foreign versions of an originator biological agent, and use of a foreign approved comparator for biosimilar development must be justified with such bridging data.
  • The conduct of comparator bridging studies comes at considerable financial cost, estimated to range between several hundred thousand to 1–2 million US dollars for each regulatory jurisdiction. In addition, these studies may be ethically questionable as they expose patients or volunteers to strictly avoidable and unnecessary risks.
  • Currently, manufacturing changes to biological agents are justified by data showing that pre- and post-change products are comparable, maintaining adequate consistency. As such, any differences between local and foreign versions of the same originator should be considered inconsequential in terms of their use as comparators for biosimilar development.
  • The authors propose that regulatory authorities accept a single reference originator product for global biosimilar development if the following criteria are met:
    • The chosen reference has been approved in a jurisdiction that has formally adopted the guidelines of the International Conference on Harmonization (ICH);
    • The formulation of the chosen reference has the same pharmaceutical form and route of administration as the reference biological agent, the same content of active pharmaceutical ingredient and, in most cases, the same composition of excipients;
    • There exists substantial evidence in the public domain that the chosen reference and the reference biological agent have been approved in their respective jurisdictions on the basis of essentially the same original data including clinical safety and efficacy data.
  • This proposal is based on the established reliability of the comparability approach currently practiced in major regulatory jurisdictions. If regulatory authorities accept the authors proposal, guidelines should be amended to clarify under which (if any) circumstances bridging studies will be required.

Webster CJ, Woollett GR. BioDrugs. 2017;31:279–286. doi:10.1007/s40259-017-0227-4.

Safety factors

Biosimilar safety factors in clinical practice

This paper provides an overview of the European Medicines Agency (EMA) and US Food and Drug Administration (FDA) positions regarding potential safety considerations associated with biosimilar development and postmarketing use.

Summary
  • To achieve biosimilar status, there must be no meaningful differences between the biosimilar and the reference product, in terms of quality, safety and efficacy.
  • Safety, particularly that associated with immunogenicity, is an important focus in the development of biosimilars. Other safety considerations include adverse events (AEs) such as infusion or injection-site reactions, hepatotoxicity, neutropenia, fever and infection.
  • An immune response may lead to altered efficacy or compromised safety, or potentially to immune complex formation resulting in:
    • Altered clearance of the product;
    • Neutralization of the activity of the biological agent.
  • Manufacturing processes must be carefully controlled at each step, as any changes may potentially alter molecular structure and biological effects. Common changes include post-translational modifications of the tertiary or quaternary structures (e.g. glycosylation). Adherence to stringent manufacturing practices consistent with FDA and EMA requirements is essential for manufacturers of reference products and of biosimilars.
  • Differences in formulation are permitted if the manufacturer can demonstrate such differences are not clinically meaningful.
  • Regulatory guidelines regarding the safety of biosimilars require that preclinical studies be conducted to resolve any uncertainties regarding biosimilarity that may remain after structural/functional characterization, and may be useful for preliminary assessment of safety, including immunogenicity.
  • At least one clinical study must be conducted during development of a biosimilar, including assessment of immunogenicity and pharmacokinetics (PK) or pharmacodynamics (PD), with such a study demonstrating similar safety in at least one of the indications for which the reference product is licenced.
  • Other important issues around safety in biosimilar development include:
    • Interchangeability – approval by regulatory authorities would allow automatic substitution at the pharmacy level;
    • Naming – naming conventions for biosimilars focus on the ability to differentiate biosimilars from each other and from their reference product, at least in part for pharmacovigilance purposes, however nomenclature for biosimilars has not yet been standardized.

Reinisch W, Smolen J. Semin Arthritis Rheum. 2015;44(6 suppl);S9–S15. doi:10.1016/j.semarthrit.2015.04.005.

Immunogenicity of biosimilars

This review provides a summary of current information on factors influencing the immunogenicity, and the evaluation of immunogenicity, of biosimilars, with a review of evidence from infliximab biosimilars.

Summary
  • Possible immune responses to a therapeutic protein range from the transient appearance of anti-drug antibodies to life-threatening severe conditions.
  • Immunogenicity may lead to:
    • Loss of response;
    • Lack of efficacy;
    • Pharmacokinetic changes;
    • Development of neutralizing antibodies;
    • Hypersensitivity reactions;
    • Infusion reactions;
    • Development of antibodies against endogenous proteins.
  • Factors that influence immunogenicity include:
    • Patient-related factors – such as genetic factors and age
    • Disease-related factors – such as chronic infections, allergies and autoimmune diseases, malnutrition, advanced malignancy, organ failure and concomitant treatment.
  • Immunogenicity testing should involve analytical assays with both the biosimilar and the reference product in a parallel blinded study.
  • Overall, equivalence clinical trials have shown that infliximab biosimilars CT-P13 and SB2 have comparative efficacy and safety to originator infliximab in rheumatoid arthritis and ankylosing spondylitis over 2 years. Observational studies in inflammatory bowel disease (IBD) also showed the favorable efficacy and safety profile of CT-P13.
  • Switching from originator infliximab to CTP-13 was efficacious and tolerable in rheumatoid arthritis and ankylosing spondylitis, but randomized-controlled trials are needed to evaluate switching in IBD.
  • Further research is required for other biosimilars and in other indications to improve our understanding of immunogenicity with these agents.

Mirkov S, Hill R. Drugs Ther Perspect. 2016;32:532–538. doi:10.1007/s40267-016-0341-2.

Assessment and monitoring

Pharmacovigilance considerations for biosimilars in the USA

This paper discusses pharmacovigilance of biosimilars in the US, focusing on the challenges and limitations of each of the two main signal detection systems: spontaneous reporting and active surveillance.

Summary
  • Given the increasing number of biosimilars likely to enter the US market in the coming years, it is important that pharmacovigilance systems can distinguish between adverse events (AEs) associated with biosimilars and those associated with their reference products.
  • In the US, there are two main types of signal detection systems:
    • Spontaneous reporting systems (SRSs); such as MedWatch and institution-based reporting) – passive surveillance that relies on voluntary reporting;
    • Active surveillance (AS) systems –methods include retrospective analyses of medical records, such as the Food and Drug Administration’s Sentinel pilot program.
  • SRSs may be useful for detection of emergent safety signals, and detection of changes in product quality throughout the product life cycle, but they can not quantify incidence of identified risks for a given product due to lack of a denominator.
  • Both AS and SRS reply on accurate identification of the product. The five product identifiers that may be included in MedWatch AE reports are:
    • Brand name – often the primary identifiers used for AE reporting;
    • Non-proprietary name;
    • National drug code;
    • Manufacturer name;
    • Lot number.
  • Challenges in product identification occur across various healthcare settings, including inpatient settings and hospital or other institutional settings, with challenges also being present at the pharmacy level.
  • The authors believe that multiple product-specific identifiers should be available for use by those reporting AEs, and that systems for reporting, as well as systems used to store patient medical records, must evolve to allow entry of essential product information so that products can be precisely identified.

Grampp G, Felix T. BioDrugs. 2015;29:309–321. doi:10.1007/s40259-015-0137-2.

Pharmacoeconomics

Pharmacoeconomics of biosimilars: what is there to gain from them?

This paper provides a discussion of the pharmacoeconomics of biosimilars in inflammatory rheumatic diseases.

Summary
  • Inflammatory rheumatic diseases present a significant individual, societal and economic burden. In recent years, the use of expensive biological agents has been identified as the leading cause of direct costs associated with these diseases.
  • Although costly, these biological agents have significantly improved the treatment of inflammatory rheumatic diseases, with current evidence pointing to cost-effectiveness of biological treatment in rheumatoid arthritis with insufficient response to disease-modifying antirheumatic drugs (DMARDs).
  • In Europe, the first biosimilar (a biosimilar of somatropin) was approved in 2006, followed by several other small peptide biosimilars. Experience in Europe with these agents demonstrates that while care has been transformed by increasing access to treatment, market uptake has not always been as high as expected.
  • Market structure and type of distribution channel, rather than price differences, might have a marked effect on market access, as well as attitudes of medical societies, many of whom suggested watchful use of biosimilars at the onset of their entrance onto the market.
  • The treatment of rheumatic diseases with monoclonal antibody biosimilars is expected to bring significant cost savings, allowing for improved patient access to biological agents. Potentially this may result in modification of clinical practice and a change in the paradigm of treatment decisions in inflammatory rheumatic diseases.
  • Overall, budget impact analyses predict that biosimilar DMARDs will be associated with significant direct cost savings and additional patients being treated, which might translate into earlier therapy escalation, increased patient access in economically constrained countries and improved long-term outcomes.

Araújo FC, Gonçalves J, Fonseca JE. Curr Rheumatol Rep. 2016;18:50. doi:10.1007/s11926-016-0601-0.

Biosimilars: The price is not right

Editorial Board member Marc Cohen analyses the various economic factors influencing the price of biosimilars over recent years in rheumatology, focusing on the United States healthcare system.

Author:
Marc D Cohen
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