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Current Market and Regulatory Landscape of Biosimilars
Valkal Bhatt, PharmD
Participating Faculty

Current Market and Regulatory Landscape of Biosimilars

Valkal Bhatt, PharmD
Immunogenicity is evaluated in biosimilar clinical trials with continued monitoring post launch. Immunogenicity is complicated by many factors and is a potential cause of efficacy loss in all biologics (both reference-biologics and biosimilars). Factors affecting immunogenicity include dosing frequency, administration route, target disease, aggregates in preparation, post-translation modifications, patient genetic profile, and drug interactions. Changes in immunogenicity from reference-biologic can theoretically result in poorer clinical outcomes.6-8 Immunogenicity is of concern among HCPs regarding switching between reference-biologic and biosimilars (interchangeability). In the PLANETRA,9 PLANETAS,10 and Tanaka et al11 studies, patients with rheumatoid arthritis or ankylosing spondylitis were switched between reference-infliximab and the biosimilar CT-P13, while a control group used reference-infliximab only. In the PLANETRA and Tanaka et al studies, clinical measures of safety and efficacy were comparable between switched and nonswitched groups.9,11 In the PLANETAS study, there was a higher proportion of patients with more than 1 treatment-emergent adverse event (TEAE) in the switched compared with nonswitched group. The rates of TEAEs in both groups, however, were within the range and were historically reported in studies of reference-infliximab use on patients with ankylosing spondylitis and thus unlikely indicative of differences in immunogenicity.12

Pharmacovigilance and Postmarket Surveillance

Postmarketing surveillance is critical in detecting rare adverse events (AEs) or spikes in immunogenicity for both biosimilars and reference-biologics.13 Postapproval safety monitoring employs 2 detection systems: spontaneous reporting systems (SRSs) and active surveillance (AS) systems. SRSs are passive methods of reporting, as they rely on voluntary reports from HCPs, pharmacists, and patients.13 SRSs are potentially useful for biosimilars as these products are sensitive to variables associated with manufacturing processes and can detect emergent safety issues related to changes in product quality throughout the product lifecycle. SRSs are limited by the inability to accurately quantify the incidence of risks for a product as the total number of treated patients is not identified.14 AS employs a retrospective analysis of medical records, drug/disease registries, and AE monitoring.13 AS methods are suited to identifying multiple potential links to safety signals. When complemented with clinical and scientific algorithms, they can be used to prove causality.15

In the United States, SRSs are managed through the FDA’s MedWatch program and reporting can originate from a variety of sources.16 The FDA Adverse Event Reporting System (FAERS) database identified patients as the reporters of serious AEs in 41% of reports, HCPs in 36% of reports, and pharmacists in 3% of reports.17 Detection requires identification of the specific product(s) administered to patients and is complicated by products from several manufacturers sharing identical nomenclature and/or coding.16 Delayed immune reactions, due to formation of antidrug antibodies, further complicate reporting through a significant time lag between administration and appearance of serious AEs, obfuscating the association of a specific product with the AE.18 The delay in AE may further affect attributing the reaction to a specific product if the patient has been switched between biologics or lots of a biosimilar product.19 Despite these limitations, SRS AE reports can be a means to early identification of product or batch-specific issues, a critical function in pharmacovigilance of biologics where multiple manufacturers develop products with clinically similar active substances.16

US Market Impact

The introduction of biosimilars into the US biologics market has the potential to drive cost savings and increase patient access. Although the United States lags Europe in availability of biosimilars, the US biosimilar market has the potential to be the largest in the world.20 Estimates for US cost savings range from 5-year savings of $256 million21 to $54 billion between 2017 and 2026.22

Potential for cost savings in the US healthcare system is partly due to market competition generated from biosimilars.20 Although the market holds substantial promise, the expectation for savings from biosimilars to be similar in scale to that gained from generic chemical drugs may be misguided due to several market differences. Biosimilars have higher development costs and manufacturing costs.23 These costs help to explain why discounts between biosimilars and reference-biologics are typically less than 30% in the European Union compared to 80% or higher for generic chemical drugs.23

The potential savings being driven by competing products has led to a great interest in developing economic models that can predict the impact of biosimilar use.20 After the adoption of new interventions, budget impact analysis (BIA) became a modeling method commonly used to consider the expected economic changes in a healthcare system.24,25 BIAs can be used alone or as a complement to a cost-effectiveness analysis (CEA).25 Many countries incorporate BIA models into formulary listing and reimbursement decision making at national, regional, and local levels.20,25 Despite the increasing importance of BIAs in healthcare, they are rarely published, and many have been found to be of poor quality by expert opinion in a systematic review.26 The International Society for Pharmacoeconomics and Outcomes Research (ISPOR) releases guidelines on BIA good practice, improving and evolving models over time.25 Improved analytic models will be necessary for US decision makers and stakeholders to predict the evolving biosimilar market, which is notably more fluid than that of the European Union because of multiple payers, more versatile formulary structure, and many choices in patient health plans.

The European Model

The European Medicines Agency (EMA) established the European regulatory framework for biosimilars in 2005. Somatropin (Omnitrope), a biosimilar recombinant human growth hormone (rhGH), was the first biosimilar approved in the European Union by the EMA in 2006.27 The first in the world, somatropin exemplified the successful establishment of a regulatory pathway for biosimilars. Within this evolving framework, more than 35 biosimilars have been approved by the EMA to date. In the European Union, biosimilars follow a structured, stepwise development process with guidelines developed jointly by the EMA, the Committee for Medicinal Products for Human Use (CHMP), the Biotechnology Working Party, and the Working Party on Similar Biological Medicinal Products.27 Development begins with comprehensive physiochemical analysis of the various levels of molecular structure.28 This is followed by quality assessment of biologic characteristics using in vivo and in vitro testing. Preclinical and clinical studies are extensive to the degree of evidence acquired in physiochemical analysis.28 The aim of clinical trials is to address differences in characteristics between biosimilars and reference-biologics, investigating differences in clinical attributes. Postmarket analyses provide sensitive comparative data, becoming an increasingly valuable stage of the developmental process in the European Union.29 

There are several key differences between EMA and FDA biosimilar regulatory pathways. The EMA does not have guidelines on assessments for pharmacy-level substitutions, whereas the FDA assesses the interchangeability of biosimilars, regulating pharmacy-level substitutions via state legislatures.27 

The European Union has achieved successful adoption of biosimilars into the market, serving as a model for the younger US biosimilar market. Understanding the key drivers of uptake in the European market will be of utmost importance to US regulatory and payer policies. Biosimilar incentive policies, although heterogeneous between individual countries of the European Union, enhance uptake and drive biosimilar market penetration.30 The market for biosimilars is very different from that of generic synthetic drugs, although expectations have been based on experiences of the latter.

There was a poor understanding of biosimilars at the time of their introduction to the EU market. Due to crucial differences in molecular structure (synthesized vs grown) and considerations for batch-to-batch and lot-to-lot variations, immunogenicity, and interchangeability, it became very apparent that biosimilars would require a different clinical and market approach than those for generic chemical drugs. In 2013, the European Commission Project Group on Market Access and Uptake of Biosimilars published a consensus information document31 to educate healthcare professionals, patients, and commission organizations about biosimilars.27 These educational documents were disseminated jointly by both reference-biologic manufacturers and biosimilar developers to provide a consensus of unbiased information. Education is crucial for incorporating biosimilars into clinical practice and has been a key factor in regulatory and market evolution. The EMA publishes a European Public Assessment Report (EPAR) for every human or veterinary medicine application, whether granted marketing authorization or not. The EPAR reflects the scientific conclusions of the EMA committee for the assessment, providing evidence for the committee’s opinion to approve or deny an application. EPARs do not consist of a single document, instead evolving with time to reflect up-to-date regulatory information. This then delivers a transparent and detailed body of information made publicly available.

To incentivize the incorporation of biosimilars into clinical practice, benefit-sharing models have been used by EU member states. Under such models, savings accrued through the use of biosimilars allows a healthcare system to reinvest those funds in patient care. The exact policies implemented depend on the EU member state, with a wide degree of heterogeneity across the European Union.

Biosimilars are approved by the EMA, receiving market authorization in the European Union; however, availability differs across the separate member states. Funding is necessary to enable patient access to biosimilars due to the relatively high manufacturing and development costs. If a specific biosimilar is available in a given country, however, it is usually due to the decision of the manufacturer and not regulatory or reimbursement bodies. Availability also differs between specific biosimilars. For example, biosimilars of filgrastim that are most commonly funded are, in descending order, Zarzio, Nivestim, Tevagrastim, and Accofil.32 Germany is the only European country to fund and make available all registered biosimilars.32 Pricing of biosimilars is determined by national authorities and in most countries is determined by a combination of mechanisms such as percentage below reference-biologic, free-pricing, market forces, and national tendering.32

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