Biosimilars Regulatory Requirements in Global Markets

Biosimilar development is based on demonstrating high similarity to a licensed reference biological product.
Global regulators generally apply a stepwise “totality of evidence” model, beginning with extensive analytical comparability and moving to targeted non-clinical and clinical studies only where residual uncertainty remains. All regulatory agencies require robust quality, manufacturing, pharmacovigilance, and comparability evidence, but differ in reference-product expectations, clinical-study flexibility, interchangeability language, and local procedural requirements.
Harmonization is increasingly shaped by ICH quality guidelines, WHO biosimilar principles, and ICMRA confidence-building initiatives.

Biosimilars Regulatory Frameworks Across Global Markets

Across major markets, regulators expect a comparability between biosimilar and originator.

EMA describes the biosimilar approach as establishing similarity in molecular and biological terms to the active substance of the reference medicinal product.

FDA requires evidence that the proposed biosimilar is highly similar to the reference product and has no clinically meaningful differences in safety, purity, and potency.

This approach is strongly aligned with the scientific assumptions of ICH Q5E, which established the concept of comparability for biological products. Although ICH Q5E was originally developed for assessing manufacturing changes, its logic supports modern biosimilar regulation. The more sensitive and complete the analytical comparability exercise, the less residual uncertainty should remain for animal or clinical studies. Additional studies should be required only when residual uncertainty remains.^1,²

Key Regulatory Principles Defining Biosimilars Development Pathways

Biosimilar regulatory frameworks are built on the principle that approval should be based on demonstrating high similarity to an already authorized reference biological product. The general biosimilar development pathway is risk-based. It starts with product selection and reference-product strategy. The pathway proceeds through deep analytical and functional characterization, then uses non-clinical and clinical studies only to answer remaining scientific questions.³

For complex biologics regulators expect particular attention to primary structure, higher-order structure, glycosylation, charge variants, purity, impurities level, Fc-mediated functions, binding, potency, degradation pathways, and stability.

Fig. 1. Process diagram for a monoclonal antibody biosimilar development pathway.

Analytical and Clinical Requirements in Biosimilars Regulatory Submissions

Analytical characterization is the core of both FDA and EMA biosimilars regulatory submissionss. Comparative analytical studies and toxicity assessment are used by FDA to decide whether residual uncertainty remains and whether comparative efficacy studies are necessary. EMA similarly requires a full quality dossier plus comparability data using appropriate physicochemical, in vitro biological, non-clinical, and clinical studies. For monoclonal antibodies, this means using multiple orthogonal techniques to evaluate critical quality attributes (CQAs).⁴

Clinical requirements are intentionally focused. FDA and EMA generally expect comparative human PK as a sensitive clinical confirmation of similarity; PD may be used when a relevant, sensitive biomarker exists. Immunogenicity assessment remains important because small differences in product- or process-related attributes can influence anti-drug antibody formation, neutralizing antibodies, hypersensitivity, loss of efficacy, or altered clearance.^3,⁵

But comparative efficacy studies are no longer viewed as automatically necessary in every case. A major emerging trend is the move toward a more tailored clinical approach in biosimilar development. Under this model, large comparative efficacy trials are no longer treated as a default requirement when robust analytical, functional, PK, PD, safety, and immunogenicity data sufficiently support biosimilarity.⁶

EMA has described this approach as a way to optimize biosimilar development while reducing the amount of clinical data required, and FDA’s updated draft recommendations similarly reflect evolving biosimilars regulatory requirements by focusing on when comparative efficacy studies are scientifically necessary. This evolution may significantly reduce development timelines, clinical trial burden, and overall costs, while maintaining regulatory confidence in biosimilar quality, safety, and efficacy.

Regulatory Expectations for Biosimilar Manufacturing and Process Control

Manufacturing expectations are shaped by the broader ICH quality framework. It establishes specification parameters for drugs and promotes quality risk management and pharmaceutical quality systems.^7,8

For biosimilars, this translates into a control strategy that links process knowledge to CQAs and clinical relevance. Regulators expect:

Validated manufacturing processes

Control of cell banks and raw materials

Viral safety

Contamination control

In-process control

Release specifications

Comparability after process changes

Stability programs

Lifecycle management

In the manufacturing of biosimilars, the manufacturer does not need to copy the originator’s process, but must consistently manufacture a product that remains highly similar to the reference product.

Regional Differences in Biosimilar Regulatory Approaches

Biosimilars regulatory requirements differ by region because each agency applies its own legal pathway, dossier format, comparator expectations, review procedure, terminology, and post-approval obligations.

MHRA (United Kingdom)

MHRA has its own guidance for licensing biosimilar products in Great Britain and the UK, updated after Brexit and the Windsor Framework.⁹ A notable UK differentiator is its explicit position that, once authorized, a biosimilar is considered interchangeable with its reference product and with other biosimilars to the same reference product, while prescribing decisions remain under healthcare-professional control.

PMDA (Japan)

Japan defines a biosimilar as a product comparable in quality, safety, and efficacy to a biotechnology-derived product already approved in Japan as an original biopharmaceutical. PMDA guidance and Q&A documents emphasize quality comparability, Japanese regulatory expectations, and case-by-case justification of clinical data, including how comparative efficacy studies may be used to address remaining quality-attribute differences.¹⁰

TGA (Australia)

TGA regulates biosimilars through registration on the Australian Register of Therapeutic Goods and provides guidance on data requirements, reference medicine requirements, in-house primary reference standards, quality comparability, extrapolation, naming, evaluation, and post-registration responsibilities. Australia has adopted relevant EMA biosimilar guidelines, but TGA clarifies that references to EU legislation inside adopted guidelines do not automatically apply to Australian evaluations.¹¹

NMPA (China)

China’s NMPA, through the Center for Drug Evaluation (CDE), has developed biosimilar technical expectations around comparative quality, non-clinical, clinical, and registration requirements. A practical differentiator is the importance of China-specific CDE technical guidance, local submission procedures, and evolving labeling expectations for biosimilars, including clearer identification of biosimilar status in product information.¹²

ANVISA (Brazil)

Brazil historically regulated follow-on biological products under RDC 55/2010, which created pathways including development by comparability. In 2024, ANVISA issued RDC 875/2024 to add provisions for biosimilar registration through the comparability development route, reflecting a move toward more explicit, modernized biosimilar-specific regulation.¹³

Aligning Biosimilar Development and Manufacturing with Global Regulatory Standards

A global biosimilars regulatory strategy usually follows the most rigorous common denominator across target markets. Sponsors typically design one integrated comparability program that can support all regulatories and WHO-aligned submissions, then add local modules for reference-product bridging, language, labeling, pharmacovigilance, administrative documents, and country-specific clinical expectations.¹⁴

Global harmonization is supported by ICH quality guidelines, which provide shared principles for comparability, specifications, risk management, pharmaceutical quality systems, and drug-substance development. WHO’s biosimilar guidelines provide globally acceptable principles for licensing biosimilars and support reliance on originator data once similarity is proven.

FAQ

Biosimilars regulatory requirements are based on demonstrating high similarity to a licensed reference product through a totality-of-evidence approach. Regulatory agencies require comprehensive analytical comparability, appropriate non-clinical and clinical data when needed, robust GMP manufacturing controls, and pharmacovigilance plans to ensure comparable quality, safety, and efficacy.

No. Modern biosimilars regulatory frameworks adopted by agencies such as the FDA and EMA increasingly support a tailored development approach in which comparative efficacy studies are only required if analytical, functional, pharmacokinetic, pharmacodynamic, safety, and immunogenicity data leave residual uncertainty. This science-based strategy can reduce development timelines while maintaining confidence in biosimilarity.

While most regulatory authorities follow similar scientific principles, they differ in legal pathways, reference product requirements, dossier formats, interchangeability policies, labeling, pharmacovigilance obligations, and country-specific procedural expectations. Sponsors typically develop a global comparability package and adapt it to local regulatory requirements.

Analytical comparability provides the most sensitive assessment of similarity between a biosimilar and its reference product. Comprehensive evaluation of critical quality attributes, biological activity, purity, glycosylation, stability, and other molecular characteristics reduces uncertainty and helps determine whether additional non-clinical or clinical studies are necessary.

Prepared by:

Jakub Knurek

Marketing Specialist

j.knurek@mabion.eu

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