Developing one biosimilar for several major markets sounds straightforward in principle. The scientific objective is broadly shared: demonstrate that the proposed biosimilar is highly similar to an established reference biologic and that any observed differences do not translate into clinically meaningful differences. The difficulty begins when that scientific principle must become an actual development program.
An effective global biosimilar regulatory strategy cannot simply duplicate one dossier across five markets. The US, European Union, UK, China and Japan are increasingly aligned around strong analytical evidence and a risk-based approach, but important differences remain in reference-product selection, bridging, clinical evidence and regulatory procedure.
In 2026, those differences matter even more because several regulators are actively reducing reliance on routine comparative clinical efficacy trials while maintaining market-specific evidentiary requirements.
Why one Global Biosimilar Strategy does not mean one Global Regulatory Package
The basic science of biosimilarity has become increasingly harmonized. Regulators generally expect development to begin with detailed comparative analytical and functional characterization. The resulting evidence is then used to determine what additional non-clinical, pharmacokinetic, pharmacodynamic, immunogenicity or efficacy evidence is needed to address residual uncertainty.
US-FDA explicitly describes comparative analytical data as the foundation of biosimilar development. EMA similarly uses a stepwise, product-specific comparability exercise in which the initial quality comparison informs the extent of later non-clinical and clinical studies, but regulatory alignment at the scientific level does not eliminate legal and procedural differences.
A global program still must account for:
- The legally acceptable reference product in each jurisdiction
- Whether a foreign-sourced comparator can be used
- What bridging evidence is needed
- Whether comparative efficacy data add meaningful information
- How PK, PD and immunogenicity should be addressed
- Whether local or ethnic clinical data are expected
- How indications can be extrapolated
- Market-specific submission and post-approval requirements
The objective should therefore be one scientifically coherent development program with planned regional adaptations, rather than five separate programs or one supposedly universal dossier.
What Does “Similarity” Actually Mean Across Major Markets?
Across mature biosimilar frameworks, similarity does not mean that the biosimilar must be an exact molecular copy of the reference product.
FDA defines biosimilarity around two core concepts: the proposed biological product must be highly similar to the reference product despite minor differences in clinically inactive components, and there must be no clinically meaningful differences in safety, purity and potency.
EMA likewise requires a comprehensive comparability exercise demonstrating high similarity to the reference medicinal product and no clinically meaningful differences in quality, safety or efficacy.
The UK applies the same underlying concept. MHRA expects high similarity in physicochemical properties, biological activity or potency and clinical profiles, while any observed differences must be justified for their potential impact on safety and efficacy.
Japan describes a biosimilar as comparable in quality, safety and efficacy to an original biotechnology-derived product approved in Japan. Its guideline emphasizes scientific evaluation of quality attributes and then tailors subsequent evidence according to the degree of similarity already demonstrated.
China’s CDE framework similarly addresses pharmaceutical or quality similarity, non-clinical similarity, clinical similarity, overall similarity and indication extrapolation. Its clinical-pharmacology guidance further supports the role of PK/PD in biosimilar assessment.
So, the central concept is increasingly consistent. What still differs is how each authority wants that similarity demonstrated.
Where US, EU, UK, China and Japan Still Differ
The differences are easiest to see when the major requirements are considered side by side.
The table also explains why the search for a simple answer to US vs EU biosimilar requirements can be misleading. The US and EU are moving in a similar scientific direction, but their legal reference-product frameworks and regulatory procedures remain different.
The 2026 Shift from Routine Clinical Trials to Tailored Evidence
This is the most important development affecting biosimilar strategy today. Historically, global programs often included comparative efficacy studies because they were viewed as a conventional component of demonstrating biosimilarity.
United States
FDA issued draft guidance in October 2025 stating that when comparative analytical assessment demonstrates that a proposed biosimilar is highly similar, an appropriately designed PK similarity study and immunogenicity assessment in biologics may be sufficient in many cases without a separate comparative efficacy study. The guidance remains draft guidance, so it should not be described as a final mandatory rule.
FDA moved further in March 2026 with revised draft Q&As addressing use of non-US comparators. Under scientifically justified circumstances, FDA indicated that certain foreign-comparator clinical data may be used without automatically requiring an additional three-way PK study involving the biosimilar, US reference product and foreign comparator.
European Union
EMA’s final Reflection Paper on a Tailored Clinical Approach in Biosimilar Development, published on 27 March 2026, states that comparative efficacy studies may not be necessary for well-characterized biological substances where analytical comparability, together with PK and appropriate safety assessment, provides sufficient evidence.
The distinction matters: EMA currently effective overarching biosimilar guideline remains the existing guideline, while a concept paper for its revision entered consultation in July 2026. The regulatory framework is therefore evolving rather than having been completely replaced overnight.
United Kingdom
The UK moved earlier. Current MHRA guidance states that, although each development program is assessed case by case, a comparative efficacy trial may not be necessary in most cases when a sound scientific justification supports its omission. MHRA continues to place substantial weight on comparative analytical and functional data and a confirmatory comparative PK study.
Japan
Japan is moving in the same direction. PMDA’s May 2026 Q&A confirms that where comparative quality data together with PK and/or PD studies sufficiently establish biosimilarity for the relevant clinical endpoint, a comparative efficacy study may not be necessary. PMDA also issued an Early Consideration document on determining when such studies add value.
China
China’s published framework also uses a stepwise assessment in which further efficacy evidence is driven by remaining uncertainty. However, global sponsors should avoid if a clinical package accepted by FDA, EMA or MHRA will automatically satisfy CDE expectations without a China-specific assessment. Reference Product and Bridging Strategy Can Make or Break Global Development.
Reference-product planning should begin before major comparative studies are locked. It is one of the easiest places for an otherwise global development program to fragment.
United States
A US 351(k) application is anchored to a US-licensed reference product.
FDA does allow data generated with a non-US-licensed comparator to support the application under appropriate circumstances. The sponsor must scientifically justify the relevance of those data and establish an acceptable relationship to the US reference product. FDA’s September 2025 analytical guidance specifically addresses comparative analytical bridging among the proposed biosimilar, US reference product and non-US comparator.
European Union
The EU application must refer to a reference medicinal product authorized in the Union/EEA.
EMA nevertheless permits certain clinical and, where needed, in-vivo non-clinical studies to use a comparator authorized outside the EEA when the applicant can demonstrate that it is representative of the EU reference product.
Analytical bridging is central to that justification, and PK/PD bridging may also be necessary depending on the product and development program.
United Kingdom
From 1 January 2025, the UK biosimilar guidance applies UK-wide. MHRA expects a UK reference medicinal product, but a non-UK reference product may be acceptable for the comprehensive comparability program when the sponsor can justify that it shares relevant regulatory history and is representative of the UK RMP.
Japan
PMDA’s guideline states that, in principle, the reference original biopharmaceutical used in quality, non-clinical and clinical comparisons should be approved in Japan. Where overseas-approved reference-product data are used, their relevance to the Japanese original product must be justified.
Japan has also become more flexible regarding where clinical data are generated. PMDA’s September 2025 Early Consideration explains that non-Japanese clinical data can support biosimilar assessment when sponsors adequately justify that ethnic factors do not materially affect the comparability conclusion.
China
China requires equally deliberate planning. NMPA guidance on imported reference drugs has stated that applicants should, where practicable, select an originator product already approved for import registration or clinical trial in China. When products from different origins are proposed, supporting comparability evidence may be necessary.
For global developers, the practical lesson is simple: Do not select comparator batches market by market after studies have started. Build the global reference-product and bridging strategy before the pivotal comparability program is finalized.
A Practical Global Biosimilar Regulatory Strategy for 2026
A strong program can be built around six decisions:
- Define the target-market sequence early.
Confirm whether the US, EU, UK, China and Japan are all first-wave markets or whether some will rely on evidence generated for earlier submissions. - Lock the reference-product strategy before pivotal studies.
Map the legally relevant reference product, comparator sources, lot availability and proposed bridging across every target market. - Invest heavily in analytical comparability.
The direction of regulation is clear: the stronger and more sensitive the analytical and functional package, the better positioned a sponsor is to justify a tailored clinical program. - Treat clinical studies as questions to be answered, not boxes to be checked.
For each proposed study, define the residual uncertainty it is intended to resolve. If sensitive analytical, functional, PK/PD or immunogenicity evidence already resolves that uncertainty, engage regulators on whether additional efficacy studies provide meaningful value. - Obtain agency advice before reducing the clinical package.
The move away from routine CES does not mean automatic waiver. FDA guidance remains partly draft, EMA’s framework is evolving, MHRA evaluates justifications case by case, and PMDA actively recommends consultation where reduced evidence is proposed. - Maintain a global core dossier with controlled regional adaptations.
Avoid developing separate scientific narratives for every market. Keep one defensible global biosimilarity story and document where individual authorities require different evidence or presentation.
International harmonization is also moving forward. ICH endorsed development of M18: Framework for Determining the Utility of Comparative Efficacy Studies in Biosimilar Development Programs in November 2025. Work continued during 2026, but M18 is still under development rather than a finalized global guideline. Its objective is directly relevant to the current challenge: creating more consistent principles for deciding when comparative efficacy studies are useful.
How DDReg Can Support Global Biosimilar Regulatory Strategy
A multi-market biosimilar program requires coordination between regulatory strategy, CMC, clinical development, regulatory intelligence and submission planning.
DDReg supports biopharmaceutical companies with global regulatory strategy, biologics and biosimilar registration in canada, CMC regulatory support, dossier planning and market-specific regulatory assessment. Its existing capabilities include biosimilar comparability strategy, regulatory gap assessment and product registration support across major jurisdictions.
For developers targeting multiple markets, the value lies in identifying differences before they become duplicated studies or submission gaps: reference-product acceptability, comparator bridging, clinical-evidence requirements, local documentation and agency engagement should all be assessed against the same global development plan.
Conclusion
The science supporting biosimilar development is becoming more globally aligned, but regulatory execution is not yet fully harmonized.
In 2026, the strongest global biosimilar regulatory strategy is not built around creating the largest possible clinical package. It is built around generating the most sensitive evidence needed to resolve uncertainty and then understanding how each authority expects that evidence to connect to its reference product and legal framework. FDA, EMA, MHRA, NMPA/CDE and PMDA are all moving toward more efficient biosimilar development, but they are not moving at the same pace or through identical rules.
For global teams, the practical model is therefore:
One global scientific core, One planned reference-product strategy, and clearly defined country-specific regulatory pathways. This approach reduces unnecessary duplication without assuming harmonization where meaningful differences still exist.
Frequently Asked Questions
No. Major regulators share the principle of demonstrating high similarity to a reference biologic, supported heavily by analytical and functional evidence. However, reference-product rules, comparator bridging, clinical evidence, local data expectations and regulatory procedures still differ between the US, EU, UK, China and Japan.
Both FDA and EMA use a science-based comparability approach, but their applications are legally anchored to different regional reference products. The US also retains a statutory interchangeable-biosimilar framework, while EU substitution decisions operate through Member State policies. Clinical-evidence expectations in both regions are becoming increasingly tailored.
Not routinely in every market or for every product. FDA, EMA, MHRA and PMDA have all moved toward approaches where strong analytical, functional and PK/PD evidence can reduce or eliminate the need for a comparative efficacy study in suitable cases. The justification remains product- and jurisdiction-specific.
Potentially, but not without planning. Regulatory applications remain anchored to jurisdiction-specific reference products. Foreign comparator data can sometimes support multiple markets when scientifically acceptable bridging is established, but the precise approach differs by regulator.
Bridging allows regulators to understand why evidence generated against one regional comparator is relevant to the legally recognized reference product in another market. A poorly planned bridging strategy can lead to additional analytical work, PK studies or even duplicated clinical development.