EMA adopts reflection paper on tailored clinical approach in biosimilar development

On 16 March 2026, the EMA CHMP adopted a reflection paper introducing a tailored clinical development approach for biosimilars, enabling reduced reliance on comparative clinical efficacy studies (CES) where robust analytical and pharmacokinetic (PK) comparability is demonstrated.

Key Regulatory Shift

EMA signals a transition toward an “analytical-first” paradigm, where:

• Analytical and functional comparability form the primary basis for biosimilarity
• CES are generally no longer required
• Clinical data requirements are tailored based on residual uncertainty

Scientific Basis

• Biosimilarity is grounded in the principle that structure determines function
• Advances in analytical methods enable highly sensitive detection of differences
• Regulatory experience indicates CES often do not provide additional meaningful evidence

When CES May Be Waived

A tailored approach without CES is acceptable when:

• Mechanism of action (MoA) is well understood
• Structure–function relationship is established
• Analytical methods can comprehensively characterise the product
• Functional assays confirm comparable biological activity
• Manufacturing process ensures consistent quality

CES may still be required where:

• MoA or structure–function relationship is uncertain
• Product is not sufficiently characterisable
• PK evaluation is not feasible

Role of Clinical Studies

• PK studies remain essential to demonstrate equivalent exposure
• Provide supportive safety and immunogenicity data
• PD studies generally not required, unless PK cannot be assessed
• Safety/immunogenicity largely inferred from analytical + PK data

Key Quality Expectations

• Demonstration of high similarity (not identity) in quality attributes
• Strong emphasis on:
  • Physicochemical and functional comparability
  • Critical quality attribute (CQA) assessment
  • Risk-based justification of differences
• Differences in critical attributes (e.g., bioactivity, structure) are generally not acceptable

Implications for Industry

• Enables streamlined biosimilar development with reduced clinical burden
• Requires:
  • Advanced analytical capabilities
  • Robust scientific justification of differences
  • Early regulatory engagement (e.g., scientific advice)
• Likely to reduce development timelines and costs

Regulatory Impact

• Represents a significant evolution in EU biosimilar guidance
• Aligns with global trends toward analytical-driven development
• Expected to apply to the majority of biosimilar candidates

Bottom Line

EMA confirms that biosimilar approval can rely primarily on analytical and PK evidence, with clinical efficacy trials becoming the exception, provided scientific justification is robust.