US and EU perspectives on the evolving nature of clinical requirements for biosimilars

The U.S. Food and Drug Administration (FDA) recently granted a waiver of clinical studies for a biosimilar version of the monoclonal antibody (mAb) product, Stelara. This is the first time to our knowledge that FDA has exercised its waiver authority under the Food, Drug, and Cosmetic Act (FDCA) to reduce the evidence that would normally be required to establish biosimilarity. FDA has approved a number of other biosimilar versions of Stelara, all of which included a clinical study demonstrating effectiveness in at least one indication. To our knowledge all other approved biosimilar mAb products have included at least one clinical efficacy study.

Similarly, the European Medicines Agency (EMA) released a reflection paper suggesting that it may reduce the data burden for showing biosimilarity. EMA's draft reflection paper proposes relying more heavily on advanced analytical and pharmacokinetic data, potentially reducing the need for comparative efficacy studies under well-defined conditions.  

FDA grants biosimilar clinical study waiver

FDA recently granted a specific waiver of clinical efficacy studies for a biosimilar version of Stelara (ustekinumab). We believe this marks a significant precedent in biosimilar approvals. The FDCA generally requires a clinical demonstration of effectiveness in at least one of the indications for which the reference product is licensed. mAbs are complex recombinant proteins. Stelara is no exception. All previously approved mAb biosimilars have required at least one Phase 3 clinical investigation. 

Under the statute, FDA may approve a biosimilar application if it includes, among other information, (1) “analytical studies that demonstrate that the biological product is highly similar to the reference product notwithstanding minor differences in clinically inactive components,” (2) “an assessment of toxicity,” and (3) “a clinical study or studies (including the assessment of immunogenicity and pharmacokinetics or pharmacodynamics) that are sufficient to demonstrate safety, purity, and potency in 1 or more appropriate conditions of use for which the reference product is licensed.” 42 USC 262(k)(2)(A)(i). Thus, the statute expressly requires clinical effectiveness in at least one indication. However, the statute also provides that FDA may, at its discretion, find that any one of these required elements is unnecessary. Id. at (k)(2)(A)(ii). Thus, it has always been within FDA's authority to waive a clinical demonstration of safety and effectiveness (safety, purity, and potency), or to waive the requirement for clinical data altogether, including pharmacokinetics (PK), pharmacodynamics (PD), and clinical immunogenicity. FDA has approved a (very) few biosimilars for much simpler proteins without a Phase 3 demonstration of effectiveness, e.g., filgrastim. But an mAb represents a different order of complexity.

This comes on the heels of other developments. Earlier this year, FDA broadcast a shift away from using animal studies for toxicology, as we wrote about here. Last year, FDA signaled that it would no longer require a separate clinical demonstration to establish that a biosimilar biological product is interchangeable with the reference product, about which we wrote here. FDA Commissioner Marty Makary has publicly advocated for reducing regulatory hurdles, including reconsidering the interchangeability designation itself, which has historically slowed biosimilar adoption.

All told, these developments signal the Agency's growing confidence in advanced analytical and other methods, short of additional clinical investigations, as reliable tools for establishing biosimilarity. In early September 2025, FDA finalized its guidance, Development of Therapeutic Protein Biosimilars: Comparative Analytical Assessment and Other Quality-Related Considerations Guidance for Industry. It allows a risk-based analysis to appropriately tailor subsequent clinical studies that may (or may not) be required. This is demonstrated in FDA's reliance on comprehensive analytical testing in its previous approvals of simpler biosimilars such as filgrastim, which have been based solely on Phase 1 immunogenicity, PK, and PD studies. FDA's approach emphasizes molecular characterization and clinical pharmacology over extensive clinical efficacy trials. 

Nonetheless, it is a leap to apply this approach to more complex biologics. It is unclear where this particular biosimilar version of Stelara stands in the approval process. Whether the data are deemed adequate to license it without a clinical demonstration of effectiveness will ultimately be a review decision. It is unclear whether FDA intends to support similar clinical trial exemptions for other complex proteins.

European Union: EMA’s established approach and suggestions for biosimilar development

On April 1, 2025, EMA published a draft reflection paper exploring a tailored clinical approach for biosimilar development, also emphasizing reliance on analytical comparability and PK over traditional comparative efficacy studies (CESs). This approach aims to streamline biosimilar approvals, particularly for products where CESs add limited value or face feasibility challenges, such as narrow indications or complex therapeutic settings. The paper highlights prerequisites, methodologies, and considerations for implementing this tailored approach.

EMA’s established guideline (CHMP/437/04) requires biosimilars to demonstrate safety and efficacy comparable to their reference medicinal product (RMP), allowing minor differences as long as they do not impact clinical safety, efficacy, or the mechanism of action (MoA). Historically, CESs have been used to address uncertainties and confirm clinical performance. However, the reflection paper suggests that under specific conditions, biosimilars could gain approval without CESs or PD studies if robust analytical comparability and human PK data sufficiently demonstrate similarity.

In this context, a successful comparability exercise requires the following prerequisites:

• A comprehensive set of relevant quality attributes using state-of-the-art analytical methods providing detailed information regarding the structural and functional properties of the biological molecule, which is essential for the demonstration of similarity between a biosimilar candidate and its RMP.
• Comprehensive knowledge regarding the molecule’s MoA.
• Availability of functional assays such as in vitro pharmacology tests, potency tests, etc.
• A validated manufacturing process and control strategy.
• A pre-established assessment protocol.

Scenarios where CESs cannot be waived are also outlined in the draft reflection paper, such as when analytical methods lack sensitivity, the MoA is poorly understood, or the structure-function relationship is unclear. Examples include cell-based medicinal products and locally applied products with negligible systemic absorption, where PK data is insufficient to establish biosimilarity. In such cases, CESs remain necessary to address uncertainties.

Applicants must justify that their data package adequately resolves any uncertainties. Comparative PK studies, combined with comprehensive analytical comparisons, remain critical components of biosimilar development.

Stakeholders are invited to send their comments on the reflection paper via an online EU Survey until September 30, 2025, after which EMA may adopt the reflection paper and officially implement its requirements to establish biosimilarity. 

What these changes mean for innovator and biosimilar sponsors

If FDA and EMA remove or lower the burden for costly efficacy studies and switching study-requirements more widely, the shift would transform product development strategy for both innovator and biosimilar sponsors, with significant implications on the global biosimilars market.

From a global perspective, this shift by FDA and EMA would help promote global harmonization, allowing for more flexible approaches that rely heavily on robust analytical and PK data rather than extensive clinical efficacy trials. This global harmonization would reduce duplication of clinical data requirements, simplify multinational development programs, and pave the way for more streamlined global approvals. For biosimilar sponsors, these regulatory developments can be expected to reduce the data burden associated with approval. Eliminating CESs and switching studies can cut development costs significantly and accelerate approval timelines, enabling faster market access and could encourage a broader range of manufacturers. The potential regulatory reform around interchangeability—aimed at simplifying pharmacist substitution of biosimilars—could fundamentally alter competitive dynamics by lowering barriers to biosimilar uptake in the U.S.

But this simplification may come at the cost of clinical validation of biosimilars before they are approved for marketing.

For innovator product sponsors, the changing regulatory and competitive landscape requires strategic adaptation to maintain market position. Although many high-revenue biologics have retained significant market share despite biosimilar competition, the potential acceleration of biosimilar approvals and the potential reform or elimination of the interchangeability designation threaten to intensify price pressures. Innovators may need to:

• Strengthen intellectual property portfolios to defend exclusivity amid growing competition.
• Diversify product lines to reduce reliance on individual blockbuster biologics.
• Increase investment in post-market real-world evidence generation to demonstrate ongoing value and safety.
• Enhance patient support programs to foster brand loyalty and optimize treatment adherence.

These trends in biosimilar development on both sides of the Atlantic challenge innovator companies to evolve their strategies to capitalize on emerging opportunities and mitigate risks in this changing regulatory landscape.

If you have questions about how these developments impact biosimilars or innovator biologic programs, please contact the authors or your usual Hogan Lovells regulatory counsel.

Authored by Ashley Grey, Julia Mischie, Jason Conaty, and Hein van den Bos