ERA at TOPRA 2025: Tailored development of biosimilars without efficacy and safety studies – is this the future?

With growing experience and coverage of the biosimilar market, regulatory strategies must evolve to balance scientific rigor with the need for efficient development.

One of the currently most debated topics in the biosimilar arena is the potential waiver for traditional efficacy and safety studies, a move that could significantly reduce development timelines and costs.

This session focused on the increasing interest in shifting the emphasis to establish similarity mainly based on CMC comparability data, as opposed to relying on results from comparative clinical efficacy trials (CES).

The session explored the scientific rationale behind using robust CMC evidence as the cornerstone of biosimilar approval, while addressing concerns regarding the adequacy of clinical data.

Experts in CMC presented their views on how advanced manufacturing technologies, analytical techniques, and product characterization can generate the necessary evidence to support a waiver for extensive efficacy and safety studies. These experts shared insights on how consistent manufacturing and comparability of biosimilars can be sufficiently demonstrated through state-of-the-art analytical methods, highlighting the potential for regulatory flexibility in this area.

On the other hand, clinical specialists provided arguments from a clinical point of view, discussing the feasibility and concerns about the lack of efficacy and safety data in these developments. They examined the implications of waiving clinical trials, particularly in terms of patient safety, real world outcomes, and public confidence in biosimilars.

By bringing together experts from both the CMC and clinical fields, this session provided a comprehensive, balanced view of the challenges and opportunities in biosimilar development.

Points to note:

There is 20 years of experience now in EU (both Industry and Regulators)

Are Clinical efficacy studies (CES) still needed?

• Analytical tools are more sensitive to detect differences than CES.
• CES can not always contribute relevantly to decision making and could not solve PK issues
• Trials can cost $100-$300 million dollars
• Biosimilar void is coming (many products off patent soon with no generics in development)
• Regulators are getting ready for less clinical data to make decisions (when appropriate)
• You do need a comparative PK study, supportive safety/immunogenicity data, CES may only be needed to answer outstanding scientific questions
• Quality and Non-clinical evidence grounded in comparability (ICH Q5E) – better knowledge of mode of action today than before

EMA/CHMP/BMWP/60916/2025 (Reflection paper – https://www.ema.europa.eu/en/reflection-paper-tailored-clinical-approach-biosimilar-development)

EMA/CHMP/138502/2017 (Reflection paper – https://www.ema.europa.eu/en/documents/scientific-guideline/reflection-paper-statistical-methodology-comparative-assessment-quality-attributes-drug-development_en.pdf – use it for discussion and clarification with Regulators. It won’t always be applicable to your product)

• Impacts on potency (discussion in dossier required), Critical Quality Attributes (CQA) risk ranking approach (examples given on how to justify)
• Quality of Reference Product can differ over time and so needs to be monitored by R&D, PK/PD study data becomes essential when CES is excluded.
• Protein quantity similarity assessment is necessary
• PK/PD could be used to supplement immunogenicity data requirements (via better assays)
• Ask Regulators not to get bogged down in differences that don’t matter (convince them in your submission)

EMA perspective:

• Quality data has evolved
• Reflection paper on statistics is a tool box of options (not a requirement).
• Industry should use Quality data as appropriate.
• Immunogenicity topic is still under discussion at EMA.
• Structural analysis needs to be robust, guideline for biosimilars is being developed.

Q&A:

• Discuss CES requirement with EMA in scientific advice – Application must be mature enough to allow for Regulator advice, see reflection paper – Approach them after batch manufacture once you can see how things are aligning
• Prescribers may need help to accept Biosimilars approved without CES.
• IPRP workshop was valuable (https://admin.iprp.global/sites/default/files/2024-07/IPRP_BWG_Final%20IPRP%20Scientific%20Workshop%20Summary%20Report_2024_0506.pdf)
• Wider community is pretty open to waivers, follow-up with NCA initiated (Reflection paper).
• WHO guidance is already followed by many countries and also mentions CES waiver.

Written by

Alice D’Alton