Author: Dr. Richard Easton. Date: 8th July 2026
Recently, the EMA adopted a document entitled “Reflection paper on a tailored clinical approach in biosimilar development” (1). Whilst not formal legal guidance, this document details how analytical data for biosimilars can be used as evidence to potentially remove the necessity of comparative efficacy studies (CES) for certain products.
This approach has been gaining momentum globally, with the MHRA first outlining this concept (2), followed by the FDA recognizing the merit of this approach (3). This EMA reflection paper gives a strong indication of where future regulatory expectations for biosimilar development may head.
Naturally, with an increased emphasis on analytical data, there is a need to clearly define what characterization expectations must be met to ensure there is sufficient information available on product structure, quality, and the manufacturing process. This not only covers the identification and assessment of critical quality attributes (CQAs), but also an understanding of the limitations of analytical methods when probing specific structural elements.
If CES are to be avoided and the proposed biosimilar is to be recognized as such, then it is of paramount importance that sufficient structural data are obtained across multiple sample batches to allow confident conclusions to be drawn regarding the safety and efficacy of the biosimilar in light of the reference medicinal product (RMP) profile.
To this end, the reflection paper states that “usually 6 or more” batches from different DS lots should be tested. Commercial scale batches, process performance batches, and any batches that may have been used in clinical trials should be included.
For the RMP material, the document states that "at least 10 RMP batches" should be used in the assessment but also notes that "...15–30 batches of the RMP are optimal...". The use of fewer than 10 batches runs the risk of generating insufficient data from which a true product profile can be established. In the absence of a clear and well-defined RMP profile, claims of biosimilarity may be more difficult to justify.
Furthermore, the reflection paper states that "continued sampling over time is meaningful to take into account potential shifts or drifts in the RMP, irrespective of the number of batches already sampled."
This may initially appear to be a significant burden of characterization, and indeed obtaining the recommended number of RMP batches is likely to require some time. However, the goal of the work is to generate a sufficiently strong body of analytical data to support confident conclusions regarding the biosimilar, and its production process in relation to a clearly defined RMP profile, that serves as the biosimilar target.
Furthermore, ongoing structural analysis enables the assessment of any shifts in the RMP profile as newer batches are manufactured. Get this right, and the need for lengthy and costly CES can be prevented, ultimately saving both time and money.
The message is clear: understand your product structure, understand your target profile, and demonstrate that your product structure is acceptable within the parameters of the target. Do that successfully, and a faster and more cost-effective biosimilar pathway will likely be achievable.
BioPharmaSpec offers independent, ICH Q6B-aligned structural characterization of biosimilar and RMP batches; using state-of-the-art instrumentation and orthogonal methods to build the analytical package that supports a CES-free regulatory pathway.
It is a requirement that analytical methods for biosimilar characterization should be state-of-the-art, which naturally extends to the instrumentation used. This is consistent with existing EMA biosimilar guidelines (4). The use of orthogonal methods follows the same well-established philosophy (4). Both expectations are logical, given the need for strong, self-supporting analytical data packages and the capabilities of modern analytical technologies across structural characterization.
One particularly interesting point raised by the document is that side-by-side comparisons are not necessarily an absolute requirement due to the precision of modern methods and instrumentation. That is not to say that this is a blanket statement since there are instances where method variability is such that side-by-side analyses will give the most reliable comparative data.
Indeed, in my opinion, side-by-side analysis remains the best and safest approach for obtaining optimal comparisons. However, this may increasingly become a case of running a bridging sample within each analytical session rather than defining a more comprehensive side-by-side biosimilar versus innovator campaign, particularly when the number of innovator batches being characterized is that much larger than the number of biosimilar batches.
Considering that analyses are likely to be performed over longer timescales due to increased batch requirements, this would seem extremely prudent. The document does go on to acknowledge that side-by-side testing can be used where inter-assay variability is observed or anticipated.
The reflection paper recommends following the well-established requirements outlined in ICH Q6B (5), for characterization, a framework already adopted by the EMA, which provides a well-founded and detailed series of analyses for assessing structural and physicochemical attributes of the product.
In the simplest case, the measured range of a given attribute for the biosimilar should fall within the range observed for the RMP. However, cases are made for situations where this does not happen, so failure to meet a specific target is not automatically failure of the product.
The document goes into some detail in terms of discussing specific analytical areas namely protein content and the need to determine this for RMP as well as biosimilar; charge variant analysis and fraction collection of charge isoforms to identify the nature of those charged species; glycosylation (if present) and the need to monitor this vitally important post-translational modification through the development of the biosimilar as well as at the final production stage; and impurities.
I have focused on the analytical requirements of the reflection paper, but the paper itself extends beyond the analytical topic and details the continued importance of PK studies and provides a consideration of the limited value of PD.
With this document, the EMA has clearly demonstrated its desire to work with the biopharmaceutical industry to use the power of state-of-the-art analytical techniques to streamline the pathway to biosimilar marketing authorization. Every effort is made to encourage the effective use of analytical techniques to support applicants to get their products through the regulatory process by generating a robust and comprehensive structural package that may negate the need for CES.
The number of batches analyzed, particularly for the RMP, needs to be sufficiently large to support meaningful comparisons of structural attributes. At the same time, full side-by-side comparisons are not necessarily absolute requirements. A thorough understanding of the analytical techniques being employed is a prerequisite for determining both their suitability and their limitations.
These analyses are therefore best undertaken by independent laboratories with extensive experience in structural characterization, access to state-of-the-art instrumentation, and a thorough understanding of orthogonal analytical approaches for data generation. Equally important is a detailed knowledge of ICH Q6B and practical experience in the design and execution of biosimilar comparability studies.
The requirement for detailed investigations of both the RMP and biosimilar may initially appear excessive. However, it must be recognized that this front-loaded strategy is designed to save a significant amount of time and cost by CES removal, an outcome that can only be achieved in light of a solid package of analysis of the product itself and the RMP landscape in which it is meant to reside.
The EMA has clearly demonstrated a desire to assist biosimilar manufacturers in bringing products to market in an efficient and cost-effective manner without compromising product safety and quality. Ultimately, this approach benefits patients and healthcare services throughout its jurisdiction.
