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BioRationality: EMA Announces Readiness to Waive Comparative Efficacy Studies of Biosimilars


Sarfaraz K. Niazi, PhD, takes a look at the European Medicines Agency's (EMA) announcement that it will investigate whether comparative efficacy tests should be needed for a biosimilar to receive regulatory approval.

researcher and data | Image credit: Deemerwha studio - stock.adobe.com

Image credit: Deemerwha studio - stock.adobe.com

It did not take long for the European Medicines Agency (EMA) to act after the FDA held a conference on “Increasing the efficiency of biosimilar development” in September 2023, which was participated by several regulatory agencies and other stakeholders, debating issues relating to removing hurdles in the approval of biosimilars.1

Now, the EMA has issued a call for comments on its intent to create a “Concept paper for the development of a Reflection Paper on a tailored clinical approach in Biosimilar development.”2 While the United Kingdom’s Medicines and Healthcare products Regulatory Agency makes a clear statement both EMA and FDA have stayed reserved in making a clear decision:3

“Although each biosimilar development requires a case-by-case evaluation, in most instances, a comparative efficacy trial may not be necessary if supported by sound scientific rationale. Therefore, a well-justified explanation for the absence of an efficacy trial should be appended to [common technical document] Module 1 of the submitted application.” [sic]

The current initiative by EMA is of high significance since both EMA and FDA have agreed to jointly resolve the inquiries by the developers of biosimilars in “FDA-EMA Parallel Scientific Advice (PSA),” making it likely that the outcome of this Reflection Paper will bring changes at both agencies.4

I have formally submitted my advice to EMA with added information to make this Reflection Paper most useful, as shown below:

EMA Statements [sic]

Author’s Analysis and Comments

With growing knowledge and the increasing possibilities of analytical and functional characterization, revisiting the need for clinical efficacy trials for biosimilars (especially recombinant proteins and monoclonal antibodies) is considered the next important step in order to keep the biosimilar pathway attractive for developers and, at the same time, guarantee future access to safe and efficacious biologics for European patients.

Differentiating between recombinant proteins and monoclonal antibodies is incorrect; both are recombinant proteins. Also, any regulatory guideline should ensure that no unnecessary study is conducted; it is not intended to make the “biosimilar pathway attractive;” such comments have led others to challenge the safety and efficacy of biosimilars.

Constantly striving for scientifically sound yet efficient processes, the biosimilar regulatory framework has constantly been evolving towards increasingly tailored developments, starting from smaller and “simpler” biologics, such as recombinant granulocyte-colony stimulating factor (rG-CSF), insulins or somatropin where the need for comparative clinical efficacy trials is in general not required any more.

Differentiating between “smaller and simpler” molecules and others is misleading since the size of molecules is unrelated to their safety concerns, and all drugs produced by biological processes face the same risks. The agencies have allowed comparative efficacy study (CES) waivers for some medications because of the proof of efficacy and safety from their pharmacodynamic properties and not because of their size or simplicity.

An ever-growing number of biosimilars has been successfully authorized through rigorous evaluation of scientific data, including the assessment of comparability for quality, non-clinical, and clinical aspects. By building upon this extensive knowledge, the EMA's Committee for Medicinal Products for Human Use (CHMP) aims to further optimize the development and evaluation process for biosimilars.

So far, the biosimilars approved have undergone unnecessary testing in the hindsight evaluation, which should be the correct statement. A recent study examining many EMA filings and approvals concludes that there is little risk in approving biosimilars with the CES—this fact is to be emphasized.5

The CHMP recognizes that there may be the potential to waive certain clinical data requirements even for complex biosimilars such as mAbs based on solid evidence of quality comparability. When the biosimilar demonstrates a high degree of similarity to the reference medicinal product (RMP) at the analytical and functional level, it may be possible to justify the omission of dedicated CES.

Both EMA and FDA have elaborated on how what constituted a “high degree of similarity” based on analytical functional attributes; the pivotal statement should be that the CES being the least sensitive of the current testing regiment, it is of little utility in the evaluation of the safety and efficacy of biosimilar candidates.

Whether and which clinical data will be required may depend on how well the clinical performance of the biosimilar can be predicted from comparative experiments on the analytical/functional level, knowledge regarding the molecule’s mode of action (primary and secondary pharmacology) and also the clinical profile of the RMP, e.g. the potential and impact of immunogenicity. More accurately, the reflection paper will explore how far well-defined analytical/functional (quality) data can be predictive for the clinical outcome.

It is imperative to iterate that a direct correlation with any attribute does not predict clinical performance, it is the disposition profile that determines the pharmacodynamic interaction (whether it is known or not), leading to pharmacological and toxicological response. However, the FDA agrees that pharmacodynamic attributes may not correlate with clinical response. These complexities must be clearly defined in the EMA conclusions.

EMA should acknowledge that the immunogenicity of biosimilars is based on misconceptions; if the primary sequence is the same then the type T-cell response cannot be different. The Type B cell response is significant only if it results in antidrug antibodies that alter the disposition profile readily tested in clinical pharmacology studies.

In consequence, it will be evaluated, whether, or not, findings from a quality comparability exercise, together with clinical pharmacokinetic/pharmacodynamic trials could prospectively lead to the conclusion of clinical similarity, without the need for large CES in patients.

This is the main perception that needs better clarification. More details are provided later in the chapter, but correlating the analytical and functional attributes to predict clinical response is neither logical nor necessary. If these profiles are highly similar, a similar clinical response should be expected since the biological product acts by binding determined by the nature of the protein and its disposition kinetics.

CHMP acknowledges the possibility for further tailoring of the clinical approach for biosimilars and emphasizes the wealth of experience gained from previous marketing authorizations, particularly in quality comparability.

A tailored clinical trial, often a personalized or precision clinical trial, is a type of medical research study designed to test the effectiveness and safety of a treatment or intervention in a specific subgroup of patients with certain characteristics or genetic traits. Unlike traditional clinical trials that typically involve a broad range of participants, tailored clinical trials aim to identify and target specific patient populations more likely to benefit from the treatment. These concepts do not apply to biosimilars whose purpose is to compare, not characterize, a population. Additionally, the focus is on waiving the CES, not modifying their design.

Biosimilar Medicinal Products Working Party (BMWP) will take account of all comments received during the public consultation on the draft Reflection Paper when preparing the final text. It is expected that the final Reflection Paper will come into operation three months after publication following adoption by CHMP.

How does EMA give weight to comments, as many are expected to enforce CES, either based on common perceptions or intended means to delay the approval of biosimilars? It is essential that the EMA made public the identity of the commenters with their affiliations to the public.

The development of the Reflection Paper will involve the EMA-BMWP Secretariat, the Biosimilar Medicines Working Party, the Biologics Working Party, the Methodology Working Party and Scientific Advice Working Party, who would be consulted, as necessary.

Engaging multiple groups for decision-making is generally unnecessary since it should only be based on scientific facts, not on common consensus.

The BMWP will appoint a rapporteur and drafting group.

The rapporteur and the drafting group should ideally be an independent entity.

The Reflection Paper will outline current thinking on the need for CES with a view to improving the efficiency of biosimilars development.

The focus should only be on identifying and removing unnecessary and redundant testing at all stages, mainly where human abuse is involved in testing. It should not be the focus to expedite approval of biosimilars, and the outcome should not be viewed as this intent.


The EMA has taken a significant step in bringing a critical issue to an end. However, the final decisions must rest only on scientific rationale and not on the desire to expedite the approval process; this mandate is necessary to avoid the opposition to waivers of CES. Numerous publications have analyzed this requirement and reported that these studies cannot fail for scientific and statistical reasons, thus categorizing them as inhumane trials.6

It is now well understood, though not established that efficacy testing of biosimilars is a redundant exercise, but gradually, the regulatory agencies are accepting this scientific rationale.7,8

I am encouraging stakeholders to submit their views to the EMA as this comment period remains open till end of April 2024.


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