EMA biosimilars policy shifts over clinical efficacy studies

Tracey Roberts, Catherine Drew and Carly van der Beek of Pinsent Masons were commenting after the European Medicines Agency (EMA) acknowledged that manufacturers of biosimilars can satisfy conditions for obtaining marketing authorisation for their products without having to undertake clinical efficacy studies (CES).

“A tailored approach for clinical development of biosimilar candidates can be envisioned,” the EMA said in a draft reflection paper opened to consultation on Tuesday.

“In certain cases, CES may no longer be required for approval of biosimilars that can be thoroughly characterised and have shown high similarity on an analytical and in vitro pharmacology level. Comparative clinical pharmacokinetic studies are still essential elements in biosimilar development but some adjustments to the data requirements, such as inclusion of immunogenicity parameters and/or modifying the study design (e.g., one-dose vs multiple-dose), could be considered,” it added.

Out-Law reported last November that the EMA planned to consult on changes to its policy on CES.

Biosimilars provide competition to originator biologics, often spurring innovation in the market from biologics and biosimilars manufacturers alike – such as new clinical indications for existing products or improved delivery mechanisms. However, developing biosimilars and taking them through the regulatory process is expensive and there are further hurdles to clear in successfully bringing biosimilars to market when originator biologics lose their market exclusivity.

Biologics contain active substances derived from biological sources, such as mammalian cells, and are often large, complex molecules with an inherent small degree of heterogeneity. This means that, unlike small molecule generic medicines where the active ingredient is chemically identical to the originator drug, biosimilars, while highly similar to the originator biologics they are developed with reference to, are never completely identical.

To satisfy conditions for obtaining marketing authorisation, biosimilars have to evidence ‘biosimilarity’ with the originator product already on the market. Currently, the EMA requires biosimilar manufacturers to carry out comprehensive scientific CES to achieve this in the majority of cases. This entails conducting expensive and time-consuming clinical trials with patients.

Drew said: “The EMA’s existing overarching guideline on biosimilars envisaged that in certain circumstances a confirmatory clinical trial may not be necessary in the biosimilarity data package. The EMA draft reflection paper appears intended to expand the circumstances in which the CES can be waived and set out more specific granular guidance on the circumstances in which that would be appropriate.”

Roberts said: “CES are there to confirm clinical equivalence of the potential biosimilar and reference product i.e. for detecting any potential product-related differences in the clinical treatment of patients. These studies also include a detailed analysis of safety including an evaluation of immunogenicity. However, these trials are expensive, time-consuming and require administration of the biosimilar to patient populations. This can create a barrier to biosimilar manufacturers making out a business case to pursue a product.”

“There has long been scientific analysis demonstrating that CES are unnecessary,” she added. “A new analysis from the IQVIA Institute in the US has revealed a massive biosimilar void: 90% of biologic drugs losing patent exclusivity over the next 10 years have no biosimilar competition in the pipeline. A similar analysis in Europe shows this void also exists. This regulatory change could make the case for more biosimilar entrants onto the European market for biosimilars that, to date, have not been pursued by biosimilar manufacturers due to costs of these trials.”

The EMA’s current policy has been out-of-step with equivalent policy operated by the Medicines and Healthcare Regulatory Authority (MHRA) since the UK regulator updated guidance in 2021. The MHRA’s guidance provides that CES may not be necessary in most cases if sound scientific rationale supports this approach. That move allows biosimilar manufacturers to rely more heavily on comparative analytical and functional data as well as what is known from clinical experience and quality attributes of the originator biologics product, to meet their regulatory requirements.

Now, however, the EMA has used its draft reflection paper to clarify how it will consider biosimilarity requirements to be evidenced without CES being undertaken. The paper is open to stakeholder comments until 30 September 2025.

Roberts said: “The MHRA removed the CES requirement in an attempt to make the UK a more attractive country to launch biosimilar products post-Brexit, and it was hoped that other regulators would follow suit. Since most manufacturers will seek to launch products across Europe, there has not been significant uptake of this change in the UK. The new paper shows the EMA is heading in the same direction and could have a more seismic change for the industry.”

Van der Beek of Pinsent Masons in Amsterdam, where the EMA is headquartered, said the planned shift in policy the EMA is consulting on could support the development of so-called ‘orphan medicines’, which target rare diseases and benefit from enhanced regulatory exclusivity. An IQVIA Institute report published in 2020 found that only about 12% of the 42 biologic products designated as orphan medicines at the time were likely to have a commercial market size across Europe in excess of €100 million per year, which it said is “limiting commercial opportunity for biosimilars in this space”.

“By reducing unnecessary clinical efficacy studies, the EMA’s approach could accelerate the development of biosimilar orphan medicines, improving access to and affordability of life-saving treatments for patients with rare conditions,” she said.

Under the new proposal, the EMA would require an assessment of a biosimilar’s quality attributes (QAs), providing detailed information on structure and functional properties essential for demonstrating similarity between biosimilar candidate and reference medicinal product (RMP). Pharmacokinetic (PK) studies would still be required in healthy volunteers to show that the product is processed in the same way in the human body. PK studies would also be used to test immunogenicity, under the revised policy.

Roberts said: “The reason this alternative approach can be used instead is because the mechanism of action of these molecules is known and is structure-based – due to their interaction with specific targets in the body. So, provided that the biosimilar is shown to be sufficiently similar in structure then its structure determines its function – i.e. same structure equals same biological activity. This can be tested in a variety of ways – characterisation of the structure using analytical techniques and functional assays such as in vitro tests for potency, receptor binding assays. These tests must show no meaningful differences.”

According to the EMA, there are some “prerequisites” for biosimilars to demonstrate comparability with reference products without the need for CES. These include that “comprehensive knowledge” regarding the molecule’s mechanism of action is available; that detailed characterisation of the structure and functionally relevant QAs is possible using orthogonal and state-of-the-art analytical methods; functional assays are available, both to assess comparability of functional properties directly, and indirectly as surrogates for higher-order structure of the molecule. Manufacturers also require a pre-established similarity assessment protocol and a “validated manufacturing process and control strategy” that can assure the EMA that the batches made will be consistent.

“These prerequisites will support that an analytical comparability exercise, expanded with in vitro pharmacology data, and data from human PK studies, as appropriate, is able to assure similarity of the biosimilar to its RMP,” the EMA said. “This similarity implies that there are no meaningful differences in structure and other QAs, that interactions with relevant receptors/targets are comparable, and therefore that comparable efficacy and safety can be inferred.”

Roberts said: “In its paper, the EMA notes that significant changes to manufacturing processes of biological medicines like monoclonal antibodies have been approved by confirmation of structural and functional comparability without the need for new clinical data – even where the master batch has changed. This is effectively the same as making a new biosimilar product, so there is previous support for the type of policy change the EMA is proposing within the current regulatory system.”

Once the consultation period ends, the EMA’s Biosimilar Medicinal Products Working Party will take account of all comments received and prepare a finalised reflections paper. That paper is then expected to come into operation three months after publication, following adoption by the EMA’s Committee for Medicinal Products for Human Use.

According to the EMA, reflection papers can be used to facilitate discussion or provide clarification, “particularly in areas where scientific knowledge is fast evolving or experience is limited”, and, while the information in them does not constitute regulatory guidance, they can be a vehicle for the EMA to “communicate the current status of discussions or to invite comment on a selected area of medicinal product development or a specific topic”.