EMA Mulls Dropping Comparative Efficacy Trials For Biosimilars

Are comparative efficacy studies always necessary to support biosimilar applications? That is the question now being pondered by the European Medicines Agency, as part of a consultation process that could end up being highly significant for the biosimilars industry.

Developers have for a long time urged a more streamlined pathway for biosimilars, arguing that comparative efficacy studies are not always necessary given the strength and understanding of the underlying science and the increasing sophistication of analytical methods, and can even be considered unethical. Moreover, these studies push up development costs, meaning that certain lower-value brand biologic targets become economically unviable for a biosimilar challenger when extensive trials are required.

And now, in a concept paper that has just been released by the EMA – in which the agency acknowledges upfront the significance of biosimilar competition in improving patient access to essential treatments – the regulator has conceded that there is a need to re-evaluate the need for comparative efficacy studies, which the EMA says “is increasingly questioned in general.”

“Currently, the required comparability exercise comprised quality data (analytical comparability exercise), in vitro and in vivo non-clinical data, and comparative pharmacokinetic, pharmacodynamic, safety and efficacy studies,” the EMA notes.

“However, considering the advances in the analytical sciences and the extensive regulatory experience gained, in vivo non-clinical data and, at least for some less complex biologicals with a straightforward mechanism of action, the importance of dedicated clinical efficacy and safety data should be re-evaluated.”

Any final action from the EMA will be more than a year away. The concept paper is being released for a three-month consultation period running to 30 April, with the agency’s Biosimilar Medicinal Products Working Party pledging to “take account of all comments received during the public consultation on the concept paper when preparing the draft guideline.” This subsequent draft reflection paper will then be published for a further six-month public consultation period, after which “BMWP will take account of all comments received during the public consultation on the draft reflection paper when preparing the final text.”

The EMA expects the final reflection paper to come into operation three months after publication following adoption by the agency’s Committee for Medicinal Products for Human Use.

Building On EMA Experience

Noting that biosimilars range “from relatively simple to more complex molecules,” the EMA notes in the concept paper that the CHMP “has accumulated substantial experience in assessing biosimilars with high complexity such as monoclonal antibodies (mAbs), resulting in a robust regulatory framework that ensures product efficacy and patient safety.” 

“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,” the paper says. “By building upon this extensive knowledge, CHMP aims to further optimize the development and evaluation process for biosimilars.”

The regulatory framework has been “constantly been evolving towards increasingly tailored developments,” in pursuit of “scientifically sound yet efficient processes,” the EMA notes, going all the way back to “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.”

“With growing knowledge and the increasing possibilities of analytical and functional characterization,” the EMA summarizes, “revisiting the need for clinical efficacy trials for biosimilars (especially recombinant proteins and mAbs) 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.”

“CHMP has gained extensive insight into assessing the quality attributes of biosimilars through the evaluation of critical quality attributes, manufacturing processes, and comparability exercises.”

The current “stringent requirements and guidance that ensure the quality of biosimilars, including biosimilar mAbs,” have been developed as the CHMP has “gained extensive insight into assessing the quality attributes of biosimilars through the evaluation of critical quality attributes, manufacturing processes, and comparability exercises,” the EMA says, with the agency having “closely examined physicochemical and functional characteristics,” as well as “overall similarity” to the reference product.

As a result, the agency explains, “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, at the analytical and functional level, it may be possible to justify the omission of dedicated comparative efficacy studies.” This approach “aims to streamline the development and evaluation process while maintaining the highest standards of safety and efficacy,” the agency underlines.

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,” the EMA suggests.

In the upcoming reflection paper, the EMA will aim to “discuss CHMP’s perspective on the development and evaluation of biosimilars, taking into account the wealth of experience gained from previous marketing authorizations, particularly in relation to analytical/functional comparability exercises.”

“More accurately,” the agency says, “the reflection paper will explore how far well-defined analytical/functional (quality) data can be predictive for the clinical outcome. In consequence, it will be evaluated, whether, or not, findings from a quality comparability exercise, together with clinical PK/PD trials could prospectively lead to the conclusion of clinical similarity, without the need for large comparative efficacy studies in patients.”

Follows Progress Made In Recent Years

The latest development comes after a series of favorable moves for biosimilars in recent years. In 2022, a statement from the EMA and Heads of Medicines Agencies on the scientific rationale supporting the interchangeability of biosimilar medicines in the EU brought “unity and clarity” to the sector, according to local off-patent industry association Medicines for Europe. (Also see "EMA-HMA Biosimilar Interchangeability Statement Offers ‘Unity And Clarity’ For Europe" - Generics Bulletin, 11 Oct, 2022.) 

And for some time, there has been open discussion among industry and regulators alike around streamlining the European regulatory pathway for biosimilars, eliminating the requirement for confirmatory efficacy trials (see sidebar).

Speaking to Generics Bulletin in a recent interview, Medicines for Europe director general Adrian van den Hoven said that moves to eliminate the need for confirmatory efficacy trials were “based on the science; the scientific evidence is clearly there that we can go in this direction.”

This was “really, really important,” he said, because “around 50% of the biologics going off-patent and losing exclusivity do not have a biosimilar targeting them.”

These were “not just niche orphan biologics,” van den Hoven pointed out. “There are a lot of volume biologics in there. But it’s just not making sense from an overall development cost perspective or the complexity of the development to do this.”

Therefore, streamlining registration requirements was “really something that’s essential” to see greater competition on these products. (Also see "The Path Ahead: Medicines For Europe Head Highlights Opportunities And Risks" - Generics Bulletin, 3 Jan, 2024.)

More widely, it was also important to align global regulatory approaches to biosimilars, he suggested. “I think we still have work to do of alignment between the big regulators: the EMA, the US Food and Drug Administration, Health Canada, etc.,” he observed. “Because even though the reference product issue is more or less solved, we’re still seeing issues with major divergences of scientific advice and things like that. And that makes it excruciating for the companies – because you have to then, in a way, double your development costs, for the clinical side of things. So that’s still a problem.”

Medicines for Europe has long pointed to the need for biosimilar regulation to move ahead in a joined-up global manner, with Julie Maréchal-Jamil – director of biosimilars policy and science at Medicines for Europe – telling Generics Bulletin in a late-2022 interview that “there’s now consensus around the science, there’s consensus around the experience, and the possibility to move the needle,” but that “to operationalize this and make an impact for patient access to biologics, we need a global implementation roadmap.” (Also see "Momentum Builds In Europe To Push Biosimilars Forwards" - Generics Bulletin, 26 Oct, 2022.)

“Without this evolution, or if it takes 10 years and multiple divergent requirements for major regulatory jurisdictions to move in that direction, or make it a principle… then operators in the system – biosimilar developers – will face massive complexity, even more than today, defeating the promise of faster development, of possible, or broader access to more regions earlier.”

“All that is hanging on: are we able to coordinate implementation?”

In the aftermath of Brexit, the UK has already pushed forward with its own biosimilars pathway that will typically not require comparative efficacy data. (Also see "UK Lays Out Reduced-Data Pathway For Biosimilars" - Generics Bulletin, 9 Oct, 2020.) (Also see "UK Could Become ‘World Leader’ On Biosimilar Regulation" - Generics Bulletin, 29 Apr, 2021.)

Meanwhile, the World Health Organization’s biosimilars guideline that was revised in April 2022 states that “an adequately powered comparative efficacy and safety trial will not be necessary if sufficient evidence of biosimilarity can be drawn from other parts of the comparability exercise.” (Also see "Clinical Efficacy And Safety Studies 'Redundant' For Most Biosimilars" - Generics Bulletin, 7 Sep, 2022.)

“Current examples of biological products that can be comprehensively characterized and have a well-established mechanism of action include (but are not limited to) teriparatide, insulin, G-CSF and somatropin,” the WHO guideline says. “The current data suggest that more-complex products such as mAbs can be sufficiently characterized by available suitable analytical methods, plus the structure–function relationships are well known and can be studied by sensitive orthogonal functional assays.”