EMA considers dropping efficacy studies for certain biosimilars

EMA released a new concept paper which proposes waiving the clinical efficacy studies if biosimilar candidate demonstrates high similarity to the reference product at analytical and functional level.
The solutions proposed by the EMA are based on extensive experience with approved biosimilars and recent calls from the industry and researchers to remove the requirement for redundant studies.
If introduced, the new regulations would accelerate the development of new biosimilars and facilitate the future access of patients to effective and safe biologics.

Regulatory agencies are slowly acknowledging the redundancy of clinical confirmatory studies (CCSs) in the biosimilar development. EMA has recently published a concept paper, which offers the option to waive the large efficacy trials if only “the biosimilar demonstrates a high degree of similarity to the RMP [Reference Medicinal Product] at the analytical and functional level”. The Agency explained that the legislation change is now feasible thanks to the growing experience with biosimilars and increasing possibilities of analytical characterization. The concept paper is open for public consultation until April 2024. The next reflection paper explaining how the well-defined analytical/functional (quality) data can be predictive for the clinical outcome will soon be published.

The new concept paper follows the recent MHRA’s decision to drop the requirement for confirmatory clinical studies of biosimilars as well as numerous scientific publications questioning the usefulness of efficacy data for biosimilar approval. One of the publications on this topic, written by Sarfaraz Niazi, an expert in biopharmaceutical manufacturing, concluded that “a clear change in the regulatory guidelines is required to change the mindset of all biosimilar stakeholders to bring a pivotal change in the availability of affordable biosimilars”. Criticizing the current thinking on biosimilar development, he pointed to the low sensitivity of clinical trials to pick up the potential differences between the biosimilar and reference product (in contrast to highly specific and sensitive analytical studies). Another paper, authored by the representatives of multiple regulatory agencies across the EU (including EMA itself), noted that in 67% of the cases the outcomes of the quality and clinical assessment were the same, that is they either supported or not supported the biosimilar approval. Importantly, they found no instance in which negative clinical data led to a negative overall decision. According to MHRA and majority of researchers, analytical similarity and clinical PK data is all that is needed for biosimilar approval.

The recent turnaround in regulatory approach is highly welcomed by the bio-tech industry, which for many years has been calling to withdraw the obligation for efficacy studies for new biosimilars. Currently, the companies are required to submit the full data package from large clinical trials spanning the PK, PD, efficacy and safety outcomes. However, experts claim that with modern technologies the extensive analytical characterization along with a relatively small PK/PD study should be sufficient to support the application, especially for molecules with straightforward mechanism of action. Of course, regulatory agencies look at the totality of evidence and if the CMC data leave a room for uncertainty regarding the product’s similarity, efficacy trials may still be required for licensure.

Typical efficacy trials last for more than 2 years and consume substantial funds, increasing the time to approval and harming smaller competitors. Waiver for such studies would certainly accelerate the development of new biosimilars and increase the market competition, making these products more affordable for the patient. Therefore, the new regulations would likely result in increased access to life-saving therapies across the EU.

Prepared by:

Adam Tuszyner

References

Eglovitch, Joanne S. “EMA proposes waiving comparative clinical studies for certain biosimilars.” RAPS Regulatory News (February 2, 2024). Link: https://www.raps.org/news-and-articles/news-articles/2024/2/ema-proposes-waiving-comparative-efficacy-studies.
European Medicines Agency (EMA) “Concept paper for the development of a Reflection Paper on a tailored clinical approach in Biosimilar development.” November 24, 2023. Link: https://www.ema.europa.eu/en/documents/other/concept-paper-development-reflection-paper-tailored-clinical-approach-biosimilar-development_en.pdf.
Eversana “MHRA Nixes Confirmatory Clinical Trial Requirement for Biosimilars.” June 16, 2021. Link: https://www.eversana.com/2021/06/16/mhra-nixes-confirmatory-clinical-trial-requirement-for-biosimilars/.
Niazi, Sarfaraz. “Scientific rationale for waiving clinical efficacy testing of biosimilars.” Drug Design, Development and Therapy (2023): 2803-2815445.
Kirsch-Stefan, Nadine, et al. “Do the outcomes of clinical efficacy trials matter in regulatory decision-making for biosimilars?.” BioDrugs 37.6 (2023): 855-871.