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Info Service on Health Issues (Apr25/05) New Delhi, 10 April (Chetali Rao): The European Medicines Agency (EMA) proposes to waive clinical efficacy studies (CES) for the marketing approval of biosimilars in most cases. This proposal is contained in the draft reflection paper (Reflection Paper), which outlines a science-driven approach where biosimilars can be authorised based on analytical comparability, in vitro pharmacology and pharmacokinetic data (PK) without comparative clinical trials. It is open for stakeholder feedback until 30 September 2025. The Reflection Paper states that “A 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” (Reference Medical Product). The Reflection Paper clearly prioritizes structural, functional, and PK comparability data over extensive CES when scientific evidence strongly supports biosimilarity. It concludes that “biosimilars may be approved without providing CES or even PD (pharmacodynamic) data if similar clinical efficacy and safety pharmacology can be inferred from a sufficiently stringent evaluation of analytical comparability, in vitro pharmacology, and a comparative clinical PK trial“. Current biosimilar regulatory frameworks in the European Union and numerous other jurisdictions mandate CES as a prerequisite for biosimilar approval. The proposal in the Reflection Paper has the potential to reduce the entry barriers of biosimilar by doing away with CES as a mandatory condition for the approval of every biosimilar. This approach would lower development expenses while accelerating the timeline for biosimilar production. It has been highlighted that CES accounts for nearly half of the biosimilar development cost. As a result the entry of biosimilars has not witnessed substantive price reductions as compared to their generic counterparts. Prices of generics can be 50-80% and even 90% lower that the originator product, largely due to limited clinical efficacy and safety testing required for regulatory approval. By comparison biosimilars are priced at 20-35% below their originator biologics, reflecting the substantial investments needed to demonstrate biosimilarity through rigorous analytical, preclinical, and finally clinical efficacy studies. [Both biosimilars and generics offer cost-effective alternatives to originator drugs, but they differ significantly in the nature of their source compounds, manufacturing processes and regulatory requirements. Generics are chemically synthesized, exact copies of small-molecule drugs, and are identical to their brand-name counterparts in terms of active ingredients, dosage, and bioequivalence. Generics rely on bioequivalence studies rather than extensive clinical trials for approval. In contrast, biosimilars are highly similar (but not identical) versions of biologic drugs – which are large, complex molecules derived from living systems (yeast, bacteria). Biosimilars require more rigorous testing, including comparative clinical studies, in demonstrating high similarity and no clinically meaningful differences in safety, efficacy, and immunogenicity to the reference biologic. This makes biosimilar development a complex, costly and time intensive process than that of generics, though both aim to increase access to treatments after the originator patent expires.] Scientific Foundation Forms the Basis of Biosimilar Development The EMA proposal is based on the premise that for a biosimilar “structure determines the function”. It reaffirms the principle that biological activity, in terms of safety and efficacy, stems from a drug’s molecular structure and its interaction with receptors. If two biologics are highly similar structurally, they will have similar functional identity i.e. they will bind to the same receptors in the same manner, resulting in identical pharmacological properties and clinical efficacy. The Reflection Paper remarks: “…in general, analytical tools are considered sensitive enough to detect differences between a biosimilar and its reference medicinal product, and CES may not add essential scientific knowledge in the decision for biosimilar approval”. Advancement in analytical technologies allows precise characterization of biosimilars, reducing reliance on CES. Current analytics suggest that CES may lack the sensitivity required to clarify key uncertainties for certain products. While clinical trials can demonstrate a product’s efficacy, they often lack the precision to discern minor differences in outcomes. The Reflection Paper clearly stresses that quality, safety, and efficacy must remain uncompromised as regulatory pathways evolve to reduce unnecessary steps. Moreover, after decades of approvals of biosimilars it has become evident that clinical studies have not added any meaningful additional information to the biosimilarity exercise. Further, the market is increasingly shifting toward biologic drugs targeting niche indications such as those for rare diseases or being employed in progressively intricate add-on therapy regimens. This trend complicates the feasibility of conducting conventional clinical trials to be considered as meaningful comparative trials. Agencies in developed countries like EMA, are embracing a paradigm shift that moves away from unnecessary CES in favour of strong physicochemical and functional characterization, which also reflects a growing confidence in advanced analytical techniques to demonstrate biosimilarity. The Reflection Paper pushes for maintaining rigorous safety standards while reducing redundant testing, potentially expediting patient access and lowering development costs. With 20 years of experience in marketing approval of biosimilars and no adverse effects, it is an opportune time to adopt a change in the biosimilar regulatory approval. Also, there is a need to critically think about the cost of biosimilar development. A recent IQVIA report highlighted that nearly 118 biologics are expected to lose patent protection and 90% do not have any biosimilar in development. Thus, despite a number of biologics with impending patent expiry, biosimilar development for these biologics remains disproportionately low. This raises grave concerns about the potential of biosimilar development even after there are no patent barriers for the biologics concerned. Biologics represent one of the most expensive categories of medicines and biosimilars offer a critical pathway to improving access and affordability. For the system to work efficiently and at the same time serve the public health interest, it is important that we must focus on streamlining regulatory requirements – avoiding redundant or “commonly” used CES – and create an environment which enables timely and competitive entry of biosimilars into the market. The EMA’s draft Reflection Paper, outlines a forward looking approval pathway that minimizes dependence on CES. The agency has laid down a structured pathway for biosimilar authorization, emphasizing that CES may no longer be mandatory. This aligns with the regulatory guidelines set forth by the United Kingdom’s Medicines and Healthcare products Regulatory Agency and the World Health Organization, which prioritise robust comparability data over redundant clinical trials. The EMA proposal after its finalisation is expected to serve as a blueprint for regulatory bodies in many developing countries. It is time that developing countries transition now to evidence-based approaches to implement contemporary biosimilar regulations, replacing the outdated and ethically questionable current regulatory requirements.+
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