Rethinking phase III trials in retinal biosimilars: Do we still need them? – Eye
Medicines and Healthcare Products Regulatory Agency (MHRA, UK)
The MHRA has been among the first major regulators to formally challenge the routine requirement for comparative clinical efficacy trials in biosimilar development. In its updated guidance published in 2023, the agency removed the expectation for animal testing and comparative efficacy studies in most cases, emphasising instead robust analytical and functional comparability as the foundation of biosimilar approval [6].
The EMA continues to endorse a totality of evidence approach, with clinical data required when residual uncertainty remains following analytical and nonclinical assessment. However, recent EMA reflection papers and consultations on a tailored clinical approach indicate a gradual shift toward de-emphasising comparative clinical efficacy trials when structural and functional similarity can be convincingly demonstrated through advanced analytics and in vitro studies [7].
In October 2025, the FDA issued updated draft guidance on demonstrating biosimilarity, signalling increased flexibility regarding the need for comparative clinical efficacy studies. The guidance states that such studies may not be required when analytical, in vitro, and pharmacokinetic data sufficiently address residual uncertainty [8]. Additional draft proposals have also suggested eliminating formal clinical switching studies for interchangeability designation, further underscoring a broader move toward reliance on analytical and nonclinical evidence [9].
Despite increasing regulatory openness toward reducing clinical trial requirements, retinal pharmacotherapy presents unique biological and practical considerations. Unlike systemic biologics, intravitreal therapies pose substantial limitations for conventional pharmacokinetic (PK) and pharmacodynamic (PD) evaluation. Robust PK/PD assessment would require repeated vitreous sampling, which is neither feasible nor ethical, and intravitreal administration of anti-VEGF agents in healthy volunteers is similarly unacceptable.
Consequently, PK and PD data for intravitreal anti-VEGF agents are derived indirectly, relying on analytical similarity, functional assays, and limited systemic exposure measurements. Importantly, systemic escape of intravitreally administered anti-VEGF agents is minimal and often approaches the lower limits of quantification, further constraining the interpretability of systemic PK data. In this context, phase III comparative clinical trials offer limited incremental insight into PK/PD uncertainty, raising questions regarding their added scientific value in biosimilar development for retinal diseases.
The extent of clinical data required for biosimilar approval is ultimately determined by regulatory authorities based on residual uncertainty following analytical and nonclinical comparability assessments. In retinal diseases, extrapolation across indications — and, in some cases, interchangeability — has been permitted based on shared mechanisms of action and the absence of indication-specific safety signals with reference products. While analytical technologies have advanced substantially, small and relatively brief phase III trials remain poorly powered to detect rare but clinically significant adverse events such as intraocular inflammation, which typically occur at rates below 1%.
Notably, no biosimilar clinical efficacy study has failed to meet its primary endpoint since the EMA approved the first biosimilar in 2006, largely reflecting limited sample sizes and short follow-up durations. Historically, clinically meaningful safety signals have emerged predominantly through post-marketing surveillance rather than pre-approval trials — a limitation that applies equally to innovator and biosimilar molecules. This was exemplified by retinal vascular occlusion associated with brolucizumab, which was identified following widespread clinical use rather than during pre-approval studies [10].
A similar pattern was observed with the first ranibizumab biosimilar, Razumab (Intas Pharmaceuticals), approved in India in 2015. Inflammatory events were detected post-marketing and were effectively addressed through refinements in the manufacturing process [11]. Since then, the molecule has been used successfully, including in sensitive populations such as premature infants.
These observations raise a fundamental question: is it justified to invest substantial time and resources in brief phase III trials that lack sufficient power to detect rare adverse events and do not meaningfully resolve PK/PD uncertainty? This debate echoes early concerns surrounding generic drugs, where extensive clinical requirements were eventually replaced by molecular characterisation, leading to broader access and significant cost reductions.
Biosimilars will meaningfully improve access and reduce the economic burden of retinal diseases only if their clinical adoption increases substantially. Such adoption, however, is intrinsically linked to the confidence of retina specialists, who ultimately determine real-world utilisation patterns. In this context, strengthening clinician trust — through transparent evidence generation, pharmacovigilance, and, where appropriate, supportive human data — remains central to realising the true access-expanding potential of biosimilars.
For retina specialists, the key question is not whether phase III trials can be removed, but whether sufficient safeguards exist to ensure clinical confidence in their absence.
The future of biosimilar development in retinal diseases will depend on striking a careful balance between scientific rigor, regulatory efficiency, and clinician confidence. While eliminating phase III trials could accelerate access and reduce costs, premature adoption without adequate safeguards risks undermining trust in biosimilars. A tailored, case-by-case approach — grounded in robust analytical data, strengthened pharmacovigilance, and selective clinical validation — may represent the most pragmatic path forward. Ultimately, the success of this paradigm shift will be determined not only by regulatory acceptance but by the confidence of the clinicians who prescribe these therapies.
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