Cochrane Corner: Anti-vascular endothelial growth factor biosimilar for macular degeneration

Background

Neovascular age-related macular degeneration (nAMD) is the advanced form of AMD, affecting 20% of patients but causing irreversible vision loss in more than 80% of AMD patients [1, 2]. Intravitreal anti-vascular endothelial growth factor (anti-VEGF) agents have been shown to successfully preserve or improve visual acuity for at least one year [3]. However, uncertainty in the injection frequency and the overall treatment duration beyond 12–24 months has imposed tremendous time and financial burden to patients and their families due to the need for continual monitoring and follow-up visits [4].

Biosimilars are biological products that have chemical structure and biological function comparable to previously patented anti-VEGF agents (the reference drug) [5]. Due to their much-reduced prices, biosimilars provide a greater accessibility than the reference drug to patients with nAMD, especially in the middle- and low-income countries [6]. Biosimilar development relies on a comprehensive head-to-head comparison of the biosimilar and the reference drug. The European Medicine Agency (EMA) conceives comparability as a stepwise process that is tailor-made for each product, with the aim of ruling out differences in clinical efficacy or safety between the biosimilar and the reference drug. The US Food and Drug Administration (FDA) approves biosimilars through an abbreviated pathway [7]. FDA may also approve a biosimilar for an indication (or a specific population) without requiring direct evidence from new trials when safety and efficacy have been confirmed for the original indication. Moreover, switching studies are typically conducted to achieve interchangeability with the original reference drug [8]. Despite these rigorous requirements by regulatory agencies [9–11], physicians and patients still have concerns about the clinical equivalence of biosimilars to the reference drug. Increased risks of intraocular infection and inflammation are particularly concerning [12].

A recently published Cochrane review by Sunaga et al. has provided up-to-date evidence on the clinical comparability of biosimilars to their reference drugs [13]. Based on findings from nine randomized controlled trials (RCT) (3814 participants, one eye per participant) comparing biosimilars to ranibizumab (once every month, seven trials) or aflibercept (once every eight weeks, two trials), the review concluded that anti-VEGF biosimilars led to little or no differences in best-corrected visual acuity (BCVA) changes from baseline to week 8–12 (7 trials, 3292 participants; moderate certainty evidence). There was no evidence of differences in proportions of participants who lost fewer than 15 letters in BCVA at week 24 to 48 either (8 trials, 3231 participants; high certainty); vision-related quality of life (very low certainty). Meanwhile, the review did not find evidence of differences in pre-defined safety outcomes—serious ocular adverse events (moderate certainty) and treatment-emergent adverse events (high certainty) during the trial period (range 12 weeks to 48 weeks). Evidence on other outcomes, such as visual acuity in Snellen equivalent of 20/40 or better (at 24–48 weeks), changes in central subfield thickness (from baseline to week 4 to 12), or incidence of anti-drug antibody, was of low certainty because of inconsistencies or imprecision.

While the included trials involved participants aged 50 years and older (range of mean 67 to 76) and of diverse geographical representation (American, European, and Asian countries), none of the included trials enrolled the very old participants (aged 80 years or older) of whom early population studies estimated that one third have early signs of nAMD [14]. Co-morbidities, reduced mobility and thus increased dependence on others, and low expectation for treatment are well-known risk factors for treatment inconsistency or nonadherence in this age group [15]. Therefore, the pooled treatment efficacy may not be directly applicable to this older subpopulation.

The market availability of biosimilars also lags the reference drug for at least 12 years due to patent exclusivity. Current review findings are only relevant to biosimilars of the earlier anti-VEGF agents indicated for nAMD (ranibizumab and aflibercept). Another 19 ongoing trials (or completed trials yet without available trial results), also investigate biosimilars of these two anti-VEGF agents. Whether the increasing number of expired reference drugs over time will further decrease the overall treatment cost, improve patients’ access to anti-VEGF agents, and preserve vision (or postpone its loss), warrants continual evaluation.

Because of the relatively short trial duration, current evidence on the efficacy and safety of biosimilars is only applicable to 48–52 weeks of treatment. Future trials to evaluate biosimilars should consider extending the follow-up period to a minimum of two or three years to facilitate a broader acceptance of biosimilars. Specifically, the review authors showed low confidence in evidence on rare safety outcomes (e.g., emergence of anti-drug antibody) because of the limited person-time under observation (small sample size or short trial duration or both).

The review has highlighted several evidence gaps in the literature, with the lack of longer-term data as a major one. Around 15% of those who do respond initially would progress (or recur) after 2 years, which has been attributed by observational studies to under-treatment [16]. With carefully examined assumptions, using observational data to emulate an equivalent RCT (“the target trial”) can provide valid estimates of comparative effectiveness and safety of several treatment strategies for nAMD when conducting the target trial is costly, time-consuming, or unethical [17]. Regulatory agencies, such as FDA of the US, have also promoted the development of rigorous methods and novel tools to best utilize existing patient cohort data by supporting several demonstration research projects [18]. For example, leveraging electronic health records or patient registry data, has been shown to generate real-world evidence to gain new insights on treatment decisions for patients with nAMD [19, 20]. Although results of target trial emulation may not always agree with those of RCTs, accumulating real-world evidence from observational studies can contribute to the evidence base to accelerate either new drug approval or off-label use of existing drugs for treating nAMD.

Author contributions

Both authors contributed to the article concept, manuscript preparation, and revision.

Funding

SL reported a grant UG1EY020522 from the National Eye Institute, National Institutes of Health, USA; payment to institution. GV reported none.

Competing interests

The authors declare no competing interests.