The evaluation of analytical similarity has been a challenging issue for the biosimilar industry because the number of lots for reference and biosimilar products available at the time of development are limited, whilst measurable quality attributes of target molecule are numerous, which can lead to potential bias or false negative/positive conclusions regarding biosimilarity. Therefore, appropriate statistical analyses are highly desirable to achieve a high level of confidence in the similarity evaluation. A recent guideline for the risk-based statistical approaches recommended by the US Food and Drug Administration provides useful tools to systematically evaluate analytical similarity of biosimilar products compared with reference products. Here, we evaluated analytical similarity of CT-P6, a biosimilar product of trastuzumab, with the reference products (EU-Herceptin® or US-Herceptin®) following these statistical approaches. Various quality attributes of trastuzumab were first ranked based on the clinical impact of each attribute and subsequently adjusted to one of three tiers (Tier 1, Tier 2 and Tier 3) considering the characteristics of the assay, the level of attribute present and the feasibility of statistical analysis. Two biological activities with highest potential clinical impact were evaluated by an equivalent test (Tier 1), and other bioactivities and structural/physicochemical properties relevant to the clinical impact were evaluated by a quality range approach (Tier 2). The attributes with low risk ranking or qualitative assay were evaluated by visual comparison (Tier 3). Analytical similarity assessment analyzed by the three tiers clearly demonstrated that CT-P6 exhibits highly similar structural and physicochemical properties, as well as functional activities, compared with the reference products. There were small differences observed in a few quality attributes between CT-P6 and the reference products, but the differences were very minor, and unlikely to impact on clinical outcome. The recently reported equivalent clinical efficacy of CT-P6 with the reference product further supports that CT-P6 is highly similar compared with the reference product in the view of totality-of-evidence.

分析相似性的评估对于生物仿制药行业而言是一个具有挑战性的问题，因为在开发时可供参考和生物仿制药的批次数量有限，而目标分子的可测量质量属性众多，这可能导致潜在的偏差或有关生物相似性的假阴性/阳性结论。因此，非常需要适当的统计分析以在相似性评估中获得较高的置信度。美国食品药品监督管理局（US Food and Drug Administration）推荐的基于风险的统计方法的最新指南提供了有用的工具，可以系统地评估与参考产品相比生物仿制药的分析相似性。在这里，我们评估了曲妥珠单抗的生物仿制药CT-P6的分析相似性，按照这些统计方法使用参考产品（EU-Herceptin®或US-Herceptin®）。首先根据每种属性的临床影响对曲妥珠单抗的各种质量属性进行排名，然后考虑到分析的特性，存在的属性水平和可行性，将其调整为三个等级（第1层，第2层和第3层）之一。统计分析。通过等效测试（方法1）评估了具有最高潜在临床影响的两种生物活性，并通过质量范围方法（方法2）评估了与临床影响相关的其他生物活性和结构/理化性质。具有低风险等级或定性分析的属性通过视觉比较进行评估（方法3）。通过三个层次的分析相似性评估清楚地表明，与参考产品相比，CT-P6表现出高度相似的结构和物理化学性质以及功能活性。在CT-P6和参考产品之间，在一些质量属性上观察到很小的差异，但是差异很小，并且不太可能影响临床结果。最近报道的CT-P6与参考产品的等效临床功效进一步支持了CT-P6与参考产品相比在总体证据方面的高度相似。在CT-P6和参考产品之间，在一些质量属性上观察到很小的差异，但是差异很小，并且不太可能影响临床结果。最近报道的CT-P6与参考产品的等效临床功效进一步支持了CT-P6与参考产品相比在总体证据方面高度相似的观点。在CT-P6和参考产品之间，在一些质量属性上观察到很小的差异，但是差异很小，并且不太可能影响临床结果。最近报道的CT-P6与参考产品的等效临床功效进一步支持了CT-P6与参考产品相比在总体证据方面高度相似的观点。