生物相似產品交替性之統計評估

Abstract

隨著生物製劑的專利期即將到期，生物相似性產品的發展愈來愈受到重視。生物相似性藥品的製程與傳統小分子藥物 (學名藥) 非常不同，因其製程、分子結構複雜且可能有嚴重的免疫反應。 目前已有一些標準可用以評估生物相似性藥品與對照生物製劑之間的相似性，其中一個重要的標準是生物相似性藥品與其對照的生物製劑必須符合可互換性。以生物相似性藥品替代原參考之生物製劑後，不須經過醫療人員的特別介入。可互換性的概念為受試者服用原廠生物製劑(R)轉換為生物相似性藥品(T)再轉換為原廠生物製劑(R)，或是由生物相似性藥品(T)轉換為原廠生物製劑(R)再轉換為生物相似性藥品(R)。因此，由T轉換為R或由R轉換為T的差異是我們在評估可互換性時需要考量的條件。而這樣的概念與側面圖分析(profile analysis)相似。我們提出一個多變量相等性檢定的方法，利用兩序列、三個時期 (2 3) 交叉設計評估可互換性。我們利用模擬研究驗證此方法的樣本數及檢定力，而實際的例子也在本論文中呈現。並提出在2 3交叉設計下評估可互換性所需樣本數的方法。

As more biological products are going off patent protection, the development of biosimilar products has received much attention. Unlike traditional small-molecule chemical drug products, which called generic drug, the development of biologic products is very different from the small-molecule drug products due to the complexity of the molecular structure, complicated manufacturing process and severe immunogenicity reactions. Several criteria are proposed to evaluate the similarity between the biosimilar product and its reference product. One of these criteria is the alternating ability. Alternative ability means that the biosimilar product may be substituted for the reference product without the intervention of the health care provider who prescribed the reference product. The concept of alternating is referred to as either the switch from test product (T) to its corresponding reference drug (R) and then switch back to T or the switch from R to T and then switch back to R. Thus, the difference between “the switch from T to R” or “the switch from R to T” and “the switch from R to T” or “the switch from T to R” needs to be assessed for addressing the concept of alternating. The concept of alternating ability was formulated as the hypotheses for profile analysis. Then we proposed a multivariate equivalence testing procedure under two sequences and three periods (2 3) crossover design to assess the alternating ability. Simulation studies were conducted to evaluate performance of the proposed procedure in terms of size and power. Numerical example illustrates the proposed procedure. Methods of sample size determination for evaluation of alternating ability under 2 3 crossover design were also proposed.