巴西品牌华法林与仿制药华法林的治疗等效性研究：WARFA 交叉随机对照试验

Examining therapeutic equivalence between branded and generic warfarin in Brazil: The WARFA crossover randomized controlled trial.

机构信息

Department of Medicine, Escola Paulista de Medicina, Universidade Federal de São Paulo (UNIFESP), São Paulo, SP, Brazil.

Departments of Medicine (Nephrology) and Health Research Methods, Evidence and Impact, McMaster University, Hamilton, ON, Canada.

出版信息

PLoS One. 2021 Apr 1;16(4):e0248567. doi: 10.1371/journal.pone.0248567. eCollection 2021.

DOI:10.1371/journal.pone.0248567

PMID:33793580

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8016229/

Abstract

OBJECTIVES

To determine whether the generic and branded warfarins used as anticoagulants in Brazil are therapeutic equivalents based on their international normalized ratio (INR) results.

METHODS

This crossover randomized controlled trial had four periods. We used the branded Marevan and two generic versions of warfarin sodium tablets, manufactured by União Química and Teuto laboratories, all purchased from retail drugstores. Eligible participants were outpatients from an anticoagulation clinic at a university hospital in São Paulo, Brazil. They had atrial fibrillation or flutter and had been using warfarin for at least 2 months with an INR therapeutic range of 2.0-3.0. Randomization was by numbered, opaque, sealed envelopes. Healthcare personnel and outcome assessors were blinded to treatments, but patients were not. The primary outcome was the variability in the INR (ΔINR) and secondary outcomes included mean INR. We accepted formulations as equivalent if the 95% confidence interval (CI) of the comparison of ΔINR between branded and generic formulations was within the limit of ±0.49.

RESULTS

One hundred patients were recruited and randomized to six sequences of treatment (four sequences with n = 17 and two sequences with n = 16). União Química generic warfarin had equivalent variability in the INR to Marevan (ΔINR +0.09 [95% CI -0.29 to +0.46], n = 84). Comparison between Teuto generic warfarin and Marevan was inconclusive (ΔINR +0.29 [95% CI -0.09 to +0.68], n = 84).

CONCLUSIONS

Marevan and União Química warfarin had equivalent therapeutic effectiveness and both could be confidently used for anticoagulation. The comparison between Marevan and TW was inconclusive and does not warrant a statement of equivalence. Our methods are especially important for comparing generic and branded drugs that raise concerns and may be subject of future investigations by regulatory agents.

TRIAL REGISTRATION

ClinicalTrials.gov NCT02017197.

摘要

目的

评估巴西临床使用的华法林仿制药与原研药是否具有治疗等效性，基于其国际标准化比值（INR）结果。

方法

本交叉随机对照试验包含四个周期。我们使用原研药 Marevan 及两种华法林钠仿制药（分别由 União Química 实验室和 Teuto 实验室生产，均从零售药店购买）。合格的参与者为来自巴西圣保罗一所大学附属医院抗凝门诊的门诊患者。他们患有心房颤动或心房扑动，且正在使用华法林至少 2 个月，INR 治疗范围为 2.0-3.0。随机化通过编号、不透明、密封信封进行。医疗保健人员和结局评估者对治疗方案设盲，但患者不设盲。主要结局是 INR 的变异性（ΔINR），次要结局包括平均 INR。如果原研药与仿制药的ΔINR 比较的 95%置信区间（CI）在±0.49 范围内，则接受两种制剂等效。

结果

共纳入 100 例患者，并随机分为六组治疗（四组每组 17 例，两组每组 16 例）。União Química 华法林仿制药与 Marevan 的 INR 变异性等效（ΔINR +0.09 [95%CI -0.29 至 +0.46]，n = 84）。TW 华法林仿制药与 Marevan 的比较结果不确定（ΔINR +0.29 [95%CI -0.09 至 +0.68]，n = 84）。