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治疗无并发症恶性疟原虫疟疾的三联和多药物组合在临床开发路径上面临的挑战。

Challenges in the clinical development pathway for triple and multiple drug combinations in the treatment of uncomplicated falciparum malaria.

机构信息

ISGlobal, Hospital Clínic - Universitat de Barcelona, Barcelona, Spain.

Centro de Investigação em Saúde de Manhiça (CISM), Maputo, Mozambique.

出版信息

Malar J. 2022 Feb 22;21(1):61. doi: 10.1186/s12936-022-04079-9.

Abstract

The addition of a third anti-malarial drug matching the pharmacokinetic characteristics of the slowly eliminated partner drug in artemisinin-based combination therapy (ACT) has been proposed as new therapeutic paradigm for the treatment of uncomplicated falciparum malaria. These triple artemisinin-based combination therapy (TACT) should in theory more effectively prevent the development and spread of multidrug resistance than current ACT. Several clinical trials evaluating TACT-or other multidrug anti-malarial combination therapy (MDACT)-have been reported and more are underway. From a regulatory perspective, these clinical development programmes face a strategic dilemma: pivotal clinical trials evaluating TACT are designed to test for non-inferiority of efficacy compared to standard ACT as primary endpoint. While meeting the endpoint of non-inferior efficacy, TACT are consistently associated with a slightly higher frequency of adverse drug reactions than currently used ACT. Moreover, the prevention of the selection of specific drug resistance-one of the main reasons for TACT development-is beyond the scope of even large-scale clinical trials. This raises important questions: if equal efficacy is combined with poorer tolerability, how can then the actual benefit of these drug combinations be demonstrated? How should clinical development plans be conceived to provide objective evidence for or against an improved management of patients and effective prevention of anti-malarial drug resistance by TACT? What are the objective criteria to ultimately convince regulators to approve these new products? In this Opinion paper, the authors discuss the challenges for the clinical development of triple and multidrug anti-malarial combination therapies and the hard choices that need to be taken in the further clinical evaluation and future implementation of this new treatment paradigm.

摘要

添加第三种抗疟药物,使其与基于青蒿素的联合疗法(ACT)中缓慢消除的联合药物的药代动力学特征相匹配,这已被提议作为治疗无并发症恶性疟原虫疟疾的新治疗范例。从理论上讲,这些三重复方青蒿素类药物疗法(TACT)应该比目前的 ACT 更有效地预防多药耐药性的发展和传播。已经报告了几项评估 TACT 或其他多药抗疟联合疗法(MDACT)的临床试验,并且还有更多正在进行中。从监管的角度来看,这些临床开发计划面临着一个战略困境:评估 TACT 的关键性临床试验旨在以非劣效性作为主要终点来测试与标准 ACT 的疗效。虽然达到了非劣效性的终点,但 TACT 与目前使用的 ACT 相比,始终与稍微更高的药物不良反应频率相关。此外,甚至大规模临床试验也无法预防特定药物耐药性的选择——这是 TACT 开发的主要原因之一。这引发了一些重要的问题:如果等效疗效与较差的耐受性相结合,那么如何证明这些药物组合的实际益处?应该如何构思临床开发计划,为 TACT 对患者的管理改善和对抗疟药物耐药性的有效预防提供客观证据?最终有哪些客观标准可以说服监管机构批准这些新产品?在这篇观点文章中,作者讨论了三重复方和多药抗疟联合疗法的临床开发面临的挑战,以及在进一步的临床评估和未来实施这一新治疗范例时需要做出的艰难选择。

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