Challenges in the clinical development pathway for triple and multiple drug combinations in the treatment of uncomplicated falciparum malaria.
Artemisinin-based combination therapy
Falciparum
Malaria
Regulatory pathway
Journal
Malaria journal
ISSN: 1475-2875
Titre abrégé: Malar J
Pays: England
ID NLM: 101139802
Informations de publication
Date de publication:
22 Feb 2022
22 Feb 2022
Historique:
received:
24
08
2021
accepted:
06
02
2022
entrez:
23
2
2022
pubmed:
24
2
2022
medline:
25
2
2022
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 35193586
doi: 10.1186/s12936-022-04079-9
pii: 10.1186/s12936-022-04079-9
pmc: PMC8864855
doi:
Substances chimiques
Antimalarials
0
Drug Combinations
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
61Informations de copyright
© 2022. The Author(s).
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