Challenges in the clinical development pathway for triple and multiple drug combinations in the treatment of uncomplicated falciparum malaria
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Challenges in the clinical development pathway for triple and multiple drug combinations in the treatment of uncomplicated falciparum malaria. / Bassat, Quique; Maïga-Ascofaré, Oumou; May, Jürgen; Clain, Jerôme; Mombo-Ngoma, Ghyslain; Groger, Mirjam; Adegnika, Ayôla A; Agobé, Jean-Claude Dejon; Djimde, Abdoulaye; Mischlinger, Johannes; Ramharter, Michael; ASAAP and Multimal Consortia.
in: MALARIA J, Jahrgang 21, Nr. 1, 22.02.2022, S. 61.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Challenges in the clinical development pathway for triple and multiple drug combinations in the treatment of uncomplicated falciparum malaria
AU - Bassat, Quique
AU - Maïga-Ascofaré, Oumou
AU - May, Jürgen
AU - Clain, Jerôme
AU - Mombo-Ngoma, Ghyslain
AU - Groger, Mirjam
AU - Adegnika, Ayôla A
AU - Agobé, Jean-Claude Dejon
AU - Djimde, Abdoulaye
AU - Mischlinger, Johannes
AU - Ramharter, Michael
AU - ASAAP and Multimal Consortia
N1 - © 2022. The Author(s).
PY - 2022/2/22
Y1 - 2022/2/22
N2 - 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.
AB - 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.
KW - Antimalarials/pharmacology
KW - Clinical Trials as Topic
KW - Drug Combinations
KW - Drug Resistance
KW - Humans
KW - Malaria, Falciparum/drug therapy
KW - Plasmodium falciparum
U2 - 10.1186/s12936-022-04079-9
DO - 10.1186/s12936-022-04079-9
M3 - SCORING: Journal article
C2 - 35193586
VL - 21
SP - 61
JO - MALARIA J
JF - MALARIA J
SN - 1475-2875
IS - 1
ER -