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

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 arte...
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Autor*in:	Bassat, Quique [verfasserIn] 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

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2022

Schlagwörter:	Malaria Artemisinin-based combination therapy Falciparum Regulatory pathway

Anmerkung:	© The Author(s) 2022

Übergeordnetes Werk:	Enthalten in: Malaria journal - London : BioMed Central, 2002, 21(2022), 1 vom: 22. Feb.
Übergeordnetes Werk:	volume:21 ; year:2022 ; number:1 ; day:22 ; month:02

Links:	Volltext

DOI / URN:	10.1186/s12936-022-04079-9

Katalog-ID:	SPR050509217

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allfields	10.1186/s12936-022-04079-9 doi (DE-627)SPR050509217 (SPR)s12936-022-04079-9-e DE-627 ger DE-627 rakwb eng Bassat, Quique verfasserin aut Challenges in the clinical development pathway for triple and multiple drug combinations in the treatment of uncomplicated falciparum malaria 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2022 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. Malaria (dpeaa)DE-He213 Artemisinin-based combination therapy (dpeaa)DE-He213 Falciparum (dpeaa)DE-He213 Regulatory pathway (dpeaa)DE-He213 Maïga-Ascofaré, Oumou aut May, Jürgen aut Clain, Jerôme aut Mombo-Ngoma, Ghyslain aut Groger, Mirjam aut Adegnika, Ayôla A. aut Agobé, Jean-Claude Dejon aut Djimde, Abdoulaye aut Mischlinger, Johannes aut Ramharter, Michael (orcid)0000-0002-9259-1885 aut Enthalten in Malaria journal London : BioMed Central, 2002 21(2022), 1 vom: 22. Feb. (DE-627)355986582 (DE-600)2091229-8 1475-2875 nnns volume:21 year:2022 number:1 day:22 month:02 https://dx.doi.org/10.1186/s12936-022-04079-9 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2031 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2061 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2190 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 21 2022 1 22 02
spelling	10.1186/s12936-022-04079-9 doi (DE-627)SPR050509217 (SPR)s12936-022-04079-9-e DE-627 ger DE-627 rakwb eng Bassat, Quique verfasserin aut Challenges in the clinical development pathway for triple and multiple drug combinations in the treatment of uncomplicated falciparum malaria 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2022 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. Malaria (dpeaa)DE-He213 Artemisinin-based combination therapy (dpeaa)DE-He213 Falciparum (dpeaa)DE-He213 Regulatory pathway (dpeaa)DE-He213 Maïga-Ascofaré, Oumou aut May, Jürgen aut Clain, Jerôme aut Mombo-Ngoma, Ghyslain aut Groger, Mirjam aut Adegnika, Ayôla A. aut Agobé, Jean-Claude Dejon aut Djimde, Abdoulaye aut Mischlinger, Johannes aut Ramharter, Michael (orcid)0000-0002-9259-1885 aut Enthalten in Malaria journal London : BioMed Central, 2002 21(2022), 1 vom: 22. Feb. (DE-627)355986582 (DE-600)2091229-8 1475-2875 nnns volume:21 year:2022 number:1 day:22 month:02 https://dx.doi.org/10.1186/s12936-022-04079-9 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2031 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2061 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2190 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 21 2022 1 22 02
allfields_unstemmed	10.1186/s12936-022-04079-9 doi (DE-627)SPR050509217 (SPR)s12936-022-04079-9-e DE-627 ger DE-627 rakwb eng Bassat, Quique verfasserin aut Challenges in the clinical development pathway for triple and multiple drug combinations in the treatment of uncomplicated falciparum malaria 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2022 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. Malaria (dpeaa)DE-He213 Artemisinin-based combination therapy (dpeaa)DE-He213 Falciparum (dpeaa)DE-He213 Regulatory pathway (dpeaa)DE-He213 Maïga-Ascofaré, Oumou aut May, Jürgen aut Clain, Jerôme aut Mombo-Ngoma, Ghyslain aut Groger, Mirjam aut Adegnika, Ayôla A. aut Agobé, Jean-Claude Dejon aut Djimde, Abdoulaye aut Mischlinger, Johannes aut Ramharter, Michael (orcid)0000-0002-9259-1885 aut Enthalten in Malaria journal London : BioMed Central, 2002 21(2022), 1 vom: 22. Feb. (DE-627)355986582 (DE-600)2091229-8 1475-2875 nnns volume:21 year:2022 number:1 day:22 month:02 https://dx.doi.org/10.1186/s12936-022-04079-9 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2031 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2061 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2190 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 21 2022 1 22 02
allfieldsGer	10.1186/s12936-022-04079-9 doi (DE-627)SPR050509217 (SPR)s12936-022-04079-9-e DE-627 ger DE-627 rakwb eng Bassat, Quique verfasserin aut Challenges in the clinical development pathway for triple and multiple drug combinations in the treatment of uncomplicated falciparum malaria 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2022 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. Malaria (dpeaa)DE-He213 Artemisinin-based combination therapy (dpeaa)DE-He213 Falciparum (dpeaa)DE-He213 Regulatory pathway (dpeaa)DE-He213 Maïga-Ascofaré, Oumou aut May, Jürgen aut Clain, Jerôme aut Mombo-Ngoma, Ghyslain aut Groger, Mirjam aut Adegnika, Ayôla A. aut Agobé, Jean-Claude Dejon aut Djimde, Abdoulaye aut Mischlinger, Johannes aut Ramharter, Michael (orcid)0000-0002-9259-1885 aut Enthalten in Malaria journal London : BioMed Central, 2002 21(2022), 1 vom: 22. Feb. (DE-627)355986582 (DE-600)2091229-8 1475-2875 nnns volume:21 year:2022 number:1 day:22 month:02 https://dx.doi.org/10.1186/s12936-022-04079-9 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2031 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2061 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2190 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 21 2022 1 22 02
allfieldsSound	10.1186/s12936-022-04079-9 doi (DE-627)SPR050509217 (SPR)s12936-022-04079-9-e DE-627 ger DE-627 rakwb eng Bassat, Quique verfasserin aut Challenges in the clinical development pathway for triple and multiple drug combinations in the treatment of uncomplicated falciparum malaria 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2022 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. Malaria (dpeaa)DE-He213 Artemisinin-based combination therapy (dpeaa)DE-He213 Falciparum (dpeaa)DE-He213 Regulatory pathway (dpeaa)DE-He213 Maïga-Ascofaré, Oumou aut May, Jürgen aut Clain, Jerôme aut Mombo-Ngoma, Ghyslain aut Groger, Mirjam aut Adegnika, Ayôla A. aut Agobé, Jean-Claude Dejon aut Djimde, Abdoulaye aut Mischlinger, Johannes aut Ramharter, Michael (orcid)0000-0002-9259-1885 aut Enthalten in Malaria journal London : BioMed Central, 2002 21(2022), 1 vom: 22. Feb. (DE-627)355986582 (DE-600)2091229-8 1475-2875 nnns volume:21 year:2022 number:1 day:22 month:02 https://dx.doi.org/10.1186/s12936-022-04079-9 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2031 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2061 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2190 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 21 2022 1 22 02
language	English
source	Enthalten in Malaria journal 21(2022), 1 vom: 22. Feb. volume:21 year:2022 number:1 day:22 month:02
sourceStr	Enthalten in Malaria journal 21(2022), 1 vom: 22. Feb. volume:21 year:2022 number:1 day:22 month:02
format_phy_str_mv	Article
institution	findex.gbv.de
topic_facet	Malaria Artemisinin-based combination therapy Falciparum Regulatory pathway
isfreeaccess_bool	true
container_title	Malaria journal
authorswithroles_txt_mv	Bassat, Quique @@aut@@ Maïga-Ascofaré, Oumou @@aut@@ May, Jürgen @@aut@@ Clain, Jerôme @@aut@@ Mombo-Ngoma, Ghyslain @@aut@@ Groger, Mirjam @@aut@@ Adegnika, Ayôla A. @@aut@@ Agobé, Jean-Claude Dejon @@aut@@ Djimde, Abdoulaye @@aut@@ Mischlinger, Johannes @@aut@@ Ramharter, Michael @@aut@@
publishDateDaySort_date	2022-02-22T00:00:00Z
hierarchy_top_id	355986582
id	SPR050509217
language_de	englisch
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author	Bassat, Quique
spellingShingle	Bassat, Quique misc Malaria misc Artemisinin-based combination therapy misc Falciparum misc Regulatory pathway Challenges in the clinical development pathway for triple and multiple drug combinations in the treatment of uncomplicated falciparum malaria
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topic_title	Challenges in the clinical development pathway for triple and multiple drug combinations in the treatment of uncomplicated falciparum malaria Malaria (dpeaa)DE-He213 Artemisinin-based combination therapy (dpeaa)DE-He213 Falciparum (dpeaa)DE-He213 Regulatory pathway (dpeaa)DE-He213
topic	misc Malaria misc Artemisinin-based combination therapy misc Falciparum misc Regulatory pathway
topic_unstemmed	misc Malaria misc Artemisinin-based combination therapy misc Falciparum misc Regulatory pathway
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title	Challenges in the clinical development pathway for triple and multiple drug combinations in the treatment of uncomplicated falciparum malaria
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title_full	Challenges in the clinical development pathway for triple and multiple drug combinations in the treatment of uncomplicated falciparum malaria
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author_browse	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
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title_sort	challenges in the clinical development pathway for triple and multiple drug combinations in the treatment of uncomplicated falciparum malaria
title_auth	Challenges in the clinical development pathway for triple and multiple drug combinations in the treatment of uncomplicated falciparum malaria
abstract	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. © The Author(s) 2022
abstractGer	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. © The Author(s) 2022
abstract_unstemmed	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. © The Author(s) 2022
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title_short	Challenges in the clinical development pathway for triple and multiple drug combinations in the treatment of uncomplicated falciparum malaria
url	https://dx.doi.org/10.1186/s12936-022-04079-9
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author2	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
author2Str	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
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Challenges in the clinical development pathway for triple and multiple drug combinations in the treatment of uncomplicated falciparum malaria

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