Table 2 Challenges for the clinical development plans of Triple Artemisinin Combination Therapies and their impact

Efficacy evaluation

Clinical phase III trials need to be conducted in regions without high failure rate of ACT and need to include African children. Recruitment at sites in the Greater Mekong Region is encouraged but is limited due to low incidence of malaria in this region.

Non-inferiority of efficacy compared to standard ACT is most appropriate primary efficacy outcome. Superiority may be demonstrated in secondary sub-analysis of sites located in regions with high prevalence of multidrug resistance.

Tolerability evaluation

Treatment with more than one drug at therapeutic dosage inevitably leads to higher frequency and severity of off-target effects. TACT are therefore associated with (slightly) worse tolerability mostly concerning gastrointestinal side effects, nausea, vomiting.

Objective quantification of adverse events is of high importance for an informed comparative assessment of TACT compared to ACT. Study designs including blinding of patients and assessors are therefore encouraged.

Safety evaluation

Evaluation for potential safety signals is of high importance when combining multiple drugs. For antimalarials a special focus should be laid on evaluation of cardiotoxicity, hepatic and renal toxicity and haematological and neurological side effects. Frequent safety issues may be identified in phase I-III trials, whereas rare but potentially clinically important safety events may only be identified in phase IV studies.

Focused investigation of ECG changes, haematological and biochemical parameters should be proactively included in study protocols to provide reassurance that potential safety signals may be detected.

Drug interactions

Pharmacokinetic drug interaction is a key issue for multiple drug combinations. Drug-drug interactions may be evaluated in silico prior to clinical trials based on the known metabolic pathways. Focussed pharmacokinetic assessment in patients is however also of high importance to allow for evaluation of increased or decreased drug exposure in vivo. Potential for drug interaction also includes the modification of efficacy, tolerability and safety by the interaction of several drugs. These pharmacodynamic drug interactions need to be assessed as detailed above.

Focused assessment of pharmacokinetic characteristics of TACT in rich and/or population pharmacokinetic assessment is of high importance and should be added early on in the clinical development plan.

Prevention of drug resistance

The effective prevention of the emergence and spread of drug resistance is one of the main rationales for TACT. Molecular (and phenotypic) drug resistance monitoring of parasites at recruitment and at time of reappearance is therefore of importance to assess whether TACT select for drug resistance or prevent it.

Realistically, these molecular investigations will not lead to clear and definitive outcomes due to the rare event of selection of drug resistance by antimalarials. However, inclusion of these components in study protocols is of importance to build up a body of evidence which may lead to conclusive evidence in the long run by meta-analysis of multiple trials and mathematic modelling. For this purpose public sharing of these data will be of high importance.

Transmission blocking potential

Reducing onwards transmission of malaria by antimalarials drugs may be an effective way of preventing the spread of drug resistance. In case of preclinical evidence for transmission blocking potential for one of the drugs, focused assessment on transmissibility is highly informative.

Focused assessment on impact on transmission shall be included in clinical trial protocols whenever justified and feasible. Again it is unclear whether individual clinical trials will provide conclusive answers but pooling of data from several trials may provide important information on this aspect of antimalarial chemotherapy.

Drug formulation of TACTs

Fixed dose combinations have several advantages compared to loose combinations including better adherence to the recommended regimen. This necessitates the administration of each drug at the same time points as the overall TACT which may be challenging when combining drugs that are administered twice daily with those administered only once daily. Also child friendly drug formulations have importantly improved the management of young children and should therefore be a priority in the clinical development of TACTs. Currently no fixed-dose or child-friendly drug formulation of TACTs is under clinical investigation.

Once TACTs are shown to be safe, well tolerated and efficacious, fixed dose drug combinations will be required for roll-out in clinical routine. For this purpose bioequivalence studies will be needed to bridge data from large clinical phase III trials with pharmacokinetic data from fixed-dose formulations.

Cost effectiveness of TACT

Addition of a third drug to a two-drug combination inevitably increases cost of the treatment. It is challenging to factor in cost savings by delaying the development of drug resistance.

Information about cost of goods and cost for individual TACTs will constitute important information for public health decision makers.

Clinical phase IV studies and post-marketing surveillance

Rare but clinically important safety signals may only be detected in large phase IV trials and post-marketing surveillance.

Provision for systematic data collection and reporting as soon as TACT will be deployed on a large scale.

Perspective for funders, pharmaceutical companies and regulators

Most likely scenario for TACT is demonstration of non-inferior efficacy, slightly worse tolerability and evidence indicating absence of clinically important and frequent safety signals compared to standard ACT. At the same time the prevention of selection of drug resistance is unlikely to be demonstrated by individual clinical trials programs.

These key features are an uncomfortable combination for funders, pharmaceutical companies and regulators alike as no clear individual benefit for patients treated with TACT may be demonstrated in individual clinical development plans. A balanced decision needs to be taken to determine whether triple or multidrug combinations should become the new treatment paradigm (in analogy to HIV and Tb where drug resistance poses a similarly important threat) or not on the assumption that TACT would more effectively reduce the risk for the selection of drug resistance than current ACT. This may come with a slightly less favourable tolerability profile than current ACT. At the same time the potential benefit of TACT on the potential to reduce the emergence of drug resistance is unlikely to be documented in the short run. TACT’s full potential may therefore only be appreciated when aggregating data over a longer period of time after implementation. This is a difficult decision for policy makers, regulators, funders but needs to be taken consciously accepting in all honesty this strategic dilemma.