Table 1 Framework for the evaluation of IVM as a potential malaria elimination tool

Efficacy

Robust empirical data coupled with modelling will be needed to support a specific target efficacy.

What epidemiological impact can be expected at different levels of mosquito survival/EIR in different endemicities?

For early development, the proposed biological surrogate for effectiveness is prevention of mosquitoes (both colonized and wild) to become infectious as measured by the proportion of mosquitoes which survive through the sporogonic cycle and sporozoite prevalence in those surviving.

Are lab and semi-field assays acceptable alternatives to field studies, and which assay(s) should be used to determine the above endpoints? (e.g. SMFA, DMFA, DFA, wild mosquito survival and EIR)

How long should the transmission suppression effect last?

The ultimate goal of reducing entomological endpoints (i.e. the sporozoite rate and the EIR) and human endpoints (the molFOI and incidence of clinical episodes in the selected strata) must be considered for proposed MDA trials.

Should this be tested as a stand-alone intervention or in combination with other transmission-blocking interventions? (i.e. primaquine, ACT)

How many encounters are needed to deliver the optimal intervention? (single encounter vs multiple)

The suggested TPP for TBV uses >85% transmission–blocking efficacy as a target [33]. This number however, should be interpreted carefully regarding ivermectin because the primary effect of ivermectin is to kill the vector, not to block transmission.

Which parasitological/human endpoints should be assessed in phase III trials?

Can a cluster randomized trial provide enough power to prove efficacy using human endpoints?

Dose

This criterion is closely related to efficacy as there is a correlation between plasma levels and mosquito mortality [14].

What target plasma levels should oral dose regimes or slow release formulations have?

The duration of effective mosquito-lethal plasma concentrations can be increased using higher dose or with novel slow release formulations.

Should target concentrations be determined in plasma or whole blood? Should the samples be obtained from venous or capillary blood, or the midgut of freshly fed mosquitoes? What limits of detection should be sought in methods to assess systemic levels?

The maximum dose administered safely to healthy volunteers was 2 mg/kg [36].

Is there a role for differential dosing based on gender, BMI or total body fat?

MDA coverage

Robust empirical data coupled with modelling will be needed to support a specific coverage target.

Is there added value in increasing coverage beyond 80% of the population?

Current MDA for onchocerciasis control use 80% of total population as target.

Is it safe in children <15 kg and pregnant/breast feeding women?

Current use of IVM excludes children <15 kg or <90 cm, as well as pregnant and breast feeding women unless their risk for LF or onchocerciasis is high.

What is the safety profile of IVM in pregnancy and breast feeding mothers?

Route of administration/ Presentation

There is extensive experience in MDA using the oral formulation.

What non-parenteral slow release formulations could be used?

Injectable formulations are not desired for human MDA.

Safety

Current MDA programmes for onchocerciasis control report no severe adverse reactions and their rate of moderate adverse reactions is ≤ 1.3% [31].

Would higher or more frequent doses translate into a higher adverse event rate?

An adverse event rate less than 1:10.000 is the referenced used in the development of new anti-malarial drugs [20].

Is there any local toxicity to be taken into account in the development of new formulations?

Drug-Drug interactions

Ivermectin is metabolized by the cytochrome P4503A4 and excreted by the P-gp [37,38].

Is there any relevant interaction of ivermectin with anti-malarial, anti-retroviral or TBC medicines?

Co-administration with Artemeter-lumefantrine has been found safe and did not alter lumefantrine concentrations [14].

IVM is commonly co-administered with other anti-helmintics such as albendazole [13].

Are these risks manageable?

IVM for onchocerciasis is commonly used in areas with high HIV and TBC prevalence.

Spectrum

Different Anopheles species, even in the same species complex, have different sensitivity to IVM. (i.e. different LC₅₀).

How would differing IVM susceptibilities of various primary malaria vectors in the same region alter efficacy of ivermectin MDA?

Any scheme should target the main vectors of areas selected for elimination.

Disease targets

The effects of IVM on co-endemic NTDs offers direct personal benefit to those treated and which may increase and advantages regarding community acceptance and compliance [34].

What additional benefits on NTDs and ectoparasites can be expected from a wider use of IVM targeting malaria?

Should the design of a new product target malaria and only have beneficial non-target side effects against NTDs or should malaria and NTDs be targeted from the beginning?

Projected stability

Current recommended storage conditions are <30°C.

What is the stability of any potential new formulation?

Ideal stability is > 60 months in hot/humid climates [20].