Clinical development of new prophylactic antimalarial drugs after the 5th Amendment to the Declaration of Helsinki

Figures & data

Table 1 Characteristics of currently available drugs for malaria prevention

Drug	Prophylaxis strategy (suppressive or causal)	Regimen	Cost for 28 day exposure in $U.S. (Bryan 2006)	Utility/resistance concerns	Tolerability	Utility against P. vivax	FDA-approved prophylaxis indications
Primaquine	PART*/continuous (causal/ anti-relapse)	Daily	102	No resistance concerns at present. Little intrinsic blood stage activity can lead to severe malaria rapidly if doses missed.	Contraindicated in G6PD deficiency. GI upset is a problem in some patients. This can be mitigated if drug administered with food.	Exhibits causal and antihypnozite activity. Useful as post-exposure prophylaxis for hypnozoites if given upon return from an endemic area.	Radical cure (prevention of relapse) of P. vivax.
Mefloquine	Continuous (suppressive)	Weekly	106	Not useful on Thai borders.	Associated with adverse CNS events in some patients. Use justifiable on basis of risk-benefit.	No activity against liver stages, therefore cannot prevent relapses. Suppresses blood stage infection.	Prevention of falciparum and vivax malaria.
Doxycycline	Continuous (suppressive, partially causal)	Daily	15	None at present.	Severe esophogitis rarely. GI upset is a problem in some patients, that is improved if drug administered with food. Some formulations are thought to be poorly tolerated, although there is no unambiguous clinical evidence of this. Contraindicated for children or in pregnancy. Photosensitivity.	No activity against hypnozoites, therefore cannot prevent relapses. Suppresses blood stage infection.	Short term prevention of falciparum malaria.
Atovaquoneproguanil	Continuous (suppressive/ causal)	Daily	182	Worldwide effectiveness but intrinsic capacity for resistance induction.	Lowest withdrawal rate amongst comparator regimens.	No activity against hypnozoites, therefore cannot prevent relapses.	Prevention of falciparum malaria.
Chloroquine	Continuous (suppressive)	Weekly	50	Not effective in most areas due to widespread resistance to chloroquine.	Higher withdrawal rate than comparator regimens when combined with proguanil.	No activity against liver stages, therefore cannot prevent relapses. Suppresses blood stage infection.	Prevention of susceptible strains of all Plasmodium spp.

Note: *Presumptive anti-relapse treatment (P. vivax); All information was obtained from recent reviews or from the sources indicated in the accompanying text.

Table 2 Characteristics of future prophylaxis drugs

Drug	Sources	Likely Regimen	Status	Advantages	Disadvantages
Primaquine	Baird et al 1995; Weiss et al 1995; SanofiSynthelabo 1999; Hill et al 2006	Daily	Recommended, but not formally approved for continuous prophylaxis – used off-label for this purpose.	Inexpensive most jurisdictions and approved for other indications.	G6PD test required. Daily administration required. Little intrinsic blood stage activity can lead to severe malaria rapidly if doses missed. Cannot be used in some populations without formal licensure.
Tafenoquine	See accompanying text	Weekly and/or pre-exposure prophylaxis	Development for pro-phylaxis halted due to DH2000 concerns. Indication switched to treatment of P. vivax.	Long half-life and apparent good activity against multi-drug resistant malaria. Activity against all parasite stages. Multiple modes of administration possible.	G6PD testing will probably be required.
Weekly Malarone	Shanks et al 1999; GSK 2004; Edstein et al 2005	Weekly and/or pre-exposure prophylaxis	Proof of concept study needed.	Potential indication supported by post-treatment recrudescence patterns.	Efficacy in a weekly mode unknown. Weekly regimen may not be sufficient to suppress P. vivax blood stages. Resistant infections may emerge with shorter proguanil half-life.
Azithromycin	Taylor et al 1999; Dunne et al 2005; Heppner et al 2005b; Miller et al 2006; Noedl et al 2006	Daily-Weekly	In development for treatment* indication in combination with chloroquine (and other antimalarials).	Approved drug and likely safe in children and pregnancy	Probable requirement for daily dosing. Incomplete (60%–90%) protective efficacy against P. falciparum will require combination with other drugs, a higher dose, or a different formulation.
Piperaquine	Davis et al 2005; Hasugian et al 2007	Weekly and/or pre-exposure prophylaxis	Being developed for treatment indication in combination with dihydroartemisinin.	Long half-life and activity against CQ-resistant malaria. Suppression of reinfection in treatment trials strongly suggest that concept would work.	Safety profile not fully characterized. Proof of concept studies for prophylaxis have not been done. Resistance may emerge rapidly with anticipated widespread use for treatment.

Note: *Intention of manufacturer is to develop azithromycin/chloroquine for IPT (Ritzhaupt et al 2007); All information was obtained from recent reviews or from the sources indicated in the accompanying text.

Figure 1 Clinical development of new drugs for malaria prevention.

Note: Antimalarial drugs have traditionally been developed for both malaria treatment and prophylaxis as outlined in the panel on the left. Malarone, the last drug approved in the United States, and developed prior to the adoption of the 5th Amendment of the Declaration of Helsinki (DH2000), is used as an example. Major pharmaceutical companies now consider this approach to be unethical because placebos must be used and the Phase III prophylaxis studies utilize semi-immune individuals in malaria-endemic countries who would not normally benefit from malaria prophylaxis. The development of Malarone^™ (atovaquone-proguanil) has also been criticized because the high cost of treatment made sustainable post-trial access to the drug difficult. Our perspective is that the traditional approach remains ethical and consistent with DH2000 for the reasons stated at the bottom of the left panel and discussed in the accompanying text. The three panels to the right outline potential alternative clinical development pathways based on studies conducted in the traditional target population for prophylaxis (Western travelers), mixed populations of endemic country and nonendemic country immunes or focused on novel forms of prophylaxis. These resolve some of the DH2000 ethical concerns but have varying degrees of feasibility as indicated in the figure and discussed in the accompanying text.

Table 3 Possible phase III-equivalent study designs

Population	Design	Surrogate markers?	Approximate sample size	Duration of exposure	Attack rate (% per month)f	Challenges
Endemic nonimmunesa	Placebo comparator test drug	No	360	3–6 months	13–27	Identification of appropriate populations.
Endemic nonimmunes	Suppressive comparator test drug	Yes	720b	3–6 months	13–27	Identification of appropriate populations. Biomarker not yet available.
Western travelers	Suppressive comparator test drug	Yes	2160–4320c	1 month	13–27	Biomarker not yet available.
Western travelersd	Comparator test drug	No	16000	2.5 weeks	1.2%	Unfeasible due to large sample size.
Safari studiese	Placebo comparator test drug	No	1080–2160c	1 month	13–27	Logistics and recruitment difficult. Ethical issues due to potential for coercement and exposure of participants to other vector borne diseases.

Notes: ^aStudy design based on WRAIR statistical modeling of a three arm prophylaxis study. Participants were to be randomized 1:1:3: to placebo:mefloquine:tafenoquine control, assuming an attack rate of 80% over a 3–6 month period.

^bSample sizes calculated assuming that exposure rates can be determined in a suppressive prophylaxis arm (mefloquine or doxycycline) using surrogate markers with 50% sensitivity.

^cApproximate sample sizes were determined by adjustment from the WRAIR study on the basis of anticipated exposure time and/or an assumed 50% sensitivity of surrogate markers in suppressive prophylaxis comparator arm.

^dStudy design from Hogh and colleagues (2000).

^eA placebo powered, natural challenge study conducted in nonimmune Western travelers recruited for study specific travel to high transmission areas of endemic countries.

^fTotal assumed attack rate was 80% over a three-six month period. This is equivalent to a 13%–27% monthly attack rate.

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