As effective case management remains the cornerstone of malaria elimination , the monitoring of antimalarial drugs resistance is essential to ensure a continued coverage of effective antimalarial treatment. With the support of resources from the Global Fund, the main objective of the new RER was to set up an expanded programme to monitor antimalarial drug resistance in Madagascar, based on sentinel sites. The selected sentinel sites were chosen at peripheral level (within public or private health facilities) to be representative of the four epidemiological strata in which the country could divided . Because of the size of the country and the availability of financial and human resources, two sites were selected by epidemiological stratum for establishing a surveillance system for in vivo drug efficacy. Seven additional sites were secondly incorporated in the RER for monitoring in vitro drug resistance (in vitro drug sensitivity assay and molecular markers) to provide complementary data and warning signals of the possible emergence of resistance or trends of declining drug efficacy.
The objective of the new RER was firstly to establish up-dated baseline data on the efficacy of the antimalarial drugs recommended by the MalMoH in its new Madagascar national policy. The methodology used was based on the WHO 2003 protocol , with some modifications (compromise between the high transmission and the low to moderate transmission protocols): (i) children enrolled in the study were aged between six months and 15 years and (ii) of P. falciparum parasitaemia on inclusion was between 1,000 and 200,000/μl. The protocol included randomized, 28-day follow-up with genotyping to discriminate recrudescence from new infections, and assessment of safety and tolerability. Despite the complexity of conducting a multi-site study in Madagascar, an excellent completion rates was achieved (> 93%) and high-quality data were collected.
The four main antimalarial drugs used and recommended by the NMCP were evaluated in five sites. In Tsiroanomandidy, ASAQ was not evaluated because this drug was already assessed in another clinical trial  and in Andapa and Farafangana, CQ was not evaluated for ethical reasons because of the too high frequency of treatment failure found in the previous clinical trial in 2006.
Two methodological points could be underline by the results of the study: (1) the necessity to extend the follow-up to a minimum of 28 days (even more for drugs with a prolonged duration of action) to avoid the underestimation of the risk of treatment failure , i.e. for CQ, most of the treatment failures occurred between 15 and 28 days after treatment, a 14 day follow-up will underestimated the OTF of 12% (32.0% for 14-days instead of 44.0% for 28-days) and (2) the necessity to enrol sufficient number of patients to allow the stratification of the result based on age (< 5 years and ≥ 5 years), i.e. the risk of CQ treatment failure in children < 5 years was 2-fold more frequent than in older patients (five to 15 years old), especially in moderate to high transmission areas (Maevatanana and Miandrivazo).
This multi-site study represents the first extent in vivo drug efficacy study performed in Madagascar since 1983 [22–24]. The CQ efficacy was signifantly different between the eight sites and ranged from moderate (Ihosy, 81%), intermediate (Miandrivazo, 60.6% and Moramanga, 63.9%) to low (Maevatanana, 46.2%; Tsiroanomandidy, 42.1% and Ejeda, 36%), showing the important of the multi-site studies. However, the results about the CQ efficacy were comparable to those found previously in the last in vivo trial carried out in Sainte Marie on the east coast in 2004 (36.9% of clinical failure within two weeks of CQ treatment). Currently, CQ remains the drug most widely available (distribution and financial criteria) and is the first drug used in most of areas in Madagascar at community level, for treating acute fever before or without laboratory diagnosis. According to Hastings et al , even with 50% of efficacy, CQ might still be perceived as very effective at community level, especially because of its antipyretic activity that alleviate symptoms and because that most of the recrudescence's which occur two to three week later after the treatment are not perceived as a failure. Based on these findings, the MalMoH must improve the HMM, as soon as possible, by withdrawing pre-packaged CQ and gradually replacing it with pre-packaged ASAQ.
The results concerning the SP efficacy were more informative, contrasting with the good effectiveness reported in previous studies in 2003–2004 [13, 14]. The more worrying was to finding even if the treatment failures were rare that the ETFs were accounting for more than one third of the SP treatment failure. There is no doubt that with the increased drug use of SP in the next few years in Madagascar as IPT for pregnant women, the monitoring of its drug resistance especially with the useful and reliable molecular makers such as Pf-dhfr and Pf-dhps  will be make it a priority for the RER.
This study also confirmed that ASAQ, the first-line treatment of the uncomplicated malaria recommended in Madagascar was very effective, particularly because of the excellent effectiveness of AQ, the partner drug associated with artesunate. Although it was not feasible to monitor for the potentially serious adverse effects associated with amodiaquine such as neutropenia or hepatotoxicity (the sample size was too small to exclude any clinically toxicity with a low frequency such as < 1:100), ASAQ was well tolerated in the study population. This combination produced also faster parasite and fever clearances than the other antimalarial treatments. These findings constitute important baseline data on the efficacy of this combination, a key tool within the framework of the elimination of the malaria .
The results from this multi-site study show that antimalarial drug resistance remains low in Madagascar, except for CQ, compared to the bordering countries in the Indian Ocean region such as the Comoros Archipelago [26, 27]. The next step must be to complete these data by providing the frequency of mutant parasites correlated with the CQ-resistance (Pfcrt) or SP-resistance (Pf-dhfr or Pf-dhps) or the in vitro response of parasites for drug for which no validate molecular marker are available such as amodiaquine, artemisinin derivatives or amino alcohols (quinine, lumefantrine). These complementary indicators should allow the early detection of the spread of P. falciparum drug resistance, especially those introduced from the Comoros Islands . Indeed, the extension of the RER at regional level is also crucial to enable the countries of the region to share national information on antimalarial drug efficacy and to help to minimize delays in implementing national antimalarial drug policy change.