There is little safety information on ACT outside clinical trials, when used in real-life settings. The availability of such information, though, is important for policy decisions; while it may be difficult to tell the different forms of ACT apart based on efficacy, better knowledge of their safety profiles, along with other practical considerations, may help guide decisions.
Pharmaco-vigilance (PV) systems are variably established in malaria-endemic countries where ACT is the first-line malaria treatment, and so far, have failed to produce information in significant amounts . PV is intended to generate signals about rare events but is less informative on the more common toxicities; typically, the absence of denominators makes it difficult, if not impossible, to estimate risks with some level of precision. Cohort event monitoring (CEM) can produce more complete information on events profiles, frequencies and associated risks factors, and this in real-life conditions. CEM is recommended by the WHO and has already been applied to ACT [5, 6].
The present study generated information not only on the safety and tolerability of ASAQ, but also on practical aspects of setting up informative, quality and sustainable information systems in peripheral settings. Strengths and weaknesses are discussed below.
The system set in place here provided for a set of pre-defined signs/symptoms to be assessed and graded before as well as after treatment. This proved very useful in differentiating disease- and treatment-related signs/symptoms. It revealed that 21% of the patients and 40% of the events that would have been reported as AEs were already present on admission.
Assessing intensity of events is difficult to teach and standardize across assessors, and could be a source of bias; this was however minimized by having the same person assessing a patient before and after treatment.
Overall, just under 10% of subjects had a total of almost 700 TESS (two per treated patient on average), three-quarters of which were mild or moderate. Children under six years of age were at lower risk of events (either pre-treatment of following treatment), but it is not clear if this finding merely reflects the challenge of obtaining reliable information from young children.
No toxicities emerged from the clinical laboratory evaluation. The incidence of SAEs (including death) was five per thousand; though, for comparison, about one-third of the rate revealed from a meta-analysis of randomized controlled trials of ASAQ in research settings , this shows that the system was accurate enough to capture serious events.
Concerning rare events, 49 cases of extra-pyramidal reaction following administration of ASAQ are reported to the Upssala Monitoring centre, including two cases of tongue protrusion in adults and one in children. In this CEM, two cases of tongue protrusion were detected within a timeframe compatible with the other reported cases; both receded within 15 minutes after administering dexamethasone . Such extrapyramidal events are generally imputed to AQ, but the mechanism is not known. Here, there was no enough information on possible concomitant intake of other medicines or traditional remedies to understand whether an interaction might have been involved.
With its ~3,700 records, one would be 80% confident that if this study detected an event, this will occur on average in at least five per 10,000. More rare, serious adverse events would require much larger numbers.
Adequacy of dosing
Records collected allowed assessing adequacy of dosing as administered by nurses or health workers at peripheral health centres following treatment recommendations and manufacturers’ instructions. Treatment was administered based on the patient weight for the loose combination, or age for the co-blistered and fixed-dose products; of note, both the tablet dosage and the age groups differed between these two forms – which explains the differences observed. Age-based dosing with the fixed-dose product was as accurate (97% and 82% of treatments were within the therapeutic ranges for AS and AQ, respectively) as weight-based dosing with the loose, individually-formulated products (93% and 86%). The total dose of AQ was also ~20% higher with the fixed than the loose combination.
The co-blistered product was clearly less amenable to dosing patients accurately than the other two, and there was indirect evidence that dosing errors (42% and 48% overdosing for AS and AQ, respectively) would be less tolerated (see below) as also implied in a previous study in the same setting . The fix-dose product is now the recommended formulation, and at the time of writing the only form available for treating malaria in Senegal.
One of the limitations of this study is that it did not allow estimating specific risks related e.g. to age or products. The reasons are that, when analysing the results, it became obvious that multiple interactions existed between variables such as the year of study, the product and the patient age. One should bear in mind that this study was conducted over a nine-year period that witnessed fundamental changes in malaria in this district: the product form used changed from loose, co-blistered, fix combination products, with overlaps between products, prevalence dropped and patient’s age increased significantly . Furthermore, reporting was not uniformly applied by health workers and nurses and over time (see below). More information was gathered on exposure to the loose (49% of ASAQ treatments enrolled in this study) and co-blistered (42%) products, and much less on the fixed product (9%), and effects were confounded by evolving age and variable health workers’ adherence to the reporting system.
It was possible, however, to quantify the risk of experiencing a toxic event (TESS) in relation to dosage by year of study. Over-dosage doubled the risk of TESS over the entire study period, but this was statistically significant only during 2003–2007, which are the years when the co-blister was either the predominant or the only product in use.
Feasibility aspects of safety monitoring
This CEM study was purposely nested within the daily routine work of the health centres. Apart from the eligibility criteria, there was no special procedure or randomization list for selecting patients to recruit into the CEM study. The nurses were to enroll as many patients as they could possibly afford within their capacity and considering their various daily commitments. The reason behind this was that it would provide useful information on the feasibility of CEM at peripheral health centres as part of daily routine. Indeed, this could have introduced a selection bias, but again, this will be an inherent feature of any CEM.
Approximately one in four (26%) of all the patients receiving ASAQ during 2001–2009 was recruited into this CEM programme, which is a reasonable proportion. However, the programme was not uniformly applied; the proportion fluctuated with time (4-99% per annum) and the facility (2-61%); 50% of the cases had been enrolled by the end of 2003. There are reasons for that. Nurses and community health workers (all literate) were trained (and retrained) to collect and record the data. At the beginning, adherence was very high. However, this was an additional task on top of their routine work, and with increasing workload while scaling-up the implementation of RDT plus ACT, the proportion of patients enrolled in the safety monitoring fell – to raise again when numbers started decreasing again. There was a clear inverse correlation between the number of patients treated with ASAQ, the proportion of these enrolled in the safety survey, and the proportion of patients reported to have events. This is exemplified by the surprisingly low (one-third) and variable accuracy of reporting on presentation, which ranged from less than 2% to almost 98% of patients (all with parasitologically-confirmed malaria) having signs/symptoms pre-treatment – which was inversely proportional to the number of patients enrolled. Workload was a recognized deterrent also for PV in other settings . This means that under-reporting and inconsistent reporting of events could not be ruled out; however, it is reassuring to see that from 2007, > 90% of patients are reported to have events pre-treatment. This may be explained by the fact that recently not only the number of cases seen (workload) has decreased, but also the age of patients has increased (now patients are older, thus easier to interrogate and obtain information). Human (motivation was not the same for all) and structural factors (staff turn-over) are important determinants, too.
There are also costs involved, related to training (and re-training), quality control, reporting and analysis. Incentives may be considered to motivate staff to carry out these additional activities on top of their daily work. Costs will increase especially if laboratory tests are added. The problem is that clinical signs and symptoms will not always reveal all toxicities, some of which may be clinically silent. Examples are asymptomatic neutropaenia and hepatitis which have been described for AQ  and AS . For a system to be more fully informative, laboratory tests should be included at least on a proportion of patients and targeted to detect known toxicities, but the costs may be prohibitive for resource-constrained settings.
In addition, there are political willingness, and (international and country) regulations. Post-marketing surveillance and pharmaco-vigilance are mandatory for manufacturers, but this does not work well in unregulated markets (where products are generics available through the private and the informal sectors), and in countries with no or suboptimal systems, as is the case in many malaria-endemic countries. No one system alone will provide reliably all the information needed. CEM is recommended by the WHO and countries should consider adopting it. However, it has advantages and disadvantages. As a pre-requisite, feasibility studies like this one should be set in place, along with realistic costing estimates of setting it up and sustaining it.
Data quality is paramount for the information to be reliable; quality checks must be run on the performance of the system. Unless minimum requirements are met, investing in such a system would not be justified. In this study, due to budget limitations, it was not possible to provide for quality control, a limitation which is clearly reflected in the abovementioned erratic performance, and which prevented more in-depth analyses. At the same time, the absence of such a system allowed to bring out practical issues that will require corrective actions, should a similar system be set in place.
Lastly, it should be clear, both at country and international level, that collecting and storing information is not enough, if not followed up by developing an updated risk-management plan informed by large databases collating data from different locations for individual drugs and ACT in general.
Overall study evaluation
The study was successful in characterizing known reactions. In particular, it was possible to quantitate frequencies (both numerator and denominator available). The size of the cohort was adequate for known reactions but probably not enough to generate a signal on yet unrecognized, rare toxicities. While lacking a comparator drug, this study provides valuable benchmarking for future assessments both locally and elsewhere, as well as for risk management.
Collecting data on the occurrence and intensity of a set of signs/symptoms pre-treatment as well as post-treatment made it possible to reduce the background noise (generated by malaria itself and individual factors) and improve the quality and specificity of the signal (possible treatment-induced events).
Data were collected that allowed assessing the adequacy of dosing with different ASAQ formulations, and analyse its effects on tolerability.
The study also generated information that could be used to improve performance. For instance, staff’s compliance was on average satisfactory (one-fourth of all ASAQ treatments enrolled) but highly variable (also in terms of completeness of information)– which may have introduced a number of biases and confounders. Higher consistency in needed. In that respect training and quality control systems will be required.
The questions that remain to be answered is whether a system like this is sustainable and under which conditions, and whether it is applicable elsewhere. Research should be done into the conditions that would make it cost-effective, including the amount and quality of data generated, and the use thereof for decision-making possibly in parallel with classical passive pharmaco-vigilance activities.