22.4: Examples of real-world effectiveness studies

4.1 The INDEPTH Effectiveness and Safety Studies (INESS) platform

The development of new drugs and drug combinations for the treatment of malaria has created the need for countries to select and integrate new anti-malarial drugs into their health systems. INESS was designed as a platform for the conduct of Phase IV studies to provide objective data on the system effectiveness and safety of artemisinin combination therapies (ACTs) in real-world settings in Ghana, Burkina Faso, Tan- Tanzania, and Mozambique. The INESS research sites are based in districts with health and demographic surveillance systems and represent a diverse range of health system capacities and malaria endemicities. INESS looks at the overall performance (effectiveness) of deployment of the drug (ACT) in the system. It illuminates how the decay in the effectiveness of the ACTs occurs from efficacy to net or ‘system’ effectiveness, and at what levels the losses are the greatest (Figure 22.1). The research focuses on human behaviour, system behaviour, and drug behaviour in real-world contexts. Usu- ally, there are lessons for all levels about how to optimize performance. By following a large number of patients with malaria who should benefit from the intervention through the system, this Phase IV study is in a powerful position to understand the net effectiveness of the intervention (see <http://www.indepth-network.org>).

Access and patient adherence seem to be the major bottlenecks creating the loss of effectiveness in the example shown in Figure 22.1. However, within each of the five compartments shown in the figure, the INESS study has identified and quantified the specific sub-determinants contributing to the loss in effectiveness. These include access failure (for example, due to distance, poverty, or lack of knowledge), diagnostics failure (for example, due to weaknesses in laboratory capacity or staff training), provider failure (for example, weaknesses in supply chain management, leading to drug or diagnostic test stock-outs, or poor prescribing), and patient adherence failure (for example, due to problems with taste, perceived side effects, stopping treatment when feeling better, or incorrect provider instructions).

INESS also conducts qualitative studies to understand community perceptions of the intervention under study, as well as the health system contexts, that help to explain the results from the quantitative system effectiveness studies. The INESS platform generates evidence that is sufficiently representative to inform local, national, and possibly global policy and practice. The results provide evidence on what human behaviour, health system, and drug issues need to be addressed and where the most urgent needs are. It also highlights issues for the industry to consider, in order to improve effectiveness. For the safety component, INESS strengthens the national spontaneous reporting system and also runs a separate event-monitoring cohort to detect and report AEs. Though initially developed to examine ACTs, the INESS platform has the potential to assess the effectiveness of other health interventions. Because the platform operates at the level of whole districts and follows a large number of exposures to the intervention, safety studies are easily incorporated.

The potential efficacy of intermittent preventive treatment for malaria in pregnancy (IPTp), infants (IPTi), and children (IPTc—now called seasonal malaria chemoprevention (SMC)) has been established in numerous safety and efficacy trials (Aponte et al., 2009). Yet, to move to public health action and promote it on a large scale, evi- dence is needed on the contextual determinants, costing, acceptability, and coverage rates. Taking IPTi using sulfadoxine–pyrimethamine (IPTi-SP) as an example, a cas- cade of activities has been undertaken by the IPTi consortium (<www.ipti- malaria.org>) to establish the real-world effectiveness of this intervention if it were to be used on a large scale. First, a pooled analysis of the efficacy and safety of IPTi-SP was undertaken (Aponte et al., 2009), based on six studies conducted in different Af- rican countries. The effect of IPTi-SP on immune responses to Expanded Programme on Immunization (EPI) vaccines and on the development of naturally acquired im- munity to malaria was also studied, as well as the effect of sulfadoxine–pyrimethamine (SP) drug resistance on the efficacy of IPTi-SP. An effectiveness study of IPTi was carried out in Tanzania and included cost-effectiveness (Manzi et al., 2008), accept- ability (Gysels et al., 2009; Pool et al., 2008), and delivery through the existing health system, as IPTi is delivered through the EPI (Manzi et al., 2009). Then, a pilot study of the implementation of IPTi was carried out in six African countries, with care- ful evaluation of implementation bottlenecks and best practices, the evaluation of the impact of IPTi-SP on EPI coverage and other malaria interventions, its cost, accept- ability, drug resistance, and pharmacoviligance safety profile. A separate study on the cost-effectiveness of IPTi followed and showed that IPTi-SP, when delivered alongside the EPI, is a highly cost-effective intervention. Overall, this series of Phase IV studies showed that IPTi-SP is a valuable addition to malaria control, but its benefits depend on the contextual factors of malaria endemicity and therapeutic efficacy of the drug. The decision on where to implement should take into account the local epidemiology of malaria. The IPTi consortium also conducted modelling of the impact of IPTi (Ross et al., 2008). One outcome of all these efforts is the IPTi decision support tool. It is a web-based tool, available at <http://ipti.lshtm.ac.uk>, and is intended to aid national and sub-national policy makers in assessing whether IPTi is a locally appropriate intervention. It includes drug resistance and cost-effectiveness components to assess the applicability of IPTi at a sub-national level.