Protocol for the economic evaluation of the diarrhea alleviation through zinc and oral rehydration salt therapy at scale through private and public providers in rural Gujarat and Uttar Pradesh, India

Worldwide, diarrhea is the fourth leading cause of mortality among children under 5, accounting for 9% of total deaths [1]. In 2011, over 700,000 children died due to diarrhea [2], with eighty percent of cases occurring in East Asia and the Pacific, South Asia, and Africa, and 33% in South Asia alone [3]. However, diarrhea mortality is a solvable health problem, with this number of deaths having fallen from 4.6 million in 1980 [4]. India is a priority area for addressing the remaining burden, recognized as one of 15 countries that account for 53% of total episodes worldwide, with 312.22 million episodes and 205,600 deaths each year nationwide [2].

Since becoming widely used for diarrhea treatment in the 1980s [5], oral rehydration salts (ORS) have been instrumental in contributing to declines in prevalence. ORS prevents mortality by reducing the loss of fluids and electrolytes and death due to dehydration [6]. However, coverage of ORS in India remains low at less than 30%, and one out of ten children nationwide continues to experience diarrhea in any 2-week period [7].

The 2004 United Nations Children’s Fund (UNICEF)/World Health Organization (WHO) Joint Statement for the Clinical Management of Acute Diarrhea revised the global standards for acute diarrhea management to include ‘20 mg per day of zinc supplementation for 10–14 days (10 mg per day for infants under 6 months old)’ [8]. The therapeutic effect of zinc is to strengthen the immune system, improve absorption of water and electrolytes in the intestines, enhance the regeneration of the gut epithelium, increase levels of enzymes in the epithelium, and help the body clear pathogens from the intestines [9]. As a complement to ORS, zinc has been shown to reduce incidence [8], prevalence [10], and duration of diarrhea episodes [8],[9],[11]-[13]. Evidence on whether zinc reduces all-cause mortality is scarce, with one trial using non-injury mortality as a proxy for diarrhea deaths [9], not testing mortality as an outcome [11], or not having sufficient power to detect a significant difference in mortality [13]. Baqui et al. (2002) showed a non-significant difference in non-injury deaths, controlling for other factors, and authors concluded that the effect on mortality was due to zinc [9]. Applying the Child Health Epidemiology Reference Group (CHERG) Rules for Evidence Review indicates that mortality reduction could be as much as 23%, and ideal data, from randomized controlled trials (RCTs), is unlikely to emerge as the strength of evidence in support of zinc makes these trials unethical [14].

In India, evidence on the effectiveness of zinc for the management of acute diarrhea is mixed between studies showing an effect [10],[15],[16], and those with no or marginal effects [17]-[19]. Of these, one was conducted in a rural community setting [10]. This randomized controlled trial was carried out in six primary health care (approximately 30,000 population each centers) in Haryana [10], which provided an intervention that included training and supply of zinc and ORS to Anganwadi Workers and primary health center staff. This intervention nearly doubled the proportion of patients that received treatment between 3 and 6 months. In addition, the intervention led to significant reductions in diarrhea prevalence and the rate of hospitalizations due to diarrhea.

Building upon the success of effectiveness trial activities in Haryana, programmatic efforts to introduce zinc and ORS have been initiated throughout the last decade in India. Between 2005–10, the Point-of-Use Water Disinfection and Zinc Treatment (POUZN) project was implemented and found to be effective in improving both supply and demand for zinc. This program worked with pharmaceutical companies, channeled zinc through both the public and private sectors, collaborated with non-governmental organizations (NGOs), recruited support from key opinion leaders, provided training to detailers, stimulated prescribing practices among rural medical providers (RMPs), and promoted products with social marketing.

In 2010, the Diarrhea Alleviation using Zinc and ORS Therapy (DAZT) program expanded upon POUZN activities in scale and scope to make zinc and ORS available for the management of diarrhea through private and public sector providers in 6 districts of Gujarat and 12 districts of Uttar Pradesh (UP) states of northern India. DAZT is similar to POUZN in the characteristics mentioned above, but differed in that DAZT did not provide point-of-use water interventions, monitored zinc purchase and sales with short messaging service (SMS) in the private sector, and promoted zinc through informational booths in private clinics and hospitals. A full description of DAZT program activities is presented in Table 1.

The objective of this study is to evaluate the cost-effectiveness of the DAZT program under real-world conditions compared to the status quo existing before the intervention was introduced in the study area. Two analytical approaches will be used to meet this objective: calculation of cost-effectiveness using a Monte Carlo Simulation method with patient level data [20], and calculation of cost-effectiveness using a net-benefit regression approach to control for covariates [21].

Both community-based [Lefevre et al. forthcoming, Bishai et al. forthcoming] and model-based evidence [4],[22] suggest that zinc supplementation to treat diarrhea is cost-effective in low- and middle-income countries (LMICs), although hospital-based studies do not find a significant difference in cost [23], effect [19], or both [24] between children receiving zinc and those that do not. These studies were conducted across a wide range of settings; however, none of them can be classified as implementation research. This study will evaluate the cost-effectiveness of the DAZT program and further discourse on approaches to economic evaluation of health programs in low- and middle-income countries. Methodologically, examples of cost-effectiveness analyses evaluating ‘before and after’ studies designs are emerging (for example [25],[26]); however, these types of studies are not well established in the literature. Thought is needed to identify special considerations that may be relevant to before and after study evaluations. The International Society for Pharmacoeconomics and Outcomes Research (ISPOR) has developed guidelines for using ‘real-world data’ [27], but guidelines for conducting cost-effectiveness analysis (CEA) alongside ‘before and after’ studies do not exist.

Alternative methods for conducting CEA are sometimes used to evaluate a single dataset to make methodological points, assess validity, and test robustness of results according to structural uncertainty [21],[28],[29]. Two of several analytical approaches available for CEA include Monte Carlo Simulation methods with patient level data [20] and net-benefit regression [21]. The latter framework combines established methodologies from economic evaluation and econometrics and has the advantage of being able to adjust for imbalances in confounding variables. Net-benefit regression methodology can be used for randomized [21],[30] and non-randomized studies [31],[32], although the case can be made that it is even more appropriate for non-randomized study designs as covariates are more likely to be unevenly distributed across study arms [33]. Bootstrapping confidence intervals presents the problem of ambiguity in incremental cost-effectiveness ratios (ICERs), although this problem can be circumvented in both methods using the net-benefit statistic, and both net-benefit regression and bootstrapping can be used to generate cost-effectiveness acceptability curves (CEACs). The bootstrap approach offers one advantage in that uncertainty around program costs can be simulated by resampling from parametric distributions fit to the data, while program costs are divided evenly across patients within each arm in the net-benefit regression approach [21] or are assumed to cancel out across study arms or phases [31]. Deterministic calculations and net-benefit regression are commonly evaluated in tandem in the literature [21],[31],[32], but scope exists to add thought on comparisons between bootstrapping and net-benefit regression. It is anticipated that documenting thought behind choosing between these analytic frameworks will be useful to researchers facing similar questions about evaluation of programs with similar study designs.

Policy recommendations from the completed research will add to the growing literature evaluating the cost-effectiveness of zinc for diarrhea treatment in low- and middle-income countries. Findings will be timely as India is developing a Health Technology Assessment (HTA) program in collaboration with the UK National Institute of Health and Care Excellence [34], in which the importance of CEA in policy making can be expected to increase. In addition, local capacity to produce zinc is rapidly expanding including Bharat Immunologicals and Biologicals Corporation Limited (BIBCOL), which is a government-owned corporation with the capacity to produce 240 million of 20 mg scored tablets of zinc sulfate per year [35]. Currently, about 40 private companies are producing zinc for local and international markets.

This article presents the DAZT program in India. Analytic methods for evaluating cost-effectiveness are described and compared, in addition to methods for assessing wealth quintile using principal components analysis. Strengths and limitations of the study are discussed, followed by arguments against targeting zinc according to subgroup, and considerations necessary for drawing conclusions about generalizability.

Economic evaluation provides insights into the appropriate allocation of resources, and yet the number of cost-effectiveness and cost-utility analyses alongside programs at scale - where large amounts of resources are invested - remains limited. When planning these studies, differences in methods adopted have implications on the validity of findings and on their generalizability. Economic evaluation has traditionally focused on the cost of an intervention to produce a desired health outcome in studies based on modeled evidence or data collected alongside randomized controlled trials. As the number of interventions with known impact on health increases, there is an increased need for evidence on ways of operationalizing delivery of these health services to ensure high coverage, quality, and cost-effectiveness.

The aims of the DAZT intervention are to improve the supply, demand, and prescribing practices for treatment of diarrhea in children with zinc and ORS. These objectives are consistent with goals of The Indian Academy of Pediatrics [55], WHO [56], and UNICEF [3] who have all endorsed zinc supplementation to ORS for the treatment of diarrhea in children. In addition, the Government of India has established the Oral Rehydration Therapy Program to increase awareness about causes of diarrhea and its treatment among mothers and communities [7], and results of this study may be used to support this program.

This study will provide an evaluation of a zinc delivery strategy in a resource-constrained setting, in addition to a comparison of methods for cost-effectiveness analysis. The calculation of results using two different methods will provide evidence about the robustness of results, while informing broader discourse on methods for carrying out economic evaluations alongside programs delivered at scale. Each method has its strengths and limitations. The Monte Carlo Simulation with patient level data approach will allow for the incorporation of uncertainty around program costs and is a more widely used technique than the net-benefit regression approach. The net-benefit regression framework will allow for cost-effectiveness to be calculated controlling for other factors, which are unbalanced across arms in this study. Comparing the two analytical approaches will stimulate discussion about when analysts should choose one over the other when planning their analyses, particularly in the context of evaluation of programs at scale.