Pediatric therapeutics and medicine administration in resource-poor settings: A review of barriers and an agenda for interdisciplinary approaches to improving outcomes☆
Introduction
It is estimated that 9.2 million children—most of them under five years of age—die annually (UNICEF, 2008). This astounding statistic is due, in part, to the lack of available, affordable pediatric drug formulations for many common infectious diseases. We define a ‘pediatric drug formulation’ as a dosage format which is suitable for accurately, safely, effectively, and adherently administering a medication to children of various ages. The World Health Organization (WHO) approximates that more than 50% of medicines prescribed for children, including many of those on the Model List of Essential Medicines for Children, do not actually exist in dosage forms appropriate for children (WHO Press Release 1/21/09). Even when pediatric formulations exist, clinical availability varies. Consequently, health workers often dispense adult dosage forms with instructions on how to achieve desired pediatric doses. This may include instructing caregivers to break tablets, crush pills, open capsules and estimate dose, or use medicines formulated for intravenous injection as oral liquids. Use of medicines in such a manner can lead to inaccurate dosing and result in potentially reduced efficacy (due to under-dosing) and/or adverse effects (due to excessive doses). An unpublished 2006–2007 WHO survey notes that countries reported using adult formulations for the treatment of children with HIV/AIDS (53% of respondents), TB (52%) and malaria (41%). Thirteen countries described problems with dosing of pediatric medicines, while 14 identified problems caused by lack of pediatric dosage forms and high prices of those available (S. Hill, pers. comm.). Formulations of drugs are fundamentally important because they help to determine whether the dose will be successfully delivered to pediatric patients; however, information on how best to prepare and administer pediatric drug formulations—in any cultural setting—is often lacking (Nunn & Williams, 2005). This is a critical global health issue.
In this article, we use pediatric tuberculosis an example of such dynamics. The WHO estimates that worldwide one in three people is infected with tuberculosis bacillus. About 8.5 million people develop TB annually and 1.8 million people die from the disease each year. Latest estimates put the number of smear-positive cases among children and adolescents at 1 million per year (Nelson and Wells, 2004, Newton et al., 2008). Currently, more than 90% of childhood TB cases occur in the developing world (Adams, 2004). In areas where HIV is also prevalent, a dangerous synergy ensues. In one Ethiopian study, TB mortality was reported as six times higher in HIV-infected children (Berggrem et al. in Adams, 2004: 689). Additionally, HIV infection has been associated with poorer TB treatment adherence in children, due to parent illness or death, as well as poorer treatment outcomes due to immune suppression (Adams, 2004).
Determining estimated TB burden in children poses particular challenges. It is difficult to establish a definitive pediatric TB diagnosis because children with TB are rarely sputum-smear positive. Furthermore, childhood TB—including clinical evaluation of new drugs—has consistently been a lower public health priority than adult TB (Adams, 2004, Burman et al., 2008, Nelson and Wells, 2004, Newton et al., 2008). Yet children are ‘sentinel’ cases: they represent recent transmission of TB into communities. Children are also at higher risk of progression to active disease than adults; this risk is greatest for infants and children under two years (Newton et al., 2008). In addition, children younger than five are more likely to develop severe forms of TB, and those who recover from primary TB disease remain sources of future active, infectious cases (Adams, 2004). The dearth of high quality (e.g. non counterfeit, expired or substandard) TB drugs at costs that are free or affordable, and that are administered through functioning health systems in pediatric dose forms hinders childhood TB control and treatment (Zucker & Rago, 2007). Fixed-dose combination pills have long been available for adults, but the ratios of medicines and doses are inappropriate for children; no fixed dose or even individual pediatric TB formulations are available. Furthermore, despite WHO recommendations for combination treatment of malaria and TB, no such products have been registered for use in children.
The need to reconcile appropriate pediatric formulations and issues of drug palatability with socioeconomic, cultural, and health systems realities with which the majority of the world's children contend (and in which most pediatric TB cases occur) is urgent. Children cannot be treated as ‘little adults’ when it comes to producing and distributing essential drugs, including frontline TB pharmaceuticals (Braine, 2007, Burman et al., 2008). The creation of actionable, informed policies and interventions aimed at addressing pediatric health inequalities demands an interdisciplinary approach. Aside from pharmacological concerns about dosage, toxicity, stability, bioavailability, and palatability, as well as the economics of drug production and distribution, an array of sociocultural issues surface in the effort to create, market, distribute, and administer essential pediatric pharmaceuticals in resource-poor settings. We not only need more clinical evidence on the efficacy and safety of medicines for children; we also require more qualitative data from diverse social ecologies about patient, caregiver, and provider knowledge, behavior, beliefs, and attitudes with regard to medicine in general and biomedical pharmaceuticals in particular. This includes efforts to understand the socioeconomic parameters within which medicines are given: how childhood illnesses are classified and explained, how definitions of a ‘child’ on the one hand, and ‘taste’ on the other, vary cross-culturally, and how these factors, in turn, impact patient, caregiver, and provider expectations and practices. Furthermore, we need to know how caregivers and providers manage to administer medicines to children under less than ideal circumstances today. We also need to know more about what their preferences are—or would be—for improved pediatric pharmaceuticals, in order to mitigate barriers to adherence in the future. The goal of this article, then, is not only to provide a comprehensive review of literature on pediatric therapeutics across the social and biomedical sciences, but also to articulate the need for an interdisciplinary research agenda which employs pharmacological, clinical, and anthropological perspectives in order to improve health outcomes among young people, particularly in resource-poor settings.
Section snippets
Background and conceptual framework
This article addresses—through the lens of children's medicines—key methodological issues raised by Nichter and Vuckovick (1994: 1509) in their “Agenda for an Anthropology of Pharmaceutical Practice.” Specifically, this review moves from a concern with patterns of curative resort that are illness-centered toward a framework that considers pediatric therapeutics and medicine administration from the perspective of the social and economic realities of prescription, to the interrelationship between
Methodology
In preparation for research which aims to describe and analyze patient, caregiver, provider, and pharmacist preferences for optimal formulations of pediatric pharmaceuticals in three East African countries,1 we conducted a review of more than 200 studies in the social sciences, public health and epidemiology, and
Palatability and physical attributes of medicines
People often evaluate medications based on color, form, and taste. In a study among the Mende of Sierra Leone, Bledsoe and Goubaud (1985) found that people assessed the strength and effects of medications largely by evaluating their physical characteristics: the size of a pill indicated its power. In a study among drug sellers and consumers in rural Nigeria, respondents associated the color of medicines with their effects and purposes; they preferred yellow to blue for, in this case,
Dosage and definitions of the child
Many experts describe pediatric TB dosage regimes, and discuss the challenges in administering these medicines (Enarson et al., 2005, Hopewell et al., 2006, Newton et al., 2008). They report that few randomized controlled trials have been done in children to establish optimum regimes; current treatment guidelines are largely inferred from adult data. Currently, WHO is working on a consensus for dose and dose-ratios for combination TB products for children, based on pharmacokinetic and
Cultural epidemiology and ethnophysiology of childhood illnesses
Among other topics, medical anthropologists examine the pluralistic nature of health care systems. Many scholars have pointed out that diversity within health care systems has not obviated the need for conceptual frameworks applicable across cultures and changing social settings (Janzen, 1978, Kleinman, 1980, Leslie, 1977, Leslie, 1980). Two key frameworks to emerge from the discipline are cultural epidemiology and ethnophysiology. Cultural epidemiology arose from efforts to apply an integrated
Perceptions and expectations of medications among caregivers and providers
The literature reveals significant differences in caregiver reports of adherence to drug regimes and physician judgments about adherence rates. Some reasons for this difference emerge directly from ethnophysiological concerns related to diet and the possibilities within a given cultural context for defining, diagnosing, and treating childhood illnesses. Other concerns are tied to duration of treatment and associated ‘pill burden’, a term which refers to the number and kinds of dose forms a
Stigma and social suitability of medicines
It is crucial to consider the roles medicines play in the construction and negotiation of specific illness identities (Nichter & Vuckovic, 1994: 1515). The ways illnesses are viewed socially bears directly on how, why, or if people seek treatment and adhere to medicine regimes. This may include social affinities or aversions to specific forms of medicines (e.g. pills or injections). Assessing the ‘social suitability’ of medicines is particularly salient in cases where forms of treatment can
Conclusions
Since 2006, a number of steps have been taken by WHO and the World Health Assembly (WHA) to address these issues (Braine, 2007, Couper and Kaplan, 2007). In May 2007, WHA identified the improved access to essential medicines for children as a prerequisite to achieving health outcomes set out in the United Nations Millennium Development Goals (MDGs) (Zucker & Rago, 2007). This was identified through resolution WHA60.20. Launched in December 2007 and spearheaded by WHO, the ‘make medicines child
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This research was supported by a grant from the World Health Organization (WHO) as part of the Better Medicines for Children project. The findings, interpretations and conclusions expressed in this paper are entirely those of the authors and should not be attributed in any manner whatsoever to WHO. The authors thank Suzanne Hill, Jane Robertson, Kalle Hoppu, Robert Whitley, and the four anonymous reviewers for their helpful comments on drafts of this manuscript.