Association Between Pediatric Clinical Trials and Global Burden of Disease

Discussion

There is substantial room for improvement in the match between allocation of clinical research resources and the worldwide impact of conditions. The correlation between pediatric clinical research activity and disease burden across conditions is only moderate among countries in all income levels, and least associated in low-income countries, where clinical research is sparse in general. High burden conditions are substantially understudied in countries in each of the income groups, including injuries, congenital anomalies, nutritional deficiencies, and respiratory infections. Clinical research in pediatric populations is unevenly distributed among countries at different income levels, with the majority of research conducted in high-income countries despite low-income countries accounting for the bulk of the global disease burden.

Previous studies have shown that the correlation between disease burden and research evidence as expressed by randomized trials or systematic reviews is low in sub-Saharan Africa and globally, respectively, whereas there is a better correlation with disease burden in countries with established market economies.^8,17 Research agendas may be driven primarily by the needs of and diseases afflicting wealthy nations. However, in the United States, a mismatch between National Institutes of Health funding and burden of disease has persisted despite 1998 Institute of Medicine recommendations to improve funding priorities.^6,7

Many of the diseases in less developed countries have a substantial prevalence in more developed countries where they are well studied, raising the question of whether the best strategy would be to apply evidence derived from trials conducted in more developed nations to populations in less developed countries and vice versa.¹⁸ The determinants of disease as well as the contexts for prevention and treatment are sometimes similar, but other times they can be vastly different in low- and middle-income countries, limiting the adoption of recommendations developed in high-income settings.^19,20 As an example, the ministry of health in Ghana recently considered adding several pediatric medications to its national drug program based on recommendations from the WHO Essential Medicines Program.²¹ In the process, they reviewed the evidence supporting their use and found that even when there was high-quality evidence on the benefits of the drugs, few trials had been conducted in Africa, and little of the existing evidence could be extended to Ghana due to differences in practice standards, issues of feasibility, and resource implications. Organophosphate and other pesticide exposures provide another example of the imperative to consider local context for therapeutic options. These poisonings occur at particularly high rates in low-income nations, and their treatment is fraught with challenges around access to health care not encountered in high-income countries, necessitating entirely different treatment approaches.²²

Noncommunicable diseases such as asthma, diabetes, depression, and cancers, are now the greatest contributors to death and disability worldwide and yet have been particularly neglected compared with infectious diseases in low- and middle-income countries.^10,19,23 Our results highlight this disparity, showing much higher correlation between clinical trials and disease burden for infectious diseases than other conditions. Increasing clinical research activity around infectious conditions in less developed nations may not only benefit local populations but also shed light on prevention and treatment strategies in more developed countries where many important infectious diseases are rare.^19,24 This would require building a strong, unbiased research agenda in less developed nations because there is currently evidence that in some cases, trials performed in these countries are subject to several biases, including selective reporting bias, because it is even more difficult to publish a negative result when the trial comes from a less developed country.¹⁸

For countries in each of the income groups, we identified a different set of conditions that require greater focus based on the distribution of pediatric disease burden. Other factors, such as the absolute number of trials addressing a condition, may also be relevant. Only 4 trials addressed pregnancy prevention and management among adolescents even though birth control, psychosocial needs, and the prevention of sexually transmitted diseases are entirely different in this patient population than in older women. Similarly, intentional injuries, which include self-inflicted injuries and child maltreatment, are studied in only 5 trials despite the unique circumstances that must be considered in the prevention and management of these injuries. Additional factors may also be important in evaluating research investments and funding decisions, including indirect benefits of certain types of research, political and social priorities, research quality, and potential for knowledge implementation.²⁵

A better understanding of which conditions are insufficiently addressed in the current research portfolio may provide guidance to organizations on how to allocate and prioritize available resources. Certain conditions, such as unintentional and intentional injuries, may be difficult to address in trials. These injuries result from road traffic accidents, drowning, poisoning, and fires. However, trials can address the prevention of these events as well as the medical management of the resulting injuries. Furthermore, heightened awareness of the limitations of medical research in certain areas may foster greater emphasis on other approaches, including national and global policies on road traffic safety interventions and legislation mandating universal child-resistant medication packaging.²⁶

There are several limitations to our study. Some trials are not registered in ClinicalTrials.gov, and other registries may be used differentially according to country income group. However, our query of trials in the International Trial Research Platform revealed that ∼83% of pediatric trials are registered in ClinicalTrials.gov, and the proportion of trials missing in each income group mirrors the distribution among the trials studied. It is also possible that our system for classifying trials into country income categories underestimated the amount of research being conducted in low-income countries. To explore this possibility, we conducted an additional analysis in which trials were assigned to the low-income country group if any study site was in the low-income category. This contributed an additional 53 trials to the low-income group but did not substantially change the correlations between clinical trials and disease burden (r = 0.51 for correlation with all trials and with RCTs, and r = 0.56 for correlation with drug RCTs). We used DALYs as the measure of disease burden, which have been previously used to assess associations between research activity and disease burden, but it is possible that other approaches may have highlighted different conditions as over- or understudied.^6,7,17 Finally, limitations inherent to the use of the trial registry include missing data and that we were unable to verify the completeness and accuracy of the information provided by investigators.