Why do neglected populations present a particular challenge?
With non-neglected conditions, sample size and inclusion criteria usually mean that data on highly refined subgroups of patients emerges from the research (i.e., the different considerations for initiating a calcium channel blocker as opposed to an ACE inhibitor for hypertension). However, for neglected conditions, a further neglect emerges – the neglect of patient complexity. The study of problems that disproportionately affect the poor can be needlessly homogenizing—ignoring individual patient characteristics which better funded conditions incorporate in their evidence-based solutions.
Another aspect of neglect hinges on the assumption of commensurability of one population for another (i.e., the idea that it is possible to extrapolate efficacy, safety and pharmacokinetic data from one population, e.g. healthy European males in their fifties to another, e.g. pregnant African women in their twenties). This assumption does not hold true in many situations, particularly where there are differences in physiology, pharmacogenetics or intercurrent disease states (e.g., renal clearance differences in pregnancy or early childhood). In cases where the research neglect relates to geopolitical or socioeconomic factors (refugees, prisoners, nomadic groups, etc.), there may be an indirect impact on pharmacokinetic parameters through intermediaries such as adherence and instability of access to food or care, but overall, it may be reasonable to extrapolate pharmacokinetic parameters from one population to another. Dietary factors may differ substantially across populations, so medicines tested in North America or Europe and then brought to Africa or Asia can encounter different dietary patterns which may affect absorption and permeability of the medicine, depending on the compound. Similarly, pharmacogenetic differences may result in clinically significant differences in drug exposure.24
Another consideration surrounds the question of when can we extrapolate safety and efficacy of repurposed drugs from one condition to another poorly understood or neglected condition, and when can we not? This can be done well in some conditions, as in the repurposing of rifamycins for leprosy prevention, and less well, as in the effort to take a “kitchen sink” approach to COVID-19 treatment based only on limited preclinical data but no rational clinical pharmacologic basis. An example of this is seen with highly protein-bound drugs’ EC50 against SARS-COV2 that cannot be clinically achieved in humans using safe doses.25 A more rational stepwise model-informed drug repurposing approach has been proposed, integrating preparatory, reactive, and retrospective action in response to new pathogens.26,27 In essence, situations of desperation call for more high-quality rational science, and not less. There is strong potential for meta-analyses of pooled individual patient data (IPD) to speed up the answering of key questions, provided they adjust for relevant heterogeneity (e.g. disease severity, dose and other drivers of drug exposure). Overall, there is an ethical imperative not to shift risk from well-controlled, carefully monitored small studies to widespread uninformed use in the general population which may be considered to amount to (often poorly controlled) experimentation. However, the latter describes the reality of how many drugs for neglected tropical diseases have been developed for special populations.
The regulatory aspects of study of drugs in special populations are complex. In some settings, strong regulatory advice that drug manufacturers study drugs in special populations such as children or orphan conditions such as XDR-TB has been incentivised with certain benefits, such as vouchers and patent extensions. There has been some criticism of this, particularly as it has not led to improvement in price or availability for many drugs that were given such incentives (e.g. miltefosine, benznidazole and several other drugs for NTDs remain difficult to obtain, prohibitively expensive or both in North America, after the pharmaceutical companies that registered them obtained hundreds of millions of dollars in benefits).28 Some have argued that the situation of inequitable study of special populations calls for a “carrot and stick approach”, where not just incentives, but strict enforcement mechanisms with punitive measures attached are needed. The passage of the Pediatric Research Equity Act (PREA) and the Best Pharmaceuticals for Children Act (BPCA), introduced as part of the FDA Safety and Innovation Act (FDASIA), took this approach.29,30 It was accompanied by guidance on how to comply with the acts, which delineated the need for study in four main age groups of children: neonates, infants, children, and adolescents. The PREA (viewed as the “stick”) requires that pharmaceutical companies submit a plan for a pediatric study with each new drug application. The drug can be launched in adults even if not yet tested in children, but the sponsor must submit its assessments in children by a certain final due date. BPCA (viewed as the “carrot”) grants sponsors who conduct pediatric studies of their products six months of market exclusivity to the company for that pediatric product. Over 85 exclusivity determinations have been granted by the FDA since September of 2007. Similar “carrot and stick” initiatives do not yet exist for pregnant, obese, or elderly individuals even though they carry disproportionately high burdens of some diseases.