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.