How can novel treatments be safely and ethically investigated?
The clinical evaluation of a potential treatment in these ‘complex’ or
‘neglected groups’ requires first a balancing of risks and benefits,
including whether or not there is better data for alternative treatments
in the vulnerable sub-population. (An example of harm caused by a skewed
balancing of these risks was treating malaria in pregnant women and
young children with chloroquine long past the point of widespread
chloroquine resistance, because it was perceived as safe for the
vulnerable, even though these groups were also at the highest risk of
the potentially severe consequences of failed malaria treatment.) It
also requires innovative approaches, including partnership between
clinical pharmacologists and pharmacometricians. Physiologically-based
pharmacokinetic modelling uses a ‘bottom-up’ approach based on knowledge
of cellular processes to predict drug exposure within a specific
population. Models can be adapted to encompass characteristics such as
nutritional status, hepatic or renal dysfunction, pregnancy, concurrent
administration of interacting medications and other factors which may
render a population ‘neglected’.31-33 This can provide
a starting point for clinical trials to confirm the predicted dosing
strategies in vulnerable and neglected patient groups. Optimal design
theory uses mathematical approaches to predict the ideal sampling
schedule for the most efficient study design. This enables the minimum
number of participants to be included with the least invasive sampling
schedule in order to yield the highest quality
information.34,35 Population pharmacokinetic modelling
explores sources of variability between individuals, and adds to the
understanding of how different ‘neglected’ characteristics may impact on
drug exposure and thereby on the appropriate dosing schedules to ensure
safe, effective treatment.36 Combinations of these
techniques have the potential to yield high quality, efficient clinical
studies and advance prompt understanding of sources of variability in
drug exposure and thus potentially efficacy and safety, particularly in
these difficult-to-study groups.37