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