Predictive testing and clinical trials in Huntington's disease: An ethical analysis

Dilemmas arise concerning how to design studies aimed at preventing or slowing Huntington’s disease (HD) in mutation-positive presymptomatic individuals. HD is an autosomal-dominant neurodegenerative disease. Each child of an HD gene expansion carrier (HDGEC) has a 50% chance of inheriting the mutation, but the clinical symptoms typically only appear in middle age. In the absence of clinical symptoms or having obtained predictive genetic testing, such a person is considered at risk for HD. Although genotyping for the HD mutation approaches 100% accuracy, the decision to undergo predictive genetic testing for a debilitating, stigmatized, and ultimately fatal disease is highly personal. Predictive testing rates in HD are <20% in Europe and only 5%-7% in the United States. We now know that the underlying neurodegeneration starts at least a decade before clinically overt symptoms appear, with the implication that it may be too late to modify the disease once signs and symptoms are apparent. Several potential HD therapeutics are now reaching clinical development, raising ethical questions of whether clinical trials should include atrisk individuals who choose not to undergo testing. Within this context, there is an important distinction in the way that the genetic status of an individual is identified. Whereas “predictive testing” is a personalized feedback process initiated by a person who wants to know if he or she carries the HD gene expansion, “research genotyping” is only done for the purposes of a study; results are not disclosed and are usually only made accessible in the form of aggregate, anonymized databases. Here we examine 3 possible trial designs for interventions in premanifest HD using the 4 basic ethical principles (autonomy, beneficence, nonmaleficence, and justice).