This thesis aimed to improve the methodology of disease-modification clinical trials in neurodegenerative disorders, with particular reference to Parkinson's disease (PD) and Alzheimer's disease. A systematic review was undertaken to determine what biomarkers for disease progression in PD exist, and whether any have sufficient evidence to be used in clinical trials. Included studies (n=183) were generally of poor quality, being cross-sectional with small numbers of participants, applying excessive inclusion/exclusion criteria, having flawed methodologies and applying simplistic statistical analyses. Insufficient evidence was, therefore, found to recommend the use of any disease progression biomarker in PD clinical trials. A subsequent review in Alzheimer's disease (n=59) demonstrated that these issues were not unique to PD. A 'roadmap' was, therefore, developed to improve future disease progression biomarker studies. The sensitivity to change of a range of PD clinical outcome measures was analysed using data from a follow-up study of an incident cohort of patients with parkinsonism. The MMSE, total UPDRS and PDQ-39 summary index were the most sensitive to change of the continuous outcome measures examined. Amongst binary outcome measures, a new 'dead or dependent' outcome measure was most sensitive to change, and was shown to be a feasible outcome measure for future PD RCTs. Finally, a systematic review was undertaken to examine the validity of differing clinical trial designs used in Alzheimer's disease and PD to demonstrate disease-modification. A variety of design strategies, including wash-in and wash-out analyses, delayed-start designs and long-term follow-up studies, have been used but have methodological limitations. No evidence was found of novel clinical trial designs having been used previously or planned for use in the future. Final recommendations are made that future disease-modification trials should be long-term follow-up studies involving newly diagnosed patients. 'Dead or 'dependent' is highlighted as an efficacious measure to use in such trials.