Design of Clinical Trials Oye Gureje

The nature of clinical trials Clinical trials are intervention studies Therapeutic intervention (secondary prevention) Preventive intervention (primary prevention) Set up to explore the superiority of one type of therapeutic intervention or preventive intervention over another Experimental in nature Exposure is introduced by investigator Why experiment? Observation is prospective rather than retrospective

Selecting the study population Reference population (to which the outcomes may apply) Nonparticipants Experimental population (considerations: size, outcome events, follow-up) Study population (fulfilling criteria, consenting, etc.)

Defining cases and controls in clinical trials Criteria for inclusion and exclusion must be rigorously defined Controls must be similar to cases in every relevant respect other than in the feature of interest Adds strength to association by reducing uncontrolled confounding Is matching necessary? Cases and controls must be representative of the population Sampling

The “cross-over” design Cases are their own controls “cases”: when exposed to intervention of interest “controls”: when not exposed to intervention of interest Observation may be affected by: changes in ambient environmental factors natural course of illness

Special features of clinical trials Human experimentation Full disclosure Informed consent Protection of human subjects Explicit criteria for withdrawal Analytic strategies for drop-outs and unequal attrition Unique problems Ethical considerations Feasibility Cost

Outcome measures in clinical trials Efficacy Side effects and interactions Time course Pharmacoeconomics Prevention

“Blinding” in clinical trials Necessary to reduce bias (e.g. observer bias) and control for placebo effect (e.g. Hawthorne effect) Types Single (simpler but with observation bias) Double (eliminates observation bias; but complex) Requirements Identical-looking interventions/preparations Multiple researchers Difficult with unique and obvious effects of interventions

Analyzing clinical trials Experiment designed to test the Null Hypothesis Sample size determination and statistical power Dependent on not just number of participants! (but also number of end points and differential attrition) Who to include in analysis Effects of multiple comparisons Type I and Type II errors