Issues in design and analysis of a randomized clinical trial to assess the safety of dental amalgam restorations in children.

The Casa Pia Study of the Health Effects of Dental Amalgams in Children is a randomized clinical trial designed to assess the safety of low-level mercury exposure from dental amalgam restorations in children. It is being carried out in 507 students (8 to 12 years of age at enrollment) of the Casa Pia school system in Lisbon, Portugal, by an interdisciplinary collaborative research team from the University of Washington (Seattle) and the University of Lisbon, with funding from the National Institute of Dental and Craniofacial Research. Since the goal of the trial is to assess the safety of a treatment currently in use, rather than the efficacy of an experimental treatment, unique design issues come into play. The requirements to identify as participants children who have extensive unmet dental treatment needs and who can be followed for 7 years after initial treatment are somewhat in conflict, since those with the most treatment needs are usually in lower socioeconomic categories and more difficult to track. The identification of a primary study outcome measure around which to design the trial is problematic, since there is little evidence to indicate how health effects from such low-level exposure would be manifested. The solution involves the use of multiple outcomes. Since there are concerns about safety, multiple interim comparisons over time between treatment groups are called for which, in conjunction with the use of multiple outcomes, require an extension of statistical methodology to meet this requirement. Ethical questions that have to be addressed include whether assent of the children participating is required or appropriate, and whether the director of the school system, who is the legal guardian for approximately 20% of the students who are wards of the state and live in school residences, should provide consent for such a large number of children. Approaches taken to address these and other design issues are described.