Nancy Santanello of Merck Research Laboratories emphasized the importance of obtaining information about risk factors and confounding influences on ADEs before and during clinical trials. Postmarketing trials and observational studies need sufficient power and length of follow-up on real-life populations with realistic end points. Concerns about observational studies include lack of randomization, lack of collection of important information for confounding variables, and the impacts of unknown cofounders. Data may be incomplete, missing, poorly measured, or invalid. Data also can be biased. Nonrandomized groups may be unequal, and unmeasured characteristics may be different. Even when risk factors for a particular disease are well known, adjustments for comorbid factors in an observational study may not be sufficient to remove the bias caused by differences between the comparison groups resulting from unmeasured risk factors. Exposures and outcomes also can be misclassified. These are not independent, and the resultant outcomes may be strongly biased in either direction even if the misclassification is nondifferential. Dr. Chan added that there is a need for studies to address comorbidity and co-medication use in real-life populations in order to improve postmarketing safety surveillance. Dr. Santello commented that “although a paradigm for the assessment of causality using observational studies exists, it must be applied cautiously and deliberately before definitive conclusions can be drawn.” She concluded that well-designed observational studies can supplement clinical trials and provide important additional information concerning the safety and effectiveness of therapeutic interventions.

Dr. Powell called for a more quantitative approach to the development of protocols and a higher level of learning throughout the entire development process. He noted that characterizing adverse events in terms of the time of onset, the relationship to when the dose is given, and how long it takes the adverse event to end is important. Unfortunately, this information is not found in many protocols. As a logical next step to resolve these issues, Dr. Powell recommended discussing safety and efficacy in the early stages of protocol development.

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