Principles of nonexperimental assessment of excess risk, with special reference to adverse drug reactions.

The risk of a particular kind of adverse reaction to a particular agent must be thought of with reference to the contemplated type of exposure and the type of person potentially exposed, and critically important in the contemplated exposure is its duration. In the general case, a distinction has to be made between risk during exposure and that after its discontinuation. For both of these risks, modifications of their magnitudes especially by previous exposure to the same agent must be considered. These risks are studied by focusing on incidence densities specific to subintervals of the total periods of risk. Assessment of these densities is generally best accomplished by following a (very large) dynamic (open) population, not specified on the basis of exposure. Cases of the adverse event, without regard for their etiology, that occur in this source population over the period of follow-up need to be identified and classified, first as to whether they arose from the study population proper or from the extraneous segment of the source population. Those arising from the study population and characterized by "recent" exposure--implying potential causation by it--need to be classified according to the attained duration of exposure and, where applicable, time since its discontinuation at the time of the inception of the adverse event. An appropriate sample of the source population over its follow-up needs to be obtained and classified in like manner.(ABSTRACT TRUNCATED AT 250 WORDS)