ABSTRACT
Sometimes questions of clinical interest such as the efficacy and safety of a treatment can be addressed only by investigations without concurrent controls that are under the supervision of the investigator (internal controls). Such studies nearly always make use of other types of comparisons (external controls), such as historical controls.
In this chapter we examine studies of clinical treatments that have weak internal controls or lack internal controls, as illustrated by examples from the New England Journal of Medicine. These studies have a small but important and unique role in clinical investigation. Five interrelated features can add to the strength of such studies: (1) an intent by the investigator, expressed before the study, that the treatment will affect the outcomes reported; (2) planning of the analysis before the data are generated; (3) articulation of a plausible hypothesis before the results are observed; (4) a likelihood that the results would still have been of interest if they had been “opposite” in some sense; and (5) reasonable grounds for generalizing the results from the study subjects to a substantially broader group of patients.
Examples of successful studies of this kind include reports of dramatic or surprising results, encouraging results of innovations in desperate circumstances, studies of unique groups, and early warnings. In each successful use, we find evidence of urgency, with timeliness of the report outweighing its tentative nature.
In spite of potential pitfalls, carefully selected and reported studies without internal controls can play a substantial part in the acquisition of scientific knowledge. They can warn of dangers, point out opportunities, and help determine the focus of more powerful controlled studies, whose strength they complement but do not duplicate.
