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Randomized, controlled clinical trials (RCTs) may be possible, permissible, and practical in certain circumstances, but ethical or practical considerations often preclude their utilization. In many such cases, ethical objections will not apply to a similarly oriented, prospective, matched-pair observational study. Additionally, if the methodological rigor associated with the RCT is maintained, potential epistemic losses due to eliminating randomization will be mitigated. It is therefore suggested that when ethics precludes randomization, prospective, protocol-driven, matched-pair observational studies be put to work. One can also envision extending observational studies beyond their traditional time-dependent bounds to encompass never-ending activities focused on the accumulation of clinical knowledge in real-world settings.