Randomized clinical trials are commonly regarded as the highest level of evidence to support clinical decisions. Good Clinical Practice (GCP) guidelines have been constructed to provide an ethical and scientific quality standard for trials that involve human subjects in a manner aligned with the Declaration of Helsinki. Originally designed to provide a unified standard of trial data to support submission to regulatory authorities, the principles may also be applied to other studies of human subjects. While the application of GCP principles generally led to improvements in the quality and consistency of trial operations, these principles have also contributed to increasing trial complexity and costs. Alternatively, growing availability of electronic health record data has facilitated the possibility for streamlined pragmatic clinical trials (PCTs). The central tenets of GCP and PCTs represent potential tensions in trial design (stringent quality and highly efficient operations). In the present manuscript, we highlight potential areas of discordance between GCP guidelines and the principles of PCTs and suggest strategies to streamline study conduct in an ethical manner to optimally carry out clinical trials in the electronic age.