Efforts to bring repurposed antiviral medications to the public for SARS-COV-2 have now been confirmed to be largely unsuccessful and have led to suboptimal care and often poorer outcomes. There are important lessons to be learned from these past endeavors. We conducted a comprehensive review of the key trials assessing these repurposed medications and found two key factors leading to unfavorable results: a) lack of knowledge of disease pathophysiology and progression resulting in ungeneralizable and difficult-to-define trial design and b) an incomplete knowledge of the exposure-response relationships for the compounds of interest in the context of a new indication. Our literature analysis of hydroxychloroquine and remdesivir trials shows that in vitro and in vivo data correlate well in context and that this pattern can be leveraged for future trial design. Though there is a temptation to expedite trials in the midst of this unprecedented global pandemic, we propose a more measured and robust translational approach for drug investigation that integrates statistical principles and trial logistics with the so-called 4Rs (right drug, right patient, right dosage, and right timing). This ensures the critical factors of dosing regimen, route of administration and/or formulation, as well as combination therapies are selected before trial initiation, leading to robust studies with the greatest chance of success.