Over-reliance on short-term trials with selected patients is built into the approval process, creating risks that medications will be approved with no consideration of their longer-term harms. This can only be rectified by a sustained public commitment of resources to longer-term trials, or, by changes to regulations to make drug approval contingent on longer-term trials. The Commission recommends expanded support for pragmatic trials of medications that enroll all individuals who are likely to receive the medication in practice. In addition to having a greater chance of detecting adverse effects, because of their heterogeneous samples, such trials also have more power to identify subgroups of patients who benefit particularly from medications. Such trials do not necessarily require public funding; manufacturers could be required to provide the funding to non-industry investigators to conduct them. Importantly, the findings of such longer-term trials should be consistently reviewed by drug approval agencies so that they can make informed judgements on whether medications approved on the basis of short-term results should be restricted or pulled from the market because of their longer-term harms.  The close monitoring of potential long-term effects of COVID-19 vaccines is a model worth applying to opioids.