Conducting research into supportive care for patients as they initiate treatment with oral oncolytic agents poses numerous new challenges. Some of these medications have very complex dosing schedules and produce symptoms that patients need to manage at home with less reliance on oncology clinicians. We describe lessons learned from a multi-site trial designed to improve adherence to these medications and self-management of symptoms among patients newly prescribed oral oncolytic agents. Identifying these challenges can assist researchers to improve the integrity of their future supportive care trials.