Patient-reported, observer-reported and performance outcomes in qualification procedures at the European Medicines Agency (EMA) 2013-2018.

We analysed the regulatory output of EMA Qualification Procedures on patient-reported outcomes (PROs), observer-reported outcomes (ObsROs) and performance outcomes (PerfOs) finalised between January 2013 and December 2018 to describe the tools, target populations, therapeutic areas, types of questions, endpoint role and the responses of EU regulators. We distilled general learnings from the procedures. Seventeen qualification programs for PROs, 6 for ObsRO tools and 11 for PerfO tools were submitted by consortia, large and small/medium companies. Gastroenterology and neurology were the most frequent therapeutic areas. There was a high level of regulators' partial agreement (above 70%) with applicant's approaches with constructive input; EMA published Letters of Support for PRO (6), ObsRO (2) and PerfO (4) tools, and qualification opinions on PROs (2), and PerfOs (1). The most frequent general issues related to Qualification Procedures on PROs raised by EU regulators related to population, appropriate studies to demonstrate ability to detect change, tool validation in interventional trials, anchoring, identification of the minimally important difference, item selection, weighting, multiple domains, and use of PROs' subdomains as clinical endpoints. In addition, specific issues for ObsROs and PerfO tools validation are identified. Overall, a need to discuss principles of validation tailored to specific settings and challenges in tool development, was evident. We encourage applicants intending to use or develop novel PRO, ObsRO and PerfO tools that will generate evidence for regulatory submissions on medicines to consider Qualification procedures for novel methods to seek feedback on the development and validation of these tools.