Incremental therapeutic value of FDA-designated “breakthrough” drugs based on ratings from four international organizations: a cross-sectional study

Abstract Objectives To assess the additional therapeutic value of Food and Drug Administration (FDA) breakthrough-designated drugs using ratings from four international organizations and to address the implications of these evaluations for the program’s limitations and effectiveness. Methods We compiled a list of all breakthrough-designated new drugs from FDA reports from the start of the program in 2012 to the end of 2022. Therapeutic value was assessed using ratings from agencies in Canada, France, and Germany, as well as a nonprofit French drug bulletin. If a drug was rated by more than one organization, then the highest rating was used. Key findings The FDA approved 121 breakthrough therapies. Therapeutic evaluations were available for 96 drugs. Twenty-two (22.9%) offered major additional therapeutic benefits, 32 (33.3%) offered moderate benefits, and 42 (43.8%) minor benefits. Our findings align with prior studies suggesting a misalignment between FDA designations and actual therapeutic value. Conclusions Less than one in four drugs with a breakthrough designation that were evaluated by external organizations offered a major therapeutic advance. Given that the FDA has approved new molecular entities with limited therapeutic gain, these findings suggest a need for greater scrutiny of breakthrough designations. The FDA should periodically reevaluate approved breakthrough drugs based on new evidence that has emerged since their initial approval and withdraw the designation when drugs are shown to fall short of the early expectations on which initial breakthrough status was based.