The European Medicines Agency has solidified its recommendations to drugmakers that want to use single-arm designs in a pivotal trial, but emphasized that any such case “needs justification.”
The regulator’s advice was detailed in an updated working paper released Monday, which makes clear that randomized, controlled trials are expected as the norm. When drugmakers use a single-arm design to create pivotal evidence, they need to clearly define the success criteria ahead of time, the regulator said.
One example of adequate predetermined success criteria, according to the agency, could be a threshold that the study’s lower or upper bound of the confidence interval must exceed.
The working paper also says that any primary endpoint in a single-arm trial must be something that occurs “only to a negligible extent” without an adequate treatment. In other words, the endpoint of a single-arm trial shouldn’t be an event that could feasibly happen to a good number of patients without any intervention.
Though the report focuses on guidelines for single-arm trial efficacy, it makes clear that assessing safety is also “fraught with substantial shortcomings.” The level of detail that the EMA is asking for on efficacy applies equally to safety, the agency wrote.
The detailed guidance comes about 18 years after the EMA began granting conditional marketing authorization, Europe’s equivalent of the accelerated approval pathway in the US. Previous research published in May 2023 found that conditional approval applications in the second half of the program’s first 14 years included 38% fewer randomized Phase 3 trials than applications in the first half.
Study data suggested “an increase in the number of uncertainties with regard to the benefit–risk, but this may also be a consequence of the European public assessment reports having become more extensive and detailed in recent years,” the authors concluded. That fewer applications had randomized data may support critiques that the conditional pathway was being used as “a rescue option,” the authors wrote, adding that it may also reflect the rarity of some of the indications being pursued.