OBJECTIVES: The tumour agnostic label for larotrectinib and entrectinib as approved by the European Medicines Agency announced a new era of personalized medicine in Europe. This study assessed whether future innovative personalized treatments entering the European market may learn lessons from tumour agnostic products, by exploring and comparing the variety of uncertainty considerations by different stakeholders (clinical trial design, regulators, health technology assessment (HTA), payers and clinical guideline developers) throughout the lifecycle?

METHODS: Uncertainty considerations for larotrectinib and entrectinib were extracted from published pivotal trials, European public assessment reports, HTA reports and clinical treatment guidelines and compared qualitatively across these stakeholders.

RESULTS: These innovations induced varying novel challenges for all healthcare decision-makers throughout the drug lifecycle. Clinical trials required unconventional basket designs, whereas their assessment by regulatory and HTA organizations made clear that assessment frameworks were not entirely suited to evaluate the benefit of these products. From the challenges and considered by the regulator (e.g. decision on orphan designation), some trickled down to the processes of national HTA organizations (e.g., lack of a clear patient population definition). Subsequently, the clinical application of tumour agnostic products in guidelines or individual treatment decisions was complicated by the challenges experienced in HTA (e.g., reimbursement for subpopulations, defining unmet medical need, lacking guidelines for the rarest subpopulations). The experiences with these two products provide a worthwhile opportunity to assess the functioning of the assessment systems from both the regulatory and HTA perspective.

CONCLUSIONS: The uncertainties considered throughout the lifecycle of tumour agnostic products varied. Novel precision treatments entering the market may learn from the specific uncertainty considerations, for example to anticipate the decision-making for orphan designations, the HTA assessments of basket trial designs and the wide heterogeneity in (small) patient populations. Insight in the uncertainty considerations across stakeholders may enhance mutual awareness across decision-makers and benefit patient access.