— Elena Nicod, Lindsay Kreill, Anna Albiero, Amanda Whittal
The rapid evolution of healthcare technologies, from gene and cell therapies to tumour-agnostic and personalised treatments, offers unprecedented potential to address unmet medical needs and transform patient outcomes. However, access to these innovations remains variable and often delayed, largely due to the limitations of traditional health technology assessment (HTA) approaches. Conventional evidence hierarchies, rooted in randomized controlled trials (RCTs) and other “gold standard” evidence, can fail to capture the full value of emerging therapies, particularly in contexts where patient populations are small, diseases are rare or rapidly progressive, or long-term outcomes cannot be measured within feasible timeframes.
This paper highlights the concept of unavoidable uncertainty, situations in which uncertainty associated with clinical evidence cannot be fully resolved, not due to a lack of rigor, but because of scientific, ethical, or practical constraints. Recognizing this spectrum of uncertainty is critical for HTA bodies seeking to balance patient access, innovation, and budget sustainability. Uncertainty ranges from fully resolvable, to reasonable uncertainty (where some gaps are tolerated to unlock meaningful
benefits), to irreducible uncertainty (which persists despite time or investment).
