Presentation (CTI)

OBJECTIVES: Health Technology Assessment (HTA) bodies favour "gold standard" clinical evidence for decision-making. However, new, innovative complex treatments, often with high potential for patient outcomes, have raised concerns about evidence uncertainty, resulting in restricted patient access. This research proposes a framework to assess uncertainty arising across different scientific and clinical contexts, to identify when certain types of uncertainty may be inevitable or unavoidable. Defining such circumstances may indicate where a more flexible approach to uncertainty may be justified.
METHODS: A conceptual framework was developed to characterise the source of evidence uncertainty. Common uncertainties were identified and reviewed through targeted literature and case studies to determine when and why uncertainties arise, and whether they are unavoidable or due to reasonable trade-off e.g. ethical, clinical, logistical or commercial. The framework was refined with input from a multi-stakeholder Advisory Board, which also considered HTA solutions to address them.
RESULTS: The framework conceptualises uncertainty as a spectrum, from cases involving reasonable trade-offs to situations where ethical, consent-related or logistical constraints make uncertainty unavoidable. Key sources of uncertainty include small sample size, cross-over designs, lack of blinding or long-term data, absence of control arm, outdated comparators, surrogate endpoints, heterogeneity, and limitations in PROMs and external validity. The sources were mapped against disease and product-specific to identify the circumstances when flexibility in evidence standards may be justified. One proposed solution is the creation of HTA “sandboxes”, that allow for delimited and structured environments to explore deviations from standard evidence requirements, inspired by regulatory models such as the EU’s 2023 pharmaceutical legislation proposal. These could enable early access to innovation while ensuring stakeholder involvement and controlled implementation.
CONCLUSIONS: Developing a more nuanced approach to handling uncertainty, through more flexible assessment approaches, can improve and accelerate patient access to promising therapies.