OBJECTIVES: Uncertainty is a fundamental component of healthcare decision-making. Framing uncertainty depends on the scientific discipline and is highly context specific. Therefore, its interpretation and the corresponding risks are a major challenge to decision-makers. Following the 2021 HTAi Global Policy Forum, an HTAi-DIA Working Group (WG) was initiated to develop guidance to facilitate uncertainty management. This guidance aims to support stakeholder dialogue on the identification and mitigation strategies for perceived uncertainties in the interface of regulatory and Health Technology Assessment (HTA)-regulatory decision-making.

METHODS: The WG consisted of 26 members with different backgrounds, and expertise relevant to the topic including the academic, regulatory, HTA, payer, developer, and patient perspective. The guidance was established through: i) six online discussions among the WG between December 2021 and September 2022 using insights from a scoping literature review and two literature case studies (larotrectinib and lumacaftor/ivacaftor), ii) a survey disseminated across the WG members and iii) applying the guidance to an ongoing case study.

RESULTS: The WG identified key terms and concepts, codified into twelve building blocks that together were perceived to define uncertainty, i.e., ‘unavailable’, ‘biased, ‘conflicting’, ‘incomprehensible’, ‘random variation’, ‘information’, ‘prediction’, ‘impact’, ‘risk’, ‘judgement’, ‘context’, ‘relevance’. The building blocks were then translated into a checklist to be able to define whether any issue constitutes a relevant uncertainty. Additionally, a regulatory-HTA-relevant taxonomy, including domains in which uncertainty may exist, was developed to facilitate the categorization of the relevant uncertainties. Functioning of the guidance and how it may be applied in dialogues on mitigation strategies was demonstrated using a case study.

CONCLUSIONS: The systematic approach for the identification of uncertainties in this guidance has the potential to ensure mutual understanding between stakeholders through improved consistency and transparency. To further support uncertainty management and stakeholder dialogue, a future step is to systematically align uncertainty identification with suitable mitigation strategies.