Health technology assessment (HTA) is a critical part of healthcare decision making in many countries. Changes in Methods and Processes (M&P) of HTA agencies can affect the time and degree of patient access to treatments. Published literature focuses on the different M&P adopted by HTA agencies, rather than on how these have come about over time. Our study investigates key HTA reforms and explores their drivers and interdependencies in a set of HTA agencies in Europe, Asia-Pacific, and North America.

We conducted a targeted literature review on M&P guidelines and subsequent changes to those, for 14 HTA agencies. We supplemented and validated initial findings with 29 semi-structured interviews with country-specific experts. We used analytical tools to create process maps, proactivity and influence networks, and clusters of HTA agencies.

We found that processes leading to M&P reforms follow similar steps across HTA agencies. The three most important drivers to reforms were HTA practice and guidelines in other countries; the healthcare policy, legal, and political context within the agency’s country; and experience of challenges in the assessment by the HTA body itself. International collaborations have the potential to accelerate the evolution of HTA systems and the implementation of reforms.

We identified PBAC (Australia), CDA-AMC (Canada), NICE (England), IQWiG (Germany), and ZIN (the Netherlands) as HTA agencies that are catalysts of HTA reforms as well as internationally influential. International collaborations may represent a useful route to accelerate changes as long as they ensure wide stakeholder engagement at an early stage.

The European Union Joint Clinical Assessment (JCA) process aligns with the regulatory process to promote faster patient access. The PICO (population, intervention, comparator, and outcome) scoping for the JCA must occur before the regulatory process concludes. The risk of indication change during this period is one of the concerns for the success of the JCA process. We investigated the frequency and type of changes that are made to proposed indications and examined how such changes could impact the PICO scoping for JCA.

Twenty-seven recently approved oncology and 15 Advanced Therapy Medicinal Products (ATMP) products were included. Observed indication changes were categorized into editorial or population changes population changes were graded based on the anticipated impact on JCA scope depending on their nature.

The majority of products had only editorial changes between proposed and approved indications (67 percent). Once amended, it was common for the indicated population to be narrowed, and rare for it to be broadened. The most common change observed was the shift to a later treatment line. The greatest risk for PICO rescoping would be when new populations would have been added, or new subpopulations or subgroups would have been omitted from the initial scope.

The impact on JCA scope depends on the proposed indication wording and how the PICO scoping would have been conducted. Rescoping warrants a considered decision, and to mitigate the risk of delays, dialogue between the assessors and the developer is recommended for informed decision-making.

Uncertainty is a fundamental component of decision making regarding access to and pricing and reimbursement of drugs. The context-specific interpretation and mitigation of uncertainty remain major challenges for decision makers. Following the 2021 HTAi Global Policy Forum, a cross-sectoral, interdisciplinary HTAi-DIA Working Group (WG) was initiated to develop guidance to support stakeholder deliberation on the systematic identification and mitigation of uncertainties in the regulatory-HTA interface.

Six online discussions among WG members (Dec 2021–Sep 2022) who examined the output of a scoping review, two literature-based case studies and a survey; application of the initial guidance to a real-world case study; and two international conference panel discussions.

The WG identified key concepts, clustered into twelve building blocks that were collectively perceived to define uncertainty: “unavailable,” “inaccurate,” “conflicting,” “not understandable,” “random variation,” “information,” “prediction,” “impact,” “risk,” “relevance,” “context,” and “judgment.” These were converted into a checklist to explain and define whether any issue constitutes a decision-relevant uncertainty. A taxonomy of domains in which uncertainty may exist within the regulatory-HTA interface was developed to facilitate categorization. The real-world case study was used to demonstrate how the guidance may facilitate deliberation between stakeholders and where additional guidance development may be needed.

The systematic approach taken for the identification of uncertainties in this guidance has the potential to facilitate understanding of uncertainty and its management across different stakeholders involved in drug development and evaluation. This can improve consistency and transparency throughout decision processes. To further support uncertainty management, linkage to suitable mitigation strategies is necessary.