Associations between uncertainties identified by the European Medicines Agency and national decision making on reimbursement by HTA agencies

Abstract

We aimed to determine whether uncertainties identified by the European Medicines Agency (EMA) were associated with negative relative effectiveness assessments (REA) and negative overall reimbursement recommendations by national health technology assessment (HTA) agencies. Therefore, we identified all HTA reports from HAS (France), NICE (England), SMC (Scotland) and ZIN (the Netherlands) for a cohort of innovative medicines that EMA had approved in 2009-2010 (excluding vaccines). Uncertainty regarding pivotal trial methodology, clinical outcomes and their clinical relevance were combined to reflect a low, medium or high level of uncertainty. We assessed associations by calculating risk ratios (RR) and 95% confidence intervals (CI), and agreement between REA and overall reimbursement recommendation outcomes. We identified 36 medicines for which 121 reimbursement recommendations had been issued by the HTA agencies between September 2009 and July 2018. High vs. low uncertainty was associated with an increased risk for negative REAs and negative overall reimbursement recommendations: RRs 1.9 (95% CI 0.9-3.9) and 1.6 (95% CI 0.7-3.5), respectively, which was supported by further sensitivity analyses. We identified a lack of agreement between 33 (27%) REA and overall reimbursement recommendation outcomes, which were mostly restricted recommendations that followed on negative REAs in case of low or medium uncertainty. In conclusion, high uncertainty identified by EMA was negatively associated with REAs and overall reimbursement recommendations. To reduce uncertainty and ultimately facilitate efficient patient access, regulators, HTA agencies and other stakeholders should discuss how uncertainties should be weighed and addressed early in the drug life cycle of innovative treatments.

The Beneluxa Initiative domain task force health technology assessment: a comparison of member countries’ past health technology assessments

“…Added benefit conclusions were categorized into higher, equal, and less therapeutic value which facilitates comparison and is in line with previous studies on this topic (11;15). Similarities between countries in added benefit conclusions were examined by setting one country as the reference through which the conclusions from the other country were compared.…”

Differences in Evidentiary Requirements Between European Medicines Agency and European Health Technology Assessment of Oncology Drugs—Can Alignment Be Enhanced?

“…This is in line with a study that researched the effect of uncertainty on HTA decisions. 8 In that study, high uncertainty was related a 1.9-fold increased risk of negative relative efficacy assessments and 1.6-fold increased risk of negative overall reimbursement recommendations. That study suggested that, with medium level of uncertainty, clinical and economic restrictions, unmet medical need, and price-related aspects could help HTA bodies consider the uncertainty as acceptable.…”

“…With oncology drugs, there is often a high unmet medical need. 8 A non-oncology-specific comparative analysis showed that a high level of full agreement was reached between European Union regulators and participating HTA bodies, through the process of parallel scientific advice. 6 This differs from our analysis, which showed a low level of full alignment between HTA bodies and EMA and a high level of partial alignment.…”

“…Regulators such as EMA appear to be more willing to accept a degree of uncertainty than HTA bodies. 7,8 Moreover, drugs following the EMA conditional MA pathway carry even more uncertainty, because of the use of immature data, and therefore are at higher risk of not being reimbursed by national HTA bodies. 9 Despite the growing awareness of the differences in assessment, no study has yet described what these differences are for oncology drugs.…”

Uncertainty management in regulatory and health technology assessment decision-making on drugs: guidance of the HTAi-DIA Working Group

“…Uncertainty management refers to carefully balancing the benefits of reducing uncertainty with the efforts of doing so and the opportunity costs of the alternatives (2). The added value of reducing uncertainty has many dimensions, for example, improved knowledge on treatment efficacy or safety, a reduced possibility for decision errors, a better understanding of the relative effectiveness or associated costs reducing the risk of healthcare displacement or efficiency in the design and implementation of solutions (2;6;10–13). The costs associated with uncertainty reduction in terms of additional evidence generation can be tackled to some extent through value of information (VOI) analyses (14).…”