With great interest, we read the article entitled “Uncertainty Management in Regulatory and Health Technology Assessment Decision-Making on Drugs: Guidance of the HTAi-DIA Working Group” by Hogervorst et al. (Reference Hogervorst, Vreman and Heikkinen1). We wish to commend HTAi, DIA, and the Working Group for selecting this important topic.

To our surprise, the guidance only references a small subset of the extensive work on the topic of uncertainty in and outside of health technology assessment (HTA). Not referenced were articles on considerations around uncertainty in health (Reference Claxton2–Reference Kalke, Studd and Scherr7), classifications of uncertainty in HTA (Reference Briggs, Weinstein and Fenwick8–Reference Grimm, Pouwels and Ramaekers11) and outside HTA (Reference Walker, Harremoes and Rotmans12–Reference Bouwknegt and Havelaar16), and methods for uncertainty assessment (Reference Wolff, Qendri, Kunst, Alarid-Escudero and Coupe17–Reference Mauskopf22), among others. For a scientific article in a scientific journal, methods and results of the scoping review are not described in sufficient detail. It remains unclear if and how the state of the art on uncertainty in HTA was used to develop the guidance.

Specifically, the part on “building blocks comprising decision-making uncertainty” bears non-negligible similarity to published work that is identified in the authors’ scoping review but not cited – the TRUST tool 2020 (Reference Grimm, Pouwels and Ramaekers11). TRUST considers the same uncertainty factors as outlined in the present article, including origin (location in TRUST), type (source in TRUST), impact/risk (same in TRUST), and relevance/judgment (appraisal in TRUST). The types of actionable uncertainty considered are also very similar: inaccurate (separated into imprecision, bias, and indirectness in TRUST); unavailable (same in TRUST); and non-understandable (transparency in TRUST). In line with existing classifications of uncertainty (Reference Briggs, Weinstein and Fenwick8;Reference Bouwknegt and Havelaar16), TRUST also considers uncertainty stemming from methodological issues. TRUST does not include uncertainty from conflicting information, as this was considered to be reflected through imprecision or bias (Reference Bilcke, Beutels, Brisson and Jit4). TRUST is readily available, validated, practical, and used in practice (e.g., in Dutch Healthcare Institute reports). It is unclear how the presented guidance improves upon this.

There is an opportunity to build upon the challenges other researchers in the area of uncertainty assessment in and outside of HTA have identified and the methods proposed to address these. The progress made on the following topics has not been sufficiently covered in the guidance, including but not limited to:

• • uncertainty identification, for example, using the TRUST tool (Reference Grimm, Pouwels and Ramaekers11) and other methods (Reference Annemans and Makady6;Reference Otten, Grimm, Ramaekers and Joore18);

• • uncertainty analysis methods including Bayesian methods (Reference Nixon, O’Hagan and Oakley23), value of information (Reference Fenwick, Steuten and Knies24–Reference Heath, Manolopoulou and Baio26), structured expert elicitation (Reference Bojke, Soares and Claxton27;Reference Ayers, Cope and Towle28), and incorporation of difficult to quantify uncertainty (Reference Strong, Oakley and Chilcott29–Reference Jackson, Bojke, Thompson, Claxton and Sharples33);

• • uncertainty communication (Reference Wolff, Qendri, Kunst, Alarid-Escudero and Coupe17;Reference Alarid-Escudero, Enns, Kuntz, Michaud and Jalal34–Reference Grimm, Pouwels and Ramaekers36);

• • link between uncertainty and evaluation of managed entry agreement (MEA) schemes (Reference Grimm, Pouwels and Ramaekers36–Reference Grimm, Strong, Brennan and Wailoo39);

• • uncertainty (in)tolerance in regulatory and HTA decision-making (Reference Grutters, van Asselt, Chalkidou and Joore3;Reference van Asselt and Vos40–Reference Salcher-Konrad, Naci and Davis42).

As a next step, the Working Group refers to the link of their proposed framework with mitigation strategies. Importantly, there are existing frameworks and tools covering this topic including frameworks for classifications of different MEA schemes (Reference Walker, Sculpher, Claxton and Palmer43;Reference Garrison, Towse and Briggs44), and approaches for assessing MEAs (Reference Grimm, Pouwels and Ramaekers36;Reference Grimm, Strong, Brennan and Wailoo39;Reference Grimm, Strong, Brennan and Wailoo45). We urge the Working Group to consider and transparently build upon these, where relevant.

To conclude, we agree with the HTAi-DIA Working Group that uncertainty is a fundamental component of decision-making. We argue that collaboration with experts in the abovementioned topics and thorough, transparent reviews of the literature to build upon the wealth of existing knowledge will make the resulting guidance stronger.