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

OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Unmet Medical Need: An Introduction to Definitions and Stakeholder Perceptions.

BACKGROUND: Despite increasing informal and formal use of unmet medical need (UMN) in drug development, regulation, and assessment, there is no insight into its definitions in use. This study aims to provide insight into the current definitions in use and to provide a starting point for a multi-stakeholder discussion on alignment. METHODS: A scoping and a gray literature review were performed to locate definitions of UMN in literature and on stakeholder websites. These definitions were categorized and then discussed among the multi-stakeholder author group via semistructured group discussions and open session workshops with a broader stakeholder audience. Issues with the formation of a common definition and mechanisms for use were discussed. RESULTS: The reviews yielded 16 definitions. Differences were evident, but all included 1 or more of the following elements: (adequacy of) available treatments (16 of 16: 100%), disease severity or burden (6 of 16: 38%), and patient population size (1 of 16: 6%). The stakeholder discussions led to a suggestion for a definition including the first 2 items and, depending on context, population size. The discussions also showed that quantification of UMN is highly dependent on the scope and the value framework in which it is used based on different stakeholder preferences and responsibilities. CONCLUSION: We encourage stakeholders that want to promote alignment on the concept of UMN to prospectively discuss the scope in which they want to apply the concept, what elements they find important for consideration in each case, and how they would measure UMN within the broader regulatory or value framework applicable.

Progression-free survival, overall survival and quality of life: What is their medicoeconomic importance in oncology?

Medico-economic evaluations estimate, for a given health technology, the added cost and the clinical benefit compared to a reference strategy. The objective here is to analyze the criteria used to measure clinical benefit as the basis for market access and reimbursement decisions for drugs in oncology both in France and in Europe. Prolonged overall survival is the criterion of choice to demonstrate the benefit of an anticancer drug; a survival gain of 2 to 3 months or more would be considered as relevant for a new product versus the comparator. In the absence of survival benefit or mature data on survival, progression-free survival or symptom-free survival and the availability of alternative curative treatments, decrease in drug toxicity and quality of life improvement may be considered. Differences in clinical benefit assessment between regulatory agencies and payers are not specific to France. Case studies show that it is difficult to find a consistency in reimbursement and pricing decisions and to identify factors that may fully explain reimbursement decisions when survival benefit is not demonstrated.

Medico-economic evaluation of healthcare products. Methodology for defining a significant impact on French health insurance costs and selection of benchmarks for interpreting results.

Decree No. 2012-1116 of 2 October 2012 on medico-economic assignments of the French National Authority for Health (Haute autorité de santé, HAS) significantly alters the conditions for accessing the health products market in France. This paper presents a theoretical framework for interpreting the results of the economic evaluation of health technologies and summarises the facts available in France for developing benchmarks that will be used to interpret incremental cost-effectiveness ratios. This literature review shows that it is difficult to determine a threshold value but it is also difficult to interpret then incremental cost effectiveness ratio (ICER) results without a threshold value. In this context, round table participants favour a pragmatic approach based on "benchmarks" as opposed to a threshold value, based on an interpretative and normative perspective, i.e. benchmarks that can change over time based on feedback.

Pharmacoepidemiology studies: what levels of evidence and how can they be reached?

In pharmacoepidemiology studies, the nature of the research question will dictate the choice of methodological approach and the conditions for optimizing the level of evidence. Thus, to document the treated population and the modes of use of a new drug in real-life prescribing conditions, a descriptive approach through cross-sectional or longitudinal studies conducted on databases, or else ad-hoc studies, will be preferred. On the other hand, evaluation of the real-life "effectiveness" of a new drug will be based on cohort, case-control or scientific modeling, depending on the drug and the disease of interest. For questions involving drug risks and safety, it is the adverse effects profile that will guide the choice of study design, both for identification of the effect (signal) and assessment of causation. In all cases, in the post-marketing authorization (MA) setting, the evidence acquired in pre-MA studies serves as the basis for generating hypotheses. Whatever the research question and the method chosen to address it, the potential biases and their impact on the results need to be identified. In certain cases, a combination of several complementary approaches may prove preferable to a single study.

Healthcare resource utilization for anemia management: current practice with erythropoiesis-stimulating agents and the impact of converting to once-monthly C.E.R.A.

UNLABELLED: Background andMethods: A prospective, observational study in 12 German and UK dialysis centers which quantified personnel time for anemia treatment using erythropoiesis-stimulating agents (ESAs). Tasks directly observable were measured through the time-and-motion method; time for non-observable tasks was estimated by healthcare staff. Using activity-based costing methods, time was converted into monetary units. Modeling was used to estimate potential time and cost savings using once-monthly C.E.R.A., a continuous erythropoietin receptor activator. RESULTS: For current ESAs in Germany and the UK, respectively: mean observed time was 1.67 and 2.67 min/patient/administration, corresponding to 31 and 42 days/year/center/100 patients; mean total time/center/100 patients/year was estimated at 79 and 95 days, equivalent to EUR 17,031 and GBP 18,739. Assuming 100% once-monthly C.E.R.A. uptake, the observed time/patient/year may decrease by 79 and 84% in Germany and the UK, respectively, compared with traditional ESAs. CONCLUSION: Conversion to once-monthly C.E.R.A. may offer the potential to reduce time spent on ESA administration in hemodialysis centers.

Managed Entry Agreements for Pharmaceuticals in the Context of Adaptive Pathways in Europe.

As per the EMA definition, adaptive pathways is a scientific concept for the development of medicines which seeks to facilitate patient access to promising medicines addressing high unmet need through a prospectively planned approach in a sustainable way. This review reports the findings of activities undertaken by the ADAPT-SMART consortium to identify enablers and explore the suitability of managed entry agreements for adaptive pathways products in Europe. We found that during 2006-2016 outcomes-based managed entry agreements were not commonly used for products with a conditional marketing authorization or authorized under exceptional circumstances. The barriers and enablers to develop workable managed entry agreements models for adaptive pathways products were discussed through interviews and a multi-stakeholder workshop with a number of recommendations made in this paper.

Erythropoietic agents in anaemic patients with cancer: a retrospective observational survey of epoetin alpha, epoetin beta and darbepoetin alpha use in routine clinical practice.

This retrospective observational survey assessed, in a routine clinical practice setting, the modalities of treatment with recombinant erythropoietic agents: alpha erythropoietic agents [epoetin alpha (Eprex) and darbepoetin alpha (Aranesp)] and epoetin beta (NeoRecormon). Evolution of haematological response parameters such as haemoglobin (Hb) during treatment of anaemic patients with cancer were contrasted for the different agents. Records of 125 consecutive adult cancer patients (42 epoetin alpha, 40 epoetin beta, 43 darbepoetin alpha) receiving chemotherapy and erythropoietic treatment for anaemia, and treated between September 2003 and February 2004, were analysed. Mean periods of observation of treatment were 103 days (epoetin alpha), 114 days (epoetin beta) and 95 days (darbepoetin alpha). The mean changes in maximum Hb level during treatment were 2.8 g/dl (epoetin alpha), 3.3 g/dl (epoetin beta) and 2.1 g/dl (darbepoetin alpha) (P=0.02, epoetin beta versus darbepoetin alpha). The proportions of patients achieving > or =1 g/ dl Hb increases were 85.7% (epoetin alpha), 87.5% (epoetin beta) and 79.1% (darbepoetin alpha). The mean cumulative doses administered to achieve these increases were 284, 722 IU; 201, 428 IU; and 208, 823 IU [dose calculated (based on equivalent peptide mass) using 1 microg darbepoetin alpha is equivalent to 200 IU epoetin], respectively. The proportions of patients achieving > or =2 g/dl Hb increases were 66.7% (epoetin alpha), 77.5% (epoetin beta) and 58.1% (darbepoetin alpha). This survey suggests that in real-life clinical conditions the available erythropoietic agents increase Hb effectively in anaemic patients with cancer, and that epoetin beta therapy may have therapeutic advantages over the other agents assessed.