A systematic review on the appropriate discounting rates for the economic evaluation of gene therapies: whether a specific approach is justified to tackle the challenges?

OBJECTIVES: Discounting the cost and effect for health intervention is a controversial topic over the last two decades. In particular, the cost-effectiveness of gene therapies is especially sensitive to the discount rate because of the substantial delay between the upfront cost incurred and long-lasing clinical benefits received. This study aims to investigate the influence of employing alternative discount rates on the incremental cost-effectiveness ratio (ICER) of gene therapies. METHODS: A systematic review was conducted to include health economic evaluations of gene therapies that were published until April 2023. RESULTS: Sensitivity or scenario analysis indicated that discount rate represented one of the most influential factors for the ICERs of gene therapies. Discount rate for cost and benefit was positively correlated with the cost-effectiveness of gene therapies, that is, a lower discount rate significantly improves the ICERs. The alternative discount rate employed in some cases could be powerful to alter the conclusion on whether gene therapies are cost-effective and acceptable for reimbursement. CONCLUSIONS: Although discount rate will have substantial influence on the ICERs of gene therapies, there lacks solid evidence to justify a different discounting rule for gene therapies. However, it is proposed that the discount rate in the reference case should be updated to reflect the real-time preference, which in turn will affect the ICERs and reimbursement of gene therapies more profoundly than conventional therapies.

Assessing the validity of a rapid review against a systematic literature review. A comparison of systematic literature reviews done by Cochrane with rapid reviews and the impact on meta-analyses results.

INTRODUCTION: Rapid reviews (RRs) offer a less rigorous and methodical approach to the process of reviewing literature in comparison to systematic reviews (SRs), which are currently a gold standard. MATERIALS AND METHODS: Three different, expedited strategies of the review process were designed in the different scopes, already reviewed in Cochrane's SRs. Then, the results of our literature searches and the study selection process were compared to the ones from SRs. The final step was assessing the impact of losing some studies on the final results of meta-analyses. RESULTS: In RR1, the initial number of references to be reviewed was reduced by half, and the inclusion list was recreated with 84% efficiency. Three out of 19 studies were missed, all having high risk of bias. Studies missed in RR1 were included in Cochrane's meta-analyses for 23 separate outcomes, and their lack impacted significantly the final results, or the possibility to run meta-analyses, in four cases. In RR2, 89% of trials included in the SR were captured (24/27); missing the three studies did not impact the final results of the meta-analyses. In RR3, the list of included studies overlapped completely with Cochrane's, despite a significantly lower workload. CONCLUSIONS: A prompt and cost-effective methodology may lead to the identification of pertinent evidence in support of healthcare policy; however, it is essential to conscientiously account for potential biases in the analysis.

Cost-Effectiveness of Recombinant Factor IX Fc Prophylaxis and Recombinant Factor IX On-Demand Treatment in Patients with Haemophilia B Without Inhibitors.

INTRODUCTION: Recombinant factor IX (rFIX) and recombinant FIX Fc fusion protein (rFIXFc) are standard half-life and extended half-life FIX replacement therapies, respectively, and represent established treatment options indicated for adults and children with haemophilia B. These FIX replacement therapies can be administered as prophylaxis (to prevent bleeding) or 'on-demand' (to stop bleeding). This analysis aimed to estimate the cost-effectiveness of once-weekly prophylaxis with rFIXFc versus on-demand treatment with rFIX in patients with haemophilia B without inhibitors in the Italian healthcare setting. METHODS: A Markov model was developed to assess a hypothetical cohort of adolescent or adult male patients (≥ 12 years) with haemophilia B (FIX level of ≤ 2 IU/dL) without inhibitors. Model inputs were derived from the pivotal phase 3 clinical studies for rFIXFc and rFIX, published literature and assumptions when published data were unavailable. The model employed a lifelong time horizon with 6-monthly transitions between health states, and it estimated total costs, total quality-adjusted life years (QALYs), number of bleeds, number of surgeries and incremental cost-effectiveness ratio. RESULTS: rFIXFc prophylaxis was associated with lower total costs per patient (€5,308,625 versus €6,564,510) and greater total QALYs per patient (15.936 versus 11.943) compared with rFIX on-demand; rFIXFc prophylaxis was therefore the dominant treatment strategy. The model also demonstrated that rFIXFc prophylaxis was associated with fewer incremental bleeds (- 682.29) and surgeries (- 0.39) compared with rFIX on-demand. CONCLUSIONS: rFIXFc prophylaxis provides improved health outcomes and lower costs, and represents a cost-effective treatment option compared with rFIX on-demand for adolescent and adult male patients with haemophilia B. This comparative assessment of cost-effectiveness should help to inform both clinicians and healthcare policy makers when making treatment decisions for patients with haemophilia B.

Cost-Effectiveness Analysis of Innovative Therapies for Patients with Non-Alcoholic Fatty Liver Disease.

OBJECTIVE: Currently there are no disease-specific approved therapies for non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH); however, several treatments are under development. This study aimed to estimate the cost-effectiveness of hypothetical innovative therapies compared with lifestyle intervention alone and combined with pioglitazone, and assess the health economic consequences of their future availability for patients. METHODS: A Markov cohort model was developed, considering fourteen disease health states and one absorbing state representing death. Transition probabilities, costs, utilities, and treatment efficacy were based on published data and assumptions. Four treatment strategies were considered, including two existing therapies (lifestyle intervention, small molecule treatment) and two hypothetical interventions (biological and curative therapy). The analysis was performed from the US third-party payer perspective. RESULTS: The curative treatment with the assumed efficacy of 70% of patients cured and assumed price of $500,000 was the only cost-effective option. Although it incurred higher costs (a difference of $188,771 vs. lifestyle intervention and $197,702 vs. small molecule), it generated more QALYs (a difference of 1.58 and 1.38 QALYs, respectively), resulting in an ICER below the willingness-to-pay threshold of $150,000 per QALY. The sensitivity analyses showed that the results were robust to variations in model parameters. CONCLUSIONS: This study highlighted the potential benefits of therapies aimed at curing a disease rather than stopping its progression. Nonetheless, each of the analyzed therapies could be cost-effective compared with lifestyle intervention at a relatively high price.

An Inclusive Civil Society Dialogue for Successful Implementation of the EU HTA Regulation: Call to Action to Ensure Appropriate Involvement of Stakeholders and Collaborators.

OBJECTIVES: Stakeholder involvement has long been considered a success factor for a joint European health technology assessment (HTA) process, and its relevance is now anchored in the EU HTA Regulation's (EU HTAR) legislative wording. Therefore, we aimed to explore the roles, challenges, and most important activities to increase the level of involvement per stakeholder group. METHODS: At the 2022 Fall Convention of the European Access Academy (EAA), working groups addressed the involvement of patients, clinicians, regulators, health technology developers (HTD), and national HTA bodies and payers within the EU HTA process. Each working group revisited the pre-convention survey results, determined key role characteristics for each stakeholder, and agreed on the most important activities to fulfill the role profile. Finally, the activities suggested per group were prioritized by plenary group. RESULTS: The prioritized actions for patients included training and capacity building, the establishment of a patient involvement committee, and the establishment of a patient unit at the EC secretariat. For clinicians, it included alignment on evidence assessment from a clinical vs. HTA point of view, capacity building, and standardization of processes. The most important actions for regulators are to develop joint regulatory-HTA guidance documents, align processes and interfaces under the regulation, and share discussions on post-licensing evidence generation. HTDs prioritized scientific advice capacity and the review of the scoping process, and further development of the scope of the assessment report fact checks. The top three actions for national HTA bodies and payers included clarification on the early HTD dialogue process, political support and commitment, and clarification on financial support. CONCLUSIONS: Addressing the activities identified as the most important for stakeholders/collaborators in the EU HTA process (e.g., in the implementation of the EU HTA Stakeholder Network and of the guidance documents developed by the EUnetHTA 21 consortium) will be key to starting an "inclusive civil society dialogue", as suggested by the European Commission's Pharmaceutical Strategy.

Real-world evidence for coverage determination of treatments for rare diseases.

Health technology assessment (HTA) decisions for pharmaceuticals are complex and evolving. New rare disease treatments are often approved more quickly through accelerated approval schemes, creating more uncertainties about clinical evidence and budget impact at the time of market entry. The use of real-world evidence (RWE), including early coverage with evidence development, has been suggested as a means to support HTA decisions for rare disease treatments. However, the collection and use of RWE poses substantial challenges. These challenges are compounded when considered in the context of treatments for rare diseases. In this paper, we describe the methodological challenges to developing and using prospective and retrospective RWE for HTA decisions, for rare diseases in particular. We focus attention on key elements of study design and analyses, including patient selection and recruitment, appropriate adjustment for confounding and other sources of bias, outcome selection, and data quality monitoring. We conclude by offering suggestions to help address some of the most vexing challenges. The role of RWE in coverage and pricing determination will grow. It is, therefore, necessary for researchers, manufacturers, HTA agencies, and payers to ensure that rigorous and appropriate scientific principles are followed when using RWE as part of decision-making.

Comprehensive evaluation of 45 augmentation drugs for schizophrenia: a network meta-analysis.

Background: Antipsychotics are the gold standard treatment for schizophrenia, but many patients who receive treatment experience persistent symptoms. The aim of this network meta-analysis was to determine the efficacy of augmentation drugs for the treatment of schizophrenia. Methods: In accordance with the PRISMA statement, the PubMed, Web of Science, Google Scholar, CENTRAL, clinical trial and EUDRACT databases were searched from inception to May 15th, 2023. To ensure the robustness of the results, only double-blind randomised controlled trials with a low risk of bias (measured by the Risk Of Bias v2 (ROB2) tool) were included. The studies were categorised according to the background regimen: participants were treated with risperidone, mixed antipsychotics or clozapine. A Bayesian network meta-analysis was conducted using a random effects model. PROSPERO register: CRD42023420964. Findings: A total of 44 trials (comprising 45 augmentation drugs and 3358 participants) were included in the analysis. One-third of the drugs (16 drugs) demonstrated significant efficacy vs. placebo for at least one outcome. The most notable effect sizes (ESs) were observed for the use of tropisetron (standard mean difference: -0.83 [95% interval confidence -1.12 to -0.55]), memantine (-0.50 [-0.66 to -0.32]) and minocycline (-0.56 [-0.72 to -0.39]) to treat negative symptoms among patients treated with risperidone (moderate-to-high ESs). Studies involving mixed antipsychotics yielded lower ESs (small-to-moderate). Sodium benzoate (-0.41 [-0.60 to -0.21]) and memantine (-0.23 [-0.36 to -0.11]) were found have significant effects on positive symptoms, while memantine demonstrated efficacy for negative symptoms (-0.32 [-0.45 to -0.19]) and general psychopathology (-0.32 [-0.44 to -0.20]). Studies focusing exclusively on patients treated with clozapine revealed that duloxetine produced the best results (negative symptoms: -1.12 [-1.35 to -0.91]). Sodium benzoate was the only augmentation drug that demonstrated efficacy in relieving persistent positive symptoms (-0.32 [-0.59 to -0.08]) among patients treated with clozapine. Treatment with clozapine in combination with antipsychotics yielded small-to-moderate ESs. Interpretation: The GRADE framework indicated that the quality of the evidence among the included studies was moderate, primarily due to the limited number of randomised controlled trials with a low risk of bias. Important drugs did not appear in these results due to insufficient low-risk-of-bias data for these medications. These results highlight new pathways for treating schizophrenia that should be incorporated into future guidelines after further validation. Funding: No funding.

Experience and impact of stigma in people with chronic hepatitis B: a qualitative study in Asia, Europe, and the United States.

BACKGROUND: People with chronic hepatitis B (CHB) commonly experience social and self-stigma. This study sought to understand the impacts of CHB-related stigma and a functional cure on stigma. METHODS: Adults with CHB with a wide range of age and education were recruited from 5 countries and participated in 90-minute qualitative, semi-structured interviews to explore concepts related to CHB-associated stigma and its impact. Participants answered open-ended concept-elicitation questions regarding their experience of social and self-stigma, and the potential impact of reduced CHB-related stigma. RESULTS: Sixty-three participants aged 25 to 71 years (15 from the United States and 12 each from China, Germany, Italy, and Japan) reported emotional, lifestyle, and social impacts of living with CHB, including prejudice, marginalization, and negative relationship and work experiences. Self-stigma led to low self-esteem, concealment of CHB status, and social withdrawal. Most participants stated a functional cure for hepatitis B would reduce self-stigma. CONCLUSIONS: CHB-related social and self-stigma are widely prevalent and affect many aspects of life. A functional cure for hepatitis B may reduce social and self-stigma and substantially improve the health-related quality of life of people with CHB. Incorporating stigma into guidelines along with infectivity considerations may broaden the patient groups who should receive treatment.

Drug pricing and transparency in Europe and the United States: what is it and how does it work?

INTRODUCTION: As drug prices are viewed to be opaque, there have been increasing societal demands on policy and decision makers to implement initiatives that promote drug price transparency. AREAS COVERED: This Perspective discusses what drug price transparency is and how it works in theory and in practice. EXPERT OPINION: Transparency on drug prices may target payers, patients and health care professionals; and may relate to prices at each stage in a drug's distribution system. Although proponents claim that drug price transparency will reduce prices and increase patient access, others expect the opposite effect. Nevertheless, a number of international organizations, countries and consumer groups have taken steps to enhance drug price transparency. This has occurred despite a lack of theoretical clarity and of evidence about its likely impact. Policy and decision makers need to consider how payers and pharmaceutical companies are likely to react to drug price transparency and need to be aware that transparency may produce different effects depending on the country to which it is applied. Even though we believe that full drug price transparency is elusive, various incremental measures can be taken to move toward it.

A practical approach for adoption of a hub and spoke model for cell and gene therapies in low- and middle-income countries: framework and case studies.

In the rapidly evolving landscape of biotechnologies, cell and gene therapies are being developed and adopted at an unprecedented pace. However, their access and adoption remain limited, particularly in low- and middle-income countries (LMICs). This study aims to address this critical gap by exploring the potential of applying a hub and spoke model for cell and gene therapy delivery in LMICs. We establish the identity and roles of relevant stakeholders, propose a hub and spoke model for cell and gene therapy delivery, and simulate its application in Brazil and the Middle East and North Africa. The development and simulation of this model were informed by a comprehensive review of academic articles, grey literature, relevant websites, and publicly available data sets. The proposed hub and spoke model is expected to expand availability of and access to cell and gene therapy in LMICs and presents a comprehensive framework for the roles of core stakeholders, laying the groundwork for more equitable access to these lifesaving therapies. More research is needed to explore the practical adoption and implications of this model.

Implicit factors influencing the HTA deliberative processes in 5 European countries: results from a mixed-methods research.

Background: Health technology assessment (HTA) bodies across Europe rely on explicit factors for decision making. However, additional undefined factors play a role. This mixed-methods research aimed to identify the implicit factors involved in HTA deliberative processes in five European countries, and to analyze their impact on decision making. Methods: Between February and May 2021, semi-structured interviews (n = 20) were conducted with HTA experts of three different profiles (chair, advisor, and committee member) from France, Germany, Italy, Spain, and the United Kingdom. The degree of influence of a set of implicit factors and attributes that play a role in the HTA deliberative process, as previously identified in a systematic literature review, was scored by the experts. Experts were also asked to make recommendations on ways of improving the deliberative process. A qualitative analysis and descriptive statistics of quantitative variables are reported. Results: Most (18/20) experts concurred that implicit factors play a role in the HTA deliberative process. Recommendations for improving the process fell into three categories: transparency, methodology improvement, and stakeholder involvement. The results suggest a need for 1) increased external involvement HTA and 2) development of a methodology to mitigate the influence of implicit factors in the deliberative process. This could be achieved by updating the current frameworks to acknowledge these implicit factors and by developing methods to address them.

Rule of Prevention: a potential framework to evaluate preventive interventions for rare diseases.

Background: The benefits of preventive interventions lack comprehensive evaluation in standard health technology assessments (HTA), particularly for rare and transmissible diseases. Objective: To identify possible considerations for future HTA using analogies between the treatment and prevention of rare diseases. Study design: An Expert panel meeting assessed whether one HTA assessment framework can be applied to assess both rare disease treatments and preventive interventions. Experts also evaluated the range of value elements currently included in HTAs and their applicability to rare, transmissible, and/or preventable diseases. Results: A broad range of value should be considered when assessing rare, transmissible disease prevention. Although standard HTA can be applied to transmissible diseases, the risk of local outbreaks and the need for large-scale prevention programs suggest a modified assessment framework, capable of incorporating prevention-specific value elements in HTAs. A 'Rule of Prevention' framework was proposed to allow broader value considerations anchored to severity, equity, and prevention benefits in decision-making for preventive interventions for rare transmissible diseases. Conclusion: The proposed prevention framework introduces an explicit initial approach to consistently assess rare transmissible diseases, and to incorporate the broader value of preventive interventions compared with treatment.

Pharmaceutical pricing and reimbursement policies in Algeria, Morocco, and Tunisia: comparative analysis.

Objectives: In this paper, we outline and compare pharmaceutical pricing and reimbursement policies for in-patent prescription medicines in three Maghreb countries, Algeria, Morocco, and Tunisia, and explore possible improvements in their pricing and reimbursement systems. Methods: The evidence informing this study comes from both an extensive literature review and a primary data collection from experts in the three studied countries. Key findings: Twenty-six local experts where interviewed Intervieweesincluded ministry officials, representatives of national regulatory authorities, health insurance organizations, pharmaceutical procurement departments and agencies, academics, private pharmaceutical-sector actors, and associations. Results show that External Reference Pricing (ERP) is the dominant pricing method for in-patent medicines in the studied countries. Value-based pricing through Health Technology Assessment (HTA) is a new concept, recently used in Tunisia to help the reimbursement decision of some in-patent medicines but not yet used in the pricing of innovative medicines in the studied countries. Reimbursement decision is mainly based on negotiations set on Internal Reference Pricing (IRP). Conclusion: Whereas each country has its specific regulations, there are many similarities in the pricing and reimbursement policies of in-patent medicines in Algeria, Morocco, and Tunisia. The ERP was found to be the dominant method to inform pricing and reimbursement decisions of in-patent medicines. Countries in the region can focus on the development of explicit value assessment systems and minimize their dependence on ERP over the longer-term. In this context, HTA will rely on local assessment of the evidence.

Systematic literature reviews over the years.

Purpose: Nowadays, systematic literature reviews (SLRs) and meta-analyses are often placed at the top of the study hierarchy of evidence. The main objective of this paper is to evaluate the trends in SLRs of randomized controlled trials (RCTs) throughout the years. Methods: Medline database was searched, using a highly focused search strategy. Each paper was coded according to a specific ICD-10 code; the number of RCTs included in each evaluated SLR was also retrieved. All SLRs analyzing RCTs were included. Protocols, commentaries, or errata were excluded. No restrictions were applied. Results: A total of 7,465 titles and abstracts were analyzed, from which 6,892 were included for further analyses. There was a gradual increase in the number of annual published SLRs, with a significant increase in published articles during the last several years. Overall, the most frequently analyzed areas were diseases of the circulatory system (n = 750) and endocrine, nutritional, and metabolic diseases (n = 734). The majority of SLRs included between 11 and 50 RCTs each. Conclusions: The recognition of SLRs' usefulness is growing at an increasing speed, which is reflected by the growing number of published studies. The most frequently evaluated diseases are in alignment with leading causes of death and disability worldwide.

Rapid literature review: definition and methodology.

Introduction: A rapid literature review (RLR) is an alternative to systematic literature review (SLR) that can speed up the analysis of newly published data. The objective was to identify and summarize available information regarding different approaches to defining RLR and the methodology applied to the conduct of such reviews. Methods: The Medline and EMBASE databases, as well as the grey literature, were searched using the set of keywords and their combination related to the targeted and rapid review, as well as design, approach, and methodology. Of the 3,898 records retrieved, 12 articles were included. Results: Specific definition of RLRs has only been developed in 2021. In terms of methodology, the RLR should be completed within shorter timeframes using simplified procedures in comparison to SLRs, while maintaining a similar level of transparency and minimizing bias. Inherent components of the RLR process should be a clear research question, search protocol, simplified process of study selection, data extraction, and quality assurance. Conclusions: There is a lack of consensus on the formal definition of the RLR and the best approaches to perform it. The evidence-based supporting methods are evolving, and more work is needed to define the most robust approaches.

The impact of amortization of gene therapies funding on the results and conclusions of CEMs and BIMs.

BACKGROUND: Gene replacement therapy (GRT) is a treatment method used to combat or prevent various diseases. Its high one-off cost constitutes a major obstacle for successful market access. This paper aims to assess and discuss the applicability of amortization in models, such as cost-effectiveness models (CEMs) and budget impact models (BIMs) informing HTA recommendations and reimbursement decisions. METHODS AND FINDINGS: A hypothetical CEA and BIA were considered. The objective was to compare the GRT with and without amortization. A straight-line amortization model was used. The CEM and BIM were considered and assessed based on two set of scenarios: considering different amortization duration or different discounting rate. The impact of amortization against the total cost of gene therapy was assessed for all the scenarios. The cost difference between GRT with and without amortization in relation to its total cost was -$58,855, thus amortization does not have a significant impact on the results and conclusions of the cost-effectiveness analysis. For BIM in the base case, amortization had no impact on the results. CONCLUSION: Amortization has negligible impact on the results of CEM and total BIM and no impact on the conclusions from the model. One exception is the budget impact in case of an amortization period longer than the time horizon of BIM, where a half of the GRT price is moved beyond the model time horizon. Amortization has a distinguishing effect from an accounting perspective, but it does not have any implication for payers.

The role of stakeholder involvement in the evolving EU HTA process: Insights generated through the European Access Academy's multi-stakeholder pre-convention questionnaire.

Involvement of all relevant stakeholders will be of utmost importance for the success of the developing EU HTA harmonization process. A multi-step procedure was applied to develop a survey across stakeholders/collaborators within the EU HTA framework to assess their current level of involvement, determine their suggested future role, identify challenges to contribution, and highlight efficient ways to fulfilling their role. The 'key' stakeholder groups identified and covered by this research included: patients', clinicians', regulatory, and Health Technology Developer representatives. The survey was circulated to a wide expert audience including all relevant stakeholder groups in order to determine self-perception by the 'key' stakeholders regarding involvement in the HTA process (self-rating), and in a second, slightly modified version of the questionnaire, to determine the perception of 'key' stakeholder involvement by HTA bodies, payers, and policymakers (external rating). Predefined analyses were conducted on the submitted responses. Fifty-four responses were received (patients 9; clinicians: 8; regulators: 4; HTDs 14; HTA bodies: 7; Payers: 5; policymakers 3; others 4). The mean self-perceived involvement score was consistently lower for each of the 'key' stakeholder groups than the respective external ratings. Based on the qualitative insights generated in the survey, a RACI Chart (Responsible/Accountable/Consulted/Informed) was developed for each of the stakeholder groups to determine their roles and involvement in the current EU HTA process. Our findings suggest extensive effort and a distinct research agenda are required to ensure adequate involvement of the key stakeholder groups in the evolving EU HTA process.

Recommendations for economic evaluations of cell and gene therapies: a systematic literature review with critical appraisal.

OBJECTIVE: No consensus exists on the ideal methodology to evaluate the economic impact and value of new, potentially curative gene therapies. We aimed to identify and describe published methodologic recommendations for the economic evaluation of gene therapies and assess whether these recommendations have been applied in published evaluations. METHODS: This study was conducted in three stages: a systematic literature review of methodologic recommendations for economic evaluation of gene therapies; an assessment of the appropriateness of recommendations; and a review to assess the degree to which the recommendations were applied in published evaluations. RESULTS: A total of 2,888 references were screened, 83 articles were reviewed to assess eligibility, and 20 papers were included. Fifty recommendations were identified, and 21 reached consensus thresholds. Most evaluations were based on naive treatment comparisons and did not apply consensus recommendations. Innovative payment mechanisms for gene therapies were rarely considered. The only widely applied recommendations related to modeling choices and methods. CONCLUSIONS: Methodological recommendations for economic evaluations of gene therapies are generally not being followed. Assessing the applicability and impact of the recommendations from this study may facilitate the implementation of consensus recommendations in future evaluations.

Mapping the EORTC QLQ-C30 onto the EQ-5D-5L index for patients with paroxysmal nocturnal hemoglobinuria in France.

Aim: To map patient-level data collected on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC) QLQ-C30 to EQ-5D-5L data for estimating health-state utilities in patients with paroxysmal nocturnal hemoglobinuria (PNH). Materials & methods: European cross-sectional PNH patient survey data populated regression models mapping EORTC QLQ-C30 domains (covariates: sex and baseline age) to utilities calculated with the EQ-5D-5L French value set. A genetic algorithm allowed selection of the best-fitting between a set of models with and without interaction terms. We validated the selected algorithm using EQ-5D-5L utilities converted from EORTC QLQ-C30 data collected in the PEGASUS phase III, randomized controlled trial of pegcetacoplan versus eculizumab in adults with PNH. Results: Selected through the genetic algorithm, the ordinary least squares model without interactions provided highly stable results across study visits (mean [±SD] utilities 0.58 [±0.42] to 0.89 [±0.10]), and showed the best predictive validity. Conclusion: The new PNH EQ-5D-5L direct mapping developed using a genetic algorithm enabled calculation of reliable health-state utility data required for cost-utility analysis in health technology assessments supporting treatments of PNH.