SUSTAIN-HTA – D1.2 – First Yearly Methodological Needs Overviews

The SUSTAIN-HTA project is funded by the European Union's Horizon Europe programme under the grant agreement No 101136318. The UK participant is supported by UKRI grant No 10106859 (National Institute for Health and Care Excellence). Views and opinions expressed are however those of the author(s) only and do not necessarily reflect those of the European Union, the United Kingdom, HaDEA or UKRI. Neither the European Union, the United Kingdom, nor the granting authorities can be held Lead contributor Saif Elayan (1 – UU), Wim Goettsch (1 – UU) and Karen Facey (1 – UU) Other contributors Shane Collins (15 – NICE), Zoe Garrett (15 – NICE), Fatima Salih (15 – NICE), Saskia Knies (4 – ZIN) and Femke Schuitmaker (4 – ZIN) Work Package WP1 – Identification, Synthesis & Prioritisation Due date 31/12/2024 Delivery date 24/01/2025 Deliverable type R Dissemination level PU – Public 101136318 – SUSTAIN-HTA Support Utilisation of Sustainable and TAilored INnovative methods for HTA D1.2 – First Yearly Methodological Needs Overviews Ref. Ares(2025)589165 - 25/01/2025 D1.2 – First Yearly Methodological Needs Overviews WP1 – Identification, Synthesis & Prioritisation Version: V1.4 Authors: Saif Elayan, Karen Facey, Shane Collins, Zoe Garrett, Fatima Salih, Saskia Knies, Femke Schuitmaker, and Wim Goettsch Dissemination: PU 2/42 © Copyright 2024 SUSTAIN-HTA Consortium TABLE OF CONTENTS DOCUMENT HISTORY ........................................................................................................ 3 DEFINITIONS ....................................................................................................................... 4 LIST OF ABBREVIATIONS ................................................................................................... 5 EXECUTIVE SUMMARY ...................................................................................................... 6 1 Introduction .................................................................................................................... 8 2 Methods ......................................................................................................................... 9 2.1 Engagement with HTA Bodies ................................................................................ 9 2.2 Targeted Literature Review ................................................................................... 10 2.2.1 Search Strategy ........................................................................................... 10 2.2.2 Eligibility Criteria .......................................................................................... 10 2.2.3 Study Selection Process .............................................................................. 10 2.2.3.2 Full-Text Review .......................................................................................... 11 2.2.3.3 Data ............................................................................................................. 11 2.3 Data Analysis ........................................................................................................ 11 3 Results ......................................................................................................................... 11 3.1 Discussion Session with HTA Bodies .................................................................... 11 3.2 Targeted Literature Review ................................................................................... 12 3.2.1 Literature Search and Study Selection ......................................................... 12 3.2.2 Study Characteristics ................................................................................... 13 3.2.3 Synthesis of Included Studies ...................................................................... 14 4 Discussion ................................................................................................................... 17 4.1 Relative Effectiveness Analysis (REA) .................................................................. 17 4.1.1 Real World Evidence (RWE) ........................................................................ 17 4.1.2 Indirect Comparisons ................................................................................... 18 4.1.3 Surrogate Endpoints .................................................................................... 19 4.1.4 Multiplicity .................................................................................................... 19 4.2 Cost-Effectiveness Analysis (CEA) ....................................................................... 20 4.2.1 Indirect Costs and Benefits .......................................................................... 20 4.2.2 Extrapolation ................................................................................................ 20 4.2.3 Uncertainty................................................................................................... 21 4.2.4 Health Gains for the Paediatric Population ................................................... 22 4.3 Elements of Value ................................................................................................. 23 4.4 Limitations ............................................................................................................ 23 5 Conclusion ................................................................................................................... 24 References ......................................................................................................................... 26 Appendices ......................................................................................................................... 29 Appendix A ...................................................................................................................... 29 Appendix B ...................................................................................................................... 36 Appendix C ...................................................................................................................... 37 Appendix D ...................................................................................................................... 38 D1.2 – First Yearly Methodological Needs Overviews WP1 – Identification, Synthesis & Prioritisation Version: V1.4 Authors: Saif Elayan, Karen Facey, Shane Collins, Zoe Garrett, Fatima Salih, Saskia Knies, Femke Schuitmaker, and Wim Goettsch Dissemination: PU 3/42 © Copyright 2024 SUSTAIN-HTA Consortium DOCUMENT HISTORY Version Date Description V1.0 19 December 2024 First Draft V1.1 20 December 2024 Second Draft for Steering Committee Review V1.2 17 January 2025 Third Draft V1.3 20 January 2025 Fourth Draft V1.4 24 January 2025 Final version D1.2 – First Yearly Methodological Needs Overviews WP1 – Identification, Synthesis & Prioritisation Version: V1.4 Authors: Saif Elayan, Karen Facey, Shane Collins, Zoe Garrett, Fatima Salih, Saskia Knies, Femke Schuitmaker, and Wim Goettsch Dissemination: PU 4/42 © Copyright 2024 SUSTAIN-HTA Consortium DEFINITIONS Partners of the SUSTAIN-HTA Consortium are referred to herein according to the following codes: 1. UU Universiteit Utrecht (Netherlands) 2. UB Universita Commerciale Luigi Bocconi (Italy) 3. EMC Erasmus Universitair Medisch Centrum Rotterdam (Netherlands) 4. ZIN Zorginstituut Nederland (Netherlands) 5. RUMC Stichting Radboud Universitair Medisch Centrum (Netherlands) 6. SRI Syreon Kutato Intezet Korlatolt Felelossegu Tarsasag (Hungary) 7. OSTEBA Fundacion Vasca de Innovacion e Investigacion Sanitarias (Spain) 8. GetReal I GetReal Institute (Netherlands) 9. SYNAPSE Research Management Partners (Spain) 10. NIPN Nemzeti Nepegészségügyi és Gyógyszerészeti Központ (Hungary) 11. AGE.NA.S Agenzia Nazionale per i Servizi Sanitari Regionali (Italy) 12. AQUAS Agencia de Qualitat i Avaluació Sanitaries de Catalunya (Spain) 13. NOMA Statens Legemiddelverk (Norway) 14. UCSC Universita Cattolica del Sacro Cuore (Italy) 15. NICE National Institute for Health and Care Excellence (United Kingdom) Grant agreement The agreement signed between the beneficiaries and the European Health and Digital Executive Agency for the undertaking of the SUSTAIN-HTA project (101136318). Project The sum of all activities carried out in the framework of the Grant Agreement. Consortium The SUSTAIN-HTA Consortium, comprising the above-mentioned legal entities. Consortium agreement Agreement concluded amongst SUSTAIN-HTA partners for the implementation of the Grant Agreement. Such an agreement shall not affect the parties’ obligations to the Community and/or to one another arising from the Grant Agreement. D1.2 – First Yearly Methodological Needs Overviews WP1 – Identification, Synthesis & Prioritisation Version: V1.4 Authors: Saif Elayan, Karen Facey, Shane Collins, Zoe Garrett, Fatima Salih, Saskia Knies, Femke Schuitmaker, and Wim Goettsch Dissemination: PU 5/42 © Copyright 2024 SUSTAIN-HTA Consortium LIST OF ABBREVIATIONS Acronym Description AI Artificial Intelligence ATMPs Advanced Therapy Medicinal Products CEA Cost-Effectiveness Analysis CGT Cell and Gene Therapy EQ-5D EuroQol-5 Dimensions HRQoL Health-Related Quality of Life HTA Health Technology Assessment HTACG The Coordination Group on Health Technology Assessment HTAR The EU Health Technology Assessment Regulation ITC Indirect Treatment Comparison JCA Joint Clinical Assessment ML Machine Learning PSM Partitioned Survival Modelling OMP Orphan Medicinal Product QALY Quality-adjusted life year RCT Randomised Controlled Trial REA Relative Effectiveness Assessment RWD Real-World Data RWE Real-World Evidence D1.2 – First Yearly Methodological Needs Overviews WP1 – Identification, Synthesis & Prioritisation Version: V1.4 Authors: Saif Elayan, Karen Facey, Shane Collins, Zoe Garrett, Fatima Salih, Saskia Knies, Femke Schuitmaker, and Wim Goettsch Dissemination: PU 6/42 © Copyright 2024 SUSTAIN-HTA Consortium EXECUTIVE SUMMARY Advancements in medical science have led to increasingly complex health technologies, whose value assessment presents significant challenges for existing Health Technology Assessment (HTA) methodologies. Simultaneously, new policies and regulations have led to accelerated access to these technologies. As a result, HTA bodies are often required to base their assessments on limited or preliminary data, making the evaluation of these technologies more challenging. In this evolving landscape, there is a pressing need to identify the methodological needs of HTA bodies. A clear understanding of these needs facilitates the development and implementation of new scientific methods that address emerging challenges. This understanding is also essential for guiding capacity-building initiatives that enhance HTA bodies' ability to assess emerging technologies effectively, ultimately supporting betterinformed healthcare resource allocation decisions. Against this backdrop, SUSTAIN-HTA is developing a new horizon-scanning tool (SUSTAINHS) to identify the methodological needs of HTA bodies in Europe. This report marks the first step in this effort, focusing on gaining a further understanding of the methodological needs relating to relative effectiveness assessment (REA) and cost-effectiveness analysis (CEA) of medicines. To this end, a targeted literature review was conducted, complemented by insights gathered from engagement with HTA bodies within the SUSTAIN-HTA network. On 29 October 2024, the SUSTAIN-HTA Network held a discussion session to explore methodological challenges in conducting REA and CEA of medicines. Representatives from seven consortium HTA body partners and seven external HTA organisations participated. Key challenges raised included leveraging target trial emulation to enhance causal inference with real-world data (RWD). Participants also highlighted the transformative potential of artificial intelligence (AI) in HTA while stressing the imperative to address biases in its applications. Persistent challenges were also noted, including the statistical handling of multiplicity in clinical studies and evidence synthesis, as well as the complexities in evaluating histology-independent treatments. The discussion also touched on broader challenges not confined to medicines and extending beyond REA and CEA. These encompassed the need for expedited scientific reporting frameworks to enhance the timeliness of HTA processes, as well as challenges in assessing companion diagnostics, handling price confidentiality, and implementing outcomes-based managed entry agreements. A targeted literature review was conducted to identify the methodological needs of European HTA bodies in conducting REA and CEA of medicines. The review consisted of peer-reviewed literature published in English between January 2019 and October 2024. Out of the 1,336 studies identified, 20 were deemed eligible for inclusion. The methodological needs identified were grouped into eight themes and categorised as REAor CEA-related, except for one theme that pertained to the appraisal process. For REA, the first theme focused on real-world D1.2 – First Yearly Methodological Needs Overviews WP1 – Identification, Synthesis & Prioritisation Version: V1.4 Authors: Saif Elayan, Karen Facey, Shane Collins, Zoe Garrett, Fatima Salih, Saskia Knies, Femke Schuitmaker, and Wim Goettsch Dissemination: PU 7/42 © Copyright 2024 SUSTAIN-HTA Consortium evidence (RWE), with a need for up-to-date guidelines for its use, practical demonstrations of advanced statistical methods, collaboration between academia and HTA bodies, and the integration of machine learning (ML) and generative AI to enhance causal inference. The second theme related to indirect comparisons, highlighting a need for methods for handling cross-trial heterogeneity, accommodating complex evidence networks, and incorporating RWE. The third theme concerned the need for advancements in methods for surrogate endpoint validation. For CEA, the needs identified included approaches to accounting for indirect costs and benefits (theme 4). Further needs were reported for advancements in methods for extrapolating outcomes (theme 5) and characterising uncertainty (theme 6), particularly for advanced therapy medicinal products (ATMPs) and orphan medicinal products (OMPs). There was also a pressing need for validated tools to assess health gains in paediatric populations, especially for children under the age of five, where such tools remain scarce (theme 7). The eighth and final theme, which pertained to the appraisal process, emphasised the need to incorporate additional attributes of value for new treatments. This review will be continually updated to incorporate new evidence as it becomes available while expanding its scope to include broader HTA domains. These updates will be supplemented by surveys and further discussions with HTA bodies to ensure a contemporary understanding of their methodological needs. D1.2 – First Yearly Methodological Needs Overviews WP1 – Identification, Synthesis & Prioritisation Version: V1.4 Authors: Saif Elayan, Karen Facey, Shane Collins, Zoe Garrett, Fatima Salih, Saskia Knies, Femke Schuitmaker, and Wim Goettsch Dissemination: PU 8/42 © Copyright 2024 SUSTAIN-HTA Consortium 1 Introduction Health Technology Assessment (HTA) is a ‘multidisciplinary process that uses explicit methods to determine the value of a health technology at different points in its lifecycle. The purpose is to inform decision-making in order to promote an equitable, efficient, and highquality health system’ [1]. Central to HTA are methodologies such as relative effectiveness assessment (REA) and cost-effectiveness analysis (CEA). Other dimensions of HTA include ethical, social, cultural and legal issues, organisational and environmental aspects, as well as wider implications for the patient, relatives, caregivers, and the population. The healthcare landscape is rapidly evolving, driven by advancements in medical science and technology-enabled healthcare systems. This evolution has led to increasingly complex health technologies, such as advanced therapy medicinal products (ATMPs) and histologyindependent treatments. Evaluating the value of these new health technologies introduces complexities that challenge existing HTA methodologies. Hogervorst et al. investigated the challenges of assessing these complex technologies for HTA organisations [2]. While most of the challenges identified in their paper were rooted in data insufficiencies, several methodological challenges in REA and CEA were highlighted. Specifically, these included heterogeneity-induced challenges in modelling and difficulties in dealing with uncertainty in selecting appropriate comparators. Further challenges arose from the low quality of health economic models delivered by health technology developers and difficulties associated with modelling cure for ATMPs. Adding to these challenges are evolving regulatory frameworks that increasingly tend toward earlier access to new health technologies. This trend often requires HTA bodies to conduct assessments based on limited or preliminary data, further straining existing REA and CEA methodologies. Another significant regulatory development is the new EU regulation on Health Technology Assessment (HTAR), which will transform how health technologies are evaluated across Europe. From January 2025, REAs will be undertaken as part of Joint Clinical Assessments (JCAs) for oncology medicines and ATMPs. Selected high-risk devices will follow in 2026, with the scope expanding to orphan medicinal products (OMPs) in 2028 and all medicinal products by 2030. This regulatory shift underscores the growing importance of robust REA methodologies. In this dynamic landscape of healthcare advancements and regulatory changes, there is a pressing need to systematically explore and anticipate the methodological needs of HTA bodies. This exploration is crucial to ensure that required new methods are developed by experts and disseminated for widespread HTA use, enabling HTA to be fit for the future. Additionally, identifying these needs can guide efforts to enhance HTA bodies’ capacity to assess emerging health technologies effectively, ultimately supporting better-informed healthcare resource allocation decisions. D1.2 – First Yearly Methodological Needs Overviews WP1 – Identification, Synthesis & Prioritisation Version: V1.4 Authors: Saif Elayan, Karen Facey, Shane Collins, Zoe Garrett, Fatima Salih, Saskia Knies, Femke Schuitmaker, and Wim Goettsch Dissemination: PU 9/42 © Copyright 2024 SUSTAIN-HTA Consortium Therefore, the main aim of Task 1.3 is to establish a horizon-scanning tool (SUSTAINHS) capable of identifying the methodological needs of HTA bodies in Europe, including the Coordination Group on Health Technology Assessment (HTACG). This report represents the first step in this effort, assessing the needs of European HTA bodies for scientific methods related to REA and CEA for medicines. Subsequent annual reports will ensure a contemporary understanding of these needs while expanding the scope to explore other types of health technologies and additional HTA domains. The research underpinning this report can be viewed as a scoping exercise aimed at identifying the methodological needs of HTA bodies concerning the value assessment of medicines, with the goal of developing learnings for future research and contributing to the construction of SUSTAIN-HS. Together with the review of methods guidance documents from HTA bodies in Task 1.4, this work will inform the development of the HTA Methods Observatory (T1.5) and the prioritisation of methods for further development and implementation (T1.6). Additionally, it will inform other activities within WP3, which focus on developing and delivering training programmes to address the methodological needs of HTA bodies. 2 Methods A task group, led by UU and including representatives from NICE and ZIN, was convened to steer the task and regular input was received from all WP1 partners at monthly meetings. The task group finalised the protocol and the scope of the study and agreed on the methods employed in this report. These methods included engagements with representatives of HTA bodies to explore their methodological needs related to REA and CEA of medicines and a targeted literature review to identify these needs. 2.1 Engagement with HTA Bodies On 29 October 2024, a 45-minute online discussion session was held as part of the SUSTAIN-HTA Network to discuss methodological challenges related to REA and CEA of medicines. The session convened seven HTA body partners of the consortium: Zorginstituut Nederland (ZIN), the National Institute for Health and Care Excellence (NICE), Nemzeti Népegészségügyi és Gyógyszerészeti Központ (NNGYK), Agenzia Nazionale per i Servizi Sanitari Regionali (AGE.NAS), the Norwegian Medicinal Products Agency (NOMA), Agencia de Qualitat i Avaluació Sanitàries de Catalunya (AQUAS), and Fundación Vasca de Innovacion e Investigacion Sanitarias – BIOEF (OSTEBA). Representatives from seven additional HTA bodies also participated: Tandvards-och Lakemedelsformansverket (TLV), HTA Department of State Expert Centre of MoH of Ukraine (SECMOH), Greek Ministry of Health, Národný inštitút pre hodnotu a technológie v zdravotníctve (NIHO), Directorate Pharmaceutical Affairs – MoH Malta, Belgian Health Care Knowledge Center (KCE), and Austrian Institute for Health Technology Assessment (AIHTA). D1.2 – First Yearly Methodological Needs Overviews WP1 – Identification, Synthesis & Prioritisation Version: V1.4 Authors: Saif Elayan, Karen Facey, Shane Collins, Zoe Garrett, Fatima Salih, Saskia Knies, Femke Schuitmaker, and Wim Goettsch Dissemination: PU 16/42 © Copyright 2024 SUSTAIN-HTA Consortium Table 1. HTA Body Methodological Needs Identified in the Literature Stratified by Tiers Overarching Theme Need Tier 1 Tier 2 REA (1) Real-World Evidence (RWE) (Living) Guidelines on RWE that update to take account of new methods ✓ × Demonstration projects to facilitate the adoption of advanced scientific methods ✓ × Collaboration and dialogue between academia and HTA bodies ✓ × Application of machine learning (ML) and generative AI to support causal inference ✓ ✓ (2) Indirect comparisons Addressing heterogeneity across studies’ populations × ✓ Accommodating complex evidence networks ✓ × Incorporating RWE evidence in indirect comparisons ✓ ✓ (3) Validation of Surrogate endpoints Fit-for-purpose validation of surrogate endpoints × ✓ CEA (4) Indirect costs and benefits Assessing the costs for and impacts on informal carers, families, and the wider society ✓ ✓ (5) Extrapolation Extrapolating surrogate or treatment outcomes beyond the duration of clinical studies ✓ ✓ (6) Uncertainty Characterising the uncertainty in long-term benefits and costs associated with ATMPs and OMPs ✓ ✓ (7) Health gains for the paediatric population Standardised and validated tools to assess health gains in the paediatric population × ✓ Appraisal (8) Elements of value Incorporating additional elements of value ✓ ✓ D1.2 – First Yearly Methodological Needs Overviews WP1 – Identification, Synthesis & Prioritisation Version: V1.4 Authors: Saif Elayan, Karen Facey, Shane Collins, Zoe Garrett, Fatima Salih, Saskia Knies, Femke Schuitmaker, and Wim Goettsch Dissemination: PU 17/42 © Copyright 2024 SUSTAIN-HTA Consortium 4 Discussion 4.1 Relative Effectiveness Analysis (REA) 4.1.1 Real World Evidence (RWE) Randomised controlled trials (RCTs) are widely regarded as the gold standard for evaluating the effectiveness of medicines [5,9,13,19,20]. However, RCTs are not always feasible, particularly in rare or orphan diseases, where small populations make well-powered trials challenging [2,3,5,9,11,13,16,17,20]. In such cases, RWE derived from RWD provides a practical alternative [4,5,9,11,13,16–20]. RWE can also complement RCTs by offering estimates of treatment effects in routine care settings and over the longer term [2,4– 6,9,13,17,19]. RWE is increasingly used to support regulatory approval of medicines, particularly for ATMPs and OMPs [5,9,16,17]. A key application of RWE is as an external control arm for single-arm clinical trials [2,3,5,9,11,13,16,17,19]. In the context of HTA, RWE can also play a role in extrapolating trial outcomes and providing inputs for health economic models, extending their utility beyond relative effectiveness, such as resource use [5,9,17,19] and treatment patterns [6,13]. However, concerns about the limitations of RWE—including confounding, information bias, selection bias, time-related bias, and issues with external validity—have restricted their acceptance by HTA bodies [5,9,11,13,16,17,19,20]. Target trial emulation studies have emerged as a promising approach to improving the quality of RWE [9,11,16]. By mimicking the principles of a ‘target’ RCT, this framework helps mitigate these limitations at the design level [9,16]. The importance of target trials was also highlighted during the discussion session with HTA bodies. Furthermore, a range of advanced scientific methods and tools is available to explore and reduce (residual) bias and improve the external validity of RWE [9,11,16,19]. Nevertheless, HTA bodies consistently cite the lack of methods to assess such evidence as a primary obstacle to adequate use in HTA [5,13]. This recurring concern signals the importance of demonstration projects as conduits for capacity building by showcasing how these advanced methods can be applied to generate robust, reliable RWE for HTA [9,13]. Similarly, structured collaboration and dialogue between academia and HTA bodies can facilitate the integration of these advancements into HTA practice [13]. Despite these advancements, there remains a lack of up-to-date, detailed guidance on the use of RWE in HTA [9,13]. Given the evolving nature of data sources and analytical methods, continuously updated “living” RWE guidelines are needed to ensure HTA bodies keep abreast of emerging methodologies and best practices [9,13]. D1.2 – First Yearly Methodological Needs Overviews WP1 – Identification, Synthesis & Prioritisation Version: V1.4 Authors: Saif Elayan, Karen Facey, Shane Collins, Zoe Garrett, Fatima Salih, Saskia Knies, Femke Schuitmaker, and Wim Goettsch Dissemination: PU 18/42 © Copyright 2024 SUSTAIN-HTA Consortium Finally, techniques such as machine learning (ML), natural language processing, and generative AI have recently shown promising utility for RWE studies. These techniques can improve the efficiency and accuracy of data extraction, confounder identification, and causal inference. However, HTA bodies remain cautious about adopting these tools due to concerns about reproducibility, reliability, validity, and accuracy [9,12,19]. 4.1.2 Indirect Comparisons While RCTs remain the cornerstone in assessing REA, conducting all the required headto-head RCTs poses several challenges. These challenges arise due to ethical concerns, small patient populations in rare diseases, and variability in standard-of-care (comparator) treatments across Member States for JCA and in regulators' acceptance of single-arm trials to support accelerated access to innovative medicines [17]. As a result, indirect treatment comparisons (ITCs) have emerged as a vital tool for maximising the value of available evidence by estimating relative effectiveness indirectly across separate clinical trials [2,4,16]. Over the past decade, ITC methods have become increasingly common and are now regarded as a standard component of HTA [16]. A variety of ITC techniques exist in the literature. However, these methods compare nonrandomised treatment groups and rely on strong assumptions, making the resulting evidence inherently subject to bias [16]. A key challenge lies in cross-study differences, particularly in treatment effect modifiers and prognostic variables that impact relative effectiveness [3,4,20]. Without appropriate adjustment, such differences can yield biased results; therefore, adjusted ITC methods are generally preferred [2]. Another significant development is the growing reliance on RWE, particularly for therapies targeting rare diseases [4,5,9,11,16–20]. While some existing ITC techniques can be applied to generate RWE, these settings can introduce additional sources of bias, challenging the reliability of indirect comparisons [3]. The demand for ITC techniques is expected to grow as JCAs are conducted across the EU. Recently, the HTACG published dual guidance documents for direct and indirect comparisons in JCA submissions. These documents outline the available ITC methods, highlight their assumptions, strengths, and weaknesses, and provide guidance on the appropriate handling and reporting of direct and indirect comparisons [22,23]. This development is a welcome step towards addressing reporting inconsistencies and improving ITC implementation quality. ITC methods continue to evolve rapidly, with advancements already emerging. In particular, efforts focusing on more comprehensive adjustments, accommodating complex evidence networks, and addressing the challenges of incorporating RWE into ITCs could be beneficial [2]. D1.2 – First Yearly Methodological Needs Overviews WP1 – Identification, Synthesis & Prioritisation Version: V1.4 Authors: Saif Elayan, Karen Facey, Shane Collins, Zoe Garrett, Fatima Salih, Saskia Knies, Femke Schuitmaker, and Wim Goettsch Dissemination: PU 19/42 © Copyright 2024 SUSTAIN-HTA Consortium 4.1.3 Surrogate Endpoints Surrogate endpoints are often employed when observing treatment effects on the final clinical outcome of interest is perceived to be too time-consuming, costly, or challenging [17]. However, before surrogate endpoints can be used, they should be validated to establish the strength of the relationship between treatment effects on the surrogate and the final outcome, as well as to predict the likely treatment effect on the final outcome for new health technologies [2,11,16,21]. Validating surrogate endpoints is particularly challenging when data are limited [16]. Traditionally, surrogate endpoint evaluation has relied on data from RCTs that are powered to detect an effect on the final outcome [11]. However, such RCT data are becoming increasingly scarce, especially for therapies targeting specific, often small, patient populations or in cancer indications where treatment switching is frequently permitted at the time of progression before the final outcome of mortality [11,16,17]. As a result, surrogate endpoints may remain unvalidated, or their validation may involve significant uncertainty regarding the association between treatment effects on the surrogate and the final outcome [17]. Furthermore, evidence suggests heterogeneity in surrogate relationships, particularly for treatments targeting subpopulations defined by genetic mutations or disease histology, such as ATMPs and histology-independent therapies. This underscores the need to investigate surrogate relationships within individual treatment classes and patient subgroups. Such investigations, however, require sufficient data, which are often unavailable at the time of assessment [10]. Given the persistent limitations in data availability, there is a clear need for methods that maximise the use of existing information, including RWE, to effectively establish surrogacy while adequately accounting for uncertainty and exploring potential heterogeneity in surrogate relationships. 4.1.4 Multiplicity Another challenge is the long-standing issue of multiplicity in REA, which was highlighted during our engagements with HTA bodies. The literature review did not identify any methodological needs related to this issue. This is not surprising, as the selected studies primarily focused on unique challenges associated with emerging complex technologies rather than universal issues, such as multiplicity. Multiplicity generally refers to the potential inflation of the type I error rate due to multiple testing. This issue can arise in clinical studies and evidence synthesis, for example, from conducting multiple subgroup comparisons, analysing multiple treatment arms, assessing multiple outcomes, or performing repeated analyses of the same outcome at different time points [24]. Multiplicity is also frequently encountered in evidence synthesis [25]. A key D1.2 – First Yearly Methodological Needs Overviews WP1 – Identification, Synthesis & Prioritisation Version: V1.4 Authors: Saif Elayan, Karen Facey, Shane Collins, Zoe Garrett, Fatima Salih, Saskia Knies, Femke Schuitmaker, and Wim Goettsch Dissemination: PU 20/42 © Copyright 2024 SUSTAIN-HTA Consortium implication of multiple testing is adjusting the overall significance level to account for these effects. Recently, the HTACG published detailed guidance specifying reporting requirements for multiplicity, which is expected to mitigate uncertainties surrounding its handling [26]. Moving forward, we plan to examine multiplicity issues more closely in subsequent reports. 4.2 Cost-Effectiveness Analysis (CEA) 4.2.1 Indirect Costs and Benefits Ill health often has significant impacts on informal carers' physical, mental, emotional, and social health. Carers frequently face emotional stress from witnessing a loved one suffer from a condition compounded by physical and mental strain resulting from caregiving responsibilities [11,15]. The burden is not limited to primary carers; close family members and others within the patient’s social network may also experience disruptions to their social functioning and overall well-being [11,15]. In addition to the impacts on carer health, ill health is associated with indirect societal costs, including those borne directly by patients, their informal carers and society [11,15,17,18]. These costs include unpaid caregiving time, which often comes at the expense of personal or professional commitments. They also include productivity losses, such as absenteeism, where workdays are missed due to caregiving responsibilities or ill health, and presenteeism, where work performance is reduced due to caregiving strain or poor health. Indirect costs can extend further to the broader society. For certain diseases, particularly genetic conditions affecting children, there may be increased reliance on special education services, social support systems, and other societal resources [17]. In some cases, these indirect costs can exceed direct healthcare expenses, underscoring their economic significance and highlighting the need for their inclusion in evaluations of treatment value [17]. Additionally, there are arguments for including future unrelated medical costs—expenses incurred during extended life years unrelated to the treated disease—in the assessment of ATMPs, particularly those associated with significant improvements in life expectancy [3]. The inclusion of caregiver impacts and societal costs in economic evaluations often improves the cost-effectiveness of treatments, but methods are not standardised or widely used [4,11,17]. While this is particularly relevant for the paediatric field [11,17], these considerations are applicable across a wide range of disease areas, including those reviewed here, such as osteoporosis [4], and hematologic malignancy [7]. 4.2.2 Extrapolation Extrapolating the long-term benefits of ATMPs and histology-independent therapies is often associated with significant uncertainty due to inherent limitations in the available D1.2 – First Yearly Methodological Needs Overviews WP1 – Identification, Synthesis & Prioritisation Version: V1.4 Authors: Saif Elayan, Karen Facey, Shane Collins, Zoe Garrett, Fatima Salih, Saskia Knies, Femke Schuitmaker, and Wim Goettsch Dissemination: PU 21/42 © Copyright 2024 SUSTAIN-HTA Consortium evidence [10,11,17,18,20,21]. These limitations include data immaturity resulting from accelerated marketing approvals, small sample sizes, and confounding due to treatment switching at the end of the randomised period [2,3,5,11,17]. The challenge is further amplified for treatments targeting younger patients, as their longer life expectancy requires projecting outcomes over extended time horizons, thereby increasing uncertainty [11,14]. Additional complexities arise from the reliance on surrogate endpoints, which introduces further uncertainty regarding their relationship with long-term outcomes [2,5,10,17]. Partitioned survival modelling (PSM) is the most widely used approach for extrapolating short-term survival data [10,17]. These models generally estimate survival by fitting a single parametric curve to the entire patient population based on the assumption of a uniform mortality rate [17]. While this assumption may be appropriate for non-curative, life-extending treatments, it introduces significant limitations when assessing treatments with curative potential, such as certain ATMPs [17,20]. Specifically, assuming a constant mortality rate across both ‘cured’ and ‘non-cured’ patient subgroups fails to account for the potential curative effects of these therapies, likely leading to a systematic underestimation of their long-term effectiveness [20]. Heterogeneity in treatment effects within patient populations presents another significant challenge, particularly for histology-independent therapies [2,10]. These treatments target molecular alteration(s) across multiple cancer types [27], where substantial variability in disease progression and treatment outcomes—such as across tumour types and anatomical sites—is highly probable. Conventional modelling approaches, including PSMs, often fail to adequately capture this heterogeneity, potentially obscuring significant differences in relative treatment effectiveness between tumour types. Overlooking these variations can result in misleading conclusions, where a treatment deemed not cost-effective for the overall population may, in fact, demonstrate cost-effectiveness within specific subgroups [10]. Insights from the HTA body workshop reinforced these concerns, emphasising the unique challenges in evaluating histology-independent therapy due to highly heterogeneous outcomes. Although several approaches have been proposed to address these challenges, each comes with important limitations [10,20]. There remains a critical need for methods that can effectively handle data immaturity, account for diverse sources of uncertainty, and comprehensively explore heterogeneity in the assessment of ATMPs and histologyindependent therapies. 4.2.3 Uncertainty Uncertainty remains a core challenge in the economic evaluation of ATMPs and OMPs [2,11,13,15,17,18,20,21]. These health technologies are often characterised by considerable parameter and structural uncertainty, stemming from limited and immature evidence, as well as the assumptions required to extrapolate treatment effects and costs beyond this limited evidence base [2,5,11,13,15,17,18,20,21]. While RWE is increasingly utilised to bridge these D1.2 – First Yearly Methodological Needs Overviews WP1 – Identification, Synthesis & Prioritisation Version: V1.4 Authors: Saif Elayan, Karen Facey, Shane Collins, Zoe Garrett, Fatima Salih, Saskia Knies, Femke Schuitmaker, and Wim Goettsch Dissemination: PU 22/42 © Copyright 2024 SUSTAIN-HTA Consortium evidence gaps, its inherently higher uncertainty remains a concern [6,13,21]. Additional uncertainties arise from challenges in identifying appropriate comparator(s) (or the lack thereof), modelling issues, and the growing reliance on surrogate endpoints rather than final outcomes [2,11,15,17,18,21]. One-off ATMPs are particularly prone to heightened uncertainty, mainly due to the oftenunknown long-term durability of their clinical effect. While the incremental cost of these therapies compared to conventional treatments is relatively clear—since most expenses are incurred upfront—substantial uncertainty persists regarding other cost components. These components include ancillary medical costs (e.g., therapy administration, complication management, follow-up care) and out-of-pocket expenses for patients and families (e.g., travel to administration sites and accommodation during follow-up monitoring) [11,17]. The lack of robust clinical and economic evidence to address these uncertainties often necessitates reliance on opinion-based assumptions, whose reliability remains questionable given the limited experience with these relatively new therapies. Consequently, conventional methods for characterising uncertainty, such as probabilistic analyses, may provide limited value in this context. 4.2.4 Health Gains for the Paediatric Population HTAs in paediatric conditions face unique challenges in measuring health-related quality of life (HRQoL) and calculating quality-adjusted life years (QALYs) [3,14,17]. These challenges primarily arise from the significant limitations in self-reporting capabilities among paediatric populations, which often necessitate using proxy reports for HRQoL assessment [3,14]. This issue is particularly pronounced in the context of ATMPs, many of which target very young children (<5 years), sometimes with cognitive impairments, who are unable to articulate their HRQoL [3,17]. Moreover, ATMPs—including those currently targeting older patients—are increasingly expected to be administered at younger ages, often before the onset of clinical symptoms and irreversible damage [3,17]. While reliance on proxy reports is often unavoidable, it introduces its own set of complexities [3]. Proxies, typically parents or carers, can accurately report observable aspects of HRQoL but may not reliably assess more subjective dimensions, such as emotional wellbeing and social functioning. Furthermore, these reports are prone to significant bias, as proxies’ own HRQoL can influence their perceptions of the child’s HRQoL [3]. These challenges are further compounded by concerns regarding the appropriateness of commonly used generic health status classifications, particularly EQ-5D, for assessing health states in paediatric populations, as well as the associated difficulties in eliciting health state utility values [3]. Beyond issues related to measurement and valuation methods, emerging evidence suggests that the general population may place greater weight on health gains achieved by children, challenging the ‘QALY egalitarianism’ underpinning the QALY maximisation approach [14,28]. Additionally, the assumption of mutual independence within D1.2 – First Yearly Methodological Needs Overviews WP1 – Identification, Synthesis & Prioritisation Version: V1.4 Authors: Saif Elayan, Karen Facey, Shane Collins, Zoe Garrett, Fatima Salih, Saskia Knies, Femke Schuitmaker, and Wim Goettsch Dissemination: PU 23/42 © Copyright 2024 SUSTAIN-HTA Consortium the QALY model is unlikely to hold in paediatric populations, as the value of a health profile can change substantially due to rapid developmental changes (e.g., in neonates and infants) [3]. While the field of paediatric HRQoL has advanced in recent years, there is still no consensus on best-practice methods to measure HRQoL in paediatric populations [29,30]. Furthermore, there is a notable lack of validated tools for assessing HRQoL in very young children (<5 years) [31]. This paucity, together with the absence of consensus and persistent methodological challenges, underscores the pressing need for standardised and validated tools to evaluate health gains in paediatric populations. 4.3 Elements of Value Several papers suggested that traditional cost-utility analyses may fail to capture the full spectrum of value offered by innovative therapies, such as ATMPs and OMPs [4,7,15–18,21]. While these approaches incorporate health gains and costs, they are reported to potentially overlook additional value elements that may be relevant for payers, patients, and society [21]. Lakdawalla et al. identified several such elements, including adherence, reduction in uncertainty, fear of contagion, insurance value, disease severity, the value of hope, real-option value, equity, and scientific spillovers [32]. For instance, for potentially curative ATMPs, the value of cure is argued to hold importance, as it may represent a disproportionate increase in value compared to incremental gains from non-curative treatments [3,11,21]. Given that these therapies are still in their early stages of development, the potential for scientific spillovers—where knowledge generated during treatment development leads to future innovations—could be relevant [11]. Other broader elements of value, such as option value, value of hope, insurance value, and productivity, are also suggested to be relevant in the context of ATMPs and OMPs. Incorporating these broader value elements—or at least consideration thereof—into economic evaluations could result in healthcare resources being allocated differently [17,21]. However, what remains unaddressed in the reviewed papers is the dominant challenge to the cost-effectiveness of ATMPs and OMPs, which, beyond their substantial costs, lies in the profound uncertainty that defines their clinical benefits [13]. This invites the question of whether, or to what extent, incorporating potential broader benefits—similarly shrouded in significant uncertainty—might favourably influence the appraisal of these therapies. 4.4 Limitations This research had several limitations that warrant consideration. The absence of a formal consensus-building process during the discussion session may have limited the validity of the conclusions, as they were based on a synthesis of opinions rather than a systematically validated agreement. Although representatives from various HTA bodies participated, the session was restricted to consortium partners and members of the SUSTAIN-HTA Network, D1.2 – First Yearly Methodological Needs Overviews WP1 – Identification, Synthesis & Prioritisation Version: V1.4 Authors: Saif Elayan, Karen Facey, Shane Collins, Zoe Garrett, Fatima Salih, Saskia Knies, Femke Schuitmaker, and Wim Goettsch Dissemination: PU 24/42 © Copyright 2024 SUSTAIN-HTA Consortium which could have introduced selection bias. Consequently, the perspectives gathered might not fully reflect the diversity of methodological needs faced by HTA bodies across Europe. Furthermore, the discussion may have been subject to dominance bias, whereby dominant participants might have disproportionately shaped the dialogue. The targeted review also had several limitations. First, it was confined to studies addressing medicines, thereby excluding other health technologies, such as medical devices and diagnostics, which may present distinct challenges and methodological needs. Second, grey literature, including reports from HTA organisations and research initiatives, was not included, potentially overlooking emerging insights into methodological needs. Third, the review was restricted to studies published in English, which may have excluded relevant research in other languages and limited the diversity of perspectives considered. Fourth, reliance on a single reviewer for screening and data extraction could have introduced some degree of bias or inaccuracies. Finally, some of the studies included in the review were funded by industry stakeholders, raising the possibility of conflicts of interest, particularly concerning discussions on including additional value elements in assessments. 5 Conclusion Advancements in medical science have driven the development of increasingly complex health technologies, whose value assessment poses significant challenges for existing HTA methodologies. These assessments are further complicated by regulatory changes that facilitate earlier access to new health technologies, often requiring HTA bodies to conduct evaluations based on limited or preliminary data. Addressing the evolving needs of HTA bodies in this dynamic landscape is essential for developing and implementing advanced, fit-for-purpose methods, as well as for guiding capacity-building initiatives to equip the pan-European HTA workforce with the skills necessary to navigate these challenges effectively. Our findings underscore the considerable challenges associated with assessing innovative, highly complex technologies, including ATMPs, histology-independent treatments, and OMPs. Regulatory approvals for these treatments frequently rely on single-armed studies using surrogate endpoints with small sample sizes and short follow-up periods. This situation leads to immature (survival) data and significant uncertainty about the durability of clinical benefits. Compounding these challenges are the inadequacies of conventional methodologies in addressing issues related to extrapolation and uncertainty. While RWE holds promise for mitigating these limitations, realising this potential hinges on the establishment of comprehensive up-to-date guidelines, innovative trial designs, enhanced knowledge sharing between academia and HTA bodies, and the application of advanced causal inference methods, including ML, AI, and indirect treatment comparisons. Our findings also highlight persistent, long-standing methodological challenges that extend beyond specific therapies, such as multiplicity issues. Similarly, the assessment and integration of indirect costs and benefits—especially those experienced by informal carers— D1.2 – First Yearly Methodological Needs Overviews WP1 – Identification, Synthesis & Prioritisation Version: V1.4 Authors: Saif Elayan, Karen Facey, Shane Collins, Zoe Garrett, Fatima Salih, Saskia Knies, Femke Schuitmaker, and Wim Goettsch Dissemination: PU 25/42 © Copyright 2024 SUSTAIN-HTA Consortium pose enduring challenges. This is particularly relevant in paediatric contexts, where caregiving often imposes substantial physical and psychological strains on families. Moreover, the evaluation of health gains in young children, especially those under five years of age, is hindered by the limitations of commonly used instruments, including insufficient validation and implementation of HRQoL tools. Building on these findings, our future research will involve annually updating the targeted review conducted in this research to incorporate emerging evidence while broadening its scope to include additional HTA domains and health technologies. These updates will be accompanied by surveys and further direct engagements with HTA bodies to ensure our work remains attuned to their evolving methodological needs. This iterative process will continuously feed comprehensive and up-to-date data into the SUSTAIN-HS tool, ensuring its capacity to effectively identify the emerging methodological needs of European HTA bodies. D1.2 – First Yearly Methodological Needs Overviews WP1 – Identification, Synthesis & Prioritisation Version: V1.3 Authors: Saif Elayan, Karen Facey, Shane Collins, Zoe Garrett, Fatima Salih, Saskia Knies, Femke Schuitmaker, and Wim Goettsch Dissemination: PU 32/42 © Copyright 2024 SUSTAIN-HTA Consortium D1.2 – First Yearly Methodological Needs Overviews WP1 – Identification, Synthesis & Prioritisation Version: V1.3 Authors: Saif Elayan, Karen Facey, Shane Collins, Zoe Garrett, Fatima Salih, Saskia Knies, Femke Schuitmaker, and Wim Goettsch Dissemination: PU 33/42 © Copyright 2024 SUSTAIN-HTA Consortium D1.2 – First Yearly Methodological Needs Overviews WP1 – Identification, Synthesis & Prioritisation Version: V1.3 Authors: Saif Elayan, Karen Facey, Shane Collins, Zoe Garrett, Fatima Salih, Saskia Knies, Femke Schuitmaker, and Wim Goettsch Dissemination: PU 34/42 © Copyright 2024 SUSTAIN-HTA Consortium D1.2 – First Yearly Methodological Needs Overviews WP1 – Identification, Synthesis & Prioritisation Version: V1.3 Authors: Saif Elayan, Karen Facey, Shane Collins, Zoe Garrett, Fatima Salih, Saskia Knies, Femke Schuitmaker, and Wim Goettsch Dissemination: PU 35/42 © Copyright 2024 SUSTAIN-HTA Consortium D1.2 – First Yearly Methodological Needs Overviews WP1 – Identification, Synthesis & Prioritisation Version: V1.3 Authors: Saif Elayan, Karen Facey, Shane Collins, Zoe Garrett, Fatima Salih, Saskia Knies, Femke Schuitmaker, and Wim Goettsch Dissemination: PU 36/42 © Copyright 2024 SUSTAIN-HTA Consortium Appendix B Table B1. PubMed and Embase Search Strategy Concept Search Terms Boolean Logic Within Block Boolean Logic Across Blocks Needs "need*", "gap*", "challeng*", "require*", "necessit*", "improv*", "shortcom*" OR AND Methodology "methodolog*", "approach*", "framework*", "process*", "technique*", "evaluat*", "assess*", "apprais*", "analys*", "procedur*", "model*" OR AND CEA/REA "relative effectiv*", "cost effectiv*", "cost utility", "cea", "rea", "comparative assess*", "clinical effectiv*", "economic evaluation", "cost assessment", “clinical benefit*”, “added benefit*”, “cost benefit*”, “economic model*”, “added value” OR AND HTA bodies "health technolog* assess*", "HTA", "HTA organization*", "HTA agenc*", "HTA bod*", "health technolog* apprais*", "national health agenc*", "health technolog* evaluat*", "health technolog* decision-making" OR AND Europe "Europ*", "EU" OR AND D1.2 – First Yearly Methodological Needs Overviews WP1 – Identification, Synthesis & Prioritisation Version: V1.3 Authors: Saif Elayan, Karen Facey, Shane Collins, Zoe Garrett, Fatima Salih, Saskia Knies, Femke Schuitmaker, and Wim Goettsch Dissemination: PU 37/42 © Copyright 2024 SUSTAIN-HTA Consortium Appendix C Table C1. Data Extraction Table Field Name Description Initial Data Extracted by and Date The initials of the reviewer who performed the initial data extraction and the extraction date. Reviewed By (Initials) The initials of the second reviewer who reviewed the extracted data. Title The full title of the document. Author(s) Names of the authors or organisation responsible for the document. Year of Publication The year the document was published. Document Type Type of document (e.g., journal article, report, etc.) Journal/Source Journal or source of publication. URL The web link to access the document. Document Aim/Purpose The stated aim or purpose of the document. Type of Medicine The type of medicine discussed (e.g., ATMPs, cancer medicines, orphan medicines, paediatrics etc.). Specific Examples of Medicines Discussed Specific medicines used as examples in the document. Document Scope The scope of the document, including the areas of health technology it covers. Stakeholders involved Stakeholders involved in the study (e.g., HTA bodies only, different stakeholder groups, etc.) Funding Information about the funding source(s) or organisation(s) that financed the study or project. Country/Geographical Region Covered The country or region discussed or relevant to the document. Methods Study design and methodological approach HTA bodies involvement How HTA bodies were involved REA-Specific Needs Needs related to Relative Effectiveness Assessment (e.g., indirect comparisons, modelling techniques, handling uncertainty). CEA-Specific Needs Needs related to Cost-Effectiveness Analysis (e.g., handling uncertainty, comparators, data availability). Explicit Rationale for the Need The rationale provided for the methodological need Implications for HTA Practice The implications of the identified needs for HTA practice in Europe. Future Research (reported by authors) Areas identified for future methodological research and proposed research questions or hypotheses for future studies. D1.2 – First Yearly Methodological Needs Overviews WP1 – Identification, Synthesis & Prioritisation Version: V1.3 Authors: Saif Elayan, Karen Facey, Shane Collins, Zoe Garrett, Fatima Salih, Saskia Knies, Femke Schuitmaker, and Wim Goettsch Dissemination: PU 38/42 © Copyright 2024 SUSTAIN-HTA Consortium Appendix D Table D2. Characteristics of Included Studies Title Author Methods Funding Health economic evaluation of gene replacement therapies: methodological issues and recommendations Aballéa et al., 2020 The paper employs a mixed-methods approach that combines: • Literature review on economic evaluations of genereplacement therapies • Interviews with eight European and US health economic experts • Targeted literature reviews on potential solutions to specific challenges Supported by Novartis Gene Therapies (formerly AveXis, Inc.). Building a Healthcare Alliance for Resourceful Medicine Offensive Against Neoplasms in Hematology Added Value Framework for Hematologic Malignancies: A Comparative Analysis of Existing Tools Cerisoli et al., 2022 • Surveys with patient organisations, key opinion leaders, pharmaceutical companies, and regulators • Structured questionnaires for health professionals • Evaluation of value frameworks for hematologic malignancy interventions Innovative Medicines Initiative 2 Joint Undertaking. This Joint Undertaking receives support from the European Union’s Horizon 2020 Research and Innovation programme and the European Federation of Pharmaceutical Industries and Associations HTA methodology and value frameworks for evaluation and policy making for cell and gene therapies Coyle et al., 2020 Literature review on the clinical and economic evaluation of cell and gene therapies Not reported D1.2 – First Yearly Methodological Needs Overviews WP1 – Identification, Synthesis & Prioritisation Version: V1.3 Authors: Saif Elayan, Karen Facey, Shane Collins, Zoe Garrett, Fatima Salih, Saskia Knies, Femke Schuitmaker, and Wim Goettsch Dissemination: PU 39/42 © Copyright 2024 SUSTAIN-HTA Consortium Title Author Methods Funding How are health technology assessment bodies responding to the assessment challenges posed by cell and gene therapy? Drummond et al., 2023 A targeted literature review on evidence requirements for the assessment of cell and gene therapies and an analysis of HTA reports Unrestricted sponsorship agreement between F. HoffmannLa Roche and Bocconi University. Assessing Technologies for COVID‑19: What are the Challenges for Health Technology Assessment Agencies? Findings From a Survey and Roundtable Workshop Elvidge & Dawoud, 2021 A mixed-methods approach, including an online survey disseminated to European and nonEuropean HTA agencies, followed by a virtual roundtable attended by survey respondents to discuss the results. European Union’s Horizon 2020 Research and Innovation programme Real-world evidence to support Payer/HTA decisions about highly innovative technologies in the EU— actions for stakeholders Facey et al., 2020 The paper employs a mixed-methods approach that combines: • Multi-stakeholder workshops and discussions involving HTA bodies, payers, regulators, government bodies, clinical research organizations, the pharmaceutical industry, patient groups, and academia. • Review of selected policy documents from the EU and U.S. • Case studies of recent Payer/HTA decisions • Consultation and feedback from experts EUCOPE, Amgen, AstraZeneca, Gilead Sciences, Hoffman-La Roche, Takeda, and Novartis. Acceptability of Using Real-World Data to Estimate Relative Treatment Effects in Health Technology Assessments: Barriers and Future Steps Gomes et al., 2024 Critical assessment of the literature and authors’ expert opinion based on their experience in RWD research in academic, HTA, and industry settings. Funded by NIHR Advanced Fellowship, F. Hoffmann-La Roche Ltd, European Health Data and Evidence Network (supported by Innovative Medicines Initiative, EU Horizon 2020, EFPIA), and D1.2 – First Yearly Methodological Needs Overviews WP1 – Identification, Synthesis & Prioritisation Version: V1.3 Authors: Saif Elayan, Karen Facey, Shane Collins, Zoe Garrett, Fatima Salih, Saskia Knies, Femke Schuitmaker, and Wim Goettsch Dissemination: PU 40/42 © Copyright 2024 SUSTAIN-HTA Consortium Title Author Methods Funding institutional support from EU Horizon 2020 and Horizon Europe programmes. Registry data for use in health technology assessments in Norway – Opportunities and challenges Hagen & Wisløff, 2021 • Descriptive overview of the Norwegian HTA system • Authors' speculation on future directions for the use of observational data in HTA Not reported Recommendations for the conduct of economic evaluations in osteoporosis: outcomes of an experts’ consensus meeting organized by the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO) and the US branch of the International Osteoporosis Foundation Hiligsmann et al., 2019 A mixed-methods approach, including literature review, expert consensus meeting, and multi-expert validation The European Society for Clinical and Economic Aspects of Osteoporosis (ESCEO), with partial funding through unrestricted grants from the International Osteoporosis Foundation (IOF) and Radius Health. Additional support was provided by the National Health and Medical Research Council (NHMRC) through grant 1127827 and the NHMRC Early Career Fellowship 1139826 for research time. Reported Challenges in Health Technology Assessment of Complex Health Technologies Hogervorst et al., 2022 A survey among European HTA organisations European Union’s Horizon 2020 Research and Innovation programme Real World Data in Health Technology Assessment of Complex Health Technologies Hogervorst, Vreman, et al., 2022 A survey among European HTA organisations European Union’s Horizon 2020 Research and Innovation programme D1.2 – First Yearly Methodological Needs Overviews WP1 – Identification, Synthesis & Prioritisation Version: V1.3 Authors: Saif Elayan, Karen Facey, Shane Collins, Zoe Garrett, Fatima Salih, Saskia Knies, Femke Schuitmaker, and Wim Goettsch Dissemination: PU 41/42 © Copyright 2024 SUSTAIN-HTA Consortium Title Author Methods Funding Advanced Therapy Medicinal Products and Health Technology Assessment Principles and Practices for Value-Based and Sustainable Healthcare Jönsson et al., 2019 Expert Panel Review comprising members with national and international expertise in HTA methodology and application from the UK, France, Germany, and Sweden Kite Pharma, a Gilead Company Challenges for Economic Evaluations of Advanced Therapy Medicinal Products: A Systematic Review Labry-Lima et al., 2023 A systematic review of economic analyses of ATMPs The Spanish Ministry of Science, Innovation and Universities Health technology assessment of paediatric medicines: European landscape, challenges and opportunities inside the conect4children project Moretti et al., 2022 Expert input from the conect4children HTA group Horizon 2020 Framework Programme and Innovative Medicines Initiative Modelling approaches for histologyindependent cancer drugs to inform NICE appraisals: a systematic review and decision-framework Murphy et al., 2021 • A targeted review of statistical literature focusing on the design and analysis of histology-independent trials. • A systematic review to identify meta-analyses evaluating response rates and duration of response as surrogate endpoints for progression-free and overall survival. • A targeted review of published NICE technology appraisals. National Institute for Health Research (NIHR) Evidence Synthesis programme HTA programme response to the challenges of dealing with orphan medicinal products: Process evaluation in selected European countries Nicod et al., 2019 • A literature review and a conceptual framework of clinical, regulatory and economic challenges for OMPs. • A questionnaire among representatives leading HTA programmes specific to OMPs • Critical assessment of HTA programmes specific to OMPs Not reported Preparing for tomorrow: Defining a future agenda O’Mahony et al., 2022 Description of a gene therapy toolkit for haemophilia decision-making Bayer