Framework for Multistakeholder Patient Registries in the Field of Rare Diseases: Focus on Neurogenetic Diseases.

Progress in genetic diagnosis and orphan drug legislation has opened doors to new therapies in rare neurogenetic diseases (RNDs). Innovative therapies such as gene therapy can improve patients' quality of life but come with academic, regulatory, and financial challenges. Registries can play a pivotal role in generating evidence to tackle these, but their development requires multidisciplinary knowledge and expertise. This study aims to develop a practical framework for creating and implementing patient registries addressing common challenges and maximizing their impact on care, research, drug development, and regulatory decision making with a focus on RNDs. A comprehensive 3-step literature and qualitative research approach was used to develop the framework. A qualitative systematic literature review was conducted, extracting guidance and practices leading to the draft framework. Subsequently, we interviewed representatives of 5 established international RND registries to add learnings from hands-on experiences to the framework. Expert input on the draft framework was sought in digital multistakeholder focus groups to refine the framework. The literature search; interviews with 5 registries; and focus groups with patient representatives (n = 4), clinicians (n = 6), regulators, health technology assessment (HTA) bodies and payers (n = 7), industry representatives (n = 7), and data/information technology (IT) specialists (n = 5) informed development of the framework. It covers the interests of different stakeholders, purposes for data utilization, data aspects, IT infrastructure, governance, and financing of rare disease registries. Key principles include that data should be rapidly accessible, independent, and trustworthy. Governance should involve multiple stakeholders. In addition, data should be highly descriptive, machine-readable, and accessible through a shared infrastructure and not spread over multiple isolated repositories. Sustainable and independent financing of registries is deemed important but remains challenging because of a lack of widely supported funding models. The proposed framework will guide stakeholders in establishing or improving rare disease registries that fulfill requirements of academics and patients as well as regulators, HTA bodies, and commercial parties. There is a need for more clarity regarding quality requirements for registries in regulatory and HTA context. In addition, independent financing models for registries should be developed, as well as well-defined policies on technical uniformity in health data.

Uncertainty in Long-Term Relative Effectiveness of Medicines in Health Technology Assessment.

OBJECTIVES: Uncertainty regarding the long-term relative effectiveness is an important factor in health technology assessment (HTA) of medicines. This study investigated how different HTA bodies address this uncertainty in their assessments. METHODS: A total of 49 HTA reports from 6 national HTA bodies, assessing 9 medicines for spinal muscular atrophy, cystic fibrosis, and hypercholesterolemia, were included. In these reports, 81 relative effectiveness assessments and 45 cost-effectiveness assessments were performed on an indication level. We collected information on included trials, assessment outcomes, uncertainty regarding the long-term effectiveness, proposed managed entry agreements, and reassessments. RESULTS: Uncertainty regarding the long-term effectiveness was an important consideration in almost all cost-effectiveness assessments (91%) and three-quarters of relative effectiveness assessments (74%), despite differences in methodologies among HTA bodies. There were considerable differences in the amount and type of long-term effectiveness data included by HTA bodies due to timing and inclusion criteria. In total 23 managed entry agreements were proposed of which 14 were linked to uncertainty regarding the long-term effectiveness. In addition, 13 reassessments were performed of which 4 led to an increase in patient access because of more available long-term effectiveness data. CONCLUSIONS: Uncertainty regarding the long-term effectiveness is an important challenge for HTA bodies. There are large differences in the acceptance of evidence among HTA bodies, which leads to heterogeneity in the inclusion of available long-term effectiveness data for decision making. In cases with large uncertainty regarding the long-term effectiveness, outcome-based agreements and reassessments are used by HTA bodies, but differently between HTA bodies and indications.

Navigating the path towards successful implementation of the EU HTA Regulation: key takeaways from the 2023 Spring Convention of the European Access Academy.

BACKGROUND: The European Regulation on Health Technology Assessment (EU HTA R), effective since January 2022, aims to harmonize and improve the efficiency of common HTA across Member States (MS), with a phased implementation from January 2025. At "midterms" of the preparation phase for the implementation of the Regulation our aim was to identify and prioritize tangible action points to move forward. METHODS: During the 2023 Spring Convention of the European Access Academy (EAA), participants from different nationalities and stakeholder backgrounds discussed readiness and remaining challenges for the Regulation's implementation and identified and prioritized action points. For this purpose, participants were assigned to four working groups: (i) Health Policy Challenges, (ii) Stakeholder Readiness, (iii) Approach to Uncertainty and (iv) Challenges regarding Methodology. Top four action points for each working group were identified and subsequently ranked by all participants during the final plenary session. RESULTS: Overall "readiness" for the Regulation was perceived as neutral. Prioritized action points included the following: Health Policy, i.e. assess adjustability of MS laws and health policy processes; Stakeholders, i.e. capacity building; Uncertainty, i.e. implement HTA guidelines as living documents; Methodology, i.e. clarify the Population, Intervention, Comparator(s), Outcomes (PICO) identification process. CONCLUSIONS: At "midterms" of the preparation phase, the focus for the months to come is on executing the tangible action points identified at EAA's Spring Convention. All action points centre around three overarching themes: harmonization and standardization, capacity building and collaboration, uncertainty management and robust data. These themes will ultimately determine the success of the EU HTA R in the long run.

The Role of Medical Societies and the Relevance of Clinical Perspective in the Evolving EU HTA Process: Insights Generated at the 2023 Fall Convention and Survey of the European Access Academy.

BACKGROUND: This work aimed to determine the role and action points for the involvement of medical societies in the European Health Technology Assessment (EU HTA) Methods: An online pre-convention survey was developed addressing four areas related to the EU HTA: (i) medical societies' role; (ii) role of clinical guidelines; (iii) interface with the European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS); and (iv) approaching 'best-available evidence' (BAE). A descriptive analysis of questionnaire outcomes was conducted to inform the European Access Academy (EAA) Fall Convention 2023. Within the working groups (WGs), action points were identified and prioritised. RESULTS: A total of 57 experts from 15 countries responded to the survey. The WGs were attended by (i) 11, (ii) 10, (iii) 12, and (iv) 12 experts, respectively, representing a variety of national backgrounds and stakeholder profiles. The most relevant action points identified were as follows: (i) incorporation of clinical context into population, intervention, comparator, outcomes (PICO) schemes, (ii) timely provision of up-to-date therapeutic guidelines, (iii) ensuring the inclusion of MCBS insights into the EU HTA process, and (iv) considering randomized controlled trials (RCTs) as the gold standard and leveraging regulatory insights if development programs only include single-arm trials. CONCLUSIONS: The involvement of medical societies is a critical success factor for the EU HTA. The identified key action points foster the involvement of patient associations and medical societies.

Creating win-win-win situations with managed entry agreements? Prioritizing gene and cell therapies within the window of opportunity.

Outcome-based reimbursement models are gaining attention for managing the clinical uncertainties and financial impact of gene and cell therapies. Little guidance exists on how such models can create win-win-win situations, benefiting health-care payers, health-technology developers and patients. Our innovative approach prospectively prioritizes therapies for which a 'window of opportunity' might occur through the analysis of health-technology assessments and product characteristics. Within this window, one size does not fit all, and depending on the extent of clinical uncertainty and potential added benefit levels, different win-win-win situations exist in the United States, the United Kingdom and the Netherlands. Dutch Horizon scanning data prioritized etranacogene dezaparvovec (Hemgenix) and mozafancogene autotemcel for their potential to benefit from outcome-based reimbursement models. These insights extend beyond gene and cell therapies, and could help to provide sustainable health care and patient access to innovative therapies.

Healthcare decision-making for tumour-agnostic therapies in Europe: lessons learned.

The tumour-agnostic authorisations of larotrectinib and entrectinib shifted the paradigm for indication setting. European healthcare decision-makers agreed on their therapeutic potential but diverged primarily in identified uncertainties concerning basket trial designs and endpoints, prognostic value of neurotrophic tropomyosin receptor kinase (NTRK) gene fusions, and resistance mechanisms. In addition, assessments of relevant comparators, unmet medical needs (UMNs), and implementation of NTRK-testing strategies diverged. In particular, the tumour-specific reimbursement recommendations and guidelines do not reflect tumour-agnostic thinking. These differences indicate difficulties experienced in these assessments and provide valuable lessons for future disruptive therapies. As we discuss here, early multistakeholder dialogues concerning minimum evidence requirements and involving clinicians are essential.

Illustrating the Financial Consequences of Outcome-Based Payment Models From a Payers Perspective: The Case of Autologous Gene Therapy Atidarsagene Autotemcel (Libmeldy®).

OBJECTIVES: To illustrate the financial consequences of implementing different managed entry agreements (managed entry agreements for the Dutch healthcare system for autologous gene therapy atidarsagene autotemcel [Libmeldy]), while also providing a first systematic guidance on how to construct managed entry agreements to aid future reimbursement decision making and create patient access to high-cost, one-off potentially curative therapies. METHODS: Three payment models were compared: (1) an arbitrary 60% price discount, (2) an outcome-based spread payment with discounts, and (3) an outcome-based spread payment linked to a willingness to pay model with discounts. Financial consequences were estimated for full responders (A), patients responding according to the predicted clinical pathway presented in health technology assessment reports (B), and unstable responders (C). The associated costs for an average patient during the time frame of the payment agreement, the total budget impact, and associated benefits expressed in quality-adjusted life-years of the patient population were calculated. RESULTS: When patients responded according to the predicted clinical pathway presented in health technology assessment reports (scenario B), implementing outcome-based reimbursement models (models 2 and 3) had lower associated budget impacts while gaining similar benefits compared with the discount (scenario 1, €8.9 million to €6.6 million vs €9.2 million). In the case of unstable responders (scenario C), costs for payers are lower in the outcome-based scenarios (€4.1 million and €3.0 million, scenario 2C and 3C, respectively) compared with implementing the discount (€9.2 million, scenario 1C). CONCLUSIONS: Outcome-based models can mitigate the financial risk of reimbursing atidarsagene autotemcel. This can be considerably beneficial over simple discounts when clinical performance was similar to or worse than predicted.

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.

Increasing uptake through collaboration in the development of core outcome sets: Lessons learned at OMERACT 2023.

OBJECTIVE: This manuscript highlights the importance of enhancing the uptake of Core Outcome Sets (COS) by building partnerships with Collaborators and addressing their needs in COS development. METHODS AND SETTING: This session was structured as a simulation, resembling a format akin to a classic television game show. The moderator posed a series of questions to eight different Collaborator groups who briefly described the importance of COS within their areas of interest. Previous studies examining the uptake of individual core outcomes revealed disparities in uptake rates. The Identified barriers to the uptake of COS include the lack of recommendations for validated instruments for each domain, insufficient involvement of patients and key Collaborator groups in COS development, and a lack of awareness regarding the existence of COS. CONCLUSIONS: This analysis underscores the need for COS development approaches that prioritize the inclusion of patients and diverse Collaborator groups at every stage. While current studies on COS uptake are limited, future research should explore the broader implementation of COS across diverse disease categories and delve into the factors that hinder or facilitate their uptake such as, the importance of COS developers extending their work to recommending domains with well validated instruments. Embracing patient leadership and multifaceted engagement is essential for advancing the relevance and impact of COS in clinical research.

Added benefit and revenues of oncology drugs approved by the European Medicines Agency between 1995 and 2020: retrospective cohort study.

OBJECTIVES: To evaluate the added benefit and revenues of oncology drugs, explore their association, and investigate potential discrepancies between added benefit and revenues across different approval pathways of the European Medicines Agency (EMA). DESIGN: Retrospective cohort study. SETTING: Oncology drugs and their indications approved by the EMA between 1995 and 2020. MAIN OUTCOME MEASURES: Added benefit was evaluated using ratings published by seven organisations: health technology assessment agencies from the United States, France, Germany, and Italy, two medical oncology societies, and a drug bulletin. All retrieved ratings were recategorised using a four point ranking scale to indicate negative or non-quantifiable, minor, substantial, or major added benefit. Revenue data were extracted from publicly available financial reports and compared with published estimates of research and development (R&D) costs. Finally, the association between added benefit and revenue was evaluated. All analyses were performed within the overall study cohort, and within subgroups based on the EMA approval pathway: standard marketing authorisation, conditional marketing authorisation, and authorisation under exceptional circumstances. RESULTS: 131 oncology drugs with 166 indications were evaluated for their added benefit by at least one organisation within the required timeframe, yielding a total of 458 added benefit ratings; 189 (41%) were negative or non-quantifiable. The median time to offset the median R&D costs ($684m, £535m, €602m, adjusted to 2020 values) was three years; 50 of 55 (91%) drugs recovered these costs within eight years. Drugs with higher added benefit ratings generally had greater revenues. Negative or non-quantifiable added benefit ratings were more frequent for conditional marketing authorisations and authorisations under exceptional circumstances than for standard marketing authorisations (relative risk 1.53, 95% confidence interval 1.23 to 1.89). Conditional marketing authorisations generated lower revenues and took longer to offset R&D costs than standard marketing authorisations (four years compared with three years). CONCLUSIONS: While revenues seem to align with added benefit, most oncology drugs recover R&D costs within a few years despite providing little added benefit. This is particularly true for drugs approved through conditional marketing authorisations, which inherently appear to lack comprehensive evidence. Policy makers should evaluate whether current regulatory and reimbursement incentives effectively promote development of the most effective drugs for patients with the greatest needs.

A literature review of quality assessment and applicability to HTA of risk prediction models of coronary heart disease in patients with diabetes.

This literature review had two objectives: to identify models for predicting the risk of coronary heart diseases in patients with diabetes (DM); and to assess model quality in terms of risk of bias (RoB) and applicability for the purpose of health technology assessment (HTA). We undertook a targeted review of journal articles published in English, Dutch, Chinese, or Spanish in 5 databases from 1st January 2016 to 18th December 2022, and searched three systematic reviews for the models published after 2012. We used PROBAST (Prediction model Risk Of Bias Assessment Tool) to assess RoB, and used findings from Betts et al. 2019, which summarized recommendations and criticisms of HTA agencies on cardiovascular risk prediction models, to assess model applicability for the purpose of HTA. As a result, 71 % and 67 % models reporting C-index showed good discrimination abilities (C-index >= 0.7). Of the 26 model studies and 30 models identified, only one model study showed low RoB in all domains, and no model was fully applicable for HTA. Since the major cause of high RoB is inappropriate use of analysis method, we advise clinicians to carefully examine the model performance declared by model developers, and to trust a model if all PROBAST domains except analysis show low RoB and at least one validation study conducted in the same setting (e.g. country) is available. Moreover, since general model applicability is not informative for HTA, novel adapted tools may need to be developed.

A blueprint for health technology assessment capacity building: lessons learned from Malta.

OBJECTIVES: The development and strengthening of health technology assessment (HTA) capacity on the individual and organizational level and the wider environment is relevant for cooperation on HTAs. Based on the Maltese case, we provide a blueprint for building HTA capacity. METHODS: A set of activities were developed based on Pichler et al.'s framework and the starting HTA capacity in Malta. Individual level activities focused on strengthening epidemiological and health economic skills through online and in-person training. On the organizational level, a new HTA framework was developed which was subsequently utilized in a shadow assessment. Awareness campaign activities raised awareness and support in the wider environment where HTAs are conducted and utilized. RESULTS: The time needed to build HTA capacity exceeded the planned two years accommodating the learning progress of the assessors. In addition to the planned trainings, webinars supplemented the online courses, allowing for more knowledge exchange. The advanced online course was extended over time to facilitate learning next to the assessors' daily tasks. Training sessions were added to implement the new economic evaluation framework, which was utilized in a second shadow assessment. Awareness by decision-makers was achieved with reports, posters, and an article on the current and developing HTA capacity. CONCLUSIONS: It takes time and much (hands-on) training to build skills for conducting complex assessment such as HTAs. Facilitating exchange with knowledgeable parties is crucial for succeeding as well as the buy-in of local managers motivating staff. Decision-makers need to be on-boarded for the continued success of HTA capacity building.

Tools for assessing quality of studies investigating health interventions using real-world data: a literature review and content analysis.

OBJECTIVES: We aimed to identify existing appraisal tools for non-randomised studies of interventions (NRSIs) and to compare the criteria that the tools provide at the quality-item level. DESIGN: Literature review through three approaches: systematic search of journal articles, snowballing search of reviews on appraisal tools and grey literature search on websites of health technology assessment (HTA) agencies. DATA SOURCES: Systematic search: Medline; Snowballing: starting from three articles (D'Andrea et al, Quigley et al and Faria et al); Grey literature: websites of European HTA agencies listed by the International Network of Agencies for Health Technology Assessment. Appraisal tools were searched through April 2022. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: We included a tool, if it addressed quality concerns of NRSIs and was published in English (unless from grey literature). A tool was excluded, if it was only for diagnostic, prognostic, qualitative or secondary studies. DATA EXTRACTION AND SYNTHESIS: Two independent researchers searched, screened and reviewed all included studies and tools, summarised quality items and scored whether and to what extent a quality item was described by a tool, for either methodological quality or reporting. RESULTS: Forty-nine tools met inclusion criteria and were included for the content analysis. Concerns regarding the quality of NRSI were categorised into 4 domains and 26 items. The Research Triangle Institute Item Bank (RTI Item Bank) and STrengthening the Reporting of OBservational studies in Epidemiology (STROBE) were the most comprehensive tools for methodological quality and reporting, respectively, as they addressed (n=20; 17) and sufficiently described (n=18; 13) the highest number of items. However, none of the tools covered all items. CONCLUSION: Most of the tools have their own strengths, but none of them could address all quality concerns relevant to NRSIs. Even the most comprehensive tools can be complemented by several items. We suggest decision-makers, researchers and tool developers consider the quality-item level heterogeneity, when selecting a tool or identifying a research gap. OSF REGISTRATION NUMBER: OSF registration DOI (https://doi.org/10.17605/OSF.IO/KCSGX).

Disease severity-based subgrouping of type 2 diabetes does not parallel differences in quality of life: the Maastricht Study.

AIMS/HYPOTHESIS: Type 2 diabetes is a highly heterogeneous disease for which new subgroups ('clusters') have been proposed based on disease severity: moderate age-related diabetes (MARD), moderate obesity-related diabetes (MOD), severe insulin-deficient diabetes (SIDD) and severe insulin-resistant diabetes (SIRD). It is unknown how disease severity is reflected in terms of quality of life in these clusters. Therefore, we aimed to investigate the cluster characteristics and cluster-wise evolution of quality of life in the previously defined clusters of type 2 diabetes. METHODS: We included individuals with type 2 diabetes from the Maastricht Study, who were allocated to clusters based on a nearest centroid approach. We used logistic regression to evaluate the cluster-wise association with diabetes-related complications. We plotted the evolution of HbA1c levels over time and used Kaplan-Meier curves and Cox regression to evaluate the cluster-wise time to reach adequate glycaemic control. Quality of life based on the Short Form 36 (SF-36) was also plotted over time and adjusted for age and sex using generalised estimating equations. The follow-up time was 7 years. Analyses were performed separately for people with newly diagnosed and already diagnosed type 2 diabetes. RESULTS: We included 127 newly diagnosed and 585 already diagnosed individuals. Already diagnosed people in the SIDD cluster were less likely to reach glycaemic control than people in the other clusters, with an HR compared with MARD of 0.31 (95% CI 0.22, 0.43). There were few differences in the mental component score of the SF-36 in both newly and already diagnosed individuals. In both groups, the MARD cluster had a higher physical component score of the SF-36 than the other clusters, and the MOD cluster scored similarly to the SIDD and SIRD clusters. CONCLUSIONS/INTERPRETATION: Disease severity suggested by the clusters of type 2 diabetes is not entirely reflected in quality of life. In particular, the MOD cluster does not appear to be moderate in terms of quality of life. Use of the suggested cluster names in practice should be carefully considered, as the non-neutral nomenclature may affect disease perception in individuals with type 2 diabetes and their healthcare providers.