The EU HTA Regulation stipulates that member states (MS) will give due consideration to Joint Clinical Assessment (JCA) reports in national HTAs of medicinal products. MS must provide information on how the JCA has been considered in their national process within 2 years of the application date, which for oncology products and advanced therapeutic medicinal products (ATMPs) is 12 January 2025. However, there may be significant heterogeneity in processes across the EU, complicating implementation for various stakeholders. This research aimed to explore differences between national reimbursement and access pathways of the 27 EU MS, specifically for oncology and ATMPs.

The Regulation (EU) 2021/2282 on health technology assessment (HTAR) entered into force in January 2022 and will apply from January 2025. The aim of the HTAR is to improve the availability of innovative technologies for EU patients and to increase efficiency through joint clinical assessment (JCA). The process foresees that, according to principals of evidence-based medicine, the PICO criteria (Patient Population, Intervention, Comparator, Outcome) are used and defined at national level. All PICO criteria are then to be addressed in the JCA. The objective of this analysis was to evaluate the overlaps and differences in the PICO criteria between different EU countries. We compared the PICO criteria of individual EU countries, explicitly France, Germany, Spain, Italy, Belgium and Netherlands. First, we compared the current methods of HTA of the EU countries according to the applicable regulations. In addition, we surveyed local HTA experts using a standardized questionnaire. We identified both overlaps as well as differences between the EU countries regarding the PICO criteria. For example, the relevant patient population can either be the population according to EMA approved indication, the study population, or the population to be reimbursed depending on the country. Equally, country differences are shown in the relevant comparator because the standard of care depends on country specific guidelines and reimbursed drugs. Concerning the outcome, the currently accepted endpoints differ between the countries. Per current EUnetHTA scoping process there will not be an aligned PICO grid. This leads to several challenges such as the generation of an extensive amount of data that was not planned a priori within a short time frame. Further, it is not possible to provide direct comparisons for all comparators based on the clinical development program. An alignment of PICO criteria requirements should therefore be considered.

Understand how different health technology assessment (HTA) bodies perceive and evaluate real world evidence (RWE) in oncology HTA submissions, and identify drivers of RWE acceptance today and in the future.

In recent years, many pharmaceutical companies have increasingly focused on optimising clinical development programmes not only to the demands of the regulators, but also to health technology assessment (HTA) bodies (HTABs), and payers. Consequently, there has been an increase in scientific advice processes involving HTABs and regulatory bodies. The objective of this study was to review scientific advice processes involving HTABs in the United Kingdom (UK), France, and Germany as well as the parallel EMA/EUnetHTA21 joint scientific consultation (JSC) process and evaluate similarities and differences between these. A review of scientific advice processes in the UK, France, Germany and JSC was performed. Each advice process was evaluated in terms of regulatory agency participation and the following key attributes: years since introduction, timeline, fees, briefing book requirements, scientific topics for discussion, output, health economic assessment, language, meeting length, number of company attendees, external expert involvement, and patient involvement. The UK, France, Germany and JSC processes were contrasted to highlight differences and similarities. The scientific advice processes may be broadly categorised into five types: 1) single-country HTAB, 2) single-country HTAB and regulators,3) multi-country HTAB4) parallel JSC with HTAB and regulators, 5) regulators only. The processes in the UK, France, Germany and the JSC process have similarities and differences in the characteristics. The most striking differences relate to the fees for engagement, the duration and outcomes of meetings, the scientific topics addressed and the extent of stakeholder involvement. Selecting an appropriate scientific advice process depends on the strategic objectives in the decision to obtain scientific advice and the specific regulatory and HTA complexities for the therapeutic area. The number of integrated scientific advice processes has increased in recent years. Manufacturers value the opportunity to test and optimise their clinical development plans to meet regulatory and HTABs requirements to facilitate reimbursement.

Increasing use of single-arm trials (SATs) has been driven, in part, by targeted therapies for niche hemato-oncological indications. However, acceptance of SAT-based Health Technology Assessment (HTA) submissions with or without external comparators (ECs) is still uncertain. The aim of this research is to provide insights and trends in the use of SATs in EMA and HTA submissions, and the use and acceptability of different EC methods in HTA submissions. Indications for drug uses approved by EMA between January 2018 and April 2022 hemato-oncology were identified. Consequently, HTA reports based solely on SAT-data of corresponding drugs from NICE (England), G-BA (Germany), HAS (France), TLV (Sweden) and ZIN (the Netherlands) were investigated. Appropriateness of ECs was determined by assessing payers' criticism in the appraisal and inclusion or exclusion in the decision justification. 51 EMA approvals in hemato-oncology were identified, of which 29% (15 indications, for 11 different drugs) were based exclusively on SAT-data. Regulatory approvals based on SATs were more common in later years: 27% (6/22) in 2018-2019 versus 31% (9/29) in 2020-2022. For these 15 indications, 48 HTA submissions with SAT-data as main type of evidence were identified. In 88% (42/48) of submissions, an EC was provided. In 83% (35/42) of submissions with an EC, at least one of the ECs had a real-world evidence (RWE) component. 57% (24/42) of ECs were found inappropriate/unusable for decision-making, 19% (8/42) of ECs were found acceptable and were used to inform the decision and 24% (10/42) of ECs were considered uncertain and/or it was unclear if they were used in the recommendation. There is an increasing proportion of SAT designs within submissions accepted by EMA, resulting in many SAT-based HTA submissions. While ECs are frequently provided in these, their acceptability by HTA bodies is still mixed.

In version 6.0 of its General Methods, IQWiG sought to address the increasing complexity of assessing minimal important differences (MIDs) for patient-reported outcomes (PROs), by stipulating that response thresholds for submitted responder analyses must be ≥ 15% of the scale range. This study investigated the impact of the General Methods update on IQWiG's assessments of PROs and how these have influenced G-BA's view on submitted PRO evidence. A comparison of IQWiG dossier assessments published six months before and six months after the publication of IQWiG's General Methods version 6.0 was conducted. The analysis focused on comparing benefit ratings and the impact of IQWiG's acceptance of PRO data on these. It further examined G-BA's consideration of responder analyses with thresholds < 15% of the scale range rejected by IQWiG, and the effect of submitting post hoc analyses during commenting procedures. Of the 58 IQWiG assessments from the 6 months before the method update, an additional benefit was concluded in 17 (29%) assessments. Of the 27 (47%) assessments that considered PRO, results from PROs affected 14 (52%) benefit ratings. Of the 78 IQWiG assessments from the 6 months after the methods update, an additional benefit was concluded in 21 (27%) assessments. Of the 32 (41%) assessments that considered PRO, results from PROs affected 15 (47%) benefit ratings. In its assessments, G-BA mentioned that discussions were still ongoing as to whether a validated MID or a 15% response threshold is preferred. Post hoc analyses were submitted during several commenting procedures, but none changed IQWiG's benefit rating in published addenda to the dossier assessment. IQWiG's General Methods update has simplified IQWiG's process for assessing responder analyses but has not had a clear impact on the proportion of dossier assessments with accepted PROs and benefit ratings affected by PROs.