BACKGROUND: For time-to-event endpoints, three additional benefit assessment methods have been developed aiming at an unbiased knowledge about the magnitude of clinical benefit of newly approved treatments. The American Society of Clinical Oncology (ASCO) defines a continuous score using the hazard ratio point estimate (HR-PE). The European Society for Medical Oncology (ESMO) and the German Institute for Quality and Efficiency in Health Care (IQWiG) developed methods with an ordinal outcome using lower and upper limits of the 95% HR confidence interval (HR-CI), respectively. We describe all three frameworks for additional benefit assessment aiming at a fair comparison across different stakeholders. Furthermore, we determine which ASCO score is consistent with which ESMO/IQWiG category.
METHODS: In a comprehensive simulation study with different failure time distributions and treatment effects, we compare all methods using Spearman\'s correlation and descriptive measures. For determination of ASCO values consistent with categories of ESMO/IQWiG, maximizing weighted Cohen\'s Kappa approach was used.
RESULTS: Our research depicts a high positive relationship between ASCO/IQWiG and a low positive relationship between ASCO/ESMO. An ASCO score smaller than 17, 17 to 20, 20 to 24, and greater than 24 corresponds to ESMO categories. Using ASCO values of 21 and 38 as cutoffs represents IQWiG categories.
CONCLUSIONS: We investigated the statistical aspects of the methods and hence implemented slightly reduced versions of all methods.
CONCLUSIONS: IQWiG and ASCO are more conservative than ESMO, which often awards the maximal category independent of the true effect and is at risk of overcompensating with various failure time distributions. ASCO has similar characteristics as IQWiG. Delayed treatment effects and underpowered/overpowered studies influence all methods in some degree. Nevertheless, ESMO is the most liberal one.
CONCLUSIONS: For the additional benefit assessment, the American Society of Clinical Oncology (ASCO) uses the hazard ratio point estimate (HR-PE) for their continuous score. In contrast, the European Society for Medical Oncology (ESMO) and the German Institute for Quality and Efficiency in Health Care (IQWiG) use the lower and upper 95% HR confidence interval (HR-CI) to specific thresholds, respectively. ESMO generously assigns maximal scores, while IQWiG is more conservative.This research provides the first comparison between IQWiG and ASCO and describes all three frameworks for additional benefit assessment aiming for a fair comparison across different stakeholders. Furthermore, thresholds for ASCO consistent with ESMO and IQWiG categories are determined, enabling a comparison of the methods in practice in a fair manner.IQWiG and ASCO are the more conservative methods, while ESMO awards high percentages of maximal categories, especially with various failure time distributions. ASCO has similar characteristics as IQWiG. Delayed treatment effects and under/-overpowered studies influence all methods. Nevertheless, ESMO is the most liberal one. An ASCO score smaller than 17, 17 to 20, 20 to 24, and greater than 24 correspond to the categories of ESMO. Using ASCO values of 21 and 38 as cutoffs represents categories of IQWiG.

From 2025, Health Technology Developers (HTDs) have to submit EU HTA dossiers. The joint clinical assessment (JCA) aims to streamline HTA processes and access to medicinal products across Europe. Currently, German HTA bodies IQWiG and G-BA actively shape the JCA methodology. Here we examine if German HTA dossier requirements are suitable for the JCA. We compare the number of safety endpoint and subgroup analyses in German dossiers with analyses considered in IQWIG\'s benefit assessment and evaluate if these analyses were considered by the G-BA. We further investigated how the number of analyses was affected by the latest change in the German dossier template. With the current template, HTDs report in median 2.6 times more analyses on adverse events (AE) and 1.1 times more subgroup categories than in the previous template. IQWiG does not consider 33% of AE analyses and 73% of the subgroup categories presented by the HTD under the current template. G-BA considered the same AE as IQWiG in 76% of cases. Subgroups were uncommented by G-BA in most cases, independent of the template (previous: 93%, current 85%) and unconsidered in the conclusion on additional benefit (previous: 77%, current 69%). Thus, changes in the dossier template drastically increased HTD workload, but additional analyses seem unconsidered by the HTA bodies. With a broader scope in JCA, this effect could be amplified. To mitigate duplicative efforts and ensure prompt availability of medicinal products as envisioned by the HTAR, we suggest well-chosen and precise dossier requirements, early consultations, and early HTD engagement.

Patient-reported outcome (PRO) data are increasingly being included in Health Technology Assessment (HTA) submissions for oncology drugs. This study aims to provide differences in PRO evidence requirements in oncology across key HTA bodies and calls for its harmonization. Method guidance provided by HTA bodies in Germany, France, and the UK, and analysis of HTA reports of 20 oncology case studies were evaluated in this review. Differences exist between HTA bodies regarding guidance on how PRO data should be collected, reported and analyzed as well as how the data are reviewed and considered in oncology HTAs. HTA bodies can play a key role to harmonize PRO method guidance in collaboration with regulators and sponsors.
Patient-reported outcomes (PRO) are information provided directly by the person who is experiencing a disease or undergoing a treatment, without additional interpretation by a clinician or caregiver. Along with other outcome measures, PROs may be included in the body of evidence used by health technology assessment bodies in their review. In this article, the authors summarize the guidance documents published by key health technology assessment agencies and reviewed 20 past cancer drug case studies to understand how different agencies use PROs when deciding on recommendations for new cancer treatments.

UNASSIGNED: To analyze how ophthalmic drugs fared in the early benefit assessment (EBA) after its introduction in Germany up to 2020 and to quantify its impact on their negotiated prices.
UNASSIGNED: Relevant documents were screened and essential content on added benefit outcomes and the underlying evidence was extracted next to pricing information. In addition to descriptive statistics, cross-stakeholder analyses and agreement statistics were implemented.
UNASSIGNED: Thirteen completed EBA were identified involving eight drugs. Only four drugs (30.8%) received an added benefit. The OR for no added benefit of ophthalmic drugs versus all other drugs was 2.971 (0.902-9.781). The agreement between manufacturers\' claims and decision-maker appraisals is fair (kappa 0.435). In all cases, evidence was derived for RCTs, but for different reasons, not all of them allowed direct comparisons with the comparator as defined by the decision-maker. The negotiated rebates on manufacturer\'s selling prices varied from 6.8% up to 47.4%. Nevertheless, the rebates for ophthalmic drugs (median 14.5%) were lower than those for all negotiated drugs (median 24%).
UNASSIGNED: Over the past decade, the EBA of ophthalmic drugs was not necessarily a success story, but in most of the cases, the drugs were successful in the market.

BACKGROUND: The question of how to set the cost-effectiveness threshold for new, innovative medicines is a matter of ongoing controversy. One prominent proposal suggests that the cost-effectiveness threshold adopted by the U.K. National Institute for Health and Care Excellence (NICE) should represent the opportunity cost for the U.K. National Health Service resulting from the adoption of new medicines. The purpose of this article is to compare this proposal for the U.K. with the approach chosen by the Institute for Quality and Efficiency in Health Care (IQWiG) in Germany, which relies on indication-specific cost-effectiveness thresholds.
UNASSIGNED: The \'ideal\' NICE and IQWiG surprisingly share the fundamental principle of inferring the willingness to pay from existing care. For this and other reasons, indication-specific thresholds based on IQWiG\'s methodology do not lead to more inefficiency at the health system\'s level than a generic threshold based on the \'ideal\' NICE (keeping other conditions the same). Also, applying either decision rule to one country will yield a similar long-term growth in population spending. Assuming that everything else is equal, both decision rules are predicted to decrease long-term expenditure growth. Convergence of the two decision rules would require, among others, ruling out waste in the \'ideal\' NICE\'s approach and, for IQWiG\'s approach, using the same relative weights for life expectancy and health-related quality of life as the quality-adjusted-life-year model.
CONCLUSIONS: This article shows that both decision rules have notable commonalities in terms of inferring the willingness to pay from existing care and the projected impact on long-term growth in population spending.

BACKGROUND: The purpose of this study was to analyse the impact of commissioned addenda by the Federal Joint Committee (FJC) to the HTA body (IQWiG) and their agreement with FJC decisions and to identify potential additional decisive factors of FJC.
METHODS: All available relevant documents up to end of 2017 were screened and essential content extracted. Next to descriptive statistics, differences between IQWiG and FJC were tested and explored by agreement statistics (Cohen\'s kappa and Fleiss\' kappa) and ordinal logistic regression.
RESULTS: Most of the 90 addenda concerned oncological products. In all contingent comparisons, positive changes in added benefit or evidence level on a subpopulation basis (n = 124) prevailed negative ones. Fleiss\' ordinal kappa for agreement of assessments, addenda, and appraisals reached a moderate strength for added benefit (0.474, 95%-CI, 0.408-0.540). Overall agreement between addenda and appraisals on a binary nominal basis is poor for added benefit (Cohen\'s kappa 0.183; 95%-CI: 0.010-0.357) ranging from \"less than by chance\" (respiratory diseases) to \"perfect\" (neurological diseases). The OR of the selected regression model showed that i) mortality, ii) unmet need, the positions of iii) the physicians\' drug commission and iv) medical societies, and v) the annual therapeutic costs of the appropriate comparative therapy had a high influence on FJC\'s appraisals deviating from IQWiG\'s addenda recommendation.
CONCLUSIONS: IQWiG\'s addenda have a high impact on decision-maker\'s appraisals offering additional analyses of supplementary evidence submitted by the manufacturers. Nevertheless, the agreement between addenda and appraisals varies, highlighting different decisive factors between IQWiG and FJC.

BACKGROUND: Since January 2011, the Federal Joint Committee (FJC) conducts early benefit assessments (EBA) of newly approved pharmaceutical drugs compared to appropriate standard therapies. The FJC commissions the Institute for Quality and Efficiency in Healthcare (IQEH) to prepare preliminary reports. We aimed to evaluate the extent, impact, and reason for different judgments on added benefit of both institutions.
METHODS: We searched EBA data on the FJC website and included completed procedures from 2011 to 2017. We conducted a quantitative analysis of the difference between FJC and IQEH on divergent judgments, a quantitative analysis of the impact of EBA on market withdrawal, and a qualitative analysis to identify potential factors contributing to divergent judgments.
RESULTS: FJC rated an added benefit in 30% (139 of 457) and IQEH in 22% (101 of 457) matching research questions (P = 0.004). In the aftermath of EBA, 28 pharmaceutical drugs were withdrawn from the German market. We identified three potential factors that might have contributed to the divergent judgments. IQEH used a unique threshold concept to define the rating, FJC conducted additional public hearings, and FJC showed more flexibility with adherence to stringent criteria and interpretation of results.
CONCLUSIONS: FJC and IQEH differed significantly in their early benefit assessment. In response to negative EBA decisions, pharmaceutical companies withdrew a considerable number of medicines from the German market. The present work uncovers the subjectivity and possible variance inherent in benefit assessment, as the two institutions observe the same rules of procedure.

BACKGROUND: The decision matrix applied by the Institute for Quality and Efficiency in Health Care (IQWiG) for the quantification of added benefit within the early benefit assessment of new pharmaceuticals in Germany with its nine fields is quite complex and could be simplified. Furthermore, the method used by IQWiG is subject to manifold criticism: (1) it is implicitly weighting endpoints differently in its assessments favoring overall survival and, thereby, drug interventions in fatal diseases, (2) it is assuming that two pivotal trials are available when assessing the dossiers submitted by the pharmaceutical manufacturers, leading to far-reaching implications with respect to the quantification of added benefit, and, (3) it is basing the evaluation primarily on dichotomous endpoints and consequently leading to an information loss of usable evidence.
OBJECTIVE: To investigate if criticism is justified and to propose methodological adaptations.
METHODS: Analysis of the available dossiers up to the end of 2016 using statistical tests and multinomial logistic regression and simulations.
RESULTS: It was shown that due to power losses, the method does not ensure that results are statistically valid and outcomes of the early benefit assessment may be compromised, though evidence on favoring overall survival remains unclear. Modifications, however, of the IQWiG method are possible to address the identified problems.
CONCLUSIONS: By converging with the approach of approval authorities for confirmatory endpoints, the decision matrix could be simplified and the analysis method could be improved, to put the results on a more valid statistical basis.

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

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