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Pre‐specification of the primary analysis model is a pre‐requisite to control the family‐wise type‐I‐error rate (T1E) at the intended level in confirmatory clinical trials. However, mixed models for repeated measures (MMRM) have been shown to be poorly specified in study protocols. The magnitude of a resulting T1E rate inflation is still unknown. This investigation aims to quantify the magnitude of the T1E rate inflation depending on the type and number of unspecified model items as well as different trial characteristics. We simulated a randomized, double‐blind, parallel group, phase III clinical trial under the assumption that there is no treatment effect at any time point. The simulated data was analysed using different clusters, each including several MMRMs that are compatible with the imprecise pre‐specification of the MMRM. T1E rates for each cluster were estimated. A significant T1E rate inflation could be shown for ambiguous model specifications with a maximum T1E rate of 7.6% [7.1%; 8.1%]. The results show that the magnitude of the T1E rate inflation depends on the type and number of unspecified model items as well as the sample size and allocation ratio. The imprecise specification of nuisance parameters may not lead to a significant T1E rate inflation. However, the results of this simulation study rather underestimate the true T1E rate inflation. In conclusion, imprecise MMRM specifications may lead to a substantial inflation of the T1E rate and can damage the ability to generate confirmatory evidence in pivotal clinical trials. [ABSTRACT FROM AUTHOR]

In studying a potential disease-modifying treatment for Alzheimer's Disease, the use of currently available symptomatic medicines—being proportional to the disease progression—can mask the disease-modifying effect. A solution in line with the Estimand framework is to adopt a hypothetical strategy for the intercurrent event "initiation of symptomatic treatment". However, there is no consensus on reliable estimators for estimands adopting this strategy. To evaluate the performance of several candidate estimators, we have (i) designed clinically realistic data-generating mechanisms based on causal Directed Acyclic Graphs; (ii) selected potentially adequate estimators, amongst other, g-estimation methods usually employed to estimate "controlled direct effect" in mediation analysis; (iii) simulated 10,000 trials for six plausible scenarios and compared the performance of the estimators. The results of our simulations demonstrate that ignoring the intercurrent event introduces a bias compared to the true value of the target estimand. In contrast, g-estimation methods are unbiased, retain nominal power, and control the Type-I error rate at the intended level. Our results can be extrapolated, from a qualitative (absence or presence of bias) but not quantitative point of view (magnitude of the bias), to clinical scenarios with a similar underlying causal structure. [ABSTRACT FROM AUTHOR]

The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use has published an addendum on estimands and sensitivity analysis in clinical trials along with related training materials. These define an estimand as a precise description of the treatment effect that reflects the scientific question of interest. In December 2022, the US Food and Drug Administration released draft guidance recommending estimands of interest be specified in bioequivalence trial protocols. However, experience in implementing estimands in clinical pharmacology trials is limited and so we introduce estimands and provide step‐by‐step considerations about the estimand thinking process in this setting. We also describe a particular case study, a bioequivalence trial, illustrating how the estimand framework can provide transparency and alignment throughout the design, conduct and analysis of the trial. This involves discussion of how to identify and handle intercurrent events, which are events that can affect interpretation of the drug or metabolite endpoints. Furthermore, we discuss the broader applicability of the estimand framework to other clinical pharmacology trials. Finally, we encourage further discussion between industry, academia, regulators and the International Council for Harmonisation on whether the estimand framework should be considered in all clinical pharmacology regulatory guidance documents. [ABSTRACT FROM AUTHOR]

In the EU, conditional marketing authorization is a pragmatic tool for early approval of a medicine that fulfills an unmet medical need. In the pharmaceutical legislation, an unmet medical need means that a condition lacks a satisfactory method for diagnosis, prevention, or treatment. If such satisfactory methods exist, the new medicinal product must hold a major therapeutic advantage for those affected, meaning that it must demonstrate an improvement in efficacy or safety over existing methods or, in exceptional cases, a major improvement in patient care. This review evaluates the approaches taken to justify a major therapeutic advantage in oncology and hematology products recommended for approval between 2006 and 2023. The review confirmed an increase in the number of conditional marketing authorizations over time. Out of a total of 65 CMAs, a satisfactory treatment method was available for 40 cases (61.5%), thereby requiring a demonstration of major therapeutic advantage to fulfill the unmet medical need requirement. Satisfactory treatments existed more often for the more recently approved medicinal products. Qualitative arguments and quantitative comparisons were common to demonstrate meaningful improvement in efficacy or safety. In the absence of head-to-head trials, indirect comparisons were often used. Most quantitative comparisons used naïve side-by-side comparisons, lacking adjustments for trial differences or quantification of uncertainty. Regulatory guidance on indirect comparisons and data requirements may be helpful to support applicants and assessors in making available promising medicines early that fulfill an unmet medical need and continue to meet rigorous efficacy and safety standards pending availability of comprehensive data post-approval., (© 2025 The Author(s). Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Objectives: In the European Union, a new orphan medicinal product must demonstrate 'significant benefit' over approved medicinal products targeting the same indication. To demonstrate a significant benefit, comparisons between the new product and the already approved medicinal products-either directly by a head-to-head comparison within a clinical trial or indirectly as a cross-trial comparison-are necessary. In this study, we investigate the types of trial designs and statistical approaches used for demonstrating a significant benefit of a new orphan medicinal product against approved comparators used between 2012 and 2022., Design: This is a cross-sectional study based on the European Medicines Agency's 'orphan maintenance' assessment documents between 2012 and 2022. All documents were manually reviewed to extract structured data on the following outcome measures:For every comparison between a new orphan medicinal product and a comparator used for demonstrating a significant benefit as part of an orphan maintenance procedure, we recorded the type and design of the data source and the type of statistical methodology used for the comparison., Results: We identified 151 EMA orphan maintenance procedures with a positive decision that required the demonstration of a significant benefit. Within these 151 procedures, 418 comparisons between medicinal products were identified. Indirect comparisons are the most common approach for comparing the new orphan medicinal product to a relevant comparator (44%, 182/418), followed by qualitative comparisons (39%, 162/418) and direct comparisons (18%, 74/418). Among the indirect comparisons, naive side-by-side comparisons are most often used (71%, 129/182), whereas inferential approaches that adjust for population differences and quantify the uncertainty of the comparison are used less often (29%, 53/182). Although there is no clear time trend in the prevalence of any specific comparison type, we find that inferential indirect comparison methods approximately doubled between the first and second half of the reviewed time frame., Conclusions: Indirect comparisons play an important role in demonstrating a significant benefit in the assessment of orphan products. Further work is needed to evaluate the appropriateness of different methodologies., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ Group.)

Despite the high prevalence and mortality of lung cancer and proven effectiveness of low-dose computed tomography (LDCT) to reduce mortality, Germany still lacks a national screening program. The German Institute for Quality and Efficiency in Health Care (IQWiG) and the Federal Office for Radiation Protection (BfS) both published positive scientific evaluations recommending a quality-controlled national screening program. IQWiG underlined the importance of a clear risk definition, integrated smoking cessation programs, and quality assurance, highlighting the necessity of procedural optimization.In the HANSE study, former and current smokers aged 55-79 years are assessed for their lung cancer risk by the NELSON and PLCO M2012 risk scores. 5000 high-risk participants, defined as PLCO M2012 6-year risk ≥ 1.58 % or fulfilling NELSON risk inclusion criteria, will be screened by LDCT at baseline and after 12 months. Lung nodules are analyzed by a modified Lung-RADS 1.1 score of the HANSE study, and values of emphysema and coronary calcium are determined and randomly reported to the participants. 7100 low-risk participants serve as a control. All patients are followed-up for up to 10 years. The sensitivity and specificity of the two risk assessments and LDCT screening, effects of the randomized LDCT reporting, efficiency of lung nodule management, and several other factors are assessed to analyze the success and quality of the holistic screening program.The HANSE study is designed as a holistic lung cancer screening study in northern Germany to answer pressing questions for a successful implementation of an effective German lung cancer screening program. · HANSE is designed to address pressing questions for the implementation of lung cancer screening in Germany.. · HANSE compares NELSON and PLCOM2012 risk assessments for optimal definition of the high-risk group. . · HANSE integrates cardiac calcium and pulmonary emphysema scoring in a holistic screening approach.. CITATION FORMAT: · Vogel-Claussen J, Lasch F, Bollmann B et al. Design and Rationale of the HANSE Study: A Holistic German Lung Cancer Screening Trial Using Low-Dose Computed Tomography. Fortschr Röntgenstr 2022; 194: 1333 - 1345., Competing Interests: The authors declare that they have the following conflicts of interest:J. Vogel-Claussen: Research project support by BMBF, Siemens Healthineers, Boehringer Ingelheim, Novartis, GlaxoSmithKline.Speaking fees by Boehringer Ingelheim, Astra Zeneca, Novartis, Siemens Healthineers, Coreline Soft.M. Reck: Speaking and consulting fees by Amgen, AstraZeneca, BMS, Beigene, Boehringer-Ingelheim, Lilly, Merck, MSD, Mirati, Novartis, Pfizer, Roche, Sanofi.B.A. Bollmann: Speaking fees by AstraZeneca, Boehringer Ingelheim, MSD, Bristol-Myers-Sqibb und Roche.G. Schmid-Bindert is an employee of AstraZeneca.The other authors declare that they have no conflict of interest., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commecial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

Purpose To quantify regional lung ventilation in patients with chronic obstructive pulmonary disease (COPD) by using free-breathing dynamic fluorinated (fluorine 19 [ 19 F]) gas magnetic resonance (MR) imaging. Materials and Methods In this institutional review board-approved prospective study, 27 patients with COPD were examined by using breath-hold 19 F gas wash-in MR imaging during inhalation of a normoxic fluorinated gas mixture (perfluoropropane) and by using free-breathing dynamic 19 F gas washout MR imaging after inhalation of the gas mixture was finished for a total of 25-30 L. Regional lung ventilation was quantified by using volume defect percentage (VDP), washout time, number of breaths, and fractional ventilation (FV). To compare different lung function parameters, Pearson correlation coefficient and Fisher z transformation were used, which were corrected for multiple comparisons with the Bonferroni method. Results Statistically significant correlations were observed for all evaluated lung function test parameters compared with median and interquartile range of 19 F washout parameters. An inverse linear correlation of median number of breaths (r = -0.82; P < .0001) and median washout times (r = -0.77; P < .0001) with percentage predicted of forced expiratory volume in 1 second (FEV 1 ) was observed; correspondingly median FV (r = 0.86; P < .0001) correlated positively with percentage predicted FEV 1 . Comparing initial with late phase, median VDP of all subjects decreased from 49% (25th-75th percentile, 35%-62%) to 6% (25th-75th percentile, 2%-10%; P < .0001). VDP at the beginning of the gas wash-in phase (VDP initial ) significantly correlated with percentage predicted FEV 1 (r = -0.74; P = .0028) and FV (r = 0.74; P = .0002). Median FV was significantly increased in ventilated regions (11.1% [25th-75th percentile, 6.8%-14.5%]) compared with the defect regions identified by VDP initial (5.8% [25th-75th percentile, 4.0%-7.4%]; P < .0001). Conclusion Quantification of regional lung ventilation by using dynamic 19 F gas washout MR imaging in free breathing is feasible at 1.5 T even in obstructed lung segments. © RSNA, 2017 Online supplemental material is available for this article.