Guidance on risk-benefit assessment of foods.

The EFSA Scientific Committee has updated its 2010 Guidance on risk-benefit assessment (RBA) of foods. The update addresses methodological developments and regulatory needs. While it retains the stepwise RBA approach, it provides additional methods for complex assessments, such as multiple chemical hazards and all relevant health effects impacting different population subgroups. The updated guidance includes approaches for systematic identification, prioritisation and selection of hazardous and beneficial food components. It also offers updates relevant to characterising adverse and beneficial effects, such as measures of effect size and dose-response modelling. The guidance expands options for characterising risks and benefits, incorporating variability, uncertainty, severity categorisation and ranking of different (beneficial or adverse) effects. The impact of different types of health effects is assessed qualitatively or quantitatively, depending on the problem formulation, scope of the RBA question and data availability. The integration of risks and benefits often involves value-based judgements and should ideally be performed with the risk-benefit manager. Metrics such as Disability-Adjusted Life Years (DALYs) and Quality-Adjusted Life Years (QALYs) can be used. Additional approaches are presented, such as probability of all relevant effects and/or effects of given severities and their integration using severity weight functions. The update includes practical guidance on reporting results, interpreting outcomes and communicating the outcome of an RBA, considering consumer perspectives and responses to advice.

Research progress and prospects of benefit-risk assessment methods for umbilical cord mesenchymal stem cell transplantation in the clinical treatment of spinal cord injury.

Over the past decade, we have witnessed the development of cell transplantation as a new strategy for repairing spinal cord injury (SCI). However, due to the complexity of the central nervous system (CNS), achieving successful clinical translation remains a significant challenge. Human umbilical cord mesenchymal stem cells (hUMSCs) possess distinct advantages, such as easy collection, lack of ethical concerns, high self-renewal ability, multilineage differentiation potential, and immunomodulatory properties. hUMSCs are promising for regenerating the injured spinal cord to a significant extent. At the same time, for advancing SCI treatment, the appropriate benefit and risk evaluation methods play a pivotal role in determining the clinical applicability of treatment plans. Hence, this study discusses the advantages and risks of hUMSCs in SCI treatment across four dimensions-comprehensive evaluation of motor and sensory function, imaging, electrophysiology, and autonomic nervous system (ANS) function-aiming to improve the rationality of relevant clinical research and the feasibility of clinical translation.

Analyzing the 7C psychological antecedents of vaccine acceptance throughout the COVID-19 pandemic among healthcare sector workers in France: A repeated cross-sectional study (CappVac-Cov).

BACKGROUND: Across various stages of the COVID-19 pandemic and related vaccine recommendations in France, we assessed the association of the 7C-psychological antecedents with vaccine uptake/intention for booster vaccination among healthcare-sector workers (HCSWs). We also assessed whether 7C-antecedent profiles changed over time. METHODOLOGY: The Research Group for the Prevention of Occupational Infections in Healthcare Workers (GERES) conducted three repeated web-surveys which were disseminated by email chain-referral among HCSWs throughout France. The questionnaires waves took place: July-November 2021, February-March 2022 and January-March 2023 (P2, P3 and P4). We also reanalysed data from a prior similar study conducted late 2020-early 2021 (Moirangthem et al. (2022)) (P1). To evaluate the association of 7C-items with vaccine uptake-intention for future vaccination, we estimated adjusted prevalence ratios (aPR) using robust variance Poisson regression. We report the 7C-item population attributable loss in vaccine intention. RESULTS: The four surveys (P1-P4) encompassed 5234, 339, 351 and 437 participants. At earlier stages of the vaccine campaign, the principal antecedents of vaccine intention were favorable perception of vaccination benefit-risk-balance (BRB) (vs. unfavorable, aPR: 2.32), reactance to employer encouragement for vaccination (motivates vs. dissuades-me, aPR:2.23), vaccine confidence (vs. not-being-confident, aPR: 1.71) and social conformism towards vaccination (favorable vs. skeptical opinion in private environment, aPR: 1.33). Under a vaccine mandate for HCSWs, only perceiving vaccination as a collective action was associated with current vaccine status (agree vs. disagree, aPR: 2.19). At later stages of the epidemic, hypothetical booster vaccine intentions were strongly associated with BRB perception (favorable vs. unfavorable, aPR: 2.07) and perceiving vaccination as a collective action (agree vs. disagree, aPR: 1.69). Fearing a severe side effect from vaccination decreased population vaccine intention by 26.2 %. CONCLUSION: Our results suggest that both 7C-antecedents and their association with vaccine behaviour can change over time, and underscore the importance of assuring confidence in vaccine safety.

Patient Preferences for Benefit and Risk Associated With High Intensity Focused Ultrasound for the Ablation of Prostate Tissue in Men With Localized Prostate Cancer.

INTRODUCTION: Food and Drug Administration must make decisions about emerging high intensity focused ultrasound (HIFU) devices that may lack relevant clinical oncologic data but present with known side effects. This study aims to capture patients' perspective by quantifying their preferences regarding the available benefit and important side effects associated with HIFU for localized prostate cancer. MATERIALS AND METHODS: Preferences for HIFU outcomes were examined using a discrete choice experiment survey. Participants were asked to choose a preferred treatment option in 9 choice questions. Each included a pair of hypothetical treatment profiles that have similar attributes/outcomes with varying levels. Outcomes included prostate biopsy outcome and treatment-related risks of erectile dysfunction (ED) and urinary incontinence (UI). We calculated the maximum risk of side effect patients were willing to tolerate in exchange for increased benefit. Preferences were further explored via clinical and demographic data. RESULTS: About 223 subjects with a mean age of 64.8 years completed the survey. Respondents were willing to accept a 1.51%-point increase in new ED risk for a 1%-point increase in favorable biopsy outcome. They were also willing to accept a 0.93%-point increase in new UI risk for a 1%-point increase in biopsy outcome. Subjects who perceived their cancer to be more aggressive had higher risk tolerance for UI. Younger men were willing to tolerate less ED risk than older men. Respondents with greater than college level of education had a lower risk tolerance for ED or UI. CONCLUSIONS: Results may inform development and regulatory evaluation for future HIFU ablation devices by providing supplemental information from the patient perspective.

Investigating Stability in Subgroup Identification for Stratified Medicine.

Subgroup analysis may be used to investigate treatment effect heterogeneity among subsets of the study population defined by baseline characteristics. Several methodologies have been proposed in recent years and with these, statistical issues such as multiplicity, complexity, and selection bias have been widely discussed. Some methods adjust for one or more of these issues; however, few of them discuss or consider the stability of the subgroup assignments. We propose exploring the stability of subgroups as a sensitivity analysis step for stratified medicine to assess the robustness of the identified subgroups besides identifying possible factors that may drive this instability. After applying Bayesian credible subgroups, a nonparametric bootstrap can be used to assess stability at subgroup-level and patient-level. Our findings illustrate that when the treatment effect is small or not so evident, patients are more likely to switch to different subgroups (jumpers) across bootstrap resamples. In contrast, when the treatment effect is large or extremely convincing, patients generally remain in the same subgroup. While the proposed subgroup stability method is illustrated through Bayesian credible subgroups method on time-to-event data, this general approach can be used with other subgroup identification methods and endpoints.

A proposal for using benefit-risk methods to improve the prominence of adverse event results when reporting trials.

Adverse events suffer from poor reporting within randomised controlled trials, despite them being crucial to the evaluation of a treatment. A recent update to the CONSORT harms checklist aims to improve reporting by providing structure and consistency to the information presented. We propose an extension wherein harms would be reported in conjunction with effectiveness outcome(s) rather than in silo to provide a more complete picture of the evidence acquired within a trial. Benefit-risk methods are designed to simultaneously consider both benefits and risks, and therefore, we believe these methods could be implemented to improve the prominence of adverse events when reporting trials. The aim of this article is to use case studies to demonstrate the practical utility of benefit-risk methods to present adverse events results alongside effectiveness results. Two randomised controlled trials have been selected as case studies, the Option-DM trial and the SANAD II trial. Using a previous review, a shortlist of 17 benefit-risk methods which could potentially be used for reporting RCTs was created. From this shortlist, three benefit-risk methods are applied across the two case studies. We selected these methods for their usefulness to achieve the aim of this paper and which are commonly used in the literature. The methods selected were the Benefit-Risk Action Team (BRAT) Framework, net clinical benefit (NCB), and the Outcome Measures in Rheumatology (OMERACT) 3 × 3 table. Results using the benefit-risk method added further context and detail to the clinical summaries made from the trials. In the case of the SANAD II trial, the clinicians concluded that despite the primary outcome being improved by the treatment, the increase in adverse events negated the improvement and the treatment was therefore not recommended. The benefit-risk methods applied to this case study outlined the data that this decision was based on in a clear and transparent way. Using benefit-risk methods to report the results of trials can increase the prominence of adverse event results by presenting them alongside the primary efficacy/effectiveness outcomes. This ensures that all the factors which would be used to determine whether a treatment would be recommended are transparent to the reader.

Assessing the benefit-risk balance of drugs. Some lessons from the COVID pandemic.

INTRODUCTION: Drug efficacy and effectiveness are assessed respectively through clinical trials and pharmaco-epidemiological studies. However, relative and absolute benefits of drugs are distinct measures that must be considered in relation to the baseline risk of disease incidence, complication or progression. On the other hand, adverse drug reactions are independent of the basic risk but depend on the characteristics of the population treated. Given these prerequisites, how can we balance the benefits and risks of drugs? AREAS COVERED: We use the example of therapeutics evaluated during Covid to describe how assessing the benefit-risk balance of drugs is a complex process. EXPERT OPINION: Clinical trials are not designed to identify rare adverse events, underscoring the necessity for a pharmacovigilance system. Evaluating the balance between the benefits and risks of drugs is an ongoing process, demanding the simultaneous analysis of data from clinical trials, potential drug-drug interactions, pharmacovigilance monitoring and pharmaco-epidemiological studies, to identify potential safety concerns. In addition, pharmacologists must play a major role in educating the general public about drugs, aiding in the accurate interpretation of the benefit-risk balance and preventing misinformation.

Fertility preservation before cancer treatment: the dilemma of saying 'no' as the price of glory.

A great deal of work has been carried out by professionals in reproductive medicine in order to raise awareness about fertility preservation (FP) techniques, particularly for women, and to ensure that FP is included in the care of young adults treated for cancer or a pathology requiring gonadotoxic treatment. If the importance of the development of our discipline is obvious, our militancy in favour of FP and our emotional projections must not make us forget that medical thinking must be carried out not only on a case-by-case basis, weighing up the benefit-risk balance, but also without losing sight that conceiving a child with one's own gametes is not a vital issue. The cultural importance given to the genetic link with offspring may bias patients' and physicians' decisions, while other ways of achieving parenthood exist, and are often more effective. Systematic information should be provided on the existence of FP techniques, but this should not lead to their systematic implementation, nor should it obscure that early information will also allow patients to begin projecting themselves in alternative options to become parents.

Exposure-Response Analyses for Belzutifan to Inform Dosing Considerations and Labeling.

Belzutifan (Welireg, Merck & Co., Inc., Rahway, NJ, USA) is an oral, potent hypoxia-inducible factor-2α inhibitor, recently approved in the United States for the treatment of von Hippel-Lindau (VHL) disease-associated renal cell carcinoma (RCC) and other VHL disease-associated neoplasms. Safety and efficacy were investigated in two clinical studies: a Phase 1 dose escalation/expansion study in solid tumors and RCC and a Phase 2 study in VHL-RCC. A population pharmacokinetic model was used to estimate belzutifan exposures to facilitate exposure-response (E-R) analyses for efficacy and safety endpoints. Relationships between exposure and efficacy (overall response rate, disease control rate, progression-free survival, best overall tumor size response, and other endpoints), safety outcomes (Grade ≥3 anemia, Grade ≥3 hypoxia, and time to first dose reduction/dose interruption), and pharmacodynamic biomarkers (erythropoietin [EPO] and hemoglobin [Hgb]) were evaluated using various regression techniques and time-to-event analyses. Efficacy E-R was generally flat with non-significant positive trends with exposure. The safety E-R analyses demonstrated a lack of relationship for Grade ≥3 hypoxia and a positive relationship for Grade ≥3 anemia, with incidences also significantly dependent on baseline Hgb. Exposure-dependent reductions in EPO and Hgb were observed. Based on the cumulative benefit-risk assessment in VHL disease-associated neoplasms using E-R, no a priori dose adjustment is recommended for any subpopulation. These analyses supported the benefit-risk profile of belzutifan 120 mg once daily dosing in patients with VHL-RCC for labeling and the overall development program.

Optimal balance of benefit versus risk for tafenoquine in the treatment of Plasmodium vivax malaria.

A single 300 mg dose of tafenoquine (an 8-aminoquinoline), in combination with a standard 3-day course of chloroquine, is approved in several countries for the radical cure (prevention of relapse) of Plasmodium vivax malaria in patients aged ≥ 16 years. Despite this, questions have arisen on the optimal dose of tafenoquine. Before the availability of tafenoquine, a 3-day course of chloroquine in combination with the 8-aminoquinoline primaquine was the only effective radical cure for vivax malaria. The World Health Organization (WHO)-recommended standard regimen is 14 days of primaquine 0.25 mg/kg/day or 7 days of primaquine 0.5 mg/kg/day in most regions, or 14 days of primaquine 0.5 mg/kg/day in East Asia and Oceania, however the long treatment courses of 7 or 14 days may result in poor adherence and, therefore, low treatment efficacy. A single dose of tafenoquine 300 mg in combination with a 3-day course of chloroquine is an important advancement for the radical cure of vivax malaria in patients without glucose-6-phosphate dehydrogenase (G6PD) deficiency, as the use of a single-dose treatment will improve adherence. Selection of a single 300 mg dose of tafenoquine for the radical cure of P. vivax malaria was based on collective efficacy and safety data from 33 studies involving more than 4000 trial participants who received tafenoquine, including over 800 subjects who received the 300 mg single dose. The safety profile of single-dose tafenoquine 300 mg is similar to that of standard-dosage primaquine 0.25 mg/kg/day for 14 days. Both primaquine and tafenoquine can cause acute haemolytic anaemia in individuals with G6PD deficiency; severe haemolysis can lead to anaemia, kidney damage, and, in some cases, death. Therefore, relapse prevention using an 8-aminoquinoline must be balanced with the need to avoid clinical haemolysis associated with G6PD deficiency. To minimize this risk, the WHO recommends G6PD testing for all individuals before the administration of curative doses of 8-aminoquinolines. In this article, the authors review key efficacy and safety data from the pivotal trials of tafenoquine and argue that the currently approved dose represents a favourable benefit-risk profile.

A Survey to Assess the Current Status of Structured Benefit-Risk Assessment in the Global Drug and Medical Device Industry.

BACKGROUND: This industry survey was conducted to gain insight into the ways structured Benefit-Risk assessment (sBRA) of medical products is approached across drug or medical device developing companies, including frameworks and methods that are currently used and areas where future work is being planned. METHODS: A survey containing 28 questions covering five key areas of sBRA was set-up and shared with representatives from the participating companies. Each company was asked to complete a single survey response including inputs across the company's multidisciplinary key representatives involved in benefit-risk assessment. RESULTS: Of the 26 participating companies, 21 (81%) are conducting sBRA. Considering these 21 qualitative frameworks were used by almost every company (19, 90%), while only 12 (57%) have used a quantitative method. Many companies have sBRA training (17, 81%), document templates (16,76%), Standard Operating Procedures (SOPs)/checklists (13, 62%), and /or best practice manuals/examples (12,57%) available. Considering all 26 companies Software tools (15, 58%) and BR planning documents (11,42%) were identified as areas into which many companies intend to put effort. CONCLUSIONS: The industry survey confirmed a wide usage of sBRA by many companies involved in research and development. Nevertheless, sBRA is evolving and several future opportunities like the implementation of visualization tools were identified by the representatives of the pharmaceutical companies. Finally, challenges like the cross-functional comprehension of the added value of sBRA are still seen.

Safety and efficacy of belantamab mafodotin with pembrolizumab in patients with relapsed or refractory multiple myeloma.

BACKGROUND: Belantamab mafodotin (belamaf) has shown promising antimyeloma activity in relapsed or refractory multiple myeloma (RRMM) as a single agent. It was hypothesized that its multimodal activity may be enhanced by programmed cell death protein 1 pathway inhibition and activation of T cell-mediated antitumor responses. This study investigated the efficacy and safety of belamaf with pembrolizumab in patients with RRMM. METHODS: DREAMM-4 (NCT03848845) was an open-label, single-arm, phase 1/2 study divided into dose-escalation (part 1) and dose-expansion (part 2) phases. Patients were ≥18 years old with ≥3 prior lines of therapy including a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 agent. Patients received belamaf (2.5 or 3.4 mg/kg, part 1; 2.5 mg/kg, part 2) and 200 mg pembrolizumab for ≤35 cycles. RESULTS: Of 41 enrolled patients, 34 (n = 6 part 1, n = 28 part 2) who received 2.5 mg/kg belamaf plus pembrolizumab were included in this final analysis. Sixteen patients (47%) achieved an overall response. Minimal residual disease negativity was achieved in three of 10 patients who had very good partial response or better. Five of eight patients who had prior anti-B-cell maturation antigen therapy achieved partial response or better, including two who had B-cell maturation antigen-refractory disease. Common grade ≥3 adverse events were keratopathy (38%) and thrombocytopenia (29%). Despite belamaf-related ocular events, quality-of-life measures remained stable over time. No new safety signals were observed. CONCLUSIONS: The results of DREAMM-4 demonstrated clinical activity and a favorable safety profile of belamaf plus pembrolizumab in patients with RRMM. This trial is registered at www. CLINICALTRIALS: gov as NCT03848845.

Structured benefit-risk assessment for enoxaparin, in the context of its label extension, for the extended treatment of deep vein thrombosis and pulmonary embolism, and prevention of its recurrence in patients with active cancer.

PURPOSE: Guidelines recommend low-molecular-weight heparins (LMWHs) for patients with cancer-associated thrombosis. However, until recently, only dalteparin and tinzaparin were approved in the European Economic Area (EEA) for these patients. This study compares the benefit-risk profile of enoxaparin with dalteparin and tinzaparin for the extended treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and prevention of recurrence in adult patients with active cancer. METHODS: A semi-quantitative structured benefit-risk assessment was conducted for the label-extension application of enoxaparin based on the benefit-risk action team descriptive framework: define decision context; determine key benefit and risk outcomes; identify data sources; extract data; interpret results. RESULTS: The key benefits were defined as reduced all-cause mortality and venous thromboembolism (VTE) recurrence (including symptomatic DVT, fatal PE or non-fatal PE); the key risks were major and non-major bleeding of clinical significance, and heparin-induced thrombocytopenia (HIT). Enoxaparin demonstrated comparable effects for the reduction of VTE recurrence and all-cause mortality versus other EEA-approved LMWHs (dalteparin, tinzaparin). There was no evidence of a significant difference between enoxaparin and the comparator groups with regard to incidence of major and non-major bleeding. The data on HIT were too limited to assess the difference between the two groups. CONCLUSIONS: The assessment demonstrated a favourable benefit-risk profile for enoxaparin similar to that of other EEA-approved LMWHs for the treatment of DVT and PE and the prevention of recurrence in patients with active cancer and thus supported the label-extension approval.

Benefit-risk assessment for the Novavax COVID-19 vaccine (NVX-CoV2373).

A benefit-risk assessment of NVX-CoV2373, a vaccine to prevent COVID-19, was conducted to determine if the benefits of vaccination outweigh the risks of myocarditis/pericarditis. This analysis used data on myocarditis/pericarditis cases observed in the NVX-CoV2373 clinical studies, real-world data of mRNA COVID vaccine effectiveness against predominant SARS-CoV-2 strains in early 2023, and recent COVID-19 burden of disease data from the United States. The benefits of NVX-CoV2373 vaccination were estimated as the number of COVID-19 cases, hospitalizations, and deaths prevented. The risks of myocarditis/pericarditis cases and related hospitalizations and deaths occurring within 7 days of vaccination were also estimated. In our analysis, vaccination with NVX-CoV2373, per 100,000 vaccinated, resulted in an estimated 1805 COVID-19 cases prevented compared with an estimated 5.3 excess myocarditis/pericarditis cases. The number of COVID-19 hospitalizations and deaths prevented were also greater than vaccine-associated myocarditis/pericarditis hospitalizations and deaths. Our analysis indicates a positive benefit-risk balance for NVX-CoV2373.

Incorporating Prior Data in Quantitative Benefit-Risk Assessments: Case Study of a Bayesian Method.

BACKGROUND: Multiple criteria decision analysis (MCDA) and stochastic multi-criteria acceptability analysis (SMAA) in their current implementation cannot incorporate prior or external information on benefits and risks. We demonstrate how to incorporate prior data using a Bayesian mixture model approach while conducting quantitative benefit-risk assessments (qBRA) for medical products. METHODS: We implemented MCDA and SMAA in a Bayesian framework. To incorporate information from a prior study, we use mixture priors on each benefit and risk attribute that mixes information from a previous study with a vague prior distribution. The degree of borrowing is varied using a mixing proportion parameter. RESULTS: A demonstration case study for qBRA using the supplementary New Drug Application (sNDA) filing for Rivaroxaban for the indication of reduction in the risk of major thrombotic vascular events in patients with peripheral artery disease (PAD) was used to illustrate the method. Net utility scores, obtained from the randomized controlled trial data to support the sNDA, from the MCDA for Rivaraxoban and comparator were 0.48 and 0.56, respectively, with Rivaroxaban being the preferred alternative only 33% of the time. We show that with only 30% borrowing from a previous RCT, the MCDA and SMAA results are favorable for Rivaroxaban, accounting for the seemingly aberrant results on all-cause death in the trial data used to support the sNDA. CONCLUSION: Our method to formally incorporate prior data in MCDA and SMAA is easy to use and interpret. Software in the form of an RShiny App is available here: https://sai-dharmarajan.shinyapps.io/BayesianMCDA_SMAA/ .

Statistical and practical considerations in planning and conduct of dose-optimization trials.

The U.S. Food and Drug Administration launched Project Optimus with the aim of shifting the paradigm of dose-finding and selection toward identifying the optimal biological dose that offers the best balance between benefit and risk, rather than the maximum tolerated dose. However, achieving dose optimization is a challenging task that involves a variety of factors and is considerably more complicated than identifying the maximum tolerated dose, both in terms of design and implementation. This article provides a comprehensive review of various design strategies for dose-optimization trials, including phase 1/2 and 2/3 designs, and highlights their respective advantages and disadvantages. In addition, practical considerations for selecting an appropriate design and planning and executing the trial are discussed. The article also presents freely available software tools that can be utilized for designing and implementing dose-optimization trials. The approaches and their implementation are illustrated through real-world examples.

Benefit-risk assessment of vaccines.

Benefit-risk assessment (BRA) is critical for decision-making throughout the vaccine life cycle. It requires scientific assessment of evidence to make an informed judgment on whether the vaccine has a favourable benefit-risk profile i.e. the benefits of the vaccine outweigh its risks for use in its intended indication. The assessment must also consider data gaps and uncertainties, using sensitivity analyses to show the impact of these uncertainties in the assessment. The BRA field has advanced considerably over the past years, including the use of structured BRA frameworks, quantitative BRA models and use of the patient experience data. Analytical tools and procedures to standardize BRA implementation have become increasingly important. A Benefit-Risk Assessment Module has been prepared to enable the planning, assessment, and communication of relevant BRA information via a structured B-R framework. The module can help facilitate the conduct and communication of defensible BRAs by vaccine developers, funders, regulators and policy makers in high, middle or low-income countries, both for regulatory submissions and in public health responses to infectious diseases, including for epidemics.

Design of a clinical trial using generalized pairwise comparisons to test a less intensive treatment regimen.

BACKGROUND/AIMS: Showing "similar efficacy" of a less intensive treatment typically requires a non-inferiority trial. Yet such trials may be challenging to design and conduct. In acute promyelocytic leukemia, great progress has been achieved with the introduction of targeted therapies, but toxicity remains a major clinical issue. There is a pressing need to show the favorable benefit/risk of less intensive treatment regimens. METHODS: We designed a clinical trial that uses generalized pairwise comparisons of five prioritized outcomes (alive and event-free at 2 years, grade 3/4 documented infections, differentiation syndrome, hepatotoxicity, and neuropathy) to confirm a favorable benefit/risk of a less intensive treatment regimen. We conducted simulations based on historical data and assumptions about the differences expected between the standard of care and the less intensive treatment regimen to calculate the sample size required to have high power to show a positive Net Treatment Benefit in favor of the less intensive treatment regimen. RESULTS: Across 10,000 simulations, average sample sizes of 260 to 300 patients are required for a trial using generalized pairwise comparisons to detect typical Net Treatment Benefits of 0.19 (interquartile range 0.14-0.23 for a sample size of 280). The Net Treatment Benefit is interpreted as a difference between the probability of doing better on the less intensive treatment regimen than on the standard of care, minus the probability of the opposite situation. A Net Treatment Benefit of 0.19 translates to a number needed to treat of about 5.3 patients (1/0.19 ≃ 5.3). CONCLUSION: Generalized pairwise comparisons allow for simultaneous assessment of efficacy and safety, with priority given to the former. The sample size required would be of the order of 300 patients, as compared with more than 700 patients for a non-inferiority trial using a margin of 4% against the less intensive treatment regimen for the absolute difference in event-free survival at 2 years, as considered here.