Properties of the weighted log‐rank test in the design of confirmatory studies with delayed effects

Proportional hazards are a common assumption when designing confirmatory clinical trials in oncology. This assumption not only affects the analysis part but also the sample size calculation. The presence of delayed effects causes a change in the hazard ratio while the trial is ongoing since at the beginning we do not observe any difference between treatment arms, and after some unknown time point, the differences between treatment arms will start to appear. Hence, the proportional hazards assumption no longer holds, and both sample size calculation and analysis methods to be used should be reconsidered. The weighted log‐rank test allows a weighting for early, middle, and late differences through the Fleming and Harrington class of weights and is proven to be more efficient when the proportional hazards assumption does not hold. The Fleming and Harrington class of weights, along with the estimated delay, can be incorporated into the sample size calculation in order to maintain the desired power once the treatment arm differences start to appear. In this article, we explore the impact of delayed effects in group sequential and adaptive group sequential designs and make an empirical evaluation in terms of power and type‐I error rate of the of the weighted log‐rank test in a simulated scenario with fixed values of the Fleming and Harrington class of weights. We also give some practical recommendations regarding which methodology should be used in the presence of delayed effects depending on certain characteristics of the trial.     

Help-Seeking for Sexual Difficulties and the Potential Role of Interactive Digital Interventions: Findings From the Third British National Survey of Sexual Attitudes and Lifestyles

Sexual difficulties are common and can negatively impact health and well-being. A wide range of support is available, but there are multiple barriers to accessing help. Interactive digital interventions (IDIs) for sexual difficulties have the potential to provide a convenient, wide-reaching, and cost-effective source of support, but little is known about who might use them. We explored the potential reach of IDIs by assessing the prevalence of help-seeking among people with distressing sexual difficulties, including who seeks which sources of help. Data came from sexually active men and women, ages 16 to 74, participating in Britain’s third National Survey of Sexual Attitudes and Lifestyles (Natsal-3) (N = 11,637). Help/advice was sought by less than half of those with distressing sexual difficulties, and help-seeking was associated with younger age in women but not men. The most popular sources of support were family doctor (47.5% to 54.8%), Internet (22.0% to 25.6%), and family/friend (20.7% to 41.8%), with older participants (≥ 35), particularly men, preferring to seek help from a family doctor, and younger participants (<35) preferring to seek help from the Internet or family/friend. Despite a paucity of good digital support sites for sexual function, the Internet is a common source of help. As Internet access continues to increase, so too does the potential for well-designed IDIs to support those with sexual difficulties.     

Information-driven coordination: experimental results with heterogeneous individuals

We study experimentally a coordination game with N heterogeneous individuals under different information treatments. We explore the effects of information on the emergence of Pareto-efficient outcomes, by means of a gradual decrease of the information content provided to the players in successive experiments. We observe that successful coordination is possible with private information alone, although not on a Pareto-optimal equilibrium. Reinforcement-based learning models reproduce the qualitative trends of the experimental results.     

Estimand framework: Are we asking the right questions? A case study in the solid tumor setting

The estimand framework requires a precise definition of the clinical question of interest (the estimand) as different ways of accounting for “intercurrent” events post randomization may result in different scientific questions. The initiation of subsequent therapy is common in oncology clinical trials and is considered an intercurrent event if the start of such therapy occurs prior to a recurrence or progression event. Three possible ways to account for this intercurrent event in the analysis are to censor at initiation, consider recurrence or progression events (including death) that occur before and after the initiation of subsequent therapy, or consider the start of subsequent therapy as an event in and of itself. The new estimand framework clarifies that these analyses address different questions (“does the drug delay recurrence if no patient had received subsequent therapy?” vs “does the drug delay recurrence with or without subsequent therapy?” vs “does the drug delay recurrence or start of subsequent therapy?”). The framework facilitates discussions during clinical trial planning and design to ensure alignment between the key question of interest, the analysis, and interpretation. This article is a result of a cross-industry collaboration to connect the International Council for Harmonisation E9 addendum concepts to applications. Data from previously reported randomized phase 3 studies in the renal cell carcinoma setting are used to consider common intercurrent events in solid tumor studies, and to illustrate different scientific questions and the consequences of the estimand choice for study design, data collection, analysis, and interpretation.