Clinical trials : journal of the Society for Clinical Trials
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Accurate information on harms arising from medical interventions is essential for assessing benefit-risk ratios. Since 2004, there has been an extension of the Consolidated Standards of Reporting Trials statement for reporting harms data in publications on randomized clinical trials. The objective of our study was to assess the quality of this reporting from academic randomized clinical trials on drugs. ⋯ Reporting of harms in French academic drug randomized clinical trials is suboptimal; moreover, this shortcoming is a critical barrier to evaluating the benefit-risk ratio of drug randomized clinical trials. Thus, the authors should be encouraged to adhere to the Consolidated Standards of Reporting Trials Harms extension.
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Background/aims In clinical trials with time-to-event outcomes, usually the significance tests and confidence intervals are based on a proportional hazards model. Thus, the temporal pattern of the treatment effect is not directly considered. This could be problematic if the proportional hazards assumption is violated, as such violation could impact both interim and final estimates of the treatment effect. ⋯ The average hazard ratio and its confidence interval indicates a treatment effect nearly a year earlier than a restricted mean survival time-based approach. Conclusion When the hazards are proportional between the comparison groups, the new methods yield results very close to the traditional approaches. When the proportional hazards assumption is violated, the new methods continue to be applicable and can potentially be more sensitive to departure from the null hypothesis.
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The US Food and Drug Administration has several regulatory programs and pathways to expedite the development and approval of therapeutic agents aimed at treating serious or life-debilitating conditions. A common feature of these programs is the regulatory flexibility, which allows for a customized approval approach that enables market authorization on the basis of less rigorous evidence, in exchange for requiring postmarket evidence generation. An increasing share of therapeutic agents approved by the Food and Drug Administration in recent years are associated with expedited programs. ⋯ In the premarket period, validity of the surrogate markers can be improved by more rigorously evaluating their correlation with patient-relevant clinical outcomes. Opportunities to reduce the duration, complexity, and cost of postmarket randomized trials should not compromise their validity and instead incorporate pragmatic "real-world" design elements. Despite recent enthusiasm for widely using real-world evidence, adaptive designs, and pragmatic trials in the regulatory setting, caution is warranted until large-scale empirical evaluations demonstrate their validity compared to more traditional trial designs.
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Pediatric rare disease presents a challenging situation of high unmet need and a limited pool of potential clinical trial participants. Understanding perspectives of parents of children who have not participated in trials may facilitate approaches to optimize participation rates. The objective of this study was to explore factors associated with parental interest in enrolling children with pediatric neuromuscular disorders in clinical trials. ⋯ We found high parental interest in pediatric neuromuscular trials that was tempered by concerns about the potential for randomization to a placebo arm. Participants perceived that their trial participation would be facilitated by additional education and guidance from their clinicians. Yet, intentions were negatively associated with frequency of provider communication, perhaps reflecting waning parental interest with a greater understanding of limitations in trial access, increased sophistication in their understanding of trial design, and appreciation of potential burden. To support parents' informed decisions, it is important to educate them to evaluate the quality of research, as well as providing lay information explaining the use of placebo, trial processes, and potential barriers to long-term drug access. Our findings should inform the development of targeted educational content, clinician training, and decision support tools.
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With increasing emphasis on pragmatic trials, new randomized clinical trial designs are being proposed to enhance the "real world" nature of the data generated. We describe one such design, appropriate for unmasked pragmatic clinical trials in which the control arm receives usual care, called "Trials within Cohorts" that is increasingly used in various countries because of its efficiency in recruitment, advantages in reducing subject burden, and ability to better mimic real-world consent processes. ⋯ Trials within Cohorts is a promising new pragmatic randomized controlled trial design that is being increasingly used in various countries. Although the asymmetric consent procedures for the experimental versus control arm subjects can initially raise ethical concerns, it is ethically superior to previous post-randomization consent designs and can have important advantages over traditional trial designs.