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.     

Active‐controlled,non‐inferiority trials in oncology: arbitrary limits,infeasible sample sizes and uninformative data analysis. Is there another way?

In oncology, it may not always be possible to evaluate the efficacy of new medicines in placebo-controlled trials. Furthermore, while some newer, biologically targeted anti-cancer treatments may be expected to deliver therapeutic benefit in terms of better tolerability or improved symptom control, they may not always be expected to provide increased efficacy relative to existing therapies. This naturally leads to the use of active-control, non-inferiority trials to evaluate such treatments. In recent evaluations of anti-cancer treatments, the non-inferiority margin has often been defined in terms of demonstrating that at least 50% of the active control effect has been retained by the new drug using methods such as those described by Rothmann et al., Statistics in Medicine 2003; 22:239-264 and Wang and Hung Controlled Clinical Trials 2003; 24:147-155. However, this approach can lead to prohibitively large clinical trials and results in a tendency to dichotomize trial outcome as either 'success' or 'failure' and thus oversimplifies interpretation. With relatively modest modification, these methods can be used to define a stepwise approach to design and analysis. In the first design step, the trial is sized to show indirectly that the new drug would have beaten placebo; in the second analysis step, the probability that the new drug is superior to placebo is assessed and, if sufficiently high in the third and final step, the relative efficacy of the new drug to control is assessed on a continuum of effect retention via an 'effect retention likelihood plot'. This stepwise approach is likely to provide a more complete assessment of relative efficacy so that the value of new treatments can be better judged.     

Minimal Risk in Pediatric Research: A Philosophical Review and Reconsideration

Despite more than thirty years of debate, disagreement persists among research ethicists about the most appropriate way to interpret the U.S. regulations on pediatric research, specifically the categories of “minimal risk” and a “minor increase over minimal risk.” Focusing primarily on the definition of “minimal risk,” we argue in this article that the continued debate about the pediatric risk categories is at least partly because their conceptual status is seldom considered directly. Once this is done, it becomes clear that the most popular strategy for interpreting “minimal risk”—defining it as a specific set of risks—is indefensible and, from a pragmatic perspective, unlikely to resolve disagreement. Primarily this is because judgments about minimal risk are both normative and heavily intuitive in nature and thus cannot easily be captured by reductions to a given set of risks. We suggest instead that a more defensible approach to evaluating risk should incorporate room for reflection and deliberation. This dispositional, deliberative framework can nonetheless accommodate a number of intellectual resources for reducing reliance on sheer intuition and improving the quality of risk evaluations.     

儿科护理学临床见习模式改革探讨

为了解决传统临床见习模式存在的弊端,提高临床教学质量,对2003级护理本科生和2004级护理专科生采用"电教、讨论与集中见习"的模式进行临床教学,并与2002级护理本科生和2003级护理专科生进行对照,结果显示该模式提高了教学效果,节约了开支,减少了浪费,具有可行性。     

Model free audit methodology for bias evaluation of tumour progression in oncology

Many oncology studies incorporate a blinded independent central review (BICR) to make an assessment of the integrity of the primary endpoint, progression free survival. Recently, it has been suggested that, in order to assess the potential for bias amongst investigators, a BICR amongst only a sample of patients could be performed; if evidence of bias is detected, according to a predefined threshold, the BICR is then assessed in all patients, otherwise, it is concluded that the sample was sufficient to rule out meaningful levels of bias. In this paper, we present an approach that adapts a method originally created for defining futility bounds in group sequential designs. The hazard ratio ratio, the ratio of the hazard ratio (HR) for the treatment effect estimated from the BICR to the corresponding HR for the investigator assessments, is used as the metric to define bias. The approach is simple to implement and ensures a high probability that a substantial true bias will be detected. In the absence of bias, there is a high probability of accepting the accuracy of local evaluations based on the sample, in which case an expensive BICR of all patients is avoided. The properties of the approach are demonstrated by retrospective application to a completed Phase III trial in colorectal cancer. The same approach could easily be adapted for other disease settings, and for test statistics other than the hazard ratio. Copyright © 2015 John Wiley & Sons, Ltd.     

A stochastically curtailed two-arm randomised phase II trial design for binary outcomes

Randomised controlled trials are considered the gold standard in trial design. However, phase II oncology trials with a binary outcome are often single-arm. Although a number of reasons exist for choosing a single-arm trial, the primary reason is that single-arm designs require fewer participants than their randomised equivalents. Therefore, the development of novel methodology that makes randomised designs more efficient is of value to the trials community. This article introduces a randomised two-arm binary outcome trial design that includes stochastic curtailment (SC), allowing for the possibility of stopping a trial before the final conclusions are known with certainty. In addition to SC, the proposed design involves the use of a randomised block design, which allows investigators to control the number of interim analyses. This approach is compared with existing designs that also use early stopping, through the use of a loss function comprised of a weighted sum of design characteristics. Comparisons are also made using an example from a real trial. The comparisons show that for many possible loss functions, the proposed design is superior to existing designs. Further, the proposed design may be more practical, by allowing a flexible number of interim analyses. One existing design produces superior design realisations when the anticipated response rate is low. However, when using this design, the probability of rejecting the null hypothesis is sensitive to misspecification of the null response rate. Therefore, when considering randomised designs in phase II, we recommend the proposed approach be preferred over other sequential designs.     

Protocol for student replication of published research

Subpart D of the Common Rule establishes 4 categories of research that may be conducted on children. One category, 45 CFR 46.406, permits research posing a minor increase over minimal risk and no prospect of direct benefit but expected to yield vital knowledge about the subjects' disorder or condition. To include other children in research posing a minor increase over minimal risk and no prospect of direct benefit requires federal review and approval of the Secretary of Health and Human Services under 45 CFR 46.407. It is widely held that children generally should not be exposed to more than minimal risk in research without the prospect of direct benefit. To justify deviating from this norm, as 406 allows, two claims must be true: (1) When there is vital knowledge to be gained from studying children, it is permissible to expose some children to a minor increase over minimal risk with no prospect of direct benefit; (2) It is permissible for locally reviewed and approved research to expose only children with the disorder or condition under investigation to greater risk with no prospect of direct benefit. The justification for (1) appears to be grounded in the magnitude of benefit to society combined with the need to study children. This article demonstrates that, even if the necessity and magnitude of benefit to society justify exposing children to increased risk, the decision to categorically restrict participation in such research to children with the disorder or condition under investigation (unless the study is federally reviewed and approved) is not justified. Subpart D should be revised.     

小儿烧伤原因及临床特点

目的分析小儿烧伤原因及临床特点,以预防和减少小儿烧伤的发生。方法对我院2005～2009年999例0～12岁小儿烧伤住院病例的发病率,患儿的年龄,性别,致伤原因,季节分布,城乡分布,烧伤程度等进行了回顾总结及分析。结果小儿烧伤占我院同期烧伤患者的59.32%,婴幼儿期发病率最高,为76.28%,夏秋季发病率为57.26%,农村患儿占89.19%,致伤原因主要以热液烫伤为主,占92.29%,烧伤程度以轻、中度烧伤为主,二者占总数的85.89%。结论重视小儿烧伤的预防,普及烧伤的安全教育,可降低小儿烧伤的发病率。     

Biomarkers in drug development: friend or foe? A personal reflection gained working within oncology

Hopes and expectations for the use and utility of new, emerging biomarkers in drug development have probably never been higher, especially in oncology. Biomarkers are exalted as vital patient selection tools in an effort to target those most likely to benefit from a new drug, and so to reduce development costs, lessen risk and expedite developments times. It is further hoped that biomarkers can be used as surrogate endpoints for clinical outcomes, to demonstrate effectiveness and, ultimately, to support drug approval. However, I perceive that all is not straightforward, and, particularly in terms of the promise of accelerated drug development, biomarker strategies may not in all cases deliver the advances and advantages hoped for.     

What Pediatric Subspecialists Need to Know About Sexual and Reproductive Health: A Review of the American Board of Pediatrics Content Outlines for Subspecialty Certifying Examinations

ABSTRACT

Many adolescents with complex medical conditions regard their subspecialty providers as an important source of clinical information including sexual and reproductive health information related to their medical condition. Thus, training for pediatric subspecialty providers should include clinically relevant sexual and reproductive content. The purpose of this study is to understand what disease-relevant sexual and reproductive health information is currently included in content outlines for each of the available pediatric subspecialty certifying examinations. The American Board of Pediatrics (ABP) offers 17 subspecialty certifying examinations; 13 content outlines are available on the ABP website which defines the body of knowledge to be tested. Each available outline underwent content analysis for sexual and reproductive health information. A team of adolescent medicine physicians identified seven thematic areas including: 1) puberty; 2) sexual behavior and identity; 3) fertility; 4) contraception; 5) sexually transmitted infections; 6) other genital pathology; 7) pregnancy. Across disciplines, learning objectives related to sexual behavior, sexual identity, fertility, contraception and pregnancy were the most limited. However, content related to puberty, sexually transmitted infections and other genital pathology was better represented. Overall, disease-and treatment-specific sexual and reproductive health information was sparse. Most subspecialty content outlines contain very little disease-specific sexual and reproductive health information despite the growing adolescent and young adult population with complex medical conditions in the care of pediatric subspecialists. Further studies are needed to explore if lack of sexual and reproductive information on board exams relates to the knowledge base and skill set of pediatric subspecialists.