Innovative Thinking on Endpoint Selection in Clinical Trials

ABSTRACT

In clinical trials, selection of appropriate study endpoints is critical for an accurate and reliable evaluation of safety and effectiveness of a test treatment under investigation. In practice, however, there are usually multiple endpoints available for measurement of disease status and/or therapeutic effect of the test treatment under study. For example, in cancer clinical trials, overall survival, response rate, and/or time to disease progression are usually considered as primary clinical endpoints for evaluation of safety and effectiveness of the test treatment under investigation. Once the study endpoints have been selected, sample size required for achieving a desired power is then determined. It, however, should be noted that different study endpoints may result in different sample sizes. In practice, it is usually not clear which study endpoint can best inform the disease status and measure the treatment effect. Moreover, different study endpoints may not translate one another although they may be highly correlated one another. In this article, we intend to develop an innovative endpoint namely therapeutic index based on a utility function to combine and utilize information collected from all study endpoints. Statistical properties and performances of the proposed therapeutic index are evaluated theoretically. A numerical example concerning a cancer clinical trial is given to illustrate the use of the proposed therapeutic index.     

A Proposal for an Alternative Approach to Particle Size Method Development During Early-Stage Small Molecule Pharmaceutical Development

Particle size analysis in the pharmaceutical industry has long been a source of debate regarding how best to define measurement accuracy; the degree to which the result of a measurement or calculation conforms to the true value. Defining a “true” value for the size of a particle can be challenging as the output of its measurement will differ because of variations in measurement approaches, instrumental differences and calculation methods. Consequently, for “real” particles, a universal “true” value does not exist and accuracy is therefore not a definable characteristic. Accordingly, precision is then a measure of the ability to reproducibly achieve a measurement of unknown relevance.This article proposes, in place of accuracy, a means to define the “appropriateness” of a measurement in line with the critical quality attributes (CQA) of the material being characterized. The decision as to whether the measurement is correct should involve a link to the CQA; that is, correlation should be demonstrated, without which the measured particle size cannot be defined as a critical material attribute.Correspondingly, methods should also be able to provide sufficient precision to demonstrate discrimination relating to variation in the CQA. The benefits and challenges of this approach are discussed.     

Bonding to industrial indirect composite blocks: A systematic review and meta-analysis

ObjectiveThe aim of this systematic review and meta-analysis was to evaluate the effect of surface conditioning methods on the bond strength of industrial indirect composite blocks (ICs).MethodsBased on the PICOS strategy, the Medline via PubMed, Embase and Web of Science (ISI – Web of Knowledge) electronic databases were searched for peer-reviewed articles in both English and Chinese, with no publication year limit. In vitro studies evaluating the effects of surface conditioning on the bond strength of ICs were selected. The meta-analysis was conducted to calculate the mean difference between surface-conditioned ICs and unconditioned controls. Subgroup analysis was performed to evaluate the different surface conditioning methods, separately for polymer-infiltrated ceramic network (PICN) material and the ICs with dispersed fillers (ICDFs). Meta-analyses were performed with a random-effects model at a significance level of 0.05.Results and SignificanceFrom 802 relevant studies, 25 were selected for full-text analysis. Nineteen studies were eligible for inclusion in this systematic review, whereas 9 studies were included in the meta-analysis. A manual search of the principal periodicals specific to the area resulted in no additional articles. The meta-analysis indicated a significant difference in bond strength between the surface-conditioned ICs and controls under both non-aged and aged conditions. The combination of mechanical and chemical conditioning yielded the highest bond strength of ICs. This meta-analysis suggests that chemical etching followed by a universal primer and alumina air abrasion followed by a silane coupling agent could be considered the best strategy for optimizing the bond strength of PICN materials and ICDFs under aged conditions, respectively.     

Measuring disease activity and response to treatment in rheumatoid arthritis

Introduction: Effective treatment of rheumatoid arthritis (RA) requires suppression of the underlying inflammation. Measurement of such inflammation, the disease activity, is mandatory to target treatment and maximize outcomes. However, this is not as straightforward as it may seem.

Areas covered: The many tools developed to measure disease activity in RA, from composite scores and patient-reported outcomes, to laboratory markers and imaging are discussed, with a focus on their utility in guiding therapy and assessing response. The complex issues in measuring disease activity in RA, whether in clinical trials or normal clinical practice, and in the context of national guidelines and recommendations, available time, and resources are considered.

Expert commentary: The key to effective management of RA is the rapid suppression of inflammation, ideally to remission, with maintenance of such remission. The aim is to prevent disability and maximize quality of life. Central to this is the ability to determine disease activity (potentially open to suppression) as opposed to damage (irreversible). A variety of measures are currently available, allowing better assessment of response to treatment. In the future, the development of predictive biomarkers allowing targeting of drugs may revolutionize this field and render the tools of today redundant.     

16种植物挥发油对柏子仁黄曲霉菌的抑制作用考察

目的:从16种植物(香茅、香叶、松节、山苍子、薄荷、干姜、丁香、姜黄、红花椒、肉桂、罗勒、迷迭香、青花椒、竹叶花椒、八角茴香、肉豆蔻)挥发油中筛选出对黄曲霉菌生长有较好抑制效果的植物挥发油。方法:采用平板培养法从柏子仁药材表面分离得到黄曲霉菌,利用水蒸气蒸馏法提取16种植物挥发油,采用滤纸片熏蒸后测定黄曲霉菌的菌落直径,对16种植物挥发油抑制黄曲霉菌生长的效果进行研究。结果:采用性状、显微及DNA条形码鉴定的方法从柏子仁药材上成功分离了黄曲霉菌,上述16种植物挥发油对黄曲霉菌的抑菌率分别为2. 93%,0. 05%,0. 37%,76. 07%,0. 34%,0. 15%,50. 05%,8. 51%,1. 43%,58. 20%,0. 07%,2. 60%,8. 73%,100. 00%,52. 62%,0. 07%。结论:16种植物挥发油对黄曲霉菌均有着不同程度的抑菌活性,其中竹叶花椒挥发油、山苍子挥发油、肉桂挥发油的抑菌效果较好,可为柏子仁生长储藏过程中防治黄曲霉菌的污染提供参考,并为植物挥发油作为中药仓储过程中的抑菌剂提供应用依据。     

缓解视疲劳功能中药复方保健产品配方规律及特点分析

目的通过检索特殊食品信息查询平台公布的具有缓解视疲劳功能的保健食品信息资料,以及药智数据网的中成药处方数据库中眼科中成药中有保健功能的产品信息资料,为具有缓解视疲劳功能的保健产品的组方与产品开发提供依据与参考。方法运用Microsoft Excel2016软件及中医传承辅助平台对检得的产品信息进行统计,分析其配方特点。结果共收集到141个具有缓解视疲劳功能的保健食品,其中64个(45.4%)保健食品配方中含有中药类原料。使用频次≥5的中药原料有6味,累计使用145次(72%),由高到低分别是菊花、枸杞子、决明子、桑椹、熟地黄、茯苓。通过无监督的熵层次聚类得到3个新处方。非中药原料在缓解视疲劳功能的保健食品中应用较为普遍,含有外来天然植物资源的60个产品,含叶黄素及维生素类的17个。统计眼科中成药中有保健功能的产品可知,使用频次≥4的中药原料有7味,累计使用32次(29%),由高到低分别是枸杞子、决明子、菟丝子、熟地黄、菊花、五味子、车前子。通过无监督的熵层次聚类得到1个新处方。结论保健食品在中药原料的选择上与中医药理论治疗视疲劳的原则基本契合,即滋补肝肾、平肝明目。但二者在中药原料选择范围、原料配伍、剂型种类等方面有所不同。此外,还在辨证保健理论指导下,尝试探讨应用文献数据处理统计方法筛选新配方、开发新产品,为中药复方保健产品的研发开辟了新思路、新方法。     

复合树脂充填物与酸蚀牙齿间密合度的扫描电镜观察

用SEM观察6种复合树脂充填物与酸蚀牙齿间密合度。结果表明6种复合树脂充填物与牙齿间均有微缝隙,其宽度多数在5μm内,最宽为10～15μm。1月后再观察,清晰见到从酸蚀牙本质小管曳出的树脂突,其曳出方向与缝隙形成可能有关。     

耳垂复合组织游离移植修复鼻小柱过短畸形

目的 探讨因鼻小柱过短所致鼻尖低平畸形的矫治方法.方法 对8例鼻尖低平伴鼻小柱过短者,采用鼻小柱切口,首先应用肋软骨或Medpor行支撑杆移植矫正撑起鼻尖,鼻小柱切口的继发创面采用耳垂复合组织游离移植修复.结果 8例游离移植的耳垂复合组织均成活良好,随访1～2年形态满意,色泽与周围组织无明显差别,供区无明显继发畸形.结论 应用耳垂复合组织游离移植修复鼻小柱过短畸形,不仅适用于外伤性缺损修复,而且也适用于鼻部的美容性修复,是一种患者容易接受、操作简单安全、疗效好、供区无后遗明显继发畸形的修复方法.     

中药敷脐治疗胸腰椎术后腹胀便秘的效果观察

目的探讨使用大黄厚朴煎剂热敷脐部治疗胸腰椎术后患者腹胀、便秘的疗效。方法选择2005年1月至2006年12月中山大学第二医院骨外科胸腰椎术后出现腹胀便秘的患者80例。分成两组,治疗组用大黄厚朴煎剂热敷脐部;对照组使用开塞露塞肛。观察两组患者肛门排气,排便,腹胀消除及停药复结情况。结果治疗组的总有效率95%,对照组总有效率70%;停药复结情况:治疗组5%,对照组42.5%;腹胀减轻情况:治疗组95%,对照组52.5%。结论大黄厚朴煎剂热敷脐能有效减轻肠胀气,软化大便,对于消除胸腰椎术后患者腹胀便秘明显优于使用开塞露塞肛效果。