Surrogate endpoints in clinical trials: definition and operational criteria

I discuss the idea of using surrogate endpoints in the context of clinical trials to compare two or more treatments or interventions in respect to some 'true' endpoint, typically a disease occurrence. In order that treatment comparison based on a surrogate response variable have a meaningful implication for the corresponding true endpoint treatment comparison, a rather restrictive criterion is proposed for use of the adjective 'surrogate'. Specifically, I propose that a surrogate for a true endpoint yield a valid test of the null hypothesis of no association between treatment and the true response. This criterion essentially requires the surrogate variable to 'capture' any relationship between the treatment and the true endpoint, a notion that can be operationalized by requiring the true endpoint rate at any follow-up time to be independent of treatment, given the preceding history of the surrogate variable. I then discuss this operational criterion in the examples of the accompanying papers and in the setting of trials aimed at the primary and secondary prevention of cancer.  

The Delphi list: a criteria list for quality assessment of randomized clinical trials for conducting systematic reviews developed by Delphi consensus

Most systematic reviews rely substantially on the assessment of the methodological quality of the individual trials. The aim of this study was to obtain consensus among experts about a set of generic core items for quality assessment of randomized clinical trials (RCTs). The invited participants were experts in the field of quality assessment of RCTs. The initial item pool contained all items from existing criteria lists. Subsequently, we reduced the number of items by using the Delphi consensus technique. Each Delphi round comprised a questionnaire, an analysis, and a feedback report. The feedback report included staff team decisions made on the basis of the analysis and their justification. A total of 33 international experts agreed to participate, of whom 21 completed all questionnaires. The initial item pool of 206 items was reduced to 9 items in three Delphi rounds. The final criteria list (the Delphi list) was satisfactory to all participants. It is a starting point on the way to a minimum reference standard for RCTs on many different research topics. This list is not intended to replace, but rather to be used alongside, existing criteria lists.  

莫沙必利治疗功能性消化不良的随机双盲对照研究

目的 评价枸橼酸莫沙必利治疗功能性消化不良的疗效及安全性。方法 采用随机对照双盲的临床试验设计方案。对象为功能性消化不良患者。试验组莫沙必利5mg,对照组多潘立酮10mg,均为每日3次,疗程4周。评价症状改善、胃排空和不良反应。结果 231例入选病例中222例(96.1％)完成治疗和随访。试验组治疗2周后对早饱、上腹胀症状的总有效率分别为84.5％和90.1％,与对照组(分别为75.9％、82.2％)相似,但改善嗳气和烧心感明显优于对照组(P<0.05)。治疗4周时试验组改善上腹胀和嗳气症状明显优于对照组(P<0.05)。治疗后症状积分总和下降幅度试验组明显大于对照组(P<0.05)。对治疗前存在胃排空障碍的患者,治疗4周后,无论胃排空恢复正常的患者比例(46.2％vs、25.9％,P=0.020)或者残留率下降幅度(46.2％vs. 24.0％,P=0.003)试验组均明显大于对照组。两组总的不良反应发生率为11.7％(试验组9.6％,对照组14.0％;P=0.30),均较轻。结论 枸橼酸莫沙必利治疗可明显改善功能性消化不良患者的症状和胃排空,不良反应少,值得临床推广应用。  

非劣性/等效性试验的样本含量估计及把握度分析

目的介绍以标准治疗为对照的非劣性/等效性试验样本含量估计及把握度分析.方法方法主要参考国际上近年有关非劣性/等效性试验设计和分析的进展,对涉及到的统计事项和相关问题进行探讨和应用.结果针对非劣性/等效性试验的特定目的,详细阐明了样本含量估计各相关要素的意义及设定方法,给出了样本含量估计及把握度计算的通用公式,结合临床试验的实际案例对样本含量和把握度进行了应用分析.结论随着我国药物临床试验与国际的接轨,应该按照非劣性/等效性来设计试验的情形会有所增多,本文所介绍的方法将为实际工作提供有效的参考.  

盐酸戊乙奎醚应用于小儿氯胺酮复合全凭静脉麻醉的临床研究

目的 评估盐酸戊乙奎醚替代阿托品作为术前用药在小儿氯胺酮复合全凭静脉麻醉中对心血管和腺体分泌等的影响.方法 40例3～10岁采用氯胺酮和丙泊酚复合全凭静脉麻醉患儿随机分为两组,麻醉前30min分别肌肉注射盐酸戊乙奎醚(P组,n=20)与阿托品(A组,n=20),观察并记录两组给药前、给药后10、20、30、60、150 min时的HR、平均动脉压(MAP)、R、唾液分泌量(SS)及不良反应等指标.结果 (1)P组和A组SS在给药后20、30、60 min时均显著低于给药前(P＜0.01),而在150 min时P组显著低于给药前及A组(P＜0.01).(2)P组在给药后各时点的MAP、HR及R与给药前比较差异无统计学意义(P＞0.05),A组HR在给药后20、30、60 min时升高(P＜0.05或＜0.01),MAP在给药后30 min和60 min时亦显著升高(P＜0.01),二者在同时点均高于P组(P＜0.05或＜0.01).结论 盐酸戊乙奎醚能有效地抑制呼吸道腺体分泌,持续时间较长,且对心率及血压几乎无影响,比阿托品更适合用于小儿床麻醉前用药.  

三组分的无细胞百白破联合疫苗安全性和免疫原性研究

葛兰素史克公司的吸附无细胞百白破联合疫苗 ,采用了分别提取百日咳毒素 (PT)、丝状血凝素 (FHA)、6 9kD外膜蛋白 (PRN ,粘附素 )三种抗原后 ,再按照各自的含量配合制备而成。为考察该疫苗的安全性和免疫原性 ,在广西壮族自治区横县选择 3～ 6月龄、足月分娩、未接种过百白破联合疫苗的健康婴儿进行了临床研究。安全性结果表明 :受试者全身中反应发生率为 1 2 % (17人次 / 1386人次 ) ,弱反应发生率为 11 5 % ,无强反应发生。受试者局部淋巴结无异常反应 ,注射部位弱反应发生率为 0 5 % (7人次 / 1386人次 ) ,无中、强反应发生。免疫原性结果为 :受试者白喉抗体阳转率为 99 2 % ;破伤风抗体阳转率为 99 2 % ;抗PT抗体的阳转率为 96 4 % ;抗百日咳FHA抗体的阳转率为 99 3% ;抗粘附素抗体水平免疫后比免疫前增长≥ 4倍的占 94 5 %。结果证明 :该疫苗接种后具有低反应性和良好的免疫原性。  

Probabilistic prediction in patient management and clinical trials

It is argued that the provision of accurate and useful probabilistic assessments of future events should be a fundamental task for biostatisticians collaborating in clinical or experimental medicine, and we explore two aspects of obtaining and evaluating such predictions. When covariate information on patients is available, logistic regression and other multivariate techniques are often used to select prognostic factors and create predictive models. An example shows how the explicit aim of prediction needs to be taken into account in such modelling, and how predictive performance may be assessed by decomposition of a scoring rule. Secondly, results from a program that provides pretrial and interim predictions in clinical trials are displayed, bringing together the use of subjective opinion, Bayesian methodology and techniques for evaluating and criticizing predictions.  

Confronting publication bias: a cohort design for meta-analysis

In evaluating therapies, clinical investigators often need to rely on the published clinical trial literature which may be biased in favour of studies with positive or 'encouraging' results and this may lead to erroneous conclusions of therapeutic effectiveness. The problem of publication bias can be magnified when the evaluation is based on a pooled analysis of clinical trial results, since in this case even small differences between treatment groups may reach statistical significance. In this paper a model is developed for pooling the results of clinical trials which is free from publication bias. It is proposed that an international registry of all clinical trials be established with the objectives and endpoints of each trial clearly defined in the register. In this way for each therapeutic issue researchers can select a cohort of clinical trials independently from the trial results. The approach is illustrated using the International Cancer Research Data Bank (ICRDB) registry of cancer clinical trials to evaluate the effect of chemotherapy on survival in advanced ovarian cancer. In this example, the conclusions based on a pooled analysis of registered trials have important differences from a more traditional review of the published trials. Implications of the results and problems in implementing the model are discussed.  

混合线性模型在临床试验中重复测量资料的应用

目的：探讨混合线性模型在临床试验重复测量资料分析中的应用。方法：利用混合线性模型分析结果指标为定量资料的重复测量资料，通过参数和标准误的估计得出统计学结论。结果：对于临床试验重复测量资料，混合线性模型能有效的考虑数据相关性，处理有缺失值的资料，可以获得组别、时间及有无交互作用的结论。结论：采用混合线性模型对临床试验重复测量资料进行统计分析，可以更客观的进行药物疗效评价。  

口服Ⅱ型胶原治疗类风湿关节炎的临床研究

目的 初步探讨口服Ⅱ型胶原（CⅡ）治疗类风湿关节炎的疗效和安全性。方法 用随机双盲和安慰剂对照的方法，70例活动性类风湿关节炎患者随机分为试验组和对照组各35例，分别口服Ⅱ型胶原每日0.1mg和安慰剂，随访12周，比较观察二组的疗效，并记录不良反应。结果 用药12周，有效率试验组和对照组分别为54.55%和12．12％（P＜0．01），显效率两组分别为18．18％和3．13％（P＜0．01），试验组明显高于对照组；口服CⅡ治疗有效患者的病程明显短于无效患者；两组不良反应表现为轻度可耐受的胃肠道反应，试验组和对照组发生率分别为15．15％和12．50％，差异无显著性。结论 口服Ⅱ型胶原蛋白治疗类风湿关节炎安全有效，不良反应轻，发病早期使用可提高有效率。