临床营养研究中随机对照研究质量评价

目的评价两种主要临床营养期刊中随机对照试验（RCT）的质量。方法查阅2000～2008年《中国临床营养杂志》和《肠外与肠内营养》发表的RCT研究,按Cochrane协作网标准评价,并进行Jadad评分。结果两种期刊共发表238篇RCT研究,Jadad评分为（1．65±0．82）分。高质量RCT仅28篇（11．76％）,评分为满分5分的仅5篇（2．10％）。随机分组的方法、组间可比性、纳入排除标准、盲法、撤除和退出的数量和理由、样本含量等方面存在各种问题。结论国内临床营养领域RCT研究的设计和质量控制还存在不足或欠缺,水平尚待提高。     

The use of baselines in clinical trials of bronchodilators

Two important qualities of controlled clinical trials are that they reduce dependence on historical standards for evaluating therapy and separate the effect of treatment from the confounding influence of time. Whatever the theory of the clinical trial, however, time has not easily been banished from the analysis of medical experiments in practice, and many doctors still prefer to evaluate treatments by comparing now with then rather than treatment with control. This is especially so in trials of bronchodilators in the treatment of asthma where, it is shown, baselines are used in ways which can increase the variability of measurement and even bias the results.     

Assessing the appropriateness of combining economic data from multinational clinical trials

Because of the potential for large variability among countries in the utilization and cost of health care resources, it is important to assess the appropriateness of combining economic data across the countries in a multinational clinical economic trial. We show how available tests for interaction can be applied to economic endpoints, including cost-effectiveness ratios and net health benefits. This analysis includes a characterization of possible interactions being quantitative or qualitative in nature. In the absence of interaction, a pooled estimate of the economic endpoint should be representative of the participating countries. We explore the analytic issues by further analysing data from the Scandinavian Simvastatin Survival Study (4S).     

A measure to aid in the interpretation of published clinical trials

The published literature contains numerous reports of clinical studies. A problem in their interpretation is that studies in which the observed efficacy of the treatment is high are much more likely to be reported than those in which the observed efficacy is average or poor. This phenomenon has had the consequence of generally discrediting the reliability of the literature, especially that of non-randomized studies. In this paper a model is developed which permits estimation of the potential magnitude by which the reported efficacy of a treatment might be inflated. This quantity is termed the publication bias. The magnitude of the bias depends on the sample size of the study and the number of similar studies conducted concurrently. Tabulated values of the bias are presented, permitting easy computation. The new measure may have potential use for physicians in clinical decision making in that it characterizes the reliability of results from a specific published study, especially when there are no definitive randomized studies. However, correction of publication bias in this manner is not a substitute for a well controlled or a randomized study. The technique merely assists in the interpretation of available evidence from the literature. Moreover, it must be used with due caution in recognition of the assumptions and approximations involved in the calculation.     

Critical reflections on clinical trials

There is often concern about the large number of patients needed for a particular clinical trial. However, one could be equally concerned that a trial is designed with a number of patients that is too small to obtain a precise enough estimate of the difference between the success rates of the treatments. The design of the trial should ensure that statistical significance is only reached if the treatment difference exceeds a specified value of clinical importance. Designs with this property generally require more than the usual number of patients. It is hoped that discussion on the ethical acceptability of this consequence will be stimulated by this paper.     

Surrogate endpoints in clinical trials: cancer

Investigators use a surrogate endpoint when the endpoint of interest is too difficult and/or expensive to measure routinely and when they can define some other, more readily measurable, endpoint, that is sufficiently well correlated with the first to justify its use as a substitute. A surrogate endpoint is usually proposed on the basis of a biologic rationale. In cancer studies with survival time as the primary endpoint, surrogate endpoints frequently employed are tumour response, time to progression, or time to reappearance of disease, since these events occur earlier and are unaffected by use of secondary therapies. In early drug development studies, tumour response is often the true primary endpoint. We discuss the investigation of the validity of carcinoembryonic antigen (a tumour marker present in the blood) as a surrogate for tumour response. In considering the validity of surrogate endpoints, one must distinguish between study endpoints that provide a basis for reliable comparisons of therapeutic effect, and clinical endpoints that are useful for patient management but have insufficient sensitivity and/or specificity to provide reproducible assessments of the effects of particular therapies.     

Tables of the number of patients required in clinical trials using the logrank test

The logrank test is commonly used in the analysis of clinical trials in chronic diseases such as cancer. Existing tables for the number of patients required in such trials are based on the direct comparison of two proportions. This paper presents tables of numbers required in clinical trials using the logrank test and describes their use. The numbers required are considerably smaller than those in existing tables when the event-free proportions are small, but otherwise comparable.     

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.     

Reporting clinical trials from the viewpoint of a patient's choice of treatment

Those who report a clinical trial should acknowledge the right of the 'consumer' to make decisions based on his own valuation of the beneficial and adverse effects which rival treatments may have. Suppose a new patient is inclined to trade one unit of benefit for c units of complication. Then he should (should not) be given the treatment if his estimated utility gain, x1-cx2, is positive (negative) and statistically significant according to the data of the trial; here x1 (x2) denotes the observed average benefit (complication level). If the estimated gain is not statistically significant, the data do not allow any firm recommendation. This c-dependent recommendation in general cannot be determined from inspection of a joint confidence region for the two means concerned. Therefore investigators should present the outcome of the significance test as a function of c (inverted inference). Typically there are several types of adverse effect or benefit, in which case the quantity c must be generalized into a vector of personal relative utility weights.     

Multicentre clinical trials: Bradford Hill's contributions and some subsequent developments

Most large comparative trials of therapeutic agents are now conducted as multicentre studies. Some of the major studies designed by Bradford Hill were also multicentre, and his methods of design and conduct remain valid today, even though improved methods for analysing the data have appeared subsequently.     

Effect of covariate measurement error in randomized clinical trials

Prognostic factors often appear as covariates in clinical trials designed to estimate treatment effects. These factors are usually subject to measurement error and lead to decreased efficiency in the estimation of the treatment effect. We use Weibull regression models and asymptotic theory to derive the efficiency of estimation obtained by adjusting for one dichotomous and one continuous covariate measured with error. An application to a clinical trial involving advanced lung cancer patients illustrates the results.     

多中心临床随机对照试验的Meta分析

目的探讨解决多中心临床随机对照试验中心效应差异的统计分析问题。方法以两项多中心临床随机对照试验数据为例,运用协方差分析及Meta分析。结果协方差分析中心间效应值差异均有统计学意义,行Meta分析,项目1异质性检验差异无统计学意义(P>0.05),采用固定效应模型分析合并效应值组间差异有统计学意义(P<0.05)。项目2异质性检验差异有统计学意义(P<0.05),采用随机效应模型分析合并效应值组间差异无统计学意义(P>0.05)。结论多中心临床随机对照试验研究中,如果存在中心间以及中心与分组间交互效应差异有统计学意义时,可根据Meta分析异质性检验结果选择适合的模型进行合并效应值的组间比较,如果协方差与Meta分析结果不一致时,建议选择Meta分析的结果较为稳妥。     

Estimating country-specific cost-effectiveness from multinational clinical trials

Because costs and outcomes of medical treatments may vary from country to country in important ways, decision makers are increasingly interested in having data based on their own country's health care situations. This paper proposes methods for estimating country-specific cost-effectiveness ratios from data available from multinational clinical trials. It examines how clinical and economic outcomes interact when estimating treatment effects on cost and proposes empirical methods for capturing these interactions and incorporating them when making country-specific estimates. We use data from a multinational phase III trial of tirilazad mesylate for the treatment of subarachnoid haemorrhage to illustrate these methods. Our findings suggest that it is possible for meaningful country-by-country differences to be found in such trial data. These differences can be useful in informing reimbursement, utilization, and other decisions taken at the country level. © 1998 John Wiley & Sons, Ltd.     

A comparison of economic modelling and clinical trials in the economic evaluation of cholesterol-modifying pharmacotherapy

There are various ways in which data for economic evaluations may be obtained, including via clinical trials and via economic modelling. There are numerous advantages and disadvantages associated with each method, although it is generally assumed that economic models lack the accuracy required for the calculation of meaningful cost-effectiveness data. In order to assess the predictive accuracy of economic modelling in the context of cholesterol-modifying pharmacotherapy it is possible to compare predicted coronary heart disease (CHD) incidence estimates obtained using CHD risk equations derived from the Framingham Heart Study (FHS) with actual CHD incidence rates achieved in a major clinical trial, the West of Scotland Coronary Prevention Study (WOSCOPS). FHS-derived CHD risk equations substantially underestimate the actual risks of nonfatal myocardial infarction obtained by WOSCOPS. However, in predicting risks of death from CHD, FHS-derived CHD risk equations estimate extremely accurately the incidence obtained by WOSCOPS. For example, from WOSCOPS the risk of an individual fulfilling the trial entry criteria incurring nonfatal myocardial infarction or CHD death in 4.9 years is 0.079 for placebo group and 0.055 for the intervention group. Therefore, the relative risk for the intervention group relative to placebo group is 0.696, implying a risk reduction of 30%. Comparable risks predicted using FHS-derived CHD risk equations are 0.116 for the placebo group and 0.088 for the intervention group. Consequent relative risks and risk reductions for the intervention relative to placebo are 0.757 and 24%, respectively. Using both model and trial estimates of CHD incidence in an economic evaluation of cholesterol-modifying pharmacotherapy, incremental costs per life year gained are £41 707 using WOSCOPS data and £36 480 using FHS-derived CHD risk equations. © 1997 John Wiley & Sons, Ltd.     

Unbiased assessment of treatment effects on disease recurrence and survival in clinical trials

Recently there has been considerable discussion concerning the analysis of data and presentation of results from clinical trials in breast cancer. A problem stems from there being several events of interest, notably disease recurrence and death. Current methods based on 'so-called' disease-free survival are criticized on the grounds that they confuse events, such as disease recurrence and death, in the treatment comparison and consequently could be very misleading. Alternative methods of analysis, based on separate measures of treatment effect are presented and illustrated.     

从贝尔蒙报告审视医疗器械临床试验的伦理问题

医疗器械临床试验是最直接最有效地检测医疗器械性能的方式,贝尔蒙报告是对基本的道德原则及方针的陈述,用来帮助在解决涉及人体实验对象的科研中所产生的道德问题。本文从贝尔蒙报告角度来审视医疗器械临床试验的伦理问题,介绍了贝尔蒙报告产生的背景概念和医疗器械临床试验的概念及基本流程;贝尔蒙报告中的三项原则尊重个人、善行和平等公正原则在医疗器械临床试验中的体现以及针对贝尔蒙报告来解决医疗器械临床试验中产生的伦理问题的重大意义。通过知情同意的具体体现、对风险和好处的评估及受试者的选择和研究成果的分配三方面来解决临床试验中产生的伦理问题。     

A method for the evaluation of dose-toxicity relationships in clinical trials

This paper considers a proportional hazards model that describes the relationship between time-dependent cumulative dose of drug and development of toxicity. We estimate probabilities of developing toxicity in both the presence and the absence of competing risks and provide variances for the latter case. Mitoxantrone data collected in Southwest Oncology Group studies illustrate the methods.