Controlled clinical trials最新文献

Clinical trials that demonstrate mortality reduction benefit from a particular therapy serve a crucial role in advancing medical care. The Heart Protection Study is one such trial, and it showed significant mortality reduction following 5 years of treatment with simvastatin compared with placebo in patients with arterial disease and/or diabetes. In this trial, by year 2 of follow-up, there was already a highly statistically significant advantage of simvastatin over placebo as regards major events (cardiac death, myocardial infarction, stroke, and revascularization). Despite these findings, the prespecified stopping rules that were contingent on proof of mortality reduction benefit were not invoked after interim analyses and the trial progressed to completion. The study raises issues concerning early termination of the trial based on benefit in major morbidity criteria even at the expense of being unable to answer the highly important question of mortality benefit. The study also engenders questions about whether interim data and analyses should be made available to physician-investigators, the trial participants, and the public. The issues are complex but need to be discussed to optimize the protection of study subjects in clinical trials.

Data entry and its verification are important steps in the process of data management in clinical studies. In Japan, a kind of visual comparison called the reading aloud (RA) method is often used as an alternative to or in addition to the double data entry (DDE) method. In a typical RA method, one operator reads previously keyed data aloud while looking at a printed sheet or computer screen, and another operator compares the voice with the corresponding data recorded on case report forms (CRFs) to confirm whether the data are the same. We compared the efficiency of the RA method with that of the DDE method in the data management system of the Japanese Registry of Renal Transplantation. Efficiency was evaluated in terms of error detection rate and expended time. Five hundred sixty CRFs were randomly allocated to two operators for single data entry. Two types of DDE and RA methods were performed. Single data entry errors were detected in 358 of 104,720 fields (per-field error rate = 0.34%). Error detection rates were 88.3% for the DDE method performed by a different operator, 69.0% for the DDE method performed by the same operator, 59.5% for the RA method performed by a different operator, and 39.9% for the RA method performed by the same operator. The differences in these rates were significant (p<0.001) between the two verification methods as well as between the types of operator (same or different). The total expended times were 74.8 hours for the DDE method and 57.9 hours for the RA method. These results suggest that in detecting errors of single data entry, the RA method is inferior to the DDE method, while its time cost is lower.

There has been considerable methodological research on response-adaptive designs for clinical trials but they have seldom been used in practice. The many reasons for this are summarized in an article by Rosenberger and Lachin, but the two main reasons generally cited are logistical difficulties and the potential for bias due to selection effects, “drift” in patient characteristics or risk factors over time, and other sources. Jennison and Turnbull consider a group sequential, response-adaptive design for continuous outcome variables that partially addresses these concerns while at the same time allowing for early stopping. The key advantage of a group sequential approach in which randomization probabilities are kept constant within sequential groups is that a stratified analysis will eliminate bias due to drift. In this article we consider binary outcomes and an algorithm for altering the allocation ratio that depends on the strength of the accumulated evidence. Specifically, patients are enrolled in groups of size n_Ak, n_Bk, k = 1, 2, … K, where n_Ak, n_Bk are the sample sizes in treatment arms A and B in sequential group k. Patients are initially allocated in a 1:1 ratio. After the kth interim analysis, if the z-value comparing outcomes in the two treatment groups is less than 1.0 in absolute value, the ratio remains 1:1; if the z-value exceeds 1.0, the next sequential group is allocated in the ratio R₁ favoring the currently better-performing treatment; if the z-statistic exceeds 1.5, the allocation ratio is R₂, and if the z-value exceeds 2.0, the allocation ratio is R₃. If the O'Brien-Fleming monitoring boundary is exceeded the trial is terminated. Group sample-sizes are adjusted upward to maintain equal increments of information when allocation ratios exceed one. The z-statistic is derived from a weighted log-odds ratio stratified by sequential group. Simulation studies and theoretical calculations were performed under a variety of scenarios and allocation rules. Results indicate that the method maintains the nominal type I error rate even when there is substantial drift in the patient population. When a true treatment difference exists, a modest reduction in the number of patients assigned to the inferior treatment arm can be achieved at the expense of smaller increases in the total sample size relative to a nonadaptive design. Limitations, such as the impact of delays in observing outcomes, are discussed, as well as areas for further research. We conclude that responsive adaptive designs may be useful for some purposes, particularly in the presence of large treatment effects, although allowing early stopping minimizes the benefits. If such a design is undertaken, the randomization and analysis should be stratified in order to avoid bias due to time trends.

A sequential clinical trial model is considered in which two treatments with immediate normally distributed responses are to be compared. The class of one-sided group-sequential tests with response-adaptive sampling developed by Jennison and Turnbull is used to investigate which of the treatments has the larger mean response. The power function for this class of tests is the same as that under nonadaptive sampling, and significant decreases in the inferior treatment number can be achieved with only minor increases in the average total sample number. Two inferential methods are considered following the design. Approximate confidence intervals for the treatment mean difference and the individual means are constructed using the pivotal method of Woodroofe, and an approximation to the bias of the maximum likelihood estimator of the treatment mean difference is studied based on the work of Whitehead. Simulation is used to assess the accuracy of both methods for various stopping boundaries and numbers of interim analyses.

The ever-increasing concern for the welfare of volunteers participating in clinical trials and for the integrity of the data derived from those trials has generated the concept of Good Clinical Practice (GCP). The Veterans Affairs Cooperative Studies Program, in anticipation of the need to comply with GCP guidelines, developed a Site Monitoring and Review Team (SMART), which consists of a Good Clinical Practice Monitoring Group and a Good Clinical Practice Review Group. The review group conducted 335 site reviews from fiscal years (FY) 1999 through 2001 to assess and encourage adherence to GCP. Data from reviews were compared for two time periods, a 2-year implementation period (FYs 1999/2000, n = 204) and a continuing follow-up period (FY 2001, n = 131). Overall, high GCP adherence was exhibited by 11.3% (n = 23) of study sites in FY 1999/2000 versus 20.6% (n = 27) in FY 2001, average to good adherence was exhibited by 84.3% (n = 172) in FY 1999/2000 versus 77.0% (n = 101) in FY 2001, and below average adherence was exhibited by 4.4% (n = 9) versus 1.5% (n = 3) in these two periods. These changes were statistically significant by chi square analysis (p = 0.029). Moreover, GCP adherence was assessed within eight GCP focus areas: patient informed consent, protocol adherence, safety monitoring, institutional review board interactions, regulatory document management, patient records in investigator file, drug/device accountability, and general site operations. Median assessment scores for all 62 GCP review elements improved from 0.82 to 0.89 (p<0.001). Median assessment scores for the 14 selected critical GCP items improved from 0.78 to 0.89 (p<0.001). Median scores for five of the eight GCP focus areas improved significantly (p<0.001) between the two time periods. These data suggest that the site-oriented activities of SMART combined with centralized quality assurance activities of the coordinating centers represent an integrated, versatile program to promote and assure GCP adherence and data integrity in Cooperative Studies Program trials.

The Surgical Treatments Outcomes Project for Dysfunctional Uterine Bleeding (STOP-DUB) was a multicenter, randomized clinical trial that assessed the efficacy and effectiveness of hysterectomy versus endometrial ablation (EA) for dysfunctional uterine bleeding (DUB) in women for whom medical management has not provided relief. Resource centers included a coordinating center, a chair's office, the American College of Obstetricians and Gynecologists, the Agency for Healthcare Research and Quality Project Office and 33 clinical centers in the United States and Canada. STOP-DUB enrolled: (1) eligible patients for whom medical treatment had not been successful and who were randomized to either hysterectomy or EA and (2) an observational cohort of patients who were “provisionally ineligible” or who were eligible but did not wish to be randomized. Enrollment began in October 1997 and ended in June 2001. The primary outcome addressed by the randomized trial was the impact of surgery on bleeding, pain, fatigue, and the major problem (symptom) that led the woman to seek treatment for her condition, measured 1 year following surgery. Additional outcomes included the impact of surgery at time points after 1 year; changes in quality of life, activity limitation, sexual functioning, and urinary incontinence; surgical complications; additional surgery; and resource utilization. The costs and the relative cost-effectiveness of the two surgeries were calculated. The main scientific objective for the observational study was to examine changes over time in terms of treatment selected, DUB-related symptoms, and quality of life.

Overweight and obesity are major contributors to both type 2 diabetes and cardiovascular disease (CVD). Moreover, individuals with type 2 diabetes who are overweight or obese are at particularly high risk for CVD morbidity and mortality. Although short-term weight loss has been shown to ameliorate obesity-related metabolic abnormalities and CVD risk factors, the long-term consequences of intentional weight loss in overweight or obese individuals with type 2 diabetes have not been adequately examined. The primary objective of the Look AHEAD clinical trial is to assess the long-term effects (up to 11.5 years) of an intensive weight loss program delivered over 4 years in overweight and obese individuals with type 2 diabetes. Approximately 5000 male and female participants who have type 2 diabetes, are 45–74 years of age, and have a body mass index ⩾25 kg/m² will be randomized to one of the two groups. The intensive lifestyle intervention is designed to achieve and maintain weight loss through decreased caloric intake and increased physical activity. This program is compared to a control condition given diabetes support and education. The primary study outcome is time to incidence of a major CVD event. The study is designed to provide a 0.90 probability of detecting an 18% difference in major CVD event rates between the two groups. Other outcomes include components of CVD risk, cost and cost-effectiveness, diabetes control and complications, hospitalizations, intervention processes, and quality of life.

This article discusses the design of an ongoing cluster-randomized trial comparing two forms of school-based sex education in terms of educational process and sexual health outcomes. Twenty-nine schools in southern England have been randomized to either peer-led sex education or to continue with their traditional teacher-led sex education. The primary objective is to determine which form of sex education is more effective in promoting young people's sexual health. The trial includes an unusually detailed evaluation of the process of sex education as well as the outcomes. The sex education programs were delivered in school to pupils ages 13–14 years who are being followed until ages 19–20. Major trial outcomes are unprotected sexual intercourse and regretted intercourse by age 16 and cumulative incidence of abortion by ages 19–20. We discuss the rationale behind various aspects of the design, including ethical issues and practical challenges of conducting a randomized trial in schools, data linkage for key outcomes to reduce bias, and integrating process and outcome measures to improve the interpretation of findings.

The design of randomized controlled trials entails decisions that have economic as well as statistical implications. In particular, the choice of an individual or cluster randomization design may affect the cost of achieving the desired level of power, other things being equal. Furthermore, if cluster randomization is chosen, the researcher must decide how to balance the number of clusters, or “sites,” and the size of each site. This article investigates these interrelated statistical and economic issues. Its principal purpose is to elucidate the statistical and economic trade-offs to assist researchers to employ randomized controlled trials that have desired economic, as well as statistical, properties.