Randomization methods in clinical trials.

In recent times there has been an enormous growth in the number of randomized controlled trials (RCTs). Their importance for clinical practice is inarguable, so it is essential for the practitioner to acquire a basic knowledge of their methodology, in order to accurately evaluate this type of study. Randomization is a central concept, since it constitutes the basis for production of results that are valid, important and applicable. In this paper we set out to show the importance of randomization by explaining its basic concepts, its practical use, the different types available, and the best ways to put them into practice.     

Cardiac disease outcomes in clinical trials.

Randomized controlled trials (RCTs) are the gold standard for determining causality in medicine. To be considered valid, the efficacy/effectiveness of a new drug must be tested and proved through this type of scientific study. This type of trial will disclose the drug's risk profile as well as the treatment effect magnitude. The proper design, development, and analysis and presentation of results from an RCT is based on a group of well-defined methodological rules, compliance with which assures the trial's internal validity, the relative and absolute importance of the results and its applicability to populations of patients different from those included in the study sample (external validity). Among the structural and methodological components of a clinical trial--randomization, allocation concealment, confounding, similarity of study groups, measures of efficacy, statistical analysis, etc.--disease markers (endpoints, outcomes) are especially important. In the end, what an RCT is good for is to detect changes in the disease process with therapy (or preventive measures), and these changes are defined beforehand based on specific measurements--disease markers. In this paper we will present general principles for the definition of disease markers, their problems and practical use. Caution should be exercised, as this is an area of clinical epidemiology that is somewhat complex, controversial and ill-defined.     

Evaluation of recent clinical trials in lupus.

Clinical trials in lupus pose many challenges, ranging from small numbers of subjects to endpoints that are difficult to quantify. Improved standardization of both design and appropriate endpoints is necessary. Recent trials have been small in number, with few randomized controlled trials. These trials have evaluated therapies such as methotrexate, cyclosporine A, bromocriptine, immunoadsorption columns, and hydroxychloroquine withdrawal. With the advent of improved techniques as well as newer therapeutic agents, options for the treatment of lupus should begin to grow over the next several years in a fashion similar to that which has been seen in rheumatoid arthritis.     

Trial-related discrimination in HIV vaccine clinical trials.

Participants in preventive HIV vaccine trials may experience negative social consequences of trial participation, including problems related to a vaccine-induced positive HIV antibody test, yet few vaccine studies have reported on this issue. From October 1995 through November 1998, 1516 AIDS Vaccine Evaluation Group (AVEG) volunteers were assessed for reports of trial-related discrimination (TRD). Ninety TRD events were reported by 76 (5%) of 1516 volunteers. The most commonly reported incidents (n = 52, 57.8%) were negative reactions of friends, family, and co-workers to the volunteer. Few incidents (approximately 10%) were reported as linked to HIV testing. The majority of events (n = 47, 52%) were described by volunteers as "resolved" at the time of reporting, 36 (40%) as "not resolved," and for 7 (8%) events volunteers did not report resolution status. Reported incidents were analyzed by logistic regression to determine their association with the volunteer's age, sex, race, sexual orientation, and HIV risk category. There was no association between volunteer characteristics and TRD. Logistic regression and analysis of variance (ANOVA) were used to analyze association of trial sites with the number of TRD events reported. After controlling for site variation in data collection and reporting, no significant differences were found between the sites in terms of the number or type of TRD reported. Fears that TRD would be widespread and severe have not been borne out by this analysis. While the results of this study are reassuring, they should be interpreted with caution, as it is unclear whether these results may be extended to phase III trials enrolling large numbers of individuals at higher risk of HIV acquisition.     

Performing clinical trials efficiently in Japan--independent clinical trials and GCP]

Part of the revision of the Pharmaceutical Affairs Law in 2002 included the establishment of a system for independent clinical trials. According to the partial revision of the Guideline for Good Clinical Practice (GCP), MHLW Ministerial Ordinance No. 106 dated June 12, 2003, independent clinical trials are now recognized in Japan. MHLW promotes to resolve the issues about compliance with good clinical practice (GCP) guideline and the management of the clinical trials, including independent clinical trials. For our nation, more effective and safer new drug applications based on domestic independent clinical trial documents will soon be reviewed by the Pharmaceuticals and Medical Devices Agency (PMDA). For the protection of human rights, important issues about quality control and quality assurance raised by GCP Audit consist of both GCP on-site review and Document-based Conformity Review by the Office of Conformity Audit of the PMDA are studied.     

Progress in clinical trials

“Progress in Clinical Trials,” a section new this month, will be published on a regular basis and will contain updates on clinical trials recently presented. The aim of this section is to present new developments in a brief, informative format that will help keep the physician abreast of the current status of important clinical trials.