Analysis of multivariate failure-time data from HIV clinical trials

We illustrate the use of marginal methods for the analysis of multivariate failure-time data using a large trial in HIV infection in which the composite endpoint of AIDS or death incorporates more than 20 events with varying severity. Multivariate failure-time methods are required to investigate whether treatment delays development of new AIDS events. AIDS events can be grouped and treatment effects estimated using only the first event to occur in each group for each individual. Alternatively, all events can be included by fitting a separate baseline hazard for development of each event, and restricting treatment effects to be common within groups of events. In either case, model-based or minimum-variance estimates of the overall effect of treatment can be constructed. The covariance matrix for the treatment-effect estimates can be used in multiple testing procedures. Results from the Delta trial suggest that combination antiretroviral therapy with AZT plus either ddI or ddC may delay progression to more severe AIDS events compared to AZT monotherapy. These late events are generally untreatable and prophylaxis is not available. Trials are not generally powered to detect treatment effects on individual events making up a composite endpoint, and therefore all analyses are exploratory rather than providing definitive evidence. However, marginal multivariate models provide an easily available approach for modeling the effect of covariates on multiple disease processes, and allow the likely effects of treatment to be presented in a manner which is easily understood. They can be used in a variety of ways to explore different patterns of treatment effects and are also useful for testing multiple hypotheses regarding treatment effects on several different composite endpoints.     

Exploratory analysis of population pharmacokinetic data from clinical trials with application to isradipine.

Drug level monitoring during routine clinical visits in the course of phase III trials provides a means to document pharmacokinetic variability in a patient population. Such a pharmacokinetic screen was performed for the new calcium antagonist isradipine. A total of 697 blood samples were collected at any time after the morning dose from 252 patients who had received oral doses of isradipine. Three approaches of data analysis based on exploratory (graphical and statistical) techniques were used to relate plasma level to patient demographic data and laboratory parameters. The pharamacokinetics of isradipine seemed to be influenced by the demographic variables of age (already detected in conventional studies) and weight, as well as by the blood serum levels of inorganic phosphorous, uric acid, alkaline phosphatase, and bilirubin, but only to a small, clinically irrelevant extent. The findings from the three approaches were complementary. They suggest that a pharmacokinetic screening in clinical trials is feasible at reasonable experimental cost and effort and provides useful data on interindividual and intraindividual pharmacokinetic variability in patients.     

Nosocomial MRSA pneumonia: data from recent clinical trials

MRSA infections, especially pneumonia have been associated with considerable morbidity and mortality and the management of MRSA infections is considered as an issue of high priority for scientific societies. Many studies which have been published during the last 10 years have provided evidence for MRSA pneumonia epidemiology, diagnosis and treatment. The main regime of antibiotic treatment recommended for MRSA pneumonia is either vancomycin or linezolid. Despite its pK/pD superiority over vancomycin, linezolid has to date failed to show clear advantage over vancomycin in recent clinical trials.     

Example-based illustrations of design,conduct, analysis and result interpretation of multi-regional clinical trials

Extensive research has been conducted in the Multi-Regional Clinical Trial (MRCT) area. To effectively apply an appropriate approach to a MRCT, we need to synthesize and understand the features of different approaches. In this paper, examples are used to illustrate considerations regarding design, conduct, analysis and interpretation of result of MRCTs. We start with a brief discussion of region definitions and the scenarios where different regions have differing requirements for a MRCT. We then compare different designs and models as well as the corresponding interpretation of the results. We highlight the importance of paying special attention to trial monitoring and conduct to prevent potential issues associated with the final trial results. Besides evaluating the overall treatment effect for the entire MRCT, we also consider other key analyses including quantification of regional treatment effects within a MRCT, and assessment of consistency of these regional treatment effects.     

Monitoring and evaluating clinical trials data

This paper presents an overview of recent developments in statistical methods for the design of clinical trials. Whilst the methods are suitable for application in a wide range of therapeutic areas, they are of particular value in intensive care medicine due to its high levels of mortality and short periods of follow-up. The paper reviews the calculation of the sample size necessary to achieve a given power requirement, and then describes the operation of a Data and Safety Monitoring Board, the mid-trial reassessment of sample size and the use of stopping rules to terminate a study as soon as sufficient evidence is available. The purpose of the paper is to encourage investigators to consider the wide range of design options which have recently become available, when planning a new clinical study.     

Montelukast: data from clinical trials in the management of asthma

OBJECTIVE: To review the pharmacology, pharmacokinetics, clinical efficacy, and adverse effects of montelukast, a leukotriene receptor antagonist used to treat asthma, and to discuss the therapeutic role of montelukast as long-term medication and difficulties associated with the management of asthma. DATA SOURCES: A MEDLINE search (up to May 1999) was conducted to identify relevant English-language publications, including preclinical studies, clinical trials, and recent reviews. STUDY SELECTION: All available published reports of controlled, clinical trials of montelukast in adults and children with asthma were summarized, including pharmacokinetic and pharmacologic effects of montelukast. DATA EXTRACTION: Information on the safety and efficacy of montelukast was evaluated on the basis of patient selection, study design, methodology, and statistical significance as compared with placebo or inhaled corticosteroid treatment. DATA SYNTHESIS: Montelukast is approved for the prophylaxis and chronic treatment of asthma at a dose of 10 mg once daily for adolescents (> or =15 y) and adults and 5 mg once daily for children (6-14 y). In placebo-controlled clinical trials, montelukast significantly improved pulmonary lung function (as measured by forced expiratory volume in 1 sec), significantly reduced beta2-agonist use, and significantly improved patient-reported end points in adults and children (> or =6 y) with chronic asthma. In adults, a similar magnitude of improvement in lung function is seen with or without inhaled corticosteroid use; the effects of montelukast may be additive to those of inhaled corticosteroids and permit the reduction of the required dose of inhaled corticosteroids. In cases of exercise-induced asthma (adults and children), montelukast treatment attenuates the fall in pulmonary function following exercise. It attenuates both the early- and late-phase responses of asthma after allergen inhalation. Improvements in asthma control are similar in asthmatic patients who are aspirin-sensitive or not aspirin-sensitive and can be seen within one day of treatment. Tolerance does not develop, and the adverse events do not differ from those of placebo. CONCLUSIONS: Montelukast is indicated for the prophylaxis of chronic asthma in adults and children (> or =6 y). It may be considered for use as first-line therapy in patients with mild persistent asthma or for additional control in patients who are still symptomatic while receiving treatment with inhaled corticosteroids. It may also be used for additional control in aspirin-sensitive asthmatic patients. Consideration may be given for using montelukast to allow tapering of the dose of inhaled corticosteroids while maintaining clinical stability. Chronic treatment with montelukast can provide additional control of symptoms during exercise, but inhaled beta2-agonists remain first-line therapy for prophylaxis and treatment.     

Validating electronic source data in clinical trials

The clinical trials industry relies heavily on paper-based source documents as the foundation for the collection of its clinical research data from human subjects and medical records. This focus on paper documents has been prevalent throughout the history of clinical trials conduct, even as computing solutions advanced throughout the past 20 years. With the advent of additional electronic capabilities recently with the growth of Internet-based products to enhance business operations in many fields, the clinical trials industry remains uniquely behind most other industries in electronic technology adoptions. Valid reasons exist for the slow growth of technology adoptions in clinical trial activities, but there are now discussions about how to use technology more effectively in clinical trial conduct. One area of enhanced clinical trial conduct is believed to be available by moving from paper-based source documents to electronic source documents, that is, eliminating paper from clinical data capture, and collecting the information initially in a computer system. An important concern in moving to electronic source data is the validation of such data. This paper summarizes the history of clinical data capture through paper and electronic advancements to date and identifies three reasons for the slow movement to more electronic source data. The paper then illustrates two methods for the validation of electronic source data.     

Maintaining data integrity in randomized clinical trials

BACKGROUND: The process of attaining and maintaining data integrity is critical to ensure a successful randomized clinical trial. Methodologic strategies to achieve data integrity when repeated measures are used has not been discussed in detail in the literature. The National Institutes of Health requires that data integrity and safety monitoring boards or plans be established for randomized clinical trials. OBJECTIVES: The objectives of this paper are to (a) examine important data collection issues nurse scientists often encounter in randomized clinical trials and (b) present a process that researchers can apply to achieve data integrity. METHODS: The process to achieve data integrity is based on strategies that were developed by an interdisciplinary hospice research team involved in an ongoing National Institutes of Health-funded clinical trial. The process and key issues are illustrated with methodologic examples from the randomized clinical trial and supporting literature. RESULTS: The process of achieving data integrity involves developing protocols in three key areas: data collection, training of data collectors, and data monitoring. The use of these protocols will increase the rigor of the clinical trial and assist in maintaining study validity. CONCLUSIONS: Investigators conducting clinical trials need to consider all issues involved in achieving data integrity and have tested protocols in place throughout the study. These approaches will not only help maintain study validity but also help ensure data of sufficient quantity and quality to achieve the desired statistical power.     

Generalizing from clinical trials

Although randomized controlled clinical trials have become the “gold standard” for evaluating new treatments, only a small subset of the population considered for treatment participate in randomized clinical trials. To what extent is it reasonable to generalize beyond the boundaries of a specific clinical trial? This paper argues that several pieces of information are necessary to determine the extent of extrapolation or generalization warranted in a specific clinical trial. The necessary items of information are derived from basic science laboratory studies; animal studies; genetic studies (where applicable); observational, clinical, and epidemiological studies; and other randomized clinical trials in similar settings or with similar treatments. An example from the field of cholesterol reduction is presented.     

Economic analysis and clinical trials

Given the increasing interest in the economics of health care, the incorporation of economic analysis in clinical trials is more often being considered, both by medical researchers and by research funding bodies. This article proposes criteria for judging the appropriateness of including economic analysis in a given trial, suggests how that analysis could be phased in order to minimize the work involved, and discusses the wider implications for medical research of more frequent attention to economic concepts.