Showing papers on "Surrogate endpoint published in 1990"

On the use of laboratory markers as surrogates for clinical endpoints in the evaluation of treatment for HIV infection.

Abstract: There are strong ethical and practical reasons for hastening decision-making about the efficacy of new treatments for human immunodeficiency virus (HIV) infection. One strategy is to use early markers of disease progression, such as CD4+ lymphocyte levels, as surrogates for ultimate clinical endpoints, such as the development of acquired immune deficiency syndrome (AIDS) or death, in the evaluation of new therapies. We used a simple model of transitions among three health states (well; alive but with an adverse marker; and having experienced a definitive clinical endpoint) to examine the extent to which treatment comparisons based on the surrogate endpoint predict ultimate clinical benefits. With parameters chosen to model the treatment of HIV infection, computer simulations of clinical trials demonstrated substantial time savings by use of the surrogate endpoint. However, reliance on the surrogate led to serious overestimates of ultimate clinical benefit if treatment entailed delayed toxicity or had only transient beneficial effects. Likewise, reliance on the surrogate led to serious underestimates of ultimate clinical benefit when the treatment had no effect on the transition from well to the marker state but did reduce the rates of transition from the marker state to the ultimate clinical endpoint and directly from the well state to the ultimate clinical endpoint.

Opportunities for enhancing efficiency and reducing cost in large scale disease prevention trials: A statistical perspective

Abstract: Randomized intervention trials play an important role in the identification of practical approaches to reducing major chronic diseases in our society. Very few such trials are likely to be possible, however, in coming years unless we adopt procedures less demanding and less costly than those used in the past. Towards this end some elements of an efficient prevention trial are discussed, including aspects of study design, criteria for eligibility and exclusion, procedures for data collection, follow-up, endpoint ascertainment, and data analysis, and for ancillary studies. For example, possibilities for enhancing efficiency in the use of endpoint events include the selection of an appropriately weighted test statistic, the use of case-control or case-cohort sampling procedures in the processing of covariate data and specimens, and the notion of replacing a disease endpoint by an earlier or less expensive surrogate endpoint. Ideas for enhancing the efficiency of prevention trials will be illustrated in the context of a proposed Dietary Fat Intervention Trial for disease prevention in women.

Efficient use of endpoints in clinical trials: A clinical perspective

Abstract: Efficiencies in the use of endpoints in clinical trials are hard won, not easy. They depend upon the shifting of study resources among clinical centres and central units, as well as between numbers of participants and the costs of the endpoint measurement. Costs of endpoint measurement and evaluation do not tell the whole story; nor do costs multiplied by the total number of patients to be recruited; other costs generated by a particular endpoint must also be taken into account. Each clinical trial must be considered separately for the efficient use of endpoints.

Obtaining Reliable Information from Randomized Controlled Trials in Congestive Heart Failure and Left Ventricular Dysfunction

Abstract: Chronic congestive heart failure (CHF) is a syndrome that is the end result of a number of different kinds of cardiac damage and compensatory mechanisms resulting in a variable prognosis. Patients usually have a high mortality rate, a high rate of morbid complications, and multiple severe symptoms. The high rates of morbidity and symptoms lead to limitations in daily activities and poor quality of life. The aim of therapy in such patients should therefore be not only the amelioration of symptoms and signs of CHF but also the prevention of morbidity, improvement in quality of life, and prolongation of survival. Because the clinical course in a particular patient is highly variable and unpredictable, the effect of a therapy can be reliably evaluated only if all sources of errors in this evaluation are minimized. In general, errors can be classified into those due to systematic biases and those due to random errors. In order to avoid a variety of systematic biases randomized double-blind controlled trials are essential. Such studies avoid biases in patient allocation, minimize imbalances at entry use of other therapy, and avoid biases in endpoint ascertainment. In this chapter, I will discuss the following issues: 1. The likely size of effect with currently available interventions. 2. Why randomized trials are essential in heart failure. 3. Why some of the trials should be much larger than those that have been conducted. 4. How some of the currently employed methods of analysis and reporting can be biased and can lead to misleading conclusions. 5. Why one may not be able to extrapolate from the effect of a particular agent on surrogate endpoints (such as exercise tolerance) to clinically relevant outcomes such as survival or morbidity. 6. How the framework of the trials and the data that are collected systematically provide an opportunity to learn more about the clinical course of patients with heart failure. 7. Examples of some large studies that are in progress.

Are there Valid Surrogate Endpoints for Mortality that can be Used to Evaluate the Effects of Antiarrhythmic Drug Therapy

Abstract: A beneficial effect or an adverse effect of drug therapy on death is difficult to assess in patients with cardiovascular diseases because the death rate is moderate (<10% per year) in most patient groups that are the target of treatment assessment Since the death rate is modest, studies must be large, long-lasting, and expensive if they are to establish either benefit or harm of a drug in terms of mortality The realization that the answer to questions about a drug’s effect on mortality will be slow in coming and expensive to get naturally raises the issue of surrogate endpoints that may provide reasonable predictions of mortality effects at less effort and cost than full-scale controlled, randomized clinical trials with mortality as an end point This discussion will focus on the question: what surrogate endpoints are valid and sufficient to establish benefit of an antiarrhythmic drug on mortality