Problems in dealing with missing data and informative censoring in clinical trials

Trials, Jan 2002

A common problem in clinical trials is the missing data that occurs when patients do not complete the study and drop out without further measurements. Missing data cause the usual statistical analysis of complete or all available data to be subject to bias. There are no universally applicable methods for handling missing data. We recommend the following: (1) Report reasons for dropouts and proportions for each treatment group; (2) Conduct sensitivity analyses to encompass different scenarios of assumptions and discuss consistency or discrepancy among them; (3) Pay attention to minimize the chance of dropouts at the design stage and during trial monitoring; (4) Collect post-dropout data on the primary endpoints, if at all possible; and (5) Consider the dropout event itself an important endpoint in studies with many.

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Problems in dealing with missing data and informative censoring in clinical trials

Current Controlled Trials in Cardiovascular Medicine CR2u0er0rv2en,ietCwontrolled Trials in Cardiovascular Medicine 3 Problems in dealing with missing data and informative censoring in clinical trials Weichung Joseph Shih 0 1 0 Cancer Institute of New Jersey, University of Medicine and Dentistry of New Jersey Robert Wood Johnson Medical School , New Brunswick, New Jersey , USA 1 Division of Biometrics, University of Medicine and Dentistry of New Jersey School of Public Health , New Brunswick, New Jersey , USA A common problem in clinical trials is the missing data that occurs when patients do not complete the study and drop out without further measurements. Missing data cause the usual statistical analysis of complete or all available data to be subject to bias. There are no universally applicable methods for handling missing data. We recommend the following: (1) Report reasons for dropouts and proportions for each treatment group; (2) Conduct sensitivity analyses to encompass different scenarios of assumptions and discuss consistency or discrepancy among them; (3) Pay attention to minimize the chance of dropouts at the design stage and during trial monitoring; (4) Collect postdropout data on the primary endpoints, if at all possible; and (5) Consider the dropout event itself an important endpoint in studies with many. informative missing data; intent to treat; longitudinal study; missing completely at random Introduction With the exception of counting deaths from all causes, a common problem in clinical trials is the missing data caused by patients who do not complete the study in full schedule and drop out of the study without further measurements. Possible reasons for patients dropping out of the study (the so-called 'withdrawals') include death, adverse reactions, unpleasant study procedures, lack of improvement, early recovery, and other factors related or unrelated to trial procedure and treatments. Missing data in a study because of dropouts may cause the usual statistical analysis for complete or available data to be subject to a potential bias. This review attempts to raise the awareness of the problem and to provide some general guidance to clinical trial practitioners. Examples Withdrawals from clinical trials are ubiquitous. The Nuremberg Code, adopted in 1947, established principles of ethical conduct in such trials. These principles demand that the subject be given the choice stop participating at any time during the clinical study. Under these principles, the investigator is obliged to stop the experiment if injury seems likely. I highlight just a few findings from recent articles in the area of cardiovascular medicine for illustration. Example 1: A multicenter, randomized, double-blind, three parallel groups trial to compare placebo, candesartan ciltexetil and enalapril in patients with mild to moderate essential hypertension [ 1 ]. The study randomized 205 to treatment, however, only 178 patients were evaluable by protocol at the end of an 8-week treatment period. 'The remaining patients were excluded from the analysis of blood pressure (BP) data because of major protocol violations, poor compliance with medical visits, or withdrawal because of adverse events.' Example 2: A multicenter, randomized, open-label, parallel-design study to compare the treatment effect of niacin and atorvastatin (for 12 weeks) on lipoprotein subfractions in patients with atherogenic dyslipidemia [ 2 ]. 'Of the total 108 patients randomized to treatment, 12 withdrew from the study. Of those who withdrew, nine were due to adverse events, two were lost to follow-up, and one did not return for the final visit.' Example 3: A multicenter, randomized, double-blind, placebo-controlled trial to assess treatment effect of pimobendan on exercise capacity in patients with chronic heart failure [ 3 ]. 'The primary pre-specified analysis of exercise time was limited to those patients who had at least the first follow up (four-week) exercise test carried out and had shown good compliance up to the day of the test. If subsequent tests were not performed, whatever the reason, or performed although compliance between tests had been poor, the last exercise time value obtained while compliance was good was carried forward.' Two hundred and forty of the 317 randomized patients had exercise test done with good compliance at four, 12, and 24 weeks. Listed reasons (and number of patients) for missing exercise time data at 24 weeks were: 'exercise test not done due to death' (n = 30), 'exercise testing contraindicated' (n = 9), and 'exercise test not done for other reasons' (n = 10). Example 4: A randomized, double-blind study to compare nifedipine-GITS and verapamil-SR on hemodynamics, left ventricular mass, and coronary vasodilatory in patients with advanced hypertension [ 4 ]. Fifty-four patients were randomized after the placebo run-in phase. 'Twenty-four failed to complete the (six-month) trial, and thus were (...truncated)


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Weichung Shih. Problems in dealing with missing data and informative censoring in clinical trials, Trials, 2002, pp. 4, 3, DOI: 10.1186/1468-6708-3-4