The impact of an end-point committee in a large multicentre, randomized, placebo-controlled clinical trial: results with and without the end-point committee?s final decision on end-points

Abstract

Background A multicentre study permits rapid recruitment of a large number of patients. However, there is a risk of heterogeneities in end-point evaluations, as complex definitions of criteria are interpreted by several local investigators from different hospitals. Reports discussing endpoint evaluation are sparse. The TRIM trial was a multicentre trial of a thrombin inhibitor in patients with unstable angina or non-Q myocardial infarction. In this study, an independent end-point committee evaluated all the reported events of death, acute myocardial infarction and refractory angina pectoris in order to obtain uniform judgements of major end-points. Study aimsTo describe the work of the end-point committee, to analyse its possible effect on the final study results and to discuss the impact on the design of future trials.Method The end-point committee consisted of four members, one from each participating country. After the data were processed by the study monitors, completed case record forms and patient files for patients with reported end-points were mailed to the national member of the end-point committee for judgement. The end-point committee met regularly and made final decisions about the end-points. The work of the end-point committee was documented on a separate case record form. ResultsThe end-point committee assessed 246 events of death, acute myocardial infarction and refractory angina pectoris in 187 of the 1209 patients (15·5%) in the TRIM trial. Misinterpretation of the index event, an inclusion myocardial infarction, as an early cardiac event was found in 12 patients. After end-point committee judgements, the number of patients with acute myocardial infarction or refractory angina pectoris during 30 days of follow-up was reduced from 177 to 153 (13·6% reduction). The classification of events was changed in 53 of 187 patients (28·3%) with death, acute myocardial infarction or refractory angina pectoris. The data assessed by the safety committee was significantly different from the final database after end-point committee judgements. ConclusionThe end-point committee corrected misinterpretations in such a high proportion of cases that the final results differed significantly from the preliminary results delivered to the safety committee. End-point judgements by an end-point committee should be performed in multicentre clinical trials to improve the quality and reliability of study results.(Eur Heart J 1999; 20: 771-777)

Effects of the End Point Adjudication Process on the Results of the Perindopril Protection Against Recurrent Stroke Study (PROGRESS)

“…1 Standardized definitions of events and protocols for their assignment are used, [2][3][4][5][6] but the possibility of misclassification remains. Accordingly, the design of most recent large-scale trials in vascular disease has included an end point adjudication committee (EPAC), [7][8][9] charged with assuring the validity of the diagnoses for key end points such as death, stroke, and coronary heart disease. An EPAC may be particularly important for stroke studies because the diagnosis of stroke subtypes is complex.…”

“…10 Likewise, where applications for new or expanded indications for a therapy are anticipated, an EPAC may be considered essential to meet regulatory requirements. There are, however, rather few data that have showed clear impact of EPACs on the main trial conclusions 1,7 which is problematic because EPACs may be resource-intensive and expensive to operate. 11 The goal of these analyses was to assess the impact of the EPAC on the conclusions of Perindopril Protection Against Recurrent Stroke Study (PROGRESS), a large double-blind randomized trial of blood pressure-lowering in patients with a history of cerebrovascular disease.…”

Lack of Concordance Between Local Investigators, Angiographic Core Laboratory, and Clinical Event Committee in the Assessment of Stent Thrombosis

“…Stringent definitions have been developed to address the uncertainty surrounding possible ST end point events. 20 Although discrepancies are known to exist between the central review groups and local investigators (LIs), [21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40] the degree to which CEC adjudication of events (using hospital source documents) is concordant with the review of an independent ACL (evaluating the actual readings) has not yet been established. The present substudy provides the first assessment of interobserver variability between these groups.…”

How can the Quality of Medical Data in Pharmacovigilance, Pharmacoepidemiology and Clinical Studies be Guaranteed?

“…Several studies have demonstrated that the classification proposed by the investigators for major cardiovascular events were changed by an independent critical events adjudication committee in a quarter to a third of cases. [2,3,4] The poor quality of medical information contained in the source data could change the conclusion of a trial. Similarly, the lack of quality of medical information contained in pharmacoepidemiology or pharmacovigilance data could have serious consequences.…”