Disagreement between site investigators and clinical event committees is common and can affect trial results

Mahaffey, K. W.; Tardiff, Barbara E.; Granger, CL; Lee, K.L.; Harrington, RA; Topol, Eric J.; Califf, Robert M.

doi:10.1016/s0735-1097(98)81442-3

Cited by 7 publications

(6 citation statements)

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“…This finding demonstrates the risk of relying on raw data in clinical decision-making. Similar experiences of disagreements between local investigators and clinical event committees in four large, randomized, multicentre clinical trials were recently presented [7] . It was found that the central adjudication process could have a substantial impact on the event rates and the trial results.…”

Section: Discussionmentioning

confidence: 57%

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

Näslund¹,

Grip²,

Fischer-Hansen³

et al. 1999

European Heart Journal

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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)

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Section: Discussionmentioning

confidence: 57%

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

Näslund¹,

Grip²,

Fischer-Hansen³

et al. 1999

European Heart Journal

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“…Suspected infarctions were identified by a computerized review of the patient database and adjudicated by a blinded clinical events committee according to clinical, electrocardiographic, and enzymatic data. 14 Significant coronary artery disease was defined by the presence of more than 50% narrowing in one of the major coronary arteries. Left ventricular function was categorized according to ejection fraction as normal (>50%), mild dysfunction (between 40% and 49%), moderate dysfunction (between 25% and 39%), and severe dysfunction (<25%) as visually assessed by the principal investigators at each site.…”

Section: Patient Populationmentioning

confidence: 99%

Variation in patient management and outcomes for acute coronary syndromes in Latin America and North America: Results from the Platelet IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) trial

Cohen¹,

Pacchiana²,

Corbalán³

et al. 2001

American Heart Journal

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“…However, for more complicated endpoints such as the clinical patient condition or results from examinations, the classification of endpoints is more problematic. In studies where the endpoints are diagnoses such as myocardial infarction or results of examinations such as blood flow after angiographic thrombolysis, the classifications made by endpoint committees have dramatic effects on the statistical significance of treatment in comparison to data given by the investigators [,]. In the SAVE trial the Classification Committee modified the initial myocardial infarction rate by using strict criteria [].…”

Section: Discussionmentioning

confidence: 99%

“…Composite endpoints are often used, necessitating strict definitions and independent endpoint classifications. Previous reports have shown that there may be important differences in the classification of events made by investigators and centralised event committees in cardiovascular studies [,]. Finally, safety monitoring of survival studies is necessary from both the ethical and scientific perspective [,].…”

Section: Introductionmentioning

confidence: 99%

Screening, endpoint classification, and safety monitoring in the Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT‐HF)

Fagerberg

2000

European J of Heart Fail

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The MERIT-HF study was designed to investigate the effect of once-daily dosing of metoprolol succinate CRrXL added to standard therapy in patients with chronic heart failure. A screening programme, aiming at identifying eligible patients for the study was used by 231 out of 313 sites, resulting in 8912 screened patients. These patients were older, more often women, had marginally higher ejection fraction and were more often in NYHA class IV compared to the finally randomised patients. There was a positive correlation between the number of screened and randomised patients and due to the high inclusion rate the number of randomised patients was increased from 3200 to 3991 patients. The clinical events were defined by a manual and were based on identical classifications made independently by two members of an Independent Endpoint Committee. Data from the case report form and the classifications made by the Endpoint Committee were in accordance for hospitalisation due to worsening heart failure on 722 occasions. On 207 occasions the data from the case report forms and the classification made by the committee differed regarding this clinical event. The Independent Safety Committee monitored safety aspects of the study by using asymmetric group sequential procedures. The study was stopped early on recommendation Ž from the Independent Safety Committee, when the second pre-specified interim analysis 50% of total number of expected . deaths showed that the criterion for stopping due to benefit had been met and exceeded. In conclusion, a screening programme facilitated patient recruitment and showed the characteristics of the background population, the event classification was improved by using an independent endpoint committee, and the safety monitoring allowed an early closure of the study due to mortality benefit, without jeopardising the final analyses of the results. ᮊ

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Disagreement between site investigators and clinical event committees is common and can affect trial results

Cited by 7 publications

References 0 publications

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

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

Variation in patient management and outcomes for acute coronary syndromes in Latin America and North America: Results from the Platelet IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) trial

Screening, endpoint classification, and safety monitoring in the Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT‐HF)

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