Effects of the Endpoint Adjudication Process on the Results of a Randomised Controlled Trial: The ADVANCE Trial

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Abstract

Background

Endpoint adjudication committees (EPAC) are widely used in clinical trials. The aim of the present analysis is to assess the effects of the endpoint adjudication process on the main findings of the ADVANCE trial (Trial registration: ClinicalTrials.gov NCT00145925).

Methods and Findings

The ADVANCE trial was a multicentre, 2×2 factorial randomised controlled trial of blood pressure lowering and intensive blood glucose control in 11140 patients with type 2 diabetes. Primary outcomes were major macrovascular (nonfatal myocardial infarction, nonfatal stroke and cardiovascular death) and microvascular (new or worsening nephropathy and retinopathy) events. Suspected primary outcomes were initially reported by the investigators at the 215 sites with subsequent adjudication by the EPAC. The EPAC also adjudicated upon potential events identified directly by ongoing screening of all reported events. Over a median follow-up of 5 years, the site investigators reported one or more primary outcomes among 2443 participants. After adjudication these events were confirmed for 2077 (85%) with 48 further events added through the EPAC-led database screening process. The estimated relative risk reductions (95% confidence intervals) in the primary outcome for the blood pressure lowering comparison were 8% (−1 to 15%) based on the investigator-reported events and 9% (0 to 17%) based on the EPAC-based events ( P for homogeneity = 0.70). The corresponding findings for the glucose comparison were 8% (1 to 15%) and 10% (2% to 18%) ( P for homogeneity = 0.60). The effect estimates were also highly comparable when studied separately for macrovascular events and microvascular events for both comparisons (all P for homogeneity>0.6).

Conclusions

The endpoint adjudication process had no discernible impact on the main findings in ADVANCE. These data highlight the need for careful consideration of the likely impact of an EPAC on the findings and conclusions of clinical trials prior to their establishment.

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Most cited references 11

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Evaluating the benefit of event adjudication of cardiovascular outcomes in large simple RCTs.

Justin D. Walter, Salim Yusuf, Janice Pogue (2009)

Event adjudication in randomized controlled trials is thought to be a necessary step to remove noise and potential bias from the results [1,2]. However, this hypothesis has not been widely evaluated. We conducted a meta-analysis of a series of cardiovascular outcomes trials and estimated the effect of adjudication on treatment estimates and on the number of outcomes included the trials. Data were retrieved from all cardiovascular outcomes trials conducted at the Population Health Research Institute (PHRI) between 1993 and 2006. These data included 10 trials with over 9000 events from 95,038 individuals. Differences in the log odds ratios between adjudicated and reported outcomes were analyzed and summarized using a ratio of odds ratios. Both masked and unmasked trials were included in this analysis. There were no effects of event adjudication on the estimates of treatment effect for the primary outcomes, myocardial infarction (MI), stroke, or cardiovascular/vascular death. For the trial primary outcomes, the effect of adjudication vs. reported events was OR ratio = 1.00 [95% confidence interval (CI): 0.97-1.02]. There were also no significant differences in the number of outcomes included in the trials. Results were the same for masked and unmasked trials. The number of unmasked trials were small, and this analysis was restricted to cardiovascular endpoints reported from trials managed by a single coordinating center, with similar sets of procedures. Individual patient data were not used for the analysis. This systematic meta-analysis failed to detect any effect of event adjudication on study conclusions and the numbers of events included in the final analyses were minimally changed. Given the considerable effort required to perform adjudication, there is a need to demonstrate that this process does indeed increase the sensitivity of trials. There is a need to conduct more systematic analyses of the effect of event adjudication in other trials to determine if this process is truly worthwhile.

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Do we need to adjudicate major clinical events?

Victor G Vogel, Gill Lawrence, Fred T. Fiedorek … (2007)

The use of centralized systems to adjudicate clinical events is common in large clinical trials, in spite of relatively little published literature concerning the rationale and justification. The purpose of this manuscript is to review the reasons for central adjudication and to discuss whether trials could be simplified by limiting or streamlining the adjudication process. We reviewed the literature concerning central adjudication and documented the experience of adjudication in several clinical trials. Since definitions for nonfatal events are generally heterogeneous and subjective, one reason for a central process of adjudication is to assist in assuring systematic application of the definition used in the trial. In open-label trials, assuring that the adjudication is done blinded to treatment assignment may provide protection against differential misclassification. Regulatory authorities, including the FDA, derive confidence in the validity of results when central adjudication is performed. The clinical community has become accustomed to a certain amount of adjudication and may criticize trials that lack adjudication. It is difficult to document the value of adjudication in trials that have reported adjudicated and nonadjudicated event rates and related treatment effects. Making rationale decisions about when and how to adjudicate is hampered by the lack of published study of when and how central adjudication is helpful to improve the quality and validity of trials and at what cost. Adjudication has not been shown to improve the ability to determine treatment effects. Thus, adjudication may be overly complex and overused in many large simple trials. The appropriate role of central adjudication - which trials, which outcomes, what methods - deserves scrutiny and further study.

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Study rationale and design of ADVANCE: action in diabetes and vascular disease--preterax and diamicron MR controlled evaluation.

(2001)

Patients with Type II (non-insulin-dependent) diabetes mellitus are at increased risk of macrovascular and microvascular disease, both of which are reduced by controlling raised blood pressure in hypertensive patients. Intensive glycaemic control has also been shown to reduce microvascular disease but the effects on macrovascular disease remain uncertain. This study will examine the hypotheses that lowering blood pressure with an ACE inhibitor-diuretic combination and intensively controlling gylcaemia with a sulphonylurea-based regimen in high-risk patients with Type II diabetes (both hypertensive and non-hypertensive) reduces the incidence of macrovascular and microvascular disease. The study is a 2 x 2 factorial randomised controlled trial that will include 10000 adults with Type II diabetes at high risk of vascular disease. Following 6 weeks on open label perindopril-indapamide combination, eligible patients are randomised to continued perindopril-indapamide or matching placebo, and to an intensive gliclazide MR-based glucose control regimen or usual guidelines-based therapy. Primary outcomes are, first, the composite of nonfatal stroke, non-fatal myocardial infarction or cardiovascular death and, second, the composite of new or worsening nephropathy or diabetic eye disease. The scheduled average duration of treatment and follow-up is 4.5 years. The study will be conducted in approximately 200 centres in Australasia, Asia, Europe and North America. ADVANCE is designed to provide reliable evidence on the balance of benefits and risks conferred by blood pressure lowering therapy and intensive glucose control therapy in high-risk diabetic patients, regardless of initial blood pressure or glucose concentrations.

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Author and article information

Contributors

Isabelle Boutron: Role: Editor

Journal

Journal ID (nlm-ta): PLoS One

Journal ID (iso-abbrev): PLoS ONE

Journal ID (publisher-id): plos

Journal ID (pmc): plosone

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, USA )

ISSN (Electronic): 1932-6203

Publication date Collection: 2013

Publication date (Electronic): 4 February 2013

Volume: 8

Issue: 2

Electronic Location Identifier: e55807

Affiliations

[1 ]The George Institute for Global Health, University of Sydney, Sydney, New South Wales, Australia

[2 ]School of Public Health, Monash University, Clayton, Victoria, Australia

[3 ]Royal North Shore Hospital, Sydney, New South Wales, Australia

[4 ]Royal Prince Alfred Hospital, Sydney, New South Wales, Australia

[5 ]Sydney Adventist Hospital Clinical School, Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia

[6 ]University of Milan-Bicocca, Milan, Italy

[7 ]Imperial College, London, United Kingdom

University Paris Descartes, France

Author notes

* E-mail: bneal@ 123456georgeinstitute.org.au

Competing Interests: The authors have read the journal's policy and have the following conflicts: SZ reports being an advisory board member for MSD, Novo Nordisk, Sanofi Aventis, Boehringer Ingelheim, Astra Zeneca, and BMS, and receiving lecture fees from Servier, MSD, Novartis, Novo Nordisk, Boheringer Ingelheim, Sanofi Aventis, Astra Zeneca and BMS. CP reports being an advisory board member for Amgen, Boehringer Ingelheim, MSD, Janssen Cilag, Reata and Abbott, and receiving lecture fees from MSD, Boehringer Ingelheim and BMS. MW reports receiving consulting fees from Roche and lecture fees from Servier and Sonofi Aventis. NP reports receiving grant support from Pfizer, Julius Clinical Research, and Novartis, and lecture fees from Gilead, Daiichi-Sankyo, Servier, Takeda, Pfizer, Novo-Nordisk, Roche, Boehringer Ingelheim, Medtronic, and Jannsen. SM reports being an advisory board member for Servier, Pfizer, and Novartis, and receiving lecture fees from Servier and Pfizer and grant support from Servier, Pfizer, and Novartis. JC reports being a member of an advisory board for Servier and receiving lecture fees and grant support from Servier. BN reports being a board member of Roche, Takeda, and Pepsico and receiving lecture fees from Amgen, AstraZeneca, GlaxoSmithKline, Novartis, Pepsico, Pfizer, Pharmacy Guild of Australia, Sanofi Aventis, Servier, and Tanabe. This study was partly funded by Servier. There are no patents, products in development, or marketed products products to declare. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials, as detailed online in the guide for authors.

Revised the manuscript critically for important intellectual content: HA SZ GF CP MA JW RJ APK TN CA MW AP GM NP SM JC BN. Conceived and designed the experiments: JH HA SZ GF CP MA JW RJ APK TN CA MW AP GM NP SM JC BN. Analyzed the data: JH. Wrote the paper: JH HA JC BN.

¶ Membership of the ADVANCE Collaborative Group is provided in the Acknowledgments.

Article

Publisher ID: PONE-D-12-35073

DOI: 10.1371/journal.pone.0055807

PMC ID: 3563633

PubMed ID: 23390553

SO-VID: 079a9e60-60f0-4e50-8775-b38895d6ac59

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

History

Date received : 7 November 2012

Date accepted : 2 January 2013

Page count

Pages: 7

Funding

The ADVANCE trial was supported by grants from the National Health and Medical Research Council of Australia (211086 and 358395; http://www.nhmrc.gov.au) and Servier ( http://www.servier.com). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Effects of the Endpoint Adjudication Process on the Results of a Randomised Controlled Trial: The ADVANCE Trial

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Abstract

Background

Methods and Findings

Conclusions

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PLOS: COVID-19 pandemic

Most cited references 11

Evaluating the benefit of event adjudication of cardiovascular outcomes in large simple RCTs.

Do we need to adjudicate major clinical events?

Study rationale and design of ADVANCE: action in diabetes and vascular disease--preterax and diamicron MR controlled evaluation.

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