Comparison of treatment effect sizes associated with surrogate and final patient relevant outcomes in randomised controlled trials: meta-epidemiological study
BMJ 2013; 346 doi: https://doi.org/10.1136/bmj.f457 (Published 29 January 2013) Cite this as: BMJ 2013;346:f457
- Oriana Ciani, PhD candidate1,
- Marc Buyse, chairman2,
- Ruth Garside, senior lecturer1,
- Toby Pavey, research fellow3,
- Ken Stein, professor1,
- Jonathan A C Sterne, professor4,
- Rod S Taylor, professor1
- 1PenTAG, Institute for Health Services Research, University of Exeter Medical School, University of Exeter, Exeter EX2 4SG, UK
- 2International Drug Development Institute, Louvain-la-Neuve, Belgium and Interuniversity Institute for Biostatistics and Statistical Bioinformatics, Hasselt University, Diepenbeek, Belgium
- 3School of Human Movement Studies, University of Queensland, Brisbane, QLD, Australia
- 4School of Social and Community Medicine, University of Bristol, Bristol, UK
- Correspondence to: O Ciani oriana.ciani{at}pcmd.ac.uk
- Accepted 29 October 2012
Abstract
Objective To quantify and compare the treatment effect and risk of bias of trials reporting biomarkers or intermediate outcomes (surrogate outcomes) versus trials using final patient relevant primary outcomes.
Design Meta-epidemiological study.
Data sources All randomised clinical trials published in 2005 and 2006 in six high impact medical journals: Annals of Internal Medicine, BMJ, Journal of the American Medical Association, Lancet, New England Journal of Medicine, and PLoS Medicine.
Study selection Two independent reviewers selected trials.
Data extraction Trial characteristics, risk of bias, and outcomes were recorded according to a predefined form. Two reviewers independently checked data extraction. The ratio of odds ratios was used to quantify the degree of difference in treatment effects between the trials using surrogate outcomes and those using patient relevant outcomes, also adjusted for trial characteristics. A ratio of odds ratios >1.0 implies that trials with surrogate outcomes report larger intervention effects than trials with patient relevant outcomes.
Results 84 trials using surrogate outcomes and 101 using patient relevant outcomes were considered for analyses. Study characteristics of trials using surrogate outcomes and those using patient relevant outcomes were well balanced, except for median sample size (371 v 741) and single centre status (23% v 9%). Their risk of bias did not differ. Primary analysis showed trials reporting surrogate endpoints to have larger treatment effects (odds ratio 0.51, 95% confidence interval 0.42 to 0.60) than trials reporting patient relevant outcomes (0.76, 0.70 to 0.82), with an unadjusted ratio of odds ratios of 1.47 (1.07 to 2.01) and adjusted ratio of odds ratios of 1.46 (1.05 to 2.04). This result was consistent across sensitivity and secondary analyses.
Conclusions Trials reporting surrogate primary outcomes are more likely to report larger treatment effects than trials reporting final patient relevant primary outcomes. This finding was not explained by differences in the risk of bias or characteristics of the two groups of trials.
Footnotes
Contributors: OC and RST conceived and designed the study. OC screened the titles and abstracts, data extracted papers, ran the analyses, and drafted the manuscript. RST screened the titles and abstracts and checked data extraction and analyses. TP checked data extraction. MB and JAS advised on methods of data analysis. All authors commented on drafts of the manuscript. RST is guarantor.
Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work. OC is currently receiving a Peninsula College of Medicine and Dentistry Doctoral studentship.
Ethical approval: Not required.
Data sharing: The dataset is available from the corresponding author at oriana.ciani{at}pcmd.ac.uk.
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