Well designed, conducted and reported randomised controlled trials (RCTs) provide rigorous evidence for evaluating health interventions. To generate such rigorous evidence that meets scientific, statistical, legal, and ethical considerations, trials have increasingly become resource and time intensive [1]. Consequently, use of surrogate endpoints instead of patient relevant final outcomes can improve trial efficiency, i.e. shorter follow-up, smaller sample size hence lower cost [1]. Furthermore, surrogates that truly inform subsequent patients longer term endpoints are particularly valuable in pragmatic trials where long-term follow up is difficult - e.g., trials of interventions to reduce long term complications of diabetes. Despite this efficiency offered by surrogate endpoints, they are concerns about their limitations. Compared to patient relevant final outcomes, surrogate endpoints in trials have been found to overestimate health benefits [2]. Furthermore, some approvals of interventions based on surrogate endpoints has led to roll out of interventions with no benefit or that were harmful due to the surrogate not being in the causal pathway of the disease or unintended effects of the intervention [3, 4]. Given these limitations, trials that use primary outcomes which are surrogate endpoints should be clear on having used a surrogate, its validity in predicting intervention effect and the uncertainty and risks associated with its use [5]. However, most trials that use surrogate primary endpoints are not transparent in this regard: an analysis of 626 trials published in 2006 and 2007 found that of the 109 using a surrogate primary endpoint, 62 (57%) reported that the primary outcome was a surrogate endpoint and only 38 (35%) discussed the validity of the surrogate [6]. Therefore, we aim to update this review and analyse the current practice in the use and reporting of surrogate endpoints in RCTs. This review is part of our project that aims to develop consensus-driven SPIRIT and CONSORT extensions for reporting surrogate primary endpoints: SPIRIT-SURROGATE and CONSORT-SURROGATE – see [7] for full project protocol. The project has four phases: literature reviews; e-Delphi survey; consensus meeting; and knowledge translation. This targeted review is part of the literature reviews phase [8] and will serve two purposes:
The review is part of the development of SPIRIT and CONSORT extensions funded by the Medical Research Council (grant number MR/V038400/1). Onyeka Obuaya is funded by the Medical Research Council, University of Edinburgh and University of Glasgow, as part of the Precision Medicine Doctoral Training Program (grant number MR/W006804/1).
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Ciani, O., A. Manyara, and R.S. Taylor, Need for better reporting of trials with surrogate endpoints: SPIRIT|CONSORT-SURROGATE extensions. Journal of Epidemiology and Community Health, 2022. 76(9): p. 769-770.
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Manyara, A.M., et al., Protocol for the development of SPIRIT and CONSORT extensions for randomised controlled trials with surrogate primary endpoints: SPIRIT-SURROGATE and CONSORT-SURROGATE. BMJ Open, 2022. 12(10): p. e064304.
Manyara, A.M., et al., Scoping and targeted reviews to support development of SPIRIT and CONSORT extensions for randomised controlled trials with surrogate primary endpoints: protocol. BMJ Open, 2022. 12(10): p. e062798.
Covidence, Covidence systematic review software, Veritas Health Innovation, Melbourne, Australia.
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