Protocol for the development of SPIRIT and CONSORT extensions for randomised controlled trials with surrogate primary endpoints: SPIRIT-SURROGATE and CONSORT-SURROGATE

Abstract

IntroductionRandomised controlled trials (RCTs) may use surrogate endpoints as substitutes and predictors of patient-relevant/participant-relevant final outcomes (eg, survival, health-related quality of life). Translation of effects measured on a surrogate endpoint into health benefits for patients/participants is dependent on the validity of the surrogate; hence, more accurate and transparent reporting on surrogate endpoints is needed to limit misleading interpretation of trial findings. However, there is currently no explicit guidance for the reporting of such trials. Therefore, we aim to develop extensions to the SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) and CONSORT (Consolidated Standards of Reporting Trials) reporting guidelines to improve the design and completeness of reporting of RCTs and their protocols using a surrogate endpoint as a primary outcome.Methods and analysisThe project will have four phases: phase 1 (literature reviews) to identify candidate reporting items to be rated in a Delphi study; phase 2 (Delphi study) to rate the importance of items identified in phase 1 and receive suggestions for additional items; phase 3 (consensus meeting) to agree on final set of items for inclusion in the extensions and phase 4 (knowledge translation) to engage stakeholders and disseminate the project outputs through various strategies including peer-reviewed publications. Patient and public involvement will be embedded into all project phases.Ethics and disseminationThe study has received ethical approval from the University of Glasgow College of Medical, Veterinary and Life Sciences Ethics Committee (project no: 200210051). The findings will be published in open-access peer-reviewed publications and presented in conferences, meetings and relevant forums.

Associations Between Surrogate Markers and Clinical Outcomes for Nononcologic Chronic Disease Treatments

“…Although correlation coefficients and coefficients of determination from meta-analyses of clinical trials are often used to evaluate the strength of association between surrogate markers and clinical outcomes, these values are purely statistical, rely on arbitrary cutoffs, and fail to capture information about the study design, target outcome, and generalizability of the evidence. Although more comprehensive methods to establish surrogacy have been proposed (eg, the Biomarker-Surrogacy Evaluation Schema), enhanced clinical trial reporting and greater availability of shared individual patient-level data will facilitate more precise analyses and estimates.…”

A framework for the definition and interpretation of the use of surrogate endpoints in interventional trials

“…While accepting treatment effects on a biomarker as a replacement for a target outcome has become increasingly commonplace in the regulatory setting, [7][8][9] there has been much less consideration for the use and implications of intermediate outcomes as surrogate endpoints in the wider context of healthcare interventional trials. [11][12][13] As part of the development of the SPIRIT and CONSORT extensions for the reporting of RCTs with a primary surrogate endpoint, 16 we undertook four linked empirical studies (a scoping review, e-Delphi study, consensus meeting, and a web survey) to inform the development of a definitional framework for the improved design, reporting, and interpretation of trials using surrogate endpoints. Our e-Delphi study showed good support for the 2016 BEST (Biomarkers, Endpoints, and other Tools) definition from the NIH-FDA Working Group that biomarkers (e.g., brain amyloid plaque protein, blood pressure, tumour response) can act as surrogate endpoints in interventional trials by acting as a substitute and predictor of treatment effects on target outcome(s) for how a patient feels, functions, and survives.…”

“…As part of a UK Medical Research Council-funded project to develop the CONSORT (Consolidated Standards of Reporting Trials) and SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) extensions for RCT protocols and final reports using surrogate endpoints, we undertook four linked empirical studies to examine the definition and interpretation of surrogate endpoints in trials. 16 , 17 This included a scoping review of current surrogate endpoint definitions, rated for their acceptability and clarity as part of an e-Delphi study, and assessment in a hybrid consensus meeting with an extension of the e-Delphi study to gauge how a sample of international stakeholders (including clinicians, trial investigators, patients and public partners, journal editors, and health technology experts) approached the judgment of intermediate outcomes in RCTs as a surrogate endpoints or target outcomes. We present a summary of these empirical studies and, using their findings, propose a definitional framework to inform the better reporting of trials using surrogate endpoints and to aid stakeholders' (including patients, clinicians, regulators, and payers) in their interpretation of surrogate endpoint evidence.…”

Protocol for the development of an artificial intelligence extension to the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) 2022

“…The structure and writing of this protocol were guided by the recently published protocol for the SPIRIT-SURROGATE and CONSORT-SURROGATE extensions (12).…”

“…However, the meeting time will be sufficient to allow discussion time for all items. Other extensions have used meetings over two days (4,5,12).…”