Reporting of randomised trials using surrogate outcomes: development of extensions to the CONSORT 2010 and SPIRIT 2013 guidance statements

OUR AIM: To improve the accuracy and reporting of surrogate outcomes in randomised trials through the development of an extension to current reporting checklists.
WHY THIS RESEARCH IS IMPORTANT: Evidence for the effectiveness of treatments ideally comes from well-designed randomised controlled trials that assess patient-centred outcomes that directly measures how a patient feels, functions, or survives. Widely adopted and evidence-based, SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) and CONSORT (Consolidated Standards of Reporting Trials) statements provide minimum recommendations for reporting protocols and results of randomised trials.
In drive to make treatments available more quickly to patients, surrogate endpoints are increasing used as the main outcomes in randomised trials. A surrogate endpoint becomes a 'substitute' for patient centred outcomes, e.g. a trial of a new drug for particular type of life-limiting cancer ultimately seeking to improve patient survival, will assess tumour size within the clinical trial instead of death (that would take much longer to occur).
Advantages of trials based on a surrogate endpoint is that they are shorter, smaller, and less expensive. However, an important potential down-side of such trials is that the therapy may turn out not to have the benefit predicted by a surrogate, e.g. the drug is licensed and made available based to patients based on evidence of a reduction in tumour size (compared to placebo) but turns out not to improve (or even worsen) patient mortality.
It is therefore recommended that trials using surrogate endpoints only use endpoints that have been proven ('validated') to predict patient centred outcomes. However, this infrequently seems to happen in practice leading to potential misleading conclusions drawn from published studies. Therefore, better reporting is needed. Improving the reporting of trials with surrogate endpoints as its outcome will add value to the existing extensions to SPIRIT and CONSORT Standards.
WHAT WE PLAN TO DO: We will adopt similar methods as used previously to develop SPIRIT and CONSORT main statements and extensions. We have already conducted a scoping review of the literature that we will use to draw up a long list of items that we consider may be useful in reporting surrogate endpoints trials. We will then conduct a Delphi, a quantitative method aimed at generating consensus comprising (1) an online survey, and (2) a virtual consensus meeting. For the online survey, we will contact stakeholders including clinical trials researchers with experience in the design/conduct/analysis/reporting of surrogate endpoints trials, knowledge users, representatives from funding bodies, journal editors, and patient and public involvement representatives. We will identify individuals from relevant publications and through our extensive research networks.
The final phase of the study involves writing and disseminating SPIRIT and CONSORT extension guidance and checklists, and an 'Explanation and Elaboration' document that provides a more detailed guide of how to use the checklists, and examples of protocol and trial reporting good practice. One of the study group who has extensive experience in acting as lay contributor to trial methodological research has been involved in writing of this application and will help us ensure public involvement in our study, if funded.
BENEFITS OF THE STUDY: CONSORT and SPIRIT extensions for surrogate primary endpoints will aid in critical appraisal and interpretation for grant reviewers, funding bodies, trial methodologists, journal editors, reviewers, and readers (including patients and members of the public). The outputs of this research are expected to reduce incomplete, unclear, or inaccurate reporting of protocols and trials assessing surrogate endpoints thus limiting erroneous conclusions about the long-term safety and efficacy of treatments.

Consolidated Standards of Reporting Trials (CONSORT) and Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) reporting standards improve completeness and transparency of research. Trials reporting a primary endpoint that is a surrogate endpoint require additional consideration in their design, analysis, and interpretation, not included in standard SPIRIT/CONSORT statements.

This study aims to improve reporting of randomised trials with a surrogate primary endpoint by developing extensions to CONSORT/SPIRIT statements. We have already undertaken a scoping literature review and we also conduct an online Delphi survey and consensus meeting of stakeholders including trials researchers, knowledge users, research funders, journal editors, and patient and public involvement representatives. We will then, produce and disseminate extension checklists and associated explanatory documents.

The scoping review will inform an initial list of items related to reporting design, conduct and analysis of surrogate endpoint trials. We anticipate invitation of ~200 participants to take part in Delphi study who will rate importance of each item on the provisional list for inclusion in guidance statements. As the Delphi process is an iterative one, results from earlier round will inform the design of subsequent round, with modifications to the checklists between rounds. Following completion of the process, items taken forward will be presented and voted on for inclusion in final checklists for SPIRIT and CONSORT extensions for trials with a primary surrogate endpoint in a virtual consensus meeting.

We will produce and extensively disseminate the extensions and supporting materials widely through communication with the public, publication, presentation at conferences and workshops, and free availability on the Equator Network and CONSORT/SPIRIT websites.