Table 1.
Surrogate endpoint definitions identified by scoping review and e-Delphi rating.
| Source (year) | Definition | Scoping review citations | e-Delphi rating |
Summary of free-text comments | |||
|---|---|---|---|---|---|---|---|
| Median (IQR) | % of rating scores |
||||||
| 1–3 | 4–6 | 7–9 | |||||
| Prentice (1989)33 | A response variable for which a test of the null hypothesis of no relationship to the treatment groups under comparison is also a valid test of the corresponding null hypothesis based on the true endpoint. | 6 (19%) records | 5 (3, 6) | 29.6 | 58.6 | 11.7 | Complex and statistical definition with limited usability in trial design—see comments of Definition 3 in Appendix. |
| Temple (1999)34 | A laboratory measurement or physical sign that is used in therapeutic trials as a substitute for a clinically meaningful end point that is a direct measure of how a patient feels, functions, or survives and is expected to predict the effect of the therapy | 10 (31%) | 7 (5, 7) | 11.6 | 31.4 | 57.0 | Not inclusive as a surrogate endpoint extends beyond laboratory measurements and signs and their use is beyond therapeutic trials—see comments of Definition 2 in Appendix |
| NIH Biomarkers Definitions Working Group (2001)35 | A biomarker that is intended to substitute for a clinical endpoint. A surrogate endpoint is expected to predict clinical benefit (or harm or lack of benefit or harm) based on epidemiologic, therapeutic, pathophysiologic, or other scientific evidence. | 12 (38%) | 7 (6,7) | 11.0 | 31.8 | 57.2 | Not inclusive as surrogate endpoints extend beyond biomarkers and clinical benefit measured could still be a surrogate endpoint—see comments of Definition 1 in Appendix |
| BEST (2016)6 | An endpoint that is used in clinical trials as a substitute for a direct measure of how a patient feels; functions; or survives. A surrogate endpoint does not measure the clinical benefit of primary interest in and of itself; but rather is expected to predict that clinical benefit or harm based on epidemiologic; therapeutic; pathophysiologic; or other scientific evidence. | 3 (9%) | 8 (7, 9) | 0.6 | 7.0 | 92.4 | A comprehensive definition although use of ‘predict’ implies a validated surrogate endpoint—see comments of Definition 4 in Appendix |
| Ciani et al. (2017)11 | A biomarker or intermediate outcome used to substitute for a patient or participant relevant final outcome (i.e., severe morbidity; health related quality of life or mortality) and reliably predicts benefit or harm based on epidemiologic; therapeutic; pathophysiologic; or other scientific evidence | Not applicablea | 8 (7, 8) | 2.3 | 14.0 | 83.6 | Support for inclusion of intermediate outcome in definition; however, there is limited understanding of ‘intermediate outcome’; not all trials seek to evaluate interventions based on severe morbidity, health related quality of life or death; and ‘predict’ implies a validated surrogate endpoint—see comments of Definition 5 in Appendix |
| Banff Workshop (2022)25 | An endpoint replacing a clinical endpoint that constitutes a basis for reliably predicting a treatment effect on the clinical endpoint in a defined context of use. | Not applicablea | 7 (5.5, 8) | 7.8 | 33.5 | 58.7 | No comments received |
NIH: National Institutes of Health; BEST: Biomarkers, Endpoints, and other Tool.
a
Not identified in the scoping review; Bold highlighted; consensus reached; Italic highlighted: consensus not reached.