Surrogate endpoint: definition evolution, evaluation and validation_Chinese Journal of Evidence-Based Medicine

Authors：

CHENG Yifan ^1,2 , LONG Youlin ^1,2 , YANG Liu ^1,2 , WANG Xinyi ^1,2 , GUO Qiong ² , LIN Yifei ² ,  DU Liang ^1,3 ,  HUANG Jin ²

1. Chinese Evidence-Based Medicine Centre, West China Hospital, Sichuan University, Chengdu 610041, P. R. China;
2. Medical Device Regulatory Research and Evaluation Centre, West China Hospital, Sichuan University, Chengdu 610041, P. R. China;
3. West China Medical Publishers, West China Hospital, Sichuan University, Chengdu 610041, P. R. China;

Corresponding author：

DU Liang, Email: duliang0606@vip.sina.com; HUANG Jin, Email: michael_huangjin@163.com

Keywords：

Surrogate endpoint; Definition evolution; Evaluation and validation methods; Information-theoretic approach

DOI：

10.7507/1672-2531.202204116

Video：

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A surrogate endpoint is intended to substitute for a clinical endpoint and is expected to predict the effect of the intervention on clinical endpoints based on epidemiologic, diagnostic, and pathophysiologic evidence. A validated surrogate endpoint can reduce sample size and follow-up duration of clinical trials; hence, the evaluation and validation methods of surrogate endpoints have been discussed for more than 30 years around the world. This paper comprehensively introduced the definition evolution, evaluation, and validation methods of surrogate endpoints, and provided references for future research.

Citation： CHENG Yifan, LONG Youlin, YANG Liu, WANG Xinyi, GUO Qiong, LIN Yifei, DU Liang, HUANG Jin. Surrogate endpoint: definition evolution, evaluation and validation. Chinese Journal of Evidence-Based Medicine, 2022, 22(8): 964-970. doi: 10.7507/1672-2531.202204116 Copy

1.	Wood PH. Where are we now with radiographic assessment of rheumatoid arthritis? Br J Rheumatol, 1983, 22(Suppl 3): 24-33.
2.	Ciani O, Grigore B, Blommestein H, et al. Validity of surrogate endpoints and their impact on coverage recommendations: a retrospective analysis across international health technology assessment agencies. Med Decis Making, 2021, 41(4): 439-452.
3.	Pedrazzi V, Figueiredo FAT, Adami LE, et al. Surrogate endpoints: when to use and when not to use. A critical appraisal of current evidences. Braz Oral Res, 2020, 34(Suppl 2): e074.
4.	Herson J. The use of surrogate endpoints in clinical trials (an introduction to a series of four papers). Stat Med, 1989, 8(4): 403-404.
5.	Ellenberg S, Hamilton JM. Surrogate endpoints in clinical trials: cancer. Stat Med, 1989, 8(4): 405-413.
6.	Wittes J, Lakatos E, Probstfield J. Surrogate endpoints in clinical trials: cardiovascular diseases. Stat Med, 1989, 8(4): 415-425.
7.	Hillis A, Seigel D. Surrogate endpoints in clinical trials: ophthalmologic disorders. Stat Med, 1989, 8(4): 427-430.
8.	Prentice RL. Surrogate endpoints in clinical trials: definition and operational criteria. Stat Med, 1989, 8(4): 431-440.
9.	Spilker B. Surrogate endpoints. In guide to clinical trials. New York: Raven Press, 1991.
10.	Boissel JP, Collet JP, Moleur P, et al. Surrogate endpoints: a basis for a rational approach. Eur J Clin Pharmacol, 1992, 43(3): 235-244.
11.	FDA. Food and drug administration modernization act (FDAMA) of 1997. Available at:https://www.docin.com/p-1775124407.html.
12.	NIH-FDA Conference. Biomarkers and surrogate endpoints: advancing clinical research and applications. abstracts. Dis Markers, 1998, 14(4): 187-334.
13.	Temple R. Are surrogate markers adequate to assess cardiovascular disease drugs. JAMA, 1999, 282(8): 790-795.
14.	Grimes DA, Schulz KF. Surrogate end points in clinical research: hazardous to your health. Obstet Gynecol, 2005, 105(5 Pt 1): 1114-1118.
15.	Baker SG. A simple meta-analytic approach for using a binary surrogate endpoint to predict the effect of intervention on true endpoint. Biostatistics, 2006, 7(1): 58-70.
16.	Gluud C, Brok J, Gong Y, et al. Hepatology may have problems with putative surrogate outcome measures. J Hepatol, 2007, 46(4): 734-742.
17.	Pryseley A, Tilahun A, Alonso A, et al. Information-theory based surrogate marker evaluation from several randomized clinical trials with continuous true and binary surrogate endpoints. Clin Trials, 2007, 4(6): 587-597.
18.	Institute of Medicine Committee on Qualification of B, Surrogate Endpoints in Chronic D. Evaluation of biomarkers and surrogate endpoints in chronic disease. Washington (DC): National Academies Press (US), 2010.
19.	FBW Group. BEST (biomarkers, endpoints, and other tools) resource, 2016. Available at: https://www.mendeley.com/catalogue/7268de67-5e7e-38bf-a771-fc9746f9e01f/.
20.	Fleming TR. Surrogate endpoints and FDA's accelerated approval process. Health Aff (Millwood), 2005, 24(1): 67-78.
21.	Parast L, Tian L, Cai T. Assessing the value of a censored surrogate outcome. Lifetime Data Anal, 2020, 26(2): 245-265.
22.	Freedman LS, Graubard BI, Schatzkin A. Statistical validation of intermediate endpoints for chronic diseases. Stat Med, 1992, 11(2): 167-178.
23.	Deprimo SE, Huang X, Blackstein ME, et al. Circulating levels of soluble KIT serve as a biomarker for clinical outcome in gastrointestinal stromal tumor patients receiving sunitinib following imatinib failure. Clin Cancer Res, 2009, 15(18): 5869-5877.
24.	Halabi S, Armstrong AJ, Sartor O, et al. Prostate-specific antigen changes as surrogate for overall survival in men with metastatic castration-resistant prostate cancer treated with second-line chemotherapy. J Clin Oncol, 2013, 31(31): 3944-3950.
25.	Medeiros FA, Lisboa R, Zangwill LM, et al. Evaluation of progressive neuroretinal rim loss as a surrogate end point for development of visual field loss in glaucoma. Ophthalmology, 2014, 121(1): 100-109.
26.	Buyse M, Molenberghs G. Criteria for the validation of surrogate endpoints in randomized experiments. Biometrics, 1998, 54(3): 1014-1029.
27.	Molenberghs G, Buyse M, Geys H, et al. Statistical challenges in the evaluation of surrogate endpoints in randomized trials. Control Clin Trials, 2002, 23(6): 607-625.
28.	Buyse M, Molenberghs G, Burzykowski T, et al. The validation of surrogate endpoints in meta-analyses of randomized experiments. Biostatistics, 2000, 1(1): 49-67.
29.	Tibaldi F, Abrahantes JC, Molenberghs G, et al. Simplified hierarchical linear models for the evaluation of surrogate endpoints. J Stat Comput Sim, 2003, 73(9): 643-658.
30.	Xie W, Halabi S, Tierney JF, et al. A systematic review and recommendation for reporting of surrogate endpoint evaluation using meta-analyses. JNCI Cancer Spectr, 2019, 3(1): pkz002.
31.	Conforti F, Pala L, Sala I, et al. Evaluation of pathological complete response as surrogate endpoint in neoadjuvant randomised clinical trials of early stage breast cancer: systematic review and meta-analysis. BMJ, 2021, 375: e066381.
32.	Gion M, Pérez-García JM, Llombart-Cussac A, et al. Surrogate endpoints for early-stage breast cancer: a review of the state of the art, controversies, and future prospects. Ther Adv Med Oncol, 2021, 13: 17588359211059587.
33.	Hackshaw A, Knight A, Barrett-Lee P, et al. Surrogate markers and survival in women receiving first-line combination anthracycline chemotherapy for advanced breast cancer. Br J Cancer, 2005, 93(11): 1215-1221.
34.	Burzykowski T, Buyse M. Surrogate threshold effect: an alternative measure for meta-analytic surrogate endpoint validation. Pharm Stat, 2006, 5(3): 173-186.
35.	Johnson KR, Freemantle N, Anthony DM, et al. LDL-cholesterol differences predicted survival benefit in statin trials by the surrogate threshold effect (STE). J Clin Epidemiol, 2009, 62(3): 328-336.
36.	Shannon C. A mathematical theory of communication. Bell Sys Tech J, 1948, 27(379): 623-656.
37.	Alonso A, Molenberghs G. Surrogate marker evaluation from an information theory perspective. Biometrics, 2007, 63(1): 180-186.
38.	Dimier N, Todd S. Assessment of the information theory approach to evaluating time-to-event surrogate and true endpoints in a meta-analytic setting. Pharm Stat, 2021, 20(2): 335-347.
39.	Ensor H, Weir CJ. Separation and the information theory surrogate evaluation approach: a penalised likelihood solution. Pharm Stat, 2022, 21(1): 55-68.
40.	Meyvisch P, Kambili C, Andries K, et al. Evaluation of six months sputum culture conversion as a surrogate endpoint in a multidrug resistant-tuberculosis trial. PLoS One, 2018, 13(7): e0200539.

1. Wood PH. Where are we now with radiographic assessment of rheumatoid arthritis? Br J Rheumatol, 1983, 22(Suppl 3): 24-33.
2. Ciani O, Grigore B, Blommestein H, et al. Validity of surrogate endpoints and their impact on coverage recommendations: a retrospective analysis across international health technology assessment agencies. Med Decis Making, 2021, 41(4): 439-452.
3. Pedrazzi V, Figueiredo FAT, Adami LE, et al. Surrogate endpoints: when to use and when not to use. A critical appraisal of current evidences. Braz Oral Res, 2020, 34(Suppl 2): e074.
4. Herson J. The use of surrogate endpoints in clinical trials (an introduction to a series of four papers). Stat Med, 1989, 8(4): 403-404.
5. Ellenberg S, Hamilton JM. Surrogate endpoints in clinical trials: cancer. Stat Med, 1989, 8(4): 405-413.
6. Wittes J, Lakatos E, Probstfield J. Surrogate endpoints in clinical trials: cardiovascular diseases. Stat Med, 1989, 8(4): 415-425.
7. Hillis A, Seigel D. Surrogate endpoints in clinical trials: ophthalmologic disorders. Stat Med, 1989, 8(4): 427-430.
8. Prentice RL. Surrogate endpoints in clinical trials: definition and operational criteria. Stat Med, 1989, 8(4): 431-440.
9. Spilker B. Surrogate endpoints. In guide to clinical trials. New York: Raven Press, 1991.
10. Boissel JP, Collet JP, Moleur P, et al. Surrogate endpoints: a basis for a rational approach. Eur J Clin Pharmacol, 1992, 43(3): 235-244.
11. FDA. Food and drug administration modernization act (FDAMA) of 1997. Available at:https://www.docin.com/p-1775124407.html.
12. NIH-FDA Conference. Biomarkers and surrogate endpoints: advancing clinical research and applications. abstracts. Dis Markers, 1998, 14(4): 187-334.
13. Temple R. Are surrogate markers adequate to assess cardiovascular disease drugs. JAMA, 1999, 282(8): 790-795.
14. Grimes DA, Schulz KF. Surrogate end points in clinical research: hazardous to your health. Obstet Gynecol, 2005, 105(5 Pt 1): 1114-1118.
15. Baker SG. A simple meta-analytic approach for using a binary surrogate endpoint to predict the effect of intervention on true endpoint. Biostatistics, 2006, 7(1): 58-70.
16. Gluud C, Brok J, Gong Y, et al. Hepatology may have problems with putative surrogate outcome measures. J Hepatol, 2007, 46(4): 734-742.
17. Pryseley A, Tilahun A, Alonso A, et al. Information-theory based surrogate marker evaluation from several randomized clinical trials with continuous true and binary surrogate endpoints. Clin Trials, 2007, 4(6): 587-597.
18. Institute of Medicine Committee on Qualification of B, Surrogate Endpoints in Chronic D. Evaluation of biomarkers and surrogate endpoints in chronic disease. Washington (DC): National Academies Press (US), 2010.
19. FBW Group. BEST (biomarkers, endpoints, and other tools) resource, 2016. Available at: https://www.mendeley.com/catalogue/7268de67-5e7e-38bf-a771-fc9746f9e01f/.
20. Fleming TR. Surrogate endpoints and FDA's accelerated approval process. Health Aff (Millwood), 2005, 24(1): 67-78.
21. Parast L, Tian L, Cai T. Assessing the value of a censored surrogate outcome. Lifetime Data Anal, 2020, 26(2): 245-265.
22. Freedman LS, Graubard BI, Schatzkin A. Statistical validation of intermediate endpoints for chronic diseases. Stat Med, 1992, 11(2): 167-178.
23. Deprimo SE, Huang X, Blackstein ME, et al. Circulating levels of soluble KIT serve as a biomarker for clinical outcome in gastrointestinal stromal tumor patients receiving sunitinib following imatinib failure. Clin Cancer Res, 2009, 15(18): 5869-5877.
24. Halabi S, Armstrong AJ, Sartor O, et al. Prostate-specific antigen changes as surrogate for overall survival in men with metastatic castration-resistant prostate cancer treated with second-line chemotherapy. J Clin Oncol, 2013, 31(31): 3944-3950.
25. Medeiros FA, Lisboa R, Zangwill LM, et al. Evaluation of progressive neuroretinal rim loss as a surrogate end point for development of visual field loss in glaucoma. Ophthalmology, 2014, 121(1): 100-109.
26. Buyse M, Molenberghs G. Criteria for the validation of surrogate endpoints in randomized experiments. Biometrics, 1998, 54(3): 1014-1029.
27. Molenberghs G, Buyse M, Geys H, et al. Statistical challenges in the evaluation of surrogate endpoints in randomized trials. Control Clin Trials, 2002, 23(6): 607-625.
28. Buyse M, Molenberghs G, Burzykowski T, et al. The validation of surrogate endpoints in meta-analyses of randomized experiments. Biostatistics, 2000, 1(1): 49-67.
29. Tibaldi F, Abrahantes JC, Molenberghs G, et al. Simplified hierarchical linear models for the evaluation of surrogate endpoints. J Stat Comput Sim, 2003, 73(9): 643-658.
30. Xie W, Halabi S, Tierney JF, et al. A systematic review and recommendation for reporting of surrogate endpoint evaluation using meta-analyses. JNCI Cancer Spectr, 2019, 3(1): pkz002.
31. Conforti F, Pala L, Sala I, et al. Evaluation of pathological complete response as surrogate endpoint in neoadjuvant randomised clinical trials of early stage breast cancer: systematic review and meta-analysis. BMJ, 2021, 375: e066381.
32. Gion M, Pérez-García JM, Llombart-Cussac A, et al. Surrogate endpoints for early-stage breast cancer: a review of the state of the art, controversies, and future prospects. Ther Adv Med Oncol, 2021, 13: 17588359211059587.
33. Hackshaw A, Knight A, Barrett-Lee P, et al. Surrogate markers and survival in women receiving first-line combination anthracycline chemotherapy for advanced breast cancer. Br J Cancer, 2005, 93(11): 1215-1221.
34. Burzykowski T, Buyse M. Surrogate threshold effect: an alternative measure for meta-analytic surrogate endpoint validation. Pharm Stat, 2006, 5(3): 173-186.
35. Johnson KR, Freemantle N, Anthony DM, et al. LDL-cholesterol differences predicted survival benefit in statin trials by the surrogate threshold effect (STE). J Clin Epidemiol, 2009, 62(3): 328-336.
36. Shannon C. A mathematical theory of communication. Bell Sys Tech J, 1948, 27(379): 623-656.
37. Alonso A, Molenberghs G. Surrogate marker evaluation from an information theory perspective. Biometrics, 2007, 63(1): 180-186.
38. Dimier N, Todd S. Assessment of the information theory approach to evaluating time-to-event surrogate and true endpoints in a meta-analytic setting. Pharm Stat, 2021, 20(2): 335-347.
39. Ensor H, Weir CJ. Separation and the information theory surrogate evaluation approach: a penalised likelihood solution. Pharm Stat, 2022, 21(1): 55-68.
40. Meyvisch P, Kambili C, Andries K, et al. Evaluation of six months sputum culture conversion as a surrogate endpoint in a multidrug resistant-tuberculosis trial. PLoS One, 2018, 13(7): e0200539.

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