Interpretation of SPIRIT-Surrogate and CONSORT-Surrogate reporting guidelines for surrogate endpoints in randomized controlled trials_Chinese Journal of Evidence-Based Medicine

Authors：

CHEN Jiahui ¹ , WANG Ziyi ² , LI Jieyun ³ , ZHANG Qiang ⁴ , WANG Haibo ⁵ , DENG Xiuxiu ⁶ ,  WANG Zhida ¹ ,  LU Cuncun ⁷

1. The First Hospital of Lanzhou University, Clinical Skills Training Center, Lanzhou 730000, P. R. China;
2. Evidence-Based Social Science Research Center, School of Public Health, Lanzhou University, Lanzhou 730000, P. R. China;
3. School of Basic Medical Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, P. R. China;
4. The First Affiliated Hospital of Henan University of CM, Zhengzhou 450000, P. R. China;
5. Department of Critical Care Medicine, Affiliated Hospital of Gansu University of Chinese Medicine, Lanzhou 730000, P. R. China;
6. Central Laboratory, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610075, P. R. China;
7. Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing 100700, P. R. China;

Corresponding author：

WANG Zhida, Email: m13609305077@163.com; LU Cuncun, Email: lu17metrics@163.com

Keywords：

Surrogate outcome; Randomized controlled trial; SPIRIT-Surrogate; CONSORT-Surrogate; Reporting guidelines

DOI：

10.7507/1672-2531.202407162

Video：

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Surrogate endpoints, defined as biomarkers or intermediate outcomes utilized in clinical trials to replace the ultimate targeted outcomes, have witnessed a growing prevalence in both clinical trials and drug-device approvals in recent years. To standardize the application and reporting of surrogate endpoints in clinical trial protocols and associated studies, relevant scholars published the SPIRIT-Surrogate and CONSORT-Surrogate reporting guidelines in the BMJ in July 2024. This article provides an interpretation of these guidelines in conjunction with published case studies, with the aim of offering references for domestic researchers, elevating the overall quality of related clinical trials, and eventually facilitating the enhancement of domestic healthcare level.

1.	Ciani O, Manyara AM, Davies P, et al. A framework for the definition and interpretation of the use of surrogate endpoints in interventional trials. EClinicalMedicine, 2023, 65: 102283.
2.	Manyara AM, Davies P, Stewart D, et al. Definitions, acceptability, limitations, and guidance in the use and reporting of surrogate end points in trials: a scoping review. J Clin Epidemiol, 2023, 160: 83-99,160-183.
3.	孙宇昕, 魏芬芳, 杨悦. 美国FDA药品审评中替代终点开发与应用. 中国药学杂志, 2017, 52(5): 414-419.
4.	Martini A, Gandaglia G, Briganti A. Evidence-based urology: surrogate endpoints - for. Eur Urol Focus, 2021, 7(6): 1217-1218.
5.	Wallach JD, Yoon S, Doernberg H, et al. Associations between surrogate markers and clinical outcomes for nononcologic chronic disease treatments. JAMA, 2024, 331(19): 1646-1654.
6.	Maeda H, Shingai R, Takeda K, et al. Assessment of surrogate end point trends in clinical trials to approve oncology drugs from 2001 to 2020 in Japan. JAMA Netw Open, 2023, 6(4): e238875.
7.	Hidano D, Dhruva SS, Redberg RF. US Food and Drug Administration-mandated postmarketing studies for high-risk cardiovascular devices approved 2015-2019. JAMA Intern Med, 2022, 182(5): 556-558.
8.	McAlpine K, Lavallée LT, Breau RH. Evidence-based urology: surrogate endpoints - con. Eur Urol Focus, 2021, 7(6): 1219-1221.
9.	Christensen R, Ciani O, Manyara AM, et al. Surrogate endpoints: a key concept in clinical epidemiology. J Clin Epidemiol, 2024, 167: 111242.
10.	Ecker BL, Lee J, Saadat LV, et al. Recurrence-free survival versus overall survival as a primary endpoint for studies of resected colorectal liver metastasis: a retrospective study and meta-analysis. Lancet Oncol, 2022, 23(10): 1332-1342.
11.	Moher D, Schulz KF, Simera I, et al. Guidance for developers of health research reporting guidelines. PLoS Med, 2010, 7(2): e1000217.
12.	杨丰文, 季昭臣, 张明妍, 等. 中医药临床研究浪费原因及对策. 中国循证医学杂志, 2018, 18(11): 1212-1215.
13.	Schulz KF, Altman DG, Moher D, et al. CONSORT 2010 statement: updated guidelines for reporting parallel group randomised trials. BMJ, 2010, 340: c332.
14.	Chan AW, Tetzlaff JM, Gøtzsche PC, et al. SPIRIT 2013 explanation and elaboration: guidance for protocols of clinical trials. BMJ, 2013, 346: e7586.
15.	魏旭煦, 刘岩, 胡嘉元, 等. 多臂平行对照随机临床试验报告规范: CONSORT2010声明扩展版. 中国循证医学杂志, 2021, 21(2): 231-240.
16.	卢存存, 张强, 雷超, 等. 使用队列和常规收集数据开展随机对照试验的报告清单(CONSORT-ROUTINE2021)解读. 中国循证医学杂志, 2022, 22(6): 731-738.
17.	Manyara AM, Davies P, Stewart D, et al. Reporting of surrogate endpoints in randomised controlled trial protocols (SPIRIT-Surrogate): extension checklist with explanation and elaboration. BMJ, 2024, 386: e078525.
18.	Manyara AM, Davies P, Stewart D, et al. Reporting of surrogate endpoints in randomised controlled trial reports (CONSORT-Surrogate): extension checklist with explanation and elaboration. BMJ, 2024, 386: e078524.
19.	赵晶晶, 龙泳, 刘学东. 2013临床试验方案规范指南(SPIRIT)及其解读. 中国循证儿科杂志, 2014, 9(5): 381-388.
20.	刘玉秀, 成琪, 刘丽霞. 2010版CONSORT声明: 平行组随机试验报告的新指南. 中国临床药理学与治疗学, 2010, 15(10): 1189-1194.
21.	Becker S, Schnitzler R, Rembecki M, et al. Individualized flow-controlled versus conventional pressure-controlled ventilation in on-pump heart surgery (FLOWVENTIN HEARTSURG): study protocol for a randomized controlled trial. Trials, 2023, 24(1): 195.
22.	Oughton JB, Collett L, Howard DR, et al. GA101 (obinutuzumab) monocLonal antibody as consolidation therapy in CLL (GALACTIC) trial: study protocol for a phase II/III randomised controlled trial. Trials, 2017, 18(1): 353.
23.	Wright ME, Delacroix E, Sonneville KR, et al. Reducing paediatric overweight and obesity through motivational interviewing: study protocol for a randomised controlled trial in the AAP PROS research network. BMJ Open, 2020, 10(7): e035720.
24.	Lioufas N, Toussaint ND, Pedagogos E, et al. Can we IMPROVE cardiovascular outcomes through phosphate lowering in CKD. Rationale and protocol for the IMpact of Phosphate Reduction On Vascular End-points in Chronic Kidney Disease (IMPROVE-CKD) study. BMJ Open, 2019, 9(2): e024382.
25.	Frampton R, Snaith JR, Hocking S, et al. Reducing cardiometabolic risk with semaglutide in type 1 diabetes (RESET1): study protocol of a phase 2 double-blinded randomised placebo-controlled trial. Diabet Med, 2024, 41(10): e15377.
26.	Jones A, Muller P, Dore CJ, et al. Belimumab after B cell depletion therapy in patients with systemic lupus erythematosus (BEAT Lupus) protocol: a prospective multicentre, double-blind, randomised, placebo-controlled, 52-week phase II clinical trial. BMJ Open, 2019, 9(12): e032569.
27.	Gwee A, Cranswick N, Donath SM, et al. Protocol for a randomised controlled trial of continuous infusions of vancomycin to improve the attainment of target vancomycin levels in young infants: the VANC trial. BMJ Open, 2018, 8(11): e022603.
28.	Koshizaka M, Ishikawa K, Ishikawa T, et al. Efficacy and safety of ipragliflozin and metformin for visceral fat reduction in patients with type 2 diabetes receiving treatment with dipeptidyl peptidase-4 inhibitors in Japan: a study protocol for a prospective, multicentre, blinded-endpoint phase IV randomised controlled trial (PRIME-V study). BMJ Open, 2017, 7(5): e015766.
29.	Shao ZX, He W, He SQ, et al. A 3D navigation template for guiding a unilateral lumbar pedicle screw with contralateral translaminar facet screw fixation: a study protocol for multicentre randomised controlled trials. BMJ Open, 2017, 7(7): e016328.
30.	Rocca B, Tosetto A, Petrucci G, et al. Long-term pharmacodynamic and clinical effects of twice- versus once-daily low-dose aspirin in essential thrombocythemia: the ARES trial. Am J Hematol, 2024, 99(8): 1462-1474.
31.	Waki K, Nara M, Enomoto S, et al. Effectiveness of DialBetesPlus, a self-management support system for diabetic kidney disease: Randomized controlled trial. NPJ Digit Med, 2024, 7(1): 104.
32.	Howard BV, Roman MJ, Devereux RB, et al. Effect of lower targets for blood pressure and LDL cholesterol on atherosclerosis in diabetes: the SANDS randomized trial. JAMA, 2008, 299(14): 1678-1689.
33.	Azizi M, Sanghvi K, Saxena M, et al. Ultrasound renal denervation for hypertension resistant to a triple medication pill (RADIANCE-HTN TRIO): a randomised, multicentre, single-blind, sham-controlled trial. Lancet, 2021, 397(10293): 2476-2486.
34.	Shah SJ, Voors AA, McMurray JJV, et al. Effect of neladenoson bialanate on exercise capacity among patients with heart failure with preserved ejection fraction: a randomized clinical trial. JAMA, 2019, 321(21): 2101-2112.
35.	彭菊聪, 孙甜甜, 李伦, 等. 复合终点. 中国循证儿科杂志, 2012, 7(4): 305-307.
36.	Palileo-Villanueva LM, Dans AL. Composite endpoints. J Clin Epidemiol, 2020, 128: 157-158.
37.	Parekh DJ, Reis IM, Castle EP, et al. Robot-assisted radical cystectomy versus open radical cystectomy in patients with bladder cancer (RAZOR): an open-label, randomised, phase 3, non-inferiority trial. Lancet, 2018, 391(10139): 2525-2536.
38.	Savarirayan R, Tofts L, Irving M, et al. Once-daily, subcutaneous vosoritide therapy in children with achondroplasia: a randomised, double-blind, phase 3, placebo-controlled, multicentre trial. Lancet, 2020, 396(10252): 684-692.
39.	杨莉, 韦彦伊, 吴迪, 等. 美国和欧盟基于替代终点的新药上市审批程序研究及启示. 中国新药杂志, 2022, 31(2): 132-141.
40.	黄慧瑶, 俞悦, 郭兰伟, 等. 抗肿瘤新药关键注册试验主要终点选择及考量. 中国肿瘤临床, 2022, 49(5): 244-248.
41.	Gharzai LA, Jiang R, Jaworski EM, et al. Meta-analysis of candidate surrogate end points in advanced prostate cancer. NEJM Evid, 2023, 2(4): EVIDoa2200195.
42.	宋嘉麒. 基于多个临床试验的纵向替代终点评价方法研究及应用. 上海: 海军军医大学, 2023.
43.	von Niederhäusern B, Guyatt GH, Briel M, et al. Academic response to improving value and reducing waste: a comprehensive framework for INcreasing QUality In patient-oriented academic clinical REsearch (INQUIRE). PLoS Med, 2018, 15(6): e1002580.

1. Ciani O, Manyara AM, Davies P, et al. A framework for the definition and interpretation of the use of surrogate endpoints in interventional trials. EClinicalMedicine, 2023, 65: 102283.
2. Manyara AM, Davies P, Stewart D, et al. Definitions, acceptability, limitations, and guidance in the use and reporting of surrogate end points in trials: a scoping review. J Clin Epidemiol, 2023, 160: 83-99,160-183.
3. 孙宇昕, 魏芬芳, 杨悦. 美国FDA药品审评中替代终点开发与应用. 中国药学杂志, 2017, 52(5): 414-419.
4. Martini A, Gandaglia G, Briganti A. Evidence-based urology: surrogate endpoints - for. Eur Urol Focus, 2021, 7(6): 1217-1218.
5. Wallach JD, Yoon S, Doernberg H, et al. Associations between surrogate markers and clinical outcomes for nononcologic chronic disease treatments. JAMA, 2024, 331(19): 1646-1654.
6. Maeda H, Shingai R, Takeda K, et al. Assessment of surrogate end point trends in clinical trials to approve oncology drugs from 2001 to 2020 in Japan. JAMA Netw Open, 2023, 6(4): e238875.
7. Hidano D, Dhruva SS, Redberg RF. US Food and Drug Administration-mandated postmarketing studies for high-risk cardiovascular devices approved 2015-2019. JAMA Intern Med, 2022, 182(5): 556-558.
8. McAlpine K, Lavallée LT, Breau RH. Evidence-based urology: surrogate endpoints - con. Eur Urol Focus, 2021, 7(6): 1219-1221.
9. Christensen R, Ciani O, Manyara AM, et al. Surrogate endpoints: a key concept in clinical epidemiology. J Clin Epidemiol, 2024, 167: 111242.
10. Ecker BL, Lee J, Saadat LV, et al. Recurrence-free survival versus overall survival as a primary endpoint for studies of resected colorectal liver metastasis: a retrospective study and meta-analysis. Lancet Oncol, 2022, 23(10): 1332-1342.
11. Moher D, Schulz KF, Simera I, et al. Guidance for developers of health research reporting guidelines. PLoS Med, 2010, 7(2): e1000217.
12. 杨丰文, 季昭臣, 张明妍, 等. 中医药临床研究浪费原因及对策. 中国循证医学杂志, 2018, 18(11): 1212-1215.
13. Schulz KF, Altman DG, Moher D, et al. CONSORT 2010 statement: updated guidelines for reporting parallel group randomised trials. BMJ, 2010, 340: c332.
14. Chan AW, Tetzlaff JM, Gøtzsche PC, et al. SPIRIT 2013 explanation and elaboration: guidance for protocols of clinical trials. BMJ, 2013, 346: e7586.
15. 魏旭煦, 刘岩, 胡嘉元, 等. 多臂平行对照随机临床试验报告规范: CONSORT2010声明扩展版. 中国循证医学杂志, 2021, 21(2): 231-240.
16. 卢存存, 张强, 雷超, 等. 使用队列和常规收集数据开展随机对照试验的报告清单(CONSORT-ROUTINE2021)解读. 中国循证医学杂志, 2022, 22(6): 731-738.
17. Manyara AM, Davies P, Stewart D, et al. Reporting of surrogate endpoints in randomised controlled trial protocols (SPIRIT-Surrogate): extension checklist with explanation and elaboration. BMJ, 2024, 386: e078525.
18. Manyara AM, Davies P, Stewart D, et al. Reporting of surrogate endpoints in randomised controlled trial reports (CONSORT-Surrogate): extension checklist with explanation and elaboration. BMJ, 2024, 386: e078524.
19. 赵晶晶, 龙泳, 刘学东. 2013临床试验方案规范指南(SPIRIT)及其解读. 中国循证儿科杂志, 2014, 9(5): 381-388.
20. 刘玉秀, 成琪, 刘丽霞. 2010版CONSORT声明: 平行组随机试验报告的新指南. 中国临床药理学与治疗学, 2010, 15(10): 1189-1194.
21. Becker S, Schnitzler R, Rembecki M, et al. Individualized flow-controlled versus conventional pressure-controlled ventilation in on-pump heart surgery (FLOWVENTIN HEARTSURG): study protocol for a randomized controlled trial. Trials, 2023, 24(1): 195.
22. Oughton JB, Collett L, Howard DR, et al. GA101 (obinutuzumab) monocLonal antibody as consolidation therapy in CLL (GALACTIC) trial: study protocol for a phase II/III randomised controlled trial. Trials, 2017, 18(1): 353.
23. Wright ME, Delacroix E, Sonneville KR, et al. Reducing paediatric overweight and obesity through motivational interviewing: study protocol for a randomised controlled trial in the AAP PROS research network. BMJ Open, 2020, 10(7): e035720.
24. Lioufas N, Toussaint ND, Pedagogos E, et al. Can we IMPROVE cardiovascular outcomes through phosphate lowering in CKD. Rationale and protocol for the IMpact of Phosphate Reduction On Vascular End-points in Chronic Kidney Disease (IMPROVE-CKD) study. BMJ Open, 2019, 9(2): e024382.
25. Frampton R, Snaith JR, Hocking S, et al. Reducing cardiometabolic risk with semaglutide in type 1 diabetes (RESET1): study protocol of a phase 2 double-blinded randomised placebo-controlled trial. Diabet Med, 2024, 41(10): e15377.
26. Jones A, Muller P, Dore CJ, et al. Belimumab after B cell depletion therapy in patients with systemic lupus erythematosus (BEAT Lupus) protocol: a prospective multicentre, double-blind, randomised, placebo-controlled, 52-week phase II clinical trial. BMJ Open, 2019, 9(12): e032569.
27. Gwee A, Cranswick N, Donath SM, et al. Protocol for a randomised controlled trial of continuous infusions of vancomycin to improve the attainment of target vancomycin levels in young infants: the VANC trial. BMJ Open, 2018, 8(11): e022603.
28. Koshizaka M, Ishikawa K, Ishikawa T, et al. Efficacy and safety of ipragliflozin and metformin for visceral fat reduction in patients with type 2 diabetes receiving treatment with dipeptidyl peptidase-4 inhibitors in Japan: a study protocol for a prospective, multicentre, blinded-endpoint phase IV randomised controlled trial (PRIME-V study). BMJ Open, 2017, 7(5): e015766.
29. Shao ZX, He W, He SQ, et al. A 3D navigation template for guiding a unilateral lumbar pedicle screw with contralateral translaminar facet screw fixation: a study protocol for multicentre randomised controlled trials. BMJ Open, 2017, 7(7): e016328.
30. Rocca B, Tosetto A, Petrucci G, et al. Long-term pharmacodynamic and clinical effects of twice- versus once-daily low-dose aspirin in essential thrombocythemia: the ARES trial. Am J Hematol, 2024, 99(8): 1462-1474.
31. Waki K, Nara M, Enomoto S, et al. Effectiveness of DialBetesPlus, a self-management support system for diabetic kidney disease: Randomized controlled trial. NPJ Digit Med, 2024, 7(1): 104.
32. Howard BV, Roman MJ, Devereux RB, et al. Effect of lower targets for blood pressure and LDL cholesterol on atherosclerosis in diabetes: the SANDS randomized trial. JAMA, 2008, 299(14): 1678-1689.
33. Azizi M, Sanghvi K, Saxena M, et al. Ultrasound renal denervation for hypertension resistant to a triple medication pill (RADIANCE-HTN TRIO): a randomised, multicentre, single-blind, sham-controlled trial. Lancet, 2021, 397(10293): 2476-2486.
34. Shah SJ, Voors AA, McMurray JJV, et al. Effect of neladenoson bialanate on exercise capacity among patients with heart failure with preserved ejection fraction: a randomized clinical trial. JAMA, 2019, 321(21): 2101-2112.
35. 彭菊聪, 孙甜甜, 李伦, 等. 复合终点. 中国循证儿科杂志, 2012, 7(4): 305-307.
36. Palileo-Villanueva LM, Dans AL. Composite endpoints. J Clin Epidemiol, 2020, 128: 157-158.
37. Parekh DJ, Reis IM, Castle EP, et al. Robot-assisted radical cystectomy versus open radical cystectomy in patients with bladder cancer (RAZOR): an open-label, randomised, phase 3, non-inferiority trial. Lancet, 2018, 391(10139): 2525-2536.
38. Savarirayan R, Tofts L, Irving M, et al. Once-daily, subcutaneous vosoritide therapy in children with achondroplasia: a randomised, double-blind, phase 3, placebo-controlled, multicentre trial. Lancet, 2020, 396(10252): 684-692.
39. 杨莉, 韦彦伊, 吴迪, 等. 美国和欧盟基于替代终点的新药上市审批程序研究及启示. 中国新药杂志, 2022, 31(2): 132-141.
40. 黄慧瑶, 俞悦, 郭兰伟, 等. 抗肿瘤新药关键注册试验主要终点选择及考量. 中国肿瘤临床, 2022, 49(5): 244-248.
41. Gharzai LA, Jiang R, Jaworski EM, et al. Meta-analysis of candidate surrogate end points in advanced prostate cancer. NEJM Evid, 2023, 2(4): EVIDoa2200195.
42. 宋嘉麒. 基于多个临床试验的纵向替代终点评价方法研究及应用. 上海: 海军军医大学, 2023.
43. von Niederhäusern B, Guyatt GH, Briel M, et al. Academic response to improving value and reducing waste: a comprehensive framework for INcreasing QUality In patient-oriented academic clinical REsearch (INQUIRE). PLoS Med, 2018, 15(6): e1002580.

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Latest ArticlesInterpretation of SPIRIT-Surrogate and CONSORT-Surrogate reporting guidelines for surrogate endpoints in randomized controlled trials

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