Expert consensus on problem-solving strategies for drug clinical trial design and implementation_Chinese Journal of Evidence-Based Medicine

Authors：

 Expert Consensus Group on Drug Clinical Trial Design and Implementation, Fuwai Hospital, Chinese Academy of Medical Sciences, National Center for Cardiovascular Diseases; Cardiovascular Clinical Research Group, Chinese Society of Cardiovascular Diseases

Corresponding author：

Expert Consensus Group on Drug Clinical Trial Design and Implementation, Fuwai Hospital, Chinese Academy of Medical Sciences, National Center for Cardiovascular Diseases; Cardiovascular Clinical Research Group, Chinese Society of Cardiovascular Diseases, Email: jing.li@fwoxford.org

Keywords：

Clinical trial design; Clinical trial implementation; Difficult problem; Expert consensus

DOI：

10.7507/1672-2531.202109156

Video：

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Clinical trials are the most reliable means for scientifically rigorous evaluation of the efficacy and safety of drugs, and are the most crucial part receiving the most investment in development and innovation in the pharmaceutical industry. In recent years, the nation has formulated a set of policies and guiding principles to encourage pharmaceutical innovation, promote the independent innovation of China’s pharmaceutical industry and enhance clinical trial capacity. To further improve Chinese researchers’ ability to perform clinical trials, the National Clinical Research Center for Cardiovascular Diseases, Fuwai Hospital, Chinese Academy of Medical Sciences and the National Center for Cardiovascular Diseases invited a multi-disciplinary team of experts from various areas including clinical trial methodology and supervision to work on this consensus. In view of the common concern and puzzles regarding the issues in clinical trials, such as recruitment and retention of participants, outcome selection, quality control, information technology application, and ethics in data security, the expert consensus is based on domestic and international guidelines, the latest advancement of clinical research, and the advice and opinions from national experts. It aims to provide reference information and guidance for clinical trial researchers, and serves as a reference for relevant authorities to formulate clinical trial management policies.

Citation： Expert Consensus Group on Drug Clinical Trial Design and Implementation, Fuwai Hospital, Chinese Academy of Medical Sciences, National Center for Cardiovascular Diseases; Cardiovascular Clinical Research Group, Chinese Society of Cardiovascular Diseases. Expert consensus on problem-solving strategies for drug clinical trial design and implementation. Chinese Journal of Evidence-Based Medicine, 2022, 22(3): 249-260. doi: 10.7507/1672-2531.202109156 Copy

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4.	Sommer C, Zuccolin D, Arnera V, et al. Building clinical trials around patients: Evaluation and comparison of decentralized and conventional site models in patients with low back pain. Contemp Clin Trials Commun, 2018, 11: 120-126.
5.	Lansey DG, Hefka TA, Carducci MA, et al. Problem solving to enhance clinical trial participation utilizing a framework-driven approach. Clin Adv Hematol Oncol, 2020, 18(8): 468-476.
6.	US Food and Drug Administration (FDA). Collection of race and ethnicity data in clinical trials: guidance for industry and food and drug Administration staff. Available at: https://www.fda.gov/media/75453/download.
7.	Torres S, de la Riva EE, Tom LS, et al. The development of a communication tool tofacilitate the cancer trial recruitment process and increase research literacy among underrepresented populations. J Cancer Educ, 2015, 30(4): 792-798.
8.	国家药品监督管理局, 国家卫生健康委. 国家药监局国家卫生健康委关于发布药物临床试验质量管理规范的公告(2020 年第 57 号). Available at: https://www.nmpa.gov.cn/xxgk/ggtg/qtggtg/20200426162401243.html.
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11.	European Medicines Agency (EMA). Guideline on multiplicity issues in clinical trials. Available at: https://www.ema.europa.eu/en/documents/scientific-guideline/draft-guideline-multiplicity-issues-clinical-trials_en.pdf.
12.	中华人民共和国中央人民政府. 国家药监局关于发布晚期非小细胞肺癌临床试验终点技术指导原则的通告(2019 年第 64 号). Available at: http://www.gov.cn/xinwen/2019-09/18/content_5430886.htm.
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17.	Baigent C, Herrington WG, Coresh J, et al. Challenges in conducting clinical trials in nephrology: conclusions from a Kidney Disease-Improving Global Outcomes (KDIGO) Controversies Conference. Kidney Int, 2017, 92(2): 297-305.
18.	Eapen ZJ, Lauer MS, Temple RJ. The imperative of overcoming barriers to the conduct of large, simple trials. JAMA, 2014, 311(14): 1397-1398.
19.	Baigent C, Landray MJ, Reith C, et al. The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): a randomised placebo-controlled trial. Lancet, 2011, 377(9784): 2181-2192.
20.	HPS2-THRIVE Collaborative Group, Landray MJ, Haynes R, et al. Effects of extended-release niacin with laropiprant in high-risk patients. N Engl J Med, 2014, 371(3): 203-212.
21.	REVEAL Collaborative Group, Bowman L, Chen F, et al. Randomized evaluation of the effects of anacetrapib through lipid-modification (REVEAL)-a large-scale, randomized, placebo-controlled trial of the clinical effects of anacetrapib among people with established vascular disease: Trial design, recruitment, and baseline characteristics. Am Heart J, 2017, 187: 182-190.
22.	US Food and Drug Administration (FDA). Guidance for industry. oversight of clinical investigations-a risk-based approach to monitoring. Available at: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/oversight-clinical-investigations-risk-based-approach-monitoring.
23.	Jones WS, Mulder H, Wruck LM, et al. Comparative effectiveness of aspirin dosing in cardiovascular disease. N Engl J Med, 2021, 384(21): 1981-1990.
24.	Inan OT, Tenaerts P, Prindiville SA, et al. Digitizing clinical trials. NPJ Digit Med, 2020, 3: 101.
25.	丁发明, 闫慧, 黄天娇. 对临床试验中运用远程智能技术的监管策略的科学建议. 中国食品药品监管, 2020, (11): 125-133.
26.	曹国英, 付海军, 何为, 等. 智能化临床研究专家共识. 中国新药与临床杂志, 2020, 39(6): 321-328.
27.	王海学, 王涛. 远程智能临床试验及数字化技术应用的探讨. 中国食品药品监管, 2020, (11): 110-116.
28.	国际医学科学组织理事会联合世界卫生组织. 涉及人的健康相关研究国际伦理准则2016. 上海: 上海交通大学出版社, 2016.
29.	国家卫生健康委医学伦理专家委员会办公室中国医院协会. 涉及人的临床研究伦理审查委员会建设指南(2020版)发布. Available at: https://www.163.com/dy/article/FQGE0J270514BKOA.html.
30.	中华人民共和国中央人民政府. 中华人民共和国人类遗传资源管理条例. Available at: http://www.gov.cn/zhengce/content/2019-06/10/content_5398829.htm.
31.	中华人民共和国中央人民政府. 中华人民共和国生物安全法. Available at: http://www.gov.cn/xinwen/2020-10/18/content_5552108.htm.
32.	中华人民共和国中央人民政府. 中华人民共和国保守国家秘密法. Available at: http://www.gov.cn/flfg/2010-04/30/content_1596420.htm.
33.	中华人民共和国中央人民政府. 中华人民共和国保守国家秘密法实施条例. Available at: http://www.gov.cn/zhengce/2020-12/27/content_5573752.htm.
34.	中共中央网络安全和信息化委员会办公室, 中华人民共和国国家互联网信息办公室. 中华人民共和国网络安全法. Available at: http://www.cac.gov.cn/2016-11/07/c_1119867116_3.htm.
35.	中华人民共和国国家卫生和计划生育委员会. 涉及人的生物医学研究伦理审查办法. Available at: http://www.nhc.gov.cn/fzs/s3576/201808/14ee8ab2388440c4a44ecce0f24e064c.shtml.
36.	全国信息安全标准化技术委员会. 信息安全技术个人信息安全规范. Available at: https://www.tc260.org.cn/front/postDetail.html?id=20180124211617.
37.	中华人民共和国中央人民政府. 中华人民共和国数据安全法. Available at: http://www.gov.cn/xinwen/2021-06/11/content_5616919.htm.
38.	国家药品监督管理局. 总局关于发布临床试验的电子数据采集技术指导原则的通告(2016年第114号). Available at: https://www.nmpa.gov.cn/xxgk/ggtg/qtggtg/20160729184001958.html.
39.	全国信息安全标准化技术委员会. 信息安全技术健康医疗数据安全指南. Available at: http://std.samr.gov.cn/gb/search/gbDetailed?id=95A3C3106830CD14E05397BE0A0AC171.
40.	国家药品监督管理局. 《医疗器械临床试验质量管理规范》(国家食品药品监督管理总局中华人民共和国国家卫生和计划生育委员会令第25号). Available at: https://www.nmpa.gov.cn/directory/web/nmpa/xxgk/fgwj/bmgzh/20160323141701747.html.

1. US Food and Drug Administration (FDA). Enhancing the diversity of clinical trial populations - eligibility criteria, enrollment practices, and trial designs guidance for industry. Available at: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/enhancing-diversity-clinical-trial-populations-eligibility-criteria-enrollment-practices-and-trial.
2. US Food and Drug Administration (FDA). Adaptive design clinical trials for drugs and biologics guidance for industry. Available at: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/adaptive-design-clinical-trials-drugs-and-biologics-guidance-industry.
3. Hamel LM, Penner LA, Albrecht TL, et al. Barriers to clinical trial enrollment in racial and ethnic minority patients with cancer. Cancer Control, 2016, 23(4): 327-337.
4. Sommer C, Zuccolin D, Arnera V, et al. Building clinical trials around patients: Evaluation and comparison of decentralized and conventional site models in patients with low back pain. Contemp Clin Trials Commun, 2018, 11: 120-126.
5. Lansey DG, Hefka TA, Carducci MA, et al. Problem solving to enhance clinical trial participation utilizing a framework-driven approach. Clin Adv Hematol Oncol, 2020, 18(8): 468-476.
6. US Food and Drug Administration (FDA). Collection of race and ethnicity data in clinical trials: guidance for industry and food and drug Administration staff. Available at: https://www.fda.gov/media/75453/download.
7. Torres S, de la Riva EE, Tom LS, et al. The development of a communication tool tofacilitate the cancer trial recruitment process and increase research literacy among underrepresented populations. J Cancer Educ, 2015, 30(4): 792-798.
8. 国家药品监督管理局, 国家卫生健康委. 国家药监局国家卫生健康委关于发布药物临床试验质量管理规范的公告(2020 年第 57 号). Available at: https://www.nmpa.gov.cn/xxgk/ggtg/qtggtg/20200426162401243.html.
9. 国家药品监督管理局. 总局关于发布药物临床试验的生物统计学指导原则的通告(2016 年第 93 号). Available at: https://www.nmpa.gov.cn/directory/web/nmpa/xxgk/ggtg/qtggtg/20160603161201857.html.
10. US Food and Drug Administration (FDA). Multiple endpoints in clinical trials; guidance for industry. Available at: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/multiple-endpoints-clinical-trials-guidance-industry.
11. European Medicines Agency (EMA). Guideline on multiplicity issues in clinical trials. Available at: https://www.ema.europa.eu/en/documents/scientific-guideline/draft-guideline-multiplicity-issues-clinical-trials_en.pdf.
12. 中华人民共和国中央人民政府. 国家药监局关于发布晚期非小细胞肺癌临床试验终点技术指导原则的通告(2019 年第 64 号). Available at: http://www.gov.cn/xinwen/2019-09/18/content_5430886.htm.
13. 国家药品监督管理局药品审评中心. 药物临床试验多重性问题指导原则(试行). Available at: https://www.cqn.com.cn/ms/att/2021-02/09/c357919b-b8ca-4c30-a8d0-8e5d2c70fb93.pdf.
14. Lewis JA. Statistical principles for clinical trials (ICH E9): an introductory note on an international guideline. Stat Med, 1999, 18(15): 1903-1942.
15. 国家药品监督管理局药品审评中心. 药物临床试验适应性设计指导原则(试行). Available at: https://www.cde.org.cn/main/news/viewInfoCommon/bc2b326bd49bac7437368272be6ec00d.
16. Fordyce CB, Roe MT, Ahmad T, et al. Cardiovascular drug development: is it dead or just hibernating. J Am Coll Cardiol, 2015, 65(15): 1567-1582.
17. Baigent C, Herrington WG, Coresh J, et al. Challenges in conducting clinical trials in nephrology: conclusions from a Kidney Disease-Improving Global Outcomes (KDIGO) Controversies Conference. Kidney Int, 2017, 92(2): 297-305.
18. Eapen ZJ, Lauer MS, Temple RJ. The imperative of overcoming barriers to the conduct of large, simple trials. JAMA, 2014, 311(14): 1397-1398.
19. Baigent C, Landray MJ, Reith C, et al. The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): a randomised placebo-controlled trial. Lancet, 2011, 377(9784): 2181-2192.
20. HPS2-THRIVE Collaborative Group, Landray MJ, Haynes R, et al. Effects of extended-release niacin with laropiprant in high-risk patients. N Engl J Med, 2014, 371(3): 203-212.
21. REVEAL Collaborative Group, Bowman L, Chen F, et al. Randomized evaluation of the effects of anacetrapib through lipid-modification (REVEAL)-a large-scale, randomized, placebo-controlled trial of the clinical effects of anacetrapib among people with established vascular disease: Trial design, recruitment, and baseline characteristics. Am Heart J, 2017, 187: 182-190.
22. US Food and Drug Administration (FDA). Guidance for industry. oversight of clinical investigations-a risk-based approach to monitoring. Available at: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/oversight-clinical-investigations-risk-based-approach-monitoring.
23. Jones WS, Mulder H, Wruck LM, et al. Comparative effectiveness of aspirin dosing in cardiovascular disease. N Engl J Med, 2021, 384(21): 1981-1990.
24. Inan OT, Tenaerts P, Prindiville SA, et al. Digitizing clinical trials. NPJ Digit Med, 2020, 3: 101.
25. 丁发明, 闫慧, 黄天娇. 对临床试验中运用远程智能技术的监管策略的科学建议. 中国食品药品监管, 2020, (11): 125-133.
26. 曹国英, 付海军, 何为, 等. 智能化临床研究专家共识. 中国新药与临床杂志, 2020, 39(6): 321-328.
27. 王海学, 王涛. 远程智能临床试验及数字化技术应用的探讨. 中国食品药品监管, 2020, (11): 110-116.
28. 国际医学科学组织理事会联合世界卫生组织. 涉及人的健康相关研究国际伦理准则2016. 上海: 上海交通大学出版社, 2016.
29. 国家卫生健康委医学伦理专家委员会办公室中国医院协会. 涉及人的临床研究伦理审查委员会建设指南(2020版)发布. Available at: https://www.163.com/dy/article/FQGE0J270514BKOA.html.
30. 中华人民共和国中央人民政府. 中华人民共和国人类遗传资源管理条例. Available at: http://www.gov.cn/zhengce/content/2019-06/10/content_5398829.htm.
31. 中华人民共和国中央人民政府. 中华人民共和国生物安全法. Available at: http://www.gov.cn/xinwen/2020-10/18/content_5552108.htm.
32. 中华人民共和国中央人民政府. 中华人民共和国保守国家秘密法. Available at: http://www.gov.cn/flfg/2010-04/30/content_1596420.htm.
33. 中华人民共和国中央人民政府. 中华人民共和国保守国家秘密法实施条例. Available at: http://www.gov.cn/zhengce/2020-12/27/content_5573752.htm.
34. 中共中央网络安全和信息化委员会办公室, 中华人民共和国国家互联网信息办公室. 中华人民共和国网络安全法. Available at: http://www.cac.gov.cn/2016-11/07/c_1119867116_3.htm.
35. 中华人民共和国国家卫生和计划生育委员会. 涉及人的生物医学研究伦理审查办法. Available at: http://www.nhc.gov.cn/fzs/s3576/201808/14ee8ab2388440c4a44ecce0f24e064c.shtml.
36. 全国信息安全标准化技术委员会. 信息安全技术个人信息安全规范. Available at: https://www.tc260.org.cn/front/postDetail.html?id=20180124211617.
37. 中华人民共和国中央人民政府. 中华人民共和国数据安全法. Available at: http://www.gov.cn/xinwen/2021-06/11/content_5616919.htm.
38. 国家药品监督管理局. 总局关于发布临床试验的电子数据采集技术指导原则的通告(2016年第114号). Available at: https://www.nmpa.gov.cn/xxgk/ggtg/qtggtg/20160729184001958.html.
39. 全国信息安全标准化技术委员会. 信息安全技术健康医疗数据安全指南. Available at: http://std.samr.gov.cn/gb/search/gbDetailed?id=95A3C3106830CD14E05397BE0A0AC171.
40. 国家药品监督管理局. 《医疗器械临床试验质量管理规范》(国家食品药品监督管理总局中华人民共和国国家卫生和计划生育委员会令第25号). Available at: https://www.nmpa.gov.cn/directory/web/nmpa/xxgk/fgwj/bmgzh/20160323141701747.html.

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Expert consensus on problem-solving strategies for drug clinical trial design and implementation

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