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.	國家藥品監督管理局, 國家衛生健康委. 國家藥監局國家衛生健康委關于發布藥物臨床試驗質量管理規范的公告(2020 年第 57 號). 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.	中華人民共和國中央人民政府. 國家藥監局關于發布晚期非小細胞肺癌臨床試驗終點技術指導原則的通告(2019 年第 64 號). 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.	丁發明, 閆慧, 黃天嬌. 對臨床試驗中運用遠程智能技術的監管策略的科學建議. 中國食品藥品監管, 2020, (11): 125-133.
26.	曹國英, 付海軍, 何為, 等. 智能化臨床研究專家共識. 中國新藥與臨床雜志, 2020, 39(6): 321-328.
27.	王海學, 王濤. 遠程智能臨床試驗及數字化技術應用的探討. 中國食品藥品監管, 2020, (11): 110-116.
28.	國際醫學科學組織理事會聯合世界衛生組織. 涉及人的健康相關研究國際倫理準則2016. 上海: 上海交通大學出版社, 2016.
29.	國家衛生健康委醫學倫理專家委員會辦公室中國醫院協會. 涉及人的臨床研究倫理審查委員會建設指南(2020版)發布. Available at: https://www.163.com/dy/article/FQGE0J270514BKOA.html.
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31.	中華人民共和國中央人民政府. 中華人民共和國生物安全法. Available at: http://www.gov.cn/xinwen/2020-10/18/content_5552108.htm.
32.	中華人民共和國中央人民政府. 中華人民共和國保守國家秘密法. Available at: http://www.gov.cn/flfg/2010-04/30/content_1596420.htm.
33.	中華人民共和國中央人民政府. 中華人民共和國保守國家秘密法實施條例. Available at: http://www.gov.cn/zhengce/2020-12/27/content_5573752.htm.
34.	中共中央網絡安全和信息化委員會辦公室, 中華人民共和國國家互聯網信息辦公室. 中華人民共和國網絡安全法. Available at: http://www.cac.gov.cn/2016-11/07/c_1119867116_3.htm.
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37.	中華人民共和國中央人民政府. 中華人民共和國數據安全法. Available at: http://www.gov.cn/xinwen/2021-06/11/content_5616919.htm.
38.	國家藥品監督管理局. 總局關于發布臨床試驗的電子數據采集技術指導原則的通告(2016年第114號). Available at: https://www.nmpa.gov.cn/xxgk/ggtg/qtggtg/20160729184001958.html.
39.	全國信息安全標準化技術委員會. 信息安全技術健康醫療數據安全指南. Available at: http://std.samr.gov.cn/gb/search/gbDetailed?id=95A3C3106830CD14E05397BE0A0AC171.
40.	國家藥品監督管理局. 《醫療器械臨床試驗質量管理規范》(國家食品藥品監督管理總局中華人民共和國國家衛生和計劃生育委員會令第25號). 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. 國家藥品監督管理局, 國家衛生健康委. 國家藥監局國家衛生健康委關于發布藥物臨床試驗質量管理規范的公告(2020 年第 57 號). Available at: https://www.nmpa.gov.cn/xxgk/ggtg/qtggtg/20200426162401243.html.
9. 國家藥品監督管理局. 總局關于發布藥物臨床試驗的生物統計學指導原則的通告(2016 年第 93 號). 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. 中華人民共和國中央人民政府. 國家藥監局關于發布晚期非小細胞肺癌臨床試驗終點技術指導原則的通告(2019 年第 64 號). Available at: http://www.gov.cn/xinwen/2019-09/18/content_5430886.htm.
13. 國家藥品監督管理局藥品審評中心. 藥物臨床試驗多重性問題指導原則(試行). 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. 國家藥品監督管理局藥品審評中心. 藥物臨床試驗適應性設計指導原則(試行). 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. 丁發明, 閆慧, 黃天嬌. 對臨床試驗中運用遠程智能技術的監管策略的科學建議. 中國食品藥品監管, 2020, (11): 125-133.
26. 曹國英, 付海軍, 何為, 等. 智能化臨床研究專家共識. 中國新藥與臨床雜志, 2020, 39(6): 321-328.
27. 王海學, 王濤. 遠程智能臨床試驗及數字化技術應用的探討. 中國食品藥品監管, 2020, (11): 110-116.
28. 國際醫學科學組織理事會聯合世界衛生組織. 涉及人的健康相關研究國際倫理準則2016. 上海: 上海交通大學出版社, 2016.
29. 國家衛生健康委醫學倫理專家委員會辦公室中國醫院協會. 涉及人的臨床研究倫理審查委員會建設指南(2020版)發布. Available at: https://www.163.com/dy/article/FQGE0J270514BKOA.html.
30. 中華人民共和國中央人民政府. 中華人民共和國人類遺傳資源管理條例. Available at: http://www.gov.cn/zhengce/content/2019-06/10/content_5398829.htm.
31. 中華人民共和國中央人民政府. 中華人民共和國生物安全法. Available at: http://www.gov.cn/xinwen/2020-10/18/content_5552108.htm.
32. 中華人民共和國中央人民政府. 中華人民共和國保守國家秘密法. Available at: http://www.gov.cn/flfg/2010-04/30/content_1596420.htm.
33. 中華人民共和國中央人民政府. 中華人民共和國保守國家秘密法實施條例. Available at: http://www.gov.cn/zhengce/2020-12/27/content_5573752.htm.
34. 中共中央網絡安全和信息化委員會辦公室, 中華人民共和國國家互聯網信息辦公室. 中華人民共和國網絡安全法. Available at: http://www.cac.gov.cn/2016-11/07/c_1119867116_3.htm.
35. 中華人民共和國國家衛生和計劃生育委員會. 涉及人的生物醫學研究倫理審查辦法. Available at: http://www.nhc.gov.cn/fzs/s3576/201808/14ee8ab2388440c4a44ecce0f24e064c.shtml.
36. 全國信息安全標準化技術委員會. 信息安全技術個人信息安全規范. Available at: https://www.tc260.org.cn/front/postDetail.html?id=20180124211617.
37. 中華人民共和國中央人民政府. 中華人民共和國數據安全法. Available at: http://www.gov.cn/xinwen/2021-06/11/content_5616919.htm.
38. 國家藥品監督管理局. 總局關于發布臨床試驗的電子數據采集技術指導原則的通告(2016年第114號). Available at: https://www.nmpa.gov.cn/xxgk/ggtg/qtggtg/20160729184001958.html.
39. 全國信息安全標準化技術委員會. 信息安全技術健康醫療數據安全指南. Available at: http://std.samr.gov.cn/gb/search/gbDetailed?id=95A3C3106830CD14E05397BE0A0AC171.
40. 國家藥品監督管理局. 《醫療器械臨床試驗質量管理規范》(國家食品藥品監督管理總局中華人民共和國國家衛生和計劃生育委員會令第25號). 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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