法国BIA 10-2474临床试验事件对我国研究者的启示

中国药物警戒 ›› 2018, Vol. 15 ›› Issue (2): 94-97.

法国BIA 10-2474临床试验事件对我国研究者的启示

李江帆^1,2,3, 薛薇^1,3, 胡欣^2,3, 李可欣^1,3,*

1 北京医院临床试验研究中心，北京 100730;
2 沈阳药科大学，辽宁沈阳 110016;
3 药物临床风险与个体化应用评价北京市重点实验室，北京 100730

收稿日期:2017-11-13 修回日期:2018-03-28 出版日期:2018-02-20 发布日期:2018-03-28
通讯作者: 李可欣，女，主任药师，生物药剂学与临床药理学。E-mail：kexinli6202@163.com
作者简介:李江帆，男，在读硕士，药事管理。

Revelation of French BIA 10-2474 Clinical Trials to Chinese Investigators

LI Jiang-fan^1,2,3, XUE Wei^1,3, HU Xin^2,3, LI Ke-xin^1,3,*

1 Clinical Trial Center of Beijing Hospital, Beijing 100730, China;
2 Shenyang Pharmaceutical University, Liaoning Shenyang 110016, China;
3 Beijing Key Laboratory of Drug Clinical Risk and Personalized Medication Evaluation, Beijing 100730, China

Received:2017-11-13 Revised:2018-03-28 Online:2018-02-20 Published:2018-03-28

摘要/Abstract

摘要： 目的通过对法国BIA 10-2474 临床试验Ⅰ期研究首次人体试验事件的详细介绍，为我国从事创新药物临床试验Ⅰ期研究首次人体试验以及相关临床试验研究的研究者提供一些建议。方法采用案例分析法，以法国BIA 10-2474 临床Ⅰ期研究首次人体试验事件过程为案例进行了深入的分析。结果与结论 对于创新药物临床试验Ⅰ期研究首次人体试验或相关临床试验研究，我国研究者应该重视起始剂量的设计、对终止递增规则做出正确决策以及制定风险控制措施，最大程度地保证受试者的安全，提升整体临床研究水平。

关键词: 法国BIA 10-2474, 创新药物, 首次人体试验, 研究者, 启示

Abstract: Objective To provide some suggestions for the investigators who are engaged in phase I clinical trial First-In-Human or related clinical trials in China through making a detailed introduction to the first human trial event in phase I of French BIA 10-2474 clinical trial. Methods A case study was conducted to analyze the clinical phase I study of BIA 10-2474 in France. Results and Conclusion To the first-in-human clinical trials, investigators in China should pay attention to the design of starting dose, making correct decision to terminate the incremental rule, setting up risk control measures, guaranteeing the safety of the subjects, enhancing the overall level of clinical research.

Key words: French BIA 10-2474, innovative drugs, first-in-human clinical trial, investigators , revelation

中图分类号:

李江帆, 薛薇, 胡欣, 李可欣. 法国BIA 10-2474临床试验事件对我国研究者的启示[J]. 中国药物警戒, 2018, 15(2): 94-97.

LI Jiang-fan, XUE Wei, HU Xin, LI Ke-xin. Revelation of French BIA 10-2474 Clinical Trials to Chinese Investigators[J]. Chinese Journal of Pharmacovigilance, 2018, 15(2): 94-97.

参考文献

[1] CDE. 2016年度药品审评报[EB/OL].(2017-03-17)[2017-11-09].http://www.cde.org.cn/news.do?method=viewInfoCommon&id=313842.
[2] 李敏, 史爱欣, 庞宏贤,等. 进食对健康受试者口服百可利咀嚼片药动学的影响[J]. 中国药学杂志, 2015, 50(2):163-166.
[3] Cravatt B F, Demarest K, Patricelli M P, et al. Supersensitivity to anandamide and enhanced endogenous cannabinoid signaling in mice lacking fatty acid amide hydrolase[J]. Pro-ceedings of the National Academy of Sciences, 2001, 98(16): 9371-9376.
[4] Roques B P, Fournié-Zaluski M C, Wurm M. Inhibiting the breakdown of endogenous opioids and cannabinoids to alleviate pain[J]. Nature reviews Drug discovery, 2012, 11(4): 292-310.
[5] Huggins J P, Smart T S, Langman S, et al. An efficient randomised, placebo-controlled clinical trial with the irreversible fatty acid amide hydrolase-1 inhibitor PF-04457845, which modulates endoca-nnabinoids but fails to induce effective analgesia in patients with pain due to osteoarthritis of the knee[J]. PAIN, 2012, 153(9): 1837-1846.
[6] ANSM. Clinical Study Protocol BIA 10-2474[EB/OL].(2016-01-22)[2017-11-09].http://ansm.sante.fr/content/download/84681/1069223/version/1/file/protocole_BIAL_102474+101-22012016131259.pdf.
[7] Kerbrat A, Ferré J C, Fillatre P, et al. Acute Neurologic Disorder from an Inhibitor of Fatty Acid Amide Hydrolase[J]. New England Journal of Medicine, 2016, 375(18):1717-1725.
[8] Bird S M, Bailey R A, Grieve A P, et al. Statistical issues in first-inhuman studies on BIA 10-2474: Neglected comparison of protocol against practice[J]. Pharmaceutical Statistics, 2017, 16(2):100.
[9] Tong J, Mizrahi R, Houle S, et al. Inhibition of fatty acid amide hydrolase by BIA 10-2474 in rat brain[J]. Journal of Cerebral Blood Flow & Metabolism Official Journal of the Interna-tional Society of Cerebral Blood Flow & Metabolism, 2016,37(11):3635-3639.
[10] ANSM. Report by the Temporary Specialist Scientific Committee (TSSC),"FAAH (Fatty Acid Amide Hydrolase)", on the Causes of the Accident during a Phase 1 Clinical Trial[EB/OL].(2016-04-25)[2017-11-09].http://www.ansm.sante.fr/var/ansm_site/storage/original/application/744c7c6daf96b141bc9509e2f85c227e.pdf.
[11] FDA. Guidance for Industry Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers[EB/OL].(2005-07-06)[2017-11-09].https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm078932.pdf.
[12] EMA.Guideline on strategies to identify and mitigate risks for first-in-human and early clinical trials with investigational medicinal products [EB/OL].(2007-09-01)[2017-11-09].http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500002988.pdf.
[13] Kaur R, Sidhu P, Singh S. What failed BIA 10-2474 Phase I clinical trial? Global speculations and recommendations for future Phase I trials[J]. Journal of Pharmacology &Pharmacotherapeutics, 2016, 7(3):120-126.
[14] FDA. FDA finds drugs under investigation in the U.S. related to French BIA 10-2474drug do not pose similar safety risks [EB/OL].(2016-08-12)[2017-11-09]. https://www.fda.gov/drugs/drugsafety/ucm482740.htm.
[15] EMA. Guideline on strategies to identify and mitigate risks for first-in-human and early clinical trials with investigational medicinal products [EB/OL].(2017-07-20)[2017-11-09].http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2017/07/WC500232186.pdf.
[16] Sibille M, Patat A, Caplain H, et al. A safety grading scale to support dose escalation and define stopping rules for healthy subject first-entry-into-man studies: Some points to consider from the French Club Phase I* working group[J]. British journal of clinical pharmacology, 2010, 70(5):736.
[17] Cohen A. Should we tolerate tolerability as an objective in early drug development?[J].British Journal of Clinical Pharmacology, 2007, 64(3):249-52.