药品不良反应主动监测中混杂因素控制的现状及挑战

中国药物警戒 ›› 2018, Vol. 15 ›› Issue (10): 595-599.

药品不良反应主动监测中混杂因素控制的现状及挑战

郭晓晶¹, 王蒙¹, 郭威¹, 叶小飞¹, 朱田田¹, 贺佳^1,2*

¹第二军医大学卫勤系卫生统计学教研室,上海 200433;
²同济大学医学院,上海 200092

收稿日期:2018-07-02 修回日期:2018-11-27 出版日期:2018-10-20 发布日期:2018-11-27
通讯作者: 贺佳,女,博士,教授·博导,药物流行病学及新药评价的统计分析。E-mail：hejia63@yeah.net
作者简介:郭晓晶, 女, 博士,讲师, 药物流行病学。
基金资助:
国家自然科学基金（81703296）：药品不良反应监测中多重性检验和低频数膨胀问题的研究;上海市自然科学基金（18ZR1449500）：疾病风险评分模型研究及在药品不良反应主动监测中的应用;国家十三五科技重大专项（2017ZX09304016)：病毒感染性疾病与肝病新药临床评价和药物肝脏安全性转化研究技术平台建设;上海市第四轮公共卫生三年行动计划重点学科建设项目循证公共卫生与卫生经济学(15GWZK0901);上海市卫计委优秀青年医学人才培养计划（2018YQ47）

Status and Challenges of Controlling Confounding Factors in Active Surveillance of Adverse Drug Reactions

GUO Xiaojing¹, WANG Meng¹, GUO Wei¹, YE Xiaofei¹, ZHU Tiantian¹, HE Jia^1,2*

¹Department of Health Statistics, Faculty of Health Service, Second Military Medical University, Shanghai 200433, China;
²Tongji University School of Medicine, Shanghai 200092, China

Received:2018-07-02 Revised:2018-11-27 Online:2018-10-20 Published:2018-11-27

摘要/Abstract

摘要： 药品不良反应监测是保证用药安全的重要手段。目前,监测模式主要包括被动监测和主动监测两种。但由于被动监测是自主上报,存在大量漏报、错报等问题,故主动监测成为了更有效的监测手段。然而主动监测的研究又面临着一系列方法学的新问题,如控制混杂偏倚,特别是利用工具变量分析控制潜在、未知混杂偏倚的问题。因此本文结合药品安全性监测的现状,介绍当前混杂因素控制的一些方法及应用中面临的挑战。

关键词: 药品不良反应, 主动监测, 混杂偏倚, 工具变量分析

Abstract: Adverse drug reaction(ADR) surveillance is an important way to ensure drug safety. So far, the surveillance system includes active ADR surveillance and passive ADR mornitoring. Since ADR reports of passive surveillance are reported voluntarily, there are a large number of problems such as underreporting and misreporting, so active surveillance has become a more effective means of monitoring. However, there is a major challenge to control confounding factors in active ADR surveillance, especially controlling the underlying and unknown confounding bias using instrumental variable analysis. In this paper, we aim to briefly introduce some Methods of controlling confounding factors based on ADR surveillance status and potential challenges in application of these Methods.

Key words: adverse drug reaction, active surveillance, confounding bias, instrumental variable analysis

中图分类号:

R994.11

郭晓晶, 王蒙, 郭威, 叶小飞, 朱田田, 贺佳. 药品不良反应主动监测中混杂因素控制的现状及挑战[J]. 中国药物警戒, 2018, 15(10): 595-599.

GUO Xiaojing, WANG Meng, GUO Wei, YE Xiaofei, ZHU Tiantian, HE Jia. Status and Challenges of Controlling Confounding Factors in Active Surveillance of Adverse Drug Reactions[J]. Chinese Journal of Pharmacovigilance, 2018, 15(10): 595-599.

参考文献

[1] Pitts P J, Louet H L, Moride Y, et al.21st century pharmacovigilance: Efforts, roles, and responsibilities[J]. Lancet Oncol, 2016, 17(11): e486-e492.
[2] 许景峰. 药物相关基因多态型与药品不良反应[J]. 中国临床医师杂志(电子版), 2010, 4(2): 188-192.
[3] 杨焕. 国内外药物不良反应监测发展概况[J]. 中国临床药理学杂志, 2009, 25(1): 75-78.
[4] Bates D W, Larizgoitia I, Prasopa-Plaizier N, et al.Global priorities for patient safety research[J]. BMJ, 2009, 338(7705):b1775.
[5] Kessler C, Ward M J, McNaughton C D. Reducing adverse drug events: The need to rethink outpatient prescribing[J]. JAMA, 2016, 316(20): 2092-2093.
[6] 国务院. 国务院关于印发“十三五”国家食品安全规划和“十三五”国家药品安全规划的通知[EB/OL]. (2017-02-21) [2018-06-20]. http://www.gov.cn/zhengce/content/2017-02/21/content_5169755.htm.
[7] 王丹. 药品不良反应主动监测及其发展趋势[J]. 中国药物警戒, 2015, 12(10): 600-602.
[8] 侯永芳, 沈璐, 刘巍, 等. 美国医疗产品安全主动监测系统概述及启示[J]. 中国药物警戒, 2017, 14(1):32-35.
[9] Xin Sun, Jing Tan, Li Tang, et al.Real world evidence: Experience and lessons from China[J]. BMJ, 2018,360:j5262.
[10] Agoritsas T, Merglen A, Shah N D, et al.Adjusted analyses in studies addressing therapy and harm: Users' guides to the medical literature[J]. JAMA, 2017, 317(7): 748-759.
[11] Novikov I, Kalter-Leibovici O.Analytic approaches to observational studies with treatment selection bias[J]. JAMA, 2007, 297(19): 2077.
[12] Armstrong K.Methods in comparative effectiveness research[J]. J Clin Oncol, 2012, 30(34): 4208-4214.
[13] 赵厚宇, 詹思延. 疾病风险评分在药物流行病学研究中的应用[J]. 中华流行病学杂志, 2017, 38(2): 261-266.
[14] FDA. Best practices for conducting and reporting pharmacoepidemiologic safety studies using electronic healthcare data [EB/OL]. (2013-05-01) [2018-06-20]. https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ ucm243537.pdf.
[15] 赵璐,叶小飞, 王超, 等. 分层分析在药品不良反应信号检测中的应用[J]. 中国药物警戒, 2011, 8(3):158-160.
[16] Wang J, Donnan P T.Propensity score methods in drug safety studies: Practice, strengths and limitations[J]. Pharmacoepidemiol Drug Saf, 2001, 10(4): 341-344.
[17] 田峰, 廖星, 谢雁鸣. 欧盟《药物流行病学研究方法学标准指导手册》译介[J]. 中国中药杂志, 2013, 38(18):2949-2957.
[18] Solomon D H, Shadick N A, Weinblatt M E, et al.Drug safety analyses in a rheumatoid arthritis registry: Application of different approaches regarding timing of exposure and confounder measurement[J]. Arthritis Res Ther, 2017, 19(1): 130.
[19] Hernandez-Diaz S, Huybrechts K F, Desai R J, et al.Topiramate use early in pregnancy and the risk of oral clefts: A pregnancy cohort study[J]. Neurology, 2018, 90(4): e342-e351.
[20] Wyss R, Ellis A R, Brookhart M A, et al.Matching on the disease risk score in comparative effectiveness research of new treatments[J]. Pharmacoepidemiol Drug Saf, 2015, 24(9): 951-961.
[21] Baiocchi M, Cheng J, Small D S.Instrumental variable methods for causal inference[J]. Stat Med, 2014, 33(13): 2297-2340.
[22] Uddin M J, Groenwold R H, Ali M S, et al.Methods to control for unmeasured confounding in pharmacoepidemiology:An overview[J]. Int J Clin Pharm, 2016, 38(3): 714-723.
[23] Uddin M J, Groenwold R H, De Boer A, et al.Application of instrumental variables method in pharmacoepidemiology: An example of beta2-agonist use and myocardial infarction[J]. Pharmacoepi-demiol Drug Saf, 2013, 22(S1): 32-33.
[24] Uddin M J, Groenwold R H, De Boer A, et al.Instrumental variables analysis using multiple databases: An example of antidepre-ssant use and risk of hip fracture[J]. Pharmacoepidemiol Drug Saf, 2016, 25(S1): 122-131.
[25] Cain L E, Cole S R, Greenland S, et al.Effect of highly active antiretroviral therapy on incident aids using calendar period as an instrumental variable[J]. Am J Epidemiol, 2009, 169(9): 1124-1132.
[26] Ionescu-Ittu R, Abrahamowicz M, Pilote L.Treatment effect estimates varied depending on the definition of the provider prescribing preference-based instrumental variables[J]. J Clin Epidemiol, 2012, 65(2): 155-162.
[27] Swanson S A.Instrumental variable analyses in pharmacoepidemiology: What target trials do we emulate?[J]. Curr Epidemiol Rep, 2017, 4(4): 281-287.
[28] Cai B, Small D S, Have T R.Two-stage instrumental variable methods for estimating the causal odds ratio: Analysis of bias[J]. Stat Med, 2011, 30(15): 1809-1824.
[29] 国家药品不良反应监测中心. 国家中心举办国家药品不良反应监测哨点授牌仪式[EB/OL]. (2017-12-14) [2018-06-20]. http://www.cdr-adr.org.cn/xwdt/201712/ t20171214_19834. html.
[30] 河南省药品不良反应监测中心. 稳步推进药品不良反应监测系统保障民生健康发展 [EB/OL]. (2018-05-24) [2018-06-20]. http://www.hnadr.org/view/1674.
[31] Zhang X, Faries D E, Li H, et al.Addressing unmeasured confounding in comparative observational research[J]. Pharmacoepi-
demiol Drug Saf, 2018, 27(4):373-382.
[32] Ertefaie A, Small D S, Flory J H, et al.A tutorial on the use of instrumental variables in pharmacoepidemiology[J]. Pharmacoepi-demiol Drug Saf, 2017, 26(4): 357-367.