Safety evaluation of abiraterone versus generics in real world: a retrospective study based on FAERS database
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摘要: 目的 评估阿比特龙原研药与仿制药在真实世界应用中的安全性, 为临床合理用药提供参考。方法 通过对美国食品药品监督管理局(FDA)不良事件报告系统(FAERS)2010年1月1日-2020年12月31日收录的不良事件(AE)报告进行回顾性分析, 筛选出使用过阿比特龙原研药(zytiga组)或仿制药(generic组)的事件报告并进行分组。分析2组患者的基线特征以及AE的分布特点, 并对严重AE患者进行预后分析。应用卡方检验统计分析这些不良事件发生在2组之间的差异。结果 本研究收集了22187例患者的报告, 其中generic组536例, zytiga组21651例。其中zytiga组中位报告时间为9(4~16) d, generic组为11(8~15) d, 差异有统计学意义(P < 0.01)。zytiga组发生严重AE的报告显著少于generic组, 差异有统计学意义(62.0% vs 93.7%, P < 0.01)。报告的AE依据国际医学用语词典(Meddra)中的系统器官分类标准(SOC)进行分类, generic组常见的且明显高于zytiga组的不良反应事件为各类检查(26.3% vs 16.5%)、胃肠系统疾病(18.7% vs 12.3%)、心脏器官疾病(18.3% vs 9.7%)等; zytiga组常见的且明显高于generic组的不良反应事件为全身性疾病及给药部位各种反应(39.5% vs 33.4%)、各种手术及医疗操作(14.4% vs 1.5%)。同时依据国际医学用语词典(Meddra)中首选语(Prefer Term)进一步分类, generic组常见的且明显高于zytiga组的不良反应事件为疼痛(10.8% vs 5.5%)、肺炎(6.2% vs 2.1%)、疾病症状进展(5.2% vs 2.6%)等; zytiga组常见的且明显高于generic组的不良反应事件为治疗终止(6.0% vs 0.4%)、产品剂量遗漏问题(3.4% vs 0.7%)、住院(2.7% vs 0)等。预后分析显示, generic组在威胁生命(9.8% vs 3.5%)、住院(50.6% vs 37.5%)、致残(3.2% vs 1.2%)的发生率都显著高于zytiga组(P < 0.01)。结论 基于FAERS的回顾性分析表明, 阿比特龙仿制药在真实世界中的不良反应特征与原研药截然不同, 且严重不良反应事件发生率显著高于原研药, 同时存在明显的漏报和缓报现象, 提示仿制药的安全性仍需要加强监控并进行大规模的真实世界研究来验证。Abstract: Objective To excavate and evaluate the safety of the brand abiraterone and generic drug of abiraterone in the real world after marketing to provide reference for rational clinical drug use.Methods Through retrospective analysis of adverse event (AE) reports from U. S. Food and Drug Administration's Adverse Event Reporting System (FAERS) between January 1st, 2010 and December 31st, 2020, abiraterone (zytiga group) and its generics group were screened and grouped. The basic information of patients and the distribution characteristics of AE were descriptively analyzed, and the prognosis of patients with severe AE (SAE) was summarized and classified. The differences in the incidence of AE between the two groups were statistically analyzed using the chi-square test.Results A total of 22187 patient reports were collected in this study, including 536 cases in the generic group and 21651 cases in the zytiga group. The median duration of reporting was 9(4-16) days in the zytiga group and 11(8-15) days in the generic group (P < 0.01). There were significantly fewer reports of SAE in the zytiga group than in the generic group, with a statistically significant difference (62.0% vs 93.7%, P < 0.01). According to the classification of Systematic Organ Classification Standard (SOC) of the International Dictionary of Medical Terms (Meddra), the common and significantly higher AEs in the generic group than in the zytiga group were various types of investigations (26.3% vs 16.5%), gastrointestinal disorders (18.7% vs 12.3%), cardiac organ disorders (18.3% vs 9.7%), etc. In the zytiga group, systemic diseases and reactions at the site of administration (39.5% vs 33.4%) and various surgical and medical procedures (14.4% vs 1.5%) were the most common AEs and were significantly higher than those in the generic group. Further classified according to the Preferred Term in Meddra, pain (10.8% vs 5.5%), pneumonia (6.2% vs 2.1%) and progression of disease symptoms (5.2% vs 2.6%) were more common and significantly higher in the generic group than in the zytiga group. AEs that were common and significantly higher in the zytiga group than in the generic group were treatment discontinuation (6.0% vs 0.4%), product dose omission issues (3.4% vs 0.7%), and hospitalization (2.7% vs 0). Prognostic analysis showed that the generic group had a significantly higher incidence of life-threatening (9.8% vs 3.5%), hospitalization (50.6% vs 37.5%), and disability (3.2% vs 1.2%) than the zytiga group(P < 0.01).Conclusion A retrospective analysis based on the self-reported data from FAERS indicates that the rate of AEs for generic drugs of abiraterone is totally different from the original abiraterone, and the incidence of SAEs was significantly higher than that of the original drug, with significant underreporting and delayed, suggesting that the safety of generic drugs still needs to be better monitored and verified in large-scale real world studies.
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Key words:
- abiraterone /
- prostate cancer /
- real world study /
- adverse drug events /
- safety
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表 1 AE报告患者基线资料
M(P25，P75) 临床信息 generic组(536例) zytiga组(21 651例) Z/χ2 P值 年龄/岁 74(71，76.5) 75(74，76) -10.597 < 0.001 体重/kg 88(79，100.5) 79(68.04，90.72) -7.199 < 0.001 使用药物/例(%) 阿比特龙 536(100.0) 21 651(100.0) 其他内分泌治疗 205(38.2) 633(2.9) 1 795.67 < 0.001 细胞毒性治疗 51(9.5) 157(0.7) 435.138 < 0.001 
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表 2 系统器官分类(SOC)的安全性评价
例(%) 系统器官 generic组
(536例)zytiga组
(21651例)差异/%
(95%CI)χ2 P值 严重不良反应事件 502(93.7) 13414(62.0) 31.7(29.5~33.9) 224.812 < 0.001 不良反应事件 全身性疾病及给药部位各种反应 179(33.4) 8558(39.5) -6.1(-10.2~-2.1) 8.237 0.004 各类检查 130(24.3) 3577(16.5) 7.7(4.1~11.4) 22.473 < 0.001 胃肠系统疾病 100(18.7) 2659(12.3) 6.4(3.0~9.7) 19.525 < 0.001 心脏器官疾病 98(18.3) 2103(9.7) 8.6(5.3~11.9) 42.993 < 0.001 各类损伤、中毒及手术并发症 83(15.5) 3270(15.1) 0.4(-2.7~3.5) 0.059 0.807 各种肌肉骨骼及结缔组织疾病 63(11.8) 1607(7.4) 4.3(1.6~7.1) 14.099 < 0.001 呼吸系统、胸及纵隔疾病 63(11.8) 1036(4.8) 7.0(4.2~9.7) 53.953 < 0.001 良性、恶性及性质不明的肿瘤 62(11.6) 1198(5.5) 6.0(3.3~8.8) 35.552 < 0.001 感染及侵染类疾病 61(11.4) 1289(6.0) 5.4(2.7~8.1) 26.959 < 0.001 代谢及营养类疾病 56(10.4) 1000(4.6) 5.8(3.2~8.4) 39.206 < 0.001 肾脏及泌尿系统疾病 52(9.7) 950(4.4) 5.3(2.8~7.8) 34.248 < 0.001 血液及淋巴系统疾病 50(9.3) 800(3.7) 5.6(3.2~8.1) 45.053 < 0.001 血管与淋巴管类疾病 45(8.4) 743(3.4) 5.0(2.6~7.3) 37.623 < 0.001 各类神经系统疾病 39(7.3) 1606(7.4) -0.1(-2.4~2.1) 0.015 0.902 内分泌系统疾病 33(6.2) 385(1.8) 4.4(2.3~6.4) 54.247 < 0.001 肝胆系统疾病 28(5.2) 591(2.7) 2.5(0.6~4.4) 11.998 0.001 精神病类 24(4.5) 818(3.8) 0.7(-1.1~2.5) 0.701 0.402 眼器官疾病 11(2.1) 263(1.2) 0.8(-0.4~2.0) 3.008 0.083 皮肤及皮下组织类疾病 9(1.7) 563(2.6) -0.9(-2.0~0.2) 1.767 0.184 免疫系统疾病 8(1.5) 214(1.0) 0.5(-0.5~1.5) 1.342 0.247 各种手术及医疗操作 8(1.5) 3126(14.4) -12.9(-14.1~-11.8) 72.264 < 0.001 妊娠期、产褥期及围生期状况 1(0.2) 29(0.1) 0.1(-0.3~0.4) — 0.520 各种先天性家族性遗传性疾病 0 8(0.0) -0.0(-0.1~-0.0) — >0.999 耳及迷路类疾病 0 131(0.6) -0.6(-0.7~-0.5) — 0.080 生殖系统及乳腺疾病 0 84(0.4) -0.4(-0.5~-0.3) — 0.273 社会环境 0 90(0.4) -0.4(-0.5~-0.3) — 0.283 产品问题 0 145(0.7) -0.7(-0.8~-0.6) — 0.053
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表 3 PT首选语分类的安全性评价
例(%) PT generic组
(536例)zytiga组
(21651例)差异/%
(95%CI)χ2 P值 疼痛 58(10.8) 1199(5.5) 5.3(2.6~7.9) 27.315 < 0.001 肺炎 33(6.2) 447(2.1) 4.1(2.0~6.1) 41.381 < 0.001 疾病症状进展 28(5.2) 571(2.6) 2.6(0.7~4.5) 13.322 < 0.001 药物无效 27(5.0) 1184(5.5) -0.4(-2.3~1.4) 0.189 0.664 疲劳 27(5.0) 1161(5.4) -0.3(-2.2~1.6) 0.109 0.741 呼吸困难 25(4.7) 395(1.8) 2.8(1.0~4.6) 22.712 < 0.001 跌倒 24(4.5) 357(1.6) 2.8(1.1~4.6) 24.798 < 0.001 贫血 24(4.5) 279(1.3) 3.2(1.4~4.9) 39.489 < 0.001 尿路感染 20(3.7) 340(1.6) 2.2(0.5~3.8) 15.302 < 0.001 PSA增高 19(3.5) 1109(5.1) -1.6(-3.2~0.0) 2.697 0.101 高血压 19(3.5) 385(1.8) 1.8(0.2~3.3) 9.131 0.003 癌症局部进展 18(3.4) 416(1.9) 1.4(-0.1~3.0) 5.630 0.018 癌症远处转移 17(3.2) 273(1.3) 1.9(0.4~3.4) 14.803 < 0.001 尿毒症 17(3.2) 234(1.1) 2.1(0.6~3.6) 20.444 < 0.001 虚弱 16(3.0) 514(2.4) 0.6(-0.8~2.1) 0.838 0.360 肌无力 16(3.0) 194(0.9) 2.1(0.6~3.5) 24.347 < 0.001 恶心 13(2.4) 526(2.4) -0.0(-1.3~1.3) 0.000 0.995 超适应证应用 13(2.4) 469(2.2) 0.3(-1.1~1.6) 0.165 0.684 食欲下降 13(2.4) 378(1.7) 0.7(-0.6~2.0) 1.395 0.238 呕吐 13(2.4) 341(1.6) 0.9(-0.5~2.2) 2.409 0.121 低钾血症 11(2.1) 337(1.6) 0.5(-0.7~1.7) 0.833 0.362 腹泻 5(0.9) 464(2.1) -1.2(-2.0~-0.4) 3.703 0.054 产品剂量遗漏问题 4(0.7) 743(3.4) -2.7(-3.5~-1.9) 11.594 0.001 热潮红 3(0.6) 546(2.5) -2.0(-2.6~-1.3) 8.345 0.004 治疗终止 2(0.4) 1289(6.0) -5.6(-6.2~-5.0) 29.722 < 0.001 住院 0 577(2.7) -2.7(-2.9~-2.5) 14.666 < 0.001
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表 4 严重不良反应的预后评价
例(%) 变量 generic组
(502例)zytiga组
(13414例)差异/%
(95%CI)χ2 P值 死亡 62(12.4) 4354(32.5) -20.1(-23.1~-17.1) 23.944 < 0.001 威胁生命 49(9.8) 466(3.5) 6.3(3.7~8.9) 112.700 < 0.001 住院 254(50.6) 5035(37.5) 13.1(8.6~17.5) 167.783 < 0.001 致残 16(3.2) 157(1.2) 2.0(0.5~3.6) 34.529 < 0.001 干预治疗 0 16(0.1) -0.1(-0.2~-0.1) — >0.999
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