Safety-related regulatory actions for biologicals approved in the United States and the European Union
Safety-related regulatory actions for biologicals approved in the United States and the European Union
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DOI：
10.1001/jama.300.16.1887
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发表时间：
2008-10-22
影响因子：
120.7
通讯作者：
Egberts, Antoine C. G.
中科院分区：
文献类型：
--
作者：
Giezen, Thijs J.;Mantel-Teeuwisse, Aukje K.;Egberts, Antoine C. G.
生物制剂是一类相对较新的具有特定风险（如免疫原性）的药物。然而，关于批准后确定的使用安全问题的性质和时间的信息有限。目的确定在美国和/或欧盟批准后生物制品安全相关监管行动的性质、频率和时间。1995年1月至2007年6月期间在美国和/或欧盟批准的一组生物制剂的设计和设置随访。疫苗、致敏产品以及用于进一步生产和输血目的的产品被排除在外。安全相关监管行动的性质、频率和时间定义为：(1)医疗保健专业信函（美国）和直接医疗保健专业通信（欧盟），(2)黑盒警告（美国），以及(3)1995年1月至2008年6月期间发布的与安全相关的营销撤回（美国和欧盟）。结果共有174种生物制剂获批，其中美国136种，欧盟105种，其中67种在美国和欧盟获批。174种不同的生物制剂中，有41种（23.6%）采取了82项与安全相关的监管行动（46份医疗保健专业信函，17份直接医疗保健专业通信，19份黑盒警告和无撤销）。Kaplan-Meier分析得出，批准后3年首次安全相关监管行动的概率为14%(95%置信区间[CI]， 9%-19%)，批准后10年为29% （95% CI, 20%-37%）。首获批准的同类生物制剂与后获批准的同类产品相比，首次安全相关监管行动的风险更高（分别为12.0/1000月和2.9/1000月；风险比为3.7 [95% CI, 1.5- 9.5]）。警告主要涉及一般疾病和给药部位状况、感染和感染、免疫系统疾病和良性、恶性和未明确的肿瘤。结论生物制品获批后发现的安全问题的性质往往与免疫调节作用（感染）有关。由于首先在一类中获得批准的生物制剂更有可能受到监管行动的影响，因此建议密切监测。
Context Biologicals are a relatively new class of medicines that carry specific risks (eg, immunogenicity). However, limited information is available on the nature and timing of safety problems with their use that were identified after approval.Objective To determine the nature, frequency, and timing of safety-related regulatory actions for biologicals following approval in the United States and/or the European Union.Design and Setting Follow-up of a group of biologicals approved in the United States and/or European Union between January 1995 and June 2007. Vaccines, allergenic products, and products for further manufacture and transfusion purposes were excluded.Main Outcome Measures Nature, frequency, and timing of safety-related regulatory actions defined as (1) dear healthcare professional letters (United States) and direct healthcare professional communications (European Union), (2) black box warnings (United States), and (3) safety-related marketing withdrawals (United States and European Union) issued between January 1995 and June 2008.Results A total of 174 biologicals were approved (136 in the United States and 105 in the European Union, of which 67 were approved in both regions). Eighty-two safety-related regulatory actions (46 dear healthcare professional letters, 17 direct healthcare professional communications, 19 black box warnings, and no withdrawals) were issued for 41 of the 174 different biologicals (23.6%). The probability of a first safety-related regulatory action, derived from Kaplan-Meier analyses, was 14% (95% confidence interval [CI], 9%-19%) 3 years after approval and 29% (95% CI, 20%-37%) 10 years after approval. Biologicals first in class to obtain approval had a higher risk for a first safety-related regulatory action compared with later approved products in that class (12.0/1000 vs 2.9/1000 months, respectively; hazard ratio, 3.7 [95% CI, 1.5- 9.5]). Warnings mostly concerned the classes general disorders and administration site conditions, infections and infestations, immune system disorders and neoplasms benign, malignant, and unspecified.Conclusions The nature of safety problems identified after approval for biologicals is often related to the immunomodulatory effect (infections). Because the biologicals first to be approved in a class were more likely to be subjected to regulatory action, close monitoring is recommended.