Giezen Thijs J, Mantel-Teeuwisse Aukje K, Straus Sabine M J M, Schellekens Huub, Leufkens Hubert G M, Egberts Antoine C G
Utrecht Institute for Pharmaceutical Sciences, Division of Pharmacoepidemiology and Pharmacotherapy, Utrecht University, Utrecht, The Netherlands.
JAMA. 2008 Oct 22;300(16):1887-96. doi: 10.1001/jama.300.16.1887.
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.
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.
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.
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.
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.
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.
生物制品是一类相对较新的药物，具有特定风险（如免疫原性）。然而，关于其批准后使用中出现的安全问题的性质和时间的信息有限。
确定美国和/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。
对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品进行随访。排除疫苗、变应原产品以及用于进一步制造和输血目的的产品。
1995年1月至2008年6月期间定义为（1）致医护人员信（美国）和直接医护人员沟通（欧盟）、（2）黑框警告（美国）以及（3）安全相关撤市（美国和欧盟）的安全相关监管行动的性质、频率和时间。
共批准了174种生物制品（美国136种，欧盟105种，其中67种在两个地区均获批准）。针对174种不同生物制品中的41种（23.6%）发布了82项安全相关监管行动（46封致医护人员信、17次直接医护人员沟通、19次黑框警告，无撤市行动）。根据Kaplan-Meier分析得出，首次安全相关监管行动的概率在批准后3年为14%（95%置信区间[CI]，9%-19%），批准后10年为29%（95%CI，20%-37%）。与该类中后来批准的产品相比，该类中首个获得批准的生物制品首次出现安全相关监管行动的风险更高（分别为12.0/1000个月和2.9/1000个月；风险比，3.7[95%CI，1.5-9.5]）。警告大多涉及全身性疾病和给药部位状况、感染和寄生虫感染、免疫系统疾病以及良性、恶性和未明确的肿瘤。
生物制品批准后发现的安全问题的性质通常与免疫调节作用（感染）有关。由于某类中首个获批的生物制品更有可能受到监管行动，因此建议进行密切监测。
