Division of Pharmacoepidemiology and Pharmacotherapy, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, 3508 TB Utrecht, the Netherlands.
Drug Saf. 2010 Feb 1;33(2):127-37. doi: 10.2165/11319870-000000000-00000.
Drugs for rare diseases, so-called orphan drugs, are often intended for serious or chronically debilitating diseases. Safety information is more limited at the time of approval for orphan drugs as a result of various factors, such as the limited number of patients in clinical trials, quality of the clinical trials and special approval procedures. Several studies have been conducted on safety-related regulatory actions for drugs, but none of these have specifically focused on orphan drugs.
To determine the frequency and nature of safety-related regulatory actions for orphan drugs in the US and EU.
This cohort study examined publicly available data from the websites of US and EU regulatory authorities on orphan drugs approved in the US and/or the EU between January 2000 and December 2007. The main outcome measures were the nature, frequency and timing of safety-related regulatory actions, defined as (i) safety withdrawals; (ii) 'black-box' warnings; and (iii) written communications to healthcare professionals issued by the US FDA or the European Medicines Agency between January 2000 and June 2008.
Ninety-five orphan drugs were approved during the study period (75 in the US, 44 in the EU, and 24 in both regions). Ten products (10.5%) received a safety-related regulatory action. No safety withdrawals, four black-box warnings and 12 written communications were identified. The probability of a first safety-related regulatory action for orphan drugs was 20.3% after 8 years of follow-up. Orphan drugs approved by accelerated approval (relative risk [RR] 3.32; 95% CI 1.06, 10.42), oncological products (RR 7.83; 95% CI 0.96, 63.82) and products for gastrointestinal and metabolism indications (RR 10.44; 95% CI 1.25, 87.27) may have a higher risk for a safety-related regulatory action.
The probability of a first safety-related regulatory action for an orphan drug was slightly lower than that reported in the literature for biologicals in one study and new molecular entities in another study. However, detection of safety issues may be complicated by the limited experience with orphan drugs in practical use due to the low prevalences of the diseases they are used for. Doctors and pharmacists should therefore be vigilant with regard to the occurrence of a safety-related issue for orphan drugs.
治疗罕见病的药物，即所谓的孤儿药，通常用于治疗严重或慢性衰弱性疾病。由于各种因素，如临床试验中患者人数有限、临床试验质量和特殊审批程序，孤儿药在获得批准时的安全性信息更为有限。已经有几项关于药物相关监管行动的安全性的研究，但没有一项专门针对孤儿药。
确定美国和欧盟孤儿药的安全性相关监管行动的频率和性质。
这项队列研究检查了美国和欧盟监管机构网站上的公开数据，这些数据涉及 2000 年 1 月至 2007 年 12 月期间在美国和/或欧盟批准的孤儿药。主要结局指标是安全性相关监管行动的性质、频率和时间，定义为（i）安全性撤回；（ii）“黑框”警告；以及（iii）2000 年 1 月至 2008 年 6 月期间由美国 FDA 或欧洲药品管理局向医疗保健专业人员发布的书面通讯。
在研究期间，有 95 种孤儿药获得批准（美国 75 种，欧盟 44 种，美国和欧盟各 24 种）。10 种产品（10.5%）收到了与安全性相关的监管行动。未发现安全性撤回、4 个黑框警告和 12 个书面通讯。经过 8 年的随访，孤儿药首次出现与安全性相关的监管行动的概率为 20.3%。通过加速审批获得批准的孤儿药（相对风险 [RR] 3.32；95%CI 1.06，10.42）、肿瘤产品（RR 7.83；95%CI 0.96，63.82）和胃肠道和代谢适应证产品（RR 10.44；95%CI 1.25，87.27）可能有更高的安全性相关监管行动风险。
孤儿药首次出现与安全性相关的监管行动的概率略低于一项研究中生物制剂和另一项研究中新分子实体的报告。然而，由于用于治疗的疾病患病率较低，孤儿药在实际应用中的经验有限，可能会使安全性问题的检测变得复杂。因此，医生和药剂师应警惕孤儿药出现安全性问题。
