FDA Center for Biologics Evaluation and Research, Office of Biostatistics and Epidemiology, Silver Spring, Maryland.
FDA Center for Drug Evaluation and Research, Office of Pharmaceutical Quality, Silver Spring, Maryland.
Pharmacoepidemiol Drug Saf. 2020 May;29(5):575-581. doi: 10.1002/pds.4982. Epub 2020 Mar 5.
In the late1990s, reacting to the outbreak of bovine spongiform encephalopathy (BSE) in the United Kingdom that caused a new variant of Creutzfeldt-Jakob disease (vCJD) in humans, manufacturers withdrew bovine heparin from the market in the United States. There have been growing concerns about the adequate supply and safety of porcine heparin. Since the BSE epidemic has been declining markedly, the US Food and Drug Administration reevaluates the vCJD risk via use of bovine heparin.
We developed a computational model to estimate the vCJD risk to patients receiving bovine heparin injections. The model incorporated information including BSE prevalence, infectivity levels in the intestines, manufacturing batch size, yield of heparin, reduction in infectivity by manufacturing process, and the dose-response relationship.
The model estimates a median risk of vCJD infection from a single intravenous dose (10 000 USP units) of heparin made from US-sourced bovine intestines to be 6.9 × 10 (2.5-97.fifth percentile: 1.5 × 10 -4.3 × 10 ), a risk of 1 in 145 million, and 4.6 × 10 (2.5-97.fifth percentile: 1.1 × 10 -2.6 × 10 ), a risk of 1 in 22 million for Canada-sourced products. The model estimates a median risk of 1.4 × 10 (2.5-97.fifth percentile: 2.9 × 10 -9.3 × 10 ) and 9.6 × 10 (2.5-97.fifth percentile: 2.1 × 10 -5.6 × 10 ) for a typical treatment for venous thromboembolism (infusion of 2-4 doses daily per week) using US-sourced and Canada-sourced bovine heparin, respectively.
The model estimates the vCJD risk from use of heparin when appropriately manufactured from US or Canadian cattle is likely small. The model and conclusions should not be applied to other medicinal products manufactured using bovine-derived materials.
20 世纪 90 年代末，针对英国爆发的牛海绵状脑病（BSE）导致人类新型克雅氏病（vCJD），制造商从美国市场撤回牛肝素。人们越来越担心猪肝素的供应充足性和安全性。由于 BSE 疫情明显下降，美国食品和药物管理局重新评估了使用牛肝素的 vCJD 风险。
我们开发了一种计算模型来估计接受牛肝素注射的患者感染 vCJD 的风险。该模型纳入了包括 BSE 流行率、肠道传染性水平、生产批次大小、肝素产量、生产过程中传染性降低以及剂量反应关系在内的信息。
该模型估计，从源自美国的牛肠道制成的每单位静脉剂量（10 000USP 单位）的肝素单次注射感染 vCJD 的中位数风险为 6.9×10 -2 （2.5-97. 第五百分位：1.5×10 -4 -3×10 -2 ），风险为 1 比 1.45 亿，源自加拿大的产品为 4.6×10 -2 （2.5-97. 第五百分位：1.1×10 -2 -2.6×10 -2 ），风险为 1 比 2200 万。该模型估计，源自美国的肝素每日输注 2-4 次，每次治疗静脉血栓栓塞症（venous thromboembolism）的中位数风险为 1.4×10 -1 （2.5-97. 第五百分位：2.9×10 -9 -3×10 -1 ），源自加拿大的产品为 9.6×10 -1 （2.5-97. 第五百分位：2.1×10 -5 -5.6×10 -1 ）。
当适当从美国或加拿大牛中制造肝素时，该模型估计使用肝素感染 vCJD 的风险可能较小。该模型和结论不应适用于使用牛源性材料制造的其他药物产品。
