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辉瑞：“西乐葆”临床用药安全受质疑
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案例主角（2004年12月）： 美国辉瑞公司是一家拥有一百五十多年历史的世界著名的研究、开发型跨国制药企业，并在心血管、内分泌、呼吸系统和感染性疾病、精神科、关节炎和其他炎症、泌尿科、癌症、眼科疾病等医学领域均保持领先水平。在中国成立的辉瑞制药有限公司是目前在华投资最大的外资制药企业之一。 公司始终恪守“关爱生命，辉瑞使命”承诺，２００５年，辉瑞上榜《财富》杂志“全美百家最适宜工作的企业”，列“胡润2005中国内地慈善企业榜”跨国公司前10名，名列中文版《福布斯》跨国公司慈善捐赠排名第六位。 案例回放：（资料来源《新快报》《广州日报》） 西乐葆（塞来昔布）是西布类非甾体抗炎药，临床上主要用于治疗骨关节炎、类风湿关节炎及家族性腺瘤息肉的辅助治疗，1998年获准在美国上市。2000年9月，国家食品药品监督管理局批准辉瑞制药有限公司的西乐葆进口分装并在中国上市。截至目前，西乐葆已获准在72个国家(地区)上市销售。 ？年9月30日默沙东(Merck&Co又称默克)公司因为患者服用万络万导致心脏病发作和中风危险性增加1倍而自愿做出全球回收行动（默沙东回收万络案例见本章第五节）。 辉瑞公司的西乐葆与万络属于同一类药物，针对万络回收事件，辉瑞公司在9月30日和10月1日连续两天发表声明表示西乐葆是安全的：“资料表明，在疼痛和关节炎治疗中，即使用药高于西乐葆推荐剂量，也不增加发生心脏病事件或脑中风的危险。” 公司宣布，将为此进行一项有关西乐葆的大规模临床试验，会有数千名有类风湿关节炎和严重心脏病史的患者参与。 美国食品药品监督管理局(FDA)12月17日公布“辉瑞公司生产的大剂量服用西乐葆有增加患者心血管的”。此消息一出，道?琼斯成分股辉瑞公司股价应声下落，跌至近7年来的新低，并拖累股市大盘。 12月20日,根据药物安全性监测委员会向辉瑞报告的信息，美国国立癌症研究所的研究发现，在应用西乐葆预防结肠腺瘤的试验中，每天服用400毫克和800毫克西乐葆组的患者发生致命和非致命心血管事件的风险大约是服用安慰剂组的25倍。 辉瑞公司董事长兼首席执行官马金龙博士表示，辉瑞将立即采取措施以全面了解这些结果，并迅速与全球药政管理部门、医生及患者对这些新信息进行沟通。辉瑞公司全球研发总裁建议，目前使用西乐葆治疗的患者应与其专业医师讨论合适的治疗选择，医师则应在处方中考虑这些新信息以及传统非甾体类抗炎药中出现的溃疡和胃肠道出血危险因素。另外，辉瑞将继续和美国食品药品管理局共同努力进行一项大型研究，以进一步评价西乐葆在伴有心血管疾病高风险的骨关节炎患者治疗中的应用。 12月21日,我国食品药品监督管理局(SFDA)发文，称西乐葆引起心血管疾病的危险性还有待进一步研究，SFDA将密切跟踪西乐葆的安全性评估进展，并要求辉瑞制药有限公司及时报告相关信息。同时提醒服用该药的患者，在出现与心血管系统相关的不适时，一定要及时咨询医生。 2005年2月19日，美国FDA(食品药品监督管理局)专家顾问委员会批准通过“西乐葆可被公众继续使用”。 案例点评: 辉瑞公司在西乐葆被质疑临床安全的事件中，表现出了其卓越的公关能力。 符合承担责任原则（40分）。 默沙东在9月30日回收万络后,虽然瑞辉公司一再表明“即使用药高于西乐葆推荐剂量，也不增加发生心脏病事件或脑中风的危险”，但10月18日辉瑞公司随即宣布投入巨资对其进行安全性实验，体现出了对消费者的责任感和制药巨头的气魄。 符合真诚沟通原则（20分）。 当美国食品药品监督管理局(FDA)12月17日公布了“辉瑞公司生产的大剂量服用西乐葆有增加患者心血管的风险”时，辉瑞公司随即要求目前使用西乐葆治疗的患者应与其专业医师讨论合适的治疗选择。 符合速度第一原则（20分）。 辉瑞公司对媒体和公众自始至终保持了坦诚开明的心胸，赢得了好感。公司不仅没有隐瞒西乐葆的真相，甚至在宣布对西乐葆进行安全实验前几天的，10月15日，辉瑞公司还公布了两项其治疗关节炎的新药（Bextra）不利的结果：研究显示在接受心血管搭桥手术的患者中，服用其第二代关节炎治疗药物Bextra，可能导致心脏病发作和中风的风险加大。 符合系统运行原则（10分）。 一方面回收药品，一方面与ＦＤＡ合作。 符合权威证实原则（10分）。 由总裁出面，表示公司对患者安全的重视。在安全性受到质疑后，辉瑞公司董事长兼首席执行官及全球研发总裁迅速向公众表明了自已的态度和建议，给消费者留下了深刻的印象。 案例评分：１００分 |
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3楼2009-03-24 18:43:44
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The Adenoma Prevention with Celecoxib and Prevention of Colorectal Sporadic Adenomatous Polyps Trials: Stepping Stones to Progress Medical science and clinical practice progress through iterative cycles of discovery and translation. Through this process, cumulative insights into carcinogenesis at the nano/molecular level have radically transformed our views of health and illness and ignited demand for improved disease prediction, prevention, and personalization (1). Interactions within and across scientific disciplines will drive progress along the translational continuum from discovery to the successful development of new/reprogrammed clinical tools, or to "productive failures" (e.g., the generation of reliable, accurate data that do not confirm the initial hypothesis), most likely in a nonlinear manner. The presence versus absence of well-maintained linkages and clean hand-offs between disciplines and research cycles will govern the rate at which we progress toward achieving these goals. The Adenoma Prevention with Celecoxib and Prevention of Colorectal Sporadic Adenomatous Polyps Trials The development of celecoxib (a cyclooxygenase-2 inhibitor or COXIB) for colorectal adenomas is a recent case in point. Together, the Adenoma Prevention with Celecoxib (APC) and the Prevention of Colorectal Sporadic Adenomatous Polyps (PreSAP) trials randomized more than 3,500 patients with prior adenomas to celecoxib (at one of three doses: 200 mg b.i.d, 400 mg q.d, or 400 mg b.i.d.) versus placebo for up to 3 years (2, 3). The trials were conceived, administered, and supported by collaborators from academia, National Cancer Institute, and industry and involved more than 200 clinical sites worldwide, creating a virtual network of clinical investigators, support staff, and monitors. Although the trials were independent, at specific junctures, the research teams worked together to assure that their data would meet rigorous scientific and regulatory standards. Both trials showed a statistically significant 33% to 45% reduction in recurrent colorectal adenomas, with greater effectiveness against advanced adenomas and in patient subsets (those with a personal history of large and/or multiple adenomas or a family history of colorectal cancer) presumed to be at higher risk for colorectal cancer. In addition, the trials inadvertently identified the potential for serious cardiovascular risks with celecoxib use (4, 5). Despite resounding and mutually confirmed efficacy, intense focus on cardiovascular risks identified in these trials has prevented us from fully probing two key questions, the answers to which may mitigate uncertainty among chemoprevention investigators and suggest a way forward. First, what did these massive efforts (and investments) achieve? Second, where do we go from here? The immediate answer is obvious. Celecoxib was definitively shown to reduce adenoma recurrence in a dose-dependent manner and drew attention to an increased risk of cardiovascular events compared with placebo in patients with prior adenomas. Importantly, celecoxib was more effective against more advanced lesions and in patients at greatest risk for colorectal cancer. Demonstration of these effects is precisely what one would hope from a highly effective chemopreventive agent. In addition, the trials showed beneficial effects across a spectrum of pathologic features (i.e., adenoma size, number, and burden), providing a measure of internal validation for inferences of efficacy. That said, we must interpret these data with caution. Although the trials were inadequately powered to do so, neither showed efficacy against a longer-term goal of interest, reduction of colorectal cancer. With regard to cardiovascular safety concerns, the APC trial showed an apparent adverse dose-response effect, with greater toxicity observed in patients receiving the higher dose. The PreSAP trial did not report a statistically significant difference in serious adverse cardiovascular events; however, it was not powered to do so. This result leaves open the important question as to whether the PreSAP trial's alternative dosing schedule (i.e., 400 mg daily), which was effective against colorectal adenomas, might convey significant cardiovascular risks. The APC and PreSAP trials, taken together with data from the Adenomatous Polyp Prevention on Vioxx trial (6) and various observational studies (7, 8), suggest that cardiovascular risks seen with celecoxib may also extend to other nonsteroidal anti-inflammatory drugs and COXIBs (e.g., etoricoxib and diclofenac). The clinical effect of these data on the public's health is difficult to estimate with precision. NSAIDs had been used for decades by millions of individuals worldwide to treat arthritis and pain before the emergence of these safety concerns. Although many NSAIDs/COXIBs are still appropriately used to treat these and other conditions, their risk/benefit profiles are now better defined. Indeed, cardiovascular risk characterization of NSAIDs/COXIBs may prove one of the more enduring contributions of this research cycle. Furthermore, these phase III trial results provide a measure of validation for the models, strategies, and studies that preceded them. The identification of cyclooxygenase as a promising target and NSAIDs/COXIBs as a promising class of compounds was derived from several converging lines of evidence-mechanistic, preclinical, and observational (9). For example, celecoxib was shown to inhibit intestinal carcinogenesis in mice with adenomatous polyposis coli mutations (10) and in rats with carcinogen-induced neoplasia (11), suggesting the usefulness of both animal models in vetting promising chemopreventive agents despite differences in the site of disease (small intestine versus colon, respectively) and certain reservations on the part of researchers. |
2楼2009-01-08 13:16:47