European Medicines Agency (EMEA), 7 Westferry circus, London E14 4HB, United Kingdom.
Eur Neuropsychopharmacol. 2010 Mar;20(3):139-45. doi: 10.1016/j.euroneuro.2009.12.002. Epub 2010 Jan 6.
In this paper we investigate mortality in short-term placebo-controlled trials conducted to demonstrate efficacy and safety of atypical antipsychotic drugs for the treatment of schizophrenic patients in the acute phase of illness. Arguments are provided, why short-term placebo-controlled studies are required. This is an integrated analysis of results from randomized placebo-controlled trials conducted pre-licensing for risperidone, olanzapine, quetiapine IR, ziprasidone, risperidone consta, aripiprazole, paliperidone, and quetiapine XR. Information was retrieved from study publications, EPAR, and from the FDA SBA, all in the public domain. 7553 patients were randomized in the remaining 23 short-term acute phase clinical trials. 2/5738 patients died after having been randomized to an active treatment. 5/1815 died in the placebo group. The crude odds-ratio for an increased death risk with placebo treatment is 7.92 (95% confidence interval (1.45 to 40.87), two sided P=0.0134). Death narratives show: (i) both deaths in active treatment groups occurred during randomized treatment period, (ii) two deaths in the placebo group of a trial in the elderly were observed in patients with severe co-morbidities not usually included in a randomized trial, and (iii) two further deaths in the placebo groups occurred 9 and 23 days after the end of the randomized treatment period. Under these circumstances the crude odds-ratio for an increased risk of death for patient with placebo as compared to active treatment is 1.58 (95% confidence interval (0.14-17.45), two sided P=0.71). Confidence intervals are generally wide indicating a still limited knowledge about a potential increase in mortality with placebo treatment. Unless, however, society is willing to take the risk that ineffective drugs are licensed and cause undetected harm thereafter, or is willing to restrict licensing to drugs that are superior to current treatments, short-term placebo-controlled trials in the acute phase of schizophrenia are necessary. Measures are proposed to minimize risks.
在本文中，我们研究了在证明治疗精神分裂症患者急性期的非典型抗精神病药物的疗效和安全性的短期安慰剂对照试验中的死亡率。提供了为什么需要短期安慰剂对照研究的论据。这是对 risperidone、olanzapine、quetiapine IR、ziprasidone、risperidone consta、aripiprazole、paliperidone 和 quetiapine XR 的许可前进行的随机安慰剂对照试验的结果进行的综合分析。信息从研究出版物、EPAR 和 FDA SBA 中检索，均为公开发布。7553 名患者被随机分配到剩余的 23 项短期急性临床试验中。在被分配到活性治疗的 5738 名患者中有 2 名死亡。1815 名患者中的 5 名在安慰剂组死亡。安慰剂治疗死亡风险增加的粗优势比为 7.92（95%置信区间（1.45 至 40.87），双侧 P=0.0134）。死亡叙述显示：（i）在活性治疗组中，两例死亡均发生在随机治疗期间；（ii）在老年患者的试验中，安慰剂组的两例死亡发生在通常不包括在随机试验中的严重合并症患者中；（iii）安慰剂组的另外两例死亡发生在随机治疗结束后 9 天和 23 天。在这种情况下，与活性治疗相比，安慰剂组患者死亡风险的粗优势比为 1.58（95%置信区间（0.14-17.45），双侧 P=0.71）。置信区间通常较宽，表明人们对安慰剂治疗可能增加死亡率的认识仍然有限。除非社会愿意承担批准无效药物并随后造成未检测到的伤害的风险，或者愿意将许可限制在优于现有治疗方法的药物上，否则在精神分裂症急性期进行短期安慰剂对照试验是必要的。提出了一些措施来降低风险。
