Evaluating clinical trial designs for investigational treatments of Ebola virus disease.
Evaluating clinical trial designs for investigational treatments of Ebola virus disease.
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DOI：
10.1371/journal.pmed.1001815
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发表时间：
2015-04
期刊：
影响因子：
15.8
通讯作者：
Whitehead J
中科院分区：
文献类型：
--
作者：
Cooper BS;Boni MF;Pan-ngum W;Day NP;Horby PW;Olliaro P;Lang T;White NJ;White LJ;Whitehead J
埃博拉病毒病（EVD）的实验性治疗可能降低EVD死亡率。不同临床试验设计确定有效治疗方法的能力存在不确定性，在埃博拉疫情期间实施单独随机对照试验的可行性也存在不确定性。采用多阶段方法（MSA）设计了用于埃博拉病毒病的治疗评估方案，其中包括两个或三个阶段，包括非随机和随机因素。比较了两种流行情况下正确或错误推荐实验治疗的概率、所需的样本量以及对100 d以上流行结果的影响，分别为MSA、包含多达20个中期分析的顺序随机对照试验（SRCT）和作为参考病例、不包含中期分析的常规随机对照试验（RCT）。假设在接受当前标准支持治疗的人群中，有50%的14天生存率，所有设计都有相似的正确识别有效治疗的概率，而MSA推荐无效治疗的可能性较小。MSA减少了接受无效治疗的病例数量，加快了高效治疗的推广。对于效果较差的治疗，MSA很有可能包括RCT成分，导致推出或排斥的时间较长。假设每天有100例新的埃博拉病毒病病例，与SRCT相比，MSA在前100天内对高效治疗的流行病死亡率降低了6%至15%。如果测试的干预措施是非常有效或有害的，那么MSA和SRCT导致的死亡人数都比传统的RCT少得多。在拟议的MSA中，对非随机成分结果有效性的主要威胁是，转诊模式、护理标准或病毒本身可能在研究期间发生变化，从而影响死亡率。如果没有同时的对照组，不良事件也更难量化。MSA可以迅速抛弃无效的治疗方法，同时可靠地提供有关有效治疗方法的证据。MSA适用于EVD治疗的临床评价。Ben Cooper和他的同事建立了不同的试验设计模型，包括包含非随机和随机元素的多阶段方法。目前爆发的埃博拉病毒病（EVD）是一种经常致命的疾病，于1976年首次出现在中非偏远村庄的人群中，自2014年初以来，几内亚、塞拉利昂和利比里亚已有2.4万多人感染，1万多人死亡。埃博拉病毒通过直接接触体液（包括血液、唾液和尿液）或感染者的器官，或通过接触被体液污染的床上用品和其他材料，从野生动物传播给人，并在人群中传播。埃博拉病毒病在感染后2-21天开始出现症状，包括发烧、头痛、呕吐、腹泻和内外出血。受感染的人在出现症状之前是没有传染性的，但只要他们的体液中含有病毒，就会保持传染性。目前尚无针对埃博拉病毒病的经证实的治疗方法或疫苗，但在严格隔离条件下提供支持性护理以防止疾病传播给其他患者或卫生保健工作者，可提高生存率。埃博拉病毒病的潜在治疗方法包括几种抗病毒药物和从埃博拉病毒病幸存者身上注射针对埃博拉病毒的抗体。在这些疗法用于临床之前，需要对其安全性和有效性进行评估，但专家们对如何进行评估意见不一。临床使用的药物通常是通过一系列的临床试验来评估的。第一阶段的试验通过给几名健康志愿者服用这种药物来确定治疗的安全性，以及人体如何应对这种药物。接下来，第二阶段的试验通过给一些病人用药来提供药物疗效的早期迹象。最后，一项大规模的多臂III期随机对照试验（RCT）通过比较随机选择接受研究药物或标准治疗的患者的结果来证实药物的疗效。这个评估过程非常漫长。此外，在埃博拉疫情期间，只有部分患者接受了可能挽救生命的药物，开展这种随机对照试验在伦理上很难证明是合理的。在这里，研究人员评估了EVD药物评估的多阶段方法（MSA），包括单臂II期研究，然后是一项或两项III期试验，其中一项可能是顺序随机对照试验（SRCT），一种允许多个中期分析的随机对照试验，每一项分析都可能导致研究终止。研究人员使用分析方法和计算机模拟比较了使用MSA、SRCT和常规RCT的EVD药物评估，没有进行中期分析。具体来说，他们估计了正确或错误推荐实验性治疗的概率，以及三种方法在100天内对流行病结果的影响。假设仅接受支持性治疗的患者在症状出现后14天的存活率为50%，所有三个试验设计都同样可能确定有效的治疗方法，但MSA比其他设计更不可能错误地推荐无效的治疗方法。值得注意的是，MSA导致接受无效治疗的患者减少，高效治疗的推广速度加快。在每天发生100例新病例的流行病中，通过高效治疗，MSA在流行病发生的前100天内导致的流行病死亡率下降幅度比SRCT高6%至15%。最后，如果被测试的干预措施是非常有效或有害的，那么MSA和SRCT导致的死亡人数都比传统的RCT少。这些发现表明，对于没有临床显著益处或死亡率大幅降低的实验性治疗，MSA可以比其他测试方法更快地提供有关药物有效性的有用信息。因此，MSA有可能减少对患者的伤害，并争取时间推出针对埃博拉病毒病的有效治疗方法。虽然其他的评估设计是可能的，但研究人员认为，在第二阶段包括一个非随机设计是对潜在治疗进行分类并决定如何进一步测试的最快方法。他们建议，对于有强有力证据表明有益的治疗方法，甚至可以在不进行随机对照试验的情况下推荐这种治疗方法。此外，对于在第二阶段只显示出适度益处的治疗方法，应该更容易（也更合乎道德）建立随机对照试验来进一步测试治疗。请通过本摘要的在线版本（http://dx.doi.org/10.1371/journal.pmed.1001815）访问这些网站。世界卫生组织（世卫组织）提供关于埃博拉病毒病的信息，关于埃博拉病毒病潜在治疗方法的信息，并定期更新当前埃博拉病毒病流行情况；世卫组织伦理工作组会议关于与埃博拉病毒病药物试验研究设计有关的伦理问题的讨论摘要已提供；世卫组织网站还提供有关在现场控制埃博拉病毒的努力和埃博拉病毒病幸存者的个人故事的信息，英国国家卫生服务选择网站提供有关埃博拉病毒病的详细信息，美国疾病控制和预防中心也提供有关埃博拉病毒病的信息，维基百科提供有关适应性临床试验设计的信息；柳叶刀全球健康博客的一篇文章讨论了为什么应该使用适应性试验设计来评估治疗埃博拉病毒病的药物
Experimental treatments for Ebola virus disease (EVD) might reduce EVD mortality. There is uncertainty about the ability of different clinical trial designs to identify effective treatments, and about the feasibility of implementing individually randomised controlled trials during an Ebola epidemic. A treatment evaluation programme for use in EVD was devised using a multi-stage approach (MSA) with two or three stages, including both non-randomised and randomised elements. The probabilities of rightly or wrongly recommending the experimental treatment, the required sample size, and the consequences for epidemic outcomes over 100 d under two epidemic scenarios were compared for the MSA, a sequential randomised controlled trial (SRCT) with up to 20 interim analyses, and, as a reference case, a conventional randomised controlled trial (RCT) without interim analyses. Assuming 50% 14-d survival in the population treated with the current standard of supportive care, all designs had similar probabilities of identifying effective treatments correctly, while the MSA was less likely to recommend treatments that were ineffective. The MSA led to a smaller number of cases receiving ineffective treatments and faster roll-out of highly effective treatments. For less effective treatments, the MSA had a high probability of including an RCT component, leading to a somewhat longer time to roll-out or rejection. Assuming 100 new EVD cases per day, the MSA led to between 6% and 15% greater reductions in epidemic mortality over the first 100 d for highly effective treatments compared to the SRCT. Both the MSA and SRCT led to substantially fewer deaths than a conventional RCT if the tested interventions were either highly effective or harmful. In the proposed MSA, the major threat to the validity of the results of the non-randomised components is that referral patterns, standard of care, or the virus itself may change during the study period in ways that affect mortality. Adverse events are also harder to quantify without a concurrent control group. The MSA discards ineffective treatments quickly, while reliably providing evidence concerning effective treatments. The MSA is appropriate for the clinical evaluation of EVD treatments. Ben Cooper and colleagues model different trial designs, including a multi-stage approach that contains non-randomized and randomized elements. The current outbreak of Ebola virus disease (EVD)—a frequently fatal disease that first appeared in human populations in 1976 in remote villages in central Africa—has infected more than 24,000 people and killed more than 10,000 people in Guinea, Sierra Leone, and Liberia since early 2014. Ebola virus is transmitted to people from wild animals and spreads in human populations through direct contact with the bodily fluids (including blood, saliva, and urine) or with the organs of infected people or through contact with bedding and other materials contaminated with bodily fluids. The symptoms of EVD which start 2–21 days after infection, include fever, headache, vomiting, diarrhea, and internal and external bleeding. Infected individuals are not infectious until they develop symptoms but remain infectious as long as their bodily fluids contain virus. There is no proven treatment or vaccine for EVD, but supportive care—given under strict isolation conditions to prevent the spread of the disease to other patients or to healthcare workers—improves survival. Potential treatments for EVD include several antiviral drugs and injections of antibodies against Ebola virus from patients who have survived EVD. Before such therapies can be used clinically, their safety and effectiveness need to be evaluated, but experts disagree about how to undertake this evaluation. Drugs for clinical use are usually evaluated by undertaking a series of clinical trials. A phase I trial establishes the safety of the treatment and how the human body copes with it by giving several healthy volunteers the drug. Next, a phase II trial provides early indications of the drug’s efficacy by giving a few patients the drug. Finally, a large-scale multi-arm phase III randomized controlled trial (RCT) confirms the drug’s efficacy by comparing outcomes in patients randomly chosen to receive the investigational drug or standard care. This evaluation process is very lengthy. Moreover, it is hard to ethically justify undertaking an RCT in which only some patients receive a potentially life-saving drug during an Ebola epidemic. Here, the researchers evaluate a multi-stage approach (MSA) to EVD drug evaluation that comprises a single-arm phase II study followed by one or two phase III trials, one of which may be a sequential RCT (SRCT), a type of RCT that allows for multiple interim analyses, each of which may lead to study termination. The researchers used analytic methods and computer simulations to compare EVD drug evaluation using the MSA, an SRCT, and a conventional RCT without interim analyses. Specifically, they estimated the probabilities of rightly or wrongly recommending the experimental treatment and the consequences for epidemic outcomes over 100 days for the three approaches. Assuming 50% survival at 14 days after symptom development in patients treated with supportive care only, all three trial designs were equally likely to identify effective treatments, but the MSA was less likely than the other designs to incorrectly recommend an ineffective treatment. Notably, the MSA led to fewer patients receiving ineffective treatments and faster roll-out of highly effective treatments. In an epidemic where 100 new cases occurred per day, for highly effective treatments, the MSA led to between 6% and 15% larger reductions in epidemic mortality over the first 100 days of the epidemic than the SRCT did. Finally, both the MSA and the SRCT led to fewer deaths than the conventional RCT if the tested interventions were either highly effective or harmful. These findings suggest that for experimental treatments that offer either no clinically significant benefit or large reductions in mortality the MSA can provide useful information about drug effectiveness faster than the other approaches tested. Thus, the MSA has the potential to reduce patient harm and the time to roll-out of an effective treatment for EVD. Although alternative evaluation designs are possible, the researchers suggest that including a non-randomized design in phase II is the quickest way to triage potential treatments and to decide how to test them further. For treatments that show strong evidence of benefit, it might even be possible to recommend the treatment without undertaking an RCT, they suggest. Moreover, for treatments that show only modest benefit in phase II, it should be easier (and more ethical) to set up RCTs to test the treatment further. Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001815. The World Health Organization (WHO) provides information about EVD, information about potential EVD therapies, and regular updates on the current EVD epidemic; a summary of the discussion of a WHO Ethics Working Group Meeting on the ethical issues related to study design for EVD drug trials is available; the WHO website also provides information about efforts to control Ebola in the field and personal stories from people who have survived EVD The UK National Health Service Choices website provides detailed information on EVD The US Centers for Disease Control and Prevention also provides information about EVD Wikipedia provides information about adaptive clinical trial design; a Lancet Global Health blog argues why adaptive trial designs should be used to evaluate drugs for the treatment of EVD
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DOI：
10.1056/nejmoa1411100
发表时间：
2014-10-16
期刊：
The New England journal of medicine
影响因子：
--
作者：
WHO Ebola Response Team;Aylward B;Barboza P;Bawo L;Bertherat E;Bilivogui P;Blake I;Brennan R;Briand S;Chakauya JM;Chitala K;Conteh RM;Cori A;Croisier A;Dangou JM;Diallo B;Donnelly CA;Dye C;Eckmanns T;Ferguson NM;Formenty P;Fuhrer C;Fukuda K;Garske T;Gasasira A;Gbanyan S;Graaff P;Heleze E;Jambai A;Jombart T;Kasolo F;Kadiobo AM;Keita S;Kertesz D;Koné M;Lane C;Markoff J;Massaquoi M;Mills H;Mulba JM;Musa E;Myhre J;Nasidi A;Nilles E;Nouvellet P;Nshimirimana D;Nuttall I;Nyenswah T;Olu O;Pendergast S;Perea W;Polonsky J;Riley S;Ronveaux O;Sakoba K;Santhana Gopala Krishnan R;Senga M;Shuaib F;Van Kerkhove MD;Vaz R;Wijekoon Kannangarage N;Yoti Z
通讯作者：
Yoti Z
影响因子：
1.9
作者：
Rosenberger, WF;Stallard, N;Ricks, ML
通讯作者：
Ricks, ML
影响因子：
2.3
作者：
Whitehead, John
通讯作者：
Whitehead, John
影响因子：
2.7
作者：
Magirr, D.;Jaki, T.;Whitehead, J.
通讯作者：
Whitehead, J.
影响因子：
2
作者：
Jovic, Gordana;Whitehead, John
通讯作者：
Whitehead, John