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为疫情期间开展随机临床试验建立框架
Creating a Framework for Conducting Randomized Clinical Trials during Disease Outbreaks


Natalie E. Dean ... 其他 • 2020.04.02
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人们逐渐认识到在传染病突发(如目前的COVID-19大流行)期间对新型干预措施开展试验是确定潜在疫苗和疗法效果的重要手段。评估试验性干预措施的临床试验是控制传染病传播和改善患者结局的更广泛工作中的一部分。然而,这种情况下可能难以获得指导今后患者治疗和公共卫生规划所需的干预措施效果证据,其中部分原因是疫情的规模、发生地点和持续时间无法预测1

 

研究结果是否要发表


由于担心发表偏倚,因此我们强调所有临床试验的结果都应发表,包括在疫情结束时提前终止且未得到明确结果的试验。这一原则包含在《赫尔辛基宣言》等关于临床试验伦理框架的各种声明中。根据这一原则,在2014—2016年西非埃博拉疫情期间开展,并因病毒传播减弱而提前终止(未达到预定的终止标准)的试验中,研究人员在试验结束时根据原计划将不明确的结果投稿发表2-4。避免发表偏倚对于制定合理政策至关重要,然而发表不明确的结果(如来自统计学功效不足的研究)可能明显加大为干预措施的疗效和安全性建立明确证据的难度5,6

疫情结束时,如果部分完成的试验发布其很有前景但并不明确的结果,则可能支持以下观点:对试验性药物与之前认可的安慰剂或标准治疗药物进行比较的确证性试验将无法再开展。这一假设会造成永久的不确定状态,导致我们无法知晓之前检验过的药物(现在可能被视为标准治疗)和目前正在评价的新药的真实效果。举例来说,这种情况已经发生于以下两种药物的超说明书范围常规用药:利巴韦林用于治疗拉沙热7和奥司他韦用于治疗重度流感。





作者信息

Natalie E. Dean, Ph.D., Pierre-Stéphane Gsell, Ph.D., Ron Brookmeyer, Ph.D., Forrest W. Crawford, Ph.D., Christl A. Donnelly, Sc.D., Susan S. Ellenberg, Ph.D., Thomas R. Fleming, Ph.D., M. Elizabeth Halloran, M.D., D.Sc., Peter Horby, Ph.D., Thomas Jaki, Ph.D., Philip R. Krause, M.D., Ira M. Longini, Ph.D., Sabue Mulangu, M.D., Jean-Jacques Muyembe-Tamfum, M.D., Martha C. Nason, Ph.D., Peter G. Smith, D.Sc., Rui Wang, Ph.D., Ana M. Henao-Restrepo, M.D., and Victor De Gruttola, Sc.D.
From the Department of Biostatistics, University of Florida, Gainesville (N.E.D., I.M.L.); the World Health Organization, Geneva (P.-S.G., A.M.H.-R.); the Department of Biostatistics, University of California, Los Angeles (R.B.); the Department of Biostatistics, Yale University, New Haven, CT (F.W.C.); the Department of Statistics (C.A.D.) and the Centre for Tropical Medicine and Global Health (P.H.), University of Oxford, Oxford, the Medical Research Council (MRC) Centre for Global Infectious Disease Analysis, Department of Infectious Disease Epidemiology, Imperial College London (C.A.D.), and the MRC Tropical Epidemiology Group, London School of Hygiene and Tropical Medicine (P.G.S.), London, and the Department of Mathematics and Statistics, Lancaster University, Lancaster (T.J.) — all in the United Kingdom; the Department of Biostatistics, Epidemiology, and Informatics, University of Pennsylvania, Philadelphia (S.S.E.); the Department of Biostatistics, University of Washington (T.R.F., M.E.H.), and the Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center (M.E.H.) — both in Seattle; the Office of Vaccines Research and Review, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring (P.R.K.), and the Biostatistics Research Branch, National Institute of Allergy and Infectious Diseases, Bethesda (M.C.N.) — both in Maryland; Institut National de Recherche Biomédicale, Kinshasa, Democratic Republic of Congo (S.M., J.-J.M.-T.); and the Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute (R.W.), and the Department of Biostatistics, Harvard T.H. Chan School of Public Health (R.W., V.D.G.) — both in Boston.

 

参考文献

1. Dean NE, Gsell P-S, Brookmeyer R, et al. Design of vaccine efficacy trials during public health emergencies. Sci Transl Med 2019;11(499):eaat0360-eaat0360.

2. Kennedy SB, Neaton JD, Lane HC, et al. Implementation of an Ebola virus disease vaccine clinical trial during the Ebola epidemic in Liberia: design, procedures, and challenges. Clin Trials 2016;13:49-56.

3. Samai M, Seward JF, Goldstein ST, et al. The Sierra Leone trial to introduce a vaccine against Ebola: an evaluation of rVSV∆G-ZEBOV-GP vaccine tolerability and safety during the West Africa Ebola outbreak. J Infect Dis 2018;217:Suppl 1:S6-S15.

4. The PREVAIL II Writing Group for the Multi-National PREVAIL II Study Team. A randomized, controlled trial of ZMapp for Ebola virus infection. N Engl J Med 2016;375:1448-1456.

5. Grant AM, Altman DG, Babiker AB, et al. Issues in data monitoring and interim analysis of trials. Health Technol Assess 2005;9:1-238.

6. Fleming TR, DeMets DL, Roe MT, et al. Data monitoring committees: promoting best practices to address emerging challenges. Clin Trials 2017;14:115-123.

7. Houlihan C, Behrens R. Lassa fever. BMJ 2017;358:j2986-j2986.

8. Mulangu S, Dodd, LE, Davey RT Jr, et al. A randomized, controlled trial of Ebola virus disease therapeutics. N Engl J Med 2019;389:2293-2303.

9. Kieny MP, Salama P. WHO R&D Blueprint: a global coordination mechanism for R&D preparedness. Lancet 2017;389:2469-2470.

10. Woodcock J, LaVange LM. Master protocols to study multiple therapies, multiple diseases, or both. N Engl J Med 2017;377:62-70.

11. DeMets DL, Lan G. The alpha spending function approach to interim data analyses. Cancer Treat Res 1995;75:1-27.

12. Steere AC, Sikand VK, Meurice F, et al. Vaccination against Lyme disease with recombinant Borrelia burgdorferi outer-surface lipoprotein A with adjuvant. N Engl J Med 1998;339:209-215.

13. Maiztegui JI, McKee KT Jr, Barrera Oro JG, et al. Protective efficacy of a live attenuated vaccine against Argentine hemorrhagic fever. J Infect Dis 1998;177:277-283.

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