临床试验阴性结果应考虑的问题

doi:10.3969/j.issn.1673－5765.2023.06.005

摘要/Abstract

摘要： 临床试验是评估新药或新疗法有效性和安全性最有效的方法，可以提供高质量的循证医学证据。近年来全球的临床试验数量逐渐增加，试验结果为阴性十分常见。当临床试验的主要结果为阴性时，并不一定就意味着研究的失败，研究者还需要多方考虑以便从中找到潜在益处的线索。本文阐述了临床试验主要结局为阴性时需要考虑的12个要点，并以吲哚布芬对比阿司匹林治疗急性缺血性卒中（indobufen versus aspirin in acute ischemic stroke，INSURE）研究为例进行讨论，以期为后续的临床试验设计和结果解读提供经验。

关键词: 临床试验; 阴性结果; 吲哚布芬; 阿司匹林

Abstract: Clinical trials are the most effective method for evaluating the efficacy and safety of new drugs or new therapies, and can provide high-quality evidence-based medical evidence. In recent years, the number of clinical trials worldwide increased gradually, negative results from clinical trials are very common. When the main result of a clinical trial is negative, it does not necessarily mean that the study is a failure, and researchers should consider multiple factors to find potential benefits. Therefore, we elaborated in detail the 12 key points to consider, when encountering the negative primary outcome, and discussed by taking indobufen versus aspirin in acute ischemic stroke (INSURE) study as an example provide reference experience for subsequent clinical research design and results interpretation.

Key words: Clinical trial; Negative result; Indobufen; Aspirin

王梦星, 潘岳松, 刘丹丹, 金奥铭. 临床试验阴性结果应考虑的问题[J]. 中国卒中杂志, 2023, 18(06): 645-650.

WANG Mengxing, PAN Yuesong, LIU Dandan, JIN Aoming. Considerations for Clinical Trial Negative Results [J]. Chinese Journal of Stroke, 2023, 18(06): 645-650.

参考文献

[1] HOPEWELL S，LOUDON K，CLARKE M J，et al. Publication bias in clinical trials due to statistical significance or direction of trial results[J/OL]. Cochrane Database Syst Rev，2009，2009（1）：MR000006[2022-08-11]. https://doi.org/10.1002/14651858.MR000006.pub3.
[2] ClinicalTrials. gov[EB/OL]. （2023-05-26）[ 2023-05-26]. https://www.clinicaltrials.gov/ct2/resources/trends#RegisteredStudiesOverTime.
[3] ANNIE S，ANDY B. China Clinical Trials Landscape[EB/OL]. （2021-09-03）[ 2023-04-30]. https://pharmaintelligence.informa.com/resources/product-content/clinical-trials-landscape.
[4] WOLFE C D，SMEETON N C，COSHALL C，et al. Survival differences after stroke in a multiethnic population：follow-up study with the South London stroke register[J]. BMJ，2005，331（7524）：431.
[5] POCOCK S J，STONE G W. The primary outcome fails - what next?[J]. N Engl J Med，2016，375（9）：861-870.
[6] SWEDBERG K，KOMAJDA M，BÖHM M，et al. Ivabradine and outcomes in chronic heart failure（SHIFT）：a randomised placebo-controlled study[J]. Lancet，2010，376（9744）：875-885.
[7] BHATT D L，STONE G W，MAHAFFEY K W，et al. Effect of platelet inhibition with cangrelor during PCI on ischemic events[J]. N Engl J Med，2013，368（14）：1303-1313.
[8] COHN J N，PFEFFER M A，ROULEAU J，et al. Adverse mortality effect of central sympathetic inhibition with sustained-release moxonidine in patients with heart failure（MOXCON）[J]. Eur J Heart Fail，2003，5（5）：659-667.
[9] DI MAIO M，AUDISIO M，CARDONE C，et al. The use of not-negative conclusions to describe results of formally negative trials presented at oncology meetings[J]. JAMA Oncol，2020，6（6）：926-927.
[10] 国家药品监督管理局. GGTG-2016-11712 药物临床试验数据管理与统计分析的计划和报告指导原则[S]. 北京：中国标准出版社，2016.
[11] 国家药品监督管理局，国家卫生健康委员会. FGWJ-2020-10001 药物临床试验质量管理规范[S]. 北京：中国标准出版社，2020.
[12] Food and Drug Administration. Guidance recap podcast multiple endpoints in clinical trials[EB/OL]. （2022-10-20）[ 2023-05-26]. https://wwwfdagov/drugs/guidances-drugs/guidance-recap-podcast-multiple-endpoints-clinical-trials.
[13] European Medicines Agency. EMA/744060/2017 ICH Topic E 9 Statistical Principles for Clinical Trials[S]. 1998.
[14] SUN X，BRIEL M，BUSSE J W，et al. The influence of study characteristics on reporting of subgroup analyses in randomised controlled trials：systematic review[J/OL]. BMJ，2011，342：d1569[2023-04-30]. https://doi.org/10.1136/bmj.d1569.
[15] POCOCK S J，STONE G W. The primary outcome is positive - is that good enough?[J]. N Engl J Med，2016，375（10）：971-979.
[16] ASSMANN S F，POCOCK S J，ENOS L E，et al. Subgroup analysis and other（mis）uses of baseline data in clinical trials[J]. Lancet，2000，355（9209）：1064-1069.
[17] ROGERS J K，POCOCK S J，MCMURRAY J J，et al. Analysing recurrent hospitalizations in heart failure：a review of statistical methodology，with application to CHARM-Preserved[J]. Eur J Heart Fail，2014，16（1）：33-40.
[18] NEAD K T，WEHNER M R，MITRA N. The use of "trend" statements to describe statistically nonsignificant results in the oncology literature[J]. JAMA Oncol，2018，4（12）：1778-1779.
[19] MACAYA F，RYAN N，SALINAS P，et al. Challenges in the design and interpretation of noninferiority trials：insights from recent stent trials[J]. J Am Coll Cardiol，2017，70（7）：894-903.
[20] POCOCK S J，ROSSELLO X，OWEN R，et al. Primary and secondary outcome reporting in randomized trials：JACC state-of-the-art review[J]. J Am Coll Cardiol，2021，78（8）：827-839.
[21] WIESCHOWSKI S，CHIN W W L，FEDERICO C，et al. Preclinical efficacy studies in investigator brochures：do they enable risk-benefit assessment?[J/OL]. PLoS Biol，2018，16（4）：e2004879[2023-04-30]. https://doi.org/10.1371/journal.pbio.2004879.
[22] YASINSKI E. Study questions animal data underlying many clinical trials[EB/OL]. （2018-04-05）[ 2023-04-30]. https://www.sciencemag.org/news/2018/04/clinical-trials-may-be-based-flimsy-animal-data.
[23] PAN Y S，MENG X，YUAN B S，et al. Indobufen versus aspirin in patients with acute ischaemic stroke in China（INSURE）：a randomised，double-blind，double-dummy，active control，non-inferiority trial[J]. Lancet Neurol，2023，22（6）：485-493. .
[24] MOHR F W，MORICE M C，KAPPETEIN A P，et al. Coronary artery bypass graft surgery versus percutaneous coronary intervention in patients with three-vessel disease and left main coronary disease：5-year follow-up of the randomised，clinical SYNTAX trial[J]. Lancet，2013，381（9867）：629-638.
[25] STONE G W，SABIK J F，SERRUYS P W，et al. Everolimus-eluting stents or bypass surgery for left main coronary artery disease[J]. N Engl J Med，2016，375（23）：2223-2235.
[26] LEE J Y，SUNG K C，CHOI H I. Comparison of aspirin and indobufen in healthy volunteers[J]. Platelets，2016，27（2）：105-109.
[27] WU H Y，XU L L，ZHAO X，et al. Indobufen or aspirin on top of clopidogrel after coronary drug-eluting stent implantation（OPTION）：a randomized，open-label，end point-blinded，noninferiority trial[J]. Circulation，2023，147（3）：212–222.