上市中成药治疗2型糖尿病随机对照试验方法学系统综述

Systematic review on methodology of randomized controlled trials of post-marketing Chinese patent drugs for treatment of type 2 diabetes

背景:临床疗效和特异性作用是治疗2型糖尿病选择用药的重要影响因素,而随机对照试验(randomized controlled trial,RCT)是评价临床疗效的有效方法。随着治疗2型糖尿病上市中成药种类的增多,其临床疗效定位及疗效评价的RCT的方法学值得探索。目的:调查治疗2型糖尿病上市中成药种类及其上市后对其进行临床疗效评价的RCT的方法学质量。检索策略:手工及电子检索《新编国家中成药》、《中华人民共和国药典临床用药须知中药卷》、国家食品药品监督管理局网站、中华人民共和国人力资源与社会保障部网站,查找治疗2型糖尿病的中成药;电子检索中文医学文献数据库:中国知网数据库、重庆维普中文科技期刊数据库、中国生物医学文献数据库网络版和万方数据。所有数据库检索时间从建库截止至2011年8月。纳入标准:筛选干预时间≥3个月的上市中成药治疗2型糖尿病的RCT报告。资料提取与分析:由两名系统评价员独立提取并筛选研究信息。以偏倚风险评价研究质量,资料提取表内容包括RCT的设计与方法、中成药种类、药品说明书报告的适应证、药品的功能主治。结果:检索出149种具有2型糖尿病治疗作用的中成药,其中以治疗阴虚热盛、气阴两虚、气阴两虚兼血瘀证候的中成药种类为主,各为48种(32%)、58种(39%)、22种(15%)。获得41篇符合纳入标准的RCT研究文献,无多中心RCT研究。偏倚风险分析显示,81%的研究只交代了使用随机分组方法但未报告随机数字产生的方法;98%的研究未报告随机序列隐藏的方法;5%的研究报告使用安慰剂;10%的研究报告了结局损耗;无1项研究报告使用意向性治疗分析;98%的研究报告了2型糖尿病诊断标准,研究对象主要是门诊为主无明显并发症的2型糖尿病患者(76%);报告的样本量为(106±60)人,最小样本量为40人,最大样本量300人;纳入研究中未见终点结局报告。结论:纳入的RCT研究报告的研究对象、诊断标准、纳入和排除标准以及临床结局指标等研究内容未能体现中成药上市后对其进行临床疗效评价的目的,也未能反映中医辨证论治特色。建议尽快制定上市中成药临床疗效评价的设计、实施及报告规范,改善对上市中成药进行临床疗效评价的方法,促进中成药的合理使用。

Randomized controlled trial （RCT） is considered as the gold standard for the efficacy assessment of medicines. With the increasing number of Chinese patent drugs for treatment of type 2 diabetes,the methodology of post-marketing RCTs evaluating the efficacy and specific effect has become more important. OBJECTIVE： To investigate post-marketing Chinese patent drugs for treatment of type 2 diabetes, as well as the methodological quality of post-marketing RCTs. SEARCH STRATEGY. Literature was searched from the books of Newly Compiled Traditional Chinese Patent Medicine and Chinese Pharmacopeia, the websites of the State Food and Drug Administration and the Ministry of Human Resources and Social Security of the People＇s Republic of China, China National Knowledge Infrastructure Database, Chongqing VlP Chinese Science and Technology Periodical Database, Chinese Biomedical Database （SinoMed） and Wanfang Data. The time period for searching ran from the commencement of each database to August 2011. INCLUSION CRITERIA： RCTs of post-marketing Chinese patent drugs for treatment of type 2 diabetes with intervention course no less than 3 months. DATA EXTRACTION AND ANALYSIS： Two authors independently evaluated the research quality of the RCTs by the checklist of risk bias assessment and the data collection forms based on the CONSORT Statement. Independent double data-extraction was performed. RESULTS： The authors identified a total of 149 Chinese patent drugs for treatment of type 2 diabetes. According to different indicative syndromes, the Chinese patent drugs can be divided into the following types, namely, yin deficiency and interior heat （n=48, 32%）, dual deficiency of qi and yin （n=58, 39%） and dual deficiency of qi and yin combined with blood stasis （n=22, 15%）. A total of 41 RCTs meeting the inclusion criteria were included. Neither multicenter RCTs nor endpoint outcome reports were found. Risk bias analysis showed that 81% of the included studies reported randomization for grouping without sequence generation, 98% of these studies did not report concealment of random numbers, 5% used placebo, 10% reported outcome attrition bias and no study employed the analysis of intention-to-treat and 98% reported the diagnostic criteria for type 2 diabetes. The participants mainly consisted of outpatients without complications （76%）. The minimum and maximum sample size was 40 and 300 （106-F60）, respectively. CONCLUSION： The inclusion and exclusion criteria and outcome measures did not match the purposes and contents of post-marketing research in the included studies. They also failed to reflect the basic principles of traditional Chinese medicine in the process of diagnosis and treatment. The demographic characteristics of the patients, the indications for medicine and the syndrome differentiation process were not reported sufficiently and transparently. In order to improve the post-marketing research and promote the rational use of Chinese patent drugs, it is recommended that phase Ⅳ clinical trials should establish clear research purpose as well as hypothesis first, and choose scientific and evidence-based study design and outcome measures. In addition, guidelines for implementation of post-marketing research should be developed.