Abstract – Day Two

Professor Taixiang Wu

(Professor, Administrator, CEO, Head of ChiCTR/中国临床试验注册心)

Clinical transparency is the most important development of the global medical research during the past 20 years. It is a throughout update of the medical ethics. Clinical transparency aims at improve the credibility of medical research thus makes it an ethical responsibility and obligation for medical researchers to fulfill.

Clinical transparency includes clinical trial registry, trial data sharing and complete trial result reporting with accuracy .

This report will cover three main topics including an introduction of the global clinical transparency, overview of WHO international clinical trial registry platform (WHO ICTRP) as well as Chinese clinical trial transparency.

临床试验透明化是近二十年来全球医学最重要的发展之一,是医学研究伦理的全面更新,旨在促进医学研究的社会公信度,是医学研究者的伦理责任和义务。

临床试验透明化包括临床试验注册、临床试验数据共享、准确完整报告临床试验结果。

本报告着重介绍全球临床试验透明化、世界卫生组织建立的全球临床试验注册制度和中国临床试验透明化的概况。

 

Maria Ming-Po LAI

(Nursing Officer/Executive Officer of CCRB, CUHK/ Administrator of WHO Clinical Trials Partner Registry)

The International Committee of Medical Journal Editor (ICMJE) is a small working group of general medical journal editors with a mandate to improve the quality of publication of medical journals. They developed the Uniform Requirements for Manuscripts (URM) and proposed to register clinical trials in a public trials registry in 2005. They have laid down the minimum requirement for the registries to be acceptable by the ICMJE. World Health Organization (WHO) Primary Registries are one of the registries that support this movement. In 2006 WHO has created the International Clinical Trials Registry Platform (ICTRP) to improve transparency, ensure accountability and prevent unnecessary duplication among the WHO Primary Registries. Since Hong Kong has a large number of both international and local clinical trials and it is also part of China, we felt that there are needs to have a local trial registry. We developed the Centre for Clinical Research and Biostatistics – Clinical Trial Registry (CCRB-CTR), a WHO Partner Registry to the Chinese Clinical Trial Registry (ChiCTR) in 2006 (not sure about the translation). After a few years of running the operations with a few hundred trials registered, we are convinced that Partner Registry has important roles valuable to both the Primary Registry as well as the local community on upholding the scientific integrity. In this talk we would discuss the roles of the Partner Registries and encourage the establishment of more local registries and by working together we would be able to be more efficient in improving the quality of the trials in the whole country.

国际临床杂志编辑委员会(ICMJE)是由医学杂志编辑组成的小型工作组,该工作组的一项任务就是要提高医学发表物的质量。该工作组制定了医学稿件的统一标准(URM)并在2005年提出在公共注册系统中注册临床试验的主张。目前,工作组提出了能被ICMJE所接受的最低的注册要求。WHO初级注册是支持此运动的部门之一。WHO于2006年提出国际临床试验注册平台(ICTRP)。该平台致力于促进临床试验透明化,确保责任制并组织注册系统中的重复。因为香港及中国其他地区存在为数不少的国际化及本土临床试验,我们认为有必要建立一个本土的临床试验注册平台。我们在2006建立了临床试验与生物统计-中国临床试验中心(CCRB-CTR),该中心对中国临床试验注册平台而言是WHO伙伴注册平台。经过近几年进行的数百临床试验注册,我们相信,伙伴注册平台在初级注册平台及本土研究的学术诚信的维持中具有重要意义。 在本次演讲中,我们将探讨伙伴注册平台的作用,并鼓励建立更多地地方注册平台。通过共同努力,我们将有能力更高效地促进本国的临床试验质量。

 

Dr. Marc Chong

(Research Assistant Professor , CUHK/香港中文大学)

Application of System Dynamic Models on Clinical Trials and Healthcare Systems with SAS

System dynamics models can be used to describe complex behaviors of elements such as people, material, information, biological, and psychological states in organizational or social systems. Although a large proportion of applications for system dynamics modeling is focus on infectious diseases transmission such as influenza, system dynamics approaches are also useful to depict the pharmacokinetics (PK) and pharmacodynamics (PD) in drug development, and the system for population health. In this presentation, Dr. Chong will briefly describe the basic concepts and the practical applications of system dynamic modeling.   Further, he will demonstrate the applications of system dynamic models to PK&PD data analysis and to patient flows in an accidental and emergency (A&E) unit. The demonstration will accompany with the use of the analytic software SAS.

系统动态模型配合SAS分析软件在临床试验及医疗体制上的应用摘要

系统动态模型能够利用数学描述个体在组织或社会制度中的复杂行为,如人类,材料,信息,生物,和心理状态。虽然相当大比例的系统动态模型应用于传染病传播的研究上(例如流感),但是系统动态模型还能够描绘药物研发中的药物动力学(PK)和药效学(PD)及人口健康的系统。在这份报告中,庄博士将简要介绍一些系统动态模型的基本概念和建模的实际应用。此外,他将展示系统动态模型在药物动力学和药效学数据分析上的应用及病人在医院意外和紧急(A&E)部门的流程。在这份报告中各应用将伴随使用分析软件SAS。

 

Dr. Lai Xin

(Assistant Lecturer, CUHK/香港中文大学)

The phase II clinical trial design based on mixed time-to-event and tumor response endpoints

The objective of phase II cancer clinical trials is to determine if a treatment has sufficient activity to warrant further study. The efficiency of a conventional phase II trial design has been the object of considerable debate, particularly when the study regimen is characteristically cytostatic. At the time of development of a phase II cancer trial, we accumulated clinical experience regarding the time to progression (TTP) for similar classes of drugs and for standard therapy. By considering the time to event (TTE) in addition to the tumor response endpoint, a mixed-endpoint phase II design may increase the efficiency and ability of selecting promising cytotoxic and cytostatic agents for further development.

We proposed a single-arm phase II trial design by extending the Zee multinomial method to fully use mixed endpoints with tumor response and the TTE. In this design, the dependence between the probability of response and the TTE outcome is modeled through a Gaussian copula.

Given the type I and type II errors and the hypothesis as defined by the response rate (RR) and median TTE, such as median TTP, the decision rules for a two-stage phase II trial design can be generated. We demonstrated through simulation that the proposed design has a smaller expected sample size and higher early stopping probability under the null hypothesis than designs based on a single-response endpoint or a single TTE endpoint.

The proposed design is more efficient for screening new cytotoxic or cytostatic agents and less likely to miss an effective agent than the alternative single-arm design.

二期癌症临床试验是用来筛选有足够疗效的治疗方案,以开展进一步的三期研究。当研究方案是抑制性药物时,传统二期临床试验设计的效力就不甚理想。在进行二期临床试验的同时,我们发现同时考虑生存时间 (time-to-event) 终点和肿瘤反应 (tumor response) 终点会改进试验设计,从而提高找到有潜力药物的机率。我们拓展了Zee的multinomial二期试验设计,基于生存时间和肿瘤反应,提出一种新的单方案 (single arm) 两阶段二期临床试验设计,其中生存时间和肿瘤反应的直接的相关性由高斯copula表述。在给定一类、二类错误以及试验假设的前提下,我们的试验设计可以提供一系列的判别准则。模拟研究发现所提出的试验设计比传统的基于肿瘤反应的设计,具有更小的预期样本量 (expected sample size), 对无效的治疗方案具有更高的早期停止机率 (early stopping probability)。从而说明所提出的二期试验设计比传统的单方案设计具有更好的筛选效力。

 

Dr. Jack Lee

(Co-founder of Health View Bioanalytics Limited, HK/康讯生物分析有限公司)

Biostatistics in Medical Device Development

Diabetes mellitus (DM) is a major public health concern and has a significant socio-economic impact. In 2011, there were 366 million diabetes patients worldwide; this figure is estimated to reach 522 million by 2030. Among all the diabetic patients, about a third shows signs of diabetic retinopathy (DR). Apart from vision loss, people with DR also suffer from excess risk of life-threatening systemic vascular complications. Yet, through systemic therapy to manage blood pressure and glycemic control, in conjunction with timely ocular surgical treatment, patients can avoid further vision loss and other complications. To prevent and treat DR, American Academy of Ophthalmology suggested that diabetes patients with mild DR supposed to be screened at least once a year for DR and twice a year for more severe DR. In Hong Kong, it is estimated that about 9.8% of Hong Kong Chinese population had type 2 diabetes in the year 2000. The increasing figure means that DR is also an important issue in Hong Kong society.

In addition to diabetes, aging is another public health challenges our society is facing. Age-related macular degeneration (AMD) is one of the most common causes of blindness in the world, and is the most important one among the elderly population of developed countries. It is a disease that causes progressive deterioration of the macular which is responsible for the central vision. Without treatment, AMD can lead to irreversible loss of central vision at its advance stage. However, it can progress from an early stage without being noticed due to the lack of obvious visual changes. Therefore, early diagnosis is a major issue in order to be able to correctly treat the disease and avoid complications.

The Division of Biostatistics developed a computer assisted device (CAD) to make use of common fundus retinal images for the screening of DR and AMD in a general setting. The important characteristics of the Automatic Retinal Image Analyzer (ARIA) are that it is automatic, convenient, fast, cost-effective and completely non-invasive. It can be used in large scale population screening.

生物统计学与医疗设备研发

糖尿病(DM)是一个重要的公共健康问题,有着显著的社会经济影响。在2011年,全球有3.66亿糖尿病患者; 这一数字预计到2030年将达到5.22亿. 在所有糖尿病患者中,约三分之一显示有糖尿病视网膜病变(DR)的迹象。除了视力减退, DR的患者也有着危及生命诸如全身血管并发症的其它风险。然而,经过系统治疗如: 管理血压和血糖控制,结合及时眼部手术治疗,患者可避免视力进一步减退以及并发症发生。为了预防和治疗DR,美国眼科学会建议,糖尿病患者有轻度DR的应该是每年进行至少一次的DR筛查, 而有着更严重DR的患者则每年两次。在2000年香港曾估计约有9.8%的香港中国人口为2型糖尿病患者, 而增长数字亦指出DR也是香港社会所面临的的一个重要问题。

除了糖尿病,老龄化是另一个我们社会正面临着的具有挑战性的公共卫生问题。年龄相关性黄斑变性/老年黄斑病变(AMD)是当今世界上最常见导致失明的原因之一,并且是发达国家老年人群中最重要的一个。它是一种导致负责中央视觉的黄斑逐渐恶化的疾病。如果不进行治疗,AMD可能会导致中心视力在其严重阶段有着不可逆转的损害。然而,在早期阶段的进展中它可以因为缺乏明显的视觉变化而不被发觉。因此,早期诊断便成为了能够正确治疗疾病及避免并发症的重大问题。

我们生物统计部门研发了一种计算机辅助设备(CAD),它能够利用常见的眼底视网膜图像对DR和AMD进行筛选。这种自主研发的自动视网膜成像系统装置(ARIA)的重大特点则在于:它是自动的,而且方便快捷,以及具有成本效益性和完全非侵入性。当然, 更重要的是它能够在大规模人群筛查中使用。

 

Prof. Benny Zee

(Professor, Head of Division of Biostatistics, CUHK/香港中文大学)

The Impact of Biostatistics in Drug and Medical Device Development

Biostatistics is traditionally being viewed as a discipline that applies statistical methods to a wide range of areas in biology and medicine. The science of biostatistics encompasses the design of biological experiments, especially in medicine and agriculture, on the collection, summarization, and analysis of data from those studies and their interpretation and inference of the results. In drug development, biostatistics traditionally contributes in the design of Phase I-III trials, sample size estimation, monitoring of safety and efficacy, and analysis methodology. In medical device development, we have identified the windows of opportunity for the development of computer assisted devices (CAD) since the advancement of science and technology has been growing rapidly and in an unprecedentedly fast pace. I believe that for CADs to be successful in the coming era, they should have one or more of the following typical characteristics: 1) Cloud and internet computing; 2) Mobile health management; 3) Machine learning and predictive analytic; 4) Robotic including automation. We believe that our Division of Biostatistics is well equipped with innovative mind set in the development of CAD as we appreciate both the impact of the medical application as well as the methodological and technological knowhow. In this talk, we will discuss some of these characteristics and our experience in the development.

生物统计对药物和医疗设备研发中的影响

生物统计学是一个将统计方法应用于生物学和医学方面的学科。生物统计学包含了生物实验设计,尤其在医学和农学方面,设计包括数据收集、总结和分析,以及对结果的解释和推断。在药物研发的过程中,生物统计学家在I-III阶段实验设计、数据量估计、安全和功效的监视和分析方法学方面做出贡献。在医疗仪器研发的过程中,随着科学和技术空前快速地发展,现在是研发计算机辅助医疗设备(CAD)的时机和机遇。为了使CAD能够未来领域中成功,它需要具备以下特点:1)云网络计算;2)手机健康管理;3)机器学习与预测分析;4)自动化机器。在CAD的研发中,我相信我们生物统计部门具备创新思想,我们感谢CAD在医疗应用以及方法和技术技巧上的意义和影响。在该项任务中,我们将探讨上述部分特点以及我们研发过场中的一些经验。