Prof. Amit Oza
(Professor of Medicine, University of Toronto, Canada/加拿大多伦多大学)
Academic Collaboration in Drug Development
Understanding biology of disease is fundamental to improving outcome. Clinical trials are increasing in complexity and design, and importantly cost. To improve efficiency and quality of trials, a number of academic groups have developed collaborative framework for designing, developing and conducting clinical trials in a rapid and cost effective manner. These collaborations also require close interaction with biotech and pharma companies to be successful.
This talk will focus on challenges and opportunities of academic collaborations in cancer drug development.
药物发展上的学术合作
理解疾病发展的生物原理对药物研发成果至关重要。临床实验的设计日趋复杂和昂贵。为了提高试验的效率和质量，数个学术小组发展出一个合作框架，用来设计、发展、进行快速和有效果的临床试验。这些合作也要求生物技术公司与药厂紧密地合作才能成功。这个演讲将会重点讨论治疗癌症药物开发中学界和工业界的合作，并其中的挑战和机遇。
Prof. Lesley Seymour
(Director, Investigational New Drug Program and Compliance, and Professor, Oncology, Queens University/皇后大学)
National and International Clinical Trials: Infrastructure and Academic Collaborations
NCIC Clinical Trial Group is a national cooperative group with the central statistical office based in Kingston, Ontario. It was first established in 1980 and has a long and successful history of conducting oncology clinical trials both nationally and internationally. NCIC CTG has two programmatic components, one including phase 3 trials (drug, surgery, radiation) and the other phase 1 and 2 trials of new cancer therapeutics. Phase I pediatric trials are also conducted. The group has conducted more than 500 trials and enrolled more than 80,000 patients on its clinical trials. Many of the trials that have been conducted have changed clinical practice or led to the approval of new therapies, including adjuvant therapies for breast and lung cancer, erlotinib for lung cancer, cetuximab for colorectal cancer and optimal treatment for Hodgkins disease.
Although very active in clinical trials, and a large geographic mass, Canada has a relatively small population (36 million). International collaborations to allow the timely completion of important trials are critical. While this has traditionally involved only phase 3 trials, increasingly international collaborations are required for phase 2 studies especially for drugs likely to be active only in targeted patient populations. Although there are many potential challenges in international collaborations, including, national variations in standards of care, health care delivery and funding, contracting and partnering with organizations or institutions, variable and changing regulatory and research ethics rules and practices, time zones and language, maintaining communication, as well as funding, such collaborations are critical for oncology drug development. NCIC CTG BR.31 tests a new immunotherapy as an adjunct to standard surgery and chemotherapy for completely resected non-small cell lung cancer and is an example of the advantages of optimal international academic collaborations.
国家与国际临床试验：结构与学术合作
NCIC临床实验团队（NCIC CTG）是一个有着综合统计办公室的国民合作团队，位于休斯顿，安大略。它最早成立于1980年，并在国内和国际的实施肿瘤学临床试验方面有着悠久光辉的历史。NCIC CTG有两个组成成分：一个包括3阶段试验（药物、手术、辐射），另一个包括1阶段和2阶段新癌症疗法的试验。1阶段小儿科试验也有进行。该团队已经进行了多于500个试验，包含多于80000的病人在这些临床试验中。许多已进行的试验已经改变了临床实践操作或指引新疗法的批准，其中包括乳腺癌、肺癌、用于肺癌的埃罗替尼、用于结肠直肠癌的西妥昔单抗以及用于霍奇金病的最佳疗法的辅助疗法。
尽管加拿大在临床试验中十分积极，但加拿大的总人口很少（3600万）。致力于完成重要的试验的国际合作是必要的。然而传统合作只包括3阶段试验，更多的国际合作需要2阶段研究，尤其对于很可能只针对病人人群的药物。尽管在国际合作中有许多潜在的挑战，包括：在标准医疗方面的国家差异、医疗保障服务和资金、与公司或研究所的承包及合作、变化的监管和研究道德标准和实践、时区和语言、保持联系，以及资金，合作对于癌症药物研发是重要的。NCIC CTG BR.31 测出一个新的免疫疗法可作为完全切除非小细胞肺癌的标准手术和化学疗法的辅助方法，NCIC CTG BR.31是一个理想国际学术合作的范例。
Ms. Pamela Degendorfer
Chief Operating Officer, Ozmosis Research Inc.; Program Director, CCRU, Princess Margaret Cancer Centre
Building an Academic CRO: Opportunities for Business Development
Ozmosis Research is a social enterprise Clinical Research Organization (CRO). Ozmosis Research is a spin-out company from the Drug Development Program at the Princess Margaret in Toronto, Canada. We are a niche oncology CRO.
This talk will explore the challenges and solutions creating and building an academic CRO. The background behind Ozmosis and the development of a private for profit company which then was changed into a social enterprise, or not-for profit, company will be discussed. Ozmosis has managed trials for over 9 years and has become well known in Canada for work on Investigator Initiated trials and for working with Biotech. Our value proposition has enabled academic investigators to run trials in Canada and internationally. Our goal is to develop relationships internationally to allow increased collaboration and attract more research into Canada.
Ozmosis研究是一个社会企业性质的临床研究机构。该研究机构是从多伦多Princess Margaret的药品研发项目中独立脱离出的公司。
本次演讲旨在探索建立学术性CRO的挑战与解决方式。此外，Ozmosis创办及其从盈利到非盈利公司的发展背景也会在此讨论。Ozmosis在过去的9年期间进行临床试验的管理，并逐步发展成为一家加拿大知名的公司。公司的业务范围主要在协助研究者发起的试验及生物技术公司的相关试验。 我们的价值定位使得研究者可以负责参与加拿大本国及国际化的临床试验。而我们的目标是开发国际关系以增加更多国际合作并吸引过多的研究进入加拿大。
Ms. Alison Urton
(NCIC CTG Group Administrator, Queen’s University皇后大学)
International Clinical Trials: Models of Collaboration
International clinical trials are essential to drug development and rapid access to emerging treatments for patients. In the current environment, the cost, complexity, and oversight of clinical trials are increasing and the pharmaceutical industry is outsourcing to Contract Research Organizations (CROs). Opportunities exist for academic research groups to collaborate and address important trial questions in a timely and cost effective manner. NCIC Clinical Trials Group (NCIC CTG) has extensive experience in the coordination and conduct of international clinical trials. The NCIC CTG network includes partnerships with academic cooperative groups and individual sites in over 40 countries involving more than 3900 investigators. Together, our network has registered over 75000 patients to trials with over 25000 from international collaborations. This trend further increased in the last decade with 50% of all trials activated involving international collaborations. The NCIC CTG Operations and Statistics office has standardized systems that support activities in the areas of trial coordination and conduct, regulatory compliance, quality assurance, finance, contracts, and group administration. Using standardized systems, intergroup and international models are applied to facilitate international collaborations. Considerations for the models include, but are not limited to, protocol development and gaining consensus, drug supply, regulatory systems, and partnership agreements. International collaboration increases applicability of results, time to execution and completion, and ultimately access to new treatments for patients. History has demonstrated that international clinical trial models are effective in addressing important trial questions. Future opportunities include new partnerships, development of academic consortia, and flexible models for collaboration to advance the research agenda.
国际临床试验：合作模式
国际临床试验在药物研发和病人的快速治疗方面是重要的。在目前的环境下，成本、复杂性和临床试验监管在不断增加，并且制药公司外包给合约研究机构。存在的为学术研究团队合作和从事解决重要的临床实验问题的机会是适时并高效的。NCIC临床试验组（NCIC CTG）在监管和实施国际临床试验有着丰富的经验。NCIC CTG的合作网络包括学术科研团队以及个体站点，在40多个国家，其中包括多余3900个研究者。同时，我们的合作网已有75000多的病人登记参与实验，其中多于25000人来自国际合作团队。近十年中，该趋势进一步增长，全部试验的50%已开启，包括国际合作团队。NCIC CTG统筹和统计办公室拥有标准化系统来支持试验监管、实施、法规、质量保证、财政经济、合约及团队管理。应用该标准化系统可促进组间和国际模式的国际合作。参考模型包括，方案设计、达成一致、药物供给、监管系统和合伙协议。国际合作可提高结果适用性、完成时长和最终的新药物研发的目标。历史事实说明了国际临床试验模式在从事研究重要实验问题方面是有效的。进一步的机遇包括新的合作伙伴、学术联盟的发展、安排合作研究议程。
Mr. Xun Xu
Executive Director of BGI-Shenzhen
Million Genomes Project
The achievement made by Human Genome Project and 1000 Genome project shows the power of the context and variation catalogue of genetics. Those help to address information of variations related to diseases and support studies with better references. Innumerable important discoveries have been found, promoting our knowledge from basic research to clinical potential. However we further find more rare but largely existing variations have not but should be solved by much larger data especially for resolving the difficult faced by personalized medicine and precise medicine. The advanced sequencing technology we developed since merged with Complete Genomics now enable us to do ‘real’ 1000 dollars genome and enable us to reach the scale of million genome per year in a more accurate, fast and cost efficient way.
We have announced million genome project two years ago and now we are more confident to reach to million scale in much shorter plan. It is million genome level project but not just simply thousands times of 1000 genomes project. The project will aim at clinical purpose driven genomic data accumulation and application. The initial 10,000 samples with impeccable clinical and tracking records already been collected and shows it will be a solid foundation stone for foreseeable good prospect. With thousands of refined individual genetic data from different ethnic groups, diseases study will be much more deeply and comprehensively. From pathogenesis to pharmacokinetics, basis research could benefit with statistical significance. Risk prediction, prevention, early diagnosis, precise medicine and prognostic caring will be ensured for better practice by ever most sophisticated knowledge of individual diversity and cohort similarity.
百万基因组计划
人类基因组计划和1000基因组计划所完成的成就展现出环境与基因变异的力量。
这些帮助提取与疾病相关的变异信息并给相关研究以参考文献支持。不计其数的重要结果被发现并促进了从基础研究到临床试验的研究。然而，我们进一步发现更多并大量存在的罕见变异问题并没有被解决，尤其对于解决个人化医疗和精准医疗中面临的困难。自从与完整基因公司合并后，我们开发的先进的测序技术现在可以让我们做真正意义上的1000美元基因组项目并能以一种更准确、快速、高效的方式，达到每年百万基因组测序的水平。
我们在两年前就已公布了百万基因组计划，现在我们更确信能够在更短时间内达到百万的规模。这是一个百万基因组水平的计划，并不是简单数千次的1000基因组测序计划。该项目将以临床为目的进行基因组数据的收集和申请。我们已收集了最初的1000个在临床追踪记录中无缺陷的样本，这些样本为该项目好的预期结果打下了坚实的基础。有了来自不同种族的数千个精炼的个体基因数据，疾病研究将会进行得更加深入、全面。从发病机理到药物学，基础研究会从中受益。前所未有的在个体多样性和群体一致性方面的经验和知识，将能保障实践中对疾病的风险预测、预防、早期诊断、精准医疗和预后。
Prof. Maggie Haitian Wang
(Professor, CUHK/香港中文大学)
Gene-gene Interaction mapping in GWAS of bipolar disorder
Genetic association study has the objective of identification of disease susceptible loci from genome-wide data. In recent years, the challenge remains in the revealing of the epistasis effect that underlies complex diseases. Many interaction methods were suggested, seeking for a balance among the complexity of methods, efficiency of computation, interpretability of results and feasibility of application for the ever increasing data volume. In this talk, we will introduce a fast and effective W-test, which has an odds ratio interpretation comparing the distributional difference between cases and controls. We will demonstrate its superior performance among alternative methods in simulated data sets under different genetic architectures and varying sample size. The W-test is applied on two real GWAS bipolar disorder data sets using a three-step procedure. Besides successfully replicating the main effect previously reported, the W-test is able to identify interesting gene-gene interactions that can be validated using two independent GWAS data sets. The validated gene-gene interaction pairs reside in key neuro-function pathways, which cannot be found from main effect. They contribute to the completion of the genetic heritability picture of bipolar disorder, and provide valuable pharmaceutical targets for treatment of the disease.
寻找与躁郁症相关的基因-基因交互作用
基因关联性研究的目标是寻找与疾病相关的位点。近年来，研究复杂性疾病中的基因与基因的交互作用出现了许多新的统计方法，不同的方法都在寻找众多挑战中的平衡点，包括方法的复杂程度、计算速度、结果的诠释度、和对海量基因数据的处理能力。在本次报告中，我们会介绍一种速度非常快和有效的W-test。我们会展示它在不同基因架构中和不同方法比较的Power 和Type I error. 此方法将用于躁郁症的两个独立GWAS数据上进行全基因组SNP-SNP交互作用分析。找到的基因交互作用在两个数据中可以被互相验证，这些位点落在神经相关的生物路径上或相关基因中。他们对解释躁郁症的遗传性有重要作用，并可以作为躁郁症的药物研发的潜在靶点。
Prof. Chen Jinfei
(Professor, Nanjing First Hospital, Nanjing/南京市第一医院)
Genome-wide association study (GWAS) of cancers in identified multiple single nucleotide polymorphisms (SNPs) which relate with susceptibility of specific cancer. Little is known about the correlations between these SNPs and clinical outcomes. Reveal the clinical significance of SNPs in gastric cancer may guide our clinical decision making in both medication and follow-up. In this study, we evaluated the association between several genes (SOD2, XRCC1, PSCA, TOX3, MYT1L, FAS, FASL and CASP8) SNPs and gastric cancer survival. Based on the retrospective study (944 postoperative gastric cancer patients, median follow-up time of 35 months to 119 months), we used the Multiplex SNaPshot technology to obtain the genotypes and also performed the Pearson chi-square test and the independent Student’s t test to investigate the relation of SNPs with each clinicopathologic feature. Additionally, Kaplan-Meier curves and log-rank tests were conducted to evaluate the Gastric cancer-specific overall survival. Multivariate Cox regression analyses of these SNPs also were applied. Results showed that these genes SNPs were involved in gastric cancer survival, which could be used as prognostic markers for molecular classification of gastric cancer. Different types of cancers arise from the stomach. Unique molecular drivers may be identified among specific genetic pathways that distinguish each disease. It is likely that presence of different biomarkers and therapeutic targets for each disease. Such distinction will allow us to begin to manage each of these diseases differently and uniquely: improve application of targeted therapies.
癌症的全基因组相关性测序研究（GWAS）在已发现的单核谷氨酸多态性（SNPs）中与特定癌症的易感性相关。但目前这些SNPs与临床结局的关系并不明确。解释胃癌SNP的临床意义有助与指导胃癌的临床决策，用药及后续随访。在本次研究中，我们研究了包括SOD2, XRCC1, PSCA, TOX3, MYT1L, FAS, FASL CASP8在内的基因的SNP及这些SNP与胃癌生存的关系。我们回顾性的分析了944个胃癌术后病人，运用SNaPshot 技术获得病人基因表型，利用Person 卡方检验及独立样本t检验探索SN与临床病例分型之间的关系。另外，我们采用Kaplan-Meier曲线和log-rank检验比较不同癌症分型的生存。多元cox回归用于控制混杂因素，分析这些SNP的生存风险。研究结果显示，基因组SNP与胃癌生存相关。不同的癌症病理类型从胃部起源。某些特殊的分子驱动物可以在特定的基因通路被发现，因此可以用于不同疾病的鉴别。另外，研究提示每种疾病可能存在某些生物标记物及治疗靶点。这些区别可以让我们在疾病管理时更加的区别化及个体化，促进靶向治疗的运用。
Prof. Chen Enfu
(Director, Zhejiang CDC, Hangzhou/浙江疾病预防控制中心)
Effective control of infectious disease depends on effective disease surveillance. After SARS crisis, unprecedented attention has been put on the infectious prevention system in China. After 10 years of hard work, infectious disease and surveillance and information technology has made tremendous development. China has built more than 20 surveillance systems at the core of a nationwide direct reporting system network. Taking Zhejiang province for example, the province has carried out more than 34 monitoring project using online and manual reporting. Information regarding case report, pathogens, hosts and environment was able to be collected and used as an important evidence for planning, implementing and evaluating disease prevention and control strategies.
Under the background of big data, data collection methods are changing. In some area of Zhejiang province, public data exchange platform has been built and successfully connect the information system between network direct reporting and hospitals. Through the real-time, automatic electronic information collection, we are able to reduce working steps, improve work efficiency and ensure the quality of reporting. In addition, Zhejiang proving is building a public health surveillance information platform to achieve a unified standard for data collection, which will lay the foundation for comprehensive data utilization and data mining.
Infectious disease data mining under Big Data background is still under exploring. Zhejiang is one of the pilot sites for national automatic infectious disease early warning system. The system uses a network-based direct reporting and daily analysis of time/space modeling to achieve the goal of early identifying and warning of potential outbreaks. In some area of Zhejiang, syndrome surveillance system was launched based on hospital HIS information. The data was used for observing trend of infectious disease and detecting early epidemics.
基于大数据的传染病监测与预警—报告摘要基于大数据的传染病监测与预警—报告摘要
有效的传染病控制依赖于有效的传染病监测。SARS危机之后，我国的传染病防控体系受到前所未有的重视。通过10余年的努力，传染病监测及其信息化取得了巨大的发展。全国已构建了以传染病网络直报系统为核心的20余个监测信息系统。浙江省目前也已开展传染病相关的监测项目多达34项，通过网络和手工填报等方式，获取包括病例个案、病原体、媒介宿主和外环境等各类大量的监测数据，作为制订、实施和评价传染病防控策略与措施的重要信息来源。
大数据背景下传染病监测数据的收集方式正在发生改变。在浙江省的部分地区，已完成搭建公共卫生数据统一采集交换平台，实现了传染病网络直报系统与医院信息系统的互联互通。通过实时地、自动地采集电子病历信息，减少了工作环节，提高了工作效率，保证了报告质量。此外，浙江省正在构建公共卫生监测信息平台，实现各类监测数据的统一规范化收集，为监测数据的综合利用与挖掘打下基础。
大数据背景下传染病监测数据的挖掘利用仍在不断探索。浙江省作为国家传染病自动预警工作的试点之一，基于网络直报的传染病监测系统，采用时间/时空预警模型每日自动运算，实现对传染病暴发的早期自动预警。在浙江省的部分地区，开展了基于各级医院HIS系统就诊数据的症状监测，用于观察传染病流行趋势，并可早期探测疾病的流行。
大数据在未来的传染病监测与预警中将发挥更大的作用。现有各类监测数据平台的整合、优化及推广，传染病监测数据与各类非卫生部门数据（气象、环境、公安、统计等）的横向综合分析，舆情监测与预警技术的应用等都是我们努力的方向。
有效的传染病控制依赖于有效的传染病监测。SARS危机之后，我国的传染病防控体系受到前所未有的重视。通过10余年的努力，传染病监测及其信息化取得了巨大的发展。全国已构建了以传染病网络直报系统为核心的20余个监测信息系统。浙江省目前也已开展传染病相关的监测项目多达34项，通过网络和手工填报等方式，获取包括病例个案、病原体、媒介宿主和外环境等各类大量的监测数据，作为制订、实施和评价传染病防控策略与措施的重要信息来源。
大数据背景下传染病监测数据的收集方式正在发生改变。在浙江省的部分地区，已完成搭建公共卫生数据统一采集交换平台，实现了传染病网络直报系统与医院信息系统的互联互通。通过实时地、自动地采集电子病历信息，减少了工作环节，提高了工作效率，保证了报告质量。此外，浙江省正在构建公共卫生监测信息平台，实现各类监测数据的统一规范化收集，为监测数据的综合利用与挖掘打下基础。
大数据背景下传染病监测数据的挖掘利用仍在不断探索。浙江省作为国家传染病自动预警工作的试点之一，基于网络直报的传染病监测系统，采用时间/时空预警模型每日自动运算，实现对传染病暴发的早期自动预警。在浙江省的部分地区，开展了基于各级医院HIS系统就诊数据的症状监测，用于观察传染病流行趋势，并可早期探测疾病的流行。
大数据在未来的传染病监测与预警中将发挥更大的作用。现有各类监测数据平台的整合、优化及推广，传染病监测数据与各类非卫生部门数据（气象、环境、公安、统计等）的横向综合分析，舆情监测与预警技术的应用等都是我们努力的方向。