我国卫生技术不同发展阶段的评估和管理
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摘要
卫生技术指用于医疗保健的药物,仪器设备,内、外科程序以及相关的组织管理系统和后勤支持系统。卫生技术的发展过程经历发展期、接受期、应用期和淘汰期。卫生技术的管理只有进行卫生技术发展全过程的管理,才能使之更好地发挥对人们防治疾病的正向能力,尽可能降低卫生技术的消极影响。
随着20世纪以来的现代科技革命的发展,加上客观上需要有效的技术来应对人群的老龄化、慢性病化的需求,新兴卫生技术层出不穷,其替代原有技术的时间也越来越短。在新技术未获得使用或未广泛使用之前,对其进行评估,是防范新技术可能产生风险的第一道屏障。而在我们国家系统性地进行新技术评估还处于初期阶段。要及时、系统性地对卫生新技术进行评估的首要步骤就是进行卫生新技术的水平扫描(horizon scanning),从而及时了解何种卫生新技术需要进行评估。
处于应用期的卫生技术是相对而言应用得最广泛的技术,在评估安全性和有效性的同时,应用期的卫生技术的经济性成为我国建立全民医保背景下很重要的评估内容。在2011年初“药物经济学应用指南”发布后,卫生技术的经济学评价提到了一个新的高度,在卫生经济学研究经历了15年的发展后,卫生经济学研究所需的基础资料的可得性成为提高研究质量的推动力之一。
而在新技术层出不穷的同时,不少原有技术存在被替代的可能性,在扫描新技术、评估现有技术的同时淘汰安全性、有效性或经济性不佳的卫生技术是保证为病人提供安全、有效、经济、伦理的卫生技术的另一个方面。
对新技术进行积极管理的同时,对现有技术进行有效管理,合理淘汰相应的卫生技术组成了让病人能使用安全、有效、经济的卫生技术的三个环节。卫生技术不同发展阶段技术的全程管理即三个环节的有效管理一起构筑了卫生技术使用的安全屏障,本研究主要对我国的新技术、应用期和淘汰卫生技术的评估和管理方面开展实证研究,并在实证研究基础上探索评估的方法和管理的框架。
研究目的：本研究通过对卫生技术不同发展阶段的评估和管理的一些关键或空白点进行实证研究,探索评估的方法和管理的框架,为医疗技术管理体系的完善提供依据。
——以对我国生物的水技术平扫描为案例作为在我国进行新技术的水平扫描的探索,为新技术的水平扫描提供经验；
——以脑卒中的疾病负担的研究作为案例探讨通过一些新方法获得经济学评价数据的可得性和可行性；
——以低强度激光血管内照射技术的评价,为淘汰卫生技术的评估提供经验,提出淘汰卫生技术的评估框架。
研究框架
本研究分为三个部分,分别是通过实证研究探讨新技术的水平扫描、应用期卫生技术经济学评价中基础数据的可得性和淘汰技术的卫生技术评估的框架和方法。(图1)在三个研究部分中,分别采用生物药物的水平扫描、脑卒中的疾病负担以及低强度激光血管内照射技术作为三个实证研究来帮助探索这三个研究领域的新方法/新框架。具体研究内容和方法见各研究部分。
第一部分卫生技术的水平扫描(horizon scanning)在中国实施的可行性
技术的发展、技术数量的增多以及公众对新技术的需求升高,越来越多的呼声要求加速对新兴技术的决策。生物技术、原子技术以及计算机技术被誉为20世纪三大技术革命。生物技术领域发展迅速、对未来卫生保健影响较大,同时因为其先进性和伦理性对技术管理的要求也比较高,生物技术领域的水平扫描可以为我国卫生新技术的水平扫描提供实证研究的经验。本部分的研究目的是以生物技术的水平扫描作为实证研究,通过优先关注技术的筛选、优先关注技术的使用和政策环境评价为卫生新技术的水平扫描积累实证研究的经验,从而为卫生新技术的水平扫描在我国开展的可行性提供依据。
研究内容和框架：研究的研究路线依据早期探测、产生预测和发展政策三个步骤通过多方面信息的综合分析在生物技术中需要优先关注的卫生新技术,就需要优先关注的卫生新技术评价其被接受程度和使用环境,从而为未来技术管理和水平扫描的实施积累经验,提供借鉴。研究方法包括1)文献检索和追溯；2).专家咨询：3)药品使用状况分析。
水平扫描的结果显示1)文献的追溯、专利和网络的信息都显示疫苗、干细胞和单克隆抗体是近几年的生物技术发展的热点之一；我国科技部的技术预见和火炬计划等显示包括靶向治疗在内的生物制药与文献追溯中疫苗和单克隆抗体方向一致；3)专家认为生物制药比干细胞治疗或组织芯片的应用更具有可行性和重要性；4)在生物产业方面的分析显示生物制药是生物技术进入临床实践的排头兵。因此将生物制药作为需要优先评价的技术。
生物技术药物大致包括激素、细胞因子、生长因子、单克隆抗体、疫苗、血液制品、核酸类产品和组织工程产品等八大类。生物技术药物与常规小分子量化学药物相比在物理化学特性、免疫学和毒理学性质、代谢过程、制剂配方等方面均存在较大的差异。国际近期新型生物技术药物的发展重点有五个类型：单克隆抗体、反义基因药物、基因治疗剂、可溶性治疗蛋白药物和疫苗。美国1996年~2006年每年FDA批准的生物类新药的批准数较为稳定；截止至2005年底,我国有18种基因工程疫苗和药物批准上市,其中3种是拥有自主知识产权的1类新药,包括8种世界上销售前十位的生物技术药物和世界首个基因治疗药物。
通过对某药品使用数据库2004—2007年生物技术药物的销量分析和四种生物制药的深入分析,显示对这些新技术的接受程度较快。生物制药政策环境评价显示政府对生物制药的研究和使用持鼓励态度,法律法规的制定有一定的基础,卫生技术的管理者和使用者对使用新技术有相当的热情。通过水平扫描、政策环境评价和使用评价为我国生物制药的评价和管理提供了经验和方向；也评价了国外的新技术水平扫描的方法学在我国使用的可行性。
第二部分现有技术的卫生技术评估中卫生经济学数据的可得性
2011年卫生经济学指南的发布为高质量的卫生经济学评价提供了方法学上的方向和指导,在研究设计质量得到一定的提高后,进行卫生经济学评价所需要数据的可得性就成为卫生经济学评估质量的重要前提和保证。本部分以脑卒中的疾病负担研究为例,探讨在中国进行脑卒中的经济学评价数据的可得性。
我国,卒中已经超过心血管疾病,成为死因第一位的疾病。卒中成本的特点之一是成本包括多次急性发作的费用、二次预防费用以及残疾带来的费用,而且后期的费用比较高。本次研究拟通过脑卒中的疾病负担的收集作为实证研究的案例,探讨通过不同方式收集卒中病人的成本数据,测算卒中的疾病经济负担,考虑采用不同方式收集数据的可行性和优劣,为以后相关的研究提供依据。研究方法包括流行病学资料的系统性综述、相关数据库挖掘成本信息和与登记研究伴行的前瞻性的成本数据收集。
流行病学的系统性综述是比较新和而且具有挑战性的领域,通过系统性综述显示我国脑卒中的发病率在43.5/10万～629/10万人年之间；患病率在0.79%～7.73%之间,死亡率在71.56/10万-117.2/10万之间。考虑到我国流行病学研究的质量参差不齐,流行病学数据的出入较大,通过系统性综述可以帮助通过统一的标准无偏倚地选取应用同一标准的数据而使流行病学数据的范围相对集中,有利于流行病学数据在卫生经济学中的应用。
数据库挖掘的结果显示在三级医院和社区卫生服务中心通过电子数据库获得卒中病人的住院费用和明细清单是可行的,而在门诊数据的获得方面因为诊断填写的不规范是数据的可得存在一定的问题,在数据挖掘的过程中所面临的最大困难就是缺乏完整数据库的有效支持,主要来自以下几个方面1)医院信息系统之间的不匹配；因为各自信息系统之间的因素设置不同,因此不同医院的信息不能直接叠加,加大了收集数据的难度。而且社区卫生服务中心的电子信息系统与三级医院的电子信息系统差别较大2)门诊数据因为两家医院在门诊输入系统中没有要求输入诊断而不能收集疾病成本。3)病人可能到不同医院就诊,而在我国类似美国的整体数据库还不可得,影响了通过数据挖掘来进行卫生经济学研究的质量和效率。
伴随成本收集是基于在医院的多中心卒中登记,相比单纯的住院成本收集,具有前瞻性、有随访的全病程成本收集,是一种介于传统的系统病例分析和基于人群的研究之间的临床研究方法,是一种系统的队列研究方法。通过这个研究我们发现这种方法的确比较节省成本、效率也比较高,主要是节省了寻找病人的时间。但研究也同时暴露出前瞻性研究随访率较低的问题。
第三部分淘汰卫生技术的管理——以低强度激光血管内照射疗法为例
淘汰卫生技术是指任何用于一种或一种以上适应症的技术其临床效果、安全性或成本效果已经明显被其他替代技术所超越。我国鲜有通过官方渠道淘汰卫生技术的案例,在学术界对于如何确定淘汰卫生技术,如何通过卫生技术评估海鸥淘汰卫生技术的研究较为缺乏。本部分的研究以低强度激光血管内照射疗法(ILLLI)为例,对国内外公开发表的有关ILLLI的安全性和有效性的文献的系统性综述,评价ILLLI的有效性、安全性,并结合此技术的技术管理经验,提出淘汰卫生技术评估的理论管理框架。研究方法系统性综述以及专家咨询。
系统性综述的结果显示低强度激光血管内照射技术的治疗机制不明确,适应症不确定；虽然有大量的临床研究的文献,但尚缺乏高质量的研究来证明低强度激光血管内照射的有效性和安全性。对于如何正确、规范地使用这项技术,还有不少关键性的问题需要解决。在疗效不能确定的情况下,因为适应症的不确定和技术标准的不确定,因此带来一定程度的临床滥用。
基于低强度激光血管内照射疗法的研究经验,提出了淘汰卫生技术评估的框架。发现需要淘汰的卫生技术是在通过专家反馈的基础上基于临床医生和研究者的网络,建立淘汰技术的探测网络；专家和研究组草拟了淘汰卫生技术确定是否优先评估的指标体系,包括9个指标,涉及疾病情况、有效性、安全性、经济性等部分的内容；通过对现有证据的系统性综述来评估此卫生技术现有的证据情况,并通过临床专家的经验了解其在临床使用中的情况,为行政决策提供依据。
Health technology includes health-care drugs, equipments, procedures of internal medicine & surgical and the relevant management system and logistic support system. The development process of Health technology involves the development stage, the acceptance stage, and application stage and obsolete period. The management of Health technology need go through the whole development process of health technology to increase the capacity of health technology for disease prevention and treatment and reduce the negative impact of health technology.
With the objective needs of effective technology to deal with the population aging, the demand of chronic disease and the revolution of modern science and technology in twentieth Century, new health technologies come out one after the other and shorten the duration of replacement.For setting up the first barrier for the risk of new technolog, we need the technology accessment before the new technology is used or use widespread. But the systematic assessment of new technology is still in its early stage in China. If we need implement timely and systematically, the first step about new health technology assessment is horizontal scanningfor understanding what health new technology need to be evaluated.
In the application phase of health technology are the most widely applied.With safety and effectiveness assessment, it is very importance to conduct the health economic evaluation under the background of building of health universal insurance in China. "The guideline of pharmacoeconomics in China " released In the early 2011, which means the new stage for the economic evaluation of health technologies in China. After the development for 15 years, the availability of data for health economics research becomes the motive force of improving the quality of research. The new technology emerges in an endless stream means many original technologies is possible to be replaced. By scanning new technology and evaluating of existing technology, we can eliminated the health technology with poor safety, effectiveness and economy to guarantee the patients with the safe, effectiveness, cost-effectiveness health technology.
It is the three stages-- active management of the new technology, effective management of the existing technology and reasonable elimination of the obesolate technology to guarantee the patients with the safe, effectiveness, cost-effectiveness health technology. The overall technology management for different stages of the technology will guarantee the safety use of health technology. This research will focus on the case study in the new direction and methodology within the three stages.
Objective:This study focus on the case studies with the key points or empty area of the assessment and management of the three stages. With the experience and learning of case studies, the feasibility of new approaches and the proposal for the management of the technology has been studied for the completation of the technology management.
Through the case study of horizon scanning for the biotechnology in China, the feasibility of horizon scanning for the new technology will be studied for the reference of future assessment and management of new technology. A study for disease burden of stroke explores the availability and feasibility of data for economic evaluation with the new approaches; A study on the assessment of the intravascular low intensity laser irradiation technology will provide the experience for the technology assessment of obsolete technology and proposal for the management of obsolete technology.
Research framework
This research is divided into three parts, respectively, through case study to explore the application of horizontal scanning for the new technology, the data availability of the health economics evaluation for the existing technology and methodology and framework for the technology assessment of obsolete technology. (Fig 1) in the three studies, using horizon scanning for the biotechnology, stroke disease burden and intravascular low intensity laser irradiation technology as of three empirical studies to help explore these three areas of research new methods/framework. The specific research contents and methods of the research could be found in the subpart of the research paper.
Fig 1 research framework
Part 1 the feasibility of implementing horizon scanning of new technology in China Technology development, technology quantity and the public about the demand of new technology rise, increasing calls for accelerated on emerging technologies for decision making. Biological technology, nuclear technology and computer technology are known as twentieth Century three technical revolution. Biological technology the rapid development of the area, on the future of health care effect, at the same time, because of its advanced nature and ethics of technology management requirements are relatively high, the field of biotechnology horizontal scanning for our health new technology horizontal scanning provide empirical research experience. This research aims to biotechnology horizontal scanning as an case study, by focusing on technology selection, priority attention to technology use and policy environment evaluation for the health of new technology of horizontal scanning accumulation of empirical research experience, so as to the health of new technology of horizontal scanning in China provide the basis for the feasibility.
Research content and framework:According to three steps research route early detection, produce prediction and development policy, evaluate the new priority health technology in biological technology by colligating many-sided information on its acceptability and utilizing environment. In order to accumulate experience and provide reference for future technology management and the implementation of horizon scan. Research methods include 1) literature retrieval and tracing; 2) expert consultation; and 3) drug application status analysis.
The results of horizontal scanning show that 1) literature tracing, patents and network information indicate that vaccine, stem cells and monoclonal antibody are the focus of the biotechnology development in recent years; 2) the forecast of China Ministry of science and technology and Torch Program etc. show that the direction of biopharmaceutical including targeted therapy consists with vaccine and monoclonal antibody in literature tracing; 3) experts believe that biopharmaceutical is more feasible and important than stem cell therapy or tissue microarray in application; 4) analysis of biological industry reveal that biopharmaceutical is the vanguard of biotechnology entering into clinical practice. Thus biopharmaceutical is considered as a techneque need priority assessment.
Biotechnology Pharmaceuticals has 8 categories including hormones, growth factors, cytokines, monoclonal antibodies, vaccines, blood products, nucleic acid products and tissue engineering products. Biotechnology Pharmaceuticals is quiet different from common small molecular chemicals in the physical and chemical properties, immunological and toxicological properties, metabolic processes, formulation etc. Recently, the priority development of international new biotechnology Pharmaceuticals has five types:monoclonal antibodies, antisense gene drugs, gene therapy agent, soluble therapeutic protein drugs and vaccines. The number of new biologic drug United States FDA approved annually remained stable in 1996-2006; until the end of 2005, there are 18 kinds of approved gene engineering vaccines and drugs in our country,3 kinds of which having independent intellectual property rights is the class I drugs, including 8 kind of world top ten biotech drugs and the world's first gene therapy drug.
According to analyzing biotechnology drug sales in a drug utilizing database in 2004-2007 and four kinds of biopharmaceuticals, the results show that these new technology is accepted quickly. Biological pharmaceutical policy environment assessment shows that government attitude on biopharmaceutical research and application is encouraging and acceptable, the formulation of laws and regulations has some foundation, and health technology managers and users has considerable enthusiasm on the new technology. Through the horizontal scanning, the policy environment assessment and the utilizing assessment provide experience and direction to biopharmaceutical assessment and management in China; and also assess the feasibility of utilizing a foreign methodology of new technology horizontal scanning in China.
PartⅡThe availability of health economics data in health technology assessment of existing technology
After the publishcation of the guidelines of pharmacoeconomic in 2011 which could provide methodological direction and guidance for high-quality designed health economics evaluation, the availability of necessary health economics data becomes the guarantee and important premise for health economics evaluation quality. In this part, stroke disease burden research will be given as an example to discuss the availability of stroke economics evaluation data in China.
In China stroke has surpassed cardiovascular disease and becomes the first cause of death. The characteristics of stroke cost are including multiple acute attack costs, secondary prevention costs and disability costs, and the subsequent cost is relatively higher. In China, average hospitalization expense rather than the total cost in the disease course of individual patient is generally used for calculating in stroke disease burden researches because of the limitation of data, and the nationwide number of stroke patients vary greatly in different researches, thus the estimated stoke disease burden also vary greatly. In this research collecting of stroke disease burden intends to be an empirical research case, cost data collected in different ways will be use to calculate the stroke disease economic burden to consider the feasibility, superiors and inferiors between different data collection ways, in order to provide evidence for further relevant studies. The research methods include epidemiological data systematic review, cost information data mining in related database and the registration accompanied prospective cost data collection.
The epidemiology systemic reviews are relatively new and challenging field, through which shows that in China the incidence of stroke is in 43.5～629/100,000 person year, the prevalence is in 0.79%～7.73%, the mortality is at 71.56～117.2/100,000. Considering uneven quality of epidemiological studies and diversity of epidemiological data, a systematic review can help to concentrate epidemiological data range relatively by selecting the unbiased data of same standard according to uniform criteria which benefits to application of epidemiologic data in the health economics.
Database mining result shows that it is feasible to obtain hospitalization costs and inventory of stroke patients through electronic databases in tertiary hospitals and community health service centers, while it is troublesome in the outpatient data for non-standard diagnosis information. The greatest difficulty in process of data mining is lack of effective support from a integrity database, mainly from the following aspects:1) Mismatch between different hospital information systems. Information from different hospital system cannot be superimposed directly for their respective setting factors, which increased the difficulty of collecting data. And there is great difference of the electronic information system between community health service centers and tertiary hospitals.2) Impossibility of collecting disease cost data of outpatient as the diagnosis information is unrequited to input into the outpatient electronic information system in two hospitals.3) In China patients may visit in different hospitals without an integrity database like the United States of America, which affect quality and efficiency of health economics research by data mining.
Accompanied cost data collection, based on hospital multi-center stroke registry, is prospective and following-up whole course cost collection compared with simple inpatient cost collection. As a systematic method of cohort study, it is a clinical research method lying between traditional systematic case analysis study and population based study. In this research we found that this method is less cost and more efficient, mainly saves the time of patient enrollment. But we also found a common problem in the prospective study that the follow-up rate is low.
Part III Management of obsolete health technology ---with Intravascular Low Intensity Laser Irradiation therapy as an example
Eliminating health technology refers to any health technology in use for one or more indications, whose clinical benefit, safety or cost-effectiveness has been significantly superseded by other available alternatives. In China there is little case about health technology obsoleted through official channels, and there is also lack of researches on how to determine the elimination of health technology and how to eliminate the health technology by health technology assessment in academic circles. In this part intravascular low intensity laser irradiation therapy (ILLLI) is took as an example. The effectiveness and safety of ILLLI are estimated by systematically reviewing the published literature both domestic and foreign about the safety and efficacy of ILLLI, and combining with the technical management experience, the theoretical management framework of eliminating health technology assessment will be proposed. Research methods are systematic review and expert consultation.
The results of systematic review show that the mechanism of ILLLI is unclear and the indications are uncertain; although there are a large number of clinical study literatures, high quality research is still lack to confirm the efficacy and safety of ILLLI. There are many key problems need to solve on how to use of this technique correctly and normative. Besides indeterminacy of the effect, there is also indeterminacy of the indications and technical standards, thus brings a certain degree of clinical abuse. The framework of obsoleting health technology assessment is proposed based on the ILLLI researching experience. The identification of the health technology need to be obsoleted is to and establish obsoleted technology supervising network by experts feedback based on clinicians and researchers network; expert and research group draft out indicator system of obsolete health technology to determine priority assessment, including nine indicators related to disease status, effectiveness, safety, economic and so on; assess available evidence of the health technology by reviewing existing evidence systematically, and understand clinical use by experience of clinical experts, it is feasible to provide evidence for decision-making in the stage.
随着20世纪以来的现代科技革命的发展,加上客观上需要有效的技术来应对人群的老龄化、慢性病化的需求,新兴卫生技术层出不穷,其替代原有技术的时间也越来越短。在新技术未获得使用或未广泛使用之前,对其进行评估,是防范新技术可能产生风险的第一道屏障。而在我们国家系统性地进行新技术评估还处于初期阶段。要及时、系统性地对卫生新技术进行评估的首要步骤就是进行卫生新技术的水平扫描(horizon scanning),从而及时了解何种卫生新技术需要进行评估。
处于应用期的卫生技术是相对而言应用得最广泛的技术,在评估安全性和有效性的同时,应用期的卫生技术的经济性成为我国建立全民医保背景下很重要的评估内容。在2011年初“药物经济学应用指南”发布后,卫生技术的经济学评价提到了一个新的高度,在卫生经济学研究经历了15年的发展后,卫生经济学研究所需的基础资料的可得性成为提高研究质量的推动力之一。
而在新技术层出不穷的同时,不少原有技术存在被替代的可能性,在扫描新技术、评估现有技术的同时淘汰安全性、有效性或经济性不佳的卫生技术是保证为病人提供安全、有效、经济、伦理的卫生技术的另一个方面。
对新技术进行积极管理的同时,对现有技术进行有效管理,合理淘汰相应的卫生技术组成了让病人能使用安全、有效、经济的卫生技术的三个环节。卫生技术不同发展阶段技术的全程管理即三个环节的有效管理一起构筑了卫生技术使用的安全屏障,本研究主要对我国的新技术、应用期和淘汰卫生技术的评估和管理方面开展实证研究,并在实证研究基础上探索评估的方法和管理的框架。
研究目的：本研究通过对卫生技术不同发展阶段的评估和管理的一些关键或空白点进行实证研究,探索评估的方法和管理的框架,为医疗技术管理体系的完善提供依据。
——以对我国生物的水技术平扫描为案例作为在我国进行新技术的水平扫描的探索,为新技术的水平扫描提供经验；
——以脑卒中的疾病负担的研究作为案例探讨通过一些新方法获得经济学评价数据的可得性和可行性；
——以低强度激光血管内照射技术的评价,为淘汰卫生技术的评估提供经验,提出淘汰卫生技术的评估框架。
研究框架
本研究分为三个部分,分别是通过实证研究探讨新技术的水平扫描、应用期卫生技术经济学评价中基础数据的可得性和淘汰技术的卫生技术评估的框架和方法。(图1)在三个研究部分中,分别采用生物药物的水平扫描、脑卒中的疾病负担以及低强度激光血管内照射技术作为三个实证研究来帮助探索这三个研究领域的新方法/新框架。具体研究内容和方法见各研究部分。
第一部分卫生技术的水平扫描(horizon scanning)在中国实施的可行性
技术的发展、技术数量的增多以及公众对新技术的需求升高,越来越多的呼声要求加速对新兴技术的决策。生物技术、原子技术以及计算机技术被誉为20世纪三大技术革命。生物技术领域发展迅速、对未来卫生保健影响较大,同时因为其先进性和伦理性对技术管理的要求也比较高,生物技术领域的水平扫描可以为我国卫生新技术的水平扫描提供实证研究的经验。本部分的研究目的是以生物技术的水平扫描作为实证研究,通过优先关注技术的筛选、优先关注技术的使用和政策环境评价为卫生新技术的水平扫描积累实证研究的经验,从而为卫生新技术的水平扫描在我国开展的可行性提供依据。
研究内容和框架：研究的研究路线依据早期探测、产生预测和发展政策三个步骤通过多方面信息的综合分析在生物技术中需要优先关注的卫生新技术,就需要优先关注的卫生新技术评价其被接受程度和使用环境,从而为未来技术管理和水平扫描的实施积累经验,提供借鉴。研究方法包括1)文献检索和追溯；2).专家咨询：3)药品使用状况分析。
水平扫描的结果显示1)文献的追溯、专利和网络的信息都显示疫苗、干细胞和单克隆抗体是近几年的生物技术发展的热点之一；我国科技部的技术预见和火炬计划等显示包括靶向治疗在内的生物制药与文献追溯中疫苗和单克隆抗体方向一致；3)专家认为生物制药比干细胞治疗或组织芯片的应用更具有可行性和重要性；4)在生物产业方面的分析显示生物制药是生物技术进入临床实践的排头兵。因此将生物制药作为需要优先评价的技术。
生物技术药物大致包括激素、细胞因子、生长因子、单克隆抗体、疫苗、血液制品、核酸类产品和组织工程产品等八大类。生物技术药物与常规小分子量化学药物相比在物理化学特性、免疫学和毒理学性质、代谢过程、制剂配方等方面均存在较大的差异。国际近期新型生物技术药物的发展重点有五个类型：单克隆抗体、反义基因药物、基因治疗剂、可溶性治疗蛋白药物和疫苗。美国1996年~2006年每年FDA批准的生物类新药的批准数较为稳定；截止至2005年底,我国有18种基因工程疫苗和药物批准上市,其中3种是拥有自主知识产权的1类新药,包括8种世界上销售前十位的生物技术药物和世界首个基因治疗药物。
通过对某药品使用数据库2004—2007年生物技术药物的销量分析和四种生物制药的深入分析,显示对这些新技术的接受程度较快。生物制药政策环境评价显示政府对生物制药的研究和使用持鼓励态度,法律法规的制定有一定的基础,卫生技术的管理者和使用者对使用新技术有相当的热情。通过水平扫描、政策环境评价和使用评价为我国生物制药的评价和管理提供了经验和方向；也评价了国外的新技术水平扫描的方法学在我国使用的可行性。
第二部分现有技术的卫生技术评估中卫生经济学数据的可得性
2011年卫生经济学指南的发布为高质量的卫生经济学评价提供了方法学上的方向和指导,在研究设计质量得到一定的提高后,进行卫生经济学评价所需要数据的可得性就成为卫生经济学评估质量的重要前提和保证。本部分以脑卒中的疾病负担研究为例,探讨在中国进行脑卒中的经济学评价数据的可得性。
我国,卒中已经超过心血管疾病,成为死因第一位的疾病。卒中成本的特点之一是成本包括多次急性发作的费用、二次预防费用以及残疾带来的费用,而且后期的费用比较高。本次研究拟通过脑卒中的疾病负担的收集作为实证研究的案例,探讨通过不同方式收集卒中病人的成本数据,测算卒中的疾病经济负担,考虑采用不同方式收集数据的可行性和优劣,为以后相关的研究提供依据。研究方法包括流行病学资料的系统性综述、相关数据库挖掘成本信息和与登记研究伴行的前瞻性的成本数据收集。
流行病学的系统性综述是比较新和而且具有挑战性的领域,通过系统性综述显示我国脑卒中的发病率在43.5/10万～629/10万人年之间；患病率在0.79%～7.73%之间,死亡率在71.56/10万-117.2/10万之间。考虑到我国流行病学研究的质量参差不齐,流行病学数据的出入较大,通过系统性综述可以帮助通过统一的标准无偏倚地选取应用同一标准的数据而使流行病学数据的范围相对集中,有利于流行病学数据在卫生经济学中的应用。
数据库挖掘的结果显示在三级医院和社区卫生服务中心通过电子数据库获得卒中病人的住院费用和明细清单是可行的,而在门诊数据的获得方面因为诊断填写的不规范是数据的可得存在一定的问题,在数据挖掘的过程中所面临的最大困难就是缺乏完整数据库的有效支持,主要来自以下几个方面1)医院信息系统之间的不匹配；因为各自信息系统之间的因素设置不同,因此不同医院的信息不能直接叠加,加大了收集数据的难度。而且社区卫生服务中心的电子信息系统与三级医院的电子信息系统差别较大2)门诊数据因为两家医院在门诊输入系统中没有要求输入诊断而不能收集疾病成本。3)病人可能到不同医院就诊,而在我国类似美国的整体数据库还不可得,影响了通过数据挖掘来进行卫生经济学研究的质量和效率。
伴随成本收集是基于在医院的多中心卒中登记,相比单纯的住院成本收集,具有前瞻性、有随访的全病程成本收集,是一种介于传统的系统病例分析和基于人群的研究之间的临床研究方法,是一种系统的队列研究方法。通过这个研究我们发现这种方法的确比较节省成本、效率也比较高,主要是节省了寻找病人的时间。但研究也同时暴露出前瞻性研究随访率较低的问题。
第三部分淘汰卫生技术的管理——以低强度激光血管内照射疗法为例
淘汰卫生技术是指任何用于一种或一种以上适应症的技术其临床效果、安全性或成本效果已经明显被其他替代技术所超越。我国鲜有通过官方渠道淘汰卫生技术的案例,在学术界对于如何确定淘汰卫生技术,如何通过卫生技术评估海鸥淘汰卫生技术的研究较为缺乏。本部分的研究以低强度激光血管内照射疗法(ILLLI)为例,对国内外公开发表的有关ILLLI的安全性和有效性的文献的系统性综述,评价ILLLI的有效性、安全性,并结合此技术的技术管理经验,提出淘汰卫生技术评估的理论管理框架。研究方法系统性综述以及专家咨询。
系统性综述的结果显示低强度激光血管内照射技术的治疗机制不明确,适应症不确定；虽然有大量的临床研究的文献,但尚缺乏高质量的研究来证明低强度激光血管内照射的有效性和安全性。对于如何正确、规范地使用这项技术,还有不少关键性的问题需要解决。在疗效不能确定的情况下,因为适应症的不确定和技术标准的不确定,因此带来一定程度的临床滥用。
基于低强度激光血管内照射疗法的研究经验,提出了淘汰卫生技术评估的框架。发现需要淘汰的卫生技术是在通过专家反馈的基础上基于临床医生和研究者的网络,建立淘汰技术的探测网络；专家和研究组草拟了淘汰卫生技术确定是否优先评估的指标体系,包括9个指标,涉及疾病情况、有效性、安全性、经济性等部分的内容；通过对现有证据的系统性综述来评估此卫生技术现有的证据情况,并通过临床专家的经验了解其在临床使用中的情况,为行政决策提供依据。
Health technology includes health-care drugs, equipments, procedures of internal medicine & surgical and the relevant management system and logistic support system. The development process of Health technology involves the development stage, the acceptance stage, and application stage and obsolete period. The management of Health technology need go through the whole development process of health technology to increase the capacity of health technology for disease prevention and treatment and reduce the negative impact of health technology.
With the objective needs of effective technology to deal with the population aging, the demand of chronic disease and the revolution of modern science and technology in twentieth Century, new health technologies come out one after the other and shorten the duration of replacement.For setting up the first barrier for the risk of new technolog, we need the technology accessment before the new technology is used or use widespread. But the systematic assessment of new technology is still in its early stage in China. If we need implement timely and systematically, the first step about new health technology assessment is horizontal scanningfor understanding what health new technology need to be evaluated.
In the application phase of health technology are the most widely applied.With safety and effectiveness assessment, it is very importance to conduct the health economic evaluation under the background of building of health universal insurance in China. "The guideline of pharmacoeconomics in China " released In the early 2011, which means the new stage for the economic evaluation of health technologies in China. After the development for 15 years, the availability of data for health economics research becomes the motive force of improving the quality of research. The new technology emerges in an endless stream means many original technologies is possible to be replaced. By scanning new technology and evaluating of existing technology, we can eliminated the health technology with poor safety, effectiveness and economy to guarantee the patients with the safe, effectiveness, cost-effectiveness health technology.
It is the three stages-- active management of the new technology, effective management of the existing technology and reasonable elimination of the obesolate technology to guarantee the patients with the safe, effectiveness, cost-effectiveness health technology. The overall technology management for different stages of the technology will guarantee the safety use of health technology. This research will focus on the case study in the new direction and methodology within the three stages.
Objective:This study focus on the case studies with the key points or empty area of the assessment and management of the three stages. With the experience and learning of case studies, the feasibility of new approaches and the proposal for the management of the technology has been studied for the completation of the technology management.
Through the case study of horizon scanning for the biotechnology in China, the feasibility of horizon scanning for the new technology will be studied for the reference of future assessment and management of new technology. A study for disease burden of stroke explores the availability and feasibility of data for economic evaluation with the new approaches; A study on the assessment of the intravascular low intensity laser irradiation technology will provide the experience for the technology assessment of obsolete technology and proposal for the management of obsolete technology.
Research framework
This research is divided into three parts, respectively, through case study to explore the application of horizontal scanning for the new technology, the data availability of the health economics evaluation for the existing technology and methodology and framework for the technology assessment of obsolete technology. (Fig 1) in the three studies, using horizon scanning for the biotechnology, stroke disease burden and intravascular low intensity laser irradiation technology as of three empirical studies to help explore these three areas of research new methods/framework. The specific research contents and methods of the research could be found in the subpart of the research paper.
Fig 1 research framework
Part 1 the feasibility of implementing horizon scanning of new technology in China Technology development, technology quantity and the public about the demand of new technology rise, increasing calls for accelerated on emerging technologies for decision making. Biological technology, nuclear technology and computer technology are known as twentieth Century three technical revolution. Biological technology the rapid development of the area, on the future of health care effect, at the same time, because of its advanced nature and ethics of technology management requirements are relatively high, the field of biotechnology horizontal scanning for our health new technology horizontal scanning provide empirical research experience. This research aims to biotechnology horizontal scanning as an case study, by focusing on technology selection, priority attention to technology use and policy environment evaluation for the health of new technology of horizontal scanning accumulation of empirical research experience, so as to the health of new technology of horizontal scanning in China provide the basis for the feasibility.
Research content and framework:According to three steps research route early detection, produce prediction and development policy, evaluate the new priority health technology in biological technology by colligating many-sided information on its acceptability and utilizing environment. In order to accumulate experience and provide reference for future technology management and the implementation of horizon scan. Research methods include 1) literature retrieval and tracing; 2) expert consultation; and 3) drug application status analysis.
The results of horizontal scanning show that 1) literature tracing, patents and network information indicate that vaccine, stem cells and monoclonal antibody are the focus of the biotechnology development in recent years; 2) the forecast of China Ministry of science and technology and Torch Program etc. show that the direction of biopharmaceutical including targeted therapy consists with vaccine and monoclonal antibody in literature tracing; 3) experts believe that biopharmaceutical is more feasible and important than stem cell therapy or tissue microarray in application; 4) analysis of biological industry reveal that biopharmaceutical is the vanguard of biotechnology entering into clinical practice. Thus biopharmaceutical is considered as a techneque need priority assessment.
Biotechnology Pharmaceuticals has 8 categories including hormones, growth factors, cytokines, monoclonal antibodies, vaccines, blood products, nucleic acid products and tissue engineering products. Biotechnology Pharmaceuticals is quiet different from common small molecular chemicals in the physical and chemical properties, immunological and toxicological properties, metabolic processes, formulation etc. Recently, the priority development of international new biotechnology Pharmaceuticals has five types:monoclonal antibodies, antisense gene drugs, gene therapy agent, soluble therapeutic protein drugs and vaccines. The number of new biologic drug United States FDA approved annually remained stable in 1996-2006; until the end of 2005, there are 18 kinds of approved gene engineering vaccines and drugs in our country,3 kinds of which having independent intellectual property rights is the class I drugs, including 8 kind of world top ten biotech drugs and the world's first gene therapy drug.
According to analyzing biotechnology drug sales in a drug utilizing database in 2004-2007 and four kinds of biopharmaceuticals, the results show that these new technology is accepted quickly. Biological pharmaceutical policy environment assessment shows that government attitude on biopharmaceutical research and application is encouraging and acceptable, the formulation of laws and regulations has some foundation, and health technology managers and users has considerable enthusiasm on the new technology. Through the horizontal scanning, the policy environment assessment and the utilizing assessment provide experience and direction to biopharmaceutical assessment and management in China; and also assess the feasibility of utilizing a foreign methodology of new technology horizontal scanning in China.
PartⅡThe availability of health economics data in health technology assessment of existing technology
After the publishcation of the guidelines of pharmacoeconomic in 2011 which could provide methodological direction and guidance for high-quality designed health economics evaluation, the availability of necessary health economics data becomes the guarantee and important premise for health economics evaluation quality. In this part, stroke disease burden research will be given as an example to discuss the availability of stroke economics evaluation data in China.
In China stroke has surpassed cardiovascular disease and becomes the first cause of death. The characteristics of stroke cost are including multiple acute attack costs, secondary prevention costs and disability costs, and the subsequent cost is relatively higher. In China, average hospitalization expense rather than the total cost in the disease course of individual patient is generally used for calculating in stroke disease burden researches because of the limitation of data, and the nationwide number of stroke patients vary greatly in different researches, thus the estimated stoke disease burden also vary greatly. In this research collecting of stroke disease burden intends to be an empirical research case, cost data collected in different ways will be use to calculate the stroke disease economic burden to consider the feasibility, superiors and inferiors between different data collection ways, in order to provide evidence for further relevant studies. The research methods include epidemiological data systematic review, cost information data mining in related database and the registration accompanied prospective cost data collection.
The epidemiology systemic reviews are relatively new and challenging field, through which shows that in China the incidence of stroke is in 43.5～629/100,000 person year, the prevalence is in 0.79%～7.73%, the mortality is at 71.56～117.2/100,000. Considering uneven quality of epidemiological studies and diversity of epidemiological data, a systematic review can help to concentrate epidemiological data range relatively by selecting the unbiased data of same standard according to uniform criteria which benefits to application of epidemiologic data in the health economics.
Database mining result shows that it is feasible to obtain hospitalization costs and inventory of stroke patients through electronic databases in tertiary hospitals and community health service centers, while it is troublesome in the outpatient data for non-standard diagnosis information. The greatest difficulty in process of data mining is lack of effective support from a integrity database, mainly from the following aspects:1) Mismatch between different hospital information systems. Information from different hospital system cannot be superimposed directly for their respective setting factors, which increased the difficulty of collecting data. And there is great difference of the electronic information system between community health service centers and tertiary hospitals.2) Impossibility of collecting disease cost data of outpatient as the diagnosis information is unrequited to input into the outpatient electronic information system in two hospitals.3) In China patients may visit in different hospitals without an integrity database like the United States of America, which affect quality and efficiency of health economics research by data mining.
Accompanied cost data collection, based on hospital multi-center stroke registry, is prospective and following-up whole course cost collection compared with simple inpatient cost collection. As a systematic method of cohort study, it is a clinical research method lying between traditional systematic case analysis study and population based study. In this research we found that this method is less cost and more efficient, mainly saves the time of patient enrollment. But we also found a common problem in the prospective study that the follow-up rate is low.
Part III Management of obsolete health technology ---with Intravascular Low Intensity Laser Irradiation therapy as an example
Eliminating health technology refers to any health technology in use for one or more indications, whose clinical benefit, safety or cost-effectiveness has been significantly superseded by other available alternatives. In China there is little case about health technology obsoleted through official channels, and there is also lack of researches on how to determine the elimination of health technology and how to eliminate the health technology by health technology assessment in academic circles. In this part intravascular low intensity laser irradiation therapy (ILLLI) is took as an example. The effectiveness and safety of ILLLI are estimated by systematically reviewing the published literature both domestic and foreign about the safety and efficacy of ILLLI, and combining with the technical management experience, the theoretical management framework of eliminating health technology assessment will be proposed. Research methods are systematic review and expert consultation.
The results of systematic review show that the mechanism of ILLLI is unclear and the indications are uncertain; although there are a large number of clinical study literatures, high quality research is still lack to confirm the efficacy and safety of ILLLI. There are many key problems need to solve on how to use of this technique correctly and normative. Besides indeterminacy of the effect, there is also indeterminacy of the indications and technical standards, thus brings a certain degree of clinical abuse. The framework of obsoleting health technology assessment is proposed based on the ILLLI researching experience. The identification of the health technology need to be obsoleted is to and establish obsoleted technology supervising network by experts feedback based on clinicians and researchers network; expert and research group draft out indicator system of obsolete health technology to determine priority assessment, including nine indicators related to disease status, effectiveness, safety, economic and so on; assess available evidence of the health technology by reviewing existing evidence systematically, and understand clinical use by experience of clinical experts, it is feasible to provide evidence for decision-making in the stage.
引文
1、 Goodman C S. HTA101-Introduction To Health Technology Assessment[EB/OL]. http://www.nlm.nih.gov/nichsr/hta101/hta101.pdf
2、银路,石忠国,王敏等.新兴技术：概念、特点和管理新思维[M].现代管理科学,2005,4：5-7
3、国家食品药品监督管理局,《2010年药品注册审批年度报告》[EB/OL]http://www.sfda.gov.cn/WS01/CL0050/65856.html,2011,10
4、 Euro, [EB/OL] http://www.euroscan.bham.ac.uk/terminology.htm
5、 Banta H D, Thacker S B. Historical Controversy in Health Technology Assessment:The Case of Electronic Fetal Monitoring[N]. OBSTETRICAL AND GYNECOLOGICAL SURVEY,2001,56(11):707-718
6、 Robert G, Stevens A, Gabbay J.'Early warning systems' for identifying new healthcare technologies[N]. Health Technol Assess 1999; 3(13)
7、苏怀德.药物研究史选讲[M].北京医科大学,中国协和医科大学联合出版社,1992
8、彭司勋.20世纪药物化学发展的回顾[M].中国药科大学学报,2001,32(1)：75-76
9、章金刚,倪道明.生物制品的现状与展望.中国输血杂志,2006,19(5)：349-351
10、 Inamuraa K, Kousakab S, Yamamotoc Y, et al. PACS development in Asia. Computerized Medical Imaging and Graphics[N],2003,27:121-128
11、 Robet [N]Nature Biotechnology,2011. July
12、 OECD, Patent database, June 2007 [R]. (www.oecd.org/sti/ipr-statistics)
13、胡蓉,谢祁阳.干细胞和新技术革命[N].医学与社会,2004,17(3)：36-37
14、 Biotechnology, http://www.fda.gov/cder/rdmt/default. htm[ER/OL]
15、胡显文等,《美国、欧盟和中国生物技术药物的比较》[N],中国生物工程杂志,2004,24(12),95—101
16、 Louis M Weiner et al,癌症的单克隆抗体免疫治疗[N],柳叶刀中文版,2009,Volume 3, Issue 11
17、医师报,盘点肿瘤学领域进展[R],2009年11月
18、 Robert G, Stevens A, Gabbay J.'Early warning systems' for identifying new healthcare technologies. Health Technol Assess 1999; 3(13)
19、. Douw K, Vondeling H, Eskildsen D, et al. Use of the Internet in Scanning the Horizon for New and Emerging Health Technologies:A Survey of Agencies Involved in Horizon Scanning. J Med Internet Res 2003,5(1):e6
20、陈文等,国内药物经济学评价研究文献的系统综述[N],中国药房,2004(15)1： 27—31
21、吴兆苏,姚崇华,赵冬.我国人群脑卒中发病率、死亡率的流行病学研究[J],中华流行病学杂志,2003,24(3)：230—239.
22、 Dewey, gihalopoulos C, et al. Cost of stroke in Australia from a societal perspective:results from the North East Melbourne Stroke Incidence Study [J]. Stroke,2001,32(10):2409-16
23、胡善联,龚向光.中国缺血性脑卒中的疾病经济负担[J].中国卫生经济,2003,22(12)：18—2014.
24、王梅,刘克军等,中国脑出血疾病的直接费用负担现状及其问题,中国卫生经济2005,24(7)：43—4
25、 Wang X, Jiang G, Choi BCK, et al. Surveillance of trend and distribution of stroke mortality by subtype, age, gender, and geographic areas in Tianjin, China, 1999-2006 [J].. International Journal of Stroke,2009,4(3):169-174.
26曾敏,吴智勇,郑茵,等.海口地区非瓣膜病性心房纤颤患者发生脑卒中的危险因素分析.[J]四川大学学报医学版,2009,40(5)：905-908.
27、 Zhou M, Offer A, Yang GH, et al. Body Mass Index, Blood Pressure, and Mortality From Stroke:A Nationally Representative Prospective Study of 212 000 Chinese Men. [J] Stroke.2008,39(3) 753-759.
28、 Jiang B, Wang WZ, Chen HL, et al. Incidence and trends of stroke and its subtypes in China:Results from three large cities. Stroke [J],2006,37(1):63-68.
29、皮延生,张薇,施侣元,等.急性心肌梗死住院患者脑卒中危险因素的研究[J].中华流行病学杂志,2002,23(6)：457-460.
30、邢海英,高惠珍,谭秀革,等.北京市农村社区人群颅内外动脉狭窄发生率及其预后[J].中华流行病学杂志,2009,30(8)：780-783.
31、杨期东,周艳宏,王文志,等.中国三城市社区人群脑卒中发病类型的分布特征[J].中华医学杂志,2002,82(13)：875-878.
32、张林峰,杨军,武阳丰,等.我国人群中缺血性和出血性脑卒中发病的相对比例[J].中华内科杂志,2003,42(2)：94-97.
33、姜勇,李晓燕,胡楠,等.2004~2005年中国居民脑血管病死亡流行病学特征[J].中华预防医学杂志,2010,44(4)：293-297.
34、吴蕴华与张金玲.2005～2007年上海市闵行区城乡居民脑卒中发病率及危险因素[J].中国慢性病预防与控制,2009,17(04)：407-408+411.
35、张梅喜,张卫东,余大海,等.安阳钢铁公司社区1789名中老年脉压与脑卒中、冠心病及高血压患病率的相关分析[J].中国临床康复,2005,9(29)：14-15.
51、 Zafirios-MFG et al. Laser-Irradiation-Induced relaxation of blood vessels in vivo. [J] Lasers in Surgery and Medicine,1990,10:524-532.
52、 Chaudhry H et al. Relaxation of vascular smooth muscle induced by low-power laser radiation. [J]Photochem-Photobiol,1993,58(5):661-669.
53、 John-EB et al. The impact of nonthermal red laser light upon vascular function and structure. [J] Presented in 36th Annual World Congress:International College of Angiology.
54、 Kipshidze-N et al. Photobiomodulation of vascular endothelial and smooth muscle cells in vitro with red laser light. [J]Proceedings-Bios Europe'96 1996,2922.
55、 Hong-MK:Restenosis after coronary angioplasty. [J] Curr Proble Cardio,1997,1 (1):7-36.
56、 Fuschman-DL et al. A randomized comparison of coronary-stent placement and balloon angioplasty in the treatment of coronary artery disease [J]. N-Engl-Med, 1994,331:496-501.
57、 Stadler I, Evans R, Kolb B, Naim JO, Narayan V, Buehner N, Lanzafame RJ.2000. In vitro effects of low-level laser irradiation at 660 nm on peripheral blood lymphocytes. [J] Lasers Surg Med.2000;27(3):255-61.
58、 Mi XQ, Chen JY, Cen Y, Liang ZJ, Zhou LW.2004. A comparative study of 632.8 and 532 nm laser irradiation on some rheological factors in human blood in vitro. [J] J Photoch Photobio B 74 (1):7-12.2004.
59、 Luo J, Tu LC, Hu ZK, et al. New experimental limit on the photon rest mass with a rotating torsion balance [J]. Phys Rev Lett.2003,90 (8):Art. No.081801.
60、 Karu T. The Science of Low-Power Laser Therapy [M]. Amsterdam:Gordon and Breach Science Publishers.1998.
61、 Tuner J and Hode L. Low Level Laser Therapy [M]. Graengesberg:Prima Books in Sweden AB.1999.
62、 Liu TCY, Jiao JL, Duan R, et al. Membrane mechanism of low intensity laser biostimulation on a cell. Simunovic Z (ED). Lasers in Medicine, Surgery and Dentistry [J]. Croatia:European Medical Laser Association.2003,83-105.
63、 Wong BC, Boyd CA, Lanzendorf SE. Randomized controlled study of human zona pellucida dissection using the Zona Infrared Laser Optical System:evaluation of blastomere damage, embryo development, and subsequent hatching [J]. Fertil Steril.2003,80 (5):1249-1254.
64、 Wolbarsht ML. Low-level laser therapy (lllt) and safety considerations [J]. J Laser Appl.1994,6 (3):170-172.
65、 Logan ID, Mckenna PG, Barnett YA. An investigation of the cytotoxic and mutagenic potential of low-intensity laser irradiation in friend-erythroleukemia cells [J]. Mutat Res Lett.1995,347 (2):67-71.
66、 Joyce KM, Downes CS, Hannigan BM. Cell-cycle delay is induced in cells of a U937 promonocytic cell line by low-intensity light irradiation at 660 nm [J]. J Photoch Photobio B.1999,52 (1-3):117-122.
67、 Applegate LA, Scaletta C, Panizzon R, et al. Induction of the putative protective protein ferritin by infrared radiation:Implications in skin repair [J]. Int J Mol Med.2000,5 (3):247-251.
68、 El Batanouny M, Korraa S, Fekry 0. Mitogenic potential inducible by He:Ne laser in human lymphocytes in vitro [J]. J Photoch Photobio B.2002,68 (1):1-7.
69、 De Scheerder IK, WangK, Kaul U, et al. Intravascular low-power laser irradiation after coronary stenting:Long-term follow-up [J]. LASER SURG MED.2001,28 (3): 212-215.
70、郭丽君,郭静萱,毛节明等.冠状动脉介入治疗辅以低能量红激光照射的近远期结果分析[J].中国激光医学杂志.2001,10(1)：17-20.
71、 Grace Wang, Technology assessment for low level laser therapy. Office of the medical Director Department of Labor and industries, May 3,2004.
72、 Christa Altenstetter, EU and member state medical devices regulation. International Jounal of technology assessment in Health Care,19:1(2003):228-248.
73、 Aaron V.Kaplan et al, Medical Device Development-from prototype to regulatory Approval.Cirrulation.2004;109:3068-3072.
74、 WHO report, Medical Device Regulation-Global overview and guiding principles.2003.
75、顾瑛,刘凡光,江忆平等.510.6nm激光诱导兔在体血管平滑肌细胞凋亡的研究[J].中国激光医学杂志.1999,8(3)：141-144.
IRobert G, Stevens A, Gabbay J.'Early warning systems'for identifying new healthcare technologies. [J] Health Technol Assess 1999; 3(13)
2、 Douw K, Vondeling H, Eskildsen D, et al. Use of the Internet in Scanning the Horizon for New and Emerging Health Technologies:A Survey of Agencies Involved in Horizon Scanning[J]. J Med Internet Res 2003,5(1): e6
3 Bozic K J, Pierce R G, Herndon J H. Health care technology assessment. Basic principles and clinical applications. [J] J Bone Joint Surg Am 2004;86:1305-1313
4、 Bodenheimer T. High and Rising Health Care Costs. Part 2: Technologic Innovation[J]. Annals of Internal Medicine,2005,142(11): 932-937
5. European Information Network on New and Changing Health Technology.[R] EuroScan:Status Report.2005
6. www.sbu.se/alert
2、银路,石忠国,王敏等.新兴技术：概念、特点和管理新思维[M].现代管理科学,2005,4：5-7
3、国家食品药品监督管理局,《2010年药品注册审批年度报告》[EB/OL]http://www.sfda.gov.cn/WS01/CL0050/65856.html,2011,10
4、 Euro, [EB/OL] http://www.euroscan.bham.ac.uk/terminology.htm
5、 Banta H D, Thacker S B. Historical Controversy in Health Technology Assessment:The Case of Electronic Fetal Monitoring[N]. OBSTETRICAL AND GYNECOLOGICAL SURVEY,2001,56(11):707-718
6、 Robert G, Stevens A, Gabbay J.'Early warning systems' for identifying new healthcare technologies[N]. Health Technol Assess 1999; 3(13)
7、苏怀德.药物研究史选讲[M].北京医科大学,中国协和医科大学联合出版社,1992
8、彭司勋.20世纪药物化学发展的回顾[M].中国药科大学学报,2001,32(1)：75-76
9、章金刚,倪道明.生物制品的现状与展望.中国输血杂志,2006,19(5)：349-351
10、 Inamuraa K, Kousakab S, Yamamotoc Y, et al. PACS development in Asia. Computerized Medical Imaging and Graphics[N],2003,27:121-128
11、 Robet [N]Nature Biotechnology,2011. July
12、 OECD, Patent database, June 2007 [R]. (www.oecd.org/sti/ipr-statistics)
13、胡蓉,谢祁阳.干细胞和新技术革命[N].医学与社会,2004,17(3)：36-37
14、 Biotechnology, http://www.fda.gov/cder/rdmt/default. htm[ER/OL]
15、胡显文等,《美国、欧盟和中国生物技术药物的比较》[N],中国生物工程杂志,2004,24(12),95—101
16、 Louis M Weiner et al,癌症的单克隆抗体免疫治疗[N],柳叶刀中文版,2009,Volume 3, Issue 11
17、医师报,盘点肿瘤学领域进展[R],2009年11月
18、 Robert G, Stevens A, Gabbay J.'Early warning systems' for identifying new healthcare technologies. Health Technol Assess 1999; 3(13)
19、. Douw K, Vondeling H, Eskildsen D, et al. Use of the Internet in Scanning the Horizon for New and Emerging Health Technologies:A Survey of Agencies Involved in Horizon Scanning. J Med Internet Res 2003,5(1):e6
20、陈文等,国内药物经济学评价研究文献的系统综述[N],中国药房,2004(15)1： 27—31
21、吴兆苏,姚崇华,赵冬.我国人群脑卒中发病率、死亡率的流行病学研究[J],中华流行病学杂志,2003,24(3)：230—239.
22、 Dewey, gihalopoulos C, et al. Cost of stroke in Australia from a societal perspective:results from the North East Melbourne Stroke Incidence Study [J]. Stroke,2001,32(10):2409-16
23、胡善联,龚向光.中国缺血性脑卒中的疾病经济负担[J].中国卫生经济,2003,22(12)：18—2014.
24、王梅,刘克军等,中国脑出血疾病的直接费用负担现状及其问题,中国卫生经济2005,24(7)：43—4
25、 Wang X, Jiang G, Choi BCK, et al. Surveillance of trend and distribution of stroke mortality by subtype, age, gender, and geographic areas in Tianjin, China, 1999-2006 [J].. International Journal of Stroke,2009,4(3):169-174.
26曾敏,吴智勇,郑茵,等.海口地区非瓣膜病性心房纤颤患者发生脑卒中的危险因素分析.[J]四川大学学报医学版,2009,40(5)：905-908.
27、 Zhou M, Offer A, Yang GH, et al. Body Mass Index, Blood Pressure, and Mortality From Stroke:A Nationally Representative Prospective Study of 212 000 Chinese Men. [J] Stroke.2008,39(3) 753-759.
28、 Jiang B, Wang WZ, Chen HL, et al. Incidence and trends of stroke and its subtypes in China:Results from three large cities. Stroke [J],2006,37(1):63-68.
29、皮延生,张薇,施侣元,等.急性心肌梗死住院患者脑卒中危险因素的研究[J].中华流行病学杂志,2002,23(6)：457-460.
30、邢海英,高惠珍,谭秀革,等.北京市农村社区人群颅内外动脉狭窄发生率及其预后[J].中华流行病学杂志,2009,30(8)：780-783.
31、杨期东,周艳宏,王文志,等.中国三城市社区人群脑卒中发病类型的分布特征[J].中华医学杂志,2002,82(13)：875-878.
32、张林峰,杨军,武阳丰,等.我国人群中缺血性和出血性脑卒中发病的相对比例[J].中华内科杂志,2003,42(2)：94-97.
33、姜勇,李晓燕,胡楠,等.2004~2005年中国居民脑血管病死亡流行病学特征[J].中华预防医学杂志,2010,44(4)：293-297.
34、吴蕴华与张金玲.2005～2007年上海市闵行区城乡居民脑卒中发病率及危险因素[J].中国慢性病预防与控制,2009,17(04)：407-408+411.
35、张梅喜,张卫东,余大海,等.安阳钢铁公司社区1789名中老年脉压与脑卒中、冠心病及高血压患病率的相关分析[J].中国临床康复,2005,9(29)：14-15.
51、 Zafirios-MFG et al. Laser-Irradiation-Induced relaxation of blood vessels in vivo. [J] Lasers in Surgery and Medicine,1990,10:524-532.
52、 Chaudhry H et al. Relaxation of vascular smooth muscle induced by low-power laser radiation. [J]Photochem-Photobiol,1993,58(5):661-669.
53、 John-EB et al. The impact of nonthermal red laser light upon vascular function and structure. [J] Presented in 36th Annual World Congress:International College of Angiology.
54、 Kipshidze-N et al. Photobiomodulation of vascular endothelial and smooth muscle cells in vitro with red laser light. [J]Proceedings-Bios Europe'96 1996,2922.
55、 Hong-MK:Restenosis after coronary angioplasty. [J] Curr Proble Cardio,1997,1 (1):7-36.
56、 Fuschman-DL et al. A randomized comparison of coronary-stent placement and balloon angioplasty in the treatment of coronary artery disease [J]. N-Engl-Med, 1994,331:496-501.
57、 Stadler I, Evans R, Kolb B, Naim JO, Narayan V, Buehner N, Lanzafame RJ.2000. In vitro effects of low-level laser irradiation at 660 nm on peripheral blood lymphocytes. [J] Lasers Surg Med.2000;27(3):255-61.
58、 Mi XQ, Chen JY, Cen Y, Liang ZJ, Zhou LW.2004. A comparative study of 632.8 and 532 nm laser irradiation on some rheological factors in human blood in vitro. [J] J Photoch Photobio B 74 (1):7-12.2004.
59、 Luo J, Tu LC, Hu ZK, et al. New experimental limit on the photon rest mass with a rotating torsion balance [J]. Phys Rev Lett.2003,90 (8):Art. No.081801.
60、 Karu T. The Science of Low-Power Laser Therapy [M]. Amsterdam:Gordon and Breach Science Publishers.1998.
61、 Tuner J and Hode L. Low Level Laser Therapy [M]. Graengesberg:Prima Books in Sweden AB.1999.
62、 Liu TCY, Jiao JL, Duan R, et al. Membrane mechanism of low intensity laser biostimulation on a cell. Simunovic Z (ED). Lasers in Medicine, Surgery and Dentistry [J]. Croatia:European Medical Laser Association.2003,83-105.
63、 Wong BC, Boyd CA, Lanzendorf SE. Randomized controlled study of human zona pellucida dissection using the Zona Infrared Laser Optical System:evaluation of blastomere damage, embryo development, and subsequent hatching [J]. Fertil Steril.2003,80 (5):1249-1254.
64、 Wolbarsht ML. Low-level laser therapy (lllt) and safety considerations [J]. J Laser Appl.1994,6 (3):170-172.
65、 Logan ID, Mckenna PG, Barnett YA. An investigation of the cytotoxic and mutagenic potential of low-intensity laser irradiation in friend-erythroleukemia cells [J]. Mutat Res Lett.1995,347 (2):67-71.
66、 Joyce KM, Downes CS, Hannigan BM. Cell-cycle delay is induced in cells of a U937 promonocytic cell line by low-intensity light irradiation at 660 nm [J]. J Photoch Photobio B.1999,52 (1-3):117-122.
67、 Applegate LA, Scaletta C, Panizzon R, et al. Induction of the putative protective protein ferritin by infrared radiation:Implications in skin repair [J]. Int J Mol Med.2000,5 (3):247-251.
68、 El Batanouny M, Korraa S, Fekry 0. Mitogenic potential inducible by He:Ne laser in human lymphocytes in vitro [J]. J Photoch Photobio B.2002,68 (1):1-7.
69、 De Scheerder IK, WangK, Kaul U, et al. Intravascular low-power laser irradiation after coronary stenting:Long-term follow-up [J]. LASER SURG MED.2001,28 (3): 212-215.
70、郭丽君,郭静萱,毛节明等.冠状动脉介入治疗辅以低能量红激光照射的近远期结果分析[J].中国激光医学杂志.2001,10(1)：17-20.
71、 Grace Wang, Technology assessment for low level laser therapy. Office of the medical Director Department of Labor and industries, May 3,2004.
72、 Christa Altenstetter, EU and member state medical devices regulation. International Jounal of technology assessment in Health Care,19:1(2003):228-248.
73、 Aaron V.Kaplan et al, Medical Device Development-from prototype to regulatory Approval.Cirrulation.2004;109:3068-3072.
74、 WHO report, Medical Device Regulation-Global overview and guiding principles.2003.
75、顾瑛,刘凡光,江忆平等.510.6nm激光诱导兔在体血管平滑肌细胞凋亡的研究[J].中国激光医学杂志.1999,8(3)：141-144.
IRobert G, Stevens A, Gabbay J.'Early warning systems'for identifying new healthcare technologies. [J] Health Technol Assess 1999; 3(13)
2、 Douw K, Vondeling H, Eskildsen D, et al. Use of the Internet in Scanning the Horizon for New and Emerging Health Technologies:A Survey of Agencies Involved in Horizon Scanning[J]. J Med Internet Res 2003,5(1): e6
3 Bozic K J, Pierce R G, Herndon J H. Health care technology assessment. Basic principles and clinical applications. [J] J Bone Joint Surg Am 2004;86:1305-1313
4、 Bodenheimer T. High and Rising Health Care Costs. Part 2: Technologic Innovation[J]. Annals of Internal Medicine,2005,142(11): 932-937
5. European Information Network on New and Changing Health Technology.[R] EuroScan:Status Report.2005
6. www.sbu.se/alert