创新药物的零期临床试验

为了引导创新药物的快速开发、控制新药研发过程中的临床风险,美国食品和药物管理局于2006年颁布了“探索性新药研究”指导原则,提出在进行传统的Ⅰ期临床试验之前开展零期临床试验的概念,并取得了一系列有意义的结果。随着我国自主创新药物的研发体系的建立和发展,能够快速筛选、降低成本、减少风险、提高新药开发效率的探索性新药临床研究方法愈来愈受到关注。但在我国零期临床研究尚处于起步阶段,没有相应的法规和指导原则,缺乏合理的研究设计和专业的研究人员,零期临床研究本身也存在一些局限。本文就创新药物的零期临床试验的概念、研究方法、检测方法、适用药物、优势与不足及与传统临床试验的区别等做一综述。     

药品上市后再评价的临床价值

1.创新药物研究.在国家十一五期间,令我国药学界科研工作者为之振奋的是国家投入了6亿人民币在重人新药创制的科研方面,这样给我们提供了机遇和挑战.在原创新药(化合物)开发的过程中.需经过化合物的合成与筛选,临床前的动物研究,临床人体试验Ⅰ～Ⅲ期,以及上市后的期Ⅵ期临床研究,才能从10000个活性化合物最终筛选出1个新药上市,而临床研究足决定创新药物研发成败的关键.     

药物经济学评价在新药临床试验中的应用与影响

新药研发具有费用高、周期长和风险大的特点,尤其是在新药临床研究阶段。在新药临床研究阶段进行药物经济学研究,将能够为决策者提供新药研发项目是否应该继续进行所需要的参考信息。为了使得这些参考信息真实可信,传统的药物临床试验必须有所改进,以适合进行经济学评价。     

新药非临床评价中几个基本问题的探讨

新药(本文中仅指创新性药物)的开发是逐步探索和评价的过程,在这一过程中,研发者会逐步对药物的作用机制、药理作用、药代特征、毒性等一系列生物学特征进行探索和评价,以保证药物的安全性和有效性。非临床评价(药理毒理评价)是新药开发过程中不可或缺的重要组成部分。新药的注册评价是基于研发工作的“事后”行为,其评价角度虽与研发者有所不同,但从技术层面而言,其目的和本质与研发者却并无二致。笔者以下对新药的非临床注册技术评价中几个理论层面的基本问题进行探讨,以期能有益于新药非临床评价和研究工作的具体实践。1临床用药的风险/…     

加速药物研发新方式——微剂量给药研究

药物研发是一项长时间、难度大、高投入的工程。近年来,新药研发成本逐年增加,经FDA批准上市的新药却呈下降趋势。为加速药物研发,欧洲EMEA在2003年7月,美国FDA在2006年1月分别颁布相关指南,提出一种新的药物研发方式：人体微剂量给药研究或称临床试验0期。微剂量研究是首次在人体身上进行的临床药物研究,仅需要少数的受试者,在短时间内给予微剂量新化学实体的研究,其目的不在于治疗或诊断,而是为了及早获得新化学实体的人体药动学信息,协助筛选最优候选化学物。由于是极低剂量给药,极大降低了药物的风险,因此其对临床前研究资料的要求大为减少。合理选择新化学实体进行微剂量研究,可以使患者更早得到安全有效的新药治疗,减少临床试验的损耗,降低研发成本及提高研发效率。     

2003年后基因组时代新药研发国际学术讨论会(第一轮通知)

中国药学会定于 2 0 0 3年 8月 13～ 15日在北京召开“2 0 0 3年后基因组时代新药研发国际学术讨论会”。会议期间 ,将邀请多位中美著名药物研究专家、院士作专题报告 ,并安排部分口头报告和墙报展览。热忱欢迎医药界同仁踊跃参加这次学术盛会 !大会报告人员陈凯先院士 (中国科学院上海药物所 ,报告题目待定 )沈倍奋院士 (军事医学科学院基础医学所 )分子免疫学与新药研究郭宗儒教授 (中国医学科学院药物所 )新抗炎药物的研究与开发李　松教授 (军事医学科学院毒物药物所 )计算机辅助药物设计饶子和教授 (清华大学生物系 )新药相关结构生物…     

创新药物转化研究中ADME的评价

新药研发是一复杂的庞大系统工程, 所涉及的学科门类众多, 研究周期长。而转化研究有助于构建创新药物的基础研究、临床前研究和临床疗效评价直至新药制造和临床应用的系统研发链, 顺畅基础医学和生物学与创新药物研发、临床医学之间的信息和研究关联, 缩短创新药物从实验室到临床应用的研发周期。在新药研发和临床应用过程中, 化合物的体内过程 (吸收、分布、代谢、排泄, ADME) 是其成药性的重要指标。化合物ADME/T性质在创新药物转化研究中发挥重要作用并贯穿研发过程。因此, 在药物设计及新药开发早期就开展药物代谢研究, 有利于提高新药研发的成功率, 降低新药开发的成本, 获得安全、有效的治疗药物。     

生物标志物在药品生命周期中的应用与展望

生物标志物(biomarker)是一种能客观测量并评价正常生物过程、病理过程或对药物干预反应的指示物,可有效提高新药研究开发决策,指导候选药物早期临床试验,降低新药研发失败的风险,其在药品生命周期中的重要作用已引起业内普遍关注。欧美等国家和地区相继出台关于生物标志物研究开发和资格鉴定程序的指南,鼓励医药企业将生物标志物作为创新药物发现的工具,在药品上市后通过生物标志物监控其安全性和有效性。本文针对我国药品生命周期特点,对生物标志物在药物基础研究、先导化合物/创新药物的设计与发现、临床前药物开发、临床研究、新药研究及上市后再评价等药品生命周期各个环节中作用情况进行综述,并对其应用前景进行展望。     

制药企业如何利用CRO提高竞争力

新药研发耗资大、周期长、风险高,使得许多制药企业在新药研究以及临床前试验、临床试验、注册等流程前望而却步,于是,合同研究组织(简称CRO)应运而生.CRO是Contract Research Organization的缩写,顾名思义,CRO是通过合同形式向制药企业提供涉及药物研究各领域服务内容的一类专业公司,涉及的主要研究内容为新药研究中的工艺研究技术服务、非临床研究、临床研究用药制备及临床研究等.它于20世纪80年代初起源于美国,目前多倾向于新药的临床研究服务.作为制药企业的一种可借用的外部资源,它可以在短时间内迅速组织起一个高度专业化的和具有丰富临床经验的临床研究队伍,并能有效降低制药企业的研发成本,提高研发效率.现在CRO服务在全球药物研究市场正在以每年20%～30%的速度增长.     

药代动力学人体预测及其在新药研发中的应用

药物代谢和药代动力学(DMPK)通过揭示药物的体内代谢处置过程,理解药物药理效应和毒副反应的体内物质基础,是连接药物分子及其性质与生物学效应的桥梁。DMPK人体预测应用模型拟合技术,由人体外试验数据和动物体内外数据预测人体药代动力学性质,并与药效动力学和毒性评价相关联,可提高新药研发效率、降低临床失败率和节省资源。经典的异速放大法和体外-体内外推法主要用于预测人体清除率和稳态表观分布容积等重要的药代动力学参数。近10年来,基于生理的药代动力学模型(PBPK)的快速发展和应用实践,推动了DMPK人体预测在新药研发、药物监管、临床合理和个体化用药中的应用。PBPK模型不仅能预测消除和分布等参数,还能用于药物人体药代动力学行为的预测,包括血药浓度-时间曲线和药物-药物相互作用,以及不同人群体内药代动力学和药代-药效预测。作为新药研发的转化科学技术以及个体化用药的指导工具,DMPK人体预测将具有更为广泛的应用价值。     

Development of radiotracers for oncology--the interface with pharmacology

There is an increasing role for positron emission tomography (PET) in oncology, particularly as a component of early phase clinical trials. As a non-invasive functional imaging modality, PET can be used to assess both pharmacokinetics and pharmacodynamics of novel therapeutics by utilizing radiolabelled compounds. These studies can provide crucial information early in the drug development process that may influence the further development of novel therapeutics. PET imaging probes can also be used as early biomarkers of clinical response and to predict clinical outcome prior to the administration of therapeutic agents. We discuss the role of PET imaging particularly as applied to phase 0 studies and discuss the regulations involved in the development and synthesis of novel radioligands. The review also discusses currently available tracers and their role in the assessment of pharmacokinetics and pharmacodynamics as applied to oncology.     

Genotoxic hazard of radiopharmaceuticals in humans: chemical and radiation aspects coupled to microdosing

Introduction To obtain the pharmacokinetic properties of drug candidates at an early stage of the development process, a microdosing (phase 0) concept to radiolabel drug candidates and administer them at subtoxic mass to a few volunteers has been suggested. Radiopharmaceuticals are special in the sense that the chemical carrier might be genotoxic, whereas it is well established that ionizing radiation coupled to the molecule is genotoxic, and that the mechanism that causes cancer is similar to certain genotoxic chemicals. Regulatory perspectives of the levels of toxicity An analysis shows that, e.g., positron emission tomography (PET) pharmaceuticals carry a mass less than what is regarded as an acceptable level of a genotoxic impurity. It has also been shown that the estimated genotoxicity hazard of the radioactivity is 10–100 times higher than that of the administered chemicals. Conclusion As radiation doses at this level are accepted in clinical trials, the conclusion is that the regulatory demands on radiopharmaceuticals produced at high specific radioactivity should be reconsidered in order to facilitate the use of the microdosing concept for drug development.     

Molecular imaging with SPECT as a tool for drug development

Molecular imaging techniques are increasingly being used as valuable tools in the drug development process. Radionuclide-based imaging modalities such as single-photon emission computed tomography (SPECT) and positron emission tomography (PET) have proven to be useful in phases ranging from preclinical development to the initial stages of clinical testing. The high sensitivity of these imaging modalities makes them particularly suited for exploratory investigational new drug (IND) studies as they have the potential to characterize in vivo pharmacokinetics and biodistribution of the compounds using only a fraction of the intended therapeutic dose (microdosing). This information obtained at an early stage of clinical testing results in a better selection among promising drug candidates, thereby increasing the success rate of agents entering clinical trials and the overall efficiency of the process. In this article, we will review the potential applications of SPECT imaging in the drug development process with an emphasis on its applications in exploratory IND studies.     

Positron emission tomography microdosing: a new concept with application in tracer and early clinical drug development

The realisation that new chemical entities under development as drug candidates fail in three of four cases in clinical trials, together with increased costs and increased demands of reducing preclinical animal experiments, have promoted concepts for improvement of early screening procedures in humans. Positron emission tomography (PET) is a non-invasive imaging technology, which makes it possible to determine drug distribution and concentration in vivo in man with the drug labelled with a positron-emitting radionuclide that does not change the biochemical properties. Recently, developments in the field of rapid synthesis of organic compounds labelled with positron-emitting radionuclides have allowed a substantial number of new drug candidates to be labelled and potentially used as probes in PET studies. Together, these factors led to the logical conclusion that early PET studies, performed with very low drug doses—PET-microdosing—could be included in the drug development process as one means for selection or rejection of compounds based on performance in vivo in man. Another important option of PET, to evaluate drug interaction with a target, utilising a PET tracer specific for this target, necessitates a more rapid development of such PET methodology and validations in humans. Since only very low amounts of drugs are used in PET-microdosing studies, the safety requirements should be reduced relative to the safety requirements needed for therapeutic doses. In the following, a methodological scrutinising of the concept is presented. A complete pre-clinical package including limited toxicity assessment is proposed as a base for the regulatory framework of the PET-microdosing concept.     

Alternative strategies in drug development: clinical pharmacological aspects

Due to the continuous increase in time and cost of drug development and the considerable amount of resources required by the traditional approach, companies can no longer afford to continue to late phase 3 with drugs which are unlikely to be therapeutically effective. The future challenge must be for the pharmaceutical industry to slash its research and development costs by achieving a significant cut in the attrition rate for drugs entering preclinical and clinical development, and to reduce the development time and to increase the probability of success in later clinical trials by streamlining the development processes. In the 100 years to 1995, the pharmaceutical industry worked on about 500 targets with a limited number of compounds, whereas now, using new technologies like genomics, high throughput screening and combinatorial chemistry, drug companies will see an explosion in the number of targets and leads it can explore. Therefore, a tough selection process for picking candidate compounds out of research and a quick kill process for the candidate, which does not measure up in advanced trials, is mandatory to avoid wasting time, energy and money. To improve the transition from research to development it is necessary to validate new targets, define success criteria for research, integrate bioinformation at every stage in drug discovery, define prerequisites for development, identify the "losers" and select the "winners" early and concentrate efforts on them, and to automate the research and development (R&D) process to optimize resource requirements versus time lines and to ensure effective flow of information from drug discovery to late phase of development. In drug development a deeper understanding of a drugs' action is necessary from animal models and phase I, IIa studies prior to taking the drug further in development. Instead of moving from discovery thorough development phases in sequential steps, drug development should be streamlined combining preclinical and early clinical development as an exploratory stage and phases IIb, III as a confirmatory stage. Preclinical and clinical-pharmacological studies in the exploratory stage of drug development should be designed for decision making in contrast to later clinical trials that require power for proof-of-safety and efficacy. Strategies to improve the quality of decisions in drug development are: the use and integration of new tools and technologies such as pharmacogenomics to improve our knowledge about the origin of the disease and to identify new therapeutic strategies; modelling and simulation of preclinical and clinical trials to bridge the gap between the early stages of the development of a new drug and its potential effects in humans; more sophisticated clinical pharmacokinetics to answer the question if the drug is present at the disease site for a sufficient time and to provide information on concentration-effect-relationships; selecting and evaluating surrogates/biomarkers for safety and efficacy; involvement of the target population as soon as possible; using information technologies to make better use of existing data. The more thorough and profound studies have been carried out during this exploratory stage of development, the earlier a decision can be made on the continuation or discontinuation of further development, thus saving development time and money and assessing and considerably reducing the risk for the patients and increasing the success-rate of the project in the later confirmatory effectiveness trial. Taking responsibility as the link between research and development gives clinical pharmacology a major opportunity to assume a pivotal role in research and development of new drugs. To reach this goal, clinical pharmacology must be fully integrated in the whole process from the candidate selection to its approval.     

Application of pre-clinical PET imaging for drug development

Positron emission tomography (PET) is a sophisticated method for the quantitative and noninvasive imaging of biological functions by monitoring the delivery of tracers labeled with positron emitters (1C, 'aN, '"O, and 8F). The distribution and kinetic patterns of a labeled compound in relation to the specific biomolecule in the target tissue are assumed to reflect specific biological functions in the living body. A wide variety of labeled compounds as molecular probes have been developed to measure biochemical and physiological parameters, such as blood flow, glucose and oxygen metabolism, protein synthesis, and neurotransmitter receptor functions. Recently, PET has gradually been introduced into the research field of drug development both in pre-clinical and clinical stages. In the present chapter, the applications of animal PET with small animals (rats and mice) and non-human primates in drug development in the pre-clinical stage will be discussed based on our own experiences. In the course of drug development, the pre-clinical studies with experimental animals are indispensable, and these studies are expected to provide useful information to facilitate the development of drug candidates with more efficacy and fewer adverse effects in the clinical stage with     

Discontinued drugs in 2008: oncology drugs

The failure of drug candidates in clinical development remains a critical issue for the pharmaceutical and biotechnology industries. This article documents those oncology drugs discontinued in 2008 and briefly reviews reasons for termination of development. Source information was derived from a search of the Pharmaprojects database for drugs reaching phase I – III clinical trials.     

Novel amphiphilic probes for [18F]-radiolabeling preformed liposomes and determination of liposomal trafficking by positron emission tomography

Positron-emission tomography (PET) is a noninvasive real-time functional imaging system and is expected to be useful for the development of new drug candidates in clinical trials. For its application with preformulated liposomes, we devised an optimized [18F]-compound and developed a direct liposome modification method that we termed the "solid-phase transition method". We were successful in using 1-[18F]fluoro-3,6-dioxatetracosane ([18F]7a) for in vivo trafficking of liposomes. This method might be a useful tool in preclinical and clinical studies of lipidic particle-related drugs.     

A Road Map to GMP Readiness for Protein Therapeutics – Drug Product Process Development for Clinical Supply

Biopharmaceuticals for human use present unique challenges during manufacturing, storage, shipment, and administration. Not all drug product process development aspects can and should be studied in detail before entering in first-in human studies (FIH) due to limited resources and the need for new drug candidates to enter phase I clinical studies quickly. Whilst activities for formulation development studies are well defined in literature, there is a lack of regulatory guidance for phase appropriate process development studies for clinical supplies. This review summarizes potential process development studies for liquid protein formulations and proposes a phase appropriate testing approach.     

Hands-on molecular imaging: real-time visualization tools bridge gaps in translational medicine

Molecular imaging tools such as CT, MRI, PET and SPECT, as well as various combinations of these instrument systems, continue to improve and evolve, offering increasingly sensitive and high-resolution images of biological processes in real time. The optimal use of these tools across the continuum of biomedical research and clinical medicine can generate the information that is needed to bridge the gaps that currently exist in drug discovery and development. These gaps negatively affect the promise and potential of translational medicine, in which the knowledge gained from multidisciplinary efforts encompassing genomics, proteomics, biomarker discovery, systems biology and bioinformatics are used to drive R&D, design experiments, predict outcomes, guide patient selection for clinical trials, and define pharmacogenomic parameters for optimizing the safety and efficacy of drug compounds. Thus, molecular imaging tools serve an important role in optimizing the drug discovery and development process.