药物临床试验伦理审查存在的问题及对策研究

依据GCP药物临床试验管理规范,分析我国药物临床试验伦理审查工作中存在的问题,从如何保障受试者知情同意、加强伦理委员伦理知识培训、全程伦理监督及引入伦理验收、加强监管力度和完善监督体制等4个方面对药物临床试验伦理审查工作提出针对性建议,以逐步完善我国药物临床试验伦理审查工作。     

医学研究伦理学的发展现状与前景

创新技术的开展和转化医学的注重给医学的发展注入了新的活力,但同时,也带来了一系列社会伦理问题和法律问题。生命医学伦理学的兴起和发展催生了医学研究伦理学分支学科形成,目的在于推进解决涉及人体的医学研究的伦理问题。当前,面临的最突出的伦理问题在于,对医学研究合法性、先进性及伦理性的把握,对医学研究伦理审查必要性的认知,对医学研究方案设计与伦理道德的匹配,对医学研究知情同意的告知,对医学研究风险与受益的平衡。逐步与国际接轨,加强伦理委员会制度建设;提高伦理审查能力建设,形成高水平的伦理审查队伍;学术组织和团体共同努力,推进医学研究伦理学的发展,这将助推医学研究伦理学的发展。     

日本在新药开发方面揭开个性化医疗的序幕

2008年9月，日本厚生劳动省公布了“关于实施利用基因组药理学进行药物临床试验的Q＆A”（药食审查发第0930007号）。虽然出台的时间推迟了很久，但根据这份规定，已经为开发新药的临床试验以及上市后的临床试验，开辟了一条从被检者身上采集DNA、进行基因型分析的途径。不仅揭开了真正意义上个性化医疗的序幕．而且也迫使现行的覆盖收集DNA的临床研究的”关于人类基因组、遗传基因分析研究的伦理方针”（3省厅基因组伦理方针）进行重新修订。     

生命伦理学委员会

生命伦理学委员会是从伦理学角度审查人体试验研究,保护受试者权益的决策咨询组织。该委员会一般由来自法学、伦理学、医学、药学等领域的专家学者组成,其审查遵循的重要依据是世界医学会制订的《赫尔基辛宣言》。近年来,伦理委员会快速发展,但各伦理委员会审查质量参差不齐。因此,相关部门尚需加强对伦理委员会成员的培训,并加强对伦理委员会的监管,方能促进我国伦理委员会的良性发展。     

我国仿制药人体生物等效性临床试验研究室建设的现状与发展路径

我国开展仿制药一致性评价最主要的困难之一是临床试验资源不足,解决办法是考虑将生物等效性临床试验资格认定调整为备案 管理。因此,对备案的医疗机构建设生物等效性试验研究室是一个潜在的挑战。文章分析了国内当前具备生物等效性 / I期临床资质的 机构、分布、承担项目能力及生物等效性临床试验机构、药物分析实验室和合同研究组织之间的关系等,对仿制药生物等效性临床试验 研究室的建设内容和规模展开讨论,供业内及监管部门参考。     

实验动物福利与动物实验伦理审查国内外进展

介绍实验动物福利与动物实验伦理审查国内外进展情况。实验动物为生命科学发展和人类健康做出了重大贡献。随着社会进步和人类文明程度不断提高,善待实验动物既是人类文明道德的体现,也是人与自然和谐发展的需要。把握实验动物福利原则、遵循实验动物福利法规、严格履行动物实验伦理审查制度是切实保障实验动物福利的有效途径。虽然经过近30年的发展,我国在实验动物福利、动物实验伦理审查等方面的管理逐步走向法制化和规范化,探索出关于动物福利和实验动物伦理方面的多种教学模式,但与国际上高水平的动物福利监管相比,仍有欠缺,有待继续发展完善。     

涉及人的医学科研项目伦理审查实践体会

本文就国内涉及人的医学科研项目伦理审查现状进行了简要介绍,并结合武汉大学中南医院医学伦理委员会近年来伦理审查的工作实际,对涉及人的医学科研项目伦理审查中存在的共性问题进行了初步探讨,提出管理部门和伦理委员会应加强对研究人员伦理知识的宣传教育,加强科研项目伦理行为的过程监督,保护受试者权益,保证医学科研的健康发展。     

基于药物临床试验项目管理系统的临床试验全程管理

我国药物临床试验机构经过多年的发展,临床试验的试验条件质量有了一定的改善,但与发达国家相比,还存在着很多不足,应用信息化管理有助于提高药物临床试验质量管理。文章对医院II～IV期药物临床试验项目管理系统的总体功能进行介绍,该系统从临床试验项目管理出发,结合药物临床试验运行特点及流程,实现临床试验项目及药物全过程化管理,并与医院信息管理系统（HIS）、实验室信息管理系统（LIS）、医学影像信息系统（PACS）接口,构建起机构办、药物管理部门、检验检查科室与研究者之间的公共信息平台,实现了数据共享。     

FDA的变化为生物技术增添信心

美国改变了对药物的审查过程(由FDA实施),这将缓解许多生物技术药物的审查程序,尤其是治疗艾滋病、神经疾病、心血管疾病以及所有归属于“严重的、危及生命的”范畴的疾病。生物技术制药业将从这两方面的改革获得最大益处:一是临床试验的国际“协调化”,二是根据治疗价值加快审批速度。FDA通过一种“双轨制”,允许在临床试验中扩大实验性HIV及艾滋病治疗手段的应用范围。唯一一项对生物技术公司没帮助的变动是动用外围审批人来清理堆积的新药申请。FDA说,     

两例药物临床试验损害赔偿案例的启示

通过介绍我院发生的两例药物临床试验出现的损害赔偿案例,分析药物临床试验损害赔偿的归责原则及赔付的主体,从而得出对医疗机构及研究者的启示,保障受试者的权益,降低临床试验的风险,希望对我国药物临床试验工作提供些许有益的思考。     

Changes in blood gas tensions and functional residual capacity in chronic asthmatics treated with disodium cromoglycate

Twenty chronic asthmatic subjects were treated with disodium cromoglycate in open trial. Although in the group as a whole spirometric findings improved, some patients showed a significant increase in arterial oxygen tension or a significant fall in functional residual capacity without any appreciable changes in spirometry. These changes may partly explain the clinical efficacy of this drug.     

The use of functional human tissues in drug development

Drug development currently depends on animal models to provide an accurate prediction of human physiology and pathophysiology. However, as is clear from clinical trial failures during phases II and III, such in vivo models do not always predict the effects that a drug can elicit in humans. Tests with human tissues, which are obviously considered to be the closest model of human in vivo function, could fill the gap between animal-based tests and trials in patients. Despite clear advantages, logistical and ethical barriers prevent fresh human tissues from being widely used during drug development. Biopta is aiming to make human tissue testing a regular element of drug development, and works to lower the barriers surrounding the availability of tissue and practicalities of experimental work.     

The basics of preclinical drug development for neurodegenerative disease indications

Preclinical development encompasses the activities that link drug discovery in the laboratory to initiation of human clinical trials. Preclinical studies can be designed to identify a lead candidate from several hits; develop the best procedure for new drug scale-up; select the best formulation; determine the route, frequency, and duration of exposure; and ultimately support the intended clinical trial design. The details of each preclinical development package can vary, but all have some common features. Rodent and nonrodent mammalian models are used to delineate the pharmacokinetic profile and general safety, as well as to identify toxicity patterns. One or more species may be used to determine the drug's mean residence time in the body, which depends on inherent absorption, distribution, metabolism, and excretion properties. For drugs intended to treat Alzheimer's disease or other brain-targeted diseases, the ability of a drug to cross the blood brain barrier may be a key issue. Toxicology and safety studies identify potential target organs for adverse effects and define the Therapeutic Index to set the initial starting doses in clinical trials. Pivotal preclinical safety studies generally require regulatory oversight as defined by US Food and Drug Administration (FDA) Good Laboratory Practices and international guidelines, including the International Conference on Harmonisation. Concurrent preclinical development activities include developing the Clinical Plan and preparing the new drug product, including the associated documentation to meet stringent FDA Good Manufacturing Practices regulatory guidelines. A wide range of commercial and government contract options are available for investigators seeking to advance their candidate(s). Government programs such as the Small Business Innovative Research and Small Business Technology Transfer grants and the National Institutes of Health Rapid Access to Interventional Development Pilot Program provide funding and services to assist applicants in preparing the preclinical programs and documentation for their drugs. Increasingly, private foundations are also funding preclinical work. Close interaction with the FDA, including a meeting to prepare for submission of an Investigational New Drug application, is critical to ensure that the preclinical development package properly supports the planned phase I clinical trial.     

What is the future of CCR5 antagonists in rheumatoid arthritis?

A clinical trial of lupus patients with nephritis was established to determine any possible role for Atacicept, a biologic drug that blocks two B-cell-activating factors (BLyS and APRIL). The trial was stopped after just six patients had been enrolled because three patients developed serious infections. Initial concerns that the biologic was the main cause of the increased susceptibility to these infections have had to be revised on close inspection of the data. The evidence clearly points to a previously unrecognised capacity for mycophenolate to cause notable drops in immunoglobulin levels as the prime suspect.     

Multistate modeling and simulation of patient trajectories after allogeneic hematopoietic stem cell transplantation to inform drug development

We present a case study for developing clinical trial scenarios in a complex progressive disease with multiple events of interest. The idea is to first capture the course of the disease in a multistate Markov model, and then to simulate clinical trials from this model, including a variety of hypothesized drug effects. This case study focuses on the prevention of graft‐versus‐host disease (GvHD) after allogeneic hematopoietic stem cell transplantation (HSCT). The patient trajectory after HSCT is characterized by a complex interplay of various events of interest, and there is no established best method of measuring and/or analyzing treatment benefits. We characterized patient trajectories by means of multistate models that we fitted to a subset of the Center for International Blood and Marrow Transplant Research (CIBMTR) database. Events of interest included acute GvHD of grade III or IV, severe chronic GvHD, relapse of the underlying disease, and death. The transition probability matrix was estimated using the Aalen‐Johansen estimator, and patient characteristics were identified that were associated with different transition rates. In a second step, clinical trial scenarios were simulated from the model assuming various drug effects on the background transition rates, and the operating characteristics of different endpoints and analysis strategies were compared in these scenarios. This helped devise a drug development strategy in GvHD prevention after allogeneic HSCT. More generally, multistate models provide a rich framework for exploring complex progressive diseases, and the availability of a corresponding simulation machinery provides great flexibility for clinical trial planning.     

Mini-review: discovery and development of platinum complexes designed to circumvent cisplatin resistance

The discovery and development of new platinum-containing anticancer drugs have represented an integral part of anticancer drug development at the Institute of Cancer Research, Sutton, over almost 20 years. As part of a collaboration with chemists at Johnson Matthey, later AnorMED, four major new classes of platinum drug have been discovered, three of which have entered clinical trial. Earlier studies led to the clinical development of the less toxic analogue carboplatin and JM216, the first orally administerable platinum drug. In recent years, the focus has been on two lead complexes designed to overcome the major mechanisms of tumour resistance to cisplatin: JM335 (trans-ammine (cyclohexylaminedichlorodihydroxo) platinum(IV)), an active trans platinum complex; and ZD0473 (cis-amminedichloro(2-methylpyridine) platinum(II)), a sterically hindered complex shown to be less reactive towards thiol-containing molecules than cisplatin. JM335 shows some circumvention of acquired cisplatin resistance in vitro and exhibits unique cellular pharmacological properties in comparison to cisplatin or its cis-isomer in terms gene-specific repair of adducts on DNA and the rate of induction of apoptosis. ZD0473 is now in phase I clinical trial. Myelosuppression is the dose-limiting toxicity at a dose of 130 mg/m2 given i.v. every 3 weeks and there has been evidence of antitumour activity. ZD0473-resistant human ovarian carcinoma cell lines have been established in vitro. Some mechanisms of resistance common to those described for cisplatin (decreased drug uptake, increased glutathione) have been observed plus, in one cell line, increased BCL2 levels and loss of the DNA mismatch repair protein MLH1.     

Expectorant Action of Bromhexine in Chronic Obstructive Bronchitis

Bromhexine was compared with a placebo in a double-blind clinical trial in bronchitic inpatients with mucoid sputum. Oral bromhexine 16 mg. thrice daily for 11 days compared with placebo resulted in a significant increase in sputum volume and significant decrease in sputum viscosity, and changed markedly the rheological characteristics of the sputum. There was, however, no improvement in ventilatory capacity or in the overall respiratory state as assessed by the patients themselves or their clinician. No patient having the drug had side-effects and there was no change in laboratory findings attributable to it.     

Human genome project: pharmacogenomics and drug development

Now that all 30,000 or so genes that make up the human genome have been deciphered, pharmaceutical industries are emerging to capitalize the custom based drug treatment. Understanding human genetic variation promises to have a great impact on our ability to uncover the cause of individual variation in response to therapeutics. The study of association between genetics and drug response is called pharmacogenomics. The potential implication of genomics and pharmacogenomics in clinical research and clinical medicine is that disease could be treated according to the interindividual differences in drug disposition and effects, thereby enhancing the drug discovery and providing a stronger scientific basis of each patient's genetic constitution. Sequence information derived from the genomes of many individuals is leading to the rapid discovery of single nucleotide polymorphisms or SNPs. Detection of these human polymorphisms will fuel the discipline of pharmacogenomics by developing more personalized drug therapies. A greater understanding of the way in which individuals with a particular genotype respond to a drug allows manufacturers to identify population subgroups that will benefit most from a particular drug. The increasing emphasis on pharmacogenomics is likely to raise ethical and legal questions regarding, among other things, the design of research studies, the construction of clinical trials and the pricing of drugs.     

Development of a Drug-Response Modeling Framework to Identify Cell Line Derived Translational Biomarkers That Can Predict Treatment Outcome to Erlotinib or Sorafenib

Development of drug responsive biomarkers from pre-clinical data is a critical step in drug discovery, as it enables patient stratification in clinical trial design. Such translational biomarkers can be validated in early clinical trial phases and utilized as a patient inclusion parameter in later stage trials. Here we present a study on building accurate and selective drug sensitivity models for Erlotinib or Sorafenib from pre-clinical in vitro data, followed by validation of individual models on corresponding treatment arms from patient data generated in the BATTLE clinical trial. A Partial Least Squares Regression (PLSR) based modeling framework was designed and implemented, using a special splitting strategy and canonical pathways to capture robust information for model building. Erlotinib and Sorafenib predictive models could be used to identify a sub-group of patients that respond better to the corresponding treatment, and these models are specific to the corresponding drugs. The model derived signature genes reflect each drug’s known mechanism of action. Also, the models predict each drug’s potential cancer indications consistent with clinical trial results from a selection of globally normalized GEO expression datasets.