探索性新药临床试验研究及其引发的思考

探索性新药临床研究（0期临床实验）在国外已经开始运用于新药开发,这种研究模式具有一定的优势,对我国创新药物开发颇有意义,为此探讨探索性新药临床研究的概念、原则、优势,分析其目前在国外研究概况,并对开发运用探索性新药临床研究模式存在的问题进行思考。     

中药注射剂开展0期临床试验思路与方法学探讨

中药注射剂临床应用广泛,疗效确切,在我国医药产业目前从“仿制药”向“创新药”转变的重要时期,中药注射剂的研发具有特殊的意义,同时中药注射剂的临床安全性问题也亟待解决.0期临床试验,也称为探索性临床试验对于创新药物的研发,尤其是先导化合物的筛选,具有重要意义.从药物研发/二次开发和上市后再评价两个方面进一步梳理中药注射剂开展0期临床试验的思路和方法,以探讨其应用于中药注射剂研发和评价的可行性.     

新药Ⅰ期临床试验健康受试者筛选失败原因分析

目的：探讨新药Ⅰ期临床试验过程中健康受试者筛选失败的主要原因及提高筛选成功率的对策。方法：针对255例健康成年受试者参加某项治疗慢性乙型肝炎（chronic hepatitis B,CHB）新药的生物等效性（bioequivalency,BE）临床试验筛选情况,分析受试者筛选失败的原因及其影响因素。结果：本试验项目筛选合格并入组的健康受试者共64例（25.10%）。受试者筛选失败的主要原因包括实验室化验检查异常(34.90%);腹部B超检查异常(10.59%);研究首次用药前3个月内参加过其他临床试验(8.24%);撤回知情同意书(8.63%)。结论：充分知情、加强受试者信息化管理及适宜的检查是提高受试者的筛选成功率的关键。     

国产一类抗癌新药盐酸博安霉素Ⅰ期临床研究

以３６例恶性肿瘤患者为观察对象，对国产一类抗癌新药盐酸博安霉素进行了Ｉ期临床研究。结果表明，主要毒副作用为发热、消化道反应、注射局部硬结，个别患者出现肌肉关节疼痛、皮疹、脱发。未见骨髓抑制作用，对心功能无影响，对肝、肾、肺功能影响较小，但可加重肾功能异常以及肺疾患、肺功能不全患者的肾、肺损伤。提出了Ⅱ期临床试用剂量，同时对６例患者进行了药代动力学研究。     

口服抗癌药右大麻酚开始Ⅰ期临床试验

e-Therapeutics公司宣布口服抗癌药右大麻酚（ETS2101,dexanabin01）开始Ⅰ期临床试验,招募了24名健康志愿者,将逐步加量,评价其药代动力学和生物利用度,预计2014年4季度完成。右大麻酚是e-Thera—peutics公司合成和确定的大麻类似物,临床前研究发现对多种癌细胞株有活性,进行2项Ⅰ期临床试验,其一是针对原发和继发脑瘤,其二是针对各种晚期实体肿瘤。     

新药Ⅱ期临床试验的管理规范

《药品临床试验质量管理规范》（GCP）是新药研究开发中所推行的一系列标准化规范之一,是被国际公认的药品临床试验标准。GCP的宗旨是为了使药物临床试验结果可靠、过程规范、保证受试者的权益并保障其安全。本文通过对以宣武医院为负责单位的猪血去蛋白提取物注射液Ⅱ期临床试验进行临床管理,充分实践GCP的相关规定。整个试验过程规范可信,结果科学可靠,入选且签署知情同意书的48名受试者的权益得到保障,临床症状有明显改善。笔者在本临床试验中深刻体会到严格遵守GCP的重要性,同时临床研究者及护理人员通过参与药品的临床试验强化了科研意识。     

药代动力学-药效学结合模型的应用进展

本文主要述评1998～2000年间药代动力学-药效学结合模型在药理学、毒理学、临床治疗以及新药开发等方面最新的应用进展,并展望发展前景.     

一种镇痛新药帕瑞昔布(帕瑞昔布钠)

帕瑞昔布是强效特异性环氧合酶-2抑制剂戊地昔布的前体药物,可静注(iv)或肌注(im)给药,正处于后期临床研究阶段.对口腔、妇科或矫形手术引发的术后疼痛患者随机、双盲、对照试验结果表明,帕瑞昔布20或40mg iv或im可产生明显优于安慰剂的镇痛效果,与酮咯酸30或60mg镇痛作用相当.帕瑞昔布有良好的耐受性,其不良反应与安慰剂相似.     

抗HIV感染新药:Raltegravir

Rahegravir是FDA2（D7年10月份批准用于抗HIV感染的新药，商品名称lsentress，由美国默克公司生产，是第一种被批准的控制HIV感染的新药，可抑制HIV病毒整合酶，降低病毒载量，提高CD4细胞计数。     

新药临床试验设计中普遍存在的问题及防范措施（英文）

新药临床试验设计中存在的问题涉及指导思想、科研设计、质量控制、统计分析等临床试验研究过程中的关键环节。本文揭示了新药临床试验设计中存在的8大问题,并提供具有可操作性的防范措施。新药临床试验研究是一个非常复杂的系统工程,在新药Ⅰ、Ⅱ、Ⅲ、Ⅳ期临床试验研究过程中,特别是在新药临床试验研究方案和临床病例报告表的研制和实施过程中,必须严格参照国家相关部门制定的政策、法规、标准和操作规程。忽视临床试验设计与数据分析的科学性与严谨性,必将导致临床试验研究的失败。     

真实世界研究：中医干预措施效果评价的新理念

解释性随机对照试验（explanatory randomized controlled trial,ERCT）得出的结论往往在真实临床环境下缺乏实际应用价值,而实用性随机对照试验（pragmatic randomized controlled trial,PRCT）在试验结果的推广上也存在一定的局限性。一些国家已开展真实世界研究（real-world study,RWS）来探讨临床干预措施或上市后药品的有效性和安全性,这是一种新的临床研究理念。通过回顾国外开展的RWS,我们总结其研究设计的基本特征,并探讨RWS和PRCT之间的区别和联系。RWS和PRCT在设计理念上具有不同之处。在RWS中,研究者倾向于在超大样本量和广泛受试人群的基础上开展长期评价,并注重有临床意义的结局指标。数据采集、管理和分析方面的严格控制对于RWS和PRCT而言都是至关重要的。鉴于中医临床干预措施及其评价的复杂性,PRCT并不完全适用于中医临床研究,将RWS运用于中医临床研究是一种很好的思路。我们可以通过PRCT来探讨中医干预措施的效力,并通过RWS来深入理解其真实临床效果。RWS将成为中医临床试验和中药上市后再评价研究的一种新方法。     

抗骨质增生丸治疗原发性骨质疏松症的临床研究

目的观察自制抗骨质增生丸治疗原发性骨质疏松症的临床疗效。方法将40例原发性骨质疏松症的患者随机分为治疗组和对照组,每组20例,治疗组以常规治疗加上抗骨质增生丸中药治疗,对照组则给予钙尔奇常规治疗,两组疗程均为6个月。对比两组治疗前后临床疗效、止痛效果、骨密度（BMD）变化,血、尿及肝肾功能。结果治疗组临床疗效、止痛效果明显优于对照组（P〈0.05）,骨密度测定两组治疗后均有明显提高,治疗组的提高程度优于对照组（P〈0.05）。血、尿及肝肾功能无异常。结论自制抗骨质增生丸对原发性骨质疏松症具有良好的止痛效果,能提高临床疗效。     

Leflunomide, a new disease-modifying drug for treating active rheumatoid arthritis in methotrexate-controlled phase Ⅱ clinical trial

Leflunomide ,anovelimmunoinhibitorwithimmunosupressiveandantiproliferativeproperties ,hasbeendemonstratedtobeeffectiveintreatingrheumatoidarthritis(RA)inanimalexperimentsandinforeignclinicaltrials ItimmediatelytransformsintotheactivemetaboliteA77172 6invivobyoraladministrationandactsthroughDHODHinhibition,preventingpyrimideoverproduction 1　Inexperimentalmodelsofchronicgraft versus hostdiseaseandsolidorgantransplantation ,leflunomidecanpreventrejectionorreverseongoingrejection 2 ,3　Bytheap…     

COVID-19 trial graph: a linked graph for COVID-19 clinical trials

ObjectiveClinical trials are an essential part of the effort to find safe and effective prevention and treatment for COVID-19. Given the rapid growth of COVID-19 clinical trials, there is an urgent need for a better clinical trial information retrieval tool that supports searching by specifying criteria, including both eligibility criteria and structured trial information.Materials and MethodsWe built a linked graph for registered COVID-19 clinical trials: the COVID-19 Trial Graph, to facilitate retrieval of clinical trials. Natural language processing tools were leveraged to extract and normalize the clinical trial information from both their eligibility criteria free texts and structured information from ClinicalTrials.gov. We linked the extracted data using the COVID-19 Trial Graph and imported it to a graph database, which supports both querying and visualization. We evaluated trial graph using case queries and graph embedding.ResultsThe graph currently (as of October 5, 2020) contains 3392 registered COVID-19 clinical trials, with 17 480 nodes and 65 236 relationships. Manual evaluation of case queries found high precision and recall scores on retrieving relevant clinical trials searching from both eligibility criteria and trial-structured information. We observed clustering in clinical trials via graph embedding, which also showed superiority over the baseline (0.870 vs 0.820) in evaluating whether a trial can complete its recruitment successfully.ConclusionsThe COVID-19 Trial Graph is a novel representation of clinical trials that allows diverse search queries and provides a graph-based visualization of COVID-19 clinical trials. High-dimensional vectors mapped by graph embedding for clinical trials would be potentially beneficial for many downstream applications, such as trial end recruitment status prediction and trial similarity comparison. Our methodology also is generalizable to other clinical trials.     

加味当归四逆汤治疗0级糖尿病足的疗效及对血清晚期糖基化终产物水平的影响：随机对照试验

背景：许多研究证实晚期糖基化终产物（advanced glycation end product,AGE）与糖尿病血管病变密切相关,中医药在该类疾病治疗中存在一定优势。 目的：评价加味当归四逆汤治疗Wagner0级糖尿病足患者的临床疗效、安全性及其对血清AGE水平的影响。设计、场所、受试者和干预措施：采用随机、阳性药物对照研究方案。将72例血瘀证、肾阳虚证Wagner0级糖尿病足患者随机分为治疗组和对照组,每组36例,均为广州中医药大学茂名市中医院门诊和住院患者。患者签署知情同意书之前已经被口头或者书面告知研究过程。该研究由广州中医药大学茂名中医院医学伦理委员会批准。治疗组口服加味当归四逆汤,对照组予西药西洛他唑治疗。两组均以14d为1个疗程,连续治疗3个疗程。主要结局指标：观察两组治疗前后临床症状、踝肱指数（ankle-brachial index,ABI）、肌电图、下肢动脉超声多普勒血流动力学指标、空腹血糖、糖基化血红蛋白、纤维蛋白原和AGE水平变化。记录实验室检查结果和不良事件作为安全性评估的依据。结果：治疗组治疗后临床症状、ABI、下肢动脉超声多普勒血流动力学和神经传导速度等指标均较对照组改善,差异有统计学意义（P〈0.05,P〈0.01）。治疗后两组血清AGE均明显下降,且治疗组与对照组比较,差异亦有统计学意义（P〈0.01）。结论：加味当归四逆汤能改善Wagner0级糖尿病足患者的临床症状,并对糖尿病血管病变有一定的治疗作用。     

Solid phase microextraction chemical biopsy tool for monitoring of doxorubicin residue during in vivo lung chemo-perfusion

Development of a novel in vivo lung perfusion (IVLP) procedure allows localized delivery of high-dose doxorubicin (DOX) for targeting residual micrometastatic disease in the lungs. However, DOX delivery via IVLP requires careful monitoring of drug level to ensure tissue concentrations of this agent remain in the therapeutic window. A small dimension nitinol wire coated with a sorbent of biocompatible morphology (Bio-SPME) has been clinically evaluated for in vivo lung tissue extraction and determination of DOX and its key metabolites. The in vivo Bio-SPME-IVLP experiments were performed on pig model over various (150 and 225 mg/m²) drug doses, and during human clinical trial. Two patients with metastatic osteosarcoma were treated with a single 5 and 7 μg/mL (respectively) dose of DOX during a 3-h IVLP. In both pig and human cases, DOX tissue levels presented similar trends during IVLP. Human lung tissue concentrations of drug ranged between 15 and 293 μg/g over the course of the IVLP procedure. In addition to DOX levels, Bio-SPME followed by liquid chromatography-mass spectrometry analysis generated 64 metabolic features during endogenous metabolite screening, providing information about lung status during drug administration. Real-time monitoring of DOX levels in the lungs can be performed effectively throughout the IVLP procedure by in vivo Bio-SPME chemical biopsy approach. Bio-SPME also extracted various endogenous molecules, thus providing a real-time snapshot of the physiology of the cells, which might assist in the tailoring of personalized treatment strategy.     

Equitable treatment for HIV/AIDS clinical trial participants: a focus group study of patients, clinician researchers, and administrators in Western Kenya

OBJECTIVES: To describe the concerns and priorities of key stakeholders in a developing country regarding ethical obligations held by researchers and perceptions of equity or "what is fair" for study participants in an HIV/AIDS clinical drug trial. DESIGN: Qualitative study with focus groups. SETTING: Teaching and referral hospital and rural health centre in Western Kenya. PARTICIPANTS: Potential HIV/AIDS clinical trial participants, clinician researchers, and administrators. RESULTS: Eighty nine individuals participated in a total of 11 focus groups over a four month period. The desire for continued drug therapy, most often life long, following an HIV/AIDS clinical trial was the most common priority expressed in all focus groups. Patients with and without HIV/AIDS also thought subsidizing of drug therapies and education were critical forms of compensation for clinical trial participation. Financial incentives were considered important primarily for purchasing drug therapy as well as obtaining food. Patients noted a concern for the potential mismanagement of any money offered. Clinician researchers and administrators felt strongly that researchers have a moral obligation to participants following a trial to provide continued drug therapy, adverse event monitoring, and primary care. Finally, clinician researchers and administrators stressed the need for thorough informed consent to avoid coercion of study participants. CONCLUSIONS: Kenyan patients, clinician researchers, and administrators believe that it would be unfair to stop antiretroviral therapy following an HIV/AIDS clinical trial and that researchers have a long term obligation to participants.     

Contemporary use of real-world data for clinical trial conduct in the United States: a scoping review

ObjectiveReal-world data (RWD), defined as routinely collected healthcare data, can be a potential catalyst for addressing challenges faced in clinical trials. We performed a scoping review of database-specific RWD applications within clinical trial contexts, synthesizing prominent uses and themes.Materials and MethodsQuerying 3 biomedical literature databases, research articles using electronic health records, administrative claims databases, or clinical registries either within a clinical trial or in tandem with methodology related to clinical trials were included. Articles were required to use at least 1 US RWD source. All abstract screening, full-text screening, and data extraction was performed by 1 reviewer. Two reviewers independently verified all decisions.ResultsOf 2020 screened articles, 89 qualified: 59 articles used electronic health records, 29 used administrative claims, and 26 used registries. Our synthesis was driven by the general life cycle of a clinical trial, culminating into 3 major themes: trial process tasks (51 articles); dissemination strategies (6); and generalizability assessments (34). Despite a diverse set of diseases studied, <10% of trials using RWD for trial process tasks evaluated medications or procedures (5/51). All articles highlighted data-related challenges, such as missing values.DiscussionDatabase-specific RWD have been occasionally leveraged for various clinical trial tasks. We observed underuse of RWD within conducted medication or procedure trials, though it is subject to the confounder of implicit report of RWD use.ConclusionEnhanced incorporation of RWD should be further explored for medication or procedure trials, including better understanding of how to handle related data quality issues to facilitate RWD use.     

3种中药复方制剂治疗高原脱适应症的随机安慰剂对照试验

背景：部队进入高原执行任务导致完成任务返回平原后出现高原脱适应的人数明显增加,但至今对高原脱适应症尚无有效的治疗方法。目的：探讨中药复方制剂对高原脱适应症的干预效果,为今后高原返回平原人群高原脱适应症的治疗提供科学依据。设计、场所、对象和干预措施：选择某部2010年4月14日～8月7日参加高原抗震救灾返回平原后出现高原脱适应症状的官兵作为观察对象,采用随机、单盲、安慰剂对照的试验设计方法,将高原返回平原出现高原脱适应反应的534名官兵按排建制分为三康胶囊组、红景天胶囊组、参芪花粉胶囊组和安慰剂组,分别给予相应药物治疗15d。主要结局指标：采用高原脱适应症状自评量表进行问卷调查。以治疗后症状改善的有效率和组间症状改善的差异评价治疗效果。结果：3种药物对高原脱适应症状均有一定改善作用,与安慰剂组比较,3组官兵的脱适应症状均明显减轻（P〈0.05）。与安慰剂比较,三康胶囊主要对头晕、乏力、心慌、咳痰、咽痛、注意力不集中等症状有明显改善作用（P〈0.05）,红景天胶囊主要对乏力、嗜睡、胸闷、心慌、眩晕、注意力不集中、记忆力减退等症状有明显改善作用（P〈0.05）,参芪花粉胶囊主要对头晕、疲倦、乏力、胸闷、心慌、咳嗽、咯痰、咽痛、记忆力减退、反应迟钝、手足麻木等症状有明显改善作用（P〈0.05）。参芪花粉胶囊症状改善率明显高于其他两种药物。结论：3种药物对高原脱适应反应均有明显的干预效果,参芪花粉胶囊的效果优于三康胶囊和三普红景天胶囊。