全国新药临床试验学术研讨会通知

中国药理学会和中国临床药理学与治疗学杂志社将于 2 0 0 4年 5月 2 8～ 30日在山东省烟台市召开“全国新药临床试验学术研讨会”。会议将邀请国家食品药品监督管理局专家 ,以及国内 30名知名学者就以下新药临床试验中的问题进行研讨 :①抗生素临床试验中的问题 ,②心脑血管药物临床试验中的若干问题 ,③复方药物临床试验的设计 ,④中药临床试验中的若干问题 ,⑤新药临床设计与统计中的若干问题 ,⑥新药Ⅰ期临床试验设计与实施 ,⑦新药药代动力学与生物等效性分析的若干问题 ,⑧监查员在新药临床试验中职责与工作技巧 ,⑨新药临床试验申报资…     

新药开发中的基因导向型个体化发展战略

药物基因组学在新药开发的多个阶段可发挥重要作用。研究者可借助基因组信息更好地发现新药的作用靶点及其作用机制,药物基因组及其相关技术的发展帮助研究者在新药开发的临床前研究阶段淘汰化学性质不良的化合物,还可指导新药开发的临床试验设计以增加药物有效性和安全性,同时降低开发所需的时间和成本。     

复方药品创新研发策略

固定剂量复方药品研发是创新过程,目前已成为突破药物研究瓶颈的新出路之一。复方药品组方必须基于药物相互作用理论,充分利用与治疗目的相同的作用和效应,进行组方论证,进行多因素多水平分析和临床联合用药验证,确定目标组方,最后进入新药规范化研究和试验。复方药品的创新研发全过程（药学、药效学、药动学、毒理学和临床试验）与全创新药物同样规范和严格,并且必须进行拆方分析。本文从复方药品组方原则、研发策略、研发技术要求规范要点等方面进行了综述。     

新药生物统计的若干问题

根据新药临床研究指导原则，结合新药申报资料及审评体会，对新药研究的设计和统计中若干问题进行了论述。在临床前药理研究中讨论了动物剂量估算，剂量对应和复方研究问题。在临床研究中介绍了10年临床研究设计方式，讨论了等效性检验，非劣性检验，多中心资料，跨年度资料等问题，在统计分析方面列出了国内外新药研究常用的统计方法，讨论了计数资料和计量资料统计分析中应注意的问题。     

全国新药临床试验学术研讨会通知

中国药理学会和“中国临床药理学与治疗学杂志社”将于2004年5月28-30日在山东省烟台市召开“全国新药临床试验学术研讨会”。 会议将邀请国家食品药品监督管理局专家,以及国内30名知名学者就以下新药临床试验中的问题进行研讨: 1.抗生素临床试验中的问题;2.心脑血管药物临床试验中的若干问题;3.复方药物临床试验的设计;4.中药     

新药研究近况

在1972年市售156种新药中新合成的药物仅占65种,其中只有两种前列腺素(前列腺素F_2α和E_2)为第一次推荐到临床使用的新类型药物。美国在72年中,33个制药厂只介绍了64种新药,其中11种是新合成的药物,在这11种中只有6种是美国试制的。在所介绍的新药中,有不少是复方药。复方药要比单个药效果好,但必须注意复方组成的合理性,要精心设计并经受临床考验,此外还需考虑到药物的相互作用。     

抗肿瘤药物Ⅱ期临床研究设计考虑要点

Ⅱ期临床试验在抗肿瘤药物研发中有重要作用,良好的Ⅱ期临床研究设计和开发策略将有助于及早淘汰无效瘤种和无效药物;从而选择有潜力的候选药物进入大规模的Ⅲ期试验.本文对抗肿瘤药物Ⅱ期临床研究设计中需关注的问题进行探讨,包括受试人群、剂量、对照、终点指标等;同时对靶向治疗药物的一些新的设计方法,以及联合用药的研究和评价策略进行介绍,期望对我国从事抗肿瘤新药研发人员有所帮助.     

临床试验阶段的抗阿尔采末病药物

阿尔采末病(Alzheimer disease,AD)是一种常见的神经退行性疾病,目前尚无有效的治疗方法。在过去的20 a中,随着AD发病机制研究的深入,目前已有很多治疗AD的新药进入临床试验阶段。本文对目前正处于临床试验阶段的AD药物进行了分析,对处于Ⅲ期临床试验阶段的药物进行了重点介绍,以期为研究者提供参考。     

新药临床试验方案设计的研究

目的研究新药临床试验设计方案。方法本文涉及临床试验设计中的研究目的、范围及对照药的剂量,以探讨试验设计的合理性。结果在众多的新药临床试验方案中发现,在研究目的、范围及对照药的剂量等方面存在很多问题,从而导致新药临床试验的失败,最终药品不能上市。为此本文通过案例为研究者及药品申办者提供了大量相关信息。结论试验设计是临床试验能否获得成功的关键之一。     

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。     

Biochemical aspects of the evaluation of fixed drug combinations

Various disciplines have to contribute to the general problem of the evaluation of fixed dose combination drugs, as for instance (clinical) pharmacology, biometry, scientific drug regulations and public health officials. The EC guideline 75/318/EWG and its eludications as well as the German "Arzneimittelprüfrichtlinien" of Dec. 14, 1989 (as referred to in the "Arzneimittelgesetz" of 1986) required that such issues concerning fixed dosage combination drugs must be considered and taken into account. In this framework it is the responsibility of biometry to both to guarantee the use of a valid study design to assure interpretation of the results and to quantify the reliability of pharmacological and clinical considerations. The following paper is concerned with biometrical aspects of the combination drug problem. Basic considerations from a clinical or a pharmacological point of view with respect to the question of whether fixed combination drugs are reasonable or not are not discussed. To support the use of combinations of drugs, a central argument is the improvement of the benefit risk relation compared with that of an adequate monotherapy. Beyond this the fixed combination drugs require additional arguments regarding the enhencement of the safety or the simplicity of the therapy fixing the ratio. It follows that fixed combination drugs have to be supported twice, first with respect to the combination itself, and second with respect to the fixed mixing ratio of its components. The biometrical aspects of the assessment of the gains from (fixed) drug combinations are related to the kind of benefit/risk improvement that is expected. In the first section we discuss some possible types of benefit and risk.(ABSTRACT TRUNCATED AT 250 WORDS)     

Bioequivalence study of a fixed dose combination of nitazoxanide and ofloxacin in Indian healthy volunteers

OBJECTIVE: The pharmacokinetics of nitazoxanide (CAS 55981-09-4) and ofloxacin (CAS 82419-36-1) has been extensively evaluated in adult human volunteers individually after oral administration of tablet formulation. However, no published data is available regarding the combined pharmacokinetics and bioavailability of this particular fixed dose combination. In light of the above, a clinical study was designed to evaluate the bioequivalence of two fixed dose combination (FDC) products of two manufacturers containing nitazoxanide 500 mg and ofloxacin 200 mg in healthy Indian male volunteers. METHODS: 24 healthy male volunteers (age 25 +/- 4.6 years; weight 74.5 +/- 7.87 kg) were enrolled in this study. Each subject received a Test fixed dose combination and a Reference fixed dose combination formulation in a randomized, single dose, fasting state, two period, crossover study design with a 1-week washout period between the doses. Extraction of the drugs from the plasma was carried out by precipitation method. Analysis of tizoxanide (active metabolite of nitazoxanide) and ofloxacin from plasma samples was done by a simple and sensitive HPLC method using UV detection developed in our laboratory. An analysis of variance was performed on the pharmacokinetic parameters Cmax, AUC(0-t), AUC(0-infinity). using general linear model (GLM) procedures in which sources of variation were subject, formulation, period. RESULTS: The results of this investigation indicated that there were no statistically significant differences between the two products in either the mean concentration-time profiles or in the obtained pharmacokinetic parameters. 90 % confidence limits for the log-transformed data of Cmax, AUC(0-t), AUC(0-infinity) were within the acceptable range of 0.80-1.25. CONCLUSION: Thus, these findings clearly indicate that the two products are bioequivalent in terms of rate and extent of drug absorption. Both the preparations were well tolerated with no adverse reactions seen throughout the study.     

Potentiation of gastric toxicity of ibuprofen by paracetamol in the rat.

A fixed dose combination of ibuprofen (400 mg) and paracetamol (325 mg) is by far the most extensively prescribed medicament for a variety of musculoskeletal disorders in India. Following clinical observations that this drug combination induces significant adverse effects, its gastric toxicity was investigated in rats. Ibuprofen (25 mg kg-1 p.o., twice daily x 5 days), paracetamol (20 mg kg-1 p.o, twice daily x 5 days), and a combination of the two, had no significant effect on free and total gastric acidity in pylorus-ligated rats. Ibuprofen induced visible gastric ulceration whereas paracetamol did not. However, the combination of these two drugs had an additive effect inducing severe gastric erosions, ulcerations and bleeding. The augmented toxicity of this drug combination appeared to be a consequence of attenuated gastric mucin activity and reduction in the gastric muco-protective barrier. This investigation indicates the likely hazard of an irrational fixed dose drug combination.     

The formulation of lipid-based nanotechnologies for the delivery of fixed dose anticancer drug combinations

The introduction of combination chemotherapeutic regimens for the treatment of childhood leukaemia in the 1960s provided the proof-of-principle that cytotoxic drugs were capable of curing cancer. However, in the four decades since this discovery, the majority of cancers still cannot be cured by chemotherapy. Clinical evidence supports the hypothesis of Goldie and Coldman that treating cancers with all the available effective agents simultaneously provides the greatest chance of eliciting a cure. Unfortunately, for traditional cytotoxic agents with narrow therapeutic indices, life-threatening toxicity precludes combination chemotherapy regimens employing multiple agents. This review discusses the concept of fixed dose combination chemotherapy with emphasis on capturing therapeutic efficacy described as synergistic as a basis for improving the effectiveness of combination chemotherapy. The use of lipid-based nanotechnologies, focusing on liposomes, as an enabling technology to facilitate the delivery of cytotoxic agents to the tumour site at concentrations and/or drug ratios judged to be synergistic will be discussed. It is envisaged that the development of this model system will be supported by cell-based screening technologies, pharmacokinetic and pharmacodynamic parameters and mathematical models describing therapeutic drug:drug interactions (the Median Effect Principle of Chou and Talalay). Experiments using preclinical models are presented to support the benefits of drug delivery systems as a foundation for fixed dose anticancer drug combinations. The ultimate goal of this research is to prepare a 'single vial' fixed dose combination product that encompasses both traditional cytotoxic agents and new molecularly targeted modalities with optimum therapeutic effects and acceptable toxicity.     

An approach to the assessment of therapeutic drug interactions with fixed combination drug products

Several complex clinical and statistical issues are involved in the development of a combination drug product. The medical rationale for the combination, the intended clinical use, drug-drug interactions, and dose response are just a few of the considerations. The factorial design is a useful experimental model for evaluating combination therapies. This paper outlines some of the considerations involved in the use of this design in the study of combination drugs. Questions related to design and methods of analysis are discussed in general and through use of an example. Such a design was applied to study the combination of a vasodilator with a diuretic in the treatment of hypertension. The sample size derivation, the evaluation of “interaction,” the use of ANOVA versus regression techniques, and methods of data display are reviewed. It is recognized that although these are complex issues, substantially more information per patient can be obtained than with standard parallel-design approaches. The

design could be an especially powerful tool early in the development of a drug.     

Adaptive Penalized D-Optimal Designs for Dose Finding Based on Continuous Efficacy and Toxicity

When a new drug is under development, a conventional dose-finding study involves learning about the dose–response curve in order to bring forward right doses of the drug to late-stage development. We propose an adaptive procedure for dose-finding in clinical trials in the presence of both efficacy and toxicity endpoints. We use the principles of optimal experimental designs for bivariate continuous endpoints.

However, instead of using the traditional D-optimal design, which favors collective ethics but neglects the individual ethics, we consider the penalized D-optimal design that achieves an appropriate balance between the efficient treatment of patients in the trial (by penalizing allocation of patients to ineffective or toxic doses) and the precise estimation of the model parameters to be used in the identification of the target dose. This is compared with the traditional fixed allocation design in terms of allocation of subjects and precision of the identified dose–response curve and selection of the target dose.     

权重配方法定量设计药物组方(英文)

目的:建立一种药物组方设计和定量分析的新方法。方法:将配方设计规范为6个配伍组,根据新的数学模型,确定各药的量效关系和交互影响,从而判断各药在配方中重要程度。以此为基础,调整配伍剂量,向最优结果逼近。其调整的优化剂量由进一步试验来验证其效应。并以尿囊素,地塞米松磷酸钠和甲硝唑组方为例,选用2个指标,作配方设计和定量分析。结果:本法能有效地分析实验中各药在组方中的地位(如主药,辅药,协同药等),并据此调整剂量,构成新的配伍,经配方优方检验,确定了最佳配伍结果。结论:权重配方法是一种高效,严谨和实用的方法,可用以设计药物组方,并作药物配伍的定量分析。     

Design and Sample Size for Evaluating Combinations of Drugs of Linear and Loglinear Dose-Response Curves

The study of drug combinations has become important in drug development due to its potential for efficacy at lower, less toxic doses and the need to move new therapies rapidly into clinical trials. The goal is to identify which combinations are additive, synergistic, or antagonistic. Although there exists statistical framework for finding doses and sample sizes needed to detect departure from additivity, e.g., the power maximized F-test, different classes of drugs of different does-response shapes require different derivation for calculating sample size and finding doses. Motivated by two anticancer combination studies that we are involved with, this article proposes dose-finding and sample size method for detecting departures from additivity of two drugs with linear and log-linear single dose-response curves. The first study involves combination of two drugs, where one single drug dose-response curve is linear and the other is log-linear. The second study involves combinations of drugs whose single drug dose-response curves are linear. The experiment had been planned with the common fixed ratio design before we were consulted, but the resulting data missed the synergistic combinations. However, the experiment based on the proposed design was able to identify the synergistic combinations as anticipated. Thus we shall summarize the analysis of the data collected according to the proposed design and discuss why the commonly used fixed ratio method failed and the implications of the proposed method for other combination studies.     

Quantitative design of drug compatibility by weighted modification method.

AIM: To set up a new method for designing and quantitatively analyzing drug compatibility. METHODS: Drugs for compatibility were divided into 6 dose levels which were evenly distributed to 6 compound groups according to a fixed design. A new mathematical model was set up to fit the dose-effect data of 6 groups. The coefficients, obtained from the model, reflected the dose-effect relationship and the important degree of every drug in combination. According to the coefficients, the drugs in compatibility could be distinguished into principal drug, synergist, inferior, antagonist, and assistant. Because compatibility in the maximal effect group was nearly (or was) an optimal one in 6 groups, the doses in the group were taken as a base for further modification which considered interaction among drugs. The results of the modification were demonstrated by further experiment. This method was applied to design and to quantitatively analyze the compatibility of allantoin, metronidazole, and dexamethasone sodium phosphate by 2 effect indices in mice. RESULTS: This new method was able to effectively determine important degree of drugs in combination, and to optimize their doses for designing compatibility. CONCLUSION: This weighted modification method is a highly efficient, accurate, and practical means for designing and quantitatively analyzing drug compatibility.     

Relationship between plasma desipramine levels and clinical outcome for RDC major depressive inpatients

Depressed patients (N = 31), who met Research Diagnostic Criteria for major affective disorder-depressed, were severely ill and maintained drug-free for a 1-week period on inpatient status. They received a fixed dose (150 mg/day) of desipramine for a 4-week period with drug plasma level determination and clinical ratings performed at fixed time intervals throughout the study. Despite these rigid criteria for entrance and clinical outcome measures, no obvious relationship between plasma desipramine level and clinical outcome was found. The clinical implications of this finding are discussed.