基于美国FDA近五年批准的新药浅谈ICH S1指导原则的实施

致癌性研究是药物非临床安全性评价的重要内容之一,致癌性试验实施的复杂程度远远超出指导原则的要求。本文对美国FDA在2014-2018年5年期间批准的213个新药进行了梳理和分析,并结合ICHS1要求、文献报道和实际工作经验,从致癌性试验的必要性、致癌性试验结果提交时间、生物制品致癌性试验的决策、致癌性试验的试验类型选择、致癌性试验的剂量设计等几方面提出意见和建议,力求为国内同行、新药研发企业和审评机构提供参考。     

FDA关于致癌性试验“特别方案评估”的流程和相关法规的介绍与探讨

目的：致癌性试验是药物非临床安全性评价和上市风险控制的重要组成部分,由于其试验周期长、费用高,且试验设计、实施以及结果评估和解释十分复杂,FDA要求申办方在致癌性试验正式开展前,预先向药品审评中心(CDER)提交“特别方案评估”(Special Protocol Assessment,SPA)的申请文件,针对拟开展的啮齿动物致癌性试验设计,征求FDA的审评意见。本文将详细介绍并探讨美国 FDA关于致癌性试验SPA的流程及相关法规的要点,以期为国内药物研发机构、临床前合同研究组织 (Contract Research Organization,CRO)、注册申报机构以及监管机构提供参考。方法：结合FDA致癌性试验“特别方案评估”指导原则的要求和相关工作经验,从致癌性试验方案提交FDA审评部门前的准备、提交程序、SPA审评文件材料内容的关注要点,以及FDA相关审评部门和致癌性评估执行委员会 (ECAC)内部审评流程等方面予以介绍。结果与结论：申办方应了解并熟悉致癌性试验SPA文件提交和评估的过程,并严格按照法规要求,加强与监管部门的沟通交流,从而获取科学性意见和建议,为顺利开展长期致癌性试验提供帮助。     

根和根茎类中药材中铅和砷致癌性风险评估研究

目的：通过对10种根和根茎类中药材中铅(Pb)和砷(As)的分析、测定及致癌性风险评估, 为相关残留限量标准的制修订提供参考依据。方法：采用电感耦合等离子体质谱(ICP-MS)法对全国范围内收集到的巴戟天等883批10种根和根茎类中药材中Pb和As的残留量进行测定和分析。同时,在美国环保署(US EPA)推荐的健康风险评估模型的基础上,结合课题组前期所获得的我国人群(包括高暴露人群和一般暴露人群)的暴露参数,建立符合中药使用特点的根和根茎类品种中致癌性金属元素的致癌风险评估模型。采用致癌风险法(CR)对其Pb和As的致癌性健康风险进行确定性评估。结果：883 批根和根茎类中药材中巴戟天的铅的均值超标。致癌性风险评估结果表明,对于一般暴露人群来讲,所有根和根茎类品种中Pb和As的致癌性健康风险均可以被忽略。而对于高暴露人群来讲,当归、三七、巴戟天的致癌性健康风险需要被关注。结论：本研究提出了符合中药使用特点的致癌性金属元素的致癌性健康风险评估模型,为建立符合中药使用特点的风险评估技术体系,以及残留限量标准和相关指导原则的制修订提供了技术支撑。     

药物致癌性的机制研究

 动物致癌性试验是药物非临床安全性评价的重要内容之一,在我国起步相对较晚。随着我国新药创制及相关领域的不断发展,初步具备了进行致癌性评价的条件。机制研究是致癌性评价的重要内容,结合暴露量分析、适应症与患者人群特征、同类化合物致癌性特征等进行利弊权衡,综合评估对人体的潜在风险,并最终通过说明书等方式进行风险控制。目前国际上正在着力于致癌机制的探索,有些已经被药品评价机构接受。文中对一些常见的机制研究进行总结分析,包括遗传毒性机制、药理学作用相关机制、苯巴比妥样CYP450诱导作用、致癌组织的种属差异等,以期为我国药物致癌性评价提供一定参考。     

毒性试验中评估化学物致癌性的数学模型

<正> 毒性试验的主要目的之一是研究化学物的致癌性。作者曾应用有关概率方法和试验的灵敏度、特异度,求得化学物在结果群条件下是致癌物的概率。这就是比值评估法。现介绍比值评估法的两种应用:(1)由一系列观察指标不同的毒性试验在不同实验室所得的     

转基因小鼠在药物致癌性评价中的应用

致癌性实验是药物非临床安全性评价的重要内容,用以考察药物对动物的潜在致癌作用,辅以机制研究等以评价和预测人体长期用药带来的风险。转基因小鼠肿瘤模型的建立为肿瘤研究带来了巨大变化,转基因动物模型也成为致癌性研究的重要选择之一。本文主要参考国际现有指导原则和已上市药品评价资料,概述当前常用转基因动物的特征及其在药物安全性评价中的实际应用情况,为我国致癌性评价中转基因动物的应用提供参考。     

谨防临床药物的致畸致癌性

随着现代医药科技的飞速发展，大量化学合成药物的问世及临床广泛应用，药物所造成的药源性疾病日趋增多、已引起医药同行的高度重视，但有些药物的致畸致癌性人们并不十分了解。本人经多年深入临床，通过询问癌症及畸形儿病史并查阅资料就具有致畸致癌性的药物作以简介。     

国际上新药致癌性试验技术要求介绍

致癌性试验主要用于评价新药的潜在致癌性风险,是安全性评价的重要内容之一。新药人体致癌性风险目前主要依赖临床前试验结果来预测,以形成新药临床试验和上市后的风险控制计划。致癌性试验周期长,花费高,试验设计和结果评价比较复杂,需要研究者和管理机构加强交流沟通。     

生物制品残留DNA分析技术的研究进展

生物制品中残留DNA可能具有感染性和致癌性,因此生物制品的纯化过程需要验证,尽可能将产品中残留DNA的水平降到最低.厂家有必要显示DNA去除过程,并有适当定量分析方法检测残留DNA的含量.当前DNA定量分析所采用的最普遍方法是定量PCR(quantitative real time polymerase chain reaction,Q-PCR).此文就残留DNA的感染性、致癌性、免疫原性等潜在风险以及残留DNA分析技术的最新进展做一综述.     

啮齿类动物致癌性试验的关注要点

啮齿类动物致癌性试验的目的是确定候选药物在动物中是否具有致癌性,以及如果存在致癌性风险,这种风险是否会转化至人类。药物相关的致癌作用可能表现为肿瘤发生率增加、背景肿瘤发生潜伏期缩短或罕见肿瘤的发生。本文重点讨论啮齿类动物致癌性试验中的一些具体而关键的内容,包括试验设计、实施、报告和结果解释分析的考虑要点。本文重点阐述致癌性试验进行的时间、试验设计的关键方面(剂量选择、种属选择、如何处理早期死亡和试验组终止等)、试验报告的一般内容和注意事项、致癌性试验数据的统计分析和结果阐述分析等。使用综合证据权重(WoE)方法解释致癌性试验结果,尤其对啮齿类动物致癌试验发现是否与人体致癌风险相关的评价是至关重要的。     

Human carcinogenic risk evaluation, Part III: Assessing cancer hazard and risk in human drug development.

Assessing cancer risk for human pharmaceuticals is important because drugs are taken at pharmacologically active doses and often on a chronic basis. Epidemiologic studies on patient populations have limited value because of the long latency period for most cancers and because these studies lack sensitivity. The Center for Drug Evaluation and Research (CDER) of the U.S. Food and Drug Administration relies on short-term surrogate assays (genetic toxicology studies) to assess risk to patients involved in clinical trials and on rodent carcinogenicity studies to assess cancer risk for drug approval. Unlike some other agencies that typically perform quantitative risk assessments on chemical pollutants or pesticide products, CDER does not perform such quantitative extrapolations. Rather, the evaluation of risk is the result of an integrated assessment of what is known about the drug, and risk is considered in the context of the clinical benefit. Mode of action of carcinogenesis and thresholds for effects are important considerations. The results of carcinogenicity studies of approved products are published in the drug labeling and individual clinicians balance risk and benefit in making prescribing decisions.     

致癌试验与人类风险评估无关的肿瘤概述

致癌试验的目的是考察药物在动物体内的潜在致癌作用,从而评价其可能对人类的相关风险,是非临床药物安全性评价的主要内容之一。啮齿动物致癌试验的结果与人类安全性评估的相关性经常引起争议,可能需要做进一步的研究来探讨其作用方式,以帮助确定是否存在对人类的潜在致癌性。当啮齿动物致癌试验出现阳性结果时,可能需要进行进一步的毒性病理学研究探讨其作用机制,来评估与人类的相关性。简要介绍动物致癌试验结果与人类相关性的必要性、致癌试验基于作用方式与人类风险评估无关的肿瘤、致癌试验基于作用方式与人类风险评估可能无关的肿瘤,以期为我国非临床药物致癌试验的结果分析和药物评价研究提供一定参考。     

Reassessing the two-year rodent carcinogenicity bioassay: A review of the applicability to human risk and current perspectives

The 2-year rodent carcinogenicity test has been the regulatory standard for the prediction of human outcomes for exposure to industrial and agro-chemicals, food additives, pharmaceuticals and environmental pollutants for over 50 years. The extensive experience and data accumulated over that time has spurred a vigorous debate and assessment, particularly over the last 10 years, of the usefulness of this test in terms of cost and time for the information obtained. With renewed interest in the United States and globally, plus new regulations in the European Union, to reduce, refine and replace sentinel animals, this review offers the recommendation that reliance on information obtained from detailed shorter-term, 6 months rodent studies, combined with genotoxicity and chemical mode of action can realize effective prediction of human carcinogenicity instead of the classical two year rodent bioassay. The aim of carcinogenicity studies should not be on the length of time, and by obligation, number of animals expended but on the combined systemic pathophysiologic influence of a suspected chemical in determining disease. This perspective is in coordination with progressive regulatory standards and goals globally to utilize effectively resources of animal usage, time and cost for the goal of human disease predictability.     

Nitrapyrin: a scientific advisory group review of the mode of action and carcinogenicity in B6C3F1 mice

Nitrapyrin has been registered as a nitrogen stabilizer in the United States for many years based on a robust set of regulatory data. These data demonstrated that nitrapyrin was not genotoxic and that there were no tumors elicited in rats or mice that were relevant for human risk assessment. A repeat carcinogenicity study in B6C3F1 mice, conducted at two substantially higher-dose levels (0, 125 or 250 mg/kg/day) than the original study (0, 5, 25 or 75 mg/kg/day) identified liver, stomach, epididymal and Harderian gland tumors. In order to assess the relevance of these findings for human risk assessment, a Scientific Advisory Group (SAG) examined relevant microscopic changes in these tissues and also evaluated genotoxicity and mechanistic data. The SAG determined that the maximum tolerated dose had been exceeded in mice given 125 or 250 mg/kg/day, based on 26-33% decreased body weight gains (males-250 mg/kg/day), hepatocellular necrosis and compensatory hepatocellular proliferation (males and females-125 and 250 mg/kg/day). The SAG believed that the increased incidences of hepatocellular foci of alteration and hepatocellular neoplasms represented an epigenetic response to hepatocellular necrosis and increased mitogenesis. Increased incidences of proliferative lesions in the forestomach mucosa were likely secondary to the irritant effects of nitrapyrin. Neither the liver nor forestomach effects were interpreted to be a direct carcinogenic effect. Higher incidences of Harderian gland adenomas (females) and undifferentiated sarcomas in the epididymis represented normal biological variations in incidence and were unrelated to nitrapyrin. Therefore, it was the SAG's opinion that nitrapyrin exposure that does not produce target organ toxicity in exposed individuals would not be expected to increase the risk of cancer.     

Prediction of rodent carcinogenic potential of naturally occurring chemicals in the human diet using high-throughput QSAR predictive modeling

Consistent with the U.S. Food and Drug Administration (FDA) Critical Path Initiative, predictive toxicology software programs employing quantitative structure-activity relationship (QSAR) models are currently under evaluation for regulatory risk assessment and scientific decision support for highly sensitive endpoints such as carcinogenicity, mutagenicity and reproductive toxicity. At the FDA's Center for Food Safety and Applied Nutrition's Office of Food Additive Safety and the Center for Drug Evaluation and Research's Informatics and Computational Safety Analysis Staff (ICSAS), the use of computational SAR tools for both qualitative and quantitative risk assessment applications are being developed and evaluated. One tool of current interest is MDL-QSAR predictive discriminant analysis modeling of rodent carcinogenicity, which has been previously evaluated for pharmaceutical applications by the FDA ICSAS. The study described in this paper aims to evaluate the utility of this software to estimate the carcinogenic potential of small, organic, naturally occurring chemicals found in the human diet. In addition, a group of 19 known synthetic dietary constituents that were positive in rodent carcinogenicity studies served as a control group. In the test group of naturally occurring chemicals, 101 were found to be suitable for predictive modeling using this software's discriminant analysis modeling approach. Predictions performed on these compounds were compared to published experimental evidence of each compound's carcinogenic potential. Experimental evidence included relevant toxicological studies such as rodent cancer bioassays, rodent anti-carcinogenicity studies, genotoxic studies, and the presence of chemical structural alerts. Statistical indices of predictive performance were calculated to assess the utility of the predictive modeling method. Results revealed good predictive performance using this software's rodent carcinogenicity module of over 1200 chemicals, comprised primarily of pharmaceutical, industrial and some natural products developed under an FDA-MDL cooperative research and development agreement (CRADA). The predictive performance for this group of dietary natural products and the control group was 97% sensitivity and 80% concordance. Specificity was marginal at 53%. This study finds that the in silico QSAR analysis employing this software's rodent carcinogenicity database is capable of identifying the rodent carcinogenic potential of naturally occurring organic molecules found in the human diet with a high degree of sensitivity. It is the first study to demonstrate successful QSAR predictive modeling of naturally occurring carcinogens found in the human diet using an external validation test. Further test validation of this software and expansion of the training data set for dietary chemicals will help to support the future use of such QSAR methods for screening and prioritizing the risk of dietary chemicals when actual animal data are inadequate, equivocal, or absent.     

Is current risk assessment of non-genotoxic carcinogens protective?

Non-genotoxic carcinogens (NGTXCs) do not cause direct DNA damage but induce cancer via other mechanisms. In risk assessment of chemicals and pharmaceuticals, carcinogenic risks are determined using carcinogenicity studies in rodents. With the aim to reduce animal testing, REACH legislation states that carcinogenicity studies are only allowed when specific concerns are present; risk assessment of compounds that are potentially carcinogenic by a non-genotoxic mode of action is usually based on subchronic toxicity studies. Health-based guidance values (HBGVs) of NGTXCs may therefore be based on data from carcinogenicity or subchronic toxicity studies depending on the legal framework that applies. HBGVs are usually derived from No-Observed-Adverse-Effect-Levels (NOAELs). Here, we investigate whether current risk assessment of NGTXCs based on NOAELs is protective against cancer. To answer this question, we estimated Benchmark doses (BMDs) for carcinogenicity data of 44 known NGTXCs. These BMDs were compared to the NOAELs derived from the same carcinogenicity studies, as well as to the NOAELs derived from the associated subchronic studies. The results lead to two main conclusions. First, a NOAEL derived from a subchronic study is similar to a NOAEL based on cancer effects from a carcinogenicity study, supporting the current practice in REACH. Second, both the subchronic and cancer NOAELs are, on average, associated with a cancer risk of around 1% in rodents. This implies that for those chemicals that are potentially carcinogenic in humans, current risk assessment of NGTXCs may not be completely protective against cancer. Our results call for a broader discussion within the scientific community, followed by discussions among risk assessors, policy makers, and other stakeholders as to whether or not the potential cancer risk levels that appear to be associated with currently derived HBGVs of NGXTCs are acceptable.     

啮齿类动物致癌实验中增生性病变的病理学评估现状

目的介绍啮齿类动物致癌实验中增生性病变的评估现状,进而阐明增生性病变在人类致癌风险性评估中的重要作用。方法从增生性病变在致癌实验中的意义入手,进一步阐述致癌实验的病理学诊断过程中对增生性病变的评价现状、增生性病变与肿瘤发生的关系以及对增生性病变评价方法的定性使用。结果增生是致癌性评估中"重要证据"的组成部分。准确评估与肿瘤产生相关的增生性病变对于某一受试物种致癌风险性的确定以及最终确定对人类致癌性的潜在风险是至关重要的。结论为从事致癌风险性识别及评估工作的毒理学家、病理学家和其他科学家们提供与致癌风险性评价相关的资料,为客观、准确地评价化合物的致癌风险性提供重要的参考信息。