ICH E14:一项新的评价新药研发中药物临床心脏安全性的国际药政法规

2005年5月，有关在临床研究中如何监督新药对心脏安全性的措施，经国际协调会议（ICH）讨论并通过了一项新的工作指南，即ICH协调性三方指南：非抗心律不齐药物的致QT／QTc间期延长和致心律失常的临床评价。本文概述并讨论了该指南要点，以期望对相关新药安全性监督起到一定指导作用。     

CIOMS and ICH initiatives in pharmacovigilance and risk management: overview and implications.

In this article we review the current initiatives by the Council for International Organizations of Medical Sciences (CIOMS) and the International Conference on Harmonisation (ICH) on pharmacovigilance planning that are due for general release during 2004. These initiatives could form the basis for applying concepts of risk management to medicines throughout their life cycle, from preclinical and clinical development to marketed use.The CIOMS VI Working Group (with 28 senior scientists worldwide from drug regulatory authorities and pharmaceutical companies) is currently developing scientific guidance that relates to clinical trials for medicines during development. It recommends a developmental pharmacovigilance concept - a 'living' concept that would start early in drug development supporting the science and ethics of research leading up to licensing (marketing authorisation) and continuing to post-authorisation (postmarketing) pharmacovigilance.This approach is seen as complementary to current ICH initiatives called 'Pharmacovigilance Planning'. ICH will introduce two concepts in pharmacovigilance management of medicinal products: the 'Pharmacovigilance Specification' and the 'Pharmacovigilance Plan'. The 'Pharmacovigilance Specification' will summarise important knowns and unknowns about the medicine. It will include safety risks identified at the licensing stage, potential risks and any key missing information. These elements will be essential to the formulation of pharmacovigilance plans.Dialogue and common understanding between regulators and the pharmaceutical industry will be a key factor for developing pharmacovigilance plans during the life cycle of medicines. Appropriate interaction with health professionals and patients should also be planned for the future as regulatory systems become more transparent.Where no significant issues are apparent at the licensing (marketing authorisation) stage, routine pharmacovigilance practices will be followed during the marketing phase. Where issues do exist or the data are limited, further study, including epidemiological approaches can be planned. All types of medicines (new drugs, biological agents, orphan drugs) may be involved in these concepts, as would major extensions to existing medicines.Currently ongoing CIOMS and ICH initiatives are in line with emerging risk-management strategies in the US, the European Union and Japan aimed at early and proactive pharmacovigilance.     

药品生命周期管理最新指南介绍与安全性评价的作用浅析

人用药品注册技术要求国际协调会（International Conference for Harmonization,ICH）于2017年12月颁布了Q12新草案,该草案补充了药品生命周期的管理内容,对药品的安全性评价和风险评估具有重要的指导意义。本文概述了ICH Q12的最新内容和Q12对安全性评价和风险评估的最新要求,总结了安全性评价在药品生命周期管理中的作用及应用现状,以期为保障药品的安全性,促进药品生命周期管理方式发展以及公众合理用药提供参考。     

Drugs, QT interval prolongation and ICH E14: the need to get it right.

Regulatory concerns on the ability of an ever-increasing number of non-cardiovascular drugs to prolong the corrected QT (QTc) interval and induce potentially fatal ventricular tachyarrhythmias have culminated in initiatives to harmonise internationally the regulatory guidance on strategies by which to evaluate new drugs for this liability. The International Conference on Harmonisation (ICH) has released consensus texts for clinical (ICH topic E14) and non-clinical (ICH topic S7B) strategies as regulatory drafts for wider consultation. Draft ICH E14 calls for a clinical 'thorough QT/QTc study' (typically in healthy volunteers) for new drugs with systemic bioavailability, regardless of the non-clinical data. This indifference to non-clinical data has sparked off a major debate, even among the regulators. The 'thorough QT/QTc study' is intended to determine whether a drug has a threshold pharmacological effect on cardiac repolarisation, as detected by QT/QTc prolongation, and proposes the use of a positive control to validate the study. The guideline recommends exploration of the effect of concentrations that are higher than those achieved following the anticipated therapeutic doses and, consequently, a negative 'thorough QT/QTc study', even in the presence of non-clinical data of concern, will almost always allow standard collection of on-therapy ECGs. The proposed threshold of a 5 ms increase in mean placebo-corrected QTc interval for designating a study as positive for an effect, with all its implications for subsequent development of the drug and its regulatory assessment and labelling, has also generated a controversy. This paper provides an overview commentary on some contentious or ambiguous aspects of draft ICH E14 with a view to stimulating a debate and inviting scientifically supported comments from stakeholders in order to ensure that the application of the ICH E14 strategy, when finalised and adopted, does not result in either restriction in the use (or even rejection) of a potentially beneficial drug or approval of an otherwise hazardous drug without the restrictions required to promote its safe use.     

Characteristics of clinical trials in oncology: pharmacist's implication

French hospital pharmacists have been officially involved in the organization of clinical trials since 1988. New responsibilities included reception of clinical treatment units and nominative dispensation of these drugs. For quality assurance, they organized all the procedures to secure drugs utilization according to good clinical practices and ICH guidelines. The pharmacists can be participate in ethical counselling and training in methodology. For oncology trials, only a few pharmacies are involved because clinical trials for evaluation of cytotoxic drugs have been regulated by very strict standardized procedures since 1960 in accordance with international rules. Using these rules, Phase I studies determine the useful dose for human administration with tolerable toxicities. Phase II studies determine the efficacy in specific cancer localizations. Good response in a particular indication is usually followed by drug approval for Phase III. New clinical and biological end points are arising especially for new non-cytotoxic therapeutic agents. This activity is at the present time limited to inpatient treatments, but with the growing development of outpatient care networks, dispensary pharmacists will come to be more involved in the necessary research and development of new anticancer agents.     

Challenges and lessons learned since implementation of the safety pharmacology guidance ICH S7A

The International Conference on Harmonization, Topic S7A guidance (ICH S7A) on safety pharmacology for human pharmaceuticals has been in effect for 3 years in Europe, the United States and Japan. Surveys of the pharmaceutical industry, regulatory agencies and the audience attending the 4th Annual Meeting of the Safety Pharmacology Society have helped identify and address areas of controversy, as well as those challenges that have emerged since implementation of the guidance worldwide. Overall, ICH S7A has been successfully implemented. The guidance provides for "Good Laboratory Practice" compliant "safety pharmacology core battery" of studies that are generally performed prior to first administration to humans. The approach is science-driven and specifies the use of robust and sophisticated in vitro and/or in vivo assays. There are, however, some areas that require further refinement/clarification such as the specifics of study design including the selection of dose/concentration, choice of species, modeling of the temporal pharmacodynamic changes in relation to pharmacokinetic profile of parent drug and major metabolites, use of an appropriate sample size, statistical power analysis as a means of demonstrating the sensitivity of the model system, testing of human-specific metabolites and demonstrating not only the model's sensitivity, but also its specificity for predicting adverse events in humans. There was also discussion of when these studies are needed in relation to the clinical development plan. Representatives from the pharmaceutical industry and regulatory agencies see the implementation of ICH S7A as a major step forward towards identifying the risk to Phase 1 and 2 volunteers and patients. It remains to be seen, however, whether and in what ways the ICH S7A-based strategy will contribute to the modification of the integrated risk assessment during the latter stages of clinical development or once drugs have been introduced to the marketplace.     

表达蛋白质组学在抗肿瘤药物研发中的应用

表达蛋白质组学主要对正常、疾病或药物处理细胞或亚细胞中的所有蛋白质进行定性或定量研究。近年来表达蛋白质组学对抗肿瘤药物的研发起到了一定的推动作用。本文通过检索相关数据库文献,对其进行梳理、总结和归纳,阐述了表达蛋白质组学在抗肿瘤药物研发中的应用,包括抗肿瘤药物靶点发现、药物作用机制阐明、临床诊断以及基于网络药理学的药物研发理念的实现等。尽管表达蛋白质组学本身还存在一些缺陷,但随着其技术的不断发展,必将进一步促进抗肿瘤创新药物的研发。     

Drugs, QTc interval prolongation and final ICH E14 guideline : an important milestone with challenges ahead.

Regulatory concerns on the ability of an ever-increasing number of non-antiarrhythmic drugs to delay ventricular repolarisation, prolong the corrected QT (QTc) interval and induce potentially fatal ventricular tachyarrhythmias have culminated in the adoption of two, internationally harmonised, regulatory guidelines. On 12 May 2005, the International Conference on Harmonisation (ICH) reached an important milestone when it adopted the final texts for clinical (ICH topic E14) and non-clinical (ICH topic S7B) strategies by which drugs should be investigated for their potential to induce these effects during their development.ICH E14 provides recommendations to sponsors concerning the design, conduct, analysis and interpretation of clinical studies to assess the potential of a drug to delay cardiac repolarisation. Specifically, it calls for a clinical 'thorough QT/QTc study' (typically conducted in healthy volunteers), which is intended to determine whether a drug has a threshold pharmacological effect on cardiac repolarisation, as detected by QT/QTc interval prolongation. The E14 recommendations are generally applicable not only to new drugs that have systemic bioavailability but also to approved drugs when a new dose, route of administration or target population that may result in an increased risk is explored. The guideline provides for exceptions when this study may not be required.Recognising the fractious relationship between ICH E14 and ICH S7B, and the persistence of a number of issues that may require clarity and/or the emergence of other new scientific issues in the future, the ICH Steering Committee has formed an Implementation Working Group that is charged with providing clarity on aspects of the guideline that are ambiguous and responding to issues on which the sponsors are uncertain. This paper provides a commentary on some of the challenges that are likely to be faced by the sponsors of drugs during the next few years of application of these two guidelines. The adoption of these guidelines has left a number of questions unanswered and raised some new ones. When in doubt, the sponsor should seek formal regulatory clarity before making key decisions that may impact further development, assessment and approval of a new chemical entity. Although the goal of developing drugs with much lower torsadogenic potential and without inappropriate restriction in the use (or even rejection) of potentially beneficial drugs is within sight, it is questionable whether the risk of drug-induced pro-arrhythmia will be eliminated completely.     

Histone deacetylase inhibitors: new hope for rheumatoid arthritis?

Histone deacetylase (HDAC) inhibitors are a new family of anti-cancer agents currently undergoing clinical investigations for various oncology indications. Their anti-inflammatory activities had been well documented and they appear to be potential therapeutic strategies for various inflammatory diseases. In this review, the anti-inflammatory activities of HDAC inhibitors with emphasis on their potential applications in rheumatoid arthritis (RA) will be summarized. The possible anti-rheumatic mechanisms, including growth arrest in rheumatoid arthritis synovial fibroblasts (RASFs), suppression of pro-inflammatory cytokines or chemokines, anti-angiogenesis as well as protective effects on bone and cartilage destruction will also be discussed. Current literatures strongly imply HDAC inhibitors as innovative anti-rheumatic drug candidates. However, long-term safety is a major concern. Future investigations should focus on identification of molecular anti-rheumatic mechanisms, development of new classes of HDAC inhibitors with better safety and selectivity profiles, combination of HDAC inhibitors with disease modifying anti-rheumatic drugs (DMARDs) and establishment of topical or intra-articular formulations.     

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。     

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...     

FDA“抗体偶联药物的考虑”供企业用的指导原则草案介绍

美国食品药品监督管理局（FDA）于2022年2月发布了“抗体偶联药物的考虑”供企业用的指导原则草案,旨在帮助企业和其他参与者开发细胞毒性小分子药物（有效载荷）的抗体偶联药物（ADC）。该指导原则阐述了FDA目前对ADC临床药理学开发方案的建议,包括生物分析方法、给药方案、剂量和暴露反应分析、内在因素、QTc评估、免疫原性和药物-药物相互作用。ADC主要用于治疗肿瘤,又是当前国内药物研发的热点。中国目前还没有类似的指导原则,详细介绍FDA的该指导原则,期望有助于国内对这类新药的研发与监管。     

当前新药非临床安全性评价的趋势(英文)

非临床药物安全性评价为新药的研发发挥了重要作用。人用药品注册技术要求国际协调会(ICH)新药研发指南M3(R2)是非临床药物安全性评价的方向性指导文献。正确的评价策略和相关毒理学研究应该一起综合考虑,以促进新药候选物高效、及时地向前发展,从而支持临床试验计划和市场登记进展。然而,随着发展成本增加和行业的竞争,毒性预测、动物模型和法规遵从性也是新药深入研发过程中非常重要的因素。此外,ICH其他指导文献,例如ICH S6和ICH S9,也是给新药深入研发带来冲击力很大的指导文献。因此,深入理解所有这些文献的本质意义对从事新药安全评价人员来说是很重要的,增强综合使用各方面总体知识的能力将促进新药深入研发更快、更好地实施。     

Toxicity of excipients--a Food and Drug Administration perspective

Excipients are essential components of drug products. They are also potential toxicants. Examples of known excipient-induced toxicities include renal failure and death from diethylene glycol, osmotic diarrhea caused by ingested mannitol, hypersensitivity reactions from lanolin, and cardiotoxicity induced by propylene glycol. Proposals to test or market new drug products in the United States should adequately address the safety of the proposed exposure to the excipients in those products. The specific safety data that may be needed will vary depending upon the clinical situation, including such factors as the duration, level, and route of exposure, but may include acute, repeat-dose, reproductive, and genetic toxicity data, carcinogenicity data, and specialized toxicology information, such as sensitization or local irritation data. Many guidances exist to aid in the development of pharmaceuticals, including the International Conference on Harmonization (ICH) documents and various Food and Drug Administration/Center for Drug Evaluation and Research (FDA/CDER) pharmacology and toxicology guidances. The FDA/CDER has recently adopted a new guidance for industry, "Nonclinical Studies for Development of Pharmaceutical Excipients," which focuses on issues associated with development of safety databases that will support clinical use of excipients in drug products. The new guidance document is introduced and discussed in this article.     

Past, current, and future safety and efficacy trends in the drug industry

In view of the enormity of the subject on which I have been asked to speak, I consider it advisable, prudent, and pragmatic to attempt to focus the scope of my discussion on the area of my immediate expertise. In my lecture, I shall attempt to survey "the past" via a very brief discussion of some of the methods used for the determination of both safety and efficacy as well as the results achieved. With respect to "current practices," I intend to present an overview of the scope of safety and efficacy evaluation with new drugs, emphasizing both the pros and cons as perceived from the vantage point of a pharmaceutical scientist dedicated to the discovery and development of new therapeutic agents that will ameliorate disease states and human suffering while, at the same time, returning profit to the industry that has generated such drugs, so as to permit continued expansion of our therapeutic armamentarium by continued research efforts.     

FDA“IND安全性报告的安全性评估指导原则”介绍

美国食品药品管理局（FDA）于2015年12月发布了“IND安全性报告的安全性评估指导原则（草案）”,包括前言、背景、安全评估组织结构、安全性评估实践、前瞻性计划等5个部分。该指导原则为按新药临床研究（IND）开发的人用药物和生物制品IND安全性报告的系统方法提供指导,对IND安全性报告的安全性评估从程序、组织架构、具体操作等方面提供了较为详细的描述。我国目前尚无这类指导原则,了解该指导原则对于新药研究者对临床试验严重不良事件和不良反应的评估和判断有所帮助,简介其主要内容。     

Metabolites in safety testing

Traditionally, only circulating concentrations of parent drug have been measured in the rodent and nonrodent test species used for drug safety assessments and served as an index of systemic exposure for comparisons to human exposures. Circulating concentrations of metabolites have generally only been measured in specialized circumstances (e.g., parent compound was extensively metabolized). Measurement of only the parent compound is usually sufficient when the metabolite profile in humans is similar to that in at least one of the animal species used in the nonclinical safety assessment. However, it is possible that metabolites formed in humans might not be present in the rodent and nonrodent test species used for drug safety assessments or the metabolites are formed at disproportionately higher concentrations in humans than in the animal test species. Generally, metabolites identified only in human plasma or metabolites present at disproportionately higher concentrations in humans than in any of the animal test species should be considered for safety assessment. The Center for Drug Evaluation and Research (CDER) published a Guidance for Industry on Safety Testing of Drug Metabolites that provides current thinking within CDER on the nonclinical safety assessment of human drug metabolites derived from drug products. The CDER guidance defines human metabolites that can raise a safety concern as those formed at greater than 10% of parent drug systemic exposure at a steady state. By contrast, the more recent International Conference on Harmonization: Guideline on Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals (ICH M3[R2]) describes the threshold as 10% of total drug-related exposure. Where they differ, the ICH guidance supersedes the CDER Guidance. The purpose of this article is to provide a perspective on the important details of these guidances from a regulatory review standpoint, as well as discuss some concerns that have arisen from the regulated industry regarding the CDER guidance. Such issues include parent drug that is extensively metabolized, metabolism by intestinal bacteria and metabolites formed by nonclinical test species but not humans.     

FDA有关仿制药和抗肿瘤药说明书的2个指导原则介绍

美国食品药品管理局（FDA）于2022年1月发布了“参比制剂（RLD）说明书修订后简化新药申请（ANDA）说明书的修订”供企业用的指导原则草案。该指导原则提供了多种获取RLD说明书变更信息的方法，还告知提交修改后的仿制药说明书的具体资料。2020年11月FDA发布了“联合方案中的抗肿瘤药物的交叉说明书”供企业用的指导原则草案。所谓“交叉说明书”是指被批准用于联合方案的抗肿瘤药物的说明书纳入的相关信息。该指导原则指出，其中新药的交叉说明书“应包括有关联合用药安全有效的信息以及仅限于各自药物的信息”；而其中已批准的药物的交叉说明书，“应包括在联合方案中该药物与其他药物合用的安全有效性信息”。该指导原则还对交叉说明书一些具体项目的内容提出了建议。而我国目前尚没有类似的指导原则。详细介绍FDA这2个指导原则，期望对中国RLD说明书修订后的仿制药说明书的修订以及联合用药方案中的抗肿瘤药的“交叉说明”的实施有帮助；对这两种情况的说明书的监管也有所启迪。     

药物杂质的毒理学评价要求及进展

 药物原料或制剂中的杂质可能引起临床不良反应。杂质毒理学评价是药物研究的重要内容。ICH关于药物及制剂杂质方面指导原则规定了杂质的报告、鉴定和质控限度,含量超过质控限度的杂质应进行毒理学评价。但指导原则对于研发阶段的药物杂质和遗传毒性杂质的限度未作明确要求。EMEA对于遗传毒性杂质制定了专门的指导原则,引入了毒理学担忧阈值（TTC）的概念对遗传毒性杂质限度进行控制,遗传毒性杂质每日接触量应小于1.5 μg。FDA也推荐采用TTC原则控制遗传毒性和致癌性杂质。本文结合ICH,EMEA及美国FDA等指导原则,对药物杂质毒理学评价的要求及其进展进行了综述。     

Perspectives on non-clinical safety evaluation of drug metabolites through the JSOT workshop

The prompt and appropriate safety assessment of drug metabolite(s) was mentioned in regulatory guidances such as an International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) guidance, entitled "Guidance on Non-clinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals" (ICH M3(R2)) implemented in January 1 of 2011 in Japan, and has become a significant issue in the drug development. Upon release of ICH M3(R2) Step 4, a survey was conducted between March and April 2010 on the safety assessment of drug metabolites in 63 member companies of the Japan Pharmaceutical Manufacturers Association (JPMA). The Pharmacokinetics Team in the Non-Clinical Evaluation Expert Committee in JPMA conducted a questionnaire survey and compiled the results to comprehend how safety of drug metabolites are currently assessed at research-based pharmaceutical companies in Japan. The assessment of "Metabolites in Safety Testing" (MIST) can be divided into three stages based on the research purpose as follows: MIST 1 is a stage of estimating human drug metabolites and predicting their potential risks, MIST 2 is a stage of deciding the necessity for non-clinical safety studies, and MIST 3 is a stage of conducting non-clinical safety studies. In this paper, we propose typical approaches on safety assessment of metabolites that meet the purpose of each stage, considering the current level of scientific technology. Our proposals are based on the results from our survey and a symposium about the safety assessment of drug metabolites at the 37th annual meeting of the Japanese Society of Toxicology held in June 2010.