A regulatory perspective on issues and approaches in characterizing human metabolites

This document captures the current thinking within FDA/CDER on the non-clinical safety assessment of human drug metabolites in new drug products. Examples are provided, which define a scientific based approach to the safety evaluation of human metabolites in new drug candidates. A discussion of the need for, and the adequacy of, the assessment of human drug metabolites with specific regard to their potential as mediators of toxicity is presented from a regulatory perspective.     

基层特殊管理药品监管现状回顾及存在问题的分析

特殊管理药品涵盖麻醉药品、精神药品、医疗用毒性药品及放射性药品、药品类易制毒化学品等范畴,存在涉及面广、涵盖品种多、风险性大等特点。基层监管部门肩负辖区药品使用、经营、科研单位监管职责。其监管重点、侧重不尽相同。本文通过汇总辖区特殊管理药品的数据,对监管现状进行回顾性分析。     

The role of scientific evidence of risks and benefits in determining risk management policies for medications

Recent changes in the regulatory environment have called attention to the need for and potential benefits of greater and more detailed evidence to inform decisions based on the risk-benefit profile of medications. Nevertheless, access to potentially beneficial therapies continues to be impeded by a lack of sufficient information that could help optimize benefits and minimize risks of treatments for patients. Over-reliance on pre-marketing clinical trials and the FDA's spontaneous reporting adverse event system to support regulatory decisions has sustained an information void. Clinical trials are the gold standard for demonstrating efficacy, but they cannot fully predict safety when drugs are used in the real world. Spontaneous reporting can identify new signals, but cannot quantify those signals or place them in appropriate clinical context. In the face of new safety signals, absence of better information on how medications are used and how they perform in the real world setting, regulators are often limited to either continuing drug marketing without significant changes or withdrawing a medication from the market. Experience shows that information collected proactively, to better understand the background risks associated with the underlying disease and to better quantify the product risks, can influence these decisions to include a wider range of options regarding a product's availability, labeling and additional risk management strategies. This article presents several case studies of medications, including those in which insufficient data were available to address important safety signals and decisions were made to withdraw products, as well as those in which epidemiologic data were available to provide reassurance of product safety and allow continued product use, even though some may be marketed with additional risk management programs. More extensive and earlier epidemiologic assessment of risks and benefits of new products will create a new standard of evidence for industry and regulators and is likely to result in more effective and balanced regulatory actions, thereby affording better care for patients.     

我国儿科药品分剂量工作现状及思考

缺乏儿童适宜剂型和规格的药品是目前儿科治疗面临的主要问题之一,由此导致药品分剂量在儿科临床治疗中极为普遍。由于缺少相应的政策支持和指南规范,我国儿科药品分剂量工作缺乏有效的管理,致使分剂量药品的质量参差不齐,存在临床用药安全隐患。本文从儿科药品分剂量的需求、风险、政策法规和职业暴露等方面总结分析了国内儿科药品分剂量工作的现状及存在问题。同时结合经验提出了思考和建议,包括鼓励开发儿童适宜药品、评估风险、完善制度保障、探索新设备新技术、优化院内药品目录、加强宣传等,为我国儿科分剂量工作施行同质化管理和质量提升提供参考。     

探讨新修订的《药品管理法》对药品监管工作的挑战和应对策略

目的：新修订的《药品管理法》引入了国际通行的药品监管理念并吸纳了近几年来药品审评审批制度改革的成果,这些新变化给药品监管工作带来了新的挑战。本文旨在通过对新变化中出现的典型问题进行分析,提出可行的应对举措和建议,推动药品监管模式创新。方法：针对目前药品监管中的实际问题和预期风险,将新修订的《药品管理法》中的新变化、新要求与ICH相应指导原则中的相关理念、技术要求进行对照分析,并结合上海市药品审评审批改革中积累的相关试点经验进行探讨。结果与结论：药品监管部门以药品上市许可持有人制度为切入点,探索建立以品种为主线的全链条监管新模式,落实新修订《药品管理法》中的监管要求,实现对药品的全生命周期监管。     

The role of adaptive trial designs in drug development

Introduction: Clinical development of new drugs is a long and costly process. There is a need to find solutions which can improve and shorten this process. By introducing flexibility in to the design of clinical trials, adaptive design contributes to this improvement and allows to reach drug development decisions in a quicker way.

Areas covered: We review the main methodological approaches to adaptive trial design, introducing key statistical concepts. For each phase of the clinical development, different uses and implementations of adaptive trial (AD) design are presented and examples of recent clinical trials are given. The guidance documents issued by the US and European regulatory authorities are also presented.

Expert commentary: Despite inevitable challenges, prospects of this rapidly evolving approach to drug development are important. Controlling the risk of type 1 error and the potential operational risks which may be associated with adaptive trial strategy is paramount in late phase studies. However, with new methodological work, these risks are now well controlled and adaptive trial design will certainly shape the future of drug development.     

Increasing the odds of effective drug development: Elevating regulatory affairs professionals to strategic partners

In today’s globalized drug development landscape, the need for regulatory professionals to be more seamlessly integrated into strategic decisions is evident. Whereas a few companies see the benefit of involving regulatory affairs professionals in strategic business decisions, many still lag behind. Limited literature and scholarly discussion is available on whether regulatory affairs professionals are given the stature and power to make a meaningful contribution during strategy formulation across all stages of the product development, launch, and life-cycle management. This article examines the current business environment for the regulated industries; discusses why it is important that regulatory affairs play an active and strategic role in this sector; and proposes a new educational perspective to facilitate the recognition and acceptance of regulatory affairs professionals as strategic partners.     

中国药品质量风险提示函机制态势分析

目的 为进一步完善中国药品抽检的质量风险提示函机制提供参考。方法 介绍中国药品质量风险提示函的情况和药品质量风险的新形势,借助SWOT方法分析提示函在新形势下的优势、劣势、机会和威胁,对提示函进行整体评价并提出完善建议。结果与结论 近年来,中国药品质量仍处于较高水平,安全形势总体平稳可控,但一般性风险仍然存在并具有不可消除性。提示函作为中国药监部门基于劝服优先的原则对一般性风险进行干预的行政措施,面临着诸多内部和外部的有利与不利因素,建议药品生产企业进一步加强提示函的利用,药检机构进一步提供技术支持,以及药监部门建立提示函的失效补救机制,对提示函进行不断加强和完善。     

A problem-oriented approach to safety issues in drug development and beyond.

Human safety issues arise throughout the life cycle of pharmaceutical products and relevant information comes from a multitude of sources. Assessment and management of risks to humans requires a problem-based analysis to bring together relevant information regardless of source. The Safety Evaluation Plan (SEP) is a tool to support problem-oriented safety analysis. Safety issues are specified and the evaluation and management of each problem is based on a status summary that integrates the most current information from all relevant sources. The status summary is updated regularly during the course of clinical development to reflect the results of new studies and new clinical trials. In the postmarketing period, relevant postmarketing data is incorporated. Recent regulatory initiatives emphasise early identification of product safety risks so that appropriate risk-management measures can be instituted at the time of approval. A problem-oriented approach supports growing regulatory expectations regarding risk assessment and risk management. The problem-oriented approach facilitates early identification of safety issues and an evidence-based approach to their evaluation. Proactive management of safety problems leads to prompt assessment of risks and timely and appropriate steps aimed at risk reduction. The SEP provides a single global assessment for each safety issue. Regulatory submissions for pharmaceutical and biological products are organised by type of information. International Conference of Harmonisation documents covering clinical safety issues structure and analyse information separately by type, for example, adverse events, serious adverse events, laboratory data, vital signs, etc. A problem-oriented analysis would need to find a place in the regulatory process. A problem-oriented approach to safety cuts across typical structures in the pharmaceutical industry where different groups handle preclinical, clinical and postmarketing safety information. The SEP can improve communication within the company and externally. Nonetheless, supporting structures need to be adapted to support such an interdisciplinary process. Overall, the problem-oriented approach, supported by a SEP, contributes to realistic expectations and sustained credibility when dealing with safety issues.     

Toxicological overview of impurities in pharmaceutical products

While the use of pharmaceuticals is always a balance of risks and benefits, the same is not true for impurities in pharmaceuticals; impurities convey only risk. A number of international guidelines and regional guidances instruct drug developers and regulatory agencies on how to evaluate and control impurities in drug substances and drug products. While impurities should always be reduced to the lowest levels that are reasonably practical, it is acknowledged that impurities cannot be reduced to zero and specifications for impurities need to be established. This chapter discusses practical and theoretical methods for qualification of different classes of impurities.     

Advancing drug discovery through systems biology

Pharmaceutical companies are facing an urgent need to both increase their lead compound and clinical candidate portfolios and satisfy market demands for continued innovation and revenue growth. Here, we outline an emerging approach that attempts to facilitate and alleviate many of the current drug discovery issues and problems. This is, in part, achieved through the systematic integration of technologies, which results in a superior output of data and information, thereby enhancing our understanding of biological function, chemico-biological interactions and, ultimately, drug discovery. Systems biology is one new discipline that is positioned to significantly impact this process.     

Bridging the efficacy-effectiveness gap: a regulator's perspective on addressing variability of drug response

Drug regulatory agencies should ensure that the benefits of drugs outweigh their risks, but licensed medicines sometimes do not perform as expected in everyday clinical practice. Failure may relate to lower than anticipated efficacy or a higher than anticipated incidence or severity of adverse effects. Here we show that the problem of benefit-risk is to a considerable degree a problem of variability in drug response. We describe biological and behavioural sources of variability and how these contribute to the long-known efficacy-effectiveness gap. In this context, efficacy describes how a drug performs under conditions of clinical trials, whereas effectiveness describes how it performs under conditions of everyday clinical practice. We argue that a broad range of pre- and post-licensing technologies will need to be harnessed to bridge the efficacy-effectiveness gap. Successful approaches will not be limited to the current notion of pharmacogenomics-based personalized medicines, but will also entail the wider use of electronic health-care tools to improve drug prescribing and patient adherence.     

2012 Annual Meeting of the Safety Pharmacology Society: spotlight on targeted oncology medicines

Introduction: The 12th Annual Meeting of the Safety Pharmacology (SP) Society (SPS) covered various subjects among which safety issues concerning oncolytic drugs are reviewed and discussed in details.

Areas covered: The challenges faced by a medical oncologist during the development of new anticancer medicines were the focus of the keynote address. Romidepsin, a drug initially abandoned because of serious cardiotoxicity in dogs, was successfully rescued for clinical evaluation by tailoring the dose regimen to mitigate cardiac toxicity risks. The integration of SP endpoints into long-term toxicology offers the advantage of determining safety on organ function during chronic exposures, whilst also supporting the principal goals of the 3Rs framework. State-of-the-art imaging technologies can provide valuable, interpretable and translational (human to mouse to human) data for the detection of myocardial function impairment. The future growth of SP was discussed in terms of areas in need of innovative approaches as identified, in particular, in a worldwide sharing of SP data and methodologies.

Expert opinion: The need for epochal changes to ensure a bright future for SP should be promoted by the SPS. These comprise chiefly the expansion of the SP birth charter from primarily a regulatory discipline to include an efficiently organized experimental discovery science for which the name Exploratory SP (ESP) is proposed. Its mission would be the early and cost-effective assessment of the safety of clinical drug candidates on organ function based on mechanistic grounds and conducted outside of current expensive and time-consuming regulatory frontiers and constraints. The implementation of a high standard ESP discipline could also promote the gradual replacement of standalone safety investigations with SP assays performed within long-term toxicity studies.     

Legal and ethical status of stem cells as medicinal products

The realisation of the full potential of products based on stem cells in a clinical setting demands robust scientific evidence, underpinned by legitimate regulatory requirements to ensure their safety and efficacy. This review examines the legal aspects of the use of stem cells in the laboratory and in the development of new therapies and pharmaceutical products. UK and European legal and regulatory documents and directives are used as the framework for discussion of the current status and future prospects.     

Pharmacovigilance regulations in India: A Step forward

Robust regulatory arrangements provide the foundation for a national method of medicine safety, and for public confidence in medicines. This article focuses on the need to sharpen the regulatory requirements for pharmacovigilance in India. To be effective the remit of drug regulatory authorities needs to go further than the approval of new medicines, to encompass a wider range of issues related to the safety of medicines. In order to achieve their respective objectives pharmacovigilance programs and drug regulatory authorities must be mutually supporting. On one hand, pharmacovigilance programs need to maintain strong links with the drug regulatory authorities to ensure that the latter are well briefed on safety issues in everyday clinical practice, whether these issues are relevant to future regulatory action or concerns that emerge in the public domain. On the other, regulators need to understand the pivotal role that pharmacovigilance plays in ensuring the ongoing safety of medicinal products. Despite global focus on the Development Safety Update Report, Indian regulators are not yet insistent on real-time update of a drug’s cumulative safety profile. Hence, the present article concludes with a strong urge to postulate regulations that create a comprehensive medicine safety system through careful strategic planning that envelope all aspects of pharmacovigilance.     

患者报告结局在药品不良反应报告中的应用和思考

目的探索患者报告结局在药品不良反应报告中的应用。方法通过文献回顾的方法,对国外药品安全性研究中纳入患者报告结局的背景、驱动因素、当前监管情况进行了全面综述。结果目前数据收集的局限性、患者和医务人员间的不一致、通过患者能获取更丰富的信息等多个因素的驱动,且美国、英国等国家对此制定了监管措施,有效推动了患者报告结局在药品安全性研究中的应用。结论患者报告结局以患者为中心,为药品使用的效益、风险和结局的全面分析提供了丰富而宝贵的信息,可用作目前药物警戒和上市后研究的补充内容,为我国将患者报告结局的方法纳入药品安全性研究提供重要参考。     

How Has CDER Prepared for the Nano Revolution? A Review of Risk Assessment,Regulatory Research,and Guidance Activities

The Nanotechnology Risk Assessment Working Group in the Center for Drug Evaluation and Research (CDER) within the United States Food and Drug Administration (FDA) was established to assess the potential impact of nanotechnology on drug products. One of the working group’s major initiatives has been to conduct a comprehensive risk management exercise regarding the potential impact of nanomaterial pharmaceutical ingredients and excipients on drug product quality, safety, and efficacy. This exercise concluded that current review practices and regulatory guidance are capable of detecting and managing the potential risks to quality, safety, and efficacy when a drug product incorporates a nanomaterial. However, three risk management areas were identified for continued focus during the review of drug products containing nanomaterials: (1) the understanding of how to perform the characterization of nanomaterial properties and the analytical methods used for this characterization, (2) the adequacy of in vitro tests to evaluate drug product performance for drug products containing nanomaterials, and (3) the understanding of properties arising from nanomaterials that may result in different toxicity and biodistribution profiles for drug products containing nanomaterials. CDER continues to actively track the incorporation of nanomaterials in drug products and the methodologies used to characterize them, in order to continuously improve the readiness of our science- and risk-based review approaches. In parallel to the risk management exercise, CDER has also been supporting regulatory research in the area of nanotechnology, specifically focused on characterization, safety, and equivalence (between reference and new product) considerations. This article provides a comprehensive summary of regulatory and research efforts supported by CDER in the area of drug products containing nanomaterials and other activities supporting the development of this emerging technology.     

Diamonds in the Rough: Protein Crystals from a Formulation Perspective

The focus of the present review is to address the use of protein crystals in formulation design. Although this idea has been present for some time, i.e., insulin crystals were first reported back in 1920s, macromolecular crystallization has not received as much attention as the other methods for stabilizing protein drug candidates. The prospective potential of crystalline protein formulations in light of new advances in the field of macromolecular crystallization was reviewed, and the basic concepts and the tools now available for developing protein crystals into drug formulations are introduced. In addition, formulation challenges and regulatory demands, along with examples of current applications of protein crystals, are presented.     

武汉市某社区居民合理用药知识水平和需求状况调查

目的:了解新医改政策实施以来社区居民合理用药知识水平的现状以及对医药知识的需求状况。方法:2011年3月,采用一对一的问卷询问方式,现况调查武汉市某社区居民合理用药知识水平和需求状况。结果:调查社区多数居民的疾病医疗方式、用药观念和用药行为基本合理,如居民身体感到轻微不适选择看医生的占47.49%,凭医生处方获取药品的占57.99%,购药首先考虑药品安全性的占57.08%。居民对合理用药和安全用药知识的主观需求意愿均高达98.17%。仍有相当数量的社区居民在购药方式、对抗菌药认识(抗菌药处方率仅为58.90%)、过期药品处理、药品用法用量等方面存在一些问题。结论:居民合理安全用药的现状基本令人满意,但仍存在一些问题,应予以重视,并应采取有效的措施予以解决。可考虑设立药品咨询服务中心或者建立类似的服务机构为社区居民提供持续药品咨询服务,同时满足居民对医药知识的需求。