模型引导的药物研发:发展历程和应用思考

使用模型和模拟(M&S)有助于提高药品研发的决策质量和效率,为监管评估提供客观证据,通过应用实例、指南颁布和政策推动。模型引导的药物研发(MIDD)已经受到越来越多制药企业和监管机构的认可和支持。本研究旨在鼓励研究者认识和理解MIDD在药物研究和法规中的作用和应用价值。     

Utilisation of pharmacokinetic-pharmacodynamic modelling and simulation in regulatory decision-making.

Modelling and simulation (M&S) play an important role in regulatory decision-making that affects both the public and industry. Technological advances in various fields related to drug development call for more focus on ways to optimise current drug development practices. Recognition of the potential of M&S by regulatory agencies inevitably has a substantial impact on drug development. The objective of the current review is to present the various regulatory initiatives for application of M&S to clinical drug development. The relevant parts of the various recommendations issued by the US Food and Drug Administration (FDA), via guidance documents and advisory committee meeting proceedings, are highlighted. Application of M&S to a variety of activities, such as integrating pharmacokinetic-pharmacodynamic knowledge across a new drug application and designing efficient trials, is discussed. Some of the challenges that pharmaceutical institutions currently face when implementing M&S projects, such as team structure, communication with regulators, training and time constraints, are also presented, and solutions are proposed.     

Special considerations concerning regulatory requirements and drug development for peptides and biotech products in the EU

The marketing authorization for a new medicinal product is based on the scientific assessment of its quality, safety and efficacy. The marketing authorization application (MAA) which covers all the relevant documentation can be filed in the EU via different application procedures. For peptides and biological products special issues have to be taken into consideration during drug development. Due to special production procedures and the complexity of the active substance itself, peptides and biotech products are subject to specific regulatory requirements. This leads to the necessity to discuss the development program of a new peptide or biotech product with the health authorities on a case by case basis. This article will focus on the special regulatory requirements for peptides and biotech products including the registration procedures as well as technical, preclinical and clinical issues.     

Granting marketing authorisation for medicines in South East European countries: The point of view of the authority

European legislation for medicines places the emphasis on an assessment of quality, safety and efficacy during the procedure for the granting of marketing authorisations for medicines, in order to protect patient health. The integrated European regulatory system involves the participation of a network of experts from the agencies of the member states that takes part in the European procedures for the authorisation of medicines. On the way to full membership in the EU, candidate countries and potential candidates have to transpose and implement the European directives for medicinal products; they must also strengthen their scientific and administrative capacities. Croatia acquired good experience in implementing the simplified marketing authorisation procedure for medicines authorised in the EU pursuant to the New Collaboration Agreement between Drug Regulatory Authorities in Central and East European Countries (nCADREAC), which helps it to exchange information and prepare for the implementation of European procedures. However, there are still some provisions to transpose before actual full membership, and also dossier upgrading, in which the marketing authorisation holder has to harmonise its documentation about a medicinal product with the requirements of the directives, if a product already on the market was not previously approved in line with current European legislation. Collaboration with the European Medicines Agency (EMA) through an Instrument for Pre-Accession (IPA) provides candidate countries and potential candidates the opportunity for education and training in some regulatory activities as well as the participation of their representatives as observers in some EMA committees and working groups. Some characteristics of the national regulatory frameworks of the countries of South East Europe in their efforts to achieve harmonisation with EU legislation are presented in this paper.     

Hurdles of environmental risk assessment procedures for advanced therapy medicinal products: comparison between the European Union and the United States

Abstract

An environmental risk assessment (ERA) consists of an analysis of the risks to human health and the environment that a medicinal product may cause due to its release during clinical development or after entering the market. Regulators in European Union (EU) and the United States (US) require that advanced therapy medicinal products (ATMPs) that are also genetically modified organisms (GMOs) undergo an ERA in order to be approved for marketing authorization. This work aims to review the regulatory issues that need to be taken into consideration for carrying out an ERA, comparing the EU and the US. The European regulatory framework for environmental procedures and the dissimilarities in its implementation across the Member States and its implications at a logistical level are analyzed in detail. In addition, this review provides a brief insight into the non-clinical and clinical assessments that should be carried out during the development of the product in order to conduct a successful ERA, and thus facilitate its marketing authorization and post-marketing monitoring. Finally, the need for a European harmonization regarding environmental procedures for ATMPs is discussed.     

药品上市许可持有人制度下药品上市后监管风险分析及监管对策研究

目的：为提升药品上市许可持有人制度下药品上市后监管的效能,本文提出了药品上市后各环节的监管对策,为完善我国药品上市许可持有人制度提供参考。方法：结合上海市试点情况,对药品上市许可持有人制度下药品上市后生产、流通、不良反应监测与评价各环节进行风险识别和风险分析,提出相应的监管策略。结果与结论：在药品上市许可持有人制度下,建议通过制定药品上市许可持有人信息上报制度,建立持有人基础数据库和药品信息追溯体系,在对持有人日常监管中从优化监管资源配置、明确日常监管检查重点、建立跨省监管合作的沟通和协调机制等方面,提升对药品上市后的监管效能。     

Reflections on Decisions Made on the Well-Established Use of Medicinal Products by EU Regulators and the ECJ

Background: In the European Union (EU), a medicinal product needs a marketing authorization (MA) to be placed on the market. The EU’s medicinal products’ legislative framework allows for a reduced application for medicines outside their data exclusivity. One such type of application is the well-established use (WEU) medicinal product application (i.e. bibliographic applications). Recently, these MA applications have been subject to arbitration procedures at the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) because of disagreements between member states during the authorisation process. This paper reflects on these cases and highlights their potential impact on future WEU applications.Methods: Decisions adopted by the European Commission on WEU applications between 2009 and 2012 were identified from the EU Community Register on medicinal products for human use. Subsequently, decisions were reviewed to understand the potential serious risk to public health (PSRPH) that EU regulators raised during MA application procedures.Results: Four decisions were adopted by the EU commission between 2009 and 2012. Three followed disagreements between member states on PSRPH grounds. One decision was the outcome of a centralised marketing authorisation application. Six key messages were identified from the four cases reviewed and presented.Conclusion: A guideline on WEU to implement the technical specifications to fulfil Annex I of Directive 2001/83/EC for MA applications is not available. Thus, reflections on recent decisions on WEU applications provide scientific direction to the industry as well as the medicinal product regulators on the documentation required to successfully file and obtain a WEU MA.     

Recommendations for the validation of immunoassays used for detection of host antibodies against biotechnology products

Most biological drug products elicit some level of anti-drug antibody (ADA) response. This antibody response can, in some cases, lead to potentially serious side effects and/or loss of efficacy. In humans, ADA often causes no detectable clinical effects, but in the instances of some therapeutic proteins these antibodies have been shown to cause a variety of clinical consequences ranging from relatively mild to serious adverse events. In nonclinical (preclinical) studies, ADA can affect drug exposure, complicating the interpretation of the toxicity, pharmacokinetic (PK) and pharmacodynamic (PD) data. Therefore, the immunogenicity of therapeutic proteins is a concern for clinicians, manufacturers and regulatory agencies. In order to assess the immunogenic potential of biological drug molecules, and be able to correlate laboratory results with clinical events, it is important to develop reliable laboratory test methods that provide valid assessments of antibody responses in both nonclinical and clinical studies. For this, method validation is considered important, and is a necessary bioanalytical component of drug marketing authorization applications. Existing regulatory guidance documents dealing with the validation of methods address immunoassays in a limited manner, and in particular lack information on the validation of immunogenicity methods. Hence this article provides scientific recommendations for the validation of ADA immunoassays. Unique validation performance characteristics are addressed in addition to those provided in existing regulatory documents pertaining to bioanalyses. The authors recommend experimental and statistical approaches for the validation of immunoassay performance characteristics; these recommendations should be considered as examples of best practice and are intended to foster a more unified approach to antibody testing across the biopharmaceutical industry.     

European regulation on orphan medicinal products: 10 years of experience and future perspectives

In 2000, regulation on orphan medicinal products was adopted in the European Union with the aim of benefiting patients who suffer from serious, rare conditions for which there is currently no satisfactory treatment. Since then, more than 850 orphan drug designations have been granted by the European Commission based on a positive opinion from the Committee for Orphan Medicinal Products (COMP), and more than 60 orphan drugs have received marketing authorization in Europe. Here, stimulated by the tenth anniversary of the COMP, we reflect on the outcomes and experience gained in the past decade, and contemplate issues for the future, such as catalysing drug development for the large number of rare diseases that still lack effective treatments.     

Unlicensed pharmaceutical preparations for clinical patient care: Ensuring safety

Most medicinal products dispensed to patients have marketing authorization (MA) to ensure high quality of the product, safety, and efficacy. However, in daily practice, to treat patients adequately, there is a medical need for drugs that do not hold MA. To meet this medical need, medicinal products are used in clinical care without MA (unlicensed), such as products prepared by (local) pharmacies: the pharmaceutical preparations. Three types of pharmaceutical preparations are distinguished: (i) reconstitution in excess of summary of product characteristics; (ii) adaptation of a licensed medicinal product (outside its official labeling); (iii) medicinal products from an active pharmaceutical ingredient. Although unlicensed, patients may expect the same quality for these unlicensed pharmaceutical preparations as for the licensed medicinal products. To assure this quality, a proper risk‐benefit assessment and proper documentation in (centralized) patient registries and linking to a national pharmacovigilance database should be in place. Based on a risk assessment matrix, requirements for quality assurance can be determined, which has impact on the level of documentation of a pharmaceutical preparation. In this paper, the approach for good documentation including quality assurance and benefit‐risk assessment will be discussed and possibilities for patient registries are described to make these crucial preparations available for regular patient care. KEY POINTS

• Ensuring pharmaceutical quality and performing a proper benefit‐risk assessment will guarantee safe use of pharmaceutical preparations.
• Good documentation of (ultra‐)orphan treatments can be collected in centralized patient registries and should be combined with existing information in (inter)national databases and self‐reflection of patients.
• Linking patient registries to a centralized database for adverse drug events is highly recommended as it increases safety control of the (ultra) orphan pharmaceutical preparations.

     

Typical pitfalls in applications for marketing authorization of biotechnological products in Europe

Although regulatory standards and procedures in Europe have improved following the establishment of the European Medicines Agency (EMEA), the number of major issues with marketing authorization applications for biotechnological products remains high. For example, the pivotal clinical trials of some late-stage failures have been found not to meet the regulatory guidelines of the European Union, and regulators are increasingly concerned that attempts to accelerate the process of biotechnological product development leads to the neglect of important issues. Based on the scientific decisions of the EMEA's major scientific committees, in this article we identify and discuss frequent concerns, and suggest approaches that might enable developers of biotechnological products to avoid these common pitfalls.     

生物药剂分类系统(BCS)及应用进展介绍

生物药剂分类系统是根据药物的溶解性和渗透性对药物进行分类的一种科学框架,目前FDA、WHO和EMEA都接受了这种分类概念.文中比较了不同管理当局对于生物药剂分类系统(BCS)的定义以及BCS在药品注册申报中支持生物等效免除的应用情况,综述了不同管理当局对于BCS的认识并提出了展望.     

'Biogenerics': the off-patent biotech products

The first patents of biopharmaceuticals derived from recombinant DNA will expire shortly, which raises the possibility of marketing generic products ('biogenerics') with limited documentation, similar to that which occurs with conventional pharmaceuticals. We propose the term off-patent biotechnological products (OPBPs) as an alternative to biogenerics when describing such products. It is questionable whether the majority of OPBPs can be classified as similar to the innovator products, considering the size and complexity of the molecules and the many factors that influence biological activity. There are three classes of OPBPs, each of which needs to meet different regulatory demands when seeking marketing authorization.     

European legislation on herbal medicines: a look into the future.

Harmonization of the market for herbal medicines is a fundamental requirement for European industries and health professionals and it will also be useful for consumers. Herbal medicines are generally sold as food supplements, but a common regulatory status in the various European countries does not exist. As a consequence, information on clinical indications for use, efficacy and safety are influenced by different opinions, according to the clinical or traditional experience of various folk medicines available in each European country. The European Directive 2004/24/EC released in 2004 by the European Parliament and by the Council of Europe provides the basis for the use of herbal medicines in Europe going forward. The Directive establishes that herbal medicines released in the market need authorization by the national regulatory authorities of each European country and that these products must have a recognized level of safety and efficacy. The safety of herbal medicinal products will be evaluated on the basis of existing scientific literature (data from clinical studies, case reports, pre-clinical studies). When data on safety are not sufficient, it will be communicated to consumers. According to the criteria of safety and efficacy, we will have two kinds of herbal medicinal products in the future: (i) 'well established use herbal medicinal products' (medicinal herbs with a recognized level of safety and efficacy); and (ii) 'traditional use herbal medicinal products'. The later category will include those medicinal herbs that do not have a recognized level of efficacy but are acceptably safe. Even though the fundamental objective of the new European herbal legislation is the harmonization of the market of herbal medicines, important regulations have been introduced, which will contribute to safer use of herbal substances if adopted by the whole of the European community.     

Non-clinical Post-Marketing Commitments for newly licenced pharmaceuticals

There are clear minimum requirements for non-clinical (toxicology) studies which are needed prior to human exposure to a potential new pharmaceutical and additional studies are needed in an ongoing manner to support clinical development and marketing [ICH, 2009. ICH M3(R2) Non-clinical safety studies for the conduct of human clinical trials and marketing authorization for pharmaceuticals (CPMP/ICH/286/95). Adopted June 2009, effective December 2009.] The pharmaceutical industry is under increasing pressure to reduce costs and reduce, refine and replace the use of animals, as far as possible. Hence any increase in regulatory requirements for non-clinical safety data could have a significant impact both on the economic and ethical considerations of drug development. It is, therefore, of interest that further non-clinical studies are required by the Regulatory Authorities for a small but increasing proportion of drug product applications at the marketing approval/data review stage. These studies are known as Post-Marketing Commitments (PMCs).     

新型冠状病毒肺炎公共卫生事件期间欧盟药品应急管理政策分析

新型冠状病毒肺炎（COVID-19）公共卫生事件，对满足公共卫生需求带来严重挑战。2020年7月，欧盟更新"COVID-19公共卫生事件期间的人用药品监管期望问答"，完善了COVID-19防治用关键药品的行政许可、生产经营、监督检查、药物警戒和包装标签等系列应急管理措施，提出例外变更管理流程、远程评估、豁免检验、差异化不良反应报告制度等灵活监管策略，与药品生产经营企业共同维持药品供应链稳定，保障药品安全、有效、可及。了解欧盟药品应急管理政策，对完善我国药品应急管理体系具有参考价值。     

Key Changes in Benefit–Risk Assessment Guidelines and Implications for Data Analysis in Drug Development

ABSTRACT

The number and complexity of regulatory and legislative policy initiatives for benefit–risk (B-R) assessments and the challenges associated with operationalizing and integrating these initiatives in the drug development process have increased exponentially in the last 10 years. Although there are some similarities in the approaches being used among regions, there are no unifying principles for a consistent approach to address various regulatory agency requirements. Therefore, some sponsors might end up with marketing authorization in one region but not in another, in spite of using the same available benefits and risks evidence without obvious differences between regions. Fortunately, however, there has been a recent global effort by the International Conference on Harmonization (ICH) to develop guidance which provides greater specificity on the format and structure of B-R evidence that is submitted with marketing applications in Module 2 of the Common Technical Document (CTD). The guidance was finalized in June 2016.

This article highlights some of the more notable proposed revisions to the ICH guidance for the B-R conclusions (Section 2.5.6) that was recently made public and some germane points to consider, particularly as it relates to effort to minimizing uncertainties associated with the B-R assessment. The discussion speaks to the dynamic nature and attendant imbalances between the pre- and post-market settings in the sources, timing and nature of the information we collect on favorable (benefits) and unfavorable (risks) effects of medicinal products, characterization of these products' attributes including the emerging role of patient input in product development, and the need to better integrate clinical trial findings and real-world clinical data to enhance our understanding of the expected performance of medical products in the intended patient population.     

Balancing early market access to new drugs with the need for benefit/risk data: a mounting dilemma

Drug regulatory agencies are increasingly pressed by the challenge of finding the appropriate balance between the need for rapid access to new drugs and the need to ensure comprehensive data on their benefits and risks. This dilemma is not new, but has been made more prominent by recent high-profile drug withdrawals and conflicting demands, including the need to improve the efficiency of drug development on one hand, and the need to avoid exposing patients to unnecessary risks or possibly ineffective treatments on the other. Here, we summarize the current demands by stakeholders and the scientific and regulatory issues at stake, describe existing and emerging regulatory approaches, and speculate on future directions, such as evolution of the current regulatory model from a one-off marketing authorization to a life-cycle approach.     

Critical review on the Environmental Risk Assessment of medicinal products for human use in the centralised procedure

In this article we analyse the Environmental Risk Assessment (ERA) of 59 medicinal products for human use authorised in the EU through the centralised procedure between 2011 and 2012, to establish whether company submissions are compliant with the European Medicines Agency (EMA) guideline and complete in terms of data and study reports provided. The most frequent questions raised by EU regulatory authorities are described, together with an evaluation of the presence and quality of ERA-related information in published regulatory assessment documents. The results of this review show recent improvement in ERA-related data presented in regulatory assessment documents available to the public while also highlighting a need to develop further guidance on environmental issues in order to assist applicants improve their ERA dossiers and overcome current shortcomings.     

Europe and medicines: role of the EMEA

F. Sauer. Ann Pharm Fr 2000, 58: 278-285. The new European authorization system has made considerable progress since 1995. The European Agency for the Evaluation of Medicinal Products (EMEA) is primarily responsible for the scientific evaluation of applications for a European marketing authorization for medicinal products derived from biotechnology and other high technology (centralised procedure). For other products, the EMEA arbitrates where mutual recognition of national marketing authorizations between the Member States is not possible (decentralised procedure). The EMEA co-ordinates the scientific resources made available by the national competent authorities of the Member States, including a network of over 2 000 European experts. The Opinions of the scientific committees of the EMEA (Committee for Proprietary Medicinal Products, CPMP, and Committee for Veterinary Medicinal Products, CVMP) are enforced by the European Commission, which has so far authorized 69 medicinal products for human and veterinary use. The confidence of industry, health professionals and consumers in the system is clear. European patients are now able to have speedier access to new drugs, usually within one year. The new system also helps to reinforce the safety of medicines for humans and animals, particularly through a pharmacovigilance network and the establishment of safe limits for residues in food-producing animals.