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.     

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.     

Biopharmaceuticals approved in the EU 1995-1999: a European Union-United States comparison.

The European Union's (EU) centralized procedure for new drug review was implemented in 1995 to unify the regulatory process and provide EU-wide marketing authorizations for innovative medicinal products. Goals were instituted to ensure the timeliness of the various steps of the process. The EU approved 27 biopharmaceutical products through the centralized procedure during 1995-1999. This study documents the success of the EU in meeting the timeline goals for the group and for separate categories of biopharmaceuticals (recombinant proteins, monoclonal antibodies, and antisense oligonucleotides). A subset of the 27 biopharmaceuticals approved in the EU were also approved in the United States (US). We compared EU and US approval times for these products by product category and by review status (exceptional/non-exceptional circumstance in the EU and priority/standard in the US).     

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.     

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.     

国外仿制药参比制剂选择简介及对我国的启示

目的：为完善我国仿制药一致性评价中参比制剂选择机制和程序提供参考,为仿制药企业在应用选择参比制剂时提供思路。方法：详细介绍了美国FDA有关参比制剂选择指南草案的最新描述,以及欧盟、日本和WHO对于参比制剂的相关要求。结合我国现阶段仿制药一致性评价工作实际,为完善参比制剂选择程序提出建议。结果与结论：美国详细规定了仿制药参比制剂的选择思路和实际操作程序,为我国仿制药参比制剂的选择提供了新的思路。我国正处于仿制药一致性评价参比制剂遴选的关键时期,制定全面、完善的参比制剂遴选体系和机制,有助于规范参比制剂的选择程序,加快一致性评价工作进程,提升我国仿制药一致性评价参比制剂选择的科学性和完整性。     

我国药品附条件批准程序实施情况及相关思考

目的：对我国药品附条件批准上市相关政策和实施情况进行深入分析和探讨,参考美国与欧盟药品附条件上市政策,对我国附条件批准上市的实施和推进提出建议。方法：通过梳理药品注册管理办法发布后国家药品监督管理局(NMPA)药品附条件批准上市申请审评审批法规政策实施情况,重点围绕当前法规中的准入条件、准入程序、上市后监管要求、撤销情形以及撤销程序进行综述,针对实施过程中发现的问题,借鉴美国食品药品管理局(FDA)药品加速审批(Accelerate Approval)与欧洲药品管理局(EMA)药品附条件批准(Conditional Marketing Authorisation)经验以及对各国附条件政策进行比较分析,探讨我国药品附条件批准上市政策的发展方向。结果与结论：为了加快具有突出价值的临床急需药品上市,缩短新技术临床应用时间,美国与欧盟均设立了相对完备的附条件上市法规政策及程序。我国的附条件批准制度虽然建立时间较短,但有欧美的经验作为参考,结合我国的临床实践和监管需要, 相关法规也在趋于完善。未来,监管部门更多需要考虑的是对程序和技术要求的细化、制度之间的衔接 (如疫苗的紧急使用授权与附条件批准制度),以及加强上市后监管等方面。     

Changes to protocol in the regulation of adverse drug reactions – historical and current European view

Adverse drug reactions (ADRs) are an inevitable part of medication use. During clinical trials, limited information was gained on drug safety. After marketing authorization (MA), more safety data is available as more patients use the drug. Major changes in drug regulation came after drug disasters, like with sulphanilamide elixir or thalidomide use. In recent history, withdrawal of rofecoxib has demonstrated the importance of post-marketing safety monitoring. Subsequently, legislation on drug safety changed both in the United States (US) and in the European Union (EU), becoming simplified and more comprehensive. New EU legislation was implemented in 2012 and has broadened ADR definition to medication errors and overdoses. In the EU, the Pharmacovigilance Risk Assessment Committee (PRAC) has been formed within the European Medicines Agency (EMA), regulating all aspects of drug safety. Referral procedures enable a thorough scientific analysis on all issues of medication safety. In both the US and the EU, ADRs can be reported directly by patients. All reports of suspected ADRs are kept on electronic databases and are analyzed regularly using new technologies. New safety signals are subsequently discovered and evaluated. This author expects that the new regulations will effectively safeguard healthcare consumers from major drug risks.     

European medicines and feed additives regulation are not in compliance with environmental legislation and policy

Environmental legislations for water and soil aim at the protection of quality of these compartments. This legislation has major consequences for product registration, amongst others the setting of environmental quality standards. A thorough risk assessment at registration of all products is crucial for the proper operationalisation of the environmental policy. A regulatory problem arises when the registration procedure is harmonised at a European level by the communautarian authority, while the authorities at the national level are responsible for maintaining the desired environmental quality. This problem can be tackled in two ways: firstly, the environmental risk assessment (ERA) should be based on common principles based on EU regulations and policy that steer the national authorities; secondly, the ERA should be developed under the supervision of competent authorities. Both options are not reflected in the forging of the ERA for medicines and feed additives. The formalisation of the contents and the procedure is not transparent nor open to input by scientists and other interested parties; the formalisation has no legal status, and European legislation cannot provide common protection goals in a global setting. The VICH Phase I and the EMEA Phase II guidance do not contain all communautarian environmental quality criteria, nor clear acceptability standards, nor harmonised methodology. Assessments are not made for all products, and the decision-making principles and practical procedures are not operational. It is therefore unlikely that any result of an ERA can be taken into consideration at registration, which undermines the legitimacy of the process. Both applicants and assessors are uncertain how to perform the risk assessment. The current developments may ultimately not only compromise product availability but also fail to protect the environment.     

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。     

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.     

欧盟仿制药参比制剂检索与确认简介（英文）

参比制剂的选择是仿制药开发和研究的一个重要环节。国家食品药品监督管理总局相关公告明确了用于仿制药质量与疗效一致性评价或仿制药申请时的参比制剂应为原研药品或国际公认的同种药物。为了帮助国内外仿制药企业正确检索和确定欧盟的参比制剂,本文详细介绍了欧盟药品的四种审评方式及相应的上市产品目录。同时以检索仿制药米非司酮片(200mg)在欧盟上市申请时须选用的参比制剂为例,结合不同的上市产品目录详细介绍了检索和确定欧盟仿制药的参比制剂过程。     

Environmental risk assessment for new human pharmaceuticals in the European Union according to the draft guideline/discussion paper of January 2001

Since 1993, an environmental risk assessment (ERA) for a new drug application has been stipulated by EU Directive 93/39/EEC amending Directive 65/65/EEC. In early 2001, after several unpublished draft versions for an ERA guideline, a draft guideline/discussion paper for an ERA for non-GMO-containing drugs was published by the European Medicines Evaluation Agency (EMEA). The draft guideline describes a step-wise, tiered procedure for the ERA. The first tier consists of deriving a crude predicted environmental concentration (PEC) in the aquatic compartment for the active pharmaceutical ingredient (API) or its major metabolites, based on predicted amounts used and specific removal rates in sewage treatment or surface waters. If this crude PEC is <0.01 microg/l and no environmental concerns are apparent, no further assessment is deemed necessary. Else, in the second tier, a crude predicted no-effect level (PNEC) for the aquatic compartment is to be extrapolated by dividing the lowest 50%-effect concentration from acute ecotoxicity tests with algae, daphnia or fish (EC(50), LC(50)) by an assessment factor (usually 1000). If the ratio PEC/PNEC is <1, no further assessment is deemed necessary. Lastly, in the third tier, further considerations on a case-by-case basis are needed. This may encompass refining the environmental fate information and thereby the PEC, considering further environmental compartments and their respective PECs (up to and including field studies), but also refining the PNEC. While the ERA addresses mainly the API, excipients of the formulated drug should be considered as well. In the case of medicinal products, the benefit for patients has relative precedence over environmental risks, meaning that even in the case of an unacceptable residual risk for new drugs after third-tier considerations, prohibition of a new API is not taken into consideration. Instead, possible mitigating or precautionary safety measures may consist of specific product labelling (i.e. package leaflets for the patients regarding returning and proper disposal of unused medicines), restricted use through in-hospital or in-surgery administration under supervision only, or the recommendation of environmental analytical monitoring up to ecological field studies.     

Rules governing pharmaceuticals in the European Community

In the interest of public health, the European community has progressively established common scientific criteria for the evaluation of human and veterinary medicines and harmonized the national authorization procedures. One major consequence of this has been that neither the tests and trials carried out to obtain authorization nor batch controls need be repeated within the European community. Henceforth the pharmaceutical industry may benefit from two types of procedures intended to facilitate the registration of their medicinal products in the member states. One, reserved for biotechnology/high technology medicinal products, involves community coordination prior to any national decision together with special protection against copies for ten years, irrespective of the position under patent law. The other enables firms to request the recognition by the other member states of an authorization previously granted by one member state. The experience gained from these two procedures will lead to the choice of the most appropriate European registration procedure for the next decade. In the interests of the European consumer, cooperation between the 12 member states and the Commission of the European Communities has progressively increased within the Committee for Proprietary Medicinal Products (adverse effects of medicines/pharmacovigilance) and the Committee for Veterinary Medicinal Products (residues). In association with these committees, several working groups of experts attempt to approximate and codify practices in the evaluation of the quality, safety, and efficacy of medicinal products (guidelines).(ABSTRACT TRUNCATED AT 250 WORDS)     

德国和日本药品上市许可持有人制度下的药品损害事件风险管理研究

目的：研究德国和日本两国药品上市许可持有人制度下的药品损害事件风险管理,为构建并完善我国的药品损害事件风险管理体系提供建议和参考。方法：通过文献分析法,对比研究德国和日本药品上市许可持有人制度下药品损害事件的法律责任适用、临床试验损害的补偿机制及上市后药品不良反应的救济机制制度。结果与结论：德国的药品损害事件适用于药品损害责任和侵权责任,临床试验和上市后药品损害的风险管理措施均为保险手段;日本的药品损害事件适用于侵权责任和产品责任,临床试验和上市后药品损害的风险管理措施为保险加救济手段。德国的风险管理措施相对平衡地照顾到了企业的承担能力和受害人的合法权益,值得我国参考和学习。     

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。     

The evolving horizon of drug registration — Europe and beyond

Summary The thalidomide tragedy gave rise to national drug regulation without thought to international harmonization. Thus from the early days of the European Community (EC), there has been a barrier to the free movement of medicinal products. Previous attempts have failed to resolve the problem and the European Commission is currently involved in attempting to establish Community drug legislation which will remove these barriers and create a single internal market.The Commission advocates two procedures (a centralized and a decentralized) largely under the control of the Committee for Proprietary Medicinal Products (CPMP) within the framework of a new European Agency for the Evaluation of Medicinal Products. The present authority of the Commission to make decisions binding on all 12 Member States will be utilized by the CPMP.While the present draft legislation should create significant improvement towards the goal of a single market, it contains some areas of potential concern. That this major venture should be a success is not only critical to the EC economy, its research-based pharmaceutical industry and the health care of its citizens but also to the achievement of global harmonization for pharmaceutical marketing authorization for which there is much evidence of enthusiasm and desire.     

Proposals for model-based paediatric medicinal development within the current European Union regulatory framework

The new paediatric European Union (EU) regulation and the consequent demand for paediatric studies on one hand and the ethical need for minimizing the burden of studies in children on the other hand necessitate optimal techniques in the assessment of safety/efficacy and use of drugs in children. Modelling and simulation (M&S) is one way to circumvent some difficulties in developing medicinal products in children. M&S allows the quantitative use of sparse sampling, characterization and prediction of pharmacokinetics/ pharmacodynamics (PK/PD), extrapolation from adults to children, interpolation between paediatric age subsets, optimal use of scientific literature and in vitro/preclinical data. Together, industry, academia and regulators recognize the usefulness of modelling and simulation in this setting. However, even if M&S is an emerging science, its integration in the EU regulatory decision making is for the time being deficient and M&S expertise is concentrated in big pharmaceutical companies and academic institutions. The European Medicines Agency, acknowledging all the above conditions, organized and hosted a Workshop on Modelling in Paediatric Medicines. The article presents the personal views of the authors on the issues presented and discussed in the workshop. We attempt to identify the regulatory framework for the use of M&S in paediatric medicinal development and to make proposals for model-based paediatric medicinal development. The objective is to open the discussion between industry, academia, paediatricians and regulators on the optimal use of M&S in paediatric medicinal development.     

The risk-based approach to ATMP development – Generally accepted by regulators but infrequently used by companies

Advanced therapy medicinal products (ATMPs) are the cutting edge of drug innovation. ATMPs have different challenges than other drug classes. To accommodate these challenges and facilitate science-driven development, flexibility in the requirements to demonstrate the safety and efficacy of this rapidly evolving drug class is necessary. To create flexibility, the European Union introduced the risk-based approach. This approach provides the possibility of omitting guideline-based studies based on risk analyses. To gain insight into the effect of the risk-based approach on the non-clinical development of ATMPs, two questions are addressed in this paper. Firstly, “Do companies use a risk-based approach for the non-clinical development of ATMPs?” and, secondly, “Does the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) accept non-clinical development programs based on the risk-based approach?” Scientific advice letters formulated by the CHMP were analyzed. The risk-based approach was used to justify deviations from the guidelines in the majority (75%) of the cases. The CHMP accepted 40% of the proposals to omit studies and stated that additional data was necessary to make an informed decision for 35% of the proposals. This indicates that the risk-based approach facilitates the science-driven development of ATMPs.     

Preclinical Development of Cell-Based Products: a European Regulatory Science Perspective

Purpose

This article describes preclinical development of cell-based medicinal products for European markets and discusses European regulatory mechanisms open to developers to aid successful product development. Cell-based medicinal products are diverse, including cells that are autologous or allogeneic, have been genetically modified, or not, or expanded ex vivo, and applied systemically or to an anatomical site different to that of their origin; comments applicable to one product may not be applicable to others, so bespoke development is needed, for all elements - quality, preclinical and clinical.

Methods

After establishing how the product is produced, proof of potential for therapeutic efficacy, and then safety, of the product need to be determined. This includes understanding biodistribution, persistence and toxicity, including potential for malignant transformation. These elements need to be considered in the context of the intended clinical development.

Results

This article describes regulatory mechanisms available to developers to support product development that aim to resolve scientific issues prior to marketing authorization application, to enable patients to have faster access to the product than would otherwise be the case.

Conclusions

Developers are encouraged to be aware of both the scientific issues and regulatory mechanisms to ensure patients can be supplied with these products.