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Older people are often affected by impaired organ and bodily functions resulting in multimorbidity and polypharmacy, turning them into the main user group of many medicines. Very often, medicines have not specifically been developed for older people, causing practical medication problems for them like limited availability of easy to swallow formulations, easy to open packaging and dosing instructions for enteral administration. In 2020, the European Medicines Agency (EMA) published a reflection paper 'Pharmaceutical development of medicines for use in the older population', which discusses how the emerging needs of an ageing European population can be addressed by medicines regulation. The paper intends to help industry to better consider the needs of older people during pharmaceutical/clinical medicines development by summarising data on the most relevant topics, providing early suggestions on how to move forward and prompting expert discussions and studies into knowledge gaps. Topics include patient acceptability, (dis)advantages of an administration route, formulation, dosage form, packaging, dosing device and user instruction. While the paper is directed at older people and the pharmaceutical industry, the reflections are also relevant to younger patients with similar disease‐related needs and of value to other stakeholders parties, e.g., healthcare professionals, academics, patients and caregivers, as the paper makes clear what can be expected from industry and where collaborative work is needed. This commentary provides an overview of the different steps in the development of the reflection paper, discusses points considered most controversial and/or subject to (multidisciplinary) expert discussions and indicates their value for real world clinical practice. [ABSTRACT FROM AUTHOR]

The recent benefit–risk framework (BRF) developed by the Food and Drug Administration (FDA) is intended to improve the clarity and consistency in communicating the reasoning behind the FDA's decisions, acting as an important advancement in US drug regulation. In the PDUFA VI implementation plan, the FDA states that it will continue to explore more structured or quantitative decision analysis approaches; however, it restricts their use within the current BRF that is purely qualitative. By contrast, European regulators and researchers have been long exploring the use of quantitative decision analysis approaches for evaluating drug benefit–risk balance. In this paper, we show how quantitative modelling, backed by decision theory, could complement and extend the FDA's BRF to better support the appraisal of evidence and improve decision outcomes. After providing relevant scientific definitions for benefit–risk assessment and describing the FDA and European Medicines Agency (EMA) frameworks, we explain the components of and differences between qualitative and quantitative approaches. We present lessons learned from the EMA experience with the use of quantitative modelling and we provide evidence of its benefits, illustrated by a real case study that helped to resolve differences of judgements among EMA regulators. [ABSTRACT FROM AUTHOR]

Therapeutic use of an unauthorised drug (or of an authorised drug for an unauthorised indication) for patients with a life-threating disease is permitted outside a clinical trial as an Expanded Access Programme (EAP).The regulations regarding EAPs is not the same all over the world. For example, the recommendation of the European Medicines Agency (EMA) in EU countries also includes within EAPs patients who have been treated in a clinical trial and who wish to continue the treatment. Nevertheless, the patients treated in a clinical trial could have the option of continuing treatment for an extended period in an Open-label Extension study, aimed to generate long-term data on efficacy, safety, tolerability and administration.The aims of this paper - based on the difficulties and incoherence encountered by an Italian Ethic Committee (EC) during the authorisation process of EAPs - are: understanding the origin of this misclassification by analysing differences and similarities among USA, European and Italian regulations concerning EAPs; and showing difficulties in classifying international study protocols as a consequence of the lack of harmonisation of definitions.We performed a critical review of the current USA, European and Italian regulations and we analysed some practical cases by retrieving protocols from Clinicaltrials.gov and the Italian Clinical Trials Registry (OsSC) containing in the title the keywords 'Expanded Access Programme', "'Expanded Access', 'Open-label Extension study' or 'Early Access'.We observed that the Food and Drug Administration ( FDA) definition of EAP is very clear while the EMA definition is similar to that of an Open-label Extension study. This lack of a clear definition generates misclassification and it is possible to find an EAP with an efficacy or safety endpoint; or an EAP managed as a clinical trial; or an EAP classified in Clinical Trials Registries as a phase II, III or IV clinical trial.The internationalisation of the studies requires a harmonisation on a global level of legislation and definitions to eliminate misclassification of protocols. For this reason, the authors suggest that: a) the EMA definition should be harmonised with the FDA definition of EAPs, b) European regulation, even if optional, should be adopted in a compulsory way by national regulations. Moreover, separate registries for both EAPs and clinical trials should be organised. [ABSTRACT FROM AUTHOR]

Pharmaceutical residues can harm the environment. Therefore any Marketing Authorisation Application (MAA) for a medicinal product for human use shall be accompanied by an "indication of any potential risks presented by the medicinal product for the environment" according to Article 8(3)(g) of the Directive 2001/83/EC. Since 2006 a guideline document from the European Medicines Agency (EMA, formerly EMEA) is available for this task, which is now called the "Environmental Risk Assessment" (ERA). Recently the EMA released a draft revision of an updated ERA guideline. The present paper provides a summary of the intended innovation. A number of options have been discontinued, but some of them cannot be easily recognised, even though they are potentially affecting the MAA and its costs in a relevant way. A new specifically tailored experimental testing course for antibiotics and a secondary poisoning assessment is introduced. The selection of required study types is altered and the environmental fate evaluation is adapted to the scientific progress. In the recent situation it is suggested that marketing authorisation applicants may reconsider the conduct of water/sediment studies for substances not requiring these according to the guideline revision. The new tailored testing approach for antibiotics avoids any vertebrate use, because it demands no fish study, therefore it may be applied henceforth. If the new prescriptions are not yet in force at the point in time of the MAA submission, appropriate waivers should be stated in the ERA. No further HPLC-study types and acute earthworm toxicity tests should be performed, since the guideline update draft does not accept them. In preclinical toxicity and pharmacokinetic studies, additional data gathering on metabolites should be considered in order to avoid unnecessary leaflet warnings. The cost for ERA may change significantly, with a tendency to increase for generic pharmaceutical MAA, but with a possible reduction for substances of low environmental concern. Earlier consideration of ERA in the drug development process is recommended. [ABSTRACT FROM AUTHOR]

New European Union (EU) pharmacovigilance legislation, effective from July 2012, introduced new concepts and procedures to optimise the way medicines are regulated within the Union and provided new channels for public health interventions. Triggered by the EU legislation, the work done by the International Conference on Harmonisation (ICH) has provided a common standard for periodic benefit-risk evaluation reporting within the ICH regions. The present paper provides a review of the concepts behind the use of periodic benefit-risk evaluation reports (PBRER) in supporting safety evaluation and assessment of benefit-risk balance and covers essential points in the documentation of safety information, risk evaluation and benefit-risk assessment. The review incorporates the experience to-date with the PBRER at EU level led by the Pharmacovigilance Risk Assessment Committee of the European Medicines Agency. The scope of the PBRER, the main content topics and the challenges relevant to the different stakeholders are highlighted together with key success factors for the report to deliver its objectives and maximise the use of the regulatory assessment procedure. It is clear that the PBRER extends beyond new ways of data presentation and analysis and reflects a further shift in pharmacovigilance in the EU towards more integrated benefit-risk assessment of marketed medicines. [ABSTRACT FROM AUTHOR]

The development of specific drug therapy for children was a paradigm‐changing event that transformed paediatric medical practice. However, a series of tragedies involving drug treatment for children resulted in a gap developing between drug regulation and practice, with the majority of drugs used in child healthcare being used off‐label, rendering children therapeutic orphans. Over the past two decades changes in drug regulation led by the US Food and Drug Administration and followed by the European Union's European Medicines Agency have led to substantial changes in how new drugs with potential use in children are studied and labelled. While these changes have substantially improved labelling for new drugs, there has been much less progress with older drugs. Although the unique challenges of conducting clinical research in children have been addressed by novel clinical trial designs, many of these innovations have not been translated into approaches accepted for the drug approval process. The regulations applying to the need for paediatric studies currently are only applicable in the United States and the European Union, and there is less impetus for paediatric labelling in other jurisdictions. This impacts on a number of issues beyond labelling, including the availability of child‐friendly formulations. Finally, the impact of Brexit on paediatric drug studies in the UK remains unclear and is subject to ongoing negotiations between the UK government and the European Union. [ABSTRACT FROM AUTHOR]

Chinese herbal medicines (CHMs) have unique advantages in the prevention and treatment of diseases, which are widely recognized in the world. More and more CHMs are becoming increasingly popular in the international markets. However, the quality control of CHMs is a significant issue for their acceptance and recognition in the international market. This review mainly focuses on the quality requirements for CHMs to enter the European Union (EU) market. Both Chinese and European regulations and quality controls are compared. Firstly, the EU medicinal regulatory system and relevant regulations were reviewed. Secondly, the key factors of the quality control of CHMs, including Chinese herbal drugs, extracts and products were compared with those of European herbal medicines in the EU market. Subsequently, three main registration routes for herbal medicinal products including Chinese herbal medicinal products entering the EU were introduced. Furthermore, the legal status of traditional Chinese medicine granules in the EU was also discussed. Through the comparison of the key quality factors for CHMs in China and the EU, the similarities and differences in terms of quality requirements and regulations are addressed, which provides a reference for the development of CHMs into the EU market. [ABSTRACT FROM AUTHOR]

The article focuses on various initiatives by the European Union (EU) to deal with medication errors. It mentions the workshop organised by the European Medicines Agency (EMA) on February 28 and March 1, 2013 to raise knowledge regarding the issue and form proposals to enhance reporting and prevention of such incidences. It tackles the European pharmacovigilance law which widened the meaning of adverse reactions to medical products, such as those induced by medication errors.

Based on an analysis of relevant laws and policies, regulator data portals, and information requests, we find that clinical data, including clinical study reports, submitted to the European Medicines Agency and Health Canada to support approval of medicines are routinely made publicly available. [ABSTRACT FROM AUTHOR]

Purpose: Various incentives are provided by the European Medicines Agency (EMA) to facilitate the development and marketing of orphan drugs. A 10-year period of market exclusivity is reserved to an orphan medicinal product. Sometimes, the sponsor renounces the designation before the expiration of that standard period. Our aim was to focus on these premature withdrawals. Methods: We retrieved all the molecules included in the Community Register of Orphan Medicinal Products for Human Use from 2000 to November 2020. We considered the active substance, therapeutic indication, sponsor, year of designation, year of approval of the corresponding medicinal product, and that of the withdrawal of the orphan designation, if occurred. Results: Overall, 2350 orphan designations were approved from 2000 to November 2020. Of these, 141 have been marketed. Premature withdrawal of orphan designation concerned 23 drugs (20 being antineoplastic agents), corresponding to 16 medicinal products. These withdrawals occurred after almost 2 years (range <1–7 years). Conclusions: A not negligible fraction of marketed orphan medicinal products underwent premature removal of their orphan designation. No motivation is requested by the EMA for this renouncement, although the peculiarity of the orphan medicinal products would need a greater transparency. We can only speculate about possible compensations in support of this decision, for instance in terms of commercial agreements between pharmaceutical companies, giving way to alternative products, as a couple of examples suggest. An open debate on this topic among members of academia, regulatory bodies, price and reimbursements committees, and pharmaceutical industry representatives will be welcome. [ABSTRACT FROM AUTHOR]

Scientific advice (SA) is an important tool offered by regulators to help developers generate robust evidence on a medicine's benefits and risks. Drawing on accumulated experience and looking at the SA provided by the European Medicines Agency in 2018 to advanced therapy medicinal products originally developed by public bodies, we discuss most commonly raised issues and the complexity and timings of the questions posed. Earlier and more frequent SA could help advanced therapy medicinal product developers to pre‐empt delays at the marketing authorisation stage. Carefully addressing quality and nonclinical issues before entering the pivotal phase of development will clear the path for a smooth clinical development and successful marketing authorisation. [ABSTRACT FROM AUTHOR]

Purpose: To review the marketing authorization of biosimilars and provide a critical analysis of the pivotal trials supporting their approval by the European Medicines Agency (EMA). Methods: EMA website to identify the biosimilars approved up to July 2019 and the European Public Assessment Report for information on pivotal trial design, duration, intervention and control, primary outcome, data on immunogenicity, and comparability margins. Results: The EMA has approved 55 biosimilars (62% in 2017–2019) of 16 biologic products, used in several clinical indications. Some biosimilars were licensed as multiple products, with different commercial names, by the same or different companies. The comparability exercise and subsequent approval of 49/55 (89%) biosimilars were based on one or more pivotal phase III trials testing their clinical efficacy. In all, biosimilars were approved on the basis of 55 trials, mostly phase III (42/55, 76%) assessing clinical efficacy; these were mainly equivalence trials (31/55, 56%). The pivotal phase III trials assessed surrogate measures of clinical effect, and 71% reported immunogenicity data. Conclusion: Analysis of the approval of biosimilars in Europe depicts a complex and heterogeneous scenario. The requirement for showing similarity in terms of clinical efficacy and safety provides a robust demonstration of comparable clinical outcomes but lays a burden on biosimilar manufacturers and may delay the introduction of the drugs. The development, licensing, and monitoring of biosimilars would benefit from new strategies to accelerate access to these drugs while reducing uncertainties about their use in practice. [ABSTRACT FROM AUTHOR]

The European Union (EU) Paediatric Regulation requires that all new medicinal products applying for a marketing authorisation (MA) in the EU provide a paediatric investigation plan (PIP) covering a clinical and non-clinical trial programme relating to the use in the paediatric population, unless a waiver applies. Conducting trials in children is challenging on many levels, including ethical and practical issues, which may affect the availability of the clinical evidence. In scientifically justified cases, extrapolation of data from other populations can be an option to gather evidence supporting the benefit-risk assessment of the medicinal product for paediatric use. The European Medicines Agency (EMA) is working on providing a framework for extrapolation that is scientifically valid, reliable and adequate to support MA of medicines for children. It is expected that the extrapolation framework together with therapeutic area guidelines and individual case studies will support future PIPs. Extrapolation has already been employed in several paediatric development programmes including biological treatment for immune-mediated diseases. This article reviews extrapolation strategies from MA applications for products for the treatment of juvenile idiopathic arthritis, paediatric psoriasis and paediatric inflammatory bowel disease. It also provides a summary of extrapolation advice expressed in relevant EMA guidelines and initiatives supporting the use of alternative approaches in paediatric medicine development. [ABSTRACT FROM AUTHOR]

The article focuses on the developments in the regulation of pharmaceutical industry. Topics discussed include guidance for importers of medicinal products, International Conference on Harmonisation (ICH), guidelines on the implementation of accelerated assessment and conditional marketing authorisation by European Medicines Agency (EMA), guidelines from Great Britain Medicines and Healthcare Products Regulatory Agency (MHRA) and the U.S. Food and Drug Administration.

The active-controlled trial with a non-inferiority design has gained popularity in recent years. However, non-inferiority trials present some methodological challenges, especially in determining the non-inferiority margin. Regulatory guidelines provide some general statements on how a non-inferiority trial should be conducted. Moreover, in a scientific advice procedure, regulators give companies the opportunity to discuss critical trial issues prior to the start of the trial. The aim of this study was to identify potential issues that may benefit from more explicit guidance by regulators. To achieve this, we collected and analyzed questions about non-inferiority trials posed by applicants for scientific advice in Europe in 2008 and 2009, as well as the responses given by the European Medicines Agency (EMA). In our analysis we included 156 final letters of advice from 2008 and 2009, addressed to 94 different applicants (manufacturers). Our analysis yielded two major findings: (1) applicants frequently asked questions ‘whether’ and ‘how’ to conduct a non-inferiority trial, 26% and 74%, respectively, and (2) the EMA regulators seem mainly concerned about the choice of the non-inferiority margin in non-inferiority trials (36% of total regulatory answers). In 40% of the answers, the EMA recommended using a stricter margin, and in 10% of the answers regarding non-inferiority margins, the EMA questioned the justification of the proposed non-inferiority margin. We conclude that there are still difficulties in selecting the appropriate methodology for non-inferiority trials. Straightforward and harmonized guidance regarding non-inferiority trials is required, for example on whether it is necessary to conduct such a trial and how the non-inferiority margin is determined. It is unlikely that regulatory guidelines can cover all therapeutic areas; therefore, in some cases regulatory scientific advice may be used as an opportunity for tailored advice. [ABSTRACT FROM AUTHOR]

In 2005, new European legislation authorised Regulatory Agencies to require drug companies to submit a risk management plan (RMP) comprising detailed commitments for post-marketing pharmacovigilance. The aim of the study is to describe the characteristics of RMP for 15 drugs approved by the European Medicines Agency (EMA) and their impact on post-marketing safety issues. Of the 90 new Chemical Entities approved through a centralised procedure by the EMA during 2006 and 2007, 15 of them were selected and their safety aspects and relative RMPs analysed. All post-marketing communications released for safety reasons related to these drugs were also considered. A total of 157 safety specifications were established for the drugs assessed. Risk minimisation activities were foreseen for 5 drugs as training activities. Post-marketing safety issues emerged for 12 of them, leading to 39 type II variations in Summary of Product Characteristics (SPC). Nearly half of such variations, 19 (49%), concerned safety aspects not envisaged by the RMPs. Besides this, 9 Safety Communications were published for 6 out of 15 drugs assessed. The present study reveals several critical points on the way RMPs have been implemented. Several activities proposed by the RMPs do not appear to be adequate in dealing with the potential risks of drugs. Poor communication of risk to practitioners and to the public, and above all limited transparency for the total assessment of risk, seem to transform RMPs into a tool to reassure the public when inadequately evaluated drugs are granted premature marketing authorisation. [ABSTRACT FROM AUTHOR]

The article presents a study concerning the regulation of orphan or special drugs in Europe. It states that orphan drugs are pharmaceutical produces which are indicated for the prevention, diagnosis and treatment of rare diseases. It mentions that the Committee for orphan medical product (COMP) of the European Medicines Agency (EMEA) is authorized to designate a drug as orphan.

The article discusses the process of evaluating new medicines in Europe conducted by regulatory authorities (RAs). It notes on the need for a greater transparency for medical regulations which has been advocated by public and scientific communities and is significant to understand the reasons on certain procedures for a successful or failed application. It indicates that the European Union (EU) has obliged the European Medicines Agency (EMA) to disclose information of drug applications.

The article focuses on the implementation of a regulation on medicinal products for pediatric use by the European Union. According to the European Federation of Pharmaceutical Industries and Associations, more medicines will soon be available across Europe, which will change the region's research and development environment. The 2007 agenda of the European Medicines Agency (EMEA) is discussed. Key information on the agency tasks for EMEA are presented.

New regulatory guidance documents from the United States Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have recently been finalized or are in draft format outlining new pathways for preclinical safety testing. The US and the European Union appear to be moving in a similar direction focussing and refining preclinical safety data requirements for both radiodiagnostics and radiotherapeutics. We here summarize these recent documents from both the US and European perspective. [ABSTRACT FROM AUTHOR]