Severely compromised supply of patch test allergens in Europe hampers adequate diagnosis of occupational and non-occupational contact allergy. A European Society of Contact Dermatitis (ESCD), European Academy of Allergy and Clinical Immunology (EAACI), European Academy of Dermatology and Venereology (EADV) task forces 'Contact Dermatitis' and 'Occupational Skin Disease' position paper.

Patch testing is the only clinically applicable diagnostic method for Type IV allergy. The availability of Type IV patch test (PT) allergens in Europe, however, is currently scarce. This severely compromises adequate diagnostics of contact allergy, leading to serious consequences for the affected patients. Against this background, the European Society of Contact Dermatitis (ESCD) has created a task force (TF) (i) to explore the current availability of PT substances in different member states, (ii) to highlight some of the unique characteristics of Type IV vs. other allergens and (iii) to suggest ways forward to promote and ensure availability of high-quality patch testing substances for the diagnosis of Type IV allergies throughout Europe. The suggestions of the TF on how to improve the availability of PT allergens are supported by the ESCD, the European Academy of Allergy and Clinical Immunology, and the European Academy of Dermatology and Venereology and intend to provide potential means to resolve the present medical crisis.

Trends in the utilization of medicines sold in the private sector post- registration in South Africa and the implications for similar countries.

BACKGROUND: Regulatory authorities register medicines for patients to access them within a reasonable period of time. There is a paucity of available data regarding the extent to which registered medicines reach the public after market authorisation is granted by the South African Health Products Regulatory Authority (SAHPRA). This is important since time spent by SAHPRA assessing medicines that are subsequently not launched onto the South African market means time wasted, which could be spent on assessing new medicines that address an unmet need in the country. Consequently, we initially analysed the time taken for registered medicines to reach patients and the relationship between medicines registered at SAHPRA and those subsequently dispensed in private pharmacies. The extent of registration of multiple sourced versus new patented medicines was also explored. METHODS: A retrospective, descriptive and quantitative investigation was conducted for medicines registered between 2014 and 2019. Registered and dispensed medicines were compared to establish accessibility post registration. Data sources included SAHPRA and IQVIA datasets. Microsoft Excel and SAS were used for data storage, analysis, and computation of descriptive statistical analysis. RESULTS: Of (N = 2175) registered medicines, only 358 (16.5%; 95% CI 15.0%-18.1%) were dispensed to patients, and out of 1735 medicines registered between 2015 and 2019, only 57 (3.3%; 95% CI 2.5%-4.2%) were dispensed during the study period. Medicines acting on the central nervous system were registered and dispensed the most at 21.0% and 18.0%, respectively, whereas antineoplastic and immunomodulation agents were registered and dispensed only 11% and 5%, respectively. A concern was that only 13.0% of registered medicines were originators, with most either as generics, including branded generics, or pseudo-generics. CONCLUSION: Regulatory measures should be implemented to ensure increased medicine access post-registration for new originators, especially for priority disease areas that benefit patients. Mental health diseases and improved access to oncology medicines require special attention and further investigation in South Africa.

The impact of accuracy and precision of analytical test methods on the determination of withdrawal periods.

Treatment of food-producing animals with veterinary medicinal products (VMPs) can result in residues in foodstuffs (e.g. eggs, meat, milk, or honey) representing a potential consumer health risk. To ensure consumer safety, worldwide regulatory concepts for setting safe limits for residues of VMPs e.g. as tolerances (US) or maximum residue limits (MRLs, EU) are used. Based on these limits so-called withdrawal periods (WP) are determined. A WP represents the minimum period of time required between the last administration of the VMP and the marketing of foodstuff. Usually, WPs are estimated using regression analysis based on residue studies. With high statistical confidence (usually 95% in the EU and 99% in the US) the residues in almost all treated animals (usually 95%) have to be below MRL when edible produce is harvested. Here, uncertainties from both sampling and biological variability are taken into account but uncertainties of measurement associated with the analytical test methods are not systematically considered. This paper describes a simulation experiment to investigate the extent to which relevant sources of measurement uncertainty (accuracy and precision) can impact the length of WPs. A set of real residue depletion data was artificially 'contaminated' with measurement uncertainty related to permitted ranges for accuracy and precision. The results show that both accuracy and precision had a noticeable effect on the overall WP. Due consideration of sources of measurement uncertainty may improve the robustness, quality and reliability of calculations upon which regulatory decisions on consumer safety of residues are based.

Environmental risk assessment of advanced therapies containing genetically modified organisms in the EU.

Gene therapy medicinal products have the potential to provide curative treatment for many diseases with current limited therapeutic options. As advanced therapy medicinal products (ATMPs), these therapies undergo a centralised, single European Union authorisation by the European Medicines Agency (EMA), but the risks and potential harm to the environment and population at large are weighted in each application, and different interpretations at national level exist. A streamlined procedure is now in place to facilitate a consistent approach for the assessment of the environmental risks of medicines containing genetically modified organisms for both clinical trial applications and marketing authorisation applications. This article provides an overview of basic requirements across the EU, an overview of the new streamlined process and discusses available guidance for developers with particular emphasis on marketing authorisation applications. All these initiatives are aimed to remove hurdles for ATMP developers and facilitate faster access to patients.

The contribution of field efficacy studies to the evaluation of applications for veterinary vaccines evaluated through the European Union centralised authorisation procedure.

To examine the contribution that field efficacy studies made to the assessment of marketing authorisation (MA) applications, a retrospective analysis was conducted for 100 veterinary vaccines that had been evaluated by the European Medicines Agency (EMA) between 1996 and 2017. For 52 veterinary vaccines, scrutiny of the European Public Assessment Report (EPAR) and/or the summary of product characteristics (SPC) identified objective evidence that field efficacy studies made an important or substantial impact on the efficacy claims and/or benefit-risk evaluation. For 24 applications, the contribution of field efficacy studies was classified as either supportive or was not detectable from the publicly available documents on which the analysis was based. For a further 24 applications, data exemptions were applied and the MAs were granted in the absence of field studies. The difficulty in achieving challenge in the field was highlighted by the observation that natural exposure was reported in less than half of the applications where field efficacy studies were conducted (34 out of 76). This analysis may help to inform policy decisions on the role, conduct and contribution that field efficacy studies make to the assessment of efficacy for veterinary vaccines.

[Combination therapies in immuno-oncology: differentiated regulatory approaches]. / Kombinationstherapien in der Immunonkologie: Differenzierte regulatorische Herangehensweisen.

Combination therapies of different drugs are an integral part of medicine. However, there is a scientific and regulatory need to understand the contribution of each drug to the overall effect, i.e., nonclinical and clinical development programs have to consider these aspects and need to be designed accordingly. Many drugs are currently under development that attempt to control malignant diseases in the long term by using and activating components of the patient's own immune system. The term immuno-oncology is often used in this context. Medicines that are developed and used for immuno-oncology can be assigned to completely different classes of medicines.This article provides an analysis of combination therapies in immuno-oncology with medicinal products produced by biotechnological manufacturing. This encompasses checkpoint inhibitors, genetically modified cell therapies, tumor vaccines, and oncolytic viruses. The challenges in clinical development are demonstrated on the basis of this heterogenous group of approved immuno-oncological drugs that have been investigated in combination therapies. Due to the different characteristics and number of combination partners, an individually tailored program must be designed for each development program and there is no standard solution.

Regulatory and Evidence Requirements and the Changing Landscape in Regulation for Marketing Authorisation.

In this chapter, we describe the changing landscape of the EU pharmaceutical legislation concerning regulation and evidence requirements for marketing authorisation. First, we describe the legal requirements for marketing authorisation and the development of EU pharmaceutical legislation and the concept of risk-benefit balance. Second, we describe special types of authorisation, such as conditional approval and approval under exceptional circumstances, and special provisions such as incentives for orphan medicinal products and paediatric investigational plans. Lastly, we describe the available methodological guidelines focussing on choice of endpoints.

Early access to health products in France: Major advances of the French "Conseil stratégique des industries de santé" (CSIS) to be implemented (modalities, regulations, funding).

In a context of perpetual evolution of treatments, access to therapeutic innovation is a major challenge for patients and the various players involved in the procedures of access to medicines. The revolutions in genomic and personalized medicine, artificial intelligence and biotechnology will transform the medicine of tomorrow and the organization of our health system. It is therefore fundamental that France prepares for these changes and supports the development of its companies in these new areas. The recent "Conseil stratégique des industries de santé" launched by Matignon makes it possible to propose a regulatory arsenal conducive to the implementation and diffusion of therapeutic innovations. In this workshop, we present a number of proposals, our approach having remained pragmatic with a permanent concern to be effective in the short term for the patients and to simplify the procedures as much as possible. This was achieved thanks to the participation in this workshop of most of the players involved (industrial companies, "Agence nationale de sécurité du médicament et des produits de santé", "Haute Autorité de santé", "Institut national du cancer", "Les entreprises du médicament", hospitals, "Observatoire du médicament, des dispositifs médicaux et de l'innovation thérapeutique"…). The main proposals tend to favor the implementation of clinical trials on our territory, especially the early phases, a wider access to innovations by favoring early access programs and setting up a process called "autorisation temporaire d'utilisation d'extension" (ATUext) that make it possible to prescribe a medicinal product even if the latter has a marketing authorisation in another indication. In addition, we propose a conditional reimbursement that will be available based on preliminary data but will require re-evaluation based on consolidated data from clinical trials and/or real-life data. Finally, in order to better carry out these assessments, with a view to access or care, we propose the establishment of partnership agreements with health agencies/hospitals in order to encourage the emergence of field experts, in order to prioritize an ascending expertise closer to patients' needs and to real life.

Pharmaceutical issues during the review of European Marketing Authorisation Applications in Malta.

The aim of this study was to identify pharmaceutical issues encountered during regulatory review in European Procedures. A database of issues from Day 70 assessment reports of 150 EU procedures was compiled; most procedures were for generics (108). Frequencies of common deficiencies have been calculated and summarised for use of all stakeholders. Out of the 150 procedures reviewed, covering 309 products, a total of 4796 concerns were identified. Of these concerns, 167 were Potential Serious Risks to Public Health, 67 were raised on drug substance and 100 on the drug product. The distribution of total concerns was as follows: 2168 concerns on drug substance and 2584 on drug product. Most concerns raised were on control of drug substance and drug product (834 & 626 for 3.2.S.4 and 3.2.P.5, respectively), followed by concerns on the manufacturing (482 & 564 for 3.2.S.2 and 3.2.P.3, respectively) and stability 147 & 398 for 3.2.S.7 and 3.2.P.8, respectively). In conclusion, the frequencies and trends of identified deficiencies together with their impact were discussed from a regulatory point of view. The main findings indicate that applicants would benefit from following published guidelines so that delays in the registration of medicines could be avoided.

[Educational material as part of risk minimisation]. / Schulungsmaterial zur Minimierung von Arzneimittelrisiken.

Educational material, for example in the form of information booklets, checklists, patient alert cards, therapeutic passports, emergency ID cards, or videos, is an important aid for the safe use of a medicinal product or drug and supplements the summary of product characteristics and package information. It is ordered, tested and approved by the competent national authorities, the Federal Institute for Drugs and Medical Devices (BfArM) and the Paul Ehrlich Institute (PEI), and made available by the respective marketing authorization holder and published on the websites of BfArM and PEI. Educational material is part of the marketing authorization of a medicinal product. Since 1 December 2016, officially approved educational material can be recognized by the blue-hand logo in Germany. There is currently specific educational material for 202 active substances with further recommendations on how to avoid or reduce risks for patients. Although educational material is one of the most common additional risk minimisation measures, little is known about its effectiveness, including related process and outcome indicators. Key elements as well as an overview of educational material are described.

Changing paradigms in bioequivalence trials submitted to the EMA for evaluation - A clinical and regulatory perspective.

BACKGROUND: The selection of a robust bioequivalence (BE) study designs for registering a generic product remains still a hard task. This task is still challenging despite the fact that generic products are much needed by health care providers in economical terms. Thus, BE study designs could be a means to allow companies to reduce costs and reach the market earlier. We therefore investigated whether different approaches in various products assessed by the European Medicines Agency during the approval phase resulted in a reduction in resources required to show bioequivalence for different medicinal products. METHODS: European Public Assessment Reports (EPARs) for off-patent medicinal products authorised within the European Union (EU) through the centralised procedure during the period 2007-2015 were retrieved and reviewed to identify the clinical studies that resulted in fewer number of subjects, the number of centres or trial duration versus the two-period crossover design. RESULTS: 7 studies out of 108 were considered as having benefitted from having a different design. Differences noted included having a different dose allocation scheme, having a different number of dosing periods, having a different number of treatment arms, and having one study evaluating different strengths. Benefits noted included a decrease in the number of subjects and centres required, decreases in study duration and a reduced number of studies required to demonstrate bioequivalence. CONCLUSION: Bioequivalence studies can be designed in a specific manner to require fewer resources to carry out. Fewer resources required to register a medicinal product, could impart an advantage to companies (such as to be first on the market) or could even translate to making medicines more accessible (such as cheaper) to patients.

Inconsistent approaches of the G-BA regarding acceptance of primary study endpoints as being relevant to patients - an analysis of three disease areas: oncological, metabolic, and infectious diseases.

BACKGROUND: Previous evaluations of oncological medicines in the German early benefit assessment (EBA) procedure have demonstrated inconsistent acceptance of endpoints by regulatory authorities and the Federal Joint Committee (G-BA). Accepted standard endpoints for regulatory purposes are frequently not considered as patient-relevant in the German EBA system. In this study the acceptance of clinically acknowledged primary endpoints (PEPs) from regulatory trials in EBAs conducted by the G-BA was evaluated across three therapeutic areas. METHODS: Medicines for oncological, metabolic and infectious diseases with EBAs finalised before 25 January 2016 were evaluated. Respective manufacturer's dossiers, regulatory assessments, G-BA appraisals and oral hearing minutes were reviewed, and PEPs were examined to determine whether they were considered relevant to patients by the G-BA. Furthermore, the acceptance of symptomatic vs asymptomatic PEPs was also analysed. RESULTS: A total of 65 EBAs were evaluated. Mortality PEPs were widely accepted as patient-relevant but were only used in a minority of EBAs and exclusively in oncological diseases. Morbidity PEPs constituted around 72 % of assessed PEPs, but were excluded from the EBA in over half of the corresponding assessments as they were not considered patient-relevant. Symptomatic endpoints were largely deemed patient-relevant, whereas acceptance of asymptomatic endpoints varied between therapeutic areas. CONCLUSIONS: This evaluation identified inconsistencies in patient relevance of morbidity-related PEPs as well as in acceptance of asymptomatic endpoints by the G-BA in all three disease areas examined. Better harmonisation between the regulatory authorities and the G-BA is still required after 5 years of AMNOG health technology assessment in Germany.

[Improving drug licensing for children and adolescents : Position paper from the More Medicines for Minors Symposion 8 June 2015 in Bonn]. / Arzneimittelzulassung für Kinder und Jugendliche verbessern : Positionspapier zum Kinderarzneimittel-Symposium am 8. Juni 2015 in Bonn.

In Germany and throughout Europe, medicinal products for adults have been developed and evaluated systematically for decades. Medicinal products for children and adolescents, however, have only been researched for the past ten years. As a result, many medicinal products have been administered to children without systematic clinical trials, for example regarding dosage or pharmaceutical form.EU Regulation 1901/2006 aimes to close the gaps in the medical treatment of children and adolescents. In order to do so, the regulation provides for paediatric use marketing authorisations (PUMA) for previously authorised products no longer covered by intellectual property rights and also grants holders of such PUMA licenses further property rights. However, only two PUMA licenses have been applied for. Thus, the PUMA license instrument is hardly being used despite the fact that many medicinal products have a great potential for closing medical gaps for children and adolescents.In order to improve the situation regarding medicinal products for children and adolescents, this scientific symposium "More Medicines for Minors" intended to promote dialogue among the parties involved and to provide an opportunity to discuss reasons for the reluctance to apply for PUMA licenses. Speakers specialised in paediatric and adolescent medicine as well as those from licensing authorities, the Federal Joint Committee (Gemeinsamer Bundesausschuss, G­BA), the pharmaceutical industry and the federal ministries presented problems and possible solutions from their point of view with the aim of making the PUMA license instrument more attractive.

An analysis of marketing authorisation applications via the mutual recognition and decentralised procedures in Europe.

PURPOSE: The aim of this study is to provide a comprehensive overview of the outcomes of marketing authorisation applications via the mutual recognition and decentralised procedures (MRP/DCP) and assess determinants of licensing failure during CMDh referral procedures. METHODS: All MRP/DCP procedures to the Co-ordination group for Mutual recognition and Decentralised procedures-human (CMDh) during the period from January 2006 to December 2013 were analysed. Reasons for starting referral procedures were scored. In addition, a survey under pharmaceutical companies was performed to estimate the frequency of licensing failure prior to CMDh referrals. RESULTS: During the study period, 10392 MRP/DCP procedures were finalized. Three hundred seventy-seven (3.6%) resulted in a referral procedure, of which 70 (19%) resulted in licensing failure, defined as refusal or withdrawal of the application. The frequency of CMDh referrals decreased from 14.5% in 2006 to 1.6% in 2013. Of all referrals, 272 (72%) were resolved through consensus within the CMDh, the remaining 105 (28%) were resolved at the level of the CHMP. Most referrals were started because of objections raised about the clinical development program. Study design issues and objections about the demonstration of equivalence were most likely to result in licensing failure. An estimated 11% of all MRP/DCP procedures resulted in licensing failure prior to CMDh referral. CONCLUSION: Whereas the absolute number of MRP/DCP procedures resulting in a referral has reduced substantially over the past years, no specific time trend could be observed regarding the frequency of referrals resulting in licensing failure. Increased knowledge at the level of companies and regulators has reduced the frequency of late-stage failure of marketing applications via the MRP/DCP.

Preclinical safety testing for cell-based products using animals.

The objectives of preclinical testing include to show why there might be therapeutic benefit in patients and to provide information on the product's toxicity. For cell-based products, given even once, there may be long term exposure and this could imply, unlike for conventional drugs, that all preclinical studies may be needed prior to first human use. The duration of exposure to cells should be studied in animals to guide toxicity assessments. Distribution of cells after administration by a route resembling that intended in humans should be studied to understand potential risks. Risk of tumour formation with the product may also need to be characterised. To the extent that this information can be generated by in vitro testing, studies in animals may not be needed and limitations on the capability of preclinical data to predict human toxicity are recognised: species-specificity make some cell products act only in humans and a human cell-product might be expected to be rejected by immunocompetent animals. Does this suggest testing in immunosuppressed animals or of development of an animal-cell product supposedly similar to the human cell product? No single answer seems to fit every situation.

Regulatory landscape for cell therapy--EU view.

This article addresses regulation of cell therapies in the European Union (EU), covering cell sourcing and applications for clinical trials and marketing authorisation applications. Regulatory oversight of cell sourcing and review of applications for clinical trials with cell therapies are handled at national level, that is, separately with each country making its own decisions. For clinical trials, this can lead to different decisions in different countries for the same trial. A regulation is soon to come into force that will address this and introduce a more efficient clinical trial application process. However, at the marketing authorisation stage, the process is pan-national: the Committee for Human Medicinal Products (CHMP) is responsible for giving the final scientific opinion on all EU marketing authorisation applications for cell therapies: favourable scientific opinions are passed to the European Commission (EC) for further consultation and, if successful, grant of a marketing authorisation valid in all 28 EU countries. In its review of applications for marketing authorisations (MAAs) for cell therapies, the CHMP is obliged to consult the Committee for Advanced Therapies (CAT), who conduct detailed scientific assessments of these applications, with assessment by staff from national regulatory authorities and specialist advisors to the regulators.

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.

[Procedure for the marketing authorization of an antibacterial agent]. / Procedimiento de registro de un antibacteriano.

The marketing authorization of a new medicinal product is the first step before being placed on the market, and includes the full investigation programme. In order to ensure their quality, safety and efficacy, medicinal products are closely regulated from their initial phases of investigation to their use in clinical practice. For registration purposes, the results of all the clinical and preclinical studies, along with quality data and the description of the manufacturing process should be submitted. All information collected is presented for review by the competent authority. The European Medicines Agency regulates the registration of medicines in Europe, and national agencies in each EU member state are responsible for the assessment of the marketing authorisation application. To facilitate the development of clinical programmes, there is a common framework for the evaluation of an antibacterial, which includes guidelines and an addendum, detailing the specific requirements that must be carried out in clinical trials to assess the efficacy and safety for most of the infections.

The life cycle of vaccines evaluated by the European Medicines Agency.

BACKGROUND: vaccines are complex products used in healthy populations. They should be carefully regulated, and benefits should clearly outweigh risks. OBJECTIVES: To describe the evidence used to support benefit-risk evaluations of vaccines centrally assessed by the European Medicines Agency (EMA), and to identify if real-world data (RWD) was used throughout the vaccine life cycle. METHODS: Cohort study of vaccines approved in the European Union. Inclusion criteria comprised having ATC code J07 and being centrally approved between 2012 and 2022. We collected data from regulatory documents, study protocols, and, when necessary, from scientific publications. Vaccines were followed from initial approval up to March 2023. RESULTS: We included 31 vaccines addressing 17 therapeutic areas. More than 390 studies were used in the process of initial marketing authorisation (MA) and monitoring, and 174 studies were listed in initial risk management plans. We also identified 93 studies in the EU PAS register. At MA, all vaccines had at least one pivotal trial and 27 vaccines had at least one supportive study. Most pivotal trials were randomized, double-blinded and active-controlled, with immunogenicity endpoints as primary outcome. RWD was used for extension of indications and monitoring of at least 4 vaccines, and the undertaking of RWE studies was foreseen in the RMP of at least 17 vaccines. DISCUSSION: Our study revealed an important reliance on randomized controlled trials with individual-level randomization, and a significant focus on immunogenicity endpoints. The use of RWD in vaccine assessments so far has been restricted to COVID-19, and despite its challenges and limitations, we believe that efforts to expand adoption of RWE in continuous benefit-risk assessments should be made. We further highlight the need to enhance data transparency and reporting standards since heterogeneity among regulatory documents made it difficult to identify all the studies considered in vaccine evaluations.

Position paper to facilitate patient access to radiopharmaceuticals: considerations for a suitable pharmaceutical regulatory framework.

BACKGROUND: Nuclear medicine has made enormous progress in the past decades. However, there are still significant inequalities in patient access among different countries, which could be mitigated by improving access to and availability of radiopharmaceuticals. MAIN BODY: This paper summarises major considerations for a suitable pharmaceutical regulatory framework to facilitate patient access to radiopharmaceuticals. These include the distinct characteristics of radiopharmaceuticals which require dedicated regulations, considering the impact of the variable complexity of radiopharmaceutical preparation, personnel requirements, manufacturing practices and quality assurance, regulatory authority interfaces, communication and training, as well as marketing authorisation procedures to ensure availability of radiopharmaceuticals. Finally, domestic and regional supply to ensure patient access via alternative regulatory pathways, including in-house production of radiopharmaceuticals, is described, and an outlook on regulatory challenges faced by new developments, such as the use of alpha emitters, is provided. CONCLUSIONS: All these considerations are an outcome of a dedicated Technical Meeting organised by the IAEA in 2023 and represent the views and opinions of experts in the field, not those of any regulatory authorities.