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Guiling Zhou,1 Stijn de Vos,1 Catharina CM Schuiling-Veninga,1 Jens Bos,1 Katrien Oude Rengerink,2 Anna Maria Gerdina Pasmooij,2 Peter GM Mol,2,3 Geertruida H de Bock,4 Eelko Hak1 1Unit of Pharmaco-Therapy, -Epidemiology and -Economics (PTEE), Department of Pharmacy, University of Groningen, Groningen, the Netherlands; 2Medicines Evaluation Board, Utrecht, the Netherlands; 3Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands; 4Department of Epidemiology, University Medical Center Groningen, University of Groningen, Groningen, the NetherlandsCorrespondence: Guiling Zhou, Unit of Pharmaco-Therapy, -Epidemiology and -Economics (PTEE), Department of Pharmacy, University of Groningen, Antonius Deusinglaan 1, Groningen, 9713 AV, the Netherlands, Tel +31 503638707, Fax +31 503632772, Email g.zhou@rug.nlBackground: Repurposing registered drugs could reduce coronavirus disease (COVID-19) burden before novel drugs are authorized. Little is known about how the pandemic and imposed restrictions changed their dispensing. We aimed to investigate the impact of COVID-19 pandemic on repurposed drugs dispensing in the Netherlands.Methods: We performed interrupted time-series study using University of Groningen prescription database IADB.nl to evaluate dispensing trends of 24 repurposed drugs before (2017-February 2020) and after (March 2020– 2021) the pandemic’ start. Primary outcomes were monthly prevalence and incidence rates. An autoregressive integrated moving average model assessed the effect of pandemic and stringency index (measuring strictness of government’s restriction policies).Results: Annual number of IADB.nl population ranged from 919,697 to 952,400. Generally, dispensing of common long-term-used drugs was not significantly affected by pandemic. The prevalence of antibacterials (− 4.20 users per 1000 people), antivirals (− 0.04), corticosteroids (− 1.29), prednisolone (− 1.32), calcium channel blocker (− 0.41), and diuretics (− 1.29) was lower than expected after the pandemic’s start, while the prevalence of ivermectin (0.07), sulfonylureas (0.15), sodium-glucose co-transporter-2 (SGLT2) inhibitor (0.17), and anticoagulants (1.95) was higher than expected. The pandemic was associated with statistically significant decreases in the incidence of antibacterials (− 1.21), corticosteroids (− 0.60), prednisolone (− 0.64) and anticoagulants (− 0.02), and increases in ivermectin (0.02), aggregated antidiabetic drugs (0.13), and SGLT2 inhibitors (0.06). These trends were positively associated with pandemic and negatively associated with stringency index.Conclusion: Dispensing of most drugs was not significantly associated with pandemic and government’s response. Despite some statistically significant disruptions, these were not necessarily clinically relevant due to small absolute differences observed.Keywords: COVID-19, drug utilization, repurposed drug, stringency index

In recent years, a small number of people with rare diseases caused by unique genetic variants have been treated with therapies developed specifically for them. This pioneering field of genetic N-of-1 therapies is evolving rapidly, giving hope for the individualized treatment of people living with very rare diseases. In this Review, we outline the concept of N-of-1 individualized therapies, focusing on genetic therapies, and illustrate advances and challenges in the field using cases for which therapies have been successfully developed. We discuss why the traditional drug development and reimbursement pathway is not fit for purpose in this field, and outline the pragmatic, regulatory and ethical challenges this poses for future access to N-of-1 therapies. Finally, we provide a roadmap for N-of-1 individualized therapy development., (© 2024. Springer Nature Limited.)

An environmental risk assessment (ERA) is mandatory for all applications for marketing authorisation of medicines in the European Union (EU). We investigated stakeholder perspectives on the role of the ERA in EU regulation of medicines for human use. We discuss the current position of the ERA and the current conduct and assessment of the ERA, such as the required expertise, data, and studies, its applicability to generic drugs, and its use in regulatory decision-making. We also discuss future perspectives, including extension of the ERA to cover antimicrobial resistance, improved risk mitigation, impact on 'over-the-counter' (OTC) status, and incorporation into reimbursement considerations., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Competing Interests: Conflicts of interest The full conflicts of interest statement for all authors is provided in Supplementary Appendix S2.

In the Netherlands, drug regulatory science is a vibrant national and internationally oriented community. In this review, we present the factors that have contributed to this successful collaboration between relevant stakeholders and that led to a surge of activities around how regulatory science became embedded in the ecosystem of medicines research, clinical pharmacology, policymaking and regulation. We distinguished three pivotal episodes: (i) TI Pharma Escher-project, (ii) Dutch Medicines Evaluation Board as catalyst of the big jump, and (iii) Regulatory Science Network Netherlands and multistakeholder engagement. The research agenda has been influenced by the dynamic evolution of legal frameworks in Europe, such as the EU orphan medicines legislation of 2001 and the EU pharmacovigilance legislation of 2012. All these developments have inspired and have raised pertinent regulatory sciences questions. Furthermore, clinical pharmacology as a discipline has been very influential in shaping regulatory science, contributing to discussions on the level of clinical evidence that is necessary to justify marketing approval of a new medicine. With a growing interest of multiple parties such as academics, European Medicines Agency, national agencies, patient organizations and EFPIA, connecting regulatory science activities is key., (© 2024 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Introduction: Although drug repurposing holds great potential in addressing unmet needs, successful practical implementation is challenging and has been less widespread than anticipated. Regulators may play a critical role in addressing this, and recent years have seen the conception of regulator-initiated and publicly-funded repurposing initiatives, with significant regulator involvement., Methods: International regulators and public funders ( n  = 8) were interviewed to obtain insight in how repurposing can be advanced from a regulatory perspective. Transcripts were thematically analyzed., Results: Most initiatives employed a broad concept of repurposing. While patient access was the main focus, label extension remained the gold standard. Commonly perceived barriers were a lack of regulatory expertise, limited downstream drug development, insufficient financial incentives, inadequate awareness of challenges, and poor collaboration. Ways for regulators to facilitate repurposing include early and accessible involvement fostering education, collaboration, and awareness. Increased stakeholder engagement, including internationally, was recommended. Legislative changes may enable the current repurposing ecosystem to evolve., Discussion: Regulators may play a central role in advancing repurposing by reconsidering their responsibilities within the current regulatory framework, both in mitigating repurposing pitfalls and actively encouraging repurposing initiatives by industry and non-traditional drug developers., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Spin, Mantel-Teeuwisse and Pasmooij.)

Epidermolysis bullosa (EB) is a heritable skin blistering disease caused by variants in genes coding for proteins that secure cell-cell adhesion and attachment of the epidermis to the dermis. Interestingly, several proteins involved in inherited EB are also associated with autoimmune blistering diseases (AIBD). In this study, we present a long-term follow-up of 15 patients suffering from recessive dystrophic or junctional EB. From these patients, 62 sera were analysed for the presence of autoantibodies associated with AIBD. We show that patients suffering from recessive dystrophic EB (RDEB) are more susceptible to developing autoantibodies against skin proteins than patients suffering from junctional EB (70% vs. 20%, respectively). Interestingly, no correlation with age was observed. Most patients showed reactivity to Type XVII collagen/linear IgA bullous dermatosis autoantigen (n = 5; 33%), followed by BP230 (n = 4; 27%), Type VII collagen (n = 4; 27%) and laminin-332 (n = 1; 7%). The pathogenicity of these autoantibodies remains a subject for future experiments., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

RNA-based medicines have potential to treat a large variety of diseases, and research in the field is very dynamic. Proactively, The European Medicines Agency (EMA) organized a virtual conference on February 2, 2023 to promote the development of RNA-based medicines. The initiative addresses the goal of the EMA Regulatory Science Strategy to 2025 to "catalyse the integration of science and technology in medicines development." The conference focused on RNA technologies (excluding RNA vaccines) and involved different stakeholders, including representatives from academia, industry, regulatory authorities, and patient organizations. The conference comprised presentations and discussion sessions conducted by panels of subject matter experts. In this meeting report, we summarize the presentations and recap the main themes of the panel discussions.

Competing Interests: Conflicts of interest P.I.S. receives departmental independent research grants for the TREAT NL registry from Pharma starting in December 2019, is involved in performing clinical trials with many pharmaceutical industries that manufacture drugs used for the treatment of, for example, psoriasis and atopic dermatitis, for which financial compensation is paid to the department/hospital, and is Chief Investigator for the Systemic and Phototherapy Atopic Eczema Registry (TREAT NL) for adults and children. She participated in the development of one of the HOME core outcome instruments (Recap of atopic eczema, RECAP), and in the development of the Outcome Measures for VAscular Malformations (OVAMA) questionnaire for vascular malformations. D.K. has served as a consultant for Amryt Pharma, Fibrx Inc. and Rheacell GmbH and is co-founder of Crowd Pharma, a company focusing on repurposing losartan for EB. V.W. acts as consultant for and holds shares of Diaderm GmbH. M.C.B. has served on the advisory boards of Amryt Pharma and Krystal Biotech Inc. E.W.H.K., P.C.v.d.A., M.L., A.M.G.P., R.R., E.V. and T.W. declare that they have no conflicts of interest regarding the scope of this work.

Repurposing is one of the key opportunities to address the unmet rare diseases therapeutic need. Based on cases of drug repurposing in small population conditions, and previous work in drug repurposing, we analyzed the most important lessons learned, such as the sharing of clinical observations, reaching out to regulatory scientific advice at an early stage, and public-private collaboration. In addition, current upcoming trends in the field of drug repurposing in rare diseases were analyzed, including the role these trends could play in the rare diseases' ecosystem. Specifically, we cover the opportunities of innovation platforms, the use of real-world data, the use of artificial intelligence, regulatory initiatives in repurposing, and patient engagement throughout the repurposing project. The outcomes from these emerging activities will help progress the field of drug repurposing for the benefit of patients, public health and medicines development., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Jonker, O’Connor, Cavaller-Bellaubi, Fetro, Gogou, ’T Hoen, de Kort, Stone, Valentine and Pasmooij.)

In the European Union, the Committee for Medicinal Products for Human Use of the European Medicines Agency (EMA) develop guidelines to guide drug development, supporting development of efficacious and safe medicines. A European Public Assessment Report (EPAR) is published for every medicine application that has been granted or refused marketing authorisation within the EU. In this work, we study the use of text embeddings and similarity metrics to investigate the semantic similarity between EPARs and EMA guidelines. All 1024 EPARs for initial marketing authorisations from 2008 to 2022 was compared to the 669 current EMA scientific guidelines. Documents were converted to plain text and split into overlapping chunks, generating 265,757 EPAR and 27,649 guideline text chunks. Using a Sentence BERT language model, the chunks were transformed into embeddings and fed into an in-house piecewise matching algorithm to estimate the full-document semantic distance. In an analysis of the document distance scores and product characteristics using a linear regression model, EPARs of anti-virals for systemic use (ATC code J05) and antihemorrhagic medicines (B02) present with statistically significant lower overall semantic distance to guidelines compared to other therapeutic areas, also when adjusting for product age and EPAR length. In conclusion, we believe our approach provides meaningful insight into the interplay between EMA scientific guidelines and the assessment made during regulatory review, and could potentially be used to answer more specific questions such as which therapeutic areas could benefit from additional regulatory guidance., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Bergman et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objective: Current evidence on the effectiveness of SARS-CoV-2 prophylaxis is inconclusive. We aimed to systematically evaluate published studies on repurposed drugs for the prevention of laboratory-confirmed SARS-CoV-2 infection and/or COVID-19 among healthy adults., Design: Systematic review., Eligibility: Quantitative experimental and observational intervention studies that evaluated the effectiveness of repurposed drugs for the primary prevention of SARS-CoV-2 infection and/or COVID-19 disease., Data Source: PubMed and Embase (1 January 2020-28 September 2022)., Risk of Bias: Cochrane Risk of Bias 2.0 and Risk of Bias in Non-Randomised Studies of Interventions tools were applied to assess the quality of studies., Data Analysis: Meta-analyses for each eligible drug were performed if ≥2 similar study designs were available., Results: In all, 65 (25 trials, 40 observational) and 29 publications were eligible for review and meta-analyses, respectively. Most studies pertained to hydroxychloroquine (32), ACE inhibitor (ACEi) or angiotensin receptor blocker (ARB) (11), statin (8), and ivermectin (8). In trials, hydroxychloroquine prophylaxis reduced laboratory-confirmed SARS-CoV-2 infection (risk ratio: 0.82 (95% CI 0.74 to 0.90), I 2 =48%), a result largely driven by one clinical trial (weight: 60.5%). Such beneficial effects were not observed in observational studies, nor for prognostic clinical outcomes. Ivermectin did not significantly reduce the risk of SARS-CoV-2 infection (RR: 0.35 (95% CI 0.10 to 1.26), I 2 =96%) and findings for clinical outcomes were inconsistent. Neither ACEi or ARB were beneficial in reducing SARS-CoV-2 infection. Most of the evidence from clinical trials was of moderate quality and of lower quality in observational studies., Conclusions: Results from our analysis are insufficient to support an evidence-based repurposed drug policy for SARS-CoV-2 prophylaxis because of inconsistency. In the view of scarce supportive evidence on repurposing drugs for COVID-19, alternative strategies such as immunisation of vulnerable people are warranted to prevent the future waves of infection., Prospero Registration Number: CRD42021292797., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The International Rare Diseases Research Consortium (IRDiRC) is an international initiative that aims to use research to facilitate rapid diagnosis and treatment of rare diseases., Objective: IRDiRC launched the Chrysalis Task Force to identify key financial and nonfinancial factors that make rare disease research and development attractive to companies., Methods: The Chrysalis Task Force was comprised of thought leaders from companies, patient advocacy groups, regulatory agencies, and research funders. The Task Force created a survey that was distributed to companies of different sizes with varied investment portfolios and interests in rare disease research. Based on the survey results, the Task Force then conducted targeted interviews., Results: The survey and interview respondents identified several factors that make rare disease research and development attractive (e.g. a good understanding of the underlying biology) as well as barriers (e.g. absence of an advocacy organization representing the affected community's needs). The concept of Return On Investment allowed the exploration of factors that were weighed differently by survey and interview respondents, depending on a number of intrinsic and extrinsic issues., Conclusions: The Chrysalis Task Force identified factors attributable to rare disease research and development that may be of interest to and actionable by funders, academic researchers, patients and their families, companies, regulators, and payers in the medium term to short term. By addressing the identified challenges, involved parties may seek solutions to significantly advance the research and development of treatments for rare diseases., Competing Interests: DJ, MCVL, JA, SF, AM, AMGP, NET, MW, DWR, and ALH declare no competing interests. KLB is an employee of Pfizer and holds stock in the company. AAR is an ad hoc consultant for PTC Therapeutics, Sarepta Therapeutics, Regenxbio, Alpha Anomeric, BioMarin Pharmaceuticals Inc., Eisai, Entrada, Takeda, Splicesense, Galapagos, and Astra Zeneca. JB is a consultant for Rocket Pharmaceuticals Inc. and receive equity and funding. MH is an employee of Takeda Pharmaceuticals Company Ltd. JL is an employee of PepGen Inc. GLR is an employee of Pfizer. VP is an employee of Sanofi., (© The Author(s), 2023.)

Introduction: Clinical research with remote monitoring technologies (RMTs) has multiple advantages over standard paper-pencil tests, but also raises several ethical concerns. While several studies have addressed the issue of governance of big data in clinical research from the legal or ethical perspectives, the viewpoint of local research ethics committee (REC) members is underrepresented in the current literature. The aim of this study is therefore to find which specific ethical challenges are raised by RECs in the context of a large European study on remote monitoring in all syndromic stages of Alzheimer's disease, and what gaps remain., Methods: Documents describing the REC review process at 10 sites in 9 European countries from the project Remote Assessment of Disease and Relapse-Alzheimer's Disease (RADAR-AD) were collected and translated. Main themes emerging in the documents were identified using a qualitative analysis approach., Results: Four main themes emerged after analysis: data management, participant's wellbeing, methodological issues, and the issue of defining the regulatory category of RMTs. Review processes differed across sites: process duration varied from 71 to 423 days, some RECs did not raise any issues, whereas others raised up to 35 concerns, and the approval of a data protection officer was needed in half of the sites., Discussion: The differences in the ethics review process of the same study protocol across different local settings suggest that a multi-site study would benefit from a harmonization in research ethics governance processes. More specifically, some best practices could be included in ethical reviews across institutional and national contexts, such as the opinion of an institutional data protection officer, patient advisory board reviews of the protocol and plans for how ethical reflection is embedded within the study., Competing Interests: The authors have read the journal’s policy and have the following competing interests: IK is a paid medical advisor for digital healthcare technology companies Five Lives SAS and Cognetivity Ltd., outside the submitted work. CA has received honoraria as speaker from F. Hoffmann-La Roche Ltd, Zambon, Nutricia, Schwabe Farma Ibérica S.A.U, outside of the submitted work. CA is a member of the Board of Directors of the Lewy Body Dementia Association, outside the submitted work. DA has received research support and/or honoraria from Astra-Zeneca, H. Lundbeck, Novartis Pharmaceuticals, Biogen, and GE Health, and served as paid consultant for H. Lundbeck, Eisai, Heptares, Mentis Cura, and Roche Diagnostics, outside the submitted work. MB is an employee of the Ace Alzheimer Center and an advisory board member for Grifols, Roche, Eli Lilly, Araclon Biotech, Merck, Zambon, Biogen, Novo Nordisk, Bioiberica, Eisai, Servier, and Schwabe Pharma, outside the submitted work. This does not alter our adherence to PLOS ONE policies on sharing data and materials. All other authors have declared that no competing interests exist. There are no patents, products in development or marketed products associated with this research to declare., (Copyright: © 2023 Muurling et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Epidermolysis bullosa (EB) is a rare, genetically and clinically heterogeneous group of skin fragility disorders. No cure is currently available, but many novel and repurposed treatments are upcoming. For adequate evaluation and comparison of clinical studies in EB, well-defined and consistent consensus-endorsed outcomes and outcome measurement instruments are necessary., Objectives: To identify previously reported outcomes in EB clinical research, group these outcomes by outcome domains and areas and summarize respective outcome measurement instruments., Methods: A systematic literature search was performed in the databases MEDLINE, Embase, Scopus, Cochrane CENTRAL, CINAHL, PsycINFO and trial registries covering the period between January 1991 and September 2021. Studies were included if they evaluated a treatment in a minimum of three patients with EB. Two reviewers independently performed the study selection and data extraction. All identified outcomes and their respective instruments were mapped onto overarching outcome domains. The outcome domains were stratified according to subgroups of EB type, age group, intervention, decade and phase of clinical trial., Results: The included studies (n = 207) covered a range of study designs and geographical settings. A total of 1280 outcomes were extracted verbatim and inductively mapped onto 80 outcome domains and 14 outcome areas. We found a steady increase in the number of published clinical trials and outcomes reported over the past 30 years. The included studies mainly focused on recessive dystrophic EB (43%). Wound healing was reported most frequently across all studies and referred to as a primary outcome in 31% of trials. Great heterogeneity of reported outcomes was observed within all stratified subgroups. Moreover, a diverse range of outcome measurement instruments (n = 200) was identified., Conclusions: We show substantial heterogeneity in reported outcomes and outcome measurement instruments in EB clinical research over the past 30 years. This review is the first step towards harmonization of outcomes in EB, which is necessary to expedite the clinical translation of novel treatments for patients with EB., Competing Interests: Conflicts of interest E.W.H.K., T.W., S.W., P.C.v.d.A., B.H., A.M.G.P. and M.L. declare that they have no conflicts of interest regarding the scope of this work. J.K. is a member of the Board of Directors of the CHORD COUSIN Collaboration. D.K. has served as a consultant for Amryt Pharma, Fibrx Inc and Rheacell GmbH and is cofounder of Crowd Pharma. V.W. acts as consultant for Diaderm GmbH and TWi Biotechnology and holds shares of Diaderm GmbH, a company with an interest in drug development for EB. M.C.B. has served on the advisory boards of Amryt Pharma and Krystal Biotech Inc., (© The Author(s) 2022. Published by Oxford University Press on behalf of British Association of Dermatologists.)

Background: Single-arm trials (SATs) can sometimes be used to support marketing authorization of anticancer medicinal products in the European Union. The level and durability of antitumor activity of the product as well as context are important aspects to determine the relevance of trial results. The aim of this study is to provide details on the contextualization of trial results and to evaluate the magnitude of benefit of medicinal products approved based on SATs., Materials and Methods: We focused on anticancer medicinal products for solid tumors approved on the basis of SAT results (2012-2021). Data were retrieved from European public assessment reports and/or published literature. The benefit of these medicinal products was evaluated via the European Society for Medical Oncology (ESMO)-Magnitude of Clinical Benefit Scale (MCBS)., Results: Eighteen medicinal products were approved based on 21 SATs-few medicinal products were supported by >1 SAT. For the majority of clinical trials, a clinically relevant treatment effect was (pre)specified (71.4%) and most often an accompanying sample size calculation was provided. For 10 studies, each testing a different medicinal product, a justification for the threshold for a clinically relevant treatment effect could be identified. At least 12 out of 18 applications included information to facilitate the contextualization of trial results, including six supportive studies. Of the pivotal SATs analyzed (n = 21), three were assigned an ESMO-MCBS score of 4, which corresponds to 'substantial' benefit., Conclusions: The clinical relevance of the treatment effects shown by medicinal products for solid tumors tested in SATs is dependent on the effect size and context. To better facilitate regulatory decision making, prespecifying and motivating a clinically relevant effect and aligning the sample size to that effect is important. External controls may facilitate in the contextualization process, but the associated limitations must be addressed., Competing Interests: Disclosure The authors have declared no conflicts of interest. Disclaimer The views expressed in this article are the personal views of the authors and may not be understood or quoted as being made on behalf of, or reflecting the position of the EMA or one of its committees, working parties, or any of the national agencies., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background : Novel or repurposed medicines for rare diseases often emerge from fundamental research or empirical findings in academia. However, researchers may be insufficiently aware of the possibilities and requirements to bring novel medicinal treatment options to the patient. This paper aims to provide an easily applicable, comprehensive roadmap designed for academic researchers to make medicines for rare diseases available for patients by addressing the relevant regulatory frameworks, including marketing authorization and alternative routes. Methods : Key points of the regulatory chapters "Placing on the Market" and "Scope" of Directive 2001/83/EC relating to medicinal products for human use were summarized. Provisions in EU directives regarding blood products, radiopharmaceuticals, and herbal and homeopathic medicinal products were excluded. Cross-referencing to other provisions was included. European case-law was retrieved from the InfoCuria database to exemplify the implications of alternative routes. Results : Medicines may only be placed on the market with a valid marketing authorization. To obtain such authorization in Europe, a "Common Technical Document" comprising reports on quality and non-clinical and clinical studies must be submitted to a "competent authority", a national medicine agency or the European Medicines Agency. Timely interaction of academic researchers with regulators via scientific advice may lead to better regulatory alignment and subsequently a higher chance for approval of academic inventions. Furthermore, reimbursement by national payers could be essential to ensure patient access. Apart from the marketing authorization route, we identified multiple alternative routes to provide (early) access. These include off-label use, named-patient basis, compassionate use, pharmacy compounding, and hospital exemption for Advanced Therapy Medicinal Products. Discussion : Aligning academic (non-)clinical studies on rare diseases with regulatory and reimbursement requirements may facilitate fast and affordable access. Several alternative routes exist to provide (early) pharmaceutical care at a national level, but case-law demonstrates that alternative routes should be interpreted strictly and for exceptional situations only. Academics should be aware of these routes and their requirements to improve access to medicines for rare diseases., Competing Interests: CH is involved in pre-marketing research with Sanofi, Protalix, and Idorsia, outside the submitted work. NR, SB, BJ, NS, HP, SV, and CH are members of platform “Medicijn voor de Maatschappij”. This is an academic initiative that aims to support sustainable access to medicines for rare diseases. SV teaches Clinical Development at Paul Janssen Futurelab Leiden for academic and industry professionals. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Rosenberg, van den Berg, Stolwijk, Jacobs, Post, Pasmooij, de Visser and Hollak.)

Important discoveries by academic drug developers hold the promise of bringing innovative treatments that address unmet medical needs to the market. However, the drug development process has proved to be challenging and demanding for academic researchers, and regulatory challenges are an important barrier to implementing academic findings in clinical practice. European regulators offer varying degrees of support services to help drug developers meet regulatory standards and requirements. "Strengthening Training of Academia in Regulatory Sciences and Supporting Regulatory Scientific Advice" (STARS) is a European Commission-funded consortium aiming to strengthen the training of academics in regulatory science and requirements. Here, we report the results of four surveys that investigated the awareness and utilization of support tools offered by European regulators and identified the regulatory challenges and support needs of researchers. The surveys targeted four main European stakeholders in academic medicines research: academic research groups (706 respondents), academic research centers (99), funding organizations (49), and regulators (22). The results show that while European regulators provide various regulatory support tools, less than half of the responding academic researchers were aware of these tools and many experienced challenges in reaching a sufficient level of regulatory knowledge. There was a general lack of understanding of the regulatory environment that was aggravated by poor communication between stakeholders. The results of this study form a foundation for an improved European medicines regulatory network, in which regulatory challenges faced by academia are tackled., (© 2022 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Background: Many studies have compared real-world clinical outcomes of immunotherapy in patients with metastatic non-small cell lung cancer (NSCLC) with reported outcomes data from pivotal trials. However, any differences observed could be only limitedly explored further for causation because of the unavailability of individual patient data (IPD) from trial participants. The present study aims to explore the additional benefit of comparison with IPD., Methods: This study compares progression free survival (PFS) and overall survival (OS) of metastatic NSCLC patients treated with second line nivolumab in real-world clinical practice (n = 141) with IPD from participants in the Checkmate-057 clinical trial (n = 292). Univariate and multivariate Cox proportional hazards models were used to construct HRs for real-world practice versus clinical trial., Results: Real-world patients were older (64 vs. 61 years), had more often ECOG PS ≥ 2 (5 vs. 0%) and were less often treated with subsequent anti-cancer treatment (28.4 vs. 42.5%) compared to trial patients. The median PFS in real-world patients was longer (3.84 (95%CI: 3.19-5.49) vs 2.30 (2.20-3.50) months) and the OS shorter than in trial participants (8.25 (6.93-13.2) vs. 12.2 (9.90-15.1) months). Adjustment with available patient characteristics, led to a shift in the hazard ratio (HR) for OS, but not for PFS (HRs from 1.13 (0.88-1.44) to 1.07 (0.83-1.38), and from 0.82 (0.66-1.03) to 0.79 (0.63-1.00), respectively)., Conclusions: This study is an example how IPD from both real-world and trial patients can be applied to search for factors that could explain an efficacy-effectiveness gap. Making IPD from clinical trials available to the international research community allows this., (© 2022. The Author(s).)

Recent results of patients with advanced melanoma treated with first-line BRAF-MEK inhibitors in clinical trials showed 5-year survival in one-third of patients with a median overall survival (OS) of more than 2 years. This study aimed to investigate these patients' real-world survival and identify the characteristics of long-term survivors. The study population consisted of patients with advanced cutaneous melanoma with a BRAF-V600 mutated tumor who were treated with first-line BRAF-MEK inhibitors between 2013 and 2017. Long-term survival was defined as a minimum OS of 2 years from start therapy. The median progression-free survival (mPFS) and median OS (mOS) of real-world patients ( n  = 435) were respectively 8.0 (95% CI, 6.8-9.4) and 11.7 (95% CI, 10.3-13.5) months. Two-year survival was reached by 28% of the patients, 22% reached 3-year survival and 19% reached 4-year survival. Real-world patients often had brain metastases (41%), stage IV M1c disease (87%), ECOG PS ≥2 (21%), ≥3 organ sites (62%) and elevated LDH of ≥250 U/I (49%). Trial-eligible real-world patients had an mOS of 17.9 months. Patients surviving more than 2 years ( n  = 116) more often had an ECOG PS ≤1 (83%), normal LDH (60%), no brain metastases (60%), no liver metastases (63%) and <3 organ sites (60%). Long-term survival of real-world patients treated with first-line BRAF-MEK inhibitors is significantly lower than that of trial patients, which is probably explained by poorer baseline characteristics of patients treated in daily practice. Long-term survivors generally had more favorable characteristics with regard to age, LDH level and metastatic sites, compared to patients not reaching long-term survival., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)

Medication adherence is a key factor impacting efficacy and safety of medicines, yet how it is dealt with in European registration trials is unknown. A cross-sectional analysis of European Medicines Agency (EMA) marketing authorization dossiers for new medicines approved through centralized procedures in the European Union between 2010 and 2020 was performed. Data were extracted from European Public Assessment Reports and Clinical Study Reports. Clinical trials covering five therapeutic areas were included: diabetes, respiratory conditions, cardiovascular diseases, infectious diseases, and oncology. Outcomes included adherence assessment, measurement methods, and rates. Overall, 102 medicines studied in 253 clinical trials were reviewed. All but one study reported measuring adherence. Two hundred twenty trials (87%) measured adherence using quantitative methods, while 32 (13%) trials monitored adherence but did not further quantify. Reported adherence rates were high (> 90%) across trials yet marked disparities in measurement methods and definitions were found. The most frequently used adherence measurement method was pill/dose count (single method: 52.7%; in combination: 37.7%; with patient diary/report: 17.3%; electronic methods: 1.4%; bioanalytical methods: 4.1%). Patient diary/report (6.4%) and electronic methods (2.7%) were also used as single methods. Electronic methods were more often used in respiratory and anti-infective trials, while bioanalytical methods were more frequently used in diabetes. Overall, adherence is measured in EMA registration trials, yet the methods used and the way in which adherence rates are presented vary widely between trials and therapeutic areas. To better understand and compare efficacy of medicines, standardization of adherence definitions and measurement methods is needed., (© 2022 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Revertant mosaicism (RM) is the intriguing phenomenon in which nature itself has successfully done what medical science is so eagerly trying to achieve: correcting the effect of disease-causing germline variants and thereby reversing the disease phenotype back to normal. RM was molecularly confirmed for the first time in a genodermatosis in 1997, the genetic skin condition junctional epidermolysis bullosa (EB). At that time, RM was considered an extraordinary phenomenon. However, several important discoveries have changed this conception in the past few decades. First, RM has now been identified in all major subtypes of EB. Second, RM has also been identified in many other genodermatoses. Third, a theoretical mathematical exercise concluded that reverse mutations should be expected in all patients with a recessive subtype of EB or any other genodermatosis. This has shifted the paradigm from RM being an extraordinary phenomenon to it being something that every physician working in the field of genodermatoses should be looking for in every patient. It has also raised hope for new treatment options in patients with genodermatoses. In this review, we summarize the current knowledge on RM and discuss the perspectives of RM for the future treatment of patients with genodermatoses.

Background: The Dutch Institute for Clinical Auditing (DICA) Medicines Program was set up in September 2018 to evaluate expensive medicine use in daily practice in terms of real-world effectiveness using only existing data sources., Objective: The aim of this study is to describe the potential of the addition of declaration data to quality registries to provide participating centers with benchmark information about the use of medicines and outcomes among patients., Methods: A total of 3 national population-based registries were linked to clinical and financial data from the hospital pharmacy, the Dutch diagnosis treatment combinations information system including in-hospital activities, and survival data from health care insurers. The first results of the real-world data (RWD) linkage are presented using descriptive statistics to assess patient, tumor, and treatment characteristics. Time-to-next-treatment (TTNT) and overall survival (OS) were estimated using the Kaplan-Meier method., Results: A total of 21 Dutch hospitals participated in the DICA Medicines Program, which included 7412 patients with colorectal cancer, 1981 patients with metastasized colon cancer, 3860 patients with lung cancer, 1253 patients with metastasized breast cancer, and 7564 patients with rheumatic disease. The data were used for hospital benchmarking to gain insights into medication use in specific patient populations, treatment information, clinical outcomes, and costs. Detailed treatment information (duration and treatment steps) led to insights into differences between hospitals in daily clinical practices. Furthermore, exploratory analyses on clinical outcomes (TTNT and OS) were possible., Conclusions: The DICA Medicines Program shows that it is possible to gather and link RWD about medicines to 4 disease-specific population-based registries. Since these RWD became available with minimal registration burden and effort for hospitals, this method can be explored in other population-based registries to evaluate real-world efficacy., (©Rawa Kamaran Ismail, Jesper van Breeschoten, Silvia van der Flier, Caspar van Loosen, Anna Maria Gerdina Pasmooij, Maaike van Dartel, Alfons van den Eertwegh, Anthonius de Boer, Michel Wouters, Doranne Hilarius. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 23.06.2022.)

There are currently four anti-cancer medicinal products approved for a tissue-agnostic indication. This is an indication based on a common biological characteristic rather than the tissue of origin. To date, the regulatory experience with tissue-agnostic approvals is limited. Therefore, we compared decision-making aspects of the first tissue-agnostic approvals between the Food and Drug Administration (FDA), European Medicines Agency (EMA) and Pharmaceuticals and Medical Devices Agency (PMDA). Post-marketing measures (PMMs) related to the tissue-agnostic indication were of specific interest. The main data source was the publicly available review documents. The following data were collected: submission date, approval date, clinical trials and datasets, and PMMs. At the time of data collection, the FDA and PMDA approved pembrolizumab, larotrectinib, and entrectinib for a tissue-agnostic indication, while the EMA approved larotrectinib and entrectinib for a tissue-agnostic indication. There were differences in analysis sets (integrated vs. non-integrated), submission dates and requests for data updates between agencies. All agencies had outstanding issues that needed to be addressed in the post-market setting. For pembrolizumab, larotrectinib and entrectinib, the number of imposed PMMs varied between one and eight, with the FDA requesting the most PMMs compared to the other two agencies. All agencies requested at least one PMM per approval to address the remaining uncertainties related to the tissue-agnostic indication. The FDA and EMA requested data from ongoing and proposed trials, while the PMDA requested data from use-result surveys. Confirmation of benefit in the post-marketing setting is an important aspect of tissue-agnostic approvals, regardless of agency. Nonetheless, each approach to confirm benefit has its inherent limitations. Post-marketing data will be essential for the regulatory and clinical decisions-making of medicinal products with a tissue-agnostic indication., Competing Interests: EV initiated and led the DRUP as one of the principal investigators. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Mulder, van Stuijvenberg, van Hennik, Voest, Pasmooij, Stoyanova-Beninska and de Boer.)

With the implementation of the new EU regulation on in vitro diagnostics (IVDR) in May 2022, notified bodies will be required to assess Companion Diagnostics (CDx). The EMA and national medicines agencies will be consulted on the performance and safety of CDx. In this paper, we report on our systematic review on how the EMA has dealt with CDx in dossiers for marketing authorization procedures, in 2017-2019, and in scientific advice procedures in 2016-2020, prior to the implementation of the new IVDR. Out of 167 medicines approved or refused by the EMA, CDx played a role for 20 medicines during assessment. Both European public assessment reports (EPARs) and the internal day 80 and day 120 assessment reports (ARs) of the EMA centralized marketing authorization procedures for these 20 medicines were analyzed in detail to determine how CDx were assessed. Likewise, in 46 of 159 cases in which scientific advice was provided, CDx were mentioned in the question-and-answer section of the scientific advice, and these were analyzed in an analogous manner. Our analysis indicates that clinical performance and analytical performance of the CDx were the most-discussed topics, being discussed 11 and seven times in the 20 EPARs and 59 and 29 times in the ARs, respectively. For scientific advice, clinical and analytical performance was discussed 65 and 22 times in the 46 retrieved mentions of scientific advice. Other aspects in relation to CDx were discussed as well, although at a lower frequency, in assessment reports and scientific advice. Overall, our analysis demonstrates that, despite the absence of an obligation from a legal point of view, EMA has gained experience on the assessment of CDx, most notably regarding its analytical and clinical performance. This experience may be useful in situations in which the EMA and national agencies of EU member states will formally be consulted by notified bodies regarding the performance and safety of CDx. In addition, the issues raised in the EPARs, ARs and scientific advice reports provide insight for applicants on aspects of CDx that need careful consideration., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Maliepaard, Nibi, Nibi and Pasmooij.)

Objectives: The In Vitro Diagnostics Regulation 2017/746 (IVDR) coming into force from May 2022, creates the first European regulatory recognition for biomarker tests linked to medicinal products, so-called companion diagnostics (CDx). Since the introduction of the IVDR is associated with uncertainties about its impact on hospital practice, it is urgent and valuable to investigate how and why CDx are currently used in hospital practice, which factors influence the choice for applying in-house or commercial CDx, and what the expectations are about how the IVDR may affect current practice., Methods: We investigated these questions using an interview-based approach and focused on 15 hospital laboratories in the Netherlands, including 7 academic and 8 general hospitals. All types of CDx were considered relevant for this research, including both genetic and protein-based biomarkers., Results: Factors found included: costs and convenience, complexity of application, and compatibility with existing workflows. Next to in-house and commercial CDx, hospital laboratories addressed compatibility by tweaking existing CDx., Conclusion: Although increased quality of CDx is welcomed, worries toward increased costs and administrative work, and decreased quality were expressed. Further, the IVDR might also hinder using optimized in-house and tweaked CDx. Additionally, increased administrative burden could decrease innovativeness toward CDx.

Pancreatic cancer has a dismal prognosis and only a few treatment options are available. In the European Union, pancreatic cancer classifies as a rare disease, allowing drug developers to apply for orphan medicinal product (OMP) designation. The aim of this study was to provide more detail on OMPs for pancreatic cancer. All applications for OMP designation submitted to the EMA between 2000 and 2019 were identified. For each medicinal product that received an OMP designation, the mode of drug action, use of protocol assistance, and current life cycle status was determined. Fifty-two medicinal products received an OMP designation. At the time of submission, eighteen OMPs were at the non-clinical and 34 OMPs were at the clinical stage of development. At least fourteen kinds of mode of action were explored in the condition. For eighteen out of 52 OMPs protocol assistance was sought. At the time of data analysis, one OMP received marketing authorisation and 24 OMPs were ongoing in development. Many medicinal products for pancreatic cancer received an OMP designation and the majority of these products was already in the clinical stage of development. Nonetheless, the success rate of OMPs for pancreatic cancer that reach the market is low, and increasing this rate is something to aspire. Fortunately, development is still ongoing for a part of the OMPs, and a few developers are planning to submit a marketing authorisation application in the near future. This however does not guarantee success, as pancreatic cancer remains a difficult disease to treat. Developers are advised to make optimal use of incentives such as protocol assistance, establishing (early) dialogue between regulators and drug developers and to agree on important topics such as clinical trial design., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Mulder, van Rossum, Mariz, Magrelli, de Boer, Pasmooij and Stoyanova-Beninska.)

After marketing authorisation, the development of a medicinal product often continues with studies investigating new therapeutic indications. Positive results can potentially lead to changes to the terms of the marketing authorisation, such as an extension of therapeutic indication(s). These studies can be initiated and sponsored by the marketing authorisation holder (MAH) or by others. When results from an investigator-initiated trial suggest that an authorised medicinal product is safe and effective for a new therapeutic indication, physicians may want to treat their patients with this medicinal product. In such a situation, it is desirable to extend the therapeutic indication(s) via the regulatory approval process, as this can facilitate patient access within the European Union. There may however be challenges when the MAH did not conduct the study and might not have access to the data. In this perspective, we focus on the possibilities to extend the therapeutic indication(s) of an already authorised medicinal product based on results from investigator-initiated trials. We address: (1) the advantages of an extension of indication; (2) the regulatory requirements for a variation application; (3) investigator-initiated trials as a basis for regulatory approval; (4) the role of the MAH in extending the indication. With this article, we want to emphasize the importance of a collaborative approach and dialogue between stakeholders with the aim to facilitate access to effective medicinal products., Competing Interests: EV initiated and led the DRUP as one of the principal investigators. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Mulder, Verjans, Verbaanderd, Pean, Weemers, Leufkens, Pignatti, de Boer, Voest, Stoyanova-Beninska and Pasmooij.)

Background: This study aimed to provide insights into the real-world use of palbociclib, dose reductions, and drug effectiveness in (older) patients with advanced breast cancer (BC)., Patients and Methods: Patients with advanced BC treated with palbociclib from 2017 to 2020 were included. The Kaplan-Meier method was used to calculate time to next treatment (TTNT) and overall survival (OS) for patients with or without dose reductions. These clinical outcomes were also compared in subgroup analyses for older patients (≥70 years) and younger patients (<70 years) and for patients discontinuing palbociclib early (<4 administrations)., Results: A total of 598 patients with advanced BC were included, with a median age of 64 years. Palbociclib dose reductions occurred in 33% of all patients. Early discontinuation of palbociclib without dose reductions occurred in 23% of the patients. Patients who required a palbociclib dose reduction were older (median age 67 years vs. 63 years). Patients with dose reductions had a significantly higher TTNT of 16.9 vs. 11.4 months (p < 0.001) and median OS of 29.7 vs. 21.9 months (p = 0.003) compared to patients without dose reductions. The TTNT in older patients was significantly longer (16.9 vs. 11.6 months, p = 0.013) than younger patients, but OS was similar (20.7 vs. 26.7 months, p = 0.051)., Conclusion: Palbociclib dose reductions occurred in real-world practice similarly to the PALOMA-3 trial. Patients with dose reductions had no poorer outcomes compared to patients not requiring a dose reduction. Older patients treated with palbociclib had more frequent dose reductions, but this did not appear to affect OS., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Epidermolysis bullosa is a group of genetic skin conditions characterized by abnormal skin (and mucosal) fragility caused by pathogenic variants in various genes. The disease severity ranges from early childhood mortality in the most severe types to occasional acral blistering in the mildest types. The subtype and severity of EB is linked to the gene involved and the specific variants in that gene, which also determine its mode of inheritance. Current treatment is mainly focused on symptomatic relief such as wound care and blister prevention, because truly curative treatment options are still at the preclinical stage. Given the current level of understanding, the broad spectrum of genes and variants underlying EB makes it impossible to develop a single treatment strategy for all patients. It is likely that many different variant-specific treatment strategies will be needed to ultimately treat all patients. Antisense-oligonucleotide (ASO)-mediated exon skipping aims to counteract pathogenic sequence variants by restoring the open reading frame through the removal of the mutant exon from the pre-messenger RNA. This should lead to the restored production of the protein absent in the affected skin and, consequently, improvement of the phenotype. Several preclinical studies have demonstrated that exon skipping can restore protein production in vitro, in skin equivalents, and in skin grafts derived from EB-patient skin cells, indicating that ASO-mediated exon skipping could be a viable strategy as a topical or systemic treatment. The potential value of exon skipping for EB is supported by a study showing reduced phenotypic severity in patients who carry variants that result in natural exon skipping. In this article, we review the substantial progress made on exon skipping for EB in the past 15 years and highlight the opportunities and current challenges of this RNA-based therapy approach. In addition, we present a prioritization strategy for the development of exon skipping based on genomic information of all EB-involved genes.

Aims: Recently, the use of novel remote monitoring technologies (RMTs) in trials has gained much interest. To facilitate regulatory learning, we evaluated qualification opinions (QOs) and advices (QAs) and scientific advices (SAs) of the Committee for Medicinal Products for Human Use (CHMP) to gain insight in the types of devices that are intended to be used in clinical trials for supporting/submitting application for obtaining marketing authorization (registration trials) and the main recommendations of the CHMP. Methods: QOs, QAs, and SAs of the CHMP that assessed RMTs between 2013 and 2019 were eligible for our study. The following information was extracted from the documents: year of advice/opinion, device and endpoints used, type of endpoint (primary, secondary, exploratory, or safety), and main recommendations of the CHMP. Results: In total two QOs, four QAs, and 59 SAs were included in our study (total of SAs between 2013 and 2019 = 4,054). In the SAs, accelerometers to measure activity and/or sleep parameters ( n = 31) were the most frequently used devices, followed by mobile applications ( n = 6) and glucose monitoring devices ( n = 6). Usually, these measures were proposed as secondary or exploratory endpoints ( n = 32). The main recommendations of the CHMP were related to relevance of the (novel) outcome measure; validation; precision, accuracy, sensitivity, and specificity; compliance; sampling interval; and data handling and privacy. Conclusions: Although there was a trend toward an increased use over time, the use of RMTs in registration trials is still relatively rare. In the absence of formal European regulatory guidance on mHealth technologies, insight in the main recommendations of the CHMP may stimulate the use of novel RMTs in a regulatory context., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Dekker, Stolk and Pasmooij.)

Aims: The field of cell-based therapies for human diseases is currently evolving from promising treatment options to established therapeutic concepts. The design of the nonclinical development program for cell-based products, intended to provide a rationale for treatment and to gain insight into the safety profile, is challenging because of limitations caused by species-specificity. The elements of the nonclinical package for cell-based products were evaluated using advice reports from the European Medicines Agency database from 2013 to 2018 to identify the approach followed for nonclinical development of these products., Methods: The number and purpose of proposed and performed in vivo studies was recorded, as well as the type and design of in vitro and in vivo studies addressing biodistribution and tumorigenicity. Subsequently, the nonclinical development program was analysed for consistency across products., Results: In vivo studies for cell-based therapies were primarily aimed at proof-of-concept (75/86), followed by addressing safety (64/86), biodistribution (49/86) and tumourigenicity (46/86). No animal studies were performed or proposed by sponsors or regulators for 6/86 products which contained cell types that have been studied in humans for a relatively long time. For one-third of the products in vivo biodistribution and/or tumourigenicity studies were not considered necessary. in vivo tumourigenicity studies were regarded as having limited value., Conclusions: Compared to more conventional medicinal products, the nonclinical development program for cell-based products was more tailored and focused on proof-of-concept. For tumourigenicity an in vitro approach may suffice. Total omission of in vivo studies appears to be possible for products with sufficient clinical experience., (© 2020 The British Pharmacological Society.)

Background: Epidermolysis bullosa (EB) is a heterogeneous group of rare and incurable genetic disorders characterized by fragility of the skin and mucosae, resulting in blisters and erosions. Several epidemiological studies in other populations have been carried out, reporting varying and sometimes inconclusive figures, highlighting the need for standardized epidemiological analyses in well-characterized cohorts., Objectives: To evaluate the epidemiological data on EB in the Netherlands, extracted from the molecularly well-characterized cohort in the Dutch EB Registry., Methods: In this observational study all EB-patients that were based in the Netherlands and captured in the Dutch EB Registry between 1988 and 2018 were included. The epidemiological outcomes were based on complete diagnostic data (clinical features, immunofluorescence, electron microscopy and mutation analysis), with longitudinal follow-up., Results: A total of 464 EB-patients (287 families) were included. The incidence and point-prevalence of EB in the Netherlands were 41.3 per million live births and 22.4 per million population, respectively. EB Simplex (EBS), Junctional EB (JEB), Dystrophic EB (DEB) and Kindler EB were diagnosed in 45.7%, 18.8%, 34.7% and 0.9% of the EB-patients, respectively, with an incidence and point-prevalence of 17.5 and 11.9 (EBS), 9.3 and 2.1 (JEB), 14.1 and 8.3 (DEB), 0.5 and 0.2 (Kindler EB). In 90.5% of the EB-patients the diagnosis was genetically confirmed. During the investigated time period 73 EB-patients died, 72.6% of whom as a direct consequence of their EB., Conclusion: The epidemiological outcomes of EB in the Netherlands are high, attributed to a high detection rate in a well-organized set-up, indicating that EB might be more common than previously assumed. These epidemiological data help to understand the extensive need for (specialized) medical care of EB-patients and is invaluable for the design and execution of therapeutic trials. This study emphasizes the importance of thorough reporting systems and registries worldwide., (© 2020 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology.)

Postapproval trials and patient registries have their pros and cons in the generation of postapproval data. No direct comparison between clinical outcomes of these data sources currently exists for advanced melanoma patients. We aimed to investigate whether a patient registry can complement or even replace postapproval trials. Postapproval single-arm clinical trial data from the Medicines Evaluation Board and real-world data from the Dutch Melanoma Treatment Registry were used. The study population consisted of advanced melanoma patients with brain metastases treated with targeted therapies (BRAF- or BRAF-MEK inhibitors) in the first line. A Cox hazard regression model and a propensity score matching (PSM) model were used to compare the two patient populations. Compared to patients treated in postapproval trials (n = 467), real-world patients (n = 602) had significantly higher age, higher ECOG performance status, more often ≥3 organ involvement and more symptomatic brain metastases. Lactate dehydrogenase levels were similar between both groups. The unadjusted median overall survival (mOS) in postapproval clinical trial patients was 8.7 (95% CI, 8.1-10.4) months compared to 7.2 (95% CI, 6.5-7.7) months (P < 0.01) in real-world patients. With the Cox hazard regression model, survival was adjusted for prognostic factors, which led to a statistically insignificant difference in mOS for trial and real-world patients of 8.7 (95% CI, 7.9-10.4) months compared to 7.3 (95% CI, 6.3-7.9) months, respectively. The PSM model resulted in 310 matched patients with similar survival (P = 0.9). Clinical outcomes of both data sources were similar. Registries could be a complementary data source to postapproval clinical trials to establish information on clinical outcomes in specific subpopulations., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc.)

Truly disruptive medicine innovation and new treatment paradigms tend to start in non-commercial research institutions. However, the lack of mutual understanding between medicine developers and regulators when it comes to medicine development significantly delays or even prevents the access of patients to these innovations. Here, we outline what regulatory-related barriers hamper the translational development of novel products or new treatment paradigms initiated in academia, and propose key steps towards improved regulatory dialogue among academia, funding bodies and regulatory authorities. Moreover, we briefly describe how the STARS (Strengthening Training of Academia in Regulatory Science) project aims to reach out to medicine innovators in academia to bridge the regulatory knowledge gap and enhance this dialogue to facilitate the implementation of academic research findings in clinical practice., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

The US Food and Drug Administration (FDA) has four expedited programs, including the breakthrough therapy designation (BTD). Recently, this program has been criticized. In this feature, we determine whether BTD oncology drugs were truly a breakthrough, based on the outcome of a validated instrument to measure clinical benefit. We find that only a few drugs were likely a breakthrough, indicating that the success rate of the BTD program is somewhat low. Despite this, we believe that programs for fast drug approval do have a place in the current regulatory practice and that the necessary efforts for their improvement should be further explored, especially considering the remaining unmet medical need for patients with cancer., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Dystrophic epidermolysis bullosa (DEB) is a devastating blistering disease affecting skin and mucous membranes. It is caused by pathogenic variants in the COL7A1 gene encoding type VII collagen, and can be inherited dominantly or recessively. Recently, promising proof-of-principle has been shown for antisense oligonucleotide (AON)-mediated exon skipping as a therapeutic approach for DEB. However, the precise phenotypic effect to be anticipated from exon skipping, and which patient groups could benefit, is not yet clear. To answer these questions, we studied new clinical and molecular data on seven patients from the Dutch EB registry and reviewed the literature on COL7A1 exon skipping variants. We found that phenotypes associated with dominant exon skipping cannot be distinguished from phenotypes caused by other dominant DEB variants. Recessive exon skipping phenotypes are generally relatively mild in the spectrum of recessive DEB. Therefore, for dominant DEB, AON-mediated exon skipping is unlikely to ameliorate the phenotype. In contrast, the overall severity of phenotypes associated with recessive natural exon skipping pivots toward the milder end of the spectrum. Consequently, we anticipate AON-mediated exon skipping for recessive DEB caused by bi-allelic null variants should lead to a clinically relevant improvement of this devastating phenotype., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Clinical application of topical gentamicin is a worthwhile option to investigate further for Nagashima-type palmoplantar keratosis and other genetic skin diseases caused by nonsense mutations. It is especially interesting to study gentamicin 1B because it may be more efficacious than other gentamicin components. Topical gentamicin has an acceptable safety profile, although prospective tracking of antibiotic resistance is warranted., (Copyright © 2017 The Author. Published by Elsevier Inc. All rights reserved.)

Revertant mosaicism, or "natural gene therapy", is the phenomenon in which germline mutations are corrected by somatic events. In recent years, revertant mosaicism has been identified in all major types of epidermolysis bullosa, the group of heritable blistering disorders caused by mutations in the genes encoding epidermal adhesion proteins. Moreover, revertant mosaicism appears to be present in all patients with a specific subtype of recessive epidermolysis bullosa. We therefore hypothesized that revertant mosaicism should be expected at least in all patients with recessive forms of epidermolysis bullosa. Naturally corrected, patient-own cells are of extreme interest for their promising therapeutic potential, and their presence in all patients would open exciting, new treatment perspectives to those patients. To test our hypothesis, we determined the probability that single nucleotide reversions occur in patients' skin using a mathematical developmental model. According to our model, reverse mutations are expected to occur frequently (estimated 216x) in each patient's skin. Reverse mutations should, however, occur early in embryogenesis to be able to drive the emergence of recognizable revertant patches, which is expected to occur in only one per ~10,000 patients. This underestimate, compared to our clinical observations, can be explained by the "late-but-fitter revertant cell" hypothesis: reverse mutations arise at later stages of development, but provide revertant cells with a selective growth advantage in vivo that drives the development of recognizable healthy skin patches. Our results can be extrapolated to any other organ with stem cell division numbers comparable to skin, which may offer novel future therapeutic options for other genetic conditions if these revertant cells can be identified and isolated.