Uptake of orphan drugs in the WHO essential medicines lists.

Objective: We evaluated the uptake of medicines licensed as orphan drugs by the United States Food and Drug Administration (FDA) or European Medicines Agency (EMA) into the WHO Model list of essential medicines and the WHO Model list of essential medicines for children from 1977 to 2021. Methods: We collated and analysed data on drug characteristics, reasons for adding or rejecting medicines, and time between regulatory approval and inclusion in the lists. We compared trends in listing orphan drugs before and after revisions to the inclusion criteria of the essential medicines lists in 2001, as well as differences in trends for listing orphan and non-orphan drugs, respectively. Findings: The proportion of orphan drugs in the essential medicines lists increased from 1.9% (4/208) in 1977 to 14.6% (70/478) in 2021. While orphan drugs for communicable diseases have remained stable over time, we observed a considerable shift towards more orphan drugs for noncommunicable diseases, particularly for cancer. The median period for inclusion in the essential medicines lists after either FDA or EMA first approval was 13.5 years (range: 1-28 years). Limited clinical evidence base and uncertainty about the magnitude of net benefit were the most frequent reasons to reject proposals to add new orphan drugs to the essential medicines lists. Conclusion: Despite lack of a global definition of rare diseases, the essential medicines lists have broadened their scope to include medicines for rare conditions. However, the high costs of many listed orphan drugs pose accessibility and reimbursement challenges in resource-constrained settings.

Use of antibiotics in the early COVID-19 pandemic in Poland, the Netherlands and Spain, from erraticism to (more) logic.

INTRODUCTION: In the Spring of 2020, the world was hit with unparalleled impact by the coronavirus pandemic. Antibiotics were widely used, even without good rationale. The aim of our study was to compare the use of antibiotics in patients with confirmed COVID-19 from three hospitals across Europe (Poland, the Netherlands and Spain) between two subsequent periods in the early days of the pandemic. METHOD: We analysed data (antibiotics used and variation in the use of antibiotics, patients, admission and disease-related characteristics) from 300 patients admitted in three hospitals (University Hospital in Cracow, University Medical Center in Utrecht and Vall d'Hebron University Hospital in Barcelona) with confirmed infection of SARS-CoV-2 during Q1 2020 and Q4 2020. RESULTS: There was ample variation in terms of patient mix and outcomes across the 3 hospitals. The majority of patients (225 out of 300) in all 3 hospitals received at least 1 antibiotic during the hospitalisation period. A minority of patients (68 out of 300) had their bacterial test results positive during their hospitalisation period. Throughout the 2 study periods, third-generation cephalosporins (ceftriaxone in 170 out of 300 patients) emerged as the most commonly used class of antibiotics. There was an apparent shift towards more rational utilisation of antibiotics, in all three hospitals. CONCLUSIONS: Our study shows that during the early stage of COVID-19 pandemic in 2020, antibiotics were frequently used in three European teaching hospitals despite the relatively low incidence of microbiologically confirmed bacterial infections. While in the early days of the COVID-19 pandemic antibiotic prescribing was full of trial and error, we could also confirm a learning curve over time.

Identifying Medicine Shortages With the Twitter Social Network: Retrospective Observational Study.

BACKGROUND: Early identification is critical for mitigating the impact of medicine shortages on patients. The internet, specifically social media, is an emerging source of health data. OBJECTIVE: This study aimed to explore whether a routine analysis of data from the Twitter social network can detect signals of a medicine shortage and serve as an early warning system and, if so, for which medicines or patient groups. METHODS: Medicine shortages between January 31 and December 1, 2019, were collected from the Dutch pharmacists' society's national catalog Royal Dutch Pharmacists Association (KNMP) Farmanco. Posts on these shortages were collected by searching for the name, the active pharmaceutical ingredient, or the first word of the brand name of the medicines in shortage. Posts were then selected based on relevant keywords that potentially indicated a shortage and the percentage of shortages with at least 1 post was calculated. The first posts per shortage were analyzed for their timing (median number of days, including the IQR) versus the national catalog, also stratified by disease and medicine characteristics. The content of the first post per shortage was analyzed descriptively for its reporting stakeholder and the nature of the post. RESULTS: Of the 341 medicine shortages, 102 (29.9%) were mentioned on Twitter. Of these 102 shortages, 18 (5.3% of the total) were mentioned prior to or simultaneous to publication by KNMP Farmanco. Only 4 (1.2%) of these were mentioned on Twitter more than 14 days before. On average, posts were published with a median delay of 37 (IQR 7-81) days to publication by KNMP Farmanco. Shortages mentioned on Twitter affected a greater number of patients and lasted longer than those that were not mentioned. We could not conclusively relate either the presence or absence on Twitter to a disease area or route of administration of the medicine in shortage. The first posts on the 102 shortages were mainly published by patients (n=51, 50.0%) and health care professionals (n=46, 45.1%). We identified 8 categories of nature of content. Sharing personal experience (n=44, 43.1%) was the most common category. CONCLUSIONS: The Twitter social network is not a suitable early warning system for medicine shortages. Twitter primarily echoes already-known information rather than spreads new information. However, Twitter or potentially any other social media platform provides the opportunity for future qualitative research in the increasingly important field of medicine shortages that investigates how a larger population of patients is affected by shortages.

Trends in orphan medicinal products approvals in the European Union between 2010-2022.

BACKGROUND: Over the last twenty years of orphan drug regulation in Europe, the regulatory framework has increased its complexity, with different regulatory paths and tools engineered to facilitate the innovation and accelerate approvals. Recently, the proposal of the new Pharmaceutical Legislation for the European Union, which will replace at least three Regulations and one Directive, was released and its new framework is raising many questions. The aim of this study was to present a characterisation of the Orphan Medicinal Products (OMPs) authorised by the European Commission (EC), between 2010 and 2022, looking into eighteen variables, contributing to the ongoing discussion on the proposal and implementation of the new Pharmaceutical Legislation proposed. METHODS: Data of the OMPs identified and approved between 2010 and 2022 were extracted from the European Public Assessment Reports (EPARs) produced by the European Medicines Agency. Information regarding legal basis of the application, applicant, protocol assistance received, type of authorization, registration status, type of molecule, ATC code, therapeutic area, target age, disease prevalence, number of pivotal clinical trials supporting the application, clinical trial designs, respective efficacy endpoints and number of patients enrolled in the pivotal clinical trials were extracted. A descriptive statistical analysis was applied. RESULTS: We identified 192 OMPs approved in the period between 2010 and 2022. 89% of the OMPs have legal basis of "full application". 86% of the sponsors received protocol assistance whereas 64% of the MAA benefited from the accelerated assessment. 53% of the active substances are small molecules; about 1 in 5 molecules are repurposed. 40% of the OMPs have oncological therapeutic indications and 56% of the OMPs are intended to treat only adults. 71% of the products were approved based on a single pivotal trial. CONCLUSIONS: This analysis of OMPs approved between 2010 and 2022 shows that a shift has occurred in the rare disease medicine development space. Through the period studied we observe an increase of non-small molecules approved, accelerated assessment received and non-standard MA's granted.

Successes and pitfalls in orphan drug development for sickle cell disease.

ABSTRACT: Sickle cell disease (SCD) is a hereditary red cell disorder with a large disease burden at a global level. In the United States and Europe, medicines may qualify for orphan designation (OD), a regulatory status that provides incentives to boost development. We evaluated the development of new therapies for SCD using data for OD granted in the United States and Europe over the last 2 decades (2000-2021). We analyzed their characteristics, pathophysiological targets, trends, and OD sponsors. We then investigated the approval outcomes, including the phase success rate and reasons for discontinuation across different variables. We identified 57 ODs for SCD: 43 (75.4%) small molecules, 32 (56.1%) for oral administration, and 36 (63.1%) for chronic use to prevent SCD complications. At the end of the study (2021), development of 34 of 57 ODs was completed. Four ODs were approved with a success rate of 11.8%. Products targeting upstream causative events of SCD pathophysiology had a 1.8 higher success rate compared with products targeting disease consequences. Large companies showed a fourfold higher success rate compared with small-medium enterprises. Failures in clinical development were mainly seen in phase 3 for a lack of efficacy on vaso-occlusive crisis as the primary study end point, likely related to variable definitions and heterogeneity of pain scoring and treatment. Both advances in SCD knowledge and regulatory incentives paved the way for new therapies for SCD. Our finding of high failure rates in late-stage clinical development signals the need for better early-stage predictive models, also in the context of meaningful clinical end points.

The Evolution of Drug Regulatory Sciences in the Netherlands: More than a Country Report.

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.

Feasibility of disease terminology systems for mapping orphan conditions and therapeutic indications of designated orphan medicines in the European Union.

BACKGROUND: In the European Union, rare diseases are defined as diseases that affect maximum 5 in 10,000 citizens. These diseases are typically associated with a high unmet medical need. To stimulate development and authorisation of medicines for rare diseases ('orphan conditions'), the European Commission (EC) can grant orphan designations. In order to enable systematic evaluation and communication of the diseases for which designated orphan medicines have (not) been developed and authorised, we aimed to investigate the feasibility of important disease terminology systems for mapping orphan conditions and therapeutic indications. METHODS: We selected all designated orphan medicines that were authorised by the EC during 2022-2023 from the EC's Union Register of medicinal products. For these medicines, we extracted orphan conditions and associated therapeutic indications at initial marketing authorisation. The orphan conditions and separate elements of therapeutic indications such as target disease or condition, severity criteria and target population were assessed for availability in six major disease terminology systems: ICD-10, ICD-11, MedDRA, MeSH, Orphanet nomenclature of rare diseases, and SNOMED CT. Descriptive statistics were used to describe the ability of each disease terminology system to map orphan conditions and elements of therapeutic indications. RESULTS: During 2022-2023, 37 designated orphan medicines were authorised that were designated for 40 orphan conditions (of which 37 unique) and granted 39 therapeutic indications (of which 37 unique). Overall, SNOMED CT covered most descriptions of orphan conditions (33/37, 89%) and target diseases or conditions within therapeutic indications (28/37, 76%). However, when allowing descriptions to be partly included and/or complemented by additional words, SNOMED CT, the Orphanet nomenclature, ICD-11 and MedDRA all had high coverage (92-97%). Other elements than target diseases or conditions within therapeutic indications were mostly lacking. CONCLUSIONS: Regulatory data concerning orphan conditions and therapeutic indications of designated orphan medicines seem to be best covered by SNOMED CT. However, which disease terminology system best facilitates systematic evaluation and communication about development and authorisation of designated orphan medicines also dependents on the specific use case. Given the frequent use of SNOMED CT in healthcare settings, it may also facilitate interoperability between regulatory and healthcare data, while for example ICD-11 may be better suited to generate statistics concerning drug development for rare diseases.