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.

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.

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.

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.

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.

Perspectives on how to build bridges between regulation, health technology assessment and clinical guideline development: a qualitative focus group study with European experts.

OBJECTIVE: Improving synergy among regulation, health technology assessment (HTA) and clinical guideline development is relevant as these independent processes are building on shared evidence-based grounds. The two objectives were first to assess how convergence of evidentiary needs among stakeholders may be achieved, and second, to determine to what extent convergence can be achieved. DESIGN: Qualitative study using eight online dual-moderator focus groups. SETTING: Discussions had a European focus and were contextualised in four case studies on head and neck cancer, diabetes mellitus, multiple sclerosis and myelodysplastic syndromes. PARTICIPANTS: Forty-two experienced (over 10 years) European regulators, HTA representatives and clinicians participated in the discussion. INTERVENTIONS: Participants received information on the case study and research topic in advance. An introductory background presentation and interview guide for the moderators were used to steer the discussion. RESULTS: Convergence may be achieved through improved communication institutionalised in multistakeholder early dialogues, shared definitions and shared methods. Required data sets should be inclusive rather than aligned. Deliberation and decision-making should remain independent. Alignment could be sought for pragmatic clinical trial designs and patient registries. Smaller and lower-income countries should be included in these efforts. CONCLUSION: Actors in the field expressed that improving synergy among stakeholders always involves trade-offs. A balance needs to be found between the convergence of processes and the institutional remits or geographical independence. A similar tension exists between the involvement of more actors, for example, patients or additional countries, and the level of collaboration that may be achieved. Communication is key to establishing this balance.

Traits, trends and hits of orphan drug designations in cystic fibrosis.

BACKGROUND: In the United States (US) and in Europe, cystic fibrosis (CF) qualifies as a rare disease, thus positioning the field to benefit from regulatory incentives provided by orphan drug designation (ODD) to boost pharmaceutical research and development. In this study, we analyzed the pool of products for the treatment of CF that received such incentives from the US Food and Drug Administration (FDA) and/or the European Medicines Agency (EMA) over the past two decades. We describe the characteristics and trends in ODDs over time and explore factors that might be determinants of successful drug development. METHODS: We collected the products that received the ODD from the registries of the FDA and the EMA from 2000 to 2021, characterizing their nature, development stage, and type of sponsor. We categorized the study drugs according to the therapeutic target addressed and described trends of drug development over the study period. A logistic regression analysis was done to assess how ODD characteristics were associated with the approval for market authorization. RESULTS: From 2000-2021, 107 ODDs were collectively granted by the FDA and the EMA for products developed for the treatment of CF. Although the trends of the number of ODDs granted remained stable over time, those targeting the CF basic protein defect increased from 6 out of 54 (11.1%) in the first half of the study period up to 20 out of 54 (37.7%) in the second half, while those treating symptoms decreased from 48/54 (88.9%) to 33/53 (62.3%). Overall, 10 products obtained marketing approval: 7 in both the US and Europe, 3 only in Europe. All the approved ODDs were chemical products for chronic use. No statistically significant difference was found across the examinated variables, but we observed possible drivers of successful drug development for ODDs targeting CFTR, as well as for those with active substances previously marketed, and for those developed by large companies and companies with experience in developing orphan drugs. By contrast, our findings suggest that financial issues most hamper the development of ODDs sponsored by small-medium enterprises. CONCLUSIONS: Although ODDs for treating infection and other CF sequelae accounted for the majority, we observed a shift of ODDs toward mechanism-based products over the study period. In line with other rare diseases, we found that approximately 1/10 ODDs for CF reached the status of marketing approval. Advances in disease genetics paved the way for a shift in CF drug development; however, we described how the convergence of pharmaceutical technology, the financial environment, and the regulatory ecosystem played a crucial role in successful marketing authorization in CF.

Post-approval quality-related regulatory actions for biopharmaceuticals approved in the European Union and the United States between 1995 and 2019.

The quality of biopharmaceuticals is carefully monitored by manufacturers and regulators to ensure safety and efficacy throughout the entire product life cycle. Quality defects can lead to post-approval regulatory actions (RAs) to inform healthcare professionals (HCPs). The present study identified quality-related RAs for biopharmaceuticals approved in the European Union and United States between 1995 and 2019. Quality-related RAs were issued due to various quality defects and required different actions by HCPs. The quality defects were not identified due to a negative impact on efficacy and/or safety, which is reassuring. The findings reflect the capability of the stringent regulatory system and quality control to capture and counter various quality defects before the affected product and batches can harm patients.

Regulatory, health technology assessment and company interactions: the current landscape and future ecosystem for drug development, review and reimbursement.

BACKGROUND: Multi-stakeholder interactions have evolved at product and policy levels. There is a need to assess the current and future landscape of interactions between companies, and regulatory and HTA agencies to address challenges and identify areas for improvement. OBJECTIVES: The aims of this study were to review the current interactions within and across regulatory and HTA agencies, and companies' experiences in engaging in these activities; to assess the added value of interactions as well as limitations; to explore the future ecosystem for stakeholder interactions. METHOD: Three separate questionnaires were developed for companies, regulators and HTA agencies, respectively, to assess their experiences and perceptions. The responses were analyzed using descriptive statistics and discussed at a multi-stakeholder workshop. Key outcomes from the surveys and workshop discussion were reported. RESULTS: All seven regulators and seven HTA agencies in the survey indicated that they had stakeholder interactions. More formal collaboration occurred with regulators compared with HTA agencies. All nine companies have taken early advice but indicated the need for future prioritization. Success indicators can be built at the product and therapy levels, with the added value of faster patient access. Four principles were proposed for the future ecosystem: separate remit and functions between regulators and HTA; align processes; converge evidence requirements where possible; increase transparency. CONCLUSIONS: This research brought together regulators, HTA agencies, companies to examine how they interact with one another. We propose measures of value and make recommendations on future evolution to enable better evidence generation and improve regulatory and HTA decision-making.

Medicine shortages: impact behind numbers.

INTRODUCTION: Current research to assess the impact that medicine shortages have on patients is limited to general aspects, such as the prevalence of shortages and product characteristics. The aim of this study is to assess the overall impact that medicine shortages have on economic, clinical, and humanistic outcomes. METHODS: A cohort of all known products in shortage in the Netherlands between 2012 and 2015 were characterized by their route of administration, anatomical therapeutic chemical class, and whether they were originator or generic products. A representative sample of 324 shortages (18% of all shortages) was rated as having low, medium, or high impact on the five elements that determine the impact of shortages on patients: availability of an alternative product, underlying disease, susceptibility of the patient, costs (for patients and society at large), and number of patients affected. Ratings were converted into numerical scores per element and multiplied to obtain an overall impact score. RESULTS: Two elements were most frequently rated as having a high impact: disease (29%) and costs (20%). Nearly half of the shortages (47%) rated high on at least one element, while nearly 10% rated high on multiple elements. Thirty percent of the shortages rated high on direct impact, which is represented by these elements: alternative product and disease. An additional 17% of the shortages rated high on indirect impact, which is represented by these elements: costs, susceptibility, and number of patients. High impact scores could not significantly be attributed to characteristics of the products in shortage. CONCLUSIONS: An assessment of the medicine shortages' impact using a framework based on economic, clinical, and economic outcomes showed that all three outcomes affect the overall impact that medicine shortages have on patients.

Impact of medicine shortages on patients - a framework and application in the Netherlands.

BACKGROUND: Medicine shortages are often described in plain numbers, suggesting all shortages have a uniform impact. However, some shortages have a direct and serious effect on patients and need a prompt reaction from stakeholders. This study aims to create a broad framework to assess the impact of a shortage. METHOD: We identified high impact shortages and selected exemplary shortages which we considered our learning cases. From five learning cases, we identified elements that had a potentially profound impact on one or more of these cases. We tested data saturation on the elements with another five test cases. Based on these elements, we created a framework to assess impact of shortages on patients and presented practical examples how to rate these different elements. Subsequently, we visualised the impact of these five learning cases on patients in radar charts. RESULTS: The five elements which we identified as potentially having a large impact were 1) alternative product, 2) disease, 3) susceptibility, 4) costs and 5) number of patients affected. The five learning cases rated high on different elements, leading to diverse and sometimes even opposite patterns of impact. CONCLUSION: We created a framework for assessing the impact of a medicine shortage on patients by means of five key elements. By rating these elements, an indication of the impact can be obtained.

Longitudinal study of Good Pharmacy Practice roles covered at the annual world pharmacy congresses 2003-2019.

BACKGROUND: Globally accepted roles of pharmacists are described in the Good Pharmacy Practice (GPP) standards, published by the World Health Organization (WHO) and the International Pharmaceutical Federation (FIP) in 2011. These standards provide a wide-ranging description of four main roles pharmacists fulfil. The global platform, where pertinent discussions around excellence and innovation in various pharmacy roles take place, is the annual congress of the pharmacy organisation representing the profession globally, FIP. OBJECTIVES: Given the world pharmacy congresses present and reflect on the most topical and contemporary matters, this longitudinal study aimed at creating a historical overview of the frequency of appearance of the different GPP roles in the programmes of the past 17 congresses (2003-2019). This is to distinguish the dominance of different roles over time and thus their relevance for the profession. METHODS: The GPP standards served as a framework to create a set of keywords that were analysed for their frequencies of appearance in the programmes through text analysis. Trends in the four overarching GPP roles and at individual keyword level were analysed descriptively over time. RESULTS: The study found that all four GPP roles appeared in the programme each year and none of them was significantly missing, neither in the decade preceding the publication of the GPP standards nor in the decade thereafter. Role 3 "Maintain and improve professional performance" was most frequently represented, also demonstrating an upward trend in appearance, together with Role 4: "Contribute to improve effectiveness of the health-care system and public health". Trends emerged towards patient-centred clinical focus and positioning pharmacy as an important player in the health-care system-observed also at individual keywords level in areas such as health promotion-away from the more traditional product-centred practice roles such as compounding. CONCLUSIONS: GPP roles have been already covered by the FIP annual congresses (long) before 2011, when the GPP roles were formally adopted, and they stayed relevant in the decade after. The more pronounced dominance toward the roles related to improving professional performance and positioning pharmacy are in line with the trend that the rather technical topics in pharmacy are increasingly covered by specialised meetings and that the FIP annual congresses have moved toward more general, scholarly platforms for dialogue and conversation.

Emergent treatments for ß-thalassemia and orphan drug legislations.

In many countries, ß-thalassemia (ß-THAL) is not uncommon; however, it qualifies as a rare disease in the US and in European Union (EU), where thalassemia drugs are eligible for Orphan Drug Designation (ODD). In this paper, we evaluate all 28 ODDs for ß-THAL granted since 2001 in the US and the EU: of these, ten have since been discontinued, twelve are pending, and six have become licensed drugs available for clinical use. The prime mover for these advances has been the increasing depth of understanding of the pathophysiology of ß-THAL; at the same time, and even though only one-fifth of ß-THAL ODDs have become licensed drugs, the ODD legislation has clearly contributed substantially to the development of improved treatments for ß-THAL.

Challenges and Opportunities for Companies to Build HTA/Payer Perspectives Into Drug Development Through the Use of a Dynamic Target Product Profile.

Background: The target product profile (TPP) outlines the desired profile of a target product aimed at a particular disease and is used by companies to plan clinical development. Considering the increasing importance of health technology assessment (HTA) in informing reimbursement decisions, a robust TPP needs to be built to address HTA needs, to guide an integrated evidence generation plan that will support HTA submissions. This study assessed current practices and experiences of companies in building HTA considerations into TPP development. Methods: An opinion survey was designed and conducted in 2019, as a cross-sectional questionnaire consisting of multiple-choice questions. The questionnaire provided a qualitative assessment of companies' strategies and experiences in building HTA considerations into the TPP. Eligible survey participants were the senior management of Global HTA/Market Access Departments at 18 top international pharmaceutical companies. Results: 11 companies responded to the survey. All companies included HTA requirements in TPP development, but the timing and process varied. The key focus of HTA input related to health problems and treatment pathways, clinical efficacy/effectiveness, and safety. Variance of HTA methods and different value frameworks were identified as a challenge for development plans. Stakeholder engagement, such as HTA scientific advice, was used to pressure test the TPP. Conclusion: This research provides insight into current practice and potential opportunities for value-based drug development. It demonstrates the evolution of the TPP to encompass HTA requirements and suggests that the TPP could have a role as an iterative communication tool for use with HTA agencies to enhance an integrated evidence generation plan.

Healthcare Professionals' Views on the Management of Medication Complexities in the Elderly With Mental Health Disorders: A Cross-Sectional Study.

Background: Many challenges in elderly pharmacotherapy are identified, including the use of Potentially Inappropriate Medications (PIMs) which may increase the odds of adverse events, especially in elderly patients with mental health disorders (e. g., behavioral, and psychological symptoms of dementia-BPSD, schizophrenia, bipolar disorder). However, information on the knowledge and practice of healthcare professionals (HCPs) about this topic is still scarce. Methods: A cross-sectional study was undertaken from July-October 2019. An online questionnaire was specifically designed and validated for this study. We sought HCPs (physicians, pharmacists, and nurses) worldwide, using (a) social media, via Facebook, Twitter, and LinkedIn; and (b) email contacts of the research team (convenience sample). Either way participants were asked to share on their social media or via e-mail the questionnaires with other HCPs (snowballing sample). The survey assessed two main domains: knowledge and practice. Knowledge was evaluated by self-report (perceived knowledge by a 5-item Likert confidence scale) and using three clinical cases, scored between 0 and 30 points (each one rated from 0 to 10 points; real knowledge). Barriers in clinical practice were evaluated using a 5-item Likert scale judging practitioners' opinion. Results: A total of 165 questionnaires were collected. HCPs were mainly female (n = 114; 69.1%), with a mean age of 35.3 ± 11.3 years old. Seventy-two percent (n = 118) were pharmacists, 21.1% (n = 35) were physicians, and 7.3% (n = 12) nurses. There was a weak correlation, albeit significant, between perceived and real knowledge (r = 0.199; p = 0.001). The mean score of the clinical vignettes regarding elderly patients with dementia and bipolar disorder were 4.59 ± 4.08 and 4.86 ± 2.97 points, respectively. Most HCPs were classified as having an intermediate knowledge (n = 100; 60.6%) about medication complexities in the elderly with mental disorders. Most HCPs agreed that lack of time (81.6%; n = 138), lack of education and training on elderly pharmacotherapy (72.2%; n = 122), and lack of tools adapted to daily practice (61.8%; n = 105) were the main barriers. Conclusions: Most of the HCPs felt confident to manage medication complexities in elder patients with mental disorders, but only a minority obtained a good score in the knowledge assessment test. The main barriers identified included structural barriers (tools unfit for practice) and process barriers (time).

Nature and timing of post-approval manufacturing changes of tumour necrosis factor α inhibitor products: A 20-year follow-up study of originators and biosimilars.

The manufacturing of biopharmaceuticals is complex, and minor changes in the process may affect quality attributes (QAs) that may, in turn, impact clinical outcomes. Regulatory documents from the European Medicines Agency were used to characterize two aspects, nature and timing, of post-approval MCs for originators and biosimilars TNF-α inhibitors that were on the European market up to May 2021. The nature of MCs was evaluated in two ways: (1) the type of MCs related to the drug substance (DS) or drug product (DP), classified as manufacturing, quality control, composition, packaging, or stability with various subtypes; and (2) the risk level according to the potential impact of the MCs on QAs, classified as low, medium, or high. Timing was defined as the date of the regulatory decision on the MC in relation to the approval date. We identified 801 post-approval MCs implemented to originators (mean: 137, range: 112-175) and biosimilars (mean: 30, range: 0-133). Most of implemented MCs for originators and biosimilars were classified as low and medium risk (88.1%), and a small fraction were considered high-risk (11.9%). The average incidence rates were comparable for both originators and biosimilars (7.0/year for MCs, 0.8/year for high-risk MCs). In 20% of MCs introduced to biosimilars, the DP manufacturing site was involved (9% for originators). In contrast, 16% of MCs introduced to originators were related to the DS manufacturing processes (only 7% for biosimilars). In conclusion, while the overall MC incidence rate and the risk level of MCs was not substantially different between TNF-α inhibitor products, we observed some differences in a few types of MCs related to DS manufacturing process and DP manufacturing site between originators and biosimilars. As far as our data shows there is no reasons to assume that post-approval MCs will lead to differences between TNF-α-i originators and biosimilars in clinical practice.

Mapping the risk of infections in patients with multiple sclerosis: A multi-database study in the United Kingdom Clinical Practice Research Datalink GOLD and Aurum.

BACKGROUND: People with multiple sclerosis (pwMS) have an increased risk of infections; risk factors include underlying disease, physical impairment and use of some disease-modifying treatments. OBJECTIVE: To quantify changes in population-level infection rates among pwMS and compare these to the general population and people with rheumatoid arthritis (pwRA), and identify patient characteristics predictive of infections after MS diagnosis. METHODS: We conducted a multi-database study using data on 23,226 people with MS diagnosis from the UK Clinical Practice Research Datalink Aurum and GOLD (January 2000-December 2020). PwMS were matched to MS-free controls and pwRA. We calculated infection rates, and estimated incidence rate ratios (IRR) and 95% confidence intervals (CI) of predictors for infections ⩽ 5 years after MS diagnosis using Poisson regression. RESULTS: Among pwMS, overall infection rates remained stable - 1.51-fold (1.49-1.52) that in MS-free controls and 0.87-fold (0.86-0.88) that in pwRA - although urinary tract infection rate per 1000 person-years increased from 98.7 (96.1-101) (2000-2010) to 136 (134-138) (2011-2020). Recent infection before MS diagnosis was most predictive of infections (1 infection: IRR 1.92 (1.86-1.97); ⩾2 infections: IRR 3.00 (2.89-3.10)). CONCLUSION: The population-level elevated risk of infection among pwMS has remained stable despite the introduction of disease-modifying treatments.

The impact of FDA and EMA regulatory decision-making process on the access to CFTR modulators for the treatment of cystic fibrosis.

BACKGROUND: Over the past decade, a new class of drugs called CFTR (cystic fibrosis transmembrane conductance regulator) modulators have shown to be able to improve clinical outcomes in patient with Cystic Fibrosis. In this analysis, we have extensively reviewed the regulatory pathways and decisions adopted by FDA and EMA to speed up the development, the review and the approval of these drugs, with the aim of identifying possible clinical and public health implications associated with differences. RESULTS: CFTR modulators have been developed towards addressing three main genetic domains: (1) F508del homozygous (F508del/F508del), (2) F508del heterozygous, and (3) genotypes not carrying F508del mutation; and expanded from adult to paediatric population. Programs to expedite the reviewing and licensing of CFTR modulators were extensively adopted by FDA and EMA. All CFTR modulators have been licensed in the US as orphan drugs, but in the EU the orphan status for LUM/IVA was not confirmed at the time of marketing authorization as results from the pivotal trial were not considered clinically significant. While FDA and EMA approved CFTR modulators on the basis of results from phase III double-blind RCTs, main differences were found on the extension of indications: FDA accepted non-clinical evidence considering a recovery of the CFTR function ≥ 10% based on chloride transport, a reliable indicator to correlate with improvement in clinical outcomes. By contrast, EMA did not deem preclinical data sufficient to expand the label of CFTR modulators without confirmatory clinical data. CONCLUSIONS: Regulators played an important role in fostering the development and approval of CFTR modulators. However, differences were found between FDA and EMA in the way of reviewing and licensing CFTR modulators, which extended beyond semantics affecting patients' eligibility and access: FDA's approach was more mechanistic/biology-driven while the EMA's one was more oriented by clinical evidence. This might refer to the connection between the EMA and the Member States, which tends to base decisions on pricing and reimbursement on clinical data rather than pre-clinical ones. Here we have proposed a two-step personalized-based model to merge the ethical commitment of ensuring larger access to all potential eligible patients (including those harboring very rare mutations) with the one of ensuring access to clinically assessed and effective medicines through Real World Data.

Four scenarios for the future of medicines and social policy in 2030.

The future of medicines is likely determined by an array of scientific, socioeconomic, policy, medical need, and geopolitical factors, with many uncertainties ahead. Here, we report from a scenario project, analyzing various trends, crucial and complex developments in the medicines' space. From a range of 'critical uncertainties' we derived two scenario drivers: global convergence, ranging from very high (trust and solidarity), to very low (fragmented ecosystems); and disease orientation, ranging from public health first to interceptive medicine. This resulted in four contrasting portraits of the future of medicines and social policy: deprioritizing the high-end; sustainable flow; transformative healing; and global divide. All those involved in drug discovery and development can use these for strengthening preparedness for the crucial challenges ahead.