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João Pedro Aguiar,1 Luís Heitor Costa,2 Filipa Alves da Costa,3,4 Hubert GM Leufkens,5 Ana Paula Martins1 1Research Institute for Medicines (iMED.ULisboa), Faculdade de Farmácia, Universidade de Lisboa, Lisboa, Portugal; 2Serviço de Medicina Interna, Centro Hospitalar Psiquiátrico de Lisboa (CHPL), Lisboa, Portugal; 3Centro de Investigação Interdisciplinar Egas Moniz (CiiEM), Instituto Universitário Egas Moniz (IUEM), Caparica, Portugal; 4Faculdade de Farmácia, Universidade de Lisboa, Lisboa, Portugal; 5Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, the Netherlands Purpose: Cardiovascular diseases (CVDs) are extremely common among the elderly, but information on the use of potentially inappropriate medications (PIMs) with cardiovascular risk is scarce. We aimed to determine the prevalence of PIMs with risk of cardiac and cerebrovascular adverse events (CCVAEs), including major adverse cardiac and cerebrovascular events (MACCE). Patients and methods: A cross-sectional study was performed using a convenience sample from four long-term care facilities and one community pharmacy in Portugal. Patients were included if they were aged 65 or older and presented at least one type of medication in their medical and pharmacotherapeutic records from 2015 until December 2017. The main outcome was defined as the presence of PIMs with risk of MACCE and was assessed by applying a PIM-MACCE list that was developed from a previous study. All medications included in this list were assessed for their availability in Portugal. Results: A total of 680 patients were included. Of those, 428 (63%) were female with a mean age of 78.4±8.1 years. Four-hundred and four (59.4%) patients were taking medications associated with CCVAEs risk (mean =1.7±1.0 drugs/patient), including 264 patients (38.8%) who used drugs with MACCE risk (mean =1.4±0.8 drugs/patient). Fifty percent of patients with a previous history of CVD (n=521) were taking PIMs with risk of CCVAEs, including 30.0% with risk of MACCE. Conclusion: Our findings show that 50% of patients with previous history of CVD were taking drugs with risk of CCAVEs and 30% with risk of MACCE. More tailored tools for the management of drug therapy in elderly patients with CVD are of major importance in clinical practice. Keywords: patient safety, therapeutic uses, outcome process assessment (health care), cardiovascular risk, NSAIDs, antipsychotics

Evans L Sagwa,1 Nunurai Ruswa,2 Farai Mavhunga,2 Timothy Rennie,3 Hubert GM Leufkens,1,4 Aukje K Mantel-Teeuwisse1 1Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, the Netherlands; 2National Tuberculosis and Leprosy Program, Ministry of Health and Social Services, Windhoek, Namibia; 3Department of Pharmacy Practice and Policy, University of Namibia School of Pharmacy, Windhoek, Namibia; 4Medicines Evaluation Board, Utrecht, the Netherlands Purpose: The health-related quality of life (HRQoL) of patients completing multidrug-resistant tuberculosis (MDR-TB) treatment in Namibia and whether the occur­rence of adverse events influenced patients’ rating of their HRQoL was evaluated. Patients and methods: A cross-sectional analytic survey of patients completing or who recently completed MDR-TB treatment was conducted. The patients rated their HRQoL using the simplified Short Form-8™ (SF-8) questionnaire consisting of eight Likert-type questions. Three supplemental questions on the adverse events that the patients may have experienced during their MDR-TB treatment were also included. Scoring of HRQoL ratings was norm-based (mean =50, standard deviation =10) ranging from 20 (worst health) to 80 (best health), rather than the conventional 0–100 scores. We evaluated the internal consistency of the scale items using the Cronbach’s alpha, performed descriptive analyses, and analyzed the association between the patients’ HRQoL scores and adverse events. Results: Overall, 36 patients (20 males, 56%) aged 17–54 years (median =40 years) responded to the questionnaire. The median (range) HRQoL score for the physical component summary was 58.6 (35.3–60.5), while the median score for the mental component summary was 59.3 (26.6–61.9), indicating not-so-high self-rating of health. There was good internal consistency of the scale scores, with a Cronbach’s alpha value of >0.80. In all, 32 (89%) of the 36 patients experienced at least one adverse drug event of any severity during their treatment (median events =3, range 1–6), of which none was life-threatening. The occurrence of adverse events was not related to HRQoL scores. For patients reporting zero to two events, the median (range) HRQoL score was 56.8 (44.4–56.8), while for those reporting three or more events, the median score was 55.2 (38.6–56.8); P=0.34 for difference between these scores. Conclusion: Patients completing treatment for MDR-TB in Namibia tended to score moderately low on their HRQoL, using the generic SF-8 questionnaire. The occurrence of adverse events did not lead to lower HRQoL scores upon treatment completion. Keywords: drug safety, patient-reported health outcomes, SF-8™ questionnaire, second-line tuberculosis drugs, Namibia

Progressive multifocal leukoencephalopathy (PML) has been identified as a serious adverse drug reaction (ADR) of several immunomodulatory biologicals. In this study, we contrasted the reporting patterns of PML for two biologicals for which the risk was identified at different points in their lifecycle: natalizumab (before reapproval) and rituximab (nine years postapproval). We found that, apart from the differences in clinical characteristics (age, gender, indication, time to event, fatality), which reflect the diversity in context of use, PML reports for natalizumab were more complete and were received sooner after occurrence. This study serves as an important reminder that spontaneous reports should only be used with great caution to quantify and compare safety profiles across products over time. The observed variability in reporting patterns and heterogeneity of PML cases presents challenges to such comparisons. Lumping uncharacterized PML reports together without taking these differences into account may result in biased comparisons and flawed conclusions about differential safety. [ABSTRACT FROM AUTHOR]

Objective: To investigate the main aims of the post-approval randomized controlled trials (RCTs) on etanercept and the extent to which they were designed to gain more comparative information. Methods: A search of the literature (Medline, Embase), trial registries (Clinical Trials.gov, Controlled Trials.com), and market authorization reports from the Food and Drug Administration (FDA) and the European Medicines Agency (EMEA) was carried out to identify all RCTs. A comparison of trial data identified unpublished trials and multiple publications relating to the same study. All RCTs completed and/or published after initial market approval was regarded as post-approval. Results: Up until 2008, we found 84 post-approval trials, 11 (13%%) trials on approved extensions of indication, another 30 (36%%) trials on the approved indications, and 43 (51%%) trials on indications not (yet) approved. Nearly half of the studies on indications not yet approved were initiated and funded by independent sponsors. After the initial approval of etanercept, six head-to-head trials were conducted on the approved indications. Overall, the main objectives of post-approval trials with etanercept were found to confirm efficacy and safety in new indications, and to gather additional information for optimal use on the approved indications. Conclusion: Post-approval RCTs on etanercept focus more on studies searching for new indications than on deepening knowledge about use. Ten years after the market entry of etanercept, one of the reasonable demands of clinical practice, for more comparative information, still remains unanswered. [ABSTRACT FROM AUTHOR]

The regulatory route leading to the definition of therapeutic indications of new compounds as well as extensions of indication (EoI) of already approved ones is a challenging process. If new anticancer drugs reach the market with a lack of complete evidence, this usually leads regulators to request additional data, post approval commitments or restrictions in therapeutic indications. This study aims at quantifying the time needed for anticancer drugs approved by the EMEA to get an extension, the rates and characteristics of extensions approved, and at exploring the regulatory process leading to the definition of new indications. A total of 103 therapeutic oncological indications, related to a cohort of 43 anticancer drugs, were retrieved between 1995 and 2008. The median time occurring between different indications for the same compound (defined as Time to New Extension, TtNE) significantly decrease from about 81 months in 1996 to 6 months in 2006. Twenty-four out of 43 approved anticancer medicines (about 56%) have only a single therapeutic indication, 12 of which were approved before 2005. When considering two different cohorts of drugs in relation to the time of approval (1995-2004 versus 2005-2008), although not statistically significant, the older cohort tended to have a decreased probability of having EoI when compared to the new cohort (OR=0.27; 95% confidence interval (CI): 0.07-1.04). With regard to the type of EoI (n=60), our findings showed that in 48% of cases the initially approved indication was extended to treat a different tumour, in 37% of cases the extension consisted in a switch of line within the same therapeutic indication. The other two types of indication broadening refer to a different tumour stage (8%) and to the inclusion of a new patient population (7%). The analysis of indication restrictions showed that in 20 cases out of 50 (40%) therapeutic indications were restricted by the Committee for Medicinal Products for Human Use (CHMP) during the assessment, with 60% of the restrictions occurring in 2006-2007. This study adds three main pieces of information: (i) the majority of anticancer drugs still have a single indication regardless of the year of approval; (ii) the time needed to obtain an extension of indication has decreased significantly over the last decade and (iii) a highest rate of regulatory restrictions is matched to shorter clinical developments. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To assess whether use of oral glucocorticoids is associated with cardiovascular and cerebrovascular morbidity. DESIGN AND SETTING: Nested case-control study within a cohort of patients (> or = 50 years old) with at least one prescription for oral or non-systemic glucocorticoids. Data were from the general practice research database. PATIENTS: 50 656 patients were identified with a first record for ischaemic heart disease (International classification of diseases, ninth revision (ICD-9) codes 410, 411, 413, and 414), ischaemic stroke or transient ischaemic attack (ICD-9 codes 430-436), or heart failure (ICD-9 code 428) between 1988 and 1998. One control was matched to each case by sex, age, general practice, underlying disease, and calendar time. MAIN OUTCOME MEASURE: Odds ratio (OR) of cardiovascular or cerebrovascular events in patients using oral glucocorticoids compared with non-users. RESULTS: There was a significant association between ever use of oral glucocorticoids and any cardiovascular or cerebrovascular outcome (adjusted OR 1.25, 95% confidence interval (CI) 1.21 to 1.29). The association was stronger for current use of oral glucocorticoids than for recent or past use. Among current users, the highest ORs were observed in the group with the highest average daily dose, although the dose-response relation was not continuous. Current use was associated with an increased risk of heart failure (adjusted OR 2.66, 95% CI 2.46 to 2.87), which was consistent between patients with rheumatoid arthritis, patients with chronic obstructive pulmonary disease, and patients without either of the two conditions. Also, current use was associated with a smaller increased risk of ischaemic heart disease (OR 1.20, 95% CI 1.11 to 1.29). CONCLUSIONS: Oral glucocorticoid use was identified as a risk factor for heart failure. However, the evidence remains observational and only a randomised controlled trial of glucocorticoid treatment versus other disease modifying agents is likely to distinguish the importance of the underlying disease activity from its treatment in predicting cardiovascular outcomes. [ABSTRACT FROM AUTHOR]

AIM: The purpose of this study was to investigate which factors determine the initiation of glucose-lowering therapy in patients with Type 2 diabetes mellitus in general practice and their future glycaemic control. METHODS: All incident Type 2 diabetic patients in the general practices in a Dutch middle-sized town from 1994 to 2000 were identified. Factors associated with initiation of glucose-lowering therapy were obtained from clinical files and examined by Cox's regression analyses. Using anova, the associations between clinical characteristics at diagnosis and future glycaemic control were investigated. RESULTS: In total, 603 newly diagnosed patients with Type 2 diabetes mellitus were included in the study. In the first month following diagnosis, 319 (53%) started with oral therapy. One, two and three years after diagnosis of diabetes, the cumulative incidences were 71% (95% CI 66-73%), 75% (71-79%) and 81% (77-84%), respectively. Age, gender, body weight, blood pressure, history of cardiovascular disease or total serum cholesterol values were not associated with time to start of drug therapy. An increased plasma glucose level at diagnosis was strongly related to faster initiation of drug therapy and worse future glycaemic control. Immediate initiation of glucose-lowering medication was not related to future glycaemic control. CONCLUSION: This study shows that the initial severity of diabetes, assessed by the degree of hyperglycaemia at time of diagnosis, is a major factor in determining the time to start of glucose-lowering drugs and the likelihood of achieving target levels of glycaemic control in the future, independent of glucose-lowering strategy. Therefore, patients with high glucose levels at diagnosis need close monitoring from the beginning of their disease. Copyright 2004 Diabetes UK [ABSTRACT FROM AUTHOR]

Objective: To study the association between use of alpha-blockers and risk of hip/femur fractures.Design: Population-based case-control study.Setting: General Practice Research Database.Subjects: Cases were defined as men, aged 40 years and older with a first diagnosis for hip/femur fracture. Controls were matched 1 : 1 on gender, year of birth and general practitioner-practice.Results: In all, 4571 cases and an equal number of controls were identified. Current use of alpha-blockers (prazosin, doxazosin, indoramin, terazosin, alfuzosin and tamsulosin) was compared with non-use of alpha-blockers. Current use of alpha-blockers on the index date was associated with an increased risk of hip/femur fracture [adjusted odds ratio (OR) 1.9, 95% confidence interval (CI): 1.1-3.0] in the overall analysis. The effect was particularly strong for first prescriptions within a treatment episode (adjusted OR 5.1, 95% CI: 1.0-31.7) and during the first month of treatment (adjusted OR 4.1, 95% CI: 0.7-23.9). Stratification according to indication of use showed that current use of alpha-blockers was not associated with hip/femur fracture in men with a diagnosis of benign prostatic hyperplasia (adjusted OR 1.0, 95% CI: 0.4-2.5), but was associated in men who used alpha-blockers for cardiovascular disease (adjusted OR 2.8, 95% CI: 1.4-5.4).Conclusion: Current use of alpha-blockers was associated with an increased risk of hip/femur fracture and with the start of a new treatment episode. The effect seemed to be confined to patients who used alpha-blockers for cardiovascular disease. Caution with respect to first-dose effects related to the initiation of a new episode of alpha-blocker treatment is advised. [ABSTRACT FROM AUTHOR]

Earlier epidemiologic studies have suggested an inverse association between non-Hodgkin's lymphoma and exposure to histamine(2) (H(2)) blockers, nonsteroidal anti-inflammatory drugs, cholesterol-lowering drugs, and antibiotics. Data from the PHARMO database were used to conduct a nested, population-based case-control study that included 1985-1998 drug-dispensing records for 300,000 residents of six Dutch cities. Included were those subjects without a previous history of cancer who were aged >/=20 years and were registered with an incident primary discharge diagnosis of non-Hodgkin's lymphoma between 1991 and 1998. This paper includes data on 211 cases and 800 controls individually matched on sex, age, community pharmacy, calendar time, and duration of follow-up. Conditional logistic regression analysis was used to evaluate the association between non-Hodgkin's lymphoma and categories of cumulative drug use in days. In multivariate analyses, nonsignificant risk reductions were found for all drugs tested, and the negative association tended to increase with increasing duration of use. For women, the odds ratio for H(2) blockers was 0.29 (95% confidence interval: 0.12, 0.69) and for analgesics was 0.40 (95% confidence interval: 0.22, 0.71). Results support an inverse association between occurrence of non-Hodgkin's lymphoma and use of H(2) blockers and analgesics among women, and they warrant confirmation in larger studies. [ABSTRACT FROM AUTHOR]

The article reports on a survey on the views of stakeholders on adaptive licensing (AL) and facilitated regulatory pathways (FRPs). It mentions that responders were randomly chosen selected from the Centre for Innovation in Regulatory Science. An overview of enforcing AL and the recognition of obstacles is also presented.

An early access pathway of conditional approval for potentially beneficial medicines is available within the European regulatory framework. However, marketing authorization does not necessarily result in recommendations for public funding by health technology assessment (HTA) agencies. As conditional approval goes along with less than complete data on benefits and risks of a treatment option for a high medical need, this raises the question how HTA decision-making is affected by these uncertainties. [ABSTRACT FROM AUTHOR]

Since 1977, the WHO Model List of Essential Medicines (EML), published by WHO, has provided advice for Member States that struggle to decide which pharmaceutical technologies should be provided to patients within their public health systems. Originating from outside WHO, an incentive system has been put in place by various governments for the development of medicines for rare diseases ('orphan drugs'). With progress in pharmaceutical research (e.g. drugs targeted for narrower indications), these medicines will feature more often on future public health agendas. However, when current definitions for selecting essential medicines are applied strictly, orphan drugs cannot be part of the WHO Essential Medicines Programme, creating the risk that WHO may lose touch with this field. In our opinion WHO should explicitly include orphan drugs in its policy sphere by composing a complementary Orphan Medicines Model List as an addition to the EML. This complementary list of 'rare essentials' could aid policy-makers and patients in, for example, emerging countries to improve access to these drugs and stimulate relevant policies. Furthermore, inconsistencies in the current EML with regard to medicines for rare diseases can be resolved. In this paper we propose selection criteria for an Orphan Medicines Model List that could form a departure point for future work towards an extensive WHO Orphan Medicines Programme. Copyright © 2006 World Health Organization [ABSTRACT FROM AUTHOR]

Cardiac arrhythmia as an adverse effect of noncardiac drugs has been an issue of growing importance during the past few years. In this population-based study, we evaluated the risk for serious cardiac arrhythmias during the use of several noncardiac QTc-prolonging drugs in day-to-day practice, and subsequently focused on several specific groups of patients who could be extremely vulnerable for drug-induced arrhythmias. We performed a case-control study in which patients (cases), hospitalized for nonatrial cardiac arrhythmias from 1987 to 1998, were compared with their matched controls regarding current use of QTc-prolonging drugs. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using multivariate conditional logistic regression, adjusting for potential confounding factors. Data were obtained from the PHARMO record linkage system. We identified 501 cases, 39 of whom used QTc-prolonging drugs. A statistically nonsignificant increased risk for arrhythmias (OR 1.2, 95% CI 0.8 to 1.9) was observed in patients who received QTc-prolonging drugs. A clearly increased risk of arrhythmias was, however, found in patients with a history of asthma (OR 9.9, 95% CI 1.0 to 100) and in patients using potassium-lowering drugs (OR 5.3, 95% CI 1.1 to. 25.9). Our data do not suggest that there is a strong overall association between the use of QTc-prolonging drugs and hospitalization for cardiac arrhythmias in the population at large. However, there appears to be clinically relevant associations of patients with a history of asthma and patients taking potassium-lowering drugs. The use of QTc-prolonging drugs should therefore be either avoided or monitored closely in these specific patients. [ABSTRACT FROM AUTHOR]

The European Commission (EC) has proposed to redefine 'unmet medical need' to steer pharmaceutical innovation and link the definition to incentives and regulatory tools and procedures. A multistakeholder meeting of the Regulatory Science Network Netherlands (RSNN) discussed the impact of this proposal. Four principles were highlighted (flexibility, feasibility, fairness, and sensitivity to risk) that were not considered sufficiently addressed. Concerns were raised about whether innovation would be incentivised, given the diverse and complex reasons why areas of unmet medical need may remain unaddressed. A more high-level definition of unmet medical need that gives guidance but allows for specification for specific uses throughout the medicine lifecycle was generally preferred. As the legislative process unfolds, stakeholder engagement will be essential to refine the definition to achieve the intended policy goals., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: The objective of this study was to assess the differential times of submission and approval of CFTR modulators in the United States (US) and the European Union (EU)., Methods: By collecting publicly available data from the websites of the Food and Drug Administration and the European Medicines Agency, we quantified differential times in submission, review duration, and approvals of initial marketing authorization and variation of indications of CFTR modulators in the US and the EU by December 31, 2023., Results: Applications regarding marketing of 4 CFTR modulators were submitted 103 (SD ±143) days later in the EU than in the US: 31 (SD ±39) days later for initial approval, and 124 (SD ±155) days for supplemental indications. The regulatory review process was completed in 181 days [IQR, 179 - 182] in the US and 325 days [IQR, 276 - 382] in the EU: 167 days [IQR, 102 - 232] in the US and 346 days [IQR, 302 - 400] in the EU for first approvals, 181 days [IQR, 181 - 182] in the US and 324 days [IQR, 264 - 382] in the EU for supplemental indication approvals. CFTR modulators were approved 267 (SD 143) days later in the EU than in the US: 220 (SD ±76) days for initial approval and 280 (SD ±157) days for supplemental indications., Conclusion: We found significant differences in times of submission and for approval of CFTR modulators between the US and EU, whereby initial approvals and subsequent indication approvals were always first granted in the US., Competing Interests: Declaration of competing interest Enrico Costa - Member of the Committee for Orphan Medicinal Products (COMP) at the EMA. The views expressed in this article are personal views and may not be understood or quoted as being made on behalf of or reflecting the position of the EMA. Silvia Girotti - None. Clément Mathieu - None. Carlo Castellani – Dr. Castellani has received payment or honoraria for lectures, presentations, speakers or educational events from Vertex Pharmaaceuticals and Chiesi, and he has participated on a Data Safety Monitoring Board or Advisory Board of Vertex Pharmaaceuticals and Chiesi. Joseph S. Ross - Dr. Ross currently receives research support through Yale University from Johnson and Johnson to develop methods of clinical trial data sharing, from the Food and Drug Administration for the Yale-Mayo Clinic Center for Excellence in Regulatory Science and Innovation (CERSI) program (U01FD005938), from the Agency for Healthcare Research and Quality (R01HS022882), and from Arnold Ventures; formerly received research support from the Medical Device Innovation Consortium as part of the National Evaluation System for Health Technology (NEST) and from the National Heart, Lung and Blood Institute of the National Institutes of Health (NIH) (R01HS025164, R01HL144644); and in addition, Dr. Ross was an expert witness at the request of Relator's attorneys, the Greene Law Firm, in a qui tam suit alleging violations of the False Claims Act and Anti-Kickback Statute against Biogen Inc. that was settled September 2022. Jennifer L. Taylor-Cousar - In the last 36 months, unrelated to this work, she has received grants to her institution from the Cystic Fibrosis Foundation, the National Institutes of Health, Vertex Pharmaceuticals Incorporated, Eloxx, and 4DMT; has received fees from Vertex Pharmaceuticals Incorporated related to consultation on clinical research design and participation on advisory boards; and has provided clinical trial design consultation for 4DMT. She served on a DMC for AbbVie. She serves as the adult patient care representative to the CFF Board of Trustees, and on the CF Foundation's Clinical Research Executive Committee, Clinical Research Advisory Board, and as immediate past chair of the CF TDN's Sexual Health, Reproduction and Gender Research Working Group, on the scientific advisory board for Emily's Entourage, and on the ATS Respiratory Health Awards Committee and is the ICC Chair-elect and served previously on the ATS Scientific Grant Review and Clinical Problems Assembly Programming Committees. She is also a member of the International Advisory Board for Lancet Respiratory Medicine and the Editorial Board for the Journal of Cystic Fibrosis. Hubert G. M. Leufkens - None., (Copyright © 2024. Published by Elsevier B.V.)

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., (©Doerine J Postma, Magali L A Heijkoop, Peter A G M De Smet, Kim Notenboom, Hubert G M Leufkens, Aukje K Mantel-Teeuwisse. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 06.08.2024.)

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.)

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., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Introduction: The COVID-19 pandemic highlighted an urgent need for harmonised requirements for the regulation of medicines. To fully implement harmonised medicines regulations across Africa, common technical standards of medicine regulations are needed. One such technical standard is the labelling of medicines on outer packaging. In this study, we compared outer packaging labelling requirements and transition terms for harmonization for countries in the Southern African Development Community (SADC) region., Methods: Data on legislation and/or regulatory guidelines for medicine outer packaging labelling from National Medicines Regulatory Authorities (NMRAs) were obtained for countries in the SADC region (n = 16) by February 2023. A detailed comparative content analysis was conducted to determine alignment with the requirements of the Southern African Development Community (SADC) harmonised labelling guidelines to assess readiness levels of each country to transition to the SADC harmonised labelling guideline for outer packaging of medicines., Results: Content analysis showed at least 11 out of 16 countries require national legal reform to transition to the SADC harmonised labelling guideline. In all cases where countries specified labelling requirements for outer packaging of medicines, these were stipulated in national medicines legislation., Conclusion: Even though there is a high level of alignment across the countries in terms of national labelling requirements, most countries in the SADC region would still require national legislative reform to transition to regional harmonised labelling requirements and then ultimately to continental requirements of the African Medicines Agency (AMA)., (© 2024. The Author(s).)

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., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

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., Competing Interests: Competing interests: WG is employed by Utrecht University and conducts research under the umbrella of the Utrecht-WHO Collaborating Centre for Pharmaceutical Policy and Regulation. The Centre has received unrestricted research funding from public sources, eg, WHO, the Netherlands Organisation for Health Research and Development (ZonMW), the Dutch National Health Care Institute (ZIN), EC Horizon 2020, the Dutch Medicines Evaluation Board (MEB) and the Dutch Ministry of Health. None of the abovementioned public funding sources had any involvement in the current study. WG is also employed by the National Health Care Institute.At the time of the project, MLDB was employed by Copenhagen Centre for Regulatory Sciences (CORS). CORS is a cross-faculty university anchored institution involving various public (Danish Medicines Agency, Copenhagen University) and private (Novo Nordisk, Lundbeck, Ferring Pharmaceuticals, LEO Pharma) stakeholders as well as patient organisations (Rare Diseases Denmark). The Centre is purely devoted to the scientific aspects of the regulatory field and with a patient-oriented focus and the research is not company-specific product or directly company related. In the past 5 years, CORS has received funding from Novo Nordisk, Lundbeck, Ferring Pharmaceuticals and LEO Pharma for projects not related to this study. Currently, MLDB is employed by Utrecht University and conducts research under the umbrella of the Utrecht-WHO Collaborating Centre for Pharmaceutical Policy and Regulation. This Centre receives no direct funding or donations from private parties, including the pharmaceutical industry. Research funding from public–private partnerships, eg, IMI, and The Escher Project (http://escher.lygature.org/) is accepted under the condition that no company-specific product or company-related study is conducted. The Centre has received unrestricted research funding from public sources, e.g. World Health Organisation (WHO), the Netherlands Organisation for Health Research and Development (ZonMW), the Dutch National Health Care Institute (ZIN), EC Horizon 2020, the Dutch Medicines Evaluation Board (MEB) and the Dutch Ministry of Health. None of the abovementioned companies had any involvement in the current study.The other authors declare no competing interests., (© 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.)

With the anticipated health challenges brought by demographic and technological changes, ensuring capacity in underlying workforce in place is essential for addressing patients' needs. Therefore, a timely identification of important drivers facilitating capacity building is important for strategic decisions and workforce planning. In 2020, internationally renowned pharmaceutical scientists (N = 92), largely from the academia and pharmaceutical industry, with mostly pharmacy and pharmaceutical sciences educational background were approached (through a questionnaire) for their considerations on influencing drivers to facilitate meeting current capacity in pharmaceutical sciences research. From a global view, based on the results of the questionnaire, the top drivers were better alignment with patient needs as well as strengthening education - both through continuous learning and deeper specialisation. The study also showed that capacity building is more than simply increasing the influx of graduates. Pharmaceutical sciences are being influenced by other disciplines, and we can expect more diversity in scientific background and training. Capacity building of pharmaceutical scientists should allow flexibility for rapid change driven by the clinic and need for specialised science and it should be underpinned by lifelong learning., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Use of Real-World Data (RWD) has gained the interest of different stakeholders in cancer care. The aim of this study was to identify and describe the use of RWD/RWE during the pre-authorization phase of products authorized by the EMA in 2018 and 2019 (n = 111), with the focus on oncology medicines (n = 24). Information was extracted from the European Public Assessment Report (EPAR) summaries and recorded for 5 stages (11 categories) of the drug development lifecycle (discovery, early development, clinical development, registration/market launch, lifecycle management). Specific chapters of full EPAR were reviewed to substantiate the findings on RWD/RWE use in clinical trial design, efficacy, safety, and effectiveness evaluation. RWD/RWE is present in all stages of the oncology drug development; 100.0 % in discovery, 37.5 % early development, 58.3 % in clinical development, 62.5 % in registration decision and 100.0 % in post-authorization lifecycle management. Examples showed that trial design supported by RWD/RWE included use of open label/single arm studies; efficacy was about using either comparison of results to historical controls, supplying survey data obtained outside the clinical trial or utilizing expert panel advice; safety about including literature findings in evidence; and effectiveness on comparison of trial results of the given product to historical data or existing standard of care. The findings of this study provide specific insights into how RWD/RWE is used in development of cancer therapeutics, how it contributes to regulatory decision making and can guide further policy developments in this field., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Sini M. Eskola conducts a part-time professional PhD at Utrecht Centre for Pharmaceutical Policy and Regulation. In her daily work, she holds a position as Director Regulatory Strategy and Team Leader at European Federation of Pharmaceutical Industries and Associations (EFPIA). This research is independent and not funded by EFPIA. Andrew Bate is a full-time employee and stock and options holder in GlaxoSmithKline. The views expressed in this article represent the author’s own thoughts and are independent of their employers. This research is independent and not funded by GSK. Hubertus G.M Leufkens, Marie L. De Bruin, and Helga Gardarsdottir are employed by Utrecht University conducting research under the umbrella of the Centre for Pharmaceutical Policy and Regulation. This centre receives no direct funding or donations from private parties, including those in the pharmaceutical industry. Research funding from public–private partnerships (e.g., IMI, The Escher Project (http://escher.lygature.org/), is accepted under the condition that no company-specific product or company-related study is conducted). The centre has received unrestricted research funding from public sources, for example, the World Health Organization (WHO), Netherlands Organization for Health Research and Development (ZonMW), the Dutch National Health Care Institute (ZIN), EC Horizon 2020, the Dutch Medicines Evaluation Board (MEB), and the Dutch Ministry of Health., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

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.

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., (© 2023. The Author(s).)

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., (© 2022. The Author(s).)