When serious medication errors (ME) are identified, communication to the field may be necessary. In the EU, communication of serious safety issues, such as medication errors associated with adverse drug reactions, is done through direct healthcare professional communications (DHPCs). We aimed to identify how often DHPCs about medication errors are distributed, and we explored factors associated with these ME DHPCs.

This study assessed to what extent women were included in all phases of drug development; whether the clinical studies in the marketing authorization application dossiers include information per sex; and explored whether there are differences between women and men in the drugs' efficacy and safety. Data were extracted from dossiers submitted to the European Medicines Agency. Twenty-two dossiers of drugs approved between 2011 and 2015 for the treatment of various diseases were included. Female animals were included in only 9% of the pharmacodynamics studies, but female and male animals were included in all toxicology studies. Although fewer women than men were included in the clinical studies used to evaluate pharmacokinetics (PK) (29 to 40% women), all dossiers contained sex-specific PK parameter estimations. In the phase III trials, inclusion of women was proportional to disease prevalence for depression, epilepsy, thrombosis, and diabetes [participation to prevalence ratio (PPR) range: 0.91-1.04], but women were considered underrepresented for schizophrenia, hepatitis C, hypercholesterolemia, HIV, and heart failure (PPR range: 0.49-0.74). All dossiers contained sex-specific subgroup analyses of efficacy and safety. There seemed to be higher efficacy for women in one dossier and a trend toward lower efficacy in another dossier. More women had adverse events in both treatment (73.0 vs. 70.6%, p < 0.001) and placebo groups (69.5 vs. 65.5%, p < 0.001). In conclusion, women were included throughout all phases of clinical drug research, and sex-specific information was available in the evaluated dossiers. The included number of women was, however, not always proportional to disease prevalence rates.

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

Over the past 15 years, three new classes of drugs, glucagon-like peptide-1 (GLP-1) receptor agonists, dipeptidyl peptidase 4 (DPP-4) inhibitors and sodium glucose cotransporter-2 (SGLT-2) inhibitors have been approved to treat type 2 diabetes based on effects on glycemic control. Although large randomized controlled trials have played an important role in characterizing the efficacy and safety of these agents on a population level, questions remain about how best to individualize therapy and target the "right" medicine to the "right" patient. In contrast, few medicines have been approved to treat diabetic kidney disease and initiatives have been launched on both sides of the Atlantic to facilitate the development of effective personalized medicines for the treatment of diabetic kidney disease. Increasingly, "omics," imaging and other biomarkers will be used to match patients with therapies to which they are likely to respond best. This review addresses regulatory considerations related to precision medicine, draws lessons learned from other therapeutic areas and discusses efforts undertaken by the European (EMA) and United States (FDA) to facilitate the development of such therapies. Moving forward, an integrated approach that makes use of predictive preclinical models, innovative trial designs, observational "real-world" data and novel statistical methodologies will likely be needed to complement inherently smaller RCTs conducted in more selected populations. Patient involvement will also be critical. Regulatory agencies are ready to engage in such approaches.

The aim of this study was to investigate whether a disease registry could serve as a suitable alternative to clinical studies to investigate safety of orphan drugs in children.

When reporting adverse drug reactions to pharmacovigilance centres, patients and consumers can describe adverse drug reactions experienced in free-text format. Recently, a patient-friendly adverse drug reaction terms list was introduced in the adverse drug reaction report form in the UK to facilitate this reporting.

A mobile app may increase the reporting of adverse drug reactions (ADRs) and improve the communication of new drug safety information. Factors that influence the use of an app for such two-way risk communication need to be considered at the development stage.

Proton pump inhibitors (PPIs) belong to the most frequently used drugs, also in patients with cirrhosis. PPIs are extensively metabolized by the liver, but practice guidance on prescribing in cirrhosis is lacking. We aim to develop practical guidance on the safe use of PPIs in patients with cirrhosis.

Previously, an app has been developed for healthcare professionals (HCPs) and patients to report adverse drug reactions (ADRs) to national medicines agencies and to receive drug safety information.

Background: In 2005, the European Medicines Agency (EMA) released guidance on pharmacokinetic studies in patients with hepatic impairment. This guidance describes the design of these studies and what information should be presented in the Summary of Product Characteristics (SmPC). We aim to evaluate the availability and clinical applicability of information on medicine use in patients with hepatic impairment in SmPCs and registrational dossiers of recently approved medicines. Methods: We reviewed SmPC information on use in patients with hepatic impairment of 51 new medicines authorized between 2015 and 2017. Per medicine, we assessed the availability of nine information items derived from the EMA guidance, i.e. type of hepatic disease studied; stratification by severity of hepatic impairment; influence of hepatic impairment on the pharmacokinetics; safety advice in mild, moderate, and severe hepatic impairments; and dosing recommendation in mild, moderate, and severe hepatic impairments. If unavailable, the European Public Assessment Report (EPAR) and study report were consulted consecutively. Of available items, clinical applicability was assessed by labeling information as "clear" or "ambiguous". Results: Of 51 medicines, 15 had no pharmacokinetic study in patients with hepatic impairment described in their SmPC. The other 36 SmPCs contained on average seven of the nine information items (range 4-9). One SmPC contained all 9 items, and after consulting, the study reports, 11 SmPCs were complete. The item "type of hepatic disease studied" was available in one SmPC, though it could be retrieved in 21 study reports. Regarding clinical applicability, there was no medicine with all information items available and clearly formulated in the SmPC. A total of 12 medicines (33%) contained only clearly formulated information, while 24 (67%) contained at least one ambiguously formulated information item (range 0-4). Items often ambiguously formulated were: "definition of mild, moderate, and severe hepatic impairment" (15 ambiguous SmPCs) and "safety advice in severe hepatic impairment" (17 ambiguous SmPCs). Conclusion: While SmPCs contain a large part of information requested by the EMA, clinical applicability seems low, as it is often unclear to which specific type of hepatic disease patient the advice applies. This can negatively influence the practical use by healthcare professionals.

Metachromatic Leukodystrophy (MLD) is a rare lysosomal disorder. Patients suffer from relentless neurological deterioration leading to premature death. Recently, new treatment modalities, including gene therapy and enzyme replacement therapy, have been developed. Those advances increase the need for high-quality research infrastructure to adequately compare treatments, execute post-marketing surveillance, and perform health technology assessments (HTA). To facilitate this, a group of MLD experts started the MLD initiative (MLDi) and initiated an academia-led European MLD registry: the MLDi. An expert-based consensus procedure, namely a modified Delphi procedure, was used to determine the data elements required to answer academic, regulatory, and HTA research questions.

Liver cirrhosis can have a major impact on drug pharmacokinetics and pharmacodynamics. Patients with cirrhosis often suffer from potentially preventable adverse drug reactions. Guidelines on safe prescribing for these patients are lacking. The aim of this study is to develop a systematic method for evaluating the safety and optimal dosage of drugs in patients with liver cirrhosis.

In rare diseases, registry-based studies can be used to provide natural history data pre-approval and complement drug efficacy and/or safety knowledge post-approval.

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

Over a period of 3 years, the European Union's Innovative Medicines Initiative WEB-RADR (Recognising Adverse Drug Reactions; https://web-radr.eu/ ) project explored the value of two digital tools for pharmacovigilance (PV): mobile applications (apps) for reporting the adverse effects of drugs and social media data for its contribution to safety signalling. The ultimate intent of WEB-RADR was to provide policy, technical and ethical recommendations on how to develop and implement such digital tools to enhance patient safety. Recommendations relating to the use of mobile apps for PV are summarised in this paper. There is a presumption amongst at least some patients and healthcare professionals that information ought to be accessed and reported from any setting, including mobile apps. WEB-RADR has focused on the use of such technology for reporting suspected adverse drug reactions and for broadcasting safety information to its users, i.e. two-way risk communication. Three apps were developed and publicly launched within Europe as part of the WEB-RADR project and subsequently assessed by a range of stakeholders to determine their value as effective tools for improving patient safety; a fourth generic app was later piloted in two African countries. The recommendations from the development and evaluation of the European apps are presented here with supporting considerations, rationales and caveats as well as suggested areas for further research.

Aims: Cardiovascular outcome trials with anti-diabetic drugs suggest that additional cardiovascular benefit can be achieved independent of improving glycaemic control. Nonetheless, dose selection of anti-diabetic drugs is typically based solely on glycaemic effects. We evaluated whether off-target drug effects are currently considered for dose justification to regulatory agencies. Methods: In the European Union, anti-diabetic drugs are registered by the European Medicines Agency. We extracted available information regarding dose selection from public assessment reports and marketing application dossiers. Descriptive statistics were used to summarise the extracted information. Results: In total, 14 drugs of three drug classes were included; sodium-glucose co-transporter-2 inhibitors (n = 4), dipeptidyl peptidase-4 inhibitors (n = 4) and glucagon-like peptide-1 receptor agonists (n = 6). For these drugs, 21 dose-finding trials were submitted including results of multiple off-target effects, of which body weight (n = 18) and low-density lipoprotein cholesterol (n = 14) were most frequently reported. Dose-response curves for off-target effects appeared to be different compared to the glycaemic dose-response curve. Glycated hemoglobin (100%) and fasting plasma glucose (42.9%), were used most frequently for the dose justification, but generally off-target effects (<25%) were not. Conclusions: Dose justification to regulatory authorities was mainly based on glycaemic effects. The dose-response relationship for the off-target effects did not necessarily follow the dose-response relationship of the on-target effects suggesting that selection of the optimal anti-diabetic dose could benefit from including off-target effects in the dose selection process as well.

Healthcare professionals (HCPs) and patients have various motives to report adverse drug reactions (ADRs) to their national agency. These motives may differ between countries.

Healthcare professionals (HCPs) are informed about new drug safety issues through Direct Healthcare Professional Communications (DHPCs). The influence of DHPC content on the impact of the communication is unclear.

To assess whether medication beliefs differ between women who use or not use medication for their somatic chronic diseases during pregnancy and whether this association varies across diseases.

Previous studies have found differences in the communication of safety issues among medicines regulatory agencies.