Regional Disparity in First-in-Class Anticancer Drug Development in the US, EU, and Japan.

A cancer diagnosis is devastating for both patients and their caregivers. With high morbidity and mortality, cancer is a serious disease area with unmet medical needs. Thus, innovative anticancer drugs are in high demand worldwide but are unequally available. Our study focused on first-in-class (FIC) anticancer drugs and investigated their actual development situation in the United States (US), European Union (EU), and Japan over the last two decades to obtain fundamental information for understanding how the aforementioned demands are met, especially to eliminate drug lags among regions. We identified FIC anticancer drugs using pharmacological classes for the Japanese drug pricing system. Most FIC anticancer drugs were first approved in the US. The median approval time for anticancer drugs in new pharmacological classes during the last two decades in Japan (5072 d) was significantly different (p = 0.043) from that in the US (4253 d), though it was not significantly different from that in the EU (4655 d). Submission and approval lags between the US and Japan were more than 2.1 years, and those between the EU and Japan were more than 1.2 years. However, those between the US and the EU were less than 0.8 years. The development rate of FIC anticancer drugs in Japan is slower than in other regions. Even among developed countries, FIC anticancer drug lags exist. Considering the high impact of FIC anticancer drugs on society worldwide, we should work together to reduce drug lag among regions using an improved international cooperative framework.

Impact of regulatory interventions to restrict the combined use of renin-angiotensin system blockers: A Danish nationwide drug utilisation study.

This study aimed to evaluate the impact of the risk minimisation measures issued by the European Medicines Agency in 2014 to restrict the combined use of renin-angiotensin system (RAS) blocking agents in Denmark. Data from the Danish National Prescription Registry covering all medications dispensed during January 2008-December 2018 was used. The outcome was monthly prevalence of patients codispensed RAS blockers. Autoregressive integrated moving average interrupted time series regression was used to evaluate dispensing trends. The prevalence of patients codispensed RAS blockers decreased from 0.01 to 0.0003%. Preintervention trend was declining and further decreased with an additional -0.45 (95% confidence interval -0.66, -0.25) codispensing per million population after the intervention. Overall, the intervention had minimal impact on the combined use of RAS blockers. However, as the combined use of RAS blockers is low, further interventions to restrict the combined use of RAS blockers may not be required in Denmark at this point.

Poor adherence and persistence to sodium glucose co-transporter 2 inhibitors in real-world settings: Evidence from a systematic review and meta-analysis.

AIMS: Despite increasing prescription of sodium glucose co-transporter 2 (SGLT2) inhibitors, there is limited insight of the patterns of use among patients with diabetes prescribed these drugs. This study aimed to summarize available real-world data on the adherence and persistence to SGLT2 inhibitors. MATERIALS AND METHODS: A systematic review for observational studies reporting the adherence and persistence to SGLT2 inhibitors was performed in Medline, Embase, and Web of Science from their inception to October 2019. Data were analysed via random-effects meta-analysis. RESULTS: A total of 22 studies (31 cohorts) comprising 123 854 individuals prescribed SGLT2 inhibitors from eight countries were included. The pooled mean proportions of days covered [PDC] at six months and one year were 0.77 (95% confidence interval [CI] 0.72-0.82) and 0.72 (95% CI 0.66-0.77), respectively. The pooled proportions adherent (PDC ≥0.80) at six months and one year were 59.5% (95% CI 52.9-65.9) and 49.0% (95% CI 42.3-55.8), respectively. The pooled proportions of people persistent at six months, one year, and two years were 80.1% (95% CI 75.8-84.0), 61.8% (95% CI 57.8-65.7), and 45.9% (95% CI 35.5-56.5), respectively. When persistence was defined as the absence of ≥90-days gap, the equivalent pooled proportions persistent were 81.5% (95% CI 73.1-88.6), 58.9% (95% CI 53.1-64.6), and 34.7% (95% CI 33.6-35.8). Adherence and persistence appeared to vary across different SGLT2 inhibitors. CONCLUSIONS: Real-world adherence and persistence to SGLT2 inhibitors is poor. Hence, targets for improving treatment adherence and persistence need to be identified and appropriate interventions implemented.

Body of evidence and approaches applied in the clinical development programme of fixed-dose combinations in the European Union from 2010 to 2016.

AIMS: To provide insights into the clinical development pathway for fixed-dose combinations (FDCs), to consider strategies, and to elucidate the path to approval by assessing the body of evidence, as summarized in the European Public Assessment Reports. METHODS: The main resource was the European Public Assessment Reports for 36 FDCs, which included 239 clinical trials with 157 514 patients. The analyses focused on how prior knowledge of the active substances or combination, use of pharmacokinetic-pharmacodynamic modelling, and clinical trial design choice impact the size and strategy of the clinical development programme. RESULTS: FDC products primarily comprised 2 previously approved components (21/36, 71%) and had only 1 approved combination (21/36, 71%). Utilizing previously approved active substances resulted in fewer clinical trials, arms and patients, but FDC doses studied in the clinical development programme. Furthermore, dose-finding trials were performed for less than half of FDCs consisting of 2 previously approved active substances. The standard approach to demonstrate contribution of active substances was through a factorial or single combination study. Finally, the use of pharmacokinetic modelling showed a significant decrease in the number of FDC doses studied. CONCLUSIONS: The field of FDCs seems to be on the rise, utilizing new molecular entities, prior knowledge and re-profiling drugs. However, a way to move FDC development forward might be through new regulatory and scientific paradigms, in which it is encouraged to utilize model-based approaches to develop FDCs with multiple dose levels and dose ratios for exposure-based treatment that will enable personalization.

Incidence of direct oral anticoagulant use in patients with nonvalvular atrial fibrillation and characteristics of users in 6 European countries (2008-2015): A cross-national drug utilization study.

AIMS: To estimate the incidence of direct oral anticoagulant drug (DOAC) use in patients with nonvalvular atrial fibrillation and to describe user and treatment characteristics in 8 European healthcare databases representing 6 European countries. METHODS: Longitudinal drug utilization study from January 2008 to December 2015. A common protocol approach was applied. Annual period incidences and direct standardisation by age and sex were performed. Dose adjustment related to change in age and by renal function as well as concomitant use of potentially interacting drugs were assessed. RESULTS: A total of 186 405 new DOAC users (age ≥18 years) were identified. Standardized incidences varied from 1.93-2.60 and 0.11-8.71 users/10 000 (2011-2015) for dabigatran and rivaroxaban, respectively, and from 0.01-8.12 users/10 000 (2012-2015) for apixaban. In 2015, the DOAC incidence ranged from 9 to 28/10 000 inhabitants in SIDIAP (Spain) and DNR (Denmark) respectively. There were differences in population coverage among the databases. Only 1 database includes the total reference population (DNR) while others are considered a population representative sample (CPRD, BIFAP, SIDIAP, EGB, Mondriaan). They also varied in the type of drug data source (administrative, clinical). Dose adjustment ranged from 4.6% in BIFAP (Spain) to 15.6% in EGB (France). Concomitant use of interacting drugs varied between 16.4% (SIDIAP) and 70.5% (EGB). Cardiovascular comorbidities ranged from 25.4% in Mondriaan (The Netherlands) to 82.9% in AOK Nordwest (Germany). CONCLUSION: Overall, apixaban and rivaroxaban increased its use during the study period while dabigatran decreased. There was variability in patient characteristics such as comorbidities, potentially interacting drugs and dose adjustment. (EMA/2015/27/PH).

Are ECG monitoring recommendations before prescription of QT-prolonging drugs applied in daily practice? The example of haloperidol.

PURPOSE: Monitoring of the QT duration by electrocardiography (ECG) prior to treatment is frequently recommended in the label of QT-prolonging drugs. It is, however, unknown how often general practitioners in daily clinical practice are adhering to these risk-minimization measures. We assessed the frequency of ECG measurements in patients where haloperidol was initiated in primary care. METHODS: Patients (≥18 years) with a first prescription of haloperidol in the UK Clinical Practice Research Datalink (2009-2013) were included. The proportion of ECGs made was determined in two blocks of 4 weeks: during the exposure period when haloperidol was initiated, and during the control period, 1 year before. Conditional logistic regression analysis was applied to calculate the relative risk of having an ECG in the exposure period compared with the control period. Subgroup analyses were performed to assess the proportion of ECG measurements in patients with one or more additional risk factors for QT prolongation. RESULTS: In total, 3420 patients were prescribed haloperidol during the exposure period, and 1.8% of them had an ECG at treatment initiation, compared with 0.8% during the control period (relative risk [RR] 2.4 [1.5-3.8]). Of the patients with additional risk factors for QT prolongation, 1.9% of the patients had an ECG at initiation of the prescription, compared with 1.0% during the control period (RR 2.1 [1.2-3.5]). CONCLUSIONS: Compliance with recommendations to perform an electrocardiogram when starting a new QT-prolonging drug is extremely low, when haloperidol is taken as an example.

Epidemiological surveillance of drug safety using cumulative sequential analysis in electronic healthcare data.

BACKGROUND: Methods for safety signal detection in electronic healthcare data analysing data sequentially are being developed to meet the limitations of spontaneous reporting systems. OBJECTIVES: This study aims to provide an overview of the literature on sequential analysis of electronic healthcare data and describe the development and testing of a novel epidemiological surveillance system. METHODS: We searched Medline, Embase, PubMed, Scopus, Web of Science, and the Cochrane Library applying similar in- and exclusion criteria as those of a previous systematic review. The proposed system consisted of repeated cohort studies and was tested in an emulated prospective setting. Two signal evaluations were performed with several sensitivity analyses and a target trial emulation. FINDINGS: In the literature, 11 studies analysed the data sequentially of which two applied traditional epidemiological methods. Epidemiological surveillance of several exposures and outcomes can be successfully conducted with the newly proposed sequential analysis of electronic healthcare data. Signal evaluation studies confirmed the results of the system. CONCLUSIONS: Very few studies in the literature analysed data at multiple time points, although this seems to be a prerequisite for testing the methods in a realistic setting. We demonstrated the feasibility of a sequential surveillance system using electronic healthcare data.

Smoking cessation strategies in patients with COPD.

Smoking cessation is the cornerstone of treatment of chronic obstructive pulmonary disease (COPD) patients. This systematic review evaluates the effectiveness of behavioural and pharmacological smoking cessation strategies in COPD patients. MEDLINE was searched from January 2002 to October 2011. Randomised controlled trials evaluating the effect of smoking cessation interventions for COPD patients, published in English, were selected. The methodological quality of included trials was assessed using the Delphi list by two reviewers independently. The relative risks of smoking cessation due to the intervention, compared with controls, were calculated. Eight studies met the inclusion criteria. Heterogeneity was observed for study population, the intervention strategy, the follow-up period and the outcome. According to the Delphi list methodological quality scores, five studies were considered to be of acceptable quality. Pharmacological therapy combined with behavioural counselling was more effective than each strategy separately. In COPD patients, the intensity of counselling did not seem to influence the results, nor did the choice of drug therapy make a difference. This systematic review makes clear that in COPD patients, pharmacological therapy combined with behavioural counselling is more effective than each strategy separately. Neither the intensity of counselling nor the type of anti-smoking drug made a difference.

Impact of a Treatment Guide on Intravenous Fluids in Minimising the Risk of Hospital-Acquired Hyponatraemia in Denmark.

Hypotonic intravenous (IV) fluids are associated with an increased risk of hospital-acquired hyponatraemia, eventually leading to brain injury and death. We evaluated the effectiveness of a treatment guide to improve prescribing practices of IV fluids. We conducted a before-and-after cross-sectional survey among physicians working at Danish emergency departments. The primary outcome was prescribing practices of IV fluids. Participants were asked which IV fluid they would select in four clinical scenarios. We applied multivariate logistic regression models to estimate the odds ratio of selecting hypotonic fluids. Secondary outcomes included knowledge about IV fluids and hyponatraemia, and the receipt, reading, and usefulness of the treatment guide. After the intervention, about a third (47/154) reported that they would use hypotonic fluids in patients with increased intracranial pressure, and a quarter (39/154) would use hypotonic maintenance fluids in children, both of which are against guideline recommendations. A total of 46% selected the correct fluid, a 3% hypertonic saline solution for a patient with hyponatraemia and severe neurological symptoms. None of the knowledge questions met the predefined criteria of success of 80% correct answers. Of the respondents, 22% had received the treatment guide. Since the implementation failed, we recommend improving distribution by applying methods from implementation science.

The role of Real-World Data and evidence in oncology medicines approved in EU in 2018-2019.

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.

Magistral Compounding with 3D Printing: A Promising Way to Achieve Personalized Medicine.

BACKGROUND: Magistral compounding has always been an integral part of pharmacy practice. The increasing demand worldwide for personalized drug treatments might be accommodated by an increase in magistral compounding. The new, flexible technology of 3D medicine printing could advance this process even further. However, the issue of how 3D medicine printing can be implemented within the existing magistral compounding infrastructure has not been explored. AIMS: To investigate how 3D printing can be integrated into the existing compounding system by taking regulatory, economic, and profession-oriented aspects into account. METHODS: Semi-structured interviews were conducted with relevant Dutch stakeholders representing various health institutions, such as health ministries and boards, professional bodies, and different types of pharmacies. Participants were identified through purposeful sampling. Content analysis was applied to identify the main themes. RESULTS: A total of 15 Dutch stakeholders were interviewed. It was found that the prevalence of compounding in community pharmacies in the Netherlands has decreased as a result of the practice shifting to specialized compounding pharmacies due to higher costs, lack of space, and the need to fulfill quality requirements. All interviewees considered 3D printing to be a promising compounding technique for community pharmacies, as it offers an automated approach with high digital flexibility and enables adapted formulations, including 'polypills.' Regulatory and quality assurance challenges were considered comparable to those of normal magistral products; however, there remain pending regulatory issues regarding quality control, particularly for Active Pharmaceutical Ingredients containing intermediate feedstock materials (e.g., prefilled cartridges) in 3D printing. 3D printing was believed to become cost effective over time. CONCLUSION: In the Netherlands, specialized compounding pharmacies have largely taken over compounding activities. 3D printing could be introduced within this system; however, challenges regarding how to regulate prefilled cartridges have yet to be addressed. Compounding using 3D printing in regular community pharmacies could enhance patients' individualized treatment; however, this activity would require incentives to stimulate the return of compounding to normal pharmacy practice.

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.

Serious arrhythmia in initiators of citalopram, escitalopram, and other selective serotonin reuptake inhibitors: A population-based cohort study in older adults.

The selective serotonin reuptake inhibitors (SSRIs) citalopram and escitalopram are associated with QT prolongation, which increases the risk of serious arrhythmia. Consequently, regulatory agencies issued safety warnings in 2011. This study aimed to investigate the risk of serious arrhythmia following initiation of citalopram or escitalopram compared to other SSRIs and the risk in the periods before and after the warnings were issued. We conducted a series of nationwide cohort studies emulating a target trial using Danish healthcare register data from January 1, 2002, to December 31, 2016. We included patients (aged ≥65 years) who filled an SSRI prescription with a 1-year washout period before the index date. The outcome was an event of serious arrhythmia. Individuals were followed for a maximum of 6 months using an intention-to-treat approach. Log-binomial regression analyses were performed, estimating risk ratios (RRs) and 95% confidence intervals (CIs) adjusting for age and sex, comorbidities, and comedications with propensity scores. Dose-response effects were not investigated because dosage instructions were not available. We included 167,366 (146,014 individuals), 40,113 (37,069 individuals), and 50,281 (44,754 individuals) person-trials of citalopram, escitalopram, and other SSRIs, respectively. In total, there were 228 events of serious arrhythmia. No difference in risk was observed in the entire study period for either citalopram (0.87 [0.62-1.22]) or escitalopram (0.85 [0.53-1.40]). We identified lower point estimates after the safety warning, RR 0.54 (95% CI 0.31-0.93) for citalopram and 0.58 (0.20-1.63) for escitalopram. Initiation of citalopram and escitalopram was not associated with an increased risk of serious arrhythmia. However, lower point estimates were observed after the safety warning.

Use of Real-World Data and Evidence in Drug Development of Medicinal Products Centrally Authorized in Europe in 2018-2019.

Real-world data/real-world evidence (RWD/RWE) are considered to have a great potential to complement, in some cases, replace the evidence generated through randomized controlled trials. By tradition, use of RWD/RWE in the postauthorization phase is well-known, whereas published evidence of use in the pre-authorization phase of medicines development is lacking. The primary aim of this study was to identify and quantify the role of potential use of RWD/RWE (RWE signatures) during the pre-authorization phase, as presented in the initial marketing authorization applications of new medicines centrally evaluated with a positive opinion in 2018-2019 (n = 111) by the European Medicines Agency (EMA). Data for the study was retrieved from the evaluation overviews of the European Public Assessment Reports (EPARs), which reflect the scientific conclusions of the assessment process and are accessible through the EMA website. RWE signatures were extracted into an RWE Data Matrix, including 11 categories divided over 5 stages of the drug development lifecycle. Nearly all EPARs included RWE signatures for the discovery (98.2%) and life-cycle management (100.0%). Half of them included RWE signatures for the full development phase (48.6%) and for supporting regulatory decisions at the registration (46.8%), whereas over a third (35.1%) included RWE signatures for the early development. RWE signatures were more often seen for orphan and conditionally approved medicines. Oncology, hematology, and anti-infectives stood out as therapeutic areas with most RWE signatures in their full development phase. The findings bring unprecedented insights about the vast use of RWD/RWE in drug development supporting the regulatory decision making.

New Information on Old Medicinal Products: A Cross-Sectional Analysis of Guidance for Paediatric Use for Substances on the European Priority List of Off-Patent Medicinal Products.

BACKGROUND: As part of the European Paediatric Regulation, the European Medicines Agency (former European Medicines Evaluation Agency) and the Paediatric Working Party (precursor for the Paediatric Committee) revised a priority list for studies on off-patent medicinal products in 2007 where a need for studies on paediatric medicinal products was emphasised. OBJECTIVES: We aimed to evaluate the status of guidance for paediatric use in the Summary of Product Characteristics for medicinal products on the priority list as well as the presence and status of Paediatric Investigation Plans for these medicinal products. METHODS: We included active pharmaceutical ingredients on the priority list authorised through the centralised procedure and/or marketed in Denmark. The status of guidance for paediatric use (indication, posology and/or contraindication) was reviewed from the most recent Summary of Product Characteristics uploaded on the European Medicines Agency or the Danish Medicines Agency website as of November 2020. Information on Paediatric Investigation Plans status (Paediatric Committee opinion, completion and waivers granted) was retrieved from the European Medicines Agency website. RESULTS: A total of 121 active pharmaceutical ingredients were included in this study. Seventy-one percent had guidance for paediatric use in the Summary of Product Characteristics for at least one paediatric subpopulation, more often concerning adolescents (70%) and children (70%) as compared with neonates (41%) and infants (49%). The guidance included a paediatric indication in 46% of the cases, but less often a contraindication (13%). Thirty-three active pharmaceutical ingredients had an agreed Paediatric Investigation Plan, six of these were completed. CONCLUSIONS: Most active pharmaceutical ingredients from the priority list had guidance for paediatric use in the Summary of Product Characteristics. However, there is still an unmet need in relation to guidance for use for the youngest paediatric subpopulation.

Investigation of the potential association between the use of fluoxetine and occurrence of acute pancreatitis: a Danish register-based cohort study.

BACKGROUND: There is currently conflicting evidence of the association between the use of selective serotonin reuptake inhibitors (SSRIs) and acute pancreatitis. The SSRI fluoxetine has been suspected to be the driver of this serious outcome. Therefore, this study aims to investigate the potential association between fluoxetine use and the occurrence of acute pancreatitis. METHODS: We conducted a nationwide cohort study using Danish register-based data from 1996 to 2016. The exposed group were new users of fluoxetine (1-year washout). The control subjects were new users of citalopram or SSRIs, excluding fluoxetine. The outcome was an incident diagnosis of acute pancreatitis with a 5-year washout. We used an intention-to-treat approach following patients for a maximum of 6 months. Cox regression analyses were performed, estimating hazard ratios (HRs) and 95% confidence intervals (CIs) adjusted for age/sex, comorbidities and co-medications, using propensity score adjustment and matching. RESULTS: In the propensity score-matched analyses, 61 783 fluoxetine users were included. The incidence rates among users of fluoxetine and other SSRIs were 5.33 (3.05-8.66) and 5.36 (3.06-8.70) per 10 000 person-years, respectively. No increased risk of acute pancreatitis was identified following fluoxetine exposure compared with either citalopram [HR 1.00, 95% CI 0.50-2.00) or other SSRIs (0.76, 0.40-1.46). CONCLUSIONS: Fluoxetine use was not associated with an increased risk of acute pancreatitis compared with citalopram or other SSRIs. The absolute risk of acute pancreatitis was low and did not vary between different SSRIs. Further research is needed to determine whether there is a class effect on the risk of acute pancreatitis.

Interchangeability of biosimilars: A study of expert views and visions regarding the science and substitution.

Healthcare systems have reached a critical point regarding the question of whether biosimilar substitution should become common practice. To move the discussion forward, the study objective was to investigate the views of experts from medicines agencies and the pharmaceutical industry on the science underpinning interchangeability of biosimilars. We conducted an empirical qualitative study using semi-structured interviews informed by a cross-disciplinary approach encompassing regulatory science, law, and pharmaceutical policy. In total 25 individuals with experience within biologics participated during September 2018-August 2019. Eight participants were EU national medicines authority regulators, and 17 had pharmaceutical industry background: five from two originator-only companies, four from two companies with both biosimilar and originator products, and eight from seven biosimilar-only companies. Two analysts independently conducted inductive content analysis, resulting in data-driven themes capturing the meaning of the data. The participants reported that interchangeability was more than a scientific question of likeness between biosimilar and reference products: it also pertained to regulatory practices and trust. Participants were overall confident in the science behind exchanging biosimilar products for the reference products via switching, i.e., with physician involvement. However, their opinions differed regarding the scientific risk associated with biosimilar substitution, i.e., without physician involvement. Almost all participants saw no need for additional scientific data to support substitution. Moreover, the participants did not believe that switching studies, as required in the US, were appropriate for obtaining scientific certainty due to their small size. It is unclear why biosimilar switching is viewed as scientifically safer than substitution; therefore, we expect greater policy debate on biosimilar substitution in the near future. We urge European and UK policymakers and regulators to clarify their visions for biosimilar substitution; the positions of these two frontrunners are likely to influence other jurisdictions on the future of biosimilar use.

Regulatory density as a means to refine current regulatory approaches for increasingly complex medicines.

The continuous scientific, societal, and technological advancements have shifted drug development toward increasingly complex and ever more targeted treatments. This creates new and unprecedented challenges for global regulatory systems. To address the increased risks and uncertainties of increasingly complex medicine, we advocate for a more tailored and flexible regulatory approach, which is explained here with the concept of 'regulatory density'. In the context of this paper, 'regulatory density' describes the relative amount of obligatory standards, measures and procedures applied to certain medicinal products or product classes and the resources required to meet these requirements. Given that risk and uncertainty are dynamic variables that can change over time, with this paper, we want to stimulate (re)thinking of regulatory approaches for managing the challenges of future complex medicines.

Surveillance of Antidepressant Safety (SADS): Active Signal Detection of Serious Medical Events Following SSRI and SNRI Initiation Using Big Healthcare Data.

INTRODUCTION: The current process for generating evidence in pharmacovigilance has several limitations, which often lead to delays in the evaluation of drug-associated risks. OBJECTIVES: In this study, we proposed and tested a near real-time epidemiological surveillance system using sequential, cumulative analyses focusing on the detection and preliminary risk quantification of potential safety signals following initiation of selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs). METHODS: We emulated an active surveillance system in an historical setting by conducting repeated annual cohort studies using nationwide Danish healthcare data (1996-2016). Outcomes were selected from the European Medicines Agency's Designated Medical Event list, summaries of product characteristics, and the literature. We followed patients for a maximum of 6 months from treatment initiation to the event of interest or censoring. We performed Cox regression analyses adjusted for standard sets of covariates. Potential safety signals were visualized using heat maps and cumulative hazard ratio (HR) plots over time. RESULTS: In the total study population, 969,667 new users were included and followed for 461,506 person-years. We detected potential safety signals with incidence rates as low as 0.9 per 10,000 person-years. Having eight different exposure drugs and 51 medical events, we identified 31 unique combinations of potential safety signals with a positive association to the event of interest in the exposed group. We proposed that these signals were designated for further evaluation once they appeared in a prospective setting. In total, 21 (67.7%) of these were not present in the current summaries of product characteristics. CONCLUSION: The study demonstrated the feasibility of performing epidemiological surveillance using sequential, cumulative analyses. Larger populations are needed to evaluate rare events and infrequently used antidepressants.

A cross-sectional survey of knowledge pertaining to IV fluid therapy and hyponatraemia among nurses working at emergency departments in Denmark.

INTRODUCTION: Inappropriate fluid therapy may induce or worsen existing hyponatraemia with potentially life-threatening consequences. Nurses have an important role in assisting physicians in IV fluid prescribing. However, research is lacking in Denmark about nurses' knowledge pertaining to IV fluid therapy and hyponatraemia. METHODS: An explorative cross-sectional survey was performed among Danish emergency department nurses in Spring 2019. Knowledge about IV fluid therapy was assessed for three common clinical scenarios, and multiple-choice questions were used to measure knowledge about hyponatraemia. RESULTS: 112 nurses responded to all scenario questions corresponding to 6.2% (112/1815) of the total population of nurses working at emergency departments in Denmark. In two of the three scenarios, a minority of nurses (8-10%) inappropriately selected hypotonic fluids. Nearly one third (31%) selected a hypotonic fluid for a patient with meningitis, which is against guideline recommendations. The study revealed limited knowledge about severe symptoms of hyponatraemia, patients at high risk, and hyperglycaemia-induced hyponatraemia. CONCLUSION: In accordance with guideline recommendation, the majority of nurses did not select hypotonic fluids in three clinical scenarios commonly encountered in the emergency department. However, when setting up an educational program, further awareness is needed regarding symptoms of hyponatraemia, high-risk patients, and hyperglycaemia-induced hyponatraemia.