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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.

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.

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.

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.

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 (5072d) was significantly different (p=0.043) from that in the US (4253d), though it was not significantly different from that in the EU (4655d). 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.

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 compou

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.

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 you

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.

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 Euro

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.

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.

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 Europea

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.

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.

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 you

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 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 a