Search

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.

Real-world data/evidence (RWD/RWE) may provide insightful information on medicines' clinical effects to guide regulatory decisions. While its contribution has been recognized for safety monitoring and disease epidemiology across medicines' life cycles, using RWD/RWE to demonstrate efficacy requires further evaluation. This study aimed to (i) characterize RWD/RWE presented by applicants to support claims on medicines' efficacy within initial marketing authorization applications (MAAs) and extension of indication applications (EoIs), and (ii) analyze the contribution of RWD/RWE to regulatory decisions on medicines' benefit–risk profile. RWD/RWE was included to support efficacy in 32 MAAs and 14 EoIs submitted 2018–2019. Of these, RWD/RWE was part of the preauthorization package of 16 MAAs and 10 EoIs, and was (i) considered supporting the regulatory decision in 10 applications (five MAAs, five EoIs), (ii) considered not supporting the regulatory decision in 11 (seven MAAs, four EoIs), and (iii) not addressed at all in the evaluation of 5 applications (four MAAs, one EoI). Common limitations of submitted RWD/RWE included missing data, lack of representativeness of populations, small sample size, absence of an adequate or prespecified analysis plan, and risk of several types of bias. The suitability of RWD/RWE in a given application still requires a case-by-case analysis considering its purpose of use, implying reflection on the data source, together with its assets and limitations, study objectives and designs, and the overall data package issued. Early interactions and continuous dialogues with regulators and relevant stakeholders is key to optimize fit-for-purpose RWE generation, enabling its broader use in medicines development.

Introduction 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. Objectives The aim of this study was to assess the effect of content elements 'frequency of the safety issue', 'seriousness of the safety issue', 'need to take action', 'life span of drug involved' and 'type of evidence supporting the safety issue' on hospital-based HCPs' preferences and responses towards DHPCs. Methods A survey study including a conjoint experiment was performed among hospital-based HCPs in the Netherlands. Hypothetical DHPCs varying on the five content elements were constructed. Each respondent received eight out of 16 hypothetical DHPCs and was asked about (1) importance to be informed (fixed-point scale), (2) preferred communication timing (multiple options) and (3) their stated actions (multiple options). Associations were tested using generalized linear mixed models. Results In total, 178 HCPs participated. DHPCs concerning more frequent or serious safety issues, or requiring action, were associated with a higher perceived importance to be informed and a preference for immediate communication. Periodic communication was preferred for DPHCs concerning less frequent or serious safety issues. The most commonly stated action was to discuss the DHPC with colleagues. Monitoring was common when this was recommended. High frequency and seriousness were associated with more prescribing-related actions. Conclusion Frequency and seriousness of the safety issue and the recommended action are likely to influence the impact of DHPCs. The timing of communication could be tailored depending on the content, where less urgent safety issues might be communicated periodically.

INTRODUCTION: The implementation of new drug safety information and Direct Healthcare Professional Communications (DHPCs) in hospitals is important for patient safety.OBJECTIVES: The aim of this study was to gain insight into which procedures and practices are in place to handle new drug safety information and particularly DHPCs in the Dutch hospital setting.METHODS: We first conducted focus groups including medical specialists and hospital pharmacists, focusing on handling of drug safety information at the individual and organisational level. A survey was then developed and distributed among hospital pharmacists in all Dutch hospitals to quantify the existence of specific procedures and committees to handle drug safety information and DHPCs.RESULTS: Eleven specialists and 14 pharmacists from six hospitals participated in focus groups. Drug safety information was usually considered before drugs were included in formularies or treatment protocols. Furthermore, drug safety information was consulted in response to patients experiencing adverse events. DHPCs were mostly dealt with by individual professionals. DHPCs could lead to actions but this was very uncommon. Completed surveys were received from 40 (53%) of the hospitals. In 32 (80%), the hospital pharmacy had procedures to deal with new drug safety information, whereas in 11 (28%) a hospital-wide procedure was in place. Drug safety was considered in committees concerning drug formulary decisions (69%) and antibiotic policies (63%). DHPCs were assessed by a hospital pharmacist in 50% of the hospitals.CONCLUSIONS: Drug safety information was used for evaluation of new treatments and in response to adverse events. Assessment of whether a DHPC requires action was primarily an individual task.

AimsThe SOLOIST-WHF trial demonstrated efficacy of sotagliflozin in patients with type 2 diabetes mellitus (T2DM) and recent worsening heart failure (HF) regardless of ejection fraction (EF). Selection criteria in trials may limit their generalizability. Therefore, we aimed to investigate eligibility for sotagliflozin based on the SOLOIST-WHF criteria in a real-world HF population.Methods and resultsSOLOIST-WHF criteria were applied to patients stabilized after HF hospitalization in the Swedish HF Registry according to (i) literal scenario (all inclusion/exclusion criteria) or (ii) pragmatic scenario (only criteria likely to influence treatment decisions). Of 5453 inpatients with T2DM and recent worsening HF, 51.4% had reduced EF (HFrEF), 19.1% mildly reduced (HFmrEF), and 29.5% preserved EF (HFpEF). Eligibility (literal) was: 27.2% (32.4% in HFrEF, 24.7% in HFmrEF, 19.7% in HFpEF) and eligibility (pragmatic) was 62.8% (69.1%, 60.3%, 53.4%, respectively). In the literal scenario, criteria limiting eligibility were HF duration 85 years, acute coronary syndrome ConclusionIn this large, real-world HF cohort with T2DM, ∼1/3 of patients were eligible for sotagliflozin in the literal and ∼2/3 of patients in the pragmatic scenario. Eligible patients had more severe HF and higher event rates, in particular CV and HF events.

Introduction 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. Objective The objective of this study was to investigate the opinion of stakeholders about key aspects of rare disease registries that are used to support regulatory decision making and to compare the responses of employees from industry to other stakeholders. Methods A web-based survey was used to gauge the importance of (1) common data elements (including safety outcomes), (2) data quality and (3) governance aspects that are generic across different rare diseases. The survey included 47 questions. The data were collected in the period April-October 2019. Results Seventy-three respondents completed ≥ 80% of the survey. Most of the respondents were from the industry (n = 42, 57%). For safety data, 31 (42%) respondents were in favour of collecting all adverse events. For data quality, the respondents found a level of 30% reasonable for source data verification. For missing data, a level of 20% was considered acceptable. Compared to responders from industry, the other stakeholders found it less relevant to share data with industry and found it less acceptable if the registry is financed by industry. Conclusions This study showed that the opinion towards data and governance is well aligned across parties, and issues of data and governance on their own should not pose a barrier to collaboration. This finding is supportive of the European Medicines Agency’s efforts to encourage stakeholders to work with existing registries when collecting data to support regulatory decision making. Supplementary Information The online version contains supplementary material available at 10.1007/s40264-021-01081-z.

Introduction 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. Methods We performed a descriptive study of all centrally authorised products (CAPs) approved before 1 May 2019 in the EU. All DHPCs issued between 1 January 2001 and 1 May 2019 were reviewed for ME content. Characteristics of CAPs were collected from the website of the European Medicines Agency. A Kaplan–Meier survival analysis was performed to estimate the 5- and 10-year probability of the occurrence of a first ME DHPC. A logistic regression was performed to explore risk factors for ME DHPCs. Results A total of 678 CAPs were included, of which 35 required an ME DHPC during the study period. The 5-year probability for a CAP to have a first ME DHPC was 2.5% (95% CI 1.1–3.9) and the 10-year probability was 4.4% (95% CI 2.2–6.5). Among products with an ME DHPC, the 5-year probability of a second ME DHPC was 21.3% (95% CI 0.2–38.0). The risk of ME DHPCs was increased for products with multiple pharmaceutical formulations, enteral liquid or parenteral injection preparations, and products classified as nervous system agents or antineoplastic and immunomodulating agents. Conclusions The absolute number of ME DHPCs for CAPs is low and does not give rise to immediate concern. We identified potential risk factors for ME DHPCs that should be taken into account during approval procedures or line extensions. Electronic supplementary material The online version of this article (10.1007/s40264-020-00995-4) contains supplementary material, which is available to authorized users.

Aim 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. Methods We used individual patient data from previously untreated patients (PUPs) with severe haemophilia A from the factor VIII (rAHF‐PFM)‐clinical study and the PedNet registry. The primary outcome was the patient characteristics at entry and the difference in inhibitor development between the clinical study and the registry‐based study at 50 exposure days. Results Clinical study patients more often had a positive family history of inhibitors (31% vs 10%) and a high‐risk F8 genotype (82% vs 63%). In the clinical study 41/55 (75%) and in the registry‐based study 162/168 (96%) patients reached 50 exposure days. Inhibitors developed in 16 of the 41 patients in the clinical study (39%) vs 44 of the 162 patients in the registry‐based study (27%); seven patients (7%) vs 28 patients (17%) had high‐titre inhibitors. The risk of developing an inhibitor during the first 50 exposure days was similar (HR 1.04; 95% CI 0.56‐1.94), when adjusted for family history of inhibitors, F8 gene mutation and intensive treatment at first exposure. Conclusion In the registry‐based study, patient numbers and completeness of follow‐up were higher. The risk of developing an inhibitor to a single product was comparable. Although the sample size of this study was too small to conclude on differences in high‐ or low‐titre inhibitors, this suggests that a registry could serve as a more suitable source for evaluation of high‐titre inhibitors in the setting of factor VIII deficiency.

Background Some drug safety issues communicated through direct healthcare professional communications (DHPCs) receive substantial media coverage, while others do not. Objectives The objective of this study was to assess the extent of coverage of drug safety issues that have been communicated through DHPCs in newspapers and social media. A secondary aim was to explore which determinants may be associated with media coverage. Methods Newspaper articles covering drug safety issues communicated through 387 DHPCs published between 2001 and 2015 were retrieved from LexisNexis Academic™. Social media postings were retrieved from Coosto™ for drugs included in 220 DHPCs published between 2010 and 2015. Coverage of DHPCs by newspapers and social media was assessed during the 2-month and 14-day time periods following issuance of the DHPC, respectively. Multivariate logistic regression was used to assess potential DHPC- and drug-related determinants of media coverage. Results 41 (10.6%) DHPC safety issues were covered in newspaper articles. Newspaper coverage was associated with drugs without a specialist indication [adjusted odds ratio 5.32; 95% confidence interval (2.64–10.73)]. Negative associations were seen for time since market approval [3–5 years 0.30; (0.11–0.82), 6–11 years 0.18; (0.06–0.58)] and year of the DHPC [0.88; (0.81–0.96)]. In the social media, 180 (81.8%) drugs mentioned in 220 DHPCs were covered. Social media coverage was associated with drugs without a specialist indication [6.92; (1.56–30.64)], and for DHPCs communicating clinical safety issues [5.46; (2.03–14.66)]. Conclusions Newspapers covered a small proportion of DHPC safety issues only. Most drugs mentioned in DHPCs were covered in social media. Coverage in both media were higher for drugs without a specialist indication. Electronic supplementary material The online version of this article (10.1007/s40264-020-00922-7) contains supplementary material, which is available to authorized users.

An under-representation of women and a lack of sex-specific analyses in COVID-19 trials has been suggested. However, the higher number of men than women who are severely affected by COVID-19 and the restricted information in scientific publications may have biased these suggestions. Therefore, we evaluated sex proportionality and sex-specific efficacy and safety data in trials of COVID-19 treatments and vaccines using both publicly available regulatory documents and confidential documents used by regulators in their review of medicinal products. Included were two treatments (ie, remdesivir and dexamethasone) and four vaccines (ie, BNT162b2 mRNA (BioNTech/Pfizer), mRNA-1273 (Moderna), ChAdOx1-S (AstraZeneca) and Ad26.COV2-S (Janssen)) that received marketing authorisation by the European Commission at the time of the study conduct. An under-representation of women was shown in three of the nine data sets for one treatment (ie, remdesivir), but the proportion of women included was representative in each of the data sets for the other five products. This indicates that there is no structural under-representation of women in the COVID-19 trials. Currently, sex-specific efficacy data are available for five of the six assessed products and sex-specific safety data are available for half of the products only. It is important that this information will also be made available for the other products. There are only small differences in efficacy and safety between men and women which are likely to be of limited clinical relevance. Sex-specific efficacy information can generally be found in the publicly available regulatory documents other than the Summary of Product Characteristics, for which more awareness might be required.

National competent authorities (NCAs) use Direct Healthcare Professional Communications (DHPCs) to communicate new drug safety issues to healthcare professionals (HCPs). More knowledge is needed about the effectiveness of DHPCs and the extent to which they raise awareness of new safety issues among HCPs.The objective was to assess and compare general practitioners' (GPs'), cardiologists', and pharmacists' familiarity with DHPCs as communication tools, their awareness of specific drug safety issues, and the sources through which they had become aware of the specific issues.GPs, cardiologists, and pharmacists from nine European countries (Croatia, Denmark, Ireland, Italy, the Netherlands, Norway, Spain, Sweden, and the UK) completed a web-based survey. The survey was conducted in the context of the Strengthening Collaboration for Operating Pharmacovigilance in Europe (SCOPE) Joint Action. Respondents were asked about their familiarity with DHPCs in general and their awareness of safety issues that had recently been communicated and involved the following drugs: combined hormonal contraceptives, diclofenac, valproate, and ivabradine. Those HCPs who were aware of the specific safety issues were subsequently asked to indicate the source through which they had become aware of them. Differences between professions in familiarity with DHPCs and awareness were tested using a Pearson χOf the 3288 included respondents, 54% were GPs, 40% were pharmacists, and 7% were cardiologists. The number of respondents ranged from 67 in Denmark to 916 in Spain. Most respondents (92%) were familiar with DHPCs, with one significant difference between the professions: pharmacists were more familiar than GPs in Italy (99 vs 90%, P = 0.004). GPs' awareness ranged from 96% for the diclofenac issue to 70% for the ivabradine issue. A similar pattern was shown for pharmacists (91% aware of the diclofenac issue to 66% of the ivabradine issue). Cardiologists' awareness ranged from 91% for the ivabradine issue to 34% for the valproate issue. Overall, DHPCs were a common source through which GPs (range: 45% of those aware of the contraceptives issue to 60% of those aware of the valproate issue), cardiologists (range: 33% for the contraceptives issue to 61% for the valproate issue), and pharmacists (range: 41% for the contraceptives issue to 51% for the ivabradine issue) had become aware of the specific safety issues, followed by information on websites or in newsletters.GPs, cardiologists, and pharmacists were to a similar extent (highly) familiar with DHPCs, but they differed in awareness levels of specific safety issues. Cardiologists were less aware of safety issues associated with non-cardiology drugs even if these had cardiovascular safety concerns. This implies that additional strategies may be needed to reach specialists when communicating safety issues regarding drugs outside their therapeutic area but with risks related to their field of specialisation. DHPCs were an important source for the different professions to become aware of specific safety issues, but other sources were also often used. NCAs should consider the use of a range of sources when communicating important safety issues to HCPs.

PURPOSE: Little is known about adverse drug events (ADEs) experienced over time during chronic drug use. The purpose of this study was to assess ADE patterns experienced by patients with diabetes.METHODS: Patients who received an oral glucose-lowering drug completed a daily diary for 13 weeks. The diary asked for experienced symptoms and whether patients related these symptoms to any drug they used. Summaries of Product Characteristics were used to check whether the ADEs were known adverse drug reactions (ADRs) of the drugs used. Patterns of weekly occurring ADEs were assessed with descriptive statistics.RESULTS: We included 78 patients. Almost half of them reported at least one ADE (N = 36; 46%). In total, 80 ADEs were reported. Of these ADEs, 71 (90%) were known ADRs. ADEs lasted less than 1 week in 27 cases (34%) and between 2 and 12 weeks in 15 cases (19%). The remaining ADEs fluctuated (16 cases; 20%) or persisted (22 cases; 28%) during the entire study period.CONCLUSIONS: ADEs experienced by patients with diabetes can fluctuate or persist over long periods of drug use.

AimsWe aimed to assess and characterize sex differences in adverse drug reactions (ADRs) reported to the national pharmacovigilance centre in the Netherlands while considering differences in drug use.MethodsADRs spontaneously reported by healthcare professionals and patients to the Netherlands pharmacovigilance centre Lareb were used. Drug-ADR combinations reported at least 10 times between 2003-2016 for drugs used by 10,000 persons in that period were included. Data about the number of drug users was obtained from the National Health Care Institute. Sex-specific ADRs, like gynaecological problems, were excluded. Sex differences in specific drug-ADR combinations were tested using bivariate logistic regression analyses in which the number of drug users per sex was taken into account.ResultsIn total, 2483 drug-ADR combinations were analysed. Possibly relevant sex differences were shown in 363 combinations (15%). Most of these drug-ADR combinations were reported more often for women (322 combinations). Drugs with the highest number of ADRs that were more often reported for women included thyroid hormones (32 combinations) and antidepressants (16 combinations for the centrally acting sympathomimetics; 14 combinations for other antidepressants). Some ADRs were predominantly reported for women across a range of drugs such as headache and dizziness whereas other ADRs such as tendon ruptures and aggression were reported more often for men.ConclusionsIdentified sex differences in reported ADRs often referred to women. These differences may have various causes, including pharmacological and behavioural causes, which need to be further assessed. The results may ultimately lead to sex-specific prescribing or monitoring recommendations.

Objective: The aim of this study was to compare the importance that patients with type 2 diabetes mellitus from the Netherlands and Turkey attach to certain drug effects of oral anti-diabetic drugs.Methods: Data were collected through a cross-sectional survey containing demographic questions and a discrete choice experiment assessing preferences for oral anti-diabetic drugs. Adults from the Netherlands and Turkey were included if they had type 2 diabetes mellitus and had received a prescription of an oral anti-diabetic drug in the last 4 months. The oral anti-diabetic drugs in the discrete choice experiment were described in terms of six attributes: effects on HbA1c, cardiovascular diseases, weight change, gastrointestinal adverse drug events hypoglycemic events, and bladder cancer. Multinomial logit models with country as an interaction factor were fitted.Results: In total, 381 patients were included, 199 from the Netherlands and 182 from Turkey. Patients’ preferences toward drug effects varied between the countries. Turkish patients attached the highest importance to reducing the risk of cardiovascular diseases (relative weight: 0.51, 95% CI 0.45–0.55), followed by reducing hypoglycemic events (relative weight: 0.16, 95% CI 0.11–0.22), and reducing gastrointestinal adverse drug events (relative weight: 0.11, 95% CI 0.07–0.18). Patients from the Netherlands attached the highest importance to gastrointestinal ADEs (relative weight: 0.22, 95% CI 0.14–0.39), followed by reducing hypoglycemic events (relative weight: 0.22, 95% CI 0.16–0.25), and reducing the risk of cardiovascular diseases (relative weight: 0.20, 95% CI 0.13–0.23).Conclusion: Patient preferences may differ across countries. Such differences should be acknowledged in regulatory decisions and clinical practice.

ObjectivesTo 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.DesignCross-sectional web-based survey.SettingMultinational study in Europe.ParticipantsPregnant women or women with children less than 1 year old from European countries and with asthma, allergy, cardiovascular, rheumatic diseases, diabetes, epilepsy and/or inflammatory bowel diseases (IBD).Primary and secondary outcome measureDifferences in scores of theBeliefs about Medicines Questionnaire(BMQ).ResultsIn total, 1219 women were included (ranging from 736 for allergy to 49 for IBD). Women using medication for their chronic disease (n=770; 63%) had higher scores on the BMQ subscalesnecessity(16.6 vs 12.1, pbenefits(16.2 vs 15.4, poveruse(12.5 vs 13.1; p=0.005) andharm(9.8 vs 10.7, pconcernssubscale (12.5 vs 12.3, p=0.484). Beliefs varied somewhat across diseases but in general more positive beliefs among women using medication were shown. Epilepsy was the disease where less differences were observed between women using and not using medication.ConclusionWomen’s beliefs were associated with medication use during pregnancy with only small differences across the diseases. Knowing pregnant women’s beliefs could help identify women who are reluctant to use medication and could guide counselling to support making well-informed treatment decisions.

Aims Understanding how much healthcare professionals (HCPs) know about medication can help in devising strategies to improve rational medication use. This study aimed to synthesize information on the level of medication knowledge of HCPs in Africa. Method We performed a systematic literature study in Embase and PubMed. We included original studies quantifying HCPs' medication knowledge, published between 2012 and 2016. We extracted disease focus, country, number and type of HCPs included and all medication-related knowledge questions and scored the quality of papers. The outcome measure was the percentage of HCPs who correctly answered medication knowledge questions. Results We identified 64 studies from 12 African countries, comprising 13 911 HCPs, mostly nurses/midwifes and physicians. We extracted 306 medication-related knowledge questions, and only 52% (SD 28) of HCPs correctly answered them. Knowledge questions were mainly about medication prescribed for communicable diseases (70%), followed by non-communicable diseases (11%), and family planning/gynaecology (10%). Most papers concluded that there was a considerable medication knowledge gap among HCPs. Conclusion We found a low level of medication knowledge across different disease areas, countries and HCPs. This underlines the continuous need to strengthen the undergraduate and postgraduate education in (clinical) pharmacology and therapeutics in Africa.

Purpose As part of the approval process, regulatory authorities often require postauthorization studies that involve patient registries; it is unknown, however, whether such registry studies are adequately completed. We investigated whether registry studies for new drugs were performed as agreed at time of approval. Methods This study reviewed protocols and follow-up reports for 73 registry studies that were proposed for 43 drugs approved by the Committee for Medicinal Products for Human Use in Europe in the period 2007 to 2010. Results The data lock point of January 1, 2016, was taken to allow a 5-year follow-up period for each drug after approval. At that time, 2 studies (3%) in registries had been finalized, 19 registries (26%) had not enrolled any patients, and 52 studies (71%) were ongoing. The median enrollment was 31% (interquartile range [IQR], 6–104) of the required number of patients for 41 registry studies that had a predefined sample size, 30% (IQR, 2–101) for nonimposed registries, and 61% (IQR, 18–144) for imposed registries. Implications Enrollment of patients into postapproval registries is poor, although the results for imposed registries seem better. Currently, registries only have a limited impact on resolving gaps in the knowledge of a drug’s benefits and risks at time of marketing authorization.

National competent authorities (NCAs) use Direct Healthcare Professional Communications (DHPCs) to communicate new drug safety issues to healthcare professionals (HCPs). More knowledge is needed about the effectiveness of DHPCs and the extent to which they raise awareness of new safety issues among HCPs.The objective was to assess and compare general practitioners' (GPs'), cardiologists', and pharmacists' familiarity with DHPCs as communication tools, their awareness of specific drug safety issues, and the sources through which they had become aware of the specific issues.GPs, cardiologists, and pharmacists from nine European countries (Croatia, Denmark, Ireland, Italy, the Netherlands, Norway, Spain, Sweden, and the UK) completed a web-based survey. The survey was conducted in the context of the Strengthening Collaboration for Operating Pharmacovigilance in Europe (SCOPE) Joint Action. Respondents were asked about their familiarity with DHPCs in general and their awareness of safety issues that had recently been communicated and involved the following drugs: combined hormonal contraceptives, diclofenac, valproate, and ivabradine. Those HCPs who were aware of the specific safety issues were subsequently asked to indicate the source through which they had become aware of them. Differences between professions in familiarity with DHPCs and awareness were tested using a Pearson chi (2) test per country and post hoc Pearson chi (2) tests in the case of statistically significant differences.Of the 3288 included respondents, 54% were GPs, 40% were pharmacists, and 7% were cardiologists. The number of respondents ranged from 67 in Denmark to 916 in Spain. Most respondents (92%) were familiar with DHPCs, with one significant difference between the professions: pharmacists were more familiar than GPs in Italy (99 vs 90%, P = 0.004). GPs' awareness ranged from 96% for the diclofenac issue to 70% for the ivabradine issue. A similar pattern was shown for pharmacists (91% aware of the diclofenac issue to 66% of the ivabradine issue). Cardiologists' awareness ranged from 91% for the ivabradine issue to 34% for the valproate issue. Overall, DHPCs were a common source through which GPs (range: 45% of those aware of the contraceptives issue to 60% of those aware of the valproate issue), cardiologists (range: 33% for the contraceptives issue to 61% for the valproate issue), and pharmacists (range: 41% for the contraceptives issue to 51% for the ivabradine issue) had become aware of the specific safety issues, followed by information on websites or in newsletters.GPs, cardiologists, and pharmacists were to a similar extent (highly) familiar with DHPCs, but they differed in awareness levels of specific safety issues. Cardiologists were less aware of safety issues associated with non-cardiology drugs even if these had cardiovascular safety concerns. This implies that additional strategies may be needed to reach specialists when communicating safety issues regarding drugs outside their therapeutic area but with risks related to their field of specialisation. DHPCs were an important source for the different professions to become aware of specific safety issues, but other sources were also often used. NCAs should consider the use of a range of sources when communicating important safety issues to HCPs.

Introduction Pharmaceutical risk minimization programs involve interventions designed to support safe and appropriate use of medicines. Currently, information regarding the evaluation of these programs is not publicly reported in a standardized and transparent manner. To address this gap, we developed and piloted a quality reporting checklist entitled the Reporting recommendations Intended for pharmaceutical risk Minimization Evaluation Studies (RIMES). Methods Checklist development was guided by three sources: (1) a theoretical framework derived from program theory and process evaluation; (2) public health intervention design and evaluation principles; and (3) a review of existing quality reporting checklists. Two raters independently reviewed 10 recently published (2012–2016) risk minimization program evaluation studies using the proposed checklist. Inter-rater reliability of the checklist was assessed using Cohen’s Kappa and Gwet’s AC1. Results A 43-item checklist was generated. Results indicated substantial inter-rater reliability overall (κ = 0.65, AC1 = 0.65) and for three (key information, design and evaluation) of the four subscales (κ ≥ 0.64, AC1 ≥ 0.64). The fourth subscale (implementation) showed low reliability based on Cohen’s Kappa, but substantial reliability based on the AC1 (κ = 0.17, AC1 = 0.61). Conclusions The RIMES statement augments relevant elements from existing quality reporting guidelines with items that address aspects of intervention design, implementation and evaluation specific to pharmaceutical risk minimization programs. Our results show that the RIMES statement reliably measures key dimensions of reporting quality. This tailored checklist is an important first step in improving the reporting quality of risk minimization evaluation studies and may ultimately help to improve the quality of these interventions themselves.

Background and objectives: RRT and doubling of serum creatinine are considered the objective hard end points in nephrology intervention trials. Because both are assumed to reflect changes in the filtration capacity of the kidney, drug effects, if present, are attributed to kidney protection. However, decisions to start RRT are not only on the basis of filtration capacity of the kidney, but also on other factors. We therefore compared the time to RRT with the time to a fixed eGFR threshold and assessed the effect of the renoprotective drug irbesartan on both components.Design, setting, participants, & measurements: Post hoc analysis of two clinical trials, the Irbesartan Diabetic Nephropathy Trial (IDNT) and Reduction of End points in Non-insulin dependent diabetes mellitus with the Angiotensin II Antagonist Losartan Trial, in patients with type 2 diabetes and nephropathy. The time to a predefined eGFR level of 11 ml/min per 1.73 m(2) (eGFR(11)), calculated by within-patient linear regression, was compared with the time to RRT or sustained serum creatinine >= 6 mg/dl.Results: A large difference was observed in the median time to RRT (779 days) compared with eGFR11 (678 days; P=0.01). We also observed a large variation in the difference between the time to RRT and eGFR11. In IDNT, the hazard ratio for the effect of irbesartan on the serum creatinine >= 6.0 mg/dl end point was 0.60 (95% confidence interval, 0.39 to 0.91; P=0.02), whereas it was smaller for the RRT end point (hazard ratio, 0.78; 95% confidence interval, 0.58 to 1.07; P=0.12).Conclusions: This study shows a difference in the time to RRT and a fixed eGFR threshold, and shows that the effect of an angiotensin receptor blocker on a filtration-based end point versus RRT varies. This implies that evaluating renoprotective effects of drugs with a combined RRT and doubling of serum creatinine end point may result in evaluating other effects beyond renoprotection alone. Future trials should consider registering all parameters that lead to RRT decisions.

Purpose: Knowledge of the benefits and risks of new drugs is incomplete at the time of marketing approval. Registries offer the possibility for additional, post-approval, data collection. For all new drugs, which were approved in the European Union between 2007 and 2010, we reviewed the frequency, the type, and the reason for requiring a registry.Methods: The European Public Assessment Reports, published on the website of the European Medicine Agency, were reviewed for drugs approved by the Committee for Medicinal Products for Human Use. We searched for key characteristics of these drugs, including therapeutic area (ATC1 level), level of innovation (the score is an algorithm based on availability of treatment and therapeutic effect), and procedural characteristics. In addition, we identified if these registries were defined by disease (disease registry) or exposure to a single drug (drug registry).Results: Out of 116 new drugs approved in the predefined period, for 43 (37%), 1 to 6 registry studies were identified, with a total of 73 registries. Of these 46 were disease registries and 27 (single) drug registries. For 9 drugs, the registry was a specific obligation imposed by the regulators. The level of innovation and the orphan status of the drugs were determinants positively predicting post-approval registries (OR 10.3 [95% CI 1.0-103.9] and OR 2.8 [95% CI 1.0-7.5], respectively).Conclusions: The majority of registries required by regulators are existing disease registries. Registries are an important and frequently used tool for post-approval data collection for orphan and innovative drugs.

Aims The aim of the present study was to evaluate the impact of adverse drug events (ADEs) and treatment satisfaction on antihypertensive medication adherence. Methods A cross-sectional study was conducted in six public hospitals in Ethiopia. We included adult ambulatory patients on antihypertensive medication. Adherence was measured using the eight-point Morisky Medication Adherence Scale, which categorizes as low (0–5), medium (6–7) and high (8) adherence. Treatment satisfaction was measured using the Treatment Satisfaction Questionnaire for Medication (TSQM) version 1.4, which included questions about ADEs. Data were analysed using generalized ordered logistic regression with 95% confidence intervals (CIs). Results We included 925 out of 968 patients. Overall, 42% of patients scored low, 37% medium and 21% high adherence. Satisfaction with treatment was low, with a mean (standard deviation) TSQM score for global satisfaction of 51 (14). A total of 193 (21%) patients experienced 421 ADEs – mainly dyspeptic symptoms (12%), headache (11%) and cough (11). Experiencing more ADEs reduced the odds of being adherent [low vs. medium/high: odds ratio (OR) OR1 0.77 (95% CI 0.67, 0.89), and low/medium vs. high: OR2 0.55 (05% CI 0.41, 0.73)]. Being more satisfied increased the odds of being adherent [low vs. medium/high: OR1 1.02 (95% CI 1.01, 1.03)]. Taking medication >1 year [OR1 = 2, 0.60 (95% CI 0.43, 0.83)] and taking calcium channel blockers [OR1 = 2 0.71 (95% CI 0.54, 0.92)] decreased the odds for both low vs. medium/high and low/medium vs. high adherence. Conclusions Only one in five patients reported perfect (high) adherence to their antihypertensive treatment regimen. Experiencing ADEs and being dissatisfied with treatment were associated with lower adherence. In addition to addressing treatment satisfaction and drug safety in first-world countries, these should also be addressed in resource-poor settings, within patient consultations, to enhance adherence.

Introduction National competent authorities (NCAs) for medicines coordinate communication relating to the safety of medicines in Europe. The effectiveness of current communication practices has been questioned, particularly with regard to reaching general practitioners (GPs). Objective The aim of this study was to assess current European NCA safety communication practices and to investigate European GPs’ awareness of and preferences for safety communications on medicines. Methods Web-based surveys were distributed among European NCAs and healthcare professionals (HCPs). The survey among regulators was emailed to a representative of each of the 27 European countries participating in the Strengthening Collaboration for Operating Pharmacovigilance in Europe (SCOPE) Joint Action. HCPs from nine European countries (Denmark, Spain, Croatia, Ireland, Italy, The Netherlands, Norway, Sweden, and the UK) were asked about their preferences through a link to the survey on websites, in newsletters, and/or in a direct email. From this survey, data from GPs were used and descriptive analyses were conducted. Results Current NCA practices were reported for 26 countries. In 23 countries (88%), NCAs published direct healthcare professional communications (DHPCs, i.e. urgent communication letters for serious safety issues) on their website in addition to distribution to individual HCPs. Educational materials were available on the NCA’s website in 10 countries (40%), and 21 NCAs (81%) indicated they had their own bulletin/newsletter, which is often presented on the NCA’s website (15 countries; 60%). More than 90% of the 1766 GPs who completed the survey were aware of DHPCs. The most preferred senders of safety information were NCAs and professional bodies, while the preferred channels for keeping up to date with safety information were medicines reference books and clinical guidelines. GPs found the repetition of safety issues useful (range of 80% in the UK to 97% in Italy). Preference for an electronic copy rather than a hardcopy varied per country (36% in Sweden to 72% in Spain). Conclusions NCAs use similar methods for safety communications on medicines. Most GPs were aware of urgent communications and preferred similar senders of safety communications; however, their preferences towards the format differed per country. Electronic supplementary material The online version of this article (doi:10.1007/s40264-017-0535-0) contains supplementary material, which is available to authorized users.

Although cardiovascular disease is a major health burden for patients with chronic kidney disease, most cardiovascular outcome trials have excluded patients with advanced chronic kidney disease. Moreover, the major cardiovascular outcome trials that have been conducted in patients with end-stage renal disease have not demonstrated a treatment benefit. Thus, clinicians have limited evidence to guide the management of cardiovascular disease in patients with chronic kidney disease, particularly those on dialysis. Several factors contribute to both the paucity of trials and the apparent lack of observed treatment effect in completed studies. Challenges associated with conducting trials in this population include patient heterogeneity, complexity of renal pathophysiology and its interaction with cardiovascular disease, and competing risks for death. The Investigator Network Initiative Cardiovascular and Renal Clinical Trialists (INI-CRCT), an international organization of academic cardiovascular and renal clinical trialists, held a meeting of regulators and experts in nephrology, cardiology, and clinical trial methodology. The group identified several research priorities, summarized in this paper, that should be pursued to advance the field towards achieving improved cardiovascular outcomes for these patients. Cardiovascular and renal clinical trialists must partner to address the uncertainties in the field through collaborative research and design clinical trials that reflect the specific needs of the chronic and end-stage kidney disease populations, with the shared goal of generating robust evidence to guide the management of cardiovascular disease in patients with kidney disease. Sin financiación 22.673 JCR (2019) Q1, 2/138 Cardiac & Cardiovascular Systems 5.883 SJR (2019) Q1, 4/362 Cardiology and Cardiovascular Medicine No data IDR 2019 UEM

BackgroundAlthough the benefits of antithrombotic drugs are indisputable to reduce thrombotic events, they carry a high risk of compromising patient safety. No previous studies investigated the implementation and (cost-) effectiveness of a hospital-based multidisciplinary antithrombotic team on bleeding and thrombotic outcomes. The primary aim of this study was to compare the proportion of patients with a composite end point consisting of one or more bleeding episodes or one or more thrombotic event from hospitalization until three months after hospitalization.Methods and findingsA prospective, multicenter before-after intervention study was conducted in two Dutch hospitals. Adult patients hospitalized between October 2015 and December 2017 treated with anticoagulant therapy were included. The primary aim was to estimate the proportion of patients with a composite end point consisting of one or more bleeding episodes or one or more thrombotic event from hospitalization until three months after hospitalization. The intervention was the implementation of a multidisciplinary antithrombotic team focusing on education, medication reviews by pharmacists, implementing of local anticoagulant therapy guidelines based on national guidelines, patient counselling and medication reconciliation at admission and discharge. The primary endpoint was analysed using segmented linear regression. We obtained data for 1,886 patients: 941 patients were included in the usual care period and 945 patients in the intervention period. The S-team study showed that implementation of a multidisciplinary antithrombotic team over time significantly reduced the composite end point consisting of one or more bleeding episodes or one or more thrombotic event from hospitalization until three months after hospitalization in patients using anticoagulant drugs (-1.83% (-2.58% to -1.08%) per 2 month period).ConclusionsThis study shows that implementation of a multidisciplinary antithrombotic team over time significantly reduces the composite end point consisting of one or more bleeding episodes or one or more thrombotic event from hospitalization until three months after hospitalization in patients using anticoagulant drugs.Trial registrationTrialregister.nl NTR4887.

Introduction Patient registries, ‘organised systems that use observational methods to collect uniform data on a population defined by a particular disease, condition, or exposure, and that is followed over time’, are potentially valuable sources of data for supporting regulatory decision-making, especially for products to treat rare diseases. Nevertheless, patient registries are greatly underused in regulatory assessments. Reasons include heterogeneity in registry design and in the data collected, even across registries for the same disease, as well as unreliable data quality and data sharing impediments. The Patient Registries Initiative was established by the European Medicines Agency in 2015 to support registries in collecting data suitable to contribute to regulatory assessments, especially post-authorisation safety and effectiveness studies. Methods We conducted a qualitative synthesis of the published observations and recommendations from an initiative-led multi-stakeholder consultation and four disease-specific patient registry workshops. We identified the primary factors facilitating the use of registry data in regulatory assessments. We generated proposals on operational measures needed from stakeholders including registry holders, patients, healthcare professionals, regulators, marketing authorisation applicants and holders, and health technology assessment bodies for implementing these. Results Ten factors were identified as facilitating registry use for supporting regulatory assessments of medicinal products. Proposals on operational measures needed for implementation were categorised according to three themes: (1) nature of the data collected and registry quality assurance processes; (2) registry governance, informed consent, data protection and sharing; and (3) stakeholder communication and planning of benefit-risk assessments. Conclusions These are the first explicit proposals, from a regulatory perspective, on operational methods for increasing the use of patient registries in medicines regulation. They apply to registry holders, patients, regulators, marketing authorisation holders/applicants and healthcare stakeholders broadly, and their implementation would greatly facilitate the use of these valuable data sources in regulatory decision-making. Electronic supplementary material The online version of this article (10.1007/s40264-019-00848-9) contains supplementary material, which is available to authorized users.

Objective To assess the proportion of all medication error reports in hospitals and primary care that involved an anticoagulant. Secondary objectives were the anticoagulant involved, phase of the medication process in which the error occurred, causes and consequences of 1000 anticoagulant medication errors. Additional secondary objectives were the total number of anticoagulant medication error reports per month, divided by the total number of medication error reports per month and the proportion of causes of 1000 anticoagulant medication errors (comparing the pre- and post-guideline phase). Design A cross-sectional study. Setting Medication errors reported to the Central Medication incidents Registration reporting system. Participants Between December 2012 and May 2015, 42 962 medication errors were reported to the CMR. Intervention N/A. Main outcome measure Proportion of all medication error reports that involved an anticoagulant. Phase of the medication process in which the error occurred, causes and consequences of 1000 anticoagulant medication errors. The total number of anticoagulant medication error reports per month, divided by the total number of medication error reports per month (comparing the pre- and post-guideline phase) and the total number of causes of 1000 anticoagulant medication errors before and after introduction of the LSKA 2.0 guideline. Results Anticoagulants were involved in 8.3% of the medication error reports. A random selection of 1000 anticoagulant medication error reports revealed that low-molecular weight heparins were most often involved in the error reports (56.2%). Most reports concerned the prescribing phase of the medication process (37.1%) and human factors were the leading cause of medication errors mentioned in the reports (53.4%). Publication of the national guideline on integrated antithrombotic care had no effect on the proportion of anticoagulant medication error reports. Human factors were the leading cause of medication errors before and after publication of the guideline. Conclusions Anticoagulant medication errors occurred in 8.3% of all medication errors. Most error reports concerned the prescribing phase of the medication process. Leading cause was human factors. The publication of the guideline had no effect on the proportion of anticoagulant medication errors.

Introduction 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. Objective Our aim was to reveal the factors that may influence healthcare professionals (HCPs) and patients to use an app for two-way risk communication. Methods Focus group discussions and face-to-face interviews were conducted in the Netherlands, Spain and the UK. Patients with type 2 diabetes mellitus, patients with a rare disease or their caregivers and adolescents with health conditions were eligible to participate. HCPs included pharmacists, paediatricians, general practitioners, internists, practice nurses and professionals caring for patients with a rare disease. Patients and HCPs were recruited through various channels. The recorded discussions and interviews were transcribed verbatim. The dataset was analysed using thematic analysis and arranged according to the Unified Theory of Acceptance and Use of Technology. Results Seven focus group discussions and 13 interviews were conducted. In total, 21 HCPs and 50 patients participated. Identified factors that may influence the use of the app were the type of feedback given on reported ADRs, how ADR reports are stored and the type of drug news. Also mentioned were other functions of the app, ease of use, type of language, the source of safety information provided through the app, security of the app, layout, the operating systems on which the app can be used and the costs. Conclusions Further research is needed to assess associations between user characteristics and the direction (positive or negative) of the factors potentially influencing app use. Electronic supplementary material The online version of this article (doi:10.1007/s40264-016-0494-x) contains supplementary material, which is available to authorized users.

Introduction In general, women more often experience metformin-associated adverse drug reactions (ADRs) than men. Objectives We aimed to assess whether sex differences in reported ADRs for metformin are observed at different times after initiation, and to explore their concurrence with sex differences in the dose of metformin over time. This may guide future studies in assessing the involved mechanisms of sex differences in metformin-associated ADRs and may guide sex-specific management of ADRs in clinical practice. Methods This study has a longitudinal design using data about patients initiating metformin collected by the Dutch National Pharmacovigilance Center Lareb through their Intensive Monitoring program. Patients were asked to complete a web-based questionnaire six times after initiation (i.e., at 2 weeks, 6 weeks and at 3, 6, 9, and 12 months). The outcome variables were the proportion of patients reporting any ADR (primary) and the dose of metformin (secondary). Sex differences in the proportions of ADRs and in the dose were tested at each assessment using Pearson Chi-Squared tests and Wilcoxon rank-sum tests, respectively. Using Bonferroni adjustment for multiple testing, a p value

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.This study aimed to assess (1) European HCPs' and patients' interest in an app for this two-way risk communication; (2) their preferences and perceptions towards specific app characteristics; and (3) which HCPs and patients are particularly interested in the app. In addition, these aspects were studied specifically for the countries where such an app was already available, i.e. Croatia, The Netherlands, and The UK.European HCPs and patients were asked to complete a web-based survey developed in the context of the Web-Recognizing Adverse Drug Reactions (Web-RADR) project. Data on app interest and preferences and perceptions towards app characteristics were analysed descriptively. Logistic regression analyses were conducted to assess the association of HCP characteristics and patient characteristics on the level of interest in the app (i.e. very interested vs. not/somewhat interested).In total, 399 HCPs and 656 patients completed the survey. About half of the patients (48%; ranging from 38% from The Netherlands to 54% from The UK), and 61% of the HCPs (ranging from 42% from The Netherlands to 54% from The UK) were very interested in the app. A faster means of reporting ADRs and easier access to the reporting form were the main perceived benefits. HCPs and patients who already use a health app were particularly interested in the app (HCPs: odds ratio [OR] 3.52; 95% confidence interval [CI] 1.96-6.30, patients: OR 1.64; 95% CI 1.19-2.27).An app is positively perceived by HCPs and patients for reporting ADRs quickly and for receiving drug safety information from national medicines agencies. In particular, HCPs and patients who already use other health apps were interested in the app.

Background: Many pharmacovigilance centers have been established in Sub Sahara Africa (SSA) in recent years. Their focus has been on ADRs to drugs for communicable diseases. Little is known about ADRs caused by drugs for cardiometabolic diseases, although its burden is increasing rapidly in SSA. Objectives: Identify characteristics of cardiometabolic ADR reports in SSA comparing those with reports from the rest of the world (ROW). Methods: Reports on suspected ADRs of cardiometabolic drugs (ATC: A10 [antidiabetes], B01 [antithrombotics] and C [cardiovascular]) were extracted from the WHO Global Individual Case Safety Report database, VigiBase (1992-2013).We used vigiPoint, a logarithmic-odds ratios (logOR) based method to study disproportional reporting between SSA and ROW. To identify the most case defining features, characteristics were only considered relevant if the lower limit of the 99% confidence interval>0.5. Results: In SSA, 3,773 (9%) of reported ADRs were for cardiometabolic drugs compared to 18% in ROW. Of these, 79% originated from South Africa and 81% were received after 2007. Most reports were for drugs acting on the renin-angiotensin system (36% SSA & 14% ROW), lipid modifying agents (18% & 20%), antidiabetics (14% & 18%), antithrombotics (13% & 20%) and calcium channel blockers (5.1% & 7.4%). Physicians reported ADRs more frequently (83% SSA vs 50% ROW; logOR 2.2 [99CI 2.1;2.3]) in SSA. Reports were more often for patients 18-44 years old (logOR 0.95 [99CI 0.80;1.09]) or had a non-fatal outcome (logOR 1.16 [99CI 1.10;1.22]). We found disproportional reporting for a cluster of 6 ADRs (cough, angioedema, lip swelling, face oedema, swollen tongue, throat irritation) related to ACE-inhibitors and for enalapril and perindopril; as well as for 2 other ADRs (drug ineffective, blood glucose abnormal) and 4 drugs (rosuvastatin, nifedipine, insulin glulisine and insulin lispro). Conclusions: ADR reporting for cardiometabolic drugs has sharply increased in SSA in recent years. The reports clearly show the well-known differential ADR profile of ACE-i in the black population. Our data would also suggest that other drugs show different risk profiles, e.g some insulins.

The fourth sentence under the heading “1.1 Use of Patient Registries for Supporting Regulatory Assessments” in “1 Introduction” section should read as below.

Introduction: Prescribing medication is an important aspect of almost all in-hospital treatment regimes. Besides their obviously beneficial effects, medicines can also cause adverse drug events (ADE), which increase morbidity, mortality and health care costs. Partially, these ADEs arise from medication errors, e. g. at the prescribing stage. ADEs caused by medication errors are preventable ADEs. Until now, medication ordering was primarily a paper-based process and consequently, it was error prone. Computerized Physician Order Entry, combined with basic Clinical Decision Support System (CPOE/CDSS) is considered to enhance patient safety. Limited information is available on the balance between the health gains and the costs that need to be invested in order to achieve these positive effects. Aim of this study was to study the balance between the effects and costs of CPOE/CDSS compared to the traditional paper-based medication ordering.Methods: The economic evaluation was performed alongside a clinical study (interrupted time series design) on the effectiveness of CPOE/CDSS, including a cost minimization and a cost-effectiveness analysis. Data collection took place between 2005 and 2008. Analyses were performed from a hospital perspective. The study was performed in a general teaching hospital and a University Medical Centre on general internal medicine, gastroenterology and geriatric wards. Computerized Physician Order Entry, combined with basic Clinical Decision Support System (CPOE/CDSS) was compared to a traditional paper based system. All costs of both medication ordering systems are based on resources used and time invested. Prices were expressed in Euros (price level 2009). Effectiveness outcomes were medication errors and preventable adverse drug events.Results: During the paper-based prescribing period 592 patients were included, and during the CPOE/CDSS period 603. Total costs of the paper-based system and CPOE/CDSS amounted to is an element of 12.37 and is an element of 14.91 per patient/day respectively. The Incremental Cost-Effectiveness Ratio (ICER) for medication errors was 3.54 and for preventable adverse drug events 322.70, indicating the extra amount (is an element of) that has to be invested in order to prevent one medication error or one pADE.Conclusions: CPOE with basic CDSS contributes to a decreased risk of preventable harm. Overall, the extra costs of CPOE/CDSS needed to prevent one ME or one pADE seem to be acceptable. (C) 2014 Elsevier Ireland Ltd. All rights reserved.

Background: Information regarding QT-prolongation in the drug label may vary between products. This could lead to suboptimal risk minimization strategies. Objective: To systematically assess the variation in the extent and content of information on QT prolongation in the summary of product characteristics (SPC) of recently approved medicinal products. Methods: Drug labels of products centrally approved in Europe between 2006 and 2012 were screened. Of drugs including the term 'QT' in the SPC, the message on QT-prolongation ('no prolongation'/'unclear drug-QT association'/'possibly QT-prolongation'/'QT-prolongation') and the advice on cautionary measures pertaining to QT-prolongation in the label were examined, as well as their association. Results: Of the 175 screened products, 44 contained information on QT in the SPC ('no QT-prolongation': 23%, 'unclear drug-QT association': 43%, 'possibly QT-prolongation': 16%, 'QT-prolongation': 18%). 62% contained advices to act with caution in patients with additional risk factors for QT-prolongation. Products that more likely to have QT-prolonging properties according to the SPC provided more information on QT-prolongation in the SPC ('no prolongation': 10% and for the category 'QT-prolongation': 100%). Conclusions: The extent and content of information on QT-prolongation varies considerably between SPCs, and in almost half of the drugs a clear message on QT-prolongation was lacking in the SPC.

OBJECTIVE: To assesses the safety and rationale of antibacterial fixed-dose combinations in the private sector in Latin America and determine the extent of their use.METHODS: Analysis of FDCs was based on retail sales data for eight Latin American countries (Argentina, Brazil, Chile, Colombia, Mexico, Peru, Uruguay and Venezuela) between 1999 and 2009. FDCs were classified according to the pre-defined criteria. Use was expressed as daily defined doses per 1000 inhabitants per day (DDD/TID).RESULTS: A total of 175 antibacterial FDCs contained a mean of 1.3 antibacterial substances and 3.2 other active substances. Thirty-seven (21%) FDCs were classified as unsafe, 124 (70%) as lacking sufficient evidence for efficacy and only 14 (9%) of all FDCs were considered rational, for example amoxicillin and clavulanic acid. Consumption of unsafe FDCs decreased by 0.011 DDD/TID (95% CI: -0.012 to -0.009) annually, from 0.173 DDD/TID in 1999 to 0.070 DDD/TID in 2009 (overall decrease, 59.7%). Consumption of FDCs lacking sufficient evidence decreased by 30.3% (-0.018 DDD/TID [95% CI: -0.028 to -0.008] annually), while use of rational FDCs increased by 17.1% (from 1.283 DDD/TID to 1.497 DDD/TID annually).CONCLUSION: The majority of antibacterial FDCs in the private sector lack therapeutic benefit. Despite the decrease in the consumption of unsafe antibacterials and those lacking sufficient evidence, their use remains high and their marketing does not fit into strategies of prudent use of antibiotics to contain antibacterial resistance.

Background: Guideline-concordant therapies have been proven to be associated with improved health and economic outcomes in the treatment of community-acquired pneumonia (CAP). However, actual use of CAP guidelines remains poor, but using tailored interventions looks promising. Based on local observations, we assessed the impact of low-intensity interventions to improve guideline use.Methods: Pre- and post-intervention study with segmented regression analysis in a large tertiary care centre [University Hospitals Leuven (UZL)] and a smaller secondary care control hospital [Ziekenhuis Oost-Limburg (ZOL)] from October 2007 through to June 2010 in Belgium.Results: A total of 477 patients were included in UZL, with 58.5% of the patients treated according to local guidelines. Guideline adherence remained stable, but a decrease (-28.6%; P=0.021) was observed during guideline re-introduction in October 2009. Further analysis showed a high correlation with the concurrent A/H1N1 influenza pandemic (r(point-biserial)=0.683; P=0.045) and with suspected influenza infection (odds ratio=2.70; P=0.038). In ZOL, 326 patients were enrolled, with 69.3% being treated concordantly. A similar, non-significant decrease in guideline adherence was observed after October 2009.Conclusions: Our interventions did not lead to a higher proportion of CAP patients receiving guideline-compliant therapy. Instead, a compliance decrease was observed, coinciding with the peak in the A/H1N1 pandemic in the population. Similar observations could be made in ZOL. The widespread attention for this pandemic may have altered the perception of needed antibiotic therapy for pulmonary infections, bypassing our interventions and decreasing actual guideline compliance. Increased vigilance and follow-up is needed when epidemics with similar impact occur in the future.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • The safety profile of new drugs is not well known at the time of market approval and serious safety issues are regularly identified for marketed drugs. • Drugs intended to meet an unmet medical need can be approved for the market with less safety data than is usually required, using the Exceptional Circumstances and Conditional Approval applications in European Central procedure. • It is unknown whether for drugs approved using Exceptional Circumstances and Conditional Approval procedures have an increased probability of serious safety issues identified post approval than for drugs approved through the standard procedures. WHAT THIS STUDY ADDS • Using the Exceptional Circumstances and Conditional Approval procedures does not lead to more post-marketing safety alerts or safety-related withdrawals when used for drugs with unmet medical needs. AIMS Regulatory requirements for new drugs have increased. Special approval procedures with priority assessment are possible for drugs with clear ‘unmet medical need’. We question whether these Exceptional Circumstances (EC) or Conditional Approval (CA) procedures have led to a higher probability of serious safety issues. METHODS A retrospective cohort study was performed of new drugs approved in Europe between 1999 and 2009. The determinant was EC/CA vs. standard procedure approval. Outcome variables were frequency and timing of a first Direct Healthcare Professional Communication (DHPC). An association between approval procedure and the time from market approval to DHPC was assessed using Kaplan-Meyer survival analysis and Cox-regression to correct for covariates. RESULTS In total 289 new drugs were approved. Forty-six (16.4%) were approved under EC or CA, of which seven received a DHPC (15%). This was similar to the standard approval drugs (243), of which 33 received one or more DHPC (14%, P= 0.77). The probability of acquiring a DHPC for standard approval drugs vs. EC/CA drugs during 11-year follow-up is 22% (95% CI 14%, 29%) and 26% (95% CI 8%, 44%), respectively (log-rank P= 0.726). This difference remained not significant in the Cox-regression model: hazard ratio 0.94 (95% CI 0.40, 2.20). Only drug type was identified as a confounding covariate. CONCLUSION The EC/CA procedure is not associated with a higher probability of DHPCs despite limited clinical development data. These data do not support the view that early drug approval increases the risk of serious safety issues emerging after market approval.