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Introduction Current research to assess the impact that medicine shortages have on patients is limited to general aspects, such as the prevalence of shortages and product characteristics. The aim of this study is to assess the overall impact that medicine shortages have on economic, clinical, and humanistic outcomes. Methods A cohort of all known products in shortage in the Netherlands between 2012 and 2015 were characterized by their route of administration, anatomical therapeutic chemical class, and whether they were originator or generic products. A representative sample of 324 shortages (18% of all shortages) was rated as having low, medium, or high impact on the five elements that determine the impact of shortages on patients: availability of an alternative product, underlying disease, susceptibility of the patient, costs (for patients and society at large), and number of patients affected. Ratings were converted into numerical scores per element and multiplied to obtain an overall impact score. Results Two elements were most frequently rated as having a high impact: disease (29%) and costs (20%). Nearly half of the shortages (47%) rated high on at least one element, while nearly 10% rated high on multiple elements. Thirty percent of the shortages rated high on direct impact, which is represented by these elements: alternative product and disease. An additional 17% of the shortages rated high on indirect impact, which is represented by these elements: costs, susceptibility, and number of patients. High impact scores could not significantly be attributed to characteristics of the products in shortage. Conclusions An assessment of the medicine shortages’ impact using a framework based on economic, clinical, and economic outcomes showed that all three outcomes affect the overall impact that medicine shortages have on patients.

Background Retrospective observational studies (ROSs) have been frequently used to investigate treatment effects of diabetes monitoring systems (DMS), i.e. medical devices to monitor blood glucose. However, due to quality concerns, the findings of such studies were often questioned by clinical, regulatory, or health technology assessment decision-makers. We aimed to conduct a systematic review to assess the methodological quality of ROSs investigating DMS effects, and to explore the trend in quality change over time. Methods Embase, PubMed, Web of Science, and Scopus were systematically searched for English-language articles published from January 2012 to March 2021. Randomized controlled trials or other prospective studies were manually excluded. The ROBINS-I (Risk Of Bias In Non-randomized Studies – of Interventions) was used for assessing RoB. To investigate the quality change over time, we divided the study into three subgroups according to publication year, and compared the proportion of studies with the same quality level among the three subgroups. Results We identified 4926 articles, of which 72 were eligible for inclusion. Twenty-six studies were published before 2018, 22 in 2018 or 2019, and 24 after 2019. The overall methodological quality was quite low, as 61 (85%) studies were graded as facing critical or serious RoB. Also, the overall methodological quality did not substantially improve over time. The major contributors to low quality included confounding, missing data, and selection of the reported results. Conclusions The retrospective observational studies investigating DMS effects generally had a high risk of bias, and this did not substantially improve in the past ten years. Thus, clinical, regulatory, or HTA decision-makers may need strategies to effectively exploit these suboptimal studies. Also, to further improve study quality, extra efforts may be needed, such as guiding the tool selection regarding quality improvement in the tools.

ObjectivesTo complement Sustainable Development Goal (SDG) indicator 3.b.3 that monitors access to medicines for all, a corresponding child-specific methodology was developed tailored to the health needs of children. This methodology could aid countries in monitoring accessibility to paediatric medicines in a validated manner and on a longitudinal basis. We aimed to provide proof of concept of this adapted methodology by applying the method to historical datasets.MethodA core set of child-appropriate medicines was selected for two groups of children: children aged 1–59 months and children aged 5–12 years. To enable calculation of affordability of medicines for children, thenumber of units needed for treatmentwas created, incorporating the recommended dosage and duration of treatment for the specific age group. The adapted methodology was applied to health facility survey data from Burundi (2013), China (2012) and Haiti (2011) for one age group. SDG indicator 3.b.3 scores and (mean) individual facility scores were calculated per country and sector.ResultsWe were able to calculate SDG indicator 3.b.3 based on historical data from Burundi, China and Haiti with the adapted methodology. In this case study, all individual facilities failed to reach the 80% benchmark of accessible medicines, resulting in SDG indicator 3.b.3 scores of 0% for all 3 countries. Mean facility scores ranged from 22.2% in Haiti to 40.3% in Burundi for lowest-price generic medicines. Mean facility scores for originator brands were 0%, 16.5% and 9.9% for Burundi, China and Haiti, respectively. The low scores seemed to stem from the low availability of medicines.ConclusionThe child-specific methodology was successfully applied to historical data from Burundi, China and Haiti, providing proof of concept of this methodology. The proposed validation steps and sensitivity analyses will help determine its robustness and could lead to further improvements.

BackgroundToo few pharmacists receive formal training on substandard and falsified (SF) medical products. Strengthening knowledge across pharmacists is considered a moral and ethical duty of academia, that is, to build the health systems’ capacities to combat this global health threat these poor-quality products represent. This study therefore aimed to evaluate whether a dedicated educational course for undergraduate pharmacy students can improve their knowledge on these products.MethodsA survey was conducted at three sub-Saharan universities. Knowledge was assessed through scores on a 20-point questionnaire with questions related to the course content. Scores were compared before and after the course, and a linear mixed-effects model analysis was used to analyse score differences. Students were furthermore asked for feedback and self-assessment. In addition, teachers were interviewed on the context of the course introduction. These data were analysed descriptively.ResultsAmong 335 out of 355 students who completed the survey (n=41/53 in Cameroon, n=244/252 in Senegal and n=50/50 in Tanzania), knowledge of SF medical products was enhanced, with increase in all countries, overall, by 3.5 (95% CI 3.1 to 3.9) score points. Students improved in all offered modules in each country. Students confirmed their improvement through self-assessment.The course was well received among students and teachers. Barriers included time constraints and access to practical means (equipment availability, room allocation, internet accessibility and affordability). These barriers can be overcome by key enablers such as the support from university leadership and early involvement of the university in the course design.ConclusionsThe course improved students’ knowledge on SF medical products. These findings encourage further full implementation of this course in existing curricula beyond the pilot and can inform possible future scale-up. This has a potential for reinforcing the capacity of health systems to protect communities from SF medicines, by empowering all pharmacist across the health systems to intervene.

Aims Studies on adherence and persistence with non-vitamin K oral anticoagulant (NOAC) treatment have relied on data from the early years of NOAC availability. We aimed to study long-term adherence and persistence with NOACs and their association with stroke risk. Methods and results From the Stockholm Healthcare database, we included 21 028 atrial fibrillation patients claiming a first NOAC prescription from July 2011 until October 2018, with more than 1000 patients having more than 5 years of follow-up (median: 2.0, interquartile range: 1.0–3.2). Persistence rates, defined as continuing to claim NOAC prescriptions within a 90-day gap, decreased to 70% at the end of follow-up. However, 85% of the patients were treated at the end of the study due to reinitiations. Adherence, calculated as medication possession rate (MPR) in 3 and 6-month intervals among persistent users, remained stable at 90%, with 75% of patients having an MPR >95% throughout the study period. Using a case–control design, we calculated associations of persistence and adherence with stroke risk, adjusting for potential confounders. The outcome was a composite of ischaemic or unspecified stroke and transient ischaemic attack. Non-persistence and poor adherence were both associated with increased stroke risk [non-persistence adjusted odds ratio (aOR): 2.05; 95% confidence interval (CI): 1.49–2.82, 1% reduction MPR aOR: 1.03; CI: 1.01–1.05]. There was no association between non-persistence or poor adherence and the falsification endpoints; fractions and respiratory infections, indicating no ‘healthy-adherer’ effect. Conclusion Persistence rates decreased slowly over time, but persistent patients had high adherence rates. Both non-persistence and poor adherence were associated with an increased stroke risk.

Background:Haemovigilance is an important element of blood regulation. It includes collecting and evaluating information on adverse events resulting from the use of blood and blood components with the aim to improve donor and patient safety. We assessed how haemovigilance is currently being implemented and performed in 10 sub-Saharan African countries. Methods:We piloted the use of the integrated WHO Global Benchmarking Tool plus Blood (GBT+ Blood) to assess the haemovigilance function of national regulatory authorities (NRAs) in Ethiopia, Kenya, Malawi, Nigeria, Liberia, Rwanda, South Africa, Tanzania, Uganda, and Zimbabwe. Data obtained from documents and face to face interviews were used to determine the status of implementation and performance of the following six indicators; legal provisions regulations and guidelines, organisation and governance, human resources, regulatory processes, transparency and accountability and finally, monitoring progress and assessing impact, by estimating median scores across 20 sub-indicators. In addition, a cluster analysis was performed.Results:The countries showed inter-organisation variability in implementation and performance of the haemovigilance function. The overall median score (all sub-indicators) was 44% (range: 7.5% - 70%). The lowest average performance scores were for the arrangement for effective organisation and coordination (35%) and human resources (35%) indicators. The highest average scores were observed for the mechanism to promote transparency and mechanism to monitor regulatory performance indicators (50% and 60%, respectively). We identified clusters of best implemented sub-indicators from the procedures for haemovigilance and poorly implemented sub-indicators from the legal provisions, regulations and guidelines for haemovigilance and human resources. Conclusions:Implementation of sub-indicators and performance of haemovigilance systems varied greatly for all countries with a few countries performing reasonably well in implementation of some sub-indicators under procedures for haemovigilance. Most countries were poorly implementing sub-indicators in the legal provisions, arrangement for effective organisation and human resources indicators. The legislative provisions in most countries were at a nascent stage. There is a need to set up targeted and customised technical support coupled with prioritised interventions to strengthen the capacities of NRAs.

Policies promoting price transparency may be an important approach to control medicine prices and achieve better access to medicines. As part of a wider review, we aimed to systematically determine whether policies promoting price transparency are effective in managing the prices of pharmaceutical products. We searched for studies published between January 1, 2004 and October 10, 2019, comparing policies promoting price transparency against other interventions or a counterfactual. Eligible study designs included randomized trials, and non-randomized or quasi-experimental studies such as interrupted time-series (ITS), repeated measures (RM), and controlled before-after studies. Studies were eligible if they included at least one of the following outcomes: price (or expenditure as a proxy for price and volume), volume, availability or affordability of pharmaceutical products. The quality of the evidence was assessed using the GRADE methodology. A total of 32011 records were retrieved, two of which were eligible for inclusion. Although based on evidence from a single study, public disclosure of medicine prices may be effective in reducing prices of medicines short-term, with benefits possibly sustained long-term. Evidence on the impact of a cost-feedback approach to prescribers was inconclusive. No evidence was found for impact on the outcomes volume, availability or affordability. The overall lack of evidence on policies promoting price transparency is a clear call for further research.

Background Malaria is the single largest cause of illness in Uganda. Since the year 2008, the Global Fund has rolled out several funding streams for malaria control in Uganda. Among these are mechanism aimed to increase availability and affordability of artemisinin-based combination therapies (ACTs). This paper examines the availability and affordability of first line malaria treatment and diagnostics in the private sector in Uganda between 2007 and 2018. MethodsCross-sectional surveys were conducted between 2007 and 2018, based on a standardized World Health Organization/Health Action International (WHO/HAI) methodology adapted to assess availability, patient prices and affordability of ACTs in private retail outlets. A minimum of 30 outlets were surveyed per year. Availability, patient prices and affordability of malaria rapid diagnostic tests (mRDTs) was also tracked from 2012 following the rollout of the test and treat policy in 2010. The median patient prices for the ACTs and mRDTs were calculated in US dollars (USD). Affordability was assessed by computing number of days’ wages the lowest paid government worker (LPGW) had to pay to purchase a treatment course for acute malaria. ResultsAvailability of artemether/lumefantrine (A/L), the first line ACT, increased from 85% to 100% in the private sector facilities during the study period. However, there was low availability of diagnostic tests in private sector facilities ranging between 13% (2012) and 37% (2018). There was a large reduction in patient prices for an adult treatment course of A/L from USD 8.8 in 2007 to USD 1.1 in 2018, while the price of diagnostics remained mostly stagnant at USD 0.5. Affordability of ACTs and mRDTs was below one day’s wages for LPGW.Conclusion Availability of ACTs in the private sector medicines retail outlets increased to 100% while the availability of diagnostics remained low. Although malaria treatment was affordable, the price of diagnostics remained stagnant and increased the cumulative cost of malaria management. Malaria stakeholders should consolidate the gains made and consider inclusion of the diagnostic kits in the subsidy program.

Robust evidence from health policy research has the potential to inform policy-making, but studies have suggested that methodological shortcomings are abundant. We aimed to identify common methodological weaknesses in pharmaceutical pricing policy analyses. A systematic review (SR) of studies examining pharmaceutical pricing policies served as basis for the present analysis. We selected all studies that were included in the SR (n = 56), and those that were excluded from the SR due to ineligible study designs only (n = 101). Risk of bias was assessed and specific study design issues were recorded to identify recurrent methodological issues. Sixty-one percent of studies with a study design eligible for the SR presented with a high risk of bias in at least one domain. Potential interference of co-interventions was a source of possible bias in 53% of interrupted time series studies. Failing to consider potential confounders was the primary cause for potential bias in difference-in-differences, regression, and panel data analyses. In 101 studies with a study design not eligible for the SR, 32% were uncontrolled before-after studies and 23% were studies without pre-intervention data. Some of the methodological issues encountered may be resolved during the design of a study. Awareness among researchers on methodological issues will help improve the rigor of health policy research in general.

Background and aims Biosimilars have been available in the European Union (EU) since 2006. However, their uptake in routine care is heterogeneous across countries. The aim of the present study was to compare the safety information of biosimilars and their originators based on the information in the European risk management plan (RMP). Methods A cross-sectional analysis on publicly available regulatory documents (RMPs and Summaries of Product Characteristics) of biosimilars and corresponding originators up to 1 November 2015 was performed. The safety concerns were extracted and merged into general safety concerns, and clinical relevance was assessed. The frequency of safety concerns and the representation of these safety concerns per general safety concern were assessed by either comparing RMPs of biosimilars and originators (if available for both) or comparing RMPs with the Summary of Product Characteristics of the originator. Results Nineteen biosimilars and six originators were included. Overall, 55 general safety concerns (12 low, 21 medium and 22 highly clinically relevant) were identified. For all active substances, except for infliximab, no or only one difference was found in the listed general safety concerns. Comparison of regulatory documents for infliximab identified three medium clinically relevant general safety concerns more for infliximab biosimilars and two general safety concerns more for its originator. Conclusion Based on publicly available information filed for regulatory purposes, no substantial differences were observed in the reporting of safety information for biosimilars and related originators. A direct comparison between biosimilars and related originators through formal postmarketing studies is needed to evaluate specific safety issues emerging during the products’ life cycle.

BACKGROUND: Several studies showed a bidirectional association between type 2 diabetes and psychiatric disorders in adults. Because there is limited information on the association between type 1 diabetes (T1D) and psychiatric disorders (including psychiatric medication use) in children and adolescents, we assessed frequency of use of these medications before and after the onset of T1D. METHODS: A population-based cohort study was conducted in the Dutch PHARMO Record Linkage System (1999-2009). Children and adolescents (

Purpose To evaluate the association between the use of streptomycin, amikacin, kanamycin and capreomycin in tuberculosis (TB) treatment and the pharmacovigilance reporting of ototoxicity (deafness or hearing loss, tinnitus and vertigo). Second, to analyze patient demographic and geographic factors that influence the reporting of ototoxicity in TB treatment. Methods A case/non-case disproportionality analysis of the VigiBase® individual case safety reports (ICSRs) of patients treated for TB using multidrug regimens that contain either of streptomycin, amikacin, kanamycin or capreomycin. Cases were reports of ototoxicity; non-cases were other adverse drug reactions (ADRs). The unit of analysis was the drug–ADR pair. We calculated reporting odds ratios (RORs) and their 95% confidence intervals (CI). The referent drug was streptomycin. Results By June 2014, there were 3361 drug–ADR pairs in VigiBase® (1693 ICSRs) where the parenteral administration of the four drugs for TB treatment was suspected of causing the reported ADRs. Deafness, tinnitus and vertigo were reported in 576 drug–ADR pairs (cases), the rest being other ADRs (non-cases). Reporting of deafness was most disproportionately associated with amikacin use (ROR 9.3; 95%CI 3.8–23.0), followed by kanamycin use (ROR 4.3; 95%CI 1.3–14.2). Reporting of vertigo was inversely associated with capreomycin use (ROR 0.1; 95%CI 0.01–0.4). Geographic region affected the reporting of ototoxicity while age and sex did not. Conclusion Spontaneous reporting of deafness cases within VigiBase® was most disproportionately associated with amikacin use, followed by kanamycin. There were regional variations in the global reporting of ototoxicity. These findings should be verified through a follow up study. Copyright © 2016 John Wiley & Sons, Ltd.

In this issue of Pharmacoepidemiology and Drug Safety, several research papers address the safe and appropriate use of opioids. This is important, given the critical situation on opioid use in the United States (US). According to preliminary data from the Centers for Disease Control and Prevention (CDC), more than 72 000 people in the United States died because of drug overdose in 2017 with over two‐thirds involving opioids.1 This situation has been declared a “national public health emergency.”2 To address the so‐called opioid epidemic, the House and Senate recently passed new legislation that aims to increase access to opioid dependence treatment and to prevent illicit opioids from entering the market, and supports research on other treatment options for pain besides opioids.3, 4 Experts and activists are skeptical whether this agreement will solve the opioid crisis, at least in part because of limited funding.3

Aim: The aim of the present study was to provide an insight into the characteristics and follow-up of postmarketing studies of medicines that were conditionally authorized in the European Union (EU). Methods: We compiled a list of all postmarketing studies attached as specific obligations to the licence of medicines that were granted conditional marketing authorization from January 2006 to April 2014. Studies were characterized based on their objective, design, status upon marketing authorization (MA) and due data set by authorities. They were linked to online study registrations (Clinicaltrials.gov, ENCePP) to determine completion date. We described and associated characteristics of studies and medicines, and determined whether studies were completed on time. Results: A total of 59 postmarketing studies were requested for 21 conditionally authorized medicines. Most studies had an interventional study design (73%), were ongoing upon MA (61%) and aimed to provide additional data on efficacy (45%). Interventional studies were more often ongoing and providing efficacy data, while observational and other studies were more often new and providing safety data. Frequent grounds for requesting postmarketing studies were ‘long-term follow-up’ and ‘increase data on subpopulations’. Of the 34 studies eligible for follow-up analysis, 26 (76%) were completed and 17 (50%) completed on time. Actual completion time took a median (interquartile range) of 274 (−121 to 556) days longer than expected. Conclusions: Our results indicated that most postmarketing studies attached to a conditional marketing authorization were eventually completed but that half were completed with a substantial delay. The observations suggest caution when broadening the use of postmarketing studies for resolving uncertainties about benefits and risks after MA.

Background: Drug shortages are a potential threat to public health. Reliable data on drug shortages is limited. The objective was to examine the extent and nature of potential drug shortages signaled by authorities and pharmacy practice in the Netherlands Materials and Methods: The primary working systems of Dutch authorities (Medicines Evaluation Board and Health and Youth Care Inspectorate) and the archives of pharmacy practice (Royal Dutch Pharmacists Association) from 2012 to 2015 were searched for number, characteristics, overlap, and date of signals on potential drug shortages. Also, the product characteristics of the potential drug shortages were analyzed from the two different sources Results: Authorities detected 2.6 times more signals on potential shortages than pharmacy practice. Only 438 (8%) out of 5,731 potential drug shortages were detected by both authorities and pharmacy practice. Signals were detected later by authorities than by pharmacy practice, especially on potential permanent shortages (median difference -180 days (IQR: -4 to -405 days)). Authorities detected by majority (72%) signals related to permanent shortages with relative overrepresentation of rectal products and anti-infectives for systemic use. In contrast, pharmacy practice detected by majority (71%) signals related to temporary shortages with relative overrepresentation of ocular and cutaneous products, anti-infectives for systemic use, products for sensory organs and dermatologicals. Conclusions: Authorities and pharmacy practice detected different signals on potential drug shortages with little overlap. Combining data from both authorities and pharmacy practice seems to be necessary in order to gain a more complete overview and maximum insight in potential drug shortages at a national level. Moreover, the finding that authorities were informed later than pharmacy practice causes concerns in terms of opportunities for authorities to assist pharmacy practice to find solutions for shortages.

Background and Purpose- The purpose of this study was to investigate the impact of improved antithrombotic treatment in atrial fibrillation after the introduction of non-vitamin K antagonist oral anticoagulants on the incidence of stroke and bleeding in a real-life total population, including both primary and secondary care. Methods- All resident and alive patients with a recorded diagnosis for atrial fibrillation during the preceding 5 years in the Stockholm County Healthcare database (Vårdanalysdatabasen) were followed for clinical outcomes during 2012 (n=41 008) and 2017 (n=49 510). Results- Pharmacy claims for oral anticoagulants increased from 51.6% to 73.8% (78.7% among those with CHA

textabstractAim The aim of the study was to document long term trends in oral antidiabetic drug (OAD) use among children and adolescents in the Netherlands. Methods A population-based cohort study was conducted using the Dutch PHARMO Database Network. All patients younger than 20 years old with at least one OAD dispensing were identified. Age-adjusted and age-specific incidence (1999-2011) and prevalence (1998-2011) rates of OAD use were calculated. Trends over time were assessed using joinpoint regression software. A subset of PHARMO Database Network (including community pharmacy dispensing records linked to general practitioner data (OPD-GP database)) was used to assess indications for OADs. Results In 2011, the overall age-adjusted incidence and prevalence rates of OAD use were 20.7/100 000 (95% CI 19.2, 22.1) person-years (PY) and 53.8/100 000 (95% CI 51.5, 56.1) persons, respectively. The average annual percentage change (AAPC) in the overall age-adjusted incidence rates from 1999 to 2011 was 18.9% (95% CI 4.5, 35.2). The incidence and prevalence rates of OAD use were higher among females and older age categories. The increases in rates of OAD use were mainly driven by metformin. For only 50% of the 98 patients in the OPD-GP database, indications for OAD prescriptions were reported with type 1 diabetes (n = 20), type 2 diabetes (n = 16), and overweight/obesity (n = 10). Conclusions Incidence and prevalence rates of OAD use in children and adolescents substantially increased in the Netherlands, especially among older age categories (10-14 and 15-19 years) and females. The main indications for use of OADs were type 1 and 2 diabetes and overweight/obesity.

OBJECTIVE: To assess the trends in the incidence and prevalence rates of type 1 diabetes (T1D) among children and adolescents in the Netherlands. METHODS: A population-based cohort study was conducted in the Dutch PHARMO record linkage system (1998-2011). All children and adolescents aged ≤19 yr with at least one insulin dispensing (as a proxy for T1D) were identified and the numbers of incident and prevalent cases (numerators) were calculated. Overall age-adjusted (0-19 yr) incidence and prevalence rates together with age- and sex-specific rates of T1D and their 95% confidence intervals (CI) were calculated using data from the Dutch Central Bureau of Statistics as denominator. Trends over time were assessed using Joinpoint regression software (National Cancer Institute, Bethesda, MD, USA). RESULTS: In 2011, the overall age-adjusted incidence and prevalence rates of T1D were 25.2/100 000 (95% CI, 23.7-26.8) person-years (PY) and 174.4/100 000 (95% CI, 170.2-178.5) children, respectively. The average annual percentage change (AAPC) in the overall age-adjusted incidence and prevalence rate was 3.7% (95% CI, 1.8-5.7) and 3.8% (95% CI, 2.4-5.2), respectively. While during the study period the largest increases in the incidence and prevalence rates of T1D were observed for the oldest age groups (10-14 and 15-19 yr), a decreasing trend was detected for the 0- to 4-yr-old category (with AAPCs of -1.8 (95% CI, -9.9 to 7.1) and -6.9% (95% CI, -11.5 to -2.1) for incidence and prevalence, respectively). CONCLUSION: Age-adjusted incidence (1999-2011) and prevalence rates (1998-2011) of T1D in Dutch children (aged 0-19 yr) continued to increase and a shift was observed to a later onset of the disease.

Background There is limited information on patterns of treatment change among new initiators of highly active antiretroviral therapy (HAART) in the regions most affected by HIV/AIDS. This makes it difficult to identify the determinants of treatment change. In this retrospective cohort study, we examined treatment change patterns over a five-year period among initiators of HAART. Methods De-identified data were obtained from the Fevers’ Unit Database at the Korle-Bu Teaching Hospital. All adult treatment-naive patients who started treatment with first line HAART between 1st January, 2008 and 31st December, 2012 were followed over a minimum period of three months. The main outcome was the first treatment change, defined as the first substitution/switch in accordance with the standard treatment guidelines. Data were analyzed stratified by year of treatment initiation. Crude and adjusted hazard ratios were calculated. Results A total of 3933 patients were followed with almost equal numbers of initiators per year. The mean age (standard deviation) at treatment initiation was 39 (10.3) years. The most prescribed HAART combination was AZT/3TC/EFV and overall for initiators zidovudine combination therapy was about 60%. Utilization of stavudine containing HAART increased gradually until 2010 and then dropped to zero. Over the study period, 44.9% of recorded deaths were from those initiated with a stavudine backbone, 41.1% from a zidovudine backbone, and 11.5% from a tenofovir backbone. Females had a significantly higher rate of treatment change compared to males (p-value = 0.0002), and d4T/3TC/EFV and d4T/3TC/NVP recorded independent treatment change hazard ratios of 12.05 (CI 9.58 to 15.16) and 12.03 (CI 9.27 to 15.61) respectively.. Kaplan-Meier curves showed that treatment change was higher among those who started treatment later in the study period compared with those who started earlier. Conclusion A major treatment change in the utilization of antiretroviral medicines in Ghana occurred during the study period which was associated with type of treatment, year of treatment, gender and disease stage. The influence of a policy change during the period may have made a significant impact.. For diseases involving life-long treatment in particular, it is important to monitor and periodically evaluation treatment utilization patterns.

Antiretroviral Therapy (ART) is effective in reducing morbidity and mortality in patients living with HIV/AIDS (PLWHA). However, Adverse Effects (AEs) to ART pose major problems and threaten adherence to therapy. We evaluated the knowledge and attitudes of patients to ART following routine adherence counselling and education in the Korle Bu Teaching Hospital in Accra, Ghana. This cross-sectional study was conducted by administering a questionnaire on socio-demographics, knowledge of AEs of antiretrovirals and attitude to AEs to 98 patients who were on antiretroviral therapy. A 3-point Likert-scale was used to assess knowledge of AEs of ART and a 5 point Likert-scale to assess attitudes to AEs. Mean rated scores for attitude to AEs were estimated and factor analysis was used to reduce the dimensions of the attitudes observed to identify relevant latent constructs. Sixty one percent of participants were females and most of the participants were aged 35-44 years (35%). Ninety nine percent of participants answered that they had been counselled on unpleasant effects of their medicines and 93% knew that all medicines could cause some unpleasant effects. Concerning attitude, 90% of study participants strongly agreed that they benefit from their medicines and get better taking them (mean rated score=4.87 ± 0.49) whilst 27% strongly agreed that medicines may have side effects (mean rated score=3.12 ± 1.55). Majority of the study participants (74%) strongly disagreed that there was no need to tell their doctor/pharmacist about AEs to antiretrovirals (mean rated score=4.60 ± 0.83). Factor analysis yielded two underlying dimensions (cognitive and behavioural/affective aspects) that described participants’ attitude towards AEs. Study participants rating for participants’ knowledge on AEs was good and exhibited positive attitudes to AEs of ART. Adherence counselling and education provided to PLWHA before initiation of antiretroviral therapy is beneficial and should be continued.

Context In 2011, the World Health Organization (WHO) published the policy guidelines Ensuring Balance in National Controlled Substances Policies—Guidance for Availability and Accessibility of Controlled Medicines , presenting a revised version of the previous guidelines from 2000. Objectives To describe the consensus process that guided the revision of the guidelines. Methods A four-stage revision process was undertaken with a panel of 29 international experts from palliative care, public health, and harm reduction: 1) a qualitative inventory of required changes by means of a structured checklist, 2) & 3) a two-round online consensus Delphi process about the draft revision of the guidelines, and 4) a WHO advisory meeting for the discussion of remaining controversies and final issues. Results The qualitative inventory resulted in a draft revision of the guidelines meeting requirements on different levels, such as a broader focus and more accurate evidence. Operationalization of the guidelines was improved by specifying measures, procedures, and responsibilities. The Delphi procedure provided concrete indications for the rewording of both the guidelines and the associated text. During the advisory meeting, any persistent disagreements were systematically discussed to achieve consensus on the new version of the guidelines. Conclusion The four-stage multimethod consensus process resulted in a substantial revision to the WHO guidelines. This takes into account the increase in knowledge about opioid medication since the first edition of the guidelines. Disagreement emerging from the process underlines the complexity of preparing guidance because of the delicate balance between need and control.

Marketing authorization application dossiers of 17 orphan drugs (ODs) and 51 non-ODs evaluated by the European Medicines Agency (EMA) in the period 2009-2010 were compared. We aimed to identify whether any differences existed between ODs and non-ODs in number and type of deficits brought forward during the EMA review, regarding the clinical development plan, clinical outcome and medical need and studied whether these deficits were similarly associated with marketing approval in the EU. In 71% of the ODs dossiers and 65% of the non-ODs dossiers marketing approval was granted. Differences in deficits were found, but similarities in the way ODs and non-ODs were reviewed and marketing approval decisions were taken, underline that regulatory standards are equally high.

Cases of the A(H1N1) 2009 influenza were first recorded in Ghana in July 2009. In June 2010 when prioritized vaccination against the novel A(H1N1) 2009 influenza virus started in the country, health workers were among the selected groups to receive the vaccination.The aim of this study was to determine the distribution and types of adverse events reported following immunization of healthcare workers at the Korle-Bu Teaching Hospital from the day vaccination started until 1 week after the end of vaccination.Safety data collected during the A(H1N1) 2009 influenza vaccination of health workers at the Korle-Bu Teaching Hospital (Accra, Ghana) were used for this study. All workers aged 18 years and over were eligible for vaccination. For uniformity, 0.5 mL of Pandemrix(®) (equivalent to 3.75 μg of hemagglutinin antigen) was administered intramuscularly into the deltoid muscle of the left arm. Each vaccinee was issued with a card and was advised to report any adverse events following immunization (AEFI) to designated health workers for follow-up. Incidence rates of adverse events were estimated and compared with the Pandemrix(®) Summary of Product Characteristics (SPC) RESULTS: A total of 5870 people (64.9 % females) with a mean age of 34.0 years were vaccinated. In total, 140 vaccinees reported adverse events. The mean age among vaccinees reporting adverse events was 36.1 years. The overall incidence of vaccinees reporting adverse events and the overall incidence of adverse events was 232 (95 % CI 199-320) per 10,000 people and 930 (95 % CI 820-1070) per 10,000 people, respectively. In particular, we found no difference in the way males reported AEFI compared with females (Chi-squared [χ(2)] = 0.59; p 0.2), and we did not find any association between age as a categorical variable and vaccine adverse event reporting (χ(2) = 5.24; p 0.1). There were only three serious cases that led to hospitalization. All three cases occurred within 24 hours of receiving the vaccine. The incidence rates for the various reported events were all lower compared with those in the Pandemrix(®) SPC, but while injection-site pain was the most frequent in the SPC and other foreign studies, we recorded headache as the most frequent. Even fatigue, muscle/joint aches and fever had higher incidence rates compared with injection-site pain. Tachycardia (n = 6), tinnitus (n = 1) and decreased appetite (n = 4) were reported although were not included in the SPC.The most prominent adverse events reported were headaches, dizziness, muscle and joint aches, weakness, fever and injection-site pain. Although similar events were reported in other studies, the incidence was different and there were a few differences in the most frequently reported events. More studies of a similar nature should be encouraged in low- and medium-income countries to bridge the information gap with the developed world.

Adverse drug reactions (ADRs) of biopharmaceuticals can be batch or product specific, resulting from small differences in the manufacturing process. Detailed exposure information should be readily available in systems for postmarketing safety surveillance of biopharmaceuticals, including spontaneous reporting systems (SRSs), in which reports of ADRs are collected. The aim of this study was to explore the current status of traceability of biopharmaceuticals in the US and the EU up to patient level in SRSs. A cross-sectional study was conducted over the period 2004–2010, including ADR reports from two major SRSs: the FDA Adverse Event Reporting System (FAERS) in the US and EudraVigilance (EV) in the EU. The availability of batch numbers was determined for biopharmaceuticals, and compared with small molecule drugs. For biopharmaceuticals for which a biosimilar has been approved for marketing in the EU, the identifiability of the product (i.e. the possibility of distinguishing the biosimilar from the reference biopharmaceutical) was determined. A total of 2,028,600 unique ADR reports were identified in the FAERS, reporting a total of 591,380 biopharmaceuticals (of which 487,065 were suspected). In EV there were 2,108,742 unique ADR reports, reporting a total of 439,971 biopharmaceuticals (356,293 suspected). Overall, for 24.0 % of the suspected biopharmaceuticals in the FAERS and 7.4 % of the suspected small molecule drugs (p

Objective: Three online surveys explored compliance with the PPP by pharmacists and dermatologists, in the Netherlands. In 2007 and 2011, two pharmacist surveys were conducted to assess improvement over time. Methods: In 2007, survey was sent to members of the Utrecht Pharmacy Panel for Education & Research (UPPER) network (n = 1000) and in 2011, to the research group of the Dutch Association of Pharmacists (KNMP) (n = 556). In 2010, a survey was sent to 564 dermatologists of the Dutch Association of Dermatology and Venereology (NVDV). Results: Both pharmacists' questionnaires had response rates of 20% and the dermatologist questionnaire of 28%. Pharmacists' checks on 30-day dispensing remained 82%, but a check whether the prescription is out-of-date decreased (61 to 53%). Pharmacists asked the patient for a negative pregnancy test in 15%, but use of contraception was checked by 44 - 49%. One hundred and five dermatologists (64%) always prescribe contraception; 35 (22%) occasionally. Ninety-three percent of the dermatologists were of the opinion that they performed the PPP. Analysis of different elements of the PPP showed that 41 (25%) were compliant. Conclusions: The observed non-adherence to the isotretinoin PPP calls for careful evaluation of risk minimisation plans and participation of all stakeholders in the development of these plans.

Several studies showed a bidirectional association between type 2 diabetes and psychiatric disorders in adults. Because there is limited information on the association between type 1 diabetes (T1D) and psychiatric disorders (including psychiatric medication use) in children and adolescents, we assessed frequency of use of these medications before and after the onset of T1D.A population-based cohort study was conducted in the Dutch PHARMO Record Linkage System (1999-2009). Children and adolescents (19 years) with at least 2 insulin dispensings from community pharmacies (T1D cohort, N = 925) were matched by age and sex (reference cohort without insulin use, N = 3591). The 5-year prevalence of psychiatric medication use (psycholeptics [ATC N05] and psychoanaleptics [ATC N06]) before and after onset of T1D were estimated, compared, and stratified by age, sex, and medication subgroup.The mean age of study participants was 10.1 years and 51% were boys. The 5-year prevalence of psychiatric medication use before the index date was significantly higher in the T1D cohort than in the reference cohort (7.2% vs 4.7%, respectively; P = .002) with the same pattern after developing T1D (10.4% vs 7.9%, respectively; P = .015). In both cohorts, adolescents (15-19 years) and boys had higher prevalences of use. This increased prevalence of psychiatric medication use both before and after the index date in T1D cohort was mainly driven by an increased use of psycholeptics (predominantly anxiolytics).Children with T1D were more likely to use psychiatric medication in the years before and after the onset of T1D which was mainly driven by psycholeptic use.

Purpose: To explore the use of the biological tumour necrosis factor alpha (TNFalpha) inhibitors used in the treatment of rheumatoid arthritis as a measure of access to treatment with new medicines. In addition, characteristics both related to national health systems and spending will be assessed to explore possible differences in international utilisation. Methods: Data from four European countries were included: Ireland, The Netherlands, Norway and Portugal. Annual utilisation rates of TNFalpha inhibitors (2003-2007) were expressed as defined daily doses (DDD5)/1000 inhabitants/day. Qualitative data such as country characteristics, national health policy characteristics, guidelines were obtained from the literature. In addition, interviews were held with leading rheumatologists of each country to put obtained results into (cultural) context. Results: Utilisation of TNFalpha inhibitors varied widely from 0.32 (Portugal) to 1.89 (Norway) DDD5/1000 inhabitants/day (2007). A major driver for the utilisation of TNFalpha inhibitors seemed to be the country's total health expenditure (R-2 = 0.81). When the use of TNFalpha inhibitors became more established, the association seemed stronger. Differences in health expenditure were nevertheless not the only determinant of usage. Cultural aspects such as difference in recognition of guidelines also come into play when looking at differences in TNFalpha utilisation between countries. Conclusions: The prospects of patients receiving TNFalpha inhibitor treatment depend on the country where they are living. In case uniformity of management and treatment would be considered to provide health benefits, the extent and the causes of variation should feature prominently on future public health agendas. (C) 2011 Elsevier Ireland Ltd. All rights reserved.

OBJECTIVE Dipeptidyl peptidase-4 (DPP-4) inhibitors are a new class of antidiabetic drugs. They inactivate incretin hormones but also have many other effects throughout the body, among which are effects on the immune system. This might result in an increased infection risk. This study assessed the association between use of DPP-4 inhibitors and the reporting of infections. RESEARCH DESIGN AND METHODS A nested case-control was conducted using VigiBase, the World Health Organization-Adverse Drug Reactions (WHO-ADR) database. The base cohort consisted of ADRs for antidiabetic drugs (Anatomical Therapeutic Chemical code A10). Cases were defined as ADRs of infection according to the Medical Dictionary for Regulatory Activities (MedDRA) classification system. All other ADRs were considered controls. Reporting odds ratios (RORs) were calculated to estimate the strength of the association between different classes of antidiabetic drugs and the reporting of infections. RESULTS We identified 305,415 suspected ADRs involving antidiabetic drugs in 106,469 case reports, of which 8,083 involved DPP-4 inhibitors monotherapy. Overall, the reporting of infections was higher for patients using DPP-4 inhibitors compared with users of biguanides (ROR 2.3 [95% CI 1.9–2.7]). Reporting of upper respiratory tract infections (ROR 12.3 [95% CI 8.6–17.5]) was significantly associated with use of DPP-4 inhibitors. CONCLUSIONS This study indicates an increased reporting of infections, in particular upper respiratory tract infections, for users of DPP-4 inhibitors compared with users of other antidiabetic drugs. However, the limitations of spontaneous reporting systems (e.g., underreporting, the Weber-effect, reporting bias) should be taken into account. Therefore, further research is needed to evaluate this suspicion and the underlying mechanism.

PURPOSE: For optimal decision making on access to and regulations around biologicals availability of national utilisation data is a prerequisite. This study characterises the main categories of critical issues in collecting available national utilisation data on tumour necrosis factor alpha (TNFalpha) inhibitors in different European countries. METHODS: Data were collected on characteristics of the nature of TNFalpha usage data and on usage of TNFalpha itself (2003-2007). Utilisation rates were expressed as defined daily doses (DDDs)/1000 inhabitants/day. Data from Denmark, Finland, Ireland, the Netherlands, Norway and Portugal were included. RESULTS: Characteristics of TNFalpha (usage settings and ways of distribution to patients) and databases (type of data collected, public availability and data sources) influenced the way data were collected and determined the type of research and policy questions that can validly be addressed. The prevailing differences in the structure of national databases are prohibitive for critical aspects of medicines utilisation studies. An increase in TNFalpha usage over time was observed in all countries and varied widely from 0.32 (Portugal) to 1.89 (Norway) DDDs/1000 inhabitants/day (2007). CONCLUSIONS: In the European countries studied data on national TNFalpha usage is not easily, if at all accessible. Intercountry collaboration and sharing of technical resources will facilitate harmonisation of data collection allowing independent, population based, health and outcomes research. (aut. ref.)

Introduction: A periodic safety update report (PSUR), composed by marketing authorization holders and submitted to regulatory authorities on predetermined time points, provides an update of the worldwide safety experience of a pharmaceutical. Information is lacking on how PSURs contribute to safety related regulatory actions. Aim: The objective of the study is to analyze the contribution of PSUR evaluations to the initiation of safety related regulatory actions of biopharmaceuticals. Methods: We performed a retrospective analysis of all safety related type II variations of biological products centrally approved in the European Union (since 1995) for which ≥1 safety-related Direct Health Healthcare Professional Communication (DHPC) was issued until December 2009. An evaluation of the role of PSUR assessments in the initiation of safety associated regulatory actions was performed through an analysis of European Public Assessment Reports and updates of the Summary of Product Characteristics (SPC). We compared “urgent” variations, defined as variations accompanied by the distribution of a DHPC, with “less urgent” variations, i.e. safety related SPC variations for which no DHPC was distributed. For each variation we determined if any reference was made to the contribution of PSUR evaluations. We determined the data source and nature of the safety issues included in the variations. Each variation could include ≥1 safety issue and ≥1 data source could contribute in a single variation. Results: We identified 133 safety related type II variations for 15 biological products. Reference to PSUR evaluations was made in 2/24 (8.4%) of all urgent type II variations and 48/109 (44.0%) of the less urgent variations (x2, p

Background: Drugs for rare diseases, so-called orphan drugs, are often intended for serious or chronically debilitating diseases. Safety information is more limited at the time of approval for orphan drugs as a result of various factors, such as the limited number of patients in clinical trials, quality of the clinical trials and special approval procedures. Several studies have been conducted on safety-related regulatory actions for drugs, but none of these have specifically focused on orphan drugs. Objective: To determine the frequency and nature of safety-related regulatory actions for orphan drugs in the US and EU. Methods: This cohort study examined publicly available data from the websites of US and EU regulatory authorities on orphan drugs approved in the US and/or the EU between January 2000 and December 2007. The main outcome measures were the nature, frequency and timing of safety-related regulatory actions, defined as (i) safety withdrawals; (ii) ‘black-box’ warnings; and (iii) written communications to healthcare professionals issued by the US FDA or the European Medicines Agency between January 2000 and June 2008. Results: Ninety-five orphan drugs were approved during the study period (75 in the US, 44 in the EU, and 24 in both regions). Ten products (10.5%) received a safety-related regulatory action. No safety withdrawals, four black-box warnings and 12 written communications were identified. The probability of a first safety-related regulatory action for orphan drugs was 20.3% after 8 years of follow-up. Orphan drugs approved by accelerated approval (relative risk [RR] 3.32; 95% CI 1.06, 10.42), oncological products (RR 7.83; 95% CI 0.96, 63.82) and products for gastrointestinal and metabolism indications (RR 10.44; 95% CI 1.25, 87.27) may have a higher risk for a safety-related regulatory action. Conclusions: The probability of a first safety-related regulatory action for an orphan drug was slightly lower than that reported in the literature for biologicals in one study and new molecular entities in another study. However, detection of safety issues may be complicated by the limited experience with orphan drugs in practical use due to the low prevalences of the diseases they are used for. Doctors and pharmacists should therefore be vigilant with regard to the occurrence of a safety-related issue for orphan drugs.

Purpose Real-life experience with anti-obesity drugs has shown that psychiatric and cardiovascular diseases may be reported as adverse drug reactions. For adequate risk assessment of these drugs knowledge on baseline risks of patients starting anti-obesity drugs and insight in patterns of use is needed. The aim was to assess whether baseline characteristics of patients starting anti-obesity drugs differ from those not being prescribed these drugs, and to study patterns of anti-obesity drug use. Methods A population-based cohort study was conducted in the IPCI database (1995–2007). The index cohort comprised all persons who started an anti-obesity drug. The reference cohort comprised up to six randomly sampled patients from the same GP practice with same index date. Baseline characteristics were assessed for both cohorts. The index cohort was followed for 1 year to study patterns of drug use. Unconditional logistic regression was used to calculate crude odds ratios and 95% confidence intervals. Results The index and reference cohort comprised 1471 and 8736 persons, respectively. Both cardiovascular and psychiatric co-morbidities were more prevalent among starters compared to non-starters. 77.7% of the patients stopped using anti-obesity drugs within 90 days. Users of amphetamine-like drugs differed from patients using orlistat or sibutramine, whereas users of orlistat and sibutramine were highly comparable. Conclusions The increased prevalence of co-morbidities constitutes a baseline risk which may translate in higher occurrence of psychiatric and cardiovascular diseases during use of anti-obesity drugs, independent of the drugs. The limited period of use might reduce possible cardiovascular benefits of weight reduction induced by these drugs. Copyright © 2009 John Wiley & Sons, Ltd.

The introduction of recombinant DNA and hybridoma techniques more than 25 years ago enabled the large-scale production of biopharmaceuticals, which resulted in important new treatments for a variety of chronic and sometimes life-threatening diseases [4,18]. The recent expiration of patents of some biopharmaceuticals, like growth hormones, granulocyte colony-stimulating factors, and erythropoietin, makes it possible for pharmaceutical companies to produce so-called “biosimilars”, which are also called “biogenerics” or “follow-on biologics” [13]. Biosimilars are defined by the European Medicines Agency (EMEA) as biopharmaceuticals claimed to be similar to a reference medicinal product based on the demonstration of the similar nature of the two products, in terms of quality, safety and efficacy. Biosimilars are approved on the basis of an abbreviated dossier, in which comparability between the reference product and the biosimilar has been shown both for efficacy and safety. In addition, it is possible to extrapolate therapeutic comparability shown for one indication to other indications of the reference medicinal product [2,3] as was done for the recombinant derived growth hormone Valtropin. For Valtropin it was agreed that data obtained in a comparative double-blind phase III study, where the reference product Humatrope was compared with Valtopin, for the indication ‘Children with growth hormone deficiency’ could be extrapolated to all indications for which the reference product Humatrope had already been approved [8]. Requirements for the dossier of the marketing application for different active substance is laid down in product specific guidelines [2,3]. Compared to small molecules biopharmaceuticals in general, have different characteristics and therefore may carry specific risks. Small molecules are synthesized chemically, whereas biopharmaceuticals are large-complicated molecules which are manufactured in living cells [4,18]. Biopharmaceuticals have a very complex production and purification process involving multiple steps. This carries the risk of influencing the characteristics of the end product, and possibly the safety profile of the end product, at

The wide availability of economic evaluations and their increasing importance for decision making emphasises the need for economic evaluations that are methodologically sound. The aim of this review was to provide users of economic evaluations of cholesterol-lowering drugs with an insight into the quality of these evaluations. By focusing on the most relevant studies, the gap between research and policy making may be narrowed. A systematic review was conducted. All Dutch and English publications on economic evaluations of cholesterol-lowering drugs were identified by searching PubMed, the Centre for Reviews and Dissemination database (CRD), the NHS Economic Evaluation Database (NHS EED), the Health Technology Assessment database (HTA) and the Database of Abstracts of Reviews of Effects (DARE). A search strategy was set up to identify the articles to be included. The quality of these articles was assessed using Drummond's checklists. The scoring was performed by at least two reviewers. When necessary, disagreement between these reviewers was decided upon in a consensus meeting. We calculated an average quality score for the included articles. The search identified 1390 articles, of which 23 were included. Most studies measured the costs per life-year gained. The overall score per study was disappointing and varied between 2.7 and 7.7, with an average of 5.5. Most studies scored high on the measurement of costs and consequences, whereas the establishment of effectiveness left room for improvement. Only two studies included a well performed incremental analysis. This study noted an increase of quality of economic evaluations over time, suggesting the value of cost-effectiveness studies for policy decisions increases over time. In general, piggy-back evaluations tended to score higher on quality and may therefore be more valuable in decision making.

The aim of the present study was to provide an insight into the characteristics and follow-up of postmarketing studies of medicines that were conditionally authorized in the European Union (EU).We compiled a list of all postmarketing studies attached as specific obligations to the licence of medicines that were granted conditional marketing authorization from January 2006 to April 2014. Studies were characterized based on their objective, design, status upon marketing authorization (MA) and due data set by authorities. They were linked to online study registrations (Clinicaltrials.gov, ENCePP) to determine completion date. We described and associated characteristics of studies and medicines, and determined whether studies were completed on time.A total of 59 postmarketing studies were requested for 21 conditionally authorized medicines. Most studies had an interventional study design (73%), were ongoing upon MA (61%) and aimed to provide additional data on efficacy (45%). Interventional studies were more often ongoing and providing efficacy data, while observational and other studies were more often new and providing safety data. Frequent grounds for requesting postmarketing studies were 'long-term follow-up' and 'increase data on subpopulations'. Of the 34 studies eligible for follow-up analysis, 26 (76%) were completed and 17 (50%) completed on time. Actual completion time took a median (interquartile range) of 274 (-121 to 556) days longer than expected.Our results indicated that most postmarketing studies attached to a conditional marketing authorization were eventually completed but that half were completed with a substantial delay. The observations suggest caution when broadening the use of postmarketing studies for resolving uncertainties about benefits and risks after MA.

Objective: A level of 95% adherence to antiretroviral therapy (ART) has been found to benefit HIV/AIDS patients. Low adherence may lead to treatment failure, and may subsequently result in treatment change. The main objective of this study was to evaluate the effect of ART adherence on treatment change Methods: Data were extracted from available written clinical and pharmacy records, and the electronic database at the Korle-Bu Teaching Hospital. Cases comprised all those (≥15 years) who experienced a first treatment change after starting first-line ART between 1/1/2004 and 31/12/2009. Controls (who did not change treatment) were sampled from the same cohort of ART starters and matched to cases on date ART was started. Adherence was determined using the proportion of days covered (PDC) approach and poor adherence was defined as PDC levels below 95%. Measures of effect were calculated using conditional logistic regression. Results: The 298 cases and 298 matched controls were similar in most baseline characteristics. Among cases 20.1% (60/298) switched to second-line therapy and the rest had treatment substitutions. Overall, 88.9% of controls compared with 79.9% of cases had adherence levels greater than or equal to 95% (p=0.003). After adjusting for possible confounders, an adherence level below 95% was associated with almost four times (ORadj=3.56 (95% CI 1.60 to 7.88)) the likelihood of having a treatment change. Conclusion: This study showed that insufficient ART adherence was associated with about four times the likelihood of treatment change. Policy makers must partner researchers to engage patients more often, to unravel the causes of non-adherence, and make the necessary interventions for patients to achieve maximum benefits from dispensed medicines.

Aim To assess dosing and determinants of the choice of statins among starters of statins. Methods Data were obtained from the PHARMO database comprising pharmacy and linked hospital discharge records of approximately 300 000 subjects in the Netherlands. All new users of statins in 1998 were selected. Patient characteristics and drug regimens were compared between starters of different statins. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using polytomous logistic regression modelling, using the start of simvastatin therapy as reference category. Results In 1998, 1738 patients started using simvastatin (41.1%), pravastatin (23.1%), fluvastatin (11.9%), atorvastatin (22.8%) or cerivastatin (1.0%). Compared with starters with simvastatin [mean dose 1.02 ± 0.39 defined daily doses (DDDs)], starters with pravastatin (1.27 ± 0.56 DDDs) and atorvastatin (1.43 ± 0.59 DDDs) received higher doses (P

BACKGROUND: Persistence with lipid-lowering drug use is important in order for patients to gain full treatment benefit. The withdrawal of cerivastatin from the market may have affected persistence due to the fear of serious adverse effects. OBJECTIVE: To assess failure of patients to continue lipid-lowering drug use following the withdrawal of cerivastatin. METHODS: A cohort study including 3.5 months follow-up after the withdrawal of cerivastatin in August 2001 was conducted using data from community pharmacies in The Netherlands, covering a population of approximately 600,000 subjects. Patients selected for inclusion in the index group were current users of cerivastatin on August 10, 2001 (the date that cerivastatin was withdrawn from the market). Reference patients were gender, age and pharmacy or region matched patients who were using any HMG-CoA reductase inhibitor other than cerivastatin on the same date. The main outcome measure was discontinuation of lipid-lowering drug use. To assess whether discontinuation had increased in the reference group, discontinuation rates were compared with discontinuation rates in the previous year. Data on these rates in 2000 were obtained from the population-based PHARMO record linkage system. RESULTS: A total of 31 pharmacies of the research network (response rate 86.1%) provided medication histories of 234 current users of cerivastatin and 431 matched patients using any other HMG-CoA reductase inhibitor. In addition, 352 current users of cerivastatin and 704 matched patients using any other HMG-CoA reductase inhibitor were obtained from the PHARMO database. Overall, 13.7% of subjects in the cerivastatin group (n=586) and 9.5% in the reference group (n=1135) discontinued lipid-lowering medication (adjusted odds ratio [OR] 1.44; 95% CI 1.04-2.00). The rate of discontinuation in the reference group was comparable to this rate in the previous year. Discontinuation was more prevalent in women who had been taking cerivastatin (adjusted OR 1.74; 95% CI 1.09-2.78), those receiving low doses of cerivastatin (adjusted OR 2.45; 95% CI 1.20-4.97), those who received their last cerivastatin prescription from a specialist (adjusted OR 1.92; 95% CI 1.02-3.60) and those who had recently started using cerivastatin (adjusted OR 2.80; 95% CI 0.98-7.98), although the latter was not statistically significant. CONCLUSIONS: Failure to continue lipid-lowering drug use was higher in patients using cerivastatin than in users of other HMG-CoA reductase inhibitors, especially in women, those using low doses of HMG-CoA reductase inhibitors and recent starters of lipid-lowering medication. The prevention of unwarranted discontinuation of drugs due to market withdrawal should be a joint task of healthcare providers, industry and regulatory bodies.

Discontinuation and poor adherence to therapy are major problems during long-term treatment, particularly with cholesterol lowering drugs. Several studies have indicated that the cholesterol lowering effect of statins differs according to apolipoprotein (apo)E genotypes. Low-density lipoprotein-cholesterol lowering capacity appears to be smaller in subjects with the epsilon(4) allele. To assess whether the use of statins in daily practice differs according to apoE genotypes, we used data from the Rotterdam Study, a population-based prospective cohort study in the Netherlands, which started in 1990 and included 7983 subjects aged 55 years or more. During follow-up, there were 798 subjects who started to use statins. We used a Cox proportional hazard model to determine the rate of discontinuation in the first 3 years of statin use. Subjects on statin therapy with epsilon(2)epsilon(2) and epsilon(4)epsilon(4) genotypes showed a trend towards higher dosages than subjects with the other genotypes. Relative to subjects with the epsilon(2)epsilon(3) genotype, those with the epsilon(4)epsilon(4) genotype had a risk of 2.28 [95% confidence interval (CI) 1.02-5.12] to discontinue statins within 3 years. In women, this relative risk was 1.70 (CI 0.53-5.42) versus 3.18 (CI 1.01-10.03) in men. The apoE genotype is associated with discontinuation of statins. This suggests that subjects who are genetically prone to develop hypercholesterolemia show the highest risk of discontinuation of treatment.