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Background Multi-stakeholder interactions have evolved at product and policy levels. There is a need to assess the current and future landscape of interactions between companies, and regulatory and HTA agencies to address challenges and identify areas for improvement. Objectives The aims of this study were to review the current interactions within and across regulatory and HTA agencies, and companies’ experiences in engaging in these activities; to assess the added value of interactions as well as limitations; to explore the future ecosystem for stakeholder interactions. Method Three separate questionnaires were developed for companies, regulators and HTA agencies, respectively, to assess their experiences and perceptions. The responses were analyzed using descriptive statistics and discussed at a multi-stakeholder workshop. Key outcomes from the surveys and workshop discussion were reported. Results All seven regulators and seven HTA agencies in the survey indicated that they had stakeholder interactions. More formal collaboration occurred with regulators compared with HTA agencies. All nine companies have taken early advice but indicated the need for future prioritization. Success indicators can be built at the product and therapy levels, with the added value of faster patient access. Four principles were proposed for the future ecosystem: separate remit and functions between regulators and HTA; align processes; converge evidence requirements where possible; increase transparency. Conclusions This research brought together regulators, HTA agencies, companies to examine how they interact with one another. We propose measures of value and make recommendations on future evolution to enable better evidence generation and improve regulatory and HTA decision-making.

Real-world data (RWD) and the derivations of these data into real-world evidence (RWE) are rapidly expanding from informing healthcare decisions at the patient and health system level to influencing major health policy decisions, including regulatory approvals and coverage. Recent examples include the approval of palbociclib in combination with endocrine therapy for male breast cancer and the inclusion of RWE in the label of paliperidone palmitate for schizophrenia. This interest has created an urgency to develop processes that promote trust in the evidence-generation process. Key stakeholders and decision-makers include patients and their healthcare providers; learning health systems; health technology assessment bodies and payers; pharmacoepidemiologists and other clinical reseachers, and policy makers interested in bioethical and regulatory issues. A key to optimal uptake of RWE is transparency of the research process to enable decision-makers to evaluate the quality of the methods used and the applicability of the evidence that results from the RWE studies. Registration of RWE studies-particularly for hypothesis evaluating treatment effectiveness (HETE) studies-has been proposed to improve transparency, trust, and research replicability. Although registration would not guarantee better RWE studies would be conducted, it would encourage the prospective disclosure of study plans, timing, and rationale for modifications. A joint task force of the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) and the International Society for Pharmacoepidemiology (ISPE) recommended that investigators preregister their RWE studies and post their study protocols in a publicly available forum before starting studies to reduce publication bias and improve the transparency of research methods. Recognizing that published recommendations alone are insufficient, especially without accessible registration options and with no incentives, a group of experts gathered on February 25 and 26, 2019, in National Harbor, Maryland, to explore the structural and practical challenges to the successful implementation of the recommendations of the ISPOR/ISPE task force for preregistration. This positioning article describes a plan for making registration of HETE RWE studies routine. The plan includes specifying the rationale for registering HETE RWE studies, the studies that should be registered, where and when these studies should be registered, how and when analytic deviations from protocols should be reported, how and when to publish results, and incentives to encourage registration. Table 1 summarizes the rationale, goals, and potential solutions that increase transparency, in addition to unique concerns about secondary data studies. Definitions of terms used throughout this report are provided in Table 2.

IntroductionReimbursement decision making is based on a relative effectiveness assessment (REA), which may be combined with a cost-effectiveness assessment, by national Health Technology Assessment (HTA) agencies. These assessments are based on clinical data where new interventions are compared to the current standard of care, which may differ between countries. Since most pivotal trials only include a limited number of interventions, indirect treatment comparisons (ITCs) can be used to compare multiple interventions. The aim of this study was to evaluate the use of ITCs in HTA decision making in the Netherlands and England.MethodsAll pharmaceutical assessments published between 2015 and 2019 by the National Health Care Institute (ZIN) and the National Institute for Health and Care Excellence (NICE) were reviewed to determine whether an ITC had been used. For detailed analysis we included all assessments of ZIN using an ITC, and a random sample of assessments of NICE using an ITC (10 assessments per publication year).ResultsBetween 2015 and 2019 a total of 106 and 265 assessments were conducted by ZIN and NICE, respectively. Of these assessments 48 from ZIN and 150 from NICE included an ITC. The detailed analysis showed that pharmaceutical assessments including indirect comparative evidence led to the REA conclusion of similar therapeutic evidence in 57 percent of 48 assessments by ZIN and in 52 percent of 50 assessments by NICE. Reimbursement recommendations including indirect comparative evidence most often resulted in positive recommendations by ZIN (57% assessments), and in restricted recommendations by NICE (50% assessments). Different methods were employed to incorporate indirect comparative evidence, such as naïve ITCs and network meta-analysis.ConclusionsOur results showed a significant variability in the use of ITCs between NICE and ZIN, which may contribute to differences in their recommendations. Further analysis will provide deeper insight in these differences and may provide suggestions for a clearer international guidance on the use of ITCs for HTA.

Performance-based managed entry agreements (PB-MEAs) might allow patient access to new medicines, but practical hurdles make competent authorities for pricing and reimbursement (CAPR) reluctant to implement PB-MEAs. We explored if the feasibility of PB-MEAs might improve by better aligning regulatory postauthorization requirements with the data generation of PB-MEAs and by active collaboration and data sharing. Reviewers from seven CAPRs provided structured assessments of the information available at the European Medicines Agency (EMA) Web site on regulatory postauthorization requirements for fifteen recently authorized products. The reviewers judged to what extent regulatory postauthorization studies could help implement PB-MEAs by addressing uncertainty gaps. Study domains assessed were: patient population, intervention, comparators, outcomes, time horizon, anticipated data quality, and anticipated robustness of analysis. Reviewers shared general comments about PB-MEAs for each product and on cooperation with other CAPRs. Reviewers rated regulatory postauthorization requirements at least partly helpful for most products and across domains except the comparator domain. One quarter of responses indicated that public information provided by the EMA was insufficient to support the implementation of PB-MEAs. Few PB-MEAs were in place for these products, but the potential for implementation of PB-MEAs or collaboration across CAPRs was seen as more favorable. Responses helped delineate a set of conditions where PB-MEAs may help reduce uncertainty. In conclusion, PB-MEAs are not a preferred option for CAPRs, but we identified conditions where PB-MEAs might be worth considering. The complexities of implementing PB-MEAs remain a hurdle, but collaboration across silos and more transparency on postauthorization studies could help overcome some barriers. ispartof: International Journal Of Technology Assessment In Health Care vol:37 issue:e83 pages:1-11 ispartof: location:England status: Published online

BACKGROUND There is a general agreement on the importance of health-related quality of life (HRQoL). This type of information is becoming increasingly important for the value assessment of health technology assessment agencies in evaluating the benefits of new health technologies, including medicines. However, HRQoL data are often limited, and additional sources that provide this type of information may be helpful. OBJECTIVE We aim to identify the HRQoL topics important to patients with melanoma based on web-based discussions on public social media forums. METHODS We identified 3 public web-based forums from the United States and the United Kingdom, namely the Melanoma Patient Information Page, the Melanoma International Forum, and MacMillan. Their posts were randomly selected and coded using qualitative methods until saturation was reached. RESULTS Of the posts assessed, 36.7% (150/409) of posts on Melanoma International Forum, 45.1% (198/439) on MacMillan, and 35.4% (128/362) on Melanoma Patient Information Page focused on HRQoL. The 2 themes most frequently mentioned were mental health and (un)certainty. The themes were constructed based on underlying and more detailed codes. Codes related to fear, worry and anxiety, uncertainty, and unfavorable effects were the most-often discussed ones. CONCLUSIONS Web-based forums are a valuable source for identifying relevant HRQoL aspects in patients with a given disease. These aspects could be cross-referenced with existing tools and they might improve the content validity of patient-reported outcome measures, including HRQoL questionnaires. In addition, web-based forums may provide health technology assessment agencies with a more holistic understanding of the external aspects affecting patient HRQoL. These aspects might support the value assessment of new health technologies and could therefore help inform topic prioritization as well as the scoping phase before any value assessment. CLINICALTRIAL

IntroductionTurkey's health reforms, which started in 2003, have led to increased access to health care and pharmaceuticals as well as rising public pharmaceutical expenditures. The need to improve healthcare decision making by implementing health technology assessment (HTA) has become an important priority for Turkey. This study sought to provide a tailor-made HTA implementation roadmap, drawing on insights from national stakeholders.Our study aimed to describe the current HTA environment in Turkey and to explore long-term perspectives and suggestions from a wide spectrum of Turkish stakeholders regarding the preferred status of HTA in ten years (by 2029).MethodsWe conducted an online survey using a questionnaire previously applied in other HTA research. We assessed the current evaluation of medical and economic decision-making processes and examined the need for HTA. We also ascertained stakeholder perspectives on potential developments that can be done together with policymakers, representatives of pharmaceutical companies, and patient organizations. We also included general information about the pharmaceutical market and decision making processes in Turkey.ResultsThe survey was sent to various stakeholders from different areas within the health system. Additional face-to-face interviews were conducted with a few respondents to clarify some of their answers. A total of twenty-seven Turkish stakeholders completed the survey. Of these, twenty-one (78%) participants were employed in the public sector and six (22%) were from the private sector. The majority of the participants would introduce HTA for all new health technologies being considered for public reimbursement and institute an additional review process for currently reimbursed technologies. Most of the respondents considered that only new technologies with significant budget impact should be evaluated in the next ten years.ConclusionsIt is clear that Turkey needs to implement an HTA process in the future. Our study shows stakeholder expectations, which will be helpful for creating an HTA implementation roadmap, and it is clear that different stakeholders have different views and expectations about HTA implementation in Turkey. The experiences of other countries will also be helpful during the implementation process.

Available online 12 September 2017. The Publisher regrets that this article is an accidental duplication of an article that has already been published, http://dx.doi.org/10.1016/j.jval.2017.08.3019. The duplicate article has therefore been withdrawn. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our-business/policies/article-withdrawal.

Objectives:Many European countries perform rapid assessments of the relative effectiveness (RE) of pharmaceuticals as part of the reimbursement decision making process. Increased sharing of information on RE across countries may save costs and reduce duplication of work. The objective of this article is to describe the development of a tool for rapid assessment of RE of new pharmaceuticals that enter the market, the HTA Core Model® for Rapid Relative Effectiveness Assessment (REA) of Pharmaceuticals.Methods:Eighteen member organisations of the European Network of Health Technology Assessment (EUnetHTA) participated in the development of the model. Different versions of the model were developed and piloted in this collaboration and adjusted accordingly based on feedback on the content and feasibility of the model.Results:The final model deviates from the traditional HTA Core Model® used for assessing other types of technologies. This is due to the limited scope (strong focus on RE), the timing of the assessment (just after market authorisation), and strict timelines (e.g. 90 days) required for performing the assessment. The number of domains and assessment elements was limited and it was decided that the primary information sources should preferably be a submission file provided by the marketing authorisation holder and the European Public Assessment Report.Conclusions:The HTA Core Model® for Rapid REA (version 3.0) was developed to produce standardised transparent RE information of pharmaceuticals. Further piloting can provide input for possible improvements, such as further refining the assessment elements and new methodological guidance on relevant areas.

In light of increasing attention towards the use of real-world evidence (RWE) in decision making in recent years, this commentary aims to reflect on the experiences gained in accessing and using RWE for comparative effectiveness research as a part of the Innovative Medicines Initiative GetReal Consortium and discuss their implications for RWE use in decision-making.

In response to a recommendation from the Pharmaceutical Forum, the European Medicines Agency and the European network for Health Technology Assessment initiated a collaboration with the aim to improve the contribution regulatory assessment reports can make to the assessment of relative effectiveness of medicinal products by health technology assessment bodies. This collaboration on improving European Public Assessment Reports (EPARs) started in February 2010 and was performed over 2 years. As a result, the templates for preparing EPARs were revised to better address the needs of heath technology organizations. The better understanding of information needs was a key outcome of the collaboration. To ascertain whether these template changes led to the inclusion of relevant information, a review of a small set of EPARs for recently approved medicinal products was carried out in parallel by both the European network for Health Technology Assessment and the European Medicines Agency. This report provides an account of this project on improving EPARs, which is part of the ongoing dialogue between regulators and health technology assessment bodies on a European level to support policymaker decisions in the future.

INTRODUCTION:Reimbursement decisions are usually based on evidence from randomized controlled trials (RCT) with high internal validity but lower external validity. Real-World Data (RWD) may provide complimentary evidence for relative effectiveness assessments (REA's) and cost-effectiveness assessments (CEA's) of treatments. This study explores to which extent RWD is incorporated in REA's and CEA's of drugs used to treat metastatic melanoma (MM) by five Health Technology Assessment (HTA) agencies.METHODS:Dossiers for MM drugs published between 1 January 2011 and 31 December 2016 were retrieved for HTA agencies in five countries: the United Kingdom (NICE), Scotland (SMC), France (HAS), Germany (IQWiG) and the Netherlands (ZIN). A standardized data-extraction form was used to extract data on RWD mentioned in the assessment and its impact on appraisal (for example, positive, negative, neutral or unknown) for both REA and CEA.RESULTS:In total, fourty-nine dossiers were retrieved: NICE = 10, SMC = 13, IQWiG = 16, HAS = 8 and ZIN = 2. Nine dossiers (18.4 percent) included RWD in REA's for several parameters: to describe effectiveness (n = 5) and/or the safety (n = 2) of the drug, and/or the prevalence of MM (n = 4). CEA's were included in 25/49 dossiers (IQWiG and HAS did not perform CEA's). Of the twenty-five CEA's, twenty (80 percent) included RWD to extrapolate long-term effectiveness (n = 19), and/or identify costs associated with treatments (n = 7). When RWD was included in REA's (n = 9), its impact on the appraisal was negative (n = 4), neutral (n = 2), unknown (n = 1) or was not discussed in the appraisal (n = 2). When RWD was included in CEA's (n = 11), its impact on the appraisal varied between positive (n = 2), negative (n = 5) and unknown (n = 4).CONCLUSIONS:Generally, RWD is more often included in CEA's than REA's (80 percent versus 18.4 percent, respectively). When included, RWD was mostly used to describe the effectiveness of the drug (REA) or to predict long-term effectiveness (CEA). The impact of RWD on the appraisal varied greatly within both REA's and CEA's.

INTRODUCTION:In 2007, the National Healthcare Institute (ZIN) initiated conditional financing (CF) of expensive hospital drugs as an example of conditional reimbursement schemes (CRS). CF is a 4-year procedure encompassing initial HTA assessment (T = 0) followed by additional data collection via outcomes research (separately assessing appropriate use & cost-effectiveness in routine practice) and re-assessment (T = 4). This study aims to review performance and experiences with CF in the Netherlands to date.METHODS:All dossiers for drugs that underwent the full CF procedure were reviewed. Using a standardized data abstraction form, two researchers independently extracted information on procedural, methodological and decision-making aspects (that is, related to implemented outcomes research, evidence assessment and appraisal). A scoring algorithm was used to assess all three aspects.RESULTS:Fourty-seven candidates were nominated for CF; fourty-four underwent T = 0 assessments and eleven T = 4 assessments. The procedure extended beyond 4 years for 10/11 candidates. For the eleven candidates, applicants clearly defined study designs and data collection methods for outcomes research proposals addressing 16/22 research questions posed in T = 0 reports. ZIN provided discussion points and recommendations regarding research proposals for 18/22 research questions. Applicants implemented recommendations fully in 8/22 cases and partially in 12/22. Sufficient data was available at T = 4 to answer 15/22 research questions posed at T = 0. However, discussion points remained regarding implemented outcomes research for all eleven candidates at T = 4. ZIN advised to continue reimbursement for nine candidates and to stop reimbursement for two. For six of the nine candidates, reimbursement was continued on the basis of conditions relating to additional evidence generation beyond T = 4.CONCLUSIONS:Theoretically, CF provides a valuable option for enabling quick but conditional access to medicines in the Netherlands. However, procedural, methodological and decision-making considerations related to scheme design and implementation may affect its value in decision-making practice.

Studies of interventions for dyslexia have focused entirely on outcomes related to literacy. In this study, we considered a broader picture assessing improved quality of life compared with costs. A model served as a tool to compare costs and effects of treatment according to a new protocol and care as usual. Quality of life was measured and valued by proxies using a general quality-of-life instrument (EQ-5D). We considered medical cost and nonmedical cost (e.g. remedial teaching). The model computed cost per successful treatment and cost per quality adjusted life year (QALY) in time. About 75% of the total costs was related to diagnostic tests to distinguish between children with severe dyslexia and children who have reading difficulties for other reasons. The costs per successful treatment of severe dyslexia were €36366. Successful treatment showed a quality-of-life gain of about 11%. At primary school, the average cost per QALY for severe dyslexia amounted to €58647. In the long term, the cost per QALY decreased to €26386 at secondary school and €17663 thereafter. The results of this study provide evidence that treatment of severe dyslexia is cost-effective when the investigated protocol is followed. Copyright # 2011 John Wiley & Sons, Ltd.

Objectives: This study aimed to identify the barriers and facilitators of the utilization of health technology assessment (HTA), a process which is infrequently applied to the selection of medicines listed in the medicine pricing and reimbursement policies in Indonesia. Methods: Semi-structured interviews were conducted to collect qualitative data. Purposive sampling was used to recruit the stakeholders, which consisted of policymakers, a pharmaceutical industry representative, healthcare providers, and patients. The data were analyzed using directed content analysis to systematically organize the data into a structured format. A COnsolidated criteria for REporting Qualitative studies (COREQ) checklist was followed to ensure a high quality and comprehensive report of the findings. Results: The twenty-five participants interviewed provided a range of barriers and promoting factors for the implementation of HTA in Indonesia. A lack of capability of local human resources, a lack of incentives, unintegrated data, as well as a lack of a clear framework were mentioned as barriers. An important promoting factor was seen in the Indonesian law which stipulated that HTA was mandatory for selecting medicines listed in the medicine pricing and reimbursement policies. Strategies suggested to overcome the barriers include setting up an HTA department in several Indonesian universities, introducing a clear framework for the implementation of HTA in the guidelines, and establishing relationships with other countries with a well-developed HTA or with HTA associations. Conclusions: Several barriers are currently preventing the implementation of HTA in medicine pricing and reimbursement policy in Indonesia, however, solutions to these issues exist.

Purpose To determine the association between opioid use and the occurrence of postoperative paralytic ileus (POI) after different types of surgery. Methods The PHARMO database was used to perform a case control study in which intramural drug utilisation data were linked to hospital discharge diagnoses. All patients admitted for digestive, abdominal or genito-urinary surgeries were selected in 1998–2003. Cases with coded POI (ICD-9-CM 560.1 and 564.4) and controls with no POI were matched 1:10. The association between coded POI and opioid use was assessed using conditional logistic regression. Results In 0.2% of all admissions (total of 180,279), patients developed POI and in 18% of all admissions, patients received opioids. Three hundred and sixty-six cases with POI were selected with their matching controls. The use of (nico)morphine was associated with the risk for developing POI (odds ratio (OR) 12.1, 95% confidence interval (CI) 5.4–27.1). The association between opioids and POI was most obvious in patients with abdominal surgery (OR 33.8, 95%CI 6.2–184.6) and patients without colon/colorectal/rectal tumours (OR 13.2, 95%CI 5.7–30.3). Conclusion This study demonstrated a distinct association between the use of opioids, in particular natural opium alkaloids, and the risk for coded POI. Copyright © 2006 John Wiley & Sons, Ltd.

Purpose To assess recent and to predict future time trends in the incidence of osteoporosis using routine databases in The Netherlands in the period 1993–2015 and to compare estimations based on hip fractures versus a proxy based on pharmacy and hospitalisation data. Methods The incidence of hip fractures was estimated over the period 1986–2002 using information from the Dutch Medical Registry, covering more than 99% of all Dutch hospitalisations. Additionally, a proxy (hospitalisation for osteoporosis or osteoporotic fractures, treatment with glucocorticosteroids or treatment with anti-osteoporosis drugs) was constructed in order to identify osteoporotic patients in the PHARMO database. Age and gender specific incidences of hip fractures and osteoporosis were calculated and extrapolated to The Netherlands. Results of both studies were extrapolated till 2015 using a power function. Results The incidence of hip fractures decreased slightly (270 per 100 000 in 1993, 260 per 100 000 in 2002). The incidence of osteoporosis using the constructed proxy decreased from 870 per 100 000 in 1993 to 700 per 100 000 in 2002. The incidence of hip fractures and osteoporosis remained fairly constant when modelled till 2015. Both studies showed the same time trends. Conclusion Both the estimations based on the hospitalisations for hip fracture and on our proxy for osteoporosis showed that the increase in the incidence of osteoporosis as observed in the 1990s is levelling off. Due to ageing of the population the absolute number of hip fractures will however increase. Our definition of osteoporosis resulted in a higher estimation of the incidence of osteoporosis and may be used in future studies to follow developments in osteoporosis prevalence and incidence. Copyright © 2006 John Wiley & Sons, Ltd.

Introduction: International guidelines on the treatment and prevention of osteoporosis recommend the use of bisphosphonates to prevent fractures in this population. However, low persistent use of bisphosphonates could considerably limit the prevention of fractures in clinical practice. Objective: This study aimed to investigate the association between persistent use of bisphosphonates and the risk of osteoporotic fractures in clinical practice. Methods: Data were obtained from the PHARMO Record Linkage System, which includes, among other databases, drug-dispensing records from community pharmacies linked to hospital discharge records of more than two million subjects in defined areas in the Netherlands. Persistence with bisphosphonate therapy was assessed during a period of 3 years. A nested matched case control study (cases:controls = 1:10) was performed to study the association between persistent bisphosphonate use and hospitalisation for osteoporotic fractures and analysed by conditional logistic regression analysis. The analyses were adjusted for patient characteristics such as previous hospitalisations for fractures, co-morbidity and co-medication. Results: 14760 new female users of bisphosphonates were identified of which 541 women had a hospitalisation for osteoporotic fracture after start of bisphosphonate treatment (1-3 years follow-up). One-year persistence rates increased from 33% with alendronate daily to 48% with alendronate weekly, an increase of 15%. Similar results were obtained with risedronate daily and weekly. One year persistent use of bisphosphonates resulted in a statistical significant 26% lower fracture rate (OR 0.74; 95%CI 0.57-0.95) whereas 2 year persistent use resulted in a 32% lower rate (OR 0.68; 95%CI 0.47-0.96). Conclusions: Persistent use of bisphosphonates decreases the risk of osteoporotic fractures in clinical practice. Approximately 6% of fractures among users of bisphosphonates could be prevented if persistence was improved by 20%. However, current persistence with bisphosphonate therapy is suboptimal and strategies that further increase persistence are likely to further prevent the number of fractures.

SummaryStudy objectivesTo assess whether prior outpatient treatment is associated with outcome in patients hospitalized for community-acquired pneumonia (CAP).Patients and methodsAll patients with a first hospital admission for CAP between 1995 and 2000 were selected. Patients were divided into two groups, one of patients with use of antibacterial agents prior to hospitalization and one of patients treated as inpatient directly. The main outcome measures were duration of hospital stay and in-hospital mortality.ResultsThe two patient groups comprised 296 and 794 patients, respectively. The median duration of hospital stay was 10 days and was similar for both groups. In patients with respiratory diseases or heart failure, the median duration of hospital stay was 12 and 14 days, respectively. The overall in-hospital mortality was 7.2% and did not largely differ between both groups. In patients with congestive heart failure, the mortality was 9.8% for controls and 23.3% for patients hospitalized after initial outpatient treatment (adjusted OR 2.78, 95% CI 1.01–7.81).ConclusionsPrior outpatient antibacterial therapy is not associated with outcome in hospitalized pneumonia patients. In patients with underlying chronic heart failure, prior outpatient antibiotic is associated with a significant increased mortality.

Results from clinical trials and clinical practice have shown statins to be generally well tolerated with a low frequency of clinically relevant side effects. Nevertheless, there are rare occasions when adverse events (AEs), sometimes serious, may occur. Rosuvastatin is the newest statin to be approved in the USA and many other countries. As part of the continued assessment of the benefit-risk profile of rosuvastatin, AstraZeneca has developed a progressive, comprehensive pharmacoepidemiology programme to complement safety data obtained from randomised clinical trials and spontaneous reporting systems, which have demonstrated that rosuvastatin has a safety profile in line with comparator statins. This programme comprises nine studies conducted in recognised centres of excellence assessing over 50 000 patients treated with rosuvastatin. It consists of three components: patient characteristics studies (four studies), safety evaluation studies (four studies); and review of data generated from the Prescription-Event Monitoring (PEM) study, designed and run by an independent third party. Patient characteristics studies are designed to describe the characteristics and drug utilisation patterns of new users of rosuvastatin compared with new users of other statins in automated databases. Safety evaluation studies will examine the rates of specific AEs in different cohorts of statin users and determine risk factors for these events using data recorded prospectively in automated databases with case adjudication via medical record review. The independent PEM study will monitor any significant events recorded by general practitioners since starting rosuvastatin treatment. This article is an overview of the rationale and methodology of the rosuvastatin pharmacoepidemiology programme. Copyright © 2006 John Wiley & Sons, Ltd.

Purpose Clinical benefits of statin therapy are accepted, but their safety profiles have been under scrutiny, particularly for the recently introduced statin, rosuvastatin, relating to serious adverse events involving muscle, kidney and liver. Therefore, a historical cohort study was performed to evaluate the association between rosuvastatin versus other statin use and the incidence of rhabdomyolysis, myopathy, acute renal failure and hepatic impairment. Methods Incident users of rosuvastatin or other statins in 2003–2004 and a cohort of patients not prescribed statins were included from the PHARMO database of >2 million Dutch residents. Cases of hospitalisations for myopathy, rhabdomyolysis, acute renal failure or hepatic impairment were identified for these cohorts. Potential cases were validated through a multi-step process using data obtained from hospital records. Additionally, cases of all cause deaths were identified from certification alone. Results In 2003 and 2004, 10 147 incident rosuvastatin users, 37 396 incident other statin users and 99 935 patients without statin prescriptions were included. There were 26 validated outcome events in the three cohorts including one case each of myopathy (other statin group) and rhabdomyolysis (non-treated group). There were no significant differences in the incidence of outcome events between rosuvastatin and other statin users. Conclusion This study indicated that the number of outcome events is less than 1 per 3000 person years. This study in more than 45 000 Dutch statin users suggests that rosuvastatin does not lead to an increased incidence of rhabdomyolysis, myopathy, acute renal failure or hepatic impairment compared to other statins. Copyright © 2006 John Wiley & Sons, Ltd.

Aims The objective of this population-based, retrospective cohort study was to investigate the incidence and initial antibiotic treatment of secondary intra-abdominal infections (sIAI) and to assess whether inappropriate initial antibiotic therapy affects patient outcomes. Methods All patients hospitalized for sIAI (1995–1998) were identified in the PHARMO Record Linkage System, a patient-centric database including pharmacy dispensing records from community pharmacies linked to hospitalization records in the Netherlands. Complementary in-hospital antibiotic drug use was obtained from the computerized inpatient pharmacy files. The patient outcomes considered were switch to second-line antibiotic treatment, re-operation, and death. In addition, a composite variable clinical failure was constructed based on the above-mentioned outcomes. Furthermore, the effect of clinical failure on length of hospital stay and costs of hospitalization was assessed. Associations between appropriateness of initial antibiotic treatment and outcomes were estimated using multivariate logistic and linear regression models. Results In the source population of 228 000 persons, 175 cases were classified as sIAI (mean age 49.3 ± 24.5, 50.9% male) resulting in an incidence of 2.3/10 000 person-years [95% confidence interval (CI) 2.0, 2.7]. Initial antibiotic treatment was appropriate for 84% of the cases. The risk of clinical failure was 17.1%. Inappropriate initial antibiotic treatment increased the risk of clinical failure 3.4-fold (95% CI 1.3, 9.1). Length of hospital stay and costs of hospitalization were significantly increased for patients with clinical failure. Conclusions Inappropriate choice of initial antibiotic therapy in sIAI patients leads to more clinical failure resulting in a longer hospital stay and higher costs of hospitalization compared with appropriate initial antibiotic therapy.

Wim Goettsch is currently the Project Leader of Work Package 5 of the European Network of Health Technology Assessment (EUnetHTA) Joint Action 2 (2012–2015). EUnetHTA is a network of the health technology assessment organizations in Europe responsible for advising or deciding on the national reimbursement of pharmaceuticals and other health technologies. In this work package, rapid joint assessments of the relative effectiveness of pharmaceuticals are piloted between more than 25 health technology assessment organizations around Europe. These pilots are based on the methodology that was developed in a similar work package in EUnetHTA JA1 (2010–2012), of which Dr Goettsch was also the Project Leader. Until the beginning of 2013, Dr Goettsch was the Deputy Secretary of the Medicinal Products Reimbursement Committee at Dutch Healthcare Insurance Board (CVZ). The Dutch Medicinal Products Reimbursement Committee advises the Dutch Minister of Health on whether new drugs need to be included in the basic insurance package. Before joining CVZ, he worked as a research manager for the PHARMO Institute (Utrecht, The Netherlands) and was responsible for the coordination of numerous pharmacoepidemiological and outcomes studies for international offices of pharmaceutical companies, such as AstraZeneca, Novartis, Pfizer and GlaxoSmithKline. Dr Goettsch has approximately 50 publications in peer-reviewed international journals.

Aim To assess determinants of treatment failure after antimicrobial therapy of urinary tract infections in women. Methods In primary care 16 703 Dutch women who received a first course (3, 5 or 7 days) of trimethoprim, nitrofurantoin or norfloxacin between 1 January 1992 through 31 December 1997 and who were between 15 and 65 years old at the day of first use were selected. Failure of the initial treatment was defined as a further prescription for one of these three antibiotics or for cotrimoxazole, amoxicillin, ciprofloxacin or ofloxacin, within 31 days after the end of the initial therapy. Results Treatment failure rate was 14.4% in patients treated with trimethoprim and nitrofurantoin and 9.6% in patients treated with norfloxacin. A multivariate analysis showed that 5 days’[RRNIT 0.67, 95% confidence interval (CI) 0.57, 0.82, RRTRI 0.82, 95% CI 0.73, 0.91] and 7 days’ (RRNIT 0.64, 95% CI 0.53, 0.77, RRTRI 0.85, 95% CI 0.71, 1.02) trimethoprim and nitrofurantoin treatment appeared to be more effective than a 3-day treatment (reference category). Other factors increasing treatment failure rates were the age of the patient, the year of therapy and previous hospitalization. Conclusions It may be concluded that 3-day courses of nitrofurantoin and trimethoprim are less effective than 5- and 7-day courses in the treatment of uncomplicated urinary tract infections in women.

BACKGROUNDUse of nonsteroidal antiinflammatory drugs (NSAIDs) is a well-known cause of gastrointestinal (GI) adverse events. To protect patients at risk, several strategies are advised, including concomitant treatment with proton-pump inhibitors or switching to cyclooxygenase (COX)-2 selective NSAIDs. It is as yet unknown how many patients at risk for NSAID-induced events are protected.OBJECTIVETo estimate the number of patients using GI preventive treatment while at risk for NSAID-induced GI events.METHODSRecords of patients using NSAIDs consecutively for at least 100 days (from 2001 to 2002) were obtained from the PHARMO system in the Netherlands (N = 1 000 000). GI preventive treatments were classified as adequate or inadequate based on evidence-based criteria. Adequate treatment was defined as concomitant use of misoprostol (>400 μg daily), histamine2-antagonists (≥2 times recommended dose) or proton-pump inhibitors (≥1 recommended dose), or alternative treatment with COX-2 selective inhibitors.RESULTSA total of 10 121 patients met the study inclusion criteria; 70% were women. One or more preventive strategies were prescribed in 4340 patients (42.9%), of which 2799 (64.5%) were adequate and 1541 (35.5%) inadequate. Prescribing of adequate preventive treatments increased with the number of risk factors, from 13.3% among those with no additional risk factors to 61.9% for those with ≥4 risk factors.CONCLUSIONSAlthough risk factors for GI damage were recognized, a large number of patients in the Netherlands were not or were inadequately protected against potential NSAID-associated GI damage. Despite recommendations, and even in the presence of ≥4 risk factors, almost 40% of these patients were not prescribed adequate GI preventive treatment.

Background: Ultraviolet radiation (UVR) is an important risk factor for skin cancer in transplant recipients. In view of the potential suppressive effect of UVR on host resistance it was examined whether exposure to UVR was also associated with the occurrence of various skin infections. Methods: In a cohort of renal transplant recipients (n = 137), lifetime exposure was assessed by means of a retrospective questionnaire on cumulative sunlight exposure. Diagnosed skin infections since renal transplantation were extracted from the patient's medical charts. Season of diagnosis was regarded as indicative of short-term exposure. Results: In comparison with winter a high rate of herpes simplex infections was found in spring [rate ratio (RR) = 4.09, 95% confidence interval (CI) 1.2–14.5], and high rates of herpes zoster infections (RR = 1.6, 95% CI: 0.8–3.5) and fungal/yeast infections in summer (RR = 2.1, 95% CI: 1.3–3.4). A higher lifetime exposure (RR = 2.31, 95% CI: 1.04–5.1) and a greater cumulative number of reported sunburns (RR = 2.3, 95% CI: 1.1–5.1) were independently associated with a higher risk of bacterial infections. Conclusions: The seasonal association with the occurrence of clinical herpes infections indicates an effect of short-term UVR. Our data suggest that the number of sunburn episodes in the past is also relevant for the susceptibility to certain skin infections.

Practicalities Of Using Real-World Evidence (Rwe) In Comparative Effectiveness Research (Cer) : Learnings From Imi-Getreal

Background Skin infection is a frequent complication in renal transplant recipients. The purpose of the study was to acquire long-term, period-specific incidence data on the most commonly occurring skin infections in renal transplant recipients. Methods A retrospective analysis was performed using medical records of 134 patients, covering a period between 10 and 29 yr. Cumulative incidences of the skin infections were calculated by counting the infections per patient for different time periods and were expressed as a percentage of the total group of patients. The incidence of the skin infections was determined for different post-transplant time periods. Results A total of 340 skin infections in 105 out of 134 patients were recorded. Some infections, such as candidal infection, herpes simplex infection, and impetigo were most prominent during the first post-transplant year and did not affect many new patients after the first year. Other infections, such as dermatomycoses, herpes zoster, and folliculitis were also affecting a substantial number of new patients after the first post-transplant year. Conclusions This study confirms that skin infections among renal transplant recipients are very common and that the spectrum of skin infections differs according to the post-transplant time period.

In continuous surveillance of routine samples from five Dutch laboratories, we studied resistance to the antibiotics most commonly prescribed for urinary tract infections (UTI) in The Netherlands, namely norfloxacin, amoxycillin, trimethoprim and nitrofurantoin, from 1989 to 1998 in >90000 Escherichia coli isolates. Resistance to norfloxacin increased from 1.3% in 1989 to 5.8% in 1998. Multiresistance, defined as resistance to norfloxacin and at least two of the other three antibiotics, increased from 0.5% in 1989 to 4. 0% in 1998. Multivariate analysis of the norfloxacin resistance demonstrated that this yearly increase (the odds ratio was 1.0 in 1989, 1.6 in 1992, 2.9 in 1995 and 6.1 in 1998) was independent of other determinants of resistance to norfloxacin, such as age, gender and origin of the isolate. Analysis of strata, classified by year, age and gender, demonstrated an association between prescription of fluoroquinolones (defined daily doses per case of UTI) and resistance to norfloxacin in E. coli (P < 0.001). There was no significant association with the prescription of nitrofuran derivatives (nitrofurantoin) and trimethoprim with or without sulphamethoxazole. The yearly increase of resistance to fluoroquinolones in E. coli from UTI may stem from increased prescription of fluoroquinolones for UTI. Resistance of E. coli to these agents is likely to increase further as fluoroquinolone use increases in future.

The prevalence of methicillin resistant Staphylococcus aureus (MRSA) in Dutch nursing homes in 1998 was higher than that found in 1989 to 1997. The increased prevalence of MRSA could lead to colonisation outside these nursing homes. A study of the prevale

Risk assessment comprises four steps: hazard identification, dose-response assessment, exposure assessment and risk characterization. As an example we have assessed the risk of decreased host resistance to infections due to effects of the immunotoxic agent - ultraviolet light. We have analysed effects of UVB radiation on basal immune functions in rats and man, and the immunological resistance to infectious diseases in rats. Non-threshold mathematical methods were used in order to estimate the risk for the human population after increased exposure to UVB radiation. These data demonstrate that UVB radiation, at doses relevant to outdoors exposure, may affect the immunological resistance to infectious diseases in human individuals. This study may also provide a basis for a strategy to assess the risk of adverse effects of exposure to immunotoxic agents.

Objective: To investigate the practical feasibility to develop evidence on drug use and cost-effectiveness in oncology practice. Patients and methods: Feasibility was examined using three Dutch case studies. Each case study investigated the degree of appropriate drug use and its incremental cost-effectiveness. Detailed data were retrospectively collected from hospital records. In total, 391, 316 and 139 patients with stage III colon cancer, metastatic colorectal cancer and multiple myeloma were included in 19, 29 and 42 hospitals, respectively. Results: The methods used in the case studies were feasible to develop evidence on some aspects of drug use including types of treatments used, dosages, dose modifications and healthcare costs. Aspects such as baseline patient characteristics, reasons to start or stop a treatment and treatment effects were less feasible because of missing values. Despite difficulties to correct for confounding by indication, it was possible to estimate incremental cost-effectiveness by synthesising evidence in two of the three case studies. Conclusion: It is possible to generate evidence about drug use and cost-effectiveness in oncology practice to facilitate informed decision-making by both payers and physicians. This can improve quality of care and enhance the efficient allocation of resources. However, the optimal approach differs between drugs and their indications. Generating high-quality evidence requires active interdisciplinary collaboration. Patient registries can facilitate data collection but cannot resolve all issues. In most circumstances it is inevitable to use data-synthesis to obtain valid incremental cost-effectiveness estimates, but for some indications it will not be feasible to derive a valid and precise estimate. (C) 2012 Elsevier Ltd. All rights reserved

— Our laboratory has demonstrated in preliminary experiments that UVB exposure using the Kromayer lamp can induce increased numbers of Trichinella spiralis larvae in carcasses of infected Wistar rats, without affecting specific antibody titers to this parasite. In this study, orally T. spiralis-infected Wistar rats were exposed to subery-themal doses of UVB radiation using FS40 lamps during different time periods before or after infection. A significant increase in the number of T. spiralis larvae was found in the carcasses of rats that were UVB irradiated daily for 7 consecutive days in the second week after infection. Additionally, increased numbers of larvae were also detected histologically in the tongue of rats that were exposed the first and the second week after infection. Lymphocyte stimulation assays using mesenteral lymph node cells indicated that UVB exposure also impaired the specific lymphocyte response to T. spiralis. Moreover, DTH responses to T. spiralis were severely impaired in rats that were UVB irradiated daily for 7 consecutive days in the second week after infection. Thus, these data combined with the data of the Kromayer study indicate that exposure of rats to FS40 irradiation following oral infection with T. spiralis leads to increased numbers of larvae in systemic sites and impaired T-cell immunity to the parasite.

A rat cytomegalovirus infection model for use in immunotoxicity testing has been developed. In resistance against viruses, natural killer cells and cytotoxic T-cells play an important role. Therefore, this model complements other rat host resistance models for immunotoxicity testing, i.e. existing bacterial and parasitic infection models in which cytotoxic T-cells and natural killer cells play a minor role. Host resistance against cytomegalovirus infections in the rat was determined by titrating infectious virus levels in organs after cytomegalovirus infection in an in vitro infectivity test denoted as the Plaque Forming Unit (PFU) Test. In this test, homogenates of different organs were investigated for infectious virus titers on rat embryonic cell monolayers. We demonstrated that in the salivary gland, the major target organ for rat cytomegalovirus, virus was detectable from 8 days onward after intraperitoneal infection. To show that this model is suitable for the detection of immunotoxicity four different methods for immunosuppression were investigated: 1. gamma-irradiation, 2. congenitally athymic rats, 3. chemically induced immunosuppression, 4. ultraviolet-B (UVB) irradiation. Rat cytomegalovirus titers in the salivary glands of irradiated (500 rad 1 day prior to infection) or congenitally athymic rats were significantly increased as compared to non-irradiated rats and euthymic control rats respectively. In TOX-Wistar rats, given 20 or 80 mg bis(tri-n-butyltin)oxide (TBTO) per kg food beginning 6 weeks before cytomegalovirus infection, a regimen known to have immunotoxic effects, cytomegalovirus titers in the salivary glands were significantly increased as compared to non-TBTO-treated cytomegalovirus infected rats.(ABSTRACT TRUNCATED AT 250 WORDS)

ObjectiveAssessment of the effectiveness compared with alternative treatment(s) plays an important role in many jurisdictions in determining the reimbursement status of pharmaceuticals. This type of assessment is often referred to as a relative effectiveness assessment (REA) and is carried out by many jurisdictions. Increased sharing of information across jurisdictions may save costs and reduce duplication. The objective of this study was to explore the main similarities and differences in the major methodological aspects of REA in multiple jurisdictions.MethodsData were gathered with a standardized data extraction form by searching publicly available information and by eliciting information from representatives at relevant organizations.ResultsOf the initially included 35 jurisdictions, data were gathered for 29 jurisdictions. There seem to be substantial similarities on the choice of the comparator, the role of indirect comparisons, and preferred end points in REAs (except for the use of health state utilities). Jurisdictions, however, differ in whether effectiveness (usual circumstances of health care practice) is estimated in case no (comparative) effectiveness data are available and how this is done.ConclusionSome important methodological aspects for REA are approached in a similar way in many jurisdictions, indicating that collaboration on assessments may be feasible. Enhanced collaboration in the development of methods and best practices for REA between jurisdictions will be a necessary first step. Important topics for developing best practice are indirect comparisons and how to handle the gap between efficacy and effectiveness data in case good quality comparative effectiveness data are not yet available at the time of reimbursement decisions.

Studies of interventions for dyslexia have focused entirely on outcomes related to literacy. In this study, we considered a broader picture assessing improved quality of life compared with costs. A model served as a tool to compare costs and effects of treatment according to a new protocol and care as usual. Quality of life was measured and valued by proxies using a general quality-of-life instrument (EQ-5D). We considered medical cost and non-medical cost (e.g. remedial teaching). The model computed cost per successful treatment and cost per quality adjusted life year (QALY) in time. About 75% of the total costs was related to diagnostic tests to distinguish between children with severe dyslexia and children who have reading difficulties for other reasons. The costs per successful treatment of severe dyslexia were €36 366. Successful treatment showed a quality-of-life gain of about 11%. At primary school, the average cost per QALY for severe dyslexia amounted to €58 647. In the long term, the cost per QALY decreased to €26 386 at secondary school and €17 663 thereafter. The results of this study provide evidence that treatment of severe dyslexia is cost-effective when the investigated protocol is followed.

Background: Several countries have developed policy frameworks allowing timely access to promising health technologies on the condition that additional evidence is generated. However, an important barrier to evidence generation is the lack of structured collaboration among health technology assessment (HTA) agencies.Objectives: One of the aims of Work Package 7 (WP7) of the European network for Health Technology Assessment (EUnetHTA) Project was to determine the types of structured collaboration that could facilitate evidence generation and to develop a Web-based toolkit to support such collaboration.Methods: Collaboration modalities were defined by all WP7 Partners. Initial emphasis was on information sharing. Standardized forms for information sharing were developed and tested. An information technology development phase followed with the creation of the Web-based toolkit (Web site).Results: Three levels of collaboration were agreed on: (i) sharing information, (ii) coordinated action, and (iii) joint action. The Web site allows access to structured and standardized forms for requesting information, posting information in response to a request, and posting information spontaneously. An online database contains all of the information requested or posted. Pilot tests on twenty-one promising technologies were satisfactory.Conclusions: This new Web site for sharing information on evidence generation should help countries reach robust decisions on the timely adoption of promising health technologies. It will only become fully operational if EUnetHTA Partners supply relevant, accurate, and updated information, and regularly use the Web site.