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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.

Objectives: 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 standardised data abstraction form, 2 researchers independently extracted information on procedural and methodological aspects (i.e. related to implemented outcomes research & evidence assessment). A scoring algorithm was used to assess both aspects. Results: Forty-seven candidates were nominated for CF; 44 underwent T= 0 assessments and 10 T= 4 assessments. The CF procedure extended beyond 4 years for 8 of the 10 candidates. For the 10 candidates, applicants clearly defined study designs and data collection methods for outcomes research proposals addressing 14 of 20 research questions posed in T= 0 reports. ZIN provided discussion points and recommendations regarding research proposals for 16 of 20 research questions. Applicants implemented recommendations fully in 2 cases and partially in 14. Sufficient data was available at T= 4 to answer 13 of 20 research questions posed at T= 0. However, discussion points remained regarding implemented outcomes research for all 10 candidates at T= 4. ZIN advised to continue reimbursement for 6 candidates and to stop reimbursement for 2. In 2 of the 6 candidates, reimbursement was continued on the condition of additional evidence generation beyond T= 4. Two candidates did not receive a final recommendation. Conclusions: Theoretically, CF provides a valuable option for enabling quick but conditional access to medicines in the Netherlands. However, procedural and methodological aspects related to scheme design and implementation may affect its value in decision-making practice.

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.

Objective Health technology assessments (HTAs) intend to inform real-world decisions. They often draw on data from explanatory trials and hence are not always applicable to the decision problem. HTAs may therefore not meet the needs of decision makers. Our objective was to develop and apply a checklist to: 1) systematically frame HTAs in a way that they are applicable to the decision problem; and 2) assess if a decision problem can be informed by an available HTA. Methods We reviewed published literature to identify factors that should be considered when framing HTAs for resource allocation decisions. The checklist was finalized in collaboration with clinicians and policy makers. We applied the checklist to the economic evaluation of trastuzumab in early breast cancer. We defined a reference case and for each study, retrieved through a systematic review, we examined if each factor was explicitly considered. Results A checklist was developed with 11 factors (e.g., clinical practice, consequences, and patient use). In the case of trastuzumab, most factors were considered by the 11 retrieved economic evaluations. Two factors, being the inclusion of all relevant comparators and professional use, were considered by none of the studies. Conclusions We developed a comprehensive checklist with 11 factors to frame HTAs and to assess the applicability of HTAs to resource allocation decisions. Economic evaluations on trastuzumab considered some of these factors, but overlooked others. The proposed checklist assists in systematically considering all factors in developing the conceptual model of an HTA, to make HTAs better reflect the decision problem.

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.

Aims: To investigate the 'real world' effectiveness of robust statin therapy, focusing on the effect of dose and early treatment discontinuation on the risk of hospitalization for acute myocardial infarction (AMI). Methods and results: In the PHARMO database, including among others drug-dispensing and hospital discharge records for more than two million subjects in the Netherlands, 59 094 new users of statins in the period 1 January 1991 until 31 December 2004, ≥ 18 years of age were identified. In these patients, exposure to statins, both in terms of persistence and dose, was determined over the first two treatment years. To determine the risk for AMI, patients were followed from this 2-year time point until the first hospital admission for AMI, death, or end of the study period. A total of 31 557 patients (53%) discontinued statin use within 2 years; 20 883 patients (35%) were persistent users with an average equipotent dose ≥ 4. A 30% reduction in risk of hospitalization for AMI with persistent statin use was observed. The protective effect increased with a higher dose (20 and 40% risk reduction with an equipotent dose ≤ 3 and ≥ 4, respectively). Conclusion: These results show that statins are suboptimally used in real life for having the maximum benefit in terms of preventing AMI.

Objective: The objective of this study is to identify the possible barriers and critical success factors for the implementation of European collaboration in the field of relative effectiveness assessment (REA) of drugs. Methods: Data were gathered through semi-structured interviews with representatives from eight European health technology assessment (HTA) organisations involved in assessment of drugs for coverage decision-making (AAZ, AIFA, AHTAPol, HAS, HVB, IQWIG, NICE and ZiN). Results: Potential barriers identified mainly relate to methodology, resources and challenges with implementation in the respective national processes (e.g. legal restrictions). The most critical success factors for production of cross-border assessments were the continuous cooperation of competent partners, and the quality and timely availability of the assessment. Conclusion: Further adaptation of the process and methods is required for optimal collaboration. In the near future it can be expected that cross-border assessments will meet in particular the needs of smaller/middle-sized European countries and also European countries with less developed HTA systems as the potential efficiency/quality gains are the highest for these countries. Therefore, national implementation of cross-border assessments is especially likely in these countries in the coming years. Once more experience is gained with cross-border assessments, and successes become more evident, efficiency/quality gains may also be likely for some larger countries with well established processes.

The concept of adaptive licensing (AL) has met with considerable interest. Yet some remain skeptical about its feasibility. Others argue that the focus and name of AL should be broadened. Against this background of ongoing debate, we examine the environmental changes that will likely make adaptive pathways the preferred approach in the future. The key drivers include: growing patient demand for timely access to promising therapies, emerging science leading to fragmentation of treatment populations, rising payer influence on product accessibility, and pressure on pharma/investors to ensure sustainability of drug development. We also discuss a number of environmental changes that will enable an adaptive paradigm. A life-span approach to bringing innovation to patients is expected to help address the perceived access vs. evidence trade-off, help de-risk drug development, and lead to better outcomes for patients.

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.

Background: Although bisphosphonates are useful in the management of osteoporosis, patients often discontinue treatment. Objectives: The aims of this study were to investigate persistence with bisphosphonates, and to assess whether the dose interval influenced persistence, among women with postmenopausal osteoporosis. 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 >1 million subjects in defined areas in The Netherlands. Women who were new users of alendronate (daily or weekly), etidronate (daily), or risedronate (daily) during the period from January 2000 through September 2003 were eligible for inclusion in the study if they were aged ≥55 years or had been hospitalized for a menopausal disorder. One-year rates of persistence with treatment (defined as the percentage of patients who used the drug for ≥365 days without failure to continue renewals) were determined by using episodes of bisphosphonate treatment. The association between persistence and dose intervals, type of bisphosphonate, and other determinants (including age, occurrence of gastrointestinal adverse events as measured by use of concomitant medications [eg, antacids, proton pump inhibitors, histamine2 (H2)-receptor antagonists, misoprostol, laxatives, antidiarrheals, bowel motility enhancers] and fractures) was assessed. To study whether persistence with bisphosphonates was associated with the former use of other antiosteoporosis medication or the presence of drug-induced osteoporosis, the use of hormone replacement therapy, raloxifene, and systemic corticosteroids in the 6 months before the index date were included as determinants. Results: The study sample included 2124 women who were new users of bisphosphonates. The mean (SD) age of the study population was 71.6 (8.7) years. After 1 year, 51.9% of weekly alendronate users and 30.1% to 42.2% of daily bisphosphonate users were persistent. In the multivariate analysis (which included age, concomitant medication, and fractures), patients using alendronate weekly were significantly more likely to persist than those using alendronate daily (relative risk [RR], 1.56 [95% CI, 1.32-1.85]). The likelihood of persistence was similar among those who used the daily regimens of risedronate, etidronate, and alendronate. The occurrence of gastrointestinal adverse events was associated with decreased persistence with bisphosphonates (Hin2)-receptor antagonists: RR, 0.71 [95% CI, 0.53-0.94]; bowel motility enhancers: RR, 0.78 [95% CI, 0.65-0.94]). Conclusions: In this study, dose interval and the occurrence of gastrointestinal adverse events were independent determinants of persistence with bisphosphonate therapy. Although the likelihood of persistence with bisphosphonate use was significantly higher among those who used a less frequently administered regimen, persistence rates were still suboptimal.

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.

Gastrointestinal stromal tumours (GIST) are identified by their specific morphology added with immunohistochemical staining with anti-CD117, the phenotypic marker for GIST in the majority of cases. In this study the reported incidence of GIST and GIST-like tumours before and after the routine availability of the specific diagnostic marker CD117 antigen was investigated. All patients with GIST or GIST-like tumours were selected from PALGA, a nation-wide network and registry of histo- and cytopathology in the Netherlands, to calculate the incidence in 1995 and longitudinally over time between 1998 and 2003. Pathological reports were retrieved to assess the type of immunostaining used and to assess the risk category for malignant behaviour according to the recently published consensus criteria. The annual incidence of GIST as distilled from the national pathology registry increased from 2.1 per million inhabitants in 1995 to 12.7 per million inhabitants in 2003. The incidence of GIST-like tumours decreased from 17.6 per million inhabitants in 1995 to 12.7 per million inhabitants in 2003. The incidences were stable from 2000 onwards. Additional analysis in 2003 indicated that more than 90% of the GIST tested was CD117 positive, compared to only 4% of the GIST-like tumours. Almost 50% of the GIST was considered to be at high-risk for malignant behaviour, according to the consensus criteria. The increased incidence of GIST 1995-2003 is related to increased understanding of GIST pathobiology and the routine availability of the diagnostic immunohistochemical antibody directed against the CD117 antigen.

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.