Luka Vončina

Multiple policies to enhance prescribing efficiency for established medicines in Europe with a particular focus on demand-side measures : findings and future implications

Introduction: The appreciable growth in pharmaceutical expenditure has resulted in multiple initiatives across Europe to lower generic prices and enhance their utilization. However, considerable variation in their use and prices. Objective: Assess the influence of multiple supply and demand-side initiatives across Europe for established medicines to enhance prescribing efficiency before a decision to prescribe a particular medicine. Subsequently utilize the findings to suggest potential future initiatives that countries could consider. Method: An analysis of different methodologies involving cross national and single country retrospective observational studies on reimbursed use and expenditure of PPIs, statins, and renin-angiotensin inhibitor drugs among European countries. Results: Nature and intensity of the various initiatives appreciably influenced prescribing behavior and expenditure, e.g., multiple measures resulted in reimbursed expenditure for PPIs in Scotland in 2010 56% below 2001 levels despite a 3-fold increase in utilization and in the Netherlands, PPI expenditure fell by 58% in 2010 vs. 2000 despite a 3-fold increase in utilization. A similar picture was seen with prescribing restrictions, i.e., (i) more aggressive follow-up of prescribing restrictions for patented statins and ARBs resulted in a greater reduction in the utilization of patented statins in Austria vs. Norway and lower utilization of patented ARBs vs. generic ACEIs in Croatia than Austria. However, limited impact of restrictions on esomeprazole in Norway with the first prescription or recommendation in hospital where restrictions do not apply. Similar findings when generic losartan became available in Western Europe. Conclusions: Multiple demand-side measures are needed to influence prescribing patterns. When combined with supply-side measures, activities can realize appreciable savings. Health authorities cannot rely on a “spill over” effect between classes to affect changes in prescribing.

Influence of demand-side measures to enhance renin–angiotensin prescribing efficiency in Europe: implications for the future

European countries strive to enhance prescribing efficiency. This includes renin–angiotensin drugs following the availability of generic angiotensin-converting enzyme inhibitors (ACEIs). Aims: To compare angiotensin receptor blocker utilization and expenditure patterns in Austria and Croatia following prescribing restrictions, as well as with other European countries introducing different supply- and demand-side measures. Lastly, to appraise the impact of generic losartan in Croatia on utilization of patented angiotensin receptor blockers. Method: Observational retrospective study principally between 2001 and 2007, using defined daily doses and €/1000 inhabitants/year. Demand-side measures were based on the four ‘E’s – education, engineering, economics and enforcement. Results: Greater intensity of follow-up of prescribing restrictions in Croatia enhanced utilization of ACEIs versus Austria. There was high utilization of ACEIs in Scotland following intensive demand-side measures, similar to Austria and Croatia. Demand-side measures in Spain (Catalonia) and Sweden also appeared to moderate angiotensin receptor blockers utilization. The combination of measures helped stabilize expenditure on renin–angiotensin drugs when adjusted for population sizes despite appreciable increases in volumes. The only exception was Portugal, with less intensive measures. Conclusion: Multiple and intensive demand-side measures enhanced prescribing efficiency. The more intense follow-up of ARB prescribing restrictions in Croatia had a greater influence on subsequent utilization patterns than Austria. Both findings confirm earlier studies. Reforms also favorably enhanced the prescribing of generic losartan once available.

Personalizing health care: feasibility and future implications.

Considerable variety in how patients respond to treatments, driven by differences in their geno- and/ or phenotypes, calls for a more tailored approach. This is already happening, and will accelerate with developments in personalized medicine. However, its promise has not always translated into improvements in patient care due to the complexities involved. There are also concerns that advice for tests has been reversed, current tests can be costly, there is fragmentation of funding of care, and companies may seek high prices for new targeted drugs. There is a need to integrate current knowledge from a payer’s perspective to provide future guidance. Multiple findings including general considerations; influence of pharmacogenomics on response and toxicity of drug therapies; value of biomarker tests; limitations and costs of tests; and potentially high acquisition costs of new targeted therapies help to give guidance on potential ways forward for all stakeholder groups. Overall, personalized medicine has the potential to revolutionize care. However, current challenges and concerns need to be addressed to enhance its uptake and funding to benefit patients.

Dabigatran - a case history demonstrating the need for comprehensive approaches to optimize the use of new drugs

Background: There are potential conflicts between authorities and companies to fund new premium priced drugs especially where there are safety and/or budget concerns. Dabigatran, a new oral anticoagulant for the prevention of stroke in patients with non-valvular atrial fibrillation (AF), exemplifies this issue. Whilst new effective treatments are needed, there are issues in the elderly with dabigatran due to variable drug concentrations, no known antidote and dependence on renal elimination. Published studies have shown dabigatran to be cost-effective but there are budget concerns given the prevalence of AF. There are also issues with potentially re-designing anticoagulant services. This has resulted in activities across countries to better manage its use. Objective: To (i) review authority activities in over 30 countries and regions, (ii) use the findings to develop new models to better manage the entry of new drugs, and (iii) review the implications for all major stakeholder groups. Methodology: Descriptive review and appraisal of activities regarding dabigatran and the development of guidance for groups through an iterative process. Results: There has been a plethora of activities among authorities to manage the prescribing of dabigatran including extensive pre-launch activities, risk sharing arrangements, prescribing restrictions, and monitoring of prescribing post-launch. Reimbursement has been denied in some countries due to concerns with its budget impact and/or excessive bleeding. Development of a new model and future guidance is proposed to better manage the entry of new drugs, centering on three pillars of pre-, peri-, and post-launch activities. Conclusion: Models for introducing new drugs are essential to optimize their prescribing especially where there are concerns. Without such models, new drugs may be withdrawn prematurely and/or struggle for funding.

Dabigatran - a continuing exemplar case history demonstrating the need for comprehensive models to optimize the utilization of new drugs.

Background: There are potential conflicts between authorities and companies to fund new premium priced drugs especially where there are effectiveness, safety and/or budget concerns. Dabigatran, a new oral anticoagulant for the prevention of stroke in patients with non-valvular atrial fibrillation (AF), exemplifies this issue. Whilst new effective treatments are needed, there are issues in the elderly with dabigatran due to variable drug concentrations, no known antidote and dependence on renal elimination. Published studies showed dabigatran to be cost-effective but there are budget concerns given the prevalence of AF. These concerns resulted in extensive activities pre- to post-launch to manage its introduction. Objective: To (i) review authority activities across countries, (ii) use the findings to develop new models to better manage the entry of new drugs, and (iii) review the implications based on post-launch activities. Methodology: (i) Descriptive review and appraisal of activities regarding dabigatran, (ii) development of guidance for key stakeholder groups through an iterative process, (iii) refining guidance following post launch studies. Results: Plethora of activities to manage dabigatran including extensive pre-launch activities, risk sharing arrangements, prescribing restrictions and monitoring of prescribing post launch. Reimbursement has been denied in some countries due to concerns with its budget impact and/or excessive bleeding. Development of a new model and future guidance is proposed to better manage the entry of new drugs, centering on three pillars of pre-, peri-, and post-launch activities. Post-launch activities include increasing use of patient registries to monitor the safety and effectiveness of new drugs in clinical practice. Conclusion: Models for introducing new drugs are essential to optimize their prescribing especially where concerns. Without such models, new drugs may be withdrawn prematurely and/or struggle for funding.

Initiatives to improve prescribing efficiency for drugs to treat Parkinson’s disease in Croatia: influence and future directions

Parkinson’s disease (PD) is the second most common neurological disease affecting older adults. Consequently, this disease should be a focus among payers, with increasing utilization of newer premium-priced patent-protected add-on therapies to stabilize or even improve motor function over time. However, expenditure can be moderated by reforms. Consequently, there is a need to assess the influence of these reforms on the prescribing efficiency for drugs to treat PD in Croatia before proposing additional measures. Prescribing efficiency is defined as increasing the use of add-on therapies for similar expenditure. An observational retrospective study of the Croatian Institute for Health Insurance database of drugs to treat patients with PD in Croatia from 2000 to 2010 was carried out, with utilization measured in defined daily doses (defined as the average maintenance dose of a drug when used in its major indication in adults). The study years were chosen to reflect recent reforms. Only reimbursed expenditure is measured from a health insurance perspective. Utilization of drugs to treat PD increased by 218% between 2000 and 2010. Reimbursed expenditure increased by 360%, principally driven by increasing utilization of premium-priced patent-protected add-on therapies, including ropinirole and pramipexole. However, following recent reforms, reducing expenditure/defined daily dose for the different drugs, as well as overall expenditure, stabilized reimbursed expenditure between 2005 and 2010. Treatment of PD is complex, and add-on therapies are needed to improve care. Reimbursed expenditure should now fall following stabilization, despite increasing volumes, as successive add-on therapies lose their patents, further increasing prescribing efficiency.

Recent policies to enhance Renin-angiotensin prescribing efficiency in Europe; implications for the future

Background: Two case reports of polymyalgia rheumatica (PMR) and one case-report of PMR and temporalis arteritis (AT) suggest that the use of statins may have triggered the development of these inflammatory rheumatic diseases. PMR is closely linked to the disease arteritis temporalis which makes it difficult for physicians to distinguish these two diseases. Data on the association between the use of statins and PMR and/or AT are scarce. Objectives: To assess the association between statin use and the occurrence of PMR/AT. Methods: A case/non-case study based on individual case safety reports (ICSR) listed in the World Health Organisation (WHO) global ICSR database (Vigibase) was conducted. According to WHO adverse reaction terminology, cases were defined as reports of PMR. Each case was matched with five non-cases by age, gender and time of reporting. Non-cases were all other ADR-reports. Use of statins was classified according to the Anatomical Therapeutic Chemical (ATC) classification code system (C10AA, C10BA, C10BX). Potential confounders in the analysis, i.e., use of corticosteroids, immunosuppressive drugs, non-steroidal anti-inflammatory drugs (NSAIDs), antidepressants, anti-epileptics, proton pump inhibitors and cardiovascular drugs were determined. Multivariate logistic regression was used to calculate the reporting odds ratios (RORs) with 95% confidence intervals (CI). In addition, three case-reports from the VigiBase were studied in detail. Results: We identified 327 reports of PMR/AT as cases and 1635 reports of other ADRs as non-cases. Among cases statins were more frequently reported as suspected agent (29.4%) compared to non-cases (2.9%). After adjustment for several covariates, statins were statistically significantly associated with reports of PMR/AT (ROR 14.21; 95% CI 9.89-20.85). Conclusions: The result of this study underlines findings of the case reports that the use of statins may be associated with the occurrence of PMR/AT.Background: In The Netherlands, the largest outbreak of Q fever worldwide is ongoing. A particular risk group concerns pregnant women in which the infection is mostly asymptomatic. Q fever during pregnancy may cause both obstetric complications as well as chronic infection in the mother. Long term antibiotic treatment of infected women may reduce the risk of complications. Objectives: A clustered randomized controlled trial to assess the effects of screening for Q fever during pregnancy is ongoing (trial register number NL30340.042.09). The primary endpoint is a maternal or obstetric complication in Q fever positive women. Methods: Midwife centers in high-risk Q fever areas were randomized to recruit pregnant women for the screening or control strategy. In both groups a blood sample was taken between 20 and 32 weeks of gestation. In the screening group this sample was immediately analyzed with indirect immunofluorescence assay for the detection of IgG and IgM antibodies. Every positive sample was fully titrated. In case of acute or chronic infection antibiotic treatment advice was given. In the control group serum was frozen for analysis after delivery. Results: In all, 55 of 99 eligible midwife centers were randomized. They recruited 1222 pregnant women from which a blood sample was taken; 534 for the screening group and 688 for the controle group. Fourteen percent in both groups had serologic evidence for an acute or previous Q fever infection. Only 7 participants in the intervention group had evidence for an acute infection and were treated with antibiotics (erythromycin or cotrimoxazole). Three of them experienced side-effects, mainly gastro-intestinal, of which one consulted the gynecologist due to the side-effects. Since a part of the participants still have to deliver, data collection on clinical outcome is still ongoing. Conclusions: Fourteen percent of the pregnant women in high-risk Q fever areas have evidence of Q fever infection. Only a very small part has an acute infection, in which treatment is though to be needed. Clinical outcome data and cost-effectiveness analyses are expected in spring and will be presented.