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.

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.

Comparing policies to enhance prescribing efficiency in Europe through increasing generic utilization: changes seen and global implications.

AIM: The aim of this article was to evaluate the influence of different demand-side measures to enhance the prescribing of generics in ambulatory care based on cross-national comparisons. METHODS: An observational retrospective study was conducted using administrative databases from across Europe, documenting changes in reimbursed utilization and expenditure of different proton pump inhibitors (PPIs) and statins between 2001 and 2007, alongside different reforms to enhance prescribing efficiency. Utilization was converted to defined daily doses (DDDs) and expenditures were converted to euros. Demand-side measures were collated under the '4 Es'--education, engineering, economics and enforcement--to enable comparisons on the nature and intensity of reforms between countries. RESULTS: There were considerable differences in the utilization of generics and patent-protected PPIs and statins among Western European countries. Decreased utilization of omeprazole and simvastatin, alongside increased utilization of esomeprazole, atorvastatin and rosuvastatin, was seen in countries with limited demand-side measures to counteract commercial pressures. Prescribing restrictions, or a combination of education, prescribing targets and financial incentives, had the greatest influence on enhancing the utilization of omeprazole and simvastatin. For example, there was a threefold reduction in the utilization of atorvastatin in Austria following prescribing restrictions. Multiple demand-side interventions generally had a greater influence than single interventions, with the impact appearing additive. Multiple interventions coupled with initiatives to lower prices of generics considerably enhanced prescribing efficiency. CONCLUSION: This cross-national study has demonstrated considerable variation in the utilization and expenditure of PPIs and statins across Europe, providing opportunities to further improve prescribing efficiency. The '4 Es' do provide an understandable methodology to document and compare the influence of different demand-side measures, with the influence varying by their extent and intensity. Further reforms are essential given current financial pressures. Consequently, further research will concentrate on the potential to develop a scoring system to help predict the possible impact of different demand-side measures on future utilization patterns.

Policies to enhance prescribing efficiency in europe: findings and future implications.

INTRODUCTION: European countries need to learn from each other to address unsustainable increases in pharmaceutical expenditures. OBJECTIVE: To assess the influence of the many supply and demand-side initiatives introduced across Europe to enhance prescribing efficiency in ambulatory care. As a result provide future guidance to countries. METHODS: Cross national retrospective observational study of utilization (DDDs - defined daily doses) and expenditure (Euros and local currency) of proton pump inhibitors (PPIs) and statins among 19 European countries and regions principally from 2001 to 2007. Demand-side measures categorized under the "4Es" - education engineering, economics, and enforcement. RESULTS: Instigating supply side initiatives to lower the price of generics combined with demand-side measures to enhance their prescribing is important to maximize prescribing efficiency. Just addressing one component will limit potential efficiency gains. The influence of demand-side reforms appears additive, with multiple initiatives typically having a greater influence on increasing prescribing efficiency than single measures apart from potentially "enforcement." There are also appreciable differences in expenditure (€/1000 inhabitants/year) between countries. Countries that have not introduced multiple demand side measures to counteract commercial pressures to enhance the prescribing of generics have seen considerably higher expenditures than those that have instigated a range of measures. CONCLUSIONS: There are considerable opportunities for European countries to enhance their prescribing efficiency, with countries already learning from each other. The 4E methodology allows European countries to concisely capture the range of current demand-side measures and plan for the future knowing that initiatives can be additive to further enhance their prescribing efficiency.

Use of Generics-A Critical Cost Containment Measure for All Healthcare Professionals in Europe?

Pharmaceutical expenditures in ambulatory care rose rapidly in Europe in the 1990s and early 2000s. This was typically faster than other components of healthcare spending, leading to reforms to moderate future growth. A number of these centered on generic medicines with measures to lower reimbursed prices as well as enhance their prescribing and dispensing. The principal objective of this paper is to review additional measures that some European countries can adopt to further reduce reimbursed prices for generics. Secondly, potential approaches to address concerns with generics when they arise to maximize savings. Measures to enhance the prescribing of generics will also briefly be discussed. A narrative review of the extensive number of publications and associated references from the co-authors was conducted supplemented with known internal or web-based articles. In addition, health authority and health insurance databases, principally from 2001 to 2007, were analyzed to assess the impact of the various measures on price reductions for generic omeprazole and generic simvastatin vs. pre-patent loss prices, as well as overall efficiency in Proton Pump Inhibitor (PPI) and statin prescribing. The various initiatives generally resulted in considerable lowering of the prices of generics as well as specifically for generic omeprazole and generic simvastatin vs. pre-patent loss prices. At one stage in the UK, generic simvastatin was just 2% of the originator price. These measures also led to increased efficiency for PPI and statin prescribing with reimbursed expenditure for the PPIs and statins either falling or increasing at appreciably lower rates than increases in utilization. A number of strategies have also been introduced to address patient and physician concerns with generics to maximize savings. In conclusion, whilst recent reforms have been successful, European countries must continue learning from each other to fund increased volumes and new innovative drugs as resource pressures grow. Policies regarding generics and their subsequent impact on reimbursement and utilization of single sourced products will continue to play a key role to release valuable resources. However, there must continue to be strategies to address concerns with generics when they exist.

Having your cake and eating it: office of fair trading proposal for funding new drugs to benefit patients and innovative companies.

There are insufficient resources in the UK to fund all new technologies and new indications approved by the National Institute for Health and Clinical Excellence (NICE). Diverting funding from existing sources will have a detrimental effect on the provision of other priority services. The UK Office of Fair Trading (OFT) recently suggested a value-based pricing approach that appears workable but has generated considerable debate. Their proposal of a 25% premium for the originator product once generics are available is more generous than seen in a number of other European countries, where typically only the lowest priced product is reimbursed. The OFT proposal for a maximum 50% premium for patent-protected products, versus the prices of generics in a class or related classes, is also more generous than the proposed reforms for the pricing of proton pump inhibitors in Sweden or current reforms in Germany. In our opinion, the OFT proposals are persuasive and in accordance with the reforms seen in other European countries, and therefore should be adopted. The alternatives to fully funding new drugs or new indications as approved by NICE are either tightening the cost per QALY threshold, giving NICE an annual national budget to fund its advice alongside suggested areas for disinvestment, proactively switching patients from high-cost brand-name drugs to generics, or further delaying funding for new drugs and new indications approved by NICE. The majority of these suggestions are not in the best interests of patients or innovative pharmaceutical companies seeking to reap the rewards of their efforts.

Modulation of agonist responses at the A(1) adenosine receptor by an irreversible antagonist, receptor-G protein uncoupling and by the G protein activation state.

Potency and intrinsic activity of agonists depend on ligand structure, but are also regulated by receptor-G protein stoichiometry. A potential functional reserve in adenosine A(1) receptor-mediated G protein activation was investigated by stimulation of guanosine-5'-(gamma-[35S]thio)-triphosphate ([35S]GTPgammaS) binding by the full agonist 2-chloro-N(6)-cyclopentyladenosine (CCPA) and the partial agonist 5'-deoxy-5'-methylthioadenosine (MeSA). Pretreatment of rat brain membranes with the irreversible antagonist 1-propyl-3-[3-[[4-(fluorosulfonyl)benzoyl]oxy]-propyl]-8-cyclopentylxanthine revealed no classical receptor reserve for either agonist. The functional significance of the G protein coupling state of the receptor and occupancy of G proteins by guanine nucleotides was assessed after partial uncoupling of receptor-G protein complexes with N-ethylmaleimide and in the presence of increasing GDP concentrations. Agonist EC(50) values in G protein activation were increased after NEM pretreatment and at higher GDP concentrations, and a decrease in the relative intrinsic activity of MeSA was observed. The shift of agonist concentration-response curves to the right, the decrease in maximal effects and the decrease in relative intrinsic activity of the partial agonist point to a functional reserve which has to be attributed to GDP-free receptor-G protein complexes. The mechanisms of action of FSCPX, NEM and GDP were fully consistent with the two-state model of receptor activation. The apparent reserve revealed by GDP reflects a shift from spontaneously active GDP-free receptor-G protein complexes (RG)(*), which can bind [35S]GTPgammaS, to (RG) occupied by GDP. The abundance of (RG)(*) is favored by agonists and by the absence of GDP.

G protein-coupled receptor for nicotinic acid in mouse macrophages.

The use of the HDL-elevating drug nicotinic acid in the treatment and prevention of atherosclerotic disease is limited by the frequent induction of skin flushing. The therapeutic effects of nicotinic acid are attributed to inhibition of lipolysis in adipose tissue via a G protein-coupled receptor, whereas the mechanism of flush induction by release of prostaglandin D(2) from macrophages is not understood. In this study, we investigated if macrophages contain nicotinic acid receptors. Specific guanine nucleotide sensitive binding sites for [(3)H]nicotinic acid were detected in membranes from mouse RAW 264.7 macrophages. Nicotinic acid and related heterocycles stimulated activation of pertussis toxin-sensitive G proteins. The rank orders of potency in macrophage membranes were identical for inhibition of [(3)H]nicotinic acid binding and G protein activation, and were pharmacologically indistinguishable from that of the G protein-coupled nicotinic acid receptor in spleen membranes. These results indicate that the effects of nicotinic acid on macrophages, spleen and probably adipocytes are mediated via an identical, unique G protein-coupled receptor.