Ongoing initiatives to improve prescribing efficiency in China : statins as a case history

Pharmaceutical expenditure rose by 16% per annum in China during the past decade, and now represents 46% of total healthcare expenditure. Initiatives to moderate growth include pricing regulations for pharmaceuticals and encouraging International Nonproprietary Name (INN) prescribing. However, there is limited monitoring of physician prescribing and current incentives encourage hospitals and physicians to profit from drug procurement. The objective was to assess changes in statin utilization and expenditure as additional generics are launched. Subsequently, compare results in China with findings among European countries to provide future guidance. We used observational retrospective study of statin utilization and procurement expenditure from 2004 to 2013 in two large teaching hospital groups. The results were that statin utilization rose 32-fold in one hospital group and 54-fold in the other. Expenditure also increased but to a lesser extent, i.e. from just over Renminbi ‘yuan’ (CNY) 0.65 million in 2004 to CNY 15.3 million in 2013 in one hospital group and from CNY 0.49 to CNY 19.3 million in the other. Atorvastatin (originator) was the most utilized statin. Utilization of each generic statin was typically low, e.g. 10% in 2013 in one hospital group. Procurement prices fell over time, greatest for generic simvastatin (-74% to -91%) mirroring data from European countries. However, no increase in their prescribing was observed. In fact, a significant decrease in generic prescribing was seen in one hospital group between 2004 and 2013. There are considerable opportunities to improve prescribing efficiency in China based on European experience. However, current incentives encouraging hospitals and physicians to profit from drug procurement need to be addressed

Different initiatives across Europe to enhance losartan utilisation post generics : impact and implications

Introduction: There is an urgent need for health authorities across Europe to fully realise potential savings from increased use of generics to sustain their healthcare systems. A variety of strategies were used across Europe following the availability of generic losartan, the first angiotensin receptor blocker [ARB] to be approved and marketed, to enhance its prescribing versus single-sourced drugs in the class. Demand-side strategies ranged from 100% copayment for patented ARBs in Denmark to no specific measures. We hypothesised this heterogeneity of approaches would provide opportunities to explore prescribing in a class following patent expiry. Objective: Contrast the impact of the different approaches among European countries and regions to the availability of generic losartan to provide future guidance. Methodology: Retrospective segmented regression analyses applying linear random coefficient models with country specific intercepts and slopes were used to assess the impact of the various initiatives across Europe following the availability of generic losartan. Utilisation measured in defined daily doses (DDDs). Price reductions for generic losartan were also measured. Results: Utilisation of losartan was over 90% of all ARBs in Denmarkby the study end. Multiple measures in Sweden and one English primary care group also appreciably enhanced losartan utilisation. Losartan utilisation actually fell in some countries with no specific demand-side measures. Considerable differences were seen in the prices of generic losartan. Conclusion: Delisting single-sourced ARBs produced the greatest increase in losartan utilisation. Overall, multiple demand-side measures are needed to change physician prescribing habits to fully realise savings from generics. There is no apparent 'spill over' effect from one class to another to influence future prescribing patterns even if these are closely related

Effects of rivaroxaban and dabigatran on global hemostasis in patients with atrial fibrillation

The study was aimed to evaluate the effects of two standard doses of rivaroxaban and dabigatran on global hemostatic assays in patients with atrial fibrillation. The study included 52 patients treated with rivaroxaban (15/20 mg), 50 on dabigatran (110/150 mg) and 20 healthy individuals. Platelet-poor plasma was used for determination of three global hemostatic assays, namely endogenous thrombin potential (ETP), calibrated automated thrombogram (CAT) and overall hemostasis potential (OHP). Rivaroxaban and dabigatran reduced ETP (P lt 0.01) although OHP (P lt 0.05) was diminished only by dabigatran. Strong correlations were noticed between ETP parameters and the plasma concentrations of rivaroxaban (ETP, rUS0.51; c-max, rUS0.85; t-lag, rU0.83; t-max, rU0.66) as well as with plasma concentration of dabigatran (ETP, rUS0.75; c-max, rUS0.74; t-lag, rU0.73; t-max, rU0.52). Analysis of dabigatran concentrations under 50 ng/ml showed that ETP parameter has area under the concentration-time curvereceiver operating characteristic value of 0.879 (95% confidence interval 0.776-0.980). Dabigatran treatment paradoxically increased area under the concentration-time curve and peak values although rivaroxaban decreased peak values (P lt 0.01). However, significant correlation between CAT parameters and plasma concentration of both direct oral anticoagulants was not observed. We confirmed that the CAT assay is inappropriate for estimation of dabigatran effects and is not fully sensitive as regards rivaroxaban. The ETP assay can potentially be the appropriate method for estimation of global hemostatic capacity as regards both direct oral anticoagulants. The role of OHP needs to be confirmed in additional studies. ETP parameter of chromogenic assay has promising potential in exclusion of high plasma concentrations of dabigatran

Platelet factor 4 enhances CD4(+)T effector memory cell responses via Akt-PGC1 alpha-TFAM signaling-mediated mitochondrial biogenesis

Background Cell metabolism drives T cell functions, while platelets regulate overall CD4(+)T cell immune responses. Objective To investigate if platelets influence cell metabolism and thus regulate CD4(+)T effector memory cell (Tem) responses. Methods Human CD4(+)Tem cells were activated with alpha CD3/alpha CD28 and cultured without or with platelets or platelet-derived mediators. Results Polyclonal stimulation induced rapid and marked Th1 and Treg cell activation of CD4(+)Tem cells. Platelet co-culture enhanced Th1 response transiently, while it persistently enhanced Treg cell activation of Tem cells, with an enhancement that plateaued by day 3. Platelet factor 4 (PF4) was the key platelet-derived mediator regulating CD4(+)Tem cell responses, which involved cellular metabolisms as indicated by mass spectrometric analyses. PF4 exerted its effects via its receptor CXCR3, attenuated Akt activity, and reduced PGC1 alpha phosphorylation, and resulted in elevations of PGC1 alpha function and mitochondrial transcription factor A (TFAM) synthesis. The latter increased mitochondrial biogenesis, and subsequently enhanced Th1 and Treg responses. Consistent with these observations, inhibition of mitochondrial function by rotenone counteracted the enhancements by recombinant PF4, and TFAM overexpression by TFAM-adenovirus infection mimicked PF4 effects. Furthermore, increased mitochondrial mass elevated oxygen consumption, and enhanced adenosine triphosphate and reactive oxygen species production, which, in turn, stimulated Th1 (T-bet) and Treg (FoxP3) transcription factor expression and corresponding CD4(+)T effector cell responses. Conclusions Platelets enhance CD4(+)T cell responses of Tem cells through PF4-dependent and Akt-PGC1 alpha-TFAM signaling-mediated mitochondrial biogenesis. Hence, PF4 may be a promising intervention target of platelet-regulated immune responses

Time to Review Authorisation and Funding for New Cancer Medicines in Europe? Inferences from the Case of Olaratumab

The potential benefits of early patient access to new medicines in areas of high unmet medical need are recognised, but uncertainties concerning effectiveness, safety and added value when new medicines are authorised, and subsequently funded based on initial preliminary data only, have important implications. In 2016 olaratumab received accelerated conditional approval from both the European Medicines Agency and the US Food and Drug Administration for the treatment of soft-tissue sarcoma, based on the claims of a substantial reduction in the risk of death with an 11.8-month improvement in median overall survival in a phase II trial in combination with doxorubicin vs. doxorubicin alone. The failure to confirm these benefits in the post-authorisation pivotal trial has highlighted key concerns regarding early access and conditional approvals for new medicines. Concerns include potentially considerable clinical and economic costs, so that patients may have received suboptimal treatment and any money spent has foregone the opportunity to improve access to effective treatments. As a result, it seems reasonable to reconsider current marketing authorisation models and approaches. Potential pathways forward include closer collaboration between regulators, pharmaceutical companies and payers to enhance the generation of rapid and comparative confirmatory trials in a safe and fair manner, with minimal patient exposure as required to achieve robust evidence. Additionally, it may be time to review early access systems, and to explore new avenues regarding who should pay or part pay for new treatments whilst information is being collected as part of any obligations for conditional marketing authorisation. Greater co-operation between countries regarding the collection of data in routine clinical care, and further research on post-marketing data analysis and interpretation, may also contribute to improved appraisal and continued access to new innovative cancer treatments