European Marketing Authorization Research Articles

Long-term effects of weight-reducing drugs in people with hypertension.

All major guidelines on antihypertensive therapy recommend weight loss; anti-obesity drugs may be able to help in this respect. To assess the long-term effects of pharmacologically induced reduction in body weight in adults with essential hypertension on all-cause mortality, cardiovascular morbidity, and adverse events (including total serious adverse events, withdrawal due to adverse events, and total non-serious adverse events). To assess the long-term effects of pharmacologically induced reduction in body weight in adults with essential hypertension on change from baseline in systolic blood pressure, change from baseline in diastolic blood pressure, and body weight reduction. We obtained studies using computerised searches of the Cochrane Hypertension Group Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), Ovid MEDLINE, Ovid EMBASE, the clinical trials registry ClinicalTrials.gov, and from handsearches in reference lists and systematic reviews (status as of 13 April 2015). Randomised controlled trials in hypertensive adults of at least 24 weeks' duration that compared long-term pharmacologic interventions for weight loss with placebo. Two review authors independently selected studies, assessed risk of bias, and extracted data. Where appropriate and in the absence of significant heterogeneity between studies (P > 0.1), we pooled studies using fixed-effect meta-analysis. When heterogeneity was present, we used the random-effects method and investigated the cause of heterogeneity. After updating the literature search, which was extended to include four new weight-reducing drugs, we identified one additional study of phentermine/topiramate, bringing the total number of studies to nine that compare orlistat, sibutramine, or phentermine/topiramate to placebo and thus fulfil our inclusion criteria. We identified no relevant studies investigating rimonabant, liraglutide, lorcaserin, or naltrexone/bupropion. No study included mortality and cardiovascular morbidity as predefined outcomes. Incidence of gastrointestinal side effects was consistently higher in those participants treated with orlistat versus those treated with placebo. The most frequent side effects were dry mouth, constipation, and headache with sibutramine, and dry mouth and paresthaesia with phentermine/topiramate. In participants assigned to orlistat, sibutramine, or phentermine/topiramate body weight was reduced more effectively than in participants in the usual-care/placebo groups. Orlistat reduced systolic blood pressure as compared to placebo by -2.5 mm Hg (mean difference (MD); 95% confidence interval (CI): -4.0 to -0.9 mm Hg) and diastolic blood pressure by -1.9 mm Hg (MD; 95% CI: -3.0 to -0.9 mm Hg). Sibutramine increased diastolic blood pressure compared to placebo by +3.2 mm Hg (MD; 95% CI: +1.4 to +4.9 mm Hg). The one trial that investigated phentermine/topiramate suggested it lowered blood pressure. In people with elevated blood pressure, orlistat and sibutramine reduced body weight to a similar degree, while phentermine/topiramate reduced body weight to a greater extent. In the same trials, orlistat and phentermine/topiramate reduced blood pressure, while sibutramine increased it. We could include no trials investigating rimonabant, liraglutide, lorcaserin, or naltrexone/bupropion in people with elevated blood pressure. Long-term trials assessing the effect of orlistat, liraglutide, lorcaserin, phentermine/topiramate, or naltrexone/bupropion on mortality and morbidity are unavailable and needed. Rimonabant and sibutramine have been withdrawn from the market, after long-term trials on mortality and morbidity have confirmed concerns about the potential severe side effects of these two drugs. The European Medicines Agency refused marketing authorisation for phentermine/topiramate due to safety concerns, while the application for European marketing authorisation for lorcaserin was withdrawn by the manufacturer after the Committee for Medicinal Products for Human Use judged the overall benefit/risk balance to be negative.

Expenditure trends of orphan drugs in Serbia: 8-Year analysis of orphan drug market in Serbia

Background/Objective: Orphan drugs are medicinal products which treat life-threatening or chronically debilitating diseases which affect small patient populations. So far there is a substantial knowledge gap on actual expenditure on orphan drugs in Serbia. Therefore, the aim of this study was to provide insight into the expenditure trends of orphan drugs in Serbia. Material and methods: Annual reports on turnover and the consumption of pharmaceuticals in Serbia published by Medicines and Medical Devices Agency of Serbia (ALIMS) for the period 2006-2013 were used to extract data on expenditure on orphan drugs. Drugs were eligible for inclusion in the analysis if they had active European orphan designation and European marketing authorization during the period covered by the study (2006-2013). Data were analysed across time series. Simple descriptive analysis and observation of chronological trends were applied. Results: Data for annual expenditure on 12 different orphan drugs were available in the analysed reports. Orphan drug expenditure and share of orphan drug expenditure in total drug expenditure increased constantly from 2006 to 2010. Both began to slightly decrease over the next two years (2011-2012), and then suddenly declined nearly threefold in 2013. Share of orphan drug expenditure didn't exceed 1% of total drug expenditure over a period of eight years. The highest share of expenditure on orphan drugs was attributed to imatinib (87.36%-97.13%), so abrupt decline in 2013 could be explained by its withdrawal from European Community Register of Orphan Medicinal Products in 2012. Conclusions: Expenditure on orphan drugs in Serbia from 2006 to 2013 was considerably low compared to total expenditure on drugs. In the last available year we noted substantial decline of orphan drug expenditure, mainly because of imatinib losing its orphan designation. A broader time horizon would be needed to investigate long term trends.

Development of Innovative Medicines for European Patients and Impact of Brexit

European patients may benefit from innovative medicines only at the end of a complex process with a sequence of positive decisions on different levels by different stakeholders. The decision of the industry to invest in a usually global clinical development must be followed by a European marketing authorization decision and a mostly national decision on price and reimbursement until finally patients and their physicians can make an individual treatment decision. Development strategies must consider the evolution of scientific and procedural requirements. Current trends are characterized by an enhanced cooperation of regulators and health technology assessment-bodies. The increasing availability of innovative personalized or precision medicines is reflected in the new procedural tools like European Medicines Agency’s priority medicines scheme and adaptive pathways concept. The UK decision to leave the EU will have consequences for their contribution to the European regulatory and health technology assessment network. Current strategies for the successful development of innovative medicines may need adjustments to address both scientific and political changes.

Actualités sur les thérapies ciblées dans les cancers bronchiques non à petites cellules, hors immunothérapie

Recently, developments of therapies that target abnormally activated signaling pathways are increasing for patients with non-small cell lung cancer. EGFR mutations are found in about 10% of lung cancers, especially in adenocarcinoma, women and non-smokers. Three EGFR inhibitors (erlotinib, gefitinib and afatinib) received a European marketing authorization for up to first line treatment of EGFR mutated NSCLC. Effectiveness of EGFR inhibitors is higher than conventional chemotherapy. Third generation EGFR inhibitors (rociletinib, AZD9291) are effective for patients who develop a resistance mutation such as T790M resistance mutation; they obtained temporary authorization for use in France in 2015. The EML4-ALK translocation is found in about 5% of NSCLC and more particularly in adenocarcinoma of young non-smoking patients. Crizotinib is a new therapeutic standard in ALK translocated NSCLC in second line. Ceritinib is a 2nd generation ALK inhibitor which received a European marketing authorization for up to treatment of ALK translocated NSCLC after progression with crizotinib. INCA supports ACSé program evaluating the efficacy of crizotinib in NSCLC amplified for MET or translocated for ROS1 and ACSé program evaluating the efficacy of vemurafenib in tumors non melanoma mutated V600E BRAF. The role of other biomarkers such as KRAS, BRAF, HER2 and PI3KCA mutations remains to be defined in NSCLC.

Integrating first-line treatment options into clinical practice

Melanoma remains a serious form of skin cancer in Europe and worldwide. Localized, early-stage melanomas can usually be treated with surgical excision. However, the prognosis is poorer for patients with advanced disease. Before 2011, treatment for advanced melanoma included palliative surgery and/or radiotherapy, and chemotherapy with or without immunotherapy, such as interleukin-2. As none of these treatments had shown survival benefits in patients with advanced melanoma, European guidelines had recommended that patients be entered into clinical trials. The lack of approved first-line options and varying access to clinical trials meant that European clinicians relied on experimental regimens and chemotherapy-based treatments when no other options were available. Since 2011, ipilimumab, an immuno-oncology therapy, and vemurafenib and dabrafenib, targeted agents that inhibit mutant BRAF, have been approved by the European Medicines Agency for the treatment of advanced melanoma. More recently, the MEK inhibitor, trametinib, received European marketing authorization for use in patients with BRAF mutation-positive advanced melanoma. In 2014, the anti-PD-1 antibody nivolumab was approved as a first-line therapy in Japan. Whereas nivolumab and another anti-PD-1 antibody, pembrolizumab, were approved as second-line therapies in the USA, their recent approval in Europe are for first-line use based on new clinical trial data in this setting. Together these agents are changing clinical practice and making therapeutic decisions more complex. Here, we discuss current and emerging therapeutic options for the first-line treatment of advanced melanoma, and how these therapies can be optimized to provide the best possible outcomes for patients.

Management of stage 1 TTR FAP: French experience

Transthyretin Familial Amyloid Polyneuropathy (TTR-FAP) is a worldwide autosomal dominant disease due to point mutation of TTR gene. The main endemic area is Portugal, associated with V30M variant and an early onset (EO) (mean age 30 yo). Phenotype is a progressive length dependent small fiber polyneuropathy with autonomic dysfunction and cardiac conduction disorders; the median survival is 12 years. France is a prototypic non endemic country, characterized by sporadic cases in 50%, a late onset (LO>50 yo) in 75%, a genetic heterogeneity (41 variants ; V30M in 55%). Liver transplantation (LT) is the gold standard treatment allows to stop progression of the neuropathy in EO V30M patients and to prolonge significantly the survival. Tafamidis, a TTR kinetic stabilizer, received marketing authorization in Europe for stage 1 FAP (walking unaided) allowing to slow progression of the neuropathy. Aims of the study was to assess the place of tafamidis in the management of TTR-FAP.

PCN322 - Opportunities with Accelerated Approval Times, but Stumbles at Hta? the Impact of a Limited Evidence Package

Accelerated approval pathways can shorten time to market for therapies treating diseases, particularly those with significant morbidity and mortality and few effective alternatives. However, little is known about payers’ reactions to submissions based on a Phase 2, single-arm trial. This study aimed to identify market access challenges for products with accelerated marketing authorization based on this limited data package. Oncology products receiving European marketing authorization since 2012 based on a Phase 2, single-arm study were identified and the associated EPARs and HTA submissions in France, Germany and the UK (NICE) reviewed. Six products were identified (Adcetris, Bosulif, Erivedge, Iclusig, Imbruvica, and Zydelig); four had orphan designation. No pivotal trials included survival as the primary endpoint, none reported HRQL and no comparative data were cited in the regulatory packages. Only one product was reviewed by NICE (England) and was not recommended (another did not submit). All six G-BA (Germany) reviews resulted in either additional benefit not proven, not quantifiable (or minor in one subgroup). In France, the ASMR ratings ranged from III to V (moderate, to no improvement compared with existing treatments). Common themes identified which could be addressed by additional evidence generation included: (1) clarity on the target patient population and unmet need; (2) establishing the current standard of care and positioning within the treatment pathway; (3) determining relative efficacy given the focus on survival benefit and the increasing weight of additional value drivers. Although marketing authorization is granted, products supported by Phase 2, single-arm trial data face significant HTA challenges; payers are being asked to make decisions based on limited data. Some evidence gaps can be addressed with additional evidence generated alongside the pivotal trial. However, uncertainty about a product’s value may result in poor HTA outcomes, and a poor position from which to negotiate price.

A forecasting model for drug utilization and expenditure integrating a Cellular Automata model with the Budget Impact Analysis approach. Preliminary results

Results The first-in-class emerging anti-diabetic dapagliflozin was selected and critically evaluated by the IHSP about 12 months before the European Marketing Authorization (MA). Other competitors already on the market were identified. A CA model describing the diffusion process of more than 200 Italian specialties of oral antidiabetic drugs (ATC A10B), sold between 2000 and 2014 has been developed and validated. A protocol for the identification of the real-world target population in the ARNO-CINECA database was set up on the grounds of the expected indication for dapaglifozin. The estimation of the budget impact of dapagliflozin is ongoing based on the estimation of market shares, through the application of the CA model, the analysis of the identified target population and the analysis of the potential variations in related healthcare costs for the treatment of type 2 diabetes, after the introduction of dapagliflozin.

GENE THERAPY FOR OBSTETRIC CONDITIONS

The first clinical trials of gene therapy in the 1990s offered the promise of a new paradigm for the treatment of genetic diseases. Over the decades that followed the challenges and setbacks which gene therapy faced often overshadowed any successes. Despite this, recent years have seen cause for renewed optimism. In 2012 Glybera™, an adeno-associated viral vector expressing lipoprotein lipase, became the first gene therapy product to receive marketing authorisation in Europe, with a licence to treat familial lipoprotein lipase deficiency. This followed the earlier licensing in China of two gene therapies: Gendicine™ for head and neck squamous cell carcinoma and Oncorine™ for late-stage nasopharyngeal cancer. By this stage over 1800 clinical trials had been, or were being, conducted worldwide, and the therapeutic targets had expanded far beyond purely genetic disorders. So far no trials of gene therapy have been carried out in pregnancy, but an increasing understanding of the molecular mechanisms underlying obstetric diseases means that it is likely to have a role to play in the future. This review will discuss how gene therapy works, its potential application in obstetric conditions and the risks and limitations associated with its use in this setting. It will also address the ethical and regulatory issues that will be faced by any potential clinical trial of gene therapy during pregnancy.

An Examination of the Regulatory and Reimbursement Processes for Biobetters and Comparison With Biosimilars.

Biosimilars and biobetters are subsequent versions of licensed innovator biotherapeutics. Whereas biosimilars are comparable to the originator product in terms of quality, safety and efficacy, biobetters incorporate intentional modifications to the originator molecular profile with the aim of producing a superior product. This distinction between biosimilars and biobetters has important implications from a regulatory perspective, with biosimilars following class-specific guidance whereas biobetters are considered innovator drugs. This study sought to examine and compare the regulatory and reimbursement approaches to the appraisal of biobetters and biosimilars. Biobetters and biosimilars of the same product class were identified, and qualitative analyses of the recommendations by indication, evidence considered, and key decision drivers were undertaken using available regulatory and HTA reimbursement decision documentation from six European countries. Findings for filgrastim are presented as an example; 7 biosimilars, and the pegylated filgrastims (pegfilgrastim and lipegfilgrastim) considered biobetters, were identified. Biosimilar filgrastims were granted European marketing authorisation based on demonstration of clinical comparability to the originator filgrastim in one indication and extrapolation of the Results to all 5 approved indications. Pegfilgrastim demonstrated clinical non-inferiority to filgrastim in one indication and was approved solely for this indication; the subsequently developed lipegfilgrastim was approved for the same indication but used pegfilgrastim as the comparator. Similar to biosimilar filgrastims, economic evidence in the form of cost-minimisation analyses was considered in HTA recommendations of both pegylated filgrastims. This differs from the approach for certain other biobetters that have demonstrated clinical superiority and cost-effectiveness versus their originator. Biosimilars and biobetters are subject to distinct regulatory processes and the decision driving factors for reimbursement also differ among currently licensed biobetters. With the development of these products gaining momentum, it will be interesting to observe how the appraisal processes evolve to address the scope and variety of emerging biobetters.

Adaptive clinical trial designs for European marketing authorization: a survey of scientific advice letters from the European Medicines Agency.

BackgroundSince the first methodological publications on adaptive study design approaches in the 1990s, the application of these approaches in drug development has raised increasing interest among academia, industry and regulators. The European Medicines Agency (EMA) as well as the Food and Drug Administration (FDA) have published guidance documents addressing the potentials and limitations of adaptive designs in the regulatory context. Since there is limited experience in the implementation and interpretation of adaptive clinical trials, early interaction with regulators is recommended. The EMA offers such interactions through scientific advice and protocol assistance procedures.MethodsWe performed a text search of scientific advice letters issued between 1 January 2007 and 8 May 2012 that contained relevant key terms. Letters containing questions related to adaptive clinical trials in phases II or III were selected for further analysis. From the selected letters, important characteristics of the proposed design and its context in the drug development program, as well as the responses of the Committee for Human Medicinal Products (CHMP)/Scientific Advice Working Party (SAWP), were extracted and categorized. For 41 more recent procedures (1 January 2009 to 8 May 2012), additional details of the trial design and the CHMP/SAWP responses were assessed. In addition, case studies are presented as examples.ResultsOver a range of 5½ years, 59 scientific advices were identified that address adaptive study designs in phase II and phase III clinical trials. Almost all were proposed as confirmatory phase III or phase II/III studies. The most frequently proposed adaptation was sample size reassessment, followed by dropping of treatment arms and population enrichment. While 12 (20%) of the 59 proposals for an adaptive clinical trial were not accepted, the great majority of proposals were accepted (15, 25%) or conditionally accepted (32, 54%). In the more recent 41 procedures, the most frequent concerns raised by CHMP/SAWP were insufficient justifications of the adaptation strategy, type I error rate control and bias.ConclusionsFor the majority of proposed adaptive clinical trials, an overall positive opinion was given albeit with critical comments. Type I error rate control, bias and the justification of the design are common issues raised by the CHMP/SAWP.

Nalmefene: a new approach to the treatment of alcohol dependence.

Reduction of alcohol consumption is not yet a widely accepted treatment objective for alcohol-dependent patients, as abstinence is often considered to be the only possible objective in this situation. However, various studies have demonstrated the value of proposing these two options to such patients. Firstly, reduction of alcohol consumption very significantly reduces the risk of alcohol-related damage, and also modifies the patient’s and the doctor’s perception of the disease, resulting in improved access to care and better patient adherence with the proposed treatment objective and consequently better clinical results. Recent studies have shown that some medicinal products can help patients reduce their alcohol consumption. One such product, nalmefene, has been granted European marketing authorization and is now being released onto the market in various countries. The ESENSE 1 and 2 studies in alcohol-dependent patients showed that, in combination with BRENDA, a psychosocial intervention focusing on reinforcement of motivation and treatment adherence, nalmefene significantly reduced the number of heavy drinking days and mean daily total alcohol consumption versus placebo. This reduction was more marked in the marketing authorization target population, ie, patients with a high or very high drinking risk level according to World Health Organization criteria. Another original feature of this molecule is that it can be used as needed if the patient perceives a risk of drinking, which is a more flexible approach and more likely to ensure the patient’s active involvement in the treatment of his/her disease. This molecule opens up interesting and original therapeutic prospects in the treatment of alcohol dependence.

PSY66 - Eight Years Experience With Availability And Uptake Of Orphan Drugs With Or Without Prior Eu Orphan Designation In Slovakia

There are currently 68 orphan drugs with European marketing authorization with orphan designation and 75 orphan drugs without prior orphan designation in EU. Current Health technology appraisal recommendations in Slovak Republic do not include any specific guidelines for reimbursement of orphan drugs (OD). Orphan drug reimbursement decisions are made on case-to-case basis and no clear rules are currently present. We evaluated market uptake of selected 90 orphan drugs and compared it to total market evolution from 2005 to 2012. Our analysis include volume and sales evolution of 90 orphan drugs in Slovak Republic from 2005 to 2012 using Health database and publicly available data. Results show that cumulative 8-years expenditure for selected list of ODs is over 1,1 billion EUR. The peak sale was reached in 2012 and that sale accounted for 18,6% from total pharmaceutical spending in 2012. The highest sales growth was in 2006 with 33,4% compared to previous year. Until 2009, we have seen strong double-digit growth following by still high single digit growth in 2010 (6,1%) and 2012 (7,6%). Total expenditure represented 10,7%, 12,4%, 12,8%, 13,5%, 14,7%, 15,2%, 16,5% and 18,6% of total medicine expenditure from 2005 to 2012 in SK, respectively. The highest expenditure burden lies on one ATC category: L- antineoplastic and immunomodulating agents with 57% share. The uptake of orphan drugs is according to EU standards very high, but it must be noted that many ODs are locally off-patent and generics expand the market. Secondly, we included into our selection ODs with and without prior orphan designation. Nevertheless, it is important to make more detailed analysis and advocate for prudent reimbursement rules for orphan drugs, mainly from local HTA perspective.

Antidepressant Approved After Success in Elderly

Vortioxetine, a new antidepressant, has been approved for treating major depressive disorder in adults. It is being marketed as Brintellix by Takeda Pharmaceuticals and Lundbeck, available in 5-mg, 10-mg, 15-mg, and 20-mg tablets. The Food and Drug Administration approved the drug last fall, and Lundbeck announced on Dec. 27 that it had obtained European marketing authorization for Brintellix. The mechanism of antidepressant effect “is thought to be related to its enhancement of serotonergic activity in the [central nervous system] through inhibition of the reuptake of serotonin (5-HT),” according to the prescribing information. In the FDA's approval statement, Mitchell Mathis, MD, said that since medi-cations affect everyone differently, “it is important to have a variety of treatment options available for patients who suffer from depression.” Dr. Mathis is acting director of the division of psychiatry products in the FDA's Center for Drug Evaluation and Research. Approval was based on six 6–8–week, randomized studies conducted in the United States and elsewhere, which found that treatment with at least one dose of the drug was more effective than placebo. Five of the studies enrolled patients aged 18–75 years, and one enrolled patients aged 64-88 years. In a long-term maintenance study, those treated with vortioxetine had a longer time to recurrence of depression than did those treated with placebo. Nausea, vomiting, and constipation were the most common adverse effects associated with the drug in clinical trials, according to the FDA statement. As with all antidepressant drugs, the prescribing information has a boxed warning and medication guide about the increased risk of suicidal thoughts and behavior in children, adolescents, and adults aged 18–24 years, during initial treatment. The warning includes the recommendation that people starting treatment with antidepressants be closely monitored for worsening depression and suicidal thoughts and behavior.

Florbetapir (18F) for brain amyloid positron emission tomography: Highlights on the European marketing approval

Florbetapir (18F) for brain amyloid positron emission tomography (PET) imaging has been recently approved in Europe to estimate β-amyloid neuritic plaque density in the brain when the subject is still alive. Such density is one of the key issues for the definitive diagnosis of Alzheimer's disease (AD) at autopsy. This capability of florbetapir (18F) is regarded as a significant improvement in the diagnostic procedures for adult patients with cognitive impairment who are being evaluated for AD and other causes of cognitive impairment. The current paper highlights the specific characteristics of the European marketing authorization of florbetapir (18F).

Analysis of Phase 3 telavancin nosocomial pneumonia data excluding patients with severe renal impairment and acute renal failure

ObjectivesTelavancin is approved in Europe for the treatment of nosocomial pneumonia caused by methicillin-resistant Staphylococcus aureus when other alternatives are not suitable. The approved European prescribing information contraindicates the use of telavancin in patients with severe renal impairment (creatinine clearance <30 mL/min, including patients on haemodialysis) and pre-existing acute renal failure owing to the higher observed mortality in these patients. Data from the ATTAIN studies were reanalysed, excluding patients with these contraindicating conditions at baseline. (At the time of submission of this article, the European marketing authorization of telavancin for the treatment of nosocomial pneumonia was suspended pending evidence of a new European Medicines Agency-approved supplier. Clinigen Healthcare Ltd, Theravance's commercialization partner for telavancin in Europe, is in the process of seeking approval of a new manufacturing source.)MethodsA post hoc analysis of data from two Phase 3 ATTAIN trials of telavancin for the treatment of Gram-positive nosocomial pneumonia assessing clinical outcomes and safety.ResultsThe all-treated population for this analysis represented 84.2% (1266/1503) of the ATTAIN all-treated population. The cure rates in the clinically evaluable population were similar in the telavancin (82.5%, 231/280) and vancomycin (81.3%, 243/299) groups [treatment difference (95% CI): 1.3% (−5.0% to 7.6%)], and were consistent with the overall ATTAIN study results. The cure rate was higher in the telavancin than the vancomycin treatment group in microbiologically evaluable patients with only Gram-positive pathogens isolated at baseline [85.0% (130/153) versus 75.2% (109/145), respectively; treatment difference (95% CI): 9.7% (0.6%–18.8%)]. The incidences of adverse events were similar between treatment groups and consistent with the overall findings of the ATTAIN study.ConclusionsThis analysis demonstrated that in the subset of patients without severe renal impairment or pre-existing acute renal failure, clinical and safety outcomes were similar in the telavancin and vancomycin treatment groups.

Edaravone Improves Functional and Structural Outcomes in Animal Models of Focal Cerebral Ischemia: A Systematic Review

Edaravone has been used in patients with acute ischemic stroke in Japan for over 10 years but does not have marketing authorization in Europe or America. Either patients in Europe and America are not receiving an effective treatment, or those in Asia are being given a treatment which is not effective. Finding out which of these is true will require further clinical trials, and a better understanding of its efficacy in animal models may help inform the design of those trials so that it might be tested under conditions where there is the greatest prospect of success. We systematically reviewed the efficacy of edaravone in animal models of focal ischemia and summarized data using weighted mean difference DerSimonian and Laird random-effects modeling. We used stratified meta-analysis and metaregression to assess the influence of study design and methodological quality. We identified 49 experiments describing outcome in 814 animals; 30 experiments (519 animals) reported functional and 35 experiments (503 animals) reported structural outcome. Edaravone improved functional and structural outcome by 30·3% (95% confidence interval 23·4-37·2%) and 25·5% (95% confidence interval, 21·1-29·9%), respectively. For functional outcome, there was an inverse relationship between study quality and effect size (P < 0·0017). Effect sizes were larger in studies where randomization or blinded assessment was not reported. There was no evidence of publication bias. Edaravone is a promising treatment for stroke. However, because of the methodological weakness in current animal studies, no sufficient preclinical evidence is available to optimize the study design of clinical trials. Higher quality animal studies are expected to inform further clinical study.

Impact of telavancin on prothrombin time and activated partial thromboplastin time as determined using point-of-care coagulometers

Telavancin is approved in the United States, Canada, and Europe (At the time of submission, the telavancin European marketing authorization for nosocomial pneumonia was suspended until Theravance provides evidence of a new European Medicines Agency approved supplier) as an antibiotic to treat certain Gram-positive bacterial skin infections. Telavancin has been shown to prolong plasmatic prothrombin (PT) and activated partial thromboplastin (aPTT) clotting times in clinical diagnostic lab-based assays. In this study, we evaluated the potential for telavancin to prolong whole blood PT/International Normalized Ratio (INR) and aPTT tests on point-of-care (POC) instruments. Whole blood collected from 8 healthy subjects was supplemented with telavancin to final concentrations of 0, 10, 20, and 100μg/ml. Final concentrations were selected to match trough, twice trough, and peak plasma levels following the approved 10mg/kg dose. Four widely employed POC coagulation instruments were chosen to be representative of the POC platforms currently in use.. These systems were the Roche Coaguchek XS, the Abbott iSTAT, the ITC Hemochron SIG+, and the Alere INRatio2 POC devices. The PT/INR measured by the Coaguchek XS showed the greatest sensitivity to the presence of telavancin. The PT/INR measured by the Hemochron SIG+ and iSTAT were sensitive to telavancin but to a lesser extent. The INRatio2 was the least sensitive to the presence of telavancin when testing the whole blood PT/INR. Only the Hemochron SIG+ device was capable of measuring aPTT and showed a concentration-dependent increase in aPTT. This study supports the current recommendation that PT and aPTT monitoring be conducted immediately to the next dose of telavancin when coagulation parameters are tested using POC instrumentation.

Italian Horizon Scanning Project

BackgroundThe often modest therapeutic value, the uncertain level of innovation, and the high costs of new drugs suggest a pressing need for early evaluation of emerging pharmaceuticals. The Italian Horizon Scanning Project (IHSP) critically reports on emerging drugs in order to timely assess their potential impact on the National Health System.MethodsIHSP identifies, filters and prioritizes emerging drugs for which a European Marketing Authorization (MA) is expected within 12–36 months. The final New Product Information Report, issued 12 months before the MA, critically reports on efficacy and safety of selected drugs, on their possible level of innovation, place in therapy and social and economic impact.ResultsSince 2008, 39 new drugs were prioritized (corresponding to 44 indications) due to (i) their potential high epidemiological and economic impact; (ii) the limited availability or the complete lack of treatments; (iii) the uncertainty of the possible place in therapy of the emerging drug; (iv) the possible better efficacy and/or safety profile or possible better compliance of the new medicine versus the available therapies. Among the 39 drugs, 14 active principles were indicated in cancer patients, eight for cardiovascular diseases, and four for multiple sclerosis.ConclusionsHorizon Scanning is a useful tool to support policy-makers in allocating resources more efficiently.

Real-life patterns of use and effectiveness of sunitinib in patients with metastatic renal cell carcinoma: The SANTORIN study.

400 Background: Until 2006, treatment options for metastatic renal cell carcinoma (mRCC) were limited to cytokine therapy and surgery. Sunitinib, an oral antiangiogenic agent, received European marketing authorisation in Jan 2007 for first-line treatment in advanced and/or mRCC. The SANTORIN study was designed to describe patterns of use and estimate survival outcomes in mRCC patients treated with sunitinib in a real-life setting. Methods: SANTORIN was an observational cohort conducted in 36 French centres including patients initiating first-line treatment with sunitinib from Jan 2008-Apr 2010, followed 2 years after treatment onset. Treatment characteristics, response (evaluated by investigator based on RECIST criteria) and survival outcomes were collected from medical files. Overall and progression-free survival (OS and PFS) results were estimated using Kaplan-Meier method. Results: Characteristics of the 302 included patients were: mean age 64.3 years; male 73.2%; clear-cell histological component 83.1%; ECOG ≥2 9.9%, prior nephrectomy 85.4%. Baseline sunitinib dose was 50 mg/day for 83.4% of patients. The median duration of first-line treatment was 10.7 months (median number of cycles: 6). Dose reduction occurred in 65.2% of patients. Reasons for discontinuation of first-line treatment were progressive disease (61.1%), death (31.2%), adverse events (6.8%), and other reasons (1.0%). OS was 70.8% at 1 year (95%CI [65.3;75.5]) and 49.5% at 2 years [43.7;55.0]. Median OS was 23.6 months [19.9;27.4] (not reached in patients with clear-cell component). PFS was 38.2% at 1 year [32.7;43.7] and 16.4% at 2 years [12.5;20.9]. Median PFS was 8.4 months [7.6;9.9] (9.5 months [8.1;11.0] in patients with clear-cell component). Overall best response was 31.1% (2.3% complete, 28.8% partial), 40.1% had stable and 18.5% progressive disease. Conclusions: Despite certain differences regarding severity of cancer, these results demonstrated that effectiveness of sunitinib in mRCC is close to efficacy reported in the pivotal clinical trial (median OS: 26.4 months [95% CI 23.0 ; 32.9], median PFS: 11.0 months [11.0 ; 13.0]), especially in patients with clear-cell component.