Relative effectiveness assessments of oncology medicines for pricing and reimbursement decisions in European countries.

BACKGROUND: There is a debate on the added clinical value of new, expensive, anticancer treatments. Among European decision makers, the relevance of commonly used end points in trials, especially overall survival (OS), progression-free survival (PFS) and quality of life (QoL), varies, leading to the available evidence being valued differently. This research studies the extent to which the value of end points for cancer medicines differs among European decision makers. METHODS: We compared guidelines and relative effectiveness assessments (REAs) of medicines for pricing or reimbursement decisions in England, France, Germany, The Netherlands, Poland, and Scotland. Anticancer medicines that received marketing authorization in Europe between 2011 and 2013 with at least four available national REAs were evaluated. A total of 79 REAs were included. RESULTS: Health technology assessment (HTA) guidelines indicate a preference for clinically and patient relevant end points such as OS and QoL above surrogate end points. Most guidelines do not specify whether PFS is considered a surrogate or patient-relevant end point. The number of REAs included per jurisdiction varied between 7 (The Netherlands) and 18 (Germany). OS data were included in all REAs and were the preferred end point by HTA agencies, but these data were not always mature or robust. QoL data are included in only 54% of the REAs, with a limited impact on the recommendations. PFS data are included in 70% of the REAs, but the extent to which HTA agencies find PFS relevant varies. CONCLUSIONS: European decision-making on relative effectiveness of anticancer medicines is affected by a gap in requested versus available clinical evidence, mainly because the regulator is willing to accept some degree of clinical uncertainty. A multi-stakeholder debate would be essential to align concrete robust evidence requirements in oncology and a collectively shared definition for relevant clinical benefit, which will benefit patients and society in general.

Increased gene expression of the cardiac endothelin system in obese mice.

Obesity is a well-known risk factor of atherosclerosis and heart failure. In the human heart, a local endothelin system containing prepro-endothelin-1, endothelin-converting enzyme-1, and endothelin receptors A and B has been described. The endothelin system is activated in heart failure; however, the impact of obesity on the cardiac endothelin system is unknown. In this study, 18-week-old male C57BL/6 mice fed either a control diet or a high-fat diet for 10 weeks were analyzed. High-fat diet significantly increased the body weight of the animals and augmented low-density lipoprotein, high-density lipoprotein, and cholesterol plasma levels, compared to control. The animal groups showed no significant differences in left ventricular size or function (heart rate, ejection fraction, fractional shortening, left ventricular posterior wall thickness, cardiac output) after control or high-fat diet. We did not observe signs of cardiac hypertrophy or changes in markers of cardiac fibrosis in these heart samples. The cardiac expression of prepro-endothelin-1 mRNA, endothelin-converting enzyme-1 mRNA, and protein and endothelin receptors A and B mRNA was increased in 18-week-old obese C57BL/6 mice compared to animals with normal weight (p<0.05 vs. control). Furthermore, endothelin-1 plasma levels showed an increasing trend. In conclusion, an increased expression of genes of the endothelin system was observed in the hearts of 18-week-old mice after high-fat diet, possibly contributing to later cardiovascular complications of obesity.

COUP-TFII is regulated by high glucose in endothelial cells.

Diabetes mellitus is an important risk factor for cardiovascular diseases. Clinical evidence supports a link between hyperglycemia, endothelial dysfunction, and vascular disorders. However, the precise molecular mechanisms causing endothelial dysfunction in diabetic patients remain unclear. An interesting novel mediator could be chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII), which plays an essential role in glucose metabolism. COUP-TFII is known to be expressed in venous endothelial cells. In this study, we show COUP-TFII expression in human umbilical vein endothelial cells (HUVECs) and human coronary artery endothelial cells. HUVECs express glucose transporters 1, 3, 6, and 10, and the insulin receptor. Insulin in combination with glucose activates protein kinase B (PKB or Akt) phosphorylation via phosphoinositide 3-kinase (PI3-kinase). Short-term (60-240 min) stimulation of HUVECs with high glucose increased COUP-TFII expression independent of insulin. Long-term (48 h) stimulation of HUVECs with high glucose augmented expression of the insulin receptor and E-selectin, but downregulated COUP-TFII protein expression. Downregulation of COUP-TFII by shRNA leads to downregulation of E-selectin and upregulation of eNOS and glucose transporters. Our data suggest that COUP-TFII is regulated by glucose in a time- and dose-dependent manner in endothelial cells. COUP-TFII might affect endothelial function in a diabetic background.

Characteristics and drug utilization patterns of new users of rosuvastatin and other statins in four countries.

AIM: This study was undertaken to increase understanding of the utilization of a newly introduced statin through evaluation of characteristics of 'real-life' patients in a pharmacoepidemiology program in the USA, the Netherlands, the UK and Canada. METHODS: This was an observational analysis of prospectively collected data from primary care patients classified as new users of rosuvastatin or any other statin. New users (naïve or switched initiators) of rosuvastatin were compared with initiators of other statins, as identified from automated healthcare databases in the first 1 to 2 years of rosuvastatin availability. Demographics, statin doses, previous statin use and other lipid-lowering therapies, and relevant comorbidities were recorded. The main outcome measure was proportion of naïve and non-naïve statin users in patients prescribed rosuvastatin or 'other statins'. RESULTS: Among 346.547 new statin users identified in the cohorts, 46.838 (13.5%) were new users of rosuvastatin and most (84.1%) were statin-naïve. Patients receiving rosuvastatin were more likely to have been previously treated with another statin or non-statin lipid-lowering therapy and tended to be younger, compared with first users of other statins. CONCLUSION: These findings suggest that rosuvastatin is preferentially prescribed to patients who have not responded satisfactorily to established treatment.

Implementing managed entry agreements in practice: The Dutch reality check.

BACKGROUND: Conditional financing (CF) of expensive hospital drugs was applied in the Netherlands between 2006 and 2012; a 4-year coverage with evidence development (CED) framework for expensive hospital drugs. This study aims to evaluate the CF framework, focusing on Health Technology Assessment (HTA) procedures. METHODS: Using a standardised data extraction form, researchers independently extracted information on procedural, methodological and decision-making aspects from HTA reports of drugs selected for CF. RESULTS: Forty-nine drugs were chosen for CF, of which 12 underwent the full procedure. The procedure extended beyond the envisioned 4 years period for 11/12 drugs. Outcomes research studies conducted as part of CF provided insufficient scientific data to reach conclusions on appropriate use and cost-effectiveness of 5/12 drugs. After re-assessment, continuation of reimbursement was advised for 10/12 drugs, with 6 necessitating yet additional conditions for evidence generation. Notably, advice to discontinue reimbursement for 2/12 drugs has not yet been implemented in Dutch healthcare practice. CONCLUSIONS: Theoretically, CF provided an option for quick but conditional access to drugs. However, numerous aspects related to the design and implementation of CF negatively affected its value in practice. Future CED schemes should aim to incorporate learnings from the CF example to increase their impact in healthcare practice.

Persistent bisphosphonate use and the risk of osteoporotic fractures in clinical practice: a database analysis study.

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: 14,760 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.

Real World Data in Adaptive Biomedical Innovation: A Framework for Generating Evidence Fit for Decision-Making.

Analyses of healthcare databases (claims, electronic health records [EHRs]) are useful supplements to clinical trials for generating evidence on the effectiveness, harm, use, and value of medical products in routine care. A constant stream of data from the routine operation of modern healthcare systems, which can be analyzed in rapid cycles, enables incremental evidence development to support accelerated and appropriate access to innovative medicines. Evidentiary needs by regulators, Health Technology Assessment, payers, clinicians, and patients after marketing authorization comprise (1) monitoring of medication performance in routine care, including the materialized effectiveness, harm, and value; (2) identifying new patient strata with added value or unacceptable harms; and (3) monitoring targeted utilization. Adaptive biomedical innovation (ABI) with rapid cycle database analytics is successfully enabled if evidence is meaningful, valid, expedited, and transparent. These principles will bring rigor and credibility to current efforts to increase research efficiency while upholding evidentiary standards required for effective decision-making in healthcare.

Deloading of the left ventricle by ventricular assist device normalizes increased expression of endothelin ET(A) receptors but not endothelin-converting enzyme-1 in patients with end-stage heart failure.

BACKGROUND: Ventricular assist devices (VAD) are implanted in patients with end-stage heart failure for bridging the time until heart transplantation, resulting in hemodynamic unloading of the failing heart, improved cardiac contractile and mitochondrial function, and reversal of cardiac hypertrophy. It is unknown whether VAD unloading may affect the cardiac endothelin (ET) system, which has been proposed as one of the putative pathomechanisms of heart failure. METHODS AND RESULTS: With the use of standard-calibrated, competitive reverse-transcription-polymerase chain reaction mRNA expression of components of the ET system was analyzed in left ventricular myocardium from nonfailing donor hearts, from failing hearts without and with ACE inhibitor therapy, and from patients with end-stage heart failure at the time of VAD implantation and 103+/-15 days after VAD implantation during removal with subsequent heart transplantation. ET receptor A (ET(A)) was markedly upregulated in failing human myocardium. This increased ET(A) expression was not affected by ACE inhibitor treatment but was normalized by VAD unloading. ET(A) expression before or after VAD implantation did not correlate with duration of VAD implantation or suppression of Pro-ANP mRNA. ET(B) mRNA expression was unaffected by heart failure or VAD. In contrast, increased ET-converting enzyme-1 mRNA and ET-1 peptide levels in failing myocardium were partially normalized by ACE inhibition but not by VAD unloading. CONCLUSIONS: We conclude that VAD implantation normalizes ET(A) expression in failing human left ventricular myocardium, probably as the result of the beneficial effects of VAD unloading.

From adaptive licensing to adaptive pathways: delivering a flexible life-span approach to bring new drugs to patients.

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.

Obesity is associated with tissue-specific activation of renal angiotensin-converting enzyme in vivo: evidence for a regulatory role of endothelin.

In the C57BL/6J mice model, we investigated whether obesity affects the function or expression of components of the tissue renin-angiotensin system and whether endothelin (ET)-1 contributes to these changes. ACE activity (nmol. L His-Leu. mg protein(-1)) was measured in lung, kidney, and liver in control (receiving standard chow) and obese animals treated for 30 weeks with a high-fat, low cholesterol diet alone or in combination with LU135252, an orally active ET(A) receptor antagonist. ACE mRNA expression was measured in the kidney, and the effects of LU135252 on purified human ACE were determined. Aortic and renal tissue ET-1 protein content was measured, and the vascular contractility to angiotensin II was assessed. Obesity was associated with a tissue-specific increase in ACE activity in the kidney (55+/-4 versus 33+/-3 nmol/L) but not in the lung (34+/-2 versus 32+/-2 nmol/L). Long-term LU135252 treatment completely prevented this activation (13.3+/-0.3 versus 55+/-4 nmol/L, P<0.05) independent of ACE mRNA expression, body weight, or renal ET-1 protein but did not affect pulmonary or hepatic ACE activity. Obesity potentiated contractions in response to angiotensin II in the aorta (from 6+/-2% to 33+/-5% KCl) but not in the carotid artery (4+/-1% to 3.6+/-1% KCl), an effect that was completely prevented with LU135252 treatment (6+/-0.4% versus 33+/-5% KCl). No effect of LU135252 on purified ACE was observed. Thus, obesity is associated with the activation of renal ACE in vivo independent of its mRNA expression and enhanced vascular contractility to angiotensin II. These effects are regulated by ET in an organ-specific manner, providing novel mechanisms by which ET antagonists may exert organ protection.

The effect of oral quercetin on UVB-induced tumor growth and local immunosuppression in SKH-1.

The effects of quercetin (4%) on UVB-induced carcinogenesis and immunosuppression were studied in hairless SKH-1 mice exposed daily to suberythemal UVB for 12/13 and 16/17 weeks. Macroscopic and microscopic examinations showed that quercetin did not affect the onset and growth of UVB-induced non-melanoma skin tumors. Quercetin prevented the UV-induced suppression of the contact hypersensitivity (CHS) and the reduction of the percentage of CD8-positive cells in spleen and lymph nodes. Other immunological parameters were not affected. Thus, the results indicate that oral intake of a high dose of quercetin does not prevent UVB-induced carcinogenesis, although it restores the skin-associated CHS response.

UV-B exposure impairs resistance to infection by Trichinella spiralis.

To assess the possibility that increases in UV-B exposure on the earth's surface could lead to impaired resistance to several infectious diseases, we studied the effect of UV-B exposure on resistance against Trichinella spiralis. Wistar rats, orally infected with T. spiralis larvae, were exposed to suberythemal doses of UV-B radiation daily for 5 days at different time periods before or after infection. A significant increase in the number of Trichinella larvae was found in the carcasses of rats irradiated with UV-B between 6 and 10 days after infection. These data indicate that exposure to UV-B radiation suppresses the resistance to a parasitic infection. We suggested that UV-B radiation especially suppresses cellular immune responses against these worms because specific IgM, IgG, and IgE titers were not significantly altered by UV-B exposure. These data indicate that UV-B irradiation plays a role in the course of infection with T. spiralis, which suggests that increases of UV-B exposure might also lead to problems with other infectious diseases and might affect vaccination because of the interaction of UV-B irradiation with memory T-cells.

Risk assessment for the harmful effects of UVB radiation on the immunological resistance to infectious diseases.

Risk assessment comprises four steps: hazard identification, dose-response assessment, exposure assessment, and risk characterization. In this study, the effects of increased ultraviolet B(UVB, 280-315 nm) radiation on immune functions and the immunological resistance to infectious diseases in rats were analyzed according to this strategy. In a parallelogram approach, nonthreshold mathematical methods were used to estimate the risk for the human population after increased exposure to UVB radiation. These data demonstrate, using a worst-case strategy (sensitive individuals, no adaptation), that exposure for approximately 90 min (local noon) at 40 degrees N in July might lead to 50% suppression of specific T-cell mediated responses to Listeria monocytogenes in humans who were not preexposed to UVB (i.e., not adapted). Additionally, a 5% decrease in the thickness of the ozone layer might shorten this exposure time by approximately 2.5%. These data demonstrate that UVB radiation, at doses relevant to outdoor exposure, may affect the specific cellular immune response to Listeria bacteria in humans. Whether this will also lead to a lowered resistance (i.e.,increased pathogenic load) in humans is not known, although it was demonstrated that UVB-induced immunosuppression in rats was sufficient to increase the pathogenic load. Epidemiology studies are needed to validate and improve estimates for the potential effects of increased UVB exposure on infectious diseases in humans.

Broader vaccination of expatriates against HBV infection: do we reach those at highest risk?

BACKGROUND: The effects of the implementation of a new Dutch hepatitis B virus (HBV) vaccination strategy (1991) for expatriates on HBV vaccination status and HBV infection prevalence were evaluated in a group of 864 expatriates returning from HBV-endemic areas. METHODS: During a routine medical examination at the participating medical centres Dutch expatriates were asked to complete a questionnaire and to donate a serum sample for HBV testing. Blood was tested for antibodies against the hepatitis B core (anti-HBc) and surface antigens (anti-HBs). The serological data were related to information gathered on aspects of residence, sexual risk behaviour and occupational risks. RESULTS: A significantly higher percentage of expatriates (37%) were vaccinated compared to a previous study in 1987-1989 (14%). However, the percentage of expatriates with HBV infection markers (5%) had not decreased significantly. Moreover, the risk for HBV infection, as determined with a questionnaire, was still affected by well-known risk factors such as homosexual contacts (odds ratio [OR] = 6.6, 95% CI: 1.7-26), more than five casual local partners (OR = 3.6, 95% CI: 1.2-11) and more than five occupational accidents in the last 3 years (OR = 20, 95% CI: 2-187). Detailed analysis of the vaccination status indicated that especially young female expatriates with low risk behaviour (65%) were protected, while older male expatriates with high risk behaviour were less protected (20%). CONCLUSION: We conclude that the new vaccination strategy has resulted in a higher percentage of expatriates protected. However, only a small proportion was reached of those at highest risk for HBV infection.

A rat cytomegalovirus infection model as a tool for immunotoxicity testing.

A rat cytomegalovirus infection model for use in immunotoxicity testing has been developed. In resistance against viruses, natural killer cells and cytotoxic T-cells play an important role. Therefore, this model complements other rat host resistance models for immunotoxicity testing, i.e. existing bacterial and parasitic infection models in which cytotoxic T-cells and natural killer cells play a minor role. Host resistance against cytomegalovirus infections in the rat was determined by titrating infectious virus levels in organs after cytomegalovirus infection in an in vitro infectivity test denoted as the Plaque Forming Unit (PFU) Test. In this test, homogenates of different organs were investigated for infectious virus titers on rat embryonic cell monolayers. We demonstrated that in the salivary gland, the major target organ for rat cytomegalovirus, virus was detectable from 8 days onward after intraperitoneal infection. To show that this model is suitable for the detection of immunotoxicity four different methods for immunosuppression were investigated: 1. gamma-irradiation, 2. congenitally athymic rats, 3. chemically induced immunosuppression, 4. ultraviolet-B (UVB) irradiation. Rat cytomegalovirus titers in the salivary glands of irradiated (500 rad 1 day prior to infection) or congenitally athymic rats were significantly increased as compared to non-irradiated rats and euthymic control rats respectively. In TOX-Wistar rats, given 20 or 80 mg bis(tri-n-butyltin)oxide (TBTO) per kg food beginning 6 weeks before cytomegalovirus infection, a regimen known to have immunotoxic effects, cytomegalovirus titers in the salivary glands were significantly increased as compared to non-TBTO-treated cytomegalovirus infected rats.(ABSTRACT TRUNCATED AT 250 WORDS)

UVB-induced decreased resistance to Trichinella spiralis in the rat is related to impaired cellular immunity.

Our laboratory has demonstrated in preliminary experiments that UVB exposure using the Kromayer lamp can induce increased numbers of Trichinella spiralis larvae in carcasses of infected Wistar rats, without affecting specific antibody titers to this parasite. In this study, orally T. spiralis-infected Wistar rats were exposed to suberythemal doses of UVB radiation using FS40 lamps during different time periods before or after infection. A significant increase in the number of T. spiralis larvae was found in the carcasses of rats that were UVB irradiated daily for 7 consecutive days in the second week after infection. Additionally, increased numbers of larvae were also detected histologically in the tongue of rats that were exposed the first and the second week after infection. Lymphocyte stimulation assays using mesenteral lymph node cells indicated that UVB exposure also impaired the specific lymphocyte response to T. spiralis. Moreover, DTH responses to T. spiralis were severely impaired in rats that were UVB irradiated daily for 7 consecutive days in the second week after infection. Thus, these data combined with the data of the Kromayer study indicate that exposure of rats to FS40 irradiation following oral infection with T. spiralis leads to increased numbers of larvae in systemic sites and impaired T-cell immunity to the parasite.

Effects of in vitro exposure to ultraviolet radiation on the functional activity of lymphocytes, with emphasis on susceptibility of different species.

In this study lymphocytes from blood and/or spleen of different species (rat, mouse, human) were exposed to different doses of ultraviolet radiation (UVR). The functional activity of these lymphocytes was determined using assays for mitogen proliferation and the mixed lymphocyte response (MLR). These experiments demonstrated that in vitro exposure to UVR causes a dose-dependent decrease of the MLR activity of the irradiated lymphocytes. Viability of lymphocytes and mitogen proliferation responses were also decreased by UVR exposure but less severe in comparison to the MLR. Lymphocytes of rats seem to be more sensitive to UVR as compared to lymphocytes of mice and humans.

Risk assessment of UVB effects on resistance to infectious diseases.

The aim of this study was to develop a quantitative risk assessment of lowered resistance to infections in humans due to (solar) ultraviolet B (UVB) exposure. We followed the steps for risk assessment as defined by the U.S. National Academy of Sciences: (1) hazard identification, (2) dose-response assessment, (3) exposure assessment, and (4) risk characterization. For step 1, the suppressory effects of UVB radiation on the immune system have been reviewed, supplemented with new data, and analyzed. Experiments on UV-induced immunosuppression cannot be performed with humans for ethical reasons, but herpes simplex virus infection appears to be the human paradigm. Thus, UVB radiation appears to be a potential hazard to immunologic functions. Step 2 is crucial, but dose-response relationships for infections have never been measured in humans. We used our earlier dose-response rat data for suppression of lymphocyte stimulation and computed that the UVB dose resulting in a 50% reduction of lymphocyte stimulation by Listeria monocytogenes is 6.800 J/m2. Using mixed skin lymphocyte response assays we found that humans are 3.8 times less sensitive than rats (interspecies variation [IEV]). To account for the 2.5 percentile of most susceptible individuals in a population, an additional factor (intraspecies variation [IAV]) was introduced (0.5 for humans). Using these data, we computed that 13.100 J/m2 of UVB radiation emitted by FS40 lamps would suppress 50% of the proliferative response of lymphocytes to L. monocytogenes in most sensitive skin type 2 humans. In step 3, we assumed the action spectrum for the responses analyzed by us as identical to an action spectrum for suppression of contact hypersensitivity that is available in the literature. This led us to step 4, where we calculated that approximately 100 min of solar exposure at around noon in Italy or Spain would suppress the resistance to infections by L. monocytogenes in the most sensitive humans.

Effects of ultraviolet-B exposure on the resistance to Listeria monocytogenes in the rat.

A rat infection model using the bacterial pathogen Listeria monocytogenes was employed to analyze the immunosuppressive activity of UVB radiation. Rats were exposed to suberythemal doses of UVB radiation for 5 or 7 consecutive days, using Kromayer or FS40 lamps respectively. Subsequently, the rats were infected subcutaneously or intravenously with Listeria. Exposure to UVB resulted in an increased number of bacteria in the spleen 4 days after infection. Listeria-specific lymphocyte proliferation assays as well as delayed-type hypersensitivity reactions demonstrated that T cell-mediated immunity to Listeria was impaired by UVB as measured 4 and 8 days after infection. In addition, UVB exposure decreased phagocytotic activity of peripheral blood macrophages. This study demonstrated that suberythemal doses of UVB radiation caused a delay in the clearance of Listeria bacteria from the spleen of the rats and that this was probably caused by impaired nonspecific phagocytosis of Listeria by macrophages in addition to an impaired activity of Listeria-specific T cells.