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.

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.

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.

Burden of illness of bacterial cellulitis and erysipelas of the leg in the Netherlands.

BACKGROUND: Information on the prevalence of bacterial cellulitis (BC) and erysipelas (ER) of the leg (BCERL) is sparse and dependent on the definitions used. There is no information available on the number of hospitalized and non-hospitalized patients with BCERL, and related treatment costs. OBJECTIVE: The purpose of this study was to assess the burden of illness for BCERL in the Netherlands in 2001. METHODS: Data were obtained from different linked databases. Hospital information was obtained from the National Morbidity Registration (known in the Netherlands as the LMR), which includes all Dutch citizens, using ICD-9-CM codes. The number of patients not admitted to hospital was estimated using a subsample with data from general practitioners (GPs) (N = 50,000). These data were extrapolated using age/gender and disease-specific standardization. The subsample was used to assess the location of the infection. Reimbursement costs were available for all resources. RESULTS: In 2001, approximately 28,000 patients presented with either BC or ER of the leg. Of these patients, 2,200 were admitted to the hospital and 4-6% had two or more episodes of ER/BC in 2001. The average costs per hospitalization for BCERL were 5,346 euros, accumulating to more than 14 million euros in 2001. Although only 7% of all patients were hospitalized, 83% of the total treatment costs could be attributed to hospitalization. CONCLUSIONS: BCERL are common and serious infections in the Netherlands. Hospitalization occurs in only one in 14 patients but contributes more than 80% of the total costs, which accumulate to 17 million euros a year.

Results from a rosuvastatin historical cohort study in more than 45,000 Dutch statin users, a PHARMO study.

PURPOSE: Clinical benefits of statin therapy are accepted, but their safety profiles have been under scrutiny, particularly for the recently introduced statin, rosuvastatin, relating to serious adverse events involving muscle, kidney and liver. Therefore, a historical cohort study was performed to evaluate the association between rosuvastatin versus other statin use and the incidence of rhabdomyolysis, myopathy, acute renal failure and hepatic impairment. METHODS: Incident users of rosuvastatin or other statins in 2003-2004 and a cohort of patients not prescribed statins were included from the PHARMO database of >2 million Dutch residents. Cases of hospitalisations for myopathy, rhabdomyolysis, acute renal failure or hepatic impairment were identified for these cohorts. Potential cases were validated through a multi-step process using data obtained from hospital records. Additionally, cases of all cause deaths were identified from certification alone. RESULTS: In 2003 and 2004, 10,147 incident rosuvastatin users, 37,396 incident other statin users and 99,935 patients without statin prescriptions were included. There were 26 validated outcome events in the three cohorts including one case each of myopathy (other statin group) and rhabdomyolysis (non-treated group). There were no significant differences in the incidence of outcome events between rosuvastatin and other statin users. CONCLUSION: This study indicated that the number of outcome events is less than 1 per 3000 person years. This study in more than 45,000 Dutch statin users suggests that rosuvastatin does not lead to an increased incidence of rhabdomyolysis, myopathy, acute renal failure or hepatic impairment compared to other statins.

Skin infections in renal transplant recipients and the relation with solar ultraviolet radiation.

BACKGROUND: Ultraviolet radiation (UVR) is an important risk factor for skin cancer in transplant recipients. In view of the potential suppressive effect of UVR on host resistance it was examined whether exposure to UVR was also associated with the occurrence of various skin infections. METHODS: In a cohort of renal transplant recipients (n = 137), lifetime exposure was assessed by means of a retrospective questionnaire on cumulative sunlight exposure. Diagnosed skin infections since renal transplantation were extracted from the patient's medical charts. Season of diagnosis was regarded as indicative of short-term exposure. RESULTS: In comparison with winter a high rate of herpes simplex infections was found in spring [rate ratio (RR) = 4.09, 95% confidence interval (CI) 1.2-14.5], and high rates of herpes zoster infections (RR = 1.6, 95% CI: 0.8-3.5) and fungal/yeast infections in summer (RR = 2.1, 95% CI: 1.3-3.4). A higher lifetime exposure (RR = 2.31, 95% CI: 1.04-5.1) and a greater cumulative number of reported sunburns (RR = 2.3, 95% CI: 1.1-5.1) were independently associated with a higher risk of bacterial infections. CONCLUSIONS: The seasonal association with the occurrence of clinical herpes infections indicates an effect of short-term UVR. Our data suggest that the number of sunburn episodes in the past is also relevant for the susceptibility to certain skin infections.

Antibiotic use and resistance of Streptococcus pneumoniae in The Netherlands during the period 1994-1999.

Antibiotic use in The Netherlands during the period 1994-1999 is described in relation to the resistance of routine isolates of Streptococcus pneumoniae. The average antibiotic use in the study period was 3.4 defined daily doses per 1000 persons per day (DDD/1000/day) penicillins, 0.066 DDD/1000/day beta-lactams other than penicillins, 2.3 DDD/1000/day tetracyclines and 0.71 DDD/1000/day trimethoprim and sulphonamides, without apparent rise or decline. In contrast, the use of macrolides doubled from 0.51 DDD/1000/day in 1994 to 1.0 DDD/1000/day in 1997 and stayed at 1.07 DDD/1000/day in 1998 and 1999. In 1994 the first pneumococci isolated from patients showed 0.7% resistance to penicillin (intermediate plus full resistance), 2.5% to erythromycin, 4.2% to co-trimoxazole and 4.7% to tetracycline. In 1999 first isolates showed 1.5% resistance to penicillin, 3.8% to erythromycin, 4.4% to co-trimoxazole and 6.6% to tetracycline. The modest but significant rise in the resistance to erythromycin may have been caused by the increased use of macrolides in the years 1994-1997. The rise in resistance to penicillin seemed not to be related to increased beta-lactam use.

Resistance in Campylobacter species: increased resistance to fluoroquinolones and seasonal variation.

To identify epidemiological features of culture-proven campylobacter infections and to determine resistance rates, we conducted a 4-year demographic survey of culture-proven campylobacteriosis in one Dutch region. Examination of 24,435 fecal specimens revealed 1,315 cases of campylobacteriosis (5.4%). The ofloxacin-resistance rate among Campylobacter isolates increased from 11% to 29%. Resistance against tetracycline fluctuated between 7% and 15%, and resistance against erythromycin remained low. Resistance against fluoroquinolones was seasonally influenced, with relatively high rates during winter. We conclude that resistance of Campylobacter isolates to fluoroquinolones is still rising, probably because of the use of fluoroquinolones (enrofloxacin) in animal husbandry.

[Infections and bacterial resistance in the community]. / Infecties en bacteriële resistentie in de open bevolking.

The frequency of resistance to antibiotics among community acquired pathogens and the number of drugs to which they are resistant are increasing world wide. Antimicrobial resistance in the Netherlands is still low. Resistance to antimicrobial drugs is clearly linked to consumption of antibiotics within and outside of the hospital. Use of antibiotics in veterinary medicine may also contribute to the occurrence of antimicrobial resistance in human pathogens. Strategies to limit the spread of resistant strains should include encouraging the judicious use of antimicrobial agents. Guidelines for antibiotic therapy should be based on results derived from well designed surveillance studies.

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.