Justifying reimbursement for Alzheimer's diagnostics and treatments: Seeking alignment on evidence.

The increasing cost of health care combined with expensive new drugs and diagnostics is leading to more frequent gaps between regulatory and subsequent reimbursement approval decisions. As a result, persons with Alzheimer's disease may have difficulty accessing the benefit of medical advances. In contrast to the long history and established structure for drug approval, payer decision making is dispersed, not standardized, and perspectives on necessary evidence and the evaluation of this evidence differ and are often poorly defined. Particularly challenging is how to demonstrate the value of drugs and diagnostics for patients who do not yet have significant functional decline. Although discussions to develop consensus continue, clinical trials should begin to incorporate health system and patient-oriented outcomes. In some situations, additional studies designed to demonstrate value and comparative effectiveness will be needed. Such studies should examine outcomes of representative populations in community settings. To assure scientific advances in diagnosis and treatment benefit in patients, developing evidence to support reimbursement will become as important as obtaining regulatory approval.

Stimulating Research and Development of New Antibiotics While Ensuring Sustainable Use and Access: Further Insights from the DRIVE-AB Project and Others.

Global discussions are ongoing on how to stimulate antibiotic research and development in order to provide patients with new antibiotics able to address the challenges of antimicrobial resistance. In this supplement, we present nine articles derived from the research performed as part of the Innovative Medicine Initiative-funded DRIVE-AB project and others. These publications provide new evidence and arguments in the debate around economic incentives to stimulate antibiotic innovation, including characteristics, implementation and governance.

Epidemiology, microbiology, and treatment patterns of pediatric patients hospitalized with pneumonia at two hospitals in China: a patient chart review study.

BACKGROUND: The etiology, epidemiology, treatment patterns, and clinical outcomes of neonatal and pediatric pneumonia patients in China are not well reported. This retrospective chart review study aimed to describe such information among neonatal (0 to 27 days) and pediatric (28 days to <18 years) pneumonia patients in two regions of China. METHODS: Electronic medical records of pneumonia hospitalizations (aged <18 years) admitted between 2008 and 2013 from four hospitals under Guangdong Provincial Hospital of Chinese Medicine (Southern China) and between 2010 and 2014 at Peking University People's Hospital (Beijing, Northern China) were reviewed. RESULTS: The average age of neonatal hospitalizations in Beijing (n=92) was 3.5 days. The mean length of hospital stay was 11.2 days, and no deaths occurred. Staphylococcus epidermidis was the most common bacteria found in Beijing patients, whereas Mycoplasma pneumoniae was the most common bacteria found in Guangdong patients. The average age of pediatric hospitalizations was 3.3 (±3.1) and 6.5 (±5.6) years in Guangdong (n=3,046) and Beijing (n=222), respectively. The mean length of hospital stay was 17.4 and 5.8 days, and overall mortality rates were 0.2% and 0.5%. CONCLUSION: The findings revealed a low level of bacterial isolation and hence microbiological diagnoses. There was a low level of in-hospital mortality due to pneumonia, and the majority of hospitalizations were discharged from hospital, suggesting that current practice was generally effective. Neonatal hospitalizations were greater than pediatric hospitalizations in Beijing along with disparity in bacterial profile when compared with Guangdong, intending a need to improve neonatal pneumonia prophylaxis and selection of appropriate treatment.

A retrospective observational analysis of post-pandemic influenza-related outcomes in the United Kingdom, 2010-2014.

This study set out to evaluate influenza- and respiratory-related illnesses recorded during primary care physician consultations in England following the H1N1 pandemic in 2009 and to enable the development of a dynamic disease model. Data were obtained from the Clinical Practice Research Datalink of primary care records over four influenza seasons (2010-2014). The primary outcome of the study was incidence of influenza- and respiratory-related diagnoses, calculated per practice and by season and age group. Upper respiratory tract infection diagnoses were most frequently recorded (mean seasonal practice level incidence; 3,762 consultations per 100,000 [SD = 1,989]), and influenza-related diagnoses were least frequently recorded across all seasons, except one. Incidence rates for the under 18 population were higher than those for the general population, in particular for upper respiratory tract infection (range of 8,024-9,950 versus 3,228-4,120, respectively) and otitis media diagnoses (2,668-3,652 versus 782-1,057, respectively). For influenza-related diagnoses, the 65+ age group, the 0 to <2 and 2 to <4 groups had a higher risk (risk ratio = 1.33, 1.12 and 1.16, respectively) than other age groups. This study provides valuable insight into the incidence of influenza- and respiratory-related diagnoses in the primary care setting in England, and suggests a higher burden of disease in young children and the elderly. The study also indicates that some influenza illness is likely to be reported under respiratory-related diagnoses, given the low incidence of influenza-related diagnoses in the study.

Characterization of circulating RSV strains among subjects in the OUTSMART-RSV surveillance program during the 2016-17 winter viral season in the United States.

BACKGROUND: Respiratory syncytial virus (RSV) is an established cause of serious lower respiratory disease in infants, elderly and high-risk populations. The OUTSMART surveillance program aims to characterize patient populations and currently circulating RSV strains, and monitor temporal and geographic evolution of RSV F and G proteins in the U.S. METHODS: The OUTSMART 2016-17 study collected RSV-positive samples from 25 RSVAlert® laboratories from 4 U.S. regions and Puerto Rico during November 2016 through March 2017. Frequencies of A and B subtypes and genotypes were determined for several demographic and geographic variables. To gauge the representativeness of the OUTSMART patients, results were compared to discharge data from the NEDS and NIS databases. RESULTS: A total of 1,041 RSV-positive samples with associated demographic data were obtained and the RSV F gene and second variable region of the G gene were sequenced. The majority of samples (76.0%) came from children under 2 years old: <1 year (48.4%), 1-2 years (27.6%). The OUTSMART patient sample was similar to NEDS and NIS for age, gender, and geographic location. Both OUTSMART and national RSV cases peaked in January. Of OUTSMART samples, 45.3% were subtype A, 53.7% were subtype B and 1.0% were mixed A and B. The percentage of RSV B cases increased with increasing age. Hospitalization (length of hospital stay, LOS, >24 hrs) occurred in 29.0% of patients of which 52.0% had RSV B. Outpatients (LOS <24 hrs) were 64.4% of total of which 73.3% were diagnosed in the ER and discharged, while only 6% were diagnosed in other outpatient settings. CONCLUSIONS: The OUTSMART 2016-17 study was representative of the U.S. RSV experience. Geographic and temporal information from the RSV surveillance program will be used to establish a molecular baseline of RSV F and G sequence variability and to help inform development of novel agents for RSV prophylaxis and treatment.

Translation of the UK Pediatric Influenza Vaccination Programme in Primary Schools to 13 European Countries Using a Dynamic Transmission Model.

Objectives: To simulate the impact of a pediatric influenza vaccination programme using quadrivalent live attenuated influenza vaccine (QLAIV) in Europe by applying coverage rates achieved in the United Kingdom during the 2014-2015 season and to compare the model outcomes to the UK results. Methods: We used a deterministic, age-structured, dynamic transmission model adapted to the demography, contact patterns and influenza incidence of 13 European countries, with a 10-year horizon. The reference strategy was the unchanged country-specific coverage rate, using quadrivalent inactivated vaccine (assumed efficacy against infection from 45% in 1-year-old children to 60% in healthy adults). In the evaluated strategy, 56.8% of 5-10-year-old children were additionally vaccinated with QLAIV (assumed efficacy 80%), as was the case in 2014-2015 in the United Kingdom's primary school pilot areas. Symptomatic influenza cases and associated medical resources (primary care consultations [PCC], hospitalization, intensive care unit [ICU] admissions) were calculated. The evaluated versus reference strategies were compared using odds ratios (ORs) for PCC in the target (aged 5-10-years) and non-target adult (aged >17 years) populations as well as number needed to vaccinate (NNV) with QLAIV to avert one PCC, hospitalization or ICU admission. Model outcomes, averaged over 10 seasons, were compared with published real-life data from the United Kingdom for the 2014-2015 season. Results: Over 13 countries and 10 years, the evaluated strategy prevented 32.8 million of symptomatic influenza cases (172.3 vs 205.2 million). The resulting range of ORs for PCC was 0.18-0.48 among children aged 5-10-years, and the published OR in the United Kingdom was 0.06 (95% confidence interval [0.01; 0.62]). In adults, the range of ORs for PCC was 0.60-0.91 (UK OR=0.41 [0.19; 0.86]). NNV ranges were 6-19 per averted PCC (UK NNV=16), 530-1524 per averted hospitalization (UK NNV=317) and 5298-15 241 per averted ICU admission (UK NNV=2205). Conclusions: Across a range of European countries, our model shows the beneficial direct and indirect impact of a paediatric vaccination programme using QLAIV in primary school-aged children, consistent with what was observed during a single season in the United Kingdom. Recommendations for the implementation of pediatric vaccination programmes are, therefore, supported in Europe.

Hospitalizations for Respiratory Syncytial Virus Among Adults in the United States, 1997-2012.

BACKGROUND: Respiratory syncytial virus (RSV) is an established cause of serious lower respiratory disease in children, but the burden in adults is less well studied. METHODS: We conducted a retrospective study of hospitalizations among adults ≥20 years from the 1997-2012 National Inpatient Sample. Trends in RSV admissions were described relative to unspecified viral pneumonia admissions. Hospitalization severity indicators were compared among immunocompromised RSV, non-immunocompromised RSV, and influenza admissions. RESULTS: An estimated 28237 adult RSV hospitalizations occurred, compared with 652818 influenza hospitalizations; 34% were immunocompromised individuals. Respiratory syncytial virus and influenza patients had similar age, gender, and race distributions, but RSV was more often diagnosed in urban teaching hospitals (73.0% for RSV vs 34.6% for influenza) and large hospitals (71.9% vs 56.4%). Respiratory syncytial virus hospitalization rates increased from 1997 to 2012, particularly for those ≥60, increasing from 0.5 to 4.6 per 100000, whereas unspecified pneumonia admission rates decreased significantly (P < .001). Immunocompromised patients with RSV hospitalization had significantly higher inpatient mortality (P = .013), use of mechanical ventilation (P = .016), mean length of stay (LOS) (P < .001), and mean cost (P < .001) than non-immunocompromised RSV hospitalizations. Overall, RSV hospitalizations were more severe than influenza hospitalizations (6.2% mortality for RSV vs 3.0% for influenza, 16.7% vs 7.2% mechanical ventilation, mean LOS of 6.0 vs 3.6 days, and mean cost of $38828 vs $14519). CONCLUSIONS: Respiratory syncytial virus hospitalizations in adults are increasing, likely due to increasing recognition and diagnosis. The burden of RSV in adults deserves attention. Although there are fewer hospitalizations than influenza, those that are diagnosed are on average more severe.

Direct and Indirect Protection with Pediatric Quadrivalent Live-Attenuated Influenza Vaccination in Europe Estimated by a Dynamic Transmission Model.

Objectives: To estimate the public health impact of annual vaccination of children with a quadrivalent live-attenuated influenza vaccine (QLAIV) across Europe. Methods: A deterministic, age-structured, dynamic model was used to simulate influenza transmission across 14 European countries, comparing current vaccination coverage using a quadrivalent inactivated vaccine (QIV) to a scenario whereby vaccination coverage was extended to 50% of 2-17 year-old children, using QLAIV. Differential equations described demographic changes, exposure to infectious individuals, recovery and immunity dynamics. For each country, the basic reproduction number (R0) was calibrated to published influenza incidence statistics. Assumed vaccine efficacy for children was 80% (QLAIV) and 59% (QIV). Symptomatic cases cumulated over 10 years were calculated per 100 000 person-years. One-way sensitivity analyses were conducted on QLAIV efficacy in 7-17 year-olds (59% instead of 80%), durations of natural (±3 years; base case: 6, 12 years for influenza A, B respectively) and QLAIV vaccine-induced immunity (100% immunity loss after 1 season; base case: 30%), and R0 (+/-10% around all-year average value). Results: Across countries, annual QLAIV vaccination additionally prevents 1366-3604 symptomatic cases per 100 000 population (average 2495 /100 000, ie, a reduction of 47.6% of the cases which occur in the reference scenario with QIV vaccination only). Among children (2-17 years), QLAIV prevents 551-1555 cases per 100 000 population (average 990 /100 000, ie, 67.2% of current cases). Among adults, QLAIV indirectly prevents 726-2047 cases per 100 000 population (average 1466 /100 000, ie, 40.0% of current cases). The most impactful drivers of total protection were duration of natural immunity against influenza A, R0 and QLAIV immunity duration and efficacy. In all evaluated scenarios, there was a large direct and even larger indirect protection compared with the reference scenario. Conclusions: The model highlights direct and indirect protection benefits when vaccinating healthy children with QLAIV in Europe, across a range of demographic structures, contact patterns and vaccination coverage rates.

Epidemiology, microbiology and treatment implications in adult patients hospitalized with pneumonia in different regions of China: a retrospective study.

BACKGROUND: Data describing epidemiology, clinical outcomes and treatment patterns, of hospitalised patients with pneumonia in China are limited. We aimed to describe such information among adult pneumonia patients in southern and northern China. METHODS: We retrospectively reviewed electronic medical records of pneumonia patients aged ≥18 years, hospitalized between 2008 and 2013 at Guangdong Provincial Hospital of Chinese Medicine (n=3,636), southern China, and between 2010 and 2014 at Peking University People's Hospital, Beijing (n=1,689), northern China, in order to collect data on patient demographics, microbiology, clinical outcomes and treatment and resistance patterns. RESULTS: The mean (SD) age of patients was 60.0 (21.4) and 64.4 (18.4) years in Guangdong and Beijing, respectively. Mean length of hospital stay was 12.1 and 20.8 days, and overall mortality was 2.9% and 8.0%, respectively. Gram-negative bacilli were most frequently isolated, predominantly Acinetobacter baumannii, Klebsiella pneumoniae and Pseudomonas aeruginosa. Infection with these bacteria was associated with unfavourable clinical outcomes, and the antibiotic resistance among these bacteria increased between 2008-2010 and 2011-2013 in both regions of China. The treatment and choice of antibiotics slightly varied between the two regions based on the susceptible pathogens identified among their populations. CONCLUSIONS: Of the pathogens identified, Staphylococcus aureus infection (particularly the methicillin-resistant S. aureus) was associated with poor clinical outcomes; however antibiotic resistance among S. aureus generally decreased during the study data collection periods. Also, disease severity was greater in Beijing as compared with Guangdong, and this may be associated with higher microbiological diagnosis rate and higher frequency of initial antibiotic modification among Beijing populations.

Impact of increased influenza vaccination in 2-3-year-old children on disease burden within the general population: A Bayesian model-based approach.

INTRODUCTION: During the 2013-2014 influenza season, Public Health England extended routine influenza vaccination to all 2- and 3-year-old children in England. To estimate the impact of this change in policy on influenza-related morbidity and mortality, we developed a disease transmission and surveillance model informed by real-world data. METHODS: We combined real-world and literature data sources to construct a model of influenza transmission and surveillance in England. Data were obtained for four influenza seasons, starting with the 2010-2011 season. Bayesian inference was used to estimate model parameters on a season-by-season basis to assess the impact of targeting 2- and 3-year-old children for influenza vaccination. This provided the basis for the construction of counterfactual scenarios comparing vaccination rates of ~2% and ~35% in the 2- and 3- year-old population to estimate reductions in general practitioner (GP) influenza-like-illness (ILI) consultations, respiratory hospitalizations and deaths in the overall population. RESULTS: Our model was able to replicate the main patterns of influenza across the four seasons as observed through laboratory surveillance data. Targeting 2- and 3-year-old children for influenza vaccination resulted in reductions in the general population of between 6.2-9.9% in influenza-attributable GP ILI consultations, 6.1-10.7% in influenza-attributable respiratory hospitalizations, and 5.7-9.4% in influenza-attributable deaths. The decrease in influenza-attributable ILI consultations represents a reduction of between 4.5% and 7.3% across all ILI consultations. The reduction in influenza-attributable respiratory hospitalizations represents a reduction of between 1.2% and 2.3% across all respiratory hospitalizations. Reductions in influenza-attributable respiratory deaths represent a reduction of between 0.9% and 2.4% in overall respiratory deaths. CONCLUSION: This study has provided evidence that extending routine influenza vaccination to all healthy children aged 2 and 3 years old leads to benefits in terms of reduced utilization of healthcare resources and fewer respiratory health outcomes and deaths.

Ceftaroline fosamil treatment outcomes compared with standard of care among hospitalized patients with complicated skin and soft tissue infections.

AIM: Compare clinical and cost outcomes associated with ceftaroline fosamil with other commonly used antibiotics in complicated skin and soft tissue infections. METHODS: Retrospective analysis of hospital records from 2010 to 2013 in Premier's Perspective comparative database for adults with complicated skin and soft tissue infection treated with intravenous ceftaroline fosamil, vancomycin, daptomycin, linezolid or tigecycline. Length of stay, inpatient costs and mortality were compared between propensity score-matched treatment groups. RESULTS & CONCLUSION: Compared with the other commonly used antibiotics, matched patients in the ceftaroline fosamil treatment group had an equivalent (1%) or lower (compared with linezolid, 2%) in-hospital mortality rate, and significantly lower (p < 0.001) average unadjusted and regression-adjusted length of stay and inpatient costs (savings of $3398.80 compared with daptomycin).

Economic evaluation of pediatric influenza immunization program compared with other pediatric immunization programs: A systematic review.

This study compared the economic value of pediatric immunisation programmes for influenza to those for rotavirus (RV), meningococcal disease (MD), pneumococcal disease (PD), human papillomavirus (HPV), hepatitis B (Hep B), and varicella reported in recent (2000 onwards) cost-effectiveness (CE) studies identified in a systematic review of PubMed, health technology, and vaccination databases. The systematic review yielded 51 economic evaluation studies of pediatric immunisation - 10 (20%) for influenza and 41 (80%) for the other selected diseases. The quality of the eligible articles was assessed using Drummond's checklist. Although inherent challenges and limitations exist when comparing economic evaluations of immunisation programmes, an overall comparison of the included studies demonstrated cost-effectiveness/cost saving for influenza from a European-Union-Five (EU5) and United States (US) perspective; point estimates for cost/quality-adjusted life-years (QALY) from dominance (cost-saving with more effect) to ≤45,444 were reported. The economic value of influenza programmes was comparable to the other vaccines of interest, with cost/QALY in general considerably lower than RV, Hep B, MD and PD. Independent of the perspective and type of analysis, the economic impact of a pediatric influenza immunisation program was influenced by vaccine efficacy, immunisation coverage, costs, and most significantly by herd immunity. This review suggests that pediatric influenza immunisation may offer a cost effective strategy when compared with HPV and varicella and possibly more value compared with other childhood vaccines (RV, Hep B, MD and PD).

Cost-effectiveness analysis of the direct and indirect impact of intranasal live attenuated influenza vaccination strategies in children: alternative country profiles.

BACKGROUND: Influenza poses a significant burden on healthcare systems and society, with under-recognition in the paediatric population. Existing vaccination policies (largely) target the elderly and other risk groups where complications may arise. OBJECTIVE: The goal of this study was to evaluate the cost-effectiveness of annual paediatric vaccination (in 2-17-year-olds) with live attenuated influenza vaccination (LAIV), as well as the protective effect on the wider population in England and Wales (base). The study aimed to demonstrate broad applications of the model in countries where epidemiological and transmission data is limited and that have sophisticated vaccination policies (Brazil, Spain, and Taiwan). METHODS: The direct and indirect impact of LAIV in the paediatric cohort was simulated using an age-stratified dynamic transmission model over a 5-year time horizon of daily cycles and applying discounting of 3.5% in the base case. Pre-existing immunity structure was based on a 1-year model run. Sensitivity analyses were conducted. RESULTS: In the base case for England and Wales, the annual paediatric strategy with LAIV was associated with improvements in influenza-related events and quality-adjusted life years (QALYs) lost, yielding an incremental cost per QALY of £6,208. The model was robust to change in the key input parameters. The probabilistic analysis demonstrated LAIV to be cost effective in more than 99% of iterations, assuming a willingness-to-pay threshold of £30,000. Incremental costs per QALY for Brazil were £2,817, and for the cases of Spain and Taiwan the proposed strategy was dominant over the current practice. CONCLUSION: In addition to existing policies, annual paediatric vaccination using LAIV provides a cost-effective strategy that offers direct and indirect protection in the wider community. Paediatric vaccination strategies using LAIV demonstrated clinical and economic benefits over alternative (current vaccination) strategies in England and Wales as well as Brazil, Spain, and Taiwan.

Assessment of Outpatient and Inpatient Antibiotic Treatment Patterns and Health Care Costs of Patients with Complicated Urinary Tract Infections.

PURPOSE: The goal of this study was to examine treatment patterns, utilization, and costs for complicated urinary tract infections (UTIs) requiring inpatient/emergency department (ED) and outpatient care. METHODS: This observational study evaluated inpatient/ED-treated and outpatient-treated patients (aged ≥18 years) with complicated UTIs from 2 large US administrative claims databases (HealthCore Integrated Research Environment and Premier Perspective Database). Patient identification depended on treatment setting: outpatients had 2 UTI diagnosis-related office visits and 2 claims for different antibiotics within 30 days, and inpatients had a UTI-related hospitalization/ED visit after 1 UTI diagnosis-related office visit plus 2 claims for different antibiotics within 30 days. The index date for outpatients was the date of the first office visit; for inpatients, it was the date of admission/ED visit. Both cohorts had continuous insurance eligibility. Outcomes were assessed by using univariate and multivariate statistics. FINDINGS: The study sample included 1118 inpatient/ED patients (76.6% female subjects; mean age, 62.4 years) and 41,605 outpatients (85.8% female subjects; mean age, 52.3 years). Mean (SD) pharmacy costs were $2971 ($7650) for inpatient/ED patients and $1882 ($3120) for outpatients during the full treatment period. Index hospitalization/ED averaged $38,422 ($51,161). Mean all-cause 90-day follow-up costs for the inpatient/ED cohort were $34,100 ($71,621) and $11,345 ($34,313) for the outpatient cohort. IMPLICATIONS: Relative to outpatient-treated patients, inpatient/ED-treated patients were older, sicker, had higher costs across treatment periods, and had reduced antibiotic use at a lower rate during the 90-day follow-up. Strategies to avoid preventable inpatient/ED visits may help reduce costs in the management of outpatients with complicated UTIs.