Overall survival benefits of cancer drugs initially approved by the US Food and Drug Administration on the basis of immature survival data: a retrospective analysis.

BACKGROUND: New cancer drugs can be approved by the US Food and Drug Administration (FDA) on the basis of surrogate endpoints while data on overall survival are still incomplete or immature, with too few deaths for meaningful analysis. We aimed to evaluate whether clinical trials with immature survival data generated evidence of overall survival benefit during the period after marketing authorisation, and where that evidence was reported. METHODS: In this retrospective analysis, we searched Drugs@FDA to identify cancer drug indications approved between Jan 1, 2001, and Dec 31, 2018, on the basis of immature survival data. We systematically collected publicly available data on postapproval overall survival results in labelling (Drugs@FDA), journal publications (MEDLINE via PubMed), and clinical trial registries (ClinicalTrials.gov). The primary outcome was availability of statistically significant overall survival benefits during the period after marketing authorisation (until March 31, 2023). Additionally, we evaluated the availability and timing of overall survival findings in labelling, journal publications, and ClinicalTrials.gov records. FINDINGS: During the study period, the FDA granted marketing authorisation to 223 cancer drug indications, 95 of which had overall survival as an endpoint. 39 (41%) of these 95 indications had immature survival data. After a minimum of 4·3 years of follow-up during the period after marketing authorisation (and median 8·2 years [IQR 5·3-12·0] since FDA approval), additional survival data from the pivotal trials became available in either revised labelling or publications, or both, for 38 (97%) of 39 indications. Additional data on overall survival showed a statistically significant benefit in 12 (32%) of 38 indications, whereas mature data yielded statistically non-significant overall survival findings for 24 (63%) indications. Statistically significant evidence of overall survival benefit was reported in either labelling or publications a median of 1·5 years (IQR 0·8-2·3) after initial approval. The median time to availability of statistically non-significant overall survival results was 3·3 years (2·2-4·5). The availability of overall survival results on ClinicalTrials.gov varied considerably. INTERPRETATION: Fewer than a third of indications approved with immature survival data showed a statistically significant overall survival benefit after approval. Notable inconsistencies in timing and availability of information after approval across different sources emphasise the need for better reporting standards. FUNDING: None.

Financial toxicity of withdrawn poly (ADP-ribose) polymerase inhibitor indications for ovarian cancer.

OBJECTIVE: We sought to quantify exposure to and financial impacts of PARPi treatments for eventually withdrawn ovarian cancer indications. METHODS: We identified in Optum's de-identified Clinformatics® Data Mart database 1695 patients with ovarian cancer diagnoses who received olaparib, rucaparib, or niraparib between January 2015 and September 2021. We describe PARPi use and out-of-pocket (OOP), total health care, and PARPi spending among ovarian cancer patients with 3 or more prior lines of therapy (LOT). RESULTS: Of the 1695 patients who received PARPi, 254 were estimated to have been heavily pretreated and exposed to eventually withdrawn indications. Cumulative total medical and pharmacy costs for these patients were $53,392,184; PARPi costs accounted for 34%. Median PARPi cost per patient was $43,347. Cumulative out-of-pockets costs totaled $533,281. CONCLUSIONS: Potential patient harm, including financial toxicity, might have been mitigated through more stringent drug approval requirements.

Childhood cancer drugs in China: An overview and comparison of regulatory approvals in China and the United States.

Different from less developed countries, 80% of children with cancers in the United States are cured. Traditional chemotherapy drugs are the mainstay of therapies; new targeted medications have become available recently. Using publicly available data, we created a database of cancer drugs with paediatric malignancy indications approved by 31 October 2020 in China and the United States. We compared numbers, type, indications and listing on the World Health Organization Model List of Essential Medicines for Children (WHO EMLc) between the two countries, assessed the correlation between paediatric indications and cancer incidences, and described evidence supporting approvals of targeted medications in the two settings. Our study showed that by 31 October 2020, 31 and 39 cancer drugs available in China and the United States were approved for use in children, corresponding to 137 and 102 paediatric cancer indications, respectively. About half of these drugs (17 in China and 18 in the United States) were listed on the WHO EMLc. The correlation between indications and burden of disease was higher in the United States (r = 0.68) than China (r = 0.59). More traditional chemotherapy drugs were approved in China (n = 27) than the United States (n = 19). Of 20 targeted childhood anticancer medicines approved in the United States, mainly on the basis of single arm trials (27/32 indications, 84.4%), only four were approved for paediatric indications in China, at a median of 2.8 years after US Food and Drug Administration approval. A harmonised, evidence-based regulatory framework is needed to ensure approvals of needed, safe and efficacious childhood cancer drugs across the world.

Treatment of depression: Are psychotropic drugs appropriately dosed in women and in the elderly? Dosages of psychotropic drugs by sex and age in routine clinical practice.

BACKGROUND: Several researchers have shown higher concentration-dose ratios of psychotropic drugs in women and the elderly. Therefore, lower dosages of psychotropic drugs may be recommended in women and the elderly. This study describes sex- and age-related dosage of psychotropic drugs prescribed to patients with major depressive disorder (MDD) in routine clinical practice. METHOD: Influence of sex and age on dosages are analysed for the 10 most commonly prescribed drugs in our dataset consisting of 32,082 inpatients with MDD. Data stems from the European drug safety program "Arzneimittelsicherheit in der Psychiatrie". The observed sex and age differences in prescriptions are compared to differences described in literature on age- and gender-related pharmacokinetics. RESULTS: Among patients over 65 years, a statistically significant decrease in dosages with increasing age (between 0.65% and 2.83% for each increasing year of age) was observed, except for zopiclone. However, only slight or no influence of sex-related adjustment of dosage in prescriptions was found. CONCLUSION: Age appears to influence adjustment of dosage in most psychotropic drugs, but to a lower extent than data on age-related pharmacokinetics suggests. Although literature also suggests that lower dosages of psychotropic drugs may be appropriate for females, this study found women are usually prescribed the same dosage as men.

Forecasting essential childhood cancer drug need: An innovative model-based approach.

BACKGROUND: Childhood cancer outcomes in low-income and middle-income countries have not kept pace with advances in care and survival in high-income countries. A contributing factor to this survival gap is unreliable access to essential drugs. METHODS: The authors created a tool (FORx ECAST) capable of predicting drug quantity and cost for 18 pediatric cancers. FORx ECAST enables users to estimate the quantity and cost of each drug based on local incidence, stage breakdown, treatment regimen, and price. Two country-specific examples are used to illustrate the capabilities of FORx ECAST to predict drug quantities. RESULTS: On the basis of domestic public-sector price data, the projected annual cost of drugs to treat childhood cancer cases is 0.8 million US dollars in Kenya and 3.0 million US dollars in China, with average median price ratios of 0.9 and 0.1, respectively, compared with costs sourced from the Management Sciences for Health (MSH) International Medical Products Price Guide. According to the cumulative chemotherapy cost, the most expensive disease to treat is acute lymphoblastic lymphoma in Kenya, but a higher relative unit cost of methotrexate makes osteosarcoma the most expensive diagnosis to treat in China. CONCLUSIONS: FORx ECAST enables needs-based estimates of childhood cancer drug volumes to inform health system planning in a wide range of contexts. It is broadly adaptable, allowing decision makers to generate results specific to their needs. The resultant estimates of drug need can help equip policymakers and health governance institutions with evidence-informed data to advance innovative procurement strategies that drive global improvements in childhood cancer drug access.

Mitochondrial Alkbh1 localizes to mtRNA granules and its knockdown induces the mitochondrial UPR in humans and C. elegans.

The Fe(II) and 2-oxoglutarate-dependent oxygenase Alkb homologue 1 (Alkbh1) has been shown to act on a wide range of substrates, like DNA, tRNA and histones. Thereby different enzymatic activities have been identified including, among others, demethylation of N3-methylcytosine (m3C) in RNA- and single-stranded DNA oligonucleotides, demethylation of N1-methyladenosine (m1A) in tRNA or formation of 5-formyl cytosine (f5C) in tRNA. In accordance with the different substrates, Alkbh1 has also been proposed to reside in distinct cellular compartments in human and mouse cells, including the nucleus, cytoplasm and mitochondria. Here, we describe further evidence for a role of human Alkbh1 in regulation of mitochondrial protein biogenesis, including visualizing localization of Alkbh1 into mitochondrial RNA granules with super-resolution 3D SIM microscopy. Electron microscopy and high-resolution respirometry analyses revealed an impact of Alkbh1 level on mitochondrial respiration, but not on mitochondrial structure. Downregulation of Alkbh1 impacts cell growth in HeLa cells and delays development in Caenorhabditis elegans, where the mitochondrial role of Alkbh1 seems to be conserved. Alkbh1 knockdown, but not Alkbh7 knockdown, triggers the mitochondrial unfolded protein response (UPRmt) in C. elegans.

Sales of anti-cancer medicines; China, Indonesia, Kazakhstan, Malaysia, Philippines and Thailand.

OBJECTIVE: To assess sales of anti-cancer medicines in the 2017 World Health Organization's WHO Model list of essential medicines in China, Indonesia, Kazakhstan, Malaysia, Philippines and Thailand from 2007 (2008 for Kazakhstan and Malaysia) to 2017. METHODS: We extracted sales volume data for 39 anti-cancer medicines from the IQVIA database. We divided the total quantity sold by the reference defined daily dose to estimate the total number of defined daily doses sold, per country per year, for three types of anti-cancer therapies (traditional chemotherapy, targeted therapy and endocrine therapy). We adjusted these data by the number of new cancer cases in each country for each year. FINDINGS: We observed an increase in sales across all types of anti-cancer therapies in all countries. The largest number of defined daily doses of traditional chemotherapy per new cancer case was sold in Thailand; however, the largest relative increase per new cancer case occurred in Indonesia (9.48-fold). The largest absolute and relative increases in sales of defined daily doses of targeted therapies per new cancer case occurred in Kazakhstan. Malaysia sold the largest number of adjusted defined daily doses of endocrine therapies in 2017, while China and Indonesia more than doubled their adjusted sales volumes between 2007 and 2017. CONCLUSION: The use of sales data can fill an important knowledge gap in the use of anti-cancer medicines, particularly during periods of insurance coverage expansion. Combined with other data, sales volume data can help to monitor efforts to improve equitable access to essential medicines.

Integrating public preferences into national reimbursement decisions: a descriptive comparison of approaches in Belgium and New Zealand.

BACKGROUND: Public health care payer organizations face increasing pressures to make transparent and sustainable coverage decisions about ever more expensive prescription drugs, suggesting a need for public engagement in coverage decisions. However, little is known about countries' approaches to integrating public preferences in existing funding decisions. The aim of this study was to describe how Belgium and New Zealand used deliberative processes to engage the public and to identify lessons learned from these countries' approaches. METHODS: To describe two countries' deliberative processes, we first reviewed key country policy documents and then conducted semi-structured interviews with five leaders of the processes from Belgium and New Zealand. We assessed each country's rationales for and approaches to engaging the public in pharmaceutical coverage decisions and identified lessons learned. We used qualitative content analysis of the interviews to describe key themes and subthemes. RESULTS: In both countries, the national public payer organization initiated and led the process of integrating public preferences into national coverage decision making. Reimbursement criteria considered outdated and changing societal expectations prompted the change. Both countries chose a deliberative process of public engagement with a multi-year commitment of many stakeholders to develop new reimbursement processes. Both countries' new reimbursement processes put a stronger emphasis on quality of life, the separation of individual versus societal perspectives, and the importance of final reimbursement decisions being taken in context rather than based largely on cost-effectiveness thresholds. CONCLUSIONS: To face the growing financial pressure of sustainable funding of medicines, Belgium's and New Zealand's public payers have developed processes to engage the public in defining the reimbursement system's priorities. Although these countries differ in context and geographic location, they came up with overlapping lessons learnt which include the need for 1) political commitment to initiate change, 2) broad involvement of all stakeholders, and 3) commitment of all to engage in a long-term process. To evaluate these changes, further research is required to understand how coverage decisions in systems with and without public engagement differ.

A new analytic tool developed to assess safe use recommendations.

PURPOSE: Develop a flexible analytic tool for the Food and Drug Administration's (FDA's) Sentinel System to assess adherence to safe use recommendations with two capabilities: characterize adherence to patient monitoring recommendations for a drug, and characterize concomitant medication use before, during, and/or after drug therapy. METHODS: We applied the tool in the Sentinel Distributed Database to assess adherence to the labeled recommendation that patients treated with dronedarone undergo electrocardiogram (ECG) testing no less often than every 3 months. Measures of length of treatment, time to first ECG, number of ECGs, and time between ECGs were assessed. We also assessed concomitant use of contraception among female users of mycophenolate per label recommendations (concomitancy 4 weeks before through 6 weeks after discontinuation of mycophenolate). Unadjusted results were stratified by age, month-year, and sex. RESULTS: We identified 21 457 new episodes of dronedarone use of greater than or equal to 90 days (July 2009 to September 2015); 86% had greater than or equal to one ECG, and 22% met the recommendation of an ECG no less often than every 3 months. We identified 21 942 new episodes of mycophenolate use among females 12 to 55 years (January 2016 to September 2015); 16% had greater than or equal to 1 day of concomitant contraception dispensed, 12% had concomitant contraception use for greater than or equal to 50% of the 4 weeks before initiation through 6 weeks after mycophenolate; younger females had more concomitancy. These results may be underestimates as the analyses are limited to claims data. CONCLUSIONS: We developed a tool for use in databases formatted to the Sentinel Common Data Model that can assess adherence to safe use recommendations involving patient monitoring and concomitant drug use over time.

Spatial release from informational masking declines with age: Evidence from a detection task in a virtual separation paradigm.

Declines in spatial release from informational masking may contribute to the speech-processing difficulties that older adults often experience within complex listening environments. The present study sought to answer two fundamental questions: (1) Does spatial release from informational masking decline with age and, if so, (2) does age predict this decline independently of age-typical hearing loss? Younger (18-34 years) and older (60-80 years) adults with age-typical hearing completed a yes/no target-detection task with low-pass filtered noise-vocoded speech designed to reduce non-spatial segregation cues and control for hearing loss. Participants detected a target voice among two-talker masking babble while a virtual spatial separation paradigm [Freyman, Helfer, McCall, and Clifton, J. Acoust. Soc. Am. 106(6), 3578-3588 (1999)] was used to isolate informational masking release. The younger and older adults both exhibited spatial release from informational masking, but masking release was reduced among the older adults. Furthermore, age predicted this decline controlling for hearing loss, while there was no indication that hearing loss played a role. These findings provide evidence that declines specific to aging limit spatial release from informational masking under challenging listening conditions.

Total and out-of-pocket expenditures among women with metastatic breast cancer in low-deductible versus high-deductible health plans.

PURPOSE: High-deductible health plan (HDHP) enrollment is expanding rapidly and might substantially increase out-of-pocket (OOP) payment burden. We examined trends in total and OOP health service expenditures overall and by insurance coverage type among women with metastatic breast cancer. METHODS: We used a longitudinal time series design to examine measures among 5364 women with metastatic breast cancer insured by a large US health insurer from 2004 to 2011. We measured outcomes during the 12 months after a first identified metastatic breast cancer diagnosis and required women to have at least 6 months of prior enrollment. We plotted enrollment measures and adjusted total and OOP spending. We fit trend lines using linear autoregressive models. RESULTS: Between 2004 and 2011, the percentage of women with metastatic breast cancer enrolled in employer-mandated HDHPs increased from 8 to 23% while the percentage enrolled in employer-mandated low-deductible plans (LDHPs) decreased from 69 to 37%. Over the same time period, estimated annual inflation-adjusted total health service spending among women with metastatic breast cancer whose employers only offered HDHPs or LDHPS increased from $96,899 to $104,688 (increase of $1197 per year; 95% confidence interval [CI]: $47,$2,348). Corresponding OOP spending values among these women with employer-mandated deductible levels were $4,496 and $5,151 ($91 per year trend; 95% CI -$13,$195). From 2004-2011, women in HDHPs and LDHPs had unchanged annual OOP spending, estimated at of $6642 (95% CI $6,268,$7016) and $4,247 (95% CI $3956,$4538), respectively. Thus, women in HDHPs experienced 55% (44%, 66%) more OOP spending than women in LDHP. CONCLUSIONS: OOP spending among women with metastatic breast cancer and employer-mandated deductible levels was 55% higher among HDHP than LDHP members, and employer-mandated HDHP enrollment increased substantially from 2004 to 2011. Stakeholders and policymakers should design health plans that protect financially vulnerable cancer patients from high OOP costs.

Impact of high-deductible insurance on adjuvant hormonal therapy use in breast cancer.

OBJECTIVE: High-deductible health plans (HDHPs) have become the predominant commercial health insurance arrangement in the US. HDHPs require substantial out-of-pocket (OOP) costs for most services but often exempt medications from high cost sharing. We examined effects of HDHPs on OOP costs and utilization of adjuvant hormonal therapy (AHT), which are fundamental care for patients with breast cancer. METHODS: This controlled quasi-experimental study used claims data (2003-2012) from a large national health insurer. We included 986 women with incident early-stage breast cancer, age 25-64 years, insured by employers that mandated a transition from low-deductible (≤ $500/year) to high-deductible (≥ $1000/year) coverage, and 3479 propensity score-matched controls whose employers offered only low-deductible plans. We examined AHT utilization and OOP costs per person-year before and after the HDHP switch. RESULTS: At baseline, the OOP costs for AHT were $40.41 and $36.55 per person-year among the HDHP and control groups. After the HDHP switch, the OOP costs for AHT were $91.76 and $72.98 per person-year among the HDHP and control groups, respectively. AHT OOP costs increased among HDHP members relative to controls but the change was not significant (relative change 13.72% [95% CI - 9.25, 36.70%]). AHT use among HDHP members did not change compared to controls (relative change of 2.73% [95% CI - 14.01, 19.48%]); the change in aromatase inhibitor use was - 11.94% (95% CI - 32.76, 8.88%) and the change in tamoxifen use was 20.65% (95% CI - 8.01, 49.32%). CONCLUSION: We did not detect significant changes in AHT use after the HDHP switch. Findings might be related to modest increases in overall AHT OOP costs, the availability of low-cost generic tamoxifen, and patient awareness that AHT can prolong life and health. Minimizing OOP cost increases for essential medications might represent a feasible approach for maintaining medication adherence among HDHP members with incident breast cancer.

State Medicaid Reimbursement for Medications for Chronic Hepatitis C Infection from 2012 through 2015.

BACKGROUND: New direct-acting antivirals (DAAs) can cure chronic hepatitis C virus (HCV) infection. High DAA prices combined with a large number of patients needing treatment may pose substantial economic burden on health systems. OBJECTIVES: To examine Medicaid reimbursement for medications for HCV infection before and after the availability of new DAAs overall and by state and to also assess the impact of Medicaid expansion on reimbursement for DAAs. METHODS: We calculated Medicaid reimbursements for medications for HCV infection between 2012 and 2015 in all 50 states and the District of Columbia. Outcomes included inflation-adjusted Medicaid reimbursement for medications for HCV infection, market share of individual DAAs, percentages of Medicaid outpatient pharmacy reimbursement for DAAs, and Medicaid reimbursement per Medicaid enrollee with HCV infection. RESULTS: Medicaid reimbursement for medications for HCV infection increased from $723 million in 2012 to $2.35 billion in 2015. We found variations in Medicaid reimbursement for DAAs between states in 2014 (up to 7.4 times HCV infection prevalence) that widened in 2015 (0.1-11.4 times HCV infection prevalence). Expansion states had significantly higher increases in reimbursement for DAAs per enrollee with HCV infection compared with non- or late-expansion states ($2178.60; 95% confidence interval $1558.90-$2798.40), controlling for pre-expansion reimbursement. CONCLUSIONS: Medicaid reimbursement for DAAs differs across states after controlling for HCV infection prevalence. A third of states contributed more than 5% to 15% of pharmacy reimbursements to DAAs. Medications for HCV infection are only one class of highly priced specialty drugs. Innovative policy strategies are needed for health systems to manage coverage for an increasing number of expensive specialty medications indicated for an increasing number of patients.

Association Between Preapproval Confirmatory Trial Initiation and Conversion to Traditional Approval or Withdrawal in the FDA Accelerated Approval Pathway.

This study examines the Food and Drug Administration's accelerated approval pathway and whether preapproval initiation was associated with faster conversion to traditional approval or withdrawal for drugs with nononcology indications.

Drivers of expenditure on primary care prescription drugs in 10 high-income countries with universal health coverage.

BACKGROUND: Managing expenditures on pharmaceuticals is important for health systems to sustain universal access to necessary medicines. We sought to estimate the size and sources of differences in expenditures on primary care medications among high-income countries with universal health care systems. METHODS: We compared data on the 2015 volume and cost per day of primary care prescription drug therapies purchased in 10 high-income countries with various systems of universal health care coverage (7 from Europe, in addition to Australia, Canada and New Zealand). We measured total per capita expenditure on 6 categories of primary care prescription drugs: hypertension treatments, pain medications, lipid-lowering medicines, noninsulin diabetes treatments, gastrointestinal preparations and antidepressants. We quantified the contributions of 5 drivers of the observed differences in per capita expenditures. RESULTS: Across countries, the average annual per capita expenditure on the primary care medicines studied varied by more than 600%: from $23 in New Zealand to $171 in Switzerland. The volume of therapies purchased varied by 41%: from 198 days per capita in Norway to 279 days per capita in Germany. Most of the differences in average expenditures per capita were driven by a combination of differences in the average mix of drugs selected within therapeutic categories and differences in the prices paid for medicines prescribed. INTERPRETATION: Significant international differences in average expenditures on primary care medications are driven primarily by factors that contribute to the average daily cost of therapy, rather than differences in the volume of therapy used. Average expenditures were lower among single-payer financing systems that appeared to promote lower prices and the selection of lower-cost treatment options.

Racial disparities in all-cause mortality among younger commercially insured women with incident metastatic breast cancer.

Racial disparities in breast cancer mortality persist and are likely related to multiple factors. Over the past decade, progress has been made in treating metastatic breast cancer, particularly in younger women. Whether disparities exist in this population is unknown. Using administrative claims data between 2000 and 2011 (OptumInsight, Eden Prairie, MN) of members insured through a large national US health insurer, we identified women aged 25-64 years diagnosed with incident metastatic breast cancer diagnosed between November 1, 2000, and December 31, 2008. We examined time from diagnosis to death, with up to 3 years of follow-up. We stratified analyses by geocoded race and socio-economic status, age-at-diagnosis, morbidity score, US region of residence, urban/non-urban, and years of diagnosis. We constructed Kaplan-Meier survival plots and analyzed all-cause mortality using multivariate Cox proportional hazard models. Among 6694 women with incident metastatic breast cancer (78 % Caucasian, 4 % African American, and 18 % other), we found higher mortality rates among women residing in predominantly African American versus Caucasian neighborhoods (hazard ratio (HR) 1.84; 95 % confidence interval, CI 1.39-2.45), women with high versus lower morbidity (HR 1.30 [1.12-1.51]), and women whose incident metastatic diagnosis was during 2000-2004 versus 2005-2008 (HR 1.60 [1.39-1.83]). Caucasian (HR 0.61 [0.52-0.71]) but not African American women (HR not significant) experienced improved mortality in 2005-2008 versus 2000-2004. Despite insured status, African American women and women with multi-morbidity had poorer survival. Only Caucasian women had improved mortality over time. Modifiable risk factors for increased mortality need to be addressed in order to reduce disparities.

Impacts of a new insurance benefit with capitated provider payment on healthcare utilization, expenditure and quality of medication prescribing in China.

OBJECTIVES: To assess a new Chinese insurance benefit with capitated provider payment for common diseases in outpatients. METHODS: Longitudinal health insurance claims data, health administrative data and primary care facility data were used to assess trajectories in outpatient visits, inpatient admissions, expenditure per common disease outpatient (CD/OP) visit and prescribing indicators over time. We conducted segmented regression analyses of interrupted time series data to measure changes in level and trend overtime, and cross-sectional comparisons against external standards. RESULTS: The number of total outpatient visits at 46 primary care facilities (on the CD/OP benefit as of July 2012) increased by 46 895 visits/month (P = 0.004, 95% CI: 15 795-77 994); the average number of CD/OP visits reached 1.84/year/enrollee in 2012; monthly inpatient admissions dropped from 6.4 (2009) to 4.3 (2012) per 1000 enrollees; the median total expenditure per CD/OP visit dropped by CNY 15.40 (P = 0.16, 95% CI: -36.95~6.15); injectable use dropped by 7.38% (P = 0.03, 95% CI: -14.08%~-0.68%); antibiotic use was not improved. CONCLUSIONS: Zhuhai's new CD/OP benefit with capitated provider payment has expanded access to primary care, which may have led to a reduction in expensive specialist inpatient services for CD/OP benefit enrollees. Cost awareness was likely raised, and rapidly growing expenditures were contained. Although having been partially improved, inappropriate prescribing of antibiotics and injectables was still prevalent. More explicit incentives and specific quality of care targets must be incorporated into the capitated provider payment to promote scientifically sound and cost-effective care and treatment.

Thirty Years of Media Coverage on High Drug Prices in the United States--A Never-Ending Story or a Time for Change?

In recent years drug prices have increasingly become a topic of debate for patients, providers, payers and policy makers. To place the current drug price debate into historical context, we searched the New York Times and Wall Street Journal from 1985 - 2015 and found that concerns about drug prices have commonly featured in the press over the study period with recently stronger calls for change. Price levels, types of innovations, stakeholder responses, and strategies to address high prices discussed in the media suggest that concerted efforts are required to enable affordable and high-value innovations.

Does Signal Degradation Affect Top-Down Processing of Speech?

Speech perception is formed based on both the acoustic signal and listeners' knowledge of the world and semantic context. Access to semantic information can facilitate interpretation of degraded speech, such as speech in background noise or the speech signal transmitted via cochlear implants (CIs). This paper focuses on the latter, and investigates the time course of understanding words, and how sentential context reduces listeners' dependency on the acoustic signal for natural and degraded speech via an acoustic CI simulation.In an eye-tracking experiment we combined recordings of listeners' gaze fixations with pupillometry, to capture effects of semantic information on both the time course and effort of speech processing. Normal-hearing listeners were presented with sentences with or without a semantically constraining verb (e.g., crawl) preceding the target (baby), and their ocular responses were recorded to four pictures, including the target, a phonological (bay) competitor and a semantic (worm) and an unrelated distractor.The results show that in natural speech, listeners' gazes reflect their uptake of acoustic information, and integration of preceding semantic context. Degradation of the signal leads to a later disambiguation of phonologically similar words, and to a delay in integration of semantic information. Complementary to this, the pupil dilation data show that early semantic integration reduces the effort in disambiguating phonologically similar words. Processing degraded speech comes with increased effort due to the impoverished nature of the signal. Delayed integration of semantic information further constrains listeners' ability to compensate for inaudible signals.

Effects of language experience on pre-categorical perception: Distinguishing general from specialized processes in speech perception.

Cross-language differences in speech perception have traditionally been linked to phonological categories, but it has become increasingly clear that language experience has effects beginning at early stages of perception, which blurs the accepted distinctions between general and speech-specific processing. The present experiments explored this distinction by playing stimuli to English and Japanese speakers that manipulated the acoustic form of English /r/ and /l/, in order to determine how acoustically natural and phonologically identifiable a stimulus must be for cross-language discrimination differences to emerge. Discrimination differences were found for stimuli that did not sound subjectively like speech or /r/ and /l/, but overall they were strongly linked to phonological categorization. The results thus support the view that phonological categories are an important source of cross-language differences, but also show that these differences can extend to stimuli that do not clearly sound like speech.