Regulatory histories of recently withdrawn ovarian cancer treatment indications of 3 PARP inhibitors in the US and Europe: lessons for the accelerated approval pathway.

Background: Withdrawals of drug indications may reveal potential inadequacies in the regulatory approval processes of new drugs. Understanding potential weaknesses of the regulatory approval process is paramount given the increasing use of expedited pathways. In this paper, we focus on three poly-ADP-ribose polymerase inhibitors (olaparib, rucaparib and niraparib) for the treatment of women with heavily pretreated, recurrent ovarian cancer, which were eventually withdrawn. Methods: We use a comparative case study approach to evaluate the regulatory histories of these drug indications in the US and Europe. Results: Two drug indications benefited from the FDA's accelerated approval pathway, which explicitly lowers the bar for evidence of efficacy at the time of approval. Following accelerated approval, manufacturers are mandated to conduct post-marketing studies to confirm clinical benefit. The FDA granted accelerated approval to olaparib and rucaparib based on data on surrogate endpoints and converted the approval to regular approval after the submission of additional data on surrogate endpoints from one of two required confirmatory trials, that is, without data on clinical benefit. Niraparib directly received regular approval based only on data on a surrogate endpoint. By contrast, the EMA granted conditional marketing authorisation to rucaparib and was quicker to restrict usage than the FDA. Conclusion: The regulatory histories of these drug indications highlight the need to reform the accelerated approval pathway by ensuring that post-marketing requirements are followed, and that regular approval is only based on evidence of clinical benefit.

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.

Cancer drug indication approvals in China and the United States: a comparison of approval times and clinical benefit, 2001-2020.

Background: Perceived delays in cancer drug approvals have been a major concern for policymakers in China. Policies have been implemented to accelerate the launch of new cancer drugs and indications. This study aimed to assess similarities and differences between China and the United States in the approvals, timing, and clinical benefit evidence of cancer drug indications between 2001 and 2020. Methods: This study retrospectively identified all cancer drugs and indications approved in both China and the United States from January 1st, 2001 to December 31, 2020, and described differences in approval times as well as in submission and review times. Information on the availability of overall survival benefit evidence by December 31, 2020, was collected. Univariate and multiple logistic regression analyses were used to assess whether evidence of benefit and other factors affected the propensity and timing of approvals of cancer drug indications in China. Findings: Between 2001 and 2020, 229 indications corresponding to 145 cancer drugs approved in the United States were identified. Of those, 80 indications (34.9%) were also approved in China by the end of 2020. Cancer drug indications were approved in China at a median of 1273.5 days after approval in the United States. The median submission and review time differences for cancer drug indications in China were 1198.0 days and 180.0 days respectively. Submission time differences accounted for most of the approval time differences (p < 0.001). Indications supported by overall survival benefit evidence had shorter median review time differences (145.0 days) than those without such evidence (235.0 days, p = 0.008). Indications with overall survival benefit evidence were 3.94 times more likely to be approved in China compared to those without such evidence (p = 0.001), controlling for approval year, cancer type, and the prevalence of cancer by site. Interpretation: FDA-approved cancer drug indications demonstrating a survival benefit were more likely to receive approvals in China with shorter regulatory review times compared to indications without such evidence. Given that manufacturer submission times were the main driver of cancer drug approval times in China, factors influencing submission timing should be explored. Funding: No funding.

The impact of speech type on listening effort and intelligibility for native and non-native listeners.

Listeners are routinely exposed to many different types of speech, including artificially-enhanced and synthetic speech, styles which deviate to a greater or lesser extent from naturally-spoken exemplars. While the impact of differing speech types on intelligibility is well-studied, it is less clear how such types affect cognitive processing demands, and in particular whether those speech forms with the greatest intelligibility in noise have a commensurately lower listening effort. The current study measured intelligibility, self-reported listening effort, and a pupillometry-based measure of cognitive load for four distinct types of speech: (i) plain i.e. natural unmodified speech; (ii) Lombard speech, a naturally-enhanced form which occurs when speaking in the presence of noise; (iii) artificially-enhanced speech which involves spectral shaping and dynamic range compression; and (iv) speech synthesized from text. In the first experiment a cohort of 26 native listeners responded to the four speech types in three levels of speech-shaped noise. In a second experiment, 31 non-native listeners underwent the same procedure at more favorable signal-to-noise ratios, chosen since second language listening in noise has a more detrimental effect on intelligibility than listening in a first language. For both native and non-native listeners, artificially-enhanced speech was the most intelligible and led to the lowest subjective effort ratings, while the reverse was true for synthetic speech. However, pupil data suggested that Lombard speech elicited the lowest processing demands overall. These outcomes indicate that the relationship between intelligibility and cognitive processing demands is not a simple inverse, but is mediated by speech type. The findings of the current study motivate the search for speech modification algorithms that are optimized for both intelligibility and listening effort.

Overall survival benefits of cancer drugs in the WHO Model List of Essential Medicines, 2015-2021.

INTRODUCTION: We examined overall survival (OS) benefits for targeted cancer drugs recommended for List of Essential Medicines (EMLs) since 2015. We assessed consistency of decisions in 2019 and 2021 with more specific criteria: OS benefit >4 months and high scores on European Society for Medical Oncology-Magnitude of Clinical Benefit Scale (ESMO-MCBS). METHODS: We identified applications for cancer drug in WHO EMLs from 2015 to 2021. We extracted evidence of OS benefit documented in WHO Technical Report Series (TRS) and compared it to evidence from pivotal trial(s) documented in Food and Drug Administration-approved labels. We retrieved published ESMO-MCBS scores. We summarised availability and magnitude of OS benefit and ESMO-MCBS scores and assessed consistency of inclusion decisions against WHO criteria. RESULTS: 22/54 targeted cancer drug indications were recommended. Among them, 68.2% and 31.8% had OS benefit evidence documented in WHO-TRS and pivotal trials, respectively. Among those not recommended, 59.4% and 56.3% had OS benefit evidence documented in WHO-TRS and pivotal trials, respectively. Of 11 cancer drug indications recommended in 2019 and 2021, 54.5% and 9.1% had evidence of OS benefit >4 months in WHO-TRS and pivotal trials, respectively; 45.5% met ESMO-MCBS criteria. Ten targeted cancer drugs had more than one application for the same indications. Five of those were eventually recommended, including three without new evidence of OS benefit. Additional factors, such as reduced cost, and increased treatment options, seemed to be important factors in the selection. CONCLUSION: While WHO has defined approval criteria for cancer drugs EML, we identified areas where adherence of these criteria and communication of the EML approval decision-making processes can be improved.

The impact of government reimbursement negotiation on targeted anticancer medicines use and cost in China: A cohort study based on national health insurance data.

Background: High prices of targeted anticancer medicines (TAMs) result in financial toxicity for patients and the health insurance system. How national price negotiation and reimbursement policy affect the accessibility of TAMs for cancer patients remains unknown. Methods: In this population-based cohort study, we used national health insurance claims data in 2017 and identified adult patients with cancer diagnoses for which price-negotiated TAMs were indicated. We estimated the half-month prevalence of price-negotiated TAMs use before and after the policy implementation in September 2017. We calculated direct medical costs, out-of-pocket (OOP) costs, and the proportion of OOP cost for each cancer patient to measure their financial burden attributable to TAMs use. We performed segmented linear and multivariable logistic regression to analyse the policy impact. Results: We included 39 391 of a total 118 655 cancer beneficiaries. After September 2017, the prevalence of price-negotiated TAMs use increased from 1.4%-2.1% to 2.9%-3.1% (P = 0.005); TAMs users' daily medical costs increased from US$261.3 to US$292.5 (P < 0.001), while median daily OOP costs (US$68.2 vs US$65.7; P = 0.134) and OOP costs as a proportion of daily medical costs persisted (28.5% vs 28.5%; P = 0.995). Compared with resident beneficiaries, the relative probability of urban employee beneficiaries on TAMs uses decreased after the policy (adjusted odds ratio (aOR) = 2.4 vs aOR = 2.2). Conclusions: The government price negotiation and reimbursement policy improved patient access to TAMs and narrowed disparities among insurance schemes. China's approach to promoting the affordability of expensive medicines provides valuable experience for health policy decision-makers.

Effect of a national antibiotic stewardship intervention in China targeting carbapenem overuse: An interrupted time-series analysis.

OBJECTIVES: To assess trends and patterns of carbapenem use and to evaluate the effects of a nationwide antibiotic stewardship policy to reduce carbapenem overuse. METHODS: In this quasi-experimental study, using longitudinal data from the national drug procurement database and interrupted time-series analyses with carbapenems as the intervention group and possible carbapenem substitutes as the comparison group, we evaluated the effects of a national stewardship policy on carbapenem consumption and expenditures, by region and types of healthcare institutions. RESULTS: The carbapenem procurement volume declined by -28.8% (95% CI -35.0 to -22.6) (-334.4 thousand defined daily doses [DDDs] per month), and carbapenem expenditures showed a relative reduction of -38.1% (-43.9 to -32.2). The gap between the use of carbapenems and each drug in the comparison group narrowed after the policy intervention, with an increase in tigecycline use (14.9 thousand DDDs [10.8-18.9]) and a slower decrease in use of certain third-generation cephalosporin combinations (-85.7 [-143.0 to -28.4]), penicillin combinations (-200.9 [-421.4-19.6]), and fourth-generation cephalosporins (-116.9 [-219.8 to -14.0]). Consumption was highest during the pre-policy period, and declines were largest following the intervention in the eastern region (-32.1%, -39.8 to -24.4) and among tertiary hospitals (-266.2 [-339.5 to -192.9] thousand DDDs per month). CONCLUSION: This population-level drug utilization research represents the first comprehensive evaluation of the effectiveness of China's nationwide carbapenem stewardship. The national policy targeting carbapenem prescribing has led to a sustained reduction in carbapenem use with limited substitution. Effects varied geographically and were concentrated in tertiary and secondary hospitals.

Marketing authorisation and pricing of FDA-approved cancer drugs in Brazil: a retrospective analysis.

Background: Most cancer drugs enter the US market first. US Food and Drug Administration (FDA) approvals of new cancer drugs may influence regulatory decisions in other settings. The study examined whether characteristics of available evidence at FDA approval influenced time-to-marketing authorisation (MA) in Brazil, and price differences between the two countries. Methods: All new FDA-approved cancer drugs from 2010 to 2019 were matched to drugs with MA and prices approved in Brazil by December 2020. Characteristics of main studies, availability of randomised controlled trials (RCTs), overall survival (OS) benefit, added therapeutic benefit, and prices were compared. Findings: Fifty-six FDA-approved cancer drugs with matching indications received a MA at the Brazilian Health Regulatory Agency (Anvisa) after a median of 522 days following US approval (IQR: 351-932). Earlier authorisation in Brazil was associated with availability of RCT (median: 506 vs 760 days, p = 0.031) and evidence of OS benefit (390 vs 543 days, p = 0.019) at FDA approval. At Brazilian marketing authorisation, a greater proportion of cancer drugs had main RCTs (75% vs 60.7%) and OS benefit (42.9% vs 21.4%) than that in the US. Twenty-eight (50%) drugs did not demonstrate added therapeutic benefit over drugs for the same indication in Brazil. Median approved prices of new cancer drugs were 12.9% lower in Brazil compared to the US (adjusted by Purchasing Power Parity). However, for drugs with added therapeutic benefit median prices were 5.9% higher in Brazil compared to the US, while 17.9% lower for those without added benefit. Interpretation: High-quality clinical evidence accelerated the availability of cancer medicines in Brazil. The combination of marketing and pricing authorisation in Brazil may favour the approval of cancer drugs with better supporting evidence, and more meaningful clinical benefit albeit with variable degree of success in achieving lower prices compared to the US. Funding: None.

The Effectiveness of Enhanced Primary Healthcare (EnPHC) interventions on Type 2 diabetes management in Malaysia: Difference-in-differences (DID) analysis.

AIMS: To evaluate the effectiveness of the Enhanced Primary Healthcare (EnPHC) interventions on process of care and intermediate clinical outcomes among type 2 diabetes patients. METHODS: This was a quasi-experimental controlled study conducted in 20 intervention and 20 control public primary care clinics in Malaysia from November 2016 to June 2019. Type 2 diabetes patients aged 30 years and above were selected via systematic random sampling. Outcomes include process of care and intermediate clinical outcomes. Difference-in-differences analyses was conducted. RESULTS: We reviewed 12,017 medical records of patients with type 2 diabetes. Seven process of care measures improved: HbA1c tests (odds ratio (OR) 3.31, 95% CI 2.13, 5.13); lipid test (OR 4.59, 95% CI 2.64, 7.97), LDL (OR 4.33, 95% CI 2.16, 8.70), and urine albumin (OR 1.99, 95% CI 1.12, 3.55) tests; BMI measured (OR 15.80, 95% CI 4.78, 52.24); cardiovascular risk assessment (OR 174.65, 95% CI 16.84, 1810.80); and exercise counselling (OR 1.18, 95% CI 1.04, 1.33). We found no statistically significant changes in intermediate clinical outcomes (i.e. HbA1c, LDL, HDL and BP control). CONCLUSIONS: EnPHC interventions was successful in enhancing the quality of care, in terms of process of care, by changing healthcare providers behaviour.

Communication of anticancer drug benefits and related uncertainties to patients and clinicians: document analysis of regulated information on prescription drugs in Europe.

OBJECTIVE: To evaluate the frequency with which relevant and accurate information about the benefits and related uncertainties of anticancer drugs are communicated to patients and clinicians in regulated information sources in Europe. DESIGN: Document content analysis. SETTING: European Medicines Agency. PARTICIPANTS: Anticancer drugs granted a first marketing authorisation by the European Medicines Agency, 2017-19. MAIN OUTCOME MEASURES: Whether written information on a product addressed patients' commonly asked questions about: who and what the drug is used for; how the drug was studied; types of drug benefit expected; and the extent of weak, uncertain, or missing evidence for drug benefits. Information on drug benefits in written sources for clinicians (summaries of product characteristics), patients (patient information leaflets), and the public (public summaries) was compared with information reported in regulatory assessment documents (European public assessment reports). RESULTS: 29 anticancer drugs that received a first marketing authorisation for 32 separate cancer indications in 2017-19 were included. General information about the drug (including information on approved indications and how the drug works) was frequently reported across regulated information sources aimed at both clinicians and patients. Nearly all summaries of product characteristics communicated full information to clinicians about the number and design of the main studies, the control arm (if any), study sample size, and primary measures of drug benefit. None of the patient information leaflets communicated information to patients about how drugs were studied. 31 (97%) summaries of product characteristics and 25 (78%) public summaries contained information about drug benefits that was accurate and consistent with information in regulatory assessment documents. The presence or absence of evidence that a drug extended survival was reported in 23 (72%) summaries of product characteristics and four (13%) public summaries. None of the patient information leaflets communicated information about the drug benefits that patients might expect based on study findings. Scientific concerns about the reliability of evidence on drug benefits, which were raised by European regulatory assessors for almost all drugs in the study sample, were rarely communicated to clinicians, patients, or the public. CONCLUSIONS: The findings of this study highlight the need to improve the communication of the benefits and related uncertainties of anticancer drugs in regulated information sources in Europe to support evidence informed decision making by patients and their clinicians.

Liraglutide demonstrates a therapeutic effect on mitochondrial dysfunction in human SGBS adipocytes in vitro.

AIMS: Liraglutide (LG), a glucagon-like peptide-1 receptor (GLP-1R) agonist, has been shown to improve white adipose tissue mitochondrial metabolism in mice but not in human adipocytes. Therefore, we explored whether LG has therapeutic efficacy in mitochondrial dysfunction in human adipocytes in vitro. METHODS: We tested the effects of short-term (ST-LG: 24 h) and long-term (LT-LG: D0-15 days) treatments in human SGBS adipocytes on mitochondrial respiration, mRNA and protein expression. GLP-1R inhibition was investigated by the co-treatment of GLP-1R inhibitor, exendin 9-39 (Ex9-39) and ST-LG treatment. We also explored the ability of ST-LG to alleviate mitochondrial dysfunction induced by tumor necrosis factor-alpha (TNFα). RESULTS: LT-LG treatment induced the formation of smaller lipid droplets and increased the expression of genes related to lipolysis. Both ST-LG and LT-LG treatments promoted mitochondrial respiration. Additionally, LT-LG treatment increased the expression of a brown adipocyte marker, uncoupling protein 1 (UCP-1), and the markers of mitochondrial biogenesis. Interestingly, ST-LG rescued TNFα-induced defects in mitochondrial energy metabolism and inflammation in SGBS adipocytes. CONCLUSION: LG stimulates mitochondrial respiration and biogenesis in human adipocytes, potentially via UCP-1-mediated adipocyte browning. Importantly, our study demonstrates for the first time that LG has a therapeutic potential on mitochondrial activity in human adipocytes.

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.

Overall Survival Benefits of Cancer Drugs Approved in China From 2005 to 2020.

Importance: Of approximately 9 million patients with cancer in China in 2020, more than half were diagnosed with late-stage cancers. Recent regulatory reforms in China have focused on improving the availability of new cancer drugs. However, evidence on the clinical benefits of new cancer therapies authorized in China is not available. Objective: To characterize the clinical benefits of cancer drugs approved in China, as defined by the availability and magnitude of statistically significant overall survival (OS) results. Design, Setting, and Participants: This mixed-methods study comprising a systematic review and cross-sectional analysis identified antineoplastic agents approved in China between January 1, 2005, and December 31, 2020, using publicly available data and regulatory review documents issued by the National Medical Products Administration. The literature published up to June 30, 2021, was reviewed to collect results on end points used in pivotal trials supporting cancer drug approvals. Main Outcomes and Measures: The primary outcome measure was a documented statistically significant positive OS difference between a new cancer therapy and a comparator treatment. Secondary outcome measures were the magnitude of OS benefit and other primary efficacy measures in pivotal trials. Results: Between 2005 and 2020, 78 cancer drugs corresponding to 141 indications were authorized in China, including 20 drugs (25.6%) (for 30 indications) approved in China only. Of all indications, 26 (18.4%) were evaluated in single-arm or dose-optimization trials, most of which were authorized after 2017. By June 30, 2021, 34 drug indications (24.1%) had a documented lack of OS gain. For 68 indications (48.2%) that had documented evidence of OS benefit, the median magnitude of OS improvement was 4.1 (range, 1.0-35.0) months. After a median follow-up of 1.9 (range, 1.0-11.1) years from approval, OS data for 13 indications (9.2%) were either not reported or were still not mature. Fewer than one-third of cancer drug indications approved in China only had documented evidence of OS benefits (9 of 30 [30.0%]), whereas more than one-half of the cancer drug indications also available in the US or Europe had OS benefits (59 of 111 [53.1%]). Conclusions and Relevance: In this study, almost half of cancer drug indications approved in China had demonstrated OS gain. With the increase of cancer drug approvals based on single-arm trials or immature survival data in recent years, these findings highlight the need to routinely monitor the clinical benefits of new cancer therapies in China.

New-Onset Cancer Cases in FDA's Sentinel System: A Large Distributed System of US Electronic Healthcare Data.

BACKGROUND: Evaluations of cancer etiology and safety and effectiveness of cancer treatments are predicated on large numbers of patients with sufficient baseline and follow-up data. To assess feasibility of FDA's Sentinel System's electronic healthcare data for surveillance of malignancy onset and examination of product safety, this study examined patterns of enrollment surrounding new-onset cancers. METHODS: Using a retrospective cohort of patients based on administrative claims, we identified incident events of 19 cancers among 292.5 million health plan members from January 2000 to February 2020 using International Classification of Diseases (ICD) diagnosis codes. Annual incident cases were stratified by sex, age, medical and drug coverage, and insurer type. Descriptive statistics were calculated for observable time prior to and following diagnosis. RESULTS: We identified 10,697,573 incident cancer events among members with medical coverage. When drug coverage was additionally required, number of incident cancers was reduced by 41%. Medicare data contributed 61% of cases, with similar duration trends as other insurers. Mean duration of follow-up prior to diagnosis ranged from 4.0 to 4.6 years, whereas follow-up post diagnosis ranged from 1.1 to 3.3 years. Approximately a third (36.1%) had at least 2 years both prior to and following diagnosis. CONCLUSIONS: The FDA Sentinel System's electronic healthcare data may be useful for characterizing relatively short latency cancer risk, examining cancer drug utilization and safety after diagnosis, and conducting surveillance for acute adverse events among patients with cancers. IMPACT: A national distributed system with electronic health data, the Sentinel system provides opportunity for rapid pharmacoepidemiologic assessments relevant in oncology.

Preventing White Adipocyte Browning during Differentiation In Vitro: The Effect of Differentiation Protocols on Metabolic and Mitochondrial Phenotypes.

Mitochondrial dysfunction in white adipose tissue is strongly associated with obesity and its metabolic complications, which are important health challenges worldwide. Human adipose-derived stromal/stem cells (hASCs) are a promising tool to investigate the underlying mechanisms of such mitochondrial dysfunction and to subsequently provide knowledge for the development of treatments for obesity-related pathologies. A substantial obstacle in using hASCs is that the key compounds for adipogenic differentiation in vitro increase mitochondrial uncoupling, biogenesis, and activity, which are the signature features of brown adipocytes, thus altering the white adipocyte phenotype towards brown-like cells. Additionally, commonly used protocols for hASC adipogenic differentiation exhibit high variation in their composition of media, and a systematic comparison of their effect on mitochondria is missing. Here, we compared the five widely used adipogenic differentiation protocols for their effect on metabolic and mitochondrial phenotypes to identify a protocol that enables in vitro differentiation of white adipocytes and can more faithfully recapitulate the white adipocyte phenotype observed in human adipose tissue. We developed a workflow that included functional assays and morphological analysis of mitochondria and lipid droplets. We observed that triiodothyronine- or indomethacin-containing media and commercially available adipogenic media induced browning during in vitro differentiation of white adipocytes. However, the differentiation protocol containing 1 µM of the peroxisome proliferator-activated receptor gamma (PPARγ) agonist rosiglitazone prevented the browning effect and would be proposed for adipogenic differentiation protocol for hASCs to induce a white adipocyte phenotype. Preserving the white adipocyte phenotype in vitro is a crucial step for the study of obesity and associated metabolic diseases, adipose tissue pathologies, such as lipodystrophies, possible therapeutic compounds, and basic adipose tissue physiology.

Use of Palliative Care Among Commercially Insured Patients With Metastatic Cancer Between 2001 and 2016.

PURPOSE: Early palliative care, concomitant with disease-directed treatments, is recommended for all patients with advanced cancer. This study assesses population-level trends in palliative care use among a large cohort of commercially insured patients with metastatic cancer, applying an expanded definition of palliative care services based on claims data. METHODS: Using nationally representative commercial insurance claims data, we identified patients with metastatic breast, colorectal, lung, bronchus, trachea, ovarian, esophageal, pancreatic, and liver cancers and melanoma between 2001 and 2016. We assessed the annual proportions of these patients who received services specified as, or indicative of, palliative care. Using Cox proportional hazard models, we assessed whether the time from diagnosis of metastatic cancer to first encounter of palliative care differed by demographic characteristics, socioeconomic factors, or region. RESULTS: In 2016, 36% of patients with very poor prognosis cancers received a service specified as, or indicative of, palliative care versus 18% of those with poor prognosis cancers. Being diagnosed in more recent years (2009-2016 v 2001-2008: hazard ratio [HR], 1.8; P < .001); a diagnosis of metastatic esophagus, liver, lung, or pancreatic cancer, or melanoma (v breast cancer, eg, esophagus HR, 1.89; P < .001); a greater number of comorbidities (American Hospital Formulary Service classes > 10 v 0: HR, 1.71; P < .001); and living in the Northeast (HR, 1.43; P < .001) or Midwest (v South: HR, 1.39; P < .001) were the strongest predictors of shorter time from diagnosis to palliative care. CONCLUSION: Use of palliative care among commercially insured patients with advanced cancers has increased since 2001. However, even with an expanded definition of services specified as, or indicative of, palliative care, < 40% of patients with advanced cancers received palliative care in 2016.

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.