Association between treatment and improvements in overall survival of patients with advanced/metastatic non-small cell lung cancer since 2011: A study in the United States, Canada, and Germany using retrospective real-world databases.

BACKGROUND: This study aimed to describe treatment patterns and overall survival (OS) in patients with advanced non-small cell lung cancer (aNSCLC) in three countries between 2011 and 2020. METHODS: Three databases (US, Canada, Germany) were used to identify incident aNSCLC patients. OS was assessed from the date of incident aNSCLC diagnosis and, for patients who received at least a first line of therapy (1LOT), from the date of 1LOT initiation. In multivariable analyses, we analyzed the influence of index year and type of prescribed treatment on OS. FINDINGS: We included 51,318 patients with an incident aNSCLC diagnosis. The percentage of patients treated with a 1LOT differed substantially between countries, whereas the number of patients receiving immunotherapies/targeted treatments increased over time in all three countries. Median OS from the date of incident diagnosis was 9.9 months in the United States vs. 4.1 months in Canada. When measured from the start of 1LOT, patients had a median OS of 10.7 months in the United States, 10.9 months in Canada, and 10.9 months in Germany. OS from the start of 1LOT improved in all three countries from 2011 to 2020 by approximately 3 to 4 months. CONCLUSIONS: Observed continuous improvement in OS among patients receiving at least a 1LOT from 2011 to 2020 was likely driven by improved care and changes in the treatment landscape. The difference in the proportion of patients receiving a 1LOT in the observed countries requires further investigation.

Is the price right? Paying for value today to get more value tomorrow.

BACKGROUND: Contemporary debates about drug pricing feature several widely held misconceptions, including the relationship between incentives and innovation, the proportion of total healthcare spending on pharmaceuticals, and whether the economic evaluation of a medicine can be influenced by things other than clinical efficacy. MAIN BODY: All citizens should have access to timely, equitable, and cost-effective care covered by public funds, private insurance, or a combination of both. Better managing the collective burden of diseases borne by today's and future generations depends in part on developing better technologies, including better medicines. As in any innovative industry, the expectation of adequate financial returns incentivizes innovators and their investors to develop new medicines. Estimating expected returns requires that they forecast revenues, based on the future price trajectory and volume of use over time. How market participants decide what price to set or accept can be complicated, and some observers and stakeholders want to confirm whether the net prices society pays for novel medicines, whether as a reward for past innovation or an incentive for future innovation, are commensurate with those medicines' incremental value. But we must also ask "value to whom?"; medicines not only bring immediate clinical benefits to patients treated today, but also can provide a broad spectrum of short- and long-term benefits to patients, their families, and society. Spending across all facets of healthcare has grown over the last 25 years, but both inpatient and outpatient spending has outpaced drug spending growth even as our drug armamentarium is constantly improving with safer and more effective medicines. In large part, this is because, unlike hospitals, drugs typically go generic, thus making room in our budgets for new and better ones, even as they often keep patients out of hospitals, driving further savings. CONCLUSION: A thorough evaluation of drug spending and value can help to promote a better allocation of healthcare resources for both the healthy and the sick, both of whom must pay for healthcare. Taking a holistic approach to assessing drug value makes it clear that a branded drug's value to a patient is often only a small fraction of the drug's total value to society. Societal value merits consideration when determining whether and how to make a medicine affordable and accessible to patients: a drug that is worth its price to society should not be rendered inaccessible to ill patients by imposing high out-of-pocket costs or restricting coverage based on narrow health technology assessments (HTAs). Furthermore, recognizing the total societal cost of un- or undertreated conditions is crucial to gaining a thorough understanding of what guides the biomedical innovation ecosystem to create value for society. It would be unwise to discourage the development of new solutions without first appreciating the cost of leaving the problems unsolved.

Acceptability of Using Real-World Data to Estimate Relative Treatment Effects in Health Technology Assessments: Barriers and Future Steps.

OBJECTIVES: Evidence about the comparative effects of new treatments is typically collected in randomized controlled trials (RCTs). In some instances, RCTs are not possible, or their value is limited by an inability to capture treatment effects over the longer term or in all relevant population subgroups. In these cases, nonrandomized studies (NRS) using real-world data (RWD) are increasingly used to complement trial evidence on treatment effects for health technology assessment (HTA). However, there have been concerns over a lack of acceptability of this evidence by HTA agencies. This article aims to identify the barriers to the acceptance of NRS and steps that may facilitate increases in the acceptability of NRS in the future. METHODS: Opinions of the authorship team based on their experience in real-world evidence research in academic, HTA, and industry settings, supported by a critical assessment of existing studies. RESULTS: Barriers were identified that are applicable to key stakeholder groups, including HTA agencies (eg, the lack of comprehensive methodological guidelines for using RWD), evidence generators (eg, avoidable deviations from best practices), and external stakeholders (eg, data controllers providing timely access to high-quality RWD). Future steps that may facilitate future acceptability of NRS include improvements in the quality, integration, and accessibility of RWD, wider use of demonstration projects to highlight the value and applicability of nonrandomized designs, living, and more detailed HTA guidelines, and improvements in HTA infrastructure relating to RWD. CONCLUSION: NRS can represent a crucial source of evidence on treatment effects for use in HTA when RCT evidence is limited.

Distributional Cost-Effectiveness Analysis of Health Technologies: Data Requirements and Challenges.

Governments and health technology assessment agencies are putting greater focus on and efforts in understanding and addressing health inequities. Cost-effectiveness analyses are used to evaluate the costs and health gains of different interventions to inform the decision-making process on funding of new treatments. Distributional cost-effectiveness analysis (DCEA) is an extension of cost-effectiveness analysis that quantifies the equity impact of funding new treatments. Key challenges for the routine and consistent implementation of DCEA are the lack of clearly defined equity concerns from decision makers and endorsed measures to define equity subgroups and the availability of evidence that allows analysis of differences in data inputs associated with the equity characteristics of interest. In this article, we detail the data gaps and challenges to build robust DCEA analysis routinely in health technology assessment and suggest actions to overcome these hurdles.

The value of innovation: association between improvements in survival of advanced and metastatic non-small cell lung cancer and targeted and immunotherapy.

BACKGROUND: Significant improvements in mortality among patients with non-small cell lung cancer (NSCLC) in the USA over the past two decades have been reported based on Surveillance, Epidemiology, and End Results (SEER) data. The timing of these improvements led to suggestions that they result from the introduction of new treatments; however, few studies have directly investigated this. The aim of this study was to investigate the extent to which population level improvements in survival of advanced and/or metastatic NSCLC (admNSCLC) patients were associated with changes in treatment patterns. METHODS: We utilized a de-identified database to select three cohorts of patients with admNSCLC: (1) patients with non-oncogene (EGFR/ALK/ROS1/BRAF) positive tumors, (2) patients with ALK-positive (ALK+) tumors, and (3) patients with EGFR-positive (EGFR+) tumors. All patients were diagnosed with admNSCLC between 2012 and 2019. Multivariable Cox models adjusting for baseline characteristics and receipt of targeted and immunotherapy were utilized to explore the relationship between these variables and changes in the hazard of death by calendar year in each cohort. RESULTS: We included 28,154 admNSCLC patients with non-oncogene positive tumors, 598 with ALK+ tumors, and 2464 with EGFR+ tumors eligible for analysis. After adjustment for differences in baseline characteristics, the hazard of death in patients who had non-oncogene positive tumors diagnosed in 2015, 2016, 2017, 2018 ,and 2019 was observed to be 12%, 11%, 17%, 20%, and 21% lower respectively than that for those diagnosed in 2012. Upon additionally adjusting for receipt of first line or second line immunotherapy, the decrease in the hazard of death by calendar year was no longer observed, suggesting improvements in survival observed over time may be explained by the introduction of these treatments. Similarly, decreases in the hazard of death were only observed in patients with ALK+ tumors diagnosed between 2017 and 2019 relative to 2012 but were no longer observed following adjustment for the use of 1st and later generation ALK inhibitors. Among patients with EGFR+ tumors, the hazard of death did not improve significantly over time. CONCLUSION: Our findings expand on the SEER data and provide additional evidence suggesting improvements in survival of patients with advanced and metastatic NSCLC over the past decade could be explained by the change in treatment patterns over this period.

Consistency of recording of chemotherapy cycles in the National Cancer Registration and Analysis Service Systemic Anti-Cancer Therapy database and the Hospital Episode Statistics Admitted Patient Care database.

Aim: We assessed the extent to which chemotherapy cycles recorded in Hospital Episode Statistics (HES) Admitted Patient Care (APC) were captured in National Cancer Registration & Analysis Service Systemic Anti-Cancer Therapy (SACT) for a cohort of lung cancer patients. Methods: All chemotherapy cycles recorded for linkage eligible lung cancer patients with a National Cancer Registration & Analysis Service diagnosis between 2012 and 2015 were identified in HES APC and SACT. Results: Among a population of 4070 lung cancer patients, 6076 chemotherapy cycles were observed in HES APC data. A total of 61% of cycles were recorded in SACT on the same day, 8% on a different day and 31% were not recorded in SACT. Conclusion: Our results suggest that SACT may not capture all chemotherapy cycles administered to a patient between 2012 and 2016; however, administrative changes mean data after this period may be more complete.

Factors associated with non-prescription of oral anticoagulant treatment in non-valvular atrial fibrillation patients with dementia: a CPRD-HES study.

Dementia is a common comorbidity in patients with atrial fibrillation (AF) and treatment guidelines recommend oral anticoagulant (OAC) therapy for AF patients with dementia unless concordance cannot be ensured by the caregiver. Despite this, the literature reports a low prescribing of OAC treatment in these patients. This study investigated possible factors associated with non-prescribing of OAC treatment in dementia patients newly diagnosed with non-valvular atrial fibrillation (NVAF) at age ≥ 65 years between 2013 and 2017 using the Clinical Practice Research Datalink and Hospital Episodes Statistics databases. Of 1090 dementia patients newly diagnosed with NVAF, 693 (63.6%) patients did not have a prescription for an OAC in the year following their diagnosis. The likelihood of experiencing a thromboembolic event was high, with 97% of the population having a CHA2DS2-VASc score > 2; however, little difference in the presence of stroke risk factors was observed between the prescribed and non-prescribed groups. The presence of bleeding risk factors was high; only 28 (2.6%) of patients did not have a previous fall or a HAS-BLED bleeding risk factor. A history of falls [OR = 0.76, 95% confidence intervals (CIs) (0.58, 0.98)], previous major bleed [OR = 0.56, 95% CI (0.43, 0.73)] and care home residence [OR = 0.47, 95% CI (0.30, 0.74)] were associated with not having an OAC prescription. The results suggest that dementia patients with NVAF and certain risk bleeding risk factors are less likely to be prescribed an OAC. Further work is needed to establish possible relationships between bleeding risk factors and other potential drivers of OAC prescribing.

The use of UK primary care databases in health technology assessments carried out by the National Institute for health and care excellence (NICE).

BACKGROUND: Real world evidence (RWE) is becoming more frequently used in technology appraisals (TAs). This study sought to explore the use and acceptance of evidence from primary care databases, a key source of RWE in the UK, in National Institute for Health and Care Excellence (NICE) technology assessments and to provide recommendations regarding their use in future submissions. METHODS: A keyword search was conducted relating to the main primary care databases in the UK on the NICE website. All NICE TAs identified through this search were screened, assessed for duplication and information on the data source and the way the data was used in the submission were extracted. Comments by the evidence review group (ERG) and the appraisal committee were also extracted and reviewed. All data extraction was performed by two independent reviewers and all decisions were reached by consensus with an additional third reviewer. RESULTS: A total of 52 NICE TAs were identified, 47 used the General Practice Research Database /Clinical Practice Research Datalink (GPRD/CPRD) database, 10 used The Health Improvement Network (THIN) database and 3 used the QResearch databases. Data from primary care databases were used to support arguments regarding clinical need and current treatment in 33 NICE TAs while 36 were used to inform input parameters for economic models. The databases were sometimes used for more than one purpose. The data from the three data sources were generally well received by the ERGs/committees. Criticisms of the data typically occurred where the results had been repurposed from a published study or had not been applied appropriately. CONCLUSIONS: The potential of UK primary care databases in NICE submissions is increasingly being realised, particularly in informing the parameters of economic models. Purpose conducted studies are less likely to receive criticism from ERGs/committees, particularly when providing clinical input into cost effectiveness models.

Identification of genetic variants affecting vitamin D receptor binding and associations with autoimmune disease.

Large numbers of statistically significant associations between sentinel SNPs and case-control status have been replicated by genome-wide association studies. Nevertheless, few underlying molecular mechanisms of complex disease are currently known. We investigated whether variation in binding of a transcription factor, the vitamin D receptor (VDR), whose activating ligand vitamin D has been proposed as a modifiable factor in multiple disorders, could explain any of these associations. VDR modifies gene expression by binding DNA as a heterodimer with the Retinoid X receptor (RXR). We identified 43,332 genetic variants significantly associated with altered VDR binding affinity (VDR-BVs) using a high-resolution (ChIP-exo) genome-wide analysis of 27 HapMap lymphoblastoid cell lines. VDR-BVs are enriched in consensus RXR::VDR binding motifs, yet most fell outside of these motifs, implying that genetic variation often affects the binding affinity only indirectly. Finally, we compared 341 VDR-BVs replicating by position in multiple individuals against background sets of variants lying within VDR-binding regions that had been matched in allele frequency and were independent with respect to linkage disequilibrium. In this stringent test, these replicated VDR-BVs were significantly (q < 0.1) and substantially (>2-fold) enriched in genomic intervals associated with autoimmune and other diseases, including inflammatory bowel disease, Crohn's disease and rheumatoid arthritis. The approach's validity is underscored by RXR::VDR motif sequence being predictive of binding strength and being evolutionarily constrained. Our findings are consistent with altered RXR::VDR binding contributing to immunity-related diseases. Replicated VDR-BVs associated with these disorders could represent causal disease risk alleles whose effect may be modifiable by vitamin D levels.

Real-world data and the patient perspective: the PROmise of social media?

Understanding the patient perspective is fundamental to delivering patient-centred care. In most healthcare systems, however, patient-reported outcomes are not regularly collected or recorded as part of routine clinical care, despite evidence that doing so can have tangible clinical benefit. In the absence of the routine collection of these data, research is beginning to turn to social media as a novel means to capture the patient voice. Publicly available social media data can now be analysed with relative ease, bypassing many logistical hurdles associated with traditional approaches and allowing for accelerated and cost-effective data collection. Existing work has shown these data can offer credible insight into the patient experience, although more work is needed to understand limitations with respect to patient representativeness and nuances of captured experience. Nevertheless, linking social media to electronic medical records offers a significant opportunity for patient views to be systematically collected for health services research and ultimately to improve patient care.

Prodromal symptoms of multiple sclerosis in primary care.

OBJECTIVE: Early diagnosis and treatment initiation significantly influence long-term disability outcome in multiple sclerosis (MS). We aimed at identifying prodromal symptoms of MS in primary care settings. METHODS: This was a nested case-control study comparing the occurrence of various symptoms in MS patients versus controls at 0 to 2, 2 to 5, and 5 to 10 years before index date (first MS record). A total of 10,204 incident MS cases were identified within the United Kingdom Clinical Practice Research Datalink between January 1, 1987 and February 28, 2016 (median age = 47 years, interquartile range [IQR] = 39-57, females = 7,308 [71.6%]). Patients were matched to 39,448 controls with no MS record by sex, year of birth, general practitioner, and year of registration (age = 47 years, IQR = 39-56, females = 28,248 [71.6%]). Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using conditional logistic regression. RESULTS: MS patients had significantly higher risk of presenting up to 10 years prior to index date with gastric, intestinal, urinary, and anorectal disturbances, anxiety, depression, insomnia, fatigue, headache, and various types of pain. MS risk progressively increased with each additional symptom presented (0-2 years: OR = 1.51, 95% CI = 1.47-1.55, p < 0.001; 2-5 years: OR = 1.29, 95% CI = 1.25-1.33, p < 0.001; 5-10 years: OR = 1.20, 95% CI = 1.15-1.26, p < 0.001). Sensitivity analyses in patients with age at index < 40 years and no neurological disturbances prior to symptoms of interest showed consistent results. INTERPRETATION: Various clinical disturbances precede MS diagnosis by several years, supporting a prodromal phase to the disease and improving our clinical knowledge of early MS. Integrating these symptoms in the diagnostic procedure may help earlier disease identification. Ann Neurol 2018.

Prevalence of Anti-JC Virus Antibody Seropositivity in Patients with Multiple Sclerosis: A Systematic Review and Meta-Analysis.

BACKGROUND: The John Cunningham virus (JCV) is the causative agent of progressive multifocal leukoencephalopathy. Anti-JCV antibody seropositivity is an important consideration in patients with multiple sclerosis (MS). The reported prevalence of JCV in MS patients has been conflicting. OBJECTIVE: We aimed to conduct a systematic review and meta-analysis to estimate the pooled prevalence of anti-JCV antibody seropositivity in cases with MS. METHODS: We searched PubMed, Scopus, EMBASE, CINAHL, Web of Science, Ovid, ProQuest, Google Scholar, and gray literature including reference of included studies, and conference abstracts which were published up to April 2019. Two independent researchers independently assessed the articles. RESULTS: The literature search found 181 articles. After eliminating duplicates, reviews, case reports, and trials, 15 articles remained. Finally, 8 articles were included for the final analysis (from Asia, Europe, the USA, and Canada). In total, 16,041 MS cases were analyzed. The prevalence of anti-JCV antibody seropositivity varied between 40 and 80%, and the pooled estimate was calculated as 60% (95% CI: 56-64%), though with significant heterogeneity (I2 = 95%, p = 0.01). CONCLUSION: The prevalence of anti-JCV antibody seropositivity is variable among MS patients in different countries, and the pooled estimate showed that this is 60% overall.

Age at menarche and risk of multiple sclerosis (MS): a systematic review and meta-analysis.

BACKGROUND: Some studies have looked at the age at menarche and risk of Multiple Sclerosis (MS).We aimed to conduct a systematic review and meta-analysis to estimate a pooled odds ratio of developing MS by increasing age at menarche. METHODS: We searched PubMed, Scopus, EMBASE, CINAHL, Web of Science, Ovid, google scholar and gray literature (references of references, congress abstracts) up to 10th April 2019. RESULTS: The literature search found 312 articles. After eliminating duplicates, reviews, case reports and trials, 18 articles remained. Three articles were ultimately included in the final analysis. Two studies were from Iran, and one from Canada. The pooled odds ratio (OR) for increasing 1 year of age at menarche was 0.88 (95% CI:0.82-0.94), with no significant heterogeneity (I2 = 49%, p = 0.1). Mean age at menarche was significantly different between case and control groups (mean difference = - 0.22, 95% CI = -0.42,-0.02). CONCLUSION: The result of this systematic review showed that the risk of MS decreases by increasing age at menarche.

Automated extraction of treatment patterns from social media posts: an exploratory analysis in renal cell carcinoma.

Aim: The use of health-related social media forums by patients is increasing and the size of these forums creates a rich record of patient opinions and experiences, including treatment histories. This study aimed to understand the possibility of extracting treatment patterns in an automated manner for patients with renal cell carcinoma, using natural language processing, rule-based decisions, and machine learning. Patients & methods: Obtained results were compared with those from published observational studies. Results: 42 comparisons across seven therapies, three lines of treatment, and two-time periods were made; 37 of the social media estimates fell within the variation seen across the published studies. Conclusion: This exploratory work shows that estimating treatment patterns from social media is possible and generates results within the variation seen in published studies, although further development and validation of the approach is needed.

Suspected cancer symptoms and blood test results in primary care before a diagnosis of lung cancer: a case-control study.

Aim: To compare symptoms and blood test results prior to cancer diagnosis in individuals who developed lung cancer and those who did not. Patients & methods: Nested case-control study, lung cancer patients were matched to up four controls with no record of cancer. Differences in symptoms and blood test results were investigated in the 2-year period prior to diagnosis. Results: 26,379 lung cancer patients were matched to 92,125 controls. Elevated C-reactive protein (CRP) was independently predictive of lung cancer at every 2-month interval 12 months prior to diagnosis. Elevated CRP in conjunction with at least one symptom was associated with greater than fourfold higher odds of lung cancer. Conclusion: CRP may be a prediagnostic marker for lung cancer, and when present with other symptoms could facilitate the investigation of high-risk individuals.

Extracting data from a chemotherapy prescription platform for real-world oncology research in the UK: a pilot study.

Aim: In the UK, there are limited data sources for evaluating real-world research questions related to oncology therapy. We conducted a pilot study to investigate the feasibility of extracting data directly from a chemotherapy prescription platform (ChemoCare®) utilized in standard care. Patients & methods: Concordance was compared with data extracted manually for patients with advanced melanoma as part of a concurrent chart review (gold-standard) using Cohen's kappa and the intraclass correlation coefficient. Results: There was high concordance between data automatically extracted from the prescription platform and chart review data. Conclusion: This pilot can be used as a framework for future studies using direct, automated extraction from prescription platforms.

Comparison of accelerometer-derived physical activity levels between individuals with and without cancer: a UK Biobank study.

Aim: To identify the difference in physical activity (PA) levels between individuals with and without cancer, and to estimate all-cause mortality associated with this difference. Methods: Current cancer, cancer survivor and cancer-free groups were identified from the UK Biobank. We used multivariate and Cox regression to estimate PA differences and association of PA with all-cause mortality. Results: Compared with the cancer-free individuals, participants in the two cancer groups had fewer minutes in moderate-to-vigorous PA per day in adjusted analyses. The PA difference was associated with higher mortality in the current cancer group. Conclusion: Patients with a history of cancer were less active than those without cancer, and PA is associated with increased mortality. PA improvement strategies in cancer patients must be explored.

Exploring the effect of vitamin D3 supplementation on the anti-EBV antibody response in relapsing-remitting multiple sclerosis.

BACKGROUND: Epstein-Barr virus (EBV) infection and vitamin D insufficiency are potentially interacting risk factors for multiple sclerosis (MS). OBJECTIVES: To investigate the effect of high-dose vitamin D3 supplements on antibody levels against the EBV nuclear antigen-1 (EBNA-1) in patients with relapsing-remitting multiple sclerosis (RRMS) and to explore any underlying mechanism affecting anti-EBNA-1 antibody levels. METHODS: This study utilized blood samples from a randomized controlled trial in RRMS patients receiving either vitamin D3 (14,000 IU/day; n = 30) or placebo ( n = 23) over 48 weeks. Circulating levels of 25-hydroxyvitamin-D, and anti-EBNA-1, anti-EBV viral capsid antigen (VCA), and anti-cytomegalovirus (CMV) antibodies were measured. EBV load in leukocytes, EBV-specific cytotoxic T-cell responses, and anti-EBNA-1 antibody production in vitro were also explored. RESULTS: The median antibody levels against EBNA-1, but not VCA and CMV, significantly reduced in the vitamin D3 group (526 (368-1683) to 455 (380-1148) U/mL) compared to the placebo group (432 (351-1280) to 429 (297-1290) U/mL; p = 0.023). EBV load and cytotoxic T-cell responses were unaffected. Anti-EBNA-1 antibody levels remained below detection limits in B-cell cultures. CONCLUSION: High-dose vitamin D3 supplementation selectively reduces anti-EBNA-1 antibody levels in RRMS patients. Our exploratory studies do not implicate a promoted immune response against EBV as the underlying mechanism.