Delivering the precision oncology paradigm: reduced R&D costs and greater return on investment through a companion diagnostic informed precision oncology medicines approach.

BACKGROUND: Precision oncology medicines represent a paradigm shift compared to non-precision oncology medicines in cancer therapy, in some situations delivering more clinical benefit, and potentially lowering healthcare costs. We determined whether employing a companion diagnostic (CDx) approach during oncology medicines development delivers effective therapies that are within the cost constraints of current health systems. R&D costs of developing a medicine are subject to debate, with average estimates ranging from $765 million (m) to $4.6 billion (b). Our aim was to determine whether precision oncology medicines are cheaper to bring from R&D to market; a secondary goal was to determine whether precision oncology medicines have a greater return on investment (ROI). METHOD: Data on oncology medicines approved between 1997 and 2020 by the US Food and Drug Administration (FDA) were analysed from the Securities and Exchange Commission (SEC) filings. Data were compiled from 10-K, 10-Q, and 20-F financial performance filings on medicines' development costs through their R&D lifetime. Clinical trial data were split into clinical trial phases 1-3 and probability of success (POS) of trials was calculated, along with preclinical costs. Cost-of-capital (CoC) approach was applied and, if appropriate, a tax rebate was subtracted from the total. RESULTS: Data on 42 precision and 29 non-precision oncology medicines from 56 companies listed by the National Cancer Institute which had complete data available were analysed. Estimated mean cost to deliver a new oncology medicine was $4.4b (95% CI, $3.6-5.2b). Costs to bring a precision oncology medicine to market were $1.1b less ($3.5b; 95% CI, $2.7-4.5b) compared to non-precision oncology medicines ($4.6b; 95% CI, $3.5-6.1b). The key driver of costs was POS of clinical trials, accounting for a difference of $591.3 m. Additional data analysis illustrated that there was a 27% increase in return on investment (ROI) of precision oncology medicines over non-precision oncology medicines. CONCLUSION: Our results provide an accurate estimate of the R&D spend required to bring an oncology medicine to market. Deployment of a CDx at the earliest stage substantially lowers the cost associated with oncology medicines development, potentially making them available to more patients, while staying within the cost constraints of cancer health systems.

From financial wealth shocks to ill-health: Allostatic load and overload.

A number of studies have associated financial wealth changes with health-related outcomes arguing that the effect is due to psychological distress and is immediate. In this paper, I examine this relationship for cumulative shocks to the financial wealth of American retirees using the allostatic load model of pathways from stress to poor health. Wealth shocks are identified from Health and Retirement Study reports of stock ownership along with significant negative discontinuities in high-frequency S&P500 index data. I find that a one standard deviation increase in cumulative shocks over two years increases the probability of elevated blood pressure by 9.5%, increases waist circumference by 1.2% and the cholesterol ratio by 6.1% for those whose wealth is all in shares. My findings suggest that the combined effect of random shocks to financial wealth over time is salient for health outcomes. This is consistent with the allostatic load model in which repeated activation of stress responses leads to cumulative wear and tear on the body.

Spend less to achieve more: Economic analysis of intermittent versus continuous cetuximab in KRAS wild-type patients with metastatic colorectal cancer.

BACKGROUND: In 2014, the COIN-B clinical trial demonstrated that intermittent cetuximab (IC) was a safe alternative to continuous cetuximab (CC), with less cytotoxic chemotherapy, in first-line treatment for KRAS wild-type metastatic colorectal cancer (mCRC). Cetuximab has been available for this indication in England since 2015, but treatment breaks beyond 6 weeks were prohibited, despite real-world evidence that therapy de-escalation maintains equivalent disease control, but with superior Quality-of-Life (QoL). We performed health economic analyses of IC versus CC and used this evidence to help underpin policy change and guide clinical practice through reduction in unnecessary treatment for mCRC patients. METHODS: Employing cost-minimization analysis, we conducted partitioned survival modelling (PSM) and Markov Chain Monte-Carlo (MCMC) simulation to determine costs and quality-adjusted-life-years for IC versus CC. RESULTS: IC reduced costs by £â€¯35,763 (PSM; p < 0.001) or £â€¯30,189 (MCMC) per patient annually, while preserving treatment efficacy and enhancing QoL. Extrapolating to all mCRC patients eligible for cetuximab therapy would have generated cost savings of ~£â€¯1.2 billion over this cohort's lifetime. These data helped underpin a request to NHS England to remove treatment break restrictions in first-line mCRC therapy, which has been adopted as an interim treatment option policy in colorectal cancer during the Covid-19 pandemic. CONCLUSIONS: Our results highlight substantial cost savings achievable by treatment de-escalation, while also reinforcing the importance of therapy breaks to potentially increase tumour responsiveness and reduce treatment toxicity. Our study also highlights how health economic evidence can influence health policy, championing reduced treatment intensity approaches without compromising patient outcomes, which is of particular relevance when addressing the reduced capacity and treatment backlogs experienced during the pandemic.

HIV treatment and worker absenteeism: Quasi-experimental evidence from a large-scale health program in South Africa.

Over the past decade, large-scale HIV antiretroviral therapy (ART) programs have proven hugely successful in improving the life expectancy of people living with HIV. However, the extent to which treatment allows patients to maintain a productive work life remains an open question. We applied an instrumental variable method based on individual CD4 counts and exogenously changing treatment guidelines to identify the causal effect of ART on health-related absenteeism rates among workers living with HIV. We used monthly data from the occupational health program of one of the world's largest mining companies in South Africa (128,052 observations among 1,924 workers, from 2009 to 2017). Eighteen months after ART initiation, the treatment significantly reduced absenteeism by 1.033 days per worker and month. Using publicly available wage and treatment cost data, we find that the cost savings due to the absenteeism effect of ART alone outweigh treatment costs in the mining sector in several sub-Saharan African countries.

The economic burden of colorectal cancer across Europe: a population-based cost-of-illness study.

BACKGROUND: Colorectal cancer is one of the leading causes of cancer morbidity and mortality in Europe. We aimed to ascertain the economic burden of colorectal cancer across Europe using a population-based cost-of-illness approach. METHODS: In this population-based cost-of-illness study, we obtained 2015 activity and costing data for colorectal cancer in 33 European countries (EUR-33) from global and national sources. Country-specific aggregate data were acquired for health-care, mortality, morbidity, and informal care costs. We calculated primary, outpatient, emergency, and hospital care, and systemic anti-cancer therapy (SACT) costs, as well as the costs of premature death, temporary and permanent absence from work, and unpaid informal care due to colorectal cancer. Colorectal cancer health-care costs per case were compared with colorectal cancer survival and colorectal cancer personnel, equipment, and resources across EUR-33 using univariable and multivariable regression. We also compared hospital care and SACT costs against 2009 data for the 27 EU countries. FINDINGS: The economic burden of colorectal cancer across Europe in 2015 was €19·1 billion. The total non-health-care cost of €11·6 billion (60·6% of total economic burden) consisted of loss of productivity due to disability (€6·3 billion [33·0%]), premature death (€3·0 billion [15·9%]), and opportunity costs for informal carers (€2·2 billion [11·6%]). The €7·5 billion (39·4% of total economic burden) of direct health-care costs consisted of hospital care (€3·3 billion [43·4%] of health-care costs), SACT (€1·9 billion [25·6%]), and outpatient care (€1·3 billion [17·7%]), primary care (€0·7 billion [9·3%]), and emergency care (€0·3 billion [3·9%]). The mean cost for managing a patient with colorectal cancer varied widely between countries (€259-36 295). Hospital-care costs as a proportion of health-care costs varied considerably (24·1-84·8%), with a decrease of 21·2% from 2009 to 2015 in the EU. Overall, hospital care was the largest proportion (43·4%) of health-care expenditure, but pharmaceutical expenditure was far higher than hospital-care expenditure in some countries. Countries with similar gross domestic product per capita had widely varying health-care costs. In the EU, overall expenditure on pharmaceuticals increased by 213·7% from 2009 to 2015. INTERPRETATION: Although the data analysed include non-homogenous sources from some countries and should be interpreted with caution, this study is the most comprehensive analysis to date of the economic burden of colorectal cancer in Europe. Overall spend on health care in some countries did not seem to correspond with patient outcomes. Spending on improving outcomes must be appropriately matched to the challenges in each country, to ensure tangible benefits. Our results have major implications for guiding policy and improving outcomes for this common malignancy. FUNDING: Department for Employment and Learning of Northern Ireland, Medical Research Council, Cancer Research UK, Health Data Research UK, and DATA-CAN.

Cost-effectiveness of precision diagnostic testing for precision medicine approaches against non-small-cell lung cancer: A systematic review.

Precision diagnostic testing (PDT) employs appropriate biomarkers to identify cancer patients that may optimally respond to precision medicine (PM) approaches, such as treatments with targeted agents and immuno-oncology drugs. To date, there are no published systematic appraisals evaluating the cost-effectiveness of PDT in non-small-cell lung cancer (NSCLC). To address this gap, we conducted Preferred Reporting Items for Systematic Reviews and Meta-Analyses searches for the years 2009-2019. Consolidated Health Economic Evaluation Reporting Standards were employed to screen, assess and extract data. Employing base costs, life years gained or quality-adjusted life years, as well as willingness-to-pay (WTP) threshold for each country, net monetary benefit was calculated to determine cost-effectiveness of each intervention. Thirty-seven studies (50%) were included for analysis; a further 37 (50%) were excluded, having failed population-, intervention-, comparator-, outcomes- and study-design criteria. Within the 37 studies included, we defined 64 scenarios. Eleven scenarios compared PDT-guided PM with non-guided therapy [epidermal growth factor receptor (EGFR), n = 5; programmed death-ligand 1 (PD-L1), n = 6]. Twenty-eight scenarios compared PDT-guided PM with chemotherapy alone (anaplastic lymphoma kinase, n = 3; EGFR, n = 17; PD-L1, n = 8). Twenty-five scenarios compared PDT-guided PM with chemotherapy alone, while varying the PDT approach. Thirty-four scenarios (53%) were cost-effective, 28 (44%) were not cost-effective, and two were marginal, dependent on their country's WTP threshold. When PDT-guided therapy was compared with a therapy-for-all patients approach, all scenarios (100%) proved cost-effective. Seven of 37 studies had been structured appropriately to assess PDT-PM cost-effectiveness. Within these seven studies, all evaluated scenarios were cost-effective. However, 81% of studies had been poorly designed. Our systematic analysis implies that more robust health economic evaluation could help identify additional approaches towards PDT cost-effectiveness, underpinning value-based care and enhanced outcomes for patients with NSCLC.

Cooperative financial institutions: A review of the literature.

Financial cooperatives play an important role in the financial systems of many countries. They act as a safe haven for deposits and are major sources of credit for households and small- and medium-sized firms. A not-for-profit orientation (in many cases) and a focus on maximising benefits to members have ensured the enduring popularity and sustainability of financial cooperatives. This is particularly evident since the global financial crisis when financial cooperatives continued to extend credit to members as many profit-orientated commercial banks restricted credit to households and firms. The overarching theme of the first part of this review is the structural and behavioural characteristics of financial cooperatives. In this part we consider, the origin and diffusion of financial cooperatives, network arrangements, the business model, relationship banking, balancing the interest of members, tax treatment and regulatory framework. The second part has performance and contribution to the real economy as the overarching theme. In this part we consider, efficiency and sustainability, mergers, acquisitions and failures, the benefits (and challenges) of FinTech and the contribution of financial cooperatives to the real economy including during times of crisis. The paper concludes with a summary of what we now know (and do not know) about financial cooperatives and provides suggestions as to where future research may usefully concentrate.

Molecular biomarkers and precision medicine in colorectal cancer: a systematic review of health economic analyses.

An increased understanding of the biology of colorectal cancer (CRC) has fuelled identification of biomarkers with potential to drive a stratified precision medicine care approach in this common malignancy. We conducted a systematic review of health economic assessments of molecular biomarkers (MBMs) and their employment in patient stratification in CRC. Our analysis revealed scenarios where health economic analyses have been applied to evaluate the cost effectiveness of MBM-guided clinical interventions: (i) evaluation of Dihydropyrimidine dehydrogenase gene (DPYD) status to identify patients susceptible to 5-Fluouracil toxicity; (ii) determination of Uridine 5'-diphospho- glucuronosyltransferase family 1 member A1 gene (UGT1A1) polymorphism status to help guide irinotecan treatment; (iii) assessment of RAS/RAF mutational status to stratify patients for chemotherapy or Epidermal Growth Factor Receptor (EGFR) therapy and (iv) multigene expression analysis (Oncotype Dx) to identify and spare non-responders the debilitating effects of particular chemotherapy interventions. Our findings indicate that Oncotype Dx is cost-effective in high income settings within specific price points, by limiting treatment toxicity in CRC patients. DPYD status testing may also be cost effective in certain settings to avoid specific 5-FU toxicities post treatment. In contrast, current research does not support UGT1A1 polymorphism status as a cost-effective guide to irinotecan dosing, while the health economic evidence to support testing of KRAS/NRAS mutational status and chemo/EGFR therapy choice was inconclusive, despite its widespread adoption in CRC treatment management. However, we also show that there is a paucity of high-quality cost-effectiveness studies to support clinical application of precision medicine approaches in CRC.

Early HIV treatment and labour outcomes: A case study of mining workers in South Africa.

This study examines whether labour outcomes of HIV-infected workers treated with antiretrovirals are associated with the stage of the disease when commencing therapy. We use data on employment separation and absenteeism from the workplace health programme of South Africa's largest coal mining company over the period of January 2009 to March 2017 in a Cox proportional hazards model. When treatment was initiated at a CD4+ T cell count above 350 cells/µl, the risk of separating from the company was 37% lower and the risk of absence was 20%t lower than initiating at a CD4 count below 200 cells/µl, and these differences persist over time. Also, we find that workers initiating antiretroviral therapy at CD4 ≥ 350 have an 8% lower risk of absence prior to treatment. Although many companies and the South African government have adopted universal test-and-treat policies aiming to initiate all HIV-infected people as early as possible, most HIV patients still start treatment late in the disease course when their CD4 counts have fallen to low levels. Our results indicate early HIV detection and treatment could have large productivity gains.

How financial strain affects health: Evidence from the Dutch National Bank Household Survey.

The mechanisms by which financial strain affects health are not well understood. In this paper, we conduct a longitudinal mediation analysis of the Dutch National Bank Household Survey. To quantify the relative importance of biological and nonbiological pathways from financial strain to health, we consider smoking, heavy drinking and being overweight as plausible behavioural responses to financial strain but find that only 4.9% of the response of self-reported health to financial strain is mediated by these behaviours. Further analysis indicates that although financial strain increases impulsivity this has little effect on unhealthy behaviours. Economic stresses therefore appear to be distinct from other forms of stress in the relatively minor influence of nonbiological pathways to ill-health.

Shooting for the Moon or Flying Too Near the Sun? Crossing the Value Rubicon in Precision Cancer Care.

In his last two State of the Union addresses, President Barack Obama has focused on the need to deliver innovative solutions to improve human health, through the Precision Medicine Initiative in 2015 and the recently announced Cancer Moonshot in 2016. Precision cancer care has delivered clear patient benefit, but even for high-impact medicines such as imatinib mesylate (Glivec) in chronic myeloid leukaemia, the excitement at the success of this practice-changing clinical intervention has been somewhat tempered by the escalating price of this 'poster child' for precision cancer medicine (PCM). Recent studies on the costs of cancer drugs have revealed significant price differentials, which are a major causative factor behind disparities in the access to new generations of immunological and molecularly targeted agents. In this perspective, we will discuss the benefits of PCM to modern cancer control, but also emphasise how increasing costs are rendering the current approaches to integrating the paradigm of PCM unsustainable. Despite the ever increasing pressure on cancer and health care budgets, innovation will and must continue. Value-based frameworks offer one of the most rational approaches for policymakers committed to improving cancer outcomes through a public health approach.

Residential segregation, dividing walls and mental health: a population-based record linkage study.

BACKGROUND: Neighbourhood segregation has been described as a fundamental determinant of physical health, but literature on its effect on mental health is less clear. While most previous research has relied on conceptualised measures of segregation, Northern Ireland is unique as it contains physical manifestations of segregation in the form of segregation barriers (or 'peacelines') which can be used to accurately identify residential segregation. METHODS: We used population-wide health record data on over 1.3 million individuals, to analyse the effect of residential segregation, measured by both the formal Dissimilarity Index and by proximity to a segregation barrier, on the likelihood of poor mental health. RESULTS: Using multilevel logistic regression models, we found residential segregation measured by the Dissimilarity Index poses no additional risk to the likelihood of poor mental health after adjustment for area-level deprivation. However, residence in an area segregated by a 'peaceline' increases the likelihood of antidepressant medication by 19% (OR=1.19, 95% CI 1.14 to 1.23) and anxiolytic medication by 39% (OR=1.39, 95% CI 1.32 to 1.48), even after adjustment for gender, age, conurbation, deprivation and crime. CONCLUSIONS: Living in an area segregated by a 'peaceline' is detrimental to mental health suggesting segregated areas characterised by a heightened sense of 'other' pose a greater risk to mental health. The difference in results based on segregation measure highlights the importance of choice of measure when studying segregation.

Did the Millennium Development Goals Change Trends in Child Mortality?

There has been little assessment of the role the Millennium Development Goals (MDGs) have had in progressing international development. There has been a 41% reduction in the under-five mortality rate worldwide from 1990 to 2011 and an acceleration in the rate of reduction since 2000. This paper explores why this has occurred, and results for all developing countries indicate that it is not due to more healthcare or public health interventions but is driven by a coincidental burst of economic growth. Although the MDGs are considered to have played an important part in securing progress against poverty, hunger and disease, there is very little evidence to back this viewpoint up. A thorough analysis of the successes and failures of the MDGs is therefore necessary before embarking on a new round of global goals. Copyright © 2015 John Wiley & Sons, Ltd.

Residential segregation and health in Northern Ireland.

Patterns of residential segregation in Northern Ireland reflect historic sectarian conflict as well as current animosities. A number of indices of segregation are examined in this paper and their relative merits in capturing localised societal divisions are discussed. The implications of such divisions on health as mediated through conflict-related stress are then considered. Costed datasets of hospital, community and anxiety/depression prescribing data have been assembled and attributed to local geographies. The association between geographical variations in these costs and levels of segregation was modelled using regression analysis. It was found that the level of segregation does not help to explain variations in costed utilisation of acute and elderly services but does explain variations in the costs of prescribing for anxiety and depression with controls for socio-economic deprivation included. Results in this paper would indicate that strategies to promote good relations in Northern Ireland have positive implications for mental health.