Value in cancer drug spending: assessing the clinical risks and benefits from a decade’s worth of innovation

There are growing questions about the value from spending on what seem like ever-more expensive cancer medicines. Rising expenditures may make it difficult for patients to access or remain compliant with life-extending therapies. Yet, some have argued that high prices may be justified if new and innovative treatments offer significant clinical benefits. Even as studies point to gains in overall survival from innovative cancer medicines, efforts to examine the value from related expenditures remain stymied by a dearth of systematic evidence on their clinical risks and benefits. This lack of evidence makes it difficult to demand more from innovation, and, where costs factor into the decision-making process, for clinicians and patients to balance preferences for the expected impact from treatment against rising drug costs

Cancer medicines: clinical impact, economics, and value

Background and Importance: There has been much debate recently over rapidly growing drug expenditures. Cancer medicines, in particular, have driven new brand spending over recent years, and US oncological expenditures have risen faster than for many other disease areas, in part because of rapidly growing drug prices, as well as increased rates of use. Objective: In the face of ongoing debates on how to reasonably control growth in pharmaceutical spending, while also providing patients with the best possible care, this thesis sets out to help address the question of whether growing pharmaceutical expenditures are providing value-for-money to patients and society. Novelty and Empirical Contributions: This thesis is based in part on a systematic review with narrative synthesis of English-language HTA appraisals of the comparative clinical risks and benefits of new cancer medicines, as well as on the novel use of methods to generate comparative evidence on their use and cost. Adapting established methods, these data are then used to examine existing questions over whether growing expenditures are worth the cost to patients and society. This thesis makes five major contributions to the literature on value-based spending on cancer medicines: 1) approximately one in three newly licensed cancer medicines provide no known overall survival benefit, while one in five provide no known overall survival, quality of life, or safety benefit; 2) novel use of methodologies to model treatment course and duration reveals that cancer drug use and costs vary greatly between individual medicines, and across Australia, France, the UK, and the US; 3) the monetized value of survival gains attributable to cancer drug innovation, net of growth in cancer drug spending, varies across individual medicines, and, at a country-level, remains unambiguously positive in Australia, France, and the UK, but negative in the US; 4) spending on new cancer medicines is often only weakly associated with their clinical benefits; and 5) the strength of this association nevertheless varies across countries, with the UK demonstrating the strongest evidence of value-based spending on new cancer medicines. Clinical and Policy Implications: Findings from this thesis provide a resource for valuebased clinical decision-making by patients and physicians. Moreover, growing expenditures on cancer medicines may only weakly be associated with meaningful clinical benefits, though the extent to which this is true differs across countries. These findings highlight the important role that health policy can have in encouraging valuebased cancer drug spending. In particular, it is argued that managed access schemes promoting access and evidence development, as well as the use of value-based spending policies, can help expedite access to new treatments, incentivize the development of clinically meaningful medicines, and rationalize growing cancer drug expenditures. Future Research Directions: The comparative clinical risks and benefits from new cancer medicines using real-world data, and how they compare with trial-based results; how evidence on the comparative impact from new treatments is measured, weighted, and rewarded in decision-making by regulators and payers; and how it is effectively linked through policy and regulation to cancer drug spending

A comparative study of drug listing recommendations and the decision-making process in Australia, the Netherlands, Sweden, and the UK

Drug listing recommendations from health technology assessment (HTA) agencies often fail to coincide with one another. We conducted a comparative analysis of listing recommendations in Australia (PBAC), the Netherlands (CVZ), Sweden (TLV) and the UK (NICE) over time, examined interagency agreement, and explored how process-related factors—including time delay between HTA evaluations, therapeutic indication and orphan drug status, measure of health economic value, and comparator—impacted decision-making in drug coverage. Agreement was poor to moderate across HTA agency listing recommendations, yet it increased as the delay between HTA agency appraisals decreased, when orphan drugs were assessed, and when low-value medicines (immunosuppressants, antineoplastics) were removed from the sample. International differences in drug listing recommendations seem to occur in part due to inconsistencies in how the supporting evidence informs assessment, but also to differences in how domestic priorities shape the value-based decision-making process

Relationship between costs and clinical benefits of new cancer medicines in Australia, France, the UK, and the US

As cancer drug prices rise, it remains unclear whether the cost of new interventions is related to their beneficial impact for patients at a societal-level. Using data for 2003–2015 from the IQVIA MIDAS® dataset, the relationship between cancer drug costs and drug clinical benefits was studied in four countries with different approaches to drug pricing. Summary measures of drug clinical effects on overall survival, quality of life, and safety were obtained from a review of health technology assessments. Mean total drug costs for a full course of treatment were estimated using standard posology for each medicine and in each country. Regression analysis was used to test whether, at a societal-level, the cost of recently licensed drugs is related to their beneficial impact for patients. Across all eligible medicines, average treatment costs were lowest in France and Australia and highest in the UK and US. Compared with Australia, France, and the UK, cancer medicines were on average between 1.2 and 1.9 times more expensive in the US, where the average total per patient cost for treatment was $68,255.17. Costs for new cancer medicines are high and, at best, only weakly associated with drug clinical benefits. The strength of this relationship nevertheless varied across countries. Some new cancer drugs—particularly in the US—may be neither affordable nor clinically beneficial over existing treatments. While all countries can benefit from strategies that more robustly align price with therapeutic benefit in cancer drugs, the US stands out in its opportunity to improve both affordability and value in cancer drug treatment

Assessment of overall survival, quality of life, and safety benefits associated with new cancer medicines

Importance: There is a dearth of evidence examining the impact of newly licensed cancer medicines on therapy. This information could otherwise support clinical practice, and promote value-based decision-making in the cancer drug market. Objective: To evaluate the comparative therapeutic value of all new cancer medicines approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) between 2003 and 2013. Design, Setting, and Participants: We used a narrative synthesis approach to systematically synthesize and analyze English, French, and Australian health technology assessments (HTAs) of all new cancer medicines licensed in the United States and Europe between 2003 and 2013. Interventions: Sixty-two new molecular entities with a primary oncology indication. Main Outcomes and Measures: Overall survival (OS), quality of life (QoL), and safety. Results: Of the 62 new active cancer molecules approved by the FDA and EMA between 2003 and 2013, 53 were appraised by English, French, or Australian HTA agencies through May 2015. Of these 53 drugs, 23 (43%) increased OS by 3 months or longer, 6 (11%) by less than 3 months, and 8 (15%) by an unknown magnitude; there was no evidence to suggest that the remaining 16 (30%) increased OS over best alternative treatments. Where overall survival gains could be quantified, all new cancer drugs were associated with a mean (SE) total increase in OS of 3.43 (0.63) months over the treatments that were available in 2003. Drug-related improvements in OS were, however, widely distributed across therapeutic targets—ranging between 0 (thyroid, ascites) and 8.48 months (breast cancers)—and were sometimes based on modeled data, indirect or nonactive comparisons, or nonvalidated evidence. Although 22 (42%) of 53 new medicines were associated with an increase in QoL, 24 (45%) were also associated with reduced patient safety. Of the 53 new cancer drugs, 42 (79%) were associated with at least some improvement in OS, QoL, or safety. Conclusions and Relevance: Although innovation in the oncology drug market has contributed to improvements in therapy, the magnitude and dimension of clinical benefits vary widely, and there may be reasons to doubt that claims of efficacy reflect real-world effectiveness exactly. These findings raise important questions for clinical decision-making and value-based policy

The relationship between off-hours admissions for primary percutaneous coronary intervention, door-to-balloon time and mortality for patients with ST-elevation myocardial infarction in England: a registry-based prospective national cohort study

Background The degree to which elevated mortality associated with weekend or night-time hospital admissions reflects poorer quality of care (' off-hours effect') is a contentious issue. We examined if off-hours admissions for primary percutaneous coronary intervention (PPCI) were associated with higher adjusted mortality and estimated the extent to which potential differences in door-to-balloon (DTB) times-a key indicator of care quality for ST elevation myocardial infarction (STEMI) patients-could explain this association. Methods Nationwide registry-based prospective observational study using Myocardial Ischemia National Audit Project data in England. We examined how off-hours admissions and DTB times were associated with our primary outcome measure, 30-day mortality, using hierarchical logistic regression models that adjusted for STEMI patient risk factors. In-hospital mortality was assessed as a secondary outcome. Results From 76 648 records of patients undergoing PPCI between January 2007 and December 2012, we included 42 677 admissions in our analysis. Fifty-six per cent of admissions for PPCI occurred during off-hours. PPCI admissions during off-hours were associated with a higher likelihood of adjusted 30-day mortality (OR 1.13; 95% CI 1.01 to 1.25). The median DTB time was longer for off-hours admissions (45 min; IQR 30-68) than regular hours (38 min; IQR 27-58; p<0.001). After adjusting for DTB time, the difference in adjusted 30-day mortality between regular and off-hours admissions for PPCI was attenuated and no longer statistically significant (OR 1.08; CI 0.97 to 1.20). Conclusion Higher adjusted mortality associated with off-hours admissions for PPCI could be partly explained by differences in DTB times. Further investigations to understand the off-hours effect should focus on conditions likely to be sensitive to the rapid availability of services, where timeliness of care is a significant determinant of outcomes

Automated Diabetic Retinopathy Image Assessment Software: Diagnostic Accuracy and Cost-Effectiveness Compared with Human Graders.

OBJECTIVE: With the increasing prevalence of diabetes, annual screening for diabetic retinopathy (DR) by expert human grading of retinal images is challenging. Automated DR image assessment systems (ARIAS) may provide clinically effective and cost-effective detection of retinopathy. We aimed to determine whether ARIAS can be safely introduced into DR screening pathways to replace human graders. DESIGN: Observational measurement comparison study of human graders following a national screening program for DR versus ARIAS. PARTICIPANTS: Retinal images from 20 258 consecutive patients attending routine annual diabetic eye screening between June 1, 2012, and November 4, 2013. METHODS: Retinal images were manually graded following a standard national protocol for DR screening and were processed by 3 ARIAS: iGradingM, Retmarker, and EyeArt. Discrepancies between manual grades and ARIAS results were sent to a reading center for arbitration. MAIN OUTCOME MEASURES: Screening performance (sensitivity, false-positive rate) and diagnostic accuracy (95% confidence intervals of screening-performance measures) were determined. Economic analysis estimated the cost per appropriate screening outcome. RESULTS: Sensitivity point estimates (95% confidence intervals) of the ARIAS were as follows: EyeArt 94.7% (94.2%-95.2%) for any retinopathy, 93.8% (92.9%-94.6%) for referable retinopathy (human graded as either ungradable, maculopathy, preproliferative, or proliferative), 99.6% (97.0%-99.9%) for proliferative retinopathy; Retmarker 73.0% (72.0 %-74.0%) for any retinopathy, 85.0% (83.6%-86.2%) for referable retinopathy, 97.9% (94.9%-99.1%) for proliferative retinopathy. iGradingM classified all images as either having disease or being ungradable. EyeArt and Retmarker saved costs compared with manual grading both as a replacement for initial human grading and as a filter prior to primary human grading, although the latter approach was less cost-effective. CONCLUSIONS: Retmarker and EyeArt systems achieved acceptable sensitivity for referable retinopathy when compared with that of human graders and had sufficient specificity to make them cost-effective alternatives to manual grading alone. ARIAS have the potential to reduce costs in developed-world health care economies and to aid delivery of DR screening in developing or remote health care settings

Availability, cost, and prescription patterns of antihypertensive medications in primary health care in China: a nationwide cross-sectional survey

Background: Around 200 million adults in China have hypertension, but few are treated or achieve adequate control of their blood pressure. Available and affordable medications are important for successfully controlling hypertension, but little is known about current patterns of access to, and use of, antihypertensive medications in Chinese primary health care. Methods: We used data from a nationwide cross-sectional survey (the China Patient-Centered Evaluative Assessment of Cardiac Events Million Persons Project primary health care survey), which was undertaken between November, 2016 and May, 2017, to assess the availability, cost, and prescription patterns of 62 antihypertensive medications at primary health-care sites across 31 Chinese provinces. We surveyed 203 community health centres, 401 community health stations, 284 township health centres, and 2474 village clinics to assess variation in availability, cost, and prescription by economic region and type of site. We also assessed the use of high-value medications, defined as guideline-recommended and low-cost. We also examined the association of medication cost with availability and prescription patterns. Findings: Our study sample included 3362 primary health-care sites and around 1 million people (613 638 people at 2758 rural sites and 478 393 people at 604 urban sites). Of the 3362 sites, 8·1% (95% CI 7·2–9·1) stocked no antihypertensive medications and 33·8% (32·2–35·4) stocked all four classes that were routinely used. Village clinics and sites in the western region of China had the lowest availability. Only 32·7% (32·2–33·3) of all sites stocked high-value medications, and few high-value medications were prescribed (11·2% [10·9–11·6] of all prescription records). High-cost medications were more likely to be prescribed than low-cost alternatives. Interpretation: China has marked deficiencies in the availability, cost, and prescription of antihypertensive medications. High-value medications are not preferentially used. Future efforts to reduce the burden of hypertension, particularly through the work of primary health-care providers, will need to improve access to, and use of, antihypertensive medications, paying particular attention to those with high value

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London