The costs of developing treatments for Alzheimer's disease: A retrospective exploration.

INTRODUCTION: With the exception of the recent accelerated approval of aducanumab, in over 26 years of research and development (R&D) investment in Alzheimer's disease (AD), only five novel drugs-all for symptomatic treatment only-have reached FDA approval. Here, we estimate the costs of AD drug development during this period in the private sector. METHODS: To estimate private R&D funding, we collected information on AD clinical trials (n = 1099; phases 1-4) conducted between January 1, 1995 and June 21, 2021 from various databases. Costs were derived using previously published methodologies and adjusted for inflation. RESULTS: Since 1995, cumulative private expenditures on clinical stage AD R&D were estimated at $42.5 billion, with the greatest costs (57%; $24,065 million) incurred during phase 3; approximately 184,000 participants were registered or are currently enrolled in clinical trials. DISCUSSION: Measures to reduce expenditures while moving toward disease-modifying therapies that alleviate the rising burden of AD require continued investment from industry, government, and academia.

Predicting quantity and quality of life with the Future Elderly Model.

The Future Elderly Model (FEM) is a microsimulation model designed to forecast health status, longevity, and a variety of economic outcomes. Compared to traditional actuarial models, microsimulation models provide greater opportunities for policy forecasting and richer detail, but they typically build upon smaller samples of data that may mitigate forecasting accuracy. We perform validation analyses of the FEM's mortality and quality of life forecasts using a version of the FEM estimated exclusively on early waves of data from the Health and Retirement Study. First, we compare FEM mortality and longevity projections to the actual mortality and longevity experience observed over the same period of time. We also compare the FEM results to actuarial forecasts of mortality and longevity during the same time. We find that FEM projections are generally in line with observed mortality rates and closely match longevity. Then, we assess the FEM's performance at predicting quality of life and longitudinal outcomes, two features missing from traditional actuarial models. Our analysis suggests the FEM performs at least as well as actuarial forecasts of mortality, while providing policy simulation features that are not available in actuarial models.

Improved survival for individuals with common chronic conditions in the Medicare population.

It is well established that the United States lags behind peer nations in life expectancy, but it is less established that there is heterogeneity in life expectancy trends. We compared mortality trends from 2004 to 2014 for the United States with 17 high-income countries for persons under and over 65. The United States ranked last in survival gains for the young but ranked near the middle for persons over 65, the group with universal access to public insurance. To explore the over-65 mortality trend, we estimated Cox proportional hazards models for individuals soon after entering Medicare. These were estimated separately by race and sex, controlling for 26 chronic conditions and condition-specific time trends. The separate regressions enabled survival comparisons for the 2004 and 2014 cohorts by race and sex, conditional on baseline health. We predicted 5-year survival for all combinations of diabetes, hyperlipidemia, hypertension, and ischemic heart disease (IHD). All 16 combinations of these conditions showed survival gains, with diabetes as a key driver. Notably, survival improved and racial disparities narrowed for individuals with diabetes, hypertension, and IHD. White females, black females, white males, and black males gained 3.61, 3.90, 3.57, and 5.89 percentage points in 5-year survival, respectively.

Multidimensional comparison of countries' adaptation to societal aging.

As long-term changes in life expectancy and fertility drive the emergence of aging societies across the globe, individual countries vary widely in the development of age-relevant policies and programs. While failure to adapt to the demographic transformation carries not only important financial risks but also social risks, most efforts to gauge countries' preparedness focus on economic indicators. Using data from the Organization for Economic Cooperation and Development (OECD) and other sources, we developed a multidimensional Aging Society Index that assesses the status of older populations across five specific domains, including productivity and engagement, well-being, equity, economic and physical security, and intergenerational cohesion. For 18 OECD countries, the results demonstrate substantial diversity in countries' progress in adapting to aging. For any given domain, there are wide differences across countries, and within most countries, there is substantial variation across domains. Overall, Norway and Sweden rank first in adaptation to aging, followed by the United States, The Netherlands, and Japan. Central and eastern European countries rank at the bottom, with huge untapped potential for successful aging. The United States ranks best in productivity and engagement, in the top half for cohesion, and in the middle in well-being, but it ranks third from the bottom in equity. Only well-being and security showed significant between-domain correlation (r = 0.59, P = 0.011), strengthening the case for a multidimensional index. Examination of heterogeneity within and across domains of the index can be used to assess the need for, and effectiveness of, various programs and policies and facilitate successful adaptation to the demographic transition.

Lifetime Burden of Adult Congenital Heart Disease in the USA Using a Microsimulation Model.

Congenital heart defects (CHD) represent a growing burden of illness among adults. We estimated the lifetime health, education, labor, and social outcomes of adults with CHD in the USA using the Future Adult Model, a dynamic microsimulation model that has been used to study the lifetime impacts of a variety of chronic diseases. We simulated a cohort of adult heads of households > 25 years old derived from the Panel Survey of Income Dynamics who reported a childhood heart problem as a proxy for CHD and calculated life expectancy, disability-free and quality-adjusted life years, lifetime earnings, education attainment, employment, development of chronic disease, medical spending, and disability insurance claiming status. Total burden of disease was estimated by comparing to a healthy cohort with no childhood heart problem. Eighty-seven individuals reporting a childhood heart problem were identified from the PSID and were used to generate the synthetic cohort simulated in the model. Life expectancy, disability-free, quality-adjusted, and discounted quality-adjusted life years were an average 4.6, 6.7, 5.3, and 1.4 years lower than in healthy adults. Lung disease, cancer, and severe mental distress were more common compared to healthy individuals. The CHD cohort earned $237,800 less in lifetime earnings and incurred higher average total medical spend by $66,600 compared to healthy individuals. Compared to healthy adults, the total burden of CHD is over $500K per adult. Despite being among the healthiest adults with CHD, there are significant decrements in life expectancy, employment, and lifetime earnings, with concomitant increases in medical spend.

Does Medicare Coverage Improve Cancer Detection and Mortality Outcomes?

Medicare is a large government health insurance program in the United States that covers about 60 million people. This paper analyzes the effects of Medicare insurance on health for a group of people in urgent need of medical care: people with cancer. We used a regression discontinuity design to assess impacts of near-universal Medicare insurance at age 65 on cancer detection and outcomes, using population-based cancer registries and vital statistics data. Our analysis focused on the three tumor sites for which screening is recommended both before and after age 65: breast, colorectal, and lung cancer. At age 65, cancer detection increased by 72 per 100,000 population among women and 33 per 100,000 population among men; cancer mortality also decreased by nine per 100,000 population for women but did not significantly change for men. In a placebo check, we found no comparable changes at age 65 in Canada. This study provides the first evidence to our knowledge that near-universal access to Medicare at age 65 is associated with improvements in population-level cancer mortality.

Trends in the Price per Median and Mean Life-Year Gained Among Newly Approved Cancer Therapies 1995 to 2017.

BACKGROUND: The prices of newly approved cancer drugs have risen over the past decades. A key policy question is whether the clinical gains offered by these drugs in treating specific cancer indications justify the price increases. OBJECTIVES: To evaluate the price per median and mean life year gained among newly approved cancer therapies from 1995 to 2017. METHODS: We collected data on the price (in 2017 USD) per life-year gained among cancer drug-indication pairs approved by the US Food and Drug Administration (FDA) between 1995 and 2017. We modeled trends using fractional polynomial and linear spline regression models that controlled for route of administration and cancer type fixed effects. RESULTS: We found that between 1995 and 2012, price increases outstripped median survival gains, a finding consistent with previous literature. Nevertheless, price per mean life-year gained increased at a considerably slower rate, suggesting that new drugs have been more effective in achieving longer-term survival. Between 2013 and 2017, price increases reflected equally large gains in median and mean survival, resulting in a flat profile for benefit-adjusted launch prices in recent years. CONCLUSIONS: Although drug costs have been rising more rapidly than median survival gains, they have been rising at about the same rate as mean survival gains. This suggests that when accounting for longer-term survival gains, the benefits of new drugs are roughly keeping pace with their costs, despite rapid cost growth.

Short-term budget affordability of hepatitis C treatments for state Medicaid programs.

BACKGROUND: With some Medicaid state programs still restricting patient access to hepatitis C (HCV) treatment, it is important to demonstrate how states could expand treatment access to a broader Medicaid population and balance short-term budget concerns. METHODS: We used the HCV Transmission and Progression (TaP) Markov model to quantify the impact of removing restrictions to HCV treatment access on the infected populations, expenditures, and net social value for the North Carolina (NC), Oregon (OR), and Wisconsin (WI) Medicaid programs. Four HCV treatment access scenarios were modeled: 1) Baseline: Patients were treated according to Medicaid disease severity and sobriety requirements in 2015; 2) Remove Sobriety Restrictions: Disease severity restrictions were maintained, but people who inject drugs (PWID) were given access to treatment; 3) Treat Early: All patients, except for PWIDs, regardless of disease severity, were eligible for treatment and the diagnosis rate increased from 50 to 66%; and 4) Remove Access Restrictions: all patients, regardless of disease severity and sobriety, were eligible for treatment. Our key model outputs were: number of infected Medicaid beneficiaries, HCV-related medical and treatment expenditures, total social value, and state Medicaid spending over 10 years. RESULTS: Across all three states, removing access restrictions resulted in the greatest benefits over 10 years (net social value relative to baseline = $408 M in NC; $408 M in OR; $271 M in WI) and the smallest infected population (5200 in NC; 2000 in OR; 614 in WI). Reduced disease transmission resulted in lower health care expenditures (-$66 M in NC; -$50 M in OR; -$54 M in WI). All of the expanded treatment access policies achieved break-even costs-where total treatment and health care expenditures fell below those of Baseline-in 4 to 8 years. Removing access restrictions yielded the greatest improvement in social value (net of medical expenditures and treatment costs, QALYs valued at $150 K per QALY). CONCLUSIONS: While increasing treatment access in Medicaid will raise short-term costs, it will also provide clear benefits relatively quickly by saving money and improving health within a 10-year window. Patients and taxpayers would benefit by considering these gains and taking a more expansive and long-term view of HCV treatment policies.

Productivity Benefits of Medical Care: Evidence from US-Based Randomized Clinical Trials.

BACKGROUND: One of the key recommendations of the Second Panel on Cost-Effectiveness in Health and Medicine is to take a societal perspective when evaluating new technologies-including measuring the productivity benefits of new treatments. Yet relatively little is known about the impact that new treatments have on labor productivity. OBJECTIVES: To examine the relationship between new drug treatments and gains in labor productivity across conditions in the United States and to evaluate which randomized clinical trials (RCTs) collected labor productivity data. METHODS: We collected data on US-based RCTs with work-ability surveys from searches of Google Scholar, PubMed, Scopus, the Cochrane Central Registry of Clinical Trials, and ClinicalTrails.gov. Combining RCT data with survey data from the Medical Expenditure Panel Survey, we assessed productivity changes from new drug treatments. RESULTS: During the last decade, some disease conditions have seen treatments that improve ability to work by as much as 60%. The annual increase in productivity gains attributable to new drug treatments was modest 1.1% (P = 0.53). Of the 5092 RCTs reviewed, ability-to-work measures were collected in 2% of trials. Work productivity surveys were more likely among prevalent medical conditions that affected individuals who worked, earned higher wages, and experienced larger reductions in hours worked as a consequence of disease diagnosis. CONCLUSIONS: From our data, we estimated that drug innovation increased productivity by 4.8 million work days per year and $221 billion in wages per year. These labor-sector benefits should be taken into account when assessing the socially optimal cost for new drug innovation.

Long-Term Health and Economic Value of Improved Mobility among Older Adults in the United States.

BACKGROUND: Mobility impairments have substantial physical and mental health consequences, resulting in diminished quality of life. Most studies on the health economic consequences of mobility limitations focus on short-term implications. OBJECTIVES: To examine the long-term value of improving mobility in older adults. METHODS: Our six-step approach used clinical trial data to calibrate mobility improvements and estimate health economic outcomes using a microsimulation model. First, we measured improvement in steps per day calibrated with clinical trial data examining hylan G-F 20 viscosupplementation treatment. Second, we created a cohort of patients 51 years and older with osteoarthritis. In the third step, we estimated their baseline quality of life. Fourth, we translated steps-per-day improvements to changes in quality of life using estimates from the literature. Fifth, we calibrated quality of life in this cohort to match those in the trial. Last, we incorporated these data and parameters into The Health Economic Medical Innovation Simulation model to estimate how mobility improvements affect functional status limitations, medical expenditures, nursing home utilization, employment, and earnings between 2012 and 2030. RESULTS: In our sample of 12.6 million patients, 66.7% were female and 70% had a body mass index of more than 25 kg/m2. Our model predicted that a 554-step-per-day increase in mobility would reduce functional status limitations by 5.9%, total medical expenditures by 0.9%, and nursing home utilization by 2.8%, and increase employment by 2.9%, earnings by 10.3%, and monetized quality of life by 3.2% over this 18-year period. CONCLUSIONS: Interventions that improve mobility are likely to reduce long-run medical expenditures and nursing home utilization and increase employment.

Insulin Fills by Medicare Enrollees and Out-of-Pocket Caps Under the Inflation Reduction Act.

This study uses data from IQVIA's National Prescription Audit to assess the association of the Inflation Reduction Act's cap on cost sharing with insulin fills by Medicare beneficiaries.

Accelerating Alzheimer's disease drug innovations from the research pipeline to patients.

In June 2017, a diverse group of experts in Alzheimer's disease convened to discuss how to accelerate getting new drugs to patients to both prevent and treat the disease. Participants concluded that we need a more robust, diversified drug development pipeline. Strategic policy measures can help keep new Alzheimer's disease therapies (whether to treat symptoms, prevent onset, or cure) affordable for patients while supporting innovation and facilitating greater information sharing among payers, providers, researchers, and the public, including a postmarket surveillance study system, disease registries, innovative payment approaches, harmonizing federal agency review requirements, allowing conditional coverage for promising therapeutics and technology while additional data are collected, and opening up channels for drug companies to communicate with payers (and each other) about data and outcomes. To combat reimbursement issues, policy makers should address the latency time between potential treatment-which may be costly and fall on private payers-and societal benefits that accrue elsewhere.

Variations in outcomes of hemodialysis vascular access by race/ethnicity in the elderly.

OBJECTIVE: Prevalence of end-stage renal disease, modality of treatment, and type of hemodialysis vascular access used varies widely by race/ethnicity in the United States, but outcomes of hemodialysis vascular access by race/ethnicity are poorly described. The objective of this study is to evaluate variations in outcomes of hemodialysis vascular access in the elderly by race/ethnicity. METHODS: Medicare outpatient, inpatient, and carrier files were queried from 2006 to 2011 for beneficiaries that were age ≥66 years and dialysis-dependent at time of index fistula/graft creation, qualified for Medicare by age only, and were continuously enrolled in Medicare 12 months before and after index fistula/graft creation. Primary outcome measures were early vascular access failure and 12-month failure-free survival, specifically, the variation in the difference between fistula and graft in non-White vs White race/ethnicity groups. RESULTS: Fistulas comprised a smaller proportion of index procedures performed in Blacks (65.9%; P < .001) and Asians (71.4%; P < .001), compared with Whites (78.0%) with no difference in Hispanics (78.7%; P = .59). Incidence of early failure after graft vs fistula was Whites, 34.9% vs 43.5% (P < .001), Blacks, 32.9% vs 49.1% (P < .001), Asians, 30.8% vs 40.5% (P = .014), and Hispanics 35.2% vs 43.2% (P = .005). The difference in early failure after fistula vs graft in Blacks was significantly larger than the difference in Whites (P < .001). The 12-month failure-free survival after index graft vs fistula was Whites 41.9% vs 38.9% (P = .008), Blacks 48.5% vs 37.3% (P < .001), Asians 51.6% vs 45.2% (P = .98), and Hispanics 51.9% vs 42.2% (P < .001). The difference in 12-month failure-free survival after graft vs fistula in Blacks and in Hispanics was larger than the difference in Whites (P < .001 and P = .02, respectively). CONCLUSIONS: Outcomes of fistulas vs grafts in the elderly vary significantly by race/ethnicity. The decreased risk of early failure after graft vs fistula creation is larger in Blacks compared with Whites. The higher failure-free survival at 12 months after graft vs fistula creation is larger in Blacks compared with Whites and trends toward being larger in Hispanics compared with Whites.

Using Self-reports or Claims to Assess Disease Prevalence: It's Complicated.

BACKGROUND: Two common ways of measuring disease prevalence include: (1) using self-reported disease diagnosis from survey responses; and (2) using disease-specific diagnosis codes found in administrative data. Because they do not suffer from self-report biases, claims are often assumed to be more objective. However, it is not clear that claims always produce better prevalence estimates. OBJECTIVE: Conduct an assessment of discrepancies between self-report and claims-based measures for 2 diseases in the US elderly to investigate definition, selection, and measurement error issues which may help explain divergence between claims and self-report estimates of prevalence. DATA: Self-reported data from 3 sources are included: the Health and Retirement Study, the Medicare Current Beneficiary Survey, and the National Health and Nutrition Examination Survey. Claims-based disease measurements are provided from Medicare claims linked to Health and Retirement Study and Medicare Current Beneficiary Survey participants, comprehensive claims data from a 20% random sample of Medicare enrollees, and private health insurance claims from Humana Inc. METHODS: Prevalence of diagnosed disease in the US elderly are computed and compared across sources. Two medical conditions are considered: diabetes and heart attack. RESULTS: Comparisons of diagnosed diabetes and heart attack prevalence show similar trends by source, but claims differ from self-reports with regard to levels. Selection into insurance plans, disease definitions, and the reference period used by algorithms are identified as sources contributing to differences. CONCLUSIONS: Claims and self-reports both have strengths and weaknesses, which researchers need to consider when interpreting estimates of prevalence from these 2 sources.

PCSK9 Inhibitors Show Value for Patients and the US Health Care System.

BACKGROUND: Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors were approved by the US Food and Drug Administration (FDA) as cholesterol-lowering therapies for patients with familial hypercholesterolemia or atherosclerotic cardiovascular disease. OBJECTIVES: To estimate the long-term health and economic value of PCSK9 inhibitors for Americans (51 years and older). METHODS: We conducted simulations using the Future Elderly Model, an established dynamic microsimulation model to project the lifetime outcomes for the US population aged 51 years and older. Health effects estimates and confidence intervals from published meta-analysis studies were used to project changes in life expectancy, quality-adjusted life-years, and lifetime medical spending resulting from the use of PCSK9 inhibitors. We considered two treatment scenarios: 1) current FDA eligibility and 2) an extended eligibility scenario that includes patients with no pre-existing cardiovascular disease but at high risk. We assumed that the price of PCSK9 inhibitors was discounted by 35% in the first 12 years and by 57% thereafter, with gradual uptake of the drug in eligible populations. RESULTS: Use of PCSK9 inhibitors by individuals covered by current FDA approval would extend life expectancy at the age of 51 years by an estimated 1.1 years and would yield a lifetime net value of $5800 per person. If use was extended to those at high risk for cardiovascular disease, PCSK9 inhibitors would generate a lifetime net benefit of $14,100 per person. CONCLUSIONS: Expanded access to PCSK9 inhibitors would offer positive long-term net value for patients and the US health care system at the current discounted prices.

Heterogeneity in action: the role of passive personalization in comparative effectiveness research.

Despite the goal of comparative effectiveness research (CER) to inform patient-centered care, most studies fail to account for the patient-centeredness of care that already exist in practice, which we denote as passive personalization (PP). Because CER studies describe the average effectiveness of treatments rather than heterogeneity in how individual patients respond to therapies, clinical or coverage policies that respond to CER results may undermine PP in clinical practice and generate worse outcomes. We study this phenomenon empirically in the context of use of antipsychotic drugs in Medicaid patients with schizophrenia using novel instrumental variable methods. We find strong support for PP in clinical practice and demonstrate that the average effects from a CER study cannot be replicated in practice because of the presence of PP. In contrast, providing physicians with evidence to further personalize treatment can produce significant benefits.

Confounding in the association of proton pump inhibitor use with risk of community-acquired pneumonia.

BACKGROUND: Use of proton pump inhibitors (PPIs) is associated with community-acquired pneumonia (CAP), an association which may be confounded by unobserved patient and prescriber characteristics. OBJECTIVE: We assessed for confounding in the association between PPI use and CAP by using a 'falsification approach,' which estimated whether PPI use is also implausibly associated with other common medical conditions for which no known pathophysiologic link exists. DESIGN: Retrospective claims-based cohort study. SETTING: Six private U.S. health plans. SUBJECTS: Individuals who filled at least one prescription for a PPI (N = 26,436) and those who never did (N = 28,054) over 11 years. INTERVENTIONS: Multivariate linear regression of the association between a filled prescription for a PPI and a diagnosis of CAP in each 3-month quarter. In falsification analyses, we tested for implausible associations between PPI use in each quarter and rates of osteoarthritis, chest pain, urinary tract infection (UTI), deep venous thrombosis (DVT), skin infection, and rheumatoid arthritis. Independent variables included an indicator for whether a prescription for a PPI was filled in a given quarter, and quarterly indicators for various co-morbidities, age, income, geographic location, and marital status. KEY RESULTS: Compared to nonusers, those ever using a PPI had higher adjusted rates of CAP in quarters in which no prescription was filled (68 vs. 61 cases per 10,000 persons, p < 0.001). Similar associations were noted for all conditions (e.g. chest pain, 336 vs. 282 cases, p < 0.001; UTI, 151 vs. 139 cases, p < 0.001). Among those ever using a PPI, quarters in which a prescription was filled were associated with higher adjusted rates of CAP (111 vs. 68 cases per 10,000, p < 0.001) and all other conditions (e.g. chest pain, 597 vs. 336 cases, p < 0.001; UTI, 186 vs. 151 cases, p < 0.001), compared to quarters in which no prescription was filled. CONCLUSION: PPI use is associated with CAP, but also implausibly associated with common medical conditions. Observed associations between PPI use and CAP may be confounded.