Journal of Medical Economics in review: high impact articles from 2022

In 2022, the Journal of Medical Economics (JME) continued its growth in publishing quality, relevant, and diverse content. This growth can be attributed to our authors, who entrust their outstanding research and scholarship to JME, and our peer reviewers, who not only provide exceptional assistance in appraising and, through their comments, refining papers, but also by assuring quality and transparency in methods and analytics.

Last year JME published its inaugural article¹ highlighting high-impact papers from 2021, and we are delighted to do so again by presenting this collection of papers published in 2022. Our approach blends a rather objective metric (number of views) with our own subjective appraisal of articles that we found remarkable. As you will discover when you read on, we are seeing a broader diversity in economic evaluations beyond cost-effectiveness analyses. Overall, the papers published in 2022 covered the entirety of the focus areas described in JME’s Aims and Scope².

The metrics for the following articles are from 31 December 2022.

Top five most read articles in 2022

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5. The societal economic value of COVID-19 vaccines in the United States³

3140 views

This fifth paper and the first paper in our list complement each other. Whereas Dr. Di Fusco and colleagues, authors of the first paper, focused on the public health benefit of one vaccine in terms of direct costs and productivity loss, this paper takes a broader societal perspective. It estimates, over a 3.5-year period since the first vaccine was rolled out in December 2020, the societal value of vaccination in terms of COVID-19 cases avoided and in terms of resuming unrestricted social and economic activity sooner. The authors acknowledge that their study was initiated during the alpha variant and does not consider subsequent virulent variants such as delta and omicron, yet this lends to their analysis an appropriate moderation. Five analyses are included, from “most conservative” to “most aggressive”, with value impacts ranging from $1.83 trillion to $9.92 trillion. At the midpoint, the base case analysis estimates the value of avoiding COVID-19 cases at $1.04 trillion in life years (LY) saved, $0.12 trillion in healthcare costs avoided, $0.11 trillion in quality of life gained, for a total value estimate of $1.27 trillion. Also, at this midpoint, the value from resuming unrestricted social and economic activity more quickly is estimated at $1.39 trillion in US gross domestic product gains, $1.87 trillion in reduced depression prevalence, $0.42 trillion in non-COVID-19 LY saved, and $0.05 trillion in non-COVID-19 healthcare costs avoided, totaling $3.73 trillion. The total value estimate for the base case is $5.0 trillion.

4. Clinical and economic benefits of lenzilumab plus standard of care compared with standard of care alone for the treatment of hospitalized patients with COVID-19 in the United States from the hospital perspective⁴

3234 views

Because of its multiple-payer system, most economic evaluations in the US are from the payer perspective. The counterpart in this are the providers, including hospitals, who must determine what the care for a patient will cost them and how this compares to what they will be reimbursed. This fourth most-read paper reports on a budget calculator to estimate whether, for a hospitalized COVID-19 patient, adding lenzilumab to the standard of care treatment is cost-efficient in light of the improved outcomes shown in the LIVE-AIR trial. Using an approach similar to the “with” and “without” scenario of a population-level budget impact analysis, the calculator is, essentially, a patient-level budget impact analysis – not to evaluate affordability (as care must be given regardless) but to understand the cost dynamics. The calculator estimates, for a newly hospitalized COVID-19 patient, the likely 28 day as well as the 1-year costs. It does so in general for patients aged <85 years and with a CRP < 150 mg/L with or without remdesivir treatment, but importantly, because of their higher risk for hospitalization and death, also for Black and African American patients. Proof-of-principle data show consistent per-patient savings; for example, from a low of $1,858 in patients without remdesivir co-treatment to $5,154 when re-hospitalization is considered to a high of $13,154 in Black and African American patients.

3. Cost-effectiveness of pembrolizumab for the first-line treatment of patients with unresectable or metastatic MSI-H/dMMR colorectal cancer in the United States⁵

3353 views

Unresectable or metastatic colorectal cancer (CRC) remains among the most difficult cancers to treat in both first and later lines. Despite significant progress over the past decade, prognosis has remained poor for approximately 4% of patients, with the microsatellite instability-high (MSI-H)/deficient mismatch repair phenotype (dMMR). In June 2020 the FDA approved pembrolizumab for this indication. This third most-read paper reports on a cost-effectiveness analysis of pembrolizumab versus standard of care (SOC). The estimated life years (LY) and quality-adjusted life year (QALY) outcomes were 5.939 LY and 4.845 QALY for pembrolizumab, including 3.732 LY and 3.178 QALY pre-progression and 2.207 LY and 1.674 QALY post-progression. The corresponding estimates for SOC were 4.124 LY and 3.232 QALY, including 1.106 LY and 0.929 QALY pre-progression and 3.018 LY and 2.323 QALY post-progression. Treatment costs totaled $381,952 for pembrolizumab versus $370,465 for SOC, for an increment of $11,486. This might appear surprising considering that the total cost of pembrolizumab exceeded that of SOC by $135,412. However, this paper is a nice example of how lower drug administration costs, more favorable adverse event profiles and therefore lower costs, and especially longer pre-progression and shorter post-progression affect monitoring and post-progression treatment costs. In the end, the incremental cost-effectiveness ratios amounted to an additional $6,211 to gain 1 LY and an additional $6,984 to gain 1 QALY.

2. Tezepelumab compared with other biologics for the treatment of severe asthma: a systematic review and indirect treatment comparison⁶

6106 views

The approval in 2003 of omalizumab brought biological therapy with monoclonal antibodies into severe asthma care, with marked improvements in patient outcomes. Omalizumab was the de facto standard of care for both allergic and eosinophilic asthma until four monoclonals were approved specifically for eosinophilic asthma between 2015 and 2018. In December 2021, the FDA approved tezepelumab, the first biologic for severe asthma that has no allergic or eosinophilic phenotype or biomarker limitation in its label – thus broadening this agent’s therapeutic reach to most patients with severe asthma. This second most-read paper reports on a systematic review and indirect treatment comparison (ITC) of the now six approved monoclonals, using the ITC methods of network meta-analysis (NMA) and simulated treatment comparison (SCT). The paper may have been read mainly for its results: in the ITCs, all biologics had similar efficacy in terms of annualized asthma exacerbation rates (AAERs) and AAERs leading to emergency room visits or hospitalization, but “tezepelumab was favorably associated with numerically lower AAERs and was ranked first in the network for both types of exacerbation outcome.” These are important clinical results, and it will be interesting to see how this plays out in economic evaluations. This paper also adds an interesting case study in its evaluation of two ITC methods to compare treatments for which no direct comparisons are available. Bayesian NMA, despite being still a relatively recent technique, is the prevailing ITC method when no individual patient data (IPD) are available. In an STC, IPD from one trial are used to simulate the efficacy relative to a comparator trial. Both methods “support the use of tezepelumab in a broad patient population of severe uncontrolled asthma of any phenotype.”

1. Public health impact of the Pfizer-BioNTech COVID-19 vaccine (BNT162b2) in the first year of rollout in the United States⁷

6134 views

In 2021, the most read paper in the Journal was “Health outcomes and economic burden of hospitalized COVID-19 patients in the United States”⁸. The most read paper in 2022 was also lead-authored by Dr. Di Fusco, and it presents an impressive investigation of the impact of the BNT162b2 vaccine (aka the “Pfizer vaccine”) in the first year that it was available in the US. A first analysis estimated the burden of COVID-19 in the absence of vaccination, whereas a second analysis assessed the outcomes averted by up to 2 doses of BNT162b2. The results demonstrated that vaccination with BNT162b2 would decrease an estimated 59.5 million (rounded) symptomatic cases by 8.7 million; lower 56 million outpatient cases and 690,000 hospitalizations by 8 million and 3.5 million, respectively, with a proportionately greater drop in severe and critical cases; and reduce 497,000 deaths and 5.7 million QALYs lost by 111,000 and 1.1 million, respectively. This translated into major reductions in direct costs and productivity loss: vaccination with BNT162b2 reduced an estimated $108 billion in direct costs and $193 billion in productivity loss by $30 billion and $44 billion, respectively. As the authors conclude, BNT162b2 “has had a profound public health impact in the US in 2021”. They also caution that “being focused on BNT162b2 makes the results ungeneralizable to other vaccines currently approved or authorized in the US.” That is technically correct, however, we can fairly assume that the findings reported in this paper may be extended, in concept and order of magnitude, to similar highly effective vaccines. It will certainly reinforce in many stakeholders – patients, providers, payers, and policy-makers – the belief in the individual and communal benefits of vaccination, especially when also considering the findings from the journals fifth most-read paper³.

Editor-in-Chief Kenneth KC Lee’s (Editor in Chief) selected articles from the 2022

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1. Economic burden of attention-deficit/hyperactivity disorder among children and adolescents in the United States: a societal perspective⁹

This paper reported that in the US, attention-deficit/hyperactivity disorder (ADHD) in children and adolescents was estimated to comprise about one-third of the total ADHD prevalence. Direct healthcare costs of children (5–11 years) and adolescents (12–17 years) with ADHD were obtained using claims data from the IBM MarketScan Research Databases (01/01/2017–12/31/2018). Direct non-healthcare and indirect costs were estimated based on literature and government publications. Each cost component was estimated using a prevalence-based approach, with per-patient costs extrapolated to the national level. The total annual societal excess costs associated with ADHD were estimated at $19.4 billion among children ($6,799 per child) and $13.8 billion among adolescents ($8,349 per adolescent). Education costs contributed to approximately half of the total excess costs in both populations ($11.6 billion [59.9%] in children; $6.7 billion [48.8%] in adolescents). Excess education costs accounted for 99.9% of the total excess non-healthcare costs and 59.9% of the total societal excess costs associated with ADHD among children in the US. These findings demonstrate the substantial economic burden of ADHD in children and adolescents in the US and highlight the current unmet need in these populations. The development of more effective, safe, convenient, and accessible intervention strategies and accompanying policies may reduce the clinical and economic burden of ADHD in children and adolescents. The findings of this study have an important impact on the future allocation of the healthcare budget.

2. Mean lifetime survival estimates following solid organ transplantation in the US and UK¹⁰

In this study, survival analyses were conducted in kidney, liver, heart, and lung transplant recipients. Mean survival was estimated using flexible cubic splines on the hazard scale fitted with three knots, based on where hazards changed direction, clinical advice, and best-fit curve using Akaike and Bayesian information criterion. The tail was extrapolated when data were no longer available. Extrapolation tails were compared with general population mortality, using age-matched life table hazards, and the highest hazards were taken at all times. Both the base-case and sensitivity analyses mean survival estimates reported here are substantially higher than the median lifetime survivals reported in previous literature since mean survival estimates allow for the inclusion of the tail-end distributions and outlier patients that are not accounted for with medians. The study hence reflects real-world survival following solid organ transplantations and demonstrate the importance of including long-term hazards in survival estimations. These estimates are important for decision-makers in situations where means are preferred over medians (e.g. population projections, budgetary estimates, and cost-effectiveness models). The study hence has a pivotal significance.

3. Evaluating the cost utility of racecadotril in addition to oral rehydration solution versus oral rehydration solution alone for children with acute watery diarrhea in four low middle-income countries: Egypt, Morocco, Philippines and Vietnam¹¹

This study adopted a cost-utility model previously developed and independently validated for use in Egypt, Morocco, Philippines, and Vietnam to compare adjunct racecadotril and oral rehydration solution (R + ORS) versus oral rehydration solution (ORS) alone for the treatment of diarrhea in children under 5. The model structure represents the country-specific clinical pathways. The target population is children under the age of five years presenting with symptoms of acute watery diarrhea to an outpatient clinic or general physician practice. The incremental cost-effectiveness ratios in each country fall in the southeast (cost-saving, more effective) quadrant. In most low-middle countries, publicly funded treatment options are available via National Formularies and Essential Medicines Lists. The decision to list treatment, in turn, depends on decision-making processes using health technology assessment (HTA). Despite certain limitations as described in the paper, which include a lack of local economic models and local expertise, the findings are in keeping with similar findings in upper-middle and high-income countries. The R + ORS treatment is shown to be favorable in low-middle-income countries for the treatment of children under five with acute watery diarrhea. The study findings should provide important reference points for international organizations such as WHO and the multinational pharmaceutical industry.

Editor-in-Chief Ivo Abraham’s selected articles from 2022

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1. How accurate are the longer-term projections of overall survival for cancer immunotherapy for standard versus more flexible parametric extrapolation methods?¹²

The study reported here tackles the general issue of the accuracy of time-to-event extrapolations based on initial trial data submitted as part of the regulatory dossier and also used in the coverage and reimbursement dossier. These dossiers tend to be based on less mature data and surrogate outcomes and proxies for overall survival such as progression-free survival. The study, which was focused on cancer immunotherapies, evaluated whether projections from these data using different methods were subsequently confirmed in projections based on additional data that may have become available. Three types of models were considered: standard parametric models (exponential, Weibull, Gompertz, log-logistic, log-normal, generalized gamma, and generalized F); spline models that apply piecewise polynomials to model the trajectory of survival curves as changes occur between time points (interval, proportional hazard, proportional odds, probit models); and mixture-cure models that assume that an observed cohort may have two (or more) subpopulations based on their response (“uncured” poor responders with negative outcomes versus “cured” good responders with positive outcomes). The main finding is that standard parametric models underestimate, and mixed cure models overestimate survival; but that the latter can be addressed by additional mortality hazards. As economic evaluations of cancer therapies are (slowly) beginning to consider patient treatment trajectories, this paper provides conceptual and technical guidance.

2. Limitations of standard cost-effectiveness methods for health technology assessment of treatments for rare, chronic diseases: a case study of treatment for cystic fibrosis¹³

The approval in 2019 of the elexacaftor/tezacaftor/ivacaftor combination (ELX/TEZ/IVA) for patients with cystic fibrosis who have at least one F508del mutation in the fibrosis transmembrane conductor regulator gene finally brought treatment for a disease that has killed many children before they have even reached adulthood. Yet, cystic fibrosis is a rare disease: patient volume is small, the regimen was expensive to develop and is expensive to make, and therefore the price is high. These factors make it difficult to apply standard cost-effectiveness methods, and this paper proposes a modified approach. First, it attempts to provide a rational and fair cost-effectiveness evaluation for a revolutionary drug that gives hope and life to 90% of the cystic fibrosis population. Second, it identifies issues inherent to conventional methods of cost-effectiveness analysis that make economic evaluations challenging and may have unintended consequences: (1) equal discounting of cost and health benefits; (2) relying on the generic, disease-agnostic and treatment-agnostic quality of life metrics, when cystic fibrosis is a lifelong disease to which patients adapt and therefore tend to rate high on quality of life (QoL) in general; (3) with extended survival, patients accrue treatment and disease management costs unrelated to their cystic fibrosis treatment but usual costs associated with longevity; (4) drug prices that are assumed to be unchanged for the full duration of the time horizon and do not reflect real-world drug pricing, including generic entry when exclusivity expires. Four solutions are proposed, and these were implemented in proof-of-principle analyses that calculated the percent reductions from the base case cost-effectiveness estimate: to lower and differentiate discount rates, applying a 1.5% rate to health benefits and a 3% rate to costs (36% reduction); to include a treatment-specific utility decrement (14% reduction); to exclude disease management costs during the extended survival (10% reduction); and, most of all, to integrate generic entry (45% reduction). Collectively, these 4 solutions reduced the ICER by 75%.

3. Modification of treatment-sequence model with a customizable number of treatments to better reflect contemporary and future clinical practice in moderate to severe psoriasis¹⁴

Most pharmaco-economic evaluations of drugs focus exclusively on one drug versus a comparator. This is done without consideration of whether the drug is a one-time treatment or whether it is used in a therapeutic trajectory that includes several lines of treatment, often with agents with different mechanisms of action. This third paper considers the case of psoriasis, where more than 10 biological treatments are available – with some differences in efficacy, though all having been shown to have therapeutic benefit. The paper compares an approach of 4 sequential lines of treatment before the transition to best support care (BSC) to an approach where first-line treatment with a biologic is followed by a “Basket of Biologics” (BoB) period in which switching is not limited. A first analysis compares annual treatment, discontinuation rates and time on treatment in a sequence of Biologic A ⟶ BoB ⟶ BSC, with BoB containing 1, 5, or 10 biologics and this against a time horizon of 60 years. Drawing on evidence, it is assumed that patients will be on Biologic A for 4.18 years before transitioning to the BoB. In the base model in which the BoB had only 1 biologic, the annual discontinuation rate was 16.4% and the model estimated that patients will be in the BoB phase for an additional 4.16 years (total active treatment: 8.34 years), followed by 28.28 years of BSC until death. When the BoB contains 5 biologics, with therefore greater opportunity for switching, the annual discontinuation rate declined to 5.9%, patients were estimated to be in the BoB phase for 9.86 years for a total of 14.04 years of active treatment and 22.58 years in the BSC phase. With 10 biologics in the BoB, the annual discontinuation rate was down to 1.2%; patients were in the BoB phase for 19.16 years and in active treatment for a total of 23.24 years, leaving only 13.29 years of BSC before death. The article also includes an incremental cost-utility analysis comparing the sequence Biologic A ⟶ BoB ⟶ BSC to the sequence Biologic B ⟶ BoB ⟶ BSC, in which A is less efficacious than B. On the aggregate, this makes the BoB for the first sequence “stronger” than the second sequence and therefore increases the total time on BoB, while also being lower in cost.

We hope you enjoyed reading this collection of articles and found them as interesting as we did. In addition to those highlighted above, we would like to draw your attention to two other key articles published in JME in 2022:

• The “Consolidated Health Economic Evaluation Reporting Standards 2022 (CHEERS 2022) Statement: Updated Reporting Guidance for Health Economic Evaluations¹⁵” was co-published in JME. Originally published in 2013, this updated CHEERS statement is more easily applied to “all types of health economic evaluation, new methods and developments in the field, as well as the increased role of stakeholder involvement including patients and the public”.

• The “Global article collection: essential reads from around the world¹⁶” was published as a follow-up to the 2021 collection of high-impact and most-read articles¹. This selection of article commentaries, written by the Journal of Medical Economics Editorial Board, focused on articles representative of JME’s globally diverse content.

As mentioned earlier, JME is focused on publishing quality, relevant, and diverse content. With that in mind, we are welcoming submissions to our upcoming special issue “HEOR: Evolving the management of healthcare under threat of future pandemics and epidemics”, which aims to provide insight into how the health economics community will adapt and evolve in a future with a higher risk of microbial disease outbreaks.

We encourage our authors and audience to contact us with submission inquiries, ideas for articles and special issues, and queries about supporting the journal as an Editorial Board member or peer reviewer.

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Acknowledgements

None reported.

Declaration of funding

No funding was received to produce this article.

Declaration statement of financial/other relationships

IA and KKCL are the Editors in Chief of the Journal of Medical Economics. MG is the Executive Editor of the Journal of Medical Economics.