key: cord-0857045-pvo45jiu
authors: Jiang, Yawen; Cai, Dan; Chen, Daqin; Jiang, Shan; Si, Lei; Wu, Jing
title: Economic evaluation of remdesivir for the treatment of severe COVID‐19 patients in China under different scenarios
date: 2021-05-05
journal: Br J Clin Pharmacol
DOI: 10.1111/bcp.14860
sha: 8d941150ffcc82994f997870d8dc8d322fa4f899
doc_id: 857045
cord_uid: pvo45jiu

AIMS: The present study aimed to evaluate the cost‐effectiveness of the 5‐day remdesivir regimen compared with standard of care among severe COVID‐19 patients in China, the evidence on which is essential to inform the necessity of securing access to remdesivir. METHODS: A dynamic transmission model that extended the susceptible–exposed–infected–recovered framework by incorporating asymptomatic, presymptomatic and waiting‐to‐be‐diagnosed patients was constructed to conduct the cost‐effectiveness analysis from the healthcare system perspective. To estimate epidemic parameters, the model was first calibrated to the observed epidemic curve in Wuhan from 23 January to 19 March 2020. Following the calibration, the infected compartment was replaced by 3 severity‐defined health states to reflect differential costs and quality of life associated with disease gravity. Costs and quality‐adjusted life year (QALY) outcomes of 9 million simulated people were accrued across time to evaluate the incremental cost‐effectiveness ratio of remdesivir. As robustness checks, an alternative modelling technique using decision tree, additional epidemic scenarios representing different epidemic intensities, and 1‐way parameter variations were also analysed. RESULTS: Remdesivir treatment cost CN¥97.93 million more than standard of care. Also, the net QALY gain from 5‐day remdesivir treatment was 6947 QALYs. As such, the incremental cost‐effectiveness ratio was CN¥14 098/QALY, substantially lower than the gross domestic product per capita threshold. The peak daily number of severe cases was 19% lower in the remdesivir treatment strategy. Overall, results were robust in alternative scenarios and sensitivity analyses. CONCLUSION: Given the cost‐effectiveness profile, access to remdesivir for severe COVID‐19 patients in China should be considered.

might improve clinical manifestation among moderate to severe COVID-19 patients. 4 An additional meta-analysis suggested that remdesivir may reduce 14-day mortality. 5 Remdesivir was also the only medication approved for hospitalized COVID-19 patients by the US Food and Drug Administration as of 23 October 2020. However, direct evidence on mortality benefit of remdesivir is still at large. In the meantime, the hefty price tags of remdesivir create uncertainty in its value profiles. The acquisition costs of the 5-day regimen of remdesivir set by the manufacturer vary across markets, totalling US $3120 for commercial payers in the USA and US$2340 for Medicare and public payers in other high-income countries. 6 The list prices are within the cost-effective range in the USA according to an analysis by the Institute for Clinical and Economic Review that assumed direct mortality benefit from remdesivir. 7 Outside of the USA, the cost-effectiveness profiles of remdesivir have not been documented to our knowledge. As such, we aimed to 

The study evaluated the incremental costs-effectiveness ratio of the 5-day remdesivir regimen from the healthcare system perspective in China. To that end, the study assessed the cost-effectiveness of using remdesivir to treat severe hospitalized COVID-19 patients compared with SoC. The analysis pertains to the policy question of whether it is cost-effective to treat severe COVID-19 patients with remdesivir in China, which is further related to whether the therapy should be accessible by severe patients. To extensively examine the costeffectiveness of remdesivir, several epidemic scenarios of adopting remdesivir were used, among which the reported epidemic intensity in Wuhan, China during January-March 2020 that represented the gravest local situation in China to date was considered the benchmark scenario.

A dynamic compartment transmission model was constructed to simulate the public health, clinical, and economic outcomes under alternative courses corresponding to different interventions. The model was constructed with 2 processes. In the first process, the conventional susceptible-exposed-infected-recovered (SEIR) framework was extended to accommodate asymptomatic and presymptomatic infectivity associated with COVID-19. [8] [9] [10] [11] Specifically, a model with a susceptible-exposed-asymptomatic-presymptomatic-awaiting diagnosis-infected-recovered (SEAPWIR) structure similar to that used in a previously published study was created. 12 The structure of the model is displayed in Figure 1A . The model can be also described using the ordinary differential equations (ODEs) in Table S1 . However, time progresses continuously in ODEs, which is not straightforward for the accrual of costs and health outcomes. Hence, a discrete-time version of the SEAPWIR compartment model was constructed. It was assumed that cases in the W and I classes might die of COVID-19 since both classes contained severe cases.

With this specification, β A , β P and β W represented the transmission rate of the A class, the P class, and the W class, respectively. These 3 classes were the infective compartments of the model. Individuals in the I class were assumed to be institutionalized and quarantined, thereby becoming incapable of transmitting the virus. Therefore, the force of infection was β A A + β P P + β W I. When homogenous mixing across classes was assumed, the SEIR model and its extensions could not reflect any flattening trends of epidemic curves far earlier than when herd immunity could be reached, which was the situation in Wuhan where the number of cases started to level off at around 50 000. For example, Hou et al. showed that the majority of people in Wuhan would be infected when the daily contact rate was toggled from 18 to 6 as long as a well-mixed SEIR model was used, even though the peak time was shifted out. 13 To incorporate the flattening trend without population immunity saturation, the original structure was modified to allow physical distancing barriers. Specifically, a proportion r of the S class individuals moved to the R class directly in each daily time step to reflect reduced risk by physical distancing barriers whereas the rest remained susceptible. Among the remaining susceptible individuals, an individual might become infected and move into the E class for a latency period, after which the individual would either become asymptomatic but infective (A) with a probability of 1 À p or become presymptomatic and infective (P) with a probability of p. Those in the P class then started to have symptom What this study adds • The 5-day remdesivir treatment is cost-effective compared with standard of care for the treatment of severe COVID-19 patients in China if priced the same as the international market.

• Ensuring access to remdesivir for severe COVID-19 patients may benefit the healthcare system in China.

onset but took some time to be diagnosed (W) as was the case in Wuhan in the first quarter of 2020. Once diagnosed, the symptomatic individuals were treated and quarantined (I). Those in the A and I classes could recover from the disease. Also, those in W and I classes might die of the disease. An inventory of the parameters of the compartment model is provided in Table 1 .

Once the SEAPWIR model was constructed in the first process, the second process was to modify the structure such that the model could also account for the differential severity-related clinical manifestations. To that end, the I class was replaced by 3 health states, Table S1 . To be in line with the SEAPWIR model, it was assumed that only cases in the W class and the S state could die of COVID-19. Also, cases could transit from mild to moderate and from moderate to severe. They could also transit back from severe to moderate. However, it was assumed that the moderate cases recover directly without having to go through the mild state while the severe cases did have to transit to moderate before recovery.

To estimate the epidemic parameters of the model in Figure 1A , it was necessary to set some of the parameters as fixed and calibrate the values of the rest of the parameters by fitting the simulated data to the observed data. 18 The parameters were set as fixed if available from the literature. Specifically, the fixed parameters included δ, p, σ, F I G U R E 1 The structures of the SEAPWIR and the SEAPWIR-Markov model. A: The structure of the SEAPWIR model; B: the structure of the SEAPWIR-Markov model in which I was replaced by M, O, and S. S, susceptible; E: exposed; A: asymptomatic; P: presymptomatic; W: waitingto-be-diagnosed; I: infected; D: dead; R: recovered; M: mild; O: moderate; S: severe ϕ, μ W , μ I and γ I , leaving β A , β P , β W and γ A to be calibrated. A study that followed the viral shedding courses of 94 COVID-19 patients estimated the incubation period to be 2.5 days. 19 Hence, δ was set at 1/2.5. A study on the Diamond Princess cruise ship, a closed system that allowed ascertainable follow-up of patients by symptoms, estimated that about 17.9% of the cases were asymptomatic throughout the infection episode, which was used as the input value for p. 20 It has also been estimated that infectiousness started 2.5 days prior to symptom onset. 19 Therefore, σ was also set as 1/2.5. Once symptomatic, it took 3.3 days on average to be diagnosed during the Wuhan epidemic, 21 giving rise to an estimate of 1/3.3 for ϕ. Confirmed cases in Wuhan had a mean institutionalized period of 17 days, the inverse of which was used as γ I . The overall mortality rate of the confirmed cases, μ I , was 0.0015/person-day. 22 Without precise information, it was assumed that those in the W class had the same severity profiles as the I class such that the morality rate of the W class, μ W , was equal to μ I . To conduct the calibration, the sum squared residuals (SSR) of the simulated and observed numbers of cumulative confirmed cases over 24 January-19 March 2020 was minimized by setting 23 January 2020 as the initial state. Numbers of individuals in classes S, A, L and I at the initial state were mandatory for the model calibration. The initial number of people in S class was assumed to be the same as the population in Wuhan. 23 These numbers were imputed using the proportions of the corresponding classes in relation to the number of confirmed cases. The values are also listed in Table 1 .

There were several spikes in the raw epidemic curve in Wuhan that were unrelated to the true number of cases, causing a fuzzy observed curve. 28, 29 Hence, we first estimated a 3-parameter logistic growth curve using the observed data on the cumulative confirmed cases from 24 January-19 March 2020 to smooth the epidemic curve. The calibration was implemented using Oracle Crystal Ball 11.

Then the proposed SEAPWIR model was fitted to the smoothed curve.

In the second process in which the I class was replaced by the Markov structure, not only the fixed and calibrated epidemic parameters but also the transition probabilities between the disease severity states as well as their neighbouring states were required. According to studies in China, 4.5% of the patients had nonpneumonia whereas 81% had no or mild pneumonia. Therefore, p M and p O were set at 0.045 and 0.765, respectively. 22, 24 Following these, p S was calculated to be 0.190. These percentages were also used to derive μ S from μ I , the former of which was therefore 0.0079/person-day. To the extent that studies on the disease progression of COVID-19 patients typically pool mild and moderate patients together, π MO and π OS were assigned the identical value in the present analysis. To obtain these values, the percentage of mild and moderate patients that had any progression over 28 days from a study in China (28.5%) was used. 25 Specifically, the value of 0.012 for π MO and π OS was estimated by solving (1 À π MO ) 28 = 0.715. Similarly, π SO was obtained by solving simple ODEs such that the cumulative proportion of severe patients who had clinical improvement matched that reported for the placebo arm of a clinical trial of remdesivir among severe patients over 28 days. 26 The recovery time of the mild cases was estimated using the duration of viral shedding among mild cases from a Japanese study subtracted by the days spent in the E, P and W compartments, the reverse of which was γ M , 27 whereas the value of γ O took that of γ I .

The interventions of interest were a 5-day remdesivir treatment strategy and SoC. According to clinical trials and meta-analyses published in the literature, the 5-day remdesivir treatment, although shorter in treatment and lower in costs, was noninferior to and probably more efficacious than its 10-day counterpart. [28] [29] [30] The intervention strategy was formally defined as allowing all individuals who entered the severe state to receive the 5-day remdesivir regimen and SoC while only providing SoC to mild and moderate patients. The comparator strategy was providing SoC to patients of any severity. Studies on the therapeutic profiles of COVID-19 patients in China indicated that SoC typically encompassed lopinavir/ritonavir, ribavirin, arbidol, chloroquine phosphate, hydroxychloroquine and glucocorticoids, most of which had no effectiveness evidence from RCTs. 31, 32 The effect of treatment was represented by the odds ratio (OR) of clinical improvement. Clinical studies typically engage ordinal scales to measure clinical improvement. In the present study, the effect of remdesivir on clinical improvement was applied to transition probabilities from relatively grave conditions to healthier states. A meta-analysis estimated that the 5-day remdesivir treatment was associated with an OR of 1.81 for clinical improvement. 30 costs, the latter of which was assumed equivalent to the pricing in high-income countries other than the USA. 6 The input values of the cost parameters are provided in Table 2 . Table 2 . Of note, simply accruing outcomes over the 55-day time horizon would lead to substantial underestimation of the benefit of the superior strategy since a sizeable fraction of the benefit as measured by QALYs were attributable to reduced mortality. To comprehensively capture the clinical benefit, it was necessary to enclose both avoided QALY loss due to fewer deaths and increased quality-adjusted life days (QALDs) due to more days spent in healthier states. To that end, the QALY loss associated with each COVID-19 death was attached to deceased individuals in the model. Using the age distribution of the deceased patients in China, we estimated that the mean age of the fatal COVID-19 cases was 69 years. 22 In 2019, the remaining life expectancy of 69-year-old individuals in China was 17 years. 37 In addition, the annual discount rate of 5% was used per the China Guideline for Pharmacoeconomic Evaluation. 38 Each death was assigned a loss of 11.27 QALYs. Given the short period of simulation, outcomes incurred within the analytic period were not discounted. Both outcomes were averaged across the population to obtain the incremental cost-effectiveness ratio (ICER) which was defined as incremental costs/QALY. A willingness-to-pay threshold of once the gross domestic product per QALY was used, which was CN¥70 892 (US$10276) in 2019. 41,42

The healthcare systems and resources in numerous parts of the world were drained during the first wave of the pandemic, highlighting the importance of healthcare capacity planning. As an exploratory outcome, the study looked at the peak numbers of severe cases under both strategies, the difference of which was considered the number of hospital beds that could be saved by the clinically superior strategy.

Whereas the present modelling analysis did consider the quarantine and costs of mild and moderate patients in temporary shelter hospitals, 43 To the extent that only the consequences to the treated patients instead of the population were of interest to specific decisionmakers in the Chinese healthcare system, a decision tree model was additionally constructed to re-analyse the research question by only modelling the severe patients. In the decision tree model, the severe patients were further split into severe and critical patients who had differential costs, HSUVs, recovery time and time to death over a 29-day followup period. The follow-up period was chosen to be consistent with the ACCT-1 trial along with the effectiveness data on time to recovery and time to death. 47 The parameters of the decision tree model are presented in Table S2 . The structure of the decision tree model is depicted in Figure S1 .

The analyses were programmed using Excel 2019 spreadsheet and VBA except the decision tree model, which was conducted using 

The calibrated parameters of the SEAPWIR epidemic model are presented in Table 1 . The observed epidemic curve, the smoothed curve, and the fitted curve using the SEAPWIR model are depicted in Figure 2 . Visually examined, the fitted curve closely resembled the smoothed curve.

The base-case cost-effectiveness results are presented in Table 3 . Figure S2 .

When r was decreased to 20% of the base-case value, over 0.83 million people would be infected over the 55-day period, accounting for almost 10% of the simulated population. In this scenario, remdesivir was still cost-effective with an ICER of CN¥25 499/QALY.

When r was increased to 5Â its original value, remdesivir remained cost-effective with an ICER of CN¥8817/QALY. Figure S3 depicts the results of the OWSA. Based on the results, the 5-day remdesivir regimen remained cost-effective in all but 1 scenario. Specifically, it was no longer cost-effective when the RR of treatment effect dropped by 30% to 1.27, which drove the ICER slightly above the threshold. Figure S4 illustrates the costeffectiveness acceptability curve based on the results of the probabilistic sensitivity analysis. The 5-day remdesivir regimen had a 98% probability of being cost-effective.

The base-case and OWSA results of the decision tree model are displayed in Figure S5 . The ICER in the base case was CN¥24 673/ QALY and remained below the WTP threshold in all scenarios.

In the present study, we investigated the cost-effectiveness of the 

The 5-day remdesivir treatment is cost-effective for the treatment of severe hospitalized COVID-19 patients under the observed epidemic intensities in China compared with SoC from the healthcare system perspective if the former is priced at CN¥16 600 (US$2340) for the full treatment course. The results were robust in alternative epidemic scenarios. Therefore, ensuring access to remdesivir in China may benefit the healthcare system when confronted with potential re-surges.

World Health Organization. WHO Coronavirus Disease (COVID-19) Dashboard. 2021

A Country Pandemic Risk Exposure Measurement Model

Organizational measures aiming to combat COVID-19 in the Russian Federation: the first experience

Drug treatments for covid-19: living systematic review and network meta-analysis

Effect of remdesivir on mortality in patients with COVID-19: A meta-analysis of randomized control trials

US purchase of world stocks sparks new "hunger games," warn observers

ICER releases pricing models for potential COVID-19 treatments

COVID-19-New Insights on a Rapidly Changing Epidemic

A familial cluster of pneumonia associated with the 2019 novel coronavirus indicating personto-person transmission: a study of a family cluster

Presumed asymptomatic carrier transmission of COVID-19

Field Briefing: Diamond Princess COVID-19 Cases

The cost-effectiveness of conducting three versus two reverse transcription-polymerase chain reaction tests for diagnosing and discharging people with COVID-19: evidence from the epidemic in Wuhan China

The effectiveness of the quarantine of Wuhan city against the Corona Virus Disease 2019 (COVID-19): well-mixed SEIR model analysis

European Centre for Disease Prevention and Control. Guidance for discharge and ending isolation in the context of widespread community transmission of COVID-19 -first update

World Health Organization. Criteria for releasing COVID-19 patients from isolation

Cost-effectiveness in health and medicine

Discrete event simulation: the preferred technique for health economic evaluations? Value Health

Modeling the initial transmission dynamics of influenza A H1N1 in Guangdong Province China

Temporal dynamics in viral shedding and transmissibility of COVID-19

Estimating the asymptomatic proportion of coronavirus disease 2019 (COVID-19) cases on board the Diamond Princess cruise ship

Incubation Period and Other Epidemiological Characteristics of 2019 Novel Coronavirus Infections with Right Truncation: A Statistical Analysis of Publicly Available Case Data

The Novel Coronavirus Pneumonia Emergency Response Epidemiology Team. Vital Surveillances: The Epidemiological Characteristics of an Outbreak of 2019 Novel Coronavirus Diseases (COVID-19) -China

5 million people left Wuhan before China quarantined the city to contain the coronavirus outbreak

Epidemiological and clinical features of the 2019 novel coronavirus outbreak in China

Risk factors for disease progression in patients with mild to moderate coronavirus disease 2019-a multi-centre observational study

Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial

Duration of viral shedding in asymptomatic or mild cases of novel coronavirus disease 2019 (COVID-19) from a cruise ship: A single-hospital experience in Tokyo Japan

Remdesivir for 5 or 10 Days in Patients with Severe Covid-19

Remdesivir for the Treatment of Covid-19 -Preliminary Report

Effectiveness of remdesivir for the treatment of hospitalized COVID-19 persons: A network meta-analysis

COVID-19 Drug Treatment in China

Chinese Therapeutic Strategy for Fighting COVID-19 and Potential Small-Molecule Inhibitors against Severe Acute Respiratory Syndrome Coronavirus

What is the cost of polymerase chain reaction test of COVID-19? Substantial heterogenity across different regions

Treatment of coronavirus disease 2019 in Shandong, China: a cost and affordability analysis

World Health Organization. Covid-19 transmission questions

Institute for Health Metrics and Evaluation. Global Burden of Disease Study 2010 (GBD 2010) Disability Weights

Life tables by country China

China guidelines for pharmacoeconomic evaluations

The impact of influenza on the health related quality of life in China: an EQ-5D survey

Measuring Quality of Life of Hospitalized Patients with Severe Acute Respiratory Infection by EQ-5D Instrument: an Exploratory Study

Understanding and improving the one and three times GDP per capita cost-effectiveness thresholds

China's economy expands 6.1% in 2019, in line with official target

Fangcang shelter hospitals: a novel concept for responding to public health emergencies. The Lancet

Does SARS-CoV-2 Has a Longer Incubation Period than SARS and MERS?

Early Transmission Dynamics in Wuhan, China, of Novel Coronavirus-Infected Pneumonia

Time Course of Lung Changes On Chest CT During Recovery From 2019 Novel Coronavirus (COVID-19) Pneumonia. 2020. Published online on Feb

Remdesivir for the Treatment of Covid-19 -Final Report

Corona-Triggered Global Macroeconomic Crisis of the Early 2020s

Predictors of (in) efficiencies of Healthcare Expenditure Among the Leading Asian Economies -Comparison of OECD and Non-OECD Nations

Costeffectiveness and resource allocation (CERA) 18 years of evolution: maturity of adulthood and promise beyond tomorrow

Real GDP growth rates and healthcare spending -comparison between the G7 and the EM7 countries

Evolving Health Expenditure Landscape of the BRICS Nations and Projections to 2025

Comparative financing analysis and political economy of noncommunicable diseases

SUPPORTING INFORMATION Additional supporting information may be found online in the Supporting Information section at the end of this article. How to cite this article

Early Career Fellowship of Australia (Grant number GNT1139826).The authors did not receive any grant from funding agencies in the public, commercial, or not-for-profit sectors for the submitted work.

All authors claim no conflict of interest related to the submitted work. 

The data analysed during the study are presented in the article and its supplementary materials. Program code used in the submitted work is available from the corresponding author upon reasonable requests.

https://orcid.org/0000-0002-0498-0662