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A Cost-Effectiveness Analysis of Remdesivir for the Treatment of Hospitalized Patients With COVID-19 in England and Wales

Published:February 20, 2022DOI:https://doi.org/10.1016/j.jval.2021.12.015

      Abstract

      Objectives

      COVID-19 is associated with significant morbidity and mortality. This study aims to synthesize evidence to assess the cost-effectiveness of remdesivir (RDV) for the treatment of hospitalized patients with COVID-19 in England and Wales.

      Methods

      A probabilistic cost-effectiveness analysis was conducted informed by 2 large trials and uses a partitioned survival approach to assess short- and long-term clinical consequences and costs associated with COVID-19 in a hypothetical cohort of hospitalized patients requiring supplemental oxygen at the start of treatment. Given that it is uncertain whether RDV reduces death, 2 analyses are presented, assuming RDV either reduces death or does not. Published sources were used for long-term clinical, quality of life, and cost parameters.

      Results

      Under the assumption that RDV reduces death, the incremental cost-effectiveness ratio for RDV is estimated at £11 881 per quality-adjusted life-year gained compared with standard of care (SoC) (probabilistic incremental cost-effectiveness ratio £12 400). The probability for RDV to be cost-effective is 74% at a willingness-to-pay threshold of £20 000 per quality-adjusted life-year gained. RDV was no longer cost-effective when the hazard ratio for overall survival compared with SoC was >0·915.

      Conclusions

      Results from this study suggest that using RDV for the treatment of hospitalized patients with COVID-19 is likely to represent a cost-effective use of National Health Service resources at current willingness-to-pay threshold in England and Wales, only if it prevents death. Results needs to be interpreted caution as vaccination was introduced and the SoC and evidence available have also evolved considerably since the analysis is conducted.

      Keywords

      Introduction

      COVID-19 is caused by the novel coronavirus severe acute respiratory syndrome coronavirus 2 and causes atypical pneumonia.
      • Li H.
      • Liu S.M.
      • Yu X.H.
      • Tang S.L.
      • Tang C.K.
      Coronavirus disease 2019 (COVID-19): current status and future perspectives.
      The disease is transmitted by inhalation or contact with infected droplets, and the incubation period is estimated to range from 2 to 14 days.
      • Singhal T.
      A review of coronavirus Disease-2019 (COVID-19).
      The symptoms are usually fever, cough, breathlessness, and fatigue, among others.
      • Singhal T.
      A review of coronavirus Disease-2019 (COVID-19).
      All populations are susceptible to severe acute respiratory syndrome coronavirus 2, with the elderly and people with underlying diseases or low immune function being more likely to become severe cases.
      • Li H.
      • Liu S.M.
      • Yu X.H.
      • Tang S.L.
      • Tang C.K.
      Coronavirus disease 2019 (COVID-19): current status and future perspectives.
      In response to the public health emergency, the National Health Service (NHS) England issued an interim commissioning policy (first published on the July 7, 2020, and updated on the November 12, 2020) for the use of remdesivir (RDV) in England and Wales,
      Interim Clinical Commissioning Policy: remdesivir for patients hospitalised with COVID-19 (adults and children 12 years and older), version 2. NHS England.
      for the treatment of hospitalized patients with COVID-19 requiring supplemental oxygen at the start of treatment (as per its European Medicines Agency marketing authorisation
      Veklury summary of product characteristics. European Medicines Agency.
      ), typically defined as those on low-flow oxygen (LFO), high-flow oxygen (HFO), or other noninvasive ventilation (NIV).
      The efficacy of RDV in hospitalized patients with COVID-19 on supplemental oxygen is described in a number of studies that are heterogeneous in terms of the included populations, study design, and outcomes. The Adaptive Covid-19 Treatment Trial 1 (ACTT-1)
      • Beigel J.H.
      • Tomashek K.M.
      • Dodd L.E.
      • et al.
      Remdesivir for the treatment of COVID-19 - final.
      is a double-blind randomized controlled trial (RCT) comparing RDV with placebo in the United States and reported a treatment effect on mortality (hazard ratio [HR]) of 0·30 (95% confidence interval [CI] 0·14-0·64) in hospitalized patients with LFO and 1·02 (95% CI 0·54-1·91) in patients with HFO or NIV at baseline. SOLIDARITY
      • Pan H.
      • Peto R.
      • Henao-Restrepo A.M.
      • et al.
      Repurposed antiviral drugs for COVID-19 - interim WHO solidarity trial results.
      was conducted after ACTT-1 and is an unblinded, multicenter RCT across 30 countries in patients who were hospitalized with COVID-19. ACTT-1 compared RDV with local standard of care (SoC) and reported a rate ratio of death of 0·85 (95% CI 0·66-1·09) for the subgroup of patients requiring any supplemental oxygen (but not mechanically ventilated). Wang et al
      • Wang Y.
      • Zhang D.
      • Du G.
      • et al.
      Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial [published correction appears in Lancet. 2020;395(10238):1694].
      (2020) was conducted in China and compared RDV with placebo in a double-blind RCT and reported a death rate ratio of 0·81 (95% CI 0·21-3·07) in hospitalized patients with LFO and 1·40 (95% CI 0·20-9·52) in patients with HFO or NIV at baseline. Therefore, there is considerable uncertainty in the effectiveness of RDV in preventing death in the overall supplemental oxygen population. These RCTs were also conducted at different phases during the pandemic making any direct comparison challenging.
      NHS England’s interim commissioning for RDV
      Interim Clinical Commissioning Policy: remdesivir for patients hospitalised with COVID-19 (adults and children 12 years and older), version 2. NHS England.
      was produced in response to the public health emergency and the rapid need for effective treatments to help reduce morbidity and mortality posed by COVID-19. This decision was not based on economic consideration. Therefore, it is unclear whether RDV represents a cost-effective use of NHS resources in England and Wales for the treatment of hospitalized patients with COVID-19 on supplemental oxygen at entry.
      The objective of this study is to assess the cost-effectiveness of RDV in England and Wales within its current marketing authorisation
      Veklury summary of product characteristics. European Medicines Agency.
      and interim NHS commissioning policy, from a health services perspective.
      Interim Clinical Commissioning Policy: remdesivir for patients hospitalised with COVID-19 (adults and children 12 years and older), version 2. NHS England.

      Strategies Compared and Population Entering the Model

      A decision-analytical model was constructed in Microsoft Excel to assess the short-term (during the hospitalization episode) and long-term (after hospital discharge) clinical consequences and costs associated with COVID-19 in a hypothetical cohort of hospitalized patients requiring supplemental oxygen at the start of treatment (defined as patients on LFO or HFO or NIV) in England and Wales.
      The intervention assessed is RDV (Veklury®) 200 mg on day 1, followed by RDV 100 mg maintenance up to 5 days, in line with current NHS England interim commissioning for RDV.
      Interim Clinical Commissioning Policy: remdesivir for patients hospitalised with COVID-19 (adults and children 12 years and older), version 2. NHS England.
      The comparator is established clinical management (previous routine use of tocilizumab [TCZ] and sarilumab [SAR]) with or without corticosteroids. RDV is assessed as an adjunct to SoC.

      Model Structure

      The structure of the decision-analytical model is depicted in Figure 1. and uses what is commonly referred to as a partitioned survival/area under the curve (AUC) approach, composed of 3 main mutually exclusive health states; (1) discharged from hospital and alive, (2) hospitalized with or without COVID-19, and (3) death from any cause (COVID-19 or because of other causes).
      Patients enter the model when hospitalized with COVID-19 and requiring supplemental oxygen (LFO, HFO or NIV) at the start of treatment. During their hospital stay (defined as the AUC between the time to death and discharge curves), patients are further separated into 5 hospitalization subhealth states based on their hospitalization/oxygen requirement according to the clinical status ordinal scale as defined in the ACTT-1 trial
      • Beigel J.H.
      • Tomashek K.M.
      • Dodd L.E.
      • et al.
      Remdesivir for the treatment of COVID-19 - final.
      (ie, no care because of COVID-19, no oxygen, LFO, HFO or NIV, and invasive ventilation), each associated with different cost and utility impact. Movements between hospitalization health states are not explicitly modeled. Instead, the partitioned model deals with health state occupancy within each time intervals.
      Due to their short duration, not everyone in trials for COVID-19 treatments will have been discharged or died at the time of outcome assessment. Therefore, time to death is extrapolated parametrically beyond the trial duration using a daily cycle length up to 70 days (35 days in the base-case), followed (weekly cycle length) by an elevated risk of death

      Ayoubkhani D, Khunti K, Nafilyan V, et al. Epidemiology of post-COVID syndrome following hospitalisation with coronavirus: a retrospective cohort study. Posted online January 15, 2021. medRxiv 2021.01.15.21249885. https://doi.org/10.1101/2021.01.15.21249885.

      compared with background mortality up to week 52 (varied between 6 months and 2 years in sensitivity analysis), and unadjusted background mortality used thereafter. Time to discharge is extrapolated parametrically until everyone either dies or is discharged.
      Discharged patients are assumed to have a reduced quality of life (QOL) (52 weeks from model entry in the base-case) to reflect emerging evidence on the effect of COVID-19 after hospital discharge.
      • Halpin Stephen J.
      • McIvor C.
      • Gemma W.
      • et al.
      Postdischarge symptoms and rehabilitation needs in survivors of COVID-19 infection: a cross-sectional evaluation.

      Evans RA, McAuley H, Harrison EM, et al. Physical, cognitive and mental health impacts of COVID-19 following hospitalization (PHOSP-COVID): a multi-centre prospective cohort study. 2021;9(11):1275–1287.

      Sigfrid L, Drake TM, Pauley E, et al. Long COVID in adults discharged from UK hospitals after COVID-19: a prospective multicentre cohort study using the ISARIC WHO Clinical Characterisation Protocol. Posted online March 25, 2021. medRxiv 2021.03.18.21253888. https://doi.org/10.1101/2021.03.18.21253888.

      Emerging evidence also suggests that some patients are at an elevated risk of multiorgan dysfunctions

      Ayoubkhani D, Khunti K, Nafilyan V, et al. Epidemiology of post-COVID syndrome following hospitalisation with coronavirus: a retrospective cohort study. Posted online January 15, 2021. medRxiv 2021.01.15.21249885. https://doi.org/10.1101/2021.01.15.21249885.

      (such as respiratory diseases, diabetes, cardiovascular, liver and kidney diseases) and may require long-term management/monitoring.
      COVID-19 rapid guideline: managing the long-term effects of COVID-19. National Institute for Health and Care Excellence.
      These potential impacts are included in this economic model as an average one-off cost and quality-adjusted life-year (QALY) loss per patient discharged.

      Model Parameters

      Baseline characteristics

      The mean age and sex distribution at entry (Table 1
      • Pan H.
      • Peto R.
      • Henao-Restrepo A.M.
      • et al.
      Repurposed antiviral drugs for COVID-19 - interim WHO solidarity trial results.
      ,

      Ayoubkhani D, Khunti K, Nafilyan V, et al. Epidemiology of post-COVID syndrome following hospitalisation with coronavirus: a retrospective cohort study. Posted online January 15, 2021. medRxiv 2021.01.15.21249885. https://doi.org/10.1101/2021.01.15.21249885.

      ,
      • Halpin Stephen J.
      • McIvor C.
      • Gemma W.
      • et al.
      Postdischarge symptoms and rehabilitation needs in survivors of COVID-19 infection: a cross-sectional evaluation.
      ,
      • Ara R.
      • Brazier J.E.
      Populating an economic model with health state utility values: moving toward better practice.
      • Wilcox Mark H.
      • Harblas A.
      • Coia John E.
      • et al.
      Impact of recurrent Clostridium difficile infection: hospitalization and patient quality of life.
      • Malen H.
      • Olatz G.
      • Mariana G.
      • Montserrat F.
      • Angela D.
      • Jordi A.
      Impact of influenza on health-related quality of life among confirmed (H1N1)2009 patients.
      Publications. British National Formulary.
      Drugs and pharmaceutical electronic market information tool (eMIT). Department of Health and Social Care.
      National cost collection for the NHS: archived reference costs. NHS.
      • Stokes E.A.
      • Wordsworth S.
      • Bargo D.
      • et al.
      Are lower levels of red blood cell transfusion more cost-effective than liberal levels after cardiac surgery? Findings from the TITRe2 randomised controlled trial.
      • Curtis L.
      • Burns A.
      Unit costs of health & social care 2020. PSSRU, University of Kent.
      ) are taken from a UK study among 47 780 hospitalized patients with COVID-19 and discharged alive.

      Ayoubkhani D, Khunti K, Nafilyan V, et al. Epidemiology of post-COVID syndrome following hospitalisation with coronavirus: a retrospective cohort study. Posted online January 15, 2021. medRxiv 2021.01.15.21249885. https://doi.org/10.1101/2021.01.15.21249885.

      Table 1Model input parameters.
      ParameterExpected valueRange for sensitivity analysisMeasure of uncertaintySource
      Lower boundUpper bound
      Baseline characteristics
      Age64·562·5
      Range assumed.
      66·5
      Range assumed.
      Normal (SD 19·2)

      Ayoubkhani D, Khunti K, Nafilyan V, et al. Epidemiology of post-COVID syndrome following hospitalisation with coronavirus: a retrospective cohort study. Posted online January 15, 2021. medRxiv 2021.01.15.21249885. https://doi.org/10.1101/2021.01.15.21249885.

      Sex distribution (female %)40·1%40%
      Range assumed.
      55%
      Range assumed.
      Beta

      Ayoubkhani D, Khunti K, Nafilyan V, et al. Epidemiology of post-COVID syndrome following hospitalisation with coronavirus: a retrospective cohort study. Posted online January 15, 2021. medRxiv 2021.01.15.21249885. https://doi.org/10.1101/2021.01.15.21249885.

      Treatment effect
      HR OS0·850·661·09Lognormal (95% CI)
      • Pan H.
      • Peto R.
      • Henao-Restrepo A.M.
      • et al.
      Repurposed antiviral drugs for COVID-19 - interim WHO solidarity trial results.
      HR time to dischargeHR1 (day 0-4): 0·56

      HR2 (day 5-9): 1·00

      HR3 (day 10-14): 1·07

      HR4 (day 15-19): 1·35

      HR5 (day 20+): 1·24
      Multivariate normal
      • Pan H.
      • Peto R.
      • Henao-Restrepo A.M.
      • et al.
      Repurposed antiviral drugs for COVID-19 - interim WHO solidarity trial results.
      Health-related QOL—utility value
      Invasive ventilation0Not variedAssumed
      Health-related QOL—applied as decrement
      Increased comorbidities at entry−0.1160
      Range assumed.
      0·15
      Range assumed.
      Normal
      SE assumed to be 10%.
      Derived from
      • Ara R.
      • Brazier J.E.
      Populating an economic model with health state utility values: moving toward better practice.
      Discharged (first 52 weeks)−0.0970·077
      Range assumed to be ±20%.
      0·116
      Range assumed to be ±20%.
      Normal
      SE assumed to be 10%.
      • Halpin Stephen J.
      • McIvor C.
      • Gemma W.
      • et al.
      Postdischarge symptoms and rehabilitation needs in survivors of COVID-19 infection: a cross-sectional evaluation.
      Hospitalized, not on oxygen−0.360·288
      Range assumed to be ±20%.
      0·432
      Range assumed to be ±20%.
      Normal
      SE assumed to be 10%.
      • Wilcox Mark H.
      • Harblas A.
      • Coia John E.
      • et al.
      Impact of recurrent Clostridium difficile infection: hospitalization and patient quality of life.
      Hospitalized, on LFO, or HFO or NIV−0.580·464
      Range assumed to be ±20%.
      0·696
      Range assumed to be ±20%.
      Normal (95% CI)
      • Malen H.
      • Olatz G.
      • Mariana G.
      • Montserrat F.
      • Angela D.
      • Jordi A.
      Impact of influenza on health-related quality of life among confirmed (H1N1)2009 patients.
      Costs
      RDV—price per vial£340Not varied
      Publications. British National Formulary.
      SoC—cost per day£0·53Not varied
      Drugs and pharmaceutical electronic market information tool (eMIT). Department of Health and Social Care.
      Hospitalization cost per day
      Hospitalized, not on oxygen and no ongoing care because of COVID£337£270
      Range assumed to be ±20%.
      £405
      Range assumed to be ±20%.
      Gamma
      SE assumed to be 10%.
      National cost collection for the NHS: archived reference costs. NHS.
      Hospitalized, not on oxygen and require care because of COVID£347£278
      Range assumed to be ±20%.
      £416
      Range assumed to be ±20%.
      Gamma
      SE assumed to be 10%.
      National cost collection for the NHS: archived reference costs. NHS.
      Hospitalized, on LFO£616£493
      Range assumed to be ±20%.
      £739
      Range assumed to be ±20%.
      Gamma
      SE assumed to be 10%.
      National cost collection for the NHS: archived reference costs. NHS.
      Hospitalized on HFO or NIV£933£747
      Range assumed to be ±20%.
      £1120
      Range assumed to be ±20%.
      Gamma
      SE assumed to be 10%.
      National cost collection for the NHS: archived reference costs. NHS.
      Hospitalized, on invasive ventilation£1518£1215
      Range assumed to be ±20%.
      £1822
      Range assumed to be ±20%.
      Gamma
      SE assumed to be 10%.
      National cost collection for the NHS: archived reference costs. NHS.
      Medium- to long-term after discharge
      Elevated risk of death7·77·28·3Lognormal (95% CI)

      Ayoubkhani D, Khunti K, Nafilyan V, et al. Epidemiology of post-COVID syndrome following hospitalisation with coronavirus: a retrospective cohort study. Posted online January 15, 2021. medRxiv 2021.01.15.21249885. https://doi.org/10.1101/2021.01.15.21249885.

      MOD QALY loss−0·023−0·011
      Range assumed to be halved or tripled.
      −0·069
      Range assumed to be halved or tripled.
      Beta
      SE assumed to be 10%.
      Appendix Table1
      MOD cost£1362£681
      Range assumed to be halved or tripled.
      £4085
      Range assumed to be halved or tripled.
      Gamma
      SE assumed to be 10%.
      Appendix Table1
      Monitoring one-off cost£364·6182·3
      Range assumed to be halved or tripled.
      1093·8
      Range assumed to be halved or tripled.
      Gamma
      SE assumed to be 10%.
      Assumed
      • Stokes E.A.
      • Wordsworth S.
      • Bargo D.
      • et al.
      Are lower levels of red blood cell transfusion more cost-effective than liberal levels after cardiac surgery? Findings from the TITRe2 randomised controlled trial.
      ,
      • Curtis L.
      • Burns A.
      Unit costs of health & social care 2020. PSSRU, University of Kent.
      CI indicates confidence interval; HFO, high-flow oxygen; HR, hazard ratio; LFO, low-flow oxygen; MOD, multiorgan dysfunction; NIV, noninvasive ventilation; OS, overall survival; QALY, quality-adjusted life-year; QOL, quality of life; RDV, remdesivir; SE, standard error; SoC, standard of care.
      Range assumed.
      SE assumed to be 10%.
      Range assumed to be ±20%.
      § Range assumed to be halved or tripled.

      Time to death in patients initiated on SoC (previous use of RDV)

      The time to death in patients for the SoC arm is taken from a large UK trial; the first RECOVERY trial that compared usual care versus corticosteroids (dexamethasone).
      • Horby P.
      • Lim W.S.
      • et al.
      RECOVERY Collaborative Group
      Dexamethasone in hospitalized patients with COVID-19.
      Since this trial was conducted, clinical practice has changed with corticosteroids widely used. Therefore, a weighted spline model (3 knots) was constructed from the pseudo-individual patient data (IPD; reconstructed based on a published algorithm
      • Guyot Patricia A.A.E.
      • Ouwens Mario J.N.M.
      • Welton Nicky J.
      • Welton N.J.
      Enhanced secondary analysis of survival data: reconstructing the data from published Kaplan-Meier survival curves.
      ) that assumes that 90% of patients are on corticosteroids (dexamethasone arm from RECOVERY
      • Horby P.
      • Lim W.S.
      • et al.
      RECOVERY Collaborative Group
      Dexamethasone in hospitalized patients with COVID-19.
      ), with the remaining not on dexamethasone (usual SoC from RECOVERY
      • Horby P.
      • Lim W.S.
      • et al.
      RECOVERY Collaborative Group
      Dexamethasone in hospitalized patients with COVID-19.
      ). A spline model with 3 knots was selected after visual inspection and statistical tests; with the addition or removal of knots not materially changing the fit within the observed or short-term extrapolation in this study. Scenario analyses are conducted using the control arm from SOLIDARITY
      • Pan H.
      • Peto R.
      • Henao-Restrepo A.M.
      • et al.
      Repurposed antiviral drugs for COVID-19 - interim WHO solidarity trial results.
      or the control arm from the RECOVERY TCZ trial
      RECOVERY Collaborative Group
      Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): preliminary results of a randomised, controlled, open-label, platform trial.
      in people with progressive COVID-19.

      Time to discharge in patients initiated on SoC (previous use of RDV)

      The time to discharge for the SoC arm is approximated by adjusting a spline model (3 knots) estimated from pseudo-IPD from the control arm from SOLIDARITY
      • Pan H.
      • Peto R.
      • Henao-Restrepo A.M.
      • et al.
      Repurposed antiviral drugs for COVID-19 - interim WHO solidarity trial results.
      using an HR we calculated so that the proportion of patients predicted to be discharged and alive at day 28 matches the proportion reported in the RECOVERY trial
      • Horby P.
      • Lim W.S.
      • et al.
      RECOVERY Collaborative Group
      Dexamethasone in hospitalized patients with COVID-19.
      (70·86% for the weighted analysis [base-case: 90% assumed to receive corticosteroids], 67.40% [n = 1755 of 2604] for usual care without dexamethasone, 72.01% [n = 921 of 1279] for the dexamethasone arm).

      Treatment effects for RDV

      The effectiveness of RDV at reducing death in patients on supplemental oxygen at entry is very uncertain and therefore 2 analyses are conducted. The base-case uses the point estimate from the on-oxygen population subgroup from SOLIDARITY
      • Pan H.
      • Peto R.
      • Henao-Restrepo A.M.
      • et al.
      Repurposed antiviral drugs for COVID-19 - interim WHO solidarity trial results.
      (ratio of death rate 0·85; 95% CI 0·66-1·09). A secondary analysis is presented assuming an HR of 1 (eg, RDV does not have an impact on survival) as the treatment effect is not statistically significant despite the large sample size for this subgroup in SOLIDARITY (n = 3639).
      • Pan H.
      • Peto R.
      • Henao-Restrepo A.M.
      • et al.
      Repurposed antiviral drugs for COVID-19 - interim WHO solidarity trial results.
      Similar findings were observed in Wang et al
      • Wang Y.
      • Zhang D.
      • Du G.
      • et al.
      Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial [published correction appears in Lancet. 2020;395(10238):1694].
      (2020). A significant treatment effect was also reported in patients with LFO in ACTT-1, but not in HFO.
      • Beigel J.H.
      • Tomashek K.M.
      • Dodd L.E.
      • et al.
      Remdesivir for the treatment of COVID-19 - final.
      The treatment effects for time to discharge are estimated from the published data (IPD reconstructed using a published algorithm
      • Guyot Patricia A.A.E.
      • Ouwens Mario J.N.M.
      • Welton Nicky J.
      • Welton N.J.
      Enhanced secondary analysis of survival data: reconstructing the data from published Kaplan-Meier survival curves.
      ) from SOLIDARITY
      • Pan H.
      • Peto R.
      • Henao-Restrepo A.M.
      • et al.
      Repurposed antiviral drugs for COVID-19 - interim WHO solidarity trial results.
      using piecewise HRs (day 0-4, 5-9, 10-14, 15-19, 20+) calculated simultaneously in a model that is stratified by time group.

      Distribution of patients by intensity of hospital care required

      The distribution of hospital care type in patients initiated on RDV is shown in Figure 2. The distribution at baseline and at day 14 are informed by the distribution (derived from the ordinal scale of clinical status) from the ACTT-1 trial
      • Beigel J.H.
      • Tomashek K.M.
      • Dodd L.E.
      • et al.
      Remdesivir for the treatment of COVID-19 - final.
      and Goldman et al
      • Goldman J.D.
      • Lye D.C.B.
      • Hui D.S.
      • et al.
      Remdesivir for 5 or 10 days in patients with severe Covid-19.
      (RDV for 5 and 10 days). We then assumed that the proportion of patients on invasive ventilation, NIV and no longer on oxygen increased linearly from day 0 to 14 and was carried forward beyond day 14 informed by the trend observed in ACTT-1 for RDV.
      • Beigel J.H.
      • Tomashek K.M.
      • Dodd L.E.
      • et al.
      Remdesivir for the treatment of COVID-19 - final.
      Figure thumbnail gr2
      Figure 2Hospital health state occupancy in patients initiated on RDV.
      RDV indicates remdesivir.
      The treatment effect for the probability of ventilation in patients initiated on SoC (compared with RDV) is taken from an unpublished UK study
      ISARIC 4C CCP-UK Remdesivir effectiveness evaluation study. Statistical Report v1.0. University of Liverpool.
      for the base-case, and assumed to be same as RDV for the secondary analysis assuming no survival difference.

      Mortality rate beyond parametric extrapolation

      The unadjusted rate of mortality for the general population is taken from the England and Wales life table 2017 to 2019. Between the end of extrapolation (day 35 in the base-case) and week 52, patients hospitalized with COVID-19 are assumed to be, on average, at an elevated risk of death of 7·7 (95% CI 7·2-8·3) compared with the general population based on the rate ratio reported by Ayoubkhani et al

      Ayoubkhani D, Khunti K, Nafilyan V, et al. Epidemiology of post-COVID syndrome following hospitalisation with coronavirus: a retrospective cohort study. Posted online January 15, 2021. medRxiv 2021.01.15.21249885. https://doi.org/10.1101/2021.01.15.21249885.

      (2021) in the UK.

      Costs

      We adopt a health service perspective. Unit costs are summarized in Table 1.
      • Pan H.
      • Peto R.
      • Henao-Restrepo A.M.
      • et al.
      Repurposed antiviral drugs for COVID-19 - interim WHO solidarity trial results.
      ,

      Ayoubkhani D, Khunti K, Nafilyan V, et al. Epidemiology of post-COVID syndrome following hospitalisation with coronavirus: a retrospective cohort study. Posted online January 15, 2021. medRxiv 2021.01.15.21249885. https://doi.org/10.1101/2021.01.15.21249885.

      ,
      • Halpin Stephen J.
      • McIvor C.
      • Gemma W.
      • et al.
      Postdischarge symptoms and rehabilitation needs in survivors of COVID-19 infection: a cross-sectional evaluation.
      ,
      • Ara R.
      • Brazier J.E.
      Populating an economic model with health state utility values: moving toward better practice.
      • Wilcox Mark H.
      • Harblas A.
      • Coia John E.
      • et al.
      Impact of recurrent Clostridium difficile infection: hospitalization and patient quality of life.
      • Malen H.
      • Olatz G.
      • Mariana G.
      • Montserrat F.
      • Angela D.
      • Jordi A.
      Impact of influenza on health-related quality of life among confirmed (H1N1)2009 patients.
      Publications. British National Formulary.
      Drugs and pharmaceutical electronic market information tool (eMIT). Department of Health and Social Care.
      National cost collection for the NHS: archived reference costs. NHS.
      • Stokes E.A.
      • Wordsworth S.
      • Bargo D.
      • et al.
      Are lower levels of red blood cell transfusion more cost-effective than liberal levels after cardiac surgery? Findings from the TITRe2 randomised controlled trial.
      • Curtis L.
      • Burns A.
      Unit costs of health & social care 2020. PSSRU, University of Kent.
      The unit costs per hospital bed day, according to the intensity of care required as measured by the ordinal scale of severity, are taken from NHS reference costs.
      National cost collection for the NHS: archived reference costs. NHS.
      The list price for RDV is taken from the BNF.
      Publications. British National Formulary.
      The number of RDV doses is taken from an unpublished UK study.
      ISARIC 4C CCP-UK Remdesivir effectiveness evaluation study. Statistical Report v1.0. University of Liverpool.
      Only drug costs for corticosteroids are included for SoC and calculated from the electronic market information tool
      Drugs and pharmaceutical electronic market information tool (eMIT). Department of Health and Social Care.
      based on the weighted average of relevant formulations.
      As the population entering the model is hospitalized, additional administration costs are likely to be minimal and are therefore not included in this economic evaluation.

      Health Utilities

      Health utility values are summarized in Table 1.
      • Pan H.
      • Peto R.
      • Henao-Restrepo A.M.
      • et al.
      Repurposed antiviral drugs for COVID-19 - interim WHO solidarity trial results.
      ,

      Ayoubkhani D, Khunti K, Nafilyan V, et al. Epidemiology of post-COVID syndrome following hospitalisation with coronavirus: a retrospective cohort study. Posted online January 15, 2021. medRxiv 2021.01.15.21249885. https://doi.org/10.1101/2021.01.15.21249885.

      ,
      • Halpin Stephen J.
      • McIvor C.
      • Gemma W.
      • et al.
      Postdischarge symptoms and rehabilitation needs in survivors of COVID-19 infection: a cross-sectional evaluation.
      ,
      • Ara R.
      • Brazier J.E.
      Populating an economic model with health state utility values: moving toward better practice.
      • Wilcox Mark H.
      • Harblas A.
      • Coia John E.
      • et al.
      Impact of recurrent Clostridium difficile infection: hospitalization and patient quality of life.
      • Malen H.
      • Olatz G.
      • Mariana G.
      • Montserrat F.
      • Angela D.
      • Jordi A.
      Impact of influenza on health-related quality of life among confirmed (H1N1)2009 patients.
      Publications. British National Formulary.
      Drugs and pharmaceutical electronic market information tool (eMIT). Department of Health and Social Care.
      National cost collection for the NHS: archived reference costs. NHS.
      • Stokes E.A.
      • Wordsworth S.
      • Bargo D.
      • et al.
      Are lower levels of red blood cell transfusion more cost-effective than liberal levels after cardiac surgery? Findings from the TITRe2 randomised controlled trial.
      • Curtis L.
      • Burns A.
      Unit costs of health & social care 2020. PSSRU, University of Kent.
      Utility values are age-adjusted as patients get older based on Ara and Brazier
      • Ara R.
      • Brazier J.E.
      Using health state utility values from the general population to approximate baselines in decision analytic models when condition-specific data are not available.
      , with the baseline utility value pre-COVID-19 estimated from the mean age at entry, adjusted by a decrement in utility taken from Ara and Brazier
      • Ara R.
      • Brazier J.E.
      Using health state utility values from the general population to approximate baselines in decision analytic models when condition-specific data are not available.
      to reflect increased comorbidities for patients with COVID-19 compared with the general population.

      Ayoubkhani D, Khunti K, Nafilyan V, et al. Epidemiology of post-COVID syndrome following hospitalisation with coronavirus: a retrospective cohort study. Posted online January 15, 2021. medRxiv 2021.01.15.21249885. https://doi.org/10.1101/2021.01.15.21249885.

      ,
      • Atkins Janice L.
      • Masoli Jane A.H.
      • Joao D.
      • et al.
      Preexisting comorbidities predicting COVID-19 and mortality in the UK Biobank community cohort.
      During the hospitalization episode, decrements in utility values are applied (subtracted) to the baseline, taken from the published literature.
      • Wilcox Mark H.
      • Harblas A.
      • Coia John E.
      • et al.
      Impact of recurrent Clostridium difficile infection: hospitalization and patient quality of life.
      ,
      • Malen H.
      • Olatz G.
      • Mariana G.
      • Montserrat F.
      • Angela D.
      • Jordi A.
      Impact of influenza on health-related quality of life among confirmed (H1N1)2009 patients.
      As with the assignment of costs, these utility decrements align with the degree of care required while in the hospital as indicated by the ordinal scale. Following hospital discharge patients with COVID-19 have a reduced QOL,

      Ayoubkhani D, Khunti K, Nafilyan V, et al. Epidemiology of post-COVID syndrome following hospitalisation with coronavirus: a retrospective cohort study. Posted online January 15, 2021. medRxiv 2021.01.15.21249885. https://doi.org/10.1101/2021.01.15.21249885.

      with QOL returning to pre-COVID-19 baseline after 52 weeks.

      Increased risks of multiorgan dysfunction and monitoring—one-off cost and QALY decrement at the point of discharge

      A one-off cost and QALY loss per patient discharged (Table 1
      • Pan H.
      • Peto R.
      • Henao-Restrepo A.M.
      • et al.
      Repurposed antiviral drugs for COVID-19 - interim WHO solidarity trial results.
      ,

      Ayoubkhani D, Khunti K, Nafilyan V, et al. Epidemiology of post-COVID syndrome following hospitalisation with coronavirus: a retrospective cohort study. Posted online January 15, 2021. medRxiv 2021.01.15.21249885. https://doi.org/10.1101/2021.01.15.21249885.

      ,
      • Halpin Stephen J.
      • McIvor C.
      • Gemma W.
      • et al.
      Postdischarge symptoms and rehabilitation needs in survivors of COVID-19 infection: a cross-sectional evaluation.
      ,
      • Ara R.
      • Brazier J.E.
      Populating an economic model with health state utility values: moving toward better practice.
      • Wilcox Mark H.
      • Harblas A.
      • Coia John E.
      • et al.
      Impact of recurrent Clostridium difficile infection: hospitalization and patient quality of life.
      • Malen H.
      • Olatz G.
      • Mariana G.
      • Montserrat F.
      • Angela D.
      • Jordi A.
      Impact of influenza on health-related quality of life among confirmed (H1N1)2009 patients.
      Publications. British National Formulary.
      Drugs and pharmaceutical electronic market information tool (eMIT). Department of Health and Social Care.
      National cost collection for the NHS: archived reference costs. NHS.
      • Stokes E.A.
      • Wordsworth S.
      • Bargo D.
      • et al.
      Are lower levels of red blood cell transfusion more cost-effective than liberal levels after cardiac surgery? Findings from the TITRe2 randomised controlled trial.
      • Curtis L.
      • Burns A.
      Unit costs of health & social care 2020. PSSRU, University of Kent.
      ) is applied in the economic model to reflect the elevated risk of multiorgan dysfunction after COVID-19 hospitalization (assumed to last a year). These are calculated from the rates reported by Ayoubkhani et al

      Ayoubkhani D, Khunti K, Nafilyan V, et al. Epidemiology of post-COVID syndrome following hospitalisation with coronavirus: a retrospective cohort study. Posted online January 15, 2021. medRxiv 2021.01.15.21249885. https://doi.org/10.1101/2021.01.15.21249885.

      (2021) in the UK in patients hospitalized with COVID-19 compared with matched-controls and assumptions on costs and QALY loss (Appendix Table 1 in Supplemental Materials found at https://doi.org/10.1016/j.jval.2021.12.015).
      Increased monitoring/follow-up is assumed to occur in the first year only. An average one-off cost (Table 1
      • Pan H.
      • Peto R.
      • Henao-Restrepo A.M.
      • et al.
      Repurposed antiviral drugs for COVID-19 - interim WHO solidarity trial results.
      ,

      Ayoubkhani D, Khunti K, Nafilyan V, et al. Epidemiology of post-COVID syndrome following hospitalisation with coronavirus: a retrospective cohort study. Posted online January 15, 2021. medRxiv 2021.01.15.21249885. https://doi.org/10.1101/2021.01.15.21249885.

      ,
      • Halpin Stephen J.
      • McIvor C.
      • Gemma W.
      • et al.
      Postdischarge symptoms and rehabilitation needs in survivors of COVID-19 infection: a cross-sectional evaluation.
      ,
      • Ara R.
      • Brazier J.E.
      Populating an economic model with health state utility values: moving toward better practice.
      • Wilcox Mark H.
      • Harblas A.
      • Coia John E.
      • et al.
      Impact of recurrent Clostridium difficile infection: hospitalization and patient quality of life.
      • Malen H.
      • Olatz G.
      • Mariana G.
      • Montserrat F.
      • Angela D.
      • Jordi A.
      Impact of influenza on health-related quality of life among confirmed (H1N1)2009 patients.
      Publications. British National Formulary.
      Drugs and pharmaceutical electronic market information tool (eMIT). Department of Health and Social Care.
      National cost collection for the NHS: archived reference costs. NHS.
      • Stokes E.A.
      • Wordsworth S.
      • Bargo D.
      • et al.
      Are lower levels of red blood cell transfusion more cost-effective than liberal levels after cardiac surgery? Findings from the TITRe2 randomised controlled trial.
      • Curtis L.
      • Burns A.
      Unit costs of health & social care 2020. PSSRU, University of Kent.
      ) is applied at the point of discharge calculated based on the assumption that discharged patients require on average 2 chest x-ray and 6 GP electronic consultations, and unit costs from Stokes et al
      • Stokes E.A.
      • Wordsworth S.
      • Bargo D.
      • et al.
      Are lower levels of red blood cell transfusion more cost-effective than liberal levels after cardiac surgery? Findings from the TITRe2 randomised controlled trial.
      (2016) and Curtis and Burns
      • Curtis L.
      • Burns A.
      Unit costs of health & social care 2020. PSSRU, University of Kent.
      (2020).

      Analysis

      In accordance with the National Institute of Clinical Excellence reference case,
      Guide to the methods of technology appraisal 2013. National Institute for Health and Care.
      patients are followed over a lifetime horizon, an NHS/personal social services perspective is used and costs and benefits are discounted at 3·5% per annum.
      Results are presented both deterministically and probabilistically to take account of the simultaneous effect of uncertainty relating to model parameter values. A total number of 1000 simulations were performed to obtain sufficient precision. Base-case results are also presented as cost-effectiveness planes and cost-effectiveness acceptability curves.
      The treatment effect for RDV on overall survival (OS) is a key driver and highly uncertain. Consequently, a threshold analysis is conducted, with results presented in terms of net monetary benefits to determine the point at which RDV is no longer cost-effective at a willingness to pay (WTP) of £20 000 under our base-case assumptions. Threshold analysis to determine the cost-effective price was also conducted. A range of sensitivity and scenario analyses are also conducted to test the robustness of results to key input parameters and assumptions (Appendix Table 2 in Supplemental Materials found at https://doi.org/10.1016/j.jval.2021.12.015).

      Results

      Base-Case Analysis: Assumption That RDV Reduces Death—Using the Point Estimate for the Treatment Effect Observed in On-Oxygen Subgroup of SOLIDARITY

      The deterministic and probabilistic results are presented in Table 1.
      • Pan H.
      • Peto R.
      • Henao-Restrepo A.M.
      • et al.
      Repurposed antiviral drugs for COVID-19 - interim WHO solidarity trial results.
      ,

      Ayoubkhani D, Khunti K, Nafilyan V, et al. Epidemiology of post-COVID syndrome following hospitalisation with coronavirus: a retrospective cohort study. Posted online January 15, 2021. medRxiv 2021.01.15.21249885. https://doi.org/10.1101/2021.01.15.21249885.

      ,
      • Halpin Stephen J.
      • McIvor C.
      • Gemma W.
      • et al.
      Postdischarge symptoms and rehabilitation needs in survivors of COVID-19 infection: a cross-sectional evaluation.
      ,
      • Ara R.
      • Brazier J.E.
      Populating an economic model with health state utility values: moving toward better practice.
      • Wilcox Mark H.
      • Harblas A.
      • Coia John E.
      • et al.
      Impact of recurrent Clostridium difficile infection: hospitalization and patient quality of life.
      • Malen H.
      • Olatz G.
      • Mariana G.
      • Montserrat F.
      • Angela D.
      • Jordi A.
      Impact of influenza on health-related quality of life among confirmed (H1N1)2009 patients.
      Publications. British National Formulary.
      Drugs and pharmaceutical electronic market information tool (eMIT). Department of Health and Social Care.
      National cost collection for the NHS: archived reference costs. NHS.
      • Stokes E.A.
      • Wordsworth S.
      • Bargo D.
      • et al.
      Are lower levels of red blood cell transfusion more cost-effective than liberal levels after cardiac surgery? Findings from the TITRe2 randomised controlled trial.
      • Curtis L.
      • Burns A.
      Unit costs of health & social care 2020. PSSRU, University of Kent.
      For the probabilistic analysis, under the assumption that RDV reduces death, the model estimates total discounted costs associated with RDV to be £12 758 compared with £9393 for established clinical management, an incremental cost of £3365. The total discounted QALYs for RDV are estimated to be 6·62 compared with 6·35 for patients treated with established clinical management, an incremental QALY gain of 0·27. The probabilistic incremental cost-effectiveness ratio (ICER) is £12 400 per QALY gained.
      We found that 89·3% of Monte Carlo simulations comparing RDV with established clinical management were in the northeast quadrant (more costly and more effective) of the cost-effectiveness plane. RDV was more costly but less effective in 10·7% of case (northwest quadrant [Fig. 3]). Cost-effectiveness acceptability curves demonstrate that RDV has a 74% probability of being a cost-effective treatment option at a £20 000 per QALY gained WTP threshold.
      Figure thumbnail gr3
      Figure 3Probabilistic sensitivity analysis cost-effectiveness plane.
      K indicates thousand; PSA, probabilistic sensitivity analysis; QALY, quality-adjusted life-year; WTP, willingness to pay.

      Secondary Analysis: RDV Does Not Reduce Death

      When it is assumed that RDV does not reduce death (Table 2), RDV is predicted to lead a very small increase in QALYs (0·00002), at an incremental cost of £1666, leading to a high ICER (>£1 million per QALY). Approximately half of Monte Carlo simulations (52·2%) were in the northeast quadrant (more costly and more effective) of the cost-effectiveness plane, with RDV having a 0% probability of being a cost-effective treatment option at a £20 000 per QALY gained WTP threshold.
      Table 2Model base-case and secondary scenario results.
      InterventionBase-case: RDV reduces deathSecondary scenario: RDV does not reduces death
      In this scenario, RDV the treatment effect for the probability of ventilation in patients initiated on SoC (compared with RDV) is assumed to be same as RDV.
      Total costs (£)Total LYG (und)Total QALYsIncr. costs (£)Incr. LYG (und)Incr. QALYsICER (£/QALY)Total costs (£)Total LYG (und)Total QALYsIncr. costs (£)Incr. LYG (und)Incr. QALYsICER (£/QALY)
      DeterministicDeterministic
      SoC£938614·346·35----£10 31114·346·35----
      RDV£12 71814·976·63£33320·640·28£11 881£11 97014·346·35£1659-0·00>£1M
      ProbabilisticProbabilistic
      SoC£939314·346·35----£10 31614·336·35----
      RDV£12 75814·956·62£33650·620·27£12 400£11 98214·336·35£1666-0·00002>£1M
      Probability CE 20K per QALY gained74%0%
      CE indicates cost-effective; ICER, incremental cost-effectiveness ratio; Incr., incremental; K, thousand; LYG, life-year gained; und, undiscounted; QALY, quality-adjusted life-year; RDV, remdesivir; SoC, standard of care; >£1M, more than £1 million.
      In this scenario, RDV the treatment effect for the probability of ventilation in patients initiated on SoC (compared with RDV) is assumed to be same as RDV.

      Threshold Analyses

      At its current list price, the threshold analysis (Fig. 3) shows that RDV is no longer cost-effective at a WTP of £20 000 per QALY gained when the HR is >0·915.
      If no survival difference is assumed between RDV and SoC (Fig. 4), the price per 100 mg vial for RDV needs to be <£18·6 for RDV to be cost-effective under current WTP threshold.
      Figure thumbnail gr4
      Figure 4Threshold analysis for the treatment effect for overall survival—NMB at a WTP threshold of £20 000 and £30 000 per QALY gained.
      K indicates thousand; NMB, net monetary benefit; QALY, quality-adjusted life-year; WTP, willingness to pay.

      Scenario Analyses

      In addition to the treatment effect for OS and list price for RDV, ICERs were affected the most by the model time horizon, the baseline curve for SoC (patients with progressive COVID-19 included in the RECOVERY TCZ trial), and inclusion of unrelated costs.

      Discussion

      This is the first study to undertake an economic evaluation of the use of RDV for the treatment of hospitalized patients with COVID-19 in England and Wales. This study found that, although RDV reduces time to recovery, it is likely to be cost-effective only if it also prevents death. Nevertheless, the effectiveness of RDV at reducing death is highly uncertain within the overall supplemental oxygen population. Evidence suggests that patients requiring LFO are more likely to derive benefits from RDV than patients on HFO or NIV. Therefore, RDV is likely to represent a cost-effective use of NHS resources in patients with LFO only. The analysis was conducted during the second wave of the pandemic. Since the analysis was conducted, vaccination was introduced in the United Kingdom and the SoC and evidence available for RDV have evolved considerably. Therefore, results from this analysis should be interpreted in this context.
      This study also sets out a framework to capture the key drivers of costs and benefits (mortality, duration of stay, and intensity of care required while in the hospital) that can be used to rapidly evaluate other treatments for hospitalized patients with COVID-19. This is important during a public health emergency because COVID-19 is associated with significant morbidity and mortality, and therefore, there is need to inform public policy rapidly and ensure that NHS resources are allocated efficiently and fairly.
      A key strength of this study is that it addresses an important public health question for decision makers in the light of uncertain information, synthesizes many sources, and reflects uncertainty. This emphasizes the value of modeling given the difficulty to conduct clinical research in a rapidly changing environment. Key strengths of this study also include that it is based on 2 large open-label trials: the RECOVERY trial
      • Horby P.
      • Lim W.S.
      • et al.
      RECOVERY Collaborative Group
      Dexamethasone in hospitalized patients with COVID-19.
      and SOLIDARITY.
      • Pan H.
      • Peto R.
      • Henao-Restrepo A.M.
      • et al.
      Repurposed antiviral drugs for COVID-19 - interim WHO solidarity trial results.
      This study also focuses on patients treated with RDV on supplemental oxygen at the start of treatment (defined as LFO, HFO, or NIV) in line with its European marketing authorization and NHS England commissioning policy.
      Interim Clinical Commissioning Policy: remdesivir for patients hospitalised with COVID-19 (adults and children 12 years and older), version 2. NHS England.
      ,
      Veklury summary of product characteristics. European Medicines Agency.
      The duration of hospitalization is calculated from the AUC of OS and time to discharge curves with outcomes extrapolated beyond the trial duration to account for the fact that a proportion of patients are neither dead nor discharged by day 28 in the respective trials. Albeit with some simplification because of limitations with the evidence base, this economic evaluation attempts to include some of the short-, medium-, and long-term effects associated with COVID-19 (elevated risk of death, reduced QOL, elevated risk of multiorgan dysfunctions, and increased monitoring) alongside movement among the different hospitalization oxygen requirements (with costs and QALYs calculated accordingly). Uncertainty in the model inputs and assumptions has also been explored extensively in a number of scenario and sensitivity analyses.
      Results are not directly comparable with other published economic evaluation for RDV
      • Campbell J.D.
      • Whittington M.D.
      • Rind D.M.
      • Pearson S.D.
      Alternative pricing models for Remdesivir and other potential treatments for COVID-19; updated report.
      • Congly S.E.
      • Varughese R.A.
      • Brown C.E.
      • Clement F.M.
      • Saxinger L.
      Treatment of moderate to severe respiratory COVID-19: a cost-utility analysis.
      • Jo Y.
      • Jamieson L.
      • Edoka I.
      • et al.
      Cost-effectiveness of remdesivir and dexamethasone for COVID-19 treatment in South Africa.
      given that there are a number of important differences in terms of population considered, comparators, methodology, and evidence used. Previous published economic evaluations
      • Campbell J.D.
      • Whittington M.D.
      • Rind D.M.
      • Pearson S.D.
      Alternative pricing models for Remdesivir and other potential treatments for COVID-19; updated report.
      • Congly S.E.
      • Varughese R.A.
      • Brown C.E.
      • Clement F.M.
      • Saxinger L.
      Treatment of moderate to severe respiratory COVID-19: a cost-utility analysis.
      • Jo Y.
      • Jamieson L.
      • Edoka I.
      • et al.
      Cost-effectiveness of remdesivir and dexamethasone for COVID-19 treatment in South Africa.
      at the time this analysis was conducted used a decision-tree approach with patients considered either recovered or dead during the first month, followed by a Markov model or payoff. The population included in previous economic evaluations
      • Campbell J.D.
      • Whittington M.D.
      • Rind D.M.
      • Pearson S.D.
      Alternative pricing models for Remdesivir and other potential treatments for COVID-19; updated report.
      • Congly S.E.
      • Varughese R.A.
      • Brown C.E.
      • Clement F.M.
      • Saxinger L.
      Treatment of moderate to severe respiratory COVID-19: a cost-utility analysis.
      • Jo Y.
      • Jamieson L.
      • Edoka I.
      • et al.
      Cost-effectiveness of remdesivir and dexamethasone for COVID-19 treatment in South Africa.
      was also broader including patients not on oxygen or on invasive ventilation at the start of treatment. This differs from the licensed indication for RDV in Europe, which specifies patients with pneumonia requiring supplemental oxygen. The duration of hospitalization is also calculated differently, derived from the OS and time to discharge extrapolated curves in our model, compared with a more simplistic approach in previous economic evaluation based on the median time to recovery in recovered patients and assumptions for those who died.
      • Campbell J.D.
      • Whittington M.D.
      • Rind D.M.
      • Pearson S.D.
      Alternative pricing models for Remdesivir and other potential treatments for COVID-19; updated report.
      In our model, hospitalized patients are also able to move (implicitly) between different hospitalization/oxygen requirements with costs and QALYs calculated accordingly. In Campbell et al
      • Campbell J.D.
      • Whittington M.D.
      • Rind D.M.
      • Pearson S.D.
      Alternative pricing models for Remdesivir and other potential treatments for COVID-19; updated report.
      (2020) for instance, hospitalization costs are calculated based on the oxygen support required as highest level of respiratory support (one-off cost not based on duration of hospitalization) and are disconnected from the starting health state and therefore only applicable for the overall ACTT-1 population. Compared with previous economic evaluations,
      • Campbell J.D.
      • Whittington M.D.
      • Rind D.M.
      • Pearson S.D.
      Alternative pricing models for Remdesivir and other potential treatments for COVID-19; updated report.
      • Congly S.E.
      • Varughese R.A.
      • Brown C.E.
      • Clement F.M.
      • Saxinger L.
      Treatment of moderate to severe respiratory COVID-19: a cost-utility analysis.
      • Jo Y.
      • Jamieson L.
      • Edoka I.
      • et al.
      Cost-effectiveness of remdesivir and dexamethasone for COVID-19 treatment in South Africa.
      our model further considers that COVID-19 patients are, on average, at an elevated risk of death, reduced QOL, and multiorgan dysfunctions after discharge. None of these effects were included in previous published economic evaluations at the time this analysis was conducted.
      • Campbell J.D.
      • Whittington M.D.
      • Rind D.M.
      • Pearson S.D.
      Alternative pricing models for Remdesivir and other potential treatments for COVID-19; updated report.
      • Congly S.E.
      • Varughese R.A.
      • Brown C.E.
      • Clement F.M.
      • Saxinger L.
      Treatment of moderate to severe respiratory COVID-19: a cost-utility analysis.
      • Jo Y.
      • Jamieson L.
      • Edoka I.
      • et al.
      Cost-effectiveness of remdesivir and dexamethasone for COVID-19 treatment in South Africa.
      As with any economic evaluation, there are limitations to be acknowledged. First, any economic evaluation for COVID-19 is challenging to conduct because of the rapidly changing environment. SoC is consistently evolving and has changed since the evidence used in this economic evaluation was published. Corticosteroids are now the SoC in England and Wales, and this has been reflected in the base-case. NHS England recently issued advice for the use of TCZ and SAR. Unlike RDV, TCZ and SAR have different mechanisms of action, and it is unclear to what to extent these treatments would be considered in patients who would have been otherwise eligible for RDV in England and Wales (and be appropriate comparators). Albeit limited to the supplemental oxygen subgroup from the respective source of evidence, this economic evaluation combines evidence from different studies that are heterogeneous in population, design, and outcomes. The level of patients’ oxygen requirement was also not reported.
      Evidence is also constantly evolving. For instance, time to discharge had to be approximated because only the proportion of events at the end of trial was reported at the time of conducting study, but new data have now been published. Using the recently published KM was explored (Appendix Table 2 in Supplemental Materials found at https://doi.org/10.1016/j.jval.2021.12.015). Therefore, the model needs to develop as more evidence is available on both the impact of treatments on COVID-19 and its long-term effect. Since this analysis was conducted, additional evidence of the effectiveness RDV has been published from a phase III, open-label, adaptive, multicenter RCT conducted in 48 sites in Europe (DisCoVeRy).
      • Ader F.
      • Bouscambert-Duchamp M.
      • Hites M.
      • et al.
      Remdesivir plus standard of care versus standard of care alone for the treatment of patients admitted to hospital with COVID-19 (DisCoVeRy): a phase 3, randomised, controlled, open-label trial.
      This study found that no clinical benefit was observed from the use of RDV in patients who were admitted to hospital for COVID-19 and requiring oxygen support.
      The model uses an AUC approach that does not allow us to track individual patients, leading to assumptions being required. A cohort partitioned survival approach was chosen in the absence of individual patient level data from the key relevant trials/studies used in this economic evaluation and necessity to work with aggregate published data. This is a limitation because patients with COVID-19 admitted to the hospital are heterogeneous, with important factors affecting the progression of their disease. It was also not possible to conduct subgroup analysis in the absence of subgroup data reported in patients on supplemental oxygen at entry. Treatment effects from studies evaluating RDV for 10 days are used as a proxy for RDV for 5 days. The assumption of equivalence for survival is likely to be reasonable and is supported by Goldman et al
      • Goldman J.D.
      • Lye D.C.B.
      • Hui D.S.
      • et al.
      Remdesivir for 5 or 10 days in patients with severe Covid-19.
      (2020) and Spinner et al
      • Spinner CD
      • Gottlieb RL
      • Criner GJ
      • et al.
      Effect of remdesivir vs standard care on clinical status at 11 days in patients with moderate COVID-19: a randomized clinical trial.
      (2020), albeit in a broader population. The trend for time to discharge is taken from SOLIDARITY where patients were treated up for to 10 days, which could have affected the decision to discharge patients. It is possible that patients on RDV in SOLIDARITY were kept longer at the hospital to finish the 10-day course.
      Analyses are conducted at list prices. Any confidential discount offered to the NHS is not considered in this analysis. It is also unclear whether RDV reduces or increases ventilation/oxygen support because of mixed evidence.
      Since this economic evaluation was conducted, 2 UK studies—the PHOSP-COVID collaborative group

      Evans RA, McAuley H, Harrison EM, et al. Physical, cognitive and mental health impacts of COVID-19 following hospitalization (PHOSP-COVID): a multi-centre prospective cohort study. 2021;9(11):1275–1287.

      and ISARIC

      Sigfrid L, Drake TM, Pauley E, et al. Long COVID in adults discharged from UK hospitals after COVID-19: a prospective multicentre cohort study using the ISARIC WHO Clinical Characterisation Protocol. Posted online March 25, 2021. medRxiv 2021.03.18.21253888. https://doi.org/10.1101/2021.03.18.21253888.

      —reported estimates on QOL before COVID-19 and for lower mean age. Therefore, it is unclear whether the additional decrement in utility associated with comorbidities included in this analysis was required and led to double counting. This was explored in a scenario analysis and led to an improvement in the ICER (Appendix Table 2 in Supplemental Materials found at https://doi.org/10.1016/j.jval.2021.12.015).
      Assumptions were required to capture the effect of COVID-19 in the medium to long term. It is unclear how long discharged COVID-19 patients are at an elevated risk of death or reduced QOL. It is also unclear whether multiorgan dysfunctions reported in the literature are acute (temporary) or chronic. The approach to capture costs and impact on QOL associated with multiorgan dysfunction is simplistic because of the heterogeneity in patients experience and does not take into account patients with post-COVID-19 syndrome and the recommendation for them to have rehabilitation. It also does not take account of other reported long-term effects on mental health that have been reported such as posttraumatic stress disorder. The duration and frequency of monitoring after discharge of patients with COVID-19 are also unknown and challenging to capture because of the heterogeneity in patient experience. The mortality, costs, and morbidity impact associated with readmission because of COVID-19 is not included separately to avoid double counting because evidence suggests that readmission because of COVID-19 occurs shortly after the initial hospitalization episode, typically within 5 to 10 days.
      • Beigel J.H.
      • Tomashek K.M.
      • Dodd L.E.
      • et al.
      Remdesivir for the treatment of COVID-19 - final.
      ,
      • Rokadiya S.
      • Gil E.
      • Stubbs C.
      • Bell D.
      • Herbert R.
      COVID-19: outcomes of patients with confirmed COVID-19 re-admitted to hospital.
      The model conservatively assumes that patients initiated on RDV or SoC experience the same long-term outcomes, in the absence of evidence. Consequently, any short-term difference in survival will translate into commensurate gain in the long-term. It is possible that outcomes for patients initiated on RDV may be worse if more patients require ventilation because of the reduced death rate.

      Conclusions

      RDV is likely to represent a cost-effective use of NHS resources if it reduces death and does not increase ventilation requirement. RDV is likely to be more cost-effective in patients requiring LFO at entry only than those requiring more intensive HFO or NIV.

      Article and Author Information

      Author Contributions: Concept and design: Rafia, Wailoo
      Acquisition of data: Martyn-St James, Harnan, Metry
      Analysis and interpretation of data: Rafia, Martyn-St James, Harnan, Metry, Hamilton, Wailoo
      Drafting of the manuscript: Rafia, Metry, Wailoo
      Critical revision of the paper for important intellectual content: Rafia, Martyn-St James, Harnan, Hamilton, Wailoo
      Statistical analysis: Rafia, Hamilton
      Provision of study materials or patients: Martyn-St James, Harnan
      Obtaining funding: Wailoo
      Administrative, technical, or logistic support: Rafia, Martyn-St James, Metry
      Supervision: Wailoo
      Conflict of Interest Disclosures: Allan Wailoo is an editor for Value in Health and had no role in the peer review process of this article. No other disclosures were reported.
      Funding/Support: This project funded by the National Institute for Health and Care Excellence through the Decision Support Unit.
      Role of the Funder/Sponsor: The funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. The funder was able to comment on previous drafts of this article and provide comments for consideration by the authors.

      Acknowledgment

      We thank Ruth Wong, School of Health and Related Research, for conducting searches for the clinical and cost-effectiveness evidence.
      Ethical Approval: This research did not collect primary data from individuals, or have any access to individual level data and therefore did not require ethical approval.

      Supplemental Materials

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      Linked Article

      • COVID-19 Health Economics: Looking Back and Scoping the Future
        Value in HealthVol. 25Issue 5
        • Preview
          As of March 2022, nearly 6 million people have died of COVID-19 globally.1 The COVID-19 pandemic has already gone through several distinct stages during the first 2 years, with noticeable health and health economics impact at each stage. The initial emergency stage resulted in lockdowns that incurred enormous societal costs, concerning gross domestic product reductions as well as (mental) health damages. Diagnostic tests were implemented on a never-before-seen scale in many healthcare systems, without health economics justification,2,3 as exemplified in a systematic review in this themed section.
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