TA878 · STA
Source documents
Interventions
Conditions
Comparators
| Name | Type | Established | Committee preferred |
|---|---|---|---|
| standard care | standard of care | — | — |
| standard care at the time of each trial | standard of care | — | — |
| best supportive care | best supportive care | — | — |
Clinical trials
| Trial | Design | Phase | Pivotal |
|---|---|---|---|
| PANORAMIC | RCT | Phase III | — |
| RECOVERY | RCT | Phase III | — |
| SOLIDARITY | RCT | Phase III | — |
| REMAP-CAP | RCT | Phase III | — |
| ACTT-1 | RCT | Phase III | — |
| EPIC-HR | RCT | — | Yes |
| EPIC-SR | RCT | — | — |
| PINETREE | RCT | — | — |
| COMET-ICE | RCT | — | — |
Economic model
Methodological decisions (34)
Definition of high-risk population eligible for treatment
Company: Some trials used broader definitions of risk; age over 50 years considered important
ERG: Assessment group modelled general population survival with starting age 56.6 years and PANORAMIC hospitalisation rates
Committee: McInnes report's definition of high risk is most robust, based on specific risk factors but not age as an independent factor. Concluded that age over 70 years is likely confounded by underlying conditions.
ICER impact: uncertain_direction
Choice of standard care comparator for economic modelling
Company: Not explicitly stated
ERG: Modelled standard care on dexamethasone arm of RECOVERY trial for severe COVID-19 setting
Committee: RECOVERY standard care more generalisable to endemic setting than SOLIDARITY standard care; REMAP-CAP and RECOVERY evidence for tocilizumab considered more generalisable given UK sites and reflection of NHS practice
ICER impact: uncertain_direction
Time to discharge for remdesivir in severe COVID-19
ERG: initially did not include ACTT-1 time to discharge data; later included it following consultee feedback, resulting in large reduction in cost-effectiveness estimates
Committee: acknowledged concerns about generalisability of early pandemic data and supported removal of time to discharge treatment effects
ICER impact: uncertain_direction
Annual per person management costs of long COVID; initially assumed comparable with chronic fatigue syndrome (£1,013); later updated to £2,267 per year (2021/2022 inflated) based on Vos-Vromans et al. 2017
Company: Consultee said AG's base-case underestimated true burden of long COVID and provided alternative higher cost from Vos-Vromans et al. 2017
ERG: AG initially considered costs had minimal impact but provided scenario analyses with increased costs (£2,500); later accepted new evidence and inflated cost to £2,267
Committee: Committee agreed with updated base-case value; agreed scenario analyses had minimal effect on cost-effectiveness estimates but considered new UK-specific evidence should be included if available
ICER impact: negligible
Administration costs for oral antivirals and neutralising monoclonal antibodies; CMDU deployment costs of £410 (oral antivirals) and £820 (monoclonal antibodies); discussion of future primary care delivery and requirements to assess contraindications
Company: Some companies disagreed with using CMDU deployment costs (include secondary care costs); some consultees proposed additional pharmacist costs (£352.49/hour) for nirmatrelvir plus ritonavir interaction assessment or suggested lower costs (£75-£117 for nirmatrelvir plus ritonavir based on e-consultations and telephone triage)
ERG: AG explained changes in administration costs can be evaluated by looking at differences in net monetary benefit; NHS England noted delivery subject to change and costs calculated before nirmatrelvir plus ritonavir implementation
Committee: Committee considered differences in administration costs in relation to net monetary benefit outcomes, noting uncertainty about future delivery models
ICER impact: uncertain_direction
Use of network meta-analyses (NMAs) from publicly available sources (COVID-NMA and metaEvidence living systematic reviews) for indirect comparisons across trials
Company: Provided NMA including SOLIDARITY and ACTT-1 trials
ERG: Conducted systematic reviews and NMAs from publicly available sources; updated analysis to include additional trials (SOLIDARITY, ACTT-1) and updated COVID-19 NMA results
Committee: Recognised limitations of systematic reviews that did not adhere to established reviewing methods and missed key trials; accepted updated scenarios including SOLIDARITY and ACTT-1; noted potential for bias from indirect comparison using pairwise analysis rather than full network
ICER impact: uncertain_direction
Relative treatment effects for mild COVID-19
Committee: pairwise analysis rather than network NMA introduces potential bias; heterogeneity of trial outputs and generalisability concerns contribute greater uncertainty
ICER impact: increases
Whether to model separate high-risk subgroups based on specific baseline characteristics or use single definition of high risk
Company: Not explicitly stated
ERG: At first meeting assumed no individual high-risk subgroups modelled by baseline characteristics; at second meeting noted limitations of attempting separate subgroup modelling
Committee: Concluded single definition of high risk should be used. Evidence at subgroup level too limited and uncertain to parameterise differential recommendations. McInnes definition most robust and provides outcomes data from vaccinated people infected with Omicron variants.
ICER impact: uncertain_direction
Whether to include treatment effects on time to discharge and clinical improvement at 28 days
ERG: included treatment effects on time to discharge
Committee: reasonable to remove treatment effects on time to discharge and clinical improvement at 28 days due to uncertainty in endemic setting
ICER impact: increases
Assumption about mortality rates for treatment in hospital compared with standard care
Company: Not explicitly stated
ERG: Initially modelled treatment mortality higher than standard care
Committee: Updated assumption to cap mortality rate to equal 1 for low-efficacy scenario in response to consultee feedback regarding implausible mortality outcomes
ICER impact: increases
Treatment of mortality assumptions in low-efficacy scenarios for hospital setting
Company: Not explicitly stated
ERG: Initial analysis resulted in treatment having higher mortality risk than standard care in hospital setting
Committee: In response to consultation feedback, AG capped mortality rate to equal 1 for low-efficacy scenario
ICER impact: increases
Method for characterising high levels of uncertainty in treatment effects due to changing pandemic context
Company: Not explicitly stated
ERG: Ran scenario analysis using mean and upper/lower confidence limits of efficacy estimates to show mean, lower, and higher efficacy scenarios
Committee: Accepted scenario analysis as attempt to address uncertainty given limitations of probabilistic sensitivity analysis; noted that heterogeneity and generalisability issues made parametrisation for probabilistic sensitivity analysis inappropriate; capped mortality rate to equal 1 for low-efficacy scenario in response to consultee feedback
ICER impact: uncertain_direction
Long COVID duration assumptions
Committee: 30% with symptoms at 2 years, 10% at 5 years, 3% at 10 years; maintained assumption of 100% in severe setting and 10% in mild setting despite consultee feedback requesting changes, as alternative evidence not available
ICER impact: negligible
Baseline hospitalisation rate for high-risk population defined by McInnes criteria; range between 2.41% (OpenSAFELY untreated eligible using McInnes) and 2.82% (DISCOVER-NOW); 4.00% upper limit for people contraindicated to nirmatrelvir plus ritonavir using advanced renal disease proxy
Company: Not explicitly stated
ERG: AG presented range of rates and acknowledged underestimation in PANORAMIC
Committee: Committee agreed that 0.77% from PANORAMIC was underestimation; concluded hospitalisation rate for McInnes high-risk group likely between 2.41% and 2.82%; 4.00% for contraindicated population
ICER impact: decreases
Clinical effectiveness of casirivimab plus imdevimab in severe COVID-19 with supplemental oxygen
Committee: not clinically effective
ICER impact: increases
Clinical evidence collected before Omicron variants became dominant. Hospitalisation and mortality rates now lower with Omicron than earlier variants, making cost-effectiveness estimates higher. Committee considered relevance of clinical data to current endemic context.
Committee: Committee acknowledged limitations of available evidence but considered cost-effectiveness estimates in light of changed epidemiology and lower hospitalisation/mortality rates with Omicron variants.
ICER impact: increases
Marketing authorisations based on evidence from populations with different definitions of high risk (e.g. different age requirements and number of risk factors). Committee acknowledged need to clearly define high risk for treatment eligibility.
Committee: Committee emphasised importance of clear definition of high risk, referencing PANORAMIC trial and independent advisory group report commissioned by Department of Health and Social Care.
ICER impact: uncertain_direction
Generalisability of evidence across trials conducted at different times during pandemic with different variants of concern, vaccinated populations, and natural immunity levels
Company: Not explicitly stated
ERG: Meta-analysing trial results may not be appropriate because weighting may not consider relevance of each trial's context, particularly regarding different variants
Committee: Acknowledged high levels of uncertainty with each treatment effect and context-specific nature of evidence. Used scenario analysis with mean, upper and lower confidence limits rather than probabilistic sensitivity analysis to characterise uncertainty.
ICER impact: uncertain_direction
Concern about age as a protected characteristic being used in treatment recommendations
Company: Age was considered an important risk factor but ongoing debate about appropriate age threshold
ERG: Not specified
Committee: Committee concerned that age-based recommendations could cause inequality. Noted NICE cardiovascular guidance does not include age-based criteria despite it being a recognised risk factor. Age is protected characteristic requiring equity impact assessment.
ICER impact: uncertain_direction
Generalisability of trial evidence to current endemic context with Omicron variant, widespread vaccination, and natural immunity
Company: Not explicitly stated
ERG: Assessed generalisability concerns including changes in population immunity, viral pathogenicity, and supportive care effectiveness
Committee: Mean-efficacy scenarios from pandemic-era trials likely represent ceiling efficacy rather than realistic effectiveness in endemic setting; relative treatment effects would lack generalisability due to interaction with contextual factors; changes in best supportive care and vaccination rates mean limited relative effects
ICER impact: decreases
Whether PANORAMIC hospitalisation rate of 0.77% adequately represents high-risk population
ERG: 0.77% likely underestimation; highest risk groups may be underrepresented
Committee: Hospitalisation rate for McInnes high-risk group is between 2.41% and 2.82% based on OpenSAFELY and DISCOVER-NOW; approximately 4% for those contraindicated to nirmatrelvir plus ritonavir
ICER impact: decreases
EPIC-HR trial population generalisability
Committee: EPIC-HR done in unvaccinated population in earlier wave; EPIC-SR showed non-significant reduction in vaccinated high-risk subgroup; substantial uncertainty due to generalisability concerns; range between mean and lower-efficacy estimates more suited to endemic setting
ICER impact: increases
Remdesivir mortality benefit generalisability to current endemic setting
Committee: SOLIDARITY data and pooled NMA reflect earlier pandemic context; standard care has considerably changed; more certain that relative mortality rate ratio would tend towards 1.00; interpreted evidence cautiously using threshold analysis with mortality rate ratios 0.85 to 1.00
ICER impact: increases
Use of network meta-analyses from living systematic reviews with different trial designs, baseline characteristics, geographical locations and pandemic contexts
Company: Company provided alternative NMA including SOLIDARITY trial
ERG: Initial approach used COVID-NMA and metaEvidence living reviews; acknowledged assumptions that relative treatment effects are transferable to current clinical management despite evolving standard care and variants
Committee: Recognised limitations but considered scenario analysis approach attempted to address uncertainty. At consultation, noted heterogeneity and generalisability issues made uncertainty difficult to parameterise for probabilistic sensitivity analysis.
ICER impact: uncertain_direction
Adequacy of systematic reviews informing network meta-analyses
Company: Company provided NMA including SOLIDARITY trial and other key trials
ERG: Initial systematic reviews did not adhere to established reviewing methods and missed SOLIDARITY and ACTT-1 trials
Committee: Accepted company-provided NMA including SOLIDARITY and scenarios including ACTT-1 data for remdesivir time to discharge
ICER impact: uncertain_direction
Use of in vitro neutralisation assays to predict clinical effectiveness against circulating variants
Company: Noted that in vitro assay methodology may affect interpretation (e.g., ACE2 over-expression in cell lines for sotrovimab)
ERG: Not explicitly stated
Committee: Commissioned in vitro expert advisory group to develop decision framework linking in vitro neutralisation data to clinical outcomes; framework applied to interpret in vitro evidence; recognised that partial reductions in neutralisation are difficult to interpret without additional clinical evidence
ICER impact: uncertain_direction
Minimal mortality benefit when HRs close to 1
Committee: for remdesivir and molnupiravir, when potential benefit is minimal (HRs close to 1), stronger clinical evidence needed to justify difference in relative clinical effects; cannot be certain of clinical efficacy
ICER impact: increases
Remdesivir mortality benefit threshold analysis with mortality rate ratios between 0.85 and 1.00
Committee: insufficient evidence for meaningful mortality difference vs standard care
ICER impact: uncertain_direction
Time to discharge as key driver of cost-effectiveness; removal of treatment effects on time to discharge and clinical improvement at 28 days to account for changing clinical context and heterogeneous population in endemic setting
Company: One consultee highlighted time to discharge data from ACTT-1 should have been included for remdesivir
ERG: AG included time to discharge data for remdesivir (resulting in large reduction in cost-effectiveness estimates); noted data collected during early pandemic stages with generalisability concerns; included scenarios removing treatment effects on time to discharge and clinical improvement
Committee: Committee noted clinical practice differences (time to discharge depends on multiple factors like negative test); considered scenarios removing these treatment effects reasonable but conservative; was uncertain about treatment benefit in endemic setting; concluded it was reasonable to remove these treatment effects
ICER impact: increases
Likelihood that neutralising monoclonal antibodies lose effectiveness over time as virus evolves to evade treatments
Company: Emphasised that sotrovimab's effectiveness depends on ACE2 expression levels and in vitro assay methodology may underestimate clinical efficacy
ERG: Not explicitly stated separately
Committee: Casirivimab plus imdevimab and tixagevimab plus cilgavimab unlikely to retain sufficient neutralisation activity against most variants circulating at time of evaluation; sotrovimab showed ambiguous in vitro evidence with uncertainty about effectiveness against BQ.1 and BQ.1.1
ICER impact: decreases
Effectiveness of neutralising monoclonal antibodies against evolving variants
Company: sotrovimab's effectiveness depends on ACE2 expression levels; in vitro over-expression may underestimate neutralising ability
Committee: casirivimab plus imdevimab and tixagevimab plus cilgavimab unlikely to retain sufficient neutralisation activity; sotrovimab clinical effectiveness likely reduced against BA.5 with uncertainty on BQ.1 and BQ.1.1; effectiveness requires continuous monitoring
ICER impact: increases
Use of UK age- and sex-adjusted utility values (EQ-5D-3L) for baseline utility estimates; no additional utility decrements for mild COVID-19 without long COVID; use of age- and sex-adjusted UK general population utility instead
Company: Stakeholders critiqued this assumption saying it may not capture full benefit of treatments compared with standard care and disadvantaged community-based treatments
ERG: AG agreed this was a simplified assumption but scenario analysis showed it had limited impact on final ICERs
Committee: Committee agreed with AG's assumption and acknowledged minor impact on ICERs
ICER impact: negligible
Use of utility decrements from cost-effectiveness analysis of remdesivir (originally from population with recurrent Clostridioides difficile infection and influenza) for severe COVID-19 setting; same in-hospital utility decrements applied across ordinal scales 3 to 5
Company: Stakeholders critiqued use of utility decrements from non-COVID-19 population; proposed alternative approach using COVID-19 severity-specific vignettes with EQ-5D-3L questionnaires; highlighted recent COVID-19 utility-specific systematic reviews
ERG: AG said vignette study would not be possible due to restricted timelines; did not find alternative COVID-19 utility decrements from stakeholder-suggested systematic reviews
Committee: Not explicitly stated in this section
ICER impact: uncertain_direction
Use of post-discharge long COVID utility decrements from Evans et al. 2022; same utility decrement assumed regardless of ordinal scale status at hospital admission
Company: Stakeholders suggested alternative source of post-discharge utility decrements split by history of ordinal scale status
ERG: AG explained model structure unable to allocate post-discharge utility based on historical ordinal scale admission status; also that utility decrements only applied for duration of long COVID and not key driver of ICERs
Committee: Committee agreed with AG's rationale and long COVID utility decrement assumptions
ICER impact: negligible
Evidence gaps
Commercial arrangement
Special considerations