Casirivimab plus imdevimab, nirmatrelvir plus ritonavir, sotrovimab and tocilizumab for treating COVID-19

Evidence-based recommendations on casirivimab plus imdevimab (Ronapreve), nirmatrelvir plus ritonavir (Paxlovid), sotrovimab (Xevudy) and tocilizumab (RoActemra) for treating COVID-19.

# Recommendations
Nirmatrelvir plus ritonavir is recommended as an option for treating COVID19 in adults, only if they:
do not need supplemental oxygen for COVID19 and
have an increased risk for progression to severe COVID19, as defined in section 5.
Sotrovimab is recommended as an option for treating COVID19 in adults and young people aged 12 years and over and weighing at least 40 kg, only if:
they do not need supplemental oxygen for COVID19 and
they have an increased risk for progression to severe COVID19, as defined in section 5 and
nirmatrelvir plus ritonavir is contraindicated or unsuitable.Sotrovimab is only recommended if the company provides it according to the commercial arrangement.
Tocilizumab is recommended, within its marketing authorisation, as an option for treating COVID19 in adults who:
are having systemic corticosteroids and
need supplemental oxygen or mechanical ventilation.Tocilizumab is only recommended if the company provides it according to the commercial arrangement.
Casirivimab plus imdevimab is not recommended, within its marketing authorisation, for treating acute COVID19 in adults.
Why the committee made these recommendations
About this evaluation
This evaluation reviews the clinical and cost effectiveness of:
casirivimab plus imdevimab, nirmatrelvir plus ritonavir and sotrovimab for mild COVID19
casirivimab plus imdevimab and tocilizumab for severe COVID19.
Most of the clinical evidence for these treatments is highly uncertain because it comes from studies done before the dominant Omicron variants of SARSCoV2 (the virus that causes COVID19).
The cost-effectiveness estimates are highly dependent on how well each treatment works compared with standard care, and hospitalisation and mortality rates. Hospitalisation and mortality rates are lower with Omicron variants than earlier variants in the pandemic. These lower rates increase the cost-effectiveness estimates.
Clinical and cost effectiveness
Clinical evidence suggests that:
nirmatrelvir plus ritonavir is effective at treating mild COVID19 compared with standard care
sotrovimab is likely to be effective at treating mild COVID19 compared with standard care but some of the evidence is uncertain
tocilizumab is effective at treating severe COVID19 compared with standard care.
Other evidence suggests that it is highly uncertain that casirivimab plus imdevimab is effective against Omicron variants of COVID19.
Nirmatrelvir plus ritonavir and tocilizumab are recommended because the likely cost-effectiveness estimates are within what NICE considers an acceptable use of NHS resources. The cost-effectiveness estimates for sotrovimab are also within what NICE considers an acceptable use of NHS resources, but only for people for whom nirmatrelvir plus ritonavir is contraindicated or unsuitable. So, sotrovimab is recommended in this group.
Casirivimab plus imdevimab is not recommended because it is unlikely to be effective at treating COVID19 and it is not possible to reliably estimate its cost effectiveness.# Information about the treatments

# Marketing authorisation indications
Casirivimab plus imdevimab (Ronapreve, Roche Products) is 'indicated for the prophylaxis and treatment of acute Covid19 infection'.
Nirmatrelvir plus ritonavir (Paxlovid, Pfizer) is 'indicated for the treatment of COVID19 in adults who do not require supplemental oxygen and who are at increased risk for progression to severe COVID19'.
Sotrovimab (Xevudy, GlaxoSmithKline) is indicated 'for the treatment of symptomatic adults and adolescents (aged 12 years and over and weighing at least 40 kg) with acute covid19 infection who do not require oxygen supplementation and who are at increased risk of progressing to severe covid infection'.
Tocilizumab (RoActemra, Roche Products) is indicated 'for the treatment of coronavirus disease 2019 (COVID19) in adults who are receiving systemic corticosteroids and require supplemental oxygen or mechanical ventilation'.

# Dosage in the marketing authorisation
The dosage schedule for casirivimab plus imdevimab is available in the summary of product characteristics for casirivimab plus imdevimab.
The dosage schedule for nirmatrelvir plus ritonavir is available in the summary of product characteristics for nirmatrelvir plus ritonavir.
The dosage schedule for sotrovimab is available in the summary of product characteristics for sotrovimab.
The dosage schedule for tocilizumab is available in the summary of product characteristics for tocilizumab.

# Price
The list price for casirivimab plus imdevimab is currently confidential.
The list price for nirmatrelvir plus ritonavir is 829 for a 20pack of 150 mg nirmatrelvir tablets and a 10pack of 100 mg ritonavir tablets (excluding VAT; MIMS online, accessed October 2022). Costs may vary in different settings because of negotiated procurement discounts.
The list price for sotrovimab is 2,209 per 500 mg/8 ml concentrate for solution for infusion vial (excluding VAT; BNF online, accessed October 2022). The company also has a commercial arrangement. This makes sotrovimab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.
The list price for tocilizumab is 256 per 200 mg/10 ml and 512 per 400 mg/20 ml concentrate for solution for infusion vial (excluding VAT; BNF online, accessed October 2022). The company has a commercial arrangement. This makes tocilizumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The evaluation committee considered evidence from several sources. See the committee papers for full details of the evidence.
This evaluation reviews:
casirivimab plus imdevimab and sotrovimab (neutralising monoclonal antibodies), and nirmatrelvir plus ritonavir (antiviral), in the mild COVID19 setting
casirivimab plus imdevimab (neutralising monoclonal antibody), and tocilizumab (anti-inflammatory) in the severe COVID19 setting (with and without supplementary oxygen).

# Background

## Impact of COVID-19
COVID19 is the acute respiratory illness caused by the SARSCoV2 virus. It can range from mild to severe. In severe disease, excessive immune response to the virus may cause severe complications associated with hospitalisation and death. The need for organ system support, particularly respiratory support, is also a key feature of severe disease and can lead to substantial longer-term morbidity. COVID19 may cause long-term symptoms that continue or develop after acute infection called 'long COVID'. These are health problems that fluctuate and can last several months or years, and which severely impact a person's physical and mental health and potentially affect their ability to work, attend school or do their usual activities. During draft guidance consultation, consultees highlighted the treatment gap for children. At the second evaluation committee meeting (referred to as 'second meeting' from now on) one clinical expert explained that COVID19 rarely makes children unwell. But, there is a small proportion of children with underlying conditions who have an increased risk of severe COVID19 comparable with adults who have underlying conditions. Many people are at increased risk of hospitalisation or death from COVID19, including people who are immunosuppressed (for example, people with primary immunodeficiency, people having chemotherapy, or people who have had a transplant) or who have comorbidities (such as heart disease, respiratory disease, diabetes, neurological conditions). Some immunocompromised people are at risk of persistent viral infection if their immune system cannot control the virus. Patient experts explained that the increased risk of hospitalisation and death has led to some people changing their treatments, lifestyle and behaviour during the COVID19 pandemic because of the need to shield. Patient organisations emphasised the need for treatments to prevent progression to severe COVID19. They considered that routine availability of these treatments would support a return to normality for many people who already have disease burden from other comorbidities. The committee agreed that the risk of hospitalisation and death, and other longer-term impacts of COVID19, can result in severe physical and mental burden and that there is an unmet need in this population.

## The rapidly evolving SARS-CoV-2 virus
The global COVID19 pandemic has caused unprecedented challenges to the healthcare system and this is reflected in the evidence collected on COVID19 and treatments for it. The SARSCoV2 virus has evolved throughout the pandemic, as has the healthcare system's ability to respond to the virus. New variants of the virus and subvariants, referred to as variants of concern, have emerged throughout the pandemic. The properties of each variant can differ, such as the levels of transmissibility and disease severity. The clinical experts explained that understanding of the disease has changed throughout the pandemic, with increasingly effective supportive care, vaccination, and greater natural immunity. The committee understood that overall hospitalisation and mortality from COVID19 has reduced, and the incidence of COVID19 pneumonitis in hospital has lowered, as has the need for supplemental oxygen or mechanical ventilation.
At the time of the first evaluation committee meeting (referred to as 'first meeting' from here on), the dominant variant of concern in the UK was the Omicron sublineage BA.5. The Omicron variant (B.1.1.529) has multiple subvariants based on mutations in specific spike proteins. The clinical experts explained that changes in the epidemiology and context of COVID19 have led to people with COVID19 having different characteristics than seen earlier in the pandemic. At the second meeting, the committee saw the updated Omicron variant data published in the UK Health Security Agency's (UKHSA's) technical briefing 49. Based on all the UK sequenced samples between 26 December 2022 and 1 January 2023, BQ.1 was the dominant 'designated variant'. BQ.1 was not expected to increase the risk of severe COVID19 compared with BA.5. The committee understood from this data that the BQ.1 subvariants account for a large proportion of the currently circulating variants in the UK. The committee noted the XBB.1.5 and CH.1.1 subvariants are some of the fastest growing variants in the UK. The clinical experts explained that people presenting at hospital with COVID19 are mainly either unvaccinated or immunocompromised, or did not have an immune response to vaccines. They reported that 'viral persistence' from chronic infection is a concern in immunocompromised people because new variants or subvariants can develop if the viral infection persists. They also noted that offering a clinically ineffective treatment unable to clear the infection may increase the risk of future variants developing. The committee noted the changing nature of SARSCoV2 and context of the pandemic affect the generalisability of the evidence for the treatments being evaluated. It agreed that the most appropriate approach would be to consider how relevant the clinical data is to the current endemic context of the disease at the time of this evaluation, but noted that the context and relevant variants are still changing at a fast pace.

# Defining high risk

## Key definitions
The committee noted that the marketing authorisations for the treatments which lower the risk of progression to severe COVID19 (casirivimab plus imdevimab, nirmatrelvir plus ritonavir and sotrovimab) were based on evidence from populations with slightly different definitions of high risk. For example, some trials included people with at least 1 risk factor for severe COVID19 whereas some had specific age requirements. Understanding of the prognostic effects of risk factors has developed throughout the pandemic, and therefore the available evidence may represent a heterogeneous population. The committee acknowledged the potential limitations of the available evidence but considered it was important to clearly define high risk and therefore treatment eligibility. PANORAMIC was a large UK platform trial that included people with many different potential risk factors, including chronic conditions and immunosuppression, and allowed enrolment of people aged over 50 years. It also allowed for clinical judgement of clinical vulnerability. The independent advisory group report commissioned by the Department of Health and Social Care ('the McInnes report' from here on) defined groups of people at highest risk for adverse COVID19 outcomes, including hospitalisation and death. The 'UK interim commissioning policy on treatments for non-hospitalised patients with COVID19' used the McInnes report to define high risk. The clinical experts noted that some treatments were available through the interim commissioning policy at the time of PANORAMIC enrolment. The interim commissioning policy's and McInnes report's high-risk definition would have influenced the risk level of people who enrolled in PANORAMIC. At the first meeting, the committee considered this in its evaluation of the clinical evidence. The committee considered the different definitions of risk and concluded that PANORAMIC included people who had a lower risk of severe COVID19 compared with the McInnes high-risk definition.

## Other key risk groups
The clinical experts gave examples of additional considerations around how high-risk groups are affected differently:
They highlighted different observed responses to vaccination. The OCTAVE study assessed vaccine response in immunocompromised people, including people with inflammatory arthritis, liver disease and kidney disease. OCTAVE showed differential antibody reactivity depending on disease group. The committee considered how this may affect who is at high risk. This is because people with a lower vaccine response have increased risk of adverse outcomes from COVID19 infection compared with the general population, particularly if they are having rituximab.
They cited an OpenSAFELY cohort analysis study that assessed the risk of severe COVID19 in people with immune-mediated inflammatory diseases. This showed that people with inflammatory diseases who are having systemic therapies had similar rates of hospitalisation and death as people having targeted therapies, except for rituximab. The committee considered the different risk of progressing to severe COVID19 may be related to which immunosuppressant drugs are being taken, but the relationship may be complex and differ in other disease areas.  At the second meeting, the committee noted the draft guidance consultation comments highlighted the need for separate 'high risk' and 'highest risk' groups, or a separate high-risk group contraindicated to nirmatrelvir plus ritonavir. The committee saw examples on how the risk group could be split based on Patel et al. (2022). The clinical experts explained that there is a small group of children who are also at high risk of severe COVID19 and may not be able to access treatment. The committee noted that the McInnes report has made additional consideration for people 12 years and over in its definition of high risk. The committee concluded that it would expect clinicians to offer treatments using the McInnes high-risk criteria when applicable across all age groups, in line with product marketing authorisations.

## Age as an independent risk factor
PANORAMIC allowed enrolment of people aged over 50 years who did not have any comorbidities. The committee questioned the inclusion of age over 50 years as an independent risk factor for progression to severe COVID19. The clinical experts considered that age was an important risk factor. They cited the International Severe Acute Respiratory and emerging Infections Consortium (ISARIC) study of mortality in the earlier stages of the pandemic that defined age over 50 years as a risk factor (Knight et al. 2020). They noted that age over 70 years may be an important determinant of mortality but also considered that the relationship between age and comorbidities is complex, particularly for immunocompromised people. One of the companies considered that age was an important risk factor but noted an ongoing debate about what age is appropriate for inclusion in the high-risk group. The clinical experts agreed it was challenging to define an exact age that defines high risk. The committee was concerned that making a recommendation based on age might cause inequality, given that age is a protected characteristic. For this reason, NICE technology appraisal guidance on medicines for cardiovascular disease do not include criteria based on age, despite it being a well-recognised risk factor. The committee noted that age is a protected characteristic and any recommendation including age would need to be assessed for impact on equity of treatment. At the first meeting, the committee concluded that more evidence was needed on the impact of age to justify including it as an independent factor that increases risk at similar levels to other risk factors defined in the McInnes report. This should include evidence, adjusted for these risk factors, from a vaccinated population who are infected with the Omicron variant. At the second meeting, the committee noted the additional evidence provided by consultees which showed a statistical relationship between age and comorbidities. The committee acknowledged that age is a risk factor for progression to severe COVID19. The committee considered that the relationship between age and comorbidities can be important in explaining risk of severe disease. The committee concluded that age over 70 years is likely to be confounded by underlying conditions which could also contribute to increased risk of severe COVID19. The committee also noted that additional evidence is needed to model age over 70 years as an independent subgroup for the mild COVID19 setting. It said the evidence should include age-adjusted hospitalisation and mortality rates for the untreated population and relative treatment effects. The committee concluded that the McInnes report's definition of high risk included the most robust evidence of people who have a high risk for progressing to severe COVID19, and this did not include age as an independent risk factor.

## High-risk definition conclusion
The assessment group (AG) explained the approach used to model high-risk groups in its economic model (see section 3.22). At the first meeting, it assumed that people had general population survival, with a starting age of 56.6 years and the same hospitalisation rate as PANORAMIC. Therefore, no individual high-risk subgroups were modelled based on specific baseline characteristics, and these characteristics were explored in sensitivity analyses that represented the entire group eligible for treatment. The clinical experts acknowledged the difficulties of defining high risk by separate subgroups. The committee recognised that the decision problem for this evaluation required a definition of who has a high risk for progressing to severe COVID19. It recognised the limitations of the model in characterising a group at high risk but considered the hospitalisation rate to be the most important variable for sensitivity to the clinical inputs (see sections 3.21 and 3.22). At the second meeting, the committee repeated these limitations of modelling separate high-risk groups and concluded that a single definition of high risk should be used. The committee noted that evidence at a subgroup level is limited and too uncertain to parameterise the model. For example, additional functionality, clinical or cost inputs and treatment-effectiveness assumptions would be required to make differential subgroup recommendations and this would not be practical or aligned with the decision problem. The committee did not see additional evidence to justify splitting the high-risk group. The committee considered that the McInnes report's definition of high risk was based on the most robust evidence of people who have a high risk for progression to severe COVID19, and this did not include age as an independent risk factor. Another benefit of using this definition is that outcomes data has been collected on this well-defined cohort over the course of the pandemic, providing some evidence from vaccinated people who were infected with Omicron variants. The committee considered the use of the QCOVID risk calculator in clinical practice but concluded it had limited applicability because of the limitations of the model. The committee noted a wider definition of risk, from PANORAMIC, was included in the marketing authorisations for each of the treatments (see section 3.4). However, it concluded that the definition of risk in the McInnes report is the most robust definition. The committee acknowledged that the McInnes definition of high risk may be revised over time. Depending on the nature of the revisions, this guidance may need to be reviewed if a difference in clinical or cost effectiveness is expected.

# Current clinical management of COVID-19

## Treatments for mild COVID-19
Current clinical management of mild COVID19 (including hospital-onset COVID19) in people who have a high risk for progression to severe COVID19 includes treatments commissioned through a UK interim commissioning policy (see section 3.4). In November 2022, the policy was:
first-line treatment: nirmatrelvir plus ritonavir (antiviral)
second-line treatment: remdesivir (antiviral)
third-line treatment: molnupiravir (antiviral; not for hospital-onset COVID19)
sotrovimab (neutralising monoclonal antibody) to be considered when the above antivirals are contraindicated or unsuitable after a multidisciplinary assessment
combination treatment with a neutralising monoclonal antibody and an antiviral is not routinely recommended.People who have symptoms and are not showing signs of a clinical recovery must start treatment as soon as possible after testing positive for COVID19. The professional organisations explained there are different aims of treatments at this stage of COVID19. Antivirals aim to reduce viral load and viral replication, which may reduce risk of severe disease. They are administered orally or intravenously. Neutralising monoclonal antibodies also aim to do this by binding to specific viral proteins to block viral infection. They are administered as injections or infusions (intravenously, intramuscularly or subcutaneously, depending on the treatment).

## Treatments for severe COVID-19
For people hospitalised with severe COVID19, anti-inflammatories are used along with antivirals, based on the UK interim clinical commissioning policies for secondary care. Anti-inflammatories treat the multisystem inflammation which develops later in the COVID19 disease pathway. The clinical experts said a hierarchical flow of treatments is followed in hospital and recommending one treatment over another is challenging. The suitability of certain interventions can vary based on respiratory support requirements, minimum COVID19 symptom duration or renal impairment status, but is generally as follows:
People admitted to hospital with COVID19 who do not need oxygen: remdesivir is an option, through the UK interim clinical commissioning policy on remdesivir, for people who are significantly immunocompromised.
People admitted to hospital with COVID19 who need low-flow oxygen or non-invasive mechanical ventilation:
dexamethasone is standard care
remdesivir or tocilizumab are offered, subject to eligibility criteria, through the UK interim clinical commissioning policies for secondary care.
People admitted to hospital with COVID19 who need high-flow oxygen:
baricitinib or tocilizumab are offered, subject to eligibility criteria, through the UK interim clinical commissioning policies for secondary care.

# Clinical effectiveness

## Assessment group's indirect comparison approach
In line with best practice guidance for assessing COVID19 treatments (Elvidge et al. 2021), the AG used systematic reviews and network meta-analyses (NMAs) from publicly available sources. These reviews (COVIDNMA and metaEvidence) are updated regularly as 'living' systematic reviews. The clinical endpoints included were:
mild COVID19 setting:
relative risk of hospitalisation or death
relative risk of all-cause mortality at 28 days
severe COVID19 setting:
hazard ratio of time to death
hazard ratio of time to discharge
relative risk of clinical improvement at 28 days.The AG highlighted some significant limitations of their approach, because of the changing nature of COVID19 (see section 3.2). Each trial included in the analysis was done at a different time in the pandemic. Most trials compared an individual treatment against the standard care at the time. Standard care has evolved in response to better understanding of the disease course, and changes in respiratory support and use of dexamethasone. The context of the disease has also changed with different circulating variants of concern, and changes in protection through vaccinations and greater natural immunity over time. Each of these limitations were compounded by significant differences in trial design, baseline characteristics and geographical locations. The AG explained that the analysis assumed any relative effect of treatment is transferable to current clinical management. The clinical experts commented that meta-analysing the trial results may not be appropriate. This is because the weighting of each trial in a meta-analysis may not consider the relevance of the context of each trial within the analysis, for example, with different variants. The committee recognised the high levels of uncertainty with each treatment effect and the context-specific nature of the evidence. To characterise the uncertainty, rather than use probabilistic sensitivity analysis, the AG ran scenarios using the mean and the upper and lower confidence limits of each efficacy estimate. This provided scenarios showing 'mean efficacy', 'lower efficacy' and 'higher efficacy' estimates. The AG cautioned the committee that the lower-efficacy and higher-efficacy scenarios had limitations because they represented a different uncertainty to that in the evidence base; they represented uncertainty on the estimates in the trial and were therefore sensitive to the number of events in each trial, rather than the context in which the trial happened. Therefore, they would not be sensitive to changes in efficacy against new circulating variants of concern. The committee understood the limitations of the scenario analysis. The committee considered it represented an attempt to address some aspects of uncertainty in the absence of alternative methods to model the uncertainty. At draft guidance consultation, consultees highlighted that the lower-efficacy scenarios were arbitrary and a probabilistic sensitivity analysis would be a better way to capture the uncertainty. The committee noted that the heterogeneity in the trial populations and the generalisability issues across the trials made the uncertainty challenging to parameterise. Therefore, the appropriate type of uncertainty would not have been captured in the probabilistic sensitivity analysis. Consultees also noted that the mortality assumptions meant that treatment in hospital had a higher mortality risk compared with standard care. In response, the AG updated this assumption and capped the mortality rate to equal 1 for the lower-efficacy scenario. The AG also included the updated COVID19 NMA results for casirivimab plus imdevimab and tocilizumab in the economic model.

## Observational evidence
The committee considered the latest data from OpenSAFELY (non-randomised observational evidence from 40% of English GP practices). The OpenSAFELY database links with other national databases including the Office for National Statistics (ONS), inpatient hospital records, renal registries and Covid Medicines Delivery Units (CMDUs). The dataset is granular, updated regularly and reflective of the McInnes high-risk group during the Omicron wave in the UK. The committee acknowledged that this analysis of OpenSAFELY was done well and made efforts to account for confounding bias when possible. The analysis was done in a dynamic environment with changing treatment practices and linkages with various data sources which can increase risk of confounding bias. The committee noted the results of Hill and Mirchandani (2022) that compared the outcomes of a randomised controlled trial with non-randomised studies on COVID19 treatments. The authors questioned the validity of non-randomised studies when their outcomes contradict the outcomes from a randomised controlled trial. The authors cautioned against using non-randomised evidence independent of randomised evidence for regulatory decisions. The committee was willing to accept the OpenSAFELY data on relative treatment effectiveness as supplementary evidence to the trial evidence and for modelling estimates for hospitalisation rates. The committee cautioned against solely relying on non-randomised evidence when making conclusions on treatment effect.

## Generalisability of trial evidence to current endemic context
The committee acknowledged that most trials informing the clinical efficacy data predated the Omicron variant, which was the dominant circulating variant of concern at the time of this evaluation. Clinical experts said extrapolating data from past trials was misleading because epidemiology and virus characteristics have changed (see section 3.2). The clinical experts and the committee considered it appropriate to consider how the clinical evidence would generalise to the endemic setting. It considered the main generalisability concerns to be:
changes in population immunity through natural immunity and vaccination
changes in the pathogenicity of the virus
increased effectiveness of supportive care as knowledge of the virus evolved
-ther differences that were specific to the context of a pandemic setting. The absolute changes in these settings were considered in the economic modelling when possible. However, the committee considered the relative risks from these trials would also lack generalisability because there would be interaction between some of these concerns and treatment effect in the trial. This would likely favour the treatments compared with standard care, because the trials were done when key outcomes of hospitalisation and mortality were significantly higher. Therefore, the committee considered that the mean-efficacy scenarios from these trials likely reflect the highest clinical effectiveness or 'ceiling efficacy' of the treatment. The committee concluded that changes in best supportive care and higher vaccination rates mean that any limited relative treatment effects seen during the pandemic setting would have less effect in an endemic setting. This is because any limited benefit in the pandemic setting would likely be further limited or potentially have no difference in treatment effect compared with standard care (hazard ratios  would tend towards 1) in an endemic setting.
The committee recognised that the treatment effects needed to be considered separately as follows:
Antiviral (nirmatrelvir plus ritonavir)  mild COVID-19 setting: Evidence on nirmatrelvir plus ritonavir was more recent and captured the Delta wave.
Anti-inflammatory (tocilizumab): Clinical trial evidence on tocilizumab was collected before the Omicron wave. The committee considered the corroborating clinical evidence from multiple trials with evidence on outcomes pooled from multiple studies. The key trial, REMAPCAP, included multiple UK sites and RECOVERY was reflective of standard care in NHS clinical practice. The committee also considered the relative treatment benefit of tocilizumab largely generalisable because the mechanism of action regulates hyperinflammation, which it did not expect would change based on variants, vaccination or natural immunity.
Neutralising monoclonal antibodies (casirivimab plus imdevimab and sotrovimab): For casirivimab plus imdevimab and sotrovimab (mild COVID19 setting), the clinical trial evidence was collected before the Delta and Omicron waves. For casirivimab plus imdevimab (severe COVID19 setting), the collected evidence partly covered the timeline of the Delta wave but was before the Omicron wave. The committee noted that considerable uncertainty remained about the relative treatment effects on hospitalisation and mortality rates. This is because of generalisability of trial evidence to the endemic setting with a widely vaccinated population with additional and natural immunity, as well as the particular sensitivity of these antibodies to changes in variants.

## In vitro evidence
In vitro (laboratory) evidence may provide additional information on whether there is a realistic clinical possibility that a treatment retains efficacy against currently circulating variants. In vitro neutralisation assays can be used to assess if treatments can neutralise new variants, which can then be used to infer whether they retain clinical effectiveness over time as the virus evolves. An advantage of in vitro evidence is that it can be generated much faster than clinical trial evidence. A large body of in vitro evidence suggests that specific COVID19 treatments may no longer show neutralisation activity against some circulating Omicron variants. In the first meeting, the committee could not comment on the validity of in vitro data and welcomed comments in response to consultation. Because of this, NICE commissioned an 'in vitro expert advisory group' made up of experts in infectious disease, virology, vaccine epidemiology, immunology and pharmacology (see the in vitro expert advisory group report in the committee papers). The group developed a decision framework to link in vitro neutralisation data to clinical outcomes and helped the committee use the framework to interpret the in vitro evidence. The committee understood this framework and also noted the latest in vitro evidence.
The in vitro evidence considered by the committee was against newly circulating variants and was available shortly before the second meeting. Because the COVID19 landscape is rapidly evolving, a systematic review of the in vitro data was not possible. Guided by the in vitro expert advisory group, the committee identified 5 in vitro studies that investigated the effectiveness of the neutralising monoclonal antibodies against currently circulating variants (BQ.1.1 and XBB). One in vitro study (Imai et al. 2023) also investigated the effectiveness of the antivirals against BQ.1.1 and XBB. The in vitro studies showed that some antiviral treatments retain the ability to neutralise a range of SARSCoV2 variants and subvariants, including those circulating at the time of this evaluation and that are rapidly increasing in prevalence. The committee also considered the in vitro evidence that was systematically collected and summarised by multiple organisations including the 'Stanford Coronavirus Resistance Database'. For further details on the in vitro evidence, see the public committee slides in vitro presentation.

## Generalisability of clinical effectiveness
By using the framework and the evidence, the committee concluded that the clinical effectiveness of anti-inflammatories (tocilizumab) are not variant-specific because of their mechanism of action. The committee concluded there was no in vitro evidence showing reduced clinical efficacy of antivirals (nirmatrelvir plus ritonavir) across the variants tested. However, as discussed in the first meeting and based on the in vitro expert advisory group framework, the committee confirmed that neutralising monoclonal antibodies (casirivimab plus imdevimab and sotrovimab) bind to spike proteins which are changing with each new variant and subvariant. The committee concluded that neutralising monoclonal antibodies may lose the ability to neutralise the virus over time, potentially as a result of the virus evolving to evade the treatments in use.
At the second meeting, the committee noted that BQ.1 and BQ.1.1 were the currently circulating Omicron subvariants (see section 3.2) in the UK. These are different to BA.5 which was prevalent at the time of the first meeting. As noted in section 3.16, the clinical effectiveness of neutralising monoclonal antibodies (casirivimab plus imdevimab and sotrovimab) is likely to differ by variant. At the second meeting, the committee carefully considered in vitro evidence for these treatments against the dominant variants. The committee understood that in vitro studies differ by how they are done and their quality. The clinical experts agreed with the in vitro expert advisory group's framework and explained that evidence showing no or limited neutralisation activity against a specific variant means there is unlikely to be any plausible clinical activity against that variant. The committee acknowledged that there was the possibility for casirivimab plus imdevimab to regain activity against future variants but considered that the likelihood of this was low. The committee noted a recent update from the European Medicines Agency's emergency task force, which cautioned that neutralising monoclonal antibodies currently authorised for COVID19 are unlikely to be effective against emerging strains of SARSCoV2. Taking account of study differences, clinical expert conclusions and the framework (see sections 3.14 to 3.16), the committee concluded that casirivimab plus imdevimab was unlikely to retain sufficient neutralisation activity against most variants circulating at the time of this evaluation. Also, this was the most useful estimate of effect against future variants. The committee concluded the clinical effectiveness of casirivimab plus imdevimab is highly uncertain in terms of reducing hospitalisation or mortality rates.
The committee noted that in vitro evidence on sotrovimab's neutralisation activity was inconsistent between the studies with some evidence suggesting a partial reduction in neutralisation activity. The clinical experts explained that partial reductions in neutralisation are difficult to interpret without additional clinical evidence such as in vivo (in animals) or pharmacodynamic and pharmacokinetic data. They explained that in such cases the in vitro data is only pieces of the puzzle rather than an individual indication of the potential clinical efficacy. The committee considered additional evidence (Addetia et al. 2023) on sotrovimab. The company explained that, unlike the other neutralising monoclonal antibodies, sotrovimab's effectiveness against the virus depends on the expression levels of angiotensin-converting enzyme 2 (ACE2) to which the SARSCoV2 receptor binds. If the cell line used in the in vitro study over-expresses ACE2 then sotrovimab may appear not to neutralise the virus in laboratory studies. The results from these in vitro studies may underestimate sotrovimab's neutralising ability against the real virus. The committee considered this added uncertainty to the interpretations of the in vitro evidence for sotrovimab. The committee compared in vitro evidence on subvariant BA.5 (dominant at the time of the first meeting) with OpenSAFELY data collected when BA.5 was circulating. The OpenSAFELY data suggested that sotrovimab's clinical effectiveness was consistent during the Omicron wave whereas the in vitro evidence showed conflicting data that sotrovimab had reduced neutralisation abilities against BA.5. Using the in vitro expert advisory group's framework and the evidence, the committee concluded that sotrovimab's clinical effectiveness is likely reduced against BA.5 but uncertainty remains about sotrovimab's clinical effectiveness against BQ.1 and BQ.1.1. The committee concluded the in vitro evidence for sotrovimab was ambiguous and the clinical effectiveness was uncertain. The committee noted that in some cases, when reduced neutralisation is seen from in vitro evidence, increasing the dosage of the treatment could result in increased neutralisation activity. The committee could not comment on whether increasing dosages outside of marketing authorisations impacts the clinical effectiveness of neutralising monoclonal antibodies. This is because the riskbenefit profiles of increased doses have not been assessed by the Medicines and Healthcare Regulatory products Agency (MHRA) and NICE must appraise treatments within their licensed doses. The committee considered it was unclear how much a reduced neutralising effect impacts clinical efficacy and therefore how that uncertainty could be characterised in the different clinical efficacy scenario analyses. The committee noted that the effectiveness of neutralising monoclonal antibodies will need continuous monitoring for each variant and subvariant.

## Relative treatment effects for mild COVID-19
For the mild COVID19 setting, the clinical experts considered the relative treatment effects of each treatment to be uncertain without considering the wider context of the trials (see section 3.2). The committee noted the potential for bias in all the comparisons because the indirect comparison used pairwise analysis rather than a network to produce its comparisons. They also noted that multiple interventions could be required and cautioned against the side-by-side comparison of treatment effects (as a fully incremental analysis). The committee considered that the heterogeneity of trial outputs and generalisability contributed greater uncertainty to the decision problem.
Discussion on nirmatrelvir plus ritonavir: The clinical experts considered that in clinical practice nirmatrelvir plus ritonavir appears to be the most effective at reducing progression to severe disease. But, they noted that there are many contraindications for nirmatrelvir plus ritonavir, including severe renal and hepatic impairment, and interactions with many common treatments. The committee noted that evidence on nirmatrelvir plus ritonavir was from 1 large randomised controlled trial (EPICHR) done in an unvaccinated population in an earlier wave of the pandemic. The committee concluded that OpenSAFELY data provided support for the continuous hospitalisation and mortality benefit of nirmatrelvir plus ritonavir seen from the older trial. The committee was mindful not to make conclusions about relative treatment effects based solely on non-randomised evidence from OpenSAFELY. The committee noted the subgroup analysis from the recent EPIC-SR trial that included people who were vaccinated and had at least 1 risk factor for severe COVID19. The committee acknowledged the EPICSR enrolment was stopped early and the results were preliminary and published only on the company's website rather than a peer-reviewed journal. However, the committee noted the preliminary outcomes showed non-significant reduction in hospitalisation rates in this vaccinated high-risk subgroup, adding to the existing generalisability concerns for EPICHR. It still considered there to be substantial uncertainty because of generalisability concerns with the mean-efficacy estimate. Therefore, the committee considered the range between the mean- and lower-efficacy estimates for nirmatrelvir plus ritonavir from the trial to be more suited to the current endemic setting, despite the limitations with this approach (see section 3.10). It noted that PANORAMIC was also recruiting a nirmatrelvir plus ritonavir treatment arm that could answer questions about effectiveness for people who have a high risk of progressing to severe COVID19 but are not defined in the McInnes high-risk group.
Discussion on sotrovimab: The committee noted the evidence on sotrovimab was from 1 randomised controlled trial (COMETICE) which reported a statistically significant reduction in all-cause hospitalisation or death. It commented that the trial was done before the Delta wave. The committee commented that OpenSAFELY data supported the continuous hospitalisation and mortality benefit of sotrovimab seen in COMETICE, although generalisability concerns remained with the trial evidence. The committee noted that OpenSAFELY showed no evidence of a difference in all-cause hospitalisation or death between the sotrovimab and nirmatrelvir plus ritonavir groups when the BA.2 and BA.5 subvariants were prevalent. It also noted that sotrovimab showed a lower risk of severe outcomes compared with molnupiravir in the overall and the advanced renal disease groups over the Omicron wave. The committee understood that sotrovimab was used as an alternative treatment in some people with high risk of severe disease when nirmatrelvir plus ritonavir was contraindicated. The committee acknowledged that observational OpenSAFELY evidence supported the clinical efficacy seen in COMETICE but was mindful not to make conclusions about relative treatment effect solely based on non-randomised evidence. The committee said considerable uncertainty remained in the clinical efficacy estimates because of the in vitro evidence showing reduced neutralisation against the prevailing BQ.1 and BQ.1.1 subvariants (see section 3.18). The committee considered there was not enough evidence from COMETICE to consider a mean-efficacy scenario and instead preferred to consider the low-efficacy scenario and a scenario between mean and low efficacy for sotrovimab.

## Relative treatment effects for severe COVID-19
For people presenting to hospital with COVID19, the clinical experts noted that standard care had significantly changed over time (see section 3.2). They also cautioned against directly comparing treatments because there is a distinct pathway of care for severe COVID19. This includes when to use respiratory support, anticoagulation treatments and corticosteroids.
Discussion on tocilizumab: For the anti-inflammatory immunomodulator treatment, tocilizumab, the committee noted statistically significant clinical-effectiveness results. The clinical expert considered that tocilizumab should be used with caution in clinical practice and noted uncertainty with relative effect in the changing context of COVID19. The committee noted that the virus is changing and there is bound to be some uncertainty in the clinical evidence. Tocilizumab acts on the complications caused by the virus, rather than attempting to neutralise the virus itself. Tocilizumab's mechanism of action is more robust to changes in the variants than the neutralising monoclonal antibodies. The committee concluded that it was more confident in the mean-efficacy results because of tocilizumab's mechanism of action and clinical trial evidence base (see section 3.13).

# Economic model

## Model structure and key drivers of cost effectiveness
The economic model for this appraisal was developed by the AG and informed by a publication (Rafia et al. 2022) that evaluated COVID19 treatment in a prehospital setting. The AG used a decision tree model structure for treatments in the mild COVID19 (non-hospital) setting that joined with a partitioned survival model in the severe COVID19 (hospital) setting. The decision tree had either an active treatment or standard care arm offered to people with COVID19. People were hospitalised at a baseline standard care rate, or not hospitalised. Those that were hospitalised entered the partitioned survival model. This section of the model had 3 mutually exclusive health states: discharged from hospital and alive, hospitalised with or without COVID19, and death (from COVID19 or any other cause). For people in hospital, the level of respiratory support was assumed based on COVID19 severity, with associated costs and disutilities by health state. The clinical inputs for each of the clinical efficacy scenarios were from the indirect treatment comparison (see section 3.10). The AG fitted parametric distributions to long COVID data from the ONS. Consultees highlighted that the long COVID duration was underestimated and should be higher than the 108.6 weeks used by the AG. In response, the AG updated the model which estimates that 30% of people will still have symptoms at 2 years, 10% at 5 years and 3% at 10 years. The AG assumed that 100% of people in the severe COVID19 setting and 10% in the mild COVID19 setting would have long COVID. Consultees noted that the proportion should be reduced for the severe COVID19 setting and increased for the mild COVID19 setting. The AG considered its original assumption to be conservative and therefore appropriate because alternative evidence was not available at the time of the second meeting. The committee noted that the treatment efficacy was highly uncertain and the most important driver of cost effectiveness, but also noted the following other key drivers of model outputs:
The key driver of the outputs in the mild COVID19 setting was the baseline rate of hospitalisation. This is because it determined how many people were included in the high-cost and low-utility hospital setting.
The key drivers of the outputs in the severe COVID19 setting were the baseline standard care assumptions for overall survival and time to discharge. The model was adjusted so the baseline standard care assumptions were reflective of current UK clinical practice. NICE's rapid guidelines on COVID-19 were used to make this adjustment.The clinical experts commented that, because of changes to the disease, the outcomes for these treatments are now more nuanced than hospitalisation and mortality. The committee considered that relative treatment effect, and reduced hospitalisation and mortality rates, are key drivers of benefit but acknowledged that the model was not sensitive to other benefits of treatment like faster resolution of symptoms (hospital setting). The committee considered the model appropriate to capture the most important outcomes and appropriate for decision making given the available evidence base for COVID19.

## Hospitalisation rates
The rate of hospitalisation is a key driver of model outputs (see section 3.21) with multiple potential evidence sources. Hospitalisation rate is one of the key model input variables that define the group at high risk. To closely align with the marketing authorisations, for the first meeting the AG used a hospitalisation rate of 0.77% from PANORAMIC in its base case to generate the decision making incremental cost-effective ratios (ICERs). PANORAMIC was reflective of the current COVID19 landscape, including the Omicron variant. However draft guidance consultation comments further highlighted that PANORAMIC would have excluded people at higher risk who were eligible for treatment through the UK interim clinical commissioning policy (see section 3.4). Consultees provided a range of hospitalisation rates identified through targeted reviews. The committee saw overall hospitalisation rates defined by the McInnes high-risk definition including: OpenSAFELY 2.41% (untreated but eligible using McInnes definition), 1.37% (untreated but eligible group without contraindications to nirmatrelvir plus ritonavir) and 2.82% (DISCOVERNOW database, UK observational study of people covered in the McInnes report). Hospitalisation rates also varied across different conditions, including between 4.15% and 4.40% for advanced renal kidney diseases and 15.90% (study of people with primary and secondary immunodeficiency ). In the first meeting, the clinical experts agreed, given the committee's preferred definition of high risk (see section 3.7), that 0.77% could be an underestimation because the highest risk group may have been underrepresented in PANORAMIC (see section 3.4). They acknowledged the difficulty of determining hospitalisation rate without analysing the baseline population and all appropriate groups at risk. The rate is likely to vary substantially based on types of underlying conditions in the high-risk group, with potentially higher rates for severely immunocompromised people, such as people who have had a transplant and people having chemotherapy. The committee acknowledged significant uncertainty in estimating the hospitalisation rate for the population who have a high risk of progression to severe COVID19. Based on the strength of the evidence it concluded that it was likely to fall between the underestimate of PANORAMIC at 0.77% and the estimate of 2.82% from the DISCOVERNOW database. The committee concluded that the hospitalisation rate for the McInnes high-risk group is between 2.41% and 2.82% based on OpenSAFELY and DISCOVERNOW. For people in whom nirmatrelvir plus ritonavir is contraindicated, the hospitalisation rate is assumed to be about 4% as an upper limit using advanced renal disease as a proxy from OpenSAFELY.

## Time to discharge
The amount of time spent in hospital is a key driver of cost effectiveness because of hospitalisation costs. Evidence on each treatment showed a relative reduction in time spent in hospital. The AG had previously noted the time to discharge evidence was collected during the early stages of the pandemic, which could lead to substantial generalisability concerns because the context of care has changed in the endemic setting. The committee noted that in clinical practice, time to discharge can sometimes overestimate time in high-cost health states because it can depend on multiple factors (for example, waiting for a negative COVID19 test). Time to discharge was also considered more important for people who are being discharged to a care home. The committee also noted that clinical experts in both meetings explained that people hospitalised with COVID19 have very different symptoms at present (the time of this evaluation) compared with early stages of the pandemic. It also noted that the population is heterogeneous (see sections 3.2 and 3.3). The AG included scenarios that removed treatment effects on time to discharge and clinical improvement at 28 days to try and account for these potential uncertainties. At the first meeting the committee considered these scenarios to be plausible but conservative if treatments had effects outside of hospitalisation and mortality. The committee was not presented with additional evidence on time to discharge or clinical improvement and was uncertain about the treatment benefit in the endemic setting. The committee concluded it was reasonable to remove these treatment effects.

# Utility values

## Utility value assumptions
The AG used UK age- and sex-adjusted utility values (EQ5D3L) for the baseline utility estimates in the model. The AG did not apply additional utility decrements in the mild COVID19 setting for people who did not have long COVID. The age- and sex-adjusted UK general population utility estimates were used for this population instead. During consultation on the AG's draft report, stakeholders critiqued this assumption. They said this may not capture the full benefit of the treatments compared with standard care and disadvantaged community-based treatments. The AG agreed this was a simplified assumption, but scenario analysis showed it had limited impact on the final ICERs. The committee agreed with the AG's assumption and acknowledged the minor impact on the ICERs. For the severe COVID19 setting, the AG used utility decrements from a recently published cost-effectiveness analysis of remdesivir (Rafia et al. 2022). The utility decrements were originally from a population with recurrent Clostridioides difficile infection and influenza. The same in-hospital utility decrements were also applied across ordinal scales 3 to 5. The ordinal scale was an 8point scale (1 to 8) used to define progression of COVID19 severity in the model. During consultation, stakeholders critiqued the use of utility decrements from a non-COVID19 population. An alternative approach for a utility study was proposed. The approach was to use COVID19 severity-specific vignettes with EQ5D3L questionnaires completed by the UK general population. Some stakeholders also highlighted recent COVID19 utility-specific systematic reviews that could be used. The AG said a vignette study would not be possible because of the restricted timelines. Across both settings, the AG did not find alternative COVID-19 utility decrements from the stakeholder-suggested systematic reviews. The AG used postdischarge long COVID utility decrements from Evans et al. (2022). The same utility decrement was assumed regardless of ordinal scale status at hospital admission. At AG report consultation, stakeholders suggested an alternative source of postdischarge utility decrements split by history of ordinal scale status. The AG explained that the model structure was unable to allocate postdischarge utility based on historical ordinal scale admission status. It also said that these utility decrements are only applied for the duration of long COVID and are not a key driver of ICERs. The committee agreed with the AG's rationale and the long COVID utility decrement assumptions.

# Costs

## Long COVID costs
In the first meeting, the AG assumed the annual per person management costs of long COVID to be comparable with chronic fatigue syndrome (1,013). The clinical experts explained there were differences between people with long COVID who were in hospital compared with those not in hospital. People in hospital would be more likely to have severe complications that incur greater costs from multisystem complications. The AG considered the costs had minimal impact on the cost-effectiveness estimates because they were only applied for the duration of long COVID. But, it also provided scenario analyses with increased average yearly costs (2,500). The committee agreed these scenarios had minimal effect on the cost-effectiveness estimates but considered that any new UK-specific evidence on long COVID costs should be included if available. During draft guidance consultation a consultee said the AG's base-case long COVID cost underestimates the true burden of long COVID and provided an alternative higher cost from Vos-Vromans et al. (2017). The AG accepted this new evidence and inflated the cost to 2,267 per year (to reflect 2021/2022). The committee agreed with the updated base-case value.

## Administration costs
The AG did not originally include administration costs for oral or subcutaneous treatments. For intravenous treatments, a cost of 221 was assumed based on NHS reference code SB12Z. After consultation, the AG updated the assumptions in the model with costs provided by NHS England. NHS England provided CMDU deployment costs for the administration of oral antivirals (410) and neutralising monoclonal antibodies (820). Some companies disagreed with using CMDU deployment costs because these include costs based in secondary care. However, future delivery may be in primary care, which would likely reduce these costs. The NHS England representative explained that the delivery of service is subject to change. In future, integrated care boards will be responsible for treatment delivery currently done by the CMDUs. They also noted that these costs were calculated before implementation of nirmatrelvir plus ritonavir which may increase resource use because of expected requirements to assess contraindications. During draft guidance consultation, consultees did not agree with the administration costs used in the AG base case. Some consultees said additional pharmacist per hour costs (about 352.49) should be added for assessment of nirmatrelvir plus ritonavir interactions with other treatments. Other consultees argued that the prescribing cost for nirmatrelvir plus ritonavir should be lower and between 75 to 117 because e-consultations and telephone triage options factor in the assessment of contraindications by clinicians already familiar with doing them. The AG explained that changes in administration costs can be evaluated by looking at differences in net monetary benefit. The committee considered the differences in administration costs in relation to the net monetary benefit outcomes, noting the uncertainty about future delivery models.

## Hospitalisation costs
The AG used unit costs per hospital bed-day from the NHS National Schedule of NHS costs. During AG report consultation, the AG updated the costs for ordinal scales 3, 4 and 5 based on stakeholder suggestions. During draft guidance consultation, consultees said the approach to costing ordinal scales 4 and 5 underestimated the true cost. The AG agreed with the changes suggested and updated the costs. The final codes were as follows:
-rdinal scale 3: weighted average of DZ11R to DZ11V (lobar, atypical or viral pneumonia, without Interventions) for a regular day or night admission
-rdinal scale 4: weighted average cost of DZ19R to DZ19V (lobar, atypical or viral pneumonia, without interventions) for non-elective long stay (see the AG report in the committee papers for further adjustments that were applied)
-rdinal scale 5: weighted average cost of DZ19N to DZ19Q (lobar, atypical or viral pneumonia, with single intervention) for non-elective long stay (see the AG report in the committee papers for further adjustments that were applied)
-rdinal scale 6: using XC07Z (adult critical care, 0 organs supported)
-rdinal scale 7: weighted average cost for adult critical care, 1 or more organs supported (XC01Z to XC06Z).The committee acknowledged the changes implemented by the AG and agreed with the AG's final approach.

# Cost-effectiveness estimates

## Treatments for mild COVID-19
For the mild COVID19 setting, ICERs and net monetary benefits were calculated for casirivimab plus imdevimab, nirmatrelvir plus ritonavir and sotrovimab. The committee looked at the pairwise ICERs compared with standard care presented by the AG. The ICERs for casirivimab plus imdevimab and sotrovimab compared with standard care cannot be reported here because of confidential prices and commercial discounts. The committee reviewed results for the low-efficacy, mean-efficacy and high-efficacy scenarios (see section 3.10). The committee noted its preferred assumptions to include combinations of the following:
hospitalisation rates between 2.41% and 2.82%, and 4.00% for people in whom nirmatrelvir plus ritonavir is contraindicated
mean-efficacy and low-efficacy relative treatment effects (noting the limitations of the scenarios in section 3.10).The committee noted substantial uncertainty with the relative treatment effects of casirivimab plus imdevimab. The committee concluded casirivimab plus imdevimab has limited and uncertain clinical effectiveness in terms of reducing hospitalisation or mortality rates (see section 3.17) and therefore the ICERs were considered very uncertain. The ICERs for nirmatrelvir plus ritonavir compared with standard care using a) mean-efficacy treatment effect and b) low-efficacy treatment effect and a 2.41% hospitalisation rate were:
a) 7,892 per quality-adjusted life-year (QALY) gained
b) 14,039 per QALY gained.Based on the committee's preferred assumptions, it considered that nirmatrelvir plus ritonavir was likely a cost-effective use of NHS resources compared with standard care, for people with high risk of severe COVID19, as defined by the McInnes report's criteria. This includes people in hospital with mild COVID19 who have a high risk of progressing to severe COVID19. The equivalent ICER for sotrovimab was above 20,000 per QALY gained, even when considering alternative lower administration costs. The committee also considered the mean-efficacy and low-efficacy scenarios using a hospitalisation rate of 0.77% from PANORAMIC which more closely approximated the marketing authorisation population for nirmatrelvir plus ritonavir. The ICERs were above 20,000 per QALY gained and nirmatrelvir plus ritonavir was likely not a cost-effective use of NHS resources in this broader lower-risk population. To explore cost effectiveness for people in whom nirmatrelvir plus ritonavir is contraindicated, the committee looked at a scenario in which the hospitalisation rate was set to 4.00%. For sotrovimab, the low-efficacy ICER versus standard care was above 20,000 per QALY gained. However, assuming the efficacy was between mean and low efficacy and with a lower administration cost (410, equivalent to the cost used for providing an oral antiviral), the ICER was within the range normally considered an acceptable use of NHS resources. The committee concluded that sotrovimab is a cost-effective use of NHS resources, but only for people for whom nirmatrelvir plus ritonavir is contraindicated or otherwise unsuitable.

## Severe COVID-19 and without supplemental oxygen
For the severe COVID19 setting without supplemental oxygen, ICERs were calculated for casirivimab plus imdevimab. Similar to the mild COVID19 setting, pairwise ICERs versus standard care were presented. The committee reviewed results for the low-efficacy and mean-efficacy scenarios (see section 3.10). The committee noted its preferred assumptions to include hazard ratioss of 1 for time to discharge and clinical improvement at 28 days. The ICERs for casirivimab plus imdevimab cannot be reported here because of confidential prices. The committee did not consider casirivimab plus imdevimab to be clinically effective (see section 3.17) and therefore the ICERs were considered very uncertain.

## Severe COVID-19 and supplemental oxygen
For the severe COVID19 with supplemental oxygen setting, ICERs were calculated for casirivimab plus imdevimab and tocilizumab. Pairwise ICERs compared with standard care were presented. The committee reviewed results for the low-efficacy and mean-efficacy scenarios (see section 3.10). The committee noted its preferred assumptions to be the same as for the severe COVID19 setting without supplemental oxygen (see section 3.29). The ICERs for casirivimab plus imdevimab and tocilizumab cannot be reported here because of confidential prices. The committee did not consider casirivimab plus imdevimab to be clinically effective (see section 3.17) and therefore the ICERs were considered very uncertain and inconclusive. The ICERs for tocilizumab compared with standard care were below 20,000 per QALY gained for the mean-efficacy scenario. The committee considered tocilizumab likely to be a cost-effective use of NHS resources compared with standard care.

# Other factors

## Uncaptured benefits
Clinical experts said hospitalisation and mortality rates are becoming less relevant clinical efficacy measures for COVID19 treatments. They explained this was because of the changing COVID19 landscape (see section 3.2). In future COVID19 evaluations, higher QALY gains or cost savings could be captured if the model includes the impact of treatments on the following outcomes:
impact on incidence and duration of long COVID
virological outcomes
ability to alter selective pressure on the virus and generation of future variants
transmission to healthcare professionals
enabling other NHS healthcare services to proceed (for example, routine operations and reducing impact on waiting lists)
access to treatment within the window of clinical effectiveness
value of treatment options available as insurance for people who are shielding.The committee considered that some of these benefits fall outside of the NICE reference case or there is limited evidence to support them. The committee noted community treatments may not limit transmission of the virus, because it mostly spreads when people are asymptomatic. The committee considered the advice in section 6.2.36 of NICE's manual on health technology evaluations. The committee concluded that it had not been presented with strong evidence that the health benefits of the technologies have been inadequately captured and may therefore misrepresent the health utility gained.

## Equality issues
The committee considered potential equality issues, including:
Disability  people for whom nirmatrelvir plus ritonavir is contraindicated: The committee noted nirmatrelvir plus ritonavir was contraindicated for concomitant use with many medicinal products. The committee evaluated alternative treatments for people who cannot take nirmatrelvir plus ritonavir. The committee considered whether, by recommending nirmatrelvir plus ritonavir, without recommending an alternative for people in whom nirmatrelvir plus ritonavir is contraindicated, it would be indirectly discriminating against people in these groups. Indirect discrimination means producing guidance that appears to apply to all but has a disproportionate adverse impact on those with a protected characteristic. The committee took this into account and considered a higher hospitalisation rate of 4% for the McInnes-defined high-risk group who were also contraindicated to nirmatrelvir plus ritonavir (see section 3.28). For the alternative treatments, assuming the higher hospitalisation rate meant that sotrovimab was considered a cost-effective use of NHS resources, for people in whom nirmatrelvir plus ritonavir is contraindicated (see section 3.28).
Disability  optimised recommendation on nirmatrelvir plus ritonavir: The committee noted the marketing authorisation for nirmatrelvir plus ritonavir is broader and included people at lower risk of severe COVID19 compared with the optimised recommendation (see section 1) which uses the narrower McInnes high-risk definition. The committee acknowledged that the optimised recommendation may exclude some people in certain high-risk groups who were included in the marketing authorisation and who have disability, which is a protected characteristic (see section 3.4). The committee considered whether, by recommending nirmatrelvir plus ritonavir only within an optimised McInnes-defined high risk, it would be indirectly discriminating against people in these groups. The committee carefully considered these issues and concluded that there was not sufficient evidence to expand the high-risk group definition and modelling uncertainties (see section 3.7) would mean the ICERs for this broader high-risk group would be highly uncertain. The committee considered this could indirectly discriminate but would be a proportionate means of achieving the legitimate aim of maximising public health.
Race: The committee was aware that people from minority ethnic family backgrounds were more likely to be diagnosed with COVID19. Also, the risk of dying from COVID19 was disproportionately higher in people from Black, Asian and other minority ethnic family backgrounds. The committee further noted that nirmatrelvir plus ritonavir was contraindicated in people with hepatic and renal impairments. The prevalence of certain comorbidities including renal impairment are known to be higher in people from these family backgrounds. Differences in prevalence cannot usually be resolved in a technology appraisal, although the committee did not consider that family background has a significant impact on access to treatment. However, the committee noted that certain minority ethnic populations suffered worse health outcomes. The committee concluded that it would consider these issues in its decision making. It noted that the recommendation of sotrovimab for people  in whom nirmatrelvir plus ritonavir is contraindicated may partially address this issue.
Age: Some stakeholders considered age was an independent relevant risk factor (see section 3.6). The committee was mindful of excluding age from its recommendations because it is a protected characteristic. The committee noted the McInnes report did not include age as an independent risk factor. The committee did not consider there was enough evidence to support a relationship between specific age cut-off points alone (for example, adjusted for comorbidities) and a high risk of progression to severe COVID19. It also could not adequately consider the impact of these changes in its cost-effectiveness analysis. A similar approach to recommendations has been taken for NICE technology appraisal guidance on treatments for cardiovascular conditions even though a strong link with age had been established in this disease area.
Treatment for children: The committee noted that the summary of product characteristics for nirmatrelvir plus ritonavir (mild COVID19 setting) and tocilizumab (severe COVID19 setting) do not recommend these treatments in people under 18 years. In the mild COVID19 setting, the committee has recommended sotrovimab for people for whom nirmatrelvir plus ritonavir is unsuitable. Sotrovimab's marketing authorisation includes adolescents (aged 12 years and over and weighing at least 40 kg), so this would be an option for them, if they have a high risk of progression to severe COVID19 as defined by the McInnes report. By only recommending tocilizumab in the severe COVID19 setting there is a risk of indirectly discriminating against children and young people.
Pregnancy and maternity: The committee notes that the summary of product characteristics for tocilizumab states it should not be used during pregnancy unless clearly necessary. By recommending tocilizumab there is a risk of indirectly discriminating against people who are pregnant. The committee considered that in the context of acute hospital treatment, no other alternative treatments for treating hyperinflammation were included in the scope of this appraisal. It considered that clinicians should use independent judgement when considering the risk factors of tocilizumab in people who are pregnant.

## Addressing health inequalities
The committee noted the equalities issues outlined in section 3.32, and considered flexibility as part of the principles that guide the development of NICE guidance and standards. This emphasises the importance of considering the distribution of health resources fairly within society as a whole, and factors other than relative costs and benefits alone. It noted that the issues raised could affect some people with protected characteristics disproportionately which would contribute to health inequality. The committee said that in theory it would be willing to accept an ICER slightly more than what is usually acceptable if it addressed such health inequalities. However, it noted that departing from NICE's usual range needs to be done with caution, because it risks displacing funding from more cost-effective treatments elsewhere in the NHS, with an overall net loss of health gain. Even considering greater flexibility, the ICERs of alternative treatments to tocilizumab and for younger children were substantially higher than what is considered a cost-effective use of resources.

# Conclusion
Setting
Recommended
Not recommended
Mild COVID19 (in people who have high risk of progression to severe disease, this setting also includes hospital-onset COVID-19)
nirmatrelvir plus ritonavir
sotrovimab (only if nirmatrelvir plus ritonavir is contraindicated or unsuitable)
casirivimab plus imdevimab
Severe COVID19 (without supplemental oxygen)
no technologies recommended
casirivimab plus imdevimab
Severe COVID19 (with supplemental oxygen)
tocilizumab
casirivimab plus imdevimab

# Supporting information on risk factors for progression to severe COVID-19
This section provides supporting information for recommendations 1.1 and 1.2. Box 1 and box 2 present risk factors for progression to severe COVID-19 defined by the independent advisory group commissioned by the Department of Health and Social Care. Box 1 details risk factors in adults and box 2 details risk factors in young people aged 12 to 17 years. The information presented in box 1 and box 2 was provided by the independent advisory group and has not been independently reviewed or verified by NICE. See the Department of Health and Social Care website for the full independent advisory group report (published March 2023).

# Box 1 Risk factors for progression to severe COVID-19 in adults
Risk factors for progression to severe COVID-19 in adults defined by the independent advisory group commissioned by the Department of Health and Social Care (June 2023)
Down's syndrome and other genetic disorders
All individuals with Down's syndrome or other chromosomal disorders known to affect immune competence
Solid cancer
metastatic or locally advanced inoperable cancer
lung cancer (at any stage)
people receiving any chemotherapy (including antibody-drug conjugates), PI3K inhibitors or radiotherapy within 12 months
people who have had cancer resected within 3 months and who received no adjuvant chemotherapy or radiotherapy
people who have had cancer resected within 3 to 12 months and receiving no adjuvant chemotherapy or radiotherapy are expected to be at less risk (and thus less priority) but still at increased risk compared with the non-cancer populations
Haematological diseases and recipients of haematological stem cell transplant (HSCT)
allogeneic HSCT recipients in the last 12 months or active graft versus host disease (GVHD) regardless of time from transplant (including HSCT for non-malignant diseases)
autologous HSCT recipients in the last 12 months (including HSCT for non-malignant diseases)
individuals with haematological malignancies who have received CAR-T cell therapy in the last 24 months, or until the lymphocyte count is within the normal range
individuals with haematological malignancies receiving systemic anti-cancer treatment (SACT) within the last 12 months, or radiotherapy in the last 12 months
all people who do not fit the criteria above, and are diagnosed with:
myeloma (excluding monoclonal gammopathy of undetermined significance )
AL amyloidosis
chronic B-cell lymphoproliferative disorders (chronic lymphocytic leukaemia, follicular lymphoma)
myelodysplastic syndrome (MDS)
chronic myelomonocytic leukaemia (CMML)
myelofibrosis
any mature T-cell malignancy
all people with sickle cell disease
people with thalassaemia or rare inherited anaemia with any of the following:
severe cardiac iron overload (T2 - less than 10 ms)
severe to moderate iron overload (T2 - greater than or equal to 10 ms) plus an additional comorbidity of concern (for example, diabetes, chronic liver disease or severe hepatic iron load on MRI)
individuals with non-malignant haematological disorders (for example, aplastic anaemia or paroxysmal nocturnal haemoglobinuria) receiving B-cell depleting systemic treatment (for example, anti-CD20, anti-thymocyte globulin  and alemtuzumab) within the last 12 months
Renal disease
renal transplant recipients (including those with failed transplants within the past 12 months), particularly those who have:
received B-cell depleting therapy within the past 12 months (including alemtuzumab, rituximab , ATG)
an additional substantial risk factor which would in isolation make them eligible for monoclonals or oral antivirals
non-transplant renal patients who have received a comparable level of immunosuppression
patients with chronic kidney disease (CKD) stage 4 or 5 (an estimated glomerular filtration rate  less than 30 ml per min per 1.73 m2) without immunosuppression
Liver diseases
people with cirrhosis Child-Pugh (CP) class A, B and C, whether receiving immune suppressive therapy or not. Those with decompensated liver disease (CP B and C) are at greatest risk
people with a liver transplant
people with liver disease on immune suppressive therapy (including people with and without cirrhosis)
Solid organ transplant recipients
Solid organ transplant recipients not in any of the above categories
Immune-mediated inflammatory disorders (diseases in which autoimmune or autoinflammation-based pathways are implicated in disease, for example, inflammatory arthritis, connective tissue diseases, inflammatory skin diseases, inflammatory gastrointestinal disease)
people who have received a B-cell depleting therapy (anti-CD20 drug, for example, rituximab, ocrelizumab, ofatumab, obinutuzumab) in the last 12 months
people who have been treated with cyclophosphamide (IV or oral) in the 6 months prior to positive PCR or relevant COVID test
people who are on corticosteroids (equivalent to or greater than 10 mg per day of prednisolone) for at least the 28 days prior to positive PCR
people who are on biologics or small molecule JAK inhibitors
people who are on current treatment with mycophenolate mofetil, oral tacrolimus, azathioprine, mercaptopurine, or similar agents (for major organ involvement such as kidney, gastro-intestinal tract, liver, lung, brain), methotrexate (for interstitial lung disease or asthma only) and/or ciclosporin. No minimum dose threshold is suggested
people who are on current treatment (or within the last 6 months) with S1P modulators (fingolimod, ponesimod or siponimod), or alemtuzumab or cladribine within the last 12 months
people who exhibit at least one of: (a) uncontrolled or clinically active disease (that is, required recent increase in dose or initiation of new immunosuppressive drug or IM steroid injection or course of oral steroids within the 3 months prior to positive PCR); and/or (b) other high risk comorbidities (for example, body mass index  greater than 30, diabetes mellitus, hypertension, major organ involvement such as significant kidney, liver, nervous system or lung inflammation or significantly impaired renal, liver, nervous system and/or lung function)
Respiratory
asthma in people on oral corticosteroids (defined above). Any asthma patient taking immunosuppressants for their asthma including but not exclusively methotrexate, ciclosporin
COPD on long term home non-invasive ventilation (NIV). Patients on long term oxygen therapy. People with moderate or severe disease (FEV1 less than or equal to 50% predicted) who have required 4 or more courses of prednisolone 30 mg for 5 days or greater in last 12 months
interstitial lung disease (ILD)  all patients with idiopathic pulmonary fibrosis
sub-types of ILD, for example, connective tissue disease related, sarcoidosis, hypersensitivity pneumonitis, NSIP (non-specific interstitial pneumonia) who have received a B-cell depleting therapy in last 12 months, or IV or oral cyclophosphamide in the 6 months prior to testing positive for COVID-19. Any ILD patient on current treatment with corticosteroids, mycophenolate mofetil, azathioprine, tacrolimus, cyclosporin or methotrexate. No minimum dose criteria
any people with any type of ILD who may not be on treatment due to intolerance but has severe disease with an FVC predicted less than 60%
NIV and tracheostomy ventilated  all patients requiring this type of support regardless of the underlying disorder (which might include COPD, obesity hypoventilation syndrome, scoliosis, bronchiectasis, neurodisability and genetic muscular diseases ).
lung cancer patients, refer to 'Solid cancer' section above
lung transplant patients (refer to solid organ transplant section)
pulmonary hypertension (PH): groups 1 and 4 from PH classification
Immune deficiencies
common variable immunodeficiency (CVID)
undefined primary antibody deficiency on immunoglobulin (or eligible for Ig)
hyper-IgM syndromes
Good's syndrome (thymoma plus B-cell deficiency)
severe combined immunodeficiency (SCID)
autoimmune polyglandular syndromes or autoimmune polyendocrinopathy, candidiasis, ectodermal dystrophy (APECED syndrome)
primary immunodeficiency associated with impaired type 1 interferon signalling
X-linked agammaglobulinaemia (and other primary agammaglobulinaemias)
any person with secondary immunodeficiency receiving, or eligible for, immunoglobulin replacement therapy
HIV/AIDS
people with high levels of immune suppression, have uncontrolled or untreated HIV (high viral load) or present acutely with an AIDS defining diagnosis
people on treatment for HIV with CD4 less than 350 cells per mm3 and stable on HIV treatment or CD4 greater than 350 cells per mm3 and additional risk factors (for example, age, diabetes, obesity, cardiovascular, liver or renal disease, homeless, alcoholic dependency)
Neurological disorders
Conditions associated with neuromuscular respiratory failure requiring chronic ventilatory support:
motor neurone disease
Duchenne muscular dystrophy
Conditions that require use of specific immunotherapies:
multiple sclerosis (MS)
myasthenia gravis (MG)
-ther immune-mediated disorders
Dementia, neurodegenerative and neuroimmune disorders when associated with severe frailty (for example, levels 7 or 8 on Clinical Frailty Scale, as part of a personalised care plan):
Alzheimer's disease, vascular disease, Lewy body disease, or frontotemporal atrophy
Parkinson's disease
Huntington's disease
progressive supranuclear palsy and multiple system atrophy
motor neurone disease
multiple sclerosis and other immune-mediated neurological disorders

# Box 2 Risk factors for progression to severe COVID-19 in young people aged 12 to 17 years
Pathway for PCR positive symptomatic cases aged older than 12 and younger than 18 years, greater than 40 kg weight, and clinical concern: defined by the independent advisory group commissioned by the Department of Health and Social Care (March 2023)
Non-hospitalised individuals in the older than 12 and younger than 18 years age range considered at high risk from COVID-19 and to be prioritised for consideration of treatment with neutralising monoclonal antibodies when symptomatic and SARSCoV2 PCR positive. Concerned clinicians should refer for regional multidisciplinary team (MDT) case discussion through local established pathways, who will confirm eligibility and consider risk benefit and whether to proceed with offer of treatment.
Children and young people (CYP) at substantial risk
Complex life-limiting neurodisability with recurrent respiratory infections or compromise.
CYP at significant risk if 2 or more of these risk factors are present
Primary immunodeficiency:
common variable immunodeficiency (CVID)
primary antibody deficiency on immunoglobulin (or eligible for immunoglobulin replacement)
hyper-IgM syndromes
Good's syndrome (thymoma plus B-cell deficiency)
severe combined immunodeficiency (SCID)
autoimmune polyglandular syndromes or autoimmune polyendocrinopathy, candidiasis, ectodermal dystrophy (APECED syndrome)
primary immunodeficiency associated with impaired type 1 interferon signalling
X-linked agammaglobulinaemia (and other primary agammaglobulinaemias)
Secondary immunodeficiency:
HIV CD4 count less than 200 cells per mm3
solid organ transplant
haematological stem cell transplant (HSCT) within 12 months, or with graft versus host disease (GVHD)
CAR-T cell therapy in last 24 months
induction chemotherapy for acute lymphoblastic leukaemia (ALL), non-Hodgkin's lymphoma, chemotherapy for acute myeloid leukaemia (AML), relapsed and/or refractory leukaemia or lymphoma
Immunosuppressive treatment:
chemotherapy within the last 3 months
cyclophosphamide within the last 3 months
corticosteroids greater than 2 mg per kg per day for 28 days in last 4 weeks
B-cell depleting treatment in the last 12 months
Other conditions:
high body mass index (BMI; greater than 95th centile)
severe respiratory disease (for example, cystic fibrosis or bronchiectasis with FEV1 less than 60%)
tracheostomy or long-term ventilation
severe asthma (paediatric intensive care unit  admission in 12 months)
neurodisability and/or neurodevelopmental disorders
severe cardiac disease
severe chronic kidney disease
severe liver disease
sickle cell disease or other severe haemoglobinopathy
trisomy 21
complex or chromosomal genetic or metabolic conditions associated with significant comorbidity
multiple congenital anomalies associated with significant comorbidity
bronchopulmonary dysplasia  decisions should be made taking into account degree of prematurity at birth and chronological age
infants less than 1 year with congenital heart disease (CHD):
cyanotic CHD
haemodynamically significant acyanotic CHD and history of prematurity
those due for corrective surgery, to avoid complications or delay due to SARSCoV2 infection