Final draft guidance – tixagevimab plus cilgavimab for preventing COVID-19

Company: Originally £41 based on 1 hour band 5 nurse time; updated to £216 (later revised to £108 for single dose); suggested delivery in routine outpatient appointments or secondary care community services

ERG: Preferred £410 per administration based on COVID-19 Medicine Delivery Unit (CMDU) cost for oral antivirals; considered this better reflected likely bespoke system needed; noted uncertainty about whether eligible patients would have routine appointments soon after availability and practical issues with 1-hour observation period

Committee: Concluded administration setting is uncertain; considered both company's and EAG's estimates in decision-making; acknowledged integrated care system preference for primary care due to simplicity, but NHS England stated setting is unclear

ICER impact: uncertain_direction

Company: Preferred Shields et al. (2022) showing 15.9% hospitalisation rate for Omicron wave in immunodeficient people without treatment

ERG: Acknowledged specific patient groups (solid organ transplants, lymphoma, leukaemia) have higher risk; preferred Patel et al. (2022) average risk of 2.8% as better aligned with marketing authorisation population; noted company's model did not consider specific subgroups

Committee: Preferred assumption closer to Patel et al. (2.8%); acknowledged Shields et al. estimate was high and unlikely to represent current risk for most eligible patients; noted OpenSAFELY validation of Patel et al. (2.4% for highest-risk group, 4.0% for renal impairment subgroup); concluded hospitalisation rate is uncertain but dependent on risk group

ICER impact: decreases

Company: Higher risk of long COVID for non-hospitalised people; longer duration; higher management costs; greater impact on long-term utility

ERG: Preferred lower risk, shorter duration, lower cost, and smaller utility impact; more closely aligned with NICE guidance on casirivimab plus imdevimab, nirmatrelvir plus ritonavir, sotrovimab and tocilizumab for treating COVID-19

Committee: Considered substantial uncertainty about long COVID effects; preferred EAG estimates as more closely aligned with other NICE COVID-19 treatment appraisals; noted unclear interaction with other modelled elements like infection risk

ICER impact: increases

Company: Used Cusinato et al. (2022) single UK hospital data averaged across first and second waves: 15.40% needing IMV

ERG: Preferred estimate based on general population data: 4.92% for year up to October 2022 or 2.51% for most recent 3 months (August-October 2022); preferred upper estimate of 4.92%

Committee: Agreed risk of needing IMV reduced since pandemic start; data from Omicron wave more generalisable; noted clinical expert view that risk may be lower in immunocompromised due to reduced hyperinflammatory reactions; preferred EAG estimate noting NICE COVID-19 treatment appraisal used 4.12%

ICER impact: decreases

Company: Model structure did not allow people infected after initial treatment period to develop long COVID

ERG: Should track people remaining at risk of long COVID over time; current structure may overestimate benefit of tix-cil

Committee: Broadly appropriate but key inputs highly uncertain; acknowledged difficulty of modelling beyond initial treatment period

ICER impact: decreases

Company: Model incorporated reduction in risk for fully shielding people plus direct utility benefit; assumed full benefit of risk reduction and full direct utility gain simultaneously

Committee: No one would have full benefit of both risk reduction and full direct utility gain from stopping shielding; company model double counts benefit; impact of interactions not explored

ICER impact: decreases

Company: Assumed 22.58% annual risk of symptomatic infection based on 7-day positive test reporting rate in general population England (August 2021 to August 2022)

ERG: Highlighted historical risks may not reflect current/future risks; data for general population not generalisable to tix-cil eligible population; explored scenarios halving and doubling the risk; noted last 3 months data (May-August 2022) provided 8% annualised risk

Committee: Acknowledged testing significantly reduced so general population data no longer representative; infection patterns now different with endemic COVID; concluded both EAG scenarios (halving and doubling risk) should be considered given high uncertainty

ICER impact: uncertain_direction

Company: Used trial results from PROVENT as basis for effectiveness estimates in economic model

ERG: Did not align inputs with heterogeneous eligible population across risk groups

Committee: PROVENT participants not representative: mostly not at high risk of severe COVID-19 outcome, unvaccinated, conducted before significant natural immunity in population; clinical effectiveness uncertain against currently dominant variants

ICER impact: increases

Company: Evidence available from older trial and observational studies conducted when BA.1, BA.2, BA.2.12.1 circulating

ERG: Concerns about generalisability to current variants

Committee: In vitro evidence more relevant than older real-world studies; at time of evaluation only 3% of circulating variants (BA.2 and BA.5) would be neutralised by tix-cil; insufficient efficacy against 97% of variants

ICER impact: decreases

Company: Initial submission included second 600 mg dose 6 months after first dose

ERG: Noted company approach not aligned with summary of product characteristics which states only single-dose studies conducted

Committee: Single dose only, as repeat dosing is outside marketing authorisation and would be off-label use; alignment with MHRA clarification and product characteristics

ICER impact: decreases

Company: Relied on neutralisation potential against variants

Committee: In vitro data showing tix–cil unlikely to prevent infection with most variants circulating at guidance production; virus rapidly evolving; substantial uncertainty in estimating efficacy for future variants

ICER impact: increases

Company: Proposed IC50 threshold of less than 10,000 nanograms per millilitre as appropriate threshold for clinical effectiveness; acknowledged loss of in vitro neutralisation equals no clinical effect

Committee: Recalled in vitro advisory group conclusion that pharmacokinetic and pharmacodynamic data needed to link in vitro data to clinical outcomes when substantial change in neutralisation activity but some retained; company's proposed threshold not appropriate for decision making; if no neutralisation activity in vitro suggests no clinical efficacy

ICER impact: decreases

Company: Hypothetical scenario modelling tixagevimab plus cilgavimab with neutralisation activity against 10% of circulating variants

ERG: Not explicitly stated

Committee: Committee noted that at time of evaluation, tixagevimab plus cilgavimab only likely retained neutralisation activity against around 3% of circulating variants; could not accept the company's hypothetical 10% scenario as evidence of current effectiveness

ICER impact: increases

Company: Assumed 6.6% RRR for infection based on 10% multiplier applied to Young-Xu et al. infection data only

ERG: Applied 10% multiplier to both infection and hospitalisation relative risk reductions from Young-Xu et al.

Committee: Preferred EAG approach but noted the 10% multiplier was hypothetical and much higher than actual efficacy (~3%) at time of evaluation

ICER impact: decreases

Company: Proposed 10% multiplier to relative risk reduction for infection only, aligned with FDA threshold of 10% susceptible variants

ERG: Preferred to apply 10% multiplier to both infection and hospitalisation relative risk reductions

Committee: Agreed with EAG approach but noted 10% multiplier was hypothetical and much higher than actual efficacy at time of evaluation (approximately 3%)

ICER impact: increases

Company: Utility study vignette asked people to imagine medicine providing protection similar to vaccination in healthy immune system; utility gain of 0.098 applied to everyone for 6 months

ERG: Multiple limitations: vignette did not align with tix-cil efficacy evidence; no evidence tix-cil provides comparable efficacy to vaccination

Committee: Agreed with EAG concerns; patient experts stated some shielding behaviours likely to continue; magnitude of utility gain overestimated

ICER impact: decreases

Company: Direct utility gain of 0.098; vignette study suggesting tix-cil provides efficacy comparable to vaccination in people with healthy immune system

ERG: Highlighted multiple limitations with vignette study and company's supportive academic in-confidence study; questioned alignment with actual efficacy evidence

Committee: Agreed with EAG concerns; magnitude of utility gain was not reflective of anticipated utility gain in clinical practice; noted patient experts' views that shielding behaviours would likely continue

ICER impact: increases

Company: Model assumed full benefit of risk reduction and full direct utility gain from stopping shielding for same population

ERG: EAG noted model inputs did not represent eligible population as a whole and did not capture heterogeneity within eligible population

Committee: Company model double-counted benefits; as efficacy reduces, reduction in shielding reduces; no population receives both full risk reduction and full utility gain simultaneously; patient expertise indicates continued caution even after treatment

ICER impact: increases

Company: Originally applied to everyone; updated to 82% of people who are shielding or partially shielding

ERG: Applied to only 50% of people based on company's own survey data showing 50% would return to pretreatment behaviour if new variant emerged; explored scenario with 10% application

Committee: Preferred EAG's scenario applying direct utility gain to only 10% of people; noted complex relationship between perceived efficacy, utility gain, and infection risk not modelled by company; concluded most people reluctant to change behaviour if treatment only prevents 1 in 10 infections

ICER impact: increases

Company: Direct utility gain applied to all eligible people receiving tixagevimab plus cilgavimab

ERG: Direct utility gain applied to only 50% of people in base case; EAG also provided scenario with 10% application

Committee: Committee considered the scenario with direct utility gain applied to only 10% of people to be most appropriate, resulting in ICER of £242,097 per QALY gained

ICER impact: increases