Draft guidance consultation

gMG is a chronic condition and most people need lifelong treatment. The clinical experts explained that people would usually have treatments outlined in the Association of British Neurologists (ABN) guidelines. But they added that, at the time of this evaluation, the ABN guidelines are being updated. The ABN (2015) guidelines recommend that people are first offered pyridostigmine at the lowest effective dose and that surgery to remove the thymus gland can be considered for people under 45 years. If symptoms continue, people should be offered prednisolone. The clinical experts explained that corticosteroids like prednisolone are associated with notable side effects and that they aim to use minimal doses to minimise side effects. The ABN guidelines recommend that people are offered a non-steroidal immunosuppressant, such as azathioprine, if remission is not achieved on corticosteroids alone. If their condition does not respond to immunosuppressants or they experience notable side effects on increasing corticosteroid doses, expert advice should be sought on the use of plasma exchange or intravenous immunoglobulin (IVIg). The NHS England commissioning criteria policy for the use of therapeutic immunoglobulin recommends IVIg should be used:

• when urgent inpatient treatment is needed and plasma exchange is not available

• in rare circumstances as a maintenance treatment when all standard treatments have failed and the person is having treatment in a specialist neuromuscular service.
  
  NHS England considers rituximab, an anti-B-cell monoclonal antibody treatment, to be an equally effective treatment to IVIg. It has stated that rituximab should be considered for several populations. The patient experts explained that existing treatments are not only associated with notable side effects but can be slow to take effect. The committee concluded that an effective and fast-acting treatment option would be welcomed by people with gMG and clinicians.

Efgartigimod has a marketing authorisation as an add-on to standard treatment for gMG. The company positioned efgartigimod as a treatment for gMG in people with uncontrolled symptoms despite established clinical management. The clinical experts considered that efgartigimod could be positioned at several points in the clinical pathway. They added that, initially, it would be used in specialist centres for gMG in people with substantial symptoms despite optimal standard treatment. But, they also explained that, in time, the treatment could be used in additional populations, including the much larger population whose symptoms remain sub-optimally controlled despite standard treatment. The clinical experts explained that this is because gMG becomes more severe over time and so they aim to use the most effective treatments as early as possible. They stated that efgartigimod could also potentially reduce the corticosteroid dose needed. The committee noted that the marketing authorisation indication for efgartigimod positions it at any point after standard treatment has started. The committee also noted that the company used efficacy data from the ADAPT trial in its model (see section 3.7). The committee considered that the inclusion criteria for ADAPT may not reflect the population that could have efgartigimod in NHS clinical practice if it was recommended within its marketing authorisation. The committee highlighted that the clinical and cost effectiveness of efgartigimod would change for different populations. It concluded that further input is needed from clinical experts to help define a population in which efgartigimod is both clinically and cost effective. It considered that the characteristics of this population should be clearly defined to enable efgartigimod's use in the NHS.

The company considered that maintenance IVIg is part of established clinical management in the NHS and that it is used by a notable proportion of the people who would be offered efgartigimod. The EAG explained that it had received clinical advice that IVIg is not regularly used as a maintenance treatment because of a shortage, and because an NHS England commissioning policy substantially restricts maintenance use (see section 3.2). The EAG excluded maintenance IVIg from its base case. At technical engagement the company updated the proportion of people that have maintenance IVIg in its base case based on data collected as part of the EAMS for efgartigimod (see section 3.8; this data is confidential so cannot reported here). At technical engagement, a commissioning expert provided an estimate of the proportion of people with gMG that have maintenance IVIg (this data is confidential so cannot be reported here), which was substantially lower than the proportion used in the company's base case. The commissioning expert said that the higher proportion of people having maintenance IVIg in the EAMS data may be because people who had efgartigimod through the EAMS were people who urgently needed treatment. At the first evaluation committee meeting the clinical experts provided estimates of the proportion of people with gMG that would likely have maintenance IVIg, for overall use and by model health state. These were substantially lower than the proportion assumed in the company's base case. The clinical experts said that the proportion of people having maintenance IVIg varies between treatment centres, noting higher use in specialist centres, and highlighted that IVIg is more frequently used for severe disease. They also explained that maintenance IVIg use can be continuous or intermittent. The committee noted that the company's model included the cost of maintenance IVIg but assumed no clinical benefits. The committee considered that this was implausible. It noted that this biases the cost-effectiveness results in favour of efgartigimod because the company model assumed substantially more IVIg use in the established clinical management arm. The committee considered that the difference in IVIg use estimates was likely because different populations were being considered. It recalled it was uncertain which population would have efgartigimod if it was recommended in line with the marketing authorisation (see section 3.3).

The clinical evidence for efgartigimod came from the ADAPT trial and ADAPT extension (ADAPT+) study. ADAPT was a phase 3, multicentre, double-blind, placebo-controlled trial. It recruited adults with an MG-ADL total score of 5 points or more with over 50% of the total score attributed to non-ocular symptoms and who were on a stable dose of established clinical treatment. Of the 167 people recruited, 129 (77%) tested positive for AChR antibodies. After the first treatment cycle, 68% of the AChR antibody-positive population who had efgartigimod had a reduction of at least 2 points on the MG-ADL scale (clinically meaningful improvement) compared with 30% of people who had placebo. ADAPT+ is an ongoing, open-label, single-arm, multicentre, 3-year extension of the ADAPT trial. Of the 151 people who rolled over from ADAPT to ADAPT+, 111 (74%) tested positive for AChR antibodies. Data from the January 2022 data cut showed that, on average, a clinically meaningful improvement was achieved in cycles 1 through 14. The committee concluded that efgartigimod as an add-on to established clinical management is more effective at improving MG-ADL score than established clinical management alone.

The EAMS aims to provide people who have a high unmet clinical need with earlier access to promising new unlicensed medicines and medicines used outside of their license. The Medicines and Healthcare Products Regulatory Agency considered that there was unmet need in the AChR antibody-positive population when gMG does not respond to currently available treatments or when these treatments are not suitable. The committee considered that this population had more severe disease than that included in the company's model, with a need for urgent treatment. Efgartigimod was available through the EAMS from May 2022 until its marketing authorisation was granted in March 2023, and since then it has been available through the EAMS+ programme. The company said that the EAMS+ programme will be open until NICE publishes final guidance on efgartigimod. The company explained that it intends to collect additional data through the EAMS to support health technology assessment. At the first meeting, the committee noted that the EAMS data was only used to inform the proportion of people who have maintenance IVIg in the company's base case.

In response to draft guidance consultation, the company updated the target population description (see section 3.4). The company said that evidence from ADAPT showed that the efficacy observed in the AChR antibody-positive population is generalisable to the updated target population. So, it did not make any changes to the modelling of clinical effectiveness. The EAG stated that there were low levels of certainty around the evidence supporting the generalisability of the clinical-effectiveness estimates. The EAG also considered that age and gender distribution of people enrolled in EAMS should be used in the model. It noted that the company's proposed target population aligned closely with the EAMS cohort. That cohort was larger than the UK cohort in the MyRealWorld MG study used by the company to inform the baseline age and gender distribution in its revised base case. The company stated that the baseline characteristics of the UK cohort in MyRealWorld MG were similar to those of the EAMS cohort. Therefore, it did not update its base case. The committee noted that no alternative approaches to the modelling of clinical effectiveness were presented to overcome the uncertainty. The committee concluded that using clinical-effectiveness results from a population broader than the updated target population was a source of uncertainty. The committee considered that baseline characteristics used in the model should align with other inputs, such as quality of life (see section 3.13) and clinical-effectiveness estimates. It therefore concluded that age and gender distribution captured in ADAPT should be used in the model.

The company used a state transition model to estimate the cost effectiveness of efgartigimod plus established clinical management compared with established clinical management alone. It included 4 health states based on the MG-ADL total score (MG-ADL below 5, MG-ADL 5 to 7, MG-ADL 8 to 9, and MG-ADL 10 or more) to capture disease severity, as well as crisis and death health states. The clinical experts explained that the MG-ADL health states used in the model should broadly capture differences in costs and quality of life. But, they further explained that there may be rare circumstances when they do not. They suggested, for example, that someone with the most severe score for a single activity while the other activities are unaffected would have a score of 3. They would therefore be included in the least severe health state. But, a person who scores 1 for all 8 activities would be included in the second-worst health state. The clinical experts also noted that MG-ADL score would not be used on its own to decide whether IVIg should be offered. gMG exacerbations needing hospitalisation were included in the model as an acute event that could occur in any of the MG-ADL health states and that was associated with an additional cost and a utility decrement. The EAG considered that the company's model structure and key assumptions were reasonable. The committee recalled that in the company's model people did not have a subsequent cycle of treatment with efgartigimod if they remained in the MG-ADL below 5 health state. The clinical experts explained that in clinical practice they would not offer efgartigimod to people with an MG-ADL score below 5 and would stop treatment if a person's MG-ADL score falls below 5. The committee concluded that the company's model structure was generally appropriate for decision making. But, there was some uncertainty with how closely MG-ADL scores inform disease severity, and significant limitations to some aspects of the modelling (see sections 3.6, 3.9, 3.11 and 3.12).

The EAG highlighted that in the company's original base case, the transition probabilities for people who had permanently discontinued efgartigimod resulted in a notable proportion of people remaining in the MG-ADL below 5 health state after 6 months. The EAG also highlighted that the company had stated in its clarification response that it was not aware of any evidence of a residual treatment effect for efgartigimod. So the EAG provided updated transition probabilities assuming that 1% of people remain in the MG-ADL below 5 health state after stopping efgartigimod permanently. At technical engagement, the company provided an additional analysis of ADAPT and ADAPT+ data, real-world evidence from the US and evidence on efgartigimod in other indications that it believed supported a residual treatment effect for efgartigimod after treatment had stopped permanently. It updated its base case to assume that 15% of people remain in the MG-ADL below 5 health state after stopping treatment with efgartigimod. The EAG considered that the company's assumption was reasonable and updated its base case to match the company's. The committee noted that this assumption had a substantial effect on the cost-effectiveness results and accounted for around 50% of incremental quality-adjusted life year (QALY) gains for efgartigimod in the EAG's base case. At the first meeting, it concluded that a residual treatment effect after treatment stops was plausible but uncertain. The committee stated it would have preferred more evidence about the possible residual treatment effect, which should include clinical expert input. At the second meeting the company maintained its base-case position, assuming that 15% of people remain in the MG-ADL below 5 health state after permanently stopping treatment with efgartigimod. It provided a statement from one clinical expert who, after reviewing the additional evidence provided at technical engagement, believed a 15% residual effect is plausible. One of the clinical experts at the meeting stated that they could not comment on the plausibility of such an effect. The EAG noted that the population in ADAPT and ADAPT+ was broader than the company's proposed target population (see section 3.4). It explained that it was uncertain if the company's proposed target population and the ADAPT populations would have a similar proportion of people with a residual treatment effect after stopping efgartigimod. In response to draft guidance consultation, NICE received a comment from a clinical expert that stated that they were unaware of evidence that some people can stop efgartigimod without a relapse. They further stated that most people seem to need 7- to 8-week cycles and become rapidly symptomatic once treatment is stopped or postponed. The committee considered that the company's approach to modelling a residual treatment effect after treatment stops continued to be plausible but highly uncertain. The committee noted that the available evidence was limited with short follow up. It further noted that it had not been presented with the reasons for discontinuation in those who maintained an MG-ADL score of below 5 after permanently stopping efgartigimod . The committee recalled that varying the percentage (from 15% to 1%) of people that remain in the MG-ADL below 5 health state after permanently stopping efgartigimod had a substantial effect on the cost-effectiveness results. The committee also noted that treatment effect after permanent discontinuation may be linked to the placebo effect (see section 3.12). But, the committee noted the EAG's comments that the company's model could not adjust the treatment effect after permanent discontinuation assumptions, while also retaining the placebo effect in the established clinical management arm. The committee considered that it would like to see further input on this issue (see section 3.23). It concluded that it would consider the company's assumption alongside other scenarios, but noted the uncertainty assocatied with these assumptions.

In the company's model, the transition probabilities for the first 4 model cycles in the established clinical management arm were derived from observations over the first 16 weeks in the placebo arm of ADAPT. After the fifth model cycle, people in the established clinical management arm were assumed to return to baseline health state distribution and remain in the same health state unless a crisis or death occurred. The company stated that this assumption was conservative because it meant that the condition would not get worse. After the first meeting, the NICE technical team asked the company to explain:

• why the observed effect in the established clinical management arm would not persist over the long term and

• if it believed the observed effect was due to any of the following mechanisms:

  • regression to the mean (a tendency for extreme values to move closer to the mean when measures are repeated over time)

  • a trial effect (benefit from being in the trial that would apply to both arms, and not in routine practice)

  • a 'true placebo' effect (benefit from the expectation that treatment may lead to improvement, which would apply to both arms, and may apply in practice).

Health-related quality of life data was collected in ADAPT using the EQ‑5D‑5L and was mapped to the EQ‑5D‑3L. At the first meeting, the company's model used utility values 0.105 higher in the efgartigimod arm than in the established clinical management arm. The company stated that MG-ADL does not fully capture the effect of efgartigimod, so the benefit of efgartigimod would be underestimated if it were only captured in the model using the transition probabilities. The EAG considered that the method the company used to derive utility values and that using higher utility values in the efgartigimod arm were reasonable. It explained that clinical advice it had received suggested some of the difference in utility values between the 2 arms may be because of differences in corticosteroid use. The committee noted the magnitude of the difference in utility values between the 2 arms and that it was greater than the utility benefit associated with transitioning to the next less-severe MG-ADL health state. The committee further noted that the company's model used higher utility values in the efgartigimod arm for the MG-ADL below 5 health state, in which the model assumed people would not have efgartigimod, which did not appear valid. The committee noted it had not seen evidence to support the higher utility values used in the efgartigimod arm for example, due to differences in corticosteroid use between arms. It considered that corticosteroid use in specific MG-ADL health states might not differ substantially between the 2 arms, and noted that in the model it was assumed people in the MG-ADL below 5 health state would not use corticosteroids. It highlighted that in the more severe MG-ADL health states, corticosteroid use would be optimised regardless of whether efgartigimod was used or not. The committee concluded that the same utility values should be used for the 2 arms. In response to draft guidance consultation, the company revised its base case to use the same utility values from the MyRealWorld MG study for the 2 arms. It considered that data from MyRealWorld MG (a prospective, observational, longitudinal study that aimed to capture the impact of MG from the perspective of people with the condition) was more accurate than data collected in ADAPT. The company proposed that because data from ADAPT was collected in a clinical trial setting, where people were monitored closely, this may have resulted in overvaluation of health state utility. It considered that using pooled data from ADAPT would include some of the effect of efgartigimod. It highlighted that data from MyRealWorld MG is representative of people having established clinical management, including immunoglobulins and rituximab. The EAG noted that the populations included in both ADAPT and MyRealWorld MG are different to the new proposed target population (see section 3.4). It further stated that it considered the MyRealWorld MG study to be at high risk of bias. The EAG considered that there remained significant uncertainty around the source of health state utility values, but that utilities from the EAMS or the subgroup in ADAPT that meets the new target population description would be more appropriate. The committee noted that the NICE health technology evaluations manual states that EQ-5D data can be sourced from the literature when it is not available in the relevant clinical trials. It recalled that EQ-5D data was available from ADAPT. The committee considered that utility values used in the model should align with other inputs, such as the baseline characteristics (see section 3.9) and clinical-effectiveness estimates. On balance, the committee concluded that pooled utility values from ADAPT should be used in decision making.

The company said that the symptoms people with gMG experience and their need for support has a substantial impact on carers. Carers' health-related quality of life was not measured in ADAPT. Instead, in its original base case, the company used a published study that reported carer disutility at different severity stages of multiple sclerosis, measured using the Patient-Determined Disease Steps (PDDS) scale, to map to the MG‑ADL and crisis health states. The company said that multiple sclerosis data was chosen because multiple sclerosis and gMG are both chronic, autoimmune conditions with similar symptoms that mainly affect young women. The EAG acknowledged that there are some similarities between multiple sclerosis and gMG. But, it noted that the conditions each have different characteristics that could have an impact on carer health-related quality of life, such as the impact on a person's mobility, which limit the generalisability of the 2 conditions. At technical engagement, the company provided the results of a survey it conducted exploring the impact of gMG on carers. It said that the survey showed that caregiver responsibilities constitute a large burden on carers. The EAG noted that the survey results should be interpreted with caution. It explained that the survey was descriptive and did not provide values that could be used directly in the model. The EAG further explained that the population who completed the survey may not be generalisable to the overall population of people with gMG in England. The EAG's base case did not include carer disutilities because it considered that the company had not provided robust evidence for their inclusion. The EAG also received clinical expert advice that most people with gMG are independent and would not need lots of caregiver time. The patient experts explained how gMG has a notable impact on carers and how carers often spend a substantial amount of time providing care. The patient experts noted that carers will sometimes need to help prevent choking and that this can have a substantial impact on their mental health and prevent carers going out and leading independent lives. The committee recognised that, depending on the severity of the condition, gMG can have a substantial impact on carers' lives. But it further noted that MG-ADL examines a range of symptoms, while the PDDS focuses on a person's ability to walk, so the committee considered that mapping between MG-ADL and PDDS was not appropriate. The committee noted that carer disutilities contributed substantially to the overall QALY gain associated with efgartigimod in the company's model. The committee considered that the carer disutilities used appeared large and that it had not seen evidence to suggest that a person with gMG and their carer would experience a similar level of disutility. The committee concluded that depending on the severity of the condition, gMG could have a substantial impact on carers' lives, which it would take into account qualitatively. But that the disutilities used in the company's model were not appropriate for decision making without further evidence.

The company said that the published literature shows that higher doses of corticosteroids are associated with higher costs from treating complications. In its original submission, the company identified 3 studies that estimated the costs for corticosteroid-related chronic complications with low- and high-dose corticosteroid use. The company's base case used corticosteroid complication costs from a study in people with systemic lupus erythematosus (SLE) done in Sweden (Bexelius et al. 2013). The company explained that it selected this study because SLE and gMG are both autoimmune conditions. It said that it could also be assumed that costs were comparable between the UK and Sweden because the 2 countries have similar socioeconomic conditions. The EAG used corticosteroid complication costs from the second study identified by the company, which was in people with asthma in the UK (Voorham et al. 2019). The EAGbelieved that this study was more representative of costs in the UK. The clinical experts explained that the costs from the Voorham et al. study are unlikely to be generalisable to gMG because asthma does not share similar characteristics. The committee noted that the third study identified by the company (Janson et al. 2018) shared similarities with the other 2 studies because it was done in Sweden and included people with asthma. The clinical experts further explained that in all 3 studies, the doses of corticosteroids and the threshold used in the company's model to define high-dose corticosteroids were notably lower than what they would expect for people with gMG. The clinical experts noted that higher doses of corticosteroids could result in different complications and therefore costs. The committee considered that the Voorham et al. study excluded key weight-related adverse events such as sleep apnoea. The committee noted that the company had not provided evidence that resource use and costs from Sweden are generalisable to the NHS. It further noted that costs from the Bexelius et al. study were notably higher than the costs from the other studies. The committee was unsure whether SLE is directly generalisable to gMG. It felt that the costs from Bexelius et al. lacked face validity and may be confounded, because the study did not account for condition severity or exclude condition-related costs. The committee concluded that none of the studies identified by the company were suitable for decision making. It also concluded that corticosteroid complication costs should be generalisable to NHS clinical practice, applicable to gMG and valued using prices relevant to the NHS.

In response to draft guidance consultation, the company stated that both subcutaneous and intravenous formulations of efgartigimod will soon be licensed. The company provided a scenario analysis that assumed 80% of people had the subcutaneous formulation while 20% had the intravenous formulation. Acquisition and administration costs were adjusted accordingly but it was assumed all other costs and outcomes were unchanged. The company stated that the subcutaneous formulation would enable faster administration, reducing burden on people with gMG, carers and healthcare providers. The clinical experts explained that it is difficult to estimate the exact proportion of people who would have the subcutaneous formulation, but that 80% was a reasonable assumption because of the potential additional benefits. The committee concluded that a scenario in which 80% of people have the subcutaneous formulation was appropriate for decision making. But, the committee recognised that it would not be able to recommend efgartigimod based on these assumptions until the subcutaneous formulation is included in the marketing authorisation.

The committee's preferred assumptions included:

• using population characteristics from ADAPT (see section 3.9)

• considering a range (1% to 15%) of people remaining in the MG-ADL below 5 health state 6 months after permanently stopping efgartigimod (see section 3.11)

• maintaining the benefit observed in the placebo arm of ADAPT over the time-horizon of the model (see section 3.12)

• using the same pooled utility values from ADAPT for both the efgartigimod and established clinical management arms (see section 3.13)

• considering carer disutilities qualitatively (see section 3.15)

• including corticosteroid complication costs only for people in the Lee et al. study who found their side effects intolerable (see section 3.17)

• 80% of people having the subcutaneous formulation and 20% having the intravenous formulation (see section 3.18).
  
  The committee considered that the company's target population (see section 3.4) broadly described the most suitable population to have add-on treatment with efgartigimod but there was still some uncertainty. The ADAPT and ADAPT+ studies recruited a broader population than the one covered by the company's target population description. So, using data from these studies to inform modelling assumptions was also associated with uncertainty (see section 3.9). The committee noted that the cost-effectiveness estimates were highly sensitive to changes in maintenance IVIg use. It considered that the evidence from the Delphi panel and the company's approach to modelling IVIg use substantially overestimated the use of maintenance IVIg. It could therefore have no confidence in these estimates.

NICE's health technology evaluations manual notes that, above a most plausible ICER of £20,000 per QALY gained, decisions about the acceptability of the technology as an effective use of NHS resources will consider the degree of uncertainty around the ICER and any benefits of the technology that were not captured in the QALY calculations. The committee will be more cautious about recommending a technology if it is less certain about the evidence presented. The committee noted the high unmet need in the company's target population (see section 3.4). The committee also noted that gMG could have a substantial impact on carers' lives (see section 3.15). The committee agreed that the maximum acceptable ICER would be at the upper end of the £20,000 to £30,000 per QALY gained range that NICE considers a cost-effective use of NHS resources. But, this would require the areas of outstanding uncertainty to be resolved (see section 3.21).

The committee outlined the analysis that it would like to see the company provide. In particular, it stated that IVIg use should be modelled to address the wide range of committee concerns (see sections 3.5 and 3.6). These concerns included:

• the IVIg use assumed for MG-ADL health states was likely overestimated because the question in the company's Delphi panel asked about eligibility rather than uptake and assumed no supply issues

• there was no discontinuation modelled for IVIg but it may be stopped, for example, because of adverse events, lack of clinically meaningful response or patient choice

• no QALY benefit was assumed for IVIg use, which biased cost-effectiveness results in favour of the efgartigimod arm

• maximum dose frequency was assumed.
  
  The committee would also like to see further analysis and input on:

• Treatment effect after permanent discontinuation (see section 3.11), including specific input on:

  • the plausibility of a residual treatment effect once efgartigimod has been stopped permanently and how this is biologically possible

  • how long a residual treatment effect may persist if an effect is plausible

  • how the effect may be linked to the placebo effect (see section 3.12)

• The generalisability of data used in the model to estimate the cost-effectiveness of efgartigimod in the company's target population (see sections 3.4, 3.7 to 3.9), including:

  • Further input on how baseline characteristics, treatment effectiveness, utility values, and other model inputs compare to what would be expected in a population with a more severe disease (as proposed by the company).

The committee noted the patient experts' comments that a person's socioeconomic status and how close they live to a gMG specialist centre may impact their ability to access efgartigimod. The committee also noted the clinical experts' comment that pregnant people may not be able to have efgartigimod until additional information is available. But, the committee noted that access to specialist centres is an implementation issue that cannot be addressed by a NICE technology appraisal recommendation. The committee considered that if efgartigimod was recommended, the decision to use efgartigimod during pregnancy should be made by a patient and their clinician if the clinical benefit outweighs the risks. No other potential equalities issues were identified.

The company and clinical experts considered efgartigimod to be innovative, stating that it had a novel mechanism of action that specifically targets the underlying cause of gMG. The clinical experts also noted that efgartigimod can be given at home, and works rapidly. The committee considered that all additional benefits of efgartigimod had already been taken into account.