Draft guidance consultation

Details of the condition

3.1 Haemophilia B is an X-linked, congenital bleeding condition characterised by a deficiency of coagulation factor IX (FIX). It mainly affects men, but can affect women in rare cases. The severity of haemophilia B generally correlates with the level of FIX in the blood and is defined as either severe (FIX level below 1%), moderate (FIX level 1% to 5%), or mild (FIX level 5% to less than 40%). Moderately severe haemophilia does not have a standard definition but is generally considered to be a FIX level below or equal to 2%. The main symptom of haemophilia is prolonged bleeding but other complications include bleeding into joints and muscles without having had an injury. Patient experts explained that bleeds are not only physically painful but can also have a substantial psychological impact on people with the condition and their family. They often have anxiety or worry about their condition, causing great mental distress. The patient experts explained that FIX prophylaxis treatment for moderately severe or severe haemophilia B (see section 3.2) often requires self-infusion or infusion by caregivers as often as every 2 to 3 days, which is a substantial treatment burden. They added that this makes planning difficult, especially when travelling, and impairs ability to be spontaneous. Because of the heavy treatment burden, 1 patient expert described a one-off treatment with etranacogene dezaparvovec, with potential to stop the need for regular FIX prophylaxis, as life-changing. The committee concluded that moderately severe or severe haemophilia B substantially affects health-related quality of life.

Treatment pathway and proposed positioning

3.2 The clinical management of haemophilia B usually involves long-term FIX prophylaxis treatment and/or on-demand treatment with FIX concentrates. FIX prophylaxis treatment involves regular administration of standard half-life FIX concentrates (every 2 to 3 days) or extended half-life FIX concentrates (every 1 to 2 weeks) to prevent bleeding. On-demand treatment is administration of FIX concentrates at the time of a bleeding event. The company noted that, despite being eligible for regular FIX prophylaxis treatment, a small number of people with the condition, opt to only have on-demand treatment because of personal choice or clinical challenges. The company proposed that etranacogene dezaparvovec would mainly replace FIX prophylaxis treatment but could also replace on-demand only treatment. The comparators included in the company submission were 4 FIX prophylaxis treatments available on the NHS:

The committee concluded that FIX prophylaxis treatment was the most appropriate comparator.

The HOPE-B trial

3.3 The primary clinical-effectiveness evidence was from the HOPE-B trial. HOPE-B is an ongoing phase 3, open-label, single-dose, single-arm multinational trial evaluating etranacogene dezaparvovec in adult males with moderately severe or severe haemophilia B who had routine FIX prophylaxis treatment (n=54). HOPE-B included a lead-in period (minimum 6 months) in which people had FIX prophylaxis treatment. After the lead-in period, people had a dose of etranacogene dezaparvovec. Because there was no control arm, outcomes assessed during the lead-in period were compared with outcomes in the post-treatment follow-up period. The company submission presented data up to 24 months after treatment with etranacogene dezaparvovec.

Annualised bleeding rate and change in FIX levels

3.4 The HOPE-B primary outcome is annualised bleeding rate (ABR). Several bleeding outcomes were reported, including various types of bleeds: all bleeds, joint bleeds, spontaneous bleeds and bleeds that needed FIX treatment. At 7 to 24 months after etranacogene dezaparvovec, results showed that:

The committee noted that at 7 to 24 months post-treatment, 27 out of 54 people had bleeds (average of 2.7 bleeds per person). It noted that the average number of bleeds after treatment was not substantially different from the lead-in period (average of 3.4 bleeds per person). A clinical expert explained that this may be because people may need a period of relearning in the first couple of years after having etranacogene dezaparvovec, to differentiate between joint pains and bleeds. However, a scan would be needed to confirm whether the pain was because of a bleed. Therefore, it was possible that people in the trial recorded bleeds in their patient diary when they were actually experiencing joint pain. A key secondary outcome was the change in FIX level between baseline and the post-treatment period. At 24 months post-treatment, the mean (least square) increase in endogenous FIX level from baseline was 34.13 IU/dl (p<0.001). The committee concluded that bleeding rates were lower after etranacogene dezaparvovec than during the lead-in period.

Calculation of change in FIX levels

3.5 The EAG highlighted that the company did not report participants' FIX levels during the lead-in period but instead estimated baseline FIX levels based on their historical haemophilia B severity. This approach meant it was not possible to compare FIX levels during routine prophylaxis treatment in the lead-in period with FIX levels after treatment with etranacogene dezaparvovec. The company said it used this approach because FIX levels would vary depending on the type, brand, dose and frequency of FIX prophylaxis treatment that people were having. It also noted that FIX levels fluctuate after FIX prophylaxis treatment so it would be challenging to identify a representative measurement. It added that a benefit of etranacogene dezaparvovec would be more stable FIX levels because of endogenous production (that is, the body producing its own FIX). The company believed that using a historical estimate of baseline FIX levels instead of actual measurements better represents endogenous FIX production in the lead-in period and leads to a fairer comparison between treatments. The EAG considered that it was not possible to determine how etranacogene dezaparvovec affects FIX levels without comparing FIX levels during FIX prophylaxis with levels after etranacogene dezaparvovec. It added that understanding the change in FIX levels after treatment with etranacogene dezaparvovec would corroborate the other clinical outcomes, and show how etranacogene dezaparvovec reduces bleeds (for example, by increasing FIX levels). A clinical expert said that FIX levels tend to fluctuate after FIX prophylaxis treatment, and that the risk of bleeds is particularly high when FIX levels are low. They added that etranacogene dezaparvovec treatment stabilises FIX levels and so reduces the risk of bleeding from low FIX levels. The committee considered that a representative measure of peoples' actual FIX levels during the lead-in period would be useful. But, it understood the company's rationale and accepted the company's approach for reporting change in FIX levels. The committee concluded that etranacogene dezaparvovec produces a clinically meaningful increase in endogenous FIX levels.

Magnitude of clinical benefits

3.6 The EAG noted the clinical benefits reported in HOPE-B may have been overestimated. It suggested that reduced physical activity during the COVID-19 pandemic may have meant there were fewer bleeding episodes needing on-demand FIX replacement. The EAG also noted that after the lead-in period, the trial protocol prohibited prophylactic FIX replacement for FIX levels of 5% or more but investigating clinicians could give FIX replacement at their discretion. The EAG considered that clinicians may be less likely to give ad hoc FIX replacement within the trial than in routine practice, to adhere as closely as possible to the preferred study procedures. It considered it plausible that use of FIX replacement would be higher in clinical practice than in HOPE-B. The company highlighted that FIX replacement use remained substantially reduced up to 24 months post-treatment. It suggested that if the COVID-19 pandemic had lowered activity levels, increased activity after the pandemic would have led to more bleeds and increased use of FIX replacement, which was not the case. It also highlighted that the reduction in annualised spontaneous bleeding rates (not related to trauma or activity) from the lead-in period to 7 to 18 months post-treatment, was maintained at 24 months post-treatment. The patient experts shared their experience that activity levels actually increased during the COVID-19 pandemic. Clinical experts added that there was no noticeable difference in reported bleeding events during the pandemic. The clinical experts also noted that decisions about giving FIX replacement would be based on normal clinical practice and not influenced by a trial setting. The committee considered it plausible that physical activity (or its intensity) may have increased during the COVID-19 pandemic and recalled that bleeding events did not noticeably change during the pandemic. The committee concluded that the COVID-19 pandemic and trial protocol did not have a substantial impact, if any, on the magnitude of clinical benefits reported in HOPE-B.

Indirect treatment comparisons

3.7 Because HOPE-B was a single-arm trial the company did indirect treatment comparisons to compare the clinical effectiveness of etranacogene dezaparvovec with FIX prophylaxis. The company used the inverse probability of treatment weight method for the comparison with Idelvion because participant-level data was available for both treatments. A matching-adjusted indirect comparison method was used for the comparisons with Alprolix, Refixia and BeneFIX because only summary data was available. The indirect treatment comparisons suggested statistically significant improvements in bleeding outcomes for etranacogene dezaparvovec compared with each of the comparators. The results are considered confidential by the company so cannot be reported here. The EAG believed that the indirect treatment comparisons used the best available methods, but the different methods used in the studies seriously undermined the results of comparisons. The EAG noted that the comparator studies differed from HOPE-B in several important ways, principally relating to analysis populations, outcome definitions and background care. The committee understood the EAG's concerns but acknowledged these limitations related to the quality of the studies used in the indirect treatment comparisons rather than the methods used to do the indirect treatment comparisons. The committee concluded that the magnitude of improvement in bleeding outcomes for etranacogene dezaparvovec compared with FIX prophylaxis treatments was uncertain and would take this into account in its decision making.

Company's modelling approach

3.8 The company presented a cohort-based Markov model. The modelled cohort moved through 4 health states which were based on bleeding events. These were 'no bleed', 'non-joint bleed', 'joint bleed' and 'death', with everyone starting in the 'no bleed' state. Bleeding rates from HOPE-B and the company's indirect treatment comparisons (see section 3.7) were used to calculate transition probabilities between the health states. The committee concluded that the company's model structre was appropriate for decision making.

Comparators in the economic model

3.9 In HOPE-B, people who had etranacogene dezaparvovec were also given ad hoc FIX replacement (on-demand) for bleeding episodes. The company's economic model excluded on-demand supplementary FIX replacement because this would be expected to be equal between arms. The EAG agreed with this approach. The company modelled treatment with etranacogene dezaparvovec followed by FIX prophylaxis treatment after etranacogene dezaparvovec failure (see section 3.10). The company's model comparison was:

The company presented both a fully incremental analysis (which included 8 treatment combinations) and a pairwise analysis (which included 4 comparisons). The clinical experts explained that in current clinical practice, the choice of FIX prophylaxis treatment is based on a variety of factors including the dosing schedule, FIX activity levels, bleeding patterns, mechanism of action and availability of each treatment. A clinical expert said that the most frequently prescribed treatments in clinical practice are extended half-life treatments. This is primarily because less-frequent dosing is needed (see section 3.2). The committee concluded that it would consider both the fully incremental and pairwise results but requested the company provide a further scenario analysis using a 'basket of comparators' weighted by market share in the NHS. The committee concluded this further scenario would be helpful in evaluating cost-effectiveness.

Definition of treatment failure

3.10 The company's economic model included a predicted failure rate of etranacogene dezaparvovec based on extrapolations of observed data from Shah et al. (2022) (see section 3.11). The company base case defined treatment failure (that is, the FIX level at which FIX prophylaxis treatment would be restarted) as a FIX level below 2%, based on advice from 8 NHS clinicians. Once etranacogene dezaparvovec failed, it was assumed that people resumed treatment with 1 of the 4 FIX prophylaxis treatments. The EAG consulted with an NHS clinician who advised that a FIX level of 2% to 5% would be considered as a 'trough' (a minimum level when people are routinely having FIX prophylaxis treatment). They also advised that this level may be too low for people to engage safely in some routine activities such as certain sports. The EAG also noted that people in HOPE-B only stopped FIX prophylaxis treatment when FIX levels were more than 5%. The EAG's base case therefore considered that FIX prophylaxis treatment was more likely to be reintroduced when FIX levels dropped below 5% rather than 2%. The clinical experts explained that restarting FIX prophylaxis treatment is based on many factors, including: bleeding symptoms, FIX level and personal preference. One clinical expert said an appropriate definition of treatment failure would be a FIX level between 2% and 3% and another said below 3%. The committee considered that the definition of treatment failure, and when people need to restart FIX prophylaxis treatment, would vary based on a number of factors, including bleeding symptoms and activity levels. The committee concluded that it is appropriate to model restarting FIX prophylaxis treatment at a FIX level between 2% and 3%. It requested the company also provide a scenario in which FIX prophylaxis treatment is restarted at a FIX level of 3%.

Durability of treatment effect

Acceptable ICER

3.13 NICE's manual for health technology evaluations notes that judgements about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the incremental cost-effectiveness ratio (ICER). The committee will be more cautious about recommending a technology if it is less certain about the ICERs presented.

The committee noted concerns around the high level of uncertainty, specifically:

Because of the high level of uncertainty in the clinical and economic evidence, the committee agreed that an acceptable ICER would be towards the lower end of the range normally considered a cost-effective use of NHS resources (£20,000 to £30,000 per quality adjusted life year [QALY] gained).

Cost-effectiveness estimates

3.14 The committee noted that neither the company nor the EAG's base cases or scenario analyses included all its preferred assumptions. The committee agreed that it would prefer to see the following scenarios:

The committee recalled that the only difference between the company's and EAG's base-case models was the definition of treatment failure which was 2% and 5%, respectively. The committee considered the company's and EAG's probabilistic base-case cost-effectiveness results. Because etranacogene dezaparvovec and the comparators have confidential commercial arrangements, the exact ICERs are confidential and cannot be reported here. The committee considered both the fully incremental and pairwise results:

In both the company and EAG base-case models:

The committee concluded that neither the company nor the EAG's base cases or scenario analyses included its preferred assumptions.

Managed access

3.15 The committee was aware that NICE's health technology evaluations manual states that a recommendation with managed access can be an option for patient access to medicines when immature evidence or evidence gaps results in significant uncertainty for committee decision making. It recognised that etranacogene dezaparvovec is a promising treatment and that the ongoing HOPE-B trial could provide further data to address some of the uncertainty about the treatment's long-term durability. However, the committee may only consider a recommendation with managed access after seeing a managed access proposal and a feasibility assessment by NICE. The committee concluded that it was unable to consider a recommendation with managed access because it had not been provided with a managed access proposal.

Equality

3.16 The committee noted that haemophilia B is rare in women and HOPE-B did not include women. It was aware of clinical advice received by the EAG that the few women who experience severe and moderately severe haemophilia B would be affected similarly as men. The committee considered that any recommendation made would not need to differentiate between men and women.

Uncaptured benefits

3.17 The committee also noted benefits of etranacogene dezaparvovec that were not included in the economic model. It noted that etranacogene dezaparvovec is expected to reduce long-term joint damage because it reduces bleeding events which are associated with joint damage. It also noted that etranacogene dezaparvovec might lower mortality, which would lead to higher QALY benefit. However, the effect of etranacogene dezaparvovec on mortality has not been shown. The committee concluded that these uncaptured benefits did not have a material effect on the decision-making at the first committee meeting. This is because they were unlikely to outweigh the committee's concerns about the cost-effectiveness estimates and the degree of uncertainty around the ICER.