The appraisal committee (section 5) considered evidence submitted by AbbVie and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.
People with hepatitis C would welcome an additional treatment option that is suitable for all genotypes and free from peginterferon
3.1 The use of interferon-based treatments has reduced substantially in clinical practice because of the introduction of newer direct-acting antivirals for all hepatitis C virus (HCV) genotypes, with the exception of genotype 2. Clinical and patient experts stated that glecaprevir–pibrentasvir is an important treatment because it is effective in all genotypes, which reduces the need for baseline genotype testing and could improve access to treatment. Unlike sofosbuvir-based regimens, glecaprevir–pibrentasvir is suitable for people with severe renal impairment. This is particularly important for genotypes 2, 3, 5 and 6 in which the only interferon-free treatments available have a sofosbuvir component. In addition to being free from interferon, ribavirin and sofosbuvir, glecaprevir–pibrentasvir has a short treatment duration of 8 weeks for disease without cirrhosis for most HCV genotypes. The committee recognised that patients and clinicians would welcome an additional effective and tolerable treatment for all HCV genotypes and concluded that glecaprevir–pibrentasvir is a valuable treatment option.
3.2 The company did not include some of the comparators listed in the NICE scope, noting that they are no longer used in clinical practice:
daclatasvir plus sofosbuvir for genotypes 1 and 4
peginterferon alfa plus ribavirin for all genotypes (except genotype 2, in people who are treatment naive, without cirrhosis, and who are eligible for treatment with interferon)
sofosbuvir plus with ribavirin for genotypes 1 and 4.
The clinical experts confirmed that these comparators are rarely used in NHS practice for those populations and could therefore be excluded. The committee concluded that the company had included the most relevant comparators.
3.3 The key clinical evidence for glecaprevir–pibrentasvir came from 7 clinical trials. Only 1 trial included an active comparator (glecaprevir–pibrentasvir compared with sofosbuvir–daclatasvir). One trial was placebo controlled and the remaining 5 trials did not have a comparator. The trials included people who had not had treatment for their hepatitis C, and people whose hepatitis C had not adequately responded to interferon-based treatment or sofosbuvir plus ribavirin. Results showed that for all genotypes, irrespective of cirrhosis stage or treatment history, the rate of sustained virological response at 12 weeks after the end of treatment ranged from 87.5% to 100.0%. The ERG noted that patient numbers in the trials were low and only 4 out of the 24 subgroups included more than 100 patients, which causes considerable uncertainty in the rates of sustained virological response. The committee was aware that patient numbers would be low in some subgroups because of the low incidence of disease of certain genotypes. The clinical experts stated that glecaprevir–pibrentasvir is considered similar in effectiveness to the new direct-acting antiviral drugs. The committee concluded that glecaprevir–pibrentasvir is effective for treating chronic hepatitis C across all subgroups and in all genotypes.
3.4 The most commonly reported adverse events with glecaprevir–pibrentasvir are headache and fatigue. The committee noted the relatively favourable safety and tolerability profile, irrespective of cirrhosis stage, treatment experience and degree of renal impairment. The clinical experts stated that glecaprevir–pibrentasvir has a similar tolerability profile to other direct-acting antiviral regimens. The committee concluded that the adverse events associated with glecaprevir–pibrentasvir were generally tolerable.
3.5 The structure of the company's model and its assumptions about the natural history of the disease including distinguishing between no cirrhosis (further subdivided into fibrosis severity) and compensated cirrhosis was similar to models used for other NICE technology appraisals for chronic hepatitis C. The model did not include onward transmission of disease or reinfection. In its scenario analyses, the ERG explored using reinfection rates from Simmons et al. (2016), which calculated the reinfection probability as 0.0033. This had no impact on the results. The committee had previously accepted similar models that excluded disease transmission and reinfection, so it concluded that the structure of the model was acceptable for decision-making.
3.6 The company used a naive indirect comparison to compare glecaprevir–pibrentasvir with the relevant comparators. Due to the lack of comparative trial data for glecaprevir–pibrentasvir and the comparators a conventional indirect treatment comparison was not feasible. The rates of sustained virological response for the comparators in the company's model were selected from individual arms of randomised controlled trials. The company had used some of the same rates of sustained virological response for comparator technologies as those used in the NICE technology appraisal guidance on sofosbuvir–velpatasvir. The rates of sustained virological response for the direct-acting antivirals were similar to those for glecaprevir–pibrentasvir in its trials. The ERG stated that the company's choice of study for each comparator was often arbitrary. The committee noted that this approach meant that the results were at risk of the kind of bias normally associated with observational studies. It concluded that the company's method of estimating efficacy in the model introduced some uncertainty in the results.
3.7 The company used the same sources for non-treatment-specific transition probabilities as those used in previous NICE technology appraisals on hepatitis C. These included Thein et al. (2008) and Kanwal et al. (2014) for fibrosis progression, and Cardoso et al. (2010) and Fattovich et al. (1997) for non-fibrosis progression. The committee was generally satisfied with this approach. In a scenario analysis, the ERG explored using Grishchenko et al. (2009) which had also been accepted for fibrosis progression in previous appraisals, but this had no impact on the results. The committee therefore concluded that the company's transition probabilities were appropriate for decision-making.
3.8 In its base-case analyses, the company used utility data from the literature (Wright et al. 2006) in line with the previous NICE technology appraisals on hepatitis C to inform the difference in utility of a health state with or without sustained virological response. In a scenario analysis the company used utility data collected from clinical trials using the EQ‑5D, but this did not change the results. The average sustained virological response-related utility increments from the company's trials (0.025 to 0.029) were smaller than that from Wright et al. (0.05), which has consistently been used in previous hepatitis C NICE technology appraisals. The ERG explored the impact of applying a zero gain in utility after sustained virological response but this also had no impact on the results. None of the other utility scenario analyses done by the ERG had any significant impact on the results. The committee therefore accepted the company's base-case utility estimates but emphasised that in future hepatitis C appraisals, utility values from the literature will no longer be considered acceptable if there are appropriate utility values collected from clinical trials.
3.9 Using the confidential price discounts for glecaprevir–pibrentasvir and its comparators (where applicable), the results showed that glecaprevir–pibrentasvir was the most cost-effective treatment in all groups (with incremental cost-effectives ratios [ICERs] substantially below £20,000 per quality-adjusted life year [QALY] gained), except for people with untreated genotype 4 HCV without cirrhosis. In this group glecaprevir–pibrentasvir was the cheapest treatment with the lowest total QALYs. The company's deterministic sensitivity analysis showed that the model was primarily driven by the rates of sustained virological response, which the committee had previously concluded led to uncertainty in the model (section 3.6). The committee was aware that the rate of sustained virological response used to inform this subgroup analysis (untreated genotype 4 HCV without cirrhosis) was based on small patient numbers and was lower than those used for the comparators. The clinical experts had stated that glecaprevir–pibrentasvir is considered similar in effectiveness to the new direct-acting antiviral drugs (section 3.3), and considered that any difference in sustained virological response rate was probably a result of the small patient numbers in the group. The committee recalled the clinical experts' comments (section 3.1) that glecaprevir–pibrentasvir is likely to be effective in all subgroups regardless of genotype, treatment history or cirrhosis status. It also recalled that glecaprevir–pibrentasvir was the most cost-effective treatment in all of the other genotype 4 subgroups. In addition, because of the small patient numbers of people with genotype 4 HCV, it had previously accepted sustained virological response rates from genotype 1 as a proxy for genotype 4 rates in some hepatitis C appraisals. Therefore on the balance of evidence available, the committee considered that glecaprevir–pibrentasvir would be equally cost effective for treating genotype 4, previously untreated chronic hepatitis C in people without cirrhosis. The committee concluded that glecaprevir–pibrentasvir could be recommended within its marketing authorisation as a cost-effective use of NHS resources for treating hepatitis C.
3.10 Previous NICE technology appraisal guidance on hepatitis C included recommendations on treatment and prescribing decisions because of capacity constraints within the NHS. The clinical experts stated that many people eligible for treatment, particularly people with cirrhosis, have now been treated, creating additional capacity to treat more. The clinical experts also stated that having more affordable drugs with shorter treatment durations also creates additional capacity. However, NHS England commented that there is considerable value in recommending that multidisciplinary teams in the operational delivery networks should prioritise treatment for people with the highest unmet clinical need. NHS England considers that the capacity constraints in the NHS have not changed sufficiently and that not including this recommendation would create major challenges. On balance, the committee accepted that it was appropriate to include the recommendation on treatment and prescribing decisions (see section 1.2) as in previous NICE guidance on hepatitis C treatments.
3.11 The committee considered whether glecaprevir–pibrentasvir could be considered innovative, and whether the company's economic analysis had captured all associated health-related benefits. The committee agreed with the company that there is an unmet need for interferon-free regimens to treat people with previously treated genotype 3 hepatitis C, particularly those with severe renal impairment. However, the committee concluded that it had taken these potential benefits into account when considering the cost effectiveness of glecaprevir–pibrentasvir.
3.12 The committee noted potential equality issues raised during the NICE scoping process that there are proportionately more people from Asian and minority ethnic groups, and more people who inject drugs, who have genotype 3 or genotype 4 HCV than other HCV genotypes. Having decided that glecaprevir–pibrentasvir should be recommended for all genotypes, the committee agreed that its recommendations for these groups would not have a different effect on people protected by equality legislation than on the wider population.