Ledipasvir–sofosbuvir for treating chronic hepatitis C

Clinical effectiveness

4.4 The Committee discussed the clinical effectiveness evidence for ledipasvir–sofosbuvir in people with genotype 1 HCV. The Committee was aware that most people enrolled into the ION studies had genotype 1 HCV without cirrhosis, and that the sustained virological responses at 12 weeks (SVR12) for people with and without cirrhosis were similar, irrespective of treatment history (that is, previously untreated or treated HCV). The Committee noted that no head‑to‑head studies of ledipasvir–sofosbuvir with any of the comparators listed in the scope were available, and the ION studies used historical controls. The company highlighted that of the 1952 people enrolled into the 3 phase III ION studies, 96.7% were cured of HCV and only 1.8% had virological relapse after treatment. The Committee heard from the clinical and patient experts that the results in people with genotype 1 HCV were impressive. The clinical experts stated that the SVR rates from the ledipasvir–sofosbuvir trials were generalisable to clinical practice. The Committee also heard from the clinical experts that people would be more likely to adhere to ledipasvir–sofosbuvir treatment than other currently available treatments, which is important for achieving an SVR, because treatment was shorter and interferon‑free. The Committee highlighted the weaknesses associated with studies that used historical controls rather than a conventional control group, but concluded that the 3 phase III ION studies showed that ledipasvir–sofosbuvir was an effective treatment in people with genotype 1 HCV.

4.5 The Committee discussed the clinical effectiveness evidence for ledipasvir–sofosbuvir in people with genotype 4 HCV. The Committee noted that there were limited data available in people with genotype 4 HCV. It agreed that this increased the uncertainty about whether the SVR rates from the genotype 4 HCV population would be seen in clinical practice. It also questioned whether the SVR rates for people with genotype 1 HCV could be generalised to people with genotype 4 HCV. The Committee acknowledged the company's view that people with genotypes 1 and 4 HCV have responded similarly to treatment in the past, and noted that the European Medicines Agency considered that the efficacy of ledipasvir–sofosbuvir for genotype 1 HCV in the ION studies was relevant to genotype 4 HCV. The Committee remained concerned about the lack of head‑to‑head trials, and the small numbers of people with genotype 4 HCV included in the evidence base. However, it concluded that it was satisfied that ledipasvir–sofosbuvir would potentially demonstrate a similar treatment effect in people with genotype 4 HCV to that shown for people with genotype 1 HCV (with or without cirrhosis).

4.6 The Committee discussed the treatment durations for ledipasvir–sofosbuvir in people with genotype 1 or 4 HCV without cirrhosis. The Committee was aware that the marketing authorisation recommends durations of 8, 12 and 24 weeks of ledipasvir–sofosbuvir, depending on genotype, treatment history, risk of progression and cirrhosis status. It recognised that the company had submitted a post‑hoc analysis to identify people for whom 8 weeks of treatment would be appropriate (see section 3.6). These were people with genotype 1 HCV that was previously untreated, who do not have cirrhosis and who have a viral load of less than 6 million international units (IU)/ml. However, the Committee was aware that although the marketing authorisation did specify that previously untreated genotype 1 HCV was suitable for 8 weeks' treatment, the viral load criterion was not specified. The Committee noted that the populations defined by the European Medicines Agency for each treatment duration of ledipasvir–sofosbuvir recommended in the marketing authorisation were open to interpretation, and heard from the clinical experts that these groups were not clearly defined in clinical practice. The Committee heard from the company that the European Medicines Agency had taken a conservative approach by recommending longer treatment durations, because the ION studies did not show any additional harm (that is, there was a similar risk–benefit profile) from increasing the duration of treatment from 8 to 12 weeks, or from 12 to 24 weeks. The company commented further that increasing the treatment duration only 'marginally increased the SVR rates'. The clinical experts stated that overall, the SVR rates in the ION studies were impressive irrespective of treatment duration, and that in general people would prefer to have shorter treatments. The Committee concluded that ledipasvir–sofosbuvir appeared similarly effective across the different durations used, and that it would make recommendations for each treatment duration for people with genotype 1 or 4 HCV without cirrhosis.

4.7 The Committee discussed the treatment durations for people with genotype 1 or 4 HCV with cirrhosis. The Committee noted that the marketing authorisation recommends 12 weeks of ledipasvir–sofosbuvir rather than 24 weeks of ledipasvir–sofosbuvir for these populations if the patient is 'deemed at low risk for clinical disease progression and has subsequent retreatment options'. The Committee heard from the company that it considered this criterion was vague in the marketing authorisation because the regulators wanted to provide clinicians with some flexibility when identifying people with cirrhosis who were eligible for 12 weeks' treatment with ledipasvir–sofosbuvir. The clinical experts at the first Appraisal Committee meeting agreed that it was challenging to distinguish between those with a high risk or low risk of clinical disease progression without any specific biomarkers. The clinical experts emphasised that 12 weeks of ledipasvir–sofosbuvir offers major advantages over currently available treatment options, especially in populations with historically difficult‑to‑treat HCV, and that the data from the ION studies showed benefits for 12 weeks' treatment in most people. The Committee acknowledged that 12 weeks' treatment with ledipasvir–sofosbuvir could be appropriate for people with genotype 1 or 4 HCV with cirrhosis. However, the Committee considered that there was a need to define 'low risk of clinical disease progression and subsequent retreatment options' that could be used to identify people with previously treated genotype 1 or 4 HCV with cirrhosis eligible for 12 weeks' treatment with ledipasvir–sofosbuvir in clinical practice. In response to consultation, a clinical expert commented that HCV treatment centres were well placed to make sound clinical judgements to identify people thought to be at low risk of clinical disease progression and with subsequent retreatment options through multidisciplinary teams. The Committee was aware that the company, in its response to consultation, had provided a definition for people with previously treated genotype 1 or 4 HCV with cirrhosis who were 'deemed at low risk of clinical disease progression and who have subsequent retreatment options' that could be used to identify these people in clinical practice (see section 3.58). The Committee understood from the clinical experts at the third Appraisal Committee meeting that all of the company's criteria were routinely assessed in clinical practice in England (for example, Child–Pugh score, platelet count, features of portal hypertension). The Committee agreed that it could make a recommendation for 12 weeks' ledipasvir–sofosbuvir for people with previously treated genotype 1 or 4 HCV with cirrhosis using the company's definition for 'low risk of clinical progression and subsequent retreatment options'.

4.8 The Committee discussed the clinical effectiveness evidence for ledipasvir–sofosbuvir plus ribavirin in people with genotype 3 HCV. The Committee was aware that limited evidence was available for people with genotype 3 HCV, particularly for the population with previously untreated HCV (n=26). The Committee acknowledged that at the time of the company's original submission (and as included in the company's economic model) data for sustained virological response at 4 weeks (SVR4) were only available for 50 people with previously treated genotype 3 HCV. The Committee heard from the company that ELECTRON‑2 was a phase II study, so small numbers of people were inevitable, but that SVR12 data were now available for the previously treated HCV population. These showed that only 1 of the 42 people who had an SVR4 did not have an SVR12. The Committee understood that people in ELECTRON‑2 had 12 weeks of ledipasvir–sofosbuvir plus ribavirin, but the marketing authorisation recommends 24 weeks of treatment in people with cirrhosis or who had prior treatment. The company commented that the European Medicines Agency conservatively recommended 24 weeks' treatment because this was historically a population with difficult‑to‑treat HCV, and because of the limited trial data available. The Committee heard from the clinical experts that it was difficult to determine whether the SVR rates in ELECTRON‑2 would be seen in clinical practice, because of the small patient numbers, but emphasised that the initial 12‑week results were impressive, and they did not signal any safety issues from extending the treatment duration to 24 weeks. The Committee concluded that although there was uncertainty about the robustness of the evidence base in people with genotype 3 HCV, there was sufficient evidence to consider ledipasvir–sofosbuvir plus ribavirin in people with genotype 3 HCV.

4.9 The Committee discussed the company's approach to estimating the effectiveness of ledipasvir–sofosbuvir (with or without ribavirin) relative to the comparators in the scope. The Committee noted that the company did not attempt a mixed treatment comparison because the ledipasvir–sofosbuvir trials were single arm. However it understood from the Evidence Review Group (ERG) that it would have been possible to do a mixed treatment comparison for the comparators for genotype 1 HCV. The Committee commented that the company's naive indirect comparison approach was not robust and leads to considerable uncertainty in determining the size of the true treatment effect. The Committee understood from previous NICE technology appraisals that the SVR rates were likely to depend on the characteristics of the populations recruited into the studies, particularly for comparator therapies such as peginterferon alfa plus ribavirin, which may affect the relative treatment effect. The Committee was concerned that the company had selected SVR rates from single studies without justification, particularly because this uncertainty was not captured in the company's estimates of cost effectiveness. The Committee heard from the company that a network could not be formed for all technologies in the relevant populations because of data limitations. The company also stated that the cost‑effectiveness results were not sensitive to the choice of SVR rates for the comparators used in its economic model. In addition, the company considered that because SVR is a hard end point, it did not consider its approach to increase uncertainty. However, the Committee heard from the ERG that the SVR rates of comparators did not need to change by much for potential conclusions around the cost effectiveness to change. The Committee concluded that the company's evidence for estimating the relative effectiveness of ledipasvir–sofosbuvir (with or without ribavirin) in people with genotype 1, 3 or 4 HCV was not robust, and therefore this uncertainty should be taken into account in the decision‑making.

Cost effectiveness

4.10 The Committee considered the company's economic model, the ERG's critique and the ERG's exploratory analyses. The Committee noted that the company's economic model structure differed slightly from that used in previous NICE technology appraisals for hepatitis C. This was because people with mild and moderate chronic hepatitis C were grouped within a single health state, and therefore the company's model distinguished only between people with and without cirrhosis. However, the Committee heard from the company that its economic model structure was similar to that in NICE's technology appraisal guidance on sofosbuvir for treating chronic hepatitis C. The clinical experts acknowledged that the model structure was consistent with how people are diagnosed in clinical practice. The Committee heard from the clinical experts that in the past, invasive liver biopsies were used to diagnose mild, moderate or severe hepatitis C. However, current practice involves less invasive diagnostic tests that do not differentiate between mild and moderate disease and can distinguish only between cirrhosis and no cirrhosis. The Committee concluded that the approach taken by the company was appropriate.

4.11 The Committee discussed the company's weighted‑average approach (or 'blended comparison'). The Committee noted that the company's base‑case analysis presented incremental cost‑effectiveness ratios (ICERs) for a combined group of people with and without cirrhosis. The Committee was aware that the presence of cirrhosis affects the recommended regimen for ledipasvir–sofosbuvir and a person's likelihood of an SVR with comparator treatments, and therefore the cost effectiveness of treatment with ledipasvir–sofosbuvir. The Committee acknowledged that the patient numbers underpinning the clinical evidence used in the company's economic model were small for the groups of people with cirrhosis (including those with genotype 1 HCV), and that the SVR rates were relatively similar to those reported for ledipasvir–sofosbuvir in people without cirrhosis. However, the Committee concluded that it was appropriate to use the approach taken in the ERG's exploratory analyses, in line with the marketing authorisation, which considered people with and without cirrhosis separately, and estimated the cost effectiveness of ledipasvir–sofosbuvir for each recommended treatment duration.

4.12 The Committee discussed the baseline characteristics of the population included in the company's economic model. The Committee noted that the ICERs were sensitive to the mean starting age used in the model. It was aware that the mean starting age was 40 years (for previously untreated HCV) and 45 years (for previously treated HCV) based on data from the HCV Research UK database, but the mean age of people in the ION studies was between 51 and 57 years. The Committee heard from the company that it chose to use the mean age from the HCV Research UK database because it more closely reflected the clinical population in England (and included a larger group of people) than the mean age of the population in the predominantly US-based ION studies. The Committee concluded that the mean age from the HCV Research UK database was more relevant to the clinical population in England.

4.13 The Committee discussed the transition probabilities used in the company's economic model. The Committee understood that the company had used transition probabilities for compensated or decompensated cirrhosis to hepatocellular carcinoma from Cardoso et al. (2010), which the company used in its revised economic model after the first consultation for NICE's technology appraisal guidance on sofosbuvir for treating chronic hepatitis C. It noted that in response to consultation, the company stated that it considered Cardoso more appropriate than Fattovich et al. (1997) (see section 3.61). The Committee noted that the ERG's exploratory analysis included transition probabilities from Fattovich et al., and was aware from the NICE guidance on sofosbuvir that although each source was associated with significant uncertainty they each had some face validity. The Committee was aware of a further source for the transition probabilities (Bruno et al. 2007), from sofosbuvir for treating chronic hepatitis C, which more closely reflected those presented in Fattovich than in Cardoso. The Committee also highlighted that there was further uncertainty relating to the company's assumption that these transition probabilities were independent of genotype. The Committee considered that in clinical practice, the rates of disease progression, and hence the transition probabilities, were likely to differ between genotype 1 or 4 HCV and genotype 3 HCV. The Committee considered that Cardoso et al. was an acceptable source for transition probabilities, but that exploring alternative sources for transition probabilities, such as Fattovich et al., was also valuable because both values could be considered plausible. The Committee concluded that the transition probabilities may lie somewhere between the Cardoso et al. and Fattovich et al. estimates, and therefore both sources should be taken into account in the decision‑making.

4.14 The Committee discussed the utility values used in the company's model. The Committee acknowledged that health‑related quality of life was assessed in the ION studies using the SF‑36 questionnaire and that none of the clinical trials collected data using the EQ‑5D. The Committee noted that the company had therefore included a utility benefit of 0.04 for people who had an SVR, taken from Vera‑Llonch et al. (2013). It noted that this was estimated with the US EQ‑5D tariff, rather than the UK EQ‑5D tariff (Wright et al. 2006, which estimated a utility benefit of 0.05). The Committee heard from the company that it chose Vera‑Llonch et al. for the utility benefit estimate because this was the most recent source used in its economic model for NICE's technology appraisal guidance on sofosbuvir for treating chronic hepatitis C. The Committee was aware that the ERG's exploratory analysis showed that the ICERs reduced slightly in favour of ledipasvir–sofosbuvir when using the utility benefit from Wright et al. However, it also noted that the exploratory analysis by the ERG, which removed a utility benefit associated with SVR, showed the ICERs for ledipasvir–sofosbuvir substantially increased. The company stated that it was unable to include utility estimates from the ION studies because data were not available at the time of its evidence submission. The Committee agreed that the health‑related quality‑of‑life data available from the ION studies suggested some benefit with ledipasvir–sofosbuvir, but the results were not consistent across the 3 phase III studies and the 4 questionnaires assessed so it was difficult to approximate how much benefit people were likely to gain. In addition, the Committee was concerned that the utility accrued over a person's lifetime in the company's model was likely to be overestimated because the utility values were not adjusted for increasing age, and therefore the utility benefit from an SVR was assumed to be maintained until death. The Committee concluded that it would have preferred to have seen the utility values determined directly from the ION studies and to have the utility values in the model adjusted for increasing age, but it was prepared to accept the utility benefit from Vera‑Llonch et al. in the economic analyses.

4.15 The Committee discussed whether it was appropriate to exclude the health effects from reinfection and transmission of HCV in the analysis. The Committee noted that excluding reinfection may overestimate the health benefits of more effective treatments and underestimate their costs, because people would be retreated with other therapies in clinical practice. The Committee understood from the clinical experts that the rate of reinfection was relatively small (approximately 1%). However, the Committee also acknowledged that most people who do not have an SVR after treatment were also likely to have further treatment in clinical practice (including people whose HCV relapses after having an initial SVR), and this too had not been accounted for in the company's economic model. The Committee recognised that excluding transmission of HCV may underestimate the health benefits of more effective treatments. The Committee commented that the ICERs were associated with some uncertainty because these health effects were omitted. It would have preferred the company to explore their inclusion further, but appreciated that this would have needed a different (and potentially more complex) model structure. The Committee concluded that ICERs excluding the health effects of reinfection and transmission of HCV were acceptable to use but this uncertainty should be taken into account in the decision‑making.

4.16 The Committee acknowledged that all the ICERs presented depended on the clinical effectiveness data, which was associated with considerable uncertainty, namely:

Genotypes 1 and 4

Genotype 3

4.23 The Committee discussed the ICERs for ledipasvir–sofosbuvir plus ribavirin in people with genotype 3 HCV. The Committee noted that the marketing authorisation only recommends a treatment duration (24 weeks) for people with cirrhosis or people who have had treatment before in the genotype 3 HCV population, but not for previously untreated HCV and people who do not have cirrhosis. The Committee received clarification from the European Medicines Agency that people with previously untreated genotype 3 HCV without cirrhosis were omitted from the recommendations in the marketing authorisation because the data were from small numbers of people and there was a lack of a direct comparison with 24 weeks' sofosbuvir plus ribavirin. The European Medicines Agency further clarified that if people with previously untreated genotype 3 HCV without cirrhosis were to be treated with ledipasvir–sofosbuvir, 'a conservative 24 weeks of therapy was advised'. The Committee emphasised their concerns about the robustness of the evidence base in people with genotype 3 HCV (see section 4.8), and concluded that the uncertainties in the methods used to estimate the relative effectiveness, and the uncertainty of excluding further treatment in the economic modelling, still applied to its decision‑making for people with genotype 3 HCV (see section 4.16).

People co-infected with HIV

4.28 The Committee discussed whether the evidence submitted by the company allowed it to make recommendations for people co‑infected with HIV. It noted that the clinical effectiveness evidence presented in the company's submission was from a single‑centre, open‑label, ongoing phase II study in adults with previously untreated genotype 1 HCV, co‑infected with HIV and without cirrhosis. The Committee acknowledged that the interim results of this study suggested that the SVR12 in people with HCV and HIV co‑infection was similar to that seen in people with HCV mono‑infection. The Committee was aware that the company had not submitted cost‑effectiveness estimates for people co‑infected with HIV and that the company considered this to be conservative because people with HCV who are co‑infected with HIV are likely to progress to severe health states more quickly if left untreated than people with HCV mono‑infection. The company stated that therefore ledipasvir–sofosbuvir was more likely to be cost effective in this population. However, the Committee noted that this assumption did not acknowledge other causes of mortality that were also likely to influence the cost‑effectiveness results. The Committee understood that the ledipasvir–sofosbuvir summary of product characteristics states that people with HCV and HIV co‑infection should have the same treatment as people with HCV mono‑infection. On balance, the Committee concluded that it was reasonable to extend the recommendations made for the mono‑infected group to those co‑infected with HCV and HIV. However, the Committee agreed that future modelling and economic analyses should be presented separately for this population.

People with advanced liver disease and after liver transplant

4.29 The Committee discussed whether the evidence submitted by the company allowed it to make recommendations for people with advanced liver disease and after liver transplant. The Committee highlighted that the marketing authorisation for ledipasvir–sofosbuvir recommends only 24 weeks of treatment plus ribavirin in people with advanced liver disease and after liver transplant. It noted that the company submitted clinical effectiveness evidence for this group using SVR4 data from 1 multicentre open‑label, phase II non‑randomised controlled trial in adults with genotype 1 or 4 HCV, but had not explored the cost effectiveness of 24 weeks of ledipasvir–sofosbuvir plus ribavirin in people with advanced liver disease and after liver transplant. The Committee was aware that the company estimated the cost effectiveness in this population for NHS England when developing an interim commissioning policy for this group of people. The Committee heard from the company that it had not presented these estimates in its evidence submission because they were based on a simplified assumption that within 1 year all people with compensated cirrhosis have decompensated cirrhosis, and were not based on evidence. The Committee noted that the ICERs in the ERG's exploratory analyses, which explored the use of 24 weeks' ledipasvir–sofosbuvir (with or without ribavirin and across all HCV genotypes, see sections 4.20–22 and 4.24–4.27), were substantially higher than the range that could be considered a cost‑effective use of NHS resources. On balance, the Committee concluded that without cost‑effectiveness estimates it was unable to make recommendations for ledipasvir–sofosbuvir plus ribavirin in people with advanced liver disease and after liver transplant.

Innovation

4.30 The Committee discussed whether ledipasvir–sofosbuvir could be considered innovative, and whether the company's economic analysis had captured all changes in health‑related quality of life. The Committee agreed that compared with current treatment, ledipasvir–sofosbuvir offers oral, shortened, interferon‑free treatment, which is particularly important to people, and a major development in the clinical management of chronic hepatitis C. The Committee therefore acknowledged that ledipasvir–sofosbuvir is a valuable new therapy for treating chronic hepatitis C. The Committee agreed that there were other benefits for people with hepatitis C (for example, possible regression of fibrosis) and wider benefits to society (for example, reduced transmission of HCV [see section 4.15], improved earning capacity) that were not captured in the QALY calculation and that, if taken into account, were likely to decrease the ICERs. However, the Committee noted that it had taken these potential benefits into account when considering the cost effectiveness of ledipasvir–sofosbuvir and concluded that its recommendations for each population remained unchanged.

NHS England

4.31 The Committee discussed NHS England's submission relating to:

4.32 The Committee heard from NHS England that up to 20,000 people could access treatment each year if NICE recommended these treatments for people with chronic hepatitis C (including people without cirrhosis). However, the Committee understood from the responses to the NHS England submission that this estimate was too high. The Committee heard from the clinical experts that a more realistic estimate for the number of people accessing treatment in England was likely to be between 7000 and 10,000 each year. The Committee was aware that NHS England considered that treating 7000 people with these new oral treatments each year would not be affordable within the current NHS budget. The Committee acknowledged that there would be significant impact on the total budget for specialised services associated with making these drugs available in the NHS. However, the Committee noted the responses from consultees on NHS England's submission that the estimates presented by NHS England were not robust, and that they omitted potential savings from reducing transmission of HCV. The Committee further understood that NHS England is exploring other ways of managing the financial impact of using these new drugs, such as tendering, and that it could be argued that the rebate provided by companies as part of the 2014 Pharmaceutical Price Regulation Scheme (PPRS) payment mechanism could be considered as a way of managing the budgetary impact of access to these treatments. The Committee understood, in this context, that one of the key objectives of the PPRS is to 'improve access to innovative medicines commensurate with the outcomes they offer patients by ensuring that medicines approved by NICE are available widely in the NHS'.

4.33 The Committee recognised that NICE's guide to the methods of technology appraisal indicates that there needs to be increasing certainty of the cost effectiveness of a technology as the NHS budget impact of its adoption increases. However, the Committee noted that the ICERs were generally considerably below £20,000 per QALY gained for ledipasvir–sofosbuvir for the populations for whom it is recommended in NICE's recommendations. The Committee emphasised that, if the uncertainties were accounted for in the modelling of the cost effectiveness (for example, incremental QALYs gained from an SVR12, the costs and benefits associated with treatment of reinfection, and savings from preventing HCV transmission), the ICERs for the recommended regimens were likely to remain substantially below £20,000 per QALY gained.

4.34 The Committee understood that, given the rapid sequential assessment of direct‑acting antiviral drug combinations now licensed for treating hepatitis C, it will be worthwhile exploring whether there are combinations or sequences of treatments (for example, by genotype, treatment experience or cirrhosis status) that could be of particular value to people with chronic hepatitis C, clinicians and the NHS. The Committee agreed that further work by NICE to support this should be started as soon as possible.

4.35 The Committee discussed comments received from NHS England on the second appraisal consultation document, which proposed an 'only in research' recommendation for people with untreated genotype 1 HCV without cirrhosis. The Committee understood from NHS England that a clinical trial, STOP‑HCV‑1, will assess SVR rates in people with untreated genotype 1 HCV without cirrhosis who have direct‑acting antiviral drugs, including ledipasvir–sofosbuvir, for shorter durations than stipulated in the marketing authorisation. The Committee was aware that the final protocol has not been agreed and STOP‑HCV‑1 has not started. It considered that the clinical effectiveness evidence available for ledipasvir–sofosbuvir for people with untreated genotype 1 HCV without cirrhosis was more robust than the evidence available for other populations considered in this technology appraisal. The Committee noted that it had recommended only the shortest duration included in the marketing authorisation for this population (8 weeks and not 12 weeks) and that the ICER was considerably below £20,000 per QALY gained. The Committee further agreed that its recommendation would not stop people from taking part in the proposed STOP‑HCV‑1 trial because the treatment of chronic hepatitis C will be managed through established operational delivery networks in the NHS. The Committee concluded that an 'only in research' recommendation was not appropriate for ledipasvir–sofosbuvir in people with untreated genotype 1 HCV without cirrhosis.

Pharmaceutical Price Regulation Scheme

4.36 The Committee considered whether it should take into account the consequences of the PPRS 2014, and in particular the PPRS payment mechanism, when appraising ledipasvir–sofosbuvir. The Committee noted NICE's position statement about this, and accepted the conclusion 'that the 2014 PPRS payment mechanism should not, as a matter of course, be regarded as a relevant consideration in its assessment of the cost effectiveness of branded medicines'. The Committee heard nothing to suggest that there is any basis for taking a different view about the relevance of the PPRS to this appraisal of ledipasvir–sofosbuvir. It therefore concluded that the PPRS payment mechanism was irrelevant in considering the cost effectiveness of ledipasvir–sofosbuvir.

Equality issues

4.37 The Committee noted the potential equality issue raised by consultees that minority ethnic groups and people with HIV co‑infection are more highly represented in the genotype 4 HCV population than in the genotype 1 or 3 HCV populations. In light of NICE's legal obligation to promote equality, the Committee considered the evidence provided by the company that included family origin by HCV genotype, and the prevalence of HIV and HCV co‑infection (see section 3.56). The Committee noted that the family origin evidence was self‑reported (and therefore could not be verified), and used broad categories. The Committee therefore considered this evidence to be uncertain, but acknowledged that the data had been published by Public Health England. The Committee acknowledged that the proportion of people in Europe with genotype 4 HCV was low, and the company was carrying out several studies of ledipasvir–sofosbuvir in people with genotype 4 HCV. The Committee considered the commercial‑in‑confidence evidence presented by the company about the genotype distribution of HCV in people with HCV and HIV co‑infection and agreed that a disproportionate number of people had genotype 4 HCV and HIV co‑infection compared with the overall population of people with HCV in England. The Committee also acknowledged a comment from the Haemophilia Society that stated many people with a bleeding disorder have genotype 4 HCV because of NHS treatment. The Committee noted that no clinical evidence or cost-effectiveness analysis had been presented specifically for people with haemophilia and HCV. The Committee was satisfied that it had sufficiently considered the evidence available for people with genotype 4 HCV, which was limited. With no mature data available, the Committee had attempted to bridge this evidence gap by considering whether the evidence available for genotype 1 HCV was generalisable to the genotype 4 HCV population. The Committee was also aware of a comment made during the appraisal of daclatasvir for treating chronic hepatitis C that genotype 3 HCV is more prevalent in people of South Asian or Pakistani family origin than other genotypes of HCV. Another consultee stated that there is evidence supporting increased rates of steatosis, hepatocellular carcinoma, cirrhosis or decompensation and death in those infected with genotype 3 HCV compared with other genotypes. The Committee understood that the consultees presented no data to support their comments. It noted that the data it had been presented with (see section 3.56) suggested that a small proportion of people with genotype 3 HCV were of Asian family origin and from other minority ethnic groups. It also noted that the proportion of people with this protected characteristic was not disproportionately higher in genotype 3 HCV compared with other genotypes (such as genotype 4 HCV). The Committee further acknowledged that the economic analysis had accounted for different rates of disease progression for each genotype. Based on the cost‑effectiveness data, it had made recommendations in line with the treatment duration and ribavirin co‑administration stated in the marketing authorisation for each genotype population. Therefore, the Committee agreed that its recommendations were fair and did not constitute an equality issue.

Summary of Appraisal Committee's key conclusions