The Department of Health has asked the National Institute for Health and Care Excellence (NICE) to produce guidance on using sofosbuvir in the NHS in England. The Appraisal Committee has considered the evidence submitted by the manufacturer and the views of non-manufacturer consultees and commentators, and clinical specialists and patient experts.

This document has been prepared for consultation with the consultees. It summarises the evidence and views that have been considered, and sets out the draft recommendations made by the Committee. NICE invites comments from the consultees and commentators for this appraisal (see section 8) and the public. This document should be read along with the evidence base (the evaluation report).

The Appraisal Committee is interested in receiving comments on the following:

• Has all of the relevant evidence been taken into account?
• Are the summaries of clinical and cost effectiveness reasonable interpretations of the evidence?
• Are the provisional recommendations sound and a suitable basis for guidance to the NHS?
• Are there any aspects of the recommendations that need particular consideration to ensure we avoid unlawful discrimination against any group of people on the grounds of race, gender, disability, religion or belief, sexual orientation, age, gender reassignment, pregnancy and maternity?

After consultation:

• The Appraisal Committee will meet again to consider the evidence, this appraisal consultation document and comments from the consultees.
• At that meeting, the Committee will also consider comments made by people who are not consultees.
• After considering these comments, the Committee will prepare the final appraisal determination (FAD).
• Subject to any appeal by consultees, the FAD may be used as the basis for NICE’s guidance on using sofosbuvir in the NHS in England.

For further details, see the Guides to the technology appraisal process.

The key dates for this appraisal are:

Closing date for comments: 4 July 2014

Second Appraisal Committee meeting: 15 July 2014

Details of membership of the Appraisal Committee are given in section 7, and a list of the sources of evidence used in the preparation of this document is given in section 8.

Note that this document is not NICE's final guidance on this technology. The recommendations in section 1 may change after consultation.

1   Appraisal Committee’s preliminary recommendations

1.1   The Committee is minded not to recommend sofosbuvir within its marketing authorisation for treating chronic hepatitis C in adults.

1.2   The Committee recommends that NICE requests further analyses from the manufacturer for sofosbuvir in combination with ribavirin, with or without peginterferon alfa compared with peginterferon alfa and ribavirin in people with genotype 1 and genotype 3 chronic hepatitis C, to be made available for the second Appraisal Committee meeting, as follows:

• Revised cost-effectiveness analyses presented separately for people with and without cirrhosis, with and without HIV-co-infection, and by treatment history. The analyses should incorporate the following assumptions:

-     a transition from the sustained virological response-cirrhotic health state to the hepatocellular carcinoma health state, using the transition probability estimates from Cardoso et al. (2010)

-     alternative sustained virological response estimates for peginterferon alfa and ribavirin including those from Hadziyannis et al. (2004) (see section 4.14)

-     alternative utility increments after sustained virological response including SF-36 values from the trials collected at 24 weeks post-treatment, and Vera-Llonch et al. (2013) (see section 4.18)

-     alternative costs for ribavirin in the model (see section 4.15)

• Sensitivity analyses that include the above mentioned assumptions and also explore the effect on the incremental cost-effectiveness ratios (ICERs) of the following:

-     assuming that up to 100% of people with genotype 3 HCV receive sofosbuvir plus ribavirin for 24 weeks (see section 4.16)

-     assuming an increased proportion of interferon-eligible people may be unwilling to have interferon treatment and therefore receive sofosbuvir plus ribavirin for 24 weeks (see section 4.17)

-     allowing people aged 35 and 55 years to enter the model (see section 4.12)

-     variation in all-cause mortality by assuming the population entering the model comprises 61% men and 39% women, in line with estimates from Wright et al. (2006) (see section 4.12).

• For all the above analyses:

-     report probabilistic ICERs

-     use a discount rate of 3.5% for costs and benefits in line with the NICE reference case

-     provide a revised fully executable economic model to check the above revisions.

 

2   The technology

2.1   Sofosbuvir (Sovaldi, Gilead Sciences) is a uridine nucleotide analogue that inhibits hepatitis C virus (HCV) polymerase, preventing viral replication. Sofosbuvir has a UK marketing authorisation for use ‘in combination with other medicinal products for treating chronic hepatitis C in adults’. The recommended dose is 1 daily 400 mg tablet, taken orally. It should be used in combination with peginterferon alfa and ribavirin, or ribavirin only. The summary of product characteristics for sofosbuvir states that peginterferon alfa and ribavirin, or ribavirin only, are the recommended co-administered medicinal products for use with sofosbuvir. Monotherapy with sofosbuvir is not recommended. The average duration of treatment is 12 or 24 weeks depending on the person’s HCV genotype and history of previous treatment with interferon. Combination treatment regimens without peginterferon alfa for people with genotype 1, 4, 5 and 6 HCV infection have not been investigated in phase III studies. According to the summary of product characteristics, treatment regimens without peginterferon alfa should be used for people with genotype 1, 4, 5 and 6 infection only if they are intolerant to or ineligible for peginterferon alfa therapy and are in urgent need of treatment. The summary of product characteristics states that, for all genotypes, consideration should be given to extending the duration of therapy from 12 to 24 weeks, especially for people who have 1 or more factors historically associated with lower response rates to interferon-based therapies. These include people with advanced liver fibrosis or cirrhosis, high baseline viral concentrations, previous unresponsiveness to peginterferon alfa and ribavirin combination therapy, or only a single nucleotide polymorphism with 2 copies of the C allele near their IL28B gene (that is, CC genotype IL28B polymorphism); or for people of African and Caribbean family origin.

2.2   The summary of product characteristics lists the following most common adverse reactions for sofosbuvir plus ribavirin, with or without peginterferon alfa: fatigue, headache, nausea and insomnia. For full details of adverse reactions and contraindications, see the summary of product characteristics.

2.3   The cost of sofosbuvir is £11,660.98 per 28-tablet pack of 400 mg tablets (excluding VAT, ‘British national formulary’ [BNF] May 2014). The cost of a 12-week course of treatment is £34,982.94 and a 24-week course is £69,965.88 (both excluding VAT), not including the cost for ribavirin and peginterferon alfa. Costs may vary in different settings because of negotiated procurement discounts.

 

3   The manufacturer’s submission

I    The Appraisal Committee (section 7) considered evidence submitted by the manufacturer of sofosbuvir and a review of this submission by the Evidence Review Group (ERG; section 8).

3.1   The manufacturer provided clinical-effectiveness evidence, identified by systematic review, consisting of 13 studies investigating the effect of sofosbuvir plus ribavirin alone or ribavirin and peginterferon alfa in adults with chronic hepatitis C. These included:

• Studies in people who have not had treatment for HCV before (described as ‘treatment-naive’ in this document) with genotype 1, 4, 5 or 6 HCV:

-     3 phase II randomised controlled trials (QUANTUM, n=50; SPARE, genotype 1 only, n=60; ATOMIC, n=332)

-     1 open label, single arm study (NEUTRINO, n=327).

• Studies in treatment-naive people or in people who have had treatment before (described as ‘treatment-experienced’ in this document) with genotype 2 and 3 HCV:

-     4 phase III randomised controlled trials (FISSION, treatment-naive people, n=499; FUSION, treatment-experienced people, n=201; POSITRON, treatment-naive and -experienced people who were considered to be interferon intolerant, ineligible for interferon or unwilling to take it, n=278; VALENCE, treatment-naive and -experienced people, n=419)

-     1 phase II randomised controlled trial in treatment-naive people (ELECTRON, n=95)

-     1 phase II open-label study in treatment-experienced people (LONESTAR-2, n=47)

-     1 open-label single cohort study in treatment-naive people (PROTON [n=25]).

• 1 open-label 4-cohort study in people with genotype 1, 2 and 3 HCV and HIV co-infection (PHOTON-1, n=223).
• 1 open-label single-arm study in people with HCV waiting for a liver transplant (P7977-2025, n=61).

II   People in the sofosbuvir trials were split between those with cirrhosis and those without, based on the results of Fibrotest (a biomarker test that uses the results of 6 blood serum tests to generate a score correlating to the degree of liver damage) and Fibroscan (a non-invasive scan allowing the measurement of liver fibrosis based on its elasticity). No liver biopsies were performed at study entry and therefore liver fibrosis according to METAVIR score (which is based on liver biopsy histology) was not available for the sofosbuvir trials.

Evidence in people with genotype 1, 4, 5 or 6 HCV

Treatment-naive population

3.2   NEUTRINO compared the efficacy and safety of sofosbuvir plus peginterferon alfa and ribavirin for 12 weeks in treatment-naive people with genotype 1, 4, 5, or 6 chronic HCV with a historical control rate of 60% using peginterferon alfa-2a and ribavirin derived from phase III telaprevir (ADVANCE) and boceprevir trials (SPRINT2). The primary outcome was sustained virological response 12 weeks after the end of treatment. The study did not include sites in the UK. Superiority to the historical control would be established if the p-value from a 2-sided 1‑sample exact test was less than 0.05. The people in the study had a median age of 54 years (age range 19 to 70 years); 64% were men; 78% had baseline HCV RNA greater than 6 log₁₀ IU/ml (viral load, or the number of virus particles in the blood; a viral load less than 6 log₁₀ IU/ml has been linked to better response to treatment); 17% had cirrhosis; 89% had genotype 1 HCV and 11% had genotype 4, 5 or 6 HCV.

3.3   Results from the NEUTRINO study showed that 12 weeks after the end of treatment with sofosbuvir plus peginterferon alfa and ribavirin, 90% (95% CI 87 to 93%, p<0.001) of treatment-naive people with genotype 1, 4, 5, or 6 HCV had a sustained virological response. Cirrhosis and non-CC IL28B polymorphism were both associated with a reduced sustained virological response at 12 weeks: 92% (95% CI 89 to 95%) for people without cirrhosis, 80% (95% CI 67 to 89%) for those with cirrhosis (p=0.0018), and 98% (95% CI 93 to 100%) for people with the IL28B CC genotype polymorphism compared with 87% (95% CI 82 to 91%) for those with the non-CC IL28B polymorphism (p=0.006). Sustained virological response at 12 weeks was 90% for people with genotype 1 HCV and 97% for people with genotype 4, 5 or 6 HCV. No patients experienced a relapse during treatment. Relapse after virological response at the end of treatment occurred in 28 of 327 people after stopping treatment, 25 of whom had completed 12 weeks of treatment and 3 who did not complete the treatment course.

3.4   ATOMIC compared the efficacy and safety of sofosbuvir plus peginterferon alfa and ribavirin in treatment-naive people with genotype 1, 4, 5, or 6 HCV. The study included 3 arms: 1 arm received sofosbuvir plus peginterferon alfa and ribavirin for 12 weeks, the second arm received the same treatment for 24 weeks, and the third arm received treatment for 12 weeks, followed by 12 weeks of sofosbuvir monotherapy (outside of the marketing authorisation for sofosbuvir, but included by the manufacturer for information). The primary outcome was sustained virological response 24 weeks after the end of treatment. Most patients had genotype 1 HCV, and no one with genotype 5 HCV was enrolled in the study. Results showed that sustained virological responses between 96 and 98% after treatment with sofosbuvir were achieved in each treatment arm.

3.5   QUANTUM compared the efficacy and safety of sofosbuvir plus ribavirin for 12 weeks with 24 weeks of treatment in treatment-naive people with genotype 1, 4, 5, or 6 HCV. The primary outcome was sustained virological response 12 weeks after the end of treatment. Results were provided by the manufacturer, as academic-in-confidence, therefore cannot be reported here.

3.6   SPARE was a 2 part study which investigated the efficacy and safety of sofosbuvir plus ribavirin treatment for 24 weeks in treatment-naive people with genotype 1 HCV. The first part was a proof of concept, 1 arm open label study on the efficacy and safety of sofosbuvir plus ribavirin treatment for 24 weeks. The second part investigated 24 weeks of sofosbuvir plus ribavirin (using the licensed weight-based dose) compared with sofosbuvir plus a low, unlicensed dose of ribavirin. The primary outcome was sustained virological response 24 weeks after the end of treatment. In part 1 of the study, sustained virological response was achieved in 90% (n=9) of participants. In part 2, 24 participants in each group (96%) achieved viral suppression by week 4 of treatment; however after completing treatment, disease relapsed in 7 people in the weight-based ribavirin group, and in 10 people in the low dose ribavirin group.

Treatment-experienced population

3.7   The manufacturer did not provide any evidence for the efficacy of sofosbuvir plus ribavirin, or sofosbuvir plus peginterferon alfa and ribavirin in treatment-experienced people with genotype 1, 4, 5 or 6 HCV.

Evidence in people with genotype 2 or 3 HCV

Treatment-naive population

3.8   FISSION compared sofosbuvir plus ribavirin for 12 weeks with peginterferon alfa-2a plus ribavirin treatment for 24 weeks in treatment-naive people with genotype 2 or 3 chronic HCV. The primary outcome was sustained virological response 12 weeks after the end of treatment. The non-inferiority of sofosbuvir plus ribavirin compared with peginterferon alfa-2a plus ribavirin for sustained virological response at 12 weeks (primary end point) was tested. Non-inferiority was demonstrated if the lower bound of the 2-sided 95% confidence interval on the difference in sustained virological response (sofosbuvir and ribavirin group minus the peginterferon alfa-2a and ribavirin group) was less than or equal to 15%. If non-inferiority was demonstrated, then the superiority of sofosbuvir plus ribavirin compared with peginterferon alfa-2a and ribavirin could also be demonstrated if the 2-sided p-value associated with the test of superiority was less than 0.05. People in the study were randomised in a 1:1 ratio and stratified by the presence or absence of cirrhosis, HCV genotype (2 or 3) and baseline HCV RNA level (<6 log₁₀ IU/ml or ≥6 log₁₀ IU/ml). People with genotype 2 or 3 HCV were enrolled in an approximately 1:3 ratio. The people in the study had a median age of 50 years (age range from 19 to 77 years); 66% were men; 57% had baseline HCV RNA levels greater than 6 log₁₀ IU/ml; 20% had cirrhosis; 72% had genotype 3 HCV.

3.9   Results from FISSION showed that at 12 weeks after the end of treatment, sustained virological response was 67% in both treatment groups. Sofosbuvir plus ribavirin was non-inferior to peginterferon alfa-2a plus ribavirin with respect to the primary end point. The absolute difference between treatment groups after adjustment for stratification was 0.3% (95% CI −7.5% to 8.0%, non-inferiority p<0.001). HCV genotype and cirrhosis were associated with differences in sustained virological response as shown in table 1.

Table 1 Sustained virological response 12 weeks after the end of treatment from FISSION

·	·                     Percentage of people with a sustained virological response 12 weeks after end of treatment (95% CI)
·	·                     Sofosbuvir plus ribavirin	·                     Peginterferon alfa-2a plus ribavirin
·                     Genotype 2	·                     97% (90 to 100%) ·                     (n=73)	·                     78% (66 to 87%) ·                     (n=67)
·                     Genotype 3	·                     56% (48 to 63%) ·                     (n=183)	·                     63% (55 to 70%) ·                     (n=176)
·                     People without cirrhosis (genotype 2 or 3)	·                     72% (65 to 78%) ·                     (n=206)	·                     74% (67 to 80%) ·                     (n=193)
·                     People with cirrhosis (genotype 2 or 3)	·                     47% (33 to 62%) ·                     (n=50)	·                     38% (25 to 53%) ·                     (n=50)
·                     Genotype 2, without cirrhosis	·                     Academic in confidence	·                     Academic in confidence
·                     Genotype 2, with cirrhosis	·                     Academic in confidence	·                     Academic in confidence
·                     Genotype 3, without cirrhosis	·                     61% (CIs academic in confidence) ·                     (n=145)	·                     71% (CIs academic in confidence) ·                     (n=139)
·                     Genotype 3, with cirrhosis	·                     34% (CIs academic in confidence) ·                     (n=38)	·                     30% (CIs academic in confidence) ·                     (n=37)

3.10   ELECTRON was a randomised, open-label study in 2 centres in New Zealand which included 8 treatments arms, only 5 of which were used by the manufacturer to inform its submission. The treatment arms presented included treatment-naive people with genotype 1, 2 and 3 HCV who received sofosbuvir plus ribavirin with or without peginterferon alfa-2a. In 4 of the treatment arms, people with genotype 2 or 3 HCV received sofosbuvir plus ribavirin for 12 weeks and either 0, 4, 8 or 12 weeks of peginterferon alfa-2a. In another treatment arm, added as a protocol amendment after the 4 previous dose-ranging treatment arms were completed, people with genotype 2 or 3 HCV received sofosbuvir plus peginterferon alfa-2a and ribavirin for 8 weeks. Across the 5 study arms which were included in the manufacturer’s submission, 100% of people with genotype 2 or 3 HCV had a sustained virological response 12 weeks after the end of treatment.

3.11   PROTON was a 2-armed open-label study in 22 centres in the United States in which treatment-naive people with genotype 1, 2 and 3 HCV received sofosbuvir plus peginterferon alfa-2a and ribavirin. The manufacturer only presented results from the study arm which included treatment-naive people with genotype 2 or 3 HCV, who received sofosbuvir plus peginterferon alfa-2a and ribavirin for 12 weeks, because the other study arm was not used to inform its regulatory submission. Results from PROTON showed that sustained virological response 12 weeks after the end of treatment was 92% (no confidence interval reported in manufacturer’s submission) across both genotypes, and 93% in people with genotype 2 HCV and 90% in people with genotype 3 HCV.

Treatment-experienced population

3.12   FUSION compared the efficacy and safety of sofosbuvir plus ribavirin for either 12 or 16 weeks in treatment-experienced people with genotype 2 or 3 chronic HCV, whose disease had no response to previous HCV treatment (25%), or had lost its initial response during or after previous HCV treatment (75%). The study did not include sites in the UK. The people in the study had a median age of 56 years (age range 24 to 70 years); 70% were men; 73% had baseline HCV RNA levels greater than 6 log₁₀ IU/ml; 34% had cirrhosis; 63% had genotype 3 HCV.

3.13   Results from FUSION showed that HCV genotype and cirrhosis were associated with differences in sustained virological response, as given in table 2.

Table 2 Sustained virological response 12 weeks after the end of treatment from FUSION

·	·                     Percentage of people with a sustained virological response 12 weeks after end of treatment
·	·                     Sofosbuvir plus ribavirin for 12 weeks	·                     Sofosbuvir plus ribavirin for 16 weeks
·                     Genotype 2 or 3	·                     50% (95%CI 40 to 60%) ·                     (n=100)	·                     73% (95% CI 63 to 81%) ·                     (n=95)
·                     Genotype 2	·                     86%* ·                     (n=36)	·                     94%* ·                     (n=32)
·                     Genotype 3	·                     30%* ·                     (n=64)	·                     62%* ·                     (n=63)
·                     Genotype 2, without cirrhosis	·                     96%* ·                     (n=26)	·                     100%* ·                     (n=23)
·                     Genotype 2, with cirrhosis	·                     60%* ·                     (n=10)	·                     78%* ·                     (n=9)
·                     Genotype 3, without cirrhosis	·                     37%* ·                     (n=38)	·                     63%* ·                     (n=40)
·                     Genotype 3, with cirrhosis	·                     19%* ·                     (n=26)	·                     61%* ·                     (n=23)
·                     *Confidence intervals not reported.

3.14   LONESTAR-2 was a single-arm open-label study that evaluated the efficacy and safety of sofosbuvir plus peginterferon alfa-2a and ribavirin for 12 weeks in treatment-experienced people with genotype 2 or 3 HCV, whose disease had no response to previous HCV treatment (15%), or had lost its initial response during or after previous HCV treatment (85%). The study included 1 site in the United States. The people in the study had a median age of 56 years (age range 39 to 72 years); 68% were men; the mean baseline HCV RNA level was 6.2 log₁₀ IU/ml (range from 4.0 to 7.2 log₁₀ IU/ml); 55% had cirrhosis; 51% had genotype 3 HCV.

3.15   Results from LONESTAR-2 showed that sustained virological response 12 weeks after the end of treatment was 89% (no confidence intervals reported in manufacturer’s submission) in people with genotype 2 or 3 HCV. HCV genotype and cirrhosis were not associated with statistically significant differences in sustained virological response. At 12 weeks after the end of treatment, sustained virological response was 96% and 83% in people with genotype 2 and genotype 3 HCV respectively. In people with genotype 2 HCV without cirrhosis, sustained virological response at 12 weeks after the end of treatment was 100% and in people with cirrhosis it was 93%. In people with genotype 3 HCV, the sustained virological response was 83% for people with and without cirrhosis.

Treatment naive or treatment-experienced

3.16   VALENCE was an unblinded study in which all people with genotype 2 HCV received sofosbuvir plus ribavirin for 12 weeks, and those with genotype 3 HCV received sofosbuvir plus ribavirin for 24 weeks. Because of changes made during the study, 11 people with genotype 3 HCV received a 12‑week course of therapy. People in the study had a median age of 51 years (age range 19 to 74 years); 60% were men; the mean baseline HCV RNA level was 6.4 log₁₀ IU/ml; 21% had cirrhosis; 78% had genotype 3 HCV. In around 65% of treatment-experienced people, initial response was lost during previous treatment, in 28% response was lost after the end of previous treatment, and 7% were interferon intolerant.

3.17   Results from VALENCE showed that sustained virological response 12 weeks after the end of treatment for people with genotype 2 HCV receiving sofosbuvir plus ribavirin for 12 weeks was 93% (no confidence intervals were reported in manufacturer’s submission). In people with genotype 3 HCV who were treated for 24 weeks the sustained virological response 12 weeks after the end of treatment was 84% (no confidence intervals were reported in the manufacturer’s submission).

Population for whom interferon treatment was unsuitable (treatment naive and treatment-experienced)

3.18   POSITRON evaluated the efficacy and safety of sofosbuvir plus ribavirin compared with placebo for 12 weeks in people with genotype 2 or 3 HCV whose disease had not responded adequately to previous peginterferon-based treatment (the manufacturer referred to this group as “interferon intolerant”), who were interferon ineligible (for medical reasons), or who were unwilling to have interferon treatment. Collectively, the people in these 3 groups are described as ‘interferon unsuitable’ throughout this document. Similar proportions of people with genotype 2 and 3 HCV were enrolled (51% and 49% respectively) in the study. People were randomised in a 3:1 ratio to receive sofosbuvir plus ribavirin or placebo, and were stratified by the presence or absence of cirrhosis. The difference in sustained virological response at 12 weeks was assessed for superiority, which would be demonstrated if the p-value was less than 0.05. People treated in the study had a median age of 54 years (age range 21 to 75 years); 54% were men; 70% had baseline HCV RNA levels greater than 6 log₁₀ IU/ml; 16% had cirrhosis. The proportions of people who were interferon intolerant, ineligible, or unwilling were 9%, 44%, and 47% respectively. Most people had not received previous treatment for chronic hepatitis C (81.3%).

3.19   Results from POSITRON showed that HCV genotype and cirrhosis were associated with differences in sustained virological response in people treated with sofosbuvir plus ribavirin, as given in table 3. The difference in sustained virological response between the sofosbuvir plus ribavirin and the placebo group was statistically significant (p<0.001) for people with genotype 2 or 3 chronic HCV.

Table 3 Sustained virological response 12 weeks after the end of treatment from POSITRON

·	·                     Percentage of people with a sustained virological response 12 weeks after end of treatment
·	·                     Sofosbuvir plus ribavirin for 12 weeks	·                     Placebo
·                     Genotype 2 or 3	·                     78% (95%CI 72 to 83%) ·                     (n=207)	·                     0% ·                     (n=71)
·                     Genotype 2	·                     93%* ·                     (n=109)	·                     - ·
·                     Genotype 3	·                     61%* ·                     (n=98)	·                     -
·                     Genotype 2, without cirrhosis	·                     92%* ·                     (n=92)	·                     -
·                     Genotype 2, with cirrhosis	·                     94%* ·                     (n=17)	·                     -
·                     Genotype 3, without cirrhosis	·                     68%* ·                     (n=84)	·                     -
·                     Genotype 3, with cirrhosis	·                     21%* ·                     (n=14)	·                     -
·                     *Confidence intervals not reported.

People with HIV and HCV co-infection

3.20   The safety and efficacy of 12 or 24 weeks of treatment with sofosbuvir plus ribavirin in people with genotype 1, 2 or 3 chronic hepatitis C who were also co-infected with HIV was evaluated in an open-label clinical study (PHOTON-1). People with genotype 2 or 3 HCV were either treatment-naive or treatment-experienced, whereas those with genotype 1 HCV were all treatment-naive. Sofosbuvir plus ribavirin was given for 12 weeks in treatment-naive people with genotype 2 or 3 HCV, and 24 weeks in treatment-experienced people with genotype 2 or 3 HCV and treatment-naive people with genotype 1 HCV. Participants were either not on antiretroviral therapy with a CD4+ cell count above 500 cells/mm³ or had virologically suppressed HIV-1 with a CD4+ cell count above 200 cells/mm³. At the time of enrolment, 95% of participants received antiretroviral therapy. Preliminary sustained virological response at 12 weeks was available for 210 people.

3.21   Results from PHOTON-1 showed that treatment with sofosbuvir plus ribavirin for 12 weeks in people with genotype 2 or 3 HCV and HIV co-infection and 24 weeks in people with genotype 1 HCV and HIV co-infection resulted in sustained virological response at 12 weeks after treatment irrespective of HCV genotype (≥93%; interim analysis). Similar safety and tolerability profiles were reported in people with HIV and HCV co-infection and in people with HCV only.

People awaiting liver transplant

3.22   An open-label clinical study (P7977-2025) in people with chronic hepatitis C awaiting a liver transplant, evaluated the safety and efficacy of sofosbuvir plus ribavirin administered before transplant to prevent post-transplant HCV reinfection. The primary end point of the study was post-transplant virological response (HCV RNA undetectable at 12 weeks after transplant). People with HCV regardless of genotype, with hepatocellular carcinoma eligible for liver transplant, received 400 mg sofosbuvir and 1000–1200 mg ribavirin daily for a maximum of 24 weeks. This was subsequently amended to 48 weeks or until the time of liver transplant, whichever occurred first. An interim analysis was conducted on 61 people who received sofosbuvir and ribavirin; most of whom had genotype 1 HCV. Of these people, 44 had a liver transplant up to 48 weeks after treatment with sofosbuvir and ribavirin; 41 had no detectable HCV RNA at the time of their transplant. Results suggested that treatment with sofosbuvir and ribavirin prevented HCV recurrence in 64% of people compared with a 100% historical risk of reinfection without prophylaxis. During treatment, HCV RNA suppression in people with well-compensated cirrhosis awaiting a liver transplant for hepatocellular carcinoma was rapid and similar to other patient populations treated with sofosbuvir regimens.

Adverse effects of treatment

3.23   The manufacturer presented data on adverse events for NEUTRINO, FISSION, FUSION, POSITRON and VALENCE. The most common adverse events among people receiving sofosbuvir and ribavirin therapy (with or without peginterferon alfa) were fatigue, headache, anaemia, nausea, insomnia, irritability, rash, pruritis, myalgia, decreased appetite, influenza-like illness, chills, pyrexia, and neutropenia. Among these events, fatigue and headache were usually the most frequent, affecting more than 40% of the people in some studies. In the studies comparing sofosbuvir plus ribavirin with placebo, common adverse events occurred more frequently or at similar frequencies in both groups, whereas in studies comparing sofosbuvir plus ribavirin with peginterferon alfa and ribavirin, the common adverse events that occurred in 10% or more of people in at least 1 group were consistently more frequent in the peginterferon alfa and ribavirin arms.

Health-related quality of life

3.24   The manufacturer assessed health-related quality of life during the phase II and III trials using the Chronic Liver Disease Questionnaire - Hepatitis C (CLDQ-HCV), the Functional Assessment of Chronic Illness Therapy-Fatigue measurement system (FACIT-F), the Work Productivity and Activity Impairment questionnaire (WPAI), or the Short Form-36 items survey (SF-36). The results from the NEUTRINO study indicated that there were differences in health-related quality of life scores between baseline and the end-of-treatment responses and that scores returned to baseline values by the post-treatment week‑12 visit. The results from the FISSION study indicated that health-related quality of life during treatment in people who received peginterferon alfa-2a plus ribavirin was statistically significantly lower than for people in the sofosbuvir plus ribavirin arm. No difference was observed between both arms 12 weeks after the end of each treatment. The CLDQ-HCV results from FUSION indicated that health-related quality of life scores did not decrease significantly in either treatment group and there were no significant differences in overall scores between the groups. The health-related quality of life data obtained from the POSITRON study showed decreases (worsening) in all SF-36 scales and the Mental Component and Physical Component scores in both treatment groups during treatment (baseline through to week 12). In the sofosbuvir plus ribavirin group the differences were statistically significant (p<0.001) from baseline in the Physical Function scale, Role Physical, Vitality, Social Functioning, Role Emotional, and Mental Health scales; however, there were no significant differences from placebo at any time point.

Mixed treatment comparison

3.25   The manufacturer conducted a mixed treatment comparison to explore the comparative data for sofosbuvir against other relevant comparators. Because of limited data, a mixed treatment comparison network could not be formed for all the relevant populations in the decision problem and the comparison was done only for treatment-naive interferon-eligible people with genotype 1, 2 or 3 HCV. In addition, the manufacturer’s economic model required that efficacy data were split by cirrhosis status and these data were not available for all trials. In people with genotype 1 HCV, a network including sofosbuvir was possible only by linking 2 small phase II trials (ATOMIC and PROTON) which included only people without cirrhosis. In people with genotype 2 or 3 HCV, the mixed treatment comparison results were based on people with and without cirrhosis combined. The results of the mixed treatment comparison showed that for treatment-naive people with genotype 1 HCV regardless of cirrhosis status, 84.9% of those treated with sofosbuvir plus peginterferon alfa and ribavirin for 12 weeks had a sustained virological response at 12 weeks after treatment, compared with 46.2% of people treated with peginterferon alfa and ribavirin for 48 weeks, 76.5% of people treated with telaprevir plus peginterferon alfa and ribavirin 69.7% of people treated with boceprevir plus peginterferon alfa and ribavirin. For treatment-naive people with genotype 2 HCV without cirrhosis, 98.6% of those treated with sofosbuvir plus peginterferon alfa and ribavirin for 12 weeks had a sustained virological response at 12 weeks after treatment, compared with 85.6% of people treated with peginterferon alfa and ribavirin for 24 weeks; for those with cirrhosis sustained virological response was achieved in 97.5% of people who received sofosbuvir plus peginterferon alfa and ribavirin, and in 67.5% of those who received peginterferon alfa and ribavirin. For treatment-naive people with genotype 3 HCV without cirrhosis, 62% of those treated with sofosbuvir plus peginterferon alfa and ribavirin for 12 weeks had a sustained virological response at 12 weeks after treatment, compared with 68.3% of people who were treated with peginterferon alfa and ribavirin for 24 weeks; for those with cirrhosis sustained virological response was similar (47.8% and 42.8% respectively) between the 2 treatment groups. The manufacturer highlighted several limitations to its mixed treatment comparison, and stated that the results could not be considered robust.

Evidence Review Group comments

3.26   The ERG reviewed the clinical evidence in the manufacturer’s submission. It considered that the manufacturer’s interpretation of the clinical evidence was overall justified and unbiased. However, the ERG cautioned that most of the evidence provided did not directly address the decision problem, because of the lack of head-to-head studies against current standard of care comparators. In addition, it highlighted that no studies were included that examined the efficacy of sofosbuvir within its licensed indication for treatment-experienced people with genotype 1 HCV. The ERG also noted that some of the evidence supporting the treatment regimens licensed for use in people with genotype 3 HCV (from VALENCE) should be interpreted with caution because randomisation was broken during the study, and some people were switched from 12 to 24 weeks of treatment with sofosbuvir plus ribavirin.

3.27   The ERG noted that the manufacturer only reported adverse events from the 5 phase 3 studies (NEUTRINO, FISSION, FUSION, POSITRON and VALENCE). Adverse events from the phase II studies were not included in the evidence submission; however the ERG confirmed that the adverse events in the phase II studies were similar to those in the phase III studies. Overall, the ERG was satisfied that the evidence indicated that treatment with sofosbuvir-based regimens was generally well tolerated and led to fewer adverse events than treatment with peginterferon alfa and ribavirin.

Cost effectiveness

3.28   The manufacturer identified 112 cost-effectiveness studies of chronic hepatitis C treatments. No studies were identified that compared sofosbuvir with alternative treatments.

3.29   To assess the cost effectiveness of sofosbuvir the manufacturer submitted a multi-state Markov model, which compared sofosbuvir plus ribavirin and sofosbuvir plus peginterferon alfa and ribavirin with the comparators defined in the decision problem (that is, boceprevir or telaprevir plus peginterferon alfa and ribavirin for people with genotype 1 HCV, and peginterferon alfa and ribavirin or placebo for people with other genotypes). The structure of the model was based on published health economic models, but was amended by the manufacturer to reflect the data available from its pivotal clinical trials and only distinguished between people with and without cirrhosis. The manufacturer used patient characteristics from the HCV research database to inform the population entering the model, including mean age at start of treatment, disease severity distribution and weight. The model had a total of 9 health states according to disease stage and treatment response. People entered the model in either the non-cirrhotic or compensated cirrhosis stages of disease. People who received antiviral treatment could move into the non-cirrhotic or sustained virological response cirrhotic health states. Those who did not clear the virus after treatment remained in their respective health states, or progressed to more severe stages of chronic HCV. The model assumed that people who experience a sustained virological response will not progress to more severe health states during or after therapy. Reversion to less severe health states was not permitted if treatment was unsuccessful.

3.30   The manufacturer applied age-specific general population mortality rates to each health state in the model. The same model structure was used for all patients irrespective of HCV genotype or treatment experience. For the first 2 years a 3-month cycle was used in the model, then the remaining cycles each lasted 1 year. A half-cycle correction was applied, which is consistent with previous hepatitis C appraisals. An NHS and personal and social services perspective was taken and a lifetime horizon was used, with costs and outcomes discounted at 3.5%.

3.31   Data from clinical trials were used to inform model inputs for treatment effects, health-related quality of life and adverse events. Treatment effect data were based on the sustained virological responses taken from the sofosbuvir clinical trials. If data for comparators were not available in these trials, they were taken from other published studies identified by the manufacturer. The manufacturer collected quality of life scores at baseline, week 12 during treatment, and at 4, 12 and 24 weeks after treatment. The SF-36 quality of life data were converted to SF-6D utility data and used in the manufacturer’s base case. The manufacturer also converted SF-36 to EQ-5D and incorporated these in a deterministic sensitivity analysis. Adverse event rates were obtained from the sofosbuvir clinical trials and published studies. The manufacturer incorporated the rates of grade 3 and 4 pruritus, diarrhoea and nausea, vomiting, rash, anaemia, thrombocytopenia, neutropenia, and depression from the trials into the model so that drug acquisition costs (from BNF 2014) could be assigned for interventions associated with managing these adverse events.

3.32   The manufacturer used transition probabilities for disease progression from 2 published UK health technology assessments and 1 UK study: Hartwell et al. (2011), Shepherd et al. (2007), and Grishchenko et al. (2009), which used estimates from the Trent database (a large sample of people with HCV who attended only non-tertiary centres in the UK).

3.33   Utility values estimated from the sofosbuvir clinical studies were not used to inform the model. Instead, the manufacturer used utility values from previous technology appraisals for hepatitis C treatments that were based on the UK trial of mild chronic hepatitis C by Wright et al. (2006). The manufacturer calculated treatment-related utilities by applying treatment-related utility decrements to the baseline utility estimates.

3.34   The manufacturer compared sofosbuvir plus ribavirin (with or without peginterferon alfa), telaprevir plus peginterferon alfa and ribavirin, boceprevir plus peginterferon alfa and ribavirin, peginterferon alfa plus ribavirin, and best supportive care. Sofosbuvir, telaprevir, boceprevir, peginterferon alfa-2a and ribavirin were used in the model according to their marketing authorisations. The manufacturer applied no stopping rules, lead-in phase, or option for sofosbuvir retreatment, in line with the sofosbuvir clinical trials.

3.35   The manufacturer used costs in the model that reflected the UK NHS perspective, comprising treatment-related costs (drug acquisition and patient monitoring), health-state costs and adverse event costs. Drug costs were based on the list price in the BNF (June 2013). The manufacturer used the BNF price of ribavirin (Copegus 400 mg, 56-tablet packs) at a cost of £246.65 in the model. Costs for the health states in the model were identified using published sources taken from the resource and costs systematic review conducted by the manufacturer. The costs of various drugs used to treat adverse events included in the model were sourced from the BNF (2014). The costs for the non-cirrhotic health state were based on a calculation of the costs associated with mild and moderate cirrhosis (Wright et al. [2006]) using an assumed 77%: 23% split between mild and moderate cirrhosis. Costs were inflated to 2011/12 prices (using the Hospital and Community Health Service pay and prices index).

3.36   Monitoring costs included resource unit costs of outpatient appointments, inpatient care, tests and investigations (virology, pathology, haematology, immunology, radiology) and procedures (liver biopsy). The source for monitoring costs was the National Schedule of Reference Costs or was taken from published studies or expert opinion.

Results

3.37   The manufacturer presented base-case analyses for sofosbuvir plus ribavirin with or without peginterferon alfa compared with current standard of care, based on HCV genotype, interferon eligibility and treatment history. The manufacturer’s results show that sofosbuvir treatment regimens increased the cost of treatment, but were associated with more quality-adjusted life years gained, a greater probability of sustained virological response (cure), and a reduction in end-stage liver disease and death.

Genotype 1

3.38   For treatment-naive, interferon-eligible people with genotype 1 HCV, the manufacturer’s base-case analysis showed that the ICER for sofosbuvir plus peginterferon alfa and ribavirin treatment for 12 weeks compared with peginterferon alfa and ribavirin treatment for 48 weeks was £14,930 per QALY gained (incremental cost £19,129; incremental QALYs 1.3). Boceprevir plus peginterferon alfa and ribavirin was dominated (a treatment is dominated when the treatment being considered is less expensive and more effective) and telaprevir plus peginterferon alfa and ribavirin was extendedly dominated (a treatment is extendedly dominated when its ICER is higher than that of the next, more effective option when compared with a common baseline). For treatment-naive people with genotype 1 HCV who were ineligible for, or unable to receive interferon treatment, the manufacturer’s base-case ICER for sofosbuvir plus ribavirin for 24 weeks compared with no treatment was £49,249 per QALY gained (incremental cost £63,903; incremental QALYs 1.3).

3.39   The manufacturer did not conduct an economic analysis for treatment-experienced people with genotype 1 HCV because there was no clinical evidence available to populate the economic model for this population.

Genotype 2

3.40   In treatment-naive, interferon-eligible people with genotype 2 HCV, the manufacturer’s base-case ICER for sofosbuvir plus peginterferon alfa and ribavirin treatment for 12 weeks compared with peginterferon alfa and ribavirin treatment for 48 weeks was £46,324 per QALY gained (incremental cost £27,779; incremental QALYs 0.6). In treatment-naive people with genotype 2 HCV who were ineligible for, or unable to receive interferon treatment, the manufacturer’s base-case ICER for sofosbuvir plus ribavirin for 12 weeks compared with no treatment was £8154 per QALY gained (incremental cost £20,051; incremental QALYs 2.5).

3.41   In treatment-experienced, interferon-eligible people with genotype 2 HCV, the manufacturer’s base-case ICER for sofosbuvir plus peginterferon alfa and ribavirin treatment for 12 weeks compared with peginterferon alfa and ribavirin treatment for 48 weeks was £9274 per QALY gained (incremental cost £21,498; incremental QALYs 2.3). In treatment-experienced people with genotype 2 HCV who were ineligible for, or unable to receive interferon treatment, the manufacturer’s base-case ICER for sofosbuvir with ribavirin treatment for 12 weeks compared with no treatment was £8591 per QALY gained (incremental cost £20,697; incremental QALYs 2.4).

Genotype 3

3.42   In treatment-naive, interferon-eligible people with genotype 3 HCV, the manufacturer’s base-case ICER for sofosbuvir plus peginterferon alfa and ribavirin treatment for 12 weeks compared with peginterferon alfa and ribavirin treatment for 48 weeks was £20,613 per QALY gained (incremental cost £24,970; incremental QALY 1.2). In treatment-naive people with genotype 3 HCV who were ineligible for, or unable to receive interferon treatment, the manufacturer’s base-case ICER for sofosbuvir plus ribavirin for 24 weeks compared with no treatment was £21,478 per QALY gained (incremental cost £55,137; incremental QALYs 2.6).

3.43   In treatment-experienced, interferon-eligible people with genotype 3 HCV, the manufacturer’s base-case ICER for sofosbuvir plus peginterferon alfa and ribavirin treatment for 12 weeks compared with peginterferon alfa and ribavirin treatment for 48 weeks was £8557 per QALY gained (incremental cost £19,634; incremental QALYs 2.3). In treatment-experienced people with genotype 3 HCV who were ineligible for, or unable to receive interferon treatment, the manufacturer’s base-case ICER for sofosbuvir plus ribavirin for 24 weeks compared with no treatment was £28,569 per QALY gained (incremental cost £58,828; incremental QALYs 2.1).

Genotypes 4, 5 or 6

3.44   In treatment-naive, interferon-eligible people with genotype 4, 5 or 6 HCV, the manufacturer’s base-case ICER for sofosbuvir plus peginterferon alfa and ribavirin treatment for 12 weeks compared with peginterferon alfa and ribavirin treatment for 48 weeks was £26,797 per QALY gained (incremental cost £23,942; incremental QALYs 0.9).

3.45   The manufacturer tested the robustness of the model using deterministic sensitivity analyses. Results showed that the ICERs were most sensitive to changes in the discount rate (varied between 0% and 6% for costs and outcomes simultaneously) and the utility increment after achieving a sustained virological response. The manufacturer concluded that the results of the deterministic sensitivity analyses showed that the ICERs for sofosbuvir remained below £20,000 per QALY gained in the following subgroups:

• treatment-naive and treatment-experienced people with genotype 2 HCV, for whom interferon treatment is unsuitable compared with no treatment
• treatment-experienced, interferon-eligible people with genotype 2 and 3 HCV compared with no treatment.

III   The results of the deterministic sensitivity analyses showed that the ICERs for sofosbuvir were between £20,000 and £30,000 per QALY gained in the following subgroups:

• treatment-naive, interferon-eligible people with genotype 1 HCV compared with peginterferon alfa and ribavirin and boceprevir plus peginterferon alfa and ribavirin
• treatment-experienced, interferon-eligible people with genotype 2 HCV compared with peginterferon alfa and ribavirin
• treatment-experienced, interferon-eligible people with genotype 3 HCV compared with peginterferon alfa and ribavirin.

IV  The results of the deterministic sensitivity analyses showed that the ICERs for sofosbuvir were above £30,000 per QALY gained in the following subgroups:

• treatment-naive, interferon-eligible people with genotype 1 HCV compared with telaprevir plus peginterferon alfa and ribavirin
• treatment-naive and people for whom interferon is unsuitable with genotype 3 HCV compared with no treatment
• treatment-naive, interferon-eligible people with genotype 3 HCV compared with peginterferon alfa and ribavirin.

3.46   The manufacturer also carried out probabilistic sensitivity analyses to explore parameter uncertainty. Although it did not draw any specific conclusions from the analyses, results suggested that sofosbuvir had less than a 50% probability of being cost effective in 6 of the base-case comparisons (at an ICER threshold of £20,000 per QALY gained).

3.47   During clarification, the manufacturer explored the effect of including a transition probability obtained from Cardoso et al. (2004) (0.005; 95% CI 0.013 and 0.002) from the sustained virological response cirrhotic health state to the hepatocellular carcinoma health state in the economic model, and varied the probability in line with the upper and lower limits of the 95% confidence interval. The ICERs from the manufacturer’s exploratory analyses were slightly higher than those estimated in the manufacturer’s base case (ranging from £7507 per QALY gained [in treatment-naive, interferon-eligible people with genotype 1 HCV for sofosbuvir plus peginterferon alfa and ribavirin compared with boceprevir plus peginterferon alfa and ribavirin] to £54,957 per QALY gained [in treatment-naive, interferon-eligible people with genotype 2 HCV for sofosbuvir plus ribavirin compared with 24 weeks of peginterferon alfa-2a and ribavirin treatment]).

HCV and HIV co-infected populations

3.48   The manufacturer provided a separate economic analysis for people co-infected with HIV and HCV. In treatment-naive, interferon-eligible people with HIV and genotype 1 HCV, the manufacturer’s base-case ICER for sofosbuvir plus ribavirin treatment for 24 weeks compared with no treatment was £28,504 per QALY gained, or £43,836 per QALY gained compared with peginterferon alfa-2a and ribavirin treatment for 48 weeks. The manufacturer’s base-case ICER for treatment-naive people with genotype 2 HCV and HIV-co-infection who received sofosbuvir plus ribavirin for 12 weeks compared with peginterferon alfa-2a and ribavirin treatment for 48 weeks was £55,867 per QALY gained. The manufacturer’s base-case ICER for treatment-experienced people with genotype 2 HCV and HIV co-infection, who received sofosbuvir plus ribavirin for 24 weeks compared with no treatment was £10,572 per QALY gained, or £128,248 per QALY gained compared with peginterferon alfa-2a and ribavirin treatment for 48 weeks. For treatment-naive people with genotype 3 HCV and HIV co-infection, 12 weeks of sofosbuvir plus ribavirin dominated treatment with peginterferon alfa and ribavirin. In treatment-experienced people with genotype 3 HCV and HIV co-infection the ICERs for 24 weeks of sofosbuvir plus ribavirin were £10,646 per QALY gained compared with no treatment and £90,822 per QALY gained compared with peginterferon alfa-2a and ribavirin for 48 weeks. The manufacturer did not provide an economic analysis for people co-infected with HIV and genotype 4, 5, or 6 HCV.

Evidence Review Group comments

3.49   The ERG reviewed the manufacturer’s model and economic systematic review. The ERG considered that the manufacturer’s methods of economic evaluation and the model produced were acceptable. It validated the manufacturer’s model by comparing the total costs and QALYs predicted by the model for the treatment-naive interferon-eligible genotype 1 HCV population with the corresponding figures for treatment with peginterferon alfa plus ribavirin with and without boceprevir or telaprevir obtained from the previous NICE technology appraisals for boceprevir for the treatment of genotype 1 chronic hepatitis C (NICE technology appraisal guidance 253) and telaprevir for the treatment of genotype 1 chronic hepatitis C (NICE technology appraisal guidance 252). The ERG found that the manufacturer’s model for sofosbuvir was broadly consistent with previous models considered in NICE technology appraisals for hepatitis C, in terms of total costs and QALYs assumed for peginterferon alfa and ribavirin, and for telaprevir. However, the ERG noted that there was a discrepancy between models in the total costs estimated for boceprevir, but it was not able to account for the differences without reviewing the data used in the boceprevir submission. The ERG also considered that the manufacturer’s economic model captured most of the important aspects of the disease pathway but noted that it does not include a transition from the sustained virological response-cirrhotic health state to the hepatocellular carcinoma health state, which has been previously included in other hepatitis C models. Despite this omission from the manufacturer’s model, the ERG showed that it did not affect the base-case ICERs substantially. The ERG considered that the manufacturer’s model extrapolates intermediate outcomes to final outcomes in a consistent way, drawing on standard sources from the literature.

3.50   The ERG noted that the transition probabilities used by the manufacturer in its economic model for the HCV and HIV co-infected population from non-cirrhotic to compensated cirrhosis health states were higher than those assumed for the mono-infected population. The ERG further noted that people with HCV and HIV co-infection are likely to have a higher mortality rate than the population with HCV only, regardless of sustained virological response, and this is not currently taken into account in the manufacturer’s model. The ERG noted that a study by Van Der Helm et al. (2013) had concluded that the effects of HCV treatment on HIV progression needed to be evaluated further. Therefore, in the ERG’s opinion the evidence needed to accurately evaluate the cost-effectiveness of sofosbuvir in the HCV and HIV co-infected population was not currently available.

Additional exploratory ERG analyses

3.51   The ERG undertook several exploratory analyses, which included:

• adding a transition probability from the sustained virological response cirrhotic health state to the hepatocellular carcinoma health state and exploring the effect of using different transition probabilities between these 2 health states
• assessing the effect on the ICERs of variations to all-cause mortality probabilities
• evaluating the effect of changing the average age of entry into the model
• using a range of alternative sustained virological response estimates from studies of comparator treatments
• assessing the effect of an alternative distribution of people with cirrhosis
• exploring the effect of the number of people receiving 24 weeks of sofosbuvir treatment compared with those receiving 12 weeks
• assessing the effect of using alternative utility increments after sustained virological response.

3.52   The ERG heard from its clinical advisers that a transition from the sustained virological response cirrhotic health state to the hepatocellular carcinoma health state should be included in models for chronic hepatitis C to reflect the clinical course of the disease. The ERG noted that this transition was not included in the manufacturer’s economic model. In addition, the ERG was unable to calculate the transition probability (0.005) between these two health states used by the manufacturer in its response to clarification based on a study by Cardoso et al. (2010) (see section 3.47). The ERG recalculated the transition probability using the Cardoso et al. study, to produce a value of 0.0123 (95% CI 0.028 to 0.0218). The effect of including this value (and also the upper and lower confidence interval values) was explored by the ERG in a sensitivity analysis to produce ICERs ranging from £7593 per QALY gained [in treatment-naive, interferon-eligible people with genotype 1 HCV for sofosbuvir plus peginterferon alfa and ribavirin compared with boceprevir plus peginterferon alfa and ribavirin] to £60,887 per QALY gained [in treatment-naive, interferon-eligible people with genotype 2 HCV for sofosbuvir plus peginterferon alfa and ribavirin compared with 24 weeks of peginterferon alfa-2a and ribavirin treatment]).

3.53   The ERG noted that the manufacturer used the simple average of mortality from men and women to calculate the age-specific mortality used in the model. The ERG commented that men are more likely to be treated in clinical practice in England, therefore a weighted average should have been used. During clarification, the manufacturer re-ran their economic model with weighted average mortality probabilities, but did not indicate what weights were used to obtain its results. The ERG conducted an exploratory analysis using a weighting of 61% men and 39% women as used in Wright et al. (2006). The ICERs from the ERG’s exploratory analyses were slightly higher than those estimated in the manufacturer’s base case (ranging from £7453 per QALY gained [in treatment-naive, interferon-eligible people with genotype 1 HCV for sofosbuvir compared with boceprevir plus peginterferon alfa and ribavirin] to £50,083 per QALY gained [in treatment–naive people for whom interferon is unsuitable with genotype 1 HCV for sofosbuvir compared with no treatment]).

3.54   The ERG noted that the manufacturer’s model used an efficacy estimate drawn from a single source in instances when multiple efficacy estimates were available for the same treatment and indication. NICE asked the ERG to carry out further exploratory analyses to inform the Appraisal Committee’s understanding of the effect on the manufacturer’s ICERs of using a range of alternative sustained virological response estimates from studies of comparator treatments. For treatment-naive people with genotype 1 HCV, the ERG used alternative estimates of sustained virological response for boceprevir plus peginterferon alfa-2b and ribavirin from the SPRINT-2 study in line with estimates used in the NICE technology appraisal of boceprevir (that is, 68.2% for people with no cirrhosis and 41.7% for people with cirrhosis compared with the manufacturer’s base case values of 64.1% for people with no cirrhosis and 55.0% for people with cirrhosis). Applying the alternative sustained virological response estimates for boceprevir gave a lower ICER than the manufacturer’s base case (the ICER was not reported by the ERG in its additional analyses).

3.55   The ERG also used alternative sustained virological response estimates for the treatment-naive, interferon-eligible genotype 3 HCV subgroup. First, the ERG modelled the effect of an alternative sustained virological response of 90.7% for sofosbuvir plus peginterferon alfa-2a and ribavirin. This response was the lower end of the 95% confidence interval for the population with no cirrhosis from the sofosbuvir trials (an estimate of 97.4% was used in the manufacturer’s base case, an average of the sustained virological response from ELECTRON and PROTON). The resulting ICER for sofosbuvir plus peginterferon alfa-2a and ribavirin compared with peginterferon alfa-2a and ribavirin for this subgroup was £23,772 per QALY gained (compared with the manufacturer’s base-case ICER of £20,613 per QALY gained). The ERG also explored the effect of an alternative sustained virological response of 92.3% for sofosbuvir plus peginterferon alfa-2a and ribavirin in treatment-naive people with genotype 3 HCV and cirrhosis. Applying this alternative response lowered the ICER to £18,187 per QALY gained.

3.56   The ERG also explored the effect of alternative assumptions about the natural history of chronic hepatitis C infection on the manufacturer’s ICERs. In particular, it investigated the effect of assuming an alternative distribution of people with cirrhosis. The ERG used a distribution for people with new and existing cirrhosis obtained from Hartwell et al. (2011) based on data from a London teaching hospital where 32% of existing patients with HCV and 10% of new patients with HCV had cirrhosis. The results of the exploratory analysis suggested that using this distribution increased the manufacturer’s base-case ICERs for treatment-naive people and reduced the ICERs for treatment-experienced people across all genotypes. In treatment-naive people with genotype 3 HCV who were interferon eligible, the ICER for sofosbuvir plus peginterferon alfa-2a and ribavirin (12 weeks) compared with peginterferon alfa and ribavirin (24 weeks) increased from £20,613 per QALY gained in the manufacturer’s base case to £30,175 per QALY gained. The ICERs for treatment-naive people with genotype 1 HCV remained above £30,000 per QALY gained (irrespective of interferon eligibility). Results for all other subgroups remained below £30,000 per QALY gained.

3.57   The ERG explored the effect of using a lower transition probability from the non-cirrhotic health state to the compensated cirrhosis health state, at age 40 years in the manufacturer’s model. The resulting ICERs increased across all subgroups and were higher than those estimated in the manufacturer’s base case (ranging from £9458 per QALY gained [in treatment-naive, interferon-eligible people with genotype 1 HCV for sofosbuvir compared with boceprevir plus peginterferon alfa and ribavirin] to £61,077 per QALY gained [in treatment-naive people with genotype 1 HCV, for whom interferon treatment is unsuitable for sofosbuvir compared with no treatment]).

3.58   The ERG explored the effect on the manufacturer’s base-case ICERs of varying the percentage of people receiving 24 weeks of sofosbuvir treatment compared with those receiving 12 weeks of treatment. The 3 subgroups who might receive 12 or 24 weeks of sofosbuvir treatment according to the marketing authorisation are people with:

• genotype 1 HCV, receiving sofosbuvir plus peginterferon alfa and ribavirin
• genotype 2 HCV, receiving sofosbuvir and ribavirin
• genotype 3 HCV, receiving sofosbuvir plus peginterferon alfa and ribavirin.

V   The ERG’s clinical specialists differed in their opinions about how long these groups would be treated. One clinical specialist stated that it would be unlikely that more than 1–2% of people would be considered better off with longer therapy and that these people would be identified in the summary of product characteristics as needing consideration for longer treatment periods. Another clinical specialist stated that at least 20% of people might need 24 weeks of therapy, especially those who are interferon intolerant or have severe cirrhosis.

3.59   The ERG pointed out that the manufacturer’s economic model allows for 12 week regimens for sofosbuvir plus ribavirin only for treatment-naive people with genotype 1 HCV who are interferon eligible and treatment-naive people with genotype 2 HCV (regardless of interferon eligibility). The economic model did have a 24 week regimen of sofosbuvir and ribavirin available for various genotype 3 HCV subgroups. The ERG therefore compared sofosbuvir plus ribavirin for 24 weeks with either peginterferon alfa and ribavirin treatment for 24 weeks in treatment-naive people with genotype 3 HCV and either no treatment or 48 weeks of peginterferon alfa and ribavirin treatment for treatment-experienced people with genotype 3 HCV. The resulting ICERs were more than double the manufacturer’s base-case results (which assumed only 12 weeks of sofosbuvir and ribavirin is given for these patient groups).

3.60   The ERG conducted sensitivity analyses to evaluate the effect of changing the average age of entry into the model. The resulting ICERs generally decreased when a lower average age of 35 years was selected for entry into the model, and were higher when the average age selected was 55 years. The lowest ICERs ranged from £6717 per QALY gained (using 35 years) to £9170 per QALY gained (using 55 years) in treatment-naive, interferon-eligible people with genotype 1 HCV for sofosbuvir compared with boceprevir plus peginterferon alfa and ribavirin. The highest ICERs ranged from £47,254 per QALY gained (using 35 years) to £60,976 per QALY gained (using 55 years) in treatment-naive, interferon-eligible people with genotype 2 HCV for sofosbuvir compared with 24 weeks of peginterferon alfa-2a and ribavirin treatment.

3.61   The ERG also conducted sensitivity analyses to explore the effect on the manufacturer’s ICERs of using different utility increments (0 and 0.04 [taken from Vera-Llonch et al. 2013], compared with the manufacturer’s estimate of 0.05) after sustained virological response. The resulting ICERs in the ERG’s sensitivity analysis were consistently higher than the manufacturer’s base-case results. When using a utility increment of 0.04, the ICERs ranged from £7899 per QALY gained in treatment-naive, interferon-eligible people with genotype 1 HCV for sofosbuvir compared with boceprevir plus peginterferon alfa and ribavirin to £53,793 per QALY gained in treatment-naive people with genotype 1 HCV, for whom interferon treatment is unsuitable, for sofosbuvir compared with no treatment. When using a utility increment of 0, the ICERs ranged from £12,732 per QALY gained in treatment-naive, interferon-eligible people with genotype 1 HCV for sofosbuvir compared with boceprevir plus peginterferon alfa and ribavirin to £92,795 per QALY gained in treatment-naive people with genotype 1 HCV, for whom interferon treatment is unsuitable, for sofosbuvir compared with no treatment.

3.62   The ERG also explored the effect on the manufacturer’s base-case ICERs for treatment-naive, interferon-eligible people with genotype 1 HCV when alternative estimates of sustained virological response for peginterferon alfa plus ribavirin to those used by the manufacturer from McHutchison et al. (2009) were applied. The ERG used estimates from Roberts et al. (2009) which reported a sustained virological response of 55% for people without cirrhosis and 24% for people with cirrhosis, and from Hadziyannis et al.(2004) which were56% and 38% respectively. Using the estimates from Roberts et al. the manufacturer’s ICER for sofosbuvir plus peginterferon alfa and ribavirin compared with peginterferon alfa and ribavirin increased to £18,209 per QALY gained. Similarly, the base-case ICER increased to £21,848 per QALY gained for the same comparison when estimates from Hadziyannis et al. were used.

3.63   The ERG also conducted a scenario analysis that considered the combined impact on the manufacturer’s ICERs of including a transition from the sustained virological response cirrhotic health state to hepatocellular carcinoma health state, alternative utility increments after a sustained virological response, and an alternative estimate of efficacy for peginterferon alfa and ribavirin in the HCV genotype treatment-naive, interferon-eligible population (using values described in sections 3.52, 3.61and 3.62). The ICERs from the ERG’s exploratory analyses were higher than those estimated in the manufacturer’s base case (ranging from £9415 per QALY gained [in treatment-naive, interferon eligible people with genotype 1 HCV for sofosbuvir plus peginterferon alfa and ribavirin compared with boceprevir plus peginterferon alfa and ribavirin] to £109,526 per QALY gained [in treatment-naive people for whom interferon is unsuitable with genotype 1 HCV for sofosbuvir plus ribavirin compared with no treatment]).

3.64   Full details of all the evidence are in the manufacturer’s submission and the ERG report

 

4   Consideration of the evidence

VI   The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of sofosbuvir, having considered evidence on the nature of chronic hepatitis C and the value placed on the benefits of sofosbuvir by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.

4.1   The Committee heard from the clinical specialists that chronic hepatitis C is often clinically asymptomatic, and that it is estimated to be undiagnosed in approximately 50% of people with the condition in England. However, when the condition progresses and cirrhosis occurs, it has a significant daily effect on the person with the virus and their carers. The Committee acknowledged the concerns of the patient experts that there is a stigma attached to having chronic hepatitis C, because of its link to injectable drug use. In addition, there is a reluctance to treat chronic hepatitis C in people who use injectable drugs, partly because of mistaken beliefs that they do not adhere to treatment and often become re-infected. The Committee heard from the patient experts that the availability of sofosbuvir and other new treatments that are expected to become available over the next 5 years will encourage more people with hepatitis C to seek diagnosis and treatment. In addition, people who use injectable drugs whose chronic hepatitis C is successfully treated may go on to address their drug use, leading to broader societal benefits that are not captured in the manufacturer’s evidence submission. The Committee recognised the effect of chronic hepatitis C on the lives of people with the virus, and concluded that treatments that give a sustained virological response (which is considered equivalent to a cure), and that consequently help reduce the rate of HCV transmission and the stigma associated with having chronic hepatitis C, are of significant importance.

4.2 The Committee discussed the clinical management of chronic hepatitis C in adults. It heard from the clinical specialists that different treatment options can have varied results, depending on the person’s HCV genotype, level of liver damage, comorbidities and previous treatment history. For people with genotype 1 chronic hepatitis C, the Committee heard that boceprevir plus peginterferon alfa and ribavirin (Boceprevir for the treatment of genotype 1 chronic hepatitis C [NICE technology appraisal guidance 253]) or telaprevir plus peginterferon alfa and ribavirin (Telaprevir for the treatment of genotype 1 chronic hepatitis C [NICE technology appraisal guidance 252]) are commonly used, and that for people with genotypes 2 to 6 HCV, peginterferon alfa plus ribavirin or watchful waiting (closely monitoring the condition but not giving any treatment) are currently the main treatment options. The clinical specialists highlighted that interferon-based treatment can be associated with side effects such as chronic fatigue, neuropsychological effects and flu-like symptoms, which can be a barrier to people wanting to start treatment, or taking their treatment for the recommended duration. The Committee also heard from the patient experts that interferon-based treatment may cause chronic side effects, such as autoimmune responses and thyroid problems, which need additional long-term management and therefore pose another barrier to people starting and completing treatment. The Committee acknowledged that the marketing authorisation for sofosbuvir offers people the option to receive shortened courses of peginterferon alfa and ribavirin, or in some circumstances to receive treatment without peginterferon alfa, thereby reducing potential side effects with interferon-based therapy. The Committee agreed with the clinical specialists and patient experts that the option to receive a shortened course of interferon-based therapy with sofosbuvir, or the possibility of sofosbuvir being used without peginterferon alfa in some circumstances, would make it a valuable treatment option for people with chronic hepatitis C.

4.3   The Committee acknowledged that the UK marketing authorisation for sofosbuvir allows for use in adults with chronic hepatitis C irrespective of genotype. It heard from the clinical specialists that in England, most people with chronic hepatitis C have genotypes 1 or 3 HCV (46% and 43% respectively), with genotype 1 HCV being associated with a poor response to antiviral therapy and an increased rate of progression to severe chronic liver disease. The Committee noted that the marketing authorisation also allows sofosbuvir to be used in people who have and have not been previously treated for chronic hepatitis C. The Committee heard from the clinical specialists that sofosbuvir is an important new treatment which will address an unmet need particularly in people who have previously been treated but did not have a sustained virological response, in people whose condition has relapsed, or in people who have become re-infected after treatment. The Committee concluded that most people with chronic hepatitis C are likely to have at least some benefit from adding sofosbuvir to their treatment regimen.

Clinical effectiveness

4.4   The Committee considered the clinical effectiveness of sofosbuvir plus ribavirin, with or without peginterferon alfa for treatment-naive and treatment-experienced people with genotype 1–6 chronic hepatitis C. It noted the concerns of the Evidence Review Group (ERG) that because of the lack of head-to-head studies against current standard of care comparators, most of the evidence provided by the manufacturer did not directly address the decision problem. The Committee acknowledged that the manufacturer was able to provide evidence from only 1 head-to-head trial (FISSION, in treatment-naive, interferon eligible people with genotype 2 or 3 HCV; sections 3.8-3.9) that was consistent with the decision problem. In addition, the Committee expressed concern about the robustness of the estimates of the clinical effectiveness of sofosbuvir across the different subgroups for which it is licensed, given that most trials were single-arm and open-label with historical controls that only included small patient numbers and provided short-term data. The Committee heard from the clinical specialists that current standard of care has been used for many years in the UK, and has been supported by numerous trials; therefore it was not unreasonable to use historical controls. The specialists also commented that hepatitis C trials are often open-label because some people realise they are taking an interferon-based regimen, potentially making blinding difficult. Furthermore, the clinical specialists highlighted to the Committee that, in their opinion, the inclusion criteria for the sofosbuvir trials were broader than for previous trials in hepatitis C; therefore there was good reason to expect that the people in the trials reflected those who are currently being treated in UK clinical practice. The Committee was aware that the number of people with cirrhosis in the clinical trials was small, and exclusion criteria meant that people who use injectable drugs were not included in any studies. The Committee acknowledged the limitations in conducting trials for hepatitis C, and concluded that there was considerable uncertainty surrounding the evidence base presented by the manufacturer, and therefore the true magnitude of the effect of sofosbuvir in each subgroup could not be robustly estimated.

4.5   The Committee acknowledged that in the NEUTRINO trial, treatment-naive people with genotype 1 (89% of people in the trial), 4, 5 or 6 HCV who received sofosbuvir plus peginterferon alfa and ribavirin had a high sustained virological response (91%) 12 weeks after treatment compared with the historical control of 60% that was presented by the manufacturer. However, it noted that no data were available on the clinical effectiveness of sofosbuvir in treatment-experienced people with these genotypes. The Committee heard from the clinical specialists that there was no reason to suspect that response in the treatment-naive population would differ from that in treatment-experienced people. However, the Committee was aware that other studies presented by the manufacturer for genotype 2 or 3 HCV showed that sustained virological response after treatment with sofosbuvir in treatment-naive people was generally better than in treatment-experienced people. Acknowledging the lack of evidence presented for treatment-experienced people with genotype 1, 4, 5 or 6 HCV, the Committee concluded that it was unable to make a recommendation on the use of sofosbuvir for these subgroups.

4.6   The Committee also discussed the design of the clinical trials for sofosbuvir plus ribavirin in people with genotype 2 and 3 HCV. It noted that the main trial evidence came from 4 trials (FISSION [treatment-naive, interferon-eligible people], FUSION [treatment-experienced people], POSITRON [treatment-naive and treatment-experienced, interferon ineligible, intolerant or unwilling people] and VALENCE [treatment-naive and treatment-experienced people]. The Committee acknowledged that FISSION was the only trial with an active comparator (peginterferon alfa-2a and ribavirin treatment for 24 weeks) but noted that it was an open label study which was susceptible to the introduction of selection bias and that when broken down by genotype and cirrhosis status, the results were based on small patient numbers. The Committee was also aware that sustained virological response in the combined study population was 67% in both the sofosbuvir plus ribavirin 12 week treatment arm and in the peginterferon alfa-2a and ribavirin 24 week treatment arm. The Committee was aware that all 4 trials in people with genotype 2 and 3 HCV had small patient numbers and different designs, and concluded that these factors introduced substantial uncertainty around the clinical effectiveness of sofosbuvir and must be taken into account when interpreting the clinical trial results.

4.7   The Committee considered the trial results for genotypes 2 and 3 HCV, which showed that longer treatment with sofosbuvir was needed for treatment-naive people with genotype 3 HCV (24 weeks rather than 12 weeks) to obtain a comparable sustained virological response to that seen in people with genotype 2 HCV (data not shown; academic-in-confidence). This was also supported by the results of the FISSION trial which showed that the sustained virological response for 12 weeks treatment with sofosbuvir and ribavirin in people with genotype 3 HCV was consistently lower than those seen in people with genotype 3 HCV receiving peginterferon alfa-2a and ribavirin for 24 weeks. The Committee also discussed the clinical effectiveness of sofosbuvir in treatment-experienced people with genotype 2 and 3 HCV, noting that the evidence for this subgroup came from the FUSION trial (which compared sofosbuvir plus ribavirin for 12 weeks [plus placebo for an extra 4 weeks] with sofosbuvir and ribavirin for 16 weeks), and from subpopulations within the VALENCE trial. The Committee noted that sustained virological response was consistently higher for people with genotype 2 HCV (86% and 94% in the 12 week and 16 week treatment groups in the FUSION trial; 93% after 12 weeks treatment in the VALENCE trial) than for people with genotype 3 HCV, who needed longer treatment with sofosbuvir and ribavirin (16 weeks and 24 weeks) for a similar response to be shown. The Committee acknowledged that people with cirrhosis also generally had a lower response than those without cirrhosis (irrespective of genotype). The Committee considered that treatment with sofosbuvir plus ribavirin was likely to lead to better sustained virological response in people with genotype 3 HCV compared with current standard of care (24 weeks of peginterferon alfa and ribavirin treatment), but only when sofosbuvir plus ribavirin treatment was extended to 24 weeks. In addition, the Committee considered it was plausible that sustained virological response in people with genotype 2 HCV after treatment with sofosbuvir plus ribavirin was likely to be better than the current standard of care when administered for 12 weeks. However, taking into account the limitations of the trial designs and the use of historical controls, the Committee concluded that there was considerable uncertainty around the true magnitude of benefit of sofosbuvir treatment regimens compared with standard of care.

4.8   The Committee considered the available evidence for sofosbuvir plus ribavirin in people co-infected with chronic hepatitis C and HIV. It noted that the interim analysis presented by the manufacturer was from an ongoing open-label study (PHOTON-1), which included people with genotype 1, 2 or 3 HCV and HIV who had not received previous treatment for hepatitis C, and people with genotype 2 or 3 HCV and HIV who had been previously treated. The Committee concluded that although there were limited data for the subgroups with HCV and HIV co-infection, the interim analysis presented suggests that the efficacy of sofosbuvir plus ribavirin is similar to that reported for people with chronic hepatitis C mono-infection, although they were mindful that the benefits of treatment were likely to be lessened because of complications and higher morbidity associated with HIV infection.

4.9   The Committee considered the adverse reactions associated with sofosbuvir plus ribavirin with and without peginterferon alfa. It noted that the adverse events reported in the main sofosbuvir clinical studies (NEUTRINO, FISSION, FUSION, POSITRON and VALENCE) were generally consistent with those reported in other studies for hepatitis C treatments. It heard from the clinical specialists that sofosbuvir is assumed to have a better safety profile than peginterferon alfa and ribavirin, and most adverse events reported in the trials were likely to be related to treatment with peginterferon alfa and ribavirin rather than sofosbuvir. The Committee concluded that the adverse reactions associated with sofosbuvir plus peginterferon alfa and ribavirin were generally tolerable and that sofosbuvir was not likely to cause additional adverse reactions compared with existing treatment regimens.

4.10 The Committee discussed the manufacturer’s mixed treatment comparison. It heard from the manufacturer that a network could not be formed for all the relevant populations and a comparison could be performed only for treatment-naive people with genotypes 1, 2 and 3 HCV because of data limitations. Therefore, results from the mixed treatment comparison were not used to inform the economic model. Instead the manufacturer adopted a conservative approach and used trial data that reported the highest sustained virological response for the comparators. The Committee agreed with the ERG’s view that the mixed treatment comparison conducted by the manufacturer was not robust and therefore it was reasonable for the manufacturer not to use it to inform its cost-effectiveness analyses.

 Cost effectiveness

4.11   The Committee considered the manufacturer’s economic model, the assumptions underlying the values of the parameters, and the critique and exploratory analyses conducted by the ERG. The Committee noted that the manufacturer’s model structure differed slightly from that used in previous technology appraisals for hepatitis C, in that people with mild and moderate chronic hepatitis C were considered collectively as a population without cirrhosis, and therefore the model distinguished only between people with and without cirrhosis. The Committee heard from the clinical specialists that this approach was reasonable and consistent with how people are currently diagnosed in clinical practice. Previously, people had invasive liver biopsies and as a result their disease was classified as mild, moderate or severe. However, current practice involves the use of less invasive diagnostic tests that do not differentiate between mild and moderate disease and can distinguish only between cirrhosis and non-cirrhosis. The Committee acknowledged that the ICERs from the manufacturer’s economic model were a weighted average of people with and without cirrhosis. The Committee agreed that overall the manufacturer’s model structure adhered to the NICE reference case for economic analysis, but concluded that individual ICERs presented for each subgroup by cirrhosis status would be useful in fully assessing the cost effectiveness of sofosbuvir.

4.12   The Committee discussed the manufacturer’s base-case assumptions used in the economic model. It noted that people entered the model at 45 years, had an average weight of 79 kg and that the number of men and women were assumed to be equal in proportion. The Committee heard from the ERG that these assumptions were consistent with other appraisals previously carried out for hepatitis C, and therefore in the ERG’s opinion were reasonable for the base-case analysis. However, the Committee acknowledged that more than 60% of people with chronic hepatitis C in England are men, and therefore it considered that it would have been useful for the manufacturer to include in its base-case analysis a sensitivity analysis that considered the effect on the ICER of assuming more men than women enter the model. The Committee acknowledged the exploratory analyses conducted by the ERG, which modelled the effect on the ICERs of varying the starting age in the model from 35 to 55 years, and including weighted average mortality probabilities by assuming the cohort comprised 61% men and 39% women. It concluded that although changes to these assumptions had minimal effect on the base-case ICERs, these assumptions were more generalisable to the UK population with chronic hepatitis C and more accurately reflected the age statistics for England.

4.13   The Committee acknowledged that the manufacturer did not allow for transition from the sustained virological response cirrhotic health state to the hepatocellular carcinoma health state in its model, despite this transition being included in previous models in other hepatitis C technology appraisals. The Committee noted that during clarification, the manufacturer incorporated this transition in its model using data from Cardoso et al. (2010), but that an incorrect transition probability had been calculated (0.005 [95% CI 0.001 to 0.014]. The Committee acknowledged that the ERG calculated the correct transition probability from the Cardoso study (that is, 0.0123 [95% CI 0.028 to 0.0218]) and that when this was included in the ERG’s exploratory analyses, the manufacturer’s base-case ICERs increased. The Committee agreed with the ERG and manufacturer that using the transition probability from Cardoso et al. was reasonable, as it falls within the range of values used in previous appraisals for chronic hepatitis C. The Committee therefore concluded that any subsequent analyses presented by the manufacturer should explore the effect of this transition probability in the base case, and sensitivity analyses using the upper and lower limits of the 95% confidence interval should be conducted.

4.14   The Committee noted that the manufacturer had not considered the effect of using alternative sustained virological responses for peginterferon alfa and ribavirin in its model, despite the fact that different estimates were available from published sources. The Committee considered the exploratory analyses conducted by the ERG, which used higher sustained virological response rates taken from Hadziyannis et al. for peginterferon alfa and ribavirin compared with those in the manufacturer’s model which used McHutchinson et al. (2009), and noted that, when included, they increased the base-case ICERs for treatment-naive people with genotype 1 HCV (see section 3.61). The Committee considered the estimates from the Hadziyannis study were most generalisable to patients with HCV in England, because the study included people with the genotypes most relevant to the UK population, that is, genotypes 1 and 3. The Committee concluded that the impact of alternative sustained virological responses for peginterferon alfa and ribavirin should have been taken into account in the manufacturer’s sensitivity analyses, and suggested that any subsequent analyses should explore the impact on the ICER of alternative estimates, including those from Hadziyannis et al.

4.15   The Committee considered the cost of ribavirin used in the manufacturer’s model. The Committee noted that the manufacturer used the cost of ribavirin (Copegus) available in the BNF. However, the Committee was aware that ribavirin is available nationally through contracts negotiated by the NHS Commercial Medicines Unit, and that the average price of ribavirin paid for by NHS Trusts over the last 12 months was £42.05(Department of Health, Commercial Medicines Unit, Electronic Market Information Tool). The Committee noted that this price is lower than the price used in the manufacturer’s model and concluded that the manufacturer should include this generic cost in any subsequent sensitivity analyses to explore its impact on the cost-effectiveness of sofosbuvir treatment.

4.16   The Committee noted that the marketing authorisation for sofosbuvir allows the treatment duration to be extended from 12 weeks to 24 weeks for people with genotype 3 HCV. The Committee noted that the possibility of extending treatment to 24 weeks was not accounted for in the manufacturer’s model. It heard from the clinical specialists that it is plausible that at least 20–30% of people, such as those with cirrhosis or who have interferon-intolerance, may need extended treatment. The Committee noted exploratory analyses conducted by the ERG that modelled the effect on the manufacturer’s base-case ICERs of increasing sofosbuvir plus ribavirin treatment from 12 to 24 weeks in people with genotype 3 HCV. In treatment-naive people the manufacturer’s ICER increased from £20,600 to £46,700 per QALY gained compared with 24 weeks of peginterferon alfa and ribavirin; whereas in treatment-experienced people the manufacturer’s ICER increased from £8,600 to £28,400 per QALY gained compared with 48 weeks of peginterferon alfa and ribavirin. The Committee concluded that the duration of treatment with sofosbuvir had a considerable effect on the ICERs in people with genotype 3 HCV, and therefore an extended treatment duration should have been accounted for by the manufacturer in its economic model by assuming that up to 100% of people with genotype 3 can receive sofosbuvir for 24 weeks.

4.17   The Committee discussed the proportion of people with genotypes 1, 3, 4, 5 or 6 HCV who might be unwilling to have treatment with interferon-based regimens. The Committee considered that as more interferon-free treatment options become available, people who are eligible for interferon may decide they would prefer to avoid it. The Committee heard from the patient expert that some people are already deferring treatment to avoid the known adverse effects associated with interferon treatment. The Committee noted that the potential increase in uptake of sofosbuvir and ribavirin therapy (without peginterferon alfa) was not explored by the manufacturer in any scenario analyses, even though it was likely to substantially affect the cost effectiveness of sofosbuvir because of the increased cost of 24 weeks of sofosbuvir and ribavirin treatment (compared with 12 weeks of sofosbuvir plus peginterferon alfa and ribavirin). The Committee concluded that the proportion of people with genotypes 1, 3, 4, 5 or 6 HCV who may be unwilling to have interferon (and therefore receive sofosbuvir plus ribavirin for 24 weeks) should have been taken into account in the manufacturer’s sensitivity analyses.

4.18   The Committee discussed the utility values used in the manufacturer’s model. It acknowledged that health-related quality of life was largely assessed in the clinical trials for sofosbuvir using the SF-36 questionnaire and that none of the clinical trials collected data using the EQ-5D quality of life measure. The Committee understood that the manufacturer obtained SF-36 health-related quality of life data at various time points, including 24 weeks after the end of treatment in some trials. The Committee appreciated that the manufacturer tried to be pragmatic in its approach to modelling the effects of treatment, but considered that sensitivity analyses that used utility data from the trial to calculate the utility increment after a sustained virological response should have been undertaken. The Committee was aware the manufacturer had instead applied a utility increment of 0.05 after sustained virological response in the manufacturer’s base-case analysis from Wright et al. (2006), but considered that this utility increment should also have been varied in sensitivity analyses using more up-to-date estimates from the literature (such as from Vera-Llonch et al. 2013 as it provided the most recent evidence for determining the utility increment of a sustained virological response), particularly since the ERG’s exploratory analyses demonstrated that the ICERs were sensitive to the utility estimate assumed (see section 3.61).

4.19   The Committee considered the manufacturer’s base-case ICERs for sofosbuvir compared with standard of care in each of the various subgroups. It noted that most analyses presented deterministic ICERs that were under £30,000 per QALY gained except for the treatment-naive subgroup with genotype 1 HCV for whom interferon is unsuitable (£49,200 per QALY gained for sofosbuvir plus peginterferon alfa and ribavirin for 24 weeks compared with no treatment) and the treatment-naive, interferon-eligible genotype 2 HCV subgroup (£46,300 per QALY gained for sofosbuvir plus ribavirin for 12 weeks compared with peginterferon alfa and ribavirin for 24 weeks). The Committee was aware that the cost-effectiveness results were based on weak and uncertain clinical estimates and that the deterministic ICERs represented a weighted average for people with and without cirrhosis. The Committee acknowledged that the shortcomings of the analyses were largely a result of the lack of robust trial evidence for each subgroup, and concluded that further exploration of the effect of alternative modelling assumptions (see sections 4.11to 4.18) was needed before it could make any recommendations on the cost-effectiveness of sofosbuvir in the different patient populations. The Committee requested that any further analyses provided by the manufacturer should present results separately for people with and without cirrhosis, and only probabilistic ICERs should be calculated.

4.20   The Committee discussed the discount rate used in the manufacturer’s model and considered whether this appraisal met the criteria for using a non-reference case discount rate for costs and health benefits that can be applied in situations when treatment restores people who would otherwise die or have a very severely impaired life to full or near full health, and when this is sustained over a very long period (normally at least 30 years), as described in the Guide to the methods of technology appraisal. The Committee noted that the manufacturer’s base-case analysis used a discount rate of 3.5% for costs and health benefits in line with the NICE reference case and that the deterministic sensitivity analysis presented by the manufacturer suggested that the ICERs were particularly sensitive to the discount used. The Committee heard from the clinical specialists that a person who does not have cirrhosis and experiences a sustained virological response could be considered cured. However, the Committee was aware that no data are available beyond the follow-up period from the trials; therefore evidence supporting the long-term durability of a sustained virological response is lacking. The Committee also noted that people with cirrhosis who experience a sustained virological response would not have their health restored. Therefore, the Committee concluded that sofosbuvir did not meet the criteria for differential discounting of health benefits, and agreed that the manufacturer’s approach to using the standard discount rate of 3.5% was appropriate.

4.21   The Committee discussed comments from the patient experts indicating that in practice the availability of treatment for people with chronic hepatitis C who use injectable drugs was limited, which could represent a potential equality consideration. The Committee heard from the clinical specialists that treatment for these people is considered on an individual basis because of concerns about safety and treatment adherence, but that clinicians would like to offer sofosbuvir to people using injectable drugs, taking into account any precautions in the summary of product characteristics. The Committee acknowledged that access to treatment for this patient group was an issue related to implementation and could not be addressed through technology appraisal recommendations. However, the Committee concluded that although people who use injectable drugs were not represented in the pivotal clinical trials for sofosbuvir, based on the current evidence available, there was no reason to deny them access to treatment; therefore any recommendations on the use of sofosbuvir would be irrespective of injectable drug use.

4.22   The Committee discussed whether sofosbuvir could be considered an innovative treatment, providing a step change in the treatment of chronic hepatitis C. The Committee agreed that sofosbuvir offers the possibility of shortened interferon-based treatment regimens, or treatment without interferon therapy in some circumstances, which is particularly important and a major development in the current clinical management of chronic hepatitis C. The Committee therefore accepted that sofosbuvir is a valuable new therapy for the treatment of chronic hepatitis C, but was aware that there is substantial uncertainty around the magnitude of benefit that it offers each subgroup. The Committee agreed with the clinical specialists and patient experts that there were other benefits to patients (such as relief of loss of cognitive ability in people with HCV) and public health benefits (such as reduced onward transmission of HCV) that were not captured in the QALY calculation and that, if taken into account, would decrease the ICERs.

4.23   The Committee was concerned about the considerable uncertainty in the supporting clinical trial data and the lack of robust cost-effectiveness data comparing sofosbuvir with other treatments currently used in clinical practice. Further, it was aware that the manufacturer was unable to provide cost-effectiveness estimates for genotype 1, 4, 5, and 6 HCV treatment-experienced subgroups. The Committee was therefore not persuaded that it could robustly make recommendations based on the current clinical and cost-effectiveness analyses of sofosbuvir for all subgroups covered by the marketing authorisation. Therefore, the Committee was minded not to recommend sofosbuvir as a cost-effective use of NHS resources for the treatment of chronic hepatitis C and asked NICE to request further analyses from the manufacturer for people with genotype 1 and genotype 3 chronic hepatitis C to be made available for the second Appraisal Committee meeting as follows:

• Revised cost-effectiveness analyses for sofosbuvir in combination with ribavirin with or without peginterferon alfa compared with peginterferon alfa and ribavirin presented separately for people with and without cirrhosis, with and without HIV-co-infection, and by treatment history. The analyses should incorporate the following assumptions:

-     a transition from the sustained virological response-cirrhotic health state to the hepatocellular carcinoma health state, using the transition probability estimates from Cardoso et al. (2010)

-     alternative sustained virological response estimates for peginterferon alfa and ribavirin, including those from Hadziyannis et al. (2004) (see section 4.14)

-     alternative utility increments after sustained virological response including SF-36 values from the trials collected at 24 weeks post-treatment, and Vera-Llonch et al. (2013) (see section 4.18)

-     alternative costs for ribavirin in the model (see section 4.15)

-      

• Sensitivity analyses that include the above mentioned assumptions and also explore the effect on the ICERs of the following:

-     assuming that up to 100% of people with genotype 3 HCV receive sofosbuvir for 24 weeks (see section 4.16)

-     assuming an increased proportion of interferon-eligible people may be unwilling to have interferon treatment and therefore receive sofosbuvir plus ribavirin for 24 weeks (see section 4.17)

-     allowing people aged 35 and 55 years to enter the model (see section 4.12)

-     variation in all-cause mortality by assuming the population entering the model comprises 61% men and 39% women, in line with estimates from Wright et al. (2006) (see section 4.12).

• For all the above analyses:

-     report probabilistic ICERs

-     use a discount rate of 3.5% for costs and benefits in line with the NICE reference case

-     provide a revised fully executable economic model to check the above revisions

VII   The Committee understood that additional work on all of the subgroups presented in the manufacturer’s original submission would be a substantial undertaking. Therefore, given that most people with chronic hepatitis C in England have genotype 1 or 3 HCV, the Committee agreed that to be most relevant for decision-making, and further analyses should focus on these groups.

Summary of Appraisal Committee’s key conclusions

·                     TAXXX	·                     Appraisal title: Sofosbuvir for treating chronic hepatitis C		·                     Section
·                     Key conclusions
·                     The Committee is minded not to recommend sofosbuvir in line with its marketing authorisation as an option for treating chronic hepatitis C. ·                       ·                     The Committee was not persuaded that it could robustly make recommendations based on the current clinical and cost-effectiveness analyses of sofosbuvir for all subgroups covered by the marketing authorisation.			·                     1.1, 4.23
·                     Current practice
·                     Clinical need of patients, including the availability of alternative treatments		·                     The Committee heard from the patient experts that the availability of sofosbuvir will encourage more people with hepatitis C to seek diagnosis and treatment. ·                     The Committee recognised the effect of chronic hepatitis C on the lives of people with the virus, and concluded that treatments that give a sustained virological response, and that consequently help reduce the rate of HCV transmission and the stigma associated with having chronic hepatitis C, are of significant importance. ·                     The Committee was aware that interferon-based treatment may cause chronic side effects, such as autoimmune responses and thyroid problems, which need additional long-term management and there pose a barrier to people starting and completing treatment. The Committee acknowledged that the marketing authorisation for sofosbuvir offers people the option to receive shortened courses of peginterferon alfa and ribavirin, or in some circumstances to receive treatment without peginterferon alfa, thereby reducing potential side effects with interferon based therapy. The Committee agreed with the clinical specialists and patient experts that the option to receive a shortened course of interferon-based therapy with sofosbuvir, or the possibility of sofosbuvir being used without peginterferon alfa in some circumstances, would make it a valuable treatment option for people with chronic hepatitis C. ·                     The Committee heard from the clinical specialists that sofosbuvir is an important new treatment which will address an unmet need particularly in people who have previously been treated but did not have a sustained virological response, in people whose condition has relapsed, or in people who have become re-infected after treatment. The Committee concluded that most people with chronic hepatitis C are likely to have at least some benefit from adding sofosbuvir to their treatment regimen.	·                     4.1, 4.2, 4.3
·                     The technology
·                     Proposed benefits of the technology ·                     How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?		·                     The Committee acknowledged that the marketing authorisation for sofosbuvir offers people the option to receive shortened courses of peginterferon alfa and ribavirin, or in some circumstances to receive treatment without peginterferon alfa, thereby reducing potential side effects with interferon based therapy. ·                     The Committee accepted that sofosbuvir was a valuable new therapy but was aware that there is substantial uncertainty around the magnitude of benefit that it offers each subgroup. It agreed that there were other benefits (such as relief of loss of cognitive ability in people with HCV) and public health benefits (such as reduced onward transmission of HCV) that were not captured in the QALY calculation and that, if taken into account, would decrease the ICERs.	·                     4.2, 4.21
·                     What is the position of the treatment in the pathway of care for the condition?		·                     . The Committee concluded that most people with chronic hepatitis C are likely to have at least some benefit from adding sofosbuvir to their treatment regimen.	·                     4.3
·                     Adverse reactions		·                     The Committee concluded that the adverse reactions associated with sofosbuvir plus peginterferon alfa and ribavirin were generally tolerable and that sofosbuvir was not likely to cause additional adverse reactions compared with existing treatment regimens.	·                     4.9
·                     Evidence for clinical effectiveness
·                     Availability, nature and quality of evidence		·                     The Committee heard from the clinical specialists that current standard of care has been used for many years in the UK, and has been supported by numerous trials; therefore it was not unreasonable to use historical controls. The specialists also commented that hepatitis C trials are often open-label because some people realise they are taking an interferon-based regimen, potentially making blinding difficult. ·                     The Committee was aware that the number of people with cirrhosis in the clinical trials was small, and exclusion criteria meant that people who use injectable drugs were not included in any studies. ·                     The Committee noted that the manufacturer provided evidence from only 1 head-to-head trial (FISSION, in treatment naïve, interferon eligible people with genotype 2 or 3 HCV) that was consistent with the decision problem. ·                     The Committee was aware that other studies presented by the manufacturer for genotype 2 or 3 HCV showed that sustained virological response after treatment with sofosbuvir in treatment-naive people was generally better than in treatment-experienced people. Acknowledging the lack of evidence presented for treatment-experienced people with genotype 1, 4, 5 or 6 HCV, the Committee concluded that it was unable to make a recommendation on the use of sofosbuvir for this subgroup. ·                     The Committee was aware that all 4 trials in people with genotype 2 and 3 had small patient numbers and different designs, and concluded that these factors introduced substantial uncertainty around the clinical effectiveness of sofosbuvir and must be taken into account when interpreting the clinical trial results. ·                     The Committee considered that treatment with sofosbuvir plus ribavirin was likely to lead to better sustained virological response in people with genotype 3 HCV compared with current standard of care (24 weeks of peginterferon alfa and ribavirin treatment), but only when sofosbuvir plus ribavirin treatment was extended to 24 weeks. In addition, the Committee considered it was plausible that sustained virological response in people with genotype 2 HCV after treatment with sofosbuvir plus ribavirin was likely to be better than the current standard of care when administered for 12 weeks. However, taking into account the limitations of the trial designs and the use of historical controls, the Committee concluded that there was considerable uncertainty around the true magnitude of benefit of sofosbuvir treatment regimens compared with standard of care. ·                     The Committee concluded that although there were limited data for the subgroups with HCV and HIV co-infection, the interim analysis of the PHOTON-1 study presented suggests that the efficacy of sofosbuvir plus ribavirin is similar to that reported for people with chronic hepatitis C mono-infection, although they were mindful that the benefits of treatment were likely to be lessened because of complications and higher morbidity associated with HIV infection.	·                     4.4, 4.5, 4.6, 4.7, 4.8
·                     Relevance to general clinical practice in the NHS		·                     The Committee was aware that the inclusion criteria for the sofosbuvir trials were broader than for previous trials in hepatitis C; therefore there was good reason to expect that the people in the trials reflected those who are currently being treated in UK clinical practice.	·                     4.4
·                     Uncertainties generated by the evidence		·                     Taking into account the limitations of the trial designs and the use of historical controls, the Committee concluded that there was considerable uncertainty around the true magnitude of benefit of sofosbuvir treatment regimens compared with standard of care. ·                     The Committee was aware that all 4 trials in people with genotype 2 and 3 HCV had small patient numbers and different designs, and concluded that these factors introduced substantial uncertainty around the clinical effectiveness of sofosbuvir and must be taken into account when interpreting the clinical trial results. ·                     The Committee concluded that, due to the design of the trials in people with genotype 2 and 3 HCV and the use of historical controls there was uncertainty relating to the true magnitude of benefit of sofosbuvir containing regiments compared with standard of care therapies.	·                     4.4, 4.6, 4.7
·                     Are there any clinically relevant subgroups for which there is evidence of differential effectiveness?		·                     The Committee was aware that other studies presented by the manufacturer for genotype 2 or 3 HCV showed that sustained virological response after treatment with sofosbuvir in treatment-naive people was generally better than in treatment-experienced people. Acknowledging the lack of evidence presented for treatment-experienced people with genotype 1, 4, 5 or 6 HCV, the Committee concluded that it was unable to make a recommendation on the use of sofosbuvir for this subgroup. ·                     The Committee acknowledged that people with cirrhosis also generally had a lower response than those without cirrhosis (irrespective of genotype). The Committee considered that treatment with sofosbuvir plus ribavirin was likely to lead to better sustained virological response in people with genotype 3 HCV compared with current standard of care (24 weeks of peginterferon alfa and ribavirin treatment), but only when sofosbuvir plus ribavirin treatment was extended to 24 weeks. In addition, the Committee considered it was plausible that sustained virological response in people with genotype 2 HCV after treatment with sofosbuvir plus ribavirin was likely to be better than the current standard of care when administered for 12 weeks. However, taking into account the limitations of the trial designs and the use of historical controls, the Committee concluded that there was considerable uncertainty around the true magnitude of benefit of sofosbuvir treatment regimens compared with standard of care.	·                     4.5, 4.7
·                     Estimate of the size of the clinical effectiveness including strength of supporting evidence		·                     The Committee acknowledged that in the NEUTRINO trial, treatment-naive people with genotype 1 (89% of people in the trial), 4, 5 or 6 HCV who received sofosbuvir plus peginterferon alfa and ribavirin had a high sustained virological response (91%) 12 weeks after treatment compared with the historical control of 60% that was presented by the manufacturer. However, it noted that no data were available on the clinical effectiveness of sofosbuvir in treatment-experienced people with these genotypes. ·                     The Committee noted that sustained virological response was consistently higher for people with genotype 2 HCV (86% and 94% in the 12 week and 16 week treatment groups in the FUSION trial; 93% after 12 weeks treatment in the VALENCE trial) than for people with genotype 3 HCV, who needed longer treatment with sofosbuvir and ribavirin (16 weeks and 24 weeks) for a similar response to be shown. ·                     The Committee agreed with the ERG’s view that the mixed treatment comparison conducted by the manufacturer was not robust and therefore it was reasonable for the manufacturer not to use it to inform its cost-effectiveness analyses.	·                     4.5, 4.7, 4.10
·                     Evidence for cost effectiveness
·                     Availability and nature of evidence		·                     The Committee agreed that overall the manufacturer’s model structure adhered to the NICE reference case for economic analysis, but concluded that individual ICERs presented for each subgroup by cirrhosis status would be useful in fully assessing the cost effectiveness of sofosbuvir.	·                     4.11
·                     Uncertainties around and plausibility of assumptions and inputs in the economic model		·                     The Committee acknowledged that the ICERs produced from the economic model were a weighted average of people with and without cirrhosis. ·                     The Committee considered that using a starting age in the model ranging from 35 to 55 years and a cohort comprised of 61% men and 39% women would be more generalisable to the UK population. ·                     The Committee acknowledged that the ERG calculated the correct transition probability from the Cardoso study (that is, 0.0123 [95% CI 0.028 to 0.0218]) and that when this was included in the ERG’s exploratory analyses, the manufacturer’s base-case ICERs increased. ·                     The Committee concluded that the duration of treatment with sofosbuvir had a considerable effect on the ICERs in people with genotype 3 HCV, and therefore an extended treatment duration should have been accounted for by the manufacturer in its economic model by assuming that up to 100% of people with genotype 3 can receive sofosbuvir for 24 weeks. ·                     The Committee noted that the potential increase in uptake of sofosbuvir and ribavirin dual therapy (without peginterferon alfa) was not explored by the manufacturer in any scenario analyses, even though it was likely to substantially affect the cost effectiveness of sofosbuvir because of the increased cost of 24 weeks of sofosbuvir and ribavirin treatment (compared with 12 weeks of sofosbuvir plus peginterferon alfa and ribavirin). The Committee concluded that the proportion of people with genotype 1, 4, 5 or 6 HCV who may be unwilling to have interferon and therefore receive sofosbuvir plus ribavirin for 24 weeks should have been taken into account in the manufacturer’s sensitivity analyses. ·	·                     4.11, 4.12, 4.13, 4.16, 4.17
·                     Incorporation of health-related quality-of-life benefits and utility values ·                     Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?		·                     The Committee understood that the manufacturer obtained SF-36 health-related quality of life data at various time points, including 24 weeks after the end of treatment for some trials. The Committee appreciated that the manufacturer tried to be pragmatic in its approach to modelling the effects of treatment, but considered that sensitivity analyses that used utility data from the trial to calculate the utility increment after a sustained virological response should have been provided. The Committee was aware the manufacturer had instead applied a utility increment of 0.05 after sustained virological response in the manufacturer’s base-case analysis from Wright et al. (2006), but considered that this utility increment should also have been varied in sensitivity analyses using more up-to-date estimates from the literature (such as from Vera-Llonch et al. 2013) as it provided the most recent evidence for determining the utility increment of a sustained virological response, particularly since the ERG’s exploratory analyses demonstrated that the ICERs were sensitive to the utility estimate assumed ·                     The Committee agreed that the possibility of shortened interferon-based treatment regimens, or treatment without interferon therapy in some circumstances that sofosbuvir offers patients is particularly important and a major development in the current clinical management of chronic hepatitis C. ·                     The Committee concluded that sofosbuvir did not meet the criteria for differential discounting of health benefits, and agreed that the manufacturer’s approach to using the standard discount rate of 3.5% was appropriate. ·                     The Committee agreed that there were other benefits (such as relief of loss of cognitive ability in people with HCV) and public health benefits (such as reduced onward transmission of HCV) that were not captured in the QALY calculation and that, if taken into account, would decrease the ICERs.	·                     4.18, 4.20, 4.22,
·                     Are there specific groups of people for whom the technology is particularly cost effective?		·                     The Committee could not make any recommendations on the cost-effectiveness of sofosbuvir until further exploration of the effect of alternative modelling assumptions was presented by the manufacturer.	·                     4.19
·                     What are the key drivers of cost effectiveness?		·                     The Committee concluded that the duration of treatment with sofosbuvir had a considerable effect on the ICERs in people with genotype 3 HCV, and therefore an increased treatment duration should have been accounted for by the manufacturer in its economic model by assuming that up to 100% of people with genotype 3 can receive sofosbuvir for 24 weeks.	·                     4.15
·                     Most likely cost-effectiveness estimate (given as an ICER)		·                     Not applicable.	·
·                     Additional factors taken into account
·                     Patient access schemes (PPRS)		·                     Not applicable	·
·                     End-of-life considerations		·                     Not applicable	·
·                     Equalities considerations and social value judgements		·                     It was raised during consultation that hepatitis C adversely affects certain populations, who could be considered at risk of being disadvantaged in terms of accessing the healthcare system and therefore at risk of inequity of access to innovative new treatments (such as certain immigrant populations, prison populations and people who inject drugs). Attendees at the scoping workshop agreed that this issue related to implementation and could not be addressed through technology appraisal recommendations. ·                     The Committee discussed comments from patient experts indicating that in practice the availability of treatment for people with chronic hepatitis C who use injectable drugs was limited, which could represent a potential equality consideration. The Committee heard from the clinical specialists that treatment for these people is considered on an individual basis because of concerns about safety and treatment adherence, but that clinicians would like to offer sofosbuvir to people using injectable drugs, taking into account any precautions in the summary of product characteristics. The Committee acknowledged that access to treatment for this patient group was an issue related to implementation and could not be addressed through technology appraisal recommendations. However, the Committee concluded that although these people were not represented in the pivotal clinical trials for sofosbuvir, based on the current evidence available, there was no reason to deny them access to treatment; therefore any recommendations on the use of sofosbuvir would be irrespective of injectable drug use.	·                     4.21

 

5   Implementation

5.1  Section 7(6) of the National Institute for Health and Care Excellence (Constitution and Functions) and the Health and Social Care Information Centre (Functions) Regulations 2013 requires clinical commissioning groups, NHS England and, with respect to their public health functions, local authorities to comply with the recommendations in this appraisal within 3 months of its date of publication.

5.2   NICE has developed tools [link to www.nice.org.uk/guidance/TAXXX] to help organisations put this guidance into practice (listed below). [NICE to amend list as needed at time of publication]

• Slides highlighting key messages for local discussion.
• Costing template and report to estimate the national and local savings and costs associated with implementation.
• Implementation advice on how to put the guidance into practice and national initiatives that support this locally.
• A costing statement explaining the resource impact of this guidance.
• Audit support for monitoring local practice.

 

6   Related NICE guidance

Details are correct at the time of consultation and will be removed when the final guidance is published. Further information is available on the NICE website.

Published

• Boceprevir for the treatment of genotype 1 chronic hepatitis C. NICE technology appraisal guidance (2012)
• Telaprevir for the treatment of genotype 1 chronic hepatitis C. NICE technology appraisal guidance 252 (2012)
• Peginterferon alfa and ribavirin for the treatment of chronic hepatitis C. NICE technology appraisal guidance 200 (2010)
• Peginterferon alfa and ribavirin for the treatment of mild chronic hepatitis C. NICE technology appraisal guidance 106 (2006)
• Interferon alfa (pegylated and non-pegylated) and ribavirin for the treatment of chronic hepatitis C. NICE technology appraisal guidance 75 (2004).
• Needle and syringe programmes. NICE public health guidance 52 (2014)

Under development

NICE is developing the following guidance (details available from www.nice.org.uk):

• Simeprevir for treating genotype 1 or 4 chronic hepatitis C. NICE technology appraisal. Publication expected January 2015.
• Faldaprevir for treating genotype 1 chronic hepatitis C. NICE technology appraisal. Publication expected June 2015.
• Hepatitis C: diagnosis and management of hepatitis C. NICE clinical guideline. Publication date to be confirmed.

NICE pathways

There is a NICE pathway on hepatitis B and C testing.

 

7  Appraisal Committee members, guideline representatives and NICE project team

Appraisal Committee members

The Appraisal Committees are standing advisory committees of NICE. Members are appointed for a 3-year term. A list of the Committee members who took part in the discussions for this appraisal appears below. There are 4 Appraisal Committees, each with a chair and vice chair. Each Appraisal Committee meets once a month, except in December when there are no meetings. Each Committee considers its own list of technologies, and ongoing topics are not moved between Committees.

Committee members are asked to declare any interests in the technology to be appraised. If it is considered there is a conflict of interest, the member is excluded from participating further in that appraisal.

The minutes of each Appraisal Committee meeting, which include the names of the members who attended and their declarations of interests, are posted on the NICE website.

Professor Gary McVeigh (Chair)
Professor of Cardiovascular Medicine, Queens University Belfast and Consultant Physician, Belfast City Hospital

Dr Lindsay Smith (Vice Chair)
GP, West Coker Surgery, Somerset

Dr Amanda Adler
Consultant Physician, Addenbrooke's Hospital

Dr Aomesh Bhatt
Regulatory and Medical Affairs Director Europe and North America, Reckitt Benckiser

Dr Andrew Black
GP, Kingsland, Herefordshire

Dr Matthew Bradley
Therapy Area Leader, Global Health Outcomes, GlaxoSmithKline

Dr Gerardine Bryant
GP, Swadlincote, Derbyshire

John Cairns
Professor of Health Economics Public Health and Policy, London School of Hygiene and Tropical Medicine

Dr Ian Campbell
Honorary Consultant Physician, Llandough Hospital, Cardiff

Dr Ian Davidson
Lecturer in Rehabilitation, University of Manchester

Dr Martin Duerden
Assistant Medical Director, Betsi Cadwaladr University Health Board, North Wales

Mrs Susan Dutton
Senior Medical Statistician, Oxford Clinical Trials Research Unit

Mrs Gillian Ells
Prescribing Advisor – Commissioning, NHS Hastings and Rother and NHS East Sussex Downs and Weald

Dr Andrew England
Senior Lecturer, Directorate of Radiography, University of Salford

Professor Carol Haigh
Professor in Nursing, Manchester Metropolitan University

Professor John Henderson
Professor of Paediatric Respiratory Medicine, University of Bristol and Bristol Royal Hospital for Children

Dr Paul Hepple
GP, Edinburgh

Professor John Hutton
Professor of Health Economics, University of York

Dr Tim Kinnaird
Lead Interventional Cardiologist, University Hospital of Wales, Cardiff

Mr Warren Linley
Senior Research Fellow, Centre for Health Economics and Medicines Evaluation, Bangor University

Dr Malcolm Oswald
Lay Member

Professor Femi Oyebode
Professor of Psychiatry & Consultant Psychiatrist, The National Centre for Mental Health

Professor Stephen Palmer
Professor of Health Economics, Centre for Health Economics, University of York

Dr John Radford
Director of Public Health, Rotherham Primary Care Trust and MBC

Dr Murray Smith
Associate Professor in Social Research in Medicines and Health, University of Nottingham

Guideline representatives

The following individuals, representing the Guideline Development Group responsible for developing NICE’s clinical guideline related to this topic, were invited to attend the meeting to observe and to contribute as advisers to the Committee.

Professor Matthew Hickman
Professor of Public Health and Epidemiology

NICE project team

Each technology appraisal is assigned to a team consisting of 1 or more health technology analysts (who act as technical leads for the appraisal), a technical adviser and a project manager.

Mr Richard Diaz and Dr Christian Griffiths
Technical Leads

Mrs Fiona Pearce
Technical Adviser

Mrs Kate Moore
Project Manager

 

8  Sources of evidence considered by the Committee

A. The Evidence Review Group (ERG) report for this appraisal was prepared by Southampton Health Technology Assessment Centre:

• Copley V, Frampton G, Pickett K, et al. Sofosbuvir for treating chronic hepatitis C, April 2014.

B. The following organisations accepted the invitation to participate in this appraisal as consultees and commentators. They were invited to comment on the draft scope, the ERG report and the appraisal consultation document (ACD). Organisations listed in I were also invited to make written submissions. Organisations listed in II and III had the opportunity to give their expert views. Organisations listed in I, II and III also have the opportunity to appeal against the final appraisal determination.

I.   Manufacturer/sponsor:

• ilead Sciences

II.   Professional/specialist and patient/carer groups:

• British Liver Trust
• Liver4Life
• The Hepatitis C Trust
• British Association for Study of the Liver
• British Association for the Study of the Liver Nurses Forum
• British HIV Association
• British Society of Gastroenterology
• Royal College of General Practitioners
• Royal College of Nursing
• Royal College of Pathologists
• Royal College of Physicians
• United Kingdom Clinical Pharmacy Association

III. Other consultees:

• Department of Health
• NHS Bromley CCG
• NHS England
• Welsh Government

IV. Commentator organisations (did not provide written evidence and without the right of appeal):

• Department of Health, Social Services and Public Safety, Northern Ireland
• Healthcare Improvement Scotland
• Janssen
• Merck Sharp & Dohme
• Roche Products
• Centre for Sexual Health & HIV Research
• Foundation for Liver Research
• MRC Clinical Trials Unit
• National Institute for Health Research Health Technology Assessment Programme
• Southampton Health Assessment Centre
• National Clinical Guideline Centre
• Public Health England

C. The following individuals were selected from clinical specialist and patient expert nominations from the consultees and commentators. They gave their expert personal view on sofosbuvir by attending the initial Committee discussion and providing written evidence to the Committee. They are invited to comment on the ACD.

• Dr Richard Aspinall, Consultant Hepatologist, nominated by the British Society of Gastroenterology – clinical specialist
• Dr Michael Jacobs, Consultant in Infectious Diseases, nominated by the Royal College of Physicians – clinical specialist
• Mr Charles Gore, Chief Executive of the Hepatitis C Trust, nominated by the Hepatitis C Trust – patient expert
• Mr Andrew Zapletal, nominated by the Hepatitis C Trust – patient expert

E. Representatives from the following manufacturer/sponsor attended Committee meetings. They contributed only when asked by the Committee chair to clarify specific issues and comment on factual accuracy.

• Gilead Sciences