3 The company's submission

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

Clinical effectiveness

3.1 The company presented 6 completed clinical trials of ombitasvir–paritaprevir–ritonavir with dasabuvir (referred to as 3D), and 1 completed trial of ombitasvir–paritaprevir–ritonavir without dasabuvir (referred to as 2D). The populations in the trials differed with respect to hepatitis C virus (HCV) genotype and subtype, whether they had cirrhosis and whether they previously had peginterferon alfa.

Genotype 1a and 1b HCV

  • SAPPHIRE I (randomised controlled trial): 12‑week treatment with 3D plus ribavirin (n=473), compared with placebo (n=158), for previously untreated HCV without cirrhosis.

  • SAPPHIRE II (randomised controlled trial): 12‑week treatment with 3D plus ribavirin (n=297), compared with placebo (n=97), for previously treated HCV without cirrhosis.

  • TURQUOISE II (randomised controlled trial): 12‑week treatment with 3D plus ribavirin (n=208), compared with 24‑week treatment with 3D plus ribavirin (n=172), for previously untreated or treated HCV with compensated cirrhosis.

Genotype 1b HCV

  • PEARL II (randomised controlled trial): 12‑week treatment with 3D plus ribavirin (n=91), compared with 3D alone (n=95), for previously treated HCV without cirrhosis.

  • PEARL III (randomised controlled trial): 12‑week treatment with 3D plus ribavirin (n=210), compared with 3D plus placebo (n=209), for previously untreated HCV without cirrhosis.

Genotype 1a HCV

  • PEARL IV (randomised controlled trial): 12‑week treatment with 3D plus ribavirin (n=100), compared with 3D plus placebo (n=205), for previously untreated HCV without cirrhosis.

Genotype 4 HCV

  • PEARL I (randomised controlled trial): 12‑week treatment with 2D for previously untreated HCV (n=44), and 12‑week treatment with 2D plus ribavirin for previously untreated (n=42) or treated (n=49) HCV.

3.2 The company submitted 2 completed and 4 ongoing clinical trials as supporting evidence:

Completed trials

  • AVIATOR and M14‑103: 3D plus ribavirin for previously untreated or treated genotype 1 HCV without cirrhosis.

Ongoing trials

  • MALACHITE I: 3D plus ribavirin compared with telaprevir plus peginterferon alfa and ribavirin, for previously untreated genotype 1 HCV.

  • MALACHITE II: 3D plus ribavirin, compared with telaprevir plus peginterferon alfa and ribavirin, for previously treated genotype 1 HCV.

  • TURQUOISE I: 3D plus ribavirin for genotype 1 HCV in adults co‑infected with HIV‑1.

  • CORAL I: 3D with ribavirin for genotype 1 HCV in adults who had a liver transplant.

The treatment groups that provided evidence for the treatments specified in the summary of product characteristics are presented in table 3.

Table 3 Trial treatment arms or subgroups that informed the treatments specified in the summary of product characteristics

Summary of product characteristics

Trial evidence

Population

Treatment (duration)

Trial

HCV genotype

Comparison

Trial arm or subgroup

Genotype 1b HCV without cirrhosis

3D (12 weeks)

PEARL II

1b

3D+RBV versus 3D

3D treatment arm (n=95)

PEARL III

1b

3D+RBV versus 3D

3D treatment arm (n=209)

Genotype 1b HCV with compensated cirrhosis

3D+RBV (12 weeks)

TURQUOISE II

1a and 1b

3D+RBV: 12 weeks versus 24 weeks

GT1b, 12 week treatment arm (n=68/208)

Genotype 1a HCV without cirrhosis

3D+RBV (12 weeks)

SAPPHIRE I

1a and 1b

3D+RBV versus placebo

GT1a, 3D+RBV arm (n=322/473)

SAPPHIRE II

1a and 1b

3D+RBV versus placebo

GT1a, 3D+RBV arm (n=173/297)

PEARL IV

1a

3D+RBV versus 3D

3D plus RBV treatment arm (n=100)

Genotype 1a HCV with compensated cirrhosis

3D+RBV (24 weeks)

TURQUOISE II

1a and 1b

3D+RBV: 12 weeks versus 24 weeks

GT1a, 24‑week treatment arm (n=121/172)

Genotype 4 HCV without cirrhosis

2D+RBV (12 weeks)

PEARL I

4

2D+RBV (TN) versus 2D (TN) and 2D+RBV (TE)

Treatment arms with 2D plus ribavirin, TN (n=42) TE (n=49)

Genotype 4 HCV with compensated cirrhosis

2D+RBV (24 weeks)

No data

Abbreviations: HCV, hepatitis C virus; GT, genotype; RBV, ribavirin; TN, treatment naive (no previous treatment); TE, treatment experienced (previously treated); 2D, ombitasvir–paritaprevir–ritonavir without dasabuvir; 3D, ombitasvir–paritaprevir–ritonavir with dasabuvir.

Treatment duration in trials was 12 weeks unless stated otherwise.

3.3 Although recommended in the marketing authorisation, 2D plus ribavirin for 24 weeks was not studied for genotype 4 HCV with cirrhosis. The European public assessment report states that data from PEARL I demonstrated that this treatment was efficacious for genotype 1b HCV with cirrhosis. Because the in vitro effects and pharmacodynamics for both components of 2D (paritaprevir and ombitasvir) are similar for genotype 1b and genotype 4 HCV, the report concluded that 24‑week treatment with 2D plus ribavirin for genotype 4 HCV with cirrhosis was likely to be as efficacious as for genotype 1b HCV with cirrhosis.

3.4 The primary outcome in all the included trials was sustained virological response at week 12 (SVR12), defined as an HCV RNA level of less than 25 IU per millilitre at 12 weeks after treatment ends. All the completed trials except PEARL I (genotype 4 HCV) planned a comparison with the historical control, telaprevir. Analyses were based on the intention‑to‑treat population (all people who were randomised) or the modified intention‑to‑treat population (all people who were randomised and had at least 1 dose of study treatment).

3.5 The results of trials of 3D and 2D, with or without ribavirin, in which treatment matched that specified in the marketing authorisation, and the results of trials included in the company's economic model, are presented in table 4.

Table 4 Sustained virological response rates at 12 weeks; outcome from trial arms or subgroups in which treatment matched the marketing authorisation

Population

Treatment (duration)

Trial

SVR12

n/N

% (95% CI)

Historical control (telaprevir, 95% CI)

Genotype 1b HCV, without cirrhosis

3D

(12 weeks)

PEARL III (previously untreated)

209/209

100.0 (98.2–100.0)

80 (75–84)

PEARL II (previously treated)

91/91

100.0 (95.9–100.0)

69 (62–75)

Genotype 1b HCV, with compensated cirrhosis

3D plus ribavirin

(12 weeks)

TURQUOISE II

67/68

98.5

(95.7–100.0)

47 (41–54)

Genotype 1a HCV, without cirrhosis

3D plus ribavirin

(12 weeks)

SAPPHIRE I (previously untreated)

308/322

95.7

(93.4–97.9)

72 (68–75)

PEARL IV (previously untreated)

97/100

97.0

(93.7–100.0)

72 (68–75)

SAPPHIRE II (previously treated)

166/173

96.0

(93.0–98.9)

59 (53–65)

Genotype 1a HCV, with compensated cirrhosis

3D plus ribavirin (24 weeks)

TURQUOISE II

115/121

95.0

(91.2–98.9)

47 (41–54)

Genotype 4 HCV, without cirrhosis

2D plus ribavirin (12 weeks)

PEARL I (previously untreated)

42/42

100.00 (91.6–100)

Not applicable

PEARL I (previously treated)

49/49

100.00 (92.7–100)

Abbreviations: SVR12, sustained virological response at week 12; CI, confidence interval; HCV, hepatitis C virus; 2D, ombitasvir–paritaprevir–ritonavir without dasabuvir; 3D, ombitasvir–paritaprevir–ritonavir with dasabuvir.

The data for telaprevir were from the clinical trials ILLUMINATE, ADVANCE and REALIZE.

Meta‑analysis

3.6 The company presented 3 meta‑analyses in which it pooled SVR12 rates from single‑arm trials evaluating 3D for genotype 1 HCV. Analyses were done on the following groups using a random‑effect model:

  • all active treatment groups in completed phase III clinical trials (SAPPHIRE I, SAPPHIRE II, PEARL II, PEARL III, PEARL IV and TURQUOISE II) plus 1 phase II study, M14–103

  • all treatment groups in the completed phase III trials in line with the marketing authorisation for 3D and

  • all active treatment groups in the clinical trial programme for genotype 1 HCV, including from the dose‑finding AVIATOR study, and interim results from 2 ongoing trials, TURQUOISE I and CORAL I.

    The pooled SVR12 rate from the meta‑analysis for the 3D treatments recommended in the marketing authorisation was 96.5%.

3.7 The company stated that a network meta‑analysis to generate relative estimates of efficacy for 3D and 2D compared with the comparators outlined in the final scope issued by NICE was not feasible.

Health‑related quality of life

3.8 The completed trials also reported data on health‑related quality of life. This was measured using the SF‑36 physical component score and mental component score; the EQ‑5D‑5L health index score and visual analogue score; and the HCV‑PRO (a patient‑reported outcome tool specific to chronic hepatitis C, which consists of 16 items focusing on physical health, emotional health, productivity, social interactions, intimacy and perception).

3.9 Results for health‑related quality of life were reported as the mean change from baseline to the last treatment visit and to 12 weeks after treatment ends. In general, no statistically significant differences in the mean change over either of these periods were seen between treatment groups in most of the trials for most of the patient‑reported outcomes.

3.10 The EQ‑5D‑5L health index scores from the trials were used to inform the on‑treatment utility values in the economic model. The EQ‑5D‑5L health index scores were obtained using country‑specific algorithms to map the 5L values to the 3L tariff scores. The US mapping algorithm to convert the 5L values to 3L was used when an individual country‑specific algorithm was not available. The EQ‑5D‑5L scores are academic in confidence and cannot be reported here.

Adverse events

3.11 The company presented data on adverse events from the 6 completed trials evaluating 3D and the trial evaluating 2D. The most frequently reported adverse events were fatigue, headache, nausea, pruritus, insomnia, irritability, diarrhoea, anaemia, asthenia, shortness of breath, cough, muscle ache, itching and rash. The proportion of people who had at least 1 adverse event ranged from 67% (for 3D in genotype 1b HCV in PEARL III) to 92% (for 3D plus ribavirin in genotype 1a HCV in PEARL IV). Generally higher rates of adverse events were seen in the groups who had longer treatment and those who had ribavirin. The proportion of people stopping treatment because of adverse events was consistently low across the trials and the highest dropout rate was seen in TURQUOISE II, in people with compensated cirrhosis (2.3% in the 24‑week arm and 1.9% in the 12‑week arm).

Cost effectiveness

Model structure

3.12 The company submitted a Markov state transition model estimating the cost effectiveness of 3D and 2D for people with genotype 1 or 4 HCV. The structure of the model was adapted from the model used in the NICE technology appraisal guidance on peginterferon alfa and ribavirin for the treatment of mild chronic hepatitis C and peginterferon alfa and ribavirin for the treatment of chronic hepatitis C. The model simulated the lifetime disease progression of people with chronic HCV infection. The model adopted a lifetime time horizon (70 years) and a cycle length of 1 year. The model applied half‑year cycle corrections. Costs and health effects were discounted at an annual rate of 3.5%. The perspective of the analysis on costs was that of the NHS and personal social services.

3.13 The model had 6 health states simulating progressive liver disease, 3 health states simulating recovery from HCV (for people who had an SVR), and 1 death state.

Health states simulating progressive liver disease:

  • mild chronic HCV (METAVIR fibrosis stage F0–F1)

  • moderate chronic HCV (METAVIR fibrosis stage F2–F3)

  • compensated cirrhosis (METAVIR fibrosis stage F4)

  • decompensated cirrhosis

  • hepatocellular carcinoma and

  • liver transplant.

Health states simulating recovery from HCV (SVR):

  • recovered, history of mild disease

  • recovered, history of moderate disease and

  • recovered, history of compensated cirrhosis.

3.14 People entered the model in one of the following health states: mild chronic HCV, moderate chronic HCV, or compensated cirrhosis. They had treatment in the first year of the model. If they had an SVR, people moved to one of the recovery states, which depended on the previous state in which they had treatment. Once in a recovery state, the disease could not progress further. However, reinfection with chronic hepatitis C was possible, with a constant risk across the time horizon. People who did not have an SVR could stay in the same state, or move through the states simulating progressive liver disease (from mild to moderate to compensated cirrhosis, depending on their previous state and the rate of fibrosis progression). From compensated cirrhosis, the disease could progress to decompensated cirrhosis or hepatocellular carcinoma. From decompensated cirrhosis, the person could develop hepatocellular carcinoma, or have a liver transplant. From hepatocellular carcinoma, the person could have a liver transplant. People in the model risked dying at any time, but those with decompensated cirrhosis, hepatocellular carcinoma, and those who had a liver transplant had an additional risk of death from liver disease.

Populations, intervention and comparators

3.15 In its original analyses, the company modelled previously untreated and previously treated HCV separately. These groups were further divided by subtype of HCV (genotypes 1a or 1b). In total, the company's original base‑case analyses included 4 different populations.

3.16 After the first Appraisal Committee meeting, the company presented revised base‑case analyses separately for previously treated and previously untreated HCV for each treatment regimen as specified in the summary of product characteristics. The results of the revised analyses supersede the original analyses. Therefore only the revised analyses are discussed here.

3.17 The baseline characteristics of people in the model, such as age, weight, sex and disease severity, were based on a clinical audit of people with HCV who had treatment at a liver clinic at a London teaching hospital. Overall, 70% of the modelled population were male. The average ages at baseline of people whose HCV was previously untreated and previously treated were 40 and 45 years respectively. The company modelled 3D with or without ribavirin for genotype 1 HCV and 2D with ribavirin for genotype 4 HCV, as per the marketing authorisation. It compared 3D and 2D with peginterferon alfa and ribavirin, sofosbuvir plus peginterferon alfa and ribavirin and simeprevir plus peginterferon alfa and ribavirin. In addition 3D was compared with telaprevir plus peginterferon alfa and ribavirin and boceprevir plus peginterferon alfa and ribavirin. The comparators were modelled in line with their respective marketing authorisations. The company estimated the durations of each modelled treatment from the rates at which people stopped that treatment in the respective clinical trials.

SVR rates and model transitions

3.18 Clinical effectiveness was modelled as the probability of moving to a recovery state, which was based on the SVR12 rates reported in the clinical trials for 3D, 2D and the comparators. The company included estimates of effectiveness from separate trials without any statistical adjustments. When SVRs were available from more than 1 trial, the company pooled the results from the different trials. Because 2D was not studied in people with genotype 4 HCV with cirrhosis the SVR for this group was assumed to be 97%, as reported for the 2D 24‑week treatment in people with genotype 1b HCV in PEARL I.

3.19 The company highlighted 2 limitations with the available clinical effectiveness data for simeprevir used in the revised base‑case analyses:

  • The marketing authorisation for simeprevir does not allow treatment in people with Q80K positive polymorphism (a genetic mutation) and SVRs for the Q80K negative subgroups were not available.

  • The definitions of mild and moderate fibrosis in the simeprevir trials were different from the definitions used in the company's model. The company used pooled SVR from the intention‑to‑treat population in QUEST I and QUEST II and the definitions of fibrosis used in the simeprevir trials in the revised base‑case analyses.

3.20 The company assumed in the model that the natural history of genotype 1 and 4 HCV was similar, and so applied the same transition probabilities for both HCV genotypes. Data were sourced from the published literature.

Utility values and costs

3.21 For the health states in the model, the company used utility values obtained from the EQ‑5D scores collected in the UK mild hepatitis C trial and valued using the UK general population tariff (see table 5).

Table 5 Health state utility values

Health state

Utility

Source

Mild HCV

0.77

Wright et al. 2006

Moderate HCV

0.66

Wright et al. 2006

Compensated cirrhosis

0.55

Wright et al. 2006

Recovered

(no HCV, history of mild fibrosis)

0.82

Calculated – add 0.05 to utility for mild HCV

Recovered

(no HCV, history of moderate fibrosis)

0.71

Calculated – add 0.05 to utility for moderate HCV

Recovered

(no HCV, history of compensated cirrhosis)s

0.60

Calculated – add 0.05 to utility for compensated cirrhosis

Decompensated cirrhosis

0.45

Wright et al. 2006

Hepatocellular carcinoma

0.45

Wright et al. 2006

Liver transplant

0.45

Wright et al. 2006

Post‑liver transplant

0.67

Wright et al. 2006

Abbreviation: HCV, hepatitis C virus.

3.22 The utility differences associated with treatment were also accounted for in the model. On‑treatment utility decrements or gains were applied during the first year (first cycle) of the model. To estimate the on‑treatment utility difference for 3D and 2D, the company calculated the difference between the EQ‑5D‑3L score at the end of treatment and baseline. EQ‑5D‑3L scores were calculated using a UK mapping algorithm from the EQ‑5D‑5L scores collected in the trials for 3D and 2D. The utility differences associated with the comparator treatments were from other NICE technology appraisal guidance and ranged from a decrement of 0.154 (for telaprevir plus peginterferon alfa and ribavirin in people who had previous treatment) to a utility gain of 0.110 (for boceprevir plus peginterferon alfa and ribavirin in people who had previous treatment).

3.23 The company also did 2 scenario analyses around utility values. In scenario 1, the company estimated the utility gain for having an SVR from the difference between the pooled EQ‑5D values collected at baseline and at 12 weeks after treatment in people who had an SVR in the trials (instead of 0.05 used in the base case). In scenario 2, the company explored using alternative values for each health state, estimated from its trials. The company marked the alternative estimate of utility gain used in scenario 1, as well as the utility values for each health state used in scenario 2, as academic in confidence and therefore they cannot be presented here.

3.24 The company included 2 categories of resource use in the model that is; health state costs and treatment costs. The health state costs were associated with managing progressive liver disease (in people whose HCV does not respond to treatment) and surveillance after stopping treatment in people who have an SVR. The company's estimate of resource use for health states was based on 2 sources:

  • A retrospective chart review of people with chronic hepatitis C that reported resource use according to disease response to treatment (SVR or non‑SVR) done in the East Midlands region of the UK (Backx et al. 2014). The company used these data to estimate costs for all 3 recovery health states and 2 disease states, moderate fibrosis and compensated cirrhosis.

  • The cost for the remaining health states, that is mild fibrosis and 3 more advanced disease states, namely decompensated cirrhosis, hepatocellular carcinoma and liver transplant, were based on the models used in the NICE technology appraisal guidance on peginterferon alfa and ribavirin for the treatment of mild chronic hepatitis C and peginterferon alfa and ribavirin for the treatment of chronic hepatitis C. The costs were updated to current values using the Personal and Social Services Research Unit pay and prices inflation index.

3.25 Treatment‑related costs included drug acquisition costs and costs associated with on‑treatment monitoring for response and adverse events.

Results

3.26 The results of the fully incremental analyses for the treatments recommended in the summary of product characteristics for different groups stratified by treatment history, as requested by the Committee, are in table 6 (using the list price for ombitasvir–paritaprevir–ritonavir with or without dasabuvir). The incremental cost‑effectiveness ratios (ICERs) for the scenario analyses are presented in table 7. Using alternative utility values estimated from the trials increased the ICERs for the 3D (genotype 1 HCV) and 2D (genotype 4 HCV) treatments modestly for most of the populations. The company commented that in the trials, EQ‑5D data at 12 weeks after treatment were collected before people knew their SVR results and therefore, did not capture the psychological and emotional benefit of being cured.

Table 6 ICERs according to treatments in the summary of product characteristics (using the list price for ombitasvir–paritaprevir–ritonavir with or without dasabuvir)

Treatment

Incremental costs

Incremental QALYs

ICER (£/QALY gained)

Genotype 1a HCV without cirrhosis; previously untreated

PR

NA

NA

NA

Boceprevir+PR

£9226

0.51

Extended dominance

Telaprevir+PR

£13,320

0.81

Extended dominance

Simeprevir+PR

£14,507

0.85

Extended dominance

3D+RBV (for 12 weeks)

£19,067

1.47

£12,949

Sofosbuvir+PR

£21,256

1.38

Dominated

Genotype 1a HCV without cirrhosis; previously treated

PR

NA

NA

NA

Telaprevir+PR

£14,231

0.86

Extended dominance

3D+RBV (for 12 weeks)

£17,617

1.84

£9589

Simeprevir+PR

£18,005

0.86

Dominated

Sofosbuvir+PR

£22,429

1.31

Dominated

Genotype 1a HCV with cirrhosis; previously untreated

PR

NA

NA

NA

Telaprevir+PR

£10,850

0.92

Extended dominance

Simeprevir+PR

£12,775

0.85

Extended dominance

Boceprevir+PR

£12,967

–0.11

Dominated

Sofosbuvir+PR

£16,290

1.70

£9555

3D+RBV (for 24 weeks)

£46,450

2.11

£75,360

Genotype 1a HCV with cirrhosis; previously treated

PR

NA

NA

NA

Telaprevir+PR

£13,823

0.68

Extended dominance

Simeprevir+PR

£17,109

0.72

Extended dominance

Sofosbuvir+PR

£18,692

1.42

£13,157

3D+RBV (for 24 weeks)

£44,105

2.38

£26,516

Genotype 1b HCV without cirrhosis; previously untreated

PR

NA

NA

NA

Boceprevir+PR

£9265

0.50

Extended dominance

Telaprevir+PR

£13,271

0.82

Extended dominance

Simeprevir+PR

£14,128

0.92

Extended dominance

3D (for 12 weeks)

£18,833

1.39

£13,515

Sofosbuvir+PR

£23,659

0.95

Dominated

Genotype 1b HCV without cirrhosis; previously treated

PR

NA

NA

NA

Telaprevir+PR

£11,633

1.29

Extended dominance

Simeprevir+PR

£14,376

1.46

Extended dominance

3D (for 12 weeks)

£15,489

2.09

£7401

Sofosbuvir+PR

£21,427

1.47

Dominated

Genotype 1b HCV with cirrhosis; previously untreated

PR

NA

NA

NA

PR+telaprevir

£10,766

0.93

Extended dominance

3D+RBV (for 12 weeks)

£12,090

2.04

£5924

Simeprevir+PR

£12,136

0.94

Dominated

PR+boceprevir

£13,033

–0.12

Dominated

Sofosbuvir+PR

£20,338

1.16

Dominated

Genotype 1b HCV with cirrhosis; previously treated

PR

NA

NA

NA

3D+RBV (for 12 weeks)

£7874

2.55

£3087

Telaprevir+PR

£9159

1.25

Dominated

Simeprevir+PR

£10,640

1.51

Dominated

Sofosbuvir+PR

£16,822

1.65

Dominated

Genotype 4 HCV without cirrhosis; previously untreated

PR

NA

NA

NA

Simeprevir+PR

£14,415

0.41

Extended dominance

2D+RBV for 12 weeks

£17,204

0.85

£20,351

Sofosbuvir+PR

£21,951

0.81

Dominated

Genotype 4 HCV without cirrhosis; previously treated

No treatment

NA

NA

NA

2D+RBV for 12 weeks

£20,350

2.27

£8977

Simeprevir+PR

£21,236

1.72

Dominated

Sofosbuvir+PR

£28,150

1.64

Dominated

Genotype 4 HCV with cirrhosis; previously untreated

PR

NA

NA

NA

Simeprevir+PR

£9555

0.96

£9902

Sofosbuvir+PR

£15,955

1.41

£14,238

2D+RBV for 24 weeks

£39,781

2.01

£40,025

Genotype 4 HCV with cirrhosis; previously treated

No treatment

NA

NA

NA

Simeprevir+PR

£20,879

1.27

Extended dominance

Sofosbuvir+PR

£22,827

1.84

£12,432

2D+RBV for 24 weeks

£44,112

2.79

£22,331

Abbreviations: HCV, hepatitis C virus; ICER, incremental cost‑effectiveness ratio; 3D, ombitasvir–paritaprevir–ritonavir with dasabuvir; 2D, ombitasvir–paritaprevir–ritonavir without dasabuvir; NA, not applicable; PR, peginterferon alfa and ribavirin; QALY, quality‑adjusted life year; RBV, ribavirin.

Dominated – treatment gives fewer QALYs at greater cost than cost than comparator.

Extended dominance – a combination of 2 of its comparators provides equal health at a reduced cost.

Incremental costs and QALYs represent increments from reference (baseline) treatment.

Table 7 ICERs (£/QALY gained) for 3D or 2D in the revised base case and scenario analyses

Population

Scenario

Previously untreated

Previously treated

No cirrhosis

Cirrhosis

No cirrhosis

Cirrhosis

Genotype 1a HCV

Revised base case

£12,949

£75,360

£9589

£26,516

Scenario 1

£17,833

£92,828

£13,613

£33,332

Scenario 2

£17,028

£65,696

£17,047

£23,296

Genotype 1b HCV

Revised base case

£13,515

£5924

£7401

£3087

Scenario 1

£18,538

£7316

£10,480

£3861

Scenario 2

£17,431

£4837

£13,831

£2477

Genotype 4 HCV

Revised base case

£20,351

£40,025

£8977

£22,331

Scenario 1

£27,422

£48,791

£13,027

£27,877

Scenario 2

£18,673

£38,911

£8370

£17,355

Abbreviations: HCV, hepatitis C virus; ICER, incremental cost‑effectiveness ratio; 3D, ombitasvir–paritaprevir–ritonavir with dasabuvir; 2D: ombitasvir–paritaprevir–ritonavir without dasabuvir; QALY, quality‑adjusted life year.

3.27 The company stated that in its opinion the marketing authorisation allows for a 12‑week treatment in some people with genotype 1a HCV with cirrhosis. The company presented separate SVRs for genotype 1a and genotype 1b HCV from TURQUOISE II. The results were further stratified for each genotype by treatment history and response to previous treatment. For genotype 1a HCV treated with a 12‑week regimen, the SVR was more than 90% for all subgroups except for people whose HCV did not respond to previous peginterferon alfa and ribavirin treatment (SVR 80%). The company stated that in its regulatory submission it proposed a 24‑week treatment only for this subgroup of people with genotype 1a HCV with cirrhosis. Results presented in the summary of product characteristics showed higher relapse rates in genotype 1a HCV treated with a 12‑week regimen than with a 24‑week regimen. In TURQUOISE II there were 13 incidences of relapse and 11 of these were in people with genotype 1a HCV treated with a 12‑week regimen.

3.28 The company did a post‑hoc analysis to identify the predictors of relapse in genotype 1a HCV treated with a 12‑week regimen and found that for people with 3 favourable baseline laboratory values (alpha fetoprotein [AFP] less than 20 ng/ml, platelets 90×109/litre or more and albumin 35 g/litre or more), relapse rates were similar with the 12 and 24‑week treatments. The company noted that the summary of product characteristics acknowledged this post‑hoc analysis. On that basis, the company considered a 12‑week regimen for people with genotype 1a HCV with cirrhosis and these favourable baseline laboratory values to be within the marketing authorisation. However, the company did not provide SVR data or any economic analyses exclusively for this group.

3.29 The company also explored scenarios assuming that some people with genotype 1a HCV with cirrhosis would have treatment for 12 weeks. It assumed that everyone except those whose HCV did not respond to previous peginterferon alfa and ribavirin treatment would have a 12‑week treatment. All people with genotype 1a HCV with cirrhosis had a 24‑week treatment in the base case. To inform these analyses the company used corresponding SVRs for each population from the subgroup analyses of TURQUOISE II. The resulting ICERs for 3D plus ribavirin compared with peginterferon alfa plus ribavirin were £5985 per quality‑adjusted life year (QALY) gained for the previously untreated HCV group and £8812 per QALY gained for the previously treated HCV group.

3.30 The company presented probabilistic sensitivity analyses for 32 different populations. These also included the 12 populations for whom the Committee requested revised base‑case analyses. The company presented the results graphically in the form of cost‑effectiveness acceptability curves. The results showed that for a maximum acceptable ICER of £30,000 per QALY gained, 3D or 2D were the optimal treatment strategies for most of the revised base‑case population except for people with genotype 1a HCV with cirrhosis and genotype 4 HCV with cirrhosis. In these 2 populations sofosbuvir plus peginterferon alfa and ribavirin was the optimal treatment strategy.

ERG comments on the clinical effectiveness

3.31 The ERG was satisfied overall with the literature searches done by the company. However, it noted that one included phase II study (AVIATOR) did not meet the inclusion criteria because dasabuvir (a component of 3D), was administered at a dose (400 mg twice daily) higher than the licensed dose (250 mg twice daily).

3.32 The ERG was concerned about the lack of randomised controlled trials for 3D and 2D, and commented that all the completed trials included in the company's submission provided non‑randomised, observational data for the primary outcome of SVR12 (from individual trial arms or subgroups).

3.33 The ERG commented that the company did not provide sufficient detail about the similarity of people in the 3D trials to those in the telaprevir trials (ADVANCE, ILLUMINATE and REALIZE) used for the historical comparison of the other comparators relevant to the decision problem. During clarification, the company stated that it was not possible to examine the baseline characteristics for the specific matched historical controls, because these individual patient data for the telaprevir studies were not available.

3.34 The ERG commented that there were higher proportions of people with mild fibrosis (that is, fibrosis scores of F0 and F1) in the 3D trials than in the telaprevir trials used for historical comparison, which may have biased the SVR estimates in favour of 3D.

3.35 The ERG commented that in some trials (for example SAPPHIRE I and SAPPHIRE II) a subgroup provided the efficacy data on the licensed treatment. The subgroups were unlikely to be powered to demonstrate non‑inferiority and superiority over the historical control (telaprevir) because power calculations were based on the sample sizes of the whole trial population.

3.36 The ERG commented that the meta‑analysis that pooled data from the study treatment arms that are in line with the marketing authorisation for 3D is the most appropriate for this appraisal. The ERG noted that the company only presented results from the random‑effect model. The ERG re‑ran the meta‑analysis using an alternative software package, for random‑effect and fixed‑effect models, and obtained similar results for SVR (random‑effect model 96.5%, 95% confidence interval [CI] 94.6 to 97.7, fixed‑effect model 96.2%, 95% CI 94.7 to 97.3).

3.37 The ERG commented that the meta‑analysis only provided illustrative information about the average efficacy of 3D across a range of the licensed treatments in people with genotype 1 HCV. It noted that the company did not use the meta‑analysis findings for the economic analyses.

3.38 The ERG agreed that it was not possible to do a robust network meta‑analysis with the trials included in the company's submission. However, it commented that a network meta‑analysis of the comparator treatments would have been preferable for estimating their effectiveness for the economic analyses. The ERG also noted that it would be possible to do a network meta‑analysis for the population included in the ongoing MALACHITE trials (which directly compare 3D with telaprevir treatments).

ERG comments on the cost effectiveness

3.39 The ERG commented that in general, the modelling approach by the company was reasonable and consistent with the sources of evidence used in developing the model.

3.40 The ERG commented that the company did not did not compare the baseline characteristics of the population in the clinical audit (used to inform the baseline characteristics of the modelled population) with the baseline characteristics of the population in the clinical trials from which the clinical data were obtained.

3.41 The ERG was concerned that the method used by the company to estimate average duration of the treatments may not fully capture early stopping rules for patients unlikely to have an SVR with peginterferon‑based treatments, or who had response‑guided treatment with telaprevir or boceprevir. It also noted that the company used the same SVRs for both interferon‑eligible and interferon‑ineligible populations without justification.

3.42 The ERG noted that using SVR for simeprevir from the intention‑to‑treat population of the trials would underestimate its effectiveness. This is because the intention‑to‑treat population included people with Q80K polymorphism, which causes resistance to simeprevir and the 'true' SVR would be higher in people for whom simeprevir is licensed.

3.43 The ERG commented that the model outcomes should be interpreted with caution because the SVRs were from different trials and there was no statistical adjustment to account for the heterogeneity between trials. The ERG suggested that an alternative to the company's approach could be to derive a consistent evidence network for the comparators in the model, then do a threshold analysis when introducing 3D and 2D into the model.

3.44 The ERG noted that to populate the model, the company generalised some SVRs across populations with different characteristics such as HCV genotype and fibrosis stage. Sometimes this relied on data from small subgroups and on analyses for which the original trials were not powered. The ERG stated that the modelling did not reflect the additional uncertainty introduced by these assumptions.

3.45 The ERG questioned the rationale for using different on‑treatment utility decrements or gains for 3D and 2D stratified by fibrosis stage and treatment history for each genotype subtype. The ERG commented that the company did not discuss the clinical interpretation or statistical interaction of the different on‑treatment utility gains or decrements identified in the trials. The ERG was concerned that the modelling of on‑treatment utility difference, which was supposed to capture the disutility associated with adverse events, showed a utility gain for a number of groups (meaning that people are better on treatment than off it). The ERG commented that this could double count the utility benefit associated with SVR, which was already captured by the change in the health state from disease to recovery.

3.46 The ERG also questioned the method used for the on‑treatment utility difference calculation. The calculation was based on people's responses at the end of treatment, which was likely to miss people who had stopped treatment because of adverse events. However, the ERG acknowledged that this is less likely to be a significant problem, because only a few people stopped treatment in the trials because of adverse events.

3.47 For scenario 1 of the utility analysis, the ERG could not independently verify the utility gain associated with SVR estimated from trials because no details were provided by the company. For scenario 2, the ERG commented that no methodological detail was provided by the company on how it estimated utility values for each health state. The ERG noted that the company used 4 different values for each health state based on HCV genotype (1 and 4) and treatment history (previously untreated or previously treated). The ERG highlighted that in some cases utility values for the recovery states were lower than the corresponding disease states, for example, the utility values for the recovery states from the compensated cirrhosis states were lower than for the compensated cirrhosis states for genotype 1 HCV (both previously untreated and previously treated) and previously untreated genotype 4 HCV.

3.48 The ERG noted that the model did not allow for the methodological uncertainty from unadjusted indirect comparisons of alternative treatments. The ERG also noted that the company did not provide any sources or rationales for variation around parameter values, except for SVRs. The ERG also noted that the company presented only charts showing multiple cost‑effectiveness acceptability curves without providing any summary results or comparison with the deterministic results and many presented analyses were not relevant to the revised base case. The ERG highlighted that the probabilistic analyses did not capture additional uncertainty introduced by data imputation as well as uncertainties arising from using SVR from different populations. Therefore the analyses were likely to underestimate the uncertainty in the cost‑effectiveness results.

Additional evidence

3.49 The company submitted revised cost‑effectiveness analyses using reduced prices for 3D and 2D based on contract pricing arrangements between the company and the Commercial Medicines Unit. The contract prices are the relevant prices paid by the NHS for 3D and 2D and are commercial in confidence. The ICERs are also commercial in confidence because they allow the contract prices to be calculated. Using the contract prices, the base‑case ICERs for 3D and 2D with or without ribavirin compared with the relevant comparators from the fully incremental analyses were below £20,000 per QALY gained for all genotypes considered, regardless of the presence of cirrhosis or treatment history.

3.50 The company also presented separate analyses using the utility assumptions in scenario 1 and scenario 2 of the original analysis (see section 3.23). For scenario 1, which was the Committee's preferred scenario, the ICERs for 3D and 2D with or without ribavirin were also below £20,000 per QALY gained, except for the untreated genotype 4 HCV subgroup without cirrhosis. In this group, the ICER for 2D and ribavirin compared with peginterferon alfa and ribavirin was above £20,000 per QALY gained but below £30,000 per QALY gained. The company emphasised that the utility in scenario 1 underestimates the quality‑of‑life benefits of an SVR because the final EQ‑5D values were collected before people were aware of their SVR status. Therefore, the psychological and emotional benefits of being cured were less likely to be captured. The company also expressed concerns that the approach taken by the Committee was inconsistent with other related hepatitis C appraisals, in which higher utility values from published studies were accepted. For scenario 2, the ICERs for 3D and 2D with or without ribavirin were all under £20,000 per QALY gained.

3.51 The ERG commented that it was able to replicate the company's results. It confirmed that the model inputs and assumptions were consistent with those in the company's original analysis, with the exception of the contract prices.

3.52 Full details of all the evidence are available.

  • National Institute for Health and Care Excellence (NICE)