4 Consideration of the evidence
The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of ombitasvir–paritaprevir–ritonavir with or without dasabuvir, having considered evidence on the nature of chronic hepatitis C and the value placed on the benefits of ombitasvir–paritaprevir–ritonavir with or without dasabuvir by people with the condition, those who represent them, and clinical experts. It also took into account the effective use of NHS resources.
4.1 The Committee heard from the clinical and patient experts about the nature of chronic hepatitis C. The patient expert stated that some people with chronic hepatitis C do not have any symptoms, but others may have chronic fatigue, mood swings and symptoms of sexual dysfunction. The severity of symptoms does not depend on the stage of fibrosis. The clinical and patient experts also commented that the psychological effect of having chronic hepatitis C can impair people's social life and ability to work, and that people can have anxiety about transmitting the virus. There is also stigma about having chronic hepatitis C because it is associated with drug use. The Committee heard from the patient expert that people who have chronic hepatitis C are a disadvantaged population. The patient expert anticipated that the availability of clinically effective treatment options of short treatment duration, such as ombitasvir–paritaprevir–ritonavir with dasabuvir (3D) and ombitasvir–paritaprevir–ritonavir without dasabuvir (2D), will encourage more people to seek diagnosis and treatment. It would also allow access to treatment for people who have found it difficult to access treatment before, such as people in prison, people who use injectable drugs and migrant populations. The Committee recognised the effect of chronic hepatitis C on the lives of people with the virus. It concluded that treatments that give very high levels of sustained virological response (which is considered equivalent to a cure), and so help reduce the rate of hepatitis C virus (HCV) transmission and the stigma associated with having chronic hepatitis C, are of major importance.
4.2 The Committee discussed the clinical management of chronic hepatitis C in adults. It heard from the clinical experts that treatment decisions and response to treatment are influenced by HCV genotype, level of liver damage, comorbidities and treatment history. The Committee was aware that 3D and 2D have a marketing authorisation in the UK for adults with genotype 1a, 1b, or 4 HCV. For people with genotype 1 HCV, the Committee noted that boceprevir plus peginterferon alfa and ribavirin or telaprevir plus peginterferon alfa and ribavirin (see NICE's technology appraisal guidance on boceprevir for the treatment of genotype 1 chronic hepatitis C and telaprevir for the treatment of genotype 1 chronic hepatitis C) are commonly used, and that for people with genotype 1 or 4 HCV, peginterferon alfa plus ribavirin is also used in clinical practice (see NICE's technology appraisal guidance on peginterferon alfa and ribavirin for the treatment of chronic hepatitis C, peginterferon alfa and ribavirin for the treatment of mild chronic hepatitis C and interferon alfa (pegylated and non-pegylated) and ribavirin for the treatment of chronic hepatitis C). The clinical experts highlighted that some people with chronic hepatitis C would choose not to have treatment with peginterferon alfa plus ribavirin because it can be associated with severe side effects, such as fatigue, neuropsychological effects and flu‑like symptoms. The Committee also heard from the clinical and patient experts that interferon‑based treatment may cause chronic side effects (such as insulin‑dependent diabetes) that need additional long‑term management. It may therefore pose another barrier to people starting and completing treatment. Without treatment people risk further disease progression, for example, to cirrhosis. The Committee recognised the importance of having further treatment options available for people with chronic hepatitis C, and that interferon‑free treatments, such as 3D and 2D, would provide a valuable treatment option.
4.3 The Committee discussed whether the technologies in the NICE scope that had recently been granted a marketing authorisation for treating adults with chronic hepatitis C were established clinical practice in England. The Committee was aware that:
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NICE's technology appraisal guidance on simeprevir for treating chronic hepatitis C recommends simeprevir plus peginterferon alfa and ribavirin as an option for treating genotype 1 and 4 chronic hepatitis C.
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NICE's technology appraisal guidance on sofosbuvir for treating chronic hepatitis C recommends sofosbuvir plus peginterferon alfa and ribavirin as an option for treating genotype 1 HCV. For genotype 4 HCV this combination is recommended only for people who have cirrhosis.
The Committee concluded that sofosbuvir plus peginterferon alfa and ribavirin, as well as simeprevir plus peginterferon alfa and ribavirin, as recommended in NICE guidance, were relevant comparators for 3D and 2D.
4.4 The Committee considered whether best supportive care was a relevant comparator for 3D and 2D. It was aware that best supportive care, which may include watchful waiting, may be considered an appropriate option for some people. However, it was also aware that this option would likely become a less common choice because direct‑acting antivirals can treat hepatitis C effectively, with relatively short durations of treatment and without interferon. The Committee noted that in addition to 3D and 2D, there are other new interferon‑free, direct‑acting antivirals, for example daclatasvir plus sofosbuvir, ledipasvir–sofosbuvir, simeprevir plus sofosbuvir, and sofosbuvir plus ribavirin. However, it was aware that these are not yet established practice in the NHS. Therefore the Committee concluded that, at present, best supportive care (watchful waiting) was still an appropriate comparator in some populations. The Committee also concluded that for people who cannot have interferon‑based treatments, best supportive care was the appropriate comparator.
4.5 The Committee discussed the treatment duration and specific treatment regimens for 3D and 2D for chronic hepatitis C. The Committee noted that the summary of product characteristics recommends different regimens of 3D in terms of concomitant administration of ribavirin and duration of treatment for the subtypes of genotype 1 HCV (1a and 1b). The Committee discussed whether subtypes of genotype 1 HCV were routinely identified in clinical practice and whether the subtypes were managed differently. The Committee heard from the clinical experts that subtypes are identified in clinical practice but that sometimes mixed genotype 1 HCV infection is identified. The Committee noted that the summary of product characteristics recommends using the treatment regimen for subtype 1a HCV if the subtype is not known or for people with mixed genotype 1 HCV infection. The Committee also heard from the clinical experts that genotype 1b HCV is easier to treat with interferon‑based regimens than genotypes 1a and 4 HCV and that genotype 1b HCV needs only a short duration of response‑guided treatment based on rapid virological response. The Committee was aware that separate clinical effectiveness data for 3D regimens were available for the 1a and 1b subtypes of genotype 1 HCV. The Committee concluded that it would examine the clinical and cost‑effectiveness evidence for treating subtypes of genotype 1 HCV separately.
4.6 The Committee was aware that for people with genotype 1a or 4 HCV and with compensated cirrhosis, the summary of product characteristics recommends a 24‑week treatment duration. However, it heard from the company that based on the results from TURQUOISE II (also presented in the summary of the product characteristics), many people with genotype 1a HCV with cirrhosis would have a 12‑week treatment, and that the 24‑week treatment would be reserved for a subgroup of people who have had treatment before and who did not respond to initial interferon‑based therapy. The clinical experts were not in a position to confirm this because there is very limited UK experience with 3D and 2D. The Committee noted that the SVRs in all subgroups of people with genotype 1a HCV with cirrhosis for both treatment durations were more than 90%, except in people who have had treatment before and who did not respond to initial interferon‑based therapy. However, the Committee understood that the Committee for Human Medicinal Products (CHMP) decided to recommend a 24‑week treatment because of the substantially higher relapse rate seen in people who had the 12‑week treatment than in those who had the 24‑week treatment in TURQUOISE II (see section 3.27). The Committee noted the company's opinion that the marketing authorisation allows for 12‑week treatment in some people with genotype 1a HCV with cirrhosis, specifically for those who have 3 favourable baseline laboratory values, that is alpha fetoprotein (AFP) less than 20 ng/ml, platelets 90×109/litre or more and albumin 35 g/litre or more (see section 3.28). The Committee discussed the CHMP's clarification of the marketing authorisation about a 12‑week treatment for people with genotype 1a HCV with cirrhosis. This stated that the cut‑offs used to define favourable characteristics were 'clinically arbitrary' and 'fraught with uncertainty' and the CHMP 'could not make any recommendation on a 12‑week treatment'. The Committee agreed that the regulatory process had not established a benefit‑risk balance for a 12‑week treatment in people with genotype 1a HCV with cirrhosis. The Committee therefore concluded that in its opinion, any treatment for a shorter duration than 24 weeks in people with genotype 1a HCV with cirrhosis would be considered outside the marketing authorisation.
Clinical effectiveness
4.7 The Committee considered the quality of the clinical trial evidence for the 3D treatments. It was aware that the trials in the company submission did not include any of the comparators listed in the final scope issued by NICE, but acknowledged that with treatments for chronic hepatitis C rapidly evolving, this was to be expected. The Committee was aware that the trials for genotype 1 HCV were designed with the European Medicines Agency, which accepted that historical comparisons with telaprevir were sufficient to demonstrate efficacy. The Committee noted that the ongoing MALACHITE I and MALACHITE II trials directly compare 3D with telaprevir in people with genotype 1 HCV. It was reassured that the interim results from these trials were in line with the results of completed trials. The Committee acknowledged the high SVR12 rates reported in all the trials and heard from the clinical and patient experts that the results in people with genotype 1 HCV were impressive. The Committee noted the weaknesses associated with studies that used historical controls rather than a conventional control group, but concluded that the trials showed that the 3D treatments were effective in people with genotype 1 HCV.
4.8 The Committee considered the clinical effectiveness evidence for 2D in people with genotype 4 HCV. The Committee noted that there were limited data available in people with genotype 4 HCV. It agreed that this increased the uncertainty about whether the SVR rates from the genotype 4 HCV population would be seen in clinical practice. The Committee noted that 2D was studied in a phase II trial that included only people with genotype 4 HCV without cirrhosis, but that the marketing authorisation also included people with genotype 4 HCV with compensated cirrhosis. The Committee was aware that this population was included in the marketing authorisation on the basis that 2D is effective in genotype 1b HCV with cirrhosis, and by extrapolation, also in genotype 4 HCV with cirrhosis. It questioned whether the SVRs for people with genotype 1b HCV could be generalised to people with genotype 4 HCV. The Committee was aware that generally genotype 1b HCV is considered easier to treat than genotype 4 or 1a HCV and discussed whether it would have been more appropriate to extrapolate SVR from genotype 1a HCV. The Committee noted that no data for the effectiveness of 2D in genotype 1a HCV were available because people with genotype 1a HCV were not included in PEARL I. The Committee remained concerned about the small numbers of people with genotype 4 HCV included in the evidence base. However, it concluded that it would accept that 2D would potentially demonstrate a similar treatment effect in people with genotype 4 HCV with cirrhosis and people with genotype 1b HCV with cirrhosis.
4.9 The Committee considered the clinical effectiveness evidence for 3D and 2D in people who cannot have interferon. The Committee understood that these people cannot have interferon because of a medical or psychiatric comorbidity or are unwilling to have interferon because of possible side effects. The Committee heard from the company that although interferon eligibility was not recorded at baseline in the trials, a post‑hoc analysis of people with depression (a contraindication to interferon treatment) from SAPPHIRE I, SAPPHIRE II and TURQUOISE II indicated that there was no significant difference in the SVR for this group and the SVR for the whole trial populations. The Committee noted that the company did not provide this post‑hoc analysis in its submission, but agreed that there was no reason to assume that the effectiveness of 3D and 2D would differ depending on eligibility for interferon.
4.10 The Committee considered the safety data included in the company's submission and noted that the adverse events reported in the trials were generally consistent with those reported in other studies for hepatitis C treatments. It heard from the clinical experts that 3D and 2D were assumed to have a better safety profile than interferon‑containing treatments, and most adverse events reported in the trials were likely to be related to ribavirin rather than 3D and 2D. The Committee concluded that the adverse events associated with 3D and 2D were generally tolerable and 3D and 2D have a better safety profile than interferon‑containing treatments.
4.11 The Committee discussed the company's approach to estimating the relative effectiveness of 3D and 2D (with or without ribavirin) compared with the comparators in the final scope issued by NICE. The Committee noted that for the licensed 3D treatments, when data were available from more than 1 trial, the company estimated SVR by simple pooling of the numbers of people whose HCV responded and the total number of people in the trials. The company compared this with the SVRs of the comparators from different trials without any statistical adjustment. The Committee noted that the company did not attempt a mixed treatment comparison because most of the efficacy data for 3D and 2D were from single treatment arms of the trials. It also noted that the results from such a comparison can be difficult to interpret because of the different characteristics of those recruited to the trials. However, it understood from the Evidence Review Group (ERG) that it would have been possible to do a mixed treatment comparison for genotype 1 HCV by including data from the ongoing MALACHITE trials. The Committee agreed that the company's approach was not robust and leads to considerable uncertainty in determining the size of the true treatment effect. The Committee also understood from previous NICE technology appraisals for hepatitis C that the SVRs were likely to depend on the characteristics of the populations recruited into the studies, particularly for comparator therapies such as peginterferon alfa plus ribavirin, which may affect the relative treatment effect. The Committee was concerned that the company had selected SVRs from single treatment arms of the trials, particularly because this uncertainty was not captured in the company's estimates of cost effectiveness. The Committee concluded that the company's evidence for estimating the relative effectiveness of 3D and 2D (with or without ribavirin) in genotypes 1 and 4 HCV was not robust, and therefore this uncertainty should be taken into account in the decision‑making.
Cost effectiveness
4.12 The Committee considered the company's economic model, the assumptions underlying the values of the parameters, additional analyses by the company and the critique and exploratory analyses from the ERG. The Committee noted that the structure of the model representing the natural history of the disease was similar to models submitted for other NICE technology appraisals for chronic hepatitis C. The Committee was aware of the ERG's concerns that the original model was developed to evaluate interferon‑based treatments and might not fully represent the course of the disease in people who are not eligible for interferon. However, the Committee concluded that the structure of the company's model was acceptable for its discussions.
4.13 The Committee noted that the company presented 3 separate analyses; the base‑case using a utility benefit of 0.05 from Wright et al., scenario 1 using utility data from the trials and scenario 2 using alternative utility data from the trials (see section 3.23). At the previous meeting, the Committee concluded that the health state values used in scenario 2 were uncertain and not reliable. Therefore it did not consider this scenario any further. At the previous meeting, the Committee also concluded that the utility benefit for SVR estimated from the trials was the most accurate estimate it had seen and that scenario 1 was the most plausible scenario to inform its decisions. However, it noted the comments during the previous meeting and the company's comments on the appraisal consultation document that the utility gain in scenario 1 underestimates the quality‑of‑life benefits of an SVR. The Committee agreed that because the final EQ‑5D values were collected before people were aware of their SVR status, the psychological and emotional benefits of being cured were less likely to be captured. The Committee was aware that higher utility benefits from Wright et al. (0.05) and Vera‑Llonch et al. (0.041) had been accepted in previous and ongoing NICE technology appraisals for chronic hepatitis C. The Committee emphasised that utility values derived from trials are preferred to those estimated from other sources. However, because the utility benefit from the trials in this appraisal was likely to be underestimated, the Committee concluded that the most appropriate estimate would likely lie between the trial estimate in scenario 1 and the estimate of 0.05 used in the base case.
4.14 The Committee considered the costs used in the company's model. It noted that the list prices of 3D and 2D were used in the original analyses, whereas confidential contract prices were used in the company's revised analyses. The Committee understood that the contract prices were the relevant prices the NHS pays for 3D and 2D. The Committee noted that NICE's guide to the methods of technology appraisal indicates a preference for using nationally available price reductions in the reference‑case analysis to reflect the price relevant to the NHS. It understood that analyses based on price reductions for the NHS would only be considered if the reduced prices are transparent and consistently available across the NHS, and if the period for which the specified prices are available is guaranteed. The Committee noted from the evidence submitted by the company that the contract prices were nationally available in England. It was also satisfied that the contract frameworks were transparent because they can easily be accessed by NHS organisations through the Commercial Medicines Unit. The Committee understood that the contract prices were fixed for the duration specified in the framework agreement, after which they will be reviewed annually, and the prices were likely to be the maximum the NHS would pay. The Committee concluded that the contract prices were the most relevant prices to the NHS and therefore the appropriate prices on which to base its decision. It also concluded that its recommendations using the contract prices are conditional on the prices not rising above those considered in this appraisal, otherwise, the guidance will need to be considered for review.
Recommendations
4.15 Having concluded that the most plausible scenario would likely lie between scenario 1 (which incorporated utility gain as estimated from the trials) and the base‑case analysis (which incorporated the utility gain of 0.05 from Wright et al. (see section 4.13), the Committee discussed the corresponding revised incremental cost‑effectiveness ratios (ICERs) for 3D and 2D with or without ribavirin compared with the relevant comparators from the fully incremental analysis.
Genotype 1b
4.16 The Committee noted that the ICERs using the contract prices for 3D or 3D plus ribavirin for the 12‑week treatment, in all subgroups based on the treatment history and presence of cirrhosis, were below £20,000 per quality‑adjusted life year (QALY) gained for both the base case and scenario 1 analyses. The Committee concluded that the 12‑week 3D treatments were a cost‑effective use of NHS resources for treating genotype 1b HCV.
Genotype 1a
4.17 The Committee noted that the ICERs using the contract prices for 3D plus ribavirin for the 12‑week treatment in people without cirrhosis and the 24‑week treatment in people with compensated cirrhosis, were below £20,000 per QALY gained regardless of treatment history, for both the base case and scenario 1 analyses. The Committee concluded that 3D plus ribavirin could be considered a cost‑effective use of NHS resources in people with genotype 1a HCV without cirrhosis (12‑week treatment duration), and with cirrhosis (24‑week treatment duration).
Genotype 4
4.18 The Committee noted that the ICERs using the contract prices for 2D plus ribavirin for the 24‑week treatment in people with genotype 4 HCV with compensated cirrhosis, regardless of treatment history, were below £20,000 per QALY gained for both the base case and scenario 1 analyses. For the 12‑week treatment in people without cirrhosis, the Committee noted that the ICER using the contract price for the previously treated subgroup was below £20,000 per QALY gained for both the base case and scenario 1 analyses. However, for the previously untreated subgroup without cirrhosis, the base‑case ICER using the contract price was below £20,000 per QALY gained, whereas the ICER for scenario 1 using the contract price was above £20,000 per QALY gained but below £30,000 per QALY gained. Based on its previous conclusion on the most appropriate scenario (see section 4.13), the Committee agreed that the most plausible ICER would likely be below or at most, approximately £20,000 per QALY gained. Therefore, the Committee concluded that 2D plus ribavirin could be considered a cost‑effective use of NHS resources in people with genotype 4 HCV without cirrhosis (12‑week treatment duration), and with cirrhosis (24‑week treatment duration).
Innovation
4.19 The Committee discussed whether 3D and 2D could be considered innovative, and whether the company's economic analysis had captured all changes in health‑related quality of life. The Committee agreed that compared with current treatment, 3D and 2D offer oral, shortened, interferon‑free treatments, which are particularly important to people, and a major development in the clinical management of chronic hepatitis C. The Committee therefore acknowledged that 3D and 2D are valuable new therapies for treating chronic hepatitis C. The Committee agreed that there were other benefits for people with chronic hepatitis C (for example, possible regression of fibrosis) and wider benefits to society (for example, reduced transmission of HCV, improved earning capacity) that were not captured in the QALY calculation and that, if taken into account, were likely to decrease the ICERs. However, the Committee considered that it had taken these potential benefits into account in its conclusions on the cost effectiveness of 3D and 2D for each population.
NHS England
4.20 The Committee discussed NHS England's submission relating to:
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the implementation of 3 oral treatments for hepatitis C in the NHS (ledipasvir–sofosbuvir, daclatasvir and ombitasvir–paritaprevir–ritonavir with or without dasabuvir)
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NICE's general duties 'to have regard to the broad balance between benefits and costs of the provision of health services or of social care in England and the degree of need of persons for health services or social care in England'.
The Committee understood that NHS England considered these new oral treatments to be excellent options, but was concerned about the increase in investment and capacity needed for their implementation. The Committee heard from the patient expert that people with chronic hepatitis C appreciated the capacity constraints placed on the NHS in delivering treatment for every eligible person. The Committee recalled that treatment decisions are influenced by clinical characteristics including HCV genotype, level of liver damage, comorbidities and treatment history (see section 4.2). With these factors in mind, people with chronic hepatitis C may accept treatment being prioritised for those with the highest unmet clinical need (including some people without cirrhosis), potentially determined by multidisciplinary teams.
4.21 The Committee heard from NHS England that up to 20,000 people could access treatment each year if NICE recommended these treatments for people with chronic hepatitis C (including people without cirrhosis). However, the Committee understood from the responses to the NHS England submission that this estimate was too high. The Committee heard from the clinical experts that a more realistic estimate for the number of people accessing treatment in England was likely to be between 7000 and 10,000 each year. The Committee was aware that NHS England considered that treating 7000 people with these new oral treatments each year would not be affordable within the current NHS budget. The Committee acknowledged that there would be significant impact on the total budget for specialised services associated with making these drugs available in the NHS. However, the Committee noted the responses from consultees on NHS England's submission that the estimates presented by NHS England were not robust, and that they omitted potential savings from reducing transmission of HCV. The Committee further understood that NHS England is exploring other ways of managing the financial impact of using these new drugs, such as tendering, and that it could be argued that the rebate provided by companies as part of the 2014 Pharmaceutical Price Regulation Scheme (PPRS) payment mechanism could be considered as a way of managing the budgetary impact of access to these treatments. The Committee understood, in this context, that one of the key objectives of the PPRS is to 'improve access to innovative medicines commensurate with the outcomes they offer patients by ensuring that medicines approved by NICE are available widely in the NHS'.
4.22 The Committee recognised that NICE's guide to the methods of technology appraisal indicates that there needs to be increasing certainty of the cost effectiveness of a technology as the NHS budget impact of its adoption increases. However, the Committee noted that the ICERs were generally below £20,000 per QALY gained for ombitasvir–paritaprevir–ritonavir with or without dasabuvir for the populations specified in the marketing authorisation. The Committee emphasised that, if the uncertainties were accounted for in the modelling of the cost effectiveness (for example, incremental QALYs gained from an SVR12, the costs and benefits associated with treatment of reinfection, and savings from preventing HCV transmission), the ICERs were likely to remain below £20,000 per QALY gained.
4.23 The Committee understood that, given the rapid sequential assessment of direct‑acting antiviral drug combinations now licensed for treating hepatitis C, it will be worthwhile exploring whether there are combinations or sequences of treatments, for example by genotype, treatment experience or cirrhosis status, that could be of particular value to people with chronic hepatitis C, clinicians and the NHS. The Committee agreed that further work by NICE to support this should be started as soon as possible.
4.24 The Committee discussed comments received from NHS England at consultation that proposed an 'only in research' recommendation for people with untreated genotype 1 HCV without cirrhosis. The Committee understood from NHS England that a clinical trial, STOP‑HCV‑1, will assess SVR rates in people with untreated genotype 1 HCV without cirrhosis who have direct‑acting antiviral drugs, including 3D, for shorter durations than stipulated in the marketing authorisation. The Committee was aware that the final protocol has not been agreed and STOP‑HCV‑1 has not started. It considered that the clinical effectiveness evidence available for 3D for people with untreated genotype 1 HCV without cirrhosis was more robust than the evidence available for other populations considered in this technology appraisal and that the ICER was below £20,000 per QALY gained. The Committee further agreed that its recommendation would not stop people from taking part in the proposed STOP‑HCV‑1 trial because the treatment of chronic hepatitis C will be managed through established operational delivery networks in the NHS. The Committee concluded that an 'only in research' recommendation was not appropriate for 3D in people with untreated genotype 1 HCV without cirrhosis.
Pharmaceutical Price Regulation Scheme
4.25 The Committee considered whether it should take into account the consequences of the PPRS 2014, and in particular the PPRS payment mechanism, when appraising ombitasvir–paritaprevir–ritonavir with or without dasabuvir. The Committee noted NICE's position statement about this, and accepted the conclusion 'that the 2014 PPRS payment mechanism should not, as a matter of course, be regarded as a relevant consideration in its assessment of the cost effectiveness of branded medicines'. The Committee heard nothing to suggest that there is any basis for taking a different view about the relevance of the PPRS to this appraisal of ombitasvir–paritaprevir–ritonavir with or without dasabuvir. It therefore concluded that the PPRS payment mechanism was irrelevant in considering the cost effectiveness of ombitasvir–paritaprevir–ritonavir with or without dasabuvir.
Equality issues
4.26 The Committee noted the potential equality issue raised by consultees that minority ethnic groups and people with HIV co‑infection are more highly represented in the genotype 4 HCV population than in the genotype 1 HCV population. The Committee also noted the consultation comment from the Haemophilia Society that any delay in access to treatment would have a significant adverse impact on people with haemophilia and other bleeding disorders. However, having decided that 3D and 2D treatments should be recommended for all the groups specified in the marketing authorisation, the Committee concluded that no further consideration of these potential equality issues was necessary to meet NICE's obligation to promote equality of access to treatment. The Committee also noted the comment from the company stating that the efficacy of 3D and 2D is not expected to differ in people with HIV co‑infection. Therefore recommendations on the use of 3D or 2D should not differ for people with or without HIV co‑infection. The Committee noted that the summary of product characteristics recommends the same treatment regimens for people with HIV co‑infection. The Committee was satisfied that its recommendations do not restrict access to 3D and 2D treatments for people with HIV co‑infection.
Summary of Appraisal Committee's key conclusions
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TA365 |
Appraisal title: Ombitasvir–paritaprevir–ritonavir with or without dasabuvir for treating chronic hepatitis C |
Section |
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Key conclusion |
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The Committee noted that the company's approach to estimating the relative effectiveness of 3D (ombitasvir–paritaprevir–ritonavir with dasabuvir) and 2D (ombitasvir–paritaprevir–ritonavir without dasabuvir) with or without ribavirin compared with the comparators was not robust, and therefore this uncertainty should be taken into account in the decision‑making. The Committee agreed that the utility benefit estimated from the trials in this appraisal was likely to be underestimated; therefore it concluded that the most appropriate estimate would likely lie between the trial estimate in scenario 1 and the estimate of 0.05 from Wright et al. used in the base case. The Committee concluded that the contract prices were the most relevant prices to the NHS and therefore the appropriate prices on which to base its decision. It also concluded that its recommendations using the contract prices are conditional on the prices not rising above those considered in this appraisal, otherwise, the guidance will need to be considered for review. The Committee concluded that:
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4.11, 4.13, 4.14, 4.16, 4.17, 4.18 |
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Current practice |
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Clinical need of patients, including the availability of alternative treatments |
Treatment decisions and response to treatment are influenced by HCV genotype, level of liver damage, comorbidities and treatment history. For people with genotype 1 HCV, the Committee heard that boceprevir plus peginterferon alfa and ribavirin or telaprevir plus peginterferon alfa and ribavirin are commonly used, and that for people with genotypes 1 or 4 HCV, peginterferon alfa plus ribavirin is also used in clinical practice. The Committee concluded that sofosbuvir and simeprevir, as recommended in NICE guidance, were relevant comparators. |
4.2, 4.3 |
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The technology |
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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 noted that treatment with peginterferon alfa plus ribavirin can cause severe side effects and interferon‑free treatments, such as 3D and 2D, would provide a valuable treatment option. The Committee agreed that there were other benefits for people with hepatitis C (for example, possible regression of fibrosis) and wider benefits to society (for example, reduced transmission of HCV, improved earning capacity). |
4.2, 4.19 |
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What is the position of the treatment in the pathway of care for the condition? |
The Committee recognised the importance of having further treatment options available for people with chronic hepatitis C, and that interferon‑free treatments, such as 3D and 2D, would provide a valuable treatment option. |
4.2 |
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Adverse reactions |
The Committee concluded that the adverse events associated with 3D and 2D were generally tolerable and 3D and 2D have a better safety profile than interferon‑containing treatments. |
4.10 |
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Evidence for clinical effectiveness |
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Availability, nature and quality of evidence |
The Committee was aware that the trials did not include any of the comparators listed in the final NICE scope and noted the weaknesses associated with studies that used historical controls. The Committee noted the limited available evidence in people with genotype 4 HCV. |
4.7, 4.8 |
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Relevance to general clinical practice in the NHS |
The Committee noted that the summary of product characteristics recommends different regimens of 3D in terms of concomitant administration of ribavirin and duration of treatment for subtypes of genotype 1 HCV (1a and 1b). The Committee heard from the clinical experts that subtypes are identified in clinical practice but that sometimes mixed genotype 1 HCV infection is identified. |
4.5 |
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Uncertainties generated by the evidence |
The Committee noted that for the licensed 3D treatments, when data were available from more than 1 trial, the company estimated sustained virological response (SVR) by simple pooling of the numbers of people whose HCV responded and the total number of people in the trials. The company compared this with the SVRs of the comparators from different trials without any statistical adjustment. The Committee agreed that the company's approach was not robust and leads to considerable uncertainty in determining the size of the true treatment effect. The Committee noted that there was limited evidence available in people with genotype 4 HCV and no data were available in people with genotype 4 HCV with compensated cirrhosis. |
4.8, 4.11 |
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Are there any clinically relevant subgroups for which there is evidence of differential effectiveness? |
The Committee recommended the treatments for all subgroups in line with the marketing authorisation. |
4.16–4.18 |
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Estimate of the size of the clinical effectiveness including strength of supporting evidence |
The Committee noted the weaknesses associated with studies that used historical controls rather than a conventional control group, but concluded that the trials showed that the 3D treatments were effective in people with genotype 1 HCV. The Committee noted that 2D was studied in a phase II trial that included only people with genotype 4 HCV without cirrhosis, but that the marketing authorisation also included people with genotype 4 HCV with compensated cirrhosis. |
4.7, 4.8 |
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Evidence for cost effectiveness |
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Availability and nature of evidence |
The Committee noted that the structure of the model representing the natural history of the disease was similar to models submitted for other NICE technology appraisals for chronic hepatitis C. |
4.12 |
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Uncertainties around and plausibility of assumptions and inputs in the economic model |
The Committee was aware of the ERG's concerns that the original model was developed to evaluate interferon‑based treatments and might not fully represent the course of the disease in people who are not eligible for interferon. The Committee emphasised that utility values derived from trials are preferred to those estimated from other sources. However, it considered that the utility benefit from the trials in this appraisal was likely to be underestimated. |
4.12, 4.13 |
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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 agreed that the utility benefit from the trials in this appraisal was likely to be underestimated; therefore it concluded that the most appropriate estimate would likely lie between the trial estimate in scenario 1 and the estimate of 0.05 from Wright et al. used in the base case. The Committee agreed that compared with current treatment, 3D and 2D offer oral, shortened, interferon‑free treatments, which are particularly important to people, and a major development in the clinical management of chronic hepatitis C. The Committee agreed that there were other benefits for people with chronic hepatitis C (for example, possible regression of fibrosis) and wider benefits to society (for example, reduced transmission of HCV, improved earning capacity) that were not captured in the quality‑adjusted life year (QALY) calculation. |
4.13, 4.19 |
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Are there specific groups of people for whom the technology is particularly cost effective? |
The Committee recommended the treatments for all subgroups in line with the marketing authorisation. |
4.16–4.18 |
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What are the key drivers of cost effectiveness? |
The prices of the drugs and the utility benefit of an SVR were the key drivers of the cost‑effectiveness results. |
3.49–3.50 |
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Most likely cost‑effectiveness estimate (given as an ICER) |
The ICERs based on the scenario 1 analysis and using the contract prices for 3D and 2D were all below £20,000 per QALY gained, except for the untreated genotype 4 HCV subgroup without cirrhosis. The ICER for this group was above £20,000 per QALY gained but below £30,000 per QALY gained. However based on the Committee's conclusion that the most plausible scenario would lie between the base case and scenario 1, the Committee concluded that the most plausible ICER for 2D plus ribavirin in the genotype 4 HCV subgroup without cirrhosis would likely be below or at most, approximately £20,000 per QALY gained. |
4.16–4.18 |
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Additional factors taken into account |
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Patient access schemes (PPRS) |
The company has agreed a nationally available price reduction for ombitasvir–paritaprevir–ritonavir with or without dasabuvir with the Commercial Medicines Unit. |
2.4 |
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End‑of‑life considerations |
Not applicable |
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Equalities considerations and social value judgements |
Having decided that 3D and 2D treatments should be recommended for all the groups specified in the marketing authorisation, the Committee concluded that no further consideration of the potential equality issues raised by consultees was necessary to meet NICE's obligation to promote equality of access to treatment. The Committee was also satisfied that its recommendations do not restrict access to 3D and 2D treatments for people with HIV co‑infection. |
4.26 |
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