NATIONAL INSTITUTE FOR HEALTH AND CLINICAL EXCELLENCE. Single Technology Appraisal (STA)

Transcription

1 NATIONAL INSTITUTE FOR HEALTH AND CLINICAL EXCELLENCE Single Technology Appraisal (STA) Telaprevir for the treatment of genotype 1 chronic hepatitis C 21 st October 2011 Page 1 of 239

2 Contents Contents... 2 List of tables... 3 List of figures... 5 List of abbreviations... 6 Executive Summary... 9 Section A Decision problem Description of technology under assessment Context Equity and equality Statement of the decision problem Section B Clinical and cost effectiveness Clinical evidence Cost effectiveness Section C Implementation Assessment of factors relevant to the NHS and other parties References APPENDICES Page 2 of 239

3 List of tables Table 1 Base case cost-effectiveness results Table 2 Unit costs of technology being appraised Table 3 Current NICE HCV guidance Table 4 Eligibility criteria for trials to be included in the systematic review Table 5 List of included RCTs Table 6 List of relevant RCTs Table 7 Comparative summary of methodology of the RCTs Table 8 Eligibility criteria in the RCTs Table 9 Characteristics of participants in the RCTs across randomised groups Table 10 Age and disease severity distribution of T12/PR and PBO/PR patients in ADVANCE Table 11 Prior response and disease severity distribution of T12/PR and PBO/PR patients in REALIZE Table 12 Primary and secondary outcomes of the RCTs Table 13 Summary of statistical analyses in RCTs Table 14 SVR rate according to patient subgroups Table 15 Quality assessment results for RCTs Table 16 VF in ADVANCE Table 17 Adherence to study drugs in ADVANCE Table 18 Reasons for discontinuation in ADVANCE Table 19 Duration of therapy in ADVANCE Table 20 EQ-5D valuation index scores over time in ADVANCE Table 21 FSS score in ADVANCE Table 22 SVR rates by IL-28B subtype Table 23 SVR rates by definition Table 24 SVR rates by disease severity Table 25 Percentage of patients with SVR in REALIZE Table 26 Percentage of patients with ervr in REALIZE Table 27 Relapse rates in REALIZE Table 28 VF in REALIZE Table 29 95% adherence to study drugs in REALIZE Table 30 Reasons for discontinuation in REALIZE Table 31 Duration of therapy in REALIZE Table 32 EQ-5D valuation index scores over time in REALIZE Table 33 FSS score Table 34 SVR rates by IL-28B subtype Table 35 SVR rates by definition Table 36 SVR rates by disease severity Table 37 Summary of AEs at week 48 in ADVANCE Table 38 Summary of AEs at week 48 in REALIZE Table 39 Rash severity during overall 48 week treatment phase Table 40 Eligibility criteria for studies in the cost effectiveness Table 41 Summary list of other cost-effectiveness evaluations Table 42 Quality assessment of cost-effectiveness studies Table 43 Key features of analysis Table 44 Virologic stopping rules in the SmPC Table 45 Number of T12/PR patients meeting stopping criteria at week Table 46 Clinical data implemented in the economic models Table 47 Percentage of patients achieving an SVR from the clinical trials Table 48 Transition probabilities incorporated into the economic models Table 49 Summary of variables applied in the naive economic model Table 50 Economic model clinical assumptions Table 51 HCC to Liver transplant transition probability calculation Table 52 All cause mortality rates Table 53 Health state utilities Table 54 Study characteristics of HRQoL papers Table 55 TTO and EQ-5D results Table 56 Telaprevir trial HRQoL values at baseline Table 57 Comparison of EQ-5D health state estimates Page 3 of 239

4 Table 58 Summary of telaprevir clinical trial on-treatment disutilities Table 59 Base case utility estimates Table 60 Base case utility estimates Table 61 HCV drug costs incorporated into the economic models Table 62 Detailed breakdowns of costs during the year of treatment Table 63 Summary of cost during the year of treatment Table 64 Summary of resource utilisation during the year of treatment Table 65 Monitoring costs per treatment Table 66 Health state costs Table 67 AE management treatment naïve model Table 68 AE management treatment experienced model Table 69 Additional rash management staff resource Table 70 Assumptions for PR alone response guided therapy in treatment naïve patients Table 71 Assumptions for telaprevir/pr response guided therapy in prior relapse patients Table 72 Applying within trial baseline decrements to Mild HCV utility value Table 73 ADVANCE HRQoL at week Table 74 REALIZE HRQoL at week Table 75 Treatment naïve within trial HRQoL scenario Table 76 Treatment experienced within trial HRQoL scenario Table 77 AE management erythropoietin for anaemia Table 78 Scenario analyses explored in the model Table 79 Summary of key inputs and ranges used in the one-way sensitivity analysis Table 80 Probabilistic sensitivity analysis parameters and distributions Table 81 Summary of model results compared with clinical data Table 82 Model outputs by clinical outcomes Table 83 Summary of treatment naïve QALY gain by health state (undiscounted) Table 84 Summary of treatment naïve costs by health state ( 000s, undiscounted) Table 85 Summary of treatment naïve predicted resource use by category of cost Table 86 Summary of treatment experienced QALY gain by health state (undiscounted) Table 87 Summary of treatment experienced costs by health state ( 000s, undiscounted) Table 88 Summary of treatment experienced predicted resource use by category of cost Table 89 Results of the treatment naïve base case analysis for telaprevir/pr v PR alone Table 90 Results of the treatment experienced base case analysis for telaprevir/pr v PR alone Table 91 Treatment naïve deterministic sensitivity analysis results Table 92 Treatment experienced deterministic sensitivity analysis results Table 93 Treatment naïve results for scenarios tested in the variability analysis Table 94 Treatment experienced results for scenarios tested in the variability analysis Table 95 IL-28B patient distribution in the REALIZE trial Table 96 Baseline demographics of REALIZE IL-28B subgroups Table 97 Baseline demographics of REALIZE trial treatment experience subgroups Table 98 Results of the treatment naïve IL28B subgroup analysis Table 99 Results of the treatment experienced IL28B subgroup analysis Table 100 Results of the treatment experienced subgroup analysis for telaprevir/pr v PR alone Table 101 Eligible patient population in England & Wales Table 102 Estimated telaprevir patient numbers Table 103 Estimated telaprevir patient numbers Table 104 Overall budget impact for the NHS in England and Wales Page 4 of 239

5 List of figures Figure 1 Duration of treatment for telaprevir treated patients (adapted from SmPC) Figure 2 Number of donors, transplants and patients on the active transplant list Figure 3 Definition of prior treatment response Figure 4 Hepatitis C current clinical treatment pathway Figure 5 Consort flow of systematic review to identify telaprevir clinical trials Figure 6 Subgroup analyses from the ADVANCE trial Figure 7 ADVANCE patient disposition (adapted from Jacobson et al 2011) Figure 8 REALIZE patient disposition (adapted from Zeuzem et al 2011) Figure 9 Percentage of patients with SVR Figure 10 Percentage of patients with SVR Figure 11 Percentage of patients with ervr by prior response subgroup Figure 12 Percentage of patients with SVR by prior response subgroup Figure 13 Adverse Event Management Plan grading Figure 14 Adverse Event Management Plan guidance Figure 15 Study exclusion flow for economic systematic review Figure 16 Schematic of the cost-effectiveness model Figure 17 Proportion of cases in each disease stage reporting problems for each dimension of the EQ- 5D from Wright et al 2006 observational study Figure 18 Study exclusion flow for the HRQoL systematic review Figure 19 Study exclusion flow for the resource use & costs systematic review Figure 20 Tornado chart of treatment naïve deterministic sensitivity analysis results Figure 21 Tornado chart of treatment experienced deterministic sensitivity analysis results Figure 22 Treatment naïve cost effectiveness plane for telaprevir/pr v PR alone Figure 23 Treatment naïve cost effectiveness acceptability curve for telaprevir/pr v PR alone Figure 24 Treatment experienced cost effectiveness plane for telaprevir/pr v PR alone Figure 25 Treatment experiencedcost effectiveness acceptability curve for telaprevir /PR v PR alone 168 Page 5 of 239

6 List of abbreviations 8h Every 8 hours µg micrograms AASLD American Association for the Study of Liver Disease AE Adverse event ALT Abnormal alanine aminotransferase ART Antiretroviral therapy AVT Antiviral therapy BASL British Association for the Study of the Liver BMI Body mass index BMJ British Medical Journal CC IL-28b subtype CCi Compensated cirrhosis CE Cost effectiveness CHC Chronic hepatitis C CHMP Committee for Medicinal Products for Human Use CI Confidence interval CROI Conference on Retroviruses and Opportunistic Infections CT IL-28b subtype DC Decompensated cirrhosis DDW Digestive Disease Week EASL European Association for the Study of the Liver EMA European Medicines Agency EPAR European Public Assessment Report EQ-5D EuroQol five dimension ervr Extended rapid viral response ESA erythropoesis stimulating agent ESLD End-stage liver disease EXP Treatment experienced FBC Full Blood Count FSS Fatigue severity scale HALT-C Hepatitis C Antiviral Long Term Treatment against Cirrhosis HCC Hepatocellular carcinoma HBV Hepatitis B HCHS Hospital and Community Staff HCV Hepatitis C HD Haemodialysis Page 6 of 239

7 HIV Human Immunodeficiency Virus HPA Health Protection Agency HRQoL Health related quality of life H/STATE Health State HUI Health Utilities Inc. ICER Incremental cost effectiveness ratio IFN Interferon IL-28B Interleukin-28B INR International Normalised Ratio ITT Intention to Treat IU International Units IWHHC International Workshop on HIV and Hepatitis Co-Infection LFT Liver function test LI Lead in mg milligrams µg micrograms ml millilitre mm millimetre Mod Moderate N or n Number of patients n/a Not available NAI Treatment naive NHS National Health Service NICE National Institute for Health and Clinical Excellence n/r Not reported P Peginterferon alpha-2a P12 12 weeks of Peginterferon alpha-2a PBO Placebo PCR Polymerase Chain Reaction Peg-IFN peginterferon PP Per protocol PR Peginterferon and ribavirin PR12 Peginterferon and ribavirin for 12 weeks PR24 Peginterferon and ribavirin for 24 weeks PR48 Peginterferon and ribavirin for 48 weeks PRISMA Preferred Reporting Items for Systematic Reviews and Meta- Analyses PSA Probabilistic sensitivity analysis PTR Post transplant recurrence QALY Quality adjusted life years Page 7 of 239

8 RBV RCT RNA RVR SAE SD SF-12 SF-36 SF-6D SHTAC SIGN SmPC SOC SVR T8/PR T12/PR T24 TA TP TT TTO TVR TX U&E UK VAT VF wbr WCM Wk Yr Ribavirin Randomised controlled trials Ribonucleic Acid Rapid Virologic Response Serious Adverse Event Standard Deviation Short Form-12 Short Form-36 Short Form- 6 dimensions Southampton Health Technology Assessments Centre Scottish Intercollegiate Guidelines Network Summary of Product Characteristics Standard of care Sustained virologic response 8 weeks of telaprevir and peginterferon and ribavirin 12 weeks of telaprevir and peginterferon and ribavirin 24 weeks of telaprevir Technology appraisal Transition probabilities IL-28b subtype Time trade off Telaprevir Treatment Urea & Electrolytes United Kingdom Value added tax Virologic failure Weight based ribavirin World Congress on Microbes Week Years Page 8 of 239

9 Executive Summary Disease background Hepatitis C (HCV) is an infectious disease of the liver caused by the HCV virus and the Health Protection Agency (HPA) estimates there are 173,000 chronically infected individuals in England & Wales 1. Of the six genetic types of HCV, genotype 1 is the most common in the UK, accounting for 40-50% of cases 2. Chronic HCV is categorised as mild, moderate or severe depending on the extent of liver damage and rate of progression from mild to severe disease is slow but variable, with a time lag of about 20 to 50 years from the time of infection 2. Progression begins with the initial inflammation of the liver caused by the virus which then starts to infect and kill off the liver cells, before the gradual scarring (fibrosis) and then the hardening of the liver tissue (cirrhosis) occurs 3. Chronic HCV is a major cause of end-stage liver disease (ESLD), accounting for 76% of all liver cancer cases 4 and 19% of all liver transplants in the UK 1. National data sources show that liver disease continues to rise in England & Wales with cases of ESLD increasing from 696 in 1999/2000 to 1,675 ten years later 1. Recent disease transmission modelling by Martin et al 2011 has shown that effective treatment with HCV therapy could reduce the transmission and prevalence of HCV 5. The primary aim of HCV treatment is to clear the virus from the blood, indicated by sustained virologic response (SVR, defined as undetectable HCV ribonucleic acid (RNA) 24 weeks after treatment completion), which is considered to indicate permanent resolution of infection 6. In genotype 1 patients only 40-50% of treatment naïve patients achieving an SVR following 48 week treatment with the current standard of care peginterferon and ribavirin (PR) 2, compared to rates of 80% and higher in other genotypes 6. In genotype 1 treatment-experienced patients, the SVR rate is even lower at 4-25%, highlighting the low likelihood of clearing the virus with current therapeutic options despite a course of treatment often lasting weeks 6. Prior null-responders have a particularly high unmet need with only one in twenty likely to clear the virus following retreatment with standard therapy 7. Despite NICE guidance supporting the cost-effectiveness of retreatment in patients whose first course of therapy fails to clear the virus, many hospitals in the UK do not routinely offer such treatment 8. This is primarily due to the low chance of clearing the virus. Published evidence indicates that even patients presenting with mild chronic HCV have a markedly reduced health related quality of life (HRQoL) due to symptoms such as fatigue, weakness and depression 9-13, Research has found a significant psychological and emotional impact of simply being diagnosed with chronic HCV 14, and as the liver disease progresses to more advanced stages, HRQoL deteriorates further. 10, 15. Page 9 of 239

10 Telaprevir Telaprevir (INCIVO ), in combination with PR, is licensed for the treatment of genotype-1 chronic HCV in adult patients with compensated liver disease (including cirrhosis): who are treatment naïve or who have been previously treated with interferon alfa (pegylated or nonpegylated) alone or in combination with ribavirin, including relapsers, partial responders and null responders. Telaprevir is a protease inhibitor, one of a new class of direct-acting antivirals for genotype-1 HCV and is a reversible, selective, covalent, tight- and slowbinding inhibitor of the HCV NS3-4A protease, which is essential in viral replication. Approved by the European Medicines Agency (EMA) on 20 th September 2011, telaprevir is an oral formulation, administered as 750mg (two 375mg tablets) every eight hours for a maximum of 12 weeks. Alongside telaprevir, treated patients should receive PR for a total of either: 24 weeks response guided therapy for treatment naïve and prior relapse patients without cirrhosis that achieve an extended rapid viral response (ervr, defined as undetectable HCV RNA at weeks 4 and 12 of treatment), or; 48 weeks for all other patients. The list price of telaprevir is 1, for 42 x 375mg tablets and 7, for 168 x 375mg tablets, equating to a maximum of 22,398 for a 12 week course of therapy, excluding VAT. The simple dosing regimen means that cost of treatment is consistent from patient to patient, while the 12-week treatment course minimises the duration of triple therapy. Telaprevir offers a step-change in the management of patients with genotype- 1 HCV, significantly improving SVR rates across all patient populations 7, 16, even those hardest to treat, while shortening total treatment durations in patients eligible for response guided therapy 17. The comparator The comparator for telaprevir/pr is current standard of care PR combination therapy alone as defined in the decision problem. Two different formulations of peginterferon therapy are available: peginterferon alfa-2a and peginterferon-alfa-2b. The majority of telaprevir clinical data relates to the use of peginterferon alfa-2a, which is the more widely used formulation in the UK. Opinion from a clinical advisory board highlighted that in clinical practice peginterferon alfa-2a and peginterferon-alfa-2b are considered to have equivalent efficacy and cost. This view is further supported by the European Association for the Study of the Liver (EASL) guidelines 6 and clinical trial data in the treatment naïve population directly comparing the two formulations 18, 19. Page 10 of 239

11 Clinical evidence The clinical evidence for telaprevir/pr is drawn from a comprehensive clinical trial programme in genotype 1 chronic HCV, including six peer reviewed publications 7, 16, 17, The key evidence presented in this submission is drawn from the following two large, Phase III, multicentre, randomised doubleblind, placebo-controlled trials directly comparing telaprevir/pr therapy with PR alone: ADVANCE in treatment naïve genotype-1 chronic HCV patients 16 ; REALIZE in treatment experienced genotype-1 chronic HCV patients, including prior relapsers, prior partial responders and prior null responders 7. REALIZE is the only published clinical trial involving a protease inhibitor in genotype 1 chronic HCV that provides efficacy and safety data for patients with a null response to prior therapy. In both of these trials the primary endpoint was SVR, which is the main outcome listed in the decision problem: In ADVANCE significantly more patients receiving telaprevir/pr achieved an SVR compared to those receiving PR alone (75% v 44%, p>0.0001). This significant result was attained with almost 60% of the telaprevir/pr treated patients receiving only 24 weeks of response guided PR therapy instead of 48 weeks, following achievement of an ervr 16. In REALIZE significantly more patients receiving telaprevir/pr also achieved an SVR compared to those receiving PR alone (64% v 17%, p>0.001). o This significant outcome was also seen across each of the prior response subgroups with telaprevir/pr achieving significantly higher SVR rates than PR alone in prior relapsers (83% v 24%, p>0.001), prior partial responders (59% v 15%, p>0.001) and prior null responders (29% v 5%, p>0.001) 7. Further analysis of both the ADVANCE and REALIZE trials have shown that telaprevir/pr increases SVR rates across all IL-28B genotypes 23, 24. The ADVANCE trial has shown that HRQoL returns to baseline levels earlier in patients achieving an ervr who complete a shorter, 24 week, response guided therapy duration, compared to those requiring 48 weeks of PR therapy. There is a need for chronic HCV treatment regimens that are simple to adhere to and maximize the probability of an SVR 25. Patients have a greater chance of successful adherence to treatment over a 24 week duration compared to a 48 week duration 26, which also sees the benefit of a reduction in the amount of costs associated with PR therapy per patient and lowers resource utilisation related to ongoing patient monitoring. Safety and tolerability data from both trials showed that many of the adverse events (AEs) reported were common to both the telaprevir/pr and PR alone. Some AEs (including rash and anaemia) occur more frequently with the use of Page 11 of 239

12 telaprevir, although in the majority of cases they were mild or moderate and rarely resulted in discontinuation of therapy 7, 16. The Company is implementing the same AE management plan from the Phase III clinical trials in clinical practice, which assists clinicians in accurately grading rash severity so that telaprevir therapy can be discontinued in those patients where it is necessary. Both the ADVANCE and REALIZE trials have shown that anaemia in telaprevir/pr patients can be successfully managed by ribavirin dose reductions, rather than introducing erythropoeitin which is not currently license for use in anaemia arising from HCV treatment. In summary, telaprevir/pr has demonstrated significiantly higher SVR rates than PR alone in the clinical trials regardless of prior treatment experience, and higher SVR rates across all IL-28B subgroups. Furthermore, responses guided therapy in patients achieving an ervr offers benefits to both patients and the health service. Economic evaluation This submission assesses the cost-effectiveness of telaprevir/pr within its licensed indication compared to current standard of care PR alone from the perspective of the NHS and Personal Social Services in England and Wales. The base case focuses on the ITT results from the pivotal Phase III head to head ADVANCE and REALIZE trials, integrating the trial outcomes into an Excel based Markov model structured identically to those used in previous HCV economic assessments and NICE appraisals 15, Patients enter the model in the Mild HCV, Moderate HCV or Compensated cirrhosis health states and receive treatment with either telaprevir/pr or PR alone. Patients achieving an SVR following treatment are assumed to have cleared the virus, whereas unsuccessfully treated patients may remain in their original health state for a period of time or progress to the more advanced stages of liver disease such as Decompensated cirrhosis (DC), Hepatocellular carcinoma (HCC), Liver transplantation or Post-liver transplant. The base case analyses resulted in incremental costs per quality adjusted life year (QALY) gained of 13,553 and 8,688 for telaprevir/pr compared to PR alone in the treatment naïve and treatment experienced patients respectively (detailed in Table 1). Deterministic and probabilistic sensitivity analyses consistently resulted in incremental cost effectiveness ratios (ICERs) less than 20,000/QALY. The probability of telaprevir/pr therapy being cost effective at a willingness to pay threshold of 20,000/QALY is calculated as 85.3% and 94.0% in the treatment naïve and treatment experienced populations, respectively. Page 12 of 239

13 Table 1 Base case cost-effectiveness results Treatment naïve Treatment experienced Telaprevir/PR PR alone Telaprevir/PR PR alone Technology acquisition cost 25,410 7,300 27,762 6,049 Other costs 10,742 17,422 16,827 28,346 Total costs 36,152 24,722 44,589 34,394 Difference in total costs - 11,430-10,195 QALYs Difference in QALYs ICER 13,553 8,688 Additional analysis has shown that telaprevir continues to be cost effective relative to PR alone regardless of response guided therapy assumptions, IL- 28B subgroups or prior treatment response subgroups specified in the decision problem. Conclusion HCV is an increasingly prevalent blood-borne disease with a significant impact on HRQoL. Current standard of care therapy clears the virus in 40-50% of genotype 1 patients, with a particularly poor prognosis for treatment experienced patients resulting in many patients being denied retreatment with PR alone. Treatment with telaprevir/pr significantly increases SVR rates versus PR alone across the licensed patient populations and regardless of IL- 28B subgroup. The economic evaluation has demonstrated that telaprevir/pr is a cost effective use of NHS resources compared to PR alone in all patients regardless of their level of treatment experience. These economic results are robust in sensitivity analysis and are maintained across prior treatment response subgroups and across IL-28B subgroups. Page 13 of 239

14 Section A Decision problem Manufacturers and sponsors will be requested to submit section A in advance of the full submission (for details on timelines, see the NICE document Guide to the single technology appraisal (STA) process A (draft) summary of product characteristics (SPC) for pharmaceuticals or information for use (IFU) for devices, a (draft) assessment report produced by the regulatory authorities (for example, the European Public Assessment Report (EPAR)), and a (draft) technical manual for devices should be provided (see section 9.1, appendix 1). 1 Description of technology under assessment 1.1 Give the brand name, approved name and, when appropriate, therapeutic class. Brand name: INCIVO Approved name: Telaprevir Therapeutic class: Linear peptidomimetic HCV NS3/4A serine protease inhibitor. 1.2 What is the principal mechanism of action of the technology? Telaprevir is a protease inhibitor, one member of a new class of direct-acting antivirals for genotype 1 HCV and is a reversible, selective, covalent, tightand slow-binding inhibitor of the HCV NS3-4A protease, which is essential in viral replication. 1.3 Does the technology have a UK marketing authorisation/ce marking for the indications detailed in this submission? If so, give the date on which authorisation was received. If not, state current UK regulatory status, with relevant dates (for example, date of application and/or expected approval dates). An Accelerated Assessment procedure was agreed upon by the Committee for Medicinal Products for Human Use (CHMP) on 18 th November CHMP approval was granted on 21 st July 2011 and Marketing Authorisation was received on 20 th September Describe the main issues discussed by the regulatory organisation (preferably by referring to the [draft] assessment report [for example, the EPAR]). If appropriate, state any special conditions attached to the marketing authorisation (for example, exceptional circumstances/conditions to the licence). Page 14 of 239

15 The European Public Assessment Report (EPAR) states that an ambitious pharmacology program has been performed with telaprevir, no issues of major concern were identified and the clinical pharmacology aspects of telaprevir were sufficiently characterised to meet the requirements to support the application 31. The EPAR concludes that substantially increased SVR rates have been demonstrated when treating HCV genotype 1 infection in patients with compensated liver disease, with telaprevir in combination with PR. Available data indicate that the SVRs obtained are durable. Most patients experiencing treatment failure with telaprevir/pr had drug resistant virus emerging. In most of these patients the follow up data showed that the resistant virus disappears with time, however at this stage it is unclear if patients can be re-treated with telaprevir since this is only now being studied. The addition of telaprevir to regimens with PR represents a major advance in the treatment of the dominant HCV genotype, including many patients in whom present standard-of-care therapy of PR alone is unlikely to be efficacious 31. Regards clinical safety, the addition of telaprevir leads to an increase in AEs and treatment discontinuations compared with PR therapy, primarily due to increased incidence of rash or anaemia. The risk management plan proposed by the Company was considered to address the safety risks in an acceptable way and there are no major safety concerns that have not been addressed. 31 Further details of the key areas of discussion in the EPAR are detailed in Appendix section What are the (anticipated) indication(s) in the UK? For devices, provide the (anticipated) CE marking, including the indication for use. Telaprevir, in combination with PR, is indicated for the treatment of genotype 1 chronic HCV in adult patients with compensated liver disease (including cirrhosis): who are treatment naïve; who have previously been treated with interferon alfa (pegylated or non pegylated) alone or in combination with ribavirin, including relapsers, partial responders and null responders Please provide details of all completed and ongoing studies from which additional evidence is likely to be available in the next 12 months for the indication being appraised. The following studies are likely to provide additional evidence for telaprevir in the next 12 months: The VX-950-TiDP24-C219 trial is an open-label, single-arm, roll-over Phase III clinical trial evaluating the efficacy, safety and tolerability of telaprevir/pr in placebo-treated patients from the REALIZE trial who Page 15 of 239

16 failed treatment for virologic reasons (ClinicalTrials.gov ID NCT ). Results will be available from October 2012 at the earliest; The VX study is an ongoing Phase IIa trial assessing the safety and efficacy of telaprevir in combination with pegylated interferon α-2a and ribavirin in treatment naïve genotype-1 chronic HCV patients co-infected with human immunodeficiency virus (HIV) (ClinicalTrials.gov ID NCT ). This randomised, double-blind, placebo controlled study incorporates the 750mg thrice daily telaprevir regimen and results are anticipated in November If the technology has not been launched, please supply the anticipated date of availability in the UK. Telaprevir was launched in the UK on 26 th September 2011, following the receipt of the Marketing Authorisation from the EMA on 20 th September Does the technology have regulatory approval outside the UK? If so, please provide details. Telaprevir has already received regulatory approval in the US (Food and Drug Administration approval granted on 23 rd May 2011), Canada (Health Canada approval granted on 22 nd August 2011), Switzerland (SwissMedic approval 8 th September 2011), the wider European Union (EMA approval on 20 th September 2011) and Japan (Pharmaceutical and Medical Device Agency approval 26 th September 2011). 1.9 Is the technology subject to any other form of health technology assessment in the UK? If so, what is the timescale for completion? The Scottish Medicines Consortium is currently reviewing telaprevir in both patient populations. The final advice from the SMC is expected to be issued in confidence to NHS Scotland on 4 th November 2011 and subsequently published on the SMC website on 12 th December For pharmaceuticals, please complete the table below. If the unit cost of the pharmaceutical is not yet known, provide details of the anticipated unit cost, including the range of possible unit costs. Page 16 of 239

17 Table 2 Unit costs of technology being appraised Pharmaceutical formulation Telaprevir film coated tablets Acquisition cost (excluding The weekly cost of telaprevir is 1, Telaprevir is administered VAT) for up to 12 weeks and therefore the maximum cost per patient is 22,398 (excluding VAT). List price per pack is: 1, for 42 x 375 milligrams (mg) tablets 7, for 168 x 375 mg tablets. Telaprevir is indicated for use in combination with PR for either 24 or 48 weeks. For example, the weekly cost for treatment is: for Pegasys (180 µg per week) for Copegus (1,000 mg per day). Method of administration Doses Dosing frequency Average length of a course of treatment Average cost of a course of treatment Anticipated average interval between courses of treatments Anticipated number of repeat courses of treatments Dose adjustments Therefore total treatment costs are: 27,234 for 12 weeks telaprevir and 24 weeks of PR (applies to treatment naïve and prior treatment relapse patients without cirrhosis that achieve undetectable HCV RNA at weeks 4 and 12 of treatment) 32,069 for 12 weeks telaprevir and 48 weeks of PR (applies to all other patients) Oral Administered as a 750 mg dose (two 375 mg tablets) 750 mg every 8 hours (8h) The licensed treatment duration for telaprevir therapy is 12 weeks. In the Phase III clinical trials the average duration of telaprevir therapy was 10.7 weeks. Based on the average duration of 10.7 weeks from the Phase III trials, telaprevir has an average cost of 19,972 (excluding VAT) per patient. Including the average durations of PR therapy in the Phase III trials, the overall cost of telaprevir/pr therapy is 25,391 and 27,749 in treatment naïve and treatment experienced patients, respectively. Not applicable. There are no clinical data on re-treating subjects who have failed an HCV NS3-4A protease inhibitor-based therapy, such as telaprevir, nor are there data on repeated courses of telaprevir treatment. The license states that if telaprevir treatment is discontinued (either due to AEs or insufficient virologic response) then telaprevir treatment should not be reinitiated. Not applicable as above. Not applicable For devices, please provide the list price and average selling price. If the unit cost of the device is not yet known, provide details of the anticipated unit cost, including the range of possible unit costs. Not applicable Are there additional tests or investigations needed for selection, or particular administration requirements for this technology? Page 17 of 239

18 There are no additional tests or investigations needed for patient selection with telaprevir/pr compared to PR alone. Telaprevir should be administered orally every 8 hours with food Is there a need for monitoring of patients over and above usual clinical practice for this technology? It is anticipated that telaprevir patients will receive the same level of monitoring as patients currently treated with PR alone. The use of response guided therapy, in non-cirrhotic treatment naïve and prior relapse patients who achieve an ervr, will reduce the overall PR treatment duration from 48 weeks, or even from 72 weeks in some cases 6, to 24 weeks, thereby reducing the time during which patient monitoring is required What other therapies, if any, are likely to be administered at the same time as the intervention as part of a course of treatment? Telaprevir must be administered in combination with PR therapy. After 12 weeks of telaprevir/pr therapy patients continue on for a further 12 or 36 weeks of therapy with PR alone, bringing the total treatment duration to 24 or 48 weeks, respectively. The 24 week response guided therapy duration applies to non-cirrhotic patients who are either treatment naïve or prior treatment relapse patients and who achieve an ervr. All other patients require 48 weeks of therapy. Figure 1 Duration of treatment for telaprevir treated patients (adapted from SmPC 32 ) Page 18 of 239

19 2 Context In this background section the manufacturer or sponsor should contextualise the evidence relating to the decision problem. 2.1 Please provide a brief overview of the disease or condition for which the technology is being used. Include details of the underlying course of the disease. HCV is an infectious disease of the liver caused by the HCV virus, which is acquired primarily through percutaneous exposure to contaminated blood 2. The 2011 HPA report on HCV estimates there are 161,000 and 12,000 chronically infected patients in England and Wales, respectively 1. National data sources indicate that HCV-related liver disease is continuing to rise: there are over 1,357 patients with HCV related ESLD in England in 2009/2010, compared to 473 a decade earlier; in Wales the number of patients with HCV related ESLD has risen from 223 to 318 in the last decade 1 - in England and and Wales combined this represents a rise from 696 to 1,675 patients. Chronic HCV is categorised as mild, moderate or severe depending on the extent of liver damage and rate of progression from mild to severe disease is slow but variable, with a time lag of about 20 to 50 years from the time of infection 2. Progression begins with the initial inflammation of the liver caused by the virus which then starts to infect and kill off the liver cells, before the gradual scarring (fibrosis) and then the hardening of the liver tissue (cirrhosis) occurs 3. About 30% of infected people develop cirrhosis within 20 to 30 years 2, with the British Liver Trust estimating that each year around 3-5% of patients with cirrhosis develop liver cancer (hepatocellular carcinoma, or HCC) 33. Approximately 76% of all liver cancer cases occur as a direct result of chronic HCV 4. Some people with ESLD or HCC may require liver transplantation 2. Between 2008 and 2010 in England, HCV accounted for 19% of all liver transplants 1. Furthermore, demand for liver transplants has been rising faster than supply, indicating a risk of shortage in the near future 34. Page 19 of 239

20 Figure 2 Number of donors, transplants and patients on the active transplant list 34 Six genetic types of HCV, known as genotypes, have been identified. Genotype 1 is the most common in the UK, accounting for 40-50% of those infected with HCV 2. The primary aim of treatment is to clear the virus from the blood. Successful treatment is usually indicated by an SVR, which is considered to indicate permanent resolution of infection. The proportion of people with HCV genotype 1 achieving an SVR after the end of initial treatment with current standard of care is about 40% to 50% 2. Compared to SVR rates of around 80% in other HCV genotypes 6, this low rate highlights a particular unmet need for effective therapy for genotype 1 patients. A substantial proportion of patients previously treated in specialist clinics in England and Wales either relapsed or failed to respond to their initial treatment 2. As shown in Figure 3, it is possible to categorise these nonresponse patients as: Prior partial responders, defined as patients with 2-log drop in HCV RNA at Week 12 of prior therapy, but who never achieved undetectable HCV RNA levels while on treatment, and Prior null responders, defined as patients with <2-log drop in HCV RNA at Week 12 of prior therapy. Page 20 of 239

21 Figure 3 Definition of prior treatment response Despite NICE guidance supporting the cost-effectiveness of retreatment in patients whose first course of therapy fails to clear the virus, many hospitals in the UK do not routinely offer such treatment 8. This is primarily due to the low chance of clearing the virus. In these treatment experienced patients the current standard of care SVR rate is around 4-14% in prior non responders and 15-25% in prior relapsers 6. For these genotype-1 patients who experienced a null response with standard of care, the probability of clearing the virus with a subsequent round of PR alone treatment is particularly low at around 5% 7. The HPA highlights that unless a significant increase in effective treatment occurs, the future burden of HCV-related disease will be substantial 1. Recent disease transmission modelling by Martin et al 2011 has shown that effective treatment of HCV therapy could reduce the transmission and prevalence of HCV 5. However, only 12,400 individuals were treated between 2006 and 2008 in England, estimated to be less than 10% of those chronically infected How many patients are assumed to be eligible? How is this figure derived? The following eligible patient number estimates are derived from data within the 2011 HPA report 1 : 173,000 chronically infected HCV patients in England and Wales (161,000 and 12,000, respectively) 28,833 of which are diagnosed (five out of six chronic HCV patients are unaware of their infection status) 17,000 of which are treated (<10% of chronically infected HCV patients are treated) 7,650 are genotype 1 (45%) Page 21 of 239

22 2.3 Please give details of any relevant NICE guidance or protocols for the condition for which the technology is being used. Specify whether any specific subgroups were addressed. NICE has competed four previous appraisals in HCV, all of which are multiple technology appraisals: TA14, The clinical and cost effectiveness of pegylated interferon alpha 2a and alpha 2b for hepatitis C, issued in October TA75, Interferon alfa (pegylated and non-pegylated) and ribavirin for the treatment of chronic hepatitis C, issued in January this is a review and extension of TA14 TA106, Peginterferon alfa and ribavirin for the treatment of mild chronic hepatitis C, issued in August this is an extension of TA75 TA200, Peginterferon alfa and ribavirin for the treatment of chronic hepatitis C, issued in September this is a part review of TA75 and TA106 Some aspects of guidance issued in earlier appraisals have been updated by more recent appraisals. Currently applicable guidance is summarised in Table 3. Table 3 Current NICE HCV guidance Appraisal Guidance TA75 36 Combination therapy with peginterferon alfa and ribavirin is recommended within its licensed indications for the treatment of people aged 18 years and over with moderate to severe chronic hepatitis C, defined as histological evidence of significant scarring (fibrosis) and/or significant necrotic inflammation. 1.2 People with moderate to severe chronic hepatitis C are suitable for treatment if they have: not previously been treated with interferon alfa or peginterferon alfa, or; been treated previously with interferon alfa (as monotherapy or in combination therapy), 1.3 People currently being treated with interferon alfa, either as combination therapy or monotherapy, may be switched to the corresponding therapy with peginterferon alfa. 1.4 Treatment for the groups identified in Sections 1 and 2 should be as follows. People infected with hepatitis C virus (HCV) of genotype 2 and/or 3 should be treated for 24 weeks; For people infected with HCV of genotype 1, 4, 5 or 6, initial treatment should be for 12 weeks. Only people showing, at 12 weeks, a reduction in viral load to less than 1% of its level at the start of treatment (at least a 2- log reduction) should continue treatment until 48 weeks. For people in whom viral load at 12 weeks exceeds 1% of its level at the start of treatment, treatment should be discontinued; - Note: Shortened treatment durations have since been assessed by NICE technology appraisal guidance 200 People infected with more than one genotype that includes one or more of genotypes 1, 4, 5, or 6 should be treated as for genotype People satisfying the conditions in Sections 1 and 2 but for whom ribavirin is Page 22 of 239

23 contraindicated or is not tolerated should be treated with peginterferon alfa monotherapy. Regardless of genotype, individuals should be tested for viral load at 12 weeks, and if the viral load has reduced to less than 1% of its level at the start of treatment, treatment should be continued for a total of 48 weeks. If viral load has not fallen to this extent, treatment should stop at 12 weeks. 1.6 People for whom liver biopsy poses a substantial risk (such as those with haemophilia, or those who have experienced an adverse event after undergoing a previous liver biopsy), and people with symptoms of extra-hepatic HCV infection sufficient to impair quality of life, may be treated on clinical grounds without prior histological classification. 1.7 There is insufficient evidence to recommend combination therapy using peginterferon alfa or interferon alfa in people who: are younger than 18 years of age, and/or; have had a liver transplantation. Treatment of CHC recurrence after liver transplantation (whether or not the person had been treated with interferon alfa or peginterferon alfa therapy at any time before transplantation) should be considered as experimental and carried out only in the context of a clinical trial. TA Combination therapy, comprising peginterferon alfa-2a and ribavirin or peginterferon alfa-2b and ribavirin, is recommended, within the licensed indications of these drugs, for the treatment of mild chronic hepatitis C. 1.2 Monotherapy with peginterferon alfa-2a or peginterferon alfa-2b is recommended, within the licensed indications of these drugs, for the treatment of mild chronic hepatitis C for people who are unable to tolerate ribavirin, or for whom ribavirin is contraindicated. 1.3 The decision on whether a person with mild chronic hepatitis C should be treated immediately or should wait until the disease has reached a moderate stage ( watchful waiting ) should be made by the person after fully informed consultation with the responsible clinician. The decision to treat need not depend on a liver biopsy to determine the stage of the disease if treatment is initiated immediately. However, a biopsy may be recommended by the clinician for other reasons or if a strategy of watchful waiting is chosen. 1.4 Recommendation 1.4 has been updated and replaced by NICE technology appraisal guidance Recommendation 1.5 has been updated and replaced by NICE technology appraisal guidance There is insufficient evidence to recommend combination therapy or monotherapy with peginterferon alfa for people with mild chronic hepatitis C who are under the age of 18 years, or those who have had a liver transplant. TA Combination therapy with peginterferon alfa (2a or 2b) and ribavirin is recommended as a treatment option for adults with chronic hepatitis C: who have been treated previously with peginterferon alfa (2a or 2b) and ribavirin in combination, or with peginterferon alfa monotherapy, and whose condition either did not respond to treatment or responded initially to treatment but subsequently relapsed or; who are co-infected with HIV. 1.2 Shortened courses of combination therapy with peginterferon alfa (2a or 2b) and ribavirin are recommended for the treatment of adults with chronic hepatitis C who: have a rapid virological response to treatment at week 4 that is identified by a highly sensitive test and; are considered suitable for a shortened course of treatment. 1.3 When deciding on the duration of combination therapy, clinicians should take into account the licensed indication of the chosen drug (peginterferon alfa-2a or Page 23 of 239

24 peginterferon alfa-2b), the genotype of the hepatitis C virus, the viral load at the start of treatment and the response to treatment (as indicated by the viral load). In June 2011, EASL also published an updated version of their Clinical Practice Guidelines for the management of HCV viral infection 6. These guidelines state that the primary goal of HCV therapy is to achieve an SVR, preventing complications of HCV-related liver disease, including necroinflammation, fibrosis, cirrhosis, HCC, and death. Intermediate assessments of viral response enable the likelihood of an SVR to be identified, with treatment duration tailored accordingly (i.e. response guided therapy). Combination of peginterferon alfa (either -2a or -2b) and ribavirin is accepted as standard of care for chronic HCV, achieving SVR rates of 40-50% in patients infected with HCV genotype 1, and there is currently no conclusive evidence that any one peginterferon should be preferred over the other. The EASL guidelines state that all treatment-naïve patients with compensated chronic liver disease related to HCV who are willing to be treated and have no contra-indication to peginterferon or ribavirin should be considered for therapy, while treatment should be initiated in patients with advanced fibrosis and strongly considered in patients with moderate fibrosis. Patients infected with HCV genotype 1 who failed to eradicate HCV after prior therapy with PR should wait for the approval of the protease inhibitors before being retreated, since they provide higher efficacy, shortened treatment in early responders, and improved patient adherence. 2.4 Please present the clinical pathway of care that depicts the context of the proposed use of the technology. Explain how the new technology may change the existing pathway. If a relevant NICE clinical guideline has been published, the response to this question should be consistent with the guideline and any differences should be explained. The following clinical pathway (Figure 4), adapted from the NHS Map of Medicine presents the current clinical pathway for chronic HCV patients considered for treatment: Page 24 of 239

25 Figure 4 Hepatitis C current clinical treatment pathway Treatment naïve population Historically the initial treatment option has been standard of care PR therapy. During their initial course of therapy, treated patients will be monitored to assess AEs and virological response and those who do not achieve at least a Page 25 of 239

26 2-log drop in HCV RNA at week 12 cease therapy. All other patients may continue therapy, typically out to week 48. However: Patients with baseline viral load 800,000 IU/mL and who achieve undetectable HCV RNA at weeks 4 and 24 may discontinue at week 24 Patients achieveing a DVR (2 log drop in HCV RNA at week 12, but detectable viral load) may continue therapy to week 72. Patients achieving an SVR are considered to have cleared the HCV virus. All other patients who have detectable HCV RNA continue to be chronically infected and require on-going monitoring of disease progression with possible re-treatment and/or liver transplantation. As a more effective therapy than PR alone, telaprevir/pr is expected to change the way patients flow through pathway, with more patients eligible for shorter response guided therapy durations and more patients clearing the virus and requiring no further HCV treatment or monitoring. Treatment experienced population Although patients who continue to carry the HCV virus after initial treatment are eligible to receive further therapy, many are currently not retreated, typically due to the low chance of successfully clearing the virus. Patients who are retreated receive PR alone for weeks, with the exception of those who stop at week 12 because a 2 log drop in HCV RNA has not been achieved. Patients whose virus is not cleared following therapy require ongoing monitoring of disease progression and their only remaining treatment option is liver transplantation. In the treatment experienced population, telaprevir/pr presents a new treatment option with SVR rates that may result in more patients being considered for therapy, although patients whose HCV virus was not cleared following initial telaprevir/pr therapy should not be retreated with telaprevir. As with the treatment naïve population, telaprevir/pr will not fundamentally change the structure of the patient pathway, but is expected to change the way patients flow through the pathway, with more patients eligible for shorter response guided therapy durations and more patients clearing the HCV virus. 2.5 Please describe any issues relating to current clinical practice, including any variations or uncertainty about best practice. There is a need for more effective treatment for genotype 1 patients, given that SVR rates are only 40-50%, compared to success rates of 80% in other genotypes 6. The majority of patients treated with PR alone will incurr the financial costs of treatment, enduring the associated AEs and impact on HRQoL, without the benefit of clearing the virus and therefore remaining at risk of further disease progression. In these treatment experienced patients, the lack of effective options are pressing, with SVR rates around 18% 38 and even lower in prior null responders 7. Page 26 of 239

27 A key finding from the 2010 All-Party Parliamentary Hepatology Group audit of hospital HCV services across England is that significant variations exist across the country 8. The report attributes these variations to the lack of uniformity in treatment policies, be they formal or informal Please identify the main comparator(s) and justify their selection. The comparator for telaprevir/pr as detailed in the decision problem is the standard of care combination therapy of PR alone. This is supported by the NICE guidance 2, 36, 37, the EASL clinical guidelines 6 and the Royal College of General Practitioners guidance 39. There are two formulations of peginterferon and quantitative market research conducted by an independent market research agency in July 2011 has shown that peginterferon alfa-2a is prescribed in 66% of patients (see Appendix section 9.2). The majority of telaprevir clinical data, including all of the Phase III data, relates to use in combination with peginterferon alfa-2a, rather than -2b, therefore peginterferon alfa-2a is incorporated into the economic model. An advisory board of clinical experts highlighted that in clinical practice peginterferon alfa-2a and -2b are considered to have equivalent efficacy and cost, which is entirely consistent with the view expressed by clinical experts at the NICE scoping meeting. This clinical view is further supported by the EASL guidelines 6 as well as clinical trial data directly comparing the two PR formulations in the treatment-naïve population which concluded that there were no statistically significant differences in SVR rates achieved 18, Please list therapies that may be prescribed to manage adverse reactions associated with the technology being appraised. As highlighted in section 1.4, anaemia and rash are considered to be the most clinically important AEs associated with telaprevir therapy. These AEs are also associated with the use of PR therapy and as such their management is reflected in the existing clinical guidelines: Anaemia. The 2011 EASL clinical guidelines recommend that if haemoglobin <10 g/dl occurs then the dose of ribavirin should be adjusted downward by 200 mg at a time, and if haemoglobin falls below 8.5 g/dl then ribavirin should be stopped 6. In some instances erythropoesis stimulating agents (ESAs) can be introduced to manage anaemia and avoid reducing the ribavirin dose, reflecting the recommendations of the 2006 Scottish Intercollegiate Guidelines Network (SIGN) guideline no However, the use of ESAs was not permitted in the pivotal Phase III telaprevir trials and results indicate that anaemia can be effectively managed via ribavirin dose adjustment without impacting SVR rates rather than relying on the introduction of additional therapies. This is important Page 27 of 239

28 for two reasons: firstly, a clinical advisory board highlighted that the use ESAs varies greatly from centre to centre, with funding affecting treatment availability; secondly, the ESAs are not currently licensed for this indication. Rash. This can be managed with emollients and topical corticosteroids. In the absence of guidelines for England and Wales, recommendations are detailed in the 2006 SIGN guideline no The telaprevir AE Management Plan involves accurate grading of rash severity and subsequent discontinuation of telaprevir in patients experiencing severe rash or discontinuation of all telaprevir/pr therapy where necessary. Further details of the AE Management Plan are provided in Section and Appendix section Please identify the main resource use to the NHS associated with the technology being appraised. Describe the location of care, staff usage, administration costs, monitoring and tests. Provide details of data sources used to inform resource estimates and values. As telaprevir is administered orally and in the patient s home, there are no anticipated costs due to location of care, staff and administration. Patient monitoring is expected to follow largely the same schedule and in the same setting as for patients treated with PR alone. However a clinician advisory board indicated that there may be a small amount of additional resource use required to assess and manage patients with rash. This amounts to an additional nurse consultation for mild rash, and an additional phone and nurse consultation for moderate rash, an additional dermatologist consultation for half the patients with moderate rash and an additional dermatologist consultation for all patients experiencing severe rash. As previously stated in section 2.4, the majority of non-cirrhotic treatment naïve and prior relapse telaprevir/pr patients achieve an ervr and are therefore require only 24 weeks of response guided therapy in total, instead of 48 weeks. Compared to PR alone durations of 48 or even 72 weeks, the shorter treatment durations with telaprevir/pr has the ability to reduce the amount of healthcare resource utilisation required treat eligible patients. 2.9 Does the technology require additional infrastructure to be put in place? None required. Page 28 of 239

29 3 Equity and equality NICE considers equity in terms of how the effects of a health technology may deliver differential benefits across the population. Evidence relevant to equity considerations may also take a variety of forms and come from different sources. These may include general-population-generated utility weightings applied in health economic analyses, societal values elicited through social survey and other methods, research into technology uptake in different population groups, evidence on differential treatment effects in different population groups, and epidemiological evidence on risks or incidence of the condition in different population groups. 3.1 Identification of equity and equalities issues Please specify any issues relating to equity or equalities in NICE guidance, or protocols for the condition for which the technology is being used. The Company is not aware of any issues relating to equity or equalities in NICE guidance or protocols for the treatment of HCV Are there any equity or equalities issues anticipated for the appraisal of this technology (consider issues relating to current legislation and any issues identified in the scope for the appraisal)? No How have the clinical and cost-effectiveness analyses addressed these issues? Not applicable. Page 29 of 239

30 4 Statement of the decision problem In this section the manufacturer or sponsor should specify the decision problem that the submission addresses. The decision problem should be derived from the final scope issued by NICE and should state the key parameters that the information in the evidence submission will address. Page 30 of 239

31 Population Intervention Comparator(s) Outcomes Economic analysis Final scope issued by NICE Decision problem addressed in the submission Rationale if different from the scope Adults with genotype 1 chronic The submission addresses the clinical and cost-effectiveness of telaprevir within its N/A hepatitis C licensed indication - who have not been previously treated - who have previously been treated Telaprevir in combination with peginterferon alfa and ribavirin Combination therapy (peginterferon alfa and ribavirin) The outcome measures to be considered include: - sustained virological response (SVR) - degree of virological response - mortality - adverse effects of treatment - health-related quality of life The reference case stipulates that the cost effectiveness of Telaprevir in combination with peginterferon alfa and ribavirin. As discussed in Section 2.6, the clinical trial data is also expected to provide a reliable estimate for the costeffectiveness of telaprevir used in combination with peginterferon alfa-2b Combination therapy peginterferon alfa and ribavirin. As discussed in Section 2.6, the comparison against peginterferon alfa-2a is expected to provide an appropriate proxy for comparison against peginterferon alfa-2b A range of outcome measures will be used to compare the clinical effectiveness of telaprevir/pr therapy to treatment with PR alone: - SVR - ervr - Relapse rates - Virologic failure - Adherence - Discontinuation rates - Mortality, both all cause mortality from national statistics and specific HCV related mortality for more advanced states of disease progression from previous published economic evaluations - Adverse effects of treatment, will be reported for telaprevir/pr and the comparator based on the results from the Phase III clinical trials - HRQoL will be assessed using the EQ-5D data from the Phase III clinical trials where possible - Fatigue, measured by the Fatigue Severity Scale (FSS) Cost-effectiveness is assessed using a Markov model that compares telaprevir/pr therapy directly with PR alone, calculating incremental cost per QALY gained. N/A N/A N/A N/A Page 31 of 239

32 Subgroups to be considered Special considerations, including issues related to equity or equality treatments should be expressed in terms of incremental cost per quality-adjusted life year. The reference case stipulates that the time horizon for estimating clinical and cost effectiveness should be sufficiently long to reflect any differences in costs or outcomes between the technologies being compared. Costs will be considered from an NHS and Personal Social Services perspective If evidence allows: - the appraisal will consider duration of course of treatment; - subgroups based on baseline IL28b should be considered separately; - the previously treated population should be divided into relapsed, partial and null responders A lifetime time horizon has been applied, consistent with previous economic models, indicating that this is an appropriate timeline for evaluating the costs and outcomes of chronic HCV. Costs are considered from an NHS and Personal Social Services perspective. The clinical and economic analysis will consider the following: - Duration of a course of treatment based on response guided therapy as per the telaprevir Summary of Product Characteristics (SmPC). For treatment naïve patients, response guided therapy is already incorporated into the Phase III trial design. For treatment experienced patients, response guided therapy may be explored via a scenario analysis for the prior relapse population. - Response according to IL28B subgroups at baseline (CC, CT and TT), based on the available data from the pivotal Phase III clinical trials. - the previously treated population will be divided into relapsed, partial and null responders, based on the data from the pivotal Phase IIItrials. None None N/A N/A Page 32 of 239

33 Section B Clinical and cost effectiveness When estimating clinical and cost effectiveness, particular emphasis should be given to adhering to the reference case (see the NICE document Guide to the methods of technology appraisal Reasons for deviating from the reference case should be clearly explained. Particularly important features of the reference case include those listed in the table below. Element of health technology assessment Defining the decision problem Comparator(s) Reference case Section in Guide to the methods of technology appraisal The scope developed by NICE and Therapies routinely used in the NHS, including technologies regarded as current best practice and Perspective costs NHS and PSS to Perspective benefits All health effects on individuals to Type of economic Cost-effectiveness analysis and evaluation Synthesis of evidence on outcomes Based on a systematic review 5.3 Measure of health effects Source of data for measurement of HRQL Source of preference data for valuation of changes in HRQL QALYs 5.4 Reported directly by patients and carers Representative sample of the public Discount rate An annual rate of 3.5% on both 5.6 costs and health effects Equity weighting An additional QALY has the same weight regardless of the other characteristics of the individuals receiving the health benefit 5.12 HRQL, health-related quality of life; NHS, National Health Service; PSS, Personal Social Services; QALY(s), quality-adjusted life year(s) Page 33 of 239

34 5 Clinical evidence Manufacturers and sponsors are requested to present clinical evidence for their technology in the following sections. This section should be read in conjunction with NICE s Guide to the methods of technology appraisal, sections 3 and to Identification of studies Describe the strategies used to retrieve relevant clinical data, both from the published literature and from unpublished data that may be held by the manufacturer or sponsor. The methods used should be justified with reference to the decision problem. Sufficient detail should be provided to enable the methods to be reproduced, and the rationale for any inclusion and exclusion criteria used should be provided. Exact details of the search strategy used should be provided in section 9.2, appendix 2. A full systematic review has been carried out to identify all randomised controlled trials (RCTs) and observational studies comparing telaprevir/pr with PR alone in patients with genotype-1 chronic HCV. Exact details of the search strategies are provided in Appendix section 9.7. Databases were searched from 1 st January 2001 up to 16 th September A comprehensive literature search of the following electronic databases has been conducted: MEDLINE (including MEDLINE In-Process) Excerpta Medica Database (EMBASE ) Cochrane Central Register of Controlled Trials (CENTRAL). MEDLINE and EMBASE were searched using the Embase.com interface. MEDLINE In-process was searched using the Pubmed.com interface. CENTRAL was searched using the Cochrane library interface. The following conference proceedings were searched from 2003 onwards: American Association for the Study of Liver Disease (AASLD) British Association for the Study of the Liver (BASL) Conference on Retroviruses and Opportunistic Infections (CROI) Digestive Disease Week (DDW) European Association for the Study of the Liver (EASL) International Worskshop on HIV and Hepatitis Co-Infection (IWHHC) World Congress on Microbes (WCM). To be included in the review, trials had to meet pre-defined eligibility criteria; studies were to have a full-text English publication/poster to be included (full Page 34 of 239

35 inclusion criteria, listed in Section 5.2). Implementation and reporting of the systematic review followed the recommendations and standards required by NICE and the Preferred Reporting Items for Systematic Reviews and Meta- Analyses (PRISMA) statement. Citations were first screened based on the title and abstract supplied with each citation. Each citation was screened by two independent reviewers, and any discrepancies between reviewers were reconciled by a third independent reviewer. Citations that did not match the eligibility criteria were excluded at this first pass, and where unclear, citations were included. Duplicates of citations (due to overlap in the coverage of the databases) were also excluded and full-text copies of all references that could potentially meet the eligibility criteria were ordered at this stage. Following this the eligibility criteria were applied to full-text citations. Each fulltext article was screened by two independent reviewers, and any discrepancies between reviewers were reconciled by a third independent reviewer. Data presented in the studies included at this stage were extracted in parallel by two independent reviewers, with reconciliation of any differences by a third independent reviewer. Where more than one publication describing a single trial was identified, the data was compiled into a single entry in the data extraction table to avoid double counting of patients. 5.2 Study selection Describe the inclusion and exclusion selection criteria, language restrictions and the study selection process. A justification should be provided to ensure that the rationale is transparent. A suggested format is provided below. Table 4 Eligibility criteria for trials to be included in the systematic review Criteria Inclusion criteria Comments Rationale Inclusion Population Adult patients (age 18+ years) The population has been criteria Genotype 1 chronic HCV restricted to match the stated decision problem for the treatment of adults with Intervention Telaprevir/PR, compared directly with PR alone genotype chronic HCV The interventions have been restricted to provide a direct comparison between the telaprevir/pr and the decision problem comparator of PR alone Study design RCTs Comparative observational Page 35 of 239 The review includes RCTs, as these are the gold standard of clinical evidence, minimising the risk of confounding factors besides allowing a comparison of the efficacy of the interventions

36 Outcomes Studies should report at least one of the following outcomes: Comparative observational studies will be included to fill the data gaps in RCT evidence. These studies usually include wider patient population and present real-life effectiveness data Exclusion criteria Language restrictions Publication timeframe Population Interventions SVR Rapid virologic response (RVR) ervr End of treatment (EoT) Response Histological liver improvement DC HCC HCV sequence HRQoL/Patient Reported Outcomes AEs English only Databases were searched from 1 st January 2001 to 16 th September 2011 Studies in children Studies in animals or in vitro studies Studies on following disease and population: o Not genotype 1 o Not focussed on adult (<18 years) o Studies on smaller population (<30) o Acute hepatitis C o Mixed hepatitis population- HCV not reported separately (i.e. studies reporting combined data on hepatitis B (HBV) and HCV etc.) Studies on other antiviral therapies that do not include telaprevir Telaprevir /PR studies with no PR alone comparator These outcomes were chosen as these are frequently measured and reported in the trials involving chronic HCV patients The restriction would not limit results substantially due to data availability in English language The timeframe will capture all relevant data for telaprevir Smaller studies were excluded since they are typically Phase I studies and dose ranging studies that aim to establish the safety profile or clinical effectiveness of telaprevir across different doses and not necessarily the licensed dose Studies that did not include telaprevir were excluded, as were telaprevir studies providing no direct comparison with PR alone Study design Editorial, letter, or comment Case-series and case-reports Page 36 of 239

37 Case control studies Cohort studies Registries were not included as they are generally smaller, noncomparative studies Outcomes See above Studies which do not report outcomes of interest were excluded Language restrictions Studies not in English The restriction would not limit results substantially due to data availability in English language A flow diagram of the numbers of studies included and excluded at each stage should be provided using a validated statement for reporting systematic reviews and meta-analyses such as the QUOROM statement flow diagram ( The total number of studies in the statement should equal the total number of studies listed in section Search of literature databases yielded 696 separate references. Due to the overlap of coverage between the databases, 32 abstracts were found to be duplicates. Following the first pass of these citations, 38 potentially relevant references were identified. Full-text reports of these citations were obtained for more detailed evaluation. Following detailed examination of the 38 references, 1 reference was excluded. Conference searches identified 326 separate citations, 112 of which were found to be duplicats. Following the first pass of these citations 32 were obtained for more detailed evaluation. Following linking of the references, 6 RCTs were included for extraction (see Figure 5). Page 37 of 239

38 Figure 5 Consort flow of systematic review to identify telaprevir clinical trials Please highlight when data from a single RCT have been drawn from more than one source (for example, a poster and a published report) and/or when trials are linked (for example, an open-label extension to an RCT), this should be made clear. Page 38 of 239

39 Table 5 List of included RCTs Study Primary study Linked publications from database PROVE1 McHutchison 2009c 21 Everson Jacobson Muir Muir Muir PROVE2 Hezode Dusheiko Hezode Kieffer Pawlotsky Zeuzem PROVE3 McHutchison Di Bisceglie Manns Manns 2010a 57 Manns 2010b 58 McHutchison McHutchison 2009a 60 McHutchison 2009b 61 Muir ADVANCE Jacobson Di Bisceglie Jacobson Kieffer Marcellin Reddy Rizzetto REALIZE Zeuzem 2011b 7 De Meyer 2011a 77 De Meyer 2011b 78 Foster Pockros Pol Younossi Zeuzem 2011a 82 Linked publications from conference proceedings Zhang Everson Foster McHutchison Zhang Everson Foster Dusheiko Adda Gavart Jacobson 2011b 23 Jacobson 2011c 71 Muir Sherman Sulkowski Dusheiko Marcellin Adda Foster 2011a 83 Lawitz Pol Zeuzem 2011b 86 Roberts Younoussi Study 110 Dieterich Sulkowski Due to the inclusion criteria of publications comparing telaprevir/pr directly with PR alone, the above list of studies does not include the ILLUMINATE Phase III trial that assessed the efficacy and safety of telaprevir/pr response guided therapy in patients achieving an ervr 17. The ILLUMINATE trial contained no placebo-controlled (PBO/PR) treatment arm, however the Page 39 of 239

40 efficacy and safety results for telaprevir/pr therapy, reported in Appendix section 9.4, confirmed the findings of the ADVANCE trial. Page 40 of 239

41 Complete list of relevant RCTs Provide details of all RCTs that compare the intervention with other therapies (including placebo) in the relevant patient group. The list must be complete and will be validated by independent searches conducted by the Evidence Review Group. Page 41 of 239

42 Table 6 List of relevant RCTs Study Intervention Comparator Population Primary study PROVE1 Telaprevir 1250 mg on day 1, followed by 750 mg every 8 hours + PR (peginterferon alfa-2a 180 microgram/week + ribavirin mg twice daily) for 12 weeks, followed by PR for 12 more weeks (T12/PR24) PBO every 8 hours + PR (peginterferon alfa-2a 180 microgram/week + ribavirin mg twice daily) for 12 weeks, followed by PR for 36 more weeks (PR48) McHutchison 2009c 21 Telaprevir 1250 mg on day 1, followed by 750 mg every 8 hours + PR (peginterferon alfa-2a 180 microgram/week + ribavirin mg twice daily) for 12 weeks, followed by PR for 36 more weeks (T12/PR48) Patients with genotype 1 chronic HCV who had not been treated previously for hepatitis C Telaprevir 1250 mg on day 1, followed by 750 mg every 8 hours + PR (peginterferon alfa-2a 180 microgram/week + ribavirin mg twice daily) for 12 weeks (T12/PR12) Telaprevir 1250 mg on day 1, followed by 750 mg every 8 hours + PR (peginterferon alfa-2a 180 microgram/week + ribavirin mg twice daily) for 12 weeks, followed by PR for 12 more weeks (T12/PR24) PROVE2 Telaprevir 1250 mg on day 1, followed by 750 mg every 8 hours + PR (peginterferon alfa-2a 180 microgram/week + ribavirin mg twice daily) for 12 weeks (T12/PR12) PBO every 8 hours + PR (peginterferon alfa-2a 180 microgram/week + ribavirin mg twice daily) for 12 weeks, followed by PR for 36 more weeks (PR48) Patients with genotype 1 chronic HCV who had not been treated previously for hepatitis C Hezode Telaprevir 1250 mg on day 1, followed by 750 mg every 8 hours + peginterferon alfa-2a 180 microgram/week for 12 weeks(t12/p12) Telaprevir 1125 mg on day 1, followed by 750 mg every 8 hours + PR (peginterferon alfa-2a 180 microgram/week + ribavirin mg twice daily) for 12 weeks, followed by PBO and PROVE3 PBO every 8hs + PR (peginterferon alfa-2a 180 microgram/week + ribavirin mg twice daily) for 24 weeks, followed by PR for 24 more Patients with genotype 1 chronic HCV McHutchison Page 42 of 239

43 Study Intervention Comparator Population Primary study PR for the next 12 weeks (T12/PR24) weeks (PR48) who had previously Telaprevir 1125 mg on day 1, followed by 750 mg every 8h + PR been treated (peginterferon alfa-2a 180 microgram/week + ribavirin for HCV 1200 mg twice daily) for 24 weeks followed by PBO and PR for infection with the next 24 weeks (T24/PR48) peginterferon alfa and ribavirin Telaprevir 1125 mg on day 1, followed by 750 mg every 8h + peginterferon alfa-2a 180 microgram/week for 24 weeks (T24/P24) ADVANCE Telaprevir 750 mg every 8h + PR (peginterferon alfa-2a 180 µg weekly + ribavirin mg twice daily) for 12 weeks, followed by PR alone for 12 or 36 more weeks (T12/PR) Telaprevir 750 mg every 8h + PR (peginterferon alfa-2a 180 µg weekly + ribavirin mg twice daily) for 8 weeks, followed by PBO every 8h + PR for 4 weeks, followed by PR alone for 12 or 36 more weeks (T8/PR) REALIZE Telaprevir 750 mg every 8h + PR (peginterferon alfa-2a 180 µg weekly + ribavirin mg twice daily) for 12 weeks, followed by PBO every 8h + PR for 4 weeks, followed by PR alone for 32 more weeks (T12/PR48) PBO every 8h + PR (peginterferon alfa-2a 180 µg weekly + ribavirin mg twice daily) for 4 weeks, followed by telaprevir 750 mg every 8h + PR for 12 weeks, followed by PR alone for 32 weeks (T12LI/PR48) Study 110 Telaprevir 750 mg every 8h + PR (peginterferon alfa-2a 180 microgram/week + ribavirin 800 mg/day) for 12 weeks, followed PBO every 8h + PR (peginterferon alfa-2a 180 µg weekly + ribavirin mg twice daily) for 12 weeks, followed by PR alone for 36 more weeks (PR48) PBO every 8h + PR (peginterferon alfa-2a 180 µg weekly + ribavirin mg twice daily) for 16 weeks, followed by PR alone for 32 more weeks (PR48) PBO every 8h for 12 weeks + PR (peginterferon alfa-2a 180 microgram/week + ribavirin (RBV) 800 Patients with genotype 1 chronic HCV who had not received prior PR therapy Patients with genotype 1 chronic HCV who failed prior PR therapy HCV genotype 1 interferon- Jacobson Zeuzem Dieterich Page 43 of 239

44 Study Intervention Comparator Population Primary study by PR alone for 36 weeks (T12/PR48) mg/day) for 48 weeks (PR48) naive patients, co-infected with HIV Telaprevir 750 mg every 8h + PR (peginterferon alfa-2a 180 microgram/week + ribavirin (RBV) 800 mg/day) for 12 weeks, followed by PR for 36 weeks. Antiretroviral therapy (ART) regimen included: Efavirenz/Tenofovir/Emtricitabine. Telaprevir dose was 1125 mg every 8h when the ART regimen included Efavirenz (T12/PR48) Telaprevir 750 mg every 8h + PR (peginterferon alfa-2a 180 microgram/week + ribavirin (RBV) 800 mg/day) for 12 weeks, followed by PR for 36 weeks; ART regimen included: Atazanavir/r + Tenofovir + Emtricitabine/Lamivudine (T12/PR48) PBO every 8h for 12 weeks + PR (peginterferon alfa-2a 180 microgram/week + ribavirin (RBV) 800 mg/day) for 48 weeks. ART regimen included: Efavirenz/ Tenofovir/Emtricitabine (PR48) PBO every 8h for 12 weeks + PR (peginterferon alfa-2a 180 microgram/week + ribavirin (RBV) 800 mg/day) for 48 weeks. ART regimen included: Atazanavir/r + Tenofovir + Emtricitabine/ Lamivudine (PR48) Page 44 of 239

45 5.2.5 Please highlight which of the RCTs identified above compares the intervention directly with the appropriate comparator(s) with reference to the decision problem. If there are none, please state this. All six of the above RCTs directly compare telaprevir/pr therapy and PR alone as per the decision problem. Treatment naïve population The dose ranging Phase II trials PROVE1 and PROVE2 and Phase III ADVANCE study all provide a direct comparison between telaprevir/pr and PR alone in treatment naïve patients. Study 110 provides a direct comparison between telaprevir/pr and PR alone in treatment naïve patients who are HIV co-infected. Treatment experienced population The Phase II dose ranging PROVE3 trial and the Phase III REALIZE trial both provide a direct comparison between telaprevir/pr and PR alone in treatment experienced patients When studies identified above have been excluded from further discussion, a justification should be provided to ensure that the rationale for doing so is transparent. For example, when studies have been identified but there is no access to the level of trial data required, this should be indicated. PROVE studies There are important limitations relating to the three Phase II PROVE trials which necessitate their exclusion from further discussion: These dose ranging trials include unlicensed loading doses of telaprevir 1250 mg on day one of the study These trials included unlicensed dosing regimens, including: T12/PR12 in PROVE1 & PROVE2; T12/P12 in PROVE2; T24/PR24 in PROVE3 and T24/PR48 in PROVE 3 The trial designs did not dose telaprevir patients according to response guided therapy, therefore even the T12/PR24 and T12/PR48 doses were not implemented according to the licensed response guided therapy durations. T12/PR24 data therefore includes patients who did not achieve an ervr and in clinical practice would now be treated with T12/PR48 according to the license, with the longer duration resulting in higher SVR rates. T12/PR48 data includes patients who did achieve an ervr and would now be treated with T12/PR24 according to the license. The trials did not incorporate the AE management plan that was included in the Phase III trials and is being implemented in clinical Page 45 of 239

46 110 study practice. This resulted in patients unnecessarily discontinuing therapy due to rash, artificially inflating discontinuations and reducing SVR rates compared to the expected outcomes in clinical practice. The 110 study in HIV co-infected patients is on-going, with interim results showing an efficacy benefit for telaprevir/pr relative to PR alone in initial 12 weeks of treatment consistent with results observed in other trials. However, the SVR results required for the economic assessment are not expected to be available until November 2012, necessitating its exclusion from this economic assessment. Other exclusions Both the ADVANCE and REALIZE studies are included in this evaluation, however, some of the data captured in these trials are excluded from further discussion for the following reasons: In the ADVANCE study the 12 week telaprevir/pr dosing schedule (T12/PR) was found to demonstrate a better benefit-risk profile than the 8 week telaprevir/pr dosing schedule (T8/PR). As a result of this finding, research around the T8/PR dosing schedule was ceased; it is not recommended as a treatment strategy and is not part of the license. The reporting of the ADVANCE trial focuses instead on the licensed T12/PR regimen and the comparator PBO/PR treatment regimen. The PR lead-in regimen in the REALIZE trial is not the recommended dosing regimen for telaprevir, since the use of a 4 week lead-in phase with PR alone does not improve SVR rates relative to T12/PR, nor does it reduce virologic failure and relapse rates. Furthermore, clinicians have stated concerns about the suitability of re-treating these experienced patients with PR alone for any period of time, given that they have previously failed on PR alone. For these reasons, the reporting of the REALIZE trial focuses instead on the recommended T12/PR regimen and the comparator PBO/PR regimen. List of relevant non-rcts Please provide details of any non-rcts (for example experimental and observational data) that are considered relevant to the decision problem and a justification for their inclusion. Full details should be provided in section 5.8 and key details should be presented in a table; the following is a suggested format. The systematic literature review did not identify any non-rct evidence relevant to the decision problem. Page 46 of 239

47 5.3 Summary of methodology of relevant RCTs As a minimum, the summary should include information on the RCT(s) under the subheadings listed in this section. Items 2 to 14 of the CONSORT checklist should be provided, as well as a CONSORT flow diagram of patient numbers ( It is expected that all key aspects of methodology will be in the public domain; if a manufacturer or sponsor wishes to submit aspects of the methodology in confidence, prior agreement must be requested from NICE. When there is more than one RCT, the information should be tabulated. Summary information on the Phase III telaprevir clinical trials (ADVANCE 16 and REALIZE 7 ) are given in Table 7 below. Results from both the ADVANCE and REALIZE studies have been published 7, 16 in the New England Journal of Medicine and data on these studies provided in this submission have been taken from the published articles where possible. These data are supplemented by unpublished sources such as the clinical study reports 91, 92, where data that directly relate to the decision problem are not available from the published literature. Methods Describe the RCT(s) design (for example, duration, degree and method of blinding, and randomisation) and interventions. Include details of length of follow-up and timing of assessments. The following tables provide a suggested format for when there is more than one RCT. Page 47 of 239

48 Table 7 Comparative summary of methodology of the RCTs Trial no. ADVANCE (acronym) Location Multicentre, International, 12 countries including the UK (Argentina, Austria, Australia, Canada, France, Germany, Israel, Italy, Poland, Spain, UK, United States) Design Randomised, double-blind, placebo-controlled, Phase III trial comparing telaprevir/pr with PR alone REALIZE Multicentre, International, 17 countries including the UK (Argentina, Australia, Austria, Belgium, Brazil, Canada, France, Germany, Israel, Italy, Netherlands, Poland, Spain, Sweden, Switzerland, UK, United States) Randomised, double-blind, placebo-controlled, Phase III trial comparing telaprevir /PR with PR alone The ADVANCE trial design incorporated the following virologic stopping rules: Time point Criteria for stopping Action Week 4* HCV RNA >1,000 IU/mL Discontinue telaprevir, continue PR Week 12 HCV RNA <2 log10 decline Discontinue all treatment Weeks 24, 28, 36, 40 HCV RNA detectable (>25 IU/mL) Discontinue all treatment * The week 4 virologic failure rule only applies to telaprevir treated patients The REALIZE trial design incorporated the following virologic stopping rules: Time point Criteria for stopping Action Weeks 4, 6, 8 after telaprevir HCV RNA >100 IU/mL Discontinue telaprevir, initiation* continue PR Week 12 HCV RNA <2 log10 decline Discontinue all treatment Weeks 24, 36 HCV RNA detectable (>25 IU/mL) Discontinue all treatment * The week 4 virologic failure rule only applies to telaprevir treated patients Duration of study 24 or 48 weeks 48 weeks Method of randomisation Patients were stratified by genotype 1 subtype (1a, 1b, 1 unknown) and baseline viral load (HCV RNA <800,000 IU/mL 800,000 or IU/mL) at screening, and then randomised in a 1:1:1 ratio to 12 weeks of telaprevir (T12/PR), 8 weeks of telaprevir followed by 4 weeks of PBO (T8/PR) or 12 Patients were stratified by prior treatment response (prior relapse v prior non-responder) and baseline viral load (HCV RNA <800,000 IU/mL or 800,000 IU/mL) at screening, and then randomised in a 2:2:1 ratio to 12 weeks of telaprevir without lead-in (T12/PR), 12 weeks of telaprevir with Page 48 of 239

49 Method of blinding weeks of PBO (PBO/PR). Results for the T8/PR regimen are provided in Appendix section 9.5 as this is an unlicensed dose of telaprevir. Randomisation was performed using an interactive web response system and was blocked and stratified to ensure a balance among the treatment groups according to genotype 1 subtype and baseline viral load To maintain double blinding during the first 12 weeks, patients in the PBO/PR group received telaprevir -matching placebo from Day 1 through to Week 12. Treatment selection was double-blinded until database lock at 72 weeks. HCV RNA results were double-blinded up to week 28. From week 28 HCV RNA results were available to the lead investigator. Unblinding was restricted to circumstances when the knowledge of a patient s treatment assignment was needed to medically manage their condition or when a pregnancy occurred in a female patient or the partner of a male patient, or to determine whether SAEs should be attributed to study drugs Intervention(s) T12/PR (n=365) T12/PR (n=266) lead-in (LI T12/PR), or PBO (PBO/PR). Results for the LI T12/PR regimen are provided in Appendix section 9.6 as this is not the recommended dosing regimen for telaprevir. Randomisation was performed using an interactive voice/web response system and was blocked and stratified to ensure a balance among the treatment groups according to baseline viral load and prior treatment response, with prior treatment response defined as follows: Prior relapse, defined as patients with detectable HCV RNA during the follow-up period after previously undetectable HCV RNA at end of previous treatment Prior non-responder, defined as patients who did not achieve undetectable HCV RNA during previous treatment. This group can be further sub-divided into: o Prior partial responder, defined as patients with 2 -log drop in HCV RNA at Week 12 of prior therapy, but who never achieved undetectable HCV RNA levels while on treatment o Prior null responder, defined as patients with <2-log drop in HCV RNA at Week 12 of prior therapy To maintain double blinding during the first 16 weeks, the LI T12 group received telaprevir -matching PBO during weeks 1-4, the T12/PR group received telaprevir -matching PBO during weeks and the PBO/PR group received telaprevir -matching placebo from Day 1 through to Week 16. Treatment assignment was double-blinded until all patients had reached week 72 or had discontinued earlier. Unblinding was restricted to circumstances when the knowledge of a patient s treatment assignment was needed to medically manage their condition or when a pregnancy occurred in a female patient or the partner of a male patient, or to determine whether SAEs should be attributed to study drugs. In addition, patients in the PBO/PR arm failing for virological reasons could be notified of their eligibility to enter an open-label Phase III telaprevir study VX-950- TiDP24-C219 Page 49 of 239

50 and comparator(s) Primary outcomes (including scoring methods and timings of assessments) Secondary outcomes (including scoring methods and timings of assessments) Duration of followup T8/PR(n=365) reported in Appendix section 9.5 LI T12/PR (n=264) reported in Appendix section 9.6 PBO/PR (Control) (n=365) PBO/PR (Control) (n=133) Proportion of patients with SVR, defined as undetectable HCV RNA at end-of-treatment visit and 24 weeks after the last planned dose of study treatment without any confirmed detectable HCV RNA in between those visits. The original published SVR rates are a pre-specified planned analysis using a conservative approach using a strict week 72 visit without imputation of missing value for SVR assessment with the limit of detectability and taking into consideration of on-treatment virologic failure. Revised SVR rates reported in the SmPC are based on a snapshot analysis where the virologic outcome was based on the HCV RNA assessment in the week 72 visit window, defined as week 12 of follow-up through to week 72. If there was more than one assessment in the window, the last measurement would be used. In case of missing data at week 72, the last HCV RNA data point from week 12 of follow-up onwards was used instead (LOCF). In addition, the limit of quantification of 25 IU/mL was used to determine the virologic response in the follow-up period in the visit window. ervr: defined as undetectable HCV RNA at 4 and 12 weeks after the start of telaprevir treatment Relapse rates, defined as undetectable HCV RNA at end of treatment, but with confirmed HCV RNA between and of treatment and up to/including the 24 week follow-up SVR assessment timepoint Virologic failure, which includes o On treatment virologic failure, defined as patients with detectable HCV RNA at weeks, 4, 12, 24, 28, 36 or end of treatment for patients completing therapy o Relapse, defined as undetectable HCV RNA at end of treatment, but detectable HCV RNA during 24 weeks of follow-up o Detectable HCV RNA at end of treatment for patients who did not complete the planned duration of therapy o Patients missing SVR data, either due to discontinuing the study during the 24-week follow-up period or missing the 24-week follow-up assessment Adherence, measured as total actual doses received versus total expected doses received, based on pill count Discontinuation rates during the trial HRQoL, evaluated using the EQ-5D questionnaire at Day 1, Week 4, 12, 24, 36 (ADVANCE only), 48, 72 and at time of early discontinuation (REALIZE only). The 72 week evaluation was undertaken before patients were aware of their SVR status Fatigue, measured by the FSS at Day 1, Week 2 (REALIZE only), 4, 12, 24, 36 (ADVANCE only), 48, 72 (ADVANCE only) and at time of early discontinuation (REALIZE only) Out to week 72 Page 50 of 239

51 Participants Provide details of the eligibility criteria (inclusion and exclusion) for the trial. The following table provides a suggested format for the eligibility criteria for when there is more than one RCT. Highlight any differences between the trials. Page 51 of 239

52 Table 8 Eligibility criteria in the RCTs Trial no. (acronym) ADVANCE Inclusion criteria No previous treatment with any approved or investigational drug for the treatment of HCV Male or female, aged years Diagnosed with detectable HCV viral load, with genotype 1 confirmed at screening. HCV confirmed as chronic by meeting at least one of the following criteria: HCV diagnosis >6 months before screening Abnormal alanine aminotransferase (ALT) levels >6 months before screening Acceptable laboratory values at screening (seronegative for HBV and HIV) Liver biopsy <1 year before screening, or agreement for liver biopsy at screening, showing evidence of hepatitis Patients or their partners must not be pregnant or planning to become pregnant in the next 72 weeks Willing and able to refrain from concomitant use of certain medications, substances or foods, including ESAs. REALIZE Failed at least one prior course of peginterferon/ribavirin therapy for the treatment of HCV Patients had to have received the last dose of peginterferon/ribavirin at least 12 weeks before the screening visit Male or female, aged years Diagnosed with detectable HCV viral load, with genotype 1 confirmed at screening. HCV confirmed as chronic by having HCV diagnosis >6 months before screening Judged by investigator to be in good health on the basis of medical history and physical examination, with chronic conditions under stable medical control Liver biopsy <18 months before screening, or agreement for liver biopsy at screening, showing evidence of hepatitis Patients with cirrhosis to have serum 50 ng/ml and normal abdominal ultrasound. Patients failing either of these criteria had to have a computerised tomography/magnetic resonance imaging scan to exclude hepatocellular carcinoma Heterosexually active females of child-bearing age or non-vasectomised males had to agree to using 2 effective forms of contraception from screening through to 6-7 months following last ribavirin dose Willing and able to refrain from concomitant use of certain medications, substances or foods, including ESAs. Exclusion criteria Patients contraindicated to peginterferon alfa-2a or ribavirin Cirrhotic patients with evidence of hepatic decompensation Patients with any other cause of significant liver disease in addition to HCV including HBV Patients with diagnosed or suspected hepatocellular carcinoma Patients with active malignant disease or history of malignant disease within the 5 previous years (with the exception of treated basal cell carcinoma) Patients with a pre-existing psychiatric condition that could have interfered with their participation in and completion of the study, including depression, schizophrenia, bipolar disorder, severe anxiety and others Patients with a history of organ transplant requiring chronic immunosuppression, with the exception of corneal transplants and skin grafts Patient currently abusing illicit drugs (narcotics or other controlled substances) or alcohol, or had a history of illicit substance or alcohol abuse within 2 years prior to screening. Patients contraindicated to peginterferon alfa-2a or ribavirin Patients who had discontinued prior peginterferon alfa-2a or ribavirin due to tolerance issues instead of a lack of response Patients that were previous non-responders classified as viral breakthrough (i.e. undetectable HCV RNA during prior therapy, but regained detectable HCV RNA before therapy ended) Patients infected with HCV genotype 1, exhibiting more than one subtype, or co-infection with any other genotype Patients with decompensated liver disease or evidence of significant liver disease in addition to HCV Patients co-infected with HIV or HBV Patients with active malignant disease or history of malignant disease within the 5 previous years (with the exception of treated basal cell carcinoma) Patients with a pre-existing psychiatric condition that could have interfered with their participation in and completion of the study, including depression, schizophrenia, bipolar disorder, severe anxiety and others Patients with a history of organ transplant requiring chronic immunosuppression, with the exception of corneal transplants and skin grafts Suspicion of alcohol, barbiturate, amphetamine recreational or narcotic drug use, currently or within 2 years prior to screening visit Inclusion and exclusion criteria were very similar between the ADVANCE and REALIZE trials with the key difference being the degree of prior treatment experience: Page 52 of 239

53 Patients in the ADVANCE trial had received no previous treatment with any approved or investigational drug for the treatment of HCV; Patients in the REALIZE trial had failed at least one prior course of peginterferon/ribavirin therapy for the treatment of HVC and had to have received the last dose of peginterferon/ribavirin at least 12 weeks before the screening visit Describe the patient characteristics at baseline. Highlight any differences between study groups. The following table provides a suggested format for the presentation of baseline patient characteristics for when there is more than one RCT. Page 53 of 239

54 Table 9 Characteristics of participants in the RCTs across randomised groups Trial no. (acronym) Baseline characteristic Randomised group (Intervention) Randomised group (Comparator) ADVANCE T12/PR (n = 363) PBO/PR (n = 361) Age Median years (range) 49 (19-69) 49 (18-69) Body mass index(bmi), mean kg/m 2 26 (18-47) 26 (17-48) (range) Gender, n (%) Male 214 (59) 211 (58) Race, n (%) Caucasian Black 325 (90) 26 (7) 318 (88) 28 (8) Ethnicity, n (%) Hispanic/Latino 35 (10) 38 (11) HCV genotype subgroup, n (%) 1a 1b 1, unknown 213 (59) 149 (41) 1 (<1) 208 (58) 151 (42) 2 (1) HCV RNA 800,000 IU/mL, n (%) 281 (77) 279 (77) Stage of fibrosis or cirrhosis*, n (%) No/minimal fibrosis Portal fibrosis Bridging fibrosis Cirrhosis 134 (37) 156 (43) 52 (14) 21 (6) 147 (41) 141 (39) 52 (14) 21 (6) REALIZE T12/PR (n = 266) PBO/PR (n =132 ) Age, mean (range) 51 (23-69) 50 (21-69) BMI, mean kg/m 2 (range) 28 (5.0) 27 (4.6) Gender, n (%) Male 183 (69) 88 (67) Race, n (%) Caucasian 246 (92) 117 (89) HCV genotype subgroup, n (%) 1a 1b 136 (52) 126 (48) 67 (52) 61 (48) HCV RNA 800,000 IU/mL, n (%) 238 (89) 114 (86) Stage of fibrosis or cirrhosis*, n (%) No/minimal fibrosis 51 (19) 35 (27) Portal fibrosis 83 (31) 38 (29) Bridging fibrosis 60 (23) 29 (22) Cirrhosis 72 (27) 30 (23) Prior response, n (%) Null responder Partial responder Relapser 72 (27) 49 (18) 145 (55) 37 (28) 27 (20) 68 (52) * No minimal or no fibrosis = Metavir F0 F1/Ishak 0 2; Portal fibrosis = Metavir F2/Ishak 3; Bridging fibrosis = Metavir F3/Ishak 4); Cirrhosis = Metavir F4/Ishak 5 6 For the treatment naïve economic model, the distribution of patients by age classification and disease severity are sourced directly from the ADVANCE trial (see Table 10). Page 54 of 239

55 Table 10 Age and disease severity distribution of T12/PR and PBO/PR patients in ADVANCE 35 years (n = 110) years (n = 175) >45 years (n = 439) Mild HCV, n (%) 70 (64) 76 (43) 135 (31) Moderate HCV, n (%) 36 (33) 71 (41) 190 (43) Compensated cirrhosis, n (%) 4 (4) 28 (16) 114 (26) For the treatment experienced economic model, the distribution of patients by prior treatment response and disease severity are sourced directly from the REALIZE trial (see Table 11). Table 11 Prior response and disease severity distribution of T12/PR and PBO/PR patients in REALIZE Prior relapse (n = 213) Prior partial response (n = 76) Prior null response (n = 109) Mild HCV, n (%) 54 (25) 17 (22) 15 (14) Moderate HCV, n (%) 65 (31) 24 (32) 32 (29) Compensated cirrhosis, n (%) 94 (44) 35 (46) 62 (57) Page 55 of 239

56 Outcomes Provide details of the outcomes investigated and the measures used to assess those outcomes. Indicate which outcomes were specified in the trial protocol as primary or secondary, and whether they are relevant with reference to the decision problem. This should include therapeutic outcomes, as well as patient-related outcomes such as assessment of health-related quality of life, and any arrangements to measure compliance. Data provided should be from pre-specified outcomes rather than post-hoc analyses. When appropriate, also provide evidence of reliability or validity, and current status of the measure (such as use within UK clinical practice). The following table provides a suggested format for presenting primary and secondary outcomes when there is more than one RCT. Page 56 of 239

57 Table 12 Primary and secondary outcomes of the RCTs Trial no. (acronym) ADVANCE Primary outcome(s) and measures Proportion of patients with SVR, defined as undetectable HCV RNA at end-oftreatment visit and 24 weeks after the last planned dose of study treatment without any confirmed detectable HCV RNA in between those visits Reliability/ validity/ current use in clinical practice SVR is the primary aim of treatment in clinical practice Secondary outcome(s) and measures ervr, defined as undetectable HCV RNA at 4 and 12 weeks after the start of treatment Relapse rates, defined as undetectable HCV RNA at end of treatment, but with confirmed HCV RNA between and of treatment and up to/including the 24 week follow-up SVR assessment timepoint Virologic response, which includes o On treatment virologic failure, defined as patients with detectable HCV RNA at weeks, 4, 12, 24, 28, 36 or end of treatment for patients completing therapy o Relapse, defined as undetectable HCV RNA at end of treatment, but detectable HCV RNA during 24 weeks of follow-up o Detectable HCV RNA at end of treatment for patients who did not complete the planned duration of therapy o Patients missing SVR data, either due to discontinuing the study during the 24-week follow-up period or missing the 24-week follow-up assessment Adherence, measured as total actual doses received versus total expected doses received, based on pill count Discontinuation rates Reliability/validity/ current use in clinical practice ervr will be required in clinical practice to identify patients eligibility for response guided therapy Relapse rates and virologic response are in concordance with clinical practice definitions and timepoints McHutchinson et al demonstrated that genotype-1 chronic HCV patients with >80% adherence to PR therapy achieved significantly higher SVR rates than those with 80% adherence Reflects virologic failure stopping rules and AEs leading to discontinuation HRQoL, evaluated using the EQ-5D questionnaire at Day 1, Week 4, 12, 24, 36, 48, and 72 Fatigue, measured by the FSS at Day 1, Week 4, 12, 24, 36, 48 and 72 Reflects impact of treatment and adverse event rates EQ-5D is the preferred measure of adult HRQoL in the 2008 NICE methods 94 REALIZE As per ADVANCE As per ADVANCE As per ADVANCE with the following exceptions: HRQoL, evaluated using the EQ-5D questionnaire at Day 1, Week 4, 12, 24, 48, 72 and at time of early discontinuation Fatigue, measured by the FSS at Day 1, Week 2, 4, 12, 24, 48 and at time of early discontinuation As per ADVANCE Page 57 of 239

58 EQ-5D The EQ-5D provides a generic measure of quality of life. The patient was asked to indicate his/her health state over five dimensions (mobility, selfcare, usual activities, pain/discomfort, and anxiety/depression), each with three possible levels (no problems, some problems, and extreme problems). The EQ-5D valuation index summarised the information of the 5 dimensions of the descriptive system into one index that attaches weights to each of the levels in each dimension. Fatigue Severity Scale The FSS was a 9-item questionnaire where each of the following items is scored between 1 and 7, with higher scores indicating a higher influence of fatigue. The 9-item responses were combined into 1 total score (FSS total score) per time point for each individual by determining the mean of (at least 6) non-missing items: My motivation is lower when I am fatigued Exercise brings on my fatigue I am easily fatigued Fatigue interferes with physical functioning Fatigue causes frequent problems for me My fatigue prevents sustained physical functioning Fatigue interferes with carrying out certain duties and responsibilities Fatigue is among my 3 most disabling symptoms Fatigue interferes with my work, family, or social life Statistical analysis and definition of study groups State the primary hypothesis or hypotheses under consideration and the statistical analysis used for testing hypotheses. Also provide details of the power of the study and a description of sample size calculation, including rationale and assumptions. Provide details of how the analysis took account of patients who withdrew (for example, a description of the intention-to-treat analysis undertaken, including censoring methods; whether a per-protocol analysis was undertaken). The following table provides a suggested format for presenting the statistical analyses in the trials when there is more than one RCT. Page 58 of 239

59 Table 13 Summary of statistical analyses in RCTs Trial no. (acronym) ADVANCE REALIZE Hypothesis objective Statistical analysis Sample size, power calculation Data management, patient withdrawals The primary objective was to demonstrate the The analysis of the primary end The planned sample size of 350 patients in each treatment group provided a power Carried out using Intention to Treat efficacy of telaprevir /PR in a response guided point was based on a logisticregression of 92% to demonstrate statistically significant treatment difference between (ITT) principles and included all regimen versus PBO/PR. To that end, the primary model, with SVR as the telaprevir /PR and PBO/PR. This was based on a 50% planned SVR in the PBO patients who had received at least efficacy variable was the proportion of subjects dependent variable and treatment, group, a 64% planned SVR among the telaprevir patients, a 2-sided continuity one dose of study drug achieving SVR, defined as undetectable HCV RNA genotype 1 subtype, and baseline corrected Chi-squared test with an overall significance level of 5% 24 weeks after the last planned study drug dosing HCV RNA plasma level as factors. The primary analysis was repeated (Week 48 for subjects in the T8/PR and T12/PR The primary end point was also for the per protocol (PP) set, which is groups who achieved ervr, and Week 72 for evaluated by an analysis of the the full analysis set excluding all subjects in the T8/PR and T12/PR groups who did consistency of the treatment effect subjects with protocol deviations not achieve ervr and all subjects in the PBO/PR48 in prespecified subgroups related to adherence to study group), regardless of whether the subject completed according to 10 baseline variables medication (major), related to all study drug dosing. concomitant medication (major), related to selection criteria (major), or related to compliance towards stopping rules of study medication (major or minor). Only ITT results The primary objective was to demonstrate superior SVR rates among the telaprevir /PR regimens versus PBO/PR in prior relapse patients and both prior non-responder groups (prior null and prior partial responders). Trial protocol amendments to the statistical methods resulted in the addition of statistical method on pooling of telaprevir treatment groups to compare with PBO in the individual subgroups of null and partial responders. The sample size and power consideration for null-responders was also added The analysis of the primary end point was based on a logisticregression model that included study group, the type of previous response (null, partial or relapse), and their interaction as factors and the baseline viral RNA as a covariate. The Hochberg procedure was used to adjust for multiple comparisons Sample sizes were calculated as follows: Relapsers. Assuming 55% telaprevir response rate and a 29% PBO response rate, a 2-sided continuity corrected Chi-squared test with an overall significance level of 5%, a 2:2:1 randomisation, sample size of 140 in each of the telaprevir treatment groups and 70 in the PBO group provided a power of approximately 90% to demonstrate statistically significant difference Non-responders. Assuming 30% telaprevir response rate and an 8% PBO response rate, a 2-sided continuity corrected Chi-squared test with an overall significance level of 5%, a 2:2:1 randomisation, sample size of 120 in each of the telaprevir treatment groups and 60 in the PBO group provided a power of approximately 90% to demonstrate statistically significant difference o Trial protocol amendments to the statistical methods resulted in the addition of statistical method on pooling of telaprevir treatment groups to compare with PBO in the individual subgroups of null and partial responders. The sample size and power consideration for null responders was also added. 650 patients were required in total, incorporating 350 prior relapsers and 300 prior non-responders are reported in the submission. Carried out using ITT principle and included all patients who had received at least one dose of study drug The primary analysis was repeated for the PP set, which is the full analysis set excluding all subjects with protocol deviations related to adherence to study medication (major), related to concomitant medication (major), related to selection criteria (major), or related to compliance towards stopping rules of study medication (major or minor). Page 59 of 239

60 5.3.7 Provide details of any subgroup analyses that were undertaken and specify the rationale and whether they were pre-planned or post-hoc. In the ADVANCE trial, pre-planned subgroup analyses were undertaken to assess the differences in SVR rate between telaprevir/pr and PR alone according to different baseline patient demographics and disease characteristics, including: gender; age; race; ethnic group; HCV subtype; baseline HCV RNA levels; fibrosis status; BMI, history of diabetes and geographic region. Figure 6 Subgroup analyses from the ADVANCE trial 16 In the REALIZE trial, pre-planned subgroup analyses of SVR according to the stage of liver fibrosis and the baseline viral load were conducted to determine the robustness of the primary analysis, results of which are summarised in Table 14. Page 60 of 239

61 Table 14 SVR rate according to patient subgroups 91 Subgroup, n, N (%) Prior relapse Prior partial response Prior null response T12/PR PBO/PR T12/PR PBO/PR T12/PR PBO/PR Sex Male 40, 47 (85) 7, 22 (32) 10, 20 (50) 1, 12 (8) 2, 16 (13) 1, 10 (10) Female 81, 98 (83) 9, 46 (20) 19, 29 (66) 3, 15 (20) 19, 56 (34) 1, 27 (4) Ethnicity Hispanic/Latino 17, 17 (100) 2, 12 (17) 1, 4 (25) 0, 5 (0) 0, 4 (0) 0, 3 (0) Not Hispanic/Latino 104, 128 (81) 14, 56 (25) 28, 45 (62) 4, 22 (18) 21, 68 (31) 2, 34 (6) Race Black 6, 7 (86) 2, 3 (67) 1, 2 (50) 2, 6 (33) 0, 2 (0) 0, 2 (0) Caucasian 109, 132 (83) 14, 61 (23) 28, 46 (61) 2, 21 (10) 19, 68 (28) 2, 35 (6) Age 45 years 27, 32 (84) 4, 18 (22) 9, 11 (82) 1, 9 (11) 8, 21 (38) 1, 13 (8) years 92, 111 (83) 12, 44 (27) 19, 36 (53) 3, 17 (18) 13, 50 (26) 1, 24 (4) >65 years 2, 2 (100) 0, 6 (0) 1, 2 (50) 0, 1 (0) 0, 1 (0) - Baseline BMI <25 (normal) 37, 45 (82) 4, 19 (21) 10, 18 (56) 2, 9 (22) 6, 22 (27) 1, 14 (7) (overweight) 52, 62 (84) 7, 29 (24) 15, 21 (71) 0, 11 (0) 10, 25 (40) 0, 13 (0) 30 (obese) 32, 38 (84) 5, 20 (25) 4, 10 (40) 2, 7 (29) 5, 25 (20) 1, 10 (10) Genotype 1a 52, 65 (80) 10, 34 (29) 13, 26 (50) 3, 16 (19) 11, 45 (24) 1, 17 (6) 1b 67, 77 (87) 6, 31 (19) 15, 22 (68) 1, 10 (10) 10, 27 (37) 1, 20 (5) Baseline HCV RNA <800,000 IU/mL 20, 21 (95) 3, 12 (25) 2, 4 (50) 0, 2 (0) 2, 3 (67) 2, 4 (50) 800,000 IU/mL 101, 124 (81) 13, 56 (23) 27, 45 (60) 4, 25 (16) 19, 69 (28) 0, 33 (0) Baseline liver disease No/minimal fibrosis 29, 34 (85) 7, 20 (35) 5, 7 (71) 0, 10 (10) 1, 10 (10) 0, 5 (0) Portal fibrosis 38, 47 (81) 5, 18 (28) 13, 17 (76) 3, 7 (43) 8, 19 (42) 1, 13 (8) Bridging fibrosis 31, 36 (86) 2, 15 (13) 5, 7 (71) 0, 5 (0) 7, 17 (41) 0, 9 (0) Cirrhosis 23, 28 (82) 2, 15 (13) 6, 18 (33) 1, 5 (20) 5, 26 (19) 1, 10 (10) Post-hoc subgroup analysis on virologic response according to IL-28b subgroup, as specified in the decision problem, have been completed and are reported in Section 6.9. Pre-planned subgroup analysis on virologic response according to prior treatment response have been completed. These analyses focus on the prior relapse, prior partial response and prior null response populations specified in the decision problem and are reported in Section 6.9. Participant flow Provide details of the numbers of patients who were eligible to enter the RCT(s), randomised, and allocated to each treatment. Provide details of, and the rationale for, patients who crossed over treatment groups and/or were lost to follow-up or withdrew from the RCT. This information should be presented as a CONSORT flow chart. The following summaries of patient flows in the ADVANCE and REALIZE trials relate to the relevant treatment arms in the submission. Page 61 of 239

62 Figure 7 ADVANCE patient disposition (adapted from Jacobson et al ) Page 62 of 239

63 Figure 8 REALIZE patient disposition (adapted from Zeuzem et al ) Page 63 of 239

64 5.4 Critical appraisal of relevant RCTs The validity of the results of an individual study will depend on the robustness of its overall design and execution, and its relevance to the decision problem. Each study that meets the criteria for inclusion should therefore be critically appraised. Whenever possible, the criteria for assessing published studies should be used to assess the validity of unpublished and part-published studies Please provide as an appendix a complete quality assessment for each RCT. See section 9.3, appendix 3 for a suggested format. Detailed quality assessments of the ADVANCE and REALIZE trials are provided in Appendix Section If there is more than one RCT, tabulate a summary of the responses applied to each of the critical appraisal criteria. A suggested format for the quality assessment results is shown below. Table 15 Quality assessment results for RCTs Study name ADVANCE Study REALIZE study Was randomisation carried out appropriately? Yes Not clear Was the concealment of treatment allocation Yes Yes adequate? Were the groups similar at the outset of the study in Yes Yes terms of prognostic factors? Were the care providers, participants and outcome Not clear Yes assessors blind to treatment allocation? Were there any unexpected imbalances in dropouts Yes Yes between groups? Is there any evidence to suggest that the authors Yes Yes measured more outcomes than they reported? Did the analysis include an intention-to-treat analysis? If so, was this appropriate and were appropriate methods used to account for missing data? Yes Yes Page 64 of 239

65 5.5 Results of the relevant RCTs Provide the results for all relevant outcome measure(s) pertinent to the decision problem. Data from intention-to-treat analyses should be presented whenever possible and a definition of the included patients provided. If patients have been excluded from the analysis, the rationale for this should be given. If there is more than one RCT, tabulate the responses. Results presented in the following section are drawn from the ITT full analysis set from the ADVANCE and REALIZE studies, which includes all randomised patients receiving at least one dose of study drug The information may be presented graphically to supplement text and tabulated data. If appropriate, please present graphs such as Kaplan-Meier plots For each outcome for each included RCT, the following information should be provided. The unit of measurement. The size of the effect; for dichotomous outcomes, the results ideally should be expressed as both relative risks (or odds ratios) and risk (or rate) differences. For time-to-event analysis, the hazard ratio is an equivalent statistic. Both absolute and relative data should be presented. A 95% confidence interval. Number of participants in each group included in each analysis and whether the analysis was by intention to treat. State the results in absolute numbers when feasible. When interim RCT data are quoted, this should be clearly stated, along with the point at which data were taken and the time remaining until completion of that RCT. Analytical adjustments should be described to cater for the interim nature of the data. Other relevant data that may assist in interpretation of the results may be included, such as adherence to medication and/or study protocol. Discuss and justify definitions of any clinically important differences. Report any other analyses performed, including subgroup analysis and adjusted analyses, indicating those pre-specified and those exploratory. Page 65 of 239

66 ADVANCE primary outcome SVR In the ADVANCE trial, conducted in treatment naïve patients, the SVR rate for the T12/PR treatment group was significantly higher than for the PBO/PR group (75% v 44%,p<0.0001). The difference in SVR rate between the two treatment arms was 31% (95% confidence interval (CI) [24-38%]). Figure 9 Percentage of patients with SVR PBO = placebo; PR = peginterferon alfa-2a and ribavirin; SVR = sustained viral response; T12 = telaprevir (12 weeks) ADVANCE secondary outcomes Extended rapid viral response (ervr) The percentage of patients achieving an ervr was significantly higher in the T12/PR treatment group than for the PBO/PR group (58% v 8%; p<0.0001, 50% difference, 95% CI [45-56%]). Page 66 of 239

67 Figure 10 Percentage of patients with SVR In the ADVANCE trial, telaprevir patients achieving an ervr received 24 weeks of PR therapy, compared to 48 weeks of therapy administered to all other patients. Of the T12/PR patients that achieved an ervr, 89% went on to achieve an SVR. Relapse The number of patients achieving undetectable HCV RNA at end of treatment was 314 and 229 for the T12/PR and PBO/PR patients respectively. Among these patients, the relapse rate of 9% (n=27) observed in the T12/PR treatment arm was low compared to the 28% (n=64) in the PBO/PR treatment arm. Virologic failure In the PBO/PR arm, 56% of patients experienced virologic failure compared to 25% of the T12/PR arm. This difference is primarily due to PBO/PR patients having a higher rate of on treatment virologic failure (32% v 8% for T12/PR) and higher relapse rates (18% v 7% for T12/PR). Table 16 VF in ADVANCE T12/PR (n=363) PBO/PR (n=361) VF, n (%) 93 (25) 203 (56) Reason for virological failure On treatment VF, n (%) 30 (8) 115 (32) Relapse, n (%) 27 (7) 64 (18) Detectable HCV RNA at end of treatment, n (%) 19 (5) 17 (5) Missing SVR data, n (%) 17 (5) 7 (2) Page 67 of 239

68 On treatment virological failure includes patients who ceased therapy prematurely due to the virologic stopping rules in the ADVANCE trial. Of the telaprevir/pr patients experiencing on treatment virological failure, 6 stopped treatment at week 4, 6 stopped at week 12 and the remaining 18 stopped during weeks Results from an ongoing study demonstrated that in patients with virologic failure, resistance mutations are replaced by wild-type virus over time 95. Adherence During the trial the majority of patients were 95% adherent to the ir study medication, however the level of adherence did vary across the different drugs. Telaprevir/PBO had the highest adherence rates (95% and 96% respectively), followed by peginterferon alfa-2a (83% and 84% for T12/PR and PBO/PR patients respectively) and then ribavirin (61% and 77% for T12/PR and PBO/PR patients respectively). Table 17 Adherence to study drugs in ADVANCE 92 Adherence category Study drug T12/PR PBO/PR 80% adherence Telaprevir/PBO, N, n 362, 362 (100) 360, 360 (100) (%) Peg-IFN, N, n (%) 363, 341 (94) 360, 339 (94) RBV, N, n (%) 363, 290 (80) 359, 324 (90) 95% adherence Telaprevir /PBO, N, n 362, 344 (95) 360, 346 (96) (%) Peg-IFN, N, n (%) 363, 300 (83) 360, 303 (84) RBV, N, n (%) 363, 222 (61) 359, 277 (77) Discontinuation rates Within the ADVANCE trial a number of patients discontinued therapy prematurely due to virologic failure, AEs or being lost to follow-up. Among the PBO/PR patients 44% discontinued one or more drug during the 48 week treatment period, compared to 26% in the T12/PR arm, with the main difference being the higher rate of virologic failure among the PBO/PR patients (33% v 10%). Table 18 Reasons for discontinuation in ADVANCE 16 T12/PR (n = 363) PBO/PR (n = 361) Discontinued treatment, n (%) 95 (26) 159 (44) Reasons for discontinuation Virologic failure 38 (10) 118 (33) AE 36 (10) 26 (7) The numbers of patients who remained on therapy at different time points throughout the ADVANCE trial are shown in Table 19. Exposure to telparevir and PBO was similar between the two treatment arms with mean durations of 75 days (10.7 weeks) and 81 days (11.6 weeks) respectively. Duration of peginterferon alfa-2a and ribavirin therapy was almost identical within each Page 68 of 239

69 treatment arm, with mean durations of 188 days (26.9 weeks) and 186 days (26.6 weeks) respectively among T12/PR patients and 254 days (36.3 weeks) for both drugs among PBO/PR patients. The difference in PR duration between each treatment arm is predominantly the result of telaprevir/pr treated patients achieving an ervr receiving the shorter 24 week PR therapy regimen, rather than 48 weeks. Table 19 Duration of therapy in ADVANCE 92 Therapy Timepoint T12/PR (n = 363) PBO/PR (n = 361) Telaprevir/PBO, n (%) 4 weeks 25 (7) 12 (3) >4 to 8 weeks 30 (8) 6 (2) >8 to 12 weeks 306 (84) 339 (94) Peg-IFN, n (%) 4 weeks 15 (4) 12 (3) >4 to 8 weeks 9 (2) 4 (1) >8 to 12 weeks 8 (2) 3 (1) >12 to 24 weeks 143 (39) 48 (13) >24 to 36 weeks 112 (31) 81 (22) >36 to 48 weeks 76 (21) 213 (59) RBV, n (%) 4 weeks 16 (4) 12 (3) >4 to 8 weeks 9 (2) 5 (1) >8 to 12 weeks 10 (3) 4 (1) >12 to 24 weeks 150 (41) 46 (13) >24 to 36 weeks 102 (28) 81 (22) >36 to 48 weeks 76 (21) 213 (59) Health Related Quality of Life (EQ-5D Valuation Index) Patients in both the T12/PR and PBO/PR treatment arms entered the ADVANCE trial with a baseline HRQoL of 0.89 which decreased to during the initial 12 week treatment phase. During the remainder of the PR alone treatment phase, HRQoL remained below 0.80, finally recovering to around/above baseline once PR therapy was discontinued. Because the majority of patients in the T12/PR treatment arm only received 24 weeks of PR therapy, their HRQoL recovered earlier than the PBO/PR patients who all received up to 48 weeks of PR therapy. Table 20 EQ-5D valuation index scores over time in ADVANCE 96 T12/PR (n, mean) PBO/PR (n, mean) Baseline 347, , 0.89 Week 4 320, , 0.79 Week , , 0.77 Week , , 0.74 Week , , 0.78 Week , , 0.80 Week , , 0.87 Fatigue Both the T12/PR and PBO/PR patients had a mean FSS score of 3.0 at baseline, which worsened to 4.8 and 4.4 respectively by week 12. After week 12 the scores improved, with the T12/PR arm improving earlier as patients on Page 69 of 239

70 shorter duration PR therapy discontinued treatment. Area under the curve analysis indicates that T12/PR patients experienced statistically significant lower levels of fatigue compared to PBO/PR patients (p=0.002). Table 21 FSS score in ADVANCE 96 T12/PR (n, mean) PBO/PR (n, mean) Baseline 346, , 3.0 Week 4 329, , 4.1 Week , , 4.4 Week , , 4.3 Week , , 4.1 Week , , 4.0 Week , , 2.9 Subgroup analyses SVR according to IL-28B subtype There are three IL-28B subtype categories: CC; CT; TT. SVR rates by IL-28B subtype have previously been presented as a conference proceeding by Jacobson et al 2011, which showed that telaprevir/pr retains a significant SVR advantage over PR alone, regardless of IL-28B subtype 23. The results of the IL-28B analyses need to be interpreted with some caution due to the following limitations to this post-hoc analysis since the IL-28 data is available for 42% patients, having been captured after the trials had commenced, and randomisation is broken within the IL-28B subgroups. Table 22 summarises SVR rates by IL-28 subgroup. Table 22 SVR rates by IL-28B subtype Telaprevir/PR PR alone IL-28B subgroup CC, n, N (%) 45, 50 (90) 35, 55 (64) CT, n, N (%) 48, 68 (71) 20, 80 (25) TT, n, N (%) 16, 22 (73) 6, 26 (23) Other analyses SVR according to definition SVR rates are very similar for both telaprevir/pr and PR alone, regardless of the SVR definition used (see definition explanations in Table 7). Table 23 SVR rates by definition SVR [95% CI] Published values 16 SmPC values 32 Telaprevir /PR PR alone Telaprevir/PR PR alone Treatment naïve patients 75 [70-79] 44 [39-49] 79 [74-83] 46 [41-51] Page 70 of 239

71 SVR according to diseases severity The economic model incorporates the following SVR rates according to disease severity, sourced directly from the ADVANCE trial (Table 24). Table 24 SVR rates by disease severity Mild Moderate CCi PR alone, n, N (%) 67, 147 (46) 67/141 (48) 24, 73 (33) Telaprevir/PR n, N (%) 109, 134 (81) 115, 156 (75) 45, 73 (62) REALIZE primary outcome - SVR In the REALIZE trial, conducted in treatment experienced patients, the primary end point of SVR rate in the T12/PR treatment group was significantly higher than in the PBO/PR group (64% v 17%; p<0.001, 47% difference, 95% CI [37-57%]). Table 25 Percentage of patients with SVR in REALIZE T12/PR (n=266) PBO/PR (n=132) SVR, n (%) 171 (64) 22 (17) P value v PBO/PR <0.001 n/a Difference v PBO/PR, %* 47 n/a Difference 95% CI v PBO/PR, % 37, 57 n/a * estimated in a logistic regression model including the following factors: treatment, type of prior response and their interaction, and baseline viral RNA as a covariate REALIZE secondary outcomes Extended rapid viral response (ervr) The secondary end point of ervr was achieved by more T12/PR48 patients than PBO/PR48 patients across the prior response subgroups. For example, within the prior relapser population an ervr was achieved by 66% and 3% of T12/PR and PBO/PR patients respectively. Table 26 Percentage of patients with ervr in REALIZE 91 T12/PR PBO/PR Prior relapser (N) ervr, n (%) 95 (66) 2 (3) Prior partial (N) ervr, n (%) 30 (61) 0 (0) Prior null (N) ervr, n (%) 16 (22) 1 (3) Page 71 of 239

72 Figure 11 Percentage of patients with ervr by prior response subgroup Prior relapse patients achieving an ervr are candidates for a 24 week total duration of response guided PR therapy, rather than 48 weeks. This means that in clinical practice around two-thirds of telaprevir treated prior relapse patients should be eligible to halve the duration of their PR therapy. Relapse In each of the prior response categories, relapse rates among patients achieving undetectable HCV RNA at end of treatment were lower in the T12/PR treatment arm than observed in the PBO/PR treated patients. Table 27 Relapse rates in REALIZE 7 T12/PR PBO/PR Prior relapser (N) Relapse, n (%) 10 (7) 30 (65) Prior partial (N) 39 0 Relapse, n (%) 8 (21) n/a Prior null (N) 30 5 Relapse, n (%) 8 (27) 3 (60) Virologic failure The PBO/PR virologic failure rates were higher than those observed among T12/PR treated patients in each of the prior treatment response categories. This difference is primarily due to PBO/PR patients having a higher rate of ontreatment virologic failure. Page 72 of 239

73 Table 28 VF in REALIZE 91 T12/PR PBO/PR Prior relapser (N) VF, n (%) 24 (17) 52 (76) Reason for VF, n (%) - On treatment VF 2 (1) 18 (26) - Relapse 10 (7) 28 (41) - Detectable HCV RNA at EOT 8 (6) 6 (9) - Missing SVR data 4 (3) 0 (0) Prior partial (N) VF, n (%) 20 (41) 23 (85) Reason for VF, n (%) - On treatment VF 9 (18) 19 (70) - Relapse 8 (16) 0 (0) - Detectable HCV RNA at EOT 2 (4) 4 (15) - Missing SVR data 1 (2) 0 (0) Prior null VF, n (%) 51 (71) 35 (95) Reason for VF, n (%) - On treatment VF 41 (57) 31 (84) - Relapse, n (%) 8 (11) 2 (5) - Detectable HCV RNA at EOT, n (%) 1 (1) 2 (5) - Missing SVR data, n (%) 1 (1) 0 (0) In addition to patients with detectable HCV RNA at end of treatment, On treatment VF includes patients that ceased therapy prematurely due to the virologic stopping rules in the REALIZE trial. Results from an ongoing study demonstrated that in patients with virologic failure, resistance mutations are replaced by wild-type virus over time 95. Adherence During the REALIZE trial the majority of patients were 95% adherent to their study medication, however the level of adherence did vary across the different drugs. Telaprevir and PBO had the highest adherence rates (94-5%), followed by peginterferon alfa-2a (89-92%) and then ribavirin (66-75%). Treatment adherence for each of the study drugs was similar across the prior response subpopulations. Table 29 95% adherence to study drugs in REALIZE 91 Study drug T12/PR PBO/PR Telaprevir/PBO, N, n (%) 264, 247 (94) 131, 125 (95) Peg-IFN, N, n (%) 263, 241 (92) 130, 116 (89) RBV, N, n (%) 263, 173 (66) 130, 97 (75) Discontinuation rates Within the REALIZE trial a number of patients discontinued therapy prematurely due to virologic failure, AEs or other reasons (including lost to follow-up etc). Among the PBO/PR patients 62% discontinued one or more drug during the 48 week treatment period, compared to 38% in the T12/PR Page 73 of 239

74 treatment arm, with the main difference being the higher rate of on-treatment virologic failure among PBO/PR patients (51% v 16%). Table 30 Reasons for discontinuation in REALIZE 7 T12/PR (n = 266) PBO/PR (n = 132) Discontinued treatment, n (%) 100 (38) 82 (62) Reasons for discontinuation AE 42 (16) 8 (6) Virologic failure 43 (16) 67 (51) Other 15 (6) 7 (5) Early discontinuations resulted in the following patient numbers remaining on therapy at the different time points of the REALIZE trial. Mean exposure to telaprevir was 75 days (10.7 weeks). Duration of peginterferon alfa-2a and ribavirin therapy was almost identical within each treatment arm, with mean durations of 270 days (38.6 weeks) versus 272 days (38.9 weeks) respectively among T12/PR patients, and 210 days (30.0 weeks) versus 213 days (30.4 weeks) among PBO/PR patients. The difference in PR duration between each treatment arm is predominantly the result of PBO/PR treated patients discontinuing therapy early due to virologic failure. Table 31 Duration of therapy in REALIZE Therapy Timepoint T12/PR (n = 266) PBO/PR (n = 132*) Telaprevir, n (%) 4 weeks 14 (5) n/a >4 to 8 weeks 33 (12) n/a >8 to 12 weeks 219 (82) n/a Peg-IFN, n (%) 4 weeks 9 (3) 1 (1) >4 to 8 weeks 10 (4) 5 (4) >8 to 12 weeks 5 (2) 1 (1) >12 to 24 weeks 31 (12) 41 (31) >24 to 36 weeks 17 (6) 31 (23) >36 to 48 weeks 194 (73) 52 (39) RBV, n (%) 4 weeks 9 (3) 1 (1) >4 to 8 weeks 12 (5) 5 (4) >8 to 12 weeks 5 (2) 0 (0) >12 to 24 weeks 31 (12) 42 (32) >24 to 36 weeks 17 (6) 30 (23) >36 to 48 weeks 194 (72) 53 (40) * In the PBO/PR treatment arm, treatment duration data is missing for one patient Health Related Quality of Life (EQ-5D Valuation Index) Patients in the T12/PR and PBO/PR treatment arms entered the REALIZE trial with HRQoL of 0.89 and 0.90 respectively, which decreased to 0.72 and 0.76 during the initial 12 week telaprevir/pbo treatment phase. During the remainder of the PR treatment phase, HRQoL remained below 0.80, finally recovering to around baseline levels at week 72, after PR therapy had been discontinued at week 48. Page 74 of 239

75 Table 32 EQ-5D valuation index scores over time in REALIZE 97 T12/PR (n, mean) PBO/PR (n, mean) Baseline 254, , 0.90 Week 4 232, , 0.81 Week , , 0.76 Week , , 0.77 Week , , 0.73 Week , , 0.88 Fatigue For patients in both the T12/PR and PBO/PR treatment arms FSS scores worsened during the 48-week treatment period. For the T12/PR treated patients scores improved after telaprevir therapy was stopped at week 12. For all patients fatigue returned to around baseline levels at week 72, following discontinuation of PR therapy at week 48. Table 33 FSS score 97 T12/PR (n, mean) PBO/PR (n, mean) Baseline 216, , 3.0 Week 4 222, , 3.7 Week , , 4.2 Week , , 4.2 Week , , 4.3 Week , , 3.1 Subgroup analysis SVR according to IL-28B subtype Results presented as conference proceeding by Pol et al show that telaprevir/pr retains a significant SVR advantage over PR alone, regardless of IL-28B subtype. Results need to be interpreted with some caution because IL-28 data is available for 80% of patients, sample sizes become small when assessing outcomes by prior treatment response subgroup and randomisation is broken within the IL-28B subgroups. Table 34 provides a summary of SVR rates by IL-28 and prior treatment response subgroups. Page 75 of 239

76 Table 34 SVR rates by IL-28B subtype n, N (%) Telaprevir/PR PR alone Prior relapsers CC 28, 33 (85) 4, 12 (33) CT 50, 59 (85) 6, 30 (20) TT 13, 15 (87) 3, 10 (30) Prior partial reponse CC 2, 3 (67) 1, 5 (20) CT 20, 30 (67) 2, 10 (20) TT 4, 6 (67) 0, 5 (0) Prior null response CC 0, 5 (0) 0, 0 (0) CT 14, 45 (31) 1, 18 (6) TT 4, 16 (25) 1, 15 (7) SVR according to prior response T12/PR patients maintained significantly higher SVR rates versus PBO/PR patients across each of the prior response subgroups, as shown in Figure 12. Figure 12 Percentage of patients with SVR by prior response subgroup Other analysis SVR according to definition SVR rates are very similar for both telaprevir/pr and PR alone, regardless of the SVR definition used (see definition explanations in Table 7). Page 76 of 239

77 Table 35 SVR rates by definition Population, SVR [95% CI] Published values 7 SmPC values 32 Telaprevir/PR PR alone Telaprevir/PR PR alone Treatment experienced patient Prior relapse 83 [76-89] 24 [14-35] 84 [77-90] 22 [13-34] Prior partial response 59 [44-73] 15 [4-34] 61 [46-75] 15 [4-34] Prior null response 29 [19-41] 5 [1-18] 31 [20-43] 5 [1-18] SVR according to diseases severity The economic model incorporates the following SVR rates according to disease severity, sourced directly from the REALIZE trial (). Table 36 SVR rates by disease severity Mild Moderate CCi Prior relapse PR alone, n, N (%) 7, 20 (35) 5, 18 (28) 4, 30 (13) Telaprevir/PR n, N (%) 29, 34 (85) 38, 47 (81) 54, 64 (84) Prior partial response PR alone, n, N (%) 0, 10 (0) 3, 7 (43) 1, 10 (10) Telaprevir/PR n, N (%) 5, 7 (71) 13, 17 (76) 11, 25 (44) Prior null response PR alone, n, N (%) 0, 5 (0) 1, 13 (8) 1, 19 (5) Telaprevir/PR n, N (%) 1, 10 (10) 8, 19 (42) 12, 43 (28) Page 77 of 239

78 5.6 Meta-analysis When more than one study is available and the methodology is comparable, a meta-analysis should be undertaken. This section should be read in conjunction with NICE s Guide to the methods of technology appraisal, sections to The following steps should be used as a minimum when presenting a meta-analysis If a meta-analysis is not considered appropriate, a rationale should be given and a qualitative overview provided. The overview should summarise the overall results of the individual studies with reference to their critical appraisal. There were only two included RCTs directly comparing telaprevir with the comparator relevant to the decision problem, PR alone. ADVANCE provides the comparison in the treatment naïve population, REALIZE provides the comparison in the treatment experienced population. Because these trials provide a direct head-to-head comparison it is not considered appropriate to conduct a meta-analysis If any of the relevant RCTs listed in response to section (Complete list of relevant RCTs) are excluded from the metaanalysis, the reasons for doing so should be explained. The impact that each exclusion has on the overall meta-analysis should be explored. Not applicable. Page 78 of 239

79 5.7 Indirect and mixed treatment comparisons Data from head-to-head RCTs should be presented in the reference-case analysis, if available. If data from head-to-head RCTs are not available, indirect treatment comparison methods should be used. This section should be read in conjunction with NICE s Guide to the methods of technology appraisal, sections to Describe the strategies used to retrieve relevant clinical data on the comparators and common references both from the published literature and from unpublished data. The methods used should be justified with reference to the decision problem. Sufficient detail should be provided to enable the methods to be reproduced, and the rationale for any inclusion and exclusion criteria used should be provided. Exact details of the search strategy used should be provided in section 9.4, appendix 4. The search strategy and methodology used to identify other clinical data on comparators relevant to the decision problem has been previously described in Section 5.2. Because the pivotal telaprevir trials identified provide a direct, head-to-head, comparison of telaprevir/pr with PR alone, it is considered that indirect/mixed treatment comparisons are not necessary to inform this submission. This view has been supported by an advisory board of clinical key opinion leaders, which cited that ADVANCE and REALIZE are the critical data sources for telaprevir and provide a reliable estimate of efficacy and safety relative to the comparator in the decision problem Please follow the instructions specified in sections 5.1 to 5.5 for the identification, selection and methodology of the trials, quality assessment and the presentation of results. Provide in section 9.5, appendix 5, a complete quality assessment for each comparator RCT identified. Not applicable Provide a summary of the trials used to conduct the indirect comparison. A suggested format is presented below. Network diagrams may be an additional valuable form of presentation. Not applicable For the selected trials, provide a summary of the data used in the analysis. Not applicable. Page 79 of 239

80 5.7.5 Please provide a clear description of the indirect/mixed treatment comparison methodology. Supply any programming language in a separate appendix. Not applicable, as an indirect comparison was not conducted Please present the results of the analysis. Not applicable, as an indirect comparison was not conducted Please provide the statistical assessment of heterogeneity undertaken. The degree of, and the reasons for, heterogeneity should be explored as fully as possible. Not applicable, as an indirect comparison was not conducted If there is doubt about the relevance of a particular trial, please present separate sensitivity analyses in which these trials are excluded. Not applicable, as an indirect comparison was not conducted Please discuss any heterogeneity between results of pairwise comparisons and inconsistencies between the direct and indirect evidence on the technologies. Not applicable, as an indirect comparison was not conducted. Page 80 of 239

81 5.8 Non-RCT evidence Non-RCT, both experimental and observational, evidence will be required, not just for those situations in which RCTs are unavailable, but also to supplement information from RCTs when they are available. This section should be read in conjunction with NICE s Guide to the methods of technology appraisal, sections to If non-rct evidence is considered (see section 5.2.7), please repeat the instructions specified in sections 5.1 to 5.5 for the identification, selection and methodology of the trials, and the presentation of results. For the quality assessments of non- RCTs, use an appropriate and validated quality assessment instrument. Key aspects of quality to be considered can be found in Systematic reviews: CRD s guidance for undertaking reviews in health care ( Exact details of the search strategy used and a complete quality assessment for each trial should be provided in sections 9.6 and 9.7, appendices 6 and 7. As highlighted in Section 5.2.7, the systematic literature review described in Section 5.1 did not identify any non-rct evidence relevant to the decision problem. Page 81 of 239

82 5.9 Adverse events This section should provide information on the adverse events experienced with the technology in relation to the decision problem. Evidence from comparative RCTs and regulatory summaries is preferred; however, findings from non-comparative trials may sometimes be relevant. For example, postmarketing surveillance data may demonstrate that the technology shows a relative lack of adverse events commonly associated with the comparator, or the occurrence of adverse events is not significantly associated with other treatments If any of the main trials are designed primarily to assess safety outcomes (for example, they are powered to detect significant differences between treatments with respect to the incidence of an adverse event), please repeat the instructions specified in sections 5.1 to 5.5 for the identification, selection, methodology and quality of the trials, and the presentation of results. Examples for search strategies for specific adverse effects and/or generic adverse-effect terms and key aspects of quality criteria for adverse-effects data can found in Systematic reviews: CRD s guidance for undertaking reviews in health care ( Exact details of the search strategy used and a complete quality assessment for each trial should be provided in sections 9.8 and 9.9, appendices 8 and 9. Both the ADVANCE and REALIZE trials were designed primarily to assess clinical efficacy outcomes and hence a full systematic review has not been undertaken. The assessment of safety outcomes was a secondary objective for both of these studies and the results for the licensed T12/PR and comparator PR alone treatment arms are reported here Please provide details of all important adverse events for each intervention group. For each group, give the number with the adverse event, the number in the group and the percentage with the event. Then present the relative risk and risk difference and associated 95% confidence intervals for each adverse event. Summaries of AEs and other safety data are based on all ITT patients from the ADVANCE and REALIZE studies that were randomised and received at least one dose of study drug. The ADVANCE trial enables a direct, head-tohead, comparison of the safety and tolerability of telaprevir/pr to be compared with PR alone in the treatment naïve patient population, while the REALIZE trial provides an equivalent comparison in the treatment experienced population AEs reported Page 82 of 239

83 Treatment naïve At 48 weeks, nearly all patients in the ADVANCE trial had experienced at least 1 AE with 99% and 98% in the T12/PR and PBO/PR treatment groups respectively. The majority of AEs were mild to moderate (grade 1 or 2), with at least 1 severe AE (SAE) experienced by 28% and 19% of patients in the T12/PR and PBO/PR patients respectively. The most common AEs (any grade) were fatigue, headache, insomnia and influenza like symptoms and occurred in a similar proportion of patients across each of the treatment groups. The other common AEs of pruritus, nausea, anaemia, rash, diarrhoea and pyrexia occurred more frequently among the telaprevir/pr treated patients. The proportion of telaprevir/pbo patients who discontinued all treatment regimens due to an AE during the overall 48-week treatment period was higher among T12/PR patients (7%) than PBO/PR patients (4%), with anaemia and rash the most frequently reported AEs leading to discontinuation. The incidence of laboratory abnormalities was generally low and comparable between the treatment groups. Haemoglobin was the exception with grade 3-4 decreased haemoglobin levels reported in 56% and 39% of the T12/PR and PBO/PR patients respectively. Page 83 of 239

84 Table 37 Summary of AEs at week 48 in ADVANCE 92 AE incidence, n (%) T12/PR (n=363) PBO/PR (n=361) Mean exposure (days) Telaprevir/PBO Peg-IFN RBV (99) 103 (28) Page 84 of (98) 68 (19) 1 AE Grade 3 (severe) 1 SAE 33 (9) 24 (7) 1 AE leading to: Dose modification of 1 study drug 165 (45) 116 (32) Permanent discontinuation of treatment 36 (10) 26 (7) Discontinuation of TVR/PBO 41 (11) 3 (1) 1 AE leading to death 0 (0) 1 (<1) AEs (any grade, 25% in any treatment arm) Fatigue Pruritus Headache Nausea Anaemia Rash Insomnia Diarrhoea Influenza-like symptoms Pyrexia 207 (57) 181 (50) 148 (41) 156 (43) 135 (37) 133 (37) 117 (32) 102 (28) 102 (28) 95 (26) 206 (57) 131 (36) 142 (39) 112 (31) 70 (19) 88 (24) 111 (31) 80 (22) 101 (28) 87 (24) AEs (grade 3, 5% in any treatment arm) Any grade 3 AE Anaemia Neutropenia Treatment experienced 103 (28) 26 (7) 17 (5) 68 (19) 7 (2) 23 (6) At 48 weeks, nearly all patients in the REALIZE trial had experienced at least 1 AE with 98% and 95% in the T12/PR and PBO/PR treatment groups respectively. The majority of AEs were mild to moderate (grade 1 or 2), with at least 1 severe (grade 3) AE experienced by 37% and 22% in the T12/PR and PBO/PR patients respectively. The most common AEs (any grade) were fatigue, pruritus, headache, rash, nausea, influenza like symptoms, anaemia, insomnia, diarrhoea, pyrexia, cough and asthenia. With the exception of pyrexia and asthenia, these symptoms tended to occur more frequently in the T12/PR treated patients. The proportion of patients who permanently discontinued their telaprevir/pbo treatment regimen due to an AE during this period was higher among T12/PR patients (15%, n=39) than PBO/PR patients (3%, n=4), with rash and anaemia the most frequently reported AEs leading to discontinuation. The incidence of laboratory abnormalities was generally low and comparable between the treatment groups. Haemoglobin was the exception, with grade 3-4 decreased haemoglobin levels reported in 58% and 35% of the T12/PR and PBO/PR patients respectively.

85 Table 38 Summary of AEs at week 48 in REALIZE 91 AE incidence, n (%) T12/PR (n=266) PBO/PR, (n=132) Mean exposure (days)* Telaprevir/PBO Peg-IFN RBV AE 260 (98) 126 (95) 1 SAE 33 (12) 7 (5) 1 AE leading to death 0 (0) 1 (<1) AEs (any grade, 25% in any treatment arm) Fatigue Pruritus Headache Rash Nausea Influenza-like symptoms Anaemia Insomnia Diarrhoea Pyrexia Cough Asthenia AEs (grade 3, 5% in any treatment arm) Any grade 3 AE Neutropenia Anaemia Leukopenia Rash 145 (55) 138 (52) 112 (42) 99 (37) 94 (35) 85 (32) 79 (30) 68 (26) 66 (25) 60 (23) 62 (23) 51 (19) 98 (37) 27 (10) 17 (6) 20 (8) n/a (40) 36 (27) 49 (37) 25 (19) 31 (23) 33 (25) 20 (15) 34 (26) 18 (14) 36 (27) 26 (20) 38 (29) 29 (22) 11 (8) 1 (1) 8 (6) During the overall 48 week treatment period in ADVANCE, rash of any grade occurred in 37% and 24% of T12/PR and PBO/PR patients respectively. Rash was primarily mild to moderate, with severe rash (grade 3, i.e. caused incapacitation or had a significant impact on the patient s daily life) occurring in 4% and <1% of T12/PR and PBO/PR patients, respectively. The incidence of rash SAEs were 1% in the telaprevir treatment arm, compared to no rash SAEs in the PBO/PR arm. During the initial telaprevir/pbo treatment phase, discontinuation due to rash was 3% in the T12/PR arm and <1% in the PBO/PR arm. In addition, pegylated interferon-α2a was discontinued due to rash in 1% of patients in the T12/PR arm compared to no patients in the PBO/PR arm, with the same results for discontinuation of ribavirn. During the overall 48 week treatment period in REALIZE, rash of any grade occurred in 37% and 19% of T12/PR and PBO/PR patients respectively. Rash was predominantly mild to moderate, with severe rash (grade 3, i.e. caused incapacitation or had a significant impact on the patient s daily life) occurring in 1% of T12/PR patients and in no PBO/PR patients. No rash SAEs were reported in any arm of the trial during the overall treatment period. Page 85 of 239

86 During the initial telaprevir/pbo treatment phase, the proportion of patients discontinuing telaprevir/pbo due to rash was 2% in the T12/PR treatment arm compared to no discontinuations in the PBO treated group. Table 39 Rash severity during overall 48 week treatment phase Rash incidence, ADVANCE REALIZE n (%) T12/PR (n=363) PBO/PR (n=361) T12/PR (n=266) PBO/PR (n=132) Grade 1 (mild) 96 (26) 75 (21) 78 (29) 22 (17) Grade 2 (moderate) 24 (7) 12 (3) 18 (7) 3 (2) Grade 3 (severe) 13 (4) 1 (<1) 3 (1) 0 (-) In both the ADVANCE and REALIZE trials, rash was managed in accordance with the Adverse Event Management Plan, summarised below in Figure 13 and Figure 14, with further details provided in Appendix section 9.3. Figure 13 Adverse Event Management Plan grading Page 86 of 239

87 Figure 14 Adverse Event Management Plan guidance A Dermatology Expert Panel, appointed by the Sponsor Company for the Phase III trials, reviewed rash cases with photographs and biopsies. The Panel concluded that with the exception of greater severity and extent, the visual appearance and histopathology of rash associated with telaprevir/pr was virtually indistinguishable from rash associated with PBO/PR Anaemia The concomitant use of ESAs was prohibited during both the ADVANCE and REALIZE studies, therefore anaemia was managed through licensed dose reductions of ribavirin therapy. These reductions did not appear to compromise the efficacy of telaprevir/pr treatment. During the overall 48 week treatment period in ADVANCE, anaemia was among the most commonly reported AEs of any grade, occurring in 37% and 19% of T12/PR and PBO/PR patients respectively. Anaemia was predominantly mild to moderate in severity, with severe (grade 3) anaemia occurring in 7% of T12/PR patients and 2% of PBO/PR treated patients. The incidence of anaemia SAEs was 2% and 1% among T12/PR and PBO/PR patients respectively. Anaemia results during the initial telaprevir/pbo treatment phase were similar to the overall results, generally presenting with mild to moderate severity, with grade 3 anaemia occurring in 7% and 1% of T12/PR and PBO/PR patients respectively. During this phase 4% patients discontinued telaprevir due to anaemia and no patients discontinued PBO due to anaemia. Following the completion of the initial telaprevir/pbo treatment phase, rates of grade 3 anaemia decreased. Page 87 of 239

88 The ADVANCE results were replicated in the REALIZE trial: 30% and 15% of T12/PR and PBO/PR patients respectively reported rash of any grade during the overall 48 week treatment period; anaemia was predominantly mild to moderate in severity, only 6% of T12/PR patients and 1% of PBO/PR patients reported severe (grade 3) anaemia; 2% of T12/PR patients and 1% of PBO/PR patients reported an anaemia SAE. Anaemia results during the initial telaprevir/pbo treatment phase were similar to the overall results, generally presenting with mild to moderate severity, with grade 3 anaemia occurring in 5% and 1% of T12/PR and PBO/PR patients respectively. During this phase 2% patients discontinued telaprevir due to anaemia and no patients discontinued PBO due to anaemia. Following the completion of the initial telaprevir/pbo treatment phase, rates of grade 3 anaemia decreased Serious adverse events While AEs were common in the ADVANCE trial, the incidence of SAEs by week 48 of the trial was much lower, reported by 9% and 7% of T12/PR and PBO/PR patients respectively. Three patients had life-threatening events, one patient in each of the T8/PR, T12/PR and PBO/PR treatment arms, and these life-threatening events were considered either unlikely to be related or unrelated to the telaprevir/pbo treatment. Similarly, in the REALIZE trial SAEs by week 48 were reported by 12% of T12/PR and 5% of PBO/PR patients, respectively Deaths In ADVANCE, one death occurred during the 48 week study treatment period, which was a suicide in the PBO/PR treatment group. Three other deaths occurred during the follow-up period: one in the T8/PR group (unspecified cause) and two in the T12/PR group (1 x suicide, 1 x exitus). All deaths were considered to be unrelated to telaprevir/pbo by the investigator. In REALIZE, two deaths occurred during the 48 week study treatment period: a malignant lung neoplasm in the LI T12/PR arm in a patient who had recently given up smoking after >25 years of smoking and died 138 days after their last dose of telaprevir (considered possibly related to telaprevir/pbo and not related to PR); one PBO/PR patient that fell into a coma and whose death was considered not related to PBO and unlikely to be related to PR. One death occurred during the follow-up phase due to cholecystitis and acute respiratory distress syndrome in a PBO/PR patient, occurring 108 days after their last PBO dose and not considered to be related to any of the three study drugs Give a brief overview of the safety of the technology in relation to the decision problem. The safety and tolerability data collected in both the ADVANCE and REALIZE trials show that many of the AEs reported were common to both the T12/PR Page 88 of 239

89 and PBO/PR treatment arms. Some AEs (including rash and anaemia) occur more frequently with the use of telaprevir, although in the majority of cases they were mild or moderate and rarely resulted in discontinuation of therapy. In both trials, the implementation of the Adverse Event Management Plan ensured appropriate discontinuation of therapy in the relatively small number of cases where this was required due to the emergence of severe rash. Page 89 of 239

90 5.10 Interpretation of clinical evidence Please provide a statement of principal findings from the clinical evidence highlighting the clinical benefit and harms from the technology. The primary clinical benefit of telaprevir/pr therapy is that it delivers a statistically significant improvement in SVR rates over current standard of care, PR alone: In the treatment naïve population, T12/PR achieved an SVR of 75% compared to 44% for PR alone (p<0.0001) In the treatment experienced population the SVR rates were 64% and 17% respectively (p<0.001). The significant improvement in SVR rate is maintained across the treatment experienced subgroups: o In prior relapsers, T12/PR achieved an SVR of 83% versus 24% for PR alone (p<0.001) o In prior partial responders, T12/PR achieved an SVR of 59% versus 15% for PR alone (p<0.001) o In prior null responders, T12/PR achieved an SVR of 29% versus 5% for PR alone (p<0.001). Importantly, these efficacy results mean that significantly more patients are able to clear the HCV virus, reducing the risk of progression to more advanced states of liver disease among the treated population. It also gives patients who have previously failed on PR therapy a much needed new treatment option. The ADVANCE trial provides data supporting the licensed use of response guided therapy, which enables a shortened 24-week duration of PR therapy in those telaprevir patients who achieve an ervr. For the estimated 58% of treatment naïve patients eligible for a shortened duration of PR therapy, this reduces exposure to PR with its associated side-effects, additional drug costs and impact on health related quality of life. Two important additional clinical benefits of shortened PR duration relate to adherence and resource utilisation: Adherence. Veldt et al 2007 highlighted the need for chronic HCV treatment regimens that are simple to adhere to and maximize the probability of an SVR 25. Adherence is important in achieving an SVR 93 and the short triple therapy treatment duration of 12-weeks coupled with the 24-week PR duration for patients achieving an ervr may help improve overall adherence levels in clinical practice. Zhang et al concluded that PR alone discontinuation rates were higher for genotype 1 HCV patients compared to some other genotypes, primarily due to the shorter 24 week treatment duration associated with the treatment of genotype 2 and 3 HCV patients. To maintain successful treatment outcomes, the Company will offer patients and healthcare professionals access to MHRA approved adherence support materials and also medicine dose reminders, treatment algorithms, a patient focused website Page 90 of 239

91 and a nurse-led 24 hour telephone support service.. It may be expected that in routine clinical practice, adherence to telaprevir/pr and PR alone will be lower than observed in the clinical trials. However, this is more likely to impact PR alone patients, since telaprevir patients have only a 12 week maximum telaprevir duration, a 24 week response guided duration of PR therapy and the adherence support program. Resource utilisation. Reducing the length of PR therapy from 48 weeks to 24 weeks reduces PR therapy costs and hospital visits for patient monitoring while on therapy. Regarding the treatment experienced population, REALIZE provides data showing that telaprevir does not require a 4-week lead-in period of PR therapy in order for treatment to be effective, as shown by the SVR results across the prior treatment cohorts. This finding supports the recommended telaprevir dosing regimens and the relatively straightforward treatment pathway for patients treated with telaprevir/pr therapy. From a safety perspective, the clinical evidence shows that some AEs (including rash and anaemia) occur more frequently with the use of telaprevir, although in the majority of cases they are mild or moderate and rarely result in discontinuation of therapy. Shorter durations of response guided PR therapy in patients treated with telaprevir reduces the length of time over which patients experience treatment-related AEs associated with PR therapy Please provide a summary of the strengths and limitations of the clinical-evidence base of the intervention. The EMA has highlighted that the telaprevir trials are well conducted with a reasonably low level of loss to follow-up. The two pivotal placebo-controlled studies, ADVANCE and REALIZE, both of which included patients from the UK, focus on the chronically infected genotype 1 HCV patients and as such provide direct head-to-head evidence for the decision problem comparator, populations and outcomes for treatment naïve and treatment experienced patients. Both ADVANCE and REALIZE are relatively large and results have been published in the New England Journal of Medicine 7, 16. In total, the clinical evidence for telaprevir incorporates six peer reviewed publications 7, 16, 17, 20-22, which present a comprehensive evidence base supporting the clinical effectiveness of telaprevir in patients with genotype-1 chronic HCV. The inclusion of prior null response patients in the REALIZE trials means that a robust clinical evidence base is available across the full range of treatment experienced patients. The prior null response patients are an important subgroup, given that SVR rates achieved with PR alone are very low at only 5%. The AE management plan within the ADVANCE and REALIZE trial designs matches the AE management plan that is being implemented in clinical Page 91 of 239

92 practice. Therefore discontinuation rates witnessed within the clinical trials is likely to represent the outcomes that will be observed in clinical practice. The ADVANCE trial design incorporated response guided therapy, providing evidence that eligible telaprevir treated patients can successfully clear the virus following the shorter 24 week duration of PR therapy rather than 48 weeks, minimising unnecessary exposure to PR. The clinical appropriateness of this response guided therapy in treatment naïve telaprevir/pr patients is further supported by the ILLUMINATE study reported in Appendix section 9.4. A theoretical limitation of the ADVANCE and REALIZE clinical trials is that they only provide a comparison against peginterferon alfa-2a and not peginterferon alfa-2b. Clinical trial data directly comparing the two PR formulations in the treatment-naïve population concluded that there were no statistically significant differences in SVR rates achieved by the different formulations 18, 19. Results from the C208 Phase IIb clinical trial indicates that peginterferon alfa-2a and -2b achieve equivalent SVR rates when used in combination with telaprevir 98 and the license approved by the European Medicines Agency stipulates that telaprevir may be co-administered with either peginterferon formulation 32. Response guided therapy is an important aspect of the telaprevir license. Although response guided therapy was not incorporated in the REALIZE trial design, the EMA saw fit to license response guided therapy for prior relapse patients based on the clinical data reported in the EPAR (Appendix Section 9.1). Response guided peginterferon therapy for treatment-naïve patients was not incorporated in the ADVANCE trial design for patients in the PR alone arm 16. Analysis detailed in Section 6.6.1, shows that 92% of PR alone patients in ADVANCE would not have been eligible for response guided therapy. A scenario analysis has been completed to explore this further. The ADVANCE and REALIZE trials both collected HRQoL data using the EQ- 5D valuation index. Unfortunately, limitations relating specifically to the HRQoL data captured which are discussed further in Section 6.4.3, constrains the ability to fully incorporate this data into the economic evaluation. Details on how this has handled in the cost-effectiveness analysis are provided in Section Please provide a brief statement of the relevance of the evidence base to the decision problem. Include a discussion of the relevance of the outcomes assessed in clinical trials to the clinical benefits experienced by patients in practice. The ADVANCE and REALIZE trials are directly relevant to the decision problem in that they both provide a direct head-to-head comparison between the licensed and recommended telaprevir/pr dosing regimen with the comparator of interest, PR alone. In addition, both trials incorporated patients from the UK. Page 92 of 239

93 In both the ADVANCE and REALIZE trials the primary clinical efficacy outcome is SVR which is entirely relevant to the clinical benefits experienced by patients in clinical practice. Both the EASL and SIGN guidelines state that the primary goal of therapy is to eradicate the HCV infection with SVR acting as the main endpoint 6, 40. Evidence indicates that following achievement of an SVR, viral relapse is uncommon 99, 100, mortality is reduced 101 and patients have a reduced risk of developing cirrhosis and primary hepatocellular carcinoma 99, 102. Achievement of an SVR has been shown to be associated with longer-term response to therapy 103, 104. For example, evidence from long term studies indicates that patients achieving an SVR have maintained undetectable HCV-RNA after 4 105, and even years following treatment cessation. This indicates that chronic HCV can be cleared or cured when an SVR is achieved 40. Furthermore, because an SVR positively alters the course of HCV, this avoids patients progressing to advanced liver disease and experiencing a decline in their HRQoL 10, 11, 13, 15, 108 or requiring a liver transplant 40, costing in the region of 50,000 for the procedure with over 10,000 of follow-up costs Identify any factors that may influence the external validity of study results to patients in routine clinical practice; for example, how the technology was used in the trial, issues relating to the conduct of the trial compared with clinical practice, or the choice of eligible patients. State any criteria that would be used in clinical practice to select patients for whom treatment would be suitable based on the evidence submitted. What proportion of the evidence base is for the dose(s) given in the SPC? The Company does not anticipate that the study results observed in the clinical trials will differ from the use of telaprevir/pr in clinical practice within the NHS, which is a view supported by the clinical advisory board. The dose of telaprevir used in the clinical trial is identical to the dose recommended in the SmPC and that will be used in UK clinical practice. Both the ADVANCE and REALIZE trials included the 12-week telaprevir/pr regimen that will be used in UK clinical practice and data from these relevant treatment arms have been used to inform this submission. These trials also incorporated the AE management plan which will be rolled out as part of the commercial launch of telaprevir in the UK. There is limited clinical data from an ongoing study assessing telaprevir in combination with peginterferon and ribavirin in treatment naïve HCV patients co-infected with HIV. This HIV co-infected patient group remains within the license pending further data. The Phase IIa trial, VX identified in Section 1.6 is ongoing and results are anticipated in November Preliminary results indicate that telaprevir retains a considerable virologic advantage over PR alone: 70% of telaprevir/pr patients achieved an RVR versus 6% of PR alone patients; 53% of telaprevir/pr patients achieved an ervr versus 0% of PR alone patients 90. These early outcomes confirm that the efficacy of PR alone is detrimentally affected in HIV co-infected patients Page 93 of 239

94 because it targets the immune system more generally, whereas telaprevir remains effective in this group of patients because it more specifically targets the HCV virus. Independent quantitative market research (see Appendix Section 9.9) has indicated, that 7% of HCV patients are co-infected with HIV making this a relatively small patient subgroup. Because of the different mechanism of action relative to PR alone, the efficacy advantage for telaprevir/pr over PR alone and the small size of the HIV co-infected patients, it is not anticipated that HIV co-infection will alter the cost-effectiveness of telaprevir in clinical practice. Page 94 of 239

95 6 Cost effectiveness 6.1 Published cost-effectiveness evaluations Identification of studies Describe the strategies used to retrieve relevant costeffectiveness studies from the published literature and from unpublished data held by the manufacturer or sponsor. The methods used should be justified with reference to the decision problem. Sufficient detail should be provided to enable the methods to be reproduced, and the rationale for any inclusion and exclusion criteria used should be provided. The search strategy used should be provided as in section 9.10, appendix 10. A full systematic review of the literature was conducted to identify all published cost-effectiveness analyses in chronic HCV. The main aim was to identify new studies that have been published since the systematic review completed by Hartwell et al , therefore any publications identified that were previously reported in the TA200, were not included in this evidence review. Databases were searched from 1 st January 2009 to 15 th September The comprehensive literature search included two electronic databases: MEDLINE (including MEDLINE In-Process) Excerpta Medica Database (EMBASE ). Clinical keywords and medical subject headings were used to search for disease and interventions, and these are fully detailed in Appendix section To be included in the review studies had to meet pre-defined eligibility criteria based on those outlined in the recent TA200 Assessment Report 109 (see Table 40) and only English language studies were included. Page 95 of 239

96 Table 40 Eligibility criteria for studies in the cost effectiveness Inclusion criteria Parameter Rationale Studies Only papers that are full economic evaluations e.g. cost utility analysis, cost effectiveness analysis, cost benefit analysis and cost minimisation analysis papers Full economic evaluations were those relevant for review Population Adults with chronic HCV This population has been restricted to match the stated decision problem for the treatment of adults with chronic HCV Interventions Outcome measures Ribavirin OR Peg-Interferon OR interferon alpha 2A OR interferon alpha 2B Cost per LYG ICER or cost/qaly Total costs Total QALYS Exclusion criteria Parameter Rationale Studies Non-model based (e.g. within trial analyses) Publications without an abstract Conference proceedings These interventions are selected to retain consistency with the previous Hartwell et al 2011 search ad identify publications relating to the comparator stated in the decision problem Some cost-effectiveness analysis papers report costs, but benefits are reported not in life years gained, but in a surrogate endpoint. Although improvements in surrogate endpoints inform clinicians, for the purposes of cost-effectiveness analysis only benefits reported as utility gained or life years gained are acceptable for current NICE submissions Non model based studies were excluded as sensitivity analysis is not able to be carried out in non model based studies. Conference proceedings were excluded as due to the nature of conference abstracts, there would not be enough information to comprehensively analyse the costeffectiveness study Population Inappropriate disease area (i.e not chronic HCV) Required to match the stated decision problem for the treatment of adults with chronic HCV Outcome measures Both costs and benefits not reported Both cost and benefits are required to Language Non-English publications assess cost-effectiveness The results of each search were exported to Reference Manager software and any duplicates were removed. Abstracts were reviewed by two independent systematic reviewers according to the pre-defined criteria (listed in Table 40). Any papers that could not be excluded at abstract review stage, were ordered and the full publication was reviewed. Any discrepancies in their decisions were resolved by a third reviewer. Two reviewers undertook data extraction of the included studies and likewise any discrepancy in the extracted data was resolved by a third reviewer. Page 96 of 239

97 Figure 15 Study exclusion flow for economic systematic review The search in MEDLINE and MEDLINE In-Process retrieved 93 results. The search in EMBASE retrieved 204 results. A total of 297 papers were retrieved by the search. After the duplicates were removed 224 abstracts were available to be reviewed against the criteria outlined in Table 40 and 201 were excluded. After the abstracts were reviewed 23 papers were ordered for full 29, 110- publication review. After the full publications were reviewed six papers 114 met the inclusion criteria and data were extracted. Description of identified studies Provide a brief overview of each study, stating the aims, methods, results and relevance to decision-making in England and Wales. Each study s results should be interpreted in light of a critical appraisal of its methodology. When studies have been identified and not included, justification for this should be provided. If more than one study is identified, please present in a table as suggested below. A brief overview of the included studies is provided in Table 41. Studies that were identified and not included are summarised in Appendix section Page 97 of 239

98 Table 41 Summary list of other cost-effectiveness evaluations Study (Year) Country Summary of model Health States used Patient population QALYs (intervention, comparator) Costs (currency) (intervention, comparator) ICER (per QALY gained) Notes Fonseca Brazil PegIFN+Rbv vs. IFN+Rbv vs. No treatment (TX); Markov Model with 12 health states. Prevalence of genotype 1 in Brazil is 74%. Simulation commences after diagnosis of CHC. Healed patients do not have recurrence of HepC. 1. Remission; 2. Mild CHC; 3. Moderate CHC; 4. Compensated Cirrhosis; 5. Ascytis; 6. Refractory Ascytis; 7. Hemorrhagic Varices; 8. Hepatic encephalopathy; 9. Hepatocarcinoma; 10. Hepatic Transplantation; 11. subsequent transplant; 12. Death Simulated patient cohorts with data from other published sources No Tx=16.8; PegIFN=20.2; IFN = 19.4 Currency = Brazilian Reais, R$ (2006) Lifetime mean cost = R$ 39, (no Tx), R$ (PegIFN), R$44, (IFN) PegIFN+Rbv vs. IFN+Rbv= R$19, PegIFN+Rbv vs. No TX = R$6, IFN+Rbv vs. No TX = R$1, ONLY genotype 1 patients PegIFN+Rbv vs. IFN+Rbv= R$23, US$1 = R$2.18 (2006) Gheorghe Romania PegIFN alfa2a+rbv vs. PegIFN alfa 2bn+Rbv; Markov model with 7 health states reflecting various stages of chronic HCV infection genotype 1. Assumptions: constant annual rate of progression, transition probabilities from published sources, time horizon = patient lifetime (median estimate from model = 56years), local mortality data used (reflecting Romanian life expectancy). 1. CHC; 2. Sustained Virological Response; 3. Compensated cirrhosis; 4. Decompensated cirrhosis; 5. Hepatocellular carcinoma; 6. Liver Transplant; 7. Death Mean age = 45; Male = 70%; reference case = 45yr male w. chronic noncirrhotic liver disease PegIFN alfa2a+rbv = QALYs; PegIFN alfa 2bn+Rbv = QALYs Currency = Romanian lei; Lifetime cost and medical care Pegasys = 107,270lei; PegIntron = 108,414lei PegIFN alfa2a+rbv vs. PegIFN alfa 2bn+Rbv = 27,175lei ( 6,455) per QALY gained 1 = 4.21 Romanian lei (Rol) Page 98 of 239

99 Grishchenko Hartwell UK UK Antiviral (Pegasys or Viraferon) vs. no treatment for each patient group; Markov model using same methodological assumptions as Grieve et al This model was extended to allow for comprehensive sub-group analyses and to incorporate new data from the TRENT HCV cohort study. Model has 3 entry points (see 1-3 in next column) Pegasys+/-Rbv vs. PegIntron+Rbv vs. best supportive care; Markov model with 8 health states. Based on a previously published SHTAC used in TA106. Saab USA PegINF+Rbv vs. No Tx; Markov chain model to asses most costeffective timing of antiviral administration in treatment of CHC genotype 1 with 4 treatment strategies (no Tx, Tx during compensated cirrhosis, Tx during decompensated cirrhosis (DC), Tx during post transplant recurrence (PTR)) 1. Mild HCV; 2. Moderate HCV; 3. Cirrhosis; 4. Antiviral Treatment; 5. SVR; 6. Decompressed cirrhosis; 7. HCC; 8. Liver related death; 9. Liver transplant; 10. Post liver transplant state; 11. All-cause death. 1. Mild HCV; 2. Moderate HCV; 3. Compensated Cirrhosis; 4. SVR; 5. Hepatocellular carcinoma; 6. Decompensated Cirrhosis; 7. Liver Transplant; 8. Death 1. Compensated Cirrhosis; 2. Hepatocellular carcinoma; 3. decompensated Cirrhosis; 4. Post transplant; 5. Post-transplant recurrent HCV (option); 6. Regression of Cirrhosis (option); 7. Death Not reported (used three subgroups pts. in their 30's, 40's and 50's) Mean age = 40 (shortened duration) & 45 (re-treated patients); Male =70%; Baseline characteristics taken from a range of published UK studies 4000 patient entry cohort of 55-year old pts, evenly divided into one of 4 tx strategies. 17 year time horizon or until death 40yo Mean QALYs: Mild HCV (treatment) & (no treatment); Moderate HCV (Tx) & (no Tx); Cirrhosis (Tx) & 7.71 (no Tx) Pegasys: Basecase (Liu et al 115 ): (standard 48wks) & (short 24wks); Base-case (Yu et al 116, 117 ): (48wks) & (24wks). PegIntron (Berg et al 118 ): (48wks) & (24wks) No TX = 9.175; Tx during CCi =10.125; Tx during DC = 9.219; Tx during PTR = Currency = (but values also in & $US); 40yo lifetime costs for mild HCV 16,104 (Tx); 12,228 (no Tx). For moderate HCV, 29,122 (Tx); 30,044 (no Tx). For cirrhosis, 34,977 (Tx); 44,539 (no Tx) Currency = British Pounds, Currency = US$; Total cost per patient = 355,473 (No Tx), 300,159 (Tx during CCi), 349,962 (Tx during DC), 352,250 (Tx during PTR) Mild HCV genotype 1 Tx vs. No Tx ICER= 3507, Moderate HCV genotype 1 Tx vs. No Tx ICER= antiviral therapy dominates, Cirrhosis genotype 1 Tx vs. No Tx ICER= 8017 ICER for re-tx pts. with Pagasys = 52,587; Tx during CCi Stratetgy Dominated. Tx during CCi vs no tx.=-$58225; Tx during DC vs no tx.=- $125,250;Tx during PTR vs no tx.=-$52,836 1 = $2; 1 = 1.46 (2007 values) Page 99 of 239

100 Siebert Germany German HepC Markov Model (GEHMO) extended to reflect patients with different HCV genotypes, 68% genotype 1. 4 tx strategies; No Tx, Tx with IFN2b+Rbv, Tx with PegIFN2b+weight based Rbv, Genotype specific dosing according to German guidelines -PegIFN2b+wb Rbv G 1. Mild CHC; 2. Moderate CHC.; 3. CCi; 4. DC or hepatocellular carcinoma; 5. Hepatocellular carcinoma; 6. Liver transplantation; 7. Death 1530 tx-naïve CHC pts from Manns et al 119, mean age = 45, male =66% No Tx = 15.22, PegIFN2b+wb Rbv G = 17.45, IFN2b+Rbv = 16.96, PegIFN2b+wb Rbv = Currency = (2005) PegIFN2b+wb Rbv G = 1,500, IFN2b+Rbv = Dominated, PegIFN2b+wb Rbv = 126,000. ICERS calculated vs next non dominated strategy, i.e. PEgIFN=weigh t based ribavirin (wbr) 24-48wk vs No antiviral therapy, PEGIFN=wbR guidelines vs PEgIFN=wbR 24-48wk Page 100 of 239

101 6.1.3 Please provide a complete quality assessment for each cost-effectiveness study identified. Use an appropriate and validated instrument, such as those of Drummond and Jefferson (1996) 1 or Philips et al. (2004) 2. For a suggested format based on Drummond and Jefferson (1996), please see section 9.11, appendix 11. The quality assessment for the six included cost-effectiveness studies is detailed in Table 42. Table 42 Quality assessment of cost-effectiveness studies Study question Fonseca Gheorghe Grishchenko Grade (yes/no/not clear/n/a) Hartwell Saab Siebert Study design 1. Was the research question stated? Yes Yes Yes Yes Yes Yes 2. Was the economic importance of the research question stated? Yes Yes Yes Yes Yes Yes 3. Was/were the viewpoint(s) of the analysis clearly stated and justified? Yes Yes Yes Yes Yes Yes 4. Was a rationale reported for the choice of the alternative programmes or interventions compared? Yes Yes Yes Yes Yes Yes 5. Were the alternatives being compared clearly described? Yes Yes Yes Yes Yes Yes 6. Was the form of economic evaluation stated? Yes Yes Yes Yes Yes Yes 7. Was the choice of form of economic evaluation justified in relation to the questions addressed? Yes Yes Yes Yes Yes Yes Data collection 8. Was/were the source(s) of effectiveness estimates used stated? Yes Yes Yes Yes Yes Yes 9. Were details of the design and results of the effectiveness study given (if based on a single study)? Yes Yes Yes Yes Yes Yes 10. Were details of the methods of synthesis or meta-analysis of estimates given (if based on an overview of a number of effectiveness studies)? N/A N/A N/A N/A N/A N/A 11. Were the primary outcome measure(s) for the economic evaluation clearly stated? Yes Yes Yes Yes Yes Yes 12. Were the methods used to value health states and other benefits stated? Yes Yes Yes Yes Yes Yes 13. Were the details of the subjects from whom valuations were obtained given? Yes Yes Not Clear Yes Not Clear Yes 1 Drummond MF, Jefferson TO (1996) Guidelines for authors and peer reviewers of economic submissions to the BMJ. The BMJ Economic Evaluation Working Party. British Medical Journal 313 (7052): Philips Z, Ginnelly L, Sculpher M, et al. (2004) Quality assessment in decision-analytic models: a suggested checklist (Appendix 3). In: Review of guidelines for good practice in decision-analytic modelling in health technology assessment. Health Technology Assessment 8: 36. Page 101 of 239

102 14. Were productivity changes (if included) reported separately? N/A N/A N/A N/A N/A N/A 15. Was the relevance of productivity changes to the study question discussed? N/A N/A N/A N/A N/A N/A 16. Were quantities of resources reported separately from their unit cost? No No No No No No 17. Were the methods for the estimation of quantities and unit costs described? Yes Yes Yes Yes Yes Yes 18. Were currency and price data recorded? Yes Yes Yes Yes Yes Yes 19. Were details of price adjustments for inflation or currency conversion given? Yes Yes Yes Yes Yes Yes 20. Were details of any model used given? Yes Yes Yes Yes Yes Yes 21. Was there a justification for the choice of model used and the key parameters on which it was based? Yes Yes Yes Yes Yes Yes Analysis and interpretation of results 22. Was the time horizon of cost and benefits stated? Yes Yes Yes Yes Yes Yes 23. Was the discount rate stated? Yes Yes Yes Yes Yes Yes 24. Was the choice of rate justified? Yes Yes Yes Yes Yes Yes 25. Was an explanation given if cost or benefits were not discounted? N/A N/A N/A N/A N/A N/A 26. Were the details of statistical test(s) and confidence intervals given for stochastic data? Yes Yes Yes Yes Yes Yes 27. Was the approach to sensitivity analysis described? Yes Yes Yes Yes Yes Yes 28. Was the choice of variables for sensitivity analysis justified? Yes No Yes Yes Yes Yes 29. Were the ranges over which the parameters were varied stated? Yes Not Clear Not Clear Yes Yes Yes 30. Were relevant alternatives compared? (That is, were appropriate comparisons made when conducting the incremental analysis?) Yes Yes Yes Yes Yes Yes 31. Was an incremental analysis reported? Yes Yes Yes Yes Yes Yes 32. Were major outcomes presented in a disaggregated as well as aggregated form? No No No Yes No No 33. Was the answer to the study question given? Yes Yes Yes Yes Yes Yes 34. Did conclusions follow from the data reported? Yes Yes Yes Yes Yes Yes 35. Were conclusions accompanied by the appropriate caveats? Yes Yes Yes Yes Yes Yes 36. Were generalisability issues addressed? Yes Not Clear Yes Yes Yes Yes Page 102 of 239

103 6.2 De novo analysis Patients What patient group(s) is(are) included in the economic evaluation? Do they reflect the licensed indication/ce marking or the population from the trials in sections 1.4 and 5.3.3, respectively? If not, how and why are there differences? What are the implications of this for the relevance of the evidence base to the specification of the decision problem? For example, the population in the economic model is more restrictive than that described in the (draft) SPC/IFU and included in the trials. This submission includes two de novo economic analyses of genotype-1 chronically infected HCV patients considered suitable candidates for treatment with telaprevir: one for treatment naïve patients and the other for treatment experienced patients. These populations reflect both the licensed indications for telaprevir/pr therapy as well as the patients recruited to the ADVANCE and REALIZE studies. Model structure Please provide a diagrammatical representation of the model you have chosen. The model structure is the same as that summarised by Hartwell et al relating to the 2010 NICE review of peginterferon alfa and ribavirin for the treatment of chronic hepatitis C (CHC), identified by the systematic review reported in Section 6.1. The same model structure is used for both the treatment naïve and treatment experienced populations (see Figure 16). Page 103 of 239

104 Figure 16 Schematic of the cost-effectiveness model Please justify the chosen structure in line with the clinical pathway of care identified in section 2.4. The model structure is based on previous HCV economic models 15, and reflects those patients in the care pathway where treatment for chronic HCV is initiated described in Section 2.4. Patients that achieve an SVR following treatment are assumed to be free of future liver complications, although compensated cirrhotic patients who achieve an SVR can remain in the Cirrhotic post SVR health state or may progress to Hepatocellular carcinoma (HCC). In the absence of successful treatment, patients may remain in their health state for a period of time or may progress from Mild CHC to Moderate CHC and from Moderate CHC to Compensated cirrhosis, as if they had not received any antiviral treatment. In patients with stable cirrhosis, decompensation may occur when patients develop various complications such as ascites, hepatic encephalopathy and hepato-renal syndrome. Retaining consistency with the approach adopted by Hartwell et al , Grishchenko et al ; Shepherd et al , Wright et al , Grieve et al and with input from UK clinical key opinion leader XXXXXXXXXXXXXX, UK health economist with substantial experience in HCV modeling XXXXXXXXXXXXXX, and ratified by an advisory board of clinical key opinion leaders, decompensated disease remains as a single health state. Attempting to split out these different manifestations, which can occur simultaneously, presents a particular challenge in the Markov structure where patients can only inhabit one health state at any one time. Page 104 of 239

105 Patients in both Compensated cirrhosis and Decompensated cirrhosis health states can progress to HCC. Patients in Decompensated cirrhosis and HCC health states might also be candidates for Liver transplant, as highlighted in Section 2.4. The schematic (Figure 16) does not show the absorbing state of Death. Consistent with Hartwell et al and prior NICE appraisals, all cause mortality is applied to each of the health states. In addition, the shaded ellipses of Decompensated cirrhosis, Hepatocellular carcinoma and Liver transplant are associated with excess mortality risk attributable to chronic liver disease Please define what the health states in the model are meant to capture. The health states in the model capture the Mild, Moderate and Compensated cirrhosis chronic HCV disease severities that patients suitable for treatment with telaprevir may initially present with. The initial cycle of the model incorporates both the cost and disutilities associated with HCV treatment. SVR is an important clinical outcome in that patient HRQoL is improved and the risk of progression to more severe health states is removed, with the exception of cirrhotic patients who clear the HCV virus but may still remain at risk of developing HCC. Patients achieving this outcome transition to the post-svr health states. The remaining health states in the model capture the patients who do not achieve an SVR. These patients may remain in their original Mild, Moderate or Compensated cirrhosis health state, or they may progress to more advanced stages of liver disease status such as Decompensated cirrhosis, HCC, Liver transplant and Post liver transplant How does the model structure capture the main aspects of the condition for patients and clinicians as identified in section 2 (Context)? What was the underlying disease progression implemented in the model? Or what treatment was assumed to reflect underlying disease progression? Please crossreference to section 2.1. The model captures two critical aspects of chronic HCV, firstly that the virus can be cleared with successful antiviral therapy, and secondly the progressive nature of the disease in those patients who do not clear the virus following treatment. Patients who do not clear the virus are assumed to progress to more severe stages of chronic HCV using transition probabilities sourced from Shepherd et al which itself draws upon published literature and have more recently been applied by Hartwell et al Transition probabilities for Mild to Page 105 of 239

106 Moderate disease and Moderate to Compensated cirrhosis are taken from Grischenko et al and are age-specific estimates of disease progression estimated via longitudinal analysis of Trent database completed by Sweeting et al in The Trent database is a reliable source of disease progression since there are no tertiary referral centres within the region and therefore disease progression estimates are considered to be representative of patients presenting in the UK Please provide a table containing the following information and any additional features of the model not previously reported. Table 43 Key features of analysis Factor Chosen values Justification Time horizon Lifetime This is an appropriate timescale for evaluating the costs and outcomes of a condition such as chronic HCV, where treatments such as telaprevir and PR can have differential costs and effects over the remainder of a patient s life. Cycle length Annual Consistent with previous economic models and reflects the relatively slow progression rate for HCV Half-cycle correction Were health effects measured in QALYs; if not, what was used? Discount of 3.5% for utilities and costs Perspective (NHS/PSS) Applied QALYs Applied NHS PSS & Consistent with previous economic model, reflects the fact that patients will be transitioning throughout the cycle and not only at the beginning/end of each cycle. Consistent with previous economic models and the NICE methods guide Consistent with previous economic models and the NICE methods guide Consistent with previous economic models and the NICE methods Reference Hartwell et al Grischenko et al Shepherd et al Grieve et al Wright et al Hartwell et al Grischenko et al Shepherd et al Grieve et al Wright et al Hartwell et al Shepherd et al Hartwell et al Grischenko et al Shepherd et al Grieve et al Wright et al NICE methods Hartwell et al Grischenko et al Grieve et al Wright et al NICE methods Hartwell et al NICE methods Page 106 of 239

107 Technology Are the intervention and comparator(s) implemented in the model as per their marketing authorisations/ce marking and doses as stated in sections 1.3 and 1.5? If not, how and why are there differences? What are the implications of this for the relevance of the evidence base to the specified decision problem? Telaprevir/PR and PR alone therapies are implemented in the model as per their marketing authorisations and licensed doses and therefore are directly relevant to the comparison listed in the decision problem Please note that the following question refers to clinical continuation rules and not patient access schemes. Has a treatment continuation rule been assumed? If the rule is not stated in the (draft) SPC/IFU, this should be presented as a separate scenario by considering it as an additional treatment strategy alongside the base-case interventions and comparators. Consideration should be given to the following. The costs and health consequences of factors as a result of implementing the continuation rule (for example, any additional monitoring required). The robustness and plausibility of the endpoint on which the rule is based. Whether the response criteria defined in the rule can be reasonably achieved. The appropriateness and robustness of the time at which response is measured. Whether the rule can be incorporated into routine clinical practice. Whether the rule is likely to predict those patients for whom the technology is particularly cost effective. Issues with respect to withdrawal of treatment from nonresponders and other equity considerations. Treatment stopping/continuation rules dependent upon virologic response are already routinely utilised in the treatment of chronic HCV 6, as descrined in Section 2.4. The stopping rules implemented in the ADVANCE and REALIZE clinical trials are previously reported in Table 7 and are incorporated into the economic models. The SmPC 121 stopping rules are similar to those implemented in the clinical trials, but differ in the following ways: The week 4 criteria for stopping treatment is HCV RNA >1,000 IU/mL in the SmPC is consistent with ADVANCE but is slightly less restrictive than REALIZE Page 107 of 239

108 The week 4 criteria results in the stopping of all therapy in the SmPC. In the trials PR was continued in order to assess whether there was a virologic benefit to continued PR therapy, but results indicated that there was no such benefit. In the SmPC the stopping rules are limited to week 4 and week 12, whereas the RCTs included stopping rules for patients continuing PR beyond week 12. Table 44 Virologic stopping rules in the SmPC 121 Time point Criteria for stopping Action Week 4 HCV RNA >1,000 IU/mL Discontinue all treatment Week 12 HCV RNA >1,000 IU/mL Discontinue all treatment It is not anticipated that the relatively minor differences between the RCT and SmPC stopping rules will have a meaningful impact on the economics presented in this submission because: Reasons other than virologic failure are more common causes for treatment discontinuation Very few patients in the ADVANCE and REALIZE trial discontinued telaprevir at week 4 on account of the virologic stopping rules Analysis has shown that the use of a >100 IU/mL versus a >1,000 IU/mL stopping criteria has little impact on the number of patients affected. Table 45 Number of T12/PR patients meeting stopping criteria at week 4 N (%) ADVANCE (n = 363) REALIZE (n = 238*) >1,000 IU/mL 6 (1.7) 10 (4.2) >100 IU/mL 13 (3.6) 16 (6.7) * In REALIZE, 28 patients do not have HCV RNA data, hence base n 266 Page 108 of 239

109 6.3 Clinical parameters and variables When relevant, answers to the following questions should be derived from, and be consistent with, the clinical-evidence section of the submission (section 5). Cross-references should be provided. If alternative sources of evidence have been used, the method of identification, selection and synthesis should be provided as well as a justification for the approach Please demonstrate how the clinical data were implemented into the model. The clinical data from the ADVANCE and REALIZE studies are directly incorporated into the economic model and are summarised below: Table 46 Clinical data implemented in the economic models Treatment naïve as estimated from ADVANCE Patient characteristics Age distribution HCV severity distribution Treatment experienced as estimated from REALIZE Age HCV severity distribution Prior response distribution Treatment characteristics SVR rates Treatment durations SVR rates Treatment durations Adverse events Rates of AEs Rates of AEs HRQoL Relative on-treatment decrements Relative on-treatment decrements Patients characteristics Patient age is incorporated into the models, enabling relevant age-specific all cause mortality rates to be applied to patients as they progress through the model. The incorporation of disease severity upon entry to the model means that disease severity specific SVR rates can be applied to the patients, reflecting the clinical reality that it is harder to clear the virus in patients where HCV disease has progressed beyond the initial mild degree of fibrosis. Within the treatment experienced model the distribution of prior treatment response is incorporated into the patient baseline distribution. As a result, the prior response specific SVR rates from the REALIZE trial are implemented in the model, reflecting the clinical reality that prior relapsers face a higher probability of achieving an SVR than prior partial responders, who in turn have a higher chance of success than prior null responders. Treatment characteristics SVR rates from the ADVANCE and REALIZE trials are directly incorporated into the treatment naïve and treatment experienced models. Page 109 of 239

110 The mean treatment durations from both the ADVANCE and REALIZE trials enable the drug acquisition costs per patient to be appropriately estimated in the treatment naïve and treatment experienced models, respectively. The clinical trial data on patients remaining on treatment out to weeks 4, 8, 12, 24, 36 and 48 are directly implemented in the model to estimate the monitoring costs of patients as they continue on therapy. Adverse events Following clinical advice, rates of Grade 3 rash, pruritus, diarrhoea and nausea from the trials are incorporated into the model so that drug acquisition costs can be assigned for interventions associated with managing these side effects. Health care professional resource utilisation is also assigned to the management of rash within the model, according to the severity of the rash grade. HRQoL EQ-5D valuation index data captured from the trials are applied to utilities during the year of treatment. This enables a differential impact on HRQoL to be appropriately implemented in the model, reflecting both the type of treatment and the duration of therapy that patients received in the ADVANCE and REALIZE trials Demonstrate how the transition probabilities were calculated from the clinical data. If appropriate, provide the transition matrix, details of the transformation of clinical outcomes or other details here. Clinical trial data have been used to calculate the probability of patients achieving an SVR following treatment. This has been calculated directly from the following SVR rates, previously reported in Sections and Table 47 Percentage of patients achieving an SVR from the clinical trials T12/PR (n=363) PBO/PR (n=361) Treatment naïve 16, % [95% CI] 75 [70-79] 44 [39-49] Treatment experienced 7 Prior relapse, [95% CI] 83 [76-89] 24 [14-35] Prior partial response, [95% CI] 59 [44-73] 15 [4-34] Prior null response, [95% CI] 29 [19-41] 5 [1-18] The clinical trials enrolled Mild HCV, Moderate HCV, and Compensated cirrhosis patients but not those from the more advance health states within the model. As with many clinical trials, the data captured does not reflect the lifetime horizon of the model. All other transition probabilities between the liver disease health states are based on the assumptions in the recent Hartwell et al economic evaluation, identified in Section 6.1. Similarly, the probability of transition to the absorbing state of death is not robustly captured in the clinical trials therefore, consistent with the Hartwell et al approach, age-specific all-cause mortality data are applied to all health Page 110 of 239

111 states in the model. Hartwell et al is also the source of excess liverrelated mortality associated with the more advanced stages of HCV disease Is there evidence that (transition) probabilities should vary over time for the condition or disease? If so, has this been included in the evaluation? If there is evidence that this is the case, but it has not been included, provide an explanation of why it has been excluded. There is evidence that chronic HCV disease progression is dependent on patient age , therefore age-specific transition probabilities drawn from the secondary care Trent database are applied to the initial Mild, Moderate and Compensated cirrhosis health states in the economic model 112, 120. Transition probabilities reported by Hartwell et al between the later, more advanced, liver disease health states are not age specific and therefore, the same transition probabilities are applied for each given health state over time, consistent with Hartwell et al , Grischenko et al , Shepherd et al , Grieve et al and Wright et al Also consistent with previous models by Hartwell et al , Grischenko et al , Shepherd et al , Grieve et al and Wright et al , age-specific general population mortality rates are also applied to all health states in the model. Transition probabilities incorporated within the economic model are summarised in Table 48. Page 111 of 239

112 Table 48 Transition probabilities incorporated into the economic models Transition probabilities Input Source From: To: Mild Moderate Age at treatment Grishchenko (2009) yrs yrs yrs Moderate Compensated cirrhosis Age at treatment Compensated cirrhosis Compensated cirrhosis- SVR Decompensated cirrhosis 30 yrs yrs yrs Grishchenko (2009) Hartwell (2011) 29 HCC Hartwell (2011) 29 Decompensated cirrhosis 0 Expert opinion HCC Assumption, Hartwell (2011) 29 Decompensated cirrhosis HCC Hartwell (2011) 29 Liver transplant 0.02 Hartwell (2011) 29 Death 0.13 Hartwell (2011) 29 HCC Liver transplant 0.04 Calculation Death 0.43 Hartwell (2011) 29 Liver transplant Death Yr Hartwell (2011) 29 Post-liver transplant Death Yr Hartwell (2011) Were intermediate outcome measures linked to final outcomes (for example, was a change in a surrogate outcome linked to a final clinical outcome)? If so, how was this relationship estimated, what sources of evidence were used, and what other evidence is there to support it? Not applicable If clinical experts assessed the applicability of values available or estimated any values, please provide the following details 3 : the criteria for selecting the experts the number of experts approached the number of experts who participated declaration of potential conflict(s) of interest from each expert or medical speciality whose opinion was sought the background information provided and its consistency with the totality of the evidence provided in the submission the method used to collect the opinions 3 Adapted from Pharmaceutical Benefits Advisory Committee (2008) Guidelines for preparing submissions to the Pharmaceutical Benefits Advisory Committee (Version 4.3). Canberra: Pharmaceutical Benefits Advisory Committee. Page 112 of 239

113 the medium used to collect opinions (for example, was information gathered by direct interview, telephone interview or self-administered questionnaire?) the questions asked whether iteration was used in the collation of opinions and if so, how it was used (for example, the Delphi technique). During the initial development of the economic model, clinical input was obtained from a UK clinical key opinion leader and health economic input obtained from an independent health economic expert in the field of modelling HCV. Input was provided during five face-to-face meetings. Following the initial development of the economic models, an advisory board of seven clinical opinion leaders reviewed the clinical assumptions within the economic model regarding the health states, treatment and monitoring of HCV patients. This UK clinical advisory board included four Hepatologists, two Infectious Disease specialists and a Senior Pharmacist. Summary of selected values Please provide a list of all variables included in the costeffectiveness analysis, detailing the values used, range (distribution) and source. Provide cross-references to other parts of the submission. Please present in a table, as suggested below. Page 113 of 239

114 Table 49 Summary of variables applied in the naive economic model Variable Value CI (distribution) Model setting both models Reference to section in submission Cycle length 1 year Section Time horizon Lifetime (70 Section years) Discount rate for costs 3.5% Section Discount rate for outcomes 3.5% Section Patient demographics treatment naïve model Age distribution 35 years years >46 years HCV severity ( 35 years) Mild Moderate Bridging fibrosis/cirrhosis HCV severity (36-45 years) Mild Moderate Bridging fibrosis/cirrhosis HCV severity (>45 years) Mild Moderate Bridging fibrosis/cirrhosis 15.2% 24.2% 60.6% 63.6% 32.7% 3.7% 43.4% 40.6% 16.0% 30.8% 43.3% 25.9% Section Section Section Section Patient demographics treatment experienced model Age 50 years Section Prior response distribution Relapse Partial Null HCV severity (Relapse) Mild Moderate Bridging fibrosis/cirrhosis HCV severity (Partial) Mild Moderate Bridging fibrosis/cirrhosis HCV severity (Null) Mild Moderate Bridging fibrosis/cirrhosis Clinical effectiveness treatment naïve model SVR rate telaprevir/pr Mild Moderate Bridging fibrosis/cirrhosis SVR rate PR alone Mild Moderate Bridging fibrosis/cirrhosis Clinical effectiveness treatment experienced model SVR rate telaprevir/pr in Relapse 53.5% 19.1% 27.4% 25.4% 30.5% 44.1% 22.4% 31.6% 46.0% 13.8% 29.4% 26.8% 81.3% 75.0% 61.6% 45.6% 47.5% 32.9% 95% CI 75-88% 68-82% 50-73% 95% CI 38-54% 39-56% 22-44% 95% CI Section Section Section Section Section Section Page 114 of 239

115 Mild Moderate Bridging fibrosis/cirrhosis SVR rate telaprevir/pr in Partial Mild Moderate Bridging fibrosis/cirrhosis SVR rate telaprevir/pr in Null Mild Moderate Bridging fibrosis/cirrhosis SVR rate PR alone in Relapse Mild Moderate Bridging fibrosis/cirrhosis SVR rate PR alone in Partial Mild Moderate Bridging fibrosis/cirrhosis SVR rate PR alone in Null Mild Moderate Bridging fibrosis/cirrhosis Treatment durations treatment naïve model Telaprevir/PR patients Mean telaprevir duration 0-4 weeks 5-8 weeks 9-12 weeks Mean PR duration 0-4 weeks 5-8 weeks 9-12 weeks weeks weeks weeks PR alone patients Mean PR duration 0-4 weeks 5-8 weeks 9-12 weeks weeks weeks weeks Treatment durations treatment experienced model Telaprevir/PR patients Mean telaprevir duration 0-4 weeks 5-8 weeks 9-12 weeks Mean PR duration 0-4 weeks 5-8 weeks 9-12 weeks weeks weeks weeks 85% 81% 84% 71% 76% 44% 10% 42% 28% 35% 28% 13% 0% 43% 10% 0% 8% 5% 10.7 weeks 6.9% 8.3% 84.3% 26.9 weeks 4.1% 2.5% 2.2% 39.4% 30.9% 20.9% 36.2 weeks 3.3% 1.1% 0.8% 13.3% 22.4% 59.0% 10.7 weeks 5.3% 12.4% 82.3% 38.6 weeks 3.4% 4.1% 1.9% 11.7% 6.4% 72.5% Page 115 of % 67-91% 73-92% 95% CI 29-96% 50-93% 24-65% 95% CI 0-45% 20-67% 15-44% 95% CI 15-59% 10-53% 4-31% 95% CI 0-0% 10-82% 0-45% 95% CI 0-0% 0-36% 0-26% Section Section Section Section Section Section Section Section Section PR alone patients Mean PR duration 30.0 weeks Section 5.5.3

116 0-4 weeks 5-8 weeks 9-12 weeks weeks weeks weeks Drug doses and costs both models Telaprevir Dose Weekly cost Pegylated interferon-2a Dose Weekly cost Ribavirin Dose Weekly cost AE incidence treatment naïve model Telaprevir/PR incidence Grade 1 rash Grade 2 rash Grade 3 rash Grade 3 pruritus Grade 3 nausea Grade 3 diarrhoea Grade 3 anaemia PR alone incidence Grade 1 rash Grade 2 rash Grade 3 rash Grade 3 pruritus Grade 3 nausea Grade 3 diarrhoea Grade 3 anaemia AE incidence treatment experienced model Telaprevir/PR incidence Grade 1 rash Grade 2 rash Grade 3 rash Grade 3 pruritus Grade 3 nausea Grade 3 diarrhoea Grade 3 anaemia PR alone incidence Grade 1 rash Grade 2 rash Grade 3 rash Grade 3 pruritus Grade 3 nausea Grade 3 diarrhoea Grade 3 anaemia AE management costs both models Cost per patient affected Grade 1 rash Grade 2 rash Grade 3 rash Grade 3 pruritus Grade 3 nausea Grade 3 diarrhoea Grade 3 anaemia Tests and monitoring treatment naïve 0.8% 3.8% 0.4% 31.7% 23.3% 40.1% 750 mg 3x/day 1, µg/week ,000mg/day % 6.6% 3.6% 0.5% 1.4% 0.5% 7.2% 20.8% 3.3% 0.3% 0.5% 0.5% 0.5% 1.9% 29.3% 6.8% 1.1% 1.1% 0.5% 0.5% 6.4% 16.7% 2.3% 0.0% 0.0% 0.5% 0.5% 0.8% Section Section Section Section Section Section Section Section Page 116 of 239

117 model Evaluation of a new patient with confirmed HCV Mild/Moderate Bridging fibrosis/cirrhosis Further investigations of a patients with HCV considered for treatment Mild/Moderate Bridging fibrosis/cirrhosis Tests and monitoring treatment experienced model Evaluation of a new patient with confirmed HCV Mild/Moderate Bridging fibrosis/cirrhosis Further investigations of a patients with HCV considered for treatment Mild/Moderate Bridging fibrosis/cirrhosis Tests and monitoring both models Monitoring during active treatment (0-4 weeks) Mild/Moderate Bridging fibrosis/cirrhosis Monitoring during active treatment (0-8 weeks) Mild/Moderate Bridging fibrosis/cirrhosis Monitoring during active treatment (0-12 weeks) Mild/Moderate Bridging fibrosis/cirrhosis Monitoring during active treatment (0-24 weeks) Mild/Moderate Bridging fibrosis/cirrhosis Monitoring during active treatment (0-36 weeks) Mild/Moderate Bridging fibrosis/cirrhosis Monitoring during active treatment (0-48 weeks) Mild/Moderate Bridging fibrosis/cirrhosis Health state costs both models Mild (SVR) Moderate (SVR) Compensated cirrhosis (SVR) Mild (no SVR) Moderate (no SVR) Compensated cirrhosis (no SVR) Decompensated cirrhosis Hepatocellular carcinoma Liver transplant Post liver transplant (0-12 months) Post liver transplant (13-24 months) Utilities both models Base line Mild Moderate Compensated cirrhosis Following SVR Mild Moderate Compensated cirrhosis Following no SVR Mild Moderate , , , , , , , , , Section Section Section Section Section Section Section Section Section Section Section Section Page 117 of 239

118 Compensated cirrhosis (no SVR) Decompensated cirrhosis Hepatocellular carcinoma Liver transplant Post liver transplant Utilities treatment naïve model Treated with telaprevir/pr Mild Moderate Compensated cirrhosis Treated with PR alone Mild Moderate Compensated cirrhosis (on PR alone) Utilities treatment experienced model Treated with telaprevir/pr Mild Moderate Compensated cirrhosis Treated with PR alone Mild Moderate Compensated cirrhosis (on PR alone) Transition probabilities both models Mild to Moderate 35 years years >46 years Moderate to CCi 35 years years >46 years CCi (no SVR) to DC CCi (no SVR) to HCC CCi (SVR) to DC CCi (SVR) to HCC DC to HCC DC to Liver transplant DC to Death HCC to Liver transplant HCC to Death Liver transplant to Death Post liver transplant to Death All cause mortality rate both models years years years years years years years years Section Section Section Section Page 118 of 239

119 6.3.7 Are costs and clinical outcomes extrapolated beyond the trial follow-up period(s)? If so, what are the assumptions that underpin this extrapolation and how are they justified? In particular, what assumption was used about the longer term difference in effectiveness between the intervention and its comparator? For the extrapolation of clinical outcomes, please present graphs of any curve fittings to Kaplan-Meier plots. Consistent with the economic models developed by Hartwell et al , Grischenko et al , Shepherd et al , Grieve et al and Wright et al , SVR rates are not extrapolated in the model over time, although the consequences of the treatment outcome (SVR or otherwise) are modelled over the life time of the model Provide a list of all assumptions in the de novo economic model and a justification for each assumption. Assumptions made regarding the model inputs are detailed in Table 50. Table 50 Economic model clinical assumptions Assumption Rationale Age-specific transition probabilities Age-specific transition probabilities from Grischenko et al from Mild CHC to Moderate CHC and means that, as patients age during the model from Moderate CHC to lifetime, the appropriate transition probabilities can be applied Decompensated Cirrhosis health to reflect their increased risk of progressing to a more severe states health state. These transition probabilities are consistent with Compensated cirrhosis patients who achieve an SVR can remain in the Compensated cirrhosis post SVR health state or may progress to Hepatocellular carcinoma (HCC). Compensated cirrhosis patients who achieve an SVR have a zero probability of progressing to Decompensated cirrhosis Compensated cirrhosis patients who achieve an SVR have a probability of progressing to HCC The transition probability from HCC to Liver transplant is Costs during the year of treatment include Fibro scan and Fibro test for all patients and transjugular biopsy in 25% of cirrhotic patients. HCV quantification at week 4. Following initial assessment and testing, patients care is nurse led and does not require consultant visits the Hartwell et al assumptions. Consistent with previous economic models 15, 28-30, 109 and supported by the clinical advisory board Based on clinical expert feedback that no further fibrosis will occur in Compensated cirrhosis patients achieving an SVR. Subsequently accepted by the clinical advisory board In the absence of data, the transition probability for Compensated cirrhosis no SVR health state to HCC. This was supported by clinical expert input. Calculated by dividing the 32 liver transplants due to HCC in the UK by the 717 HCV patients with HCC in the UK (see Table 51), in order to reflect clinical reality in the UK Assumption provided based on clinical expert opinion regarding the clinical management of patients. Costs for these tests were provided by a clinical expert. Required in order to assess ervr status. This was supported by the clinical advisory board. Based on clinical advisory board feedback that on-going patient management is nurse led. Page 119 of 239

120 Grade 3 rash, pruritus, diarrhoea and nausea require drug intervention. Anaemia requires nurse and/or consultant time dependent on severity. During treatment, patients are assumed to experience a decrement in HRQoL resulting from treatment AEs. Patients that achieve an SVR experience an improvement over their baseline HRQoL. Age-specific general population mortality rates are applied to all health states in the model (see Table 52) Based on clinical advisory board feedback regarding the management of AEs in clinical practice. Based on clinical advisory board feedback regarding the management of AEs in clinical practice. This is consistent with established economic models 15, 30 and HRQoL data captured within the telaprevir trials. The absolute EQ-5D valuation index utility decrement from baseline during the year of treatment is directly incorporated from the pivotal Phase III trials Consistent with established models, with post-svr Mild CHC and Moderate CHC health state utilities sourced directly from Wright et al In the absence of data, Compensated cirrhotic SVR patients are assumes to experience the same increment as Moderate CHC SVR patients. Accepted by both the clinical and health economic expert input. Consistent with previous economic models 15, 28-30, 112, appropriate all cause mortality rates are applied as patients age through later cycles. Accepted by both the clinical and health economic advisory boards Table 51 HCC to Liver transplant transition probability calculation Patient type Value Source Liver transplants due to HCC in the UK 32 Muhlberger (2009) 129 HCC patients in the UK 2,867 Cancer Research UK (2008) 130 Of which are attributable to HCV 25% 717 Perz (2006) or 4% Calculation Table 52 All cause mortality rates 132 Age group Mortality rate years years years years years years years years Page 120 of 239

121 6.4 Measurement and valuation of health effects This section should be read in conjunction with NICE s Guide to the methods of technology appraisal, section 5.4. The HRQL impact of adverse events should still be explored regardless of whether they are included in cost-effectiveness analysis. All parameters used to estimate cost effectiveness should be presented clearly in tabular form and include details of data sources. For continuous variables, mean values should be presented and used in the analyses. For all variables, measures of precision should be detailed. Patient experience Please outline the aspects of the condition that most affect patients quality of life. Chronic HCV is a major cause of chronic liver disease, cirrhosis and liver cancer in the developed world 10. Signs and symptoms such as fatigue, weakness and depression present even in patients with early or mild disease and research has shown HCV patients have impaired HRQoL compared to the general population Younossi et al 2007 found that symptoms of both fatigue and depression are common and can have a profound effect on patient well-being 133. Fatigue experienced by HCV patients is often debilitating with Obhrai et al identifying significantly greater fatigue in patients with HCV compared to healthy controls 134. Similarly, Obrahi et al found that depression is highly prevalent among HCV patients 134. The psychological and emotional impact of an HCV diagnosis is significant, even in the absence of significant liver disease. Castera et al found that being diagnosed with HCV is significantly more stressful than job dismissal and home removal 14. Patients considered diagnosis with HCV to be more severe than being diagnosed with diabetes mellitus and hypertension 14. Overall, the published evidence indicates that patients presenting with chronic 9-11, 13, HCV have a markedly reduced HRQoL compared to healthy individuals 15, 108 and that those with advanced liver disease experience a decline in their health related quality of life 10, 15 (see Figure 17). Page 121 of 239

122 Figure 17 Proportion of cases in each disease stage reporting problems for each dimension of the EQ-5D from Wright et al 2006 observational study Please describe how a patient s HRQL is likely to change over the course of the condition. As illustrated by the Hartwell et al , HRQoL declines as HCV disease progresses to more advanced disease health states (see Table 53). Patients with mild disease have an average utility of 0.77 for mild patients, falling to 0.66 in moderate patients, 0.55 in compensated cirrhosis and 0.45 in patients with more advanced liver disease such as decompensated cirrhosis, HCC or undergoing liver transplantation. The Hartwell et al utility estimates are consistent with those cited by previous economic evaluations, including Grishchenko et al ; Shepherd et al ; Wright et al and Grieve et al Table 53 Health state utilities 29 Health state Baseline On treatment Post SVR (with PR alone) Mild CHC Moderate CHC Compensated cirrhosis 0.55 Decompensated cirrhosis 0.45 HCC 0.45 Liver transplant 0.45 Post liver transplant 0.67 Page 122 of 239