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The Department of Health has asked the National Institute for Health and Clinical Excellence (NICE or the Institute) to conduct a single technology appraisal (STA) of telbivudine for the treatment of chronic hepatitis B and provide guidance on its use to the NHS in England and Wales. The Appraisal Committee has had its first meeting to consider both the evidence submitted by the manufacturer and the views put forward by non-manufacturer consultees and commentators, and by the clinical specialist and patient expert representatives nominated for this appraisal by non-manufacturer consultees and commentators. The Committee has developed preliminary recommendations on the use of telbivudine.

This document has been prepared for consultation with the formal consultees. It summarises the evidence and views that have been considered and sets out the preliminary recommendations developed by the Committee. The Institute is now inviting comments from the formal consultees in the appraisal process (the consultees for this appraisal are listed on the NICE website, www.nice.org.uk). This document should be read in conjunction with the evidence base for this appraisal (the evaluation report) which is available from www.nice.org.uk

Note that this document does not constitute the Institute's formal guidance on this technology. The recommendations made in section 1 are preliminary and may change after consultation.

The process the Institute will follow after the consultation period is summarised below. For further details, see the 'Guide to the single technology appraisal process' (this document is available on the Institute's website, www.nice.org.uk).

• The Appraisal Committee will meet again to consider the original evidence and this appraisal consultation document in the light of the views of the formal consultees.
• At that meeting, the Committee will also consider comments made on the document by people who are not formal consultees in the appraisal process.
• After considering feedback from the consultation process, the Committee will prepare the final appraisal determination (FAD) and submit it to the Institute.
• Subject to any appeal by consultees, the FAD may be used as the basis for the Institute's guidance on the use of the appraised technology in the NHS in England and Wales.

The key dates for this appraisal are:

• Closing date for comments: 30 April 2008
• Second Appraisal Committee meeting: 8 May 2008

Details of membership of the Appraisal Committee are given in appendix A, and a list of the sources of evidence used in the preparation of this document is given in appendix B.

Note that this document does not constitute the Institute's formal guidance on this technology. The recommendations made in section 1 are preliminary and may change after consultation.

1. Appraisal Committee's preliminary recommendations

This preliminary guidance does not apply to people with chronic hepatitis B known to be co-infected with hepatitis C, hepatitis D or HIV

1.1 Telbivudine is not recommended for the treatment of chronic hepatitis B.

1.2 People currently receiving telbivudine should have the option to continue therapy until they and their clinicians consider it appropriate to stop.

2 The technology

2.1 Telbivudine (Sebivo, Novartis) is a synthetic thymidine nucleoside analogue with activity against hepatitis B virus deoxyribonucleic acid (DNA) polymerase responsible for viral replication. Telbivudine is licensed for the treatment of chronic hepatitis B in adult patients with compensated liver disease and evidence of viral replication, persistently elevated serum alanine aminotransferase (ALT) levels and histological evidence of active inflammation and/or fibrosis.

2.2 The most common side effects associated with telbivudine include dizziness, headache, cough, diarrhoea, nausea, abdominal pain, rash, fatigue and increased levels of blood creatine phosphokinase, ALT and amylase. Uncommon side effects include malaise, arthralgia, myalgia, peripheral neuropathy and myopathy. For full details of side effects and contraindications, see the summary of product characteristics.

2.3 The recommended dose for telbivudine is 600mg (one tablet) once daily, taken orally, with or without food. The optimal treatment duration is unknown (see the summary of product characteristics for criteria for treatment discontinuation). Telbivudine costs £290.33 for 28 × 600-mg tablets (excluding VAT; 'British national formulary' edition 55). Costs may vary in different settings because of negotiated procurement discounts.

3 The manufacturer's submission

The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of telbivudine and a review of this submission by the Evidence Review Group (ERG; appendix B).

3.1 The manufacturer's decision problem specified telbivudine monotherapy as the intervention of interest in a population comprising adults with compensated liver disease and active chronic hepatitis B (that is, evidence of viral replication and active liver inflammation and/or fibrosis). The manufacturer did not consider telbivudine in combination with other antiviral treatments; arguing that there was not enough evidence and that combination therapy was not within the current marketing authorisation for telbivudine. The intended comparator specified by the manufacturer was lamivudine as first-line oral antiviral treatment. The health outcomes considered included seroconversion rates of hepatitis B e antigen (HBeAg); virological response, that is, a reduction in hepatitis B virus (HBV) DNA; histological improvement (in inflammation and fibrosis); biochemical changes (for example, reduction in serum ALT); and development of viral resistance to treatment. The manufacturer's decision problem considered people with compensated liver disease and treated HBeAg-positive and HBeAg-negative chronic hepatitis B disease as separate subgroups.

3.2 The manufacturer's submission presented evidence on the clinical effectiveness of telbivudine monotherapy based on the GLOBE trial, which was a randomised, double-blind trial comparing the efficacy, safety and tolerability of telbivudine (600 mg/day) with lamivudine (100 mg/day) for 104 weeks. In total, 1397 patients were recruited; of whom, 921 had HBeAg-positive chronic hepatitis B (458 in the telbivudine arm and 463 in the lamivudine arm) and 446 had HBeAg-negative chronic hepatitis B (222 in the telbivudine arm and 224 in the lamivudine arm). Patients were recruited from 20 countries and were nucleoside-naive with HBeAg-positive or HBeAg-negative compensated liver disease. Patients were randomised (1:1) to receive telbivudine or lamivudine (each with matching placebo for blinding purposes) once daily as oral tablets. The primary endpoint was therapeutic response, which was defined as suppression of HBV DNA to < 5 log10 copies/ml plus either clearance of detectable HBeAg or ALT normalisation.

3.3 In patients with HBeAg-positive disease, there was a statistically significantly higher therapeutic response rate in the telbivudine group (63.3%) compared with the lamivudine group (48.2%) at week 104. That is an absolute difference of 15.1 percentage points (95% confidence interval [CI] 8.6 to 21.6, p < 0.0001). The mean reduction in baseline HBV DNA level was statistically significantly greater in the telbivudine group (?5.74 log10 copies/ml) compared with the lamivudine group (?4.42 log10 copies/ml) at week 104 in patients with HBeAg-positive disease (p < 0.0001). In patients with HBeAg-negative disease, there was also a statistically significantly higher therapeutic response rate in the telbivudine group (77.5%) compared with the lamivudine group (66.1%). That is an absolute difference of 11.4 percentage points (95% CI 2.9 to 19.9, p = 0.0069). A statistically significant reduction in HBV DNA levels was also observed in patients with HBeAg-negative disease: the mean reduction in HBV DNA levels from baseline to week 104 in the telbivudine group was ?5.00 log10 copies/ml compared with ?4.17 log10 copies/ml in the lamivudine group (p = 0.0002).

3.4 In the HBeAg-positive disease group, the proportion of patients with HBV DNA undetectable by polymerase chain reaction (PCR) assay at week 104 was statistically significantly higher in the telbivudine arm (55.6%) compared with the lamivudine arm (38.5%) (p < 0.0001). Virological breakthrough (as defined in the trial protocol) in patients with HBeAg-positive disease was statistically significantly lower in the telbivudine arm (23.3%) than in the lamivudine arm (37.1%) (p < 0.0001). Virologic breakthrough (defined as > 1 log10 above nadir) was statistically significantly lower in the telbivudine arm (28.6%) than in the lamivudine arm (45.5%). HBV resistance (as defined in the trial protocol) in patients with HBeAg-positive disease was statistically significantly lower in the telbivudine group (21.7%) compared with the lamivudine group (34.1%) (p < 0.0001).

3.5 Similar treatment effects were observed in the HBeAg-negative disease group, where the proportion of patients with HBV DNA undetectable by PCR was also statistically significantly higher for telbivudine (82.0%) compared with lamivudine (56.7%) (p < 0.0001). In patients with HBeAg-negative disease, virological breakthrough (as defined in the trial protocol) was also statistically significantly lower in the telbivudine arm (8.4%) than in the lamivudine arm (19.7%) (p = 0.0013). Virologic breakthrough (defined as > 1 log10 above nadir) was statistically significantly lower in the telbivudine arm (12.2%) than in the lamivudine arm (30.4%). HBV resistance was statistically significantly lower in the telbivudine arm (8.4%) than in the lamivudine arm (20.2%) (p = 0.0008).

3.6 The ERG considered that on the whole the manufacturer's submission appeared to represent an unbiased estimate of the anti-viral treatment effects of telbivudine. However, the ERG suggested that whilst the results from the GLOBE trial were statistically significant, the clinical significance of the difference was open to question. When the proportion of patients who discontinued treatment due to disease progression or lack of efficacy (0.8% versus 2.6% for telbivudine and lamivudine respectively) were considered in the analysis of the trial outcomes, there is an absolute difference of only about 2 percentage points for telbivudine over lamivudine. According to the ERG, although virologic breakthrough (defined as >1 log10 above nadir) at two years was lower in the telbivudine arm (28.6%) than in the lamivudine arm (45.5%), this was still high at the clinical level. In addition, it is not clear the GLOBE trial was powered to detect differences in subgroups defined by race or serum ALT levels, and over-representation of HBeAg-positive patients in the trial may have influenced the results in the HBeAg-negative disease group. The ERG noted that no health-related quality of life data from the GLOBE trial was reported in the manufacturer's submission.

3.7 The manufacturer's submission presented an analysis of the cost effectiveness of telbivudine in patients with chronic hepatitis B whose serum ALT levels are more than or equal to twice the upper normal limit. Two Markov state transition models were provided in the manufacturer's submission: a seroconversion model (applicable to only HBeAg-positive disease) and a viral load model (applicable to both HBeAg-positive and HBeAg-negative disease). Both viral and seroconversion models adopted a lifetime horizon. The comparators included in the seroconversion model were lamivudine and adefovir dipivoxil as part of treatment algorithms (that included adefovir dipivoxil, lamivudine or telbivudine as a salvage therapy for patients whose disease develops resistance after the first drug) and best supportive care (BSC). No comparisons were made in the seroconversion model of telbivudine against adefovir dipivoxil or lamivudine as separate treatments. In the viral load model, the only comparator considered was lamivudine.

3.8 In the viral load model submitted by the manufacturer, patients were assumed to enter the model in the chronic hepatitis state without cirrhosis. Health states associated with the progression of the disease were divided by serum ALT and viral load levels, resulting in a large number of possible health states. Consequently the data available from the GLOBE trial to populate the viral load model were sparse. In an attempt to deal with this, the manufacturer used values of 0.0 and 0.5 (which they referred to as 'non-informative priors') to correct for the probabilities of health state transitions for which there were one or more zero observations and no data available.

3.9 The results of the economic analysis were presented as incremental costs per quality-adjusted life year (QALY) gained for telbivudine relative to lamivudine in the viral load model. In the seroconversion model, a comparison between a set of treatment algorithms relative to BSC was made. The manufacturer's main submission did not report on univariate sensitivity analyses and the base case results were taken from probabilistic sensitivity analysis (PSA). Following the identification of errors in the manufacturer's original economic model by the ERG, amended base-case analyses were presented.

3.10 The base-case analysis of the viral load model (based on PSA) comparing telbivudine with lamivudine and assuming a 'non-informative prior' of 0.0 produced an incremental cost-effectiveness ratio (ICER) of £15,377 per additional QALY in HBeAg-positive disease; the corresponding ICER with a 'non-informative' prior of 0.5 was £8,542 per additional QALY. In HBeAg-negative disease, the ICER for a comparison of telbivudine with lamivudine with a 'non-informative prior' of 0.0 produced an ICER of £20,256 per additional QALY. The corresponding ICER with a 'non-informative prior' of 0.5 produced an ICER of £27,801 per additional QALY. Deterministic base-case analyses (requested from the manufacturer) of the viral load model comparing telbivudine with lamivudine (with a 'non-informative prior' of 0.0) produced an (ICER) of £12,278 per additional QALY gained in HBeAg-positive disease. The corresponding ICER (with a 'non-informative prior' of 0.5) was £8669 per additional QALY gained. In HBeAg-negative disease, the ICER for a comparison of telbivudine with lamivudine was £20,383 per additional QALY gained (with a 'non-informative prior' of 0.0); the corresponding ICER (with a 'non-informative prior' of 0.5) was £57,419 per additional QALY gained.

3.11 The seroconversion model (HBeAg-positive disease only) gave an ICER of £13,193 per additional QALY gained (95% CI £7788 to £25,194) for a comparison of telbivudine alone (followed by BSC if appropriate) with BSC alone. A comparison of the treatment strategy of telbivudine followed by adefovir dipivoxil and then BSC against BSC alone gave an ICER of £15,684 per additional QALY gained (95% CI £9491 to £28,151). The treatment strategy of adefovir dipivoxil followed by telbivudine and then BSC compared with BSC alone gave an ICER of £18,388 per additional QALY gained (95% CI £11,707 to £30,357). Adefovir dipivoxil followed by lamivudine and then BSC compared with BSC alone gave an ICER of £17,398 per additional QALY gained (95% CI £11,063 to £28,322).

3.12 The ERG considered that the seroconversion model structure used to assess the cost effectiveness of telbivudine was consistent with methods adopted in previous technology appraisals in chronic hepatitis B. However, the ERG identified a number of issues and uncertainties relating to the economic evidence presented by the manufacturer. The ERG noted the economic models presented in the manufacturer's submission contained an insufficient discussion of uncertainty; in particular, no univariate sensitivity analyses were presented in the main body of the submission for either the viral load model or the seroconversion model. Although the submitted viral load model included a worksheet that contained univariate sensitivity analysis, these results were not discussed in the submission itself. The ERG noted that there was no explanation of the results of the univariate sensitivity analysis, the rationale for the choice of variables included or excluded, and no explanation was provided on the choice of the ranges used for the variables. This made it difficult to ascertain the key drivers of the economic model. In addition, there was no detailed discussion about the probabilistic sensitivity analysis conducted.

3.13 The ERG noted that evidence on the clinical and cost effectiveness of adefovir dipivoxil was not adequately identified and no attempts were made to justify or investigate the assumptions made about the clinical and cost effectiveness of adefovir dipivoxil. The ERG further noted that entecavir was not included as a comparator in the economic models and did not consider the justification of methodological concerns about indirect comparisons an adequate reason for not including this comparator. In addition, little account was taken of a possible better resistance profile of entecavir relative to telbivudine. There was no consideration given to alternative approaches to populating the model - in particular, the possibility of developing statistical risk models to address the sparsity of observed data from the GLOBE trial. Impacts of the so-called 'non-informative priors' on the economic results could not be adequately assessed by the ERG.

3.14 The ERG noted discrepancies in the calibration factors in the risk equations used for the compensated cirrhosis and hepatocellular carcinoma states in the original and resubmitted economic models and those listed in the appendices to the manufacturer's submission. In general, the ERG noted that the manufacturer's submission did not provide summaries of the model parameters, and there was an excessive reliance on visual basic coding, so it was difficult to ascertain which parameters had or had not been included in the economic analyses. Further, the ERG noted that the manufacturer's submission did not provide a discussion on the power of the GLOBE trial to detect statistically significant effects of treatment in the subgroup of patients with serum ALT levels greater than or equal to twice the upper limit of normal. Data used to populate the economic models were taken from this subgroup of patients. In addition, no information was provided on the baseline characteristics of this subgroup of patients.

3.15 The ERG carried out scenario analyses on the viral load model (with a 'non-informative prior' of 0.0) using non-constant age-specific utilities, increasing the proportion of cirrhotic patients at treatment initiation to 15% and applying model calibration factors (for risk of advanced liver disease). The cumulative effects of varying these parameters in HBeAg-positive disease gave an ICER of £16,100 per additional QALY gained. The corresponding ICER in HBeAg-negative disease was £26,200 per additional QALY gained. The ERG conducted scenario analyses on the seroconversion model assuming no treatment with telbivudine for people with decompensated liver disease, removing treatment-resistant patients from the denominators used to calculate transition probabilities for HBeAg seroconversion, increasing the proportion of cirrhotic patients at the start of treatment to 15% and assuming treated people with cirrhosis seroconvert at the same rate as people with treated non-cirrhotic chronic hepatitis B. The cumulative effects of varying these parameters gave an ICER of £8,400 per additional QALY gained.

3.16 The ERG conducted a PSA using the viral load model with a 'non-informative prior' of 0.0 only; replacing constant health state utilities with non-constant age-specific utilities and applying model calibration factors for risk of advanced liver disease. The effect of the ERG's PSA for the viral load model was to reduce the probability of telbivudine being cost effective for a given willingness to pay (cost effectiveness) threshold. The ERG also conducted a PSA using the seroconversion model; the results differed from the manufacturer's analysis in that over a cost effectiveness threshold of £20,000 to £25,000 per additional QALY, the optimal strategy in the ERG's analysis was lamivudine followed by adefovir whilst telbivudine was the optimal strategy in the manufacturer's PSA.

3.17 Full details of all the evidence are in the manufacturer's submission and the ERG report, which are available from www.nice.org.uk/TAxxx

4 Consideration of the evidence

4.1 The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of telbivudine for the treatment of chronic hepatitis B, having considered evidence on the nature of the condition and the value placed on the benefits of telbivudine by people with chronic hepatitis B, those who represent them, and clinical specialists. It was also mindful of the need to take account of the effective use of NHS resources.

4.2 The Committee discussed the decision problem and evidence presented in the manufacturer's submission. It discussed with the clinical specialists the importance and relevance of the various surrogate markers of both disease expression and response to treatment that may be used. The Committee was advised by the patient experts about the impact of hepatitis B on their quality of life and the importance of having a variety of treatments available. The Committee was also mindful of the long-term risk of progression to cirrhosis or hepatocellular carcinoma associated with chronic hepatitis B infection and the resulting impact in terms of costs, mortality and health-related quality of life. The Committee agreed that avoidance of these adverse consequences was the most important goal in the treatment of chronic hepatitis B and that the relationship between any surrogate endpoints measured in clinical studies and these outcomes should be taken fully into consideration.

4.3 The Committee was advised by the clinical specialists of the difference between HBeAg-positive and HBeAg-negative disease. It acknowledged that, in the main, rather than different infections, HBeAg-positive and -negative disease represent different stages of the infection because HBeAg-negative chronic hepatitis B most commonly develops when the virus that was originally suppressed following HBeAg/antibody seroconversion mutates and the infection re emerges from immune control. The Committee also understood that hepatitis in the HBeAg-negative phase of the disease carries a high risk of progression to cirrhosis or hepatocellular carcinoma. Therefore, it was important to maintain a low viral load in these patients.

4.4 The Committee was advised by the clinical specialists of the relative importance of different tests in the diagnosis and management of chronic hepatitis B and was persuaded that measurement of viral load (HBV DNA) is an important predictor of future liver damage and can be used to identify patterns of viral resistance to treatment. The specialists also confirmed that, in HBeAg-positive disease, reductions in HBV DNA levels by antiviral treatment may accelerate seroconversion. The Committee heard from the clinical specialists that in HBeAg-positive disease, seroconversion would be an indication that treatment could be stopped although current clinical practice is to continue for 6 months after seroconversion has been achieved. The Committee understood that this endpoint of treatment was not applicable to HBeAg-negative disease and that assessment of when to stop treatment was more difficult, and in many cases treatment would need to be lifelong. The clinical specialists stated that serum ALT levels were usually inversely correlated with HBV DNA levels and consequently serum ALT levels would be expected to normalise with a reduction in HBV DNA levels. The Committee also heard from the specialists that, in HBeAg-positive disease, the process of spontaneous HBeAg/antibody seroconversion is associated with high serum ALT levels and that high serum ALT alone, without histological evidence of liver disease, was not an indication for treatment. The Committee heard that it is current clinical practice to initiate antiviral treatment only on the basis of confirmed liver inflammation (via biopsy) irrespective of serum ALT levels, as reflected in the marketing authorisation of telbivudine.

4.5 The Committee considered the treatment options available for patients with chronic hepatitis B in the UK. The Committee discussed with the patient experts and clinical specialists the relevance of previous NICE guidance on chronic hepatitis B and where in the treatment pathway telbivudine should be considered. The Committee heard from the clinical specialists that telbivudine was most likely to be used in place of lamivudine in the treatment pathway. The Committee further considered evidence of the efficacy of telbivudine in the subgroup identified from the GLOBE trial population in the manufacturer's submission, of patients with serum ALT levels greater than or equal to twice the upper limit of normal. The Committee was advised by the clinical specialists that estimates of the efficacy of telbivudine in this subgroup were subject to some uncertainty because they were based on a post-hoc analysis, and randomisation was not stratified according to serum ALT levels. The Committee expressed concerns over the relevance of the GLOBE trial population to UK practice, but it was persuaded by the clinical specialists that the ethnic mix of the UK patient population was similar to that in the trial.

4.6 The Committee discussed the ERG critique of the efficacy results from the GLOBE trial, in particular concerns that health-related quality of life data were not reported. The Committee however concluded on the basis of the clinical evidence from the GLOBE trial and the testimonies from the clinical specialists and patient expert that telbivudine was likely to be more effective than lamivudine for several of the outcomes measured, notably the primary endpoint (suppression of HBV DNA to < 5 log10 copies/ml plus either clearance of detectable HBeAg or ALT normalisation). The Committee additionally noted that based on 2 year data there was a lower rate of viral resistance to treatment than seen with lamivudine. However the Committee noted that resistance to telbivudine was nevertheless likely to be problematic in the long term and that comparisons with treatment strategies involving the addition of other antivirals, such as adefovir dipivoxil, were the most appropriate for the evaluation of cost effectiveness.

4.7 The Committee discussed the economic analysis presented in the manufacturer's submission and the ERG's critique of the submission and the exploratory analyses undertaken by the ERG. In particular, the Committee discussed the complexity of the structure of the economic models used for the analysis presented. Although it acknowledged that the complexity of the natural history of the disease required a number of health states to be defined in the economic models, the Committee noted that the viral load model in particular involved such a large number of health states that the data available from clinical studies were not sufficient to support clearly the transition probabilities indicated. The Committee considered that this complexity resulted in a lack of transparency that undermined the validity of economic results and that the methods used to deal with the sparseness of the data had led to further uncertainty about the ICERs generated by the manufacturer's economic models.

4.8 The Committee noted that the manufacturer did not consider alternative approaches that might have reduced the complexity of the economic models, especially the viral load model and this, together with appropriate risk modelling, might have reduced the data requirements for populating the economic models. The Committee noted that the economic results generated by the viral load model appeared sensitive to the choice of 'priors' and noted that the manufacturer did not present any univariate sensitivity analyses that identified what the key drivers of cost effectiveness were in the viral load or seroconversion models.

4.9 Putting aside concerns about the complexity of the economic models, the Committee considered that the transparency of the models was reduced by the lack of detail provided in the manufacturer's submission about which parameters were used. The Committee had concerns about the focus of the economic analysis on a subset of the GLOBE trial population (specifically only those with serum ALT levels greater than or equal to twice the upper limit of normal), the lack of detail on the analyses used to generate data for the model, the lack of appropriate descriptions of the model parameters, the selection of comparators to telbivudine, and the face validity of economic results presented in the manufacturer's submission.

4.10 Overall, the Committee agreed that there was evidence that telbivudine was likely to be better than lamivudine in terms of clinical effectiveness and resistance profile. However, it did not agree with the manufacturer that the evidence presented on the cost effectiveness of telbivudine could be used as a reliable basis for decision-making. In light of the economic models and evidence presented, the Committee concluded that telbivudine, within its licensed indication, would not be a cost-effective use of NHS resources for the treatment of chronic hepatitis B.

5 Implementation

5.1 The Healthcare Commission assesses the performance of NHS organisations in meeting core and developmental standards set by the Department of Health in 'Standards for better health' issued in July 2004. The Secretary of State has directed that the NHS provides funding and resources for medicines and treatments that have been recommended by NICE technology appraisals normally within 3 months from the date that NICE publishes the guidance. Core standard C5 states that healthcare organisations should ensure they conform to NICE technology appraisals.

5.2 'Healthcare standards for Wales' was issued by the Welsh Assembly Government in May 2005 and provides a framework both for self-assessment by healthcare organisations and for external review and investigation by Healthcare Inspectorate Wales. Standard 12a requires healthcare organisations to ensure that patients and service users are provided with effective treatment and care that conforms to NICE technology appraisal guidance. The Assembly Minister for Health and Social Services issued a Direction in October 2003 that requires local health boards and NHS trusts to make funding available to enable the implementation of NICE technology appraisal guidance, normally within 3 months.

5.3 NICE has developed tools to help organisations implement this guidance (listed below). These are available on our website (www.nice.org.uk/TAXXX).

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

6 Related NICE guidance

Published

• Adefovir dipivoxil and peginterferon alfa-2a for the treatment of chronic hepatitis B. NICE technology appraisal guidance 96 (2006). Available from www.nice.org.uk/TA96

Under development

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

Entecavir for the treatment of chronic hepatitis B. NICE technology appraisal guidance (publication expected August 2008). Available from www.nice.org.uk/TAXXX

7 Proposed date for review of guidance

7.1 The review date for a technology appraisal refers to the month and year in which the Guidance Executive will consider whether the technology should be reviewed. This decision will be taken in the light of information gathered by the Institute, and in consultation with consultees and commentators.

7.2 It is proposed that the guidance on this technology is considered for review in February 2009. The review of the NICE technology appraisal guidance 96 (2006) on adefovir dipivoxil and peginterferon is scheduled for this date. The Institute would particularly welcome comment on this proposed date.

David Barnett
Chair, Appraisal Committee
March 2008

Appendix A: Appraisal Committee members and NICE project team

A  Appraisal Committee members

The Appraisal Committee is a standing advisory committee of the Institute. Its members are appointed for a 3-year term. A list of the Committee members who took part in the discussions for this appraisal appears below. The Appraisal Committee meets three times a month except in December, when there are no meetings. The Committee membership is split into three branches, each with a chair and vice chair. Each branch considers its own list of technologies, and ongoing topics are not moved between the branches.

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

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

Professor David Barnett
Professor of Clinical Pharmacology, University of Leicester

Dr David W Black
Director of Public Health, Derbyshire County PCT

Dr Carol Campbell
Senior Lecturer, University of Teesside

Dr Peter Clarke
Consultant Medical Oncologist, Clatterbridge Centre for Oncology

Dr Christine Davey
Senior Researcher, North Yorkshire Alliance R & D Unit

Dr Mike Davies
Consultant Physician, Manchester Royal Infirmary

Dr Dyfrig Hughes
Senior Research Fellow in Pharmacoeconomics, Centre for the Economics of Health and Policy in Health, University of Wales

Dr Catherine Jackson
Clinical Lecturer in Primary Care Medicine, Alyth Health Centre

Dr Peter Jackson
Clinical Pharmacologist, Sheffield Teaching Hospitals NHS Foundation Trust

Professor Peter Jones
Pro Vice Chancellor for Research & Enterprise, Keele University

Ms Rachel Lewis
Practice Development Facilitator, Manchester PCT

Professor Jonathan Michaels
Professor of Vascular Surgery, University of Sheffield

Dr Eugene Milne
Deputy Medical Director, North East Strategic Health Authority

Dr Simon Mitchell
Consultant Neonatal Paediatrician, St Mary's Hospital, Manchester

Dr Richard Alexander Nakielny
Consultant Radiologist, Royal Hallamshire Hospital, Sheffield

Dr Katherine Payne
Health Economics Research Fellow, University of Manchester

Dr Philip Rutledge
GP and Consultant in Medicines Management, NHS Lothian

Mr Miles Scott
Chief Executive, Bradford Teaching Hospitals NHS Foundation Trust

Dr Surinder Sethi
Consultant in Public Health Medicine, North West Specialised Services Commissioning Team

Professor Andrew Stevens
Chair of Appraisal Committee C

Mr William Turner
Consultant Urologist, Addenbrookes Hospital

B NICE project team

Each technology appraisal is assigned to a team consisting of one or more health technology analysts (who act as technical leads for the appraisal), a technical adviser and a project manager.
Ebenezer Tetteh
Technical Lead(s)
Janet Robertson
Technical Adviser
Chris Feinmann
Project Manager

Appendix B: Sources of evidence considered by the Committee

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

• Hartwell D et al. Telbivudine as treatment for chronic hepatitis B, February 2008

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

I Manufacturer/sponsor:

• Novartis Pharmaceuticals UK Ltd (telbivudine)

II Professional/specialist and patient/carer groups:

• Association of Clinical Microbiologists
• Association of Medical Microbiologists
• British Association for the Study of the Liver
• British Association for the Study of the Liver Nurses Forum (BASLNF)
• British Infection Society
• British Society of Gastroenterology
• Chinese National Healthy Living Centre
• Hepatitis B Foundation UK
• Royal College of Nursing
• Royal College of Pathologists
• Royal College of Physicians
• South Asian Health Foundation

III Other consultees

• Bury PCT
• Department of Health
• Welsh Assembly Government
• Worcestershire PCT

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

• Bristol-Myers Squibb Pharmaceuticals Ltd (entecavir)
• Department of Health, Social Services and Public Health Safety for Northern Ireland
• Gilead Sciences (adefovir dipivoxil)
• National Collaborating Centre for Women and Children's Health
• National Coordinating Centre for Health Technology Assessment
• NHS Quality Improvement Scotland
• Roche Products Limited (interferon alfa 2a, peginterferon alfa 2a)
• Schering-Plough Ltd (interferon alfa 2a, interferon alfa 2b)
• Southampton Health Technology Assessment Centre (SHTAC)

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

• Professor Howard Thomas, nominated by the British Society of Gastroenterologists - clinical specialist
• Dr Elizabeth Boxall, nominated by the Association of Clinical Microbiologists - clinical specialist
• Professor Geoffrey Dusheiko, nominated by the Royal College of Physicians - clinical specialist
• Penny Wilson Webb, nominated by Hepatitis B Foundation UK - patient expert
• Robert Windsor, nominated by Hepatitis B Foundation UK - patient expert