1                                Appraisal Committee?s preliminary recommendations

1.1                           The Committee is minded not to recommend infliximab within its licensed indication for the treatment of adults with moderate to severe plaque psoriasis.

1.2                           The Committee recommends that the Institute requests further clarification from the manufacturer of infliximab, which should be made available for the second Appraisal Committee meeting, on the following relevant issues.

·     The impact on cost effectiveness of infliximab compared with all relevant comparators of the use of alternative assumptions for the utilities assigned to the health states in the submitted economic model for the patient group defined as those with a PASI score of at least 10 and a DLQI score greater than 10. The utilities should be based on the short-form 36 (SF-36) data collected in the EXPRESS randomised controlled trial (RCT).

·     The impact on the cost-effectiveness analysis of infliximab compared with all relevant comparators of increasing the costs of administering infliximab infusions to better reflect clinical practice. This should take account of the difference in cost between a standard outpatient appointment and an appointment for an infliximab infusion. 

·     The estimated cost effectiveness, using the adjusted model resulting from the two previous bullet points, in a subgroup of patients with severity of disease equivalent to the 4th quartile dermatology life quality index (DLQI) population used in the submitted economic model. This should give consideration to the generalisability of the clinical results from the patient group defined as those with a PASI score of at least 10 and a DLQI score greater than 10 to the 4th quartile group.

2                                The technology

2.1                           Infliximab (Remicade, Schering-Plough) is indicated for the treatment of moderate to severe plaque psoriasis in adults whose condition has failed to respond to, or who have a contraindication to, or who are intolerant of other systemic therapy including ciclosporin, methotrexate, and psoralen and long-wave ultraviolet radiation (PUVA).

2.2                           The most common adverse events reported during infliximab therapy include acute infusion-related reactions, infections and delayed hypersensitivity reactions. Infliximab is contraindicated in people with moderate or severe heart failure and active infections. Before treatment is initiated, people must be screened for both active and inactive tuberculosis. The SPC lists a number of uncommon but serious adverse events related to the immunomodulatory activity. For full details of side effects and contraindications, see the SPC.

2.3                           Infliximab costs £419.62 per 100-mg vial (?British national formulary? [BNF] edition 53). It is given as a 5-mg/kg intravenous infusion over a 2-hour period followed by additional 5-mg/kg infusion doses at 2 and 6 weeks after the first infusion, then every 8 weeks thereafter. The average annual cost per patient is estimated to be £11,749.36 by the manufacturer. If no response is shown after 14 weeks, no additional treatment with infliximab should be given. 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 infliximab and a review of this submission by the Evidence Review Group (ERG; appendix B).

3.1                           The manufacturer based its evidence submission on the assessment report and model from ?Etanercept and efalizumab for the treatment of adults with psoriasis?, NICE technology appraisal guidance 103 (TA103). In this document these are referred to as the York report and the York model, respectively. The manufacturer stated that the population of interest should be people with a psoriasis area and severity index (PASI) score of at least 10 and a DLQI score of greater than 10 in line with the recommendations in TA103. The manufacturer compared infliximab with etanercept, efalizumab and supportive care. In TA103, etanercept is recommended for intermittent use in which treatment stops when remission is achieved. However, the manufacturer argued that in current clinical practice etanercept is used continuously and therefore continuous etanercept was a more appropriate comparator than intermittent etanercept.  

3.2                           The manufacturer identified four RCTs that compared infliximab with placebo: Chaudhari et al. (n = 33, 10-week duration), a phase III, randomised, double-blind, placebo-controlled trial based in the USA; SPIRIT (n = 249, 10-week duration, 30-week follow-up), a phase II induction safety and efficacy study based in the USA; and EXPRESS (n = 378, 10-week duration, 50-week follow-up) and EXPRESS II (n = 835, 10-week duration, 36-week follow-up), phase III multicentre, multinational, randomised, double-blind, placebo-controlled, parallel trials. No trials were identified that compared infliximab with the relevant comparators.

3.3                           The results of all four RCTs showed statistically significant improvements in the percentage of people with a PASI 75 (a 75% improvement in the PASI score) after 10 weeks with infliximab compared with placebo (relative risk [RR] 4.5, 14.9, 31 and 39.2, respectively). In the SPIRIT and EXPRESS and EXPRESS II studies, statistically significant improvements were also observed in the percentage of people with PASI 50 and PASI 90. In the EXPRESS and EXPRESS II studies, after week 24 the differences were no longer statistically significant, but the manufacturer attributed this to crossover.

3.4                           In the absence of any direct trials comparing infliximab to etanercept or efalizumab, the manufacturer carried out an indirect comparison using a meta-analysis and Bayesian hierarchical model. The manufacturer used data from four infliximab trials, four efalizumab trials and three etanercept trials. The pooled RR using a random effects model of 10-week data for infliximab resulted in an RR of 20.49 (95% confidence interval [CI] 16.28 to 25.37), indicating a statistically significant difference in favour of infliximab compared with placebo. The pooled RR calculated from the four trials of efalizumab was 7.41 (95% CI 5.96 to 9.09), indicating a statistically significant difference in favour of efalizumab compared with placebo. A similar result was found for 25-mg intermittent etanercept, with pooled data for the three trials of the drug giving an RR of 9.06 (95% CI 7.03 to 11.53).

3.5                           The manufacturer based its cost-effectiveness analysis on the York model. This was a two-state Markov model (the two states were on-treatment and off-treatment); alterations were made to include the new data from the infliximab studies. The rates of transitions between states in the model were informed by response rates and withdrawal rates from the RCTs. The economic analysis included comparisons with etanercept 25 mg, both intermittent and continuous, efalizumab and supportive care. There were no trials identified for continuous etanercept so the manufacturer used the RR for intermittent etanercept in subsequent analyses. The model had a 10-year time horizon and included a trial period after which treatment could be switched to efalizumab or supportive care if the patient?s condition had not responded to initial therapy (defined as achieving PASI 75). The cost and resource use data were obtained from the York report (inflated to present values), NHS reference costs and BNF 53, and were also supported by data that the manufacturer had on file and clinical opinion. The utility data were obtained from TA103. These utilities were based on values from etanercept trials that linked DLQI with PASI; a linear transformation was used to calculate Euro quality of life questionnaire (EQ-5D) scores. The manufacturer used a subgroup of the whole patient population, defined as the 4th quartile DLQI, for their base-case analysis. The manufacturer did not provide specific reasoning for focussing on the 4th quartile group; however the evidence presented suggested that this was in order to concentrate on patients with severe psoriasis. The 4th quartile group of patients is the 25% with the most severe scores on the DLQI.

3.6                           The manufacturer?s base-case analysis (4th quartile DLQI) against continuous etanercept resulted in a cost of £26,095 per quality-adjusted life year (QALY) gained. The incremental cost-effectiveness ratio (ICER) for infliximab compared with supportive care was £22,240 per QALY gained. The manufacturer carried out one-way sensitivity analyses. This demonstrated that changes in response rates and patient weight had the greatest impact on the ICER. The probabilistic sensitivity analysis (PSA) gives a probability of being cost effective at £20,000 and £30,000 thresholds of 10% and 73%, respectively.

3.7                           The manufacturer presented in an appendix an ICER compared with supportive care using the all patient utilities of £41,351 per QALY gained. The manufacturer did not present the ICER for infliximab compared with continuous etanercept. The PSA gives a probability of being cost effective at £30,000 threshold of 0%.

3.8                           The ERG had three main areas of concern over the modelling.

·     The ERG expressed concern regarding the reasoning behind the exclusive use of the 4th quartile DLQI utility values. This does not correspond to the total population in the decision problem (that is those with a PASI score of at least 10 and a DLQI score greater than 10) or the data used for the indirect clinical effectiveness estimation. The ERG indicated that since the manufacturer had chosen to present the ICER for the 4th quartile subgroup of the whole population, it would have been appropriate to also present corresponding figures for the remainder of the population to be considered in the decision problem.

·     The assumed annual drop-out rate in the model was considered by the ERG to be an underestimate because it was based on 6-month rather than annual data. The ERG postulated that the drop-out rate might be as high as 50%. This would result in the ICER against continuous etanercept increasing to approximately £37,000 per QALY gained.

·     The ERG considered that the cost of an inpatient stay might have been overestimated because it was based on an elective inpatient code rather than elective and non-elective codes with excess bed days incorporated. The cost of an inpatient day would be reduced from £6189 to £5091 using elective codes and to £5488 using a combination of codes for elective and non-elective admissions. Using a cost of £5091 would increase the ICER against continuous etanercept to approximately £30,000 per QALY gained.

3.9                           The ERG produced a cumulative scenario analysis in which all of the changes arising from the assumptions described in section 3.7 were combined. This increased the ICER of infliximab compared with continuous etanercept from £26,095 to approximately £41,000 per QALY gained when the drop out rate and inpatient costs were combined. When the all patient utility was included the ICER to increased to approximately £77,000 The ERG also extended the manufacturer?s PSA to include extra variables including annual drop-out rate, cost of infliximab, length of inpatient stay and number of outpatient visits. The combined result of these changes is to give an ICER of £33,200 and a 38% probability of being cost effective at a £30,000 threshold.

3.10                       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 infliximab for the treatment of adults with psoriasis, having considered evidence on the nature of the condition and the value placed on the benefits of infliximab by people with psoriasis, 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 nature of the effects of moderate to severe psoriasis on patients and the variability in the extent and fluctuations over time of the skin manifestations. In particular, the Committee understood that the effect of psoriasis on the quality of life of patients is related to both the degree of skin involvement and the body sites affected.

4.3                           The Committee considered the comparator technologies identified by the scope and decision problem, taking into account TA103 on the use of etanercept and efalizumab in the treatment of psoriasis. The Committee considered that the principal comparator should be etanercept, given intermittently in line with NICE guidance. The Committee noted, however, that according to the clinical specialists, the patient experts, the manufacturer and the ERG, etanercept is given continuously in routine UK clinical practice. The Committee was therefore persuaded that continuous etanercept was also an appropriate comparator.

4.4                           The Committee additionally accepted that for this single technology appraisal efalizumab when used in patients who do not respond to etanercept could not be considered an appropriate comparator to infliximab. However, for those patients in whom etanercept is contraindicated or who are intolerant to etanercept, efalizumab should be considered to be an appropriate comparator.

               Clinical effectiveness

4.5                           The Committee discussed the RCT evidence of infliximab compared with placebo in the treatment of psoriasis and concluded that the evidence supported a clinically important effect on both the extent of skin disease (reduction in PASI score) and the quality of life of patients with moderate to severe psoriasis. The Committee heard from the clinical specialists and patient experts that infliximab is an effective and rapidly acting treatment. 

4.6                           The Committee discussed the clinical effectiveness of infliximab compared with etanercept or efalizumab. It understood that there were no RCTs comparing infliximab directly with either etanercept or efalizumab. The Committee considered the indirect comparison compared with standard UK practice undertaken by the manufacturer. It accepted that there was sufficient clinical evidence to inform the decision model for an indirect comparison, as undertaken by the manufacturer. Nevertheless, the Committee noted that there was considerable uncertainty in interpreting the results of the indirect comparison due to heterogeneity between the trials used in the meta-analysis. In view of these uncertainties, the Committee was not able to conclude definitively whether or not infliximab is statistically significantly more clinically effective than intermittent etanercept or efalizumab. However, it heard from clinical specialists and patient experts that in clinical practice infliximab is associated with a higher response rate and a more rapid and longer-lasting response than alternative therapies with a comparable adverse effect profile. The Committee also accepted that due to the absence of RCT evidence to demonstrate any clinical difference between intermittent and continuous etanercept that it was reasonable to assume, as had been done in TA103, that there was no difference in clinical outcomes between continuous and intermittent. The Committee was therefore persuaded that infliximab could be more clinically effective than intermittent etanercept or efalizumab.

               Cost effectiveness

4.7                           The Committee discussed the input parameters used in the manufacturer?s model and base-case analysis. It considered that utility values based on patients in the more severe group (that is those with DLQI scores above the 4th quartile) were not representative of the broader population to be considered within the scope, the proposed decision problem and the clinical effectiveness evidence of the appraisal (that is those with a PASI score of at least 10 and a DLQI score greater than 10). The Committee noted that the ICER using the utilities for the broader patient group was £41,351 per QALY gained against standard care. The corresponding ICER compared with continuous etanercept was not presented, but the Committee thought it was likely to be higher than £41,351. This suggested that infliximab would not be a cost-effective use of NHS resources in the broader population. Additionally the Committee noted that the manufacturer did not use utilities based on the SF-36 data derived from the EXPRESS trial in its analysis. The Committee considered that it would be important to consider a cost-effectiveness analysis based on these data in conjunction with utility classification instrument such as the short form six dimensions (SF-6D). It concluded that clarification on this issue should be requested.

4.8                           The Committee considered that the manufacturer?s base case was represented by a subgroup with particularly severe disease as identified by selecting those in the 4th quartile of DLQI. The Committee was not persuaded that this very severe subgroup had been sufficiently defined (in terms of DLQI at baseline) or that it was reasonable to assume the same clinical response in this very severe group as in the whole population. Therefore the ICER of £26,095 was not considered a robust estimate of the cost effectiveness of infliximab compared with etanercept in the 4th quartile of DLQI subgroup. The Committee considered it would be more appropriate for the ICER for this more severely affected group to be estimated using SF-36 data from the EXPRESS RCT as a basis for utility assumptions. The Committee noted that it was not clear from the data submitted what DLQI score would be used in practice to identify the severely affected group. It concluded that clarification on these points should be requested.   

4.9                           The Committee considered the cost of administering infliximab. The cost of a standard outpatient visit was used in the economic model. The Committee heard from clinical specialists and patient experts that a 2-hour infusion was usually required, followed by a period of observation (of up to 1 hour). It understood that patients often need to spend at least half a day in hospital. The Committee did not consider the outpatient visit cost to be sufficient to reflect the true costs of administering the infusion and recommended that a more representative value should be used instead. Therefore the Committee requested that clarification should be sought on this issue.

4.10                       The Committee considered the cost effectiveness of infliximab compared to efalizumab for those patients in whom etanercept would be contraindicated or who would be intolerant to etanercept. It noted that the manufacturer had not provided ICERs of infliximab versus efalizumab for these patients, both in the all patient group and the 4^th quartile DLQI group and decided that clarification should be sought on this issue.

4.11                       In summary, the Committee concluded that it was minded not to recommend infliximab for the treatment of moderate to severe plaque psoriasis. It recommended that further clarification should be requested from the manufacturer to address the various areas of uncertainty in the economic analysis.

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 which 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). [NICE to amend list as needed at time of publication]

·       Slides highlighting key messages for local discussion.

·       Local costing template incorporating a costing report 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 criteria to monitor local practice.

6                                Proposed recommendations for further research

6.1                           The Committee made no recommendations for further research.

7                                Related NICE guidance

7.1                           NICE has issued the following related technology appraisal guidance.

·     Etanercept and efalizumab for the treatment of adults with psoriasis. NICE technology appraisal guidance 103 (2006). Available from: www.nice.org.uk/TA103

·     Etanercept and infliximab for the treatment of psoriatic arthritis. NICE technology appraisal guidance 104 (2006). Available from: www.nice.org.uk/TA104

8                                Proposed date for review of guidance

8.1                           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.

8.2                           It is proposed that the guidance on this technology is considered for review in August 2010. The Institute would particularly welcome comment on this proposed date.

David Barnett
Chair, Appraisal Committee
August 2007

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 twice a month except in December, when there are no meetings. The Committee membership is split into three branches, with the chair, vice-chair and a number of other members attending meetings of the three branches. 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 Keith Abrams
Professor of Medical Statistics, University of Leicester

Dr Jeff Aronson
Reader in Clinical Pharmacology, Radcliffe Infirmary, Oxford

Dr Darren Ashcroft
Senior Clinical Lecturer, School of Pharmacy and Pharmaceutical Sciences, University of Manchester

Professor David Barnett (Chair)
Professor of Clinical Pharmacology, University of Leicester

Dr Peter Barry
Consultant in Paediatric Intensive Care, Leicester Royal Infirmary

Professor Stirling Bryan
Director of the Health Economics Facility, University of Birmingham

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

Dr Mark Charkravarty
Head of Government Affairs and NHS Policy, Procter and Gamble Pharmaceuticals (UK)

Professor Jack Dowie
Health Economist, London School of Hygiene and Tropical Medicine

Ms Lynn Field
Nurse Director, Pan Birmingham Cancer Network

Professor Christopher Fowler
Professor of Surgical Education, University of London

Dr Fergus Gleeson
Consultant Radiologist, Churchill Hospital

Ms Sally Gooch
Former Director of Nursing & Workforce Development, Mid Essex Hospital Services NHS Trust

Mrs Barbara Greggains
Lay member

Mr Sanjay Gupta
Former Service Manager in Stroke, Gastroenterology, Diabetes and Endocrinology, Basildon and Thurrock University Hospitals Foundation NHS Trust

Dr Mike Laker
Medical Director, Newcastle Hospitals NHS Trust

Mr Terence Lewis
Mental Health Consultant, National Institute for Mental Health in England

Professor Gary McVeigh
Professor of Cardiovascular Medicine, Queens University, Belfast

Dr Ruairidh Milne
Senior Lecturer in Health Technology Assessment, National Coordinating Centre for Health Technology

Dr Neil Milner
General Medical Practitioner, Tramways Medical Centre, Sheffield

Dr Rubin Minhas
General Practitioner, Coronary Heart Disease Clinical Lead, Medway Primary Care Trust

Dr John Pounsford
Consultant Physician, North Bristol NHS Trust

Dr Rosalind Ramsay
Consultant Psychiatrist, Adult Mental Health Services, Maudsley Hospital, London

Dr Christa Roberts
UK Country Manager, Abbott Vascular

Dr Stephen Saltissi
Consultant Cardiologist, Royal Liverpool University Hospital

Dr Lindsay Smith
General Practitioner, East Somerset Research Consortium

Mr Roderick Smith
Director of Finance, West Kent Primary Care Trust

Mr Cliff Snelling
Lay member

Professor Ken Stein
Professor of Public Health, Peninsula Technology Assessment Group (PenTAG), University of Exeter

Professor Andrew Stevens
Professor of Public Health, University of Birmingham

Dr Rod Taylor
Associate Professor in Health Services Research, Peninsula Medical School, Universities of Exeter and Plymouth

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.

Prashanth Kandaswamy and Nicola Hay
Technical Leads

Helen Chung
Technical Adviser

Reetan Patel
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 Assessment Centre, University of Southampton:

                  Loveman E, Turner D, Hartwell D et al. Infliximab for the treatment of adults with psoriasis (July, 2007)

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 gave their expert views on infliximab by providing a written statement to the Committee. Organisations listed in I and II have the opportunity to appeal against the final appraisal determination.

I                 Manufacturer/sponsor:

·               Schering-Plough

II               Professional/specialist and patient/carer groups:

·               Psoriasis Association

·               Psoriatic Arthropathy Alliance

·               British Association of Dermatologists

·               British Dermatological Nursing Group 

·               Primary Care Dermatology Society

·               Primary Care Rheumatology Society

·               Royal College of General Practitioners

·               Royal College of Nursing

·               Royal College of Paediatrics and Child Health

·               Royal College of Physicians

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

·               British National Formulary

·               Department of Health, Social Services and Public Safety for Northern Ireland

·               Medicines and Healthcare products Regulatory Agency (MHRA)

·               NHS Quality Improvement Scotland

·               Serono (efalizumab)

·               Wyeth (etanercept, methotrexate)

·               Novartis (ciclosporin)

·               Bristol Myers Squibb (hydroxycarbamide)

·               Cochrane Skin Group (Centre of Evidence Based Dermatology, University of Nottingham)

·               National Coordinating Centre for Health Technology Assessment

·               Southampton Health Technology Assessment Centre, University of Southampton

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 infliximab by attending the initial Committee discussion and providing written evidence to the Committee. They are invited to comment on the ACD.

·               Dr Chris Griffiths, nominated by the Royal College of Physicians ? clinical specialist

·               Professor Jonathan Barker, nominated by the British Association of Dermatologists ? clinical specialist

·               Mrs Karina Jackson, nominated by the British Dermatological Nursing Group ? clinical specialist

·               Ms Gladys Edwards, nominated by the Psoriasis Association ? patient expert

·               Mr Ray Jobling, nominated by the Psoriasis Association ? patient expert