An economic evaluation of positron emission tomography (PET) and positron emission tomography/computed tomography (PET/CT) for the diagnosis of breast cancer recurrence

Identifying studies

Prevalence data

We populated the decision model with the prevalence estimated in the meta-analysis of the systematic review carried out by Pennant et al. 17 We estimated an average of the whole-body prevalence values reported in the study for use in the model. 17 However, the data reported in the review were noted to be variable and, whereas in the base case we use an estimated prevalence of 0.69, the range in the literature was from 0.19 to 0.93 (Table 1). We explored the effect of the wide range on prevalence in the sensitivity analysis. The distribution associated with the 95% CI is explored in the probabilistic sensitivity analysis.

Test accuracy data

Test accuracy data used in the model-based economic evaluation are based on the values estimated by the authors of the clinical systematic review. 17 The most reliable results from the systematic review are the relative sensitivity and specificity of the test, but these could not be accommodated in the model, which requires absolute sensitivity and specificity. The choice of which accuracy estimates are used as parameters is therefore likely to have an impact on the cost-effectiveness estimates.

The sensitivity and specificity of PET (see Table 1, row 1) of 91% and 86%, respectively, are estimated by the review authors from an indirect comparison between PET and conventional work-up (referred to as conventional imaging in their report) and presented in Table 8 (row 2) of that report. 17 The relevant tables from Pennant et al. 17 are presented in Appendix 2.2.

The sensitivity and specificity of PET/CT (see Table 1, row 2) of 95% and 89%, respectively, are also estimated by indirect comparison between PET/CT and conventional work-up and are presented in Table 11 (row 2) of Pennant et al. 17

The sensitivity and specificity of conventional work-up (see Table 1, row 3) of 80% and 76%, respectively, have been derived by the current authors for use in the economic model from data presented by Pennant et al. ,17 and have not been estimated by the review authors. The sensitivity of conventional work-up is based on an average of 81% and 78%. Eighty-one per cent is the sensitivity of conventional work-up [referred to as conventional imaging test (CIT)] estimated as an indirect comparison of PET versus conventional work-up in Table 8 of the report by Pennant et al. 17 Seventy-eight per cent is the sensitivity of CIT estimated as an indirect comparison of PET/CT versus conventional work-up, presented in Table 11 of the report by Pennant et al. 17 The conventional work-up in these two tables (i.e. Tables 8 and 11 of Pennant et al. 17) is based on slightly different techniques, which is why an average of the two is used. The specificity estimate of 76% is an average of 73% and 79% from the same tables (8 and 11 respectively), for the reasons given above.

The sensitivity and specificity of PET/CT as an adjunct to conventional work-up (see Table 1, row 4) have also been derived by the current authors. We assumed that the overall result would be positive if either test is positive on its own. As a result of this rule, the sensitivity increases as a result of combining the two tests – as all individual patients who test positive on either (but not necessarily both) test are considered a potential positive case. This very interpretation means that there will be more false-positives, and so the specificity of the combined test is necessarily lower than the specificity of either test individually. In the base case, we assumed that testing errors were statistically independent between the two tests. Then the specificity of the combined test is simply the product of the two individual test specificities: in the base case, this becomes 0.89 × 0.76 = 0.68, while for the sensitivity (sens) we have the formula

which can be rearranged to give

where CW refers to conventional work-up. In the base case, this gives a combined sensitivity of (0.95 + 0.80) – (0.95 × 0.80) = 0.99. For probabilistic sensitivity analysis, we preserved the relationship between these characteristics by sampling the test characteristics for PET/CT and conventional work-up separately, and then calculating the test characteristics for the combined test using the methods just described. The methods we have used have been used elsewhere53–55 and are referred to by some authors as the ‘either positive rule’. 55

In the sensitivity analysis, we considered the situation in which the sensitivity of the test increases, as per the base case, but we assumed that these additional positive cases were ‘true-positives’ and so we maintained the specificity at the level estimated for conventional work-up alone – for which the value is 0.76.

The data presented in Table 1 require a number of cautionary explanations. First, the number of indirect comparisons described above is necessary to estimate accuracy data, because the systematic review of accuracy studies found no studies that had made the relevant direct comparison. 17 For instance, an indirect comparison was used to estimate the accuracy data for conventional work-up (see Table 1, row 3) because there are no primary studies comparing PET/CT with conventional work-up.

Second, when PET and PET/CT are introduced into clinical practice, it would be a fair assumption, that their introduction is in the role of an adjunct to conventional management (referred to as conventional work-up in the current study) in clinical practice. Therefore, to many familiar with this sort of technology, the data in rows 1 and 2 of Table 1 would be assumed to represent the diagnostic tests of both PET and PET/CT as an adjunct to the conventional work-up. However, it was very apparent to Pennant et al. ,19 who had scrutinised the papers in their review, that the tests reported in the papers had been introduced not as an adjunct, but as a replacement. It was apparently clear in these studies that previous test results were not consulted or considered in the interpretation of the PET and PET/CT results. Hence, we present these data (see Table 1, rows 1–3) as representing the accuracy of the individual test alone, and we derived the data presented in Table 1, row 4, in which the accuracy of PET/CT is combined with conventional work-up to represent the strategy of PET/CT as an adjunct to conventional work-up.

It was also noted by Pennant et al. 19 that PET as a strategy was never really introduced into clinical practice, it was soon subsumed by PET/CT, and so for this reason we carried out a sensitivity analysis in which PET as a single strategy was removed from the analysis.

Costs and resource data

The costs of resources utilised were those that were directly incurred by the NHS. Resources included were the costs of the index, confirmatory tests and blood tests, and treatment costs. Costs that were not considered were those incurred during the primary diagnosis and the treatment of breast cancer. Costs for long-term and end-of-life care were also not included. As stated earlier, recurrence is assumed to occur once only. Diagnostic procedure costs were taken from published sources. Cost estimates for PET were taken from Jacklin et al. ,51 and were adjusted to 2008 prices by the use of the Hospital and Community Health Services combined pay and price inflation index. 56 Estimated costs for conventional work-up included costs of ultrasound, bone scintigraphy, radiography, CT and measurement of serum tumour markers. These cost data were taken from the NHS national schedule for reference costs 2002–3,57 2007–858 and published sources. 59 As a result of a paucity of cost-effectiveness studies comparing PET/CT as an adjunct to conventional work-up, we assumed an additive procedural cost of PET/CT as an adjunct to conventional work-up as shown in Table 2. All costs were adjusted to 2007–8 prices and not discounted as the time period of the model was 1 year.

The treatment cost presented in Table 2 is based on an estimate of the most cost-effective treatment strategy estimated in a study reported by NICE which presents estimates of costs for treatment received by patients with confirmatory diagnosis of breast cancer recurrence. 52 The authors of the NICE report conducted an economic evaluation to determine the most cost-effective treatment strategy for breast cancer using chemotherapy. The treatment cost used in the current model is based on the treatment cost for the most cost-effective strategy (strategy 14) in their results. 52 The assumptions regarding population, treatment, survival and cost estimation upon which their analysis is based are presented in Appendix 2.1. The authors concluded that docetaxel (monotherapy) used as a first-line treatment followed by capecitabine (monotherapy) as a second-line treatment then ‘no chemotherapy’ (supportive and palliative care) as a final treatment was the most cost-effective strategy at the £20,000 threshold. The treatment cost for this strategy was £18,118 in 2007 prices. This estimate was updated to £18,643 in 2008 prices using the Hospital and Community Health Services combined pay and price inflation index. 56

Outcomes

We used three different effectiveness/outcome measures in the model.

Analysis

The decision tree model was constructed and programmed to select the base-case model input parameters. The model estimated the mean cost associated with each diagnostic procedure and assumed that patients entering the model would be aged 50–75 years.

The results of the cost-effectiveness analysis are presented in terms of the incremental cost-effectiveness ratios (ICERs). It was appropriate to use this method of presentation as it gives the benefit associated with an additional cost per QALY. The base-case analysis is based on a number of outcomes. The primary outcome is cost per QALY, but secondary outcome measures of case of recurrent cancer appropriately diagnosed and treated and cost per diagnostic error avoided are also considered.

A deterministic analysis was carried out for the base-case results for the primary and secondary outcome measures.

In addition, a number of sensitivity analyses were required, and these have been highlighted where appropriate during the description of the data. The sensitivity analyses that we carried out are summarised below:

1. Threshold-focused sensitivity analyses were carried out, deterministically, to establish the critical values for the cost and accuracy of PET/CT that could change deterministic results in terms of the ICERs, in such a way that might affect the decisions of policy-makers.

2. A deterministic sensitivity analysis was carried out on the extreme values in the range of prevalence (0.19–0.93) found in the systematic review by Pennant et al. 17

3. In response to the ‘either positive rule’ used in the base case for the derivation of the sensitivity and specificity for the strategy of PET/CT as an adjunct to conventional work-up, we carried out a deterministic analysis using the derived sensitivity which was used in the base case, but instead of using the derived specificity value used in the base case of 0.68, which was necessarily low to reflect increased number of false-positives, we used the specificity for conventional work-up alone (value 0.76) to explore the assumption that the additional cases detected were in fact true-positive (0.76 is the lower of the two specificities for the tests being combined).

4. It was clear to the authors of the accuracy review17 that PET alone was never introduced into clinical practice, so we carry out sensitivity analysis which removes this diagnostic strategy from the base case.

Probabilistic sensitivity analysis was undertaken to determine the uncertainty of the model input parameters of prevalence, sensitivity and specificity, treatment costs and expected QALYs. We carried out probabilistic sensitivity analysis based on an outcome of cost per QALY only. In probabilistic sensitivity analysis, each model parameter is assigned a distribution reflecting the amount and pattern of its variation, and cost-effectiveness results are calculated by simultaneously selecting random values from each distribution. The process is repeated 10,000 times in a Monte Carlo simulation of the model to give an indication of how variation in the model parameters leads to variation in the ICERs for a given test combination. The appropriate distribution for the data on test accuracy (sensitivity and specificity) and prevalence is a beta distribution. The beta and normal distributions that were used in the probabilistic sensitivity analysis are presented in Appendix 2.3.

For the cost and effectiveness of treatment, only point estimates were available from the report. 52 For the purpose of probabilistic sensitivity analysis, we placed independent normal distributions around each figure, taking the standard deviation to be 0.1 times the mean. This assumption ensures that both cost and QALY outcomes will remain positive. Given the arbitrary nature of this assumption, we also carried out probabilistic sensitivity analysis in which these values were fixed at the point estimates.

Threshold analysis to find a value for cost and positron emission tomography/computed tomography test accuracy at which positron emission tomography/computed tomography might be considered cost-effective

Changing the prevalence to use the extreme values of the range identified in the literature review

Two analyses, the first using the upper and the second using the lower limit from the range (0.93–0.19) of prevalence estimates identified by the clinical literature review, were used in the model to see the impact on the ICERs. 17 Reducing the prevalence increased the ICERs and, thus, reduced cost-effectiveness, while increasing the prevalence had the effect of improving the ICERs, but only slightly under the base-case values.

Changing the specificity of positron emission tomography/computed tomography as an adjunct to conventional work-up to 0.76

The effect of changing the specificity when PET/CT is used as an adjunct to conventional work-up, from the base case of 0.68 (calculated according to the ‘either positive rule’) to 0.76, the value representing the lowest for either of the two individual tests – represented by the specificity of conventional work-up. The change makes no difference to the results and, as before (sensitivity analysis 1b, Table 6), this may be related to the assumption about biopsy.

Omitting positron emission tomography from the analysis

Removing PET from the analysis provides a direct comparison between PET/CT and conventional work-up. Exploring the impact on this is important because, in practice, it appears that the use of PET has not been implemented at all. The removal of PET from the analysis produces an ICER for PET/CT versus conventional work-up of £29,700 per QALY. Compared with the base-case results, this ICER represents a weighted average of the ‘ICER for PET/CT versus PET’ and the ‘ICER for PET versus conventional work-up’ as expected.

Given the increasingly clear irrelevance of PET in the reviews of the clinical literature,17 the strategy of PET/CT versus PET should be interpreted with some scepticism as to its meaning, as PET alone is not really used in practice. The ICER for the comparison of PET/CT versus conventional work-up is calculated by taking the weighted average of the ICER of PET/CT versus PET and the ICER of PET versus conventional work-up. Thus, the results for such a comparison would be only slightly different from that presented in the middle column of results for Table 6 (PET/CT vs PET), and can be estimated intuitively. As a result, the analysis for PET/CT versus conventional work-up has not been repeated for all the items explored in the sensitivity analysis.

Database: EMBASE 1980 to week 22 2009

1. exp emission tomography/ (64,606)

2. exp whole body imaging/or whole body ct/or whole body pet/ (3384)

3. (positron adj2 emission adj2 tomograph$).tw. (21,306)

4. (emission adj2 comput$adj2 tomograph$).tw. (9371)

5. (radionuclide adj2 cat scan$).tw. (3)

6. (radionuclide adj2 ct scan$).tw. (22)

7. (radionuclide-comput$adj2 tomograph$).tw. (12)

8. (scintigraph$adj2 comput$adj2 tomograph$).tw. (332)

9. (tomograph$adj2 emission adj2 comput$).tw. (9601)

10. (pet or petct).tw. (29,731)

11. or/1-10 (75,284)

12. exp breast cancer/ (154,137)

13. exp breast tumor/ (161,246)

14. (breast$adj5 (cancer$or carcinoma$or adenocarcinoma$or carcinogen$or sarcoma$or malignan$or tumo?r$or neoplas$)).tw. (128,069)

15. or/12-14 (177,409)

16. 11 and 15 (2224)

17. (recur$or relaps$or metasta$or restag$or re-stag$).mp. (529,809)

18. 16 and 17 (1096)

19. from 18 keep 1-1000 (1000)

Database: Ovid MEDLINE(R) 1950 to week 5 May 2009

1. exp tomography, emission-computed/ (53,082)

2. (emission adj2 comput$adj2 tomograph$).tw. (9756)

3. (tomograph$adj2 emission adj2 comput$).tw. (9987)

4. (radionuclide-comput$adj2 tomograph$).tw. (19)

5. (radionuclide adj2 cat scan$).tw. (4)

6. (radionuclide adj2 ct scan$).tw. (29)

7. (scintigraph$adj2 comput$adj2 tomograph$).tw. (373)

8. (positron adj2 emission adj2 tomograph$).tw. (21,497)

9. (pet or petct).tw. (30,376)

10. or/1-9 (66,222)

11. exp breast neoplasms/ (162,938)

12. (breast$adj5 (cancer$or carcinoma$or adenocarcinoma$or carcinogen$or sarcoma$or malignan$or tumo?r$or neoplas$)).tw. (149,549)

13. or/11-12 (191,686)

14. 10 and 13 (1433)

15. from 14 keep 1-1000 (1000)

Database: EMBASE May 2009 to week 4 April 2010

1. exp emission tomography/ (72,363)

2. exp whole body imaging/or whole body ct/or whole body pet/ (3920)

3. (positron adj2 emission adj2 tomograph$).tw. (23,570)

4. (emission adj2 comput$adj2 tomograph$).tw. (10,282)

5. (radionuclide adj2 cat scan$).tw. (3)

6. (radionuclide adj2 ct scan$).tw. (22)

7. (radionuclide-comput$adj2 tomograph$).tw. (12)

8. (scintigraph$adj2 comput$adj2 tomograph$).tw. (348)

9. (tomograph$adj2 emission adj2 comput$).tw. (10,623)

10. (pet or petct).tw. (33,611)

11. or/1-10 (84,228)

12. exp breast cancer/ (167,175)

13. exp breast tumor/ (175,984)

14. (breast$adj5 (cancer$or carcinoma$or adenocarcinoma$or carcinogen$or sarcoma$or malignan$or tumo?r$or neoplas$)).tw. (139,514)

15. or/12-14 (193,763)

16. 11 and 15 (2633)

17. (recur$or relaps$or metasta$or restag$or re-stag$).mp. (575,047)

18. 16 and 17 (1321)

19. limit 18 to yr=“2009 -Current” (257)

20. from 19 keep 1-257 (257)

Database: Ovid MEDLINE(R) May 2009 to week 4 April 2010

1. exp tomography, emission-computed/ (57,549)

2. (positron adj2 emission adj2 tomograph$).tw. (23,435)

3. (emission adj2 comput$adj2 tomograph$).tw. (10,528)

4. (radionuclide adj2 cat scan$).tw. (4)

5. (radionuclide adj2 ct scan$).tw. (29)

6. (radionuclide-comput$adj2 tomograph$).tw. (19)

7. (scintigraph$adj2 comput$adj2 tomograph$).tw. (387)

8. (tomograph$adj2 emission adj2 comput$).tw. (10,852)

9. (pet or petct).tw. (33,726)

10. or/1-9 (71,942)

11. exp breast neoplasms/ (172,296)

12. (breast$adj5 (cancer$or carcinoma$or adenocarcinoma$or carcinogen$or sarcoma$or malignan$or tumo?r$or neoplas$)).tw. (159,884)

13. or/11-12 (203,535)

14. 10 and 13 (1622)

15. (recur$or relaps$or metasta$or restag$or re-stag$).mp. (671,924)

16. 14 and 15 (832)

17. limit 16 to yr=“2009 -Current” (107)

18. from 17 keep 1-107 (107)

Beta distributions

Normal distributions

Background

Breast cancer is a serious life-threatening disease. Treatment options have developed significantly over the past decade and have affected survival. Inevitably, recurrence of breast cancer has increased and its diagnosis is important, as early appropriate treatment also has small but clear associated advantage for survival.

Breast cancer recurrence may be local (in the breast), regional (lymph nodes, collar bone, etc., same side of body as original cancer) or distant (in other body tissues such as bone, liver, lungs and brain), and is associated with symptoms such as weight loss, abdominal pain, respiratory symptoms, bone pain and neurological signs. Women with a past history of breast cancer may present with symptoms that may be innocent or the first indication of recurrence. The nature of these symptoms will dictate the nature of the investigation, but tests will often include bone scans, chest X-rays, CT scans and ultrasound.

Positron emission spectroscopy and, more recently, PET/CT are new tools that may be used to diagnose breast cancer recurrence. These technologies trace radioactive isotopes in the body. Isotopes of glucose, most commonly fluorodeoxyglucose, are used for the detection of tumours as glucose is taken up and retained in tumour tissue, making it visible in PET images.

As well as exploring whether PET/CT is more effective than conventional diagnostic strategies and PET alone, there is a need to investigate and establish its relative cost-effectiveness in the diagnosis of breast cancer recurrence.

Objectives

This study aims to explore the cost-effectiveness of PET/CT in the diagnosis and treatment of breast cancer recurrence by modelling the relative costs and benefits accruing from the use of PET/CT as replacement to PET, as well as a replacement for, or in addition to, conventional work-up involving conventional X-rays, CT, ultrasound, bone scintigraphy and measurement of serum tumour markers.

Population

As in the main report,1 the population to be studied are patients with a history of breast cancer who have previously been treated for primary disease and are under investigation for the diagnosis of recurrence or secondary metastases (distinct from the primary disease).

Index tests and reference standard

The index test under assessment is PET/CT. It may be used in addition to standard tests, e.g. in combination with clinical examination/bone scanning, etc., and also instead of standard tests. Studies in which whole-body PET/CT is conducted as well as studies using only breast imaging may be considered. The reference standard used to define the true disease status of patients may be histological diagnosis (operation/biopsy) or clinical follow-up/autopsy findings.

Comparators

The study will set out to compare the costs and benefits associated with the use of PET/CT:

• as a replacement for PET

• as a replacement for conventional work-up consisting of ultrasound, bone scintigraphy, X-rays, CT and measurement or serum tumour markers

• as a supplement to conventional work-up.

It is noted that, although PET scanners have ceased to be produced and can be found only in a limited number of hospitals, it is possible to carry out PET testing in isolation by using PET/CT scanners. The uncertainty on whether a comparison between PET and PET/CT is policy relevant will be explored further and this will be taken into account in possible changes in the study comparators.

Methods

Prioritisation Group

1. Director, NIHR HTA programme, Professor of Clinical Pharmacology, University of Liverpool

2. Professor Imti Choonara, Professor in Child Health, Academic Division of Child Health, University of Nottingham

   Chair – Pharmaceuticals Panel

3. Dr Bob Coates, Consultant Advisor – Disease Prevention Panel

4. Dr Andrew Cook, Consultant Advisor – Intervention Procedures Panel

5. Dr Peter Davidson, Director of NETSCC, Health Technology Assessment

6. Dr Nick Hicks, Consultant Adviser – Diagnostic Technologies and Screening Panel, Consultant Advisor–Psychological and Community Therapies Panel

7. Ms Susan Hird, Consultant Advisor, External Devices and Physical Therapies Panel

8. Professor Sallie Lamb, Director, Warwick Clinical Trials Unit, Warwick Medical School, University of Warwick

   Chair – HTA Clinical Evaluation and Trials Board

9. Professor Jonathan Michaels, Professor of Vascular Surgery, Sheffield Vascular Institute, University of Sheffield

   Chair – Interventional Procedures Panel

10. Professor Ruairidh Milne, Director – External Relations

11. Dr John Pounsford, Consultant Physician, Directorate of Medical Services, North Bristol NHS Trust

    Chair – External Devices and Physical Therapies Panel

12. Dr Vaughan Thomas, Consultant Advisor – Pharmaceuticals Panel, Clinical

    Lead – Clinical Evaluation Trials Prioritisation Group

13. Professor Margaret Thorogood, Professor of Epidemiology, Health Sciences Research Institute, University of Warwick

    Chair – Disease Prevention Panel

14. Professor Lindsay Turnbull, Professor of Radiology, Centre for the MR Investigations, University of Hull

    Chair – Diagnostic Technologies and Screening Panel

15. Professor Scott Weich, Professor of Psychiatry, Health Sciences Research Institute, University of Warwick

    Chair – Psychological and Community Therapies Panel

16. Professor Hywel Williams, Director of Nottingham Clinical Trials Unit, Centre of Evidence-Based Dermatology, University of Nottingham

    Chair – HTA Commissioning Board

    Deputy HTA Programme Director

HTA Commissioning Board

1. Professor of Dermato-Epidemiology, Centre of Evidence-Based Dermatology, University of Nottingham

2. Professor of General Practice, Department of Primary Health Care, University of Oxford Programme Director,

3. Professor of Clinical Pharmacology, Director, NIHR HTA programme, University of Liverpool

1. Professor Ann Ashburn, Professor of Rehabilitation and Head of Research, Southampton General Hospital

2. Professor Deborah Ashby, Professor of Medical Statistics and Clinical Trials, Queen Mary, Department of Epidemiology and Public Health, Imperial College London

3. Professor Peter Brocklehurst, Director, National Perinatal Epidemiology Unit, University of Oxford

4. Professor John Cairns, Professor of Health Economics, London School of Hygiene and Tropical Medicine

5. Professor Peter Croft, Director of Primary Care Sciences Research Centre, Keele University

6. Professor Jenny Donovan, Professor of Social Medicine, University of Bristol

7. Professor Jonathan Green, Professor and Acting Head of Department, Child and Adolescent Psychiatry, University of Manchester Medical School

8. Professor John W Gregory, Professor in Paediatric Endocrinology, Department of Child Health, Wales School of Medicine, Cardiff University

9. Professor Steve Halligan, Professor of Gastrointestinal Radiology, University College Hospital, London

10. Professor Freddie Hamdy, Professor of Urology, Head of Nuffield Department of Surgery, University of Oxford

11. Professor Allan House, Professor of Liaison Psychiatry, University of Leeds

12. Dr Martin J Landray, Reader in Epidemiology, Honorary Consultant Physician, Clinical Trial Service Unit, University of Oxford

13. Professor Stephen Morris, Professor of Health Economics, University College London, Research Department of Epidemiology and Public Health, University College London

14. Professor E Andrea Nelson, Professor of Wound Healing and Director of Research, School of Healthcare, University of Leeds

15. Professor John David Norris, Chair in Clinical Trials and Biostatistics, Robertson Centre for Biostatistics, University of Glasgow

16. Dr Rafael Perera, Lecturer in Medical Statisitics, Department of Primary Health Care, University of Oxford

17. Professor James Raftery, Chair of NETSCC and Director of the Wessex Institute, University of Southampton

18. Professor Barney Reeves, Professorial Research Fellow in Health Services Research, Department of Clinical Science, University of Bristol

19. Professor Martin Underwood, Warwick Medical School, University of Warwick

20. Professor Marion Walker, Professor in Stroke Rehabilitation, Associate Director UK Stroke Research Network, University of Nottingham

21. Dr Duncan Young, Senior Clinical Lecturer and Consultant, Nuffield Department of Anaesthetics, University of Oxford

1. Dr Morven Roberts, Clinical Trials Manager, Health Services and Public Health Services Board, Medical Research Council

HTA Clinical Evaluation and Trials Board

1. Director, Warwick Clinical Trials Unit, Warwick Medical School, University of Warwick and Professor of Rehabilitation, Nuffield Department of Orthopaedic, Rheumatology and Musculoskeletal Sciences, University of Oxford

2. Professor of the Psychology of Health Care, Leeds Institute of Health Sciences, University of Leeds

3. Director, NIHR HTA programme, Professor of Clinical Pharmacology, University of Liverpool

1. Professor Keith Abrams, Professor of Medical Statistics, Department of Health Sciences, University of Leicester

2. Professor Martin Bland, Professor of Health Statistics, Department of Health Sciences, University of York

3. Professor Jane Blazeby, Professor of Surgery and Consultant Upper GI Surgeon, Department of Social Medicine, University of Bristol

4. Professor Julia M Brown, Director, Clinical Trials Research Unit, University of Leeds

5. Professor Alistair Burns, Professor of Old Age Psychiatry, Psychiatry Research Group, School of Community-Based Medicine, The University of Manchester & National Clinical Director for Dementia, Department of Health

6. Dr Jennifer Burr, Director, Centre for Healthcare Randomised trials (CHART), University of Aberdeen

7. Professor Linda Davies, Professor of Health Economics, Health Sciences Research Group, University of Manchester

8. Professor Simon Gilbody, Prof of Psych Medicine and Health Services Research, Department of Health Sciences, University of York

9. Professor Steven Goodacre, Professor and Consultant in Emergency Medicine, School of Health and Related Research, University of Sheffield

10. Professor Dyfrig Hughes, Professor of Pharmacoeconomics, Centre for Economics and Policy in Health, Institute of Medical and Social Care Research, Bangor University

11. Professor Paul Jones, Professor of Respiratory Medicine, Department of Cardiac and Vascular Science, St George‘s Hospital Medical School, University of London

12. Professor Khalid Khan, Professor of Women’s Health and Clinical Epidemiology, Barts and the London School of Medicine, Queen Mary, University of London

13. Professor Richard J McManus, Professor of Primary Care Cardiovascular Research, Primary Care Clinical Sciences Building, University of Birmingham

14. Professor Helen Rodgers, Professor of Stroke Care, Institute for Ageing and Health, Newcastle University

15. Professor Ken Stein, Professor of Public Health, Peninsula Technology Assessment Group, Peninsula College of Medicine and Dentistry, Universities of Exeter and Plymouth

16. Professor Jonathan Sterne, Professor of Medical Statistics and Epidemiology, Department of Social Medicine, University of Bristol

17. Mr Andy Vail, Senior Lecturer, Health Sciences Research Group, University of Manchester

18. Professor Clare Wilkinson, Professor of General Practice and Director of Research North Wales Clinical School, Department of Primary Care and Public Health, Cardiff University

19. Dr Ian B Wilkinson, Senior Lecturer and Honorary Consultant, Clinical Pharmacology Unit, Department of Medicine, University of Cambridge

1. Ms Kate Law, Director of Clinical Trials, Cancer Research UK

2. Dr Morven Roberts, Clinical Trials Manager, Health Services and Public Health Services Board, Medical Research Council

Diagnostic Technologies and Screening Panel

1. Scientific Director of the Centre for Magnetic Resonance Investigations and YCR Professor of Radiology, Hull Royal Infirmary

2. Professor Judith E Adams, Consultant Radiologist, Manchester Royal Infirmary, Central Manchester & Manchester Children’s University Hospitals NHS Trust, and Professor of Diagnostic Radiology, University of Manchester

3. Mr Angus S Arunkalaivanan, Honorary Senior Lecturer, University of Birmingham and Consultant Urogynaecologist and Obstetrician, City Hospital, Birmingham

4. Dr Stephanie Dancer, Consultant Microbiologist, Hairmyres Hospital, East Kilbride

5. Dr Diane Eccles, Professor of Cancer Genetics, Wessex Clinical Genetics Service, Princess Anne Hospital

6. Dr Trevor Friedman, Consultant Liason Psychiatrist, Brandon Unit, Leicester General Hospital

7. Dr Ron Gray, Consultant, National Perinatal Epidemiology Unit, Institute of Health Sciences, University of Oxford

8. Professor Paul D Griffiths, Professor of Radiology, Academic Unit of Radiology, University of Sheffield

9. Mr Martin Hooper, Public contributor

10. Professor Anthony Robert Kendrick, Associate Dean for Clinical Research and Professor of Primary Medical Care, University of Southampton

11. Dr Anne Mackie, Director of Programmes, UK National Screening Committee, London

12. Mr David Mathew, Public contributor

13. Dr Michael Millar, Consultant Senior Lecturer in Microbiology, Department of Pathology & Microbiology, Barts and The London NHS Trust, Royal London Hospital

14. Mrs Una Rennard, Public contributor

15. Dr Stuart Smellie, Consultant in Clinical Pathology, Bishop Auckland General Hospital

16. Ms Jane Smith, Consultant Ultrasound Practitioner, Leeds Teaching Hospital NHS Trust, Leeds

17. Dr Allison Streetly, Programme Director, NHS Sickle Cell and Thalassaemia Screening Programme, King’s College School of Medicine

18. Dr Alan J Williams, Consultant Physician, General and Respiratory Medicine, The Royal Bournemouth Hospital

1. Dr Tim Elliott, Team Leader, Cancer Screening, Department of Health

2. Dr Catherine Moody, Programme Manager, Medical Research Council

3. Professor Julietta Patrick, Director, NHS Cancer Screening Programme, Sheffield

4. Dr Kay Pattison, Senior NIHR Programme Manager, Department of Health

5. Professor Tom Walley, CBE, Director, NIHR HTA programme, Professor of Clinical Pharmacology, University of Liverpool

6. Dr Ursula Wells, Principal Research Officer, Policy Research Programme, Department of Health

Disease Prevention Panel

1. Professor of Epidemiology, University of Warwick Medical School, Coventry

2. Dr Robert Cook, Clinical Programmes Director, Bazian Ltd, London

3. Dr Colin Greaves, Senior Research Fellow, Peninsula Medical School (Primary Care)

4. Mr Michael Head, Public contributor

5. Professor Cathy Jackson, Professor of Primary Care Medicine, Bute Medical School, University of St Andrews

6. Dr Russell Jago, Senior Lecturer in Exercise, Nutrition and Health, Centre for Sport, Exercise and Health, University of Bristol

7. Dr Julie Mytton, Consultant in Child Public Health, NHS Bristol

8. Professor Irwin Nazareth, Professor of Primary Care and Director, Department of Primary Care and Population Sciences, University College London

9. Dr Richard Richards, Assistant Director of Public Health, Derbyshire Country Primary Care Trust

10. Professor Ian Roberts, Professor of Epidemiology and Public Health, London School of Hygiene & Tropical Medicine

11. Dr Kenneth Robertson, Consultant Paediatrician, Royal Hospital for Sick Children, Glasgow

12. Dr Catherine Swann, Associate Director, Centre for Public Health Excellence, NICE

13. Professor Carol Tannahill, Glasgow Centre for Population Health

14. Mrs Jean Thurston, Public contributor

15. Professor David Weller, Head, School of Clinical Science and Community Health, University of Edinburgh

1. Ms Christine McGuire, Research & Development, Department of Health

2. Dr Kay Pattison Senior NIHR Programme Manager, Department of Health

3. Professor Tom Walley, CBE, Director, NIHR HTA programme, Professor of Clinical Pharmacology, University of Liverpool

External Devices and Physical Therapies Panel

1. Consultant Physician North Bristol NHS Trust

2. Reader in Wound Healing and Director of Research, University of Leeds

3. Professor Bipin Bhakta, Charterhouse Professor in Rehabilitation Medicine, University of Leeds

4. Mrs Penny Calder, Public contributor

5. Dr Dawn Carnes, Senior Research Fellow, Barts and the London School of Medicine and Dentistry

6. Dr Emma Clark, Clinician Scientist Fellow & Cons. Rheumatologist, University of Bristol

7. Mrs Anthea De Barton-Watson, Public contributor

8. Professor Nadine Foster, Professor of Musculoskeletal Health in Primary Care Arthritis Research, Keele University

9. Dr Shaheen Hamdy, Clinical Senior Lecturer and Consultant Physician, University of Manchester

10. Professor Christine Norton, Professor of Clinical Nursing Innovation, Bucks New University and Imperial College Healthcare NHS Trust

11. Dr Lorraine Pinnigton, Associate Professor in Rehabilitation, University of Nottingham

12. Dr Kate Radford, Senior Lecturer (Research), University of Central Lancashire

13. Mr Jim Reece, Public contributor

14. Professor Maria Stokes, Professor of Neuromusculoskeletal Rehabilitation, University of Southampton

15. Dr Pippa Tyrrell, Senior Lecturer/Consultant, Salford Royal Foundation Hospitals’ Trust and University of Manchester

16. Dr Sarah Tyson, Senior Research Fellow & Associate Head of School, University of Salford

17. Dr Nefyn Williams, Clinical Senior Lecturer, Cardiff University

1. Dr Kay Pattison, Senior NIHR Programme Manager, Department of Health

2. Professor Tom Walley, CBE, Director, NIHR HTA programme, Professor of Clinical Pharmacology, University of Liverpool

3. Dr Ursula Wells, Principal Research Officer, Policy Research Programme, Department of Health

Interventional Procedures Panel

1. Professor of Vascular Surgery, University of Sheffield

2. Consultant Colorectal Surgeon, Bristol Royal Infirmary

3. Mrs Isabel Boyer, Public contributor

4. Mr David P Britt, Public contributor

5. Mr Sankaran ChandraSekharan, Consultant Surgeon, Breast Surgery, Colchester Hospital University NHS Foundation Trust

6. Professor Nicholas Clarke, Consultant Orthopaedic Surgeon, Southampton University Hospitals NHS Trust

7. Ms Leonie Cooke, Public contributor

8. Mr Seamus Eckford, Consultant in Obstetrics & Gynaecology, North Devon District Hospital

9. Professor David Taggart, Consultant Cardiothoracic Surgeon, John Radcliffe Hospital

10. Professor Sam Eljamel, Consultant Neurosurgeon, Ninewells Hospital and Medical School, Dundee

11. Dr Adele Fielding, Senior Lecturer and Honorary Consultant in Haematology, University College London Medical School

12. Dr Matthew Hatton, Consultant in Clinical Oncology, Sheffield Teaching Hospital Foundation Trust

13. Dr John Holden, General Practitioner, Garswood Surgery, Wigan

14. Professor Nicholas James, Professor of Clinical Oncology, School of Cancer Sciences, University of Birmingham

15. Dr Fiona Lecky, Senior Lecturer/Honorary Consultant in Emergency Medicine, University of Manchester/Salford Royal Hospitals NHS Foundation Trust

16. Dr Nadim Malik, Consultant Cardiologist/ Honorary Lecturer, University of Manchester

17. Mr Hisham Mehanna, Consultant & Honorary Associate Professor, University Hospitals Coventry & Warwickshire NHS Trust

18. Dr Jane Montgomery, Consultant in Anaesthetics and Critical Care, South Devon Healthcare NHS Foundation Trust

19. Professor Jon Moss, Consultant Interventional Radiologist, North Glasgow Hospitals University NHS Trust

20. Dr Simon Padley, Consultant Radiologist, Chelsea & Westminster Hospital

21. Dr Ashish Paul, Medical Director, Bedfordshire PCT

22. Dr Sarah Purdy, Consultant Senior Lecturer, University of Bristol

23. Professor Yit Chiun Yang, Consultant Ophthalmologist, Royal Wolverhampton Hospitals NHS Trust

1. Dr Kay Pattison, Senior NIHR Programme Manager, Department of Health

2. Dr Morven Roberts, Clinical Trials Manager, Health Services and Public Health Services Board, Medical Research Council

3. Professor Tom Walley, CBE, Director, NIHR HTA programme, Professor of Clinical Pharmacology, University of Liverpool

4. Dr Ursula Wells, Principal Research Officer, Policy Research Programme, Department of Health

Pharmaceuticals Panel

1. Professor in Child Health, University of Nottingham

2. Senior Lecturer in Clinical Pharmacology, University of East Anglia

3. Dr Martin Ashton-Key, Medical Advisor, National Commissioning Group, NHS London

4. Mr John Chapman, Public contributor

5. Dr Peter Elton, Director of Public Health, Bury Primary Care Trust

6. Dr Ben Goldacre, Research Fellow, Division of Psychological Medicine and Psychiatry, King’s College London

7. Dr James Gray, Consultant Microbiologist, Department of Microbiology, Birmingham Children’s Hospital NHS Foundation Trust

8. Ms Kylie Gyertson, Oncology and Haematology Clinical Trials Manager, Guy’s and St Thomas’ NHS Foundation Trust London

9. Dr Jurjees Hasan, Consultant in Medical Oncology, The Christie, Manchester

10. Dr Carl Heneghan Deputy Director Centre for Evidence-Based Medicine and Clinical Lecturer, Department of Primary Health Care, University of Oxford

11. Dr Dyfrig Hughes, Reader in Pharmacoeconomics and Deputy Director, Centre for Economics and Policy in Health, IMSCaR, Bangor University

12. Dr Maria Kouimtzi, Pharmacy and Informatics Director, Global Clinical Solutions, Wiley-Blackwell

13. Professor Femi Oyebode, Consultant Psychiatrist and Head of Department, University of Birmingham

14. Dr Andrew Prentice, Senior Lecturer and Consultant Obstetrician and Gynaecologist, The Rosie Hospital, University of Cambridge

15. Ms Amanda Roberts, Public contributor

16. Dr Martin Shelly, General Practitioner, Silver Lane Surgery, Leeds

17. Dr Gillian Shepherd, Director, Health and Clinical Excellence, Merck Serono Ltd

18. Mrs Katrina Simister, Assistant Director New Medicines, National Prescribing Centre, Liverpool

19. Professor Donald Singer, Professor of Clinical Pharmacology and Therapeutics, Clinical Sciences Research Institute, CSB, University of Warwick Medical School

20. Mr David Symes, Public contributor

21. Dr Arnold Zermansky, General Practitioner, Senior Research Fellow, Pharmacy Practice and Medicines Management Group, Leeds University

1. Dr Kay Pattison, Senior NIHR Programme Manager, Department of Health

2. Mr Simon Reeve, Head of Clinical and Cost-Effectiveness, Medicines, Pharmacy and Industry Group, Department of Health

3. Dr Heike Weber, Programme Manager, Medical Research Council

4. Professor Tom Walley, CBE, Director, NIHR HTA programme, Professor of Clinical Pharmacology, University of Liverpool

5. Dr Ursula Wells, Principal Research Officer, Policy Research Programme, Department of Health

Psychological and Community Therapies Panel

1. Professor of Psychiatry, University of Warwick, Coventry

2. Consultant & University Lecturer in Psychiatry, University of Cambridge

3. Professor Jane Barlow, Professor of Public Health in the Early Years, Health Sciences Research Institute, Warwick Medical School

4. Dr Sabyasachi Bhaumik, Consultant Psychiatrist, Leicestershire Partnership NHS Trust

5. Mrs Val Carlill, Public contributor

6. Dr Steve Cunningham, Consultant Respiratory Paediatrician, Lothian Health Board

7. Dr Anne Hesketh, Senior Clinical Lecturer in Speech and Language Therapy, University of Manchester

8. Dr Peter Langdon, Senior Clinical Lecturer, School of Medicine, Health Policy and Practice, University of East Anglia

9. Dr Yann Lefeuvre, GP Partner, Burrage Road Surgery, London

10. Dr Jeremy J Murphy, Consultant Physician and Cardiologist, County Durham and Darlington Foundation Trust

11. Dr Richard Neal, Clinical Senior Lecturer in General Practice, Cardiff University

12. Mr John Needham, Public contributor

13. Ms Mary Nettle, Mental Health User Consultant

14. Professor John Potter, Professor of Ageing and Stroke Medicine, University of East Anglia

15. Dr Greta Rait, Senior Clinical Lecturer and General Practitioner, University College London

16. Dr Paul Ramchandani, Senior Research Fellow/Cons. Child Psychiatrist, University of Oxford

17. Dr Karen Roberts, Nurse/Consultant, Dunston Hill Hospital, Tyne and Wear

18. Dr Karim Saad, Consultant in Old Age Psychiatry, Coventry and Warwickshire Partnership Trust

19. Dr Lesley Stockton, Lecturer, School of Health Sciences, University of Liverpool

20. Dr Simon Wright, GP Partner, Walkden Medical Centre, Manchester

1. Dr Kay Pattison, Senior NIHR Programme Manager, Department of Health

2. Dr Morven Roberts, Clinical Trials Manager, Health Services and Public Health Services Board, Medical Research Council

3. Professor Tom Walley, CBE, Director, NIHR HTA programme, Professor of Clinical Pharmacology, University of Liverpool

4. Dr Ursula Wells, Principal Research Officer, Policy Research Programme, Department of Health

Expert Advisory Network

1. Professor Douglas Altman, Professor of Statistics in Medicine, Centre for Statistics in Medicine, University of Oxford

2. Professor John Bond, Professor of Social Gerontology & Health Services Research, University of Newcastle upon Tyne

3. Professor Andrew Bradbury, Professor of Vascular Surgery, Solihull Hospital, Birmingham

4. Mr Shaun Brogan, Chief Executive, Ridgeway Primary Care Group, Aylesbury

5. Mrs Stella Burnside OBE, Chief Executive, Regulation and Improvement Authority, Belfast

6. Ms Tracy Bury, Project Manager, World Confederation of Physical Therapy, London

7. Professor Iain T Cameron, Professor of Obstetrics and Gynaecology and Head of the School of Medicine, University of Southampton

8. Professor Bruce Campbell, Consultant Vascular & General Surgeon, Royal Devon & Exeter Hospital, Wonford

9. Dr Christine Clark, Medical Writer and Consultant Pharmacist, Rossendale

10. Professor Collette Clifford, Professor of Nursing and Head of Research, The Medical School, University of Birmingham

11. Professor Barry Cookson, Director, Laboratory of Hospital Infection, Public Health Laboratory Service, London

12. Dr Carl Counsell, Clinical Senior Lecturer in Neurology, University of Aberdeen

13. Professor Howard Cuckle, Professor of Reproductive Epidemiology, Department of Paediatrics, Obstetrics & Gynaecology, University of Leeds

14. Professor Carol Dezateux, Professor of Paediatric Epidemiology, Institute of Child Health, London

15. Mr John Dunning, Consultant Cardiothoracic Surgeon, Papworth Hospital NHS Trust, Cambridge

16. Mr Jonothan Earnshaw, Consultant Vascular Surgeon, Gloucestershire Royal Hospital, Gloucester

17. Professor Martin Eccles, Professor of Clinical Effectiveness, Centre for Health Services Research, University of Newcastle upon Tyne

18. Professor Pam Enderby, Dean of Faculty of Medicine, Institute of General Practice and Primary Care, University of Sheffield

19. Professor Gene Feder, Professor of Primary Care Research & Development, Centre for Health Sciences, Barts and The London School of Medicine and Dentistry

20. Mr Leonard R Fenwick, Chief Executive, Freeman Hospital, Newcastle upon Tyne

21. Mrs Gillian Fletcher, Antenatal Teacher and Tutor and President, National Childbirth Trust, Henfield

22. Professor Jayne Franklyn, Professor of Medicine, University of Birmingham

23. Mr Tam Fry, Honorary Chairman, Child Growth Foundation, London

24. Professor Fiona Gilbert, Consultant Radiologist and NCRN Member, University of Aberdeen

25. Professor Paul Gregg, Professor of Orthopaedic Surgical Science, South Tees Hospital NHS Trust

26. Bec Hanley, Co-director, TwoCan Associates, West Sussex

27. Dr Maryann L Hardy, Senior Lecturer, University of Bradford

28. Mrs Sharon Hart, Healthcare Management Consultant, Reading

29. Professor Robert E Hawkins, CRC Professor and Director of Medical Oncology, Christie CRC Research Centre, Christie Hospital NHS Trust, Manchester

30. Professor Richard Hobbs, Head of Department of Primary Care & General Practice, University of Birmingham

31. Professor Alan Horwich, Dean and Section Chairman, The Institute of Cancer Research, London

32. Professor Allen Hutchinson, Director of Public Health and Deputy Dean of ScHARR, University of Sheffield

33. Professor Peter Jones, Professor of Psychiatry, University of Cambridge, Cambridge

34. Professor Stan Kaye, Cancer Research UK Professor of Medical Oncology, Royal Marsden Hospital and Institute of Cancer Research, Surrey

35. Dr Duncan Keeley, General Practitioner (Dr Burch & Ptnrs), The Health Centre, Thame

36. Dr Donna Lamping, Research Degrees Programme Director and Reader in Psychology, Health Services Research Unit, London School of Hygiene and Tropical Medicine, London

37. Professor James Lindesay, Professor of Psychiatry for the Elderly, University of Leicester

38. Professor Julian Little, Professor of Human Genome Epidemiology, University of Ottawa

39. Professor Alistaire McGuire, Professor of Health Economics, London School of Economics

40. Professor Neill McIntosh, Edward Clark Professor of Child Life and Health, University of Edinburgh

41. Professor Rajan Madhok, Consultant in Public Health, South Manchester Primary Care Trust

42. Professor Sir Alexander Markham, Director, Molecular Medicine Unit, St James’s University Hospital, Leeds

43. Dr Peter Moore, Freelance Science Writer, Ashtead

44. Dr Andrew Mortimore, Public Health Director, Southampton City Primary Care Trust

45. Dr Sue Moss, Associate Director, Cancer Screening Evaluation Unit, Institute of Cancer Research, Sutton

46. Professor Miranda Mugford, Professor of Health Economics and Group Co-ordinator, University of East Anglia

47. Professor Jim Neilson, Head of School of Reproductive & Developmental Medicine and Professor of Obstetrics and Gynaecology, University of Liverpool

48. Mrs Julietta Patnick, Director, NHS Cancer Screening Programmes, Sheffield

49. Professor Robert Peveler, Professor of Liaison Psychiatry, Royal South Hants Hospital, Southampton

50. Professor Chris Price, Director of Clinical Research, Bayer Diagnostics Europe, Stoke Poges

51. Professor William Rosenberg, Professor of Hepatology and Consultant Physician, University of Southampton

52. Professor Peter Sandercock, Professor of Medical Neurology, Department of Clinical Neurosciences, University of Edinburgh

53. Dr Philip Shackley, Senior Lecturer in Health Economics, Sheffield Vascular Institute, University of Sheffield

54. Dr Eamonn Sheridan, Consultant in Clinical Genetics, St James’s University Hospital, Leeds

55. Dr Margaret Somerville, Director of Public Health Learning, Peninsula Medical School, University of Plymouth

56. Professor Sarah Stewart-Brown, Professor of Public Health, Division of Health in the Community, University of Warwick, Coventry

57. Dr Nick Summerton, GP Appraiser and Codirector, Research Network, Yorkshire Clinical Consultant, Primary Care and Public Health, University of Oxford

58. Professor Ala Szczepura, Professor of Health Service Research, Centre for Health Services Studies, University of Warwick, Coventry

59. Dr Ross Taylor, Senior Lecturer, University of Aberdeen

60. Dr Richard Tiner, Medical Director, Medical Department, Association of the British Pharmaceutical Industry

61. Mrs Joan Webster, Consumer Member, Southern Derbyshire Community Health Council

62. Professor Martin Whittle, Clinical Co-director, National Co-ordinating Centre for Women’s and Children’s Health, Lymington