Ofatumumab (Arzerra®) for the treatment of chronic lymphocytic leukaemia in patients who are refractory to fludarabine and alemtuzumab: a critique of the submission from GSK

Report commissioned by: NIHR HTA Programme

On behalf of: The National Institute for Health and Clinical Excellence (NICE)

Produced by: Peninsula Technology Assessment Group (PenTAG), Peninsula Medical School, University of Exeter

Authors:

Martin Hoyle, Research Fellow, PenTAG, University of Exeter

Louise Crathorne, Associate Research Fellow, PenTAG, University of Exeter

Tiffany Moxham, Information Scientist, PenTAG, University of Exeter

Ruth Garside, Senior Research Fellow, PenTAG, University of Exeter

Chris Hyde, Professor of Public Health and Clinical Epidemiology, PenTAG, University of Exeter

Correspondence to: XXXX XXXX

PenTAG

Peninsula College of Medicine and Dentistry

Veysey Building

Salmon Pool Lane

Exeter EX2 4SG

XXXX [email protected]

Date completed: 6 April 2010

1 About the Peninsula Technology Assessment Group (PenTAG): The Peninsula Technology Assessment Group is part of the Institute of Health and Social Care Research at the Peninsula Medical School. PenTAG was established in 2000 and carries out independent Health Technology Assessments for the UK HTA Programme and other local and national decision-makers. The group is multi-disciplinary and draws on individuals’ backgrounds in public health, health services research, computing and decision analysis, systematic reviewing, statistics and health economics. The Peninsula Medical School is a school within the Universities of Plymouth and Exeter. The Institute of Health and Social Care Research is made up of discrete but methodologically related research groups, among which Health Technology Assessment is a strong and recurring theme.

Source of funding: This report was commissioned by the NIHR HTA programme as project number 09/96/01.

Competing interests of authors: None

Acknowledgements: We particularly acknowledge the help of Dr Claudius Rudin (Consultant Haematologist, Royal Devon & Exeter NHS Trust) who provided clinical input on the project. With many thanks to Sue Whiffin (PenTAG) for administrative project support.

Disclaimer: The views expressed in this report are those of the authors and not necessarily those of the NIHR HTA Programme. Any errors are the responsibility of the authors.

Report should be referenced as follows: Hoyle M, Crathorne L, Moxham T, Garside R, Hyde C. Ofatumumab (Arzerra®) for the treatment of chronic lymphocytic leukaemia in patients who are refractory to fludarabine and alemtuzumab: a critique of the submission from GSK. 2010. University of Exeter. (Report)

Contributions of authors

Martin Hoyle Critiqued the model provided by industry and wrote the economic evaluation chapter

Louise Project management, critiqued the effectiveness evaluation provided by Crathorne the manufacturers, report writing and editing

Tiffany Undertook literature searches for the report, and commented on the Moxham searches provided by industry

Ruth Garside Project management, critiqued the effectiveness evaluation provided by the manufacturers, and contributed to the writing of the report

Chris Hyde Contributed to the critique of the industry submission, and report writing and editing. He is the guarantor for this report

2 Abbreviations and acronyms

AE Adverse Event ASCO American Society of Clinical Oncology ASCT Allogenic Stem Cell Transplantation ASH American Society of Haematology AUC Area Under the Curve BCSH British Committee for Standards in Haematology BFR Bulky Refractory Disease BNF British National Formulary BSC Best Supportive Care BSH British Society of Haematology CEAC Cost-effectiveness Acceptability Curve CHMP Committee for Medicinal Products for Human Use CHOP Cyclophosphamide, Doxorubicin, Vincristine, Prednisolone CI Confidence Interval CiC Commerical in Confidence CLL Chronic Lymphocytic Leukaemia CR Complete Remission CRD Centre for Reviews and Dissemination CT Computed Tomography CVP Cyclophosphamide, Vincristine, Prednisolone DMC Data Monitoring Committee DR Double Refractory ECOG Eastern Cooperative Oncology Group EHA European Haematology Association EMEA European Medicine's Agency EQ5D EuroQol-5 Dimension ERG Evidence Review Group FAS Full Analysis Set FC Fludarabine + Cyclophosphamide FCA Fludarabine, Cyclophosphamide + Alemtuzumab FCAR Fludarabine, Cyclophosphamide, Alemtuzumab + Rituximab FCM Fludarabine, Cyclophosphamide + Mitoxantrone FCMR Fludarabine, Cyclophosphamide, Mitoxantrone + Rituximab FCR Fludarabine +Cyclophosphamide + Rituximab FDA Food and Drug Administration GSK Glaxo SmithKline HRQL Health-related Quality of Life HTAs Health Technology Appraisals ICER Incremental Cost Effectiveness Ratio IRC Independent Review Committee ISPOR International Society of Pharmacoeconomics and Outcomes Research ITT Intention-to-Treat IV Intravenous LRF Leukaemia Research Foundation NBS National Blood Service NCI-WG National Cancer Institute Working Group NHS National Health Service NHS EED NHS Economic Evaluation Database NICE National Institute for Health and Clinical Excellence nPR Nodular Partial Response ORR Overall Response Rate OS Overall Survival 3 PAS Patient Access Scheme PD Progressive Disease PenTAG Peninsula Technology Assessment Group PFS Progression Free Survival PR Partial Response PSS Personal Social Services QALY Quality Adjusted Life Year QoL Quality of Life RCT Randomised Controlled Trial SD Stable Disease SD Standard Deviation SmPC Summary of Product Characteristics STA Single Technology Appraisal

4 Table of Contents

1 SUMMARY ...... 9 1.1 Scope of the submission ...... 9 1.2 Summary of submitted clinical effectiveness evidence ...... 9 1.3 Summary of submitted cost effectiveness evidence ...... 10 1.4 Commentary on the robustness of submitted evidence ...... 10 1.4.1 Strengths ...... 10 1.4.2 Weaknesses ...... 11 1.4.3 Areas of uncertainty ...... 11 1.5 Key issues ...... 12 2 BACKGROUND ...... 13 2.1 Critique of manufacturer’s description of underlying health problem ...... 13 2.1.1 Epidemiology ...... 13 2.1.2 Diagnosis ...... 14 2.1.3 Prognosis ...... 14 2.1.4 Clinical features/symptoms ...... 15 2.1.5 Burden and quality of life ...... 16 2.2 Critique of manufacturer’s overview of current service provision ...... 16 3 CRITIQUE OF MANUFACTURER’S DEFINITION OF DECISION PROBLEM ...... 19 3.1 Population ...... 19 3.2 Intervention ...... 19 3.3 Comparators ...... 20 3.4 Outcomes ...... 21 3.5 Timeframe ...... 21 3.6 Other relevant factors ...... 21 4 CLINICAL EFFECTIVENESS ...... 25 4.1 Critique of manufacturer’s approach ...... 25 4.1.1 Description of manufacturers search strategy and comment on whether the search strategy was appropriate...... 25 4.1.2 Statement of the inclusion/exclusion criteria used in the study selection and comment on whether they were appropriate...... 26 4.1.3 Table of identified studies. What studies were included in the submission and what were excluded? ...... 29 4.1.4 Details of any relevant studies that were not included in the submission ...... 30 4.1.5 Description and critique of manufacturer’s approach to validity assessment ...... 30 4.1.6 Description and critique of manufacturer’s outcome selection ...... 33 4.1.7 Describe and critique the statistical approach used ...... 34 4.1.8 Summary statement ...... 35 4.2 Summary of submitted evidence ...... 35 4.2.1 Summary of results ...... 35 4.2.2 Summary of submitted evidence synthesis: including threats to validity ...... 42 5 ECONOMIC EVALUATION ...... 47 5.1 Overview of manufacturer’s economic evaluation ...... 47 5.1.1 Summary of GSK’s systematic review of cost-effectiveness studies ...... 47 5.1.2 GSK’s economic model submitted to NICE ...... 48 5.1.3 Natural history ...... 48 5.1.4 Treatment effectiveness ...... 49 5.1.5 Health related quality of life ...... 51 5 5.1.6 Resources and costs ...... 52 5.1.7 Discounting ...... 55 5.1.8 Sensitivity analysis ...... 55 5.1.9 Model validation ...... 55 5.2 Critique of approach used ...... 55 5.2.1 Critical appraisal frameworks ...... 55 5.2.2 Critique of the modelling approach and structure ...... 59 5.2.3 Data inputs ...... 59 5.2.4 Assessment of uncertainty ...... 68 5.3 Results included in manufacturer’s submission ...... 68 5.4 Comments on validity of results presented with reference to methodology used ...... 72 5.4.1 Data inputs ...... 72 5.4.2 Assessment of consistency ...... 74 5.4.3 Assessment of uncertainty ...... 75 5.5 Summary of uncertainties and issues ...... 75 6 ADDITIONAL WORK UNDERTAKEN BY THE ERG...... 77 7 DISCUSSION ...... 79 7.1 Summary of clinical effectiveness issues ...... 79 7.2 Summary of cost effectiveness issues ...... 79 7.3 Implications for research ...... 80 7.4 Assessment of factors related to the NHS and other parties ...... 81 APPENDIX 1: GSK RESPONSE DOCUMENT – 10 MARCH 2010 ...... 86

6 Tables

Table 1. Binet classification[6] ...... 15 Table 2. Rai clinical staging system[6] ...... 15 Table 5. Eligibility criteria used in search strategy ...... 26 Table 6. Critical appraisal of study Hx-CD20-406...... 31 Table 7. Summary of responses in Hx-CD20-406 assessed by IRC (DR population) ...... 36 Table 8. Summary of assessment of ORR in Hx-CD20-406 by Investigator and Sponsor (DR population) ...... 36 Table 9. Objective response rate in Hx-CD20-406 by baseline characteristics (IRC assessment, DR population) ...... 38 Table 10. Baseline characteristics by response at 24 weeks (IRC assessment, DR population) ...... 39 Table 11. Secondary endpoints in Hx-CD20-406 (IRC assessment, DR population) ...... 40 Table 12. Summary of clinical improvement for ≥2 months in Hx-CD20-406 (DR population) . 41 Table 13. Threats to validity: effect on results from Hx-CD20-406 for stated outcome (clinical effectiveness) ...... 44 Table 14. Weibull parameters in GSK model ...... 51 Table 15. Utilities for CLL from Ferguson et al (2008)[16] ...... 52 Table 16: Critical appraisal checklist based on NICE Reference Case[20] ...... 56 Table 17: Critical appraisal checklist from Drummond et al[21] ...... 57 Table 18: Critical appraisal checklist of Philips et al (2006)[22] for model-based analyses ...... 58 Table 19. Base case results of GSK’s model (mean per patient) assuming ofatumumab costs ******per mg ...... 69 Table 20. GSK sensitivity analyses ...... 71 Table 21: Derivation of alternative deterministic ICER for ofatumumab vs. BSC based on our proposed alternative assumptions ...... 77 Table 22. Important scenario analyses applied separately to GSK’s base case versus proposed alternative base case ...... 78 Table 23. Estimated budget impact of ofatumumab over the next five years: 15 eligible patients ...... 81 Table 24. Estimated budget impact of ofatumumab over the next five years: 39 eligible patients ...... 82 Table 25. Estimated budget impact of ofatumumab over the next five years assuming 100% uptake of 15 patients ...... 83 Table 26. Estimated budget impact of ofatumumab over the next 5 years assuming 100% uptake of 39 patients ...... 83

7 Figures

Figure 1. A treatment algorithm for chronic lymphocytic leukaemia ...... 18 Figure 2. GSK estimated vs. actual PFS for ofatumumab and BSC ...... 50 Figure 3. GSK estimated vs. actual OS for ofatumumab and BSC ...... 50

8 1 SUMMARY

Indented, italicized, single-line spaced text, tables or figures have been copied from the submission (or GSK’s response to requests for clarification [Appendix 1]), hereafter referred to as ‘the submission’. References which appear within this text within brackets (author, year) refer to those cited within GSK’s submission.

1.1 Scope of the submission

The submission from GSK considered the use of ofatumumab (Arzerra®) for the treatment of chronic lymphocytic leukaemia in patients who are refractory to fludarabine and alemtuzumab.

The comparator in the submission was best supportive care (BSC) which was taken to mean:

Symptomatic management of cytopenias with blood products/colony stimulating factors (CSFs); anti-infective prophylaxis and treatment; corticosteroids (not high dose); and, regular monitoring via outpatient clinic. (Source: GSK Submission, Page 4)

The clinical effectiveness outcomes considered were, objective response rate, time to onset of response, duration of response, progression free survival, time to next CLL therapy, overall survival, reduction in tumour size as well as safety and pharmacokinetic endpoints.

The outcomes for the economic analysis were progression free survival and overall survival. The time horizon for the economic analysis was 10 years and costs were considered from an NHS and personal social services (PSS) perspective.

The scope of the manufacturer’s submission is consistent with the components of the question and approach outlined in NICE’s final scope, although not all comparators were considered.[1]

1.2 Summary of submitted clinical effectiveness evidence

The submission from GSK includes one study; a non-randomised, single-arm study, Hx-CD20- 406. From a total of 138 patients treatment effectiveness is taken exclusively from the 59 DR patients. This is in line with the licensed indication for ofatumumab. After Week 28, disease status evaluation (physical examination, spleen and liver measurement, and blood samples) took place every three months until Month 24.

Two other potentially relevant studies in the DR CLL population were identified: Tam et al 2007 and Dungarwalla et al 2008.[2,3] These were ruled out by GSK because they are non- comparative and provide evidence for therapies other than ofatumumab. However, the manufacturer uses Tam et al (2007) data as a comparator to the single-arm study in the narrative summary of clinical effectiveness evidence, stating that the patient populations in the

9 two studies were ‘highly comparable’ and that the patients in the two studies were ‘treated in similar settings and in a similar manner’.

In the Hx-CD20-406 study the ORR was 58% (99% CI, 40% to 74%; p<0.001) Complete resolution of constitutional symptoms and improved performance status occurred in 57% of patients. Median progression free survival and overall survival times were 5.7 and 13.7 months respectively.

The most common adverse events during treatment were infusion reactions and infections, which were primarily grade 1 or 2 events. The AE profile is consistent with that seen with other monoclonal antibody therapies. However, using a single-arm study – Hx-CD20-406 – there is no way of assessing the AE profile truly related to the intervention

1.3 Summary of submitted cost effectiveness evidence

The manufacturer used a cohort-based ‘area under the curve’ (AUC) model to project expected clinical and economic outcomes for patients with double refractory (DR) chronic lymphocytic leukaemia (CLL) who received either ofatumumab or BSC. The model had three states structure: ‘Alive Pre-Progression’; ‘Alive Post-Progression’ and ‘Dead’.

GSK’s base case analysis produced an ICER of £38,421 per QALY. When we update GSK’s model with what we think are more appropriate assumptions, the ICER increases to at least £81,500 / QALY.

1.4 Commentary on the robustness of submitted evidence

1.4.1 Strengths

Clinical effectiveness

. The searches are appropriate and include all relevant studies.

Cost-effectiveness

. The overall modelling approach is reasonable given the dearth of available clinical evidence for the drug in this population. There are no logical errors in the economic model. However, there are some weaknesses and areas of uncertainty which are discussed later in this section.

10

1.4.2 Weaknesses

Clinical effectiveness

. The evidence is based on one non-randomised, single-arm study. The outcome data reported are from a planned interim analysis with no recent data available.

. The patient population is small as only data from the double refractory (DR) subgroup are presented in the submission (n=59) of which 14 are from the UK. However, the patient population is in line with the approved indication for ofatumumab.

. It is difficult to measure adverse events (AEs) attributable to ofatumumab as all patients are exposed to the intervention.

. The Hx-CD20-406 study did not record HRQL.

Cost effectiveness

. In their economic evaluation, the best supportive care (BSC) arm uses data from those patients in the Hx-CD20-406 study who did not respond to ofatumumab treatment – ‘non responders’. The ofatumumab arm of the model uses data from all those treated in the Hx-CD20-406 study. It is difficult to tell how this reflects the actual population.

. GSK’s choice of utilities biases cost-effectiveness in favour of ofatumumab.

. The omission of 17p and 11q chromosonal deletions as factors in their Cox proportional hazards models for PFS and OS biases in favour of ofatumumab.

. The omission of the costs of drugs in progressive disease biases in favour of ofatumumab.

1.4.3 Areas of uncertainty

. The effect on overall response rate (ORR), progression-free survival (PFS) and overall survival (OS) is uncertain as it is not self-evident that the design employed will necessarily lead to an overestimate of the treatment effect.

. GSK’s base case ICER of £38,400 / QALY and our proposed alternative ICER of >£81,500 / QALY are uncertain for the following three reasons:

11  1: the effectiveness of the ofatumumab and BSC treatment arms were not taken from a randomised trial. Instead, the effectiveness for BSC was taken from non-responders in the single-arm ofatumumab study, which is methodologically very dubious. Nonetheless, since the survival data for the non- responder group in the ofatumumab study is similar to that in the historical Tam et al study (2007),[3] this offers some support for the use of this group as an appropriate proxy for the BSC arm.

 2: there is extensive extrapolation of OS, with approximately 40% of patients still alive at maximum follow-up.

 3: there are concerns about the methodology of the study from which utilities are taken. This is important because cost-effectiveness is sensitive to the utilities.

1.5 Key issues

. The use of a non-randomised, single-arm study makes it difficult to determine what the nature and extent of the bias might be

. It is difficult to determine the impact of ofatumumab on global QoL as it has not been measured.

. The impact on the measured effect of outcomes; for example, infection which could either be attributable to lack of response or to adverse effects of ofatumumab

. The true effect of ofatumumab treatment on ORR, PFS and OS is uncertain. It is unclear whether the design employed will necessarily lead to an overestimate of the treatment effect.

12 2 BACKGROUND

2.1 Critique of manufacturer’s description of underlying health problem

Section 2.1 of the manufacturer’s submission (GSK submission, Section 2.1, p17–19) provides a brief overview of the nature, epidemiology, diagnosis, prognosis, clinical features/symptoms, burden and impact on quality of life and nature of associated infections with chronic lymphocytic leukaemia (CLL).

The submission notes the nature of CLL as a malignancy of B-lymphocytes which accumulate progressively in the blood, bone marrow, lymph nodes, liver and spleen (GSK Submission, Section 2.1, p17).

2.1.1 Epidemiology

The submission notes that CLL is the most common form of leukaemia among Caucasians, affecting a mainly older population, median age 65–70, with a 2:1 ratio of men to women (decreasing with age) (GSK Submission, Section 2.1, p17).

The GSK submission acknowledges that incident data are difficult to obtain (GSK Submission, Section 2.1, p17), however they supply one estimate and this is later used for their calculation of the population likely to be affected by the current guidance (GSK Submission, Section 2.2, Table 2.1, p19). This uses an estimate of 3/100,000 age adjusted incidence in the UK (based on data from BCSH, 2004; LRF 2009). Other estimates are, however, available. Based on ONS data, NICE Guidance on Cancer Services: Improving outcomes in haematological cancers – the manual (Table 1, p11) suggest a rate of 3.9/100,000[4] and, as practitioners note that this may be an underestimation due to reporting difficulties, a panel of experts consulted for the manual (Table 2, p12) suggested that 8/100,000 may be more appropriate.[4] Although numbers remain small in absolute terms, the size of the eligible population is clearly difficult to estimate, and this second method more than doubles it compared to the initial one (see GSK Submission, Section 7.7, p157).

In November 2008, the European Medicines Agency (EMEA) granted ofatumumab orphan drug status based on an understanding that CLL prevalence was around 3.5 people per 10,000 in the European Union.[5]

Given that the calculation for the pertinent population shown in Table 2.1 of the GSK Response Document uses incidence in the UK as its starting point, this may mean that, although still only in double digits, the number of double refractory CLL patients may be larger than the 15 13 suggested. We asked for clarification about the GSK market research which produced the estimate of 1.2% of CLL patients refractory to fludarabine and alemtuzumab (see Appendix 1: GSK Response Document – 10 March 2010). An alternative method of calculation was proposed which increased the annual eligible population to 39.

2.1.2 Diagnosis

Details of clinical CLL diagnosis, based on increased numbers of lymphocytes in the blood (lymphocytosis) of >5x109, is given in the submission (Source: GSK Submission, Section 2.1, p17).

2.1.3 Prognosis

The submission notes the highly variable prognosis and clinical course for patients with CLL. Five-year survival for patients with CLL is 73%, however, for individual patients huge variation is seen.[6] The submission notes that the disease tends to present in three distinct forms:

Approximately one-third of patients never need treatment for CLL and have long survival; another third have an indolent phase of disease followed by disease progression promoting the initiation of treatment; remaining third have aggressive disease at the time of diagnosis and need immediate treatment (Source: GSK Submission, Section 2.3, p.23).

Staging systems such as the Binet (which assesses the number of areas of involvement) and Rai systems (Table 1 and Table 2) may also be used;[6] however, within these groups wide variation is seen and prognosis may be further influenced by additional factors. The submission notes that high levels of CD38 or ZAP-70 expression on leukaemic lymphocytes, and 17p or 11q chromosomal deletions are known to indicate poorer prognosis. Resistance to purine analogues, such as fludarabine, also defines a subset of patients with poorer prognosis (Source: GSK submission Section 2.1 p.17).

14 Table 1. Binet classification[6]

Stage Clinical features Median survival (yrs) A Lymphocytosis (in blood and bone marrow)* with <3 areas 12 of nodal involvement No anaemia or thrombocytopenia B Lymphocytosis* with 3+ areas of nodal involvement,† with or 7 without splenomegaly and/or hepatomegaly No anaemia or thrombocytopenia C Lymphocytosis* with anaemia (haemoglobin <11 g/dL in 2–4 men and <10mg/dL in women) or thrombocytopenia‡ (platelets <100 x 109/L) regardless of the number of areas of nodal involvement, splenomegaly, or hepatomegaly * Lymphocytes >5 x 109/L in the peripheral blood and comprising >30% of total nucleated cells in the bone marrow; † Each cervical, axillary, and inguinal area (whether unilateral or bilateral), spleen, and liver count as one area. Therefore, the number of areas of nodal involvement ranges from 1 to 5; ‡ excluding immune-mediated anaemia or thrombocytopenia

Table 2. Rai clinical staging system[6]

Risk level Stage Clinical features Median survival (yrs) Low 0 Lymphocytosis only (in blood and bone marrow)* 10 Intermediate I Lymphocytosis* with lymphadenopathy 7 II Lymphocytosis* with splenomegaly and/or hepatomegaly 7 with or without lymphadenopathy High III Lymphocytosis* with anaemia† (haemoglobin <11 g/dL) 1.5–4 with or without lymphadenopathy, splenomegaly or hepatomegaly IV Lymphocytosis* with thrombocytopenia† (platelets <100 1.5–4 x 109/L) with or without anaemia and/or lymphadenopathy, splenomegaly or hepatomegaly * Lymphocytes >5 x 109/L in the peripheral blood and comprising >30% of nucleated cells in the bone marrow; † Excluding immune-mediated anaemia or thrombocytopenia

2.1.4 Clinical features/symptoms

While patients may present with swollen lymph nodes (lymphadenopathy), symptoms of anaemia or infection, experiencing tiredness, night sweats or weight loss, the submission states that 50–80% are asymptomatic and diagnosed incidentally at a routine blood count (GSK Submission, Section 2.1, p18):

Patients can also present with swollen lymph glands and non-specific symptoms such as fatigue, malaise, weakness and abdominal discomfort. Constitutional ‘B’ symptoms; such as fever, night sweats, weight loss and extreme fatigue, are present in only about 15% of patients at diagnosis. The most common physical finding in CLL is lymphadenopathy, followed by splenomegaly, and less frequently, hepatomegaly. Patients may develop anaemia resulting in dyspnoea, and/or, thrombocytopenia with consequent bleeding and bruising, as normal bone marrow cells are progressively replaced by malignant cells.(O’Brien, 2009) Extra nodal involvement of the tonsils and skin has been observed, whereas involvement of the gastrointestinal tract, lungs, pleura, 15 central nervous system, kidney and bones is uncommon. (Yee, 2006) (GSK submission, Section 2.1, p18)

2.1.5 Burden and quality of life

The submission notes the limited range of quality of life information available for those with CLL (GSK Submission, Section 2.1, p18) some of which appears contradictory:

Studies using the European Organization for Research and Treatment of Cancer quality of life questionnaire (EORTC QLQ-C30) found that CLL patients reported a lower HRQL in almost every domain compared with healthy controls, with the greatest differences being in the areas of physical functioning, role functioning, fatigue and sleep disturbance. (Holzner 2004; Else 2008) Female patients tend to have lower HRQL scores in the areas of emotional and social functioning than males. (Holzner 2004)

Shanafelt et al, on the other hand found that, apart from emotional well-being scores, patients’ HRQL scores were similar to or better than published population norms. HRQL scores were lower among individuals with advanced stage disease (p<0.05). Treatment status was also related to HRQL. Factors associated with lower HRQL included older age, greater fatigue, severity of co-morbid health conditions and current treatment. (Shanafelt 2007) (GSK Submission Section 2.1, p18)

The Shanafelt study uses a web-based survey, in which less than one-half of invited respondents participated, with a median age of 59, while the Holzner study had a 78% response rate and a median age of 68, which may be possible contributory factors given the highly self selected nature of the Shanafelt study.[7,8] In addition, although the study by Holzner failed to identify any significant deterioration in HRQL over a year of follow up, one-third of participants were lost to follow-up, including for ‘deterioration of health condition’.[7]

It is noted that patients with CLL are highly susceptible to infections, and that this is particular concern for those heavily pre-treated, refractory patients who are the concern of this submission. However, no information about the impact of infection and their treatment on patient quality of life (QoL) is given (GSK Submission, Section 2.1, p18–19).

2.2 Critique of manufacturer’s overview of current service provision

In Section 2.3 of the submission, the manufacturer notes that there are guidelines for the treatment of CLL: diagnosis and treatment guidelines from the International Workshop on Chronic Lymphocytic Leukemia (2008) which updated 1996 guidelines from the National Cancer Institute - Working Group (NCI-WG),[9] and guidelines for diagnosis and treatment were also published by the British Society for Haematology (BSH) in 2004 (GSK submission, Section 2.3, p20).[10] The International guidelines define refractory disease as treatment failure (i.e. any response – stable disease (SD), non-response, progressive disease (PD), or death – other than complete remission [CR] or partial response [PR]), or treatment failure within six months 16 of the last treatment. However, there is no explicit suggestion about how to treat double refractory (DR) patients, only the suggestion that they should be considered for clinical trials.[9] Similarly, the BSH guidelines consider initial treatment, advanced or progressive disease, and a population resistant to fludarabine regimes, or with bulky nodes, (for whom alemtuzumab or high-dose methylprednisolone is recommended). No specific advice is given about the DR population.

It is worth nothing that although there is little published data on its effectiveness, high-dose methylprednisolone has been suggested as a possible alternative for the treatment of DR CLL patients.[10]

Several pieces of National Institute for Health and Clinical Excellence (NICE) guidance pertinent to this submission are identified by GSK (GSK Submission, Section 2.3, p20):

. 2003 publication Improving Outcomes in Haematological Cancers[4]

. 2009 guidance on fludarabine monotherapy as first line treatment in advanced CLL (TA119)[11]

. 2009 guidance on rituxumab as a first line treatment (TA174)[12]

. 2009 guidance on rituxumab for relapsed or refractory CLL[13]

None of the above guidance is pertinent to the population suggested for ofatumumab.

Pages 21–23 of the GSK submission outline current treatment for CLL, including presenting a treatment algorithm which indicate the anticipated place for ofatumumab (GSK Submission, Section 2.3, Figure 1, p23); this is reproduced in Figure 1.

17 Figure 1. A treatment algorithm for chronic lymphocytic leukaemia

Untreated ~33% CLL prevalent Watch and Wait Population1

Old, frail, ‘unfit’ Treated ~66% ‘Fit’ patients patients

Fludarabine + cyclophosphamide (FC) Chlorambucil FC + rituximab (FCR)3 (+ rituximab)3 FCA / FCAR (17p del pts)3,4

Relapse ≥ 12 Relapse < 12 Relapse ≥ 12 Relapse < 12 months months months months

Retreat ≥ 2nd line2 nd Retreat ≥ 2 line FCR3 CHOP/CVP FCM Low dose FC R + other chemo comb (e.g. FCMR)3 4 Alemtuzumab Alemtuzumab4 High-dose steroids FCA / FCAR (17p del pts)3,4 5 Investigational therapies High-dose steroids Investigational therapies5 ASCT

Patients refractory to Patients refractory to fludarabine and alemtuzumab Consider for fludarabine and alemtuzumab (Double refractory, DR) Ofatumumab6 (Double refractory, DR) Best supportive care (BSC) Best supportive care (BSC)

CHOP, cyclophosphamide,doxorubicin, vincristine, and prednisolone; CVP, cyclophosphamide, vincristine, prednisolone; FC, fludarabine, cyclophosphamide; FCR, fludarabine, cyclophosphamide, rituximab; FCA, fludarabine, cyclophosphamide, alemtuzumab; FCM, fludarabine, cyclophosphamide, mitoxantrone; FCMR, fludarabine, cyclophosphamide, mitoxantrone, rituximab; FCAR, fludarabine, cyclophosphamide, alemtuzumab, rituximab; ASCT, allogenic stem cell transplantation Notes: Approximately a third of patients never need treatment for CLL and have long survival; another third have an indolent phase disease followed by disease progression prompting the initiation of treatment; remaining third have aggressive disease at time of diagnosis and need immediate treatment (Dighiero 2003). There is no clearly defined treatment pathway for the second-line and subsequent treatment of CLL. Rituximab is licensed in combination with chemotherapy in both first-line and relapsed/refractory settings but recommended by NICE only in combination with fludarabine + cyclophosphamide (FCR); FCR is not recommended by NICE in relapsed/refractory patients when refractory to fludarabine and/or previously treated with rituximab Alemtuzumab may be considered in chemo-refractory patients (e.g. patients with 17p deletions) Investigational therapies may include bendamustine, lenalidomide, oblimersen, lumiliximab Patients eligible for ofatumumab should be refractory to a fludarabine-containing regimen and an alemtuzumab-containing regimen (double refractory, DR). Refractory disease is defined as the failure to achieve at least a partial response to treatment or disease progression while taking a drug or within 6 months of the last dose of treatment. (Source: GSK submission, Figure 1, Section 2.3, p23)

18 3 Critique of manufacturer’s definition of decision problem

3.1 Population

The population considered by the submission is:

…patients who are refractory to a fludarabine-containing regimen and also refractory to an alemtuzumab-containing regimen (Source: GSK Submission, Section 5.2.1, p39)

Patient characteristics for this population in study Hx-CD20-406 are reported as follows:

The median age of patients was 64 years, the majority were male and they were mostly white. Over half of patients had an impairment of their daily living abilities (ECOG performance status 1 or 2). The majority had high risk CLL at baseline (more than 50% were Rai stage III or IV and Binet stage C). Over two-thirds of the DR group had a chromosomal abnormality associated with adverse outcomes in CLL (17p or 11q deletions). Approximately 60% of DR patients had constitutional symptoms and organomegaly and more than 90% had bulky lymphadenopathy. Baseline cytopenias observed were consistent with advanced CLL. Nearly all patients had a concurrent medical condition, with patients most often affected by hypertension and anaemia (occurring in ≥20%). The DR study population was heavily pre-treated. Nearly half had received more than five previous treatment regimens for CLL (median 5 [range 1–14]). Most patients (93%) had received a regimen incorporating an alkylating agent. All patients had received fludarabine with 85% having received a regimen that included fludarabine plus one other drug. Nearly 60% of patients had received a rituximab- containing regimen. (Source: GSK Submission, Section 5.8.4, pp51–52)

This is an adequate description of the population, and concurs with that defined in the NICE Scope.[1] Overall, the ERG considers the population to be reflective of the actual clinical population in England and Wales.

The Hx-CD20-406 study was a multi-national study involving five sites in the UK, which recruited 24 patients of the total 154. Data from each of the subgroups (DR, BFR, ‘other’) have been analysed separately. Only data from the DR group are presented in this submission in line with the approved indication for ofatumumab. The total DR patient population is 59 of which 14 were from the UK.

3.2 Intervention

The intervention is ofatumumab (Arzerra®, GSK). It received US Food and Drug Administration (FDA) approval for the treatment of patients with CLL refractory to fludarabine and alemtuzumab in October 2009. In January 2010 EMEA’s Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion recommending the grant of a conditional marketing authorisation for the treatment of CLL in patients who are refractory to fludarabine and alemtuzumab (i.e. DR patients). The manufacturer anticipates that ofatumumab will 19 receive marketing authorisation at the end of March / early April 2010 and will be made commercially available in the UK during 2Q 2010.

In addition the manufacturer notes:

Ofatumumab was granted Orphan Drug Designation in November 2008 for the treatment of chronic lymphocytic leukaemia in patients who have failed therapy with fludarabine and alemtuzumab or in patients who have failed therapy with a fludarabine- containing regimen and have bulky lymphadenopathy. (Source: GSK Submission, Section 1.3, p11)

Ofatumumab is available as a 20 mg/ml concentrate solution for infusion in 100 mg (5 ml) vials and required dilution under aseptic conditions in 0.9% sodium chloride prior to infusion. Ofatumumab is given as a single course of treatment, comprising a weekly infusion for 8 consecutive weeks, followed by monthly infusions for 4 months. The dose for the first infusion is 300 mg and 2,000 mg for subsequent infusions. Repeat courses are not anticipated. Pre-medication with paracetamol, anti-histamine and i.v. corticosteroid therapy is advised in order to attenuate infusion-related adverse events. (Source: GSK Submission, Page 4)

3.3 Comparators

The single comparator presented in the submission was best supportive care (BSC), where BSC comprised:

symptomatic management of cytopenias with blood products/colony stimulating factors (CSFs); anti-infective prophylaxis and treatment; corticosteroids (not high dose); and, regular monitoring via outpatient clinic. (Source: GSK Submission, Section 2.6, p24)

GSK’s description of BSC fits well with current clinical practice in England and Wales.

The choice of BSC as a comparator is in line with the final scope.[1] There is no standard of care, or consensus for active treatment in this DR population with guidelines focusing on first- and second-line treatment, as discussed in Section 2.2.[14] The final scope lists other comparators including; cyclophosphamide, doxorubicin, vincristine, prednisolone (CHOP) with or without rituximab; rituximab in combination with chemotherapy (other than fludarabine- containing chemotherapy [subject to ongoing NICE appraisal]; and, high-dose corticosteroids. Patients in study Hx-CD20-406 were heavily pre-treated – 27 (46%) of patients had more than five prior CLL therapies – and it is likely that they will have exhausted most therapeutic options including those suggested as comparators in the final scope.[1] Providing the individual patient treatment histories would have confirmed absolutely that most patients in study Hx-CD20-406 were indeed heavily pre-treated particularly the small number of patients receiving one or two treatments. However, this information was not available when requested from GSK – see Appendix 1: GSK Response Document – 10 March 2010.

20 3.4 Outcomes

The pivotal Phase III study Hx-CD20-406 was used to provide efficacy and adverse event (AE) data for ofatumumab. The primary outcome measure was:

Objective response as measured over a 24-week period from start of treatment, assessed by an IRC according to the NGI-WG-CLL guidelines criteria [Cheson, 1996]. (Source: GSK Submission, Section 5.8.2, Table 5.4, p48)

Secondary outcome measures included:

. time to onset of response

. duration of response

. progression free survival

. time to next CLL therapy

. overall survival

. reduction in tumour size

. safety and pharmacokinetic endpoints.

The outcome measures are in line with the scope;[1] however, HRQL is not measured in or alongside the study and is therefore not reported.

The outcomes for the economic analysis were progression free survival (PFS) and overall survival (OS). This is consistent with clinical outcomes used in oncology trials.

3.5 Timeframe

The time horizon evaluated in the model was ten years which approximates a lifetime time horizon for DR CLL patients; no additional benefits were assumed beyond this timeframe. This is an appropriate length of follow-up at time of interim analysis.

3.6 Other relevant factors

Of note is that the clinical effectiveness data were taken from the interim analysis at 19th May 2008 of study Hx-CD20-406. Although the ERG requested more recent data; GSK stated that none were available.

Study Hx-CD20-406 is an ongoing, Phase III, single arm, non-randomised study. GSK justify the use of a single-arm study design as follows:

21 A non-randomised study design was chosen for Hx-CD20-406 to ensure that all patients had the opportunity to derive potential clinical benefit from ofatumumab, on the basis that:

 salvage therapies have been associated with low response rates and high rates of complications in these populations  a Phase I/II study of ofatumumab (2,000mg dose group) had shown substantial activity and a favourable safety profile in refractory CLL patients  a study involving randomization to a comparator expected to have low efficacy and substantial toxicity or to best supportive care (BSC) was deemed to be unethical. (Source: GSK Submission, Section 5, p36)

However, the ERG note that the effectiveness of other last-line cancer treatments have certainly been successfully evaluated using trials with parallel BSC groups for comparison with historical controls; for example, everolimus for the treatment of advanced renal cell carcinoma.

Some historical data are reported in the Tam study, which describes the outcomes seen with salvage therapies in DR CLL patients.[3] The manufacturer acknowledges that Tam 2007 might offer possible comparator data but argue that it is not appropriate to use this in the economic analysis, citing the following reasons:

the study was conducted at an international centre of excellence (MD Anderson Cancer Centre, Texas) and hence the outcomes seen are not readily generalisable to other centres; the regimens used tend to be aggressive, experimental, and do not reflect UK practice;

the study reports only overall survival (OS) and not progression-free survival (PFS) data, hence a number of assumptions would need to be made using the relationship seen between OS and PFS;

the study is retrospective with data reported historically over a 20 year period;

data for 21 different salvage therapies are reported, but the numbers of patients receiving each individual treatment are very small such that an analysis for each treatment becomes difficult to interpret.(GSK submission, Section 2.6, p25)

However, this is in contrast to the information included in their response to PenTAG requests for clarification (see Appendix 1: GSK Response Document – 10 March 2010). Provided as commercial in confidence (CiC) data, this reproduces the GSK response to EMEA***************************************************************************************************** ************************************************************************************************************ ************************************************************************************************************ ************************************************************************************************************ ************************************************************************************************************ ************************************************************************************************************ ************************************************************************************************************ ************************************************************************************************************

22 ************************************************************************************below***************** ************************************************************************************************************ *********

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************************* ************************* * ********** ********** ********** *********** ************************ ********** *********** *********** *********** ************************************ *** *** *** *** ************************* *********** *********** *********** *********** * * ***************************** *********** *********** ********* ******** ****************** * ** **** ****

24 4 CLINICAL EFFECTIVENESS

4.1 Critique of manufacturer’s approach

4.1.1 Description of manufacturers search strategy and comment on whether the search strategy was appropriate.

Manufacturer searches were performed in the following databases on 22 October, 2009:

. OVID MEDLINE 1950 to present

. OVID MEDLINE (R) In-process & Other non-indexed Citations

. OVID EMBASE

. The Cochrane Library (CENTRAL and NHS EED)

Separate search strategies were provided for EMBASE, Medline with Medline in-process, and The Cochrane Library. The Medline and EMBASE search strategies used were conducted in the format:

[Chronic lymphatic leukaemia] AND [(terms identifying ofatumumab) OR (terms identifying drugs currently used to treat CLL as various stages) OR (bone marrow transplantation)] AND [(study type filter) OR (utility terms)]. For each term, a combination of thesaurus headings (where possible) and free-text search-words was used. No additional limitations or search filters were utilised. The Cochrane Library search utilitsed the format: [Chronic lymphatic leukaemia] AND [(terms identifying ofatumumab) OR (terms identifying drugs currently used to treat CLL as various stages) OR (bone marrow transplantation)]

Searches were also carried out in the following conference proceedings from 2004 to 2009:

. American Society of Clinical Oncology (ASCO)

. American Society of Hematology (ASH)

. European Haematology Association (EHA)

. Additionally the manufacturer searched www.clinicaltrials.gov for ongoing trials.

Additional reference list searching was conducted in clinical trial publication, systematic reviews, and qualitative reviews in the disease area.

25 All the combination of terms within the search strategies to define the chronic lymphatic leukaemia population and/or the intervention and resources used were appropriate, replicable, and the resulting hits appear correct given the search date and database/interface used. The study type filter was predominantly aimed at controlled trials with an additional heading for prospective studies. The utilities filter was a combination of method of gaining the utility (e.g. time trade off) and general quality of life terms and utility measures such as EQ5D. We ran a search within the same databases on ofatumumab to look for any adverse events related to the drug and for any potential additional trials along with a limited utilities search.

4.1.2 Statement of the inclusion/exclusion criteria used in the study selection and comment on whether they were appropriate.

The submission included the following kinds of studies of clinical effectiveness:

Table 3. Eligibility criteria used in search strategy

Inclusion Population Patients with relapsed or refractory CLL with any criteria disease stage (Binet stage A, B or C, or Rai stage 0 to IV)  Patients aged ≥ 18 years with no restriction on gender or race.  As explained earlier, on the basis of the anticipated indication for ofatumumab at the time this review was initiated two sub-populations were considered:  Patients who are refractory to a fludarabine-containing regimen and also refractory to an alemtuzumab-containing regimen (double-refractory [DR] patients)  Patients who are refractory to a fludarabine-containing regimen and also have bulky lymphadenopathy (bulky- fludarabine refractory [BFR] patients) Note: For the purposes of this review, refractory was defined as failure to achieve at least a partial response (PR) or disease progression within 6 months of last dose of treatment. Lymphadenopathy (bulky disease) was defined as at least one lymph node ≥5cm. Studies were accepted if these definitions were absent or different but this has been noted

Interventions Interventions:

Stem cell/bone marrow transplant: Autologous / Allogeneic

Corticosteroids: Methylprednisolone

Monoclonal antibodies: Rituximab; Alemtuzumab; Ofatumumab

26 Chemotherapy agents: Chlorambucil (oral alkylating agent); Cylophosphamide (oral alkylating agent); Fludarabine (purine analogue); Bendamustine (purine analogue); Oblimersen

Stem cell/bone marrow transplant: Autologous / Allogeneic

Any combination regimens of the above.

Comparator/controls:

Any of the above medications or placebo, best supportive care (BSC), standard care (SoC), no treatment.

There were no restrictions on dose, formulation or mode of delivery (e.g. i.v./oral).

Outcomes Efficacy outcomes:

 Overall survival (OS)  Event-free survival  Progression free survival (PFS)  Response to treatment (objective response rates [ORR], complete response [CR] rates and partial response [PR] rates)  Time to and duration of response  Symptom improvement

Quality of life (HRQL):

 Any HRQL outcome reported

Safety and tolerability:

 Withdrawals for any reason, due to lack of efficacy and adverse events (AEs)  Incidences of any AE reported with a particular focus on  Infusion-related reactions  Infection rates  Haematological toxicities  Mortality – all cause / specific cause where reported

Economic outcomes:

 Hospitalisations and associated costs  Drug acquisition/pharmacy costs  Administration costs  Supportive care/monitoring costs  Costs associated with adverse event management  Physician charges  Laboratory fees.

Note: Economic outcomes were reviewed in a broader 27 relapsed/refractory CLL population due to the scarcity of data in the DR and BFR populations specific to this review.

Study design  Prospective and retrospective studies  Randomised controlled trials (RCTs)  Non-RCTs, including single arm, observational and cohort studies and case series  Studies of cost-effectiveness in relapsed / refractory CLL Date No restriction on date restriction

Language No restriction, based on the databases searched restriction

Exclusion Population Any study not including at least one patient with either criteria DR or BFR CLL was excluded

Interventions Any study not including at least one of the interventions listed above for the treatment of either DR or BFR patients was excluded

Outcomes Any study not reporting data for at least one of the above outcome measures was excluded

Study design Due to the limited number of studies relevant to the decision problem, no studies were excluded on the basis of study design

Language Based on the databases searched, no studies were restriction excluded on the basis of language

(Source: GSK Submission, Section 5.2.1, Table 5.1, pp39–41)

Studies were included / excluded on the basis of the criteria in Table 3. Eligibility criteria used in search strategyand the results of each stage of the inclusion / exclusion process are summarised in Figure 5.1. to be included in the first-pass, the study was required to have a purine analogue/fludarabine-refractory population treated with a specific intervention. A total of 20 relevant publications were identified as meeting the inclusion criteria for the review. No RCTs were identified and these were all non-RCTs. (Source: GSK Submission, Section 5.2.2, p41)

These inclusion and exclusion criteria are appropriate. The manufacturer notes in Section 9.6.6 that:

…At the time this systematic review was initiated in October 2009, the anticipated indication for ofatumumab was for the treatment of patients with chronic lymphocytic leukaemia (CLL) who have failed therapy with fludarabine and alemtuzumab (i.e. double refractory [DR] patients) or in patients who have failed therapy with a fludarabine containing regimen and have bulky lymphadenopathy (i.e. bulky fludarabine refractory [BFR] patients). The Committee for Medicinal Products for Human use (CHMP) has since (January 2010) adopted a positive opinion, recommending the granting of a conditional marketing authorization for the treatment of chronic lymphocytic leukaemia (CLL) in 28 patients who are refractory to fludarabine and alemtuzumab (i.e. DR patients only). As the review was commissioned prior to GSK receiving the positive opinion, the protocol for the review was written to encompass the data requirements of the broader anticipated indication and therefore include studies identified in both DR and BFR populations. (Source: GSK Submission, Section 9.6.6, p187)

The submission explains the processes used in study selection and data extraction which is in line with the standard review process. Details of the excluded studies were not presented in the report.

4.1.3 Table of identified studies. What studies were included in the submission and what were excluded?

The search results presented by the manufacturer did not identify any randomised controlled trials (RCTs) directly comparing ofatumumab with an appropriate comparator. Twenty non- RCTs including CLL patients with DR and/or BFR disease were identified by the systematic review. Of the studies identified:

...six reported outcome data specifically for these sub-populations (primary studies). This comprises one single-arm study (Hx-CD20-406) providing evidence for ofatumumab, the intervention under consideration, and five other non-comparative studies providing evidence for other therapies that have been used in these DR and/or BFR settings. Only three studies reported outcome data specifically for DR patients, one of which is the ofatumumab study… A further 14 studies were identified which included at least one DR and/or BFR patient but which did not report outcome data stratified for these populations. (Source: GSK Submission, Section 5.2.7, pp43-44)

Of the three studies reporting outcome data specifically for DR patients (Hx-CD20-406; Tam et al; and, Dungarwalla et al),[2,3] only the ofatumumab study is described further in the main body of this submission. Although GSK state:

Since the other studies [Tam et al and Dungarwalla et al] are non-comparative and provide evidence for therapies other than ofatumumab, an indirect/mixed treatment comparison with ofatumumab was not possible. These studies are not therefore discussed in the main body of this submission,… (Source: GSK Submission, Section 5.2.7, p43) the manufacturer cross references the Tam study in the clinical effectiveness section.

29 4.1.4 Details of any relevant studies that were not included in the submission

We did not identify any relevant studies that were not included in the submission.

4.1.5 Description and critique of manufacturer’s approach to validity assessment

Currently there is no agreed ‘gold standard’ appraisal tool for the assessment of non- randomised studies. There are no tools which have been specifically designed to identify the main threats to validity which are likely to exist for the design employed in study Hx-CD20-406; i.e. a single-arm study.

The manufacturer reports the quality assessment of Hx-CD20-406 using a Centre for Reviews and Dissemination (CRD) quality assessment tool for case series with the addition of some questions from NICE’s guidance to manufacturers on Single Technology Appraisals (STAs). Details of GSK’s critical appraisal of study Hx-CD20-406 alongside our critique can be seen in Table 4 below. Please note that italicised text has been cited directly from the submission (cross references are given).

30 Table 4. Critical appraisal of study Hx-CD20-406

Critical GSK assessment ERG comment appraisal criterion Was a Yes – see Table 5.8 Based on advice from clinical experts, it was estimated justification for (Source: GSK that the ORR on best supportive care (BSC) in these the sample Submission, Section patient populations was 15% and that an ORR of 30% size provided? 5.8.8, Table 5.9, p62–63) on ofatumumab would be a clinically important observation. Assuming that the ORR was 30%, the probability that the two-sided 99% confidence interval (CI) would exclude an ORR of 15% was 63%, based on data from 66 patients (primary endpoint interim analysis) and 92% based on data from 100 patients (primary endpoint analysis). This applied equally for both the DR and BFR subgroups. A maximum of approximately 225 patients was therefore expected to be enrolled. (Source: GSK Submission, Section 5.8.6, Table 5.8, p59) In the total DR population of 59 the ORR is 58% which is greater than anticipated. Were selection Yes – see Table 5.5 Yes, the study eligibility criteria are specified and match criteria (Source: GSK those outlined in the final scope: adequately Submission, Section Patients aged ≥18 years with active CLL (1996 NCI-WG reported? 5.8.8, Table 5.9, p62–63) criteria) [NCI-WG, 1996] indicated for treatment, tumour immunophenotype of CD5+/20+/23+, Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2, and life expectancy of ≥6 months were eligible for enrolment. There were no restrictions based on blood counts or transfusion requirements. Patients were required to be refractory to at least one fludarabine-containing regimen and either refractory to at least one alemtuzumab-containing regimen or considered less suitable for alemtuzumab as a result of bulky (>5cm) lymphadenopathy. Bulky lymphadenopathy was confirmed either by physical examination or computed tomography (CT) scan at screening. Refractoriness to fludarabine (at least two cycles) and alemtuzumab (at least 12 doses) was defined as failure to achieve at least partial response by 1996 NCI-WG criteria or disease progression during treatment or within 6 months of the last dose of each agent (see GSK Submission, Section 5.8.3, Table 5.5, pp50–51).

The process of determining selection is also specified. An independent review committee (IRC), comprising five experts in the treatment of CLL (including two authors of the 1996 NCI-WG guidelines), was used to determine patient eligibility for the study. The IRC made determinations of eligibility independently and was blinded to the assessments of other IRC members. At least two IRC members evaluated eligibility for each subject. The presence of bulky lymphadenopathy was determined by CT scan (Source: GSK Submission, Section 5.8.3, p 50).

31

Were patients Yes (Source: GSK Yes, patients were recruited prospectively. recruited Submission, Section prospectively? 5.8.8, Table 5.9, p62–63) Were patients Not reported (Source: Not reported. It is particularly difficult to judge as the recruited GSK Submission, number of recruiting centres is large relative to the total consecutively? Section 5.8.8, Table 5.9, number of patients recruited. Concerning the issue p62–63) underlying this question, it is not known if all the patients with the stated inclusion criteria available in the recruiting centres were actually included in this study, and indeed is probably not amenable to accurate estimation. Was follow-up Yes. Subjects were Overall follow-up until Month 48; however, for the interim adequate and followed for survival until analysis subjects were followed up for 24 months. was loss to Month 48 (Source: GSK Additional information on censoring time-to-event follow-up Submission, Section analyses would have been reassuring. Although there reported or 5.8.8, Table 5.9, p62–63) may have been minimal loss to follow-up for survival this explained? also needs to be considered separately for each outcome assessed. Many of these outcomes do however seem to account for all 59 patients in the DR series. Were the Open-label study. The study was a single-arm study in which all patients individuals Objective responses were on ofatumumab. As such no blinding was possible. undertaking were assessed by an Although objective responses were assessed by an the outcomes Independent Review Independent Review Committee blinded to the results of assessment Committee (IRC) blinded other IRC member’s determinations and to investigators’ aware of to the results of other response determinations bias in the measurement of allocation? IRC member’s outcomes is likely especially outcomes with a subjective determinations and to component. It seems likely that knowledge of response investigators’ response status will influence perceptions of subsequent determinations (Source: outcomes like AEs. In response to request for GSK Submission, clarification the manufacturer acknowledged that there Section 5.8.8, Table 5.9, was disagreement between individual IRC readers p62–63) assessments of response. Was the study Yes. Multicentre trial Yes, Hx-CD20-406 was an international, multicentre conducted in conducted in the US and study. Patients were enrolled from 41 centres in ten the UK (or Europe, including five countries; five sites were in the UK which recruited 16 were one or sites in the UK which patients. more centres recruited 16 patients of the (Source: GSK As with any multicentre trial there is uncertainty multinational Submission, Section surrounding the applicability; moreso because the DR study located 5.8.8, Table 5.9, p62–63) population was small (n=59) of which 14 were from the in the UK)? UK. Were Yes. Patients in the study The characteristics of patients recruited to the study participants allocated to the DR were similar to the DR population in England and Wales, included in the (refractory to both and in line with the proposed indication for ofatumumab. study reflective fludarabine and of patients alemtuzumab) & BFR likely to receive (refractory to fludarabine the intervention & inappropriate for in UK clinical alemtuzumab due to practice? bulky disease) groups reflect the indication for ofatumumab (see

32 Section 5.10.4) How does the Dosage regimen used in Dosage regimen used in the study is the same as the dosage the study is the same as dosage regimen proposed on the Summary of Product regimen used the dosage regimen Characteristics (SmPC). However, as already noted the in the study proposed on SmPC manufacturer suggests the dose: is greater than will be compare with (Source: GSK used in future indications currently under investigation. that detailed in Submission, Section The drug price suggested in the Patient Access Scheme the Summary 5.8.8, Table 5.9, p62–63) (PAS) appears to have been set, in part, to reflect this. of Product Characteristics (SmPC)? Were the Yes – see Section 5.8.6 The approach to the statistical analysis of the Hx-CD20- statistical (Source: GSK 406 study was appropriate for the study design analyses used Submission, Section employed – see Section 4.1.7.1 of the ERG report for appropriate? 5.8.8, Table 5.9, p62–63) further detail. We note that the analysis was pre-planned interim analysis of data from 19 May 2008, although more recent data were requested by the ERG the manufacturer advised that none were available. Were Yes (Source: GSK 95% CIs and/or P values are available for most appropriate Submission, Section outcomes reported. measures of 5.8.8, Table 5.9, p62–63) variability reported? Was an No as the study was non- As indicated, the analysis adopts ‘intention to treat’ intention-to - randomised but the full principles appropriate to the study design employed. treat analysis analysis set (FAS) undertaken? comprised all patients exposed to the trial drug (Source: GSK Submission, Section 5.8.8, Table 5.9, p62–63) Were there any No (Source: GSK This is incorrect. The comparison between the whole DR confounding Submission, Section population and non-responders (the basis of the factors that 5.8.8, Table 5.9, p62–63) effectiveness derived from study Hx-CD20-406 used in may attenuate the economic analysis) is clearly confounded as the indicated by the imbalance of prognostic factors; e.g. interpretation 17p deletions (see Table 5.6 [Section 5.8.4, p52), which of the results of alone might account for the effects observed and the study? attributed to ofatumumab. It is for this reason that adjustment to take into account the estimates of OS and PFS used in the economic analysis. Did the study Yes – see Section We highlight the imbalance in the ‘treatment’ and report data for 5.8.9.4 (Source: GSK ‘control’ group in prognostic factors. relevant Submission, Section prognostic 5.8.8, Table 5.9, p62–63) factors?

4.1.6 Description and critique of manufacturer’s outcome selection

The primary outcome measure in study Hx-CD20-406 was objective response as measured over a 24-week period from start of treatment, assessed by an IRC according to the NCI-WG CLL guidelines criteria (Source: GSK Submission, Section 5.8.5, pp53–58). Secondary

33 outcome measures included duration of response (time from the initial response to progression or death) and the following events calculated from time of first ofatumumab infusion: time to response, PFS and OS. (Source: GSK Submission, Section 5.8.5, pp53–58).

The manufacturer uses outcome measures used in the Hx-CD20-406 study which concurs with the outcome measures used in the final scope;[1] however, HRQL is not measured in or alongside the trial and is therefore not reported. Throughout the clinical effectiveness section the manufacturer refers narratively to historical data reported in the Tam study, which describes the outcomes seen with salvage therapies in DR CLL patients.

4.1.7 Describe and critique the statistical approach used

4.1.7.1 Hx-CD20-CLL: statistical analysis

The interim analysis was triggered when primary endpoint data were available from 66 DR patients, which was the minimum number of patients that would enable a reasonable power to test the null hypothesis. (Source: GSK Submission, Section 5.8.6, Table 5.8, p59)

Based on advice from clinical experts, it was estimated that the ORR on best supportive care (BSC) in these patient populations was 15% and that an ORR of 30% on ofatumumab would be a clinically important observation. Assuming that the ORR was 30%, the probability that the two-sided 99% confidence interval (CI) would exclude an ORR of 15% was 63%, based on data from 66 patients (primary endpoint interim analysis) and 92% based on data from 100 patients (primary endpoint analysis). This applied equally for both the DR and BFR subgroups. A maximum of approximately 225 patients was therefore expected to be enrolled.

A superiority and a futility analysis was performed by the Data Monitoring Committee (DMC), including an independent statistician. If the CI for the ORR excluded a 15% response rate for either of the DR or BFR subgroups, the DMC was required to notify the sponsor that the criteria for superiority for that subgroup had been met. If the conditional power for the corresponding subgroup under the alternative hypothesis was below 10%, the DMC was to recommend stopping recruitment of more patients to that subgroup due to futility. (Source: GSK Submission, Section 5.8.6, Table 5.8, p59)

Sensitivity analyses of the interim primary endpoint were conducted based on investigators’ assessments and assessments by the sponsor. (Source: GSK Submission, Section 5.8.6, Table 5.8, p59)

Interim analyses of secondary endpoints were conducted at the time of interim primary endpoint analysis. A sensitivity analysis of PFS was conducted based on investigator assessment of progression. (Source: GSK Submission, Section 5.8.6, Table 5.8, p59)

Time to event endpoints (time to and duration of response, PFS and OS) were evaluated using Kaplan-Meier estimates from which median times have been derived. Associate between response and OS was evaluated using a post hoc ‘landmark analysis’ [Anderson, 2008] of responders vs non-responders alive at 12 weeks. (Source: GSK Submission, Section 5.8.6, Table 5.8, p59)

Adverse events (AEs) and clinical safety data were summarized using descriptive statistics. 34 There were three trial sub-populations which were analysed separately. Data presented in this submission are for the DR population only. Patients were classified as responders or non- responders based on objective response over a 24-week period, where patients with a complete remission (CR), nodular partial response (nPR) and partial response (PR) have been classified as responders while patients with stable disease (SD) and progressive disease (PD) are classified as non-responders. Pre-planned sub-group analyses of the primary endpoint by baseline characteristics: age, gender, prior treatment, prognostic factors were carried out. However, the trial was not powered to detect differences in these subgroups.

The approach to the statistical analysis of the Hx-CD20-406 study was generally sound. However, the statistical analysis uses interim data from study Hx-CD20-406 as at 19 May 2008. The ERG requested more recent data but the manufacturer advised that these were not available. The manufacturer reports, ‘the interim analysis was triggered when primary endpoint data were available from 66 DR patients’ yet the submission reports primary endpoint data for 59 patients rather than 66 patients as stated in the above.

4.1.8 Summary statement

The submission contains all the relevant studies and the relevant data within those studies. The submitted evidence also adequately reflects the decision problem defined in the submission.

The main source of evidence on effectiveness is the Hx-CD20-406 study, although the manufacturer draws comparisons with the Tam study (2007) throughout the clinical effectiveness section.

4.2 Summary of submitted evidence

4.2.1 Summary of results

4.2.1.1 Primary endpoint results

4.2.1.1.1 Overall response rate (ORR) The ORR was 58% for the DR group in the IRC evaluation for the Full Analysis Set (FAS), surpassing the pre-specified 15% criterion for superiority (p<0.0001). This result was reflected in the overall study population (n=138) which found an ORR of 52% (95% CI: 41,62; p<0.0001) by IRC assessment. All responses in DR patients were PRs. Stable disease was noted in an additional 31% of DR patients. The ORR in the per protocol (PP) population was higher than in the FAS population (DR n=41, 73% (99% CI: 52%, 89%), p<0.0001). (Source: GSK Submission, Section 5.8.9.3, p64)

35 Table 5. Summary of responses in Hx-CD20-406 assessed by IRC (DR population)

DR (N=59) Objective Response Rate Responders, n (%) 34 (58) 99% CI (%) (40, 74) p value p<0.0001 Response CR, n (%) 0 nPR, n (%) 0 PR, n (%) 34 (58) SD, n (%) 18 (31) PD, n (%) 2 (3) NE, n (%) 5 (8) CI, confidence interval; CR, complete remission; NE, not evaluable* ; nPR, nodular partial response; PD, progressive disease; PR, partial response; SD, stable disease * not evaluable due to patient withdrawal, refusal, non-trial drug related AEs and death 99% CI: Two-sided 99% exact CIs were calculated based on the binomial distribution p-value taken from two-sided exact binomial test of H0: CR rate = 15% (Source: GSK Submission, Section 5.8.9.3, Table 5.11, p64)

In order to test the robustness of the ORR, sensitivity analyses using investigator- based assessments and a sponsor programmed algorithm were applied. The response rates by each method exceeded the pre-specified 15% superiority criterion (excluding 15% at the lower limit of the CI) and the target for meaningful clinical efficacy of 30% (Table 5.12 [Table 6 of the ERG report below]), confirming the activity of ofatumumab in this population. (Source: GSK Submission, Section 5.8.9.3, p64)

Table 6. Summary of assessment of ORR in Hx-CD20-406 by Investigator and Sponsor (DR population)

DR (N=59) Investigator assessment Responders, n (%) 25 (42) 99% CI (%) (26, 60) p value p<0.0001 Sponsor-calculated assessment Responders, n (%) 22 (37) 99% CI (%) (22, 55) p value N/A CI, confidence interval 99% CI: Two-sided exact confidence intervals were calculated based on the binomial distribution p-value taken from the two-

sided exact binomial test of H0: CR rate = 15% (Source: GSK Submission, Section 5.8.9.3, Table 5.12, p65)

Differences in the response rate according to the three methods largely reflected differences in clinical assessment of transient changes (for example, in lymphocyte

36 counts) that an expert would not necessarily interpret as evidence of disease progression. The algorithmic approach by the sponsor did not account for this and so represented the most stringent test of the response rate. Nevertheless, the concordance rates between the IRC and sponsor were 80% for the DR group. (Source: GSK Submission, Section 5.8.9.3, p65)

Pre-specified subgroup analyses of ORR (IRC assessment) by selected baseline characteristics were conducted and the results are shown in Table 5.13 (see Table 7 of the ERG report below). Advanced age or the number of prior CLL treatment regimens did not appear to influence the response to ofatumumab in the DR group. Use of steroid pre- medication did not have an additive effect on the response to ofatumumab in this group. Prior treatment with rituximab did not appear to have a significant effect on ofatumumab efficacy. Deletions of 17p and 11q are often associated with a poor response to CLL treatment. In the DR group, 17p deletion was associated with a lower but, nevertheless, reasonable response rate and those with 11q deletions had similar response rates as those without. (Source: GSK Submission, Section 5.8.9.3, p65)

37 Table 7. Objective response rate in Hx-CD20-406 by baseline characteristics (IRC assessment, DR population)

DR (N=59) Characteristic n/N (%) p-value* Age <65 years 20/32 (63) 0.4400 ≥65 years 14/27 (52) <70 years 28/49 (57) 1.0000 ≥70 years 6/10 (60) Gender Female 10/15 (67) 0.5484 Male 24/44 (55) Number of prior therapies >2 prior therapies 30/52 (58) 0.3550 ≤2 prior therapies 4/7 (57) Prior rituximab Prior use 19/35 (54) 0.5984 No prior use 15/24 (63) Prior FCR Refractory to FCR† 8/16 (50) 0.5585 Other† 26/43 (60) Prior FC (any) Refractory to FC‡ 21/33 (64) 0.4264 Other‡ 13/26 (50) Palpable lymph node size >5cm 24/43 (56) 1.0000 ≤5cm 6/11 (55) Disease stage Rai stage I or II 15/26 (58) 1.0000 Rai stage III or IV 18/32 (56) ECOG PS ECOG PS 0–1 27/46 (59) 1.0000 ECOG PS 2 7/12 (58) Steroid pre-medication 100% use of steroid pre-medication 28/52 (54) 0.221 <100% use of steroid pre-medication 6/7 (86) FISH cytogenetic abnormalities 17p deletion 7/17 (41) 0.1429 No 17p deletion 26/40 (65) 11q deletion 15/24 (63) 0.5963 No 11q deletion 18/33 (55) 12q trisomy 1/3 (33) 0.5669 No 12q trisomy 32/54 (59) 13q deletion 4/5 (80) 0.3851 No 13q deletion 29/52 (56) ECOG PS, Eastern Cooperative Oncology Group performance status; FCR, fludarabine in combination with cyclophosphamide plus rituximab; FC, fludarabine in combination with cyclophosphamide * Two-sided Fischer’s exact test. † Patients considered refractory to FCR, with or without other drugs; other represents patients refractory to a fludarabine-based regimen other than that containing FCR; ‡ Patients considered refractory to FC, with or without other drugs; other represents patients refractory to a fludarabine-based regimen other than that containing FC. (Source: GSK Submission, Section 5.8.9.3, Table 5.14, p65)

38 Examining the baseline characteristics of responders versus non-responders (based on the 24-week assessment) indicates that the responders and non-responders in the DR group were similar for age, performance status and disease stage. Responders had had a diagnosis of CLL for longer and were slightly more heavily pre-treated. Non-responders were more likely to have 17p deletions and less likely to have 11q deletions. [see Table 8 below] (Source: GSK Submission, Section 5.8.9.3, Table 5.12, p65)

Table 8. Baseline characteristics by response at 24 weeks (IRC assessment, DR population)

Characteristic Non- Responder All responder (n=34) (N=59) (n=25) Age Mean (SD) 62 (9) 63 (8) 63 (9) Median (IQR) 65 (56–68) 62 (59–68) 64 (59–68) Age ≥70 years, n (%) 4 (16) 6 (18) 6.8 (4.1) Male sex, n (%) 20 (80.0) 24 (70.6) 6.0 (3.5–9.3) Years from CLL diagnosis Mean (SD) 5.1 (3.1) 8.0 (4.3) 5.5 (2.6) Median (IQR) 4.8 (2.8–5.9) 7.8 (5.3–9.7) 5.0 (4.0–7.0) No. of prior treatments Mean (SD) 4.9 (2.2) 6.0 (2.8) 37 (63) Median (IQR) 5.0 (3.0–6.0) 6.0 (4.0–8.0) 5.0 (4.0–7.0) No. of prior treatments ≥5, n (%) 13 (52) 24 (71) 37 (63) Rai score ≥3, n (%) 14 (56) 18 (53) 32 (54) ECOG 1 or 2, n (%) 13 (52) 18 (53) 31 (53) 17p deletion, n (%) 10 (40) 7 (21) 17 (29) 11q deletion, n (%) 9 (36) 15 (44) 24 (41) Prior rituximab, n (%) 16 (64) 19 (56) 35 (59) CLL, chronic lymphocytic leukaemia; ECOG, Eastern Cooperative Oncology Group; IQR, interquartile range; SD, standard deviation; (Source: GSK Submission, Section 5.8.9.3, Table 5.14, p66)

4.2.1.2 Secondary endpoint results

Secondary outcome measures included: time to onset of response; duration of response; progression free survival; time to next CLL therapy; overall survival; reduction in tumour size as well as safety and pharmacokinetic endpoints.

4.2.1.2.1 Time-to-event endpoints Response to treatment was rapid (median time to response: 1.8 months) and of a clinically meaningful duration (median duration: 7.1 months) in DR subjects. Median PFS was 5.7 months and median OS was 13.7 months in the total DR population, again, exceeding that seen with salvage therapies (8 months). [Tam, 2007] A post hoc analysis including only those patients who were alive at 12 weeks showed that response to ofatumumab was significantly correlated with longer survival time; responding patients had an increase of ≥10 months compared with non-responders. A post hoc sub-group analysis identified no differences in median PFS between patients who had previously received a rituximab-containing regimen and those who had no prior rituximab exposure. (Source: GSK Submission, Section 5.10.1, p83) Results for time-to-event endpoints based on assessment by the IRC in DR patients are presented in Table 9 below. 39 Table 9. Secondary endpoints in Hx-CD20-406 (IRC assessment, DR population) DR (N=59) Time to onset of response (median, months) Responders (95% CI) 1.8 (1.0, 1.9) Duration of response (median, months) Responders (95% CI) 7.1 (3.7, 7.6) Duration of response after last infusion (median, months) 2.5 (0.9, 5.0) Responders (95% CI) Progression-free survival (median, months) Responders (95% CI) 8.0 (5.5, 8.7) Non-responders (95% CI) 4.1 (2.6, 5.5) All patients (95% CI)* 5.7 (4.5, 8.0) Time to next CLL therapy (median, months) Responders (95% CI) 9.3 (7.3, 10.9) Non-responders (95% CI) 8.5 (2.8, 11.1) All patients (95% CI) 9.0 (7.3, 10.7) Overall survival (median, months) Responders (95% CI) NR Non-responders (95% CI) 8.4 (2.9, 13.7) All patients (95% CI) 13.7 (9.4, NR) CI, confidence interval; DR, double refractory; NR, not reached yet (Source: GSK Submission, Section 5.8.9.6, Table 5.15, p67)

4.2.1.2.2 Improvements in individual components of the response criteria The anti-tumour activity of ofatumumab is demonstrated not only by the high response rates but also by improvements from baseline in other CLL disease-related parameters. Ofatumumab treatment was associated with considerable relief of constitutional symptoms and improvements in performance status, even among patients who did not qualify as responders strictly based on the NCI-WG criteria. Around half of patients in the DR group achieved complete resolution of splenomegaly and hepatomegaly, for at least two consecutive months. Although fewer patients achieved complete resolution of lymphadenopathy, 62% had a meaningful reduction (≥50%) in tumour size for at least two months. (Source: GSK Submission, Section 5.10.1, p83)

See results presented in Table 10 below.

An increase in median haemoglobin and platelet counts was observed in the DR group, regardless of response and in subjects with baseline anaemia and thrombocytopenia. Improvements were sustained throughout the treatment period and did not decline to baseline after the end of treatment. The effect on neutrophils was less pronounced; however, median neutrophils remained above normal (>1.5 x 109/L) during the treatment and follow-up periods. In subjects with baseline neutropenia, the median counts did not worsen in the DR group. A rapid reduction in lymphocytes and malignant B-cells was also noted in DR patients, which was sustained beyond the end of treatment. (Source: GSK Submission, Section 5.10.1, p83)

See results presented in Table 10 below.

40 Table 10. Summary of clinical improvement for ≥2 months in Hx-CD20-406 (DR population)

DR N=59 N* n(%)† Complete resolution of constitutional symptoms‡ 31 15 (48) ≥50% improvement in lymphadenopathy# 55 34 (62) Complete resolution of lymphadenopathy# 55 9 (16) ≥50% improvement in splenomegaly# 30 16 (53) Complete resolution of splenomegaly# 30 14 (47) ≥50% improvement in hepatomegaly# 18 11 (61) Complete resolution of hepatomegaly# 18 9 (50) Haemoglobin (from <11g/dL to >11g/dL post- 26 8 (31) baseline) Platelet counts (<100 x 109/L to >50 x 109/L 29 12 (41) post-baseline) Neutrophils (<1.5 x 109/L to >1.5 x 109/L post- 19 1 (5) baseline) ≥50% improvement in lymphocyte count 42 31 (74) Normalisation of lymphocyte count 42 20 (48) *Number of patients with abnormal clinical characteristics at baseline; † % of patients with improvement lasting for ≥2 months from baseline to Week 24; ‡ Defined as the presence of any symptoms at baseline (fever, night sweats, fatigue and weight loss) followed by no symptoms present; # lymphadenopathy measured by the sum of products of greatest diameters (SPD) as assessed by physical examination Source: GSK Submission, Section 5.8.9.6.2, Table 5.17, p69)

4.2.1.2.3 Safety An overview of adverse events (AEs) reported during treatment and follow-up in study Hx- CD20-406 is given.

The most common AEs associated with ofatumumab were infusion-related reactions and infections, each occurring in over 60% of patients in the DR population.

Infusion-related adverse events are commonly observed in association with infusions of monoclonal antibodies. Forty-eight (81%) patients in the DR group experienced an AE after the start of an infusion on any infusion day, 45 (46%) of which were mild to moderate (grade 1 or 2). Infusion-related reactions were reported to be most common with the first two infusions and declined in frequency with subsequent infusions. The most common infusion reactions were reported as: rash (14%), dyspnoea (12%), cough (12%), anaphylactoid events (10%), pain (8%), and cardiac events (8%). Overall, events classified as ‘infusion-related reactions’ were seen in 64% (n=38) of DR patients.

The majority of infections were grades 1 or 2. Major infections occurred in 32% of DR patients. Pneumonia and septic events were the most common infectious complications in the DR population. Haematological AEs (neutropenia, anaemia and thrombocytopenia) were observed in less than 20% of subjects treated with ofatumumab in Hx-CD20-406; however, in many 41 cases cytopenias were present at baseline due to prior therapy and underlying disease. Baseline cytopenias observed were consistent with advanced stage CLL.

The AE profile is consistent with that seen with other monoclonal antibody therapies. However, using a single-arm study – Hx-CD20-406 – there is no way of assessing the AE profile truly related to the intervention.

4.2.2 Summary of submitted evidence synthesis: including threats to validity

. The submission from GSK includes one study; a non-randomised, single-arm study, (Hx-CD20-406). From a total of 138 patients treatment effectiveness is taken exclusively from the 59 DR patients. Data for ofatumumab is taken from all 59 patients, and, crucially, data for BSC arm patients is taken from all non-responders for the economic analysis. After Week 28, disease status evaluation (physical examination, spleen and liver measurement, and blood samples) took place every three months until Month 24.

. Two other studies were identified: Tam et al 2007 and Dungarwalla et al 2008,[2,3] that were ruled out because they are non-comparative and provide evidence for therapies other than ofatumumab. However, the manufacturer uses Tam et al (2007) data as a comparator to the single-arm trial, stating that the patient populations in the two studies were ‘highly comparable’ and that the patients in the two studies were ‘treated in similar settings and in a similar manner’.

. In the Hx-CD20-406 study the ORR was 58% (99% CI, 40% to 74%; p<0.001) Complete resolution of constitutional symptoms and improved performance status occurred in 57% of patients. Median progression free survival and overall survival times were 5.7 and 13.7 months respectively.

. The most common adverse events during treatment were infusion reactions and infections, which were primarily grade 1 or 2 events. The AE profile is consistent with that seen with other monoclonal antibody therapies. However, using a single-arm study – Hx-CD20-406 – there is no way of assessing the AE profile truly related to the intervention

4.2.2.1 Threats to validity

The most challenging aspect of the critique of the submitted evidence on clinical effectiveness is the impact of the chosen study design which is essentially a case-series in which all patients receive the drug of interest, and so become the intervention group, the control group being 42 defined by non-response. This is an unusual approach to assessing effectiveness, which although understandable given the target population and having some logical basis, still presents a major challenge of interpretation both for the ERG and the Appraisal Committee. There is clearly potential for additional bias relative to that which might be expected in a double-blind randomised controlled trial comparing ofatumumab + BSC with BSC alone. Table 11 is an attempt to clearly identify these biases and indicate where possible what the effect might be on the various key outcomes. We have confirmed with other ERGs that this study design has not been encountered before in STAs and further that there appears to be no methodological research to indicate what the nature and extent of the bias in such a design might be. There have been attempts to assess the openness of bias in non-randomised studies generally. However, the study design employed in this STA is highly particular and we are not confident that this methodological research is applicable. In response to our request for clarification the manufacturer also acknowledged that they are not aware of methodological research which might underpin the approach they have taken.

The key points arising from our assessment of validity (Table 11) are:

. The effect on ORR, PF-S and OS is uncertain. It is not self-evident that the design employed will necessarily lead to an overestimate of the treatment effect, although superficially tempting to conclude that this is the most likely impact of the bias

. The AEs measured are unlikely to be those attributable to ofatumumab as both ‘treatment’ and ‘control’ are exposed to the intervention

. The impact on the measured effect of outcomes such as infection is difficult to predict as it could be attributable to either lack of response to or AEs attributable to ofatumumab

. The impact on global QoL has not been measured

43 Table 11. Threats to validity: effect on results from Hx-CD20-406 for stated outcome (clinical effectiveness)

Selection bias Important imbalances Bias in favour of Bias in favour of Possible if Difficult to predict as Not measured in between ‘treatment’ (all) and ‘treatment’ as non- ‘treatment’ as non- prognostic factors some infections may Hx-CD20-406 ‘control’ (NR) in prognostic responders have responders have influence the be a consequence factors higher levels of poor higher levels of severity and of non-response to prognostic factors. poor prognostic frequency of treatment and others Given ORR and factors. adverse events an adverse event. PFS is an Given OS is an overestimate overestimate Performance Key issue is that both Bias in favour of Bias in favour of Unable to estimate As above Not measured in bias ‘treatment’ (all) and ‘control’ ‘control’ as non- ‘control’ as non- AEs attributable to Hx-CD20-406 (NR) receive intervention of responders have responders have treatment because interest. Also possible that received treatment received treatment both ‘treatment’ (all) there are differences in the and accrue benefit and accrue low and ‘control’ (NR) ancillary treatment of which does not levels of benefit receive ‘treatment’ (all) and ‘control’ reach the level of a which which are ofatumumab. AE’s (NR) influenced by response ‘response’. likely to contribute given are not those status which could in turn Given ORR and to improved OS. attributable to conceivably influence PFS is an Given OS is an ofatumumab outcome underestimate underestimate Detection bias No blinding possible. Bias in Arguably no bias Outcome Bias possible. As above Not measured in especially measurement of outcomes because designation sufficiently Direction arguably Hx-CD20-406 blinding likely especially in outcomes of ‘treatment’ and objective that bias most likely to be in with a subjective ‘control’ is unknown unlilkely. favour of ‘control’ as component. Plausible that at the time adverse events knowledge of response assessment of automatically status will influence response is made attributed to assessment of outcomes intervention rather such AEs than being a normal occurrence Attrition bias No additional bias. Follow- No effect No effect No effect No effect Not measured in up appears to be complete Hx-CD20-406 with no evidence of difference in loss to follow- up between ‘treatment’ (all) and ‘control’ (NR)

44

Threat to Source of threat in study Effect on results from Hx-CD20-406 for stated outcome† validity* Hx-CD20-406 ORR and PFS‡ OS AEs Infections HRQL Net effect N/A Two biases Two biases Effect arising from Difficulty of Not measured in operating in operating in consideration of prediction because Hx-CD20-406 opposite directions. opposite performance bias of uncertainty Impossible to predict directions. predominates. AE’s whether infection is whether one Impossible to given are not those a consequence of outweighs the other. predict whether attributable to non-response or one outweighs the ofatumumab adverse event other. operates across the majority of the biases Impact of N/A There is adjustment Same concern as Same concern as In absence of direct evidence utilities in modelling for confounders above impacts AE above impacts the model are derived from separate approach which would make event data used in infection data used elicitation exercises. The construction of the main bias the model in the model scenarios used in these studies is of operating concern given the clear uncertainty performance bias about the true effects of ofatumumab on which favours the AE and infection in particular “control”. However, this is off-set by the ERG observation that the adjustment does not include the important prognostic factor 17p deletion which is much more prevalent in NR Notes: * Based on general categories identified by Cochrane Collaboration see Cochrane Handbook Table 8.4.a; † Answers question ‘What additional bias results from using Hx-CD20-406 (comparison of all participants vs non-responders) as an estimate of the effect of ofatumumab + BSC vs BSC alone as measured in a double-blinded RCT RCT, if that were possible’; ‡ Effect on ORR and PFS argued to be similar because PFS depends fundamentally on the validity of the assessment of response Abbreviations: ORR – objective response rate; PFS – progression-free survival; OS – overall survival; AE – adverse events; HRQL – health-related quality of life; NR – non-responders

45 Summary of clinical effectiveness

. The submission from GSK includes one study; a non-randomised, single-arm study, (Hx-CD20- 406). From a total of 138 patients treatment effectiveness is taken exclusively from the 59 DR patients. Data for ofatumumab is taken from all 59 patients, and, crucially, data for BSC arm patients is taken from all ‘non-responders’ for the economic analysis. After Week 28, disease status evaluation (physical examination, spleen and liver measurement, and blood samples) took place every three months until Month 24.

. In the Hx-CD20-406 study the ORR was 58% (99% CI, 40% to 74%; p<0.001). Complete resolution of constitutional symptoms and improved performance status occurred in 57% of patients. Median progression free survival and overall survival times were 5.7 and 13.7 months respectively. The effect on ORR, PF-S and OS is uncertain. It is not self-evident that the design employed will necessarily lead to an overestimate of the treatment effect, although superficially tempting to conclude that this is the most likely impact of the bias

. The most common adverse events during treatment were infusion reactions and infections, which were primarily grade 1 or 2 events. The AE profile is consistent with that seen with other monoclonal antibody therapies. However, using a single-arm study – Hx-CD20-406 – there is no way of assessing the AE profile truly related to the intervention. The AEs measured are unlikely to be those attributable to ofatumumab as both ‘treatment’ and ‘control’ are exposed to the intervention. The impact on the measured effect of outcomes such as infection is difficult to predict as it could be attributable to either lack of response to or AEs attributable to ofatumumab

. The impact on global QoL has not been measured.

. Two other studies were identified: Tam et al 2007 and Dungarwalla et al 2008,[2,3] that were ruled out because they are non-comparative and provide evidence for therapies other than ofatumumab. However, the manufacturer uses Tam et al (2007) data as a comparator to the single- arm trial, stating that the patient populations in the two studies were ‘highly comparable’ and that the patients in the two studies were ‘treated in similar settings and in a similar manner’.

. 46 5 Economic evaluation

In this chapter, we assess the cost-effectiveness analysis submitted by GSK. The overall approach to modelling is reasonable with no logical errors in the economic model. Key areas of our critique include:

. choice of utilities

. omission of 17p and 11q chromosonal deletions as factors in their Cox proportional hazards model for PFS and OS

. omission of the costs of drugs in progressive disease.

In this chapter, we start with a summary of the systematic review of cost-effectiveness studies presented by GSK and the methods used in the economic evaluation (Section 5.1, p47). Then we present a critique of the methods they used (Section 5.2, p55). This is followed by a description of GSK’s results (Section 5.3, p68) and our comment on their validity (Section 5.4, p72). We present a summary of the uncertainties in the economic evaluation (Section 5.5, p75). Finally, we derive our proposed alternative base case ICER, and present several important scenario analyses in Section 6, p77.

5.1 Overview of manufacturer’s economic evaluation

5.1.1 Summary of GSK’s systematic review of cost-effectiveness studies

5.1.1.1 Description and appropriateness of manufacturer’s search strategy

Manufacturer searches were performed in the following databases on 22 October 2009:

. OVID MEDLINE 1950 to present

. OVID MEDLINE (R) In-process & Other non-indexed Citations

. OVID EMBASE

. The Cochrane Library (NHS EED for the economic section)

Separate search strategies were provided for EMBASE, Medline with Medline in-process, and The Cochrane Library (Source: GSK Submission, Appendix 10, p191–193). All database searches were based on thesaurus (where possible) and free-text words with no limitation applied. Medline and EMBASE searches were in the format: population (Chronic Lymphatic

47 Leukemia) AND (terms related to costs and resources). The Cochrane Library search used the population term (CLL) and then downloaded those results within the NHSEED database.

Searches were also carried out in the following conference proceedings from 2004 to 2009:

. American Society of Clinical Oncology (ASCO)

. American Society of Hematology (ASH)

. European Haematology Association (EHA)

Additional reference list searching was conducted in clinical trial publications, systematic reviews, and qualitative reviews in the disease area (Source: GSK Submission, Section 9.6.5, p187).

All the combinations of terms in the search strategies to define the chronic lymphocytic leukaemia population and the resources used were appropriate, replicable, and the resulting hits appear correct given the search date and database/interface used. The filter used for the cost-effectiveness section is limited in that it does not make use of thesaurus terms or terms related to any modelling that may have been done. This is considered reasonable in the context of this submission.

5.1.1.1.1 Search results

GSK identified no cost-effectiveness studies directly relevant to the appraisal of ofatumumab for the treatment of DR CLL (Source: GSK Submission, Section 6.1.2, p90). This is confirmed by our search for published economic evaluations of ofatumumab for CLL which also identified no such studies.

5.1.2 GSK’s economic model submitted to NICE

We now turn to the economic evaluation that GSK presented to NICE. They report cost per QALY estimates for ofatumumab versus BSC for the treatment of chronic lymphocytic leukaemia for patients who are refractory to fludarabine and alemtuzumab. The model is written in Microsoft Excel, and is described in detail in Section 6, p90–153 of GSK’s report. Here, we summarise the main features of the model.

5.1.3 Natural history

GSK use an ‘area under the curve’ (AUC) or ‘partitioned-survival’ model (Source: GSK Submission, Section 6.2.2, p92), which has been previously used for health technology appraisals (HTAs) of drugs for cancers.[15] There are three discrete health states: PFS, PD and

48 death. All patients enter the model in PFS, where they remain until disease progression or death. Once patients enter PD, they remain there until death.

For ofatumumab and for BSC separately, a Weibull curve describes the number of patients alive over time (OS), and another Weibull curve describes the number of patients in PFS over time (Source: GSK Submission, Figures 6.3 and 6.4, p98). Fitting of these curves to trial data is described in Section 5.1.4 of this report. For each treatment, the number of patients in PD at any time is calculated as the number alive minus the number in PFS at that time.

The time horizon of the model is 10 years (not five years as stated by GSK in Section 6.2.6, p95 of their report) and the model cycle length is one day; therefore, a half-cycle correction is not modelled.

5.1.4 Treatment effectiveness

Treatment effectiveness is taken exclusively from the 59 DR patients from the interim analysis at 19 May 2008 of the single-arm study of ofatumumab, Hx-CD20-406. In the health economic model data for ofatumumab is taken from all patients in the study; and, crucially, data for BSC arm patients is taken from all ‘non-responders’ in the study (Source: GSK Submission, Section 6.3.1, p97).

The upper Kaplan-Meier curve in Figure 2 corresponds to ofatumumab and the lower Kaplan- Meier curve corresponds to BSC. The upper Kaplan-Meier curve in Figure 3 corresponds to ofatumumab and the lower Kaplan-Meier curve corresponds to BSC.

Weibull curves were fitted to the individual patient data by the method of maximum likelihood, using the SAS function PROC LIFEREG (Source: GSK Submission, Section 6.3.1, p97). GSK considered two methods (described below) for fitting the PFS and OS curves (see Figure 2, Figure 3);

Method A. In the first method, shown by the paler line for ofatumumab in Figure 2 and Figure 3, a Cox proportional hazards regression model was fitted with the following factors: all patients vs. non-responders, sex, age range (< vs. > median), Rai score range (<3 vs. ≥3), ECOG (1 or 2 vs. not 1 or 2), number of prior therapies (< vs. > median) and years since diagnosis (< vs. > median). Importantly, GSK did not include the presence of 17p and 11q chromosonal deletions as factors, even though there is evidence that the presence of these deletions tends to correspond to poor survival (Source: GSK Submission, Section 2, p17). The Weibull curve for BSC was fitted, and the Weibull curve for ofatumumab was calculated by multiplying the Weibull scale parameter  for the BSC curve by the hazard ratio between all patients and non- responders. 49 Method B. In the second method, shown by the darker line for ofatumumab in Figure 2 and Figure 3, Weibull curves for ofatumumab and BSC were fitted independently.

Figure 2. GSK estimated vs. actual PFS for ofatumumab and BSC

A Progression-Free Survival

100 Non-Responders Kaplan Meier Ofatumumab independent fit 90 Non-Responders Independent Weibull Ofatumumab prop 80 All Patients Kaplan Meier 70 All Patients Independent Weibull 60 All Patients Cox PH Weib 50 40

30

Progression-Free Surival (%) Surival Progression-Free 20

10

0 03691215 Time (Months) No. at risk Non-Responders 25143100 All Patients 59 45 19 6 2 0

(Source: GSK Submission, Section 6.3.1, Figure 6.6, p102)

Figure 3. GSK estimated vs. actual OS for ofatumumab and BSC

B Overall Survival 100 Non-Responders Kaplan Meier 90 Non-Responders Independent Weibull 80 All Patients Kaplan Meier 70

60 All Patients Independent Weibull

50 All Patients Cox PH Weib

Survival (%) 40 Ofatumumab proportional hazards 30

20 BSC Ofatumumab independent fit 10

0 0 1224364860 Time (Months) No. at risk Non-Responders 2550000 All Patients 59 19 0 0 0 0

(Source: GSK Submission, Section 6.3.1, Figure 6.7, p102)

50 GSK used Method A in their base case. Method B was used in a sensitivity analysis. The Weibull parameters under these two methods are given in Table 12, where time is measured in days.

Table 12. Weibull parameters in GSK model

PFS OS lambda gamma lambda gamma BSC 0.00015 1.76274 0.00327 0.97905 (Methods A & B)§ Ofatumumab (Method A)† 0.000077 1.76274 0.00174 0.97905 Ofatumumab (Method B)¶ 0.000037 1.8871 0.000720 1.1366 § Source: GSK Submission, Section 6.3.1, Table 6.2, p99, † Source: Values for BSC multiplied by hazard ratios given in Table 6.4, Section 6.3.1, p100 of the GSK submission. ¶ Source: Taken directly from GSK’s Excel model, worksheet ‘MainInputs’, cells F16, F17, F26, F27, N16, N17, N26, N27

GSK did not perform subgroup analysis within the DR population.

5.1.5 Health related quality of life

GSK cite studies showing that CLL can have a profound effect on HRQL (Source: GSK Submission, Section 6.4.1, p110).[8,16] In particular, previously treated patients and those on treatment show lower quality of life (QoL) than those untreated or not on active treatment. Utility values were not collected in the Hx-CD20-406 study. GSK cite some studies that report HRQL for patients with CLL. However, GSK dismiss these, saying that their relevance is not clear to DR patients who have advanced disease and are heavily pre-treated. Instead, utilities are taken from Ferguson et al (2008), presented as a poster at the 11th ISPOR Conference.[16] Disease state descriptions (not supplied) were developed based on evidence from published literature, clinical guidelines, and an interview with a specialist. Preferences for health states were obtained by structured interviews with 60 members of the UK general public. Utilities were obtained using the Time Trade Off method. Mean utilities decreased as patients moved down successive lines of therapy, and as they moved from PFS to PD after each line of treatment (Table 13).

51 Table 13. Utilities for CLL from Ferguson et al (2008)[16]

State Mean SE 95% CI First-line treatment with alemtuzumab 0.619 0.029 0.562 0.676 First-line treatment with chlorambucil 0.623 0.028 0.568 0.678 Following First-line treatment: progression free 0.777 0.024 0.730 0.824 Following First-line treatment: progressive disease 0.540 0.026 0.489 0.591 Following Second-line treatment: progression free 0.650 0.027 0.597 0.703 Following Second-line treatment: progressive disease 0.470 0.028 0.415 0.525 Following final (Third-line) treatment: progression free 0.428 0.028 0.373 0.483 Following final (Third-line) treatment: progressive disease 0.279 0.027 0.226 0.332

In their base case (independent of treatment), GSK chose utilities for PFS and PD of 0.65 (corresponding to the ‘Following second-line treatment: progression free’), and 0.47 (‘Following second-line treatment: progressive disease’) (Table 13) (Source: GSK Submission, Section 6.4.9, p113).

Due to the paucity of published utility data in the patient population, GSK have commissioned a health state preference study to generate utilities for PFS (in ‘responders’ and ‘non- responders’) and PD, and disutilities for the treatment-related AEs of thrombocytopenia, neutropenia and severe infection. The study method involved valuation of disease states by members of the UK general public, and is currently ongoing (no data were supplied in the submission) (Source: GSK Submission, Section 6.4.5, p111).

GSK did not model disutility due to AEs due to the paucity of data (Source: GSK Submission, Section 6.2.2, p93).

5.1.6 Resources and costs

Costs are based on the NHS and PSS perspective, and are for drug acquisition, drug administration, disease management (such as monitoring, X-rays, laboratory tests, prophylaxis against infections, transfusions), and AEs (Source: GSK Submission, Section 6.5.6, p120).

5.1.6.1.1 Drug costs and drug administration costs

In the model, patients are assumed to be given ofatumumab until disease progression, death, or completion of the six-month course (Source: GSK Submission, Section 6.2.2, p92).

In their base case and in all but one sensitivity analysis, GSK assume that a Patient Access Scheme applies, whereby the unconfirmed list price of ofatumumab of £1.58 / mg is reduced to ********** (Source: GSK Submission, Section 6.5.9, p128–129).

52 Ofatumumab requires a clinic visit for each infusion. GSK estimate the cost of administration as £237 for the first administration, and £220 for subsequent administrations, based on NHS reference costs for day case administration of chemotherapy. As per the dosage schedule in Hx-CD20-406 and the ofatumumab draft SmPC, the first dose was assumed to be 300mg, and subsequent doses 2,000mg. Doses 2–8 were assumed to be administered at weeks 1, 2, 3, 4, 5, 6, and 7, and doses 9–12 at weeks 11, 15, 19, and 24 (Source: GSK Submission, Section 6.5.9, Table 6.10 p118–119). Along with each dose of ofatumumab, patients were assumed to receive paracetamol 500mg, chlorphenamine 10mg, and hydrocortisone 200mg as in Hx- CD20-406. GSK state that there would be no drug wastage because ofatumumab is administered as a fixed dose, and the dosages can be made exactly from the 100mg vials.

The costs of dispensing per dose, at £8, were based on an assumption that each administration would last 15 minutes. To avoid double counting, the costs of routine follow-up care were subtracted from administration costs. We presume this is because routine follow-up and administration of ofatumumab was assumed to occur on the same hospital visit. The costs of laboratory tests and concomitant medications were assumed to be included in the NHS reference costs and therefore were not considered separately (Source: GSK Submission, Section 6.5.5, p117).[17]

5.1.6.2 Disease management costs

GSK collected information from two experts, based on direct interviews, telephone interviews and questionnaires, to estimate the following resource use (Source: GSK Submission, Section 6.3.6, Table 6.6, p104-6). Monthly routine follow-up costs were assumed to be the same for ofatumumab and BSC, and for PFS and PD. They included the costs of quarterly chest x-rays, monthly clinic visits and laboratory tests including a full blood count, lactose dehydrogenase tests, and blood glucose levels (Source: GSK Submission, Section 6.5.6, Table 6.11, p120). Unit costs of visits and chest x-rays were based on NHS reference costs (NHS Reference Costs 2008),[17] yielding a total follow-up cost of £158 per month.

Patients receiving ofatumumab were assumed to require prophylaxis against infections due to treatment for CLL with co-trimoxazole, acyclovir, and itraconazole (Source: GSK Submission, Table 6.12, p121). Patients receiving BSC were conservatively assumed to receive no such prophylaxis, even though they are at risk of infections due to CLL. Dosages for these medications were based on expert opinion, and unit costs were obtained from the British National Formulary No. 58.[18] Infection prophylaxis was assumed to be administered from treatment initiation until two months after progression (Source: GSK Submission, Section 6.5.6, p121). The cost of the additional two months of infection prophylaxis was handled in the model

53 as a ‘one-off’ cost associated with progression. The total cost was £104 per month plus an additional £207 on progression.

GSK also model the costs of transfusions of red blood cells and whole blood, transfusions of platelets, and courses of CSFs, because of their high costs and frequent use amongst patients with CLL. Utilisation for ofatumumab was based on mean utilisation amongst all patients in the Hx-CD20-406 study (i.e. not on the subgroup of DR patients on whom the effectiveness estimates are based). For patients receiving BSC, utilisation was based on the mean use amongst non-responders. Transfusion costs were obtained by multiplying estimates of the mean number of units of service by corresponding unit costs. Unit costs of red blood cells, whole blood and platelets were obtained from the National Blood Service (NBS) National Blood and Blood Components Price List.[19] Details are given in Tables 6.13, 6.14 and 6.15 of GSK’s submission, but in summary, the cost of a red blood cell and whole blood transfusion was estimated as £374, a platelet transfusion £543 and a course of CSF, £928. GSK assumed 2.16 and 2.58 courses per patient of red blood cell and whole blood transfusion for non-responders and all patients respectively, 0.40 and 1.42 platelet transfusions per patient for non-responders and all patients respectively, and 0.48 and 0.39 CSF courses, based on utilisation of patients in the Hx-CD20-406 study. This yielded an expected cost of transfusions and courses of CSF of £2,099 and £1,471 per patient in the ofatumumab and BSC arms respectively.

GSK assumed no cost of death.

5.1.6.3 Adverse events costs

The model only included costs for hospitalisation for Grade 3 and 4 AEs, with an incidence of at least 3% among either non-responders or all patients, as well as Grade 1–2 CMV reactivation, and thrombocytopenia (Source: GSK Submission, Section 6.5.7, p125). The incidence of these events, given in Table 6.5, p103, of GSK’s submission, were taken from the Hx-CD20-406 study. Costs of follow-up visits, tests and medications for adverse events were assumed captured elsewhere. Unit costs were taken from NHS Reference Costs.[17] As for PFS and OS, AEs for BSC were taken from data from non-responders. GSK state that Grade 3+ ‘disease progression’, ‘confusional state’ and ‘fall’ were not included, even though these events were observed in ≥3% of patients, as they were not likely to be due to either the disease or the treatment, or were captured elsewhere in the model. Estimated costs per event are given in Table 6.17, p125 of GSK’s submission and the estimated cost of AEs per patient is given in Table 6.18, p126. In summary GSK estimate that patients incur a mean cost of £1,356 and £1,680 in the ofatumumab and BSC arms respectively.

54 5.1.7 Discounting

Future costs and benefits are discounted at 3.5% as specified in the NICE reference case.[20]

5.1.8 Sensitivity analysis

One-way sensitivity analyses and probabilistic sensitivity analyses are reported (Source: GSK Submission, Section 6.5.9, p128–129). The following parameters were varied in the probabilistic sensitivity analysis: utilities, non-drug costs and PFS and OS curve fits (Source: GSK Submission, p104–105). The utility for PFS was modelled as a beta distribution, and the decrement between the utilities PFS – PPS was assumed log-normal. AE rates were modelled as beta distributions, and all non-drug costs were modelled by log-normal distributions. The parameters of the Weibull distributions for PFS and OS and the hazard ratios between ofatumumab and BSC were all assumed log-normal.

GSK present cost-effectiveness acceptability curves (CEACs) and scatter plots of incremental costs versus QALYs in the Results section of their submission (GSK Submission, Section 6.6, pp137–146).

5.1.9 Model validation

GSK cite the following steps to validate their model (Source: GSK Submission, p148). First, one-way sensitivity analyses were performed and model output was compared to expectation. Next, random checks were made on model inputs. The model was reviewed by an independent economic agency; no specific details of the review were provided. Finally, GSK find that the Weibull survival functions for PFS and OS are very close to the empirical Kaplan-Meier distributions.

5.2 Critique of approach used

In this section, we comment on GSK’s analysis. First, we consider the model against checklists of good practice, in Section 5.2.1. Then we critically appraise the model structure and data, in Section 5.2.2. In Section 5.4, p72, we comment on GSKs’ results with reference to their methods.

5.2.1 Critical appraisal frameworks

We considered GSK’s economic evaluation against the following widely-used study quality checklists: NICE Reference Case[20] (Table 14), Drummond et al (1997)[21] (Table 15), and Philips et al (2006)[22] (Table 16) for decision model-based economic evaluations. Note the problems with the data for health-related quality of life (Table 14).

55 Table 14: Critical appraisal checklist based on NICE Reference Case[20]

NICE reference case requirement Critical Reviewer comment Appraisal Defining the The scope  decision problem developed by the Institute Comparator Therapies routinely  Comparator is BSC. The used in the NHS, following alternative scoped including comparators were not technologies considered: cyclophosphamide, regarded as current doxorubicin, vincristine, best practice prednisolone (CHOP) with or without rituximab, rituximab in combination with chemotherapy (other than fludarabine- containing chemotherapy; subject to ongoing NICE appraisal), high-dose corticosteroids. Perspective on NHS and PSS  costs Perspective on All health effects on  Disutility of adverse events not outcomes individuals modelled directly. Type of economic Cost-effectiveness  evaluation analysis Synthesis of Based on a  Single-arm study Hx-CD20-406 evidence on systematic review of ofatumumab. outcomes Measure of health QALYs  benefits Source of data for Reported directly by X The EQ5D, which is the measurement of patients and/or preferred questionnaire, is not HRQL carers used. Furthermore, preferences regarding health states are judged by clinicians, not by patients. Source of Representative  Representative sample of public preference data for sample of the public used, which is appropriate. valuation of Time Trade Off method used, changes in HRQL which is appropriate. Discount rate 3.5% pa for costs  and health effects Equity weighting An additional QALY  has the same weight regardless of the other characteristics of the individuals receiving the health benefit

56 Table 15: Critical appraisal checklist from Drummond et al[21]

Item Critical Reviewer Comment Appraisal Is there a well defined  - question? Is there a clear description  Ofatumumab v. BSC for patients with chronic of alternatives (i.e. who did lymphocytic leukaemia refractory to what to whom, where, and fludarabine and alemtuzumab how often)? Has the correct patient  No patient subgroups. group / population of interest been clearly stated? Is the correct comparator Partially BSC, but the appropriateness of using non- used? responders on ofatumumab to represent BSC is unclear. See Table 14 for alternative scoped treatments not considered by GSK. Is the study type  ‘Area-under the curve’ cost-utility model reasonable? Is the perspective of the  UK NHS & PSS analysis clearly stated? Is the perspective  - employed appropriate? Is effectiveness of the Partially The overall response rate of ofatumumab in intervention established? study Hx-CD20-406 as assessed by an Independent Review Committee was 58% in the DR group, exceeding the 30% target response rate for clinically meaningful efficacy (Source: GSK Submission, p148). However, given that the trial was single-arm, the relative efficacy of ofatumumab versus BSC can only be estimated. Has a lifetime horizon  10-year time horizon used in the model but been used for analysis, if reported as five years by GSK (see GSK not has a shorter time Submission, Section 6.2.6, p95). After 10 horizon been justified? years, virtually all modelled patients are dead. Hence the time horizon is effectively life time, and appropriate. Are the costs and  All costs from UK NHS & PSS perspective. consequences consistent with the perspective employed? Is differential timing  - considered? Is incremental analysis  - performed? Is sensitivity analysis  Univariate and probabilistic sensitivity undertaken and presented analyses presented. clearly?

57 Table 16: Critical appraisal checklist of Philips et al (2006)[22] for model-based analyses

Dimension of quality Comments Structure S1 Statement of  Ofatumumab vs. BSC for patients with chronic decision lymphocytic leukaemia refractory to fludarabine and problem/objective alemtuzumab. S2 Statement of  NHS and PSS perspective. Cost and benefit inputs are scope/perspectiv consistent with the perspective. Scope of model stated. e S3 Rationale for  Cohort model is appropriate. structure S4 Structural  Model assumptions are explained clearly in the report. assumptions Overall, we are satisfied with the structural assumptions. Weibull functions were fitted to PFS and OS from the single-arm trial. S5 Strategies / ? See S1. The appropriateness of using non-responders on comparators ofatumumab to represent BSC is unclear. S6 Model type  Cohort model is appropriate. See Table 14 for alternative scoped treatments not considered by GSK. S7 Time horizon  The model time horizon is 10 years. but reported as five years by GSK (see GSK Submission, Section 6.2.6, p95). Ten years is long enough, as after this time the great majority of patients are modelled to have died. Since OS is fairly immature, extrapolation is necessary. S8 Disease states /  The disease states: PFS, PD, death are appropriate and pathways commonly used for terminal cancers. S9 Cycle length  One day is appropriate. Data D1 Data identification  Data identification methods are well described. D2 Pre-model data  Method of fitting clinical effectiveness data by Cox analysis regression model and estimation of resource costs well described. D2a Baseline data  Baseline data from the single-arm trial RCT, which is appropriate. D2b Treatment effects X BSC treatment efficacy taken from the single-arm trial of ofatumumab. This is methodologically unsound, but possibly reasonable given the lack of randomised evidence. We believe that GSK’s omission of the 17p and 11q chromosonal deletions in their regression models is inappropriate (see p60). D2c Quality of life ? Health-related quality of life was not recorded in the weights (utilities) single-arm trial. Instead, health-related quality of life was taken from Ferguson et al (2008). Health state descriptions were taken from the literature, clinical guidelines and from specialist nurses/clinician, whereas NICE guidelines state that health state descriptions should come from patients.[20] We believe that GSK’s choice of utilities for the base case is inappropriate (see Section 5.2.3.6, p65). See Table 14 for further commentary on utilities.

58

D3 Data  Data incorporated in the model is referenced, generally incorporation well described and transparent. For the PSA, the choice of distribution for each parameter has been described and justified. D4 Assessment of ? Most types of uncertainty assessed. However, it is uncertainty assumed that there is no correlation between the lambda and gamma parameters of the Weibull distribution for PFS and OS, which is incorrect (Section 5.2.4.1, p68). D4a Methodological  Single type of model, which is adequate. D4b Structural  Structural sensitivity analyses performed. D4c Heterogeneity  No patient subgroups, as appropriate. D4d Parameter  Probabilistic and univariate sensitivity analyses performed. Consistency C1 Internal  We found no logical errors in GSK’s model. They state consistency that the model was checked by an independent team – Abacus International. C2 External  GSK compare the modelled efficacy against the efficacy consistency experienced in the main trial. Notes:  indicates ‘no concerns’; X indicates ‘concerns’; ? indicates ‘some concerns’

5.2.2 Critique of the modelling approach and structure

The structure of GSK’s cohort-based ‘AUC’ cost-effectiveness model is simple, appropriate and widely used for terminal cancers. The use of PFS and PD health states is appropriate and consistent with clinical outcomes in oncology trials.

A 10-year time horizon was used. As very few patients (0.5% on ofatumumab) are predicted to survive 10 years after starting treatment, the time horizon is effectively lifetime and is appropriate. The model cycle is one day, which is appropriate and sufficiently short so that a half-cycle model correction is unnecessary.

5.2.3 Data inputs

In this section, we consider the data used in the cost-effectiveness model.

5.2.3.1 Patient group

The Hx-CD20-406 study was a multi-national study involving five sites in the UK, which recruited 24 of the total 154 patients. Data from each of the subgroups (DR, BFR, ‘other’) were analysed separately. Only data from the DR group are presented in this submission in line with the approved indication for ofatumumab. The total DR (CLL patients refractory to fludarabine and alemtuzumab) patient population is 59 of which 14 were from the UK.

59 The modelled patient population is appropriate and is taken directly from the DR patient population of the Hx-CD20-406 study. However, the extent to which patients from any trial are representative of patients in routine practice is always uncertain.

5.2.3.2 Clinical effectiveness data

The effectiveness of ofatumumab and BSC were taken from the interim analysis at 19th May 2008 of study Hx-CD20-406. As previously stated see Section 3.6) no further data were available despite our request to GSK. On a related issue, the OS data is rather immature with median survival not yet reached. The Kapan-Meier curve showing that approximately 40% of patients are still alive at maximum follow-up (see Figure 3, p50). Extrapolation of OS therefore increases the uncertainty in the estimated cost-effectiveness of ofatumumab.

There were only 59 DR patients in the single-arm study of ofatumumab, which further increases the uncertainty in cost-effectiveness. However, this uncertainty is reflected in the probabilistic sensitivity analysis.

5.2.3.2.1 BSC treatment arm

GSK acknowledge that their method of modelling the BSC treatment arm from patients who did not respond to ofatumumab treatment in the single treatment study Hx-CD20-406 is the main weakness of their analysis (Source: GSK Submission, p150), and that they are not aware of any previous analyses that use this methodology (see Appendix 1: GSK Response Document – 10 March 2010, A3). GSK claim that it is not possible to say how their method biases cost- effectiveness, as follows:

This may be considered a conservative approach because patients in Hx-CD20-406 classified as non-responders included those who had stabilisation of their disease, and were therefore possibly receiving some benefits from treatment. However, we recognise also that such a benefit might be tempered by side effects associated with ofatumumab therapy, and potential selection bias towards poorer prognosis patients in the non- responder group. (Source: GSK Submission, p5)

Despite these methodological issues, we agree that this is a reasonable approach, given the lack of randomised evidence. Furthermore, given that only the single arm trial is used, we agree with their approach of using all patient data for the ofatumumab arm and non-responders for the BSC arm.

Given the serious shortcomings of the data used for the model’s BSC treatment arm, we are surprised that GSK did not perform a sensitivity analysis using the data from Tam et al (2007)[3] for the BSC arm (see also Section 3.6). GSK justify this decision as follows:

60 The study was conducted at an international centre of excellence (MD Anderson Cancer Centre, Texas) and therefore the outcomes seen are not readily generalisable to other centres; the regimens used tend to be aggressive, experimental, and do not reflect UK practice;

The study reports only overall survival (OS) and not progression-free survival (PFS) data, hence a number of assumptions would need to be made using the relationship seen between OS and PFS;

The study is retrospective with data reported historically over a 20-year period;

Data for 21 different salvage therapies are reported, however the patient numbers for each individual treatment are such that an analysis for each treatment becomes difficult to interpret.

We believe that it is worth considering this data as a sensitivity analysis for the following reasons. First, only a minority of patients (24 out of 138 [total population]) in the Hx-CD20-406 study were from the UK (14 out of 59 in the DR population), therefore the same criticism can be levelled at this source of data.

Concerning the second criticism, the study does report some time to treatment failure data, closely associated with PFS: the median time to treatment failure for double-refractory patients and for fludarabine-refractory and bulky lymphadenopathy patients combined was two months for patients receiving monoclonal antibodies, single-agent cytotoxics and intensive combination chemotherapy, and three months for purine analogue combinations.[3] These figures are consistent with the modelled PFS for BSC of four months. Furthermore, modelled cost- effectiveness is far less sensitive to PFS for BSC than to OS for BSC, therefore it is less important to have a precise estimate of PFS for BSC.

Concerning the third criticism, in fact, DR patients were treated over a relatively short period of 8 years, compared to the bulky fludarabine-refractory patients, who were treated over 19 years.[3] Of course, use of this data entails the major methodological flaw that randomisation is broken given that data for the two treatment arms are taken from different trials. Nonetheless, the median OS of eight months reported for double-refractory patients is the same as predicted for the BSC arm in GSK’s model.[3] This therefore gives us more confidence in the appropriateness of the non-responder effectiveness data used for the BSC arm in GSK’s model. Furthermore, our clinical advisor asserts that the median OS for BSC of eight months is reasonable.

Finally, in their response to the EMEA who were concerned by the lack of randomisation in the single-arm trial of ofatumumab, *************************************************************************************************************

61 ************************************************************************************************************ **********************************************************

5.2.3.2.2 17p and 11q chromosonal deletions

GSK’s method of using Cox regression (described in Section 5.1.4, p49) to control for any imbalances in patients characteristics (e.g. gender, ECOG) between the BSC and ofatumumab arms is largely appropriate (Source: GSK Submission, Section 5.10.2, p84). This is especially important because the analysis is based on a single-arm study rather than patients being randomised to an ofatumumab and a BSC arm. As stated (see Table 16), GSK did not include the presence of 17p and 11q chromosomal deletions as factors in the Cox regressions for PFS and OS despite imbalances in these markers, saying that there were too few patients with the deletions: 17 patients with 17p deletion (and 42 patients without) and 24 patients with 11q deletion (and 35 patients without) (Source: GSK Submission, Section 5.8.9.4, Table 5.14, p66). We believe that these factors should have been included in the Cox regressions for the following two reasons:

. Given that GSK make the very substantive assumption that patients on BSC would have the same OS and PFS as patients who did not respond to ofatumumab treatment then, at the very least, all important factors should be included in the Cox regression in order to allow for differences in patient characteristics between treatment arms. Furthermore, there is a priori evidence that 17p and 11q chromosonal deletions correspond to poor survival (Source: GSK Submission, p17). Indeed, in study Hx-CD20-406, the response rate was lower with the 17p deletion, but patients with 11q deletions had similar response rates to those without.

. GSK argue that the factors should not be included because there were too few patients with the deletions (17 patients with 17p deletion and 24 patients with the 11q deletion). However, these numbers seem reasonably well balanced. Furthermore, GSK include gender as a factor in the analysis, although the patient numbers are more imbalanced than for 17p and 11q deletions, with 15 females (and 44 males). It is worth noting that the following factors are also included in the regressions, but are not perfectly balanced: ECOG 1 or 2 (31 people) vs. not ECOG 1 or 2 (28 people) and Rai score I or II vs. Rai score III or IV with 26 patients Rai I or II (and 32 Rai III or IV).

When the deletions are included in the regressions, the mean overall survival for patients on ofatumumab decreases, and the mean PFS on ofatumumab increases slightly, hence the ICER for ofatumumab vs. BSC increases, see Section 5.4.1.1, p72. 62 5.2.3.2.3 Independent curve fits for ofatumumab PFS and OS

GSK fit PFS and OS for ofatumumab independently of BSC (Source: GSK Submission, p102) in a scenario analysis, although they do not present the corresponding cost-effectiveness results. They state that this results in more favourable PFS and OS for ofatumumab than by fitting using a Cox regression, and that therefore their base case method of using a Cox regression may be conservative (Source: GSK Submission, p101). However, using the Weibull parameters corresponding to the independent curve fits for ofatumumab (Table 12, p51), we do not think that this results in a conservative estimate of cost-effectiveness for ofatumumab. Instead, we find that the independent fitting method results in a more favourable estimate of PFS, but a less favourable estimate for OS for ofatumumab, as displayed in Figure 2 (p50), Figure 3 (p50), and the base case ICER increases from £38,421 to £49,600 / QALY. GSK’s base case approach of performing Cox regression to attempt to control for any imbalances in patients characteristics inappropriate. The independent curve fitting method should be seen as an important sensitivity analysis.

5.2.3.3 Drug costs and drug administration costs

In their base case and in all but one sensitivity analysis, GSK assume that a Patient Access Scheme will apply whereby the provisional list price of ofatumumab of £1.58 / mg is reduced to *********** NICE have instructed us to assume that the Patient Access Scheme is appropriate.

Given that ofatumumab is taken intravenously, GSK reasonably assume costs for administration of ofatumumab.

5.2.3.3.1 Acquisition cost of ofatumumab

GSK assume that patients take ofatumumab until disease progression, death, or completion of the six-month course. However, in the Hx-CD20-406 study, some patients continued to take ofatumumab after disease progression (Source: GSK Submission, p107). This might suggest that GSK have underestimated the mean per patient cost of ofatumumab; however, the reverse is true: GSK state that in the Hx-CD20-406 study, the mean total dose of ofatumumab was 18,202mg for DR patients, whereas GSK state that their model assumes a greater mean dose of 19,275mg (Source: GSK Submission, Section 6.5.5, p117). However, we find from the Excel spreadsheets that their model assumes a mean per patient dose of 18,931mg (setting the cost discount rate to zero and dividing the total cost of ofatumumab in cell B16 in worksheet ‘BaseCaseResults’ by ********), which is still slightly higher than in the trial. In response to our query, GSK assure us that the figure of 18,202mg reflects no censoring of patients, i.e. the

63 interim analysis was conducted after all patients had completed at least 24 weeks on study, and so had the opportunity to receive the full course of ofatumumab. We believe that it is preferable to model the dose of ofatumumab of 18,202mg from the trial (see Section 5.4.1.2, p73, below for the impact of this assumption).

5.2.3.3.2 Drugs in progressive disease

In their model, GSK assume that patients in progressive disease receive no further drugs to treat CLL. However, in the Hx-CD20-406 study, 31 (53%) double-refractory patients took further drugs when disease progressed (Source: GSK Submission p67). Given that GSK base their clinical effectiveness data on this trial, we believe that they should have also modelled the costs of these additional drugs in progressive disease. We asked GSK for the mean per patient dose of each drug received in progressive disease so that we could estimate the costs of drug treatment in progressive disease. GSK replied that the Case Report Form in Hx-CD20-406 contained only the name of each drug and the date started for each patient (see

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85 Appendix 2: Drugs taken by patients in progressive disease in study Hx-CD20-406). The doses were not recorded (GSK replies to our queries, 10th March 2010). Some of these drugs, such as fludarabine, oxaliplatin, revlimid and rituximab (see

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107 Appendix 2: Drugs taken by patients in progressive disease in study Hx-CD20-406) are expensive. Therefore, we believe that if the costs of these drugs were included in GSK’s model, the estimates of cost-effectiveness of ofatumumab might be altered substantially. We predict that the ICER would increase, because patients in the ofatumumab treatment arm typically spend longer in progressive disease than patients in the BSC arm (1.2 vs. 0.6 years respectively, Table 17, p69).

5.2.3.4 Disease management costs

The NHS and PSS perspective is assumed, which is appropriate.[20] We do not expect the use of ofatumumab to incur substantial costs or savings to other government departments.

GSKs’ assumptions for resource use are appropriate.

GSK do not state that costs were inflated to 2010/11 prices. However, if they were not inflated, any associated error will be minimal as costs appear to be recent (2006/7/8/9). If prices were inflated, incremental costs, and therefore the ICER, would increase slightly.

5.2.3.5 Adverse event costs

We believe that GSK’s approach to modelling the costs of adverse events is appropriate, namely taking the incidence of adverse events from study Hx-CD20-406, and modelling only Grade 3 and 4 events, which is common practice.

5.2.3.6 Health-related quality of life

As stated in Section 5.1.5, p51, of this report health state utilities were taken from Ferguson et al (2008).[16] The valuation of health state descriptions in this study uses the time trade-off method (which is appropriate), from a representative sample of the general public (n=60). However, the health state descriptions were taken from the literature, clinical guidelines and from specialist nurses/clinician, but the NICE reference case explicitly states that health state descriptions should come from patients.[20] Indeed, GSK acknowledge this weakness (Source: GSK Submission, p150). Also, it would have been useful to see the health state descriptions, but GSK told us that they did not have these. In particular, the domains covered in the health state descriptions are not supplied. This makes it very difficult to consider the QoL of the descriptions compared to the QoL that might have been experienced by patients during treatment. Nonetheless, despite these drawbacks, we agree that Ferguson et al (2008) is the most relevant source for utilities.[16]

However, importantly, we do not believe GSK’s choice of utilities from this study is appropriate. In their base case, GSK chose utilities for PFS and PD of 0.65 and 0.47 respectively, 108 corresponding to ‘Following second-line treatment: progression free’ and ‘Following second-line treatment: progressive disease’ (Table 13, p52 this document). However, patients in study Hx- CD20-406 had received a median of five previous treatments (Source: GSK Submission, p52). Therefore, we believe that it is preferable to assume utilities for PFS and PD of 0.428 and 0.279, corresponding to ‘Following final (third-line) treatment: progression free’ and ‘Following final (third-line) treatment: progressive disease’ respectively (Table 13, p52). This change has a major impact on the cost-effectiveness of ofatumumab (Section 5.4.1.5).

We asked GSK why they chose to use utilities associated with ‘following second-line treatment’. GSK replied as follows (see Appendix 1: GSK Response Document – 10 March 2010):

The original utilities proposed for the economic model were those quoted by Ferguson et al (2008) corresponding to ‘following final treatment’ (i.e. 0.279 and 0.428 for progressed and progression free disease respectively).

To assist with the development of the economic model, an advisory board was held during November 2009, at which the opinions of three health economists were sought to inform the modelling approach and assumptions. During discussion at the advisory board, the consensus of opinion was that the Ferguson et al utilities ‘following final treatment’ were very low when considered in the context of utilities cited in the recently- published ACD for a similar monoclonal antibody therapy, for use in CLL (i.e. 0.6 and 0.8 for the progressed and progression-free survival health states respectively; ACD for rituximab for the treatment of relapsed or refractory chronic lymphocytic leukaemia, NICE, 10th November 2009).

Given the disparity between the values considered appropriate in the STA of rituximab in refractory CLL (0.6, 0.8) and those proposed in the STA of ofatumumab (0.279, 0.428), the economists GSK consulted suggested that a reasonable approach to take in the cost effectiveness analysis would be to use the utilities quoted by Ferguson et al ‘following second-line treatment’ (i.e. 0.47 and 0.65) as the base case. It was also suggested that GSK conduct sensitivity analyses with the utilities ‘following final treatment’ (0.279 and 0.428) and ‘following first-line treatment’ (0.540 and 0.777). These sensitivity analyses were presented in the submission in Scenario 6.

Given this reply, we still propose alternative utilities for PFS and PD of 0.428 and 0.279, corresponding to ‘following final (third-line) treatment’, this is an evidence-based source, given that patients in the Hx-CD20-406 study had had a median of 5 pervious lines of treatment. Concerning the utilities in the STA of rituximab in refractory CLL, Section 3.13 of the appraisal consultation document (ACD) states:

The utility values used in the manufacturer’s submission were taken from a health technology assessment report that assessed the cost effectiveness of fludarabine as a first-line treatment for chronic lymphocytic leukaemia. A utility value of 0.8 was attached to the progression-free survival health state and 0.6 to the progressed health state. The estimates of utility were not preference based, and were estimated by the authors of the report from condition-specific health-related quality-of-life data Source: http://www.nice.org.uk/guidance/index.jsp?action=article&o=46066 109 Documentation about the cost-effectiveness of fludarabine for first-line treatment for CLL on the NICE website gives no information on the utilities used.[11] Therefore, we are unable to trace the source of utilities used by GSK, although the utilities would appear to be inappropriate given that they were used for first-line CLL treatment, while ofatumumab is a treatment for DR patients.

As previously stated in Section 5.1.5 of this report (p51), GSK commissioned a health state valuation study for fludarabine-refractory CLL. We asked GSK for interim results of this study. They replied that a draft report of the study has been written and is currently under review. They continued:

During development of the disease states for valuation in the study, descriptions of each proposed state were reviewed by 2 specialist clinicians with experience of treating CLL patients on a regular basis, and an internal GSK clinician experienced in haematology. Feedback from these clinicians indicated that patients’ response to treatment would be an important determinant of their HRQL. Therefore, the proposed progression-free survival (PFS) state was subdivided into two distinct states, differentiating patients who were responding to treatment from those who were not.

The results of the study, which used the Time Trade Off method are as follows: mean utility in PFS with response = 0.671, in PFS without response = 0.394, in disease progression = 0.214. GSK continued:

As the health state valuation study was undertaken subsequent to the development of the economic model, the model was not structured to accommodate the different states of ‘response’ or ‘non-response’ to treatment, within the progression free survival curve for ofatumumab. Therefore, the values obtained from the study cannot presently be incorporated in the model.

Whether it is possible to amend the economic model to include the study results is currently under investigation.)

Despite GSK’s claim that the utilities cannot be incorporated into their model, we believe that they can be used. We can set the utility in progressive disease for both treatment arms equal to 0.214. We can set the utility for patients in the BSC arm equal to the PFS ‘no-responders’, which equals 0.394. Ideally, to use the study utilities for ofatumumab, we would have to subdivide the PFS health state for ofatumumab into ‘PFS and responding’ and ‘PFS and not responding’. However, instead, we can keep the single PFS health state and assume a utility equal to the average of 0.671 and 0.394, weighted by the proportion of patients in the single- arm trial who achieved a response (58%). This yields a utility of 0.555 for patients in PFS in the ofatumumab arm compared to 0.65 as in GSK’s base case. This represents an upper bound, because we assume that all ofatumumab patients who achieve a response keep the response until disease progression. We used these utilities in GSK’s model as a sensitivity analysis (see Section 5.4.1.5). We caution that we do not have the details of GSK’s study of utilities and are 110 therefore unable to comment on the quality and appropriateness of the design of the utility study.

Although not stated in Ferguson et al (2008),[16] given that ofatumumab is a very new drug, it is unlikely that any of the health state descriptions reflect treatment with ofatumumab. However, our expert advisor suggests that the health-related quality of life for patients taking ofatumumab might be slightly higher than for patients receiving BSC, and this is supported by the results of GSK’s QoL study, described above. Indeed, GSK note that patients got relief of symptoms in the Hx-CD20-406 study (Source: GSK Submission, p83). Nonetheless, it is impossible to quantify any such difference in utility between treatments, and we suggest that the utilities of 0.428 and 0.279 for PFS and PD (corresponding to ‘following third-line treatment’) for both treatments should have been used in the base case.

A New Zealand based economic evaluation of third-line treatment of CLL with alemtuzumab assumed a single utility of 0.82 in the base case, which is far higher than assumed by GSK or by ourselves.[23] The authors cite two sources for this value: from a cost-utility analysis of Hodgkin’s disease and from a study on the QoL of patients with acute leukaemia in China. We mention this study to demonstrate that there is much uncertainty about the choice of utility values in CML.

5.2.4 Assessment of uncertainty

5.2.4.1 Probabilistic sensitivity analysis

The distributions for the parameters for the probabilistic sensitivity analysis are appropriate.[24] However, although GSK model the variance of parameters lambda and gamma of the Weibull distributions for PFS and OS, they do not model the covariance between these parameters. Simulation with an adjusted PenTAG model (see Section 5.4.2.1, p74) concluded that this omission has the effect of over-estimating the uncertainty in cost-effectiveness.

5.3 Results included in manufacturer’s submission

In this section, we summarise GSK’s results. See pages 130 to147 of GSK’s submission for further details. In their base case, GSK assume a cost of ofatumumab of ***********under a PAS. Treatment with ofatumumab is predicted to yield a mean of 0.74 extra life years, and 0.35 extra discounted QALYs, compared to BSC (see Table 17). Treatment with ofatumumab is expected to cost £13,600 more per person than BSC, which is largely explained by the acquisition cost of ofatumumab (expected ****** per patient). Together this yields a base case ICER of £38,421 / QALY.

111 Table 17. Base case results of GSK’s model (mean per patient) assuming ofatumumab costs ******per mg

Ofatumumab BSC Ofatumumab – BSC Time in PFS (= time on ofatumumab in 0.524 0.357† 0.168 ofatumumab arm) (years)¶ Time in PD (years)¶ 1.169 0.596†† 0.574 Life years¶ 1.693 0.952††† 0.741 QALYs§ 0.850 0.497 0.353

Drug cost§ ****** ** ****** Drug administration§ £1,692 £0 £1,692 Adverse events§ £1,340 £1,666 –£326 Other in PFS§ ****** ****** ****** Other in PD§ ****** ****** ****** Total costs§ £18,449 £4,885 £13,565

ICERs Cost / life-year gained £19,708

Cost / QALY £38,421

Probability ofatumumab cost 6% effective at £20,000 / QALY WTP

Probability ofatumumab cost effective at £30,000 / QALY WTP 28% NB all values taken directly from GSK’s model. Some values differ slightly to those given in Table 6.25, p132, of GSK’s submission ¶ Undiscounted § Discounted † Incorrectly quoted as 4.25 months by GSK (GSK submission, p131) †† Incorrectly quoted as 5.08 months by GSK (GSK submission, p131) ††† Incorrectly quoted as 9.33 months by GSK (GSK submission, p131)

GSK also performed several one-way sensitivity analyses (Source: GSK Submission, p133), (Table 18 in this report). All but one analysis assumes an ofatumumab cost of ******per mg. The following analyses are particularly important, either because they have a large impact on cost-effectiveness, or because we consider them to be plausible. Assuming the provisional list price of ofatumumab of £1.58 / mg, the ICER increases substantially, to £96,000 / QALY (see Table 18). Next, assuming the maximum possible dose of ofatumumab for all patients, the ICER increases moderately, to £43,300 / QALY. When 17p and 11q deletions are included as covariates in the Cox regressions for PFS and OS, the ICER increases substantially, to £50,300 / QALY. When the utilities for PFS and PD are set to 0.428 and 0.279 respectively, corresponding to values for patients following final, third-line, treatment from Ferguson et al

112 (2008),[16] the ICER increases substantially, to £62,700 / QALY. Conversely, when the utilities for PFS and PD are both set to 0.80, corresponding to values of the healthy UK general population[25], which may be useful if ofatumumab is deemed to satisfy the ‘End of Life’ criteria, the ICER falls to £24,600 / QALY.

In addition, GSK give three further scenarios: a ‘best case’, a ‘worst case’ and a ‘most realistic’ scenario (Source: GSK Submission, pp141–145).

In the ‘best case’ scenario, a 50% decrement is applied to the BSC arm PFS and OS and higher utility values are applied, (0.777 for PFS and 0.540 for PD), yielding an ICER of £24,000 / QALY.

In the ‘worst case’ scenario, 17p and 11q deletions are included as factors in the Cox regression models and lower utility values are applied, 0.428 for PFS and 0.279 for PD, yielding an ICER of £81,500 / QALY.

In Section 6, (p77) we explain why we believe that this scenario is the most likely of all those presented by GSK. In this scenario, there is a 13% chance that ofatumumab is cost-effective at a willingness to pay of £20,000 / QALY, and a 28% chance at £30,000 / QALY. In the scenario that GSK consider ‘most realistic’ scenario, a 20% decrement is applied to PFS and OS for BSC, yielding an ICER of £32,200 / QALY.

113 Table 18. GSK sensitivity analyses

Base case Sensitivity analysis ICER (cost/QALY) Ofatumumab vs. BSC

Base case £38,421 *************** £1.58 per mg Costs

Cost of ofatumumab £96,000

Pharmacist time to 15 minutes 45 minutes £38,800 dispense one dose of (£8) (£24) ofatumumab Mean total dose of 19,275mg 22,300mg £43,300 ofatumumab (per (maximum possible) patient)

Clinical Both shorter-tailed (Weibull £34,800 effectiveness scale parameters of BSC PFS and OS increased by factor 1.1)

ditto factor 1.2 £32,200 BSC PFS and OS ditto factor 1.3 £30,400 ditto factor 1.4 £28,900 ditto factor 1.5 £27,800 17p and 11q factors in excluded included £50,300 Cox regressions for PFS and OS PFS = 0.428, PD = 0.279 PFS = 0.650, (Following final, 3rd-line, PD = 0.470 treatment) [16] £62,700† Utilities (Following PFS = 0.777, PD = 0.540 2nd-line, (Following 1st-line £33,100 treatment) [16] treatment)[16] PFS = PD = 0.80 (UK £24,600 population norm)[25] † Incorrectly quoted as £81,537 by GSK (p135 GSK submission)

Note that the heading of Table 6.23 in GSK’s Submission (p132) should refer to overall survival, not to QALYs.

114 5.4 Comments on validity of results presented with reference to methodology used

In this section, we generate alternative ICERs when we suggest changes to GSKs’ assumptions or for interesting scenario analyses. These results are summarised in Section 6 of this report.

5.4.1 Data inputs

5.4.1.1 Clinical effectiveness data

5.4.1.1.1 BSC treatment arm

GSK acknowledge that their method of modelling the BSC treatment arm from patients who did not respond to ofatumumab treatment in the single treatment study Hx-CD20-406 is the main weakness of their analysis (Source: GSK Submission, Section 6.9, p150). However, we repeat (Section 5.2.3.2, p60) that we are reasonably satisfied with the modelled efficacy of BSC treatment given the lack of randomised evidence and given the close agreement with the BSC efficacy as measured by Tam et al (2007).[3]

Given the paucity of data for BSC, we estimated the best possible cost-effectiveness of ofatumumab by setting total QALYs and costs for the BSC arm to zero. This can be seen as an extension of the sensitivity analyses performed by GSK, where PFS and OS for BSC are successively modelled to be shorter-tailed, by adjusting the scale parameters of the Weibull survival curves. In this case, GSK’s base case ICER of £38,400 / QALY reduces to £21,700 / QALY and our proposed alternative ICER of >£81,500 / QALY reduces to >£38,400 / QALY.

5.4.1.1.2 17p and 11q chromosonal deletions

As stated in Section 5.2.3.2, p60 of this report, we believe the use of Cox regression to control for any imbalances in patients characteristics (e.g. gender, ECOG) between the BSC and ofatumumab arms is appropriate (Source: GSK Submission, p84). This is especially important because patients were not randomised to an ofatumumab arm and to a BSC arm. However, we believe that GSK should have included 17p and 11q chromosonal deletions as factors in the Cox regressions for PFS and OS. In this case, GSK’s base case ICER increases from £38,421 to £50,300 / QALY (Source: GSK Submission, p136).

5.4.1.1.3 Independent curve fits for ofatumumab

As stated in Section 5.2.3.2, p60 of this report, when we fit PFS and OS curves for ofatumumab independently of the curves for BSC, GSK’s base case ICER of £38,400 / QALY 115 increases to £49,600 / QALY, and our proposed alternative ICER of >£81,500 / QALY decreases slightly to >£79,700 / QALY. We repeat that these should be viewed as sensitivity analyses, not as base cases, because this method does not control for any imbalances in patient characteristics between treatment arms.

5.4.1.2 Drug costs and drug administration costs

In their base case and in all but one sensitivity analysis, GSK assume that a Patient Access Scheme will apply, whereby the provisional list price of ofatumumab of £1.58 / mg is reduced to ******/ mg. We have been instructed by NICE to assume that the Patient Access Scheme is appropriate although it has not yet been agreed. However, when we use the provisional list price of £1.58 / mg, GSK’s base case ICER of £38,400 / QALY increases to £96,000 / QALY, and our proposed alternative ICER of >£81,500 / QALY increases to >£207,200 / QALY.

5.4.1.2.1 Acquisition cost of ofatumumab

As stated in Section 5.2.3.3 (p63) of this report, we believe that GSK have slightly overestimated the mean per patient cost of acquisition of ofatumumab: GSK state that in the Hx-CD20-406 study, the mean total dose of ofatumumab was 18,202mg for DR patients, whereas their model assumes a greater mean dose of 18,931mg (not 19,275mg as they claim). However, assuming the actual mean dose in the trial, GSK’s base case ICER of £38,400 / QALY decreases only marginally, to £37,400 / QALY, and our proposed alternative base case of >£81,500 / QALY decreases only marginally, to >£79,300 / QALY. Given that the changes in ICERs are so slight, we do not consider this issue any further.

5.4.1.2.2 Drugs in progressive disease

As stated in Section 5.2.3.3, p63, we believe that GSK should have modelled the costs of drug treatment in progressive disease. Given the lack of dosing information, we cannot explore the costs of these drugs in the GSK model, however, we predict that the ICER would increase by several thousand pounds per QALY, because patients in the ofatumumab treatment arm typically spend longer in progressive disease than patients in the BSC arm (1.2 vs. 0.6 years respectively, Table 17, p69).

5.4.1.3 Disease management costs

As noted in Section 5.2.3.4 (p64) of this report, GSK’s disease management costs seem appropriate.

116 5.4.1.4 Adverse event costs

We believe that the costs of treating adverse events have been appropriately incorporated in the model. The incremental costs associated with treatment of adverse events accounts for only a tiny fraction of the total incremental costs (Table 17, p69 this report).

5.4.1.5 Health related quality of life

As stated in Section 5.2.3.6, p65 of this report, we do not think GSK’s choice of base case utilities are appropriate: 0.65 in PFS and 0.47 in PD, corresponding to ‘Following second-line treatment: progression free’ and ‘Following second-line treatment: progressive disease’ (Table 13, p52 this report). Given that patients in the study Hx-CD20-406 had received a median of five previous treatments (Source: GSK Submission, Section 5.8.4, p52), we believe that it is preferable to assume utilities for PFS and PD of 0.428 and 0.279, corresponding to ‘Following final (third-line) treatment: progression free’ and ‘Following final (third-line) treatment: progressive disease’ respectively (Table 13, p52), with the PFS utility for patients on ofatumumab slightly higher than 0.428. This change has a major impact on the cost- effectiveness of ofatumumab. GSK’s base case ICER increases from £38,400 to a maximum of £62,700 / QALY (not £81,500 / QALY as stated by GSK (Source: GSK Submission, Section 6.6.7, p135) although this error was acknowledged by GSK in their reply to our queries [see Appendix 1: GSK Response Document – 10 March 2010]) and [Table 18, p71]).

As stated in Section 5.2.3.6, p65 of this report, as a sensitivity analysis, we suggest the following utilities, adapted from GSK’s ongoing utility study: PFS BSC = 0.394, PFS ofatumumab = 0.555, progressive disease both treatments = 0.214. GSK’s base case ICER of £38,400 / QALY then increases to £52,100 / QALY, and our proposed alternative ICER decreases from >£81,500 to >£60,500 / QALY.

As stated in Section 5.3, p68 of this report, when the utilities for PFS and PD are both set to 0.80, corresponding to values of the healthy UK general population,[25] which may be useful if ofatumumab is deemed to satisfy the ‘end of life’ criteria, GSK’s base case ICER falls from £38,400 to £24,600 / QALY, and our proposed alternative ICER decreases from >£81,500 to >£32,900 / QALY.

5.4.2 Assessment of consistency

5.4.2.1 Internal consistency

We have thoroughly checked the mathematics, statistics, internal logic and implementation of GSK’s model in Excel, as well as the cost-effectiveness results presented by GSK. We chose a

117 completely independent method of checking GSK’s model results. We copied the economic model for four drugs for renal cell carcinoma, which we developed as part of the HTA programme for NICE, and then adapted it to the economic evaluation of ofatumumab for CLL.[15] This was a reasonably simple task because our renal cell carcinoma model and GSK’s CLL model considered the same health states, namely PFS and PD, and modelled PFS and OS by the ‘AUC’ method, using Weibull curves. Our adapted model yielded almost identical results to GSK’s model in the base case and in all sensitivity analyses. This is an excellent check of the logical accuracy of GSK’s model, given that our renal cell carcinoma model has been extensively checked both by ourselves and by the manufacturers of the four drugs for renal cell carcinoma, we do not think that there are any internal model flaws.

5.4.2.2 External consistency

Given that there are no published models of ofatumumab for CLL, there are no cost- effectiveness results against which GSK can check their results. They do, however, appropriately compare the modelled efficacy of ofatumumab with that experienced in the main trial.

5.4.3 Assessment of uncertainty

5.4.3.1 One-way sensitivity analyses

GSK present one-way sensitivity analyses (see Table 18, p71 [of this report]) In additional, we present several further analyses in Section 6, p77.

5.4.3.2 Probabilistic sensitivity analysis

As stated in Section 5.2.4.1 (p68) of this report the distributions for the parameters for the probabilistic sensitivity analysis are appropriate. However, although GSK model the variance of parameters lambda and gamma of the Weibull distributions for PFS and OS, they do not model the covariance between these parameters. We believe that this omission has the effect of over- estimating the uncertainty in cost-effectiveness. However, it is impossible to quantify this.

5.5 Summary of uncertainties and issues

Overall, we found GSK’s evaluation to be good, with no logical errors in the economic model. However, we do not think the most appropriate decisions have been made about;

. the choice of utilities (GSK’s choice biases cost-effectiveness in favour of ofatumumab),

118 . the omission of 17p and 11q chromosonal deletions as factors in their Cox proportional hazards models for PFS and OS (GSK’s omission biases in favour of ofatumumab),

. the omission of the costs of drugs in progressive disease (GSK’s omission biases in favour of ofatumumab).

When we update GSK’s model with what we think are more appropriate assumptions, the ICER increases in all three cases. When we correct for all three, the ICER increases from £38,400 / QALY to at least £81,500 / QALY.

GSK’s base case ICER of £38,400 / QALY and our proposed alternative ICER of >£81,500 / QALY are rather uncertain for the following three reasons. First, the effectiveness of the ofatumumab and BSC treatment arms were not taken from a randomised trial. Instead, the effectiveness for BSC was taken from non-responders in the single-arm ofatumumab trial, which is methodologically very dubious. Nonetheless, since the survival data for the non- responder group in the ofatumumab trial is very similar to that in the Tam et al (2007) trial,[3] this offers some support for the use of this group as an appropriate proxy for the BSC arm.

Second, uncertainty in the cost-effectiveness of ofatumumab is further increased due to the extensive extrapolation of OS, with approximately 40% of patients still alive at maximum follow- up (p60) of this report.

Third, we and GSK have concerns about the methodology of the study from which utilities are taken (Section 5.2.3.6, p65). This is important because cost-effectiveness is sensitive to the utilities.

Finally, we believe that GSK’s probabilistic sensitivity analyses over-estimates the extent of parameter uncertainty in cost-effectiveness because GSK have assumed that the two parameters of the Weibull distributions for PFS and separately for OS are independent, whereas they will be correlated to some extent.

119 6 Additional work undertaken by the ERG

Here, we quantify the impact of using alternative assumptions for items discussed in the last chapter, both individually and cumulatively. We derive an alternative ICER of >£81,500 / QALY by updating the model for the items where we believe that alternative assumptions are more appropriate (Table 19). We then consider a range of important scenario analyses applied separately to GSK’s base case and our proposed alternative base case (Table 20).

Table 19: Derivation of alternative deterministic ICER for ofatumumab vs. BSC based on our proposed alternative assumptions

Item ICER Ofatumumab vs. BSC (£/QALY) GSK base case £38,400 1a Include 17p and 11q chromosomal deletions in Cox £50,300 regressions of PFS and OS 2b Utility in PFS = 0.428, PD = 0.279 as opposed to slightly less than £62,700c 0.650 and 0.470 in GSK’s base case 3d Include costs of drugs in progressive disease > £38,400 by £thousands

Alternative (combination of all items) > £81,500 by £thousands a See Section 5.4.1.1 b See Section 5.4.1.5 c ‘slightly less than’ reflects our prediction that the utility for patients on ofatumumab is slightly higher than for patients on BSC d See Section 5.4.1.2

120 Table 20. Important scenario analyses applied separately to GSK’s base case versus proposed alternative base case

Item Revised ICER Revised ICER from GSK base case from proposed alternative base case

Base case £38,400 > £81,500 by £thousands 1 a PFS and PD utilities = 0.80 [25] £24,600 > £32,900 by £thousands 2 b Utilities from GSK study (PFS BSC £52,100 > £60,500 by £thousands = 0.394, PFS ofatumumab = 0.555, PD both treatments = 0.214)

3 c Cost of ofatumumab equal to £96,000 > £207,200 by £thousands provisional list price of £1.58 / mg (from ******/ mg under PAS) 4 d PFS and OS fitted independently £49,600 > £79,700 by £thousands for BSC and ofatumumab (i.e. not by Cox proportional hazards) 5 e Costs and QALYs of BSC both zero £21,700 > £38,400 by £thousands a See Section 5.4.1.5 b See Section 5.4.1.5 c See Section 5.4.1.2 d See Section 5.4.1.1 e See Section 5.4.1.1

121 7 Discussion

7.1 Summary of clinical effectiveness issues

. The submission from GSK includes one study; a non-randomised, single-arm study, (Hx-CD20-406). From a total of 138 patients treatment effectiveness is taken exclusively from the 59 DR patients. Data for ofatumumab is taken from all 59 patients, and, crucially, data for BSC arm patients is taken from all non-responders for the economic analysis.

. Two other studies were identified: Tam et al 2007 and Dungarwalla et al 2008,[2,3] that were ruled out as historical comparators because they are non-comparative and provide evidence for therapies other than ofatumumab. However, the manufacturer uses Tam et al (2007) data as a comparator to the single-arm trial, stating that the patient populations in the two studies were ‘highly comparable’ and that the patients in the two studies were ‘treated in similar settings and in a similar manner’.

. After Week 28, disease status evaluation (physical examination, spleen and liver measurement, and blood samples) took place every three months until Month 24.

. In the Hx-CD20-406 study the ORR was 58% (99% CI, 40% to 74%; p<0.001) Complete resolution of constitutional symptoms and improved performance status occurred in 57% of patients. Median progression free survival and overall survival times were 5.7 and 13.7 months respectively.

. The most common adverse events during treatment were infusion reactions and infections, which were primarily grade 1 or 2 events. The AE profile is consistent with that seen with other monoclonal antibody therapies. However, using a single-arm study – Hx-CD20-406 – there is no way of assessing the AE profile truly related to the intervention

7.2 Summary of cost effectiveness issues

The overall approach to modelling is reasonable, with no logical errors in the economic model. However. necessarily limited by the dearth of clinical effectiveness data available. We do not think the most appropriate decisions have been made about:

. their choice of utilities (GSK’s choice biases cost-effectiveness in favour of ofatumumab),

122 . their omission of 17p and 11q chromosonal deletions as factors in their Cox proportional hazards models for PFS and OS (GSK’s omission biases in favour of ofatumumab),

. their omission of the costs of drugs in progressive disease (GSK’s omission biases in favour of ofatumumab).

When we update GSK’s model with what we think are more appropriate assumptions, the ICER increases in all three cases. When we correct for all three, the ICER increases from GSK’s base case of £38,400 / QALY to at least £81,500 / QALY.

GSK’s base case ICER of £38,400 / QALY and our proposed alternative ICER of >£81,500 / QALY are rather uncertain for the following three reasons. First, the effectiveness of the ofatumumab and BSC treatment arms were not taken from a randomised trial. Instead, the effectiveness for BSC was taken from non-responders in the single-arm ofatumumab trial, which is methodologically very dubious. Nonetheless, since the survival data for the non- responder group in the ofatumumab trial is very similar to that in the Tam et al (2007) trial[3] observational study, this offers some support for the use of this group as an appropriate proxy for the BSC arm.

Second, uncertainty in the cost-effectiveness of ofatumumab is further increased due to the extensive extrapolation of OS, with approximately 40% of patients still alive at maximum follow- up (p60 of this report).

Third, we and GSK have concerns about the methodology of the study from which utilities are taken (Section 5.2.3.6, p65). This is important because cost-effectiveness is sensitive to the utilities.

Finally, we believe that GSK’s probabilistic sensitivity analyses over-estimates the extent of parameter uncertainty in cost-effectiveness because GSK have assumed that the two parameters of the Weibull distributions for PFS and separately for OS are independent, whereas they will be correlated to some extent.

7.3 Implications for research

. An RCT of ofatumumab versus BSC for double-refractory CLL patients is required to improve the estimate of cost-effectiveness of ofatumumab. However, we appreciate that this may not be possible for ethical reasons.

123 . The effectiveness of ofatumumab and BSC were taken from the interim analysis at 19th May 2008 of study Hx-CD20-406. This analysis is already nearly two years out of date. GSK’s model should be run using more up to date effectiveness data from this trial to improve the estimate of cost-effectiveness of ofatumumab.

. The valuation of health state descriptions in Ferguson et al. (2008)[16] uses the time trade-off method, from a representative sample of the general public, which is appropriate. However, the health state descriptions were taken from the literature, clinical guidelines and from specialist nurses/clinician, but the NICE reference case[20] explicitly states that health state descriptions should come from patients. Therefore, if a RCT of ofatumumab versus BSC is performed, the accuracy of cost-effectiveness estimates would be improved by the use of an EQ-5D survey, completed by double- refractory CLL patients. This would also give us utility values for patients taking ofatumumab.

7.4 Assessment of factors related to the NHS and other parties

As discussed in Section 2.1.1, in their response to our queries, GSK suggested higher numbers of people potentially forming the ofatumumab eligible, double refractory CLL patient group annually, than was originally suggested in their initial submission (n=15 [GSK Submission, Section 2.2 p. 19]; n=39 [Appendix 1: GSK Response Document – 10 March 2010,A12]). This affects the projected budget impact for ofatumumab in the NHS in England and Wales over the next five years which forms Section 7 of the GSK submission. Table 1 below reproduces the GSK submission calculation which assesses the impact on the budget based on 15 eligible patients annually, uptake starting at 3% and increasing to 34% at Year 5, and assuming the reduced cost of ofatumumab under the planned PAS. Table 22 shows these figures recalculated assuming the revised numbers for DR CLL incidence, increasing annual impact from ********************at Year 5.*Table 21. Estimated budget impact of ofatumumab over the next five years: 15 eligible patients

124 Year 0 Year 1 Year 2Year 3Year 4 Year 5 2010 2011 2012 2013 2014 2015 Double Refractory Patient Population Estimated patient numbers 15 15 15 15 15 15

Estimated % uptake of ofatumumab 3 22 30 33 34 34 (patient numbers) 0 3 5 5 55

Drug cost of ofatumumab ***** ***** ***** ***** ***** ***** *****per patient per course Administration costs of ofatumumab £764 £5,603 £7,641 £8,405 £8,660 £8,660 £1698 per patient per course

Adverse event costs £610 £4,475 £6,102 £6,712 £6,916 £6,916 £1356 per patient

Budget Impact ***** ***** ***** ***** ***** *****

*Note: Discrepancies in figures are due to rounding. (Source: GSK submission, Section 7.7, Table 7.3, p. 157) *Table 22. Estimated budget impact of ofatumumab over the next five years: 39 eligible patients

2010 2011 2012 2013 2014 2015 DR patient population Estimated patient numbers 39 39 39 39 39 39

Est. % uptake of ofatumumab 3 22 30 33 34 34 Patient numbers 1 9 12 13 13 13

Drug cost of ofatumumab ****** ****** ******* ******* ******* ******* *******per patient per course Admin cost of ofatumumab 1987 14,569 19,867 21,853 22,516 22,516 £1,698 per patient per course AE costs £1,356 per patient 1,587 11,635 15,865 17,452 17,981 17,981

Budget Impact ******* ******** ******** ******** ******** ******** Note: Discrepancies in figures are due to rounding.

GSK also provided information about the budget impact were ofatumumab to be taken by the whole eligible population and this is reproduced in Table 23, with our recalculation based on an annual incidence of 39 shown in Table 24. This shows a projected increase from ******************************. Note that none of these cost calculations includes inflation.

125 Table 23. Estimated budget impact of ofatumumab over the next five years assuming 100% uptake of 15 patients

Year 0 Year 1 Year 2 Year 3 Year 4Year 5 2010 2011 2012 2013 2014 2015 Double Refractory Patient Population Estimated patient numbers 15 15 15 15 15 15

Estimated % uptake of ofatumumab 100 100 100 100 100 100 (patient numbers) 15 15 15 15 15 15

Drug cost of ofatumumab ***** ***** ***** ***** ***** ***** *****per patient per course Administration costs of ofatumumab £25,470 £25,470 £25,470 £25,470 £25,470 £25,470 £1698 per patient per course Adverse event costs £20,340 £20,340 £20,340 £20,340 £20,340 £20,340 £1356 per patient

Budget Impact ***** ***** ***** ***** ***** *****

*Note: Discrepancies in figures are due to rounding. (Source: GSK submission, Section 7.7, Table 7.4, p. 157)

Table 24. Estimated budget impact of ofatumumab over the next 5 years assuming 100% uptake of 39 patients

2010 2011 2012 2013 2014 2015 DR patient population Estimated patient numbers 39 39 39 39 39 39

Est. % uptake of ofatumumab 3 22 30 33 34 34 Patient numbers 39 39 39 39 39 39

Drug cost of ofatumumab ******* ******* ******* ******* ******* ******* *******per patient per course Admin cost of ofatumumab 66,222 66,222 66,222 66,222 66,222 66,222 £1,698 per patient per course AE costs £1,356 per patient 52,884 52,884 52,884 52,884 52,884 52,884

Budget Impact ******** ******** ******** ******** ******** ******** Note: Discrepancies in figures are due to rounding.

126 References

1 National Institute for Health and Clinical Excellence. Single Technology Appraisal: Ofatumumab for the Treatment of Refractory Chronic Lymphocytic Leukaemia – Final Scope. London: NICE; 2009 Nov.

2 Dungarwalla M, Evans SO, Riley U, Catovsky D, Dearden CE, Matutes E. High dose methylprednisolone and rituximab is an effective therapy in advanced refractory chronic lymphocytic leukemia resistant to fludarabine therapy. Haematologica 2008 Mar;93(3):475- 6.

3 Tam CS, O'Brien S, Lerner S, Khouri I, Ferrajoli A, Faderl S, et al. The natural history of fludarabine-refractory chronic lymphocytic leukemia patients who fail alemtuzumab or have bulky lymphadenopathy. Leuk Lymphoma 2007 Oct;48(10):1931-9.

4 National Institute for Health and Clinical Excellence. Guidance on Cancer Services: improving outcomes in haematological cancers - the manual. London: National Institute for Health and Clinical Excellence; 2003.

5 European Medicines Agency. Public summary of positive opinion for orphan designation of ofatumumab for the treatment of chronic lymphocytic leukaemia. http://www ema europa eu/pdfs/human/comp/opinion/48024408en pdf 2010 March 2Available from: URL: http://www.ema.europa.eu/pdfs/human/comp/opinion/48024408en.pdf

6 Yee KW, O'Brien SM. Chronic lymphocytic leukemia: diagnosis and treatment. Mayo Clin Proc 2006 Aug;81(8):1105-29.

7 Holzner B, Kemmler G, Kopp M, Nguyen-Van-Tam D, Sperner-Unterweger B, Greil R. Quality of life of patients with chronic lymphocytic leukemia: results of a longitudinal investigation over 1 yr. Eur J Haematol 2004 Jun;72(6):381-9.

8 Shanafelt TD, Bowen D, Venkat C, Slager SL, Zent CS, Kay NE, et al. Quality of life in chronic lymphocytic leukemia: an international survey of 1482 patients. Br J Haematol 2007 Oct;139(2):255-64.

9 Hallek M, Cheson BD, Catovsky D, Caligaris-Cappio F, Dighiero G, Dohner H, et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines. Blood 2008 Jun 15;111(12):5446-56.

10 Oscier D, Fegan C, Hillmen P, Illidge T, Johnson S, Maguire P, et al. Guidelines on the diagnosis and management of chronic lymphocytic leukaemia. Br J Haematol 2004 May;125(3):294-317.

11 National Institute for Health and Clinical Excellence. Fludarabine monotherapy for the first line treatment of chronic lymphocytic leukaemia. London: National Institute for Health and Clinical Excellence; 2007. Report No.: Techonolgy Appraisal Guidance 118.

12 National Institute for Health and Clinical Excellence. Rituximab for the first line treatment of lymphocytic leukaemia. London; 2009. Report No.: Technology Appraisal Guidance 174.

13 National Institute for Health and Clinical Excellence. Leukemia (chronic lymphocytic, relapsed) - rituximab: Appraisal Consultation Document. 2009. 127 14 British Committee for Standards in Haematology. Guidelines on the diagnosis and management of chronic lymphocytic leukaemia. Br J Haematol 2004;125:294-317.

15 Thompson-Coon J, Hoyle M, Green C, Liu Z, Welch K, Moxam T, et al. Bevacizumab, sorafenib tosylate, sunitinib and temsirolimus for renal cell carcinoma: a systematic review and economic evaluation. Health Technology Assessment 2010;14(2).

16 Ferguson J, Tolley K, Gilmour L, Priaulx J. Health state preference study mapping the changes over the course of the disease process in chronic lymphocytic leukemia. 2008 Nov 8; 2008.

17 NHS. NHS Reference Costs. 2008. Ref Type: Internet Communication

18 British Medical Association, Royal Pharmaceutical Society of Great Britain. British National Formulary 58. Online edition 2009. http://www bnf org/bnf/ 2009 [cited 2009 Mar 26];

19 NBS. National Blood Service. National Blood and Blood Components Price List. 2009. Ref Type: Internet Communication

20 National Institute for Health and Clinical Excellence. Guide to the Methods of Technology Appraisal. 2008. London, NICE. Ref Type: Generic

21 Drummond M, O'Brien B, Stoddart G, Torrance G. Methods for the economic evaluation of health care programmes. Oxford, UK: Oxford University Press; 1997.

22 Philips Z, Bojke L, Sculpher M, Claxton K, Golder S. Good Practice Guidelines for Decision- Analytic Modelling in Health Technology Assessment: A Review and Consolidation of Quality Assessment. Pharmacoeconomics 2006;24(4):355-71.

23 Scott WG, Scott HM. Economic evaluation of third-line treatment with alemtuzumab for chronic lymphocytic leukaemia. Clinical Drug Investigation 2007;27:755-64.

24 Briggs A, Sculpher M, Claxton K. Decision modelling for health economic evaluation. Oxford, UK.: Oxford University Press; 2006.

25 Kind P, Hardman G, Macran S. UK Population Norms for EQ-5D. York: The University of York: Centre for Health Economics; 1999. Report No.: Discussion Paper 172.

128 Appendix 1: GSK Response Document – 10 March 2010

Section A: Clarification on clinical effectiveness data

General

A1. The appendices from the clinical trial report - HXCD20406 provided are locked. Please provide the appendices in an accessible format.

The PDF of the clinical trial report links to separate documents containing the appendices. The appendices are not available at present, however we will endeavour to supply these as soon as possible.

A2. It could be important in the appraisal if the patients were heavily pre-treated and what the nature of the pre-treatment was. Aggregated data are available in the submission and the trial report, but leaves uncertainty where the number of prior treatments is small. Given the relatively small number of patients in the study, please provide the precise nature of the prior treatments for each patient.

The only information available at present is the aggregated data by treatment available in the CSR for Hx-CD20-406 CSR as Table 1.9.

A3. Do you have any evidence that a responder/non-responder analysis provides similar results to the analysis from a traditional RCT when an RCT has been possible and that using responder/ non-responder groups as proxies for treatment and comparator groups is appropriate?

GSK are not aware of any previous analysis using this methodology.

A4. The study design employed does not provide sufficient information about the impact of adverse events associated with ofatumumab as these are experienced by both the intervention and the ‘comparator’ group. Is there any evidence, ideally with an untreated or a placebo treated comparator, possibly from other conditions where the drug has been studied, to give an indication of the disutility which might results from adverse events? If so, please provide this evidence.

No additional information is available from comparative trials with ofatumumab.

Due to the paucity of available data on the disutility of adverse events, the health state valuation study, commissioned by GSK, to provide utility measures for the fludarabine-

129 refractory CLL disease states, was also designed to investigate the impact of three adverse events (neutropenia, infection and thrombocytopenia) on patients’ HRQL. Although all the disease states in the study described patients receiving treatment with ofatumumab, the adverse events were not attributed definitively to being either a consequence of ofatumumab treatment or the CLL disease process, which reflects clinical reality of adverse events seen in this population.

The summary results of the above study for adverse events, obtained using the Time Trade Off (TTO) method, are presented in Table 1 below, reproduced from the draft study report currently under review.

Table 1: Descriptive distributions for TTO scores: disutilities for treatment-related adverse events

N=110 AEs Utility Disutility Media 25% 75% Min Max (DS) (AE) n percentile percentile mean mean with thrombocytopenia 0.563 0.108 0.583 0.4 0.75 0.017 1 with neutropenia, no 0.508 0.163 0.492 0.392 0.692 0.025 0.992

PFS infection

response with infection 0.476 0.195 0.484 0.3 0.65 0.017 0.992

with infection 0.333 0.061 0.321 0.175 0.45 0 0.992 PFS non- PFS response response

A5. In an unblinded study the quality of assessment of the outcomes is particularly important. Is there any additional information about the levels of disagreement, ideally inter-rater reliability measures, between the two assessors of response? If so, please provide this evidence.

The magnitude of the objective response rate (ORR) determined was dependent upon the assessor of response (i.e. trial investigators or independent review committee [IRC]). In the DR subgroup, a higher response rate was determined by the IRC than by the trial investigators (58% vs. 42%). The FDA review of the case report forms yielded an ORR which was similar to that of the investigators (FDA briefing document Oncology Drugs Advisory Committee Meeting, May 29, 2009).

130 The ORR is based on the 1996 NCIWG criteria. The IRC determination was dependent on the investigators’ measurements of lymph nodes, spleen, and liver on physical examination, and review of laboratory data.

The IRC consisted of 5 members, at least two of whom independently evaluated each patient’s response. For every patient visit, each IRC reviewer independently determined a response by reviewing the investigator’s clinical assessments and laboratory components of the primary efficacy data from electronic CRFs. When making their assessments, the IRC reviewers were blinded to the investigators’ response determinations. If the initial two IRC reviewers’ overall objective response assessments were not in agreement, the response was independently adjudicated by a third IRC member. If the adjudicator’s assessment did not agree with either of the two initial reviewers, then a panel of at least 2 of the 5 members was convened to re-review the data and provide a consensus reading.

Table 2 summarises the efficacy results.

Table 2: Summary of ORR DR (N=59) IRC ORR (N) 58% (34) CR 0 nPR*/PR 58% (34) 99% CI (40%, 74%) Investigator ORR (N) 42% (25) 99% CI (26%, 60%)

In order to have consistent application, tumour response criteria should ideally be unambiguous such that given the same data, similar conclusions will be drawn by all assessors of response. The FDA statistical reviewer conducted an analysis of the IRC response assessments using the ‘per visit’ response data generated by each IRC reader. Table 3 shows the frequency of response disagreement between IRC readers and the number of cases that went to adjudication. Note that in no cases were there disagreements related to radiographic findings.

131 Table 3. Variability in response assessments of IRC members

To investigate the robustness of the IRC results, GSK performed a computer algorithm-based analysis of the IRC response assessments (Table 5). The algorithm should be considered as a strict application of the NCIWG 1996 guidelines, excluding any clinical judgments (for example, transient changes in lymphocyte counts). The algorithm is as follows (extracted directly from the 1996 guidelines):

132

Table 4. Summary of ORR by IRC and by computer-based Algorithm

DR (N=59) IRC ORR (N) 58% (34) CR 0 nPR*/PR 58% (34) 99% CI (40%, 74%) Computer-algorithm ORR (N) 37% (22) 99% CI (22%, 55%)

An assessment of response by each of the three applied methods confirmed that the response rate in each group reached or exceeded the target 30% objective response rate (excluding 15% at the lower limit of the 99% confidence interval), and confirmed the efficacy of ofatumumab.

133 A6. Usually a search for ongoing trials is undertaken as part of the systematic review. Please provide a list of potentially relevant ongoing studies of ofatumumab.

There are no ongoing trials in this specific population double refractory (DR) CLL. Please see Table 6 for ongoing studies evaluating the use of ofatumumab monotherapy or combination therapy for CLL at different disease stages.

134 Table 5. Ongoing ofatumumab clinical studies

Study Phase Patient Characteristics Regimen Number Number of patients

Relapsed/Refractory Ongoing Studies

Hx-CD20- Phase Refractory to fludarabine and Ofatumumab 225 406 (follow- III alemtuzumab, refractory to up) fludarabine and bulky lymphadenopathy

110913 Phase Relapsed Ofatumumab, fludarabine 274 III plus cyclophosphamide versus fludarabine plus cyclophosphamide

Front-line Ongoing Studies

Hx-CD20- Phase Front-line Ofatumumab, fludarabine 56 407 II plus cyclophosphamide

110911 Phase Front-line Ofatumumab plus 444 III Chlorambucil versus Chlorambucil

Specific

A7. Page 11: ‘The main issue highlighted during the regulatory process has been the lack of randomisation in the pivotal study (Hx-CD20-406). GSK has prepared detailed responses to address the questions of the regulatory agency regarding this matter. The regulatory procedure is still ongoing.’ Is there additional information available that has not been included in the submission; if so, please provide further details.

In the day 120 questions, a question from the EMEA addressed the lack of randomisation in the pivotal study. The complete GSK response to the question is presented in Appendix A.

135 Following the assessment of the safety and efficacy data GSK provided in response to the questions raised by the regulatory agency, the CHMP has now issued a positive opinion for a conditional marketing authorisation for ofatumumab.

The conditions of the marketing authorisation and GSK’s committments (as listed in Annex 2 of the Annexes at positive opinion) are outlined below.

Section C of the Annex (GSK’s obligations) specifically addresses the concern regarding lack of randomisation in the pivotal trial. Please note that the information quoted from Annex 2 remains Commercial in Confidence pending publication of the EPAR, which is currently anticipated at the end of March 2010.

Annex 2:

B. CONDITIONS OF THE MARKETING AUTHORISATION

· CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE IMPOSED ON THE MARKETING AUTHORISATION HOLDER

Medicinal product subject to restricted medical prescription (See Annex I: Summary of Product Characteristics, section 4.2).

· CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT

Not applicable.

· OTHER CONDITIONS

Pharmacovigilance system

The MAH must ensure that the system of pharmacovigilance, as described in version 7.2 presented in Module 1.8.1. of the Marketing Authorisation Application, is in place and functioning before and whilst the product is on the market.

Risk Management Plan

The MAH commits to performing the studies and additional pharmacovigilance activities detailed in the Pharmacovigilance Plan, as agreed in version 1.4 of the Risk Management Plan (RMP) presented in Module 1.8.2. of the Marketing Authorisation Application and any subsequent updates of the RMP agreed by the CHMP.

136 As per the CHMP Guideline on Risk Management Systems for medicinal products for human use, the updated RMP should be submitted at the same time as the next Periodic Safety Update Report (PSUR).

In addition, an updated RMP should be submitted

× When new information is received that may impact on the current Safety Specification, Pharmacovigilance Plan or risk minimisation activities

× Within 60 days of an important (pharmacovigilance or risk minimisation) milestone being reached

× At the request of the EMEA

C. SPECIFIC OBLIGATIONS TO BE FULFILLED BY THE MARKETING AUTHORISATION HOLDER

The Marketing Authorisation Holder shall complete the following programme of studies within the specified time frame, the results of which shall form the basis of the annual reassessment of the benefit/risk profile.

Clinical aspects

1. To conduct an open label, multicenter study investigating the safety and efficacy of ofatumumab therapy versus physicians’ choice in patients with bulky fludarabine refractory chronic lymphocytic leukaemia (CLL). The final protocol will be submitted for CHMP agreement within 3 months of conditional marketing authorisation date. The study report is to be submitted by December 2014, but the timing will be confirmed at the time of submission of the final protocol, when feasibility will be complete

2. To conduct a phase IV observational study to provide further data on the clinical efficacy and safety of ofatumumab. The final protocol will be submitted for CHMP agreement within 3 months of conditional marketing authorisation date. The time needed to recruit the target number of subjects (100) will depend on the date of availability on the market of Arzerra across EU, degree of use and on the willingness of patients and physicians to participate in the study. The study report is to be submitted by June 2013, but the timing may be changed at the time of submission of the final protocol.

A8. Page 14: ‘The diluted solution for infusion should either be stored below 25 ºC and used immediately or should be stored at 2-8 ºC and used within

137 24 hours of preparation. Any unused solution remaining after this time should be discarded.’ Please state how much, if any, solution is likely to be discarded in practice.

The recommended doses of ofatumumab (300 mg initial dose and 2000 mg weekly dose) are fixed doses. Ofatumumab dosing is not weight based therefore the entire diluted solution should be infused. Therefore there is likely to be no discard. If a patient experiences an infusion reaction, dose modification guidelines should be followed.

In the case of a patient experiencing a Grade 4 infusion reaction the infusion should be stopped. Any unused product or waste material should be disposed of in accordance with local requirements. Question A17 details the average dosage of ofatumumab received.

The proportion of patients who had an AE on any infusion day requiring action to be taken decreased from 32% of DR patients at the first infusion to 6% of patients at the 12th infusion. The majority of infections were grades 1 or 2. Serious adverse events on any infusion day in the DR population were 5% (3 out of 59, 4 events).

In the economic modelling it is assumed patients received full infusion volumes (a conservative analysis).Therefore any product wastage on the day of an infusion is already accounted for in the cost-effectiveness modelling.

A9. Page 47 and Page 62: Two different figures are cited in the report for the number of trial patients who came from the UK – page 62 cites 16 ‘Multicentre trial conducted in US and Europe, including 5 sites in the UK which recruited 16 patients.’ but elsewhere (e.g. p47) cites 24 ‘Multicentre trial conducted at 41 sites across the US and 9 European countries, including 5 sites recruiting a total of 24 patients in the UK.’ Please confirm which is correct.

There was a typographical error on page 62, with the second statement (p47) being correct.

Hx-CD20-406 was conducted at 41 sites in 10 countries: Czech Republic (4 sites), Denmark (2 sites), France (4 sites), Germany (7 sites), Italy (2 sites), Poland (5 sites), Spain (1 site), Sweden (2 sites), United Kingdom (5 sites) and the United States (9 sites). In addition, there were 3 sites (1 in Germany, 1 in France and 1 in Italy) that screened patients, but did not treat any. There were a total of 24 patients recruited in the United Kingdom.

A10. We note that the data provided comes from an interim analysis undertaken in May 2008 (page 51: ’As of 19 May 2008 (clinical cut-off date for a planned interim analysis)…’) This data does not contain information about median survival in the 138 responder group or the upper bound of the CI for all patients. Please provide more up- to-date data, if available.

At the present time more up to date information is not available. The upper bound of the CI has not yet been reached, however full results are anticipated in 2011.

A11. Page 67: ‘subsequent therapy was received by 31 (53%) DR patients…’ Please provide the mean dose of each drug received after ofatumumab was stopped. Please provide this separately for all patients combined and for non-responders only.

The Case Report Form (CRF) in Hx-CD20-406 only collected the name of the drug and the date started – no information was gathered on the dose. Table 1.6 in the CSR for Hx-CD20- 406 contains information on the drug and the dates, and is reproduced in Table 6.

Table 6. New anti-CLL treatment in Hx-CD20-406

139

140 A12. Page 19 Table 2.1 shows the calculation for the number of patients who are refractory to both fludarabine and alemtuzumab, which is based on GSK market research. Please supply more details about how the 1.2% figure was arrived at by forwarding the relevant information from this April 2009 study.

The ‘data on file’ (Double Helix, April 2009), to which this question refers have been reviewed since the submission, and an alternative method of calculation of the number of eligible DR patients proposed, which we believe to be more robust than the previous method.

The revised calculation for the estimated number of DR patients replaces the ‘data on file’ with the overall response rate from the alemtuzumab pivotal study in fludarabine-refractory patients and alemtuzumab sales. These figures are used to calculate the number of patients receiving alemtuzumab annually. To this, the proportion of patients failing treatment with alemtuzumab has then been applied.

The new calculation for the estimated number of patients eligible for ofatumumab treatment in 2010 is illustrated below:

Patients receiving alemtuzumab in 2009:  In the year from Q4 2008 to Q3 2009 (inclusive) 1,310 vials containing 30mg of alemtuzumab were sold1 i.e. a total of 39,300mg  The median cumulative dose per patient of alemtuzumab is estimated to be 673mg2  Hence, the number of patients receiving alemtuzumab in 2009 is estimated to be 58 (i.e. 39,300/673) Estimate of the number of patients eligible for ofatumumab per year:  Keating et al2 reported that the ORR for alemtuzumab in fludarabine-refractory patients is 33% i.e. 67% of patients are estimated to fail alemtuzumab therapy and become eligible for ofatumumab  The number of patients eligible for ofatumumab per year is approximately 39 (i.e. 67% x 58) Data sources :

1. IMS BPI/HPA data for Q3 2009

2. Keating MJ et al. “Therapeutic role of alemtuzumab (Campath-1H) in patients who have failed fludarabine: results of a large international study”, Blood 2002; 99: 3554- 3561

141 Section B: Clarification on cost-effectiveness data

General

A13. Please provide further details and justification as to why the comparison in the model was ‘all patients vs non-responders’. This in contrast to the clinical effectiveness section where the main comparison is between ‘responders vs non-responders’.

A cohort of treated patients will include both responders and non-responders, and is therefore representative of the population which would receive ofatumumab in clinical practice. The outcomes in these patients were compared with those of the 'non- responder' group which was assumed to be an approximation of an untreated cohort of patients.

In the clinical effectiveness section, data was provided for all patients, responders, and non-responders.

A14. Please provide any further detail on the paper by Ferguson et al. (ISPOR Poster, 2008). The detailed descriptions of each state would be particularly valuable. However, we acknowledge that it may be easier for us to write to the authors directly as there does not seem to be any obvious connection with GSK. Please let us know as soon as possible if this is the case so that we can follow-up directly.

GSK can confirm that we do not have any further detail on the study by Ferguson et al, other than what was published in the poster provided as a reference with the submission.

As advised in our email of 23rd February, GSK does not have a detailed understanding of the original study and agrees that it would be expedient for the ERG to write to the authors directly.

A15. Please provide the price of an intravenous infusion pump - SmartSite Extension Sets®.

We assume that this question is referring to the SmartSite Extension Sets® filter.

To administer diluted ofatumumab the following disposable equipment is required: infusion bag, infusion set, in-line filter set (provided by GSK) and cannula. An infusion pump is standard NHS equipment.

Each box of ofatumumab contains two SmartSite Extension Sets® filters. Each infusion requires just one filter set, a spare one is provided for convenience.

142

GSK believes that it is unlikely that for the administration of ofatumumab, additional SmartSite Extension Sets® will be required, and therefore the cost of the filters is included in the acquisition costs for ofatumumab.

A16. For your base case, you have chosen utilities from Ferguson et al. (2008) corresponding to ‘following 2nd-line treatment’. However, patients in the pivotal trial had received a median of five previous treatments (p52 GSK report). Please explain why you did not use the utilities from Ferguson et al. (2008) corresponding to ‘following final treatment’ in your base case.

The original utilities proposed for the economic model were those quoted by Ferguson et al (2008) corresponding to “following final treatment” (i.e. 0.279 and 0.428 for progressed and progression free disease respectively).

To assist with the development of the economic model, an advisory board was held during November 2009, at which the opinions of three health economists were sought to inform the modelling approach and assumptions. During discussion at the advisory board, the consensus of opinion was that the Ferguson et al utilities “following final treatment” were very low when considered in the context of utilities cited in the recently-published ACD for a similar monoclonal antibody therapy, for use in CLL (i.e. 0.6 and 0.8 for the progressed and progression-free survival health states respectively; ACD for rituximab for the treatment of relapsed or refractory chronic lymphocytic leukaemia, NICE, 10th November 2009).

Given the disparity between the values considered appropriate in the STA of rituximab in refractory CLL (0.6, 0.8) and those proposed in the STA of ofatumumab (0.279, 0.428), the economists GSK consulted suggested that a reasonable approach to take in the cost effectiveness analysis would be to use the utilities quoted by Ferguson et al “following second- line treatment” (i.e. 0.47 and 0.65) as the base case. It was also suggested that GSK conduct sensitivity analyses with the utilities “following final treatment” (0.279 and 0.428) and “following first-line treatment” (0.540 and 0.777). These sensitivity analyses were presented in the submission in Scenario 6.

A17. The mean total dose of ofatumumab is cited as 18,202mg. Were there any patients at data cut-off still receiving ofatumumab, i.e. does the 18,202mg include censored patients?

No patients are censored in the submitted analysis. The interim analysis (19th May 2008) for this study was conducted after all subjects had completed at least 24 weeks on study, and so had the opportunity to receive the full course of ofatumumab. 143 Specific

A18. Page 25: ’…However, such a benefit might be tempered by side effects associated with ofatumumab therapy and potential selection bias towards poorer prognosis patients in non-responder group. These issues will be explored in sensitivity analyses varying the hazard ratios for disease progression and overall survival in the economic evaluation.’ Please explain how the sensitivity analyses undertaken help explore the issue mentioned in the penultimate sentence.

The final sentence should read:

This issue will be explored in a sensitivity analyses using alternative curve fitting assumptions for disease progression and overall survival in the economic evaluation"

The approach taken (the use of a non-responder group as a control arm) attempts to correct for any selection bias by the use of a Cox-regression for parameters such as age and sex. If this approach was not taken, an unadjusted comparison may have led to bias. A further attempt is made to control for any selection biases in scenario 7, in which additional covariates are included in the regression equation.

A19. Page 34: ’A health state valuation study was commissioned to provide utility measures for the fludarabine-refractory CLL disease states. However, as this study is ongoing, values were drawn from the literature.’ Please provide interim or final values from this study? If this is not possible, please advise when data from this study will be available?

A draft report of the results of this study has been written, and is currently under review_msocom_1.

During development of the disease states for valuation in the study, descriptions of each proposed state were reviewed by 2 specialist clinicians with experience of treating CLL patients on a regular basis, and an internal GSK clinician experienced in haematology. Feedback from these clinicians indicated that patients’ response to treatment would be an important determinant of their HRQL. Therefore, the proposed progression-free survival (PFS) state was subdivided into two distinct states, differentiating patients who were responding to treatment from those who were not.

The summary results of the study for the primary disease states (Progression Free Survival, PFS and Disease Progression) obtained using the Time Trade Off (TTO) method are presented in Table 7, which has been reproduced from the draft study report currently under review.

144 Table 7. Descriptive distribution for TTO scores: primary disease states.

N=110 Mean SD Median 25% 75% Min Max percentile percentile

PFS, 0.671 0.236 0.7 0.55 0.85 0.075 1 response

PFS, non- 0.394 0.219 0.392 0.2 0.55 0.017 1 response

Disease 0.214 0.18 0.188 0.075 0.3 0 0.892 progression

Anchor 0.549 0.231 0.592 0.45 0.683 0.025 0.992 state

As the health state valuation study was undertaken subsequent to the development of the economic model, the model was not structured to accommodate the different states of ‘response’ or ‘non-response’ to treatment, within the progression free survival curve for ofatumumab. Therefore, the values obtained from the study cannot presently be incorporated in the model.

Whether it is possible to amend the economic model to include the study results is currently under investigation.

A20. Page 100: Please update Table 6.4 to include factors for 17p and 11q deletions in the Cox regression.

The results of the Cox model including 17p and 11q deletions are shown in Table 8, which is an update of table 6.4 in the main submission document.

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Table 8. Results of Cox proportional hazards regression on PFS and OS for all patients vs. non-reponders in the Hx-CD20-406 study

PFS OS

Group Model Variable HR (95%CI) P HR (95%CI) P

DR Un- Non-Repsonder vs 0.49 (0.28-0.89) 0.02 0.55 (0.30-1.03) 0.06 adjusted all

Adjusted Non-Repsonder vs 0.54 (0.28-1.04) 0.06 0.58 (0.29-1.15) 0.12 all

Male 1.18 (0.56-2.48) 0.67 0.71 (0.31-1.65) 0.43

Age < Median 0.55 (0.27-1.11) 0.09 0.35 (0.16-0.76) 0.01

Rai Score ≥ 3 0.92 (0.48-1.77) 0.81 1.29 (0.60-2.77) 0.52

ECOG 1 or 2 2.35 (1.18-4.65) 0.01 3.05 (1.44-6.47) 0.00

No. prior therapies 0.47 (0.21-1.05) 0.07 0.48 (0.20-1.18) 0.11 < Median

Years since 3.45 (1.59-7.47) 0.00 4.35 (1.88-10.08) 0.00 diagnosis < Median

Prior rituximab 1.01 (0.48-2.12) 0.98 1.17 (0.46-2.99) 0.75

Lymph nodes > 5 3.39 (1.43-8.01) 0.01 2.22 (0.85-5.79) 0.10 cm

11q deletion 1.52 (0.66-3.48) 0.32 1.69 (0.60-4.73) 0.32

17p deletion 3.64 (1.37-9.69) 0.01 7.70 (2.57-23.06) 0.00

146 A20. Please confirm the following values for the lambda and gamma for BSC and for ofatumumab when the two deletions are allowed for in the Cox regression (time measured in days). (NB: these values were calculated from data on p207 for Scenario 7):

PFS_gamma_BSC 1.88710 OS_gamma_BSC 1.13662

PFS_lambda_BSC 0.00006912 OS_lambda_BSC 0.00123921

PFS_gamma_ofatumumab 1.88710 OS_gamma_ofatumumab 1.13662

PFS_lambda_ofatumumab 0.00003702 OS_lambda_ofatumumab 0.000720

The above values may produce similar results, however are not those used in the GSK analysis (which are detailed in Appendix 17 of the main submission document, and reproduced in Table 9).

Table 9. Lambda, gamma and hazard ratio values for PFS and OS including 17p and 11q deletions (NB: time value set in months)

PFS_gamma_BSC - OS_gamma_BSC - PFS_lambda_BSC - OS_lambda_BSC - HRPFS_Comp2 1.867 HROS_Comp2 1.721 PFS_gamma_ofatumumab 0.023294 OS_gamma_ofatumumab 0.034922 PFS_lambda_ofatumumab 1.8871 OS_lambda_ofatumumab 1.13662 HRPFS_Comp1 1.00 HOS_Comp1 1.00

147 A21. Page 99: The lambda and gamma for progression-free survival and overall survival for non-responders are given in Table 6.2. Please confirm that for the independent curve fit for ofatumumab, the following values are correct: for PFS, lambda= 0.00003702 and gamma= 1.8871 and for OS, lambda= 0.000720 and gamma= 1.136621 (corresponding curves displayed graphically in Figs 6.6 and 6.7).

The lambda and gamma values provided in table 6.2 of the submission document are accurate and detail the curve fitting to the ofatumumab non-responders, this table is reproduced as Table 10.

Table 10. Weibull function parameters for days of PFS and OS for non-responders in the DR group of the Hx-CD20-406 study (Table 6.2, main submission document)

Lambda (Scale) Gamma (Shape) Outcome Estimate SE Estimate SE PFS 0.0001516 0.0000384 1.7627358 0.0009488 OS 0.0032653 0.0008002 0.9790484 0.0007423

The values quoted for ofatumumab in question A21 are those used in the stratified Weibull model, and are not used in any GSK analysis. The economic approach submitted to NICE utilises a Proportional Hazard approach, in which ofatumumab treated patients have hazard ratios of 0.51 for PFS, and 0.534 for OS applied to the non-responder patients (in whom the values in table 6.2 are appropriate).

It is possible to delete the values in the stratified Weibull model inputs without affecting the analysis used in the GSK submission.

A22. Page 102: Have the OS and PFS Kaplan-Meier curves shown in Figs 6.6 and 6.7 been published, so that we can compare the GSK curve fits against the Kaplan-Meier curves? If so, please provide references for the publications.

The Kaplan Meier curves for PFS and OS for all patients by prior treatment (DR and BFR) were reported in the Hx-CD-20-406 CSR.

The Kaplan-Meier curves for PFS and OS for non-responders at 24 weeks had not been published at the time of the submission. However, as of 1st March 2010, they have been published online in the Journal of Clinical Oncology, in advance of the printed journal

148 publication. The latest version of the article is available at: http://jco.ascopubs.org/cgi/doi/10.1200/JCO.2009.25.3187

A23. Page 135: An ICER of £81,537 / QALY is quoted in Table 6.31 using the lowest utilities from Ferguson et al. (2008). Please confirm that this figure should read approx. £62,700 / QALY gained. Please also confirm that the £81,537 / QALY gained relates instead to using the lower utilities and including 17p and 11q deletions in the Cox regression as shown on p143, Table 6.35.

We apologise for the error. The figure on page 135 should read £62,254 / QALY. Corrected values can be found in Table 11.

Table 11. Corrected values for table 6.31: Sensitivity: Low Ferguson et al. (2008) values: 0.49 pre-progression 0.28 post-progression

Incremental cost Incremental Cost- Incremental Incremental Incremental Treatment Total costs Life Years QALYs per Life year Effectiveness costs Life Years QALYs Gained Ratio (£) BSC DR £4,885 0.922 0.310 - - - - - Ofatumumab DR £18,449 1.611 0.527 £13,565 0.688 0.217 £19,708 £62,654 QALY = Quality Adjusted Life Year, all values discounted

As correctly identified by the reviewer, the value of £81,537 / QALY (page 143) is achieved when using these lower utility values and including 17p and 11q deletions in the Cox regression.

A24. Page 106: Please confirm that in Table 6.6 the cost under “Health state costs per month: OS: Routine follow-up and monitoring: BSC” should equal £0 as is stated.

Routine follow-up and monitoring

Ofatumumab £158.00Lognormal £39.50

BSC £0.00 £0.00

The value of £0.00 was stated in error in Table 6.6; both values should be equal to £158.00 per month, with a lognormal distribution and SE of £39.50.

The economic model does not contain the error, with routine follow-up costs set to £158.00 for both ofatumumab and BSC in all analyses conducted.

149 A25. Pages 104–106: Table 6.6 seems to suggest that some cycles of ofatumumab are given free of charge. Please clarify why that should occur.

The “free of charge” variables in the model are used to model the different stages of ofatumumab therapy. Dosage information for each of the 3 stages of treatment (300 mg dose on day 1, 7 weekly doses of 2000 mg beginning on day 8, and 4 doses every 28 days of 2000 mg beginning on day 49) is entered in the corresponding fields for Drugs 1 to 3 respectively.

To avoid double counting, doses during prior dosing stages are set to zero using the “free of charge” variable. For example, for the second dosing stage (entered as Drug 2), the number of free (7 day) cycles is set to 1, to avoid double counting doses during the first week (which would incur costs for the 300mg dose, and a 2,000mg dose). Similarly, for the third dosing stage (entered as Drug 3), the number of free (28 day) cycles is set to 3 to avoid double counting doses during the first 12 weeks.

APPENDIX A: GSK Response to the EMEA

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157 Appendix 1: Expert statements

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172 Appendix 2: Drugs taken by patients in progressive disease in study Hx-CD20-406

GSK gave us the following data in response to our request.

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