REVIEW ARTICLE

Ruxolitinib for the Treatment of Myelofibrosis:A NICE Single Technology Appraisal

Ros Wade • Micah Rose • Aileen Rae Neilson •

Lisa Stirk • Rocio Rodriguez-Lopez •

David Bowen • Dawn Craig • Nerys Woolacott

Published online: 31 August 2013

� Crown Copyright 2013

Abstract The National Institute for Health and Care

Excellence (NICE) invited the manufacturer of ruxolitinib

(Novartis) to submit clinical and cost-effectiveness evi-

dence for ruxolitinib within its licensed indication (the

treatment of disease-related splenomegaly or symptoms in

adult patients with myelofibrosis), according to the Insti-

tute’s Single Technology Appraisal process. The Centre for

Reviews and Dissemination and Centre for Health Eco-

nomics at the University of York were commissioned to act

as the independent Evidence Review Group (ERG). This

article provides a description of the company submission,

the ERG review and the resulting NICE guidance TA289

issued in June 2013. The ERG critically reviewed the

evidence presented in the manufacturer’s submission and

identified areas requiring clarification, for which the man-

ufacturer provided additional evidence. The main clinical

effectiveness data were derived from two phase III, mul-

ticentre, randomised controlled trials (RCTs): Controlled

myelofibrosis study with oral JAK inhibitor treatment

(COMFORT)-II compared ruxolitinib with best available

therapy (BAT), and COMFORT-I compared ruxolitinib

with placebo. These RCTs demonstrated that ruxolitinib

confers significant benefits in terms of spleen size reduc-

tion and improvement in symptom burden. In the COM-

FORT-II trial, a reduction in spleen volume of C35 % was

achieved in 28 % of ruxolitinib-treated patients compared

with 0 % of patients in the BAT group (p \ 0.001) at

48 weeks, and there was a mean change in spleen volume

of -30.1 versus ?7.3 % (p \ 0.001). Ruxolitinib also

provided significant improvements in myelofibrosis-asso-

ciated symptoms and health-related quality-of-life com-

pared with BAT and placebo. The ERG concluded that

ruxolitinib appears to reduce splenomegaly and its associ-

ated symptoms, but that there was considerable uncertainty

surrounding the manufacturer’s cost-effectiveness esti-

mates due to limitations in the manufacturer’s model. The

manufacturer’s model did not allow for disease progres-

sion, did not accurately capture symptomatic relief, had

several implausible or unjustified assumptions, and there

were several parameter choices that the ERG found sub-

optimal. ERG sensitivity analyses found that nearly all

plausible adjustments to the model reduced the cost

effectiveness of ruxolitinib. It is very likely that the base-

case incremental cost-effectiveness ratio of £73,980/qual-

ity-adjusted life-year presented by the manufacturer rep-

resents a best-case scenario. The NICE Appraisal

Committee concluded that ruxolitinib was clinically

effective, but could not be considered a cost effective use

of National Health Service (NHS) resources for treating

disease-related splenomegaly or symptoms in adults with

myelofibrosis. Ruxolitinib is not recommended for the

treatment of disease-related splenomegaly or symptoms in

adult patients with primary myelofibrosis (also known as

chronic idiopathic myelofibrosis), post-polycythaemia vera

myelofibrosis and post-essential thrombocythaemia mye-

lofibrosis in NICE TA289.

R. Wade (&) � M. Rose � A. R. Neilson � L. Stirk �R. Rodriguez-Lopez � D. Craig � N. Woolacott

Centre for Reviews and Dissemination (CRD),

University of York, York YO10 5DD, UK

e-mail: ros.wade@york.ac.uk

D. Bowen

St James’s Institute of Oncology, Leeds, UK

PharmacoEconomics (2013) 31:841–852

DOI 10.1007/s40273-013-0083-0

Key points for decision makers

• Ruxolitinib is effective at reducing splenomegaly and

its associated symptoms (such as itch and fatigue) in

patients with myelofibrosis.

• Only limited data were presented to support

improvement in symptom scores, corresponding

quality-of-life outcomes and overall survival; there-

fore these results are uncertain.

• Around two-thirds of patients required dose inter-

ruptions or reductions due to adverse events, most

commonly thrombocytopenia and anaemia.

• There is uncertainty concerning the long-term effec-

tiveness and tolerability of ruxolitinib.

• There was considerable uncertainty surrounding the

manufacturer’s cost-effectiveness estimates due to

limitations in their model. The Evidence Review

Group sensitivity analyses found that nearly all

plausible adjustments to the model reduced the cost

effectiveness of ruxolitinib. They concluded that the

base-case incremental cost-effectiveness ratio (ICER)

presented by the manufacturer represents a best-case

scenario. A scenario analysis using alternative

assumptions to combine several of the uncertainties

used in the model resulted in a substantial increase in

the ICER.

• The National Institute for Health and Care Excellence

(NICE) Appraisal Committee concluded that ruxo-

litinib was clinically effective, but could not be

considered a cost effective use of National Health

Service resources for treating disease-related

splenomegaly or symptoms in adults with myelofi-

brosis. Ruxolitinib was not recommended by the

NICE (TA289 issued June 2013) for the treatment of

disease-related splenomegaly or symptoms in adult

patients with myelofibrosis. People currently receiv-

ing ruxolitinib should be able to continue treatment

until they and their clinician consider it appropriate to

stop.

1 Introduction

The National Institute for Health and Care Excellence

(NICE) is an independent organization responsible for

providing national guidance to the National Health Service

(NHS) in England and Wales on the use of selected new

health technologies. Single technology appraisals (STAs)

evaluate a single product, device or other technology that

has a single indication; for example, a new pharmaceutical

product or licensed indication [1]. The manufacturer (or

sponsor of the technology) submits the principal evidence

supporting the clinical and cost effectiveness of the product,

and an external independent academic organization [the

Evidence Review Group (ERG)] is commissioned to pro-

duce a review and critique of the evidence submitted [2].

Clinical specialists, NHS commissioning experts and

patient experts also provide evidence for consideration by

the NICE Appraisal Committee in formulating their guid-

ance [1]. Once published, NICE technology guidance pro-

vides a legal obligation for NHS providers to reimburse

technologies that have been approved [1]. This article pre-

sents a summary of the ERG report and subsequent devel-

opment of NICE guidance for the use of ruxolitinib within

its licensed indication for the treatment of patients with

myelofibrosis. This paper is one in a series of STA sum-

maries being published in PharmacoEconomics [3–23].

Full details of the relevant appraisal documents,

including appraisal scope, manufacturer submission, ERG

report, Appraisal Consultation Document (ACD), Final

Appraisal Determination (FAD) and responses to these

documents, can be found on the NICE website [24].

2 The Decision Problem

Myelofibrosis is a myeloproliferative neoplasm (a neo-

plasm of the bone marrow, in which excess cells are pro-

duced). Myelofibrosis can be primary, or secondary to a

number of haematological conditions, most commonly

polycythaemia vera (in which too many red blood cells are

produced in the bone marrow) and essential thrombocy-

thaemia (in which too many platelets are produced in the

bone marrow). Primary myelofibrosis (PMF), post-poly-

cythaemia vera myelofibrosis (PPV-MF) and post-essential

thrombocythaemia myelofibrosis (PET-MF) patients share

a common transformation in the early haematopoietic stem

cell of the Janus-associated kinase (JAK) 2 gene. The bone

marrow becomes replaced with scar tissue, resulting in

bone marrow failure and extramedullary haematopoiesis

(blood cell production outside the bone marrow; in the liver

and spleen), which causes liver and spleen swelling.

Myelofibrosis is rare; the estimated annual incidence is

0.34–0.76 per 100,000 [25–27], equating to approximately

187–420 individuals diagnosed with myelofibrosis in

England and Wales annually. The estimated prevalence of

PMF is 2.7 per 100,000 population [28], with PET-MF and

PPV-MF affecting 0.1 per 100,000 population [29]. Life

expectancy is associated with a range of risk factors; using

the most recent and clinically relevant risk stratification

scale [Dynamic International Prognostic Scoring System

(DIPSS) Plus], intermediate-2 risk patients have a median

survival of 2.9 years, whilst high-risk patients have a

median survival of 1.3 years [30]. Using the risk stratifi-

cation scale used in the COMFORT trials [31, 32]

842 R. Wade et al.

[International Prognostic Scoring System (IPSS)], inter-

mediate-2 risk patients have a median survival of 4 years

and high-risk patients have a median survival of 2.3 years

[30].

Early myelofibrosis can be asymptomatic, but progres-

sive disease can lead to splenomegaly, fatigue, abdominal

pain, dyspnoea, early satiety, weight loss, night sweats,

pruritis and progressive anaemia. At later stages of the

disease, up to 23 % of patients may transform to acute

myeloid leukaemia [33]. The only curative treatment for

myelofibrosis is stem cell transplantation, which is

unsuitable for most patients and bears considerable risk of

complications, some potentially fatal. Clinical management

usually focuses on symptom control, using drug therapies

such as hydroxycarbamide and thalidomide, which do not

have US FDA or European Medicines Agency (EMA)

approval for the specific treatment of myelofibrosis. Other

treatment options include observation alone, splenectomy

or splenic irradiation.

JAK2 inhibitors are a novel therapy for myelofibrosis,

targeting the molecular mechanisms underlying the disease

rather than only symptom alleviation. Ruxolitinib is a

JAK2 inhibitor licensed for the treatment of disease-related

splenomegaly or symptoms in adult patients with PMF,

PPV-MF or PET-MF [34]. The NICE appraisal scope

requested clinical and cost-effectiveness evidence for rux-

olitinib, within this licensed indication, compared with

standard therapy without ruxolitinib.

3 The Independent Evidence Review Group Review

The manufacturer provided a submission to NICE on the

use of ruxolitinib in the treatment of patients with inter-

mediate-2 or high-risk myelofibrosis.

The ERG critically reviewed the evidence presented in

the manufacturer’s submission by assessing (i) whether the

submission conformed to NICE methodological guidelines;

(ii) whether the manufacturer’s interpretation and analysis

of the evidence were appropriate; and (iii) the presence of

other evidence or alternative interpretations of the evi-

dence. In addition, the ERG identified areas requiring

clarification, for which the manufacturer provided addi-

tional evidence [2].

3.1 Clinical Evidence

The manufacturer’s submission incorporated a systematic

review of the clinical effectiveness of ruxolitinib in the

treatment of patients with intermediate-2 or high-risk

myelofibrosis. This is a narrower, higher risk population

than specified in the license (treatment of disease-related

splenomegaly or symptoms in adult patients with PMF,

PPV-MF or PET-MF) [34]. However, this reflects the

likely use of ruxolitinib in clinical practice in the UK.

Two phase III, multicentre, randomised controlled trials

(RCTs)—COMFORT-II, which compared ruxolitinib with

best available therapy (BAT), [31] and COMFORT-I,

which compared ruxolitinib with placebo [32]—and an

uncontrolled phase I/II trial [35], met the inclusion criteria.

The ERG did not identify any additional relevant trials.

Both RCTs assessed ruxolitinib at starting doses of

15 mg or 20 mg twice daily (depending on baseline

platelet count) in patients with splenomegaly and inter-

mediate-2 or high-risk PMF, PPV-MF and PET-MF [31,

32]. The phase I/II trial aimed to identify the most effective

and well-tolerated dose of ruxolitinib; the starting dose of

ruxolitinib ranged from 10 mg twice daily to 200 mg once

daily [35]. The licensed dose of ruxolitinib is 5–25 mg

twice daily; therefore, the use of ruxolitinib in the RCTs

was directly relevant to the decision problem, whilst the

phase I/II trial was not.

The RCTs demonstrated that ruxolitinib confers signif-

icant benefits in terms of spleen size reduction compared

with BAT or placebo (Table 1). In the COMFORT-II trial,

a reduction in spleen volume of C35 % was achieved in

28 % of ruxolitinib-treated patients compared with 0 % in

the BAT group (p \ 0.001) at 48 weeks, with a mean

change in spleen volume of -30.1 versus ?7.3 %

(p \ 0.001). Median time to initial response was

12.3 weeks in the ruxolitinib group, with 80 % of patients

in the ruxolitinib group maintaining a response at a median

follow-up of 12 months [31]. The COMFORT-I trial

reported similar results compared with placebo.

The COMFORT-II trial found that ruxolitinib provided

significant improvements in myelofibrosis-associated

symptoms and health-related quality-of-life (HRQoL) at

48 weeks compared with patients treated with BAT, mea-

sured using the disease-specific European Organization for

Research and Treatment Quality of Life Questionnaire

(EORTC QLQ-C30) and the Functional Assessment of

Cancer Therapy-Lymphoma (FACT-Lym) scale [31].

Similarly, the COMFORT-I trial found significant

improvements in HRQoL at 24 weeks compared with

placebo, using the EORTC QLQ-C30 [32], and that sig-

nificantly more patients in the ruxolitinib group achieved a

50 % or more reduction in Total Symptom Score (TSS),

measured using the modified Myelofibrosis Symptom

Assessment Form (MFSAF) version 2, at week 24 than in

the placebo group (45.9 vs. 5.3 %; p \ 0.001). The mean

TSS reduced to almost half the baseline level in the rux-

olitinib group at 24 weeks, compared with an increase in

TSS in the placebo group; therefore, this result is also

likely to be clinically significant [32].

Ruxolitinib for the Treatment of Myelofibrosis 843

Table 1 Efficacy and safety data of ruxolitinib in the COMFORT trials [31, 32]

Outcome COMFORT-II [31] COMFORT-I [32]

Spleen volume

Patients achieving C35 % spleen volume reduction

At week 12 30 vs 1 % (n = 144/146 ruxolitinib,

n = 72/73 BAT)

39 vs 0 % (n = 155/155 ruxolitinib,

n = 153/154 placebo)

At week 24 32 vs 0 %, p \ 0.001 (n = 144/146

ruxolitinib, n = 72/73 BAT)

42 vs 1 %; p \ 0.001a; OR 134.4; 95 %

CI 18.0–1004.9 (n = 155/155

ruxolitinib, n = 153/154 placebo)

At week 48 28 vs 0 %, p \ 0.001a (n = 144/146

ruxolitinib, n = 72/73 BAT)

-

Mean change in spleen volume from baseline

At week 24 -29.2 vs ?2.7 %, p \ 0.001 (n = 125/

146 ruxolitinib, n = 45/73 BAT)

-31.6 vs ?8.1 % (n = 139/155

ruxolitinib, n = 106/154 placebo)

At week 48 -30.1 vs ?7.3 %, p \ 0.001 (n = 98/146

ruxolitinib, n = 34/73 BAT)

-

Symptoms

Patients achieving C50 % reduction in TSS at

week 24

- 45.9 vs 5.3 %; p \ 0.001; OR 15.3; 95 %

CI 6.9–33.7 (n = 149/155 ruxolitinib,

n = 152/154 placebo)

Mean change from baseline in TSS at week 24 - 46.1 vs -41.8 %; p \ 0.001 (n = 129/

155 ruxolitinib, n = 103/154 placebo).

Mean absolute change in symptom

score: -8.6 vs 3.2

PGIC: patients rating condition much/very much

improved at week 24, %

- 66.9 vs 11.2 % (n = 139/155 ruxolitinib,

n = 107/154 placebo)

HRQoL

Mean change from baseline in Global Health Status/

QoL (EORTC QLQ-C30)

At week 48: ?9.1 vs ?3.4 (n = 66/146

ruxolitinib, n = 27/73 BAT)

At week 24: ?12.3 vs -3.4; p \ 0.001

(n = 136/155 ruxolitinib, n = 104/154

placebo)

Mean change from baseline in FACT-Lym total score

at week 48

At week 48: ?11.3 vs -0.9 (n = 70/146

ruxolitinib, n = 29/73 BAT)

-

Survival

Overall survival At median follow-up of 61 weeks: 92.0 vs

95.0 %, (HR 1.01; 95 % CI 0.32–3.24)

At median follow-up of 112 weeks: 86 vs

78 %, (HR 0.52; 95 % CI 0.27–1.00)

At median follow-up of 51 weeks: 91.6 vs

84.4 % (HR 0.50; 95 % CI 0.25–0.98;

p = 0.04)

At median follow-up of 102 weeks: 27

ruxolitinib patients died vs 41 placebo

patients (HR 0.58; 95 % CI 0.36–0.95;

p = 0.028)

Progression-free survival At week 48: 69.9 vs 74.0 %, (HR 0.81;

95 % CI 0.47–1.39)

-

Adverse events

Anaemia 40.4 vs 12.3 %b 96.1 vs 86.8 %c

Grade 3/4 anaemia 42 % (40.4 %e) vs 31 % (23.3 %e) 45.2 % (52.2 %d) vs 19.2 %

Thrombocytopenia 44.5 vs 9.6 %b 69.7 vs 30.5 %c

Grade 3/4 thrombocytopenia 8 % (9.6 %e) vs 7 % (9.6 %e) 12.9 % (16.2 %d) vs 1.3 %

Non-haematological adverse events affecting [20 % of either treatment group

Diarrhoea 23 vs 12 % 23.2 vs 21.2 %c

Peripheral oedema 22 vs 26 % 18.7 vs 22.5 %c

Fatigue – 25.2 vs 33.8 %c

Abdominal pain – 10.3 vs 41.1 %c

Bruising – 23.2 vs 14.6 %c

844 R. Wade et al.

The COMFORT-II trial assessed progression-free sur-

vival; there was no evidence of an improvement with

ruxolitinib (70 %) compared with BAT (74 %) [31].

A significant increase in overall survival was observed

for ruxolitinib over placebo in the COMFORT-I trial at

51 weeks [hazard ratio (HR) 0.5 (95 % CI 0.25–0.98)] and

102 weeks (HR 0.58; 95 % CI 0.36–0.95; p = 0.03) [32]

and the survival benefit compared with BAT reached bor-

derline significance at 112 weeks in COMFORT-II (HR

0.52; 95 % CI 0.27–1.00) [31]. Neither RCT was powered

to detect statistically significant differences in overall

survival between treatment groups. Furthermore, after the

randomised phase of the trials, long-term follow-up was

confounded by permitted crossover from placebo/BAT to

ruxolitinib, potentially diluting treatment differences. The

results at later time points are subject to uncertainty due to

the small number of patients at risk in the analyses. For

example, in the COMFORT-I trial, at 108 weeks only

44/155 ruxolitinib patients and 32/154 placebo patients

were at risk; at 120 weeks the numbers were 6/155 and

7/154, respectively [32]. The equivalent ‘at risk’ figures for

the 112-week time point in COMFORT-II, when the sur-

vival benefit of ruxolitinib over BAT reaches borderline

statistical significance, were not reported [31].

Safety data were consistent across the three studies and

indicated that ruxolitinib is generally well tolerated. The

incidence of adverse events (AEs) leading to discontinua-

tion in both RCTs was low in the ruxolitinib groups (8 and

11 %) and comparable to those for the control groups (6

and 11 %) [31, 32]. Serious AEs (SAEs) were reported in

approximately 30 % of ruxolitinib-treated patients in both

studies and this was comparable to the incidence of SAEs

reported for BAT. All individual SAEs in the ruxolitinib

groups occurred at an incidence of 5 % or less. Anaemia

was the most frequently reported grade 3 or 4 AE in both

treatment groups in the two RCTs, reflecting the frequent

manifestation of severe anaemia as part of the underlying

disease, but was effectively managed with red blood cell

transfusions. Thrombocytopenia was the only other grade 3

or 4 AE reported in 8 % of patients or more (in either

treatment group) in both studies and was effectively man-

aged by dose reductions or interruptions.[31, 32] Sixty-

three percent of patients required dose interruptions or

reductions due to AEs, most commonly thrombocytopenia

and anaemia. Dose interruptions or discontinuation resulted

in worsening of symptoms of myelofibrosis, reverting to

baseline levels over the period of around 1 week.

3.1.1 Critique of the Clinical Evidence

The manufacturer’s systematic review correctly identified

two good quality RCTs. The RCTs were conducted in

patients with splenomegaly and intermediate-2 or high-risk

myelofibrosis. Patients with an absolute neutrophil count

B1 9 109/L or platelet count \100 9 109/L and patients

suitable for allogeneic haematopoietic stem cell trans-

plantation at the time of study enrolment were excluded

from the trials. Therefore, the clinical effectiveness of

ruxolitinib has only been assessed in this narrower, higher

risk population, not in the full licensed population. In

addition, the systematic review identified a phase I/II dose-

finding trial [39].

Whilst the evidence from the two good-quality RCTs

demonstrated that ruxolitinib was more effective than BAT

and placebo at achieving a C35 % reduction in spleen

volume, the ERG believed the use of this outcome may

have generated an optimistic response rate. The primary

outcome measure in both RCTs was the proportion of

patients achieving a C35 % reduction in spleen volume

from baseline. Splenomegaly is only one symptom of

myelofibrosis; other symptoms include haematological

symptoms, such as anaemia and thrombocytopenia, which

were only assessed as adverse events. Ruxolitinib treatment

worsened these symptoms, in the short term, for some

patients.

Ruxolitinib was associated with improvements in

symptom scores and corresponding quality-of-life. How-

ever, data were missing for a large proportion of patients

Table 1 continued

Outcome COMFORT-II [31] COMFORT-I [32]

Blood transfusion 51 vs 38 % –

ASH American Society for Hematology, BAT best available therapy, CI confidence interval, COMFORT controlled myelofibrosis study with oral

JAK inhibitor treatment, EORTC QLQ-C30 European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire, FACT-

Lym Functional Assessment of Cancer Therapy-Lymphoma, HR hazard ratio, HRQoL health-related quality-of-life, OR odds ratio, PGIC

Patient’s Global Impression of Change, TSS Total Symptom Scorea Primary endpointb Data from Harrison et al. [36]c Data from Verstovsek et al. [32]d Updated data from Verstovsek et al. ASH abstract [37]e Updated data from Cervantes et al. ASH abstract [38]

Ruxolitinib for the Treatment of Myelofibrosis 845

for some of these symptom and quality-of-life results

without justification. Therefore, the reliability and gener-

alisability of these results was unclear.

Overall survival was found to be statistically signifi-

cantly better with ruxolitinib compared with placebo but

not compared with BAT at a median follow-up of around

1 year. Although the comparison with BAT reached bor-

derline statistical significance at 112 weeks, there were

some difficulties with the interpretation of these results

because the crossover from placebo or BAT to ruxolitinib

was not adjusted for in the analysis. Furthermore, neither of

the COMFORT trials was sufficiently powered to detect a

significant difference in survival outcomes, and only a

small number of patients were at risk at the later time

points (in the COMFORT-I trial only 6/155 ruxolitinib

patients and 7/154 placebo patients were at risk at

120 weeks). Overall, the ERG considered the COMFORT-

II trial survival data to be the most appropriate because it

included a relevant comparator group, and fewer control

patients crossed over to ruxolitinib or discontinued from

the study than in the COMFORT-I trial.

There is uncertainty concerning the long-term effec-

tiveness and tolerability of ruxolitinib, with limited data

beyond 2 years.

3.2 Cost-Effectiveness Evidence

The manufacturer submitted a de novo state-transition

Markov model-based economic evaluation in which the

primary outputs were quality-adjusted life-years (QALYs)

and costs. The model structure included health states rel-

evant to treatment (treatment responder, treatment non-

responder, discontinuation and death) which were informed

by the pivotal trials. The model time-horizon was lifetime,

which the manufacturer estimated as 35 years. Long-term

survival was simulated using a combination of HRs derived

from a phase I/II trial [39] in a cohort of patients treated

with ruxolitinib, and survival estimates for standard care

based on an observational study conducted to parameterise

the International Working Group for Myelofibrosis

Research and Treatment’s (IWG-MRT) IPSS prognostic

tool [40]. Quality-of-life data were derived from a previ-

ously published NICE STA of eribulin for the treatment of

metastatic breast cancer [41]. Data on healthcare resource

use was drawn from the COMFORT-II trial and augmented

using external data sources, manufacturer assumptions and

clinical opinion. The primary model driver was the treat-

ment response criterion used in the clinical trial (C35 %

spleen volume reduction).

In the model, patients were split into responders and

non-responders according to whether they achieved a

C35 % spleen volume reduction. After treatment initiation,

patients were assumed to stay on treatment for the first

24 weeks, at which point, if they had not achieved a

response on ruxolitinib, they would be classified as non-

responders and remain on BAT for the remainder of the

model. Patients were assumed to continue responding with

the same benefits until discontinuation or death. Discon-

tinuation and death were assumed at constant rates from

24 weeks onward. Disease progression and leukaemic

transformation were not included in the model base case,

and complications related and unrelated to splenomegaly

were only applied to model non-responders.

The manufacturer’s economic analysis suggested that

the plausible incremental cost-effectiveness ratio (ICER)

for ruxolitinib versus BAT was £73,980/QALY in the base

case. This finding was consistent across most sensitivity

analyses, as the vast majority of deterministic sensitivity

analyses conducted by the manufacturer rarely had an

ICER below £70,000/QALY [30]. Probabilistic sensitivity

analysis found that ruxolitinib had a 0 % chance of cost

effectiveness at £30,000/QALY.

3.2.1 Critique of the Cost-Effectiveness Evidence

The economic analysis presented by the manufacturer was

inadequate to fully address the decision problem specified in

the NICE scope. The model structure did not adequately

represent the progressive nature of myelofibrosis, and may

not have fully captured symptomatic and quality-of-life-

related aspects of the disease due to limitations in the choice

of response variable. Model assumptions such as constant

HRs over time, constant discontinuation rates after

24 weeks, constant mortality and complications only

applying to non-responders, were not justified and may have

been inappropriate. In addition, since up to 23 % of patients

may transform to acute myeloid leukaemia [33], the ERG

felt that the omission of leukaemic transformation in the

base case was inappropriate; sensitivity analyses including

leukaemic transformation should be considered more plau-

sible than those omitting leukaemic transformation. The

35-year time horizon of the manufacturer’s model greatly

increased the uncertainty caused by inappropriate constant

rate and ratio assumptions in the model. These long-term

constant assumptions appeared inappropriate for a myelo-

fibrosis population given that IPSS-estimated median sur-

vival for intermediate-2 risk myelofibrosis patients was only

4 years [40]. In an attempt to reduce the level of uncertainty,

the ERG felt that a shorter 15-year time horizon might better

reflect clinical knowledge about estimated myelofibrosis

survival and reduce the effect of assumptions.

The ERG also felt that there was considerable uncer-

tainty surrounding the choice of utility data. The manu-

facturer used utility scores derived from metastatic breast

cancer that had been mapped from the EORTC QLQ-C30

to the EuroQol Group Five Dimensions (EQ-5D) generic

846 R. Wade et al.

preference questionnaire value set [41]. The manufacturer

had presented a conference poster [42] and conference

abstract [43] for a study mapping EORTC QLQ-C30 scores

from the COMFORT-II ruxolitinib trial to the EQ-5D, but

these results had not been presented with the manufac-

turer’s submission, nor included in the manufacturer’s

model. The NICE reference case stipulates that, ideally,

utility measurements should be from the population of

interest, derived from EQ-5D, using the UK tariff [44]. The

mapped utilities from the COMFORT-II trial [36] more

precisely fit the NICE reference case than those submitted

with the model. The ERG conducted sensitivity analyses

using these alternate utilities.

The response criterion used in the trial and the model

was spleen volume reduction greater than 35 %, which the

ERG considered favourable to ruxolitinib. Currently, BAT

tend to focus on treating other symptoms of myelofibrosis

and are not specifically addressing splenomegaly. As such,

it is likely that BAT patients do not experience greater than

35 % spleen volume reductions, although other symptoms

may greatly improve. As a consequence of the definition of

response used, within the model BAT patients are consid-

ered as non-responders. This leads to BAT patients

receiving no improvement in quality-of-life from treatment

in the model. While splenomegaly is an important char-

acteristic of the disease, and factors into IWG-MRT clin-

ical improvement criteria [45], symptomatic burden is not

completely determined by spleen size [43]. In COMFORT-

I, more patients achieved 50 % TSS reductions than a

C35 % reduction in spleen volume, including BAT

patients [32]. In COMFORT-II less than half of the patients

had constitutional symptoms [42], and the average BAT

patient, who had no improvement in splenomegaly, had an

improvement in quality-of-life.

An absence of evidence concerning long-term survival,

discontinuation, costs and outcomes resulted in consider-

able uncertainty in the model. The manufacturer conducted

several sensitivity analyses, but these analyses did not

overcome the fact that the model was an oversimplification

of a complex, chronic condition. The ERG conducted

additional analyses, but these analyses were based on the

same model and did not overcome the model limitations.

These additional ERG analyses emphasised the consider-

able uncertainty surrounding the results of the economic

evaluation, and showed that the most plausible adjustments

to the model parameters resulted in ICERs in excess of

£70,000 per QALY. The key results from these sensitivity

analyses are presented in Table 2. ICER estimates includ-

ing leukaemic transformation assumed a 3.6 % annual rate

for all patients, and included a correction of an error in the

manufacturer’s model.

The ERG created an alternative plausible scenario to

demonstrate the effect of altering several of the model

characteristics simultaneously. This alternative scenario

used HRs from COMFORT-II, utilities mapped from

COMFORT-II, included leukaemic transformation and

transfusion dependence, and had a time horizon of

15 years. The resultant ICER was £148,867/QALY. The

ERG did not consider the ICER from this scenario any

more or less plausible than that presented as the manu-

facturer’s base case, but presented it to illustrate the huge

uncertainty around the ICER. The ERG believed that some

elements included in their sensitivity analysis warranted

consideration in any base case. It is possible that including

disease progression in the model could further increase the

ICER. However, given the basic structure of the model this

analysis was not possible.

3.3 Conclusions of the ERG Review

The ERG concluded that evidence from two good-quality

RCTs demonstrated that ruxolitinib was effective at

reducing splenomegaly and its associated symptoms.

However, important haematological symptoms of myelo-

fibrosis (in particular anaemia and thrombocytopenia) were

worsened by ruxolitinib in some patients, at least in the

short term, requiring dose interruptions and reductions, as

well as blood transfusions. There was no evidence of an

improvement in progression-free survival with ruxolitinib.

There was some evidence that overall survival may be

increased with ruxolitinib, although these data were less

reliable.

The economic evaluation conducted by the manufac-

turer was marred by questionable parameter choices,

structural assumptions, and limited long-term trial data

compounded by considerable missing data. The ERG felt

that the high level of uncertainty in these key elements

made the results presented both by the manufacturer and

the ERG highly uncertain. It is likely that the ICER pre-

sented in the manufacturer’s base case is a best-case sce-

nario; however, it is unclear what the full impact of

addressing all of the model limitations would be. It is just

as feasible based on the manufacturer’s submission that the

ICER could be greatly increased, as demonstrated by the

ERG’s alternative scenario.

3.4 Key Methodological Issues

3.4.1 Clinical Effectiveness

The main areas of uncertainty in terms of clinical efficacy

and drug safety were (i) the clinical effectiveness of rux-

olitinib has only been assessed in the narrower, higher risk

population of patients with splenomegaly and intermediate-

2 or high-risk myelofibrosis; (ii) the primary outcome

measure in both RCTs was the proportion of patients

Ruxolitinib for the Treatment of Myelofibrosis 847

achieving a C35 % reduction in spleen volume from

baseline, haematological symptoms of myelofibrosis were

only assessed in terms of AEs; and (iii) long-term survival

data were confounded by the crossover of placebo and

BAT patients to ruxolitinib treatment, and the small num-

ber of patients at risk at the later time points increases the

uncertainty around the survival results.

3.4.2 Cost Effectiveness

Key methodological concerns in the cost-effectiveness

evidence included the use of a response criterion that does

not capture potential quality-of-life improvements

achieved with BAT, a model structure unable to capture

disease progression, base-case health state utilities derived

from a non-myelofibrosis population, and several ques-

tionable modelling assumptions as outlined above.

4 The National Institute for Health and Clinical

Excellence (NICE) Appraisal Committee:

Consideration of All Available Evidence

The NICE Appraisal Committee considered the evidence

presented in the manufacturer’s submission, the ERG

report and from additional sources, including statements

from non-manufacturer consultees and commentators, and

clinical specialist and patient experts. Representatives of

the manufacturer were in attendance at the Committee

meetings in order to provide responses to any queries on

their submission. The main aims of the NICE Appraisal

Committee were to consider whether:

• all of the relevant evidence had been taken into

account;

• the summaries of clinical and cost effectiveness were

reasonable interpretations of the evidence;

• the provisional recommendations were sound and a

suitable basis for guidance to the NHS;

• there were any equality-related issues that need special

consideration and that were not covered in the ACD

[46].

The main areas discussed by the Committee and docu-

mented in the ACD [46] along with the recommendations of

the Committee, are summarised in the following sections.

4.1 The Clinical Effectiveness of Ruxolitinib

The Committee concluded that symptoms (especially

severe itch and fatigue) and spleen size were both

Table 2 Results of Evidence Review Group sensitivity analyses

Model scenario No leukaemic transformation (£) Leukaemic transformation (£)

Manufacturer base case 73,980 78,642

Weibull regression for survival 74,274 79,303

HRs from COMFORT-I (0.58 HR)a 86,086 90,557

HRs from COMFORT-II (0.52 HR)b 83,129 88,278

Missing patients assumed as non-responders 75,571 80,677

Strict IWG-MRT response criteriac 81,110 82,525

Response defined by symptom reductiond 79,536 82,282

COMFORT-II long-term discontinuation rate 83,680 88,622

COMFORT-II initial discontinuation rate 74,616 79,436

Mapped utilities from COMFORT-IIe 97,105 109,092

Hydroxycarbamide substituted for lenalidomide 75,141 80,086

Eight GP visits instead of six 73,902 78,504

Ten GP visits instead of six 73,824 78,366

Ratio of medical costs for responders (0.1) 71,834 76,410

Ratio of medical costs for responders (0.5) 76,125 80,874

ASH American Society for Hematology, COMFORT controlled myelofibrosis study with oral JAK inhibitor treatment, GP general practitioner,

HR hazard ratio, IWG-MRT International Working Group for Myelofibrosis Research and Treatmenta Derived from ASH abstract [37]b Derived from ASH abstract [38]c Strict following of IWG-MRT response criteria would require that patients with spleen enlargement less than 10 cm below the left intercostal

margin have their spleen become unpalpable to be classified as achieving a response [45]; 32 % of COMFORT-II patients had spleen

enlargement less than 10 cm, these patients were not included as respondersd COMFORT-I measurements of 50 % reduction in symptoms were utilised to formulate a new response criterione Mapped utilities from a COMFORT-II conference abstract [43] were used in place of metastatic breast cancer utilities

848 R. Wade et al.

important outcomes for patients with myelofibrosis. It

further concluded that ruxolitinib was effective in reducing

spleen size and symptoms.

The Committee noted that an overall survival benefit

was observed in COMFORT-I [32] (compared with pla-

cebo) and at one of the two centres of the NCT00509899

trial [47], the M.D. Anderson Cancer Center (MDACC),

but was not observed in COMFORT-II [31] (compared

with BAT) or at the Mayo Clinic Centre in the

NCT00509899 trial [48]. The Committee acknowledged

that the impact of ruxolitinib on myelofibrosis progression

remained unknown. The Committee concluded that it was

plausible that ruxolitinib could offer a survival benefit,

however the reason for this benefit remained unclear.

The Committee noted that there are no clinically rele-

vant subgroups for which there is evidence of differential

effectiveness.

4.2 The Cost Effectiveness of Ruxolitinib

The Committee considered both the economic model pro-

vided in the manufacturer’s submission and the ERG’s

exploratory analysis. The Committee concluded that the

base-case ICER presented by the manufacturer (£74,000

per QALY gained) was likely to be an underestimate

because of structural limitations of the model. However, it

also considered that the ERG’s alternative scenario

(£149,000 per QALY gained) may have overestimated the

ICER because of the uncertainty in the utility and survival

estimates. On balance, the Committee concluded that the

ICER was likely to be closer to £149,000 per QALY gained

than £74,000 per QALY gained.

The Committee heard from the ERG that the most

important drivers in the model were the time horizon,

utilities and survival.

The Committee noted that it may be plausible to

apply end-of-life criteria to a subgroup of patients with

myelofibrosis classified by IPSS as high risk. However,

no analysis was provided for this subgroup and therefore

the Committee agreed that end-of-life criteria did not

apply.

4.3 Preliminary Guidance

The preliminary NICE recommendation, recorded in the

ACD, was that ruxolitinib was not recommended for

treating disease-related splenomegaly or symptoms in adult

patients with PMF, PPV-MF or PET-MF. In addition, the

preliminary ACD recommendations concluded that people

currently receiving ruxolitinib should be able to continue

treatment until they and their clinician considered it

appropriate to stop [46]. The Committee recognised that

ruxolitinib was not a cost-effective use of NHS resources,

because the ICER could be approaching £149,000 per

QALY gained, and the base-case ICER presented by the

manufacturer, of £74,000 per QALY gained, was likely to

be an underestimate. Therefore, the Committee concluded

that ruxolitinib was clinically effective, but could not be

considered a cost effective use of NHS resources, compared

with BAT, for treating disease-related splenomegaly or

symptoms in adults with myelofibrosis.

4.3.1 Comments in Response to the ACD Consultation

Comments on the preliminary guidance were received from

professional bodies and patients, who reiterated that rux-

olitinib is clinically effective at reducing spleen size and

constitutional symptoms for patients with myelofibrosis.

Alongside their ACD comments, the manufacturer

requested permission to submit additional evidence and a

revised economic analysis. This was approved by NICE

and considered by the Committee. The manufacturer pro-

vided updated survival HRs from the COMFORT-II trial, a

dose-intensity adjustment, additional utility values and

estimates of carer costs. The revised economic analysis

reduced the ICER to £56,963 per QALY gained.

4.3.2 Evidence Review Group Critique of the Additional

Evidence and Revised Economic Analyses Submitted

by the Manufacturer in Response to the ACD

Consultation

The ERG reviewed the updated survival estimates from the

COMFORT-II trial and concluded that they were likely to

favour ruxolitinib, as only patients with a long-term

response were included in the analysis. The ERG recog-

nised that some savings may be made through dosing

adjustments, although it is unclear whether these would be

realised in clinical practice. The ERG considered that the

additional utility values presented were no more certain

than those used in the original economic model and that the

new analysis did not reduce the uncertainty surrounding the

utility values assigned. The new utilities submitted were

derived from a population of healthy Australian individuals

using the standard gamble method, a population and

methodology that are not in accord with the NICE refer-

ence case [44]. The ERG considered that the estimates of

carer costs had poor methodological reporting and justifi-

cation, and that their appropriateness was uncertain. In

addition, the ERG’s clinical advisor commented that the

proportion of patients stated by the manufacturer as likely

to receive care appeared higher than that observed in

clinical practice.

In the revised economic analyses, the key driver of the

difference in ICER compared with the original analyses

was the dose-intensity adjustment.

Ruxolitinib for the Treatment of Myelofibrosis 849

Overall, the ERG found that the additional submissions

by the manufacturer did not reduce uncertainty surrounding

the ICER.

4.4 The Appraisal Committee’s Final Guidance

The responses to the preliminary guidance summarised in

the ACD, [46] and the additional evidence and revised

economic analysis submitted by the manufacturer, as well

as the ERG’s critique of this, were considered during a

second meeting at which the Committee produced a FAD.

Having considered evidence on the nature of spleno-

megaly in people with myelofibrosis and the value placed

on the benefits of ruxolitinib by people with the condition,

those who represent them, and clinical specialists, and

taking into account the effective use of NHS resources, the

NICE Appraisal Committee did not recommend ruxolitinib

for the treatment of disease-related splenomegaly or

symptoms in adult patients with myelofibrosis.

The FAD forms the basis of the NICE guidance for the

use of ruxolitinib in the NHS in England and Wales [49].

5 NICE Guidance

Following the consultation on the preliminary guidance,

the NICE Appraisal Committee released the following final

guidance to the NHS (TA289) [49]:

‘‘Ruxolitinib is not recommended within its market-

ing authorisation, that is, for the treatment of disease-

related splenomegaly or symptoms in adult patients

with PMF (also known as chronic idiopathic myelo-

fibrosis), post polycythaemia vera myelofibrosis or

post essential thrombocythaemia myelofibrosis.’’

‘‘People currently receiving ruxolitinib should be able

to continue treatment until they and their clinician

consider it appropriate to stop.’’

6 Interpretation of the Guidance

Although the clinical data were sufficient to demonstrate

that ruxolitinib warrants a place amongst the treatments

available for patients with myelofibrosis, the case of cost-

effectiveness was hugely uncertain and even the lowest

estimates far exceeded those that can normally be recom-

mended by NICE. This should mean that ruxolitinib is not

available for NHS patients. However, although ruxolitinib

was not recommended by NICE for the treatment of dis-

ease-related splenomegaly or symptoms in adult patients

with myelofibrosis, it is on the National Cancer Drugs Fund

List (updated 30 April 2013) for the treatment of

symptomatic splenomegaly and/or constitutional symptoms

in PMF, PPV-MF or PET-MF in patients unsuitable for

stem cell transplant.

Acknowledgments This project was funded by the National Insti-

tute for Health Research (NIHR) Health Technology Assessment

(HTA) Programme (project number 11/79/01) and will be published

as part of a compendium of ERG articles in Health Technology

Assessment. See the HTA programme website (http://www.hta.ac.uk)

for further project information. This summary of the ERG report was

compiled after the Appraisal Committee’s review and incorporates

additional information and comment from the authors on the STA

process and iterations of the NICE guidance not covered by the HTA

report.

The views and opinions expressed herein are those of the authors

and do not necessarily reflect those of the NICE or the Department of

Health. The authors would like to thank Professor Stephen Palmer,

Centre for Health Economics, for providing advice throughout the

project.

This work is Crown copyright (UK).

Author contributions Ros Wade reviewed the clinical evidence

submitted and wrote most sections of the manuscript.

Micah Rose reviewed the cost-effectiveness evidence submitted

and wrote the cost-effectiveness sections of the manuscript.

Aileen Rae Neilson reviewed the cost-effectiveness evidence

submitted and provided comments on drafts of the manuscript.

Lisa Stirk reviewed the search strategies and provided comments

on drafts of the manuscript.

Rocio Rodriguez-Lopez reviewed the search strategies and pro-

vided comments on drafts of the manuscript.

David Bowen provided clinical advice throughout the project and

comments on drafts of the manuscript. In terms of conflicts of

interest, Professor David Bowen has received payments from

Novartis, although not directly related to ruxolitinib. He attended a

Novartis UK Advisory Board in 2011 to discuss the management of

myeloproliferative disease and the position of ruxolitinib within the

current agents used. In addition he works closely with Novartis in

other areas and has the following relationships with them: member of

Trial Steering Committee for a global commercial phase III study

(TELESTO) for which he is paid per hour; co-chair of SC for

EUMDS Registry programme, an academic study funded by Novartis

via the University of Nijmegen and for which no direct funding is

received by Professor Bowen personally. In addition, he has attended

Advisory Boards for various agents, for which he is paid honoraria.

Dawn Craig took responsibility for the cost-effectiveness evidence

appraisal and contributed to all aspects of the review of the evidence

submitted and provided comments on drafts of the manuscript.

Nerys Woolacott took overall managerial responsibility for the

project, contributed to all aspects of the review of the evidence

submitted and provided comments on drafts of the manuscript.

Ros Wade, Micah Rose, Aileen Rae Neilson, Lisa Stirk, Rocio

Rodriguez-Lopez, Dawn Craig and Nerys Woolacott have no

conflicts of interest to declare.

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