Pharmacoeconomics 2011; 29 (5): 387-401

REVIEW ARTICLE 1170-7690/11/0005-0387/$49.95/0

ª 2011 Adis Data Information BV. All rights reserved.

Cost Effectiveness of Treatments for

Inflammatory Bowel Disease
Keith Bodger
Department of Gastroenterology, University of Liverpool, Liverpool, UK

Contents
Abstract. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 387
1. Clinical and Economic Burden of Illness . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 388
2. Cost Effectiveness of Rival Therapies for Inflammatory Bowel Disease . . . . . . . . . . . . . . . . . . . . . . . . . . 389
2.1 Ulcerative Colitis (UC) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 389
2.1.1 Oral 5-Aminosalicylic Acid (5-ASA) Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 389
2.1.2 Oral Corticosteroids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 391
2.1.3 Biological Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 392
2.1.4 Colonoscopic Surveillance for Cancer in Longstanding UC . . . . . . . . . . . . . . . . . . . . . . . . 392
2.2 Crohn’s Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 393
2.2.1 Oral 5-ASA Drugs. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 393
2.2.2 Oral Corticosteroids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 393
2.2.3 Nutritional Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 393
2.2.4 Anti-Tumour Necrosis Factor (TNF)-a Agents for Moderate-to-Severely Active or
Fistulizing Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 394
2.2.5 Anti-TNF-a Agents as Early, ‘Top-Down’ Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 399
3. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 399

Abstract Traditionally, half of the direct costs associated with chronic inflam-
matory bowel diseases (IBD) [Crohn’s disease (CD) and ulcerative colitis
(UC)] have related to hospital inpatient treatment for a sub-group of more
severely affected, often therapy-resistant individuals. The advent of effective
but relatively expensive biological agents has increased the contribution of
drugs to overall medical care costs. This has focussed interest on the relative
cost effectiveness of rival therapies for IBD and, in particular, on the af-
fordability of long-term biological therapy. The purpose of this article is
to review the available literature on this topic and to identify areas for future
research.
Head-to-head trials of competing treatment options are uncommon and
clinical trials have seldom addressed cost effectiveness. In UC, models have
explored the cost utility of ‘high-’ versus ‘standard-’ dose 5-aminosalicylic
acid (5-ASA) therapy and the theoretical impact of improved adherence with
once-daily formulations. In CD, cost-utility models for anti-tumour necrosis
factor (TNF) drugs versus standard care have suggested consistently that
incremental benefits are achieved at increased overall cost. However, studies
388
of varying design have produced a wide spectrum of incremental cost-effectiveness
ratio estimates, which highlights the challenges and limitations of existing
modelling techniques.
The two major types of inflammatory bowel
disease (IBD) are Crohn’s disease (CD) and ul-
cerative colitis (UC). CD may affect any part of
the gastrointestinal (GI) tract, leading to seg-
ments of full-thickness gut inflammation with
potential for both stricture and fistula formation.
UC is confined to the colon, with superficial in-
flammation extending in continuity from the
lower rectum for a variable distance ranging from
a few centimetres (‘proctitis’) to the entire colon
(‘pancolitis’). Both forms of IBD are character-
ized by a tendency to occur for the first time in
early adult life and to run a relapsing-remitting
clinical course over many decades. Symptoms
common to both conditions include diarrhoea
and abdominal pain, with other manifestations
varying according to disease type and anatomical
extent. Disease severity may vary from a quies-
cent, symptom-free state (‘remission’) through
stages of mild, moderate and severe activity includ-
ing fulminant and potentially life-threatening
complications. Systemic features, such as fatigue,
anaemia and weight loss characterize more active
disease, and specific extra-intestinal features may
add to the clinical burden.
A wide array of medical and surgical interven-
tions is available to treat these conditions. Although
radical surgery in the form of total colectomy
(panproctocolectomy) can cure UC, there are no
curative drug treatments for either form of IBD
and no surgical cure for CD. Drug treatments for
IBD aim to induce remission during flares of the
disease and then to maintain this quiescent state
in the long term. Pharmacological options in-
clude topical (e.g. enema) or oral 5-aminosalicylic
acid (5-ASA) formulations; topical, oral or in-
travenous corticosteroids; traditional immunosup-
pressants (e.g. azathioprine/6-mercaptopurine or
methotrexate); and newer biological agents that
target specific molecules in the inflammatory
cascade (e.g. anti-tumour necrosis factor [TNF]-a
drugs). The purpose of this article is to review the
ª 2011 Adis Data Information BV. All rights reserved.
Bodger
current literature on the relative cost effectiveness
of alternative treatments for IBD.
1. Clinical and Economic Burden
of Illness
The macroeconomics of IBD has been re-
viewed previously by the author[1,2] and others[3]
but a brief overview is helpful before focusing on
issues of cost effectiveness. Epidemiological stud-
ies in North American and European popula-
tions have given estimates for the prevalence of
CD of approximately 150 per 100 000 and that of
UC of around 250 per 100 000.[4,5] A recent esti-
mate of the total economic impact of CD,[3] based
on a review of published costing studies, sug-
gested that the annual economic burden of the
condition (direct and indirect costs) was up to
$US15.5 billion in the US and h16.7 billion in
Europe (year 2006 values). Equivalent estimates
for UC are not available but, based on older
studies of both forms of IBD,[6] the total burden
is likely to be of a similar order to that of CD. As
relatively uncommon diseases, the contribution
of IBD to annual healthcare budgets is small, but
lifetime costs per individual patient rival those of
major diseases such as diabetes mellitus.[7]
A number of studies have estimated direct
medical costs associated with IBD.[6-17] Most of
these studies were undertaken prior to the intro-
duction of expensive biological agents (the ‘pre-
biological era’) and hence their results reflect the
costs of ‘standard care’ using well established drug
therapies and conventional surgery. The method-
ology has varied from study to study and the
relative costs of different health resource items
(e.g. drug costs vs hospital costs) vary from one
health economy to another. Nevertheless, studies
in the pre-biological era had reported some con-
sistent findings that applied to both forms of
IBD. Key amongst these was the observation that
approximately half of all annual direct medical
Pharmacoeconomics 2011; 29 (5)
Cost Effectiveness of Treatments for Inflammatory Bowel Disease
costs associated with IBD related to inpatient
care (i.e. medical and/or surgical admission), al-
though only a minority of severely affected
patients are admitted each year. In our own work
in the UK,[1,8] we found that 49% of secondary
care costs over a 6-month period were consumed
by 14% of the IBD patient population, who re-
quired inpatient treatment. Compared with am-
bulatory patients attending the clinic who were in
clinical remission, a flare-up of disease treated in
the outpatient (office) setting resulted in a 2- to
3-fold escalation of 6-month costs, whereas a
flare-up that required hospitalization led to a 20-
fold increase compared with remission costs.[8]
All published studies have confirmed the highly
skewed nature of costs of illness for IBD, with a
small group of hospitalized cases accounting for a
large share of total costs. Patients with severe
disease have direct costs that are 3- to 9-fold
greater than those in remission.[3]
Studies undertaken in the pre-biological era
had suggested that drug costs accounted for less
than a quarter of total direct medical costs of
IBD.[8,9,17] This situation is changing as the rela-
tively costly anti-TNF agents are becoming an
increasingly routine therapy for CD. In the US,
analysis of medical insurance claims data from
the late 1980s suggested that drug costs ac-
counted for 10% of all annual costs for CD.[6,14]
Infliximab appeared on the scene in the late 1990s
as the first biological agent licensed for use in CD.
A more recent analysis of claims data for 2003–4
identified that pharmaceutical claims accounted
for 35% of CD-related direct healthcare costs in
the US.[18]
Indirect costs associated with lost productivity
are likely to equal or exceed the direct healthcare
costs.[1-3] However, the decision-making per-
spective taken for most health economic analyses
is generally that of the health service provider or
payer, with a focus on managing direct medical
costs that fall on the healthcare system.
2. Cost Effectiveness of Rival Therapies
for Inflammatory Bowel Disease
The two main forms of IBD share many
treatments in common and have similar overall
ª 2011 Adis Data Information BV. All rights reserved.
389
cost-of-illness profiles. Both are characterized by
having a relatively wide choice of drugs and for-
mulations with which to treat them, often in se-
ries or in various combinations, and with the
competing option of surgical intervention. Acute
‘flares’ of disease characterize both conditions,
with the induction of remission being the key
short-term therapeutic goal. Maintenance of re-
mission and the avoidance of disease relapse rep-
resent the medium- to long-term goals for these
conditions. To evaluate the cost effectiveness of
rival treatments for IBD it is necessary to con-
sider carefully formulated decision questions that
take account of disease type, severity and thera-
peutic goal (induction of remission, maintenance
of remission or both). A review of all potential
rival treatment decisions is beyond the scope of
this review and the aim is instead to focus on
those areas that have been subject to some form
of economic evaluation.
As with any disease area, there are a number of
potential approaches for gaining information
about cost effectiveness of therapies. Ideally, data
would be obtained from well designed, pragmatic
trials comparing new interventions against ‘stan-
dard’ care and that collect the sort of health out-
come and costing data needed for calculating
incremental cost-effectiveness ratios (ICERs).
However, the scale and duration required for
such gold-standard studies is considerable and
there are only rare examples.[19] Hence, most of
the available cost-effectiveness data generated for
IBD has taken the form of economic modelling,
whereby trial data are synthesized in mathe-
matical models with information from various
sources, including the literature and expert opin-
ion. Uncontrolled, observational audit data of
profiles of cost before and after specific inter-
ventions have contributed to knowledge in this
area but such studies cannot address questions of
relative cost effectiveness of rival options.
2.1 Ulcerative Colitis (UC)
2.1.1 Oral 5-Aminosalicylic Acid (5-ASA) Drugs
The oral 5-ASA drugs represent a standard
first-line treatment option for the induction of
remission in mild-to-moderately active UC and
Pharmacoeconomics 2011; 29 (5)
390
have proven their efficacy as long-term mainte-
nance therapy to reduce risk of relapse. Various
oral formulations are available, with differing
delivery or release mechanisms and varying costs,
including some lower cost ‘generic’ versions.
Clinical trials comparing the efficacy and toler-
ability of alternative formulations are scarce and
no trials have examined cost effectiveness.
A decision-tree model considered the alterna-
tives of high-dose (4.8 g per day) versus standard
dose (2.4 g per day) oral mesalazine preparation
(Asacol) for treating a mild-to-moderate flare
of UC from the perspective of the UK NHS.[20]
The relevant clinical trial data[21-23] suggested an
advantage of high-dose therapy of 14% in terms
of ‘treatment success’ at 6 weeks (partial response
or full remission). The clinical course of non-
responding patients was modelled to include es-
calation of therapy to outpatient oral steroids,
inpatient intensive medical therapy (intravenous
[IV] steroids – ciclosporin) and surgery according
to a 12-week treatment pathway. Using data from
the published literature and expert panel consen-
sus, including efficacy estimates for second-line
and subsequent therapies, patient-level UK cost
estimates from our earlier work[8] and published
data for utility scores for defined disease states,
the aim of this study was to model whether a
modest increment in clinical effectiveness achieved
with double dose of oral 5-ASA treatment would
prove cost effective overall (despite doubling expen-
diture on the drug for the acute phase of 5-ASA
treatment).
A probabilistic sensitivity analysis using plau-
sible ranges for key assumptions explored un-
certainty in the model and found that high-dose
therapy appeared cost effective in 72% of simu-
lations, based on a ceiling of d30 000 per QALY.
The model predicted that high-dose treatment
would lead to a very small reduction in hospital-
ization (absolute difference of 2% vs standard
dose) and surgery (absolute difference of 1% vs
standard dose) among the minority of patients
who did not respond to outpatient treatment.
Nevertheless, these small reductions in need for
inpatient care were sufficient to offset a doubling
of first-line drug costs for the high-dose group.
Whether reductions in risk of hospital care of this
ª 2011 Adis Data Information BV. All rights reserved.
Bodger
order are realistic for the drug in question re-
mains to be proven in practice but the model
illustrates how an acute drug treatment capable
of lowering the risk of surgery by 10% (e.g. from
10% to 9%) could prove a cost-effective inter-
vention even if the acquisition cost of the drug
was double that of standard (2.4 g) treatment.
This study did not explicitly quantify drug adverse
effects but did account for steroid intolerance.
In another study,[24] again based on efficacy
data from selected clinical trials, the cost effec-
tiveness of a once daily oral 5-ASA formulation
(Mezavant XL) was compared with a standard
‘rival’ formulation (Asacol) that is adminis-
tered two or three times daily. A non-significant
trend suggesting better 8-week remission rates for
the new formulation (40.5% vs 32.6%) was ob-
served in the relevant trial.[25] A 5-year Markov
cohort model simulated the impact of the alter-
native drugs on induction and then longer term
maintenance of remission from the perspective of
the UK NHS. It was assumed that all patients
would be given maintenance 5-ASA therapy to
reduce relapse risk. The base-case model was
further developed to include an estimate of the
effect of drug compliance (‘adherence’) on cost
effectiveness based on extrapolation of compli-
ance data for established 5-ASA drugs. Here the
assumption was that 5-ASA adherence rates for
patients in remission would be slightly higher for
a once-daily versus a twice-daily dosing schedule
(42% vs 39% at 6 months). UK costs,[8] and utility
estimates for defined states, were based on our
previous work.
In the base-case 5-year model, using current
market prices (costing year 2008) for the rival
drugs, the new once-daily agent had an ICER of
d749 per QALY compared with the standard
5-ASA preparation, with small gains in QALYs
and days spent in remission but 12% fewer hos-
pitalizations and 12% fewer surgical episodes
achieved at a minimal increase in overall cost.
Probabilistic sensitivity analysis indicated that
the once-daily formulation was dominant in 62%
of simulations and would be cost effective on 74%
of occasions (ceiling d20 000 per QALY). Unsur-
prisingly, the modelling of improved drug ad-
herence for once-daily (as opposed to twice-daily)
Pharmacoeconomics 2011; 29 (5)
Cost Effectiveness of Treatments for Inflammatory Bowel Disease
dosing increased the apparent dominance of the
new once-daily preparation.
The practice of prescribing long-term 5-ASA
maintenance therapy is well established based on
unequivocal clinical benefits but the cost effec-
tiveness of this approach has not been proven. An
American study considered the alternatives of
standard maintenance 5-ASA treatment (2.4 g
daily) using a commonly prescribed modern for-
mulation versus no maintenance therapy in a
2-year Markov model.[26] Rates of relapse were
derived from published sources, and UC patients
transiting to a relapse state were assumed to fol-
low a standard pathway that included escalation
to a number of medical treatments and surgery
(colectomy) according to available estimates of
treatment effect. The authors reported that the
ICER for maintenance therapy was $US224 000
per QALY gained – well beyond the conventional
threshold for affordability. However, assuming
that a cheaper ‘generic’ 5-ASA (sulfasalazine)
would achieve the same efficacy and tolerability
(an unproven assumption), the authors reported
an ICER of just d16 300 per QALY, illustrating
the sensitivity of the model to drug acquisition
cost when modelling over a 2-year period.
Another study involved a two-stage decision-
analysis approach that first modelled the cost
associated with 5-ASA treatment failure (based
on American treatment guidelines and published
efficacy data) and then estimated costs and a
disease-specific outcome (‘days without symptoms
or steroids’) for rival 5-ASAs using comparative
trial data.[27] The author compared balsalazide
with a specific formulation of mesalazine and
found that the former agent was dominant, with
greater efficacy and improved cost, although
this model had a number of methodological
limitations.
The option of using ‘off-patent’ 5-ASA for-
mulations manufactured and marketed at a lower
price by new suppliers has not been considered in
available models. Whether these cheaper prod-
ucts exhibit efficacy identical to branded versions
is unproven, as there are no head-to-head trials.
It is unclear whether a cost-minimization ap-
proach to drug choice is the correct way forward
– relatively small differences in efficacy (10–15%)
ª 2011 Adis Data Information BV. All rights reserved.
391
may justify quite large differences in drug costs
(200%) for short-term acute treatment,[20] where-
as the cost effectiveness of prolonged mainten-
ance therapy may be influenced more heavily by
drug acquisition cost.[26]
2.1.2 Oral Corticosteroids
Traditional oral corticosteroids are highly ef-
fective at inducing remission in UC. However,
steroids are associated with significant adverse
effects.[28] Models that do not allow for steroid-
induced adverse events will tend to overestimate
the benefits associated with escalating to steroid
treatment after failure of a first-line drug option,
since oral corticosteroids are both inexpensive
and highly effective at improving disease-specific
outcome measures and achieving ‘remission’.
During acute treatment, cumulative global health
gain (utility) arising from a steroid-induced re-
mission is likely to be lower than health gains
obtained for a remission induced by less toxic
drugs. In other words, it may matter ‘how’ remis-
sion is achieved, and simplified models may not
capture the impact of drug adverse effects on
overall health gains. The development of oral
corticosteroids with low systemic bioavailability
(e.g. beclometasone or budesonide) offers the
potential for reducing systemic adverse effects.
There is a substantial price differential between
generic prednisolone and the newer steroids, and
the relative cost effectiveness of these alternatives
has not been defined in UC.
Repeated or prolonged steroid treatment is
a risk factor for osteoporosis and fractures.
Bisphosphonates have proven their ability to re-
duce fracture risk in those with osteoporosis and
appear cost effective in elderly at-risk popula-
tions.[29] The theoretical cost effectiveness of
alternative osteoprotective treatments for pre-
venting fractures specifically in IBD has been
explored in a German modelling study.[29] A
10-year Markov model sought to compare the
cost utility of ibandronate versus cheaper mineral/
vitamin D supplements using efficacy extra-
polated data from a randomized trial and taking
a societal perspective. Monte Carlo simulations
explored uncertainty and the authors reported
that the probability of ibandronate achieving an
Pharmacoeconomics 2011; 29 (5)
392
ICER below a threshold of h50 000 per QALY
was only about £20%. As might be predicted,
ICERs appeared particularly high for younger
females with osteopenia only as opposed to older
patients with established osteoporosis who are at
highest risk.[29]
2.1.3 Biological Agents
The clinical effectiveness of anti-TNF-a ther-
apy for UC has proven to be somewhat less im-
pressive than for CD (see section 2.2.4).[30]
Nevertheless, clinical trial evidence has demon-
strated some efficacy of infliximab in patients
resistant to standard therapies. Unlike for CD,
surgery in UC is potentially curative.
A Markov model was developed to explore the
cost utility of regular maintenance infliximab in
UC, incorporating eight health states (remission,
mild, moderate-severe, temporary discontinuers,
surgery, post-surgery remission, post-surgery
complications and death). Transition probabilities
for responder and non-responder states were de-
rived from the regulatory clinical trials (ACT
[Acute ulcerative Colitis Treatment] I and II
trials),[31] using data for infliximab and place-
bo arms, respectively, for biological and standard
care.[32] Transition probabilities for surgery and
post-surgery states were taken from separate ob-
servational studies, and transition to surgery was
assumed to occur only from the moderate-to-
severe state rather than from milder states. Cost
inputs were based on applying unit costs to esti-
mates of resource use provided largely from ex-
pert opinion, and utility estimates were derived
from sparse published data.
In the ‘responder’ strategy, all patients ex-
periencing a clinical response to infliximab were
assumed to continue maintenance therapy,
whereas, in the ‘remission’ strategy, only patients
experiencing full remission were continued on
biological therapy in the model. Compared with
standard care, the ICERs for the base-case anal-
ysis were reported at d27 066 and d19 696 per
QALY for ‘responder’ and ‘remission’ strategies
at 10 years. Shorter time horizons resulted in less
favourable ICERs. Given the high efficacy of
definitive surgery in UC and the relatively modest
clinical efficacy of infliximab in this condition,
ª 2011 Adis Data Information BV. All rights reserved.
Bodger
these positive findings require independent rep-
lication before drawing firm conclusions. Cer-
tainly, the avoidance of life-changing surgery is a
high priority for patients, and these data at least
suggest that infliximab may be a cost-effective
option.
2.1.4 Colonoscopic Surveillance for Cancer
in Longstanding UC
Patients with longstanding UC are at increased
risk of colorectal cancer, and the practice of per-
forming regular colonoscopic surveillance for
detecting early neoplastic change is widespread.
Colonoscopy with multiple biopsies of each
colonic segment is a relatively invasive, time-
consuming and costly test with a small level of
risk. Definitive surgery (colectomy) for patients
found to have pre-neoplastic change or cancer
has recognized morbidity and a low-level mor-
tality risk and there is a potential for sub-optimal
post-surgical outcomes. The effectiveness of colo-
noscopic screening has not been proven in long-
term clinical trials. The cost effectiveness of this
practice is likely to depend on the magnitude
of cancer risk in the specific sub-population
of colitis patients who are selected for screening
programmes.[33,34]
This question has been explored in a health
economic model that sought to compare a strat-
egy of ‘no surveillance’ (investigations under-
taken for symptoms suspicious of cancer) and
‘surveillance’ (scheduled colonoscopy, with co-
lectomy performed for low-grade dysplasia).[35]
Various surveillance strategies were examined,
with annual examinations ranging from every
1–5 years. In the absence of trial data, obser-
vation studies were used to inform estimates of
neoplasia risk and other key inputs were taken
from the literature. A Markov process was used
to simulate 10 000 patients from the point of de-
ciding to survey or not, through to death. Life-
time direct costs ($US, year 1998 values) from the
perspective of a US-based Health Maintenance
Organization were considered and outcomes
measured in terms of life expectancy. ICERs were
expressed in terms of incremental cost divided
by the increase in life expectancy for surveillance
strategies versus no surveillance ($US per life-year
Pharmacoeconomics 2011; 29 (5)
Cost Effectiveness of Treatments for Inflammatory Bowel Disease
gained [LYG]). The authors reported ICERs of
$US4700 per LYG for surveillance every 5 years
rising to $US247 200 per LYG for yearly colon-
oscopy. The latter figure was comparable to
similar estimates available for cervical cancer
smear-test based screening programmes.[35] As
expected, results were sensitive to the magnitude
of risk of cancer in UC. Threshold analyses ex-
plored the optimum screening strategy according
to a range of ceilings for a policy maker’s will-
ingness to pay for a LY.
2.2 Crohn’s Disease
2.2.1 Oral 5-ASA Drugs
5-ASA drugs are frequently prescribed for CD
although their efficacy both for inducing and for
maintaining disease remission is modest.[36] The
contribution of 5-ASA therapy to long-term costs
of care for CD was estimated in a Markov model
using data from a 24-year population-based CD
cohort.[7] 5-ASAs were estimated to account for
29% of total lifetime direct costs, with surgery
accounting for 44%.[7] Despite the widespread
and costly use of maintenance 5-ASAs, there are
no robust evaluations of their cost effectiveness.
A simplistic calculation based on the findings of a
meta-analysis of the effectiveness of maintenance
5-ASA treatment suggested that the drug expen-
diture for preventing a relapse in CD was between
$US4000 and $US10 000 (publication year: 1994).[36]
2.2.2 Oral Corticosteroids
As already discussed for UC, newer cortico-
steroids are available and have the advantage of
low systemic bioavailability and reduced risk of
adverse effects. In the case of CD, this has led to
interest in ‘maintenance’ steroid therapy,[37] a
strategy to be avoided for conventional steroids.
The cost effectiveness of this approach has not
been subject to direct study. A decision-analytic
model was used to estimate the costs and out-
comes of maintenance therapy for Crohn’s dis-
ease with a specific controlled ileal release (CIR)
formulation of budesonide versus no mainte-
nance therapy in a European setting.[38] Direct
costs from a third-party payer perspective were
compared for each therapy over a period of
12 four-week cycles, including the costs of routine
ª 2011 Adis Data Information BV. All rights reserved.
393
patient care and the consequences of failure (re-
lapse, acute therapies, hospitalization and sur-
gery). Outcome was measured as the average
number of days in remission per patient per
12-cycle period, with incremental cost effective-
ness expressed as the cost per added day in re-
mission. The model suggested that budesonide
CIR capsules was associated with a reduction of
16.6 (26%) days in relapse (i.e. a 6% increase in
days in remission) over a 1-year period compared
with no maintenance therapy. Direct healthcare
costs were increased by 6%, leading to an ICER
of Swedish kronor (SEK)101 per added day in
remission for budesonide CIR capsules versus no
maintenance ($US1 = SEK7.6; publication year:
1998). Whether no maintenance therapy is the
relevant comparator is debatable and how this
strategy would compare with azathioprine (an
effective and inexpensive immunomodulator) is
unclear.
2.2.3 Nutritional Therapy
The use of defined formula polymeric[39] or
elemental[40] feeds as sole nutrition for the in-
duction of remission in active CD is an estab-
lished practice, particularly in paediatric patients
where avoidance of corticosteroids is a significant
concern. Treatment is typically continued for
several weeks prior to reintroduction of normal
diet. This is relatively costly treatment when com-
pared with traditional therapy with oral cortico-
steroids – a single day’s treatment costs more
than a 1-month supply of prednisolone tablets.
A decision-analytic model considered the cost
utility of elemental diet versus 6-mercaptopurine
(6-MP) in patients with steroid-refractory CD;
the authors argued, perhaps controversially, that
first-line use of dietary therapy was illogical be-
cause of the low cost and superior efficacy of
corticosteroids.[41] A time horizon of 4 months
was taken, this being suggested as the relevant
interval for expecting remission. For elemental
diet, in the base case, the authors estimated a 50%
response rate, a 10% rate of intolerance, a 1%
chance of complication (costs of $US300) and a
monthly cost of diet at $US900 per month. For
the conventional 6-MP option, efficacy was as-
sumed to be 60%, complication rate 5% (with a
Pharmacoeconomics 2011; 29 (5)
394
cost of $US7100 for toxic complication of
immunosuppression) and drug costs of $US212.
Utility for response without complication was
taken as 1.0, no response as 0.5, response with
complication of elemental diet treatment (gen-
erally mild) as 0.98, and response with compli-
cation of 6-MP (potentially more severe) as 0.85.
The cost of laboratory monitoring was con-
sidered for 6-MP but hospitalization and surgery
for non-response to treatments were not specifi-
cally modelled. The cost-per-QALY for the two
options in the base-case scenario was estimated at
$US3084 (elemental diet) and $US1285 (6-MP).
However, ICERs were not reported. Univariate
sensitivity analysis suggested the cost of ele-
mental diet would need to be reduced to a sixth of
the base-case estimate to give a cost-per-QALY
comparable to 6-MP. Assuming a more rapid
response for dietary therapy (1 month rather than
4 months), and a reduction in diet costs by one-
third, the authors reported that the two treatments
would be equivalent.[41] The cost and utility in-
puts for this model were based largely on expert
opinion. The finding that the cost effectiveness of
dietary therapy was strongly influenced by the
acquisition cost of the diets, rather than variation
in other parameters over plausible limits, seems
reasonable given the disparity in pricing of diet
versus drug therapy.
2.2.4 Anti-Tumour Necrosis Factor (TNF)-a Agents for
Moderate-to-Severely Active or Fistulizing Disease
The effectiveness of anti-TNF-a drugs in CD
is beyond doubt. Infliximab was the first agent to
be licensed and is administered by IV infusion.
Adalimumab is delivered by subcutaneous injec-
tion. Both are licensed for use in the UK. For
these two agents there have been large placebo-
controlled trials involving patients with moder-
ate-to-severe disease, which have demonstrated
clinical benefits both for induction regimens[42]
and longer term scheduled maintenance to pre-
vent relapse in those who responded to the in-
duction phase of treatment.[43] The effectiveness
of other agents (e.g. certolizumab pegol) is less
well defined. The clinical trials have included adults
with (mainly) non-fistulizing disease, adults se-
lected for the presence of fistulae, or children and
ª 2011 Adis Data Information BV. All rights reserved.
Bodger
young people. The main outcome measure for the
trials has been the CD activity index (CDAI), a
valid clinical scoring system based on eight vari-
ables (weighted according to their ability to pre-
dict disease activity). Fistula-specific clinical
scoring systems have been reported as outcomes
for the fistula trials. There are no head-to-head
trial data for rival anti-TNF-a agents but the
clinical trials for infliximab and adalimumab
were of very similar design and produced com-
parable estimates of efficacy both for induction
of remission and for long-term maintenance of
remission in moderate-to-severe CD.[42-44]
Although the clinical benefits of infliximab
and adalimumab are clear, doubts remain about
their affordability and cost effectiveness. Com-
pared with traditional drug therapies for IBD, the
biological drugs are substantially more expen-
sive. In the UK, for example, the cost of daily
therapy with a standard oral immunosuppressant
(azathioprine, 150 mg per day) is less than d100
for a year, whereas a single infusion of infliximab
costs over d1500 (5 mg/kg for a 75 kg adult).[45]
The anti-TNF agents were originally evaluated in
patients with moderate-to-severely active CD in
whom traditional drug therapies (including
azathioprine/6-MP) had often failed. Without an
alternative drug treatment, such patients may
experience long-term disability and repeated ex-
posure to relatively toxic corticosteroid therapy
or may require surgical intervention. Surgery can
prove highly effective for some but it is not
curative and may not be an option for all those
with drug-refractory CD (e.g. due to widespread
disease or because of previous extensive surgery).
There have been no pragmatic randomized
trials to directly measure the relative cost effec-
tiveness of biological therapy versus standard
care (including surgery) for moderate-to-severely
active CD. This is unsurprising given the size,
duration and complexity that would be involved
in designing a trial with sufficient power to an-
swer questions of cost effectiveness in this con-
dition. However, the potential for anti-TNF
drugs to reduce the need for expensive hospitali-
zation and surgery presents the possibility that
these drugs might prove to be a cost-effective
option.
Pharmacoeconomics 2011; 29 (5)
Cost Effectiveness of Treatments for Inflammatory Bowel Disease
Data from clinical trials have suggested lower
rates of hospitalization and surgery in CD
patients receiving scheduled maintenance with
active drug versus placebo. The ACCENT I trial
(A Crohn’s Disease Clinical Trial Evaluating In-
fliximab in a New Long-term Treatment Regi-
men) focussed on maintenance therapy over a
54-week period for moderate-to-severely active
CD in subjects who demonstrated a clinical re-
sponse to their first infusion of infliximab.[46]
Patients receiving scheduled active treatment
(5 or 10 mg/kg every 8 weeks) were more likely to
sustain remission than placebo-treated patients
(odds ratio: 2.7). A subsequent analysis demon-
strated, unsurprisingly, that rates of hospitali-
zation and surgery decreased as the percentage
of time spent in remission increased,[47] indicat-
ing a lower rate of inpatient treatment required
by responders to biological therapy. An addition-
al analysis of patients treated with infliximab
in the ACCENT I trial showed a significant re-
duction in both hospitalization and surgery for
patients who were allocated to scheduled main-
tenance therapy compared with those who re-
ceived episodic biological treatment.[48] The
ACCENT II trial examined maintenance ther-
apy in fistulating CD, again comparing active
drug with placebo in responders to initial ther-
apy.[49] Compared with placebo, fistula patients
receiving maintenance infliximab experienced
significantly fewer hospitalization days (mean:
0.5 vs 2.5) and inpatient surgeries and procedures
(7 vs 41).[50]
The CHARM (Crohn’s trial of the fully Human
antibody Adalimumab for Remission Main-
tenance) trial of adalimumab compared main-
tenance treatment versus placebo in subjects
with moderate-to-severely active CD.[51] As in
ACCENT I, responders to induction treatment
with an anti-TNF agent were randomized to
placebo or scheduled maintenance regimens. At
56 weeks, those receiving active drug were more
than twice as likely to be in remission. Subse-
quent publication of 12-month follow-up data
revealed that the rate of major surgery per 100 pa-
tients (i.e. per 100 patient-years) was 3.8 in the
placebo arm compared with 0.4 in those treated
with adalimumab every other week.[52]
ª 2011 Adis Data Information BV. All rights reserved.
395
These data derived from the pivotal clinical
trials do suggest a potential for reduced second-
ary care resource use over 12 months for primary
responders who continue on maintenance treat-
ment. The extent to which the reduction in costs
for inpatient care for this ‘responder’ group
compensates for the substantial drug costs is not
clear. It should be remembered that approxi-
mately 40% of patients who receive induction
therapy will not demonstrate a clinical response,
despite having received these agents. Loss of drug
response over periods beyond the timeframe for
the clinical trials is well recognized and this may
translate into a postponement rather than long-
term avoidance of surgery for some patients. Fur-
thermore, patients selected for biological therapy
are more severely afflicted than the overall CD
population and are likely to have a higher relapse
rate. Data from the pre-biological era suggest
that surgery can achieve long periods of remis-
sion for some patients. A population-based
observational study of the clinical course of 174
patients with CD (median follow-up of 10 years)
reported that 85 patients underwent surgery and
achieved a post-surgical remission state (no
medication required), which lasted a median of
766 days (range: 2–7550 days).[7]
Uncontrolled, observational data have been
published detailing the healthcare resources con-
sumed by cohorts of CD patients before and after
starting treatment with biological therapy.[53,54]
In the US setting, one study reported the fre-
quency of key medical interventions for 79 CD
patients treated at a single centre in the year be-
fore and after infliximab therapy. Compared with
the year before biological treatment, there was a
reduction in annual incidence of all surgery
(38%), gastrointestinal surgery (18%), endoscopy
(43%), ED visits (66%), clinic visits (16%) and
radiology procedures (12%).[54] Expenditures on
infliximab were not reported and so it is unclear
whether or not overall healthcare spending was
reduced in the year after biological therapy was
started. A multicentre study from the UK re-
ported the frequency of key medical interventions
and direct healthcare costs (d, year 2005 values)
for 205 CD patients in the 6 months before and
after infliximab treatment.[53] Compared with
Pharmacoeconomics 2011; 29 (5)
396
pre-treatment, there were 21 fewer clinic visits,
99 fewer diagnostic procedures, 1093 fewer inpa-
tient days, 7 fewer surgical operations and 6 fewer
examinations under anaesthesia. Despite a cost
of over d500 000 million for infliximab, the au-
thors reported that average costs were d138 less
per patient in the 6 months after therapy than in
the same period before treatment.[53]
Recent data from a longitudinal study of
614 CD patients treated with infliximab suggest-
ed that before therapy, the rate of major abdo-
minal surgery was between 6.98 and 9.33 operations
per 100 patient-years. After infliximab, the rate of
surgery was 3.2 in those with sustained response
compared with 18.35 in primary non-responders
to infliximab.[55]
None of the above ‘before-and-after’ studies
included a control group of similar patients
treated with ongoing standard care rather than
infliximab. Patient outcomes are reported to be
improved after treatment but there is no explicit
linkage of care costs to formal measures of qual-
ity of life (QOL). It is unclear whether hospitali-
zation and surgery is permanently avoided or
merely delayed for these patients. It is possible
that there is an intensification of medical in-
vestigations prior to initiating biological therapy
and such tests would not be repeated over short
time periods, leading to an apparent reduction in
investigation costs.
Several economic modelling studies have been
undertaken in an attempt to compare the cost
effectiveness of biological therapy versus stan-
dard (non-biological) care in CD. These have in-
cluded both independent and industry-sponsored
studies, some published in full in peer-reviewed
journals and others published in varying levels of
detail in health technology appraisal reports.
This has been an area of considerable controversy
and different groups have produced quite varied
results that have proved difficult to reconcile.[56]
The available studies differ in the precise choice
of decision question, the perspective and health-
care system of interest, the modelling technique
that was employed, the timeframe for analysis,
the key structural model assumptions (including
which health states were included) and in the
sources of probability data and inputs for costs
ª 2011 Adis Data Information BV. All rights reserved.
Bodger
and outcomes. Table I summarizes those studies
that have been published in peer-reviewed jour-
nals or as independent reports.[57-63]
Many gaps in knowledge have made the
modelling process challenging, including a rela-
tive lack of primary inputs for costs of care and
for QOL (utility) estimates for defined disease
states. It is not possible to simply ‘piggy-back’
economic measures onto the placebo-controlled
trials, since the placebo arms of these studies are
not true ‘standard care’ arms – the long-term
maintenance trials recruited only responders to
initial induction therapy and the clinical outcome
of non-responders is not known. The economi-
cally important events are hospitalization and
surgery but in the placebo-controlled trials these
outcomes will lead to patients exiting from future
follow-up. Hence, long-term data for outcomes
of interest are not available for patients who did
not respond to induction treatment, exited the
trials for any reason or were treated surgically.
To consider the overall cost effectiveness of the
anti-TNF-a option, long-term cost and outcome
data is needed for all categories of patients who
receive initial treatment (i.e. an intention-to-treat
analysis).
Several economic models[58-60,63] have simu-
lated the long-term course of CD under standard
care using data from an observational study of
a population-based cohort of CD patients, the
‘Olmsted County’ cohort.[7] Transition prob-
abilities between eight discrete disease states (in-
cluding the important surgical state and death)
are reported in this observational study that is
based on 1957 patient-years of retrospective chart
review covering the period 1970–93 for 174 pa-
tients. As we have shown,[63] this approach to
modelling the clinical course of CD will predict
lower rates of surgery than are reported for
modern cohorts of patients selected for biological
therapy. The average clinical course of patients in
the Olmsted County cohort is likely to be more
benign than that of patients selected for anti-
TNF agents (who have often proven to be refrac-
tory to standard treatments). This may bias the
models in favour of standard care, both by over-
estimating the potential for ongoing standard
medical care to achieve future clinical benefits
Pharmacoeconomics 2011; 29 (5)
ª 2011 Adis Data Information BV. All rights reserved.
Table I. Cost-utility analyses for biological therapies in Crohn’s disease (CD)
Patient group (study)
Perianal fistulae in CD
(Arseneau et al.[57])
Chronic active CD
resistant to conventional
therapy (Marshall
et al.[58])
Chronic active CD (Clark
et al.[59])
Chronic active CD
(Jaisson-Hot et al.[60])
Severely active luminal
CD or fistulizing CD
(Lindsay et al.[61])
Severe or moderate-to-
severe active CD (Loftus
et al.[62])
Pharmacoeconomics 2011; 29 (5)
Moderate-to-severely
active CD (Bodger
et al.[63])
6-MP = 6-mercaptopurine; ADA = adalimumab; ICER = incremental cost-effectiveness ratio; IFX = infliximab; maint. = maintenance; SC = standard care; tx = treatment.
Cost Effectiveness of Treatments for Inflammatory Bowel Disease
Timeframe; cost perspective Treatment alternatives Base-case ICER Author comments (refer to main
(currency, cost year) (cost per QALY) text)
1 y only; direct medical costs, i. SC (6-MP + metronidazole) Comparator Definitive surgical intervention
US third-party payer system ii. Induction (three infusions IFX) then SC 355 450 was not considered in the model
($US, 1999)
iii. Induction with repeat IFX for tx failure 360 900
iv. SC with IFX for tx failure 377 000
1 y only; direct medical costs, i. SC Comparator SC was modelled on Olmsted
Canadian provincial health ii. Single infusion of IFX, then SC only 181 201 County cohort.
ministry ($Can, 2001)
iii. Episodic IFX for disease flares 480 111
iv. Maint. IFX (8-weekly) 696 078
1 y only; direct medical costs, i. SC Comparator Independent analysis of
UK NHS (£, 2001) ii. Single infusion of IFX then SC 35 000 unpublished company model;
SC was modelled on Olmsted
iii. Episodic IFX for disease flares 39 000
County cohort; maint. tx not
considered; cost inputs based
on limited data
Lifetime only; direct medical i. Surgical tx followed by SC Comparator Model assumed all those on SC
costs, French third-party payer ii. Episodic IFX for disease flares 63 700 receive initial surgery; SC was
system (h, 2004) modelled on Olmsted County
iii. Maint. tx 784 057
cohort
Cost inputs based on expert
opinion only
5 y only; direct medical costs, i. SC Comparator Episodic tx not considered; non-
UK NHS (£, 2005–6) ii. Induction then maint. IFX 26 128 (‘luminal’); biological care was modelled on
or 29 752 placebo-arm trial data
(‘fistulizing’)
1 y in base case, up to lifetime; i. SC ‘non-biological’ Comparator Episodic tx not considered; non-
UK NHS (£, 2006–7) ii. Induction then maint. ADA 6550 (‘severe’ CD); biological care was modelled on
placebo-arm trial data
for responders or 17 873
(‘moderate-to-
severe’)
1 y in base case, up to lifetime; i. SC Comparator Episodic tx not considered; SC
direct medical costs, UK NHS ii. Induction then maint. IFX for 19 050 was modelled on Olmsted
(£, 2006–7) responders County cohort
iii. Induction then maint. ADA 7190
for responders
397
398
and by underestimating the rates of surgery. Cer-
tainly, initial models using this approach reported
relatively high ICERs for infliximab, particularly
for maintenance therapy, which exceeded tradi-
tional thresholds of affordability.[58,60]
Although episodic anti-TNF-a treatment ap-
peared to have lower ICERs than maintenance
therapy in the available economic studies,[58,60]
the use of regular, scheduled treatment has be-
come the favoured approach clinically.[64] There
has been considerable interest in the UK setting
as to the affordability of this approach in antic-
ipation of a reappraisal of national guidelines
governing the use of biological agents in CD.[65]
Recent industry-sponsored models have avoided
using the Olmsted County data as a source for
standard care but instead adapted placebo-arm
data from the key clinical trials.[61,62] This ap-
proach has yielded more favourable ICERs for
infliximab and adalimumab when used as main-
tenance therapy, with both commercial models
reporting base-case values below the d30 000 per
QALY threshold.
There is considerable heterogeneity between
the available economic models in terms of both
methodology and findings. It is therefore rela-
tively difficult to identify consistent messages from
the base-case results and sensitivity analyses. The
time horizon for analysis and the anticipated
duration of maintenance treatment appear to be
important determinants of cost effectiveness.
‘Lifelong’ maintenance treatment yielded un-
favourable ICERs in two non-commercial studies
when analysed over a lifetime horizon.[60,63]
Industry-sponsored studies reported that con-
tinuous maintenance anti-TNF-a treatment ap-
peared cost effective in the UK setting when
analysed over a relatively short time horizon of
1 year (adalimumab)[62] or 5 years (infliximab).[61]
However, we found that restricting the time hori-
zon to 1–2 years resulted in ICERs in excess of
d30 000 per QALY for maintenance therapy,
whereas our threshold analysis based on a lifetime
horizon suggested that either agent could be cost
effective if used continuously for 4 years and pos-
sibly even longer in the case of adalimumab.[63]
The balance of these published data suggest
that scheduled maintenance therapy is probably a
ª 2011 Adis Data Information BV. All rights reserved.
Bodger
cost-effective option when prescribed for periods
of ‘a few’ years (e.g. 1–5 years) but not ‘for life’.
In the absence of clinical trials spanning decades
of maintenance treatment, the clinical debate
about the benefits of ‘lifelong’ therapy is unre-
solved.[66,67] There is much uncertainty in pre-
dicting long-term outcome both for standard care
(medical and surgical) and for patients treated
with biological agents. The cost-utility models
have not considered the long-term tendency for
loss of efficacy during maintenance anti-TNF
therapy and the implications of dose escalation or
reductions in dosing intervals.[68] Nor have the
existing models explicitly considered subgroups
of patients for whom surgery offers little prospect
of health improvement by virtue of diffuse gut
involvement or previous extensive resection. The
‘lack of memory’ of traditional Markov models
means that transition probabilities do not vary
over time or between patients – essentially every
patient in a specific health state faces the same
‘average’ future course of disease, irrespective
of their prior interventions. This problem may
be particularly relevant to modelling the impact
of surgical interventions, since repeat surgery
is likely to be more costly and less effective than a
first intervention.
Relatively little attention has been given to
modelling the impact of varying price levels for
the anti-TNF-a agents. The market prices set by
the manufacturers seek to recoup investment in
R&D and generate profit to sustain and grow
business. Until recently, companies have been free
to set their own prices in the UK within very
broad profit constraints (‘profit cap and price
cut’ scheme). However, a patient-focussed ‘value-
based’ pricing scheme is to replace this system
after 2014, whereby prices are intended to explicitly
reflect therapeutic benefits.[69-71] One modelling
study from the US explored the influence of the
acquisition cost of infliximab on cost-utility esti-
mates for initial medical management of perianal
fistulae.[57] The baseline model predicted very
unfavourable ICERs for strategies involving in-
fliximab in comparison with standard care.[57]
A threshold analysis suggested that a reduction
in wholesale cost of infliximab infusion from
$US2030 to $US304 (i.e. by 85%) would result in
Pharmacoeconomics 2011; 29 (5)
Cost Effectiveness of Treatments for Inflammatory Bowel Disease
a change in ICERs from >$US350 000 per QALY
to between $US54 050 and $US127 200 per QALY
for the strategies involving infliximab.
2.2.5 Anti-TNF-a Agents as Early, ‘Top-Down’
Therapy
Much interest in now focussed on the clinical
potential of using anti-TNF-a agents at an earlier
point in disease course rather than reserving treat-
ment for a subgroup with moderate-to-severe dis-
ease unresponsive to traditional therapies.[72,73]
Clinical trial data are awaited and hence eco-
nomic studies have yet to specifically address this
‘top-down’ approach. However, it could be ar-
gued that results from cost-utility models built on
the Olmsted County data might be relevant to
this decision question. These models simulate the
course of disease for an ‘average’ patient with
CD, based on risks of relapse and surgery derived
from the whole disease population, rather than a
refractory sub-population. If the clinical efficacy
of biological treatment in a more general disease
population proves comparable or superior to that
achieved in a more refractory subgroup, these
existing models may lend indirect support to the
potential cost effectiveness of treating any ‘aver-
age’ patient experiencing a sufficient level of dis-
ease activity.
3. Conclusions
Much uncertainty surrounds the relative cost
effectiveness of different treatment options for
IBD, and future clinical trials should seek to gen-
erate data that better informs the process of eco-
nomic appraisal. However, the lifelong nature of
IBD means that pragmatic trials of sufficient size
and duration are unlikely to be performed to give
definitive answers to questions of long-term cost
effectiveness. Economic modelling will remain a
tool for simulating long-term costs and outcomes
in the absence of definitive trials. The cost effec-
tiveness of anti-TNF-a agents in CD has been
subject to most theoretical modelling and the
difficulties encountered in reconciling the results
of different models highlights the limitations of
current techniques. Nevertheless, the emerging
literature suggests that biological agents may well
ª 2011 Adis Data Information BV. All rights reserved.
399
represent a cost-effective approach to the long-
term management of CD, even though the opti-
mum duration of therapy is yet to be defined.
Areas for future research include better val-
uation of the utility associated with defined dis-
ease states and the impact of drug adverse effects
and surgical interventions on global health outcome.
There is a need for longer term observational
data on the clinical course and costs incurred by
patients selected for biological therapy, including
non-responders, those losing response and those
who undergo surgery. The potential to use biolo-
gical agents at an earlier point in the clinical course
of CD[74] means that the cost effectiveness of these
agents will remain a major focus of interest.
Acknowledgements
Dr Bodger has received research support funding through
grants/contracts with his employing institutions from Procter
& Gamble UK Ltd, Abbott Laboratories and Shire Pharma-
ceuticals.
No sources of funding were used to conduct this study or
prepare this review.
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Correspondence: Dr Keith Bodger, Gastroenterology,
Department of Medicine, Clinical Sciences Centre, University
Hospital Aintree, Liverpool, L69 3GA, UK.
E-mail: kbodger@liverpool.ac.uk
Pharmacoeconomics 2011; 29 (5)
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