The document summarizes a budget impact analysis comparing a top-down therapy approach using Remicade (infliximab) to conventional step-up therapy for moderate to severe Crohn's disease. The analysis found that a top-down approach using infliximab improved rates of steroid-free remission and delayed time to surgery compared to step-up therapy. It also found that this approach would save a third-party payer like BC/BS MA an average of $2,641 per patient per year and $13,609 over 5 years due to lower rates of hospitalization and surgery compared to step-up therapy.

1. Comparing a top-down therapy approach with Remicade (infliximab) to conventional
step-up therapy in moderate to severe Crohn’s disease: a budget impact analysis
Amirana S, Chen L, Gandhi P, Ofokansi R, Salamo K, Seagren R
1 School of Pharmacy, Bouvé College of Health Sciences, Northeastern University, Boston, MA
PHMD 6270: Economic Evaluation of Pharmaceuticals and Pharmacy Practice Final Project, April 2014
Introduction to Crohn’s Disease
Definition:
An autoimmune, inflammatory bowel disease (IBD) resulting in chronic inflammation
potentially involving any location of the gastrointestinal (GI) tract, which can interfere with
the digestion of food, absorption of nutrients, and elimination of waste. Patients will go
through phases of acute flares and periods of remission.
Complications:
Fistulas, strictures leading to intestinal blockage, perforation, perirectal abscesses,
pseudopolyps, anal fissures, toxic megacolon, colon cancer, and psychological
complications (such as anxiety, stress, and depression).
Disease Burden:
• Approximately 1.4 million Americans currently have inflammatory bowel disease. IBD
is a term that encompasses Crohn’s disease (CD) and ulcerative colitis (UC)
• CD affects an average of 200 out of 100,000 people in the US according to the
National Institute of Health
• Complications in the GI tract occur in 33% of patients at the time of diagnosis, and
then in at least 50% of patients within 20 years of diagnosis
• IBD accounts for on average:
• > 700,000 physician visits
• 100,000 hospitalizations
• 119,000 disabilities annually
Treatment:
Results Discussion
Our findings show, in terms of clinical efficacy, a top-down approach using infliximab
therapy compared to step-up therapy improved rates of steroid-free clinical remission,
improved mucosal healing, and delayed time to surgery. When using a top-down therapy
approach, infliximab has been proven to be cost-effective compared to step-up therapy.
The budget impact analysis showed that BC/BS MA will save on average $2,641 per
patient per year with diagnosed CD and an average of $13,609 over the next 5 years.
Although the estimated cost of one year of infliximab therapy is much higher than the
estimated cost of standard step-up therapy ($33,280 for infliximab compared to $13,348
with 6 relapses for step-up), the rates of surgery and hospitalizations were much greater
in patients using a step-up therapy approach.
Additional complications of the disease such as renal disease, liver disease,
cholelithiasis, joint complications, and skin and eye complications, were not taken into
account in the BIA. If infliximab prevents disease progression, then it is very likely that it
will prevent or delay these complications. Running a sensitivity analysis showed that
these complications can cost up to $1.77M annually, not taking into account surgeries or
hospitalizations related to these complications. Although infliximab has come with its
own set of serious complications, such as malignancies and infusion-related reactions,
these complications are very rare and are seen more frequently in doses greater than
10mg/kg, which is not FDA approved in CD.
Weaknesses we have identified with our BIA are primarily a result of the usual course of
the disease. Each patient requires individualized therapy based on symptom severity
and possible disease complications. There were many assumptions when considering
top-down compared to step-up therapy such as the weight of the patient, the number of
clinical relapses, and other comorbid conditions. However, what is unique about our
analysis is that it is the first to evaluate the clinical and economic impact of top-down
therapy with infliximab in moderate-severe CD patients in a real-world clinical setting.
Step-Up Therapy Top-Down Therapy
• Acute: Steroids (prednisone 40-60mg
daily) until resolution of symptoms
• Maintenance:
• Azathioprine (AZA)
• 6-mercaptopurine (6-MP)
• Methotrexate (MTX)
• May take up to 4 months to be
effective and up to 50% of patients
will become “steroid dependent”
• Biologic therapy only considered in
refractory patients
• Biologic therapy: tumor necrosis factor-
alpha inhibitor (anti-TNF! agent)
• Remicade (infliximab)
• Humira (adalimumab)
• Cimzia (certolizumab)
• Treatment with infliximab has shown to
be more effective in maintaining steroid-
free clinical remission than AZA in
moderate-severe Crohn’s disease
Objectives
1. Identify and analyze conclusions drawn from clinical literature about clinical efficacy of
top-down therapy in Crohn’s disease
2. Identify and analyze conclusions drawn from economic literature about cost-
effectiveness and budget impact analysis of top-down therapy in Crohn’s disease
3. Implement a budget impact analysis from a 3rd party payer perspective of top-down
therapy in Crohn’s disease patients
Methods
Economic Impact
Overall, examining all the cost-effectiveness
articles with a good or fair evidence grade,
infliximab fell below the incremental cost-
effective ratio (ICER) threshold assigned in
the studies proving to be cost-effective. The
studies primarily focused on adult patients at
an average weight with moderate to severe
luminal or fistulizing CD while a few included
pediatric patients as well. Varying from a
one-year to a five-year time horizon, the trials
extrapolated and performed various one-way
sensitivity analyses based on the time
horizon, patient weight and age, and all-cause
mortality. Even these sensitivity analyses
indicated that infliximab and other biologics
are generally more cost-effective as
compared to standard therapy.
Clinical Efficacy
Overall, results of primary randomized, double-
blind trials such as the ACCENT-I trial and the
SONIC trial showed that infliximab was more
effective in providing longer steroid-free clinical
remission with a decreased need for surgery. The
ACCENT-I trial showed that infliximab as
maintenance therapy was superior to placebo when
given as a 5mg/kg infusion every 8 weeks in terms
of clinical remission and steroid discontinuation. The
SONIC trial showed that therapies with infliximab
(whether as monotherapy or in combination with
AZA) were superior to AZA monotherapy in the
duration of steroid-free clinical remission and
mucosal healing. Other retrospective studies
showed that a top-down therapy approach with anti-
TNF agents reduced the risk of CD-related surgery
when compared to conventional step-up therapy.
Conclusions
In conclusion, 3rd party payers should consider a top-down therapy approach in patients with
moderate to severe CD, which, not only saves costs for the payers, but also benefits the patients in
terms of improved quality of life. From the overall analysis, we recommend that every patient’s
treatment be individualized based on past experience, treatment preference, and potential side
effects as some patients may not respond to infliximab therapy or may have side effects resulting in
nonadherence. However, this statement remains true for a step-up approach as well. Overall, the
BIA shows that the benefits for using infliximab outweigh the risks, and from our results, top-down
therapy with infliximab exhibits cost savings and improvements in quality of life when compared to
step-up therapy from a 3rd party payer perspective.
Acknowledgements
We would like to thank Steven Pizer, PhD and Mark Douglass, PharmD for their guidance with this analysis.
Search Strategy:
• Sources: PubMed, Medline
• Search terms: infliximab, Crohn’s disease, clinical
efficacy, top-down, budget impact, cost effectiveness,
United States
• Findings: We found a total of 36 articles for clinical
efficacy and 30 articles for economic impact. We
eliminated articles from analysis if infliximab was not
considered as a biologic agent of choice. We also
considered moderate to severe CD as a CDAI of 220 – 450
Budget Impact Analysis:
• Cost calculator approach using a one-way sensitivity analysis
• Assumptions: 0.2% prevalence rate equal between male and female, AZA therapy will require a minimum of 1 treatment course of prednisone per year, dosing
based on 60kg patient, costs inflated to 2012 pricing, and discount rate of 3%
Analytic Framework:
Patients with
diagnosed
moderate-severe
Crohn’s disease
(CDAI 220-450)
Treat-
ment
Treatment Approach:
! Top-down therapy
with infliximab 5mg/kg
IV infusion at weeks
0, 2, 6, and then
every 8 weeks
thereafter
! Step-up therapy with
steroids and/or AZA,
6-MP, MTX
! Surgery
Outcomes:
! Duration of
steroid-free
clinical
remission
! Mucosal
healing
! Surgery
prevention
KQ1 KQ2 KQ3
0
50
100
150
200
250
300
Average Low High
Cost(inmillions)
Budget Impact (Per Budget Holder)
over a 5-Year Time Horizon
Step-Up Therapy Infliximab Budget Impact
Our budget impact analysis was a 5 year duration starting in
2012 from the perspective of a 3rd party payer, specifically, Blue
Cross / Blue Shield HMO of Massachusetts (BC/BS MA). As
shown from the graph, costs of step-up therapy are much
higher than infliximab, due to a higher rate of hospitalizations
and required surgeries in this cohort.
BC/BS MA spent $12.8 billion dollars in 2012. Choosing a top-
down therapy approach for their patients with moderate-severe
CD would save them on average $79 million over a 5 year
period. These costs include the costs of diagnostics, surgeries
due to CD, and hospitalizations due to CD. This is consistent
with the findings of the economic impact research that is
currently available for a top-down therapy approach in
moderate-severe CD patients.
For our sensitivity analysis, an estimated 1.5% was used for
inflation costs and a compounded 3% per year discount rate was
applied over the 5 year duration. Hospitalizations and surgery
rates of step-up therapy compared to top-down therapy with
infliximab were the primary inputs. As noted from the tables, there
was an average savings of $1.96M from hospitalizations and a
$14.3M savings from surgeries if a top-down therapy approach
with infliximab was utilized. Even when different patient weights
were considered, average savings were still $16.3M per year with
infliximab therapy.
Average Rate of
Hospitalizations
Average Cost of
Hospitalizations
Low Rate of
Hospitalizations
Low Cost of
Hospitalizations
High Rate of
Hospitalizations
High Cost of
Hospitalizations Average
Step-Up 26.00% $16.8M 24.15% $15.5M 27.85% $18M Savings
Infliximab 23.00% $14.8M 21.08% $13.5M 24.92% $16.1M
Difference $2M $2M $1.9M $1.96M
Average Rate of
Surgeries
Average Cost of
Surgeries
Low Rate of
Surgeries
Low Cost of
Surgeries
High Rate of
Surgeries
High Rate of
Surgeries Average
Step-Up 16.53% $26.1M 14.45% $22.8M 18.61% $29.4M Savings
Infliximab 7.44% $11.8M 5.13% $8.1M 9.75% $15.4M
Difference $14.3M $14.7 $14M $14.3M
Annual Hospitalization Rates
Annual Surgery Rates
Weight Dose Yearly
Cost of
Treatment Savings
40kg $2.6K $23.7K $36.55M $16.28M
60kg $3.7K $33.3K $36.56M $16.27M
80kg $4.8K $42.8K $36.57M $16.26M
100kg $5.8K $52.4K $36.58M $16.25M
120kg $6.9K $61.9K $36.59M $16.24M
Average $16.3M
Patient Weight
Low Cost of Step-Up $48.4M
High Cost of Infliximab $41.5M
Total Savings $6.9M
Best Case for Step-Up Therapy
Even when analyzing the “best case scenario” for step-up
therapy, infliximab costs were still lower, which saved the 3rd
party payer an average of $6.9M per year. Therefore, it can
be said that even when rates of surgery and hospitalizations
are higher than anticipated in a top-down approach, this is
still a more cost effective option.