Cost-per-remission analysis of infliximab compared to adalimumab among adults with moderate-to-severe ulcerative colitis

Abstract

Objective:

To compare cost per remission (CPR) of infliximab (IFX) versus adalimumab (ADA) for the treatment of moderately-to-severely active UC.

Methods:

This is CPR model comparing IFX and ADA in the treatment of UC using clinical trial data. Clinical outcome measures include clinical remission and sustained clinical remission (SCR). Economic endpoints were modeled as medication costs. CPR ratios and number needed to treat (NNT) costs were computed at 8, 52, and 54 weeks.

Results:

CPR for bio-naïve patients for IFX and ADA at weeks 8, 52, and 54 was $42,086 vs. $79,558: $147,379 vs. $320,097; $147,379 vs. $330,767, respectively. CPR for all patients for IFX and ADA at weeks 8, 52, and 54 was $42,086 vs. $113,812; $147,379 vs. $349,197; $147,379 vs. $360,836, respectively. Cost per SCR for bio-naïve patients and all patients for IFX and ADA was $203,205 vs. $682,873 and $203,205 vs. $698,393, respectively. NNT and NNT costs for clinical remission for bio-naïve patients at weeks 8, 52, and 54 were lower for IFX (4 vs.10, $40,235 vs. $81,945; 5 vs.10, $134,115 vs. $307,293; 5 vs. 10, $134,115 vs. $317,536, respectively) than for ADA. NNT and NNT costs for clinical remission for all patients at weeks 8, 52, and 54 were lower for IFX (4 vs.14, $40,235 vs. $114,723; 5 vs.11, $134,115 vs. $338,022; 5 vs. 11, $134,115 vs. $349,290, respectively) than for ADA. NNT and NNT costs for SCR for bio-naïve and all patients were lower for IFX (8 vs. 22, $214,584 vs. $676,045; 8 vs.23, $214,584 vs. $706,774) than for ADA. Study limitations include lack of head-to-head trial data, different primary endpoints between the two clinical trials, and indirect costs were not included.

Conclusion:

IFX had lower CPR and cost per SCR than ADA in the treatment of moderately to severely active UC.

Keywords::

• Health economics
• Anti-TNF
• Ulcertive colitis
• Cost effectiveness

Background

Ulcerative colitis is a form of inflammatory bowel disease. In North America, the disease prevalence ranges from 150 to 200 patients per 100,0001. Onset can occur at any age, but typically occurs between the ages of 15 and 30 and between 60 and 80 years of age2. Ulcerative colitis is a disease of relapsing and remitting mucosal inflammation involving the colon or rectum, and patients typically experience chronic abdominal pain, diarrhea, and gastrointestinal bleeding1. Ulcerative colitis often requires hospitalization and intensive and expensive therapies to control patients’ symptoms3. A significant portion of patients eventually require surgical intervention4. Extra intestinal manifestations are also common, and they include serious skin disorders such as pyoderma gangrenosum5, sclerosing cholangitis6 and thromboembolic events7,8, which are thought to be related to the pro-inflammatory state of the disease. Patients have an increased risk of colon cancer9.

Pharmacologic treatment represents an important tool in the management of this condition. Studies have shown that the anti-tumor necrosis factor (anti-TNF) treatments infliximab and adalimumab are efficacious in treating moderately to severely active ulcerative colitis10–12. Infliximab is indicated for reducing signs and symptoms, inducing and maintaining clinical remission and mucosal healing, and eliminating corticosteroid use in adult patients with moderately to severely active disease who have had an inadequate response to conventional therapy13. The recommended dose of infliximab is 5 mg/kg given as a 2-hour intravenous induction regimen at 0, 2, and 6 weeks followed by a maintenance regimen of 5 mg/kg every 8 weeks thereafter for the treatment of adult patients with moderately to severely active ulcerative colitis13.

Adalimumab is indicated for inducing and sustaining clinical remission in adult patients with moderately to severely active ulcerative colitis who have had an inadequate response to immunosuppressants such as corticosteroids, azathioprine or 6-mercaptopurine (6-MP)14. The effectiveness of adalimumab has not been established in patients who have lost response to or were intolerant to TNF blockers14. The recommended adalimumab dose regimen for adult patients with ulcerative colitis administered by subcutaneous injection is 160 mg initially on day 1 followed by 80 mg 2 weeks later (day 15), and then 2 weeks later (day 29) continue with a dose of 40 mg every other week14. It is recommended to only continue adalimumab in patients who have shown evidence of clinical remission by 8 weeks (day 57) of therapy14.

While clinical evidence is available, no studies to date have examined the cost per remission of infliximab and adalimumab for ulcerative colitis. In addition, no head-to-head studies have been conducted comparing the effectiveness of infliximab and adalimumab for the treatment of moderate-to-severe ulcerative colitis. Therefore, the objective of this study was to compare the cost per remission of infliximab versus adalimumab for the study endpoints that the medications share, clinical remission and sustained clinical remission for the treatment of moderately to severely active ulcerative colitis, from the perspective of managed care.

Methods

This cost per remission analysis was performed using clinical information for infliximab from the ACT 1 trial10 and for adalimumab from Sandborn et al.11. It is reasonable to use these two studies to compare infliximab and adalimumab for several reasons. First, both studies examined similar time points, using similar definitions for each outcome: clinical remission and sustained clinical remission. The inclusion criteria of the studies were similar (See Table 1): ulcerative colitis diagnosis, confirmation of diagnosis and Mayo score. In addition, the baseline characteristics of the study participants were nearly identical in terms of demographic characteristics (percent male, mean age and percent Caucasian). Patients in the adalimumab study appear to have a somewhat longer duration of disease. However, these duration data are for the entire study population (bio-naïve and bio-experienced), and duration of treatment results may be different for the bio-naïve patients. A key difference between the two studies is that the adalimumab study included both bio-experienced and bio-naïve patients, while the infliximab ACT 1 study included only bio-naïve patients. In order to fairly compare these two therapies, this cost per remission analysis examined bio-naïve patients as well as the entire population from Sandborn et al.11.

Table 1. Study inclusion criteria for ULTRA 211 and ACT 110.

	ULTRA 2	ACT 1
	Sandborn et al.	Rutgeerts et al.
	Adalimumab	Infliximab
	(n = 494)	(n = 364)
Male (mean)	60%	61%
Age (weighted mean)	40 years	41.9 years
Caucasian (%)	95%	93%
Mayo score (weighted mean)	8.9	8.4
Conventional therapy	Steroids, 6-MP, and/or AZA	Steroids, 6-MP, and/or AZA
UC disease duration (weighted mean)	8.3 years	6.8 years

In summary, given similarities between the studies in (1) inclusion criteria, (2) baseline patient characteristics, (3) short-term time points (8 weeks), (4) long-term time points (week 52 and week 54), and (5) definitions for efficacy, these studies provide comparable parameters to support a cost per remission analysis.

Outcome measures

The outcome measures for the analysis include clinical remission and sustained clinical remission. Clinical remission10,11 is defined by a Mayo score ≤2 with no individual subscore >1. Sustained clinical remission for infliximab is defined as patients who were in clinical remission at weeks 8, 30, and 5410. For adalimumab, sustained clinical remission was defined as patients who achieved clinical remission at both weeks 8 and 5211.

The analysis utilized outcome measures at weeks 8, 52 and 54 for the models in accordance with the time points of the clinical trials10,11. All rates were placebo-adjusted. The rationale for doing this is to control for placebo effects in each trial, providing a more complete measure of the clinical efficacy of each treatment15.

Baseline placebo-adjusted rate for infliximab at week 8 was 23.9% for clinical remission (Table 2). Baseline placebo-adjusted rates for adalimumab at week 8 were: 10.3% for clinical remission for bio-naïve patients and 7.2% for clinical remission for all patients. Table 2 lists rates of clinical remission for infliximab and adalimumab at weeks 54 and 52, respectively. For infliximab, the rates of clinical remission observed at week 54 were used to model cost per remission for week 52 (Table 2). Likewise, for adalimumab, rates of clinical remission observed at week 52 were utilized for week 54 modeling (Table 2). Lastly, Table 2 lists the rates of sustained clinical remission for infliximab and adalimumab.

Table 2. Baseline model values: clinical remission and sustained clinical remission.

Dosing

The number of medication doses was based on the dosing schedules followed in the clinical trials10,11. For infliximab, as per the clinical trial, the model used the United States (US) Food and Drug Administration (FDA)-recommended dosing of 5 mg/kg and assumed a patient of 80 kg as in ACT 110,13. Infliximab dosing was calculated as 5-mg/kg doses administered at weeks 0, 2, and 6, then every 8 weeks up to week 46. Therefore, at week 8, a total of three infusions of infliximab had been given and by week 54, a total of eight infusions of infliximab had been given. For adalimumab, the model used the US FDA-recommended dosing of 160 mg at week 0, 80 mg at week 2, and 40 mg doses every other week up to week 50 as in the ULTRA 2 study11,14. Therefore, at week 8, a total of eight injections of adalimumab had been given and by week 50, a total of 30 injections of adalimumab had been given. For the 54-week analysis, the assumption was made that an additional 40-mg dose of adalimumab would be given at week 52 for a total of 31 injections. Therefore, this additional dose was included in the week-54 model.

Costs

This study modeled medication costs, which were calculated as the unit cost per dose multiplied by the number of doses received. The medication unit costs for infliximab ($773.97 per 100-mg vial) and adalimumab ($1024.31 per 40-mg injection) were obtained from the September 2012 wholesale acquisition cost (WAC)16. The WAC does not take into account negotiated medication discounts or rebates. Infliximab is a weight-based product. Therefore, in order to calculate the infliximab costs, we used the mean patient weight, 80 kg, from the clinical trials10. The medication cost of each infliximab infusion was (5 mg/kg × 80 kg × $773.97/100-mg vial) $3095.88. Therefore, the infliximab medication costs at 8, 52, and 54 weeks were $9288, $24,767, and $24,767, respectively. For adalimumab, the medication costs at 8, 52, and 54 weeks were $8194, $30,729, and $31,754, respectively.

Infliximab infusion costs were based on a study by Wong et al. (2011)17. This study analyzed the medication and administrative costs allowed by US private and public third-party payers for three intravenous biologic agents for the treatment of rheumatoid arthritis17. Infliximab is infused over a period of 2 hours, for both rheumatoid arthritis and ulcerative colitis. Wong et al. estimated infliximab administration costs to be $257 per infusion17. Therefore, the infliximab administration costs at 8, 52, and 54 weeks were $771, $2056, and $2056, respectively.

The total costs of therapy for infliximab are equal to the sum of the infliximab medication costs and the infusion costs at 8, 52, and 54 weeks. Therefore, the total costs of therapy for infliximab at 8, 52, and 54 weeks are $10,059, $26,832, and $26,832, respectively. For adalimumab, since it is self-administered as a subcutaneous injection, there are no administrative costs. Therefore, the total costs of therapy for adalimumab are equal to the medication costs.

Sensitivity analysis

A sensitivity analysis was conducted for the infusion costs of infliximab that were lower and higher than those used in the base case analysis. For the lower limit of infusion costs, we used the 2012 Medicare Physician Fee Schedule (National Unadjusted Rate) infusion rates, calculated as $169.16 ($138.53 for the first hour of an infusion (current procedural terminology code [CPT] 96413) plus an additional $30.63 for the second hour of the infusion [CPT code 96415])18. Therefore, the infliximab infusion costs at 8, 52, and 54 weeks were $507, $1353, and $1353, respectively.

For the upper limit of infusion costs, the infusion costs were based on a study by Ollendorf and Lidsky (2006)19. This study analyzed the medication and administrative costs among commercially-insured patients receiving infliximab for Crohn’s disease19. Infliximab is infused over a period of 2 hours, for both Crohn’s disease and ulcerative colitis. Ollendorf and Lidsky (2006)19 found that the mean reimbursed amount for infliximab infusion costs to be $2793 per infusion. Therefore, the infliximab infusion costs at 8, 52, and 54 weeks were $8379, $22,344, and $22,344, respectively.

Number needed to treat cost analysis

In addition to a cost per remission analysis, we conducted a number needed to treat (NNT) cost analysis. NNT indicates the number of patients that need to be treated for one more treatment success to occur with values varying from 1 to ∞. Lower NNT values indicate that the treatment is more effective in achieving a specific endpoint.

NNT may be used to compare to mortality or other clinical outcomes in treatment and control groups. The advantage of NNT analyses is that they are (1) easily understood, (2) straightforward to calculate, and unlike other measures such as relative risk, (3) less sensitive to event rates in the control group.

In this study NNT was calculated for clinical remission for adalimumab and infliximab compared to their respective control arms of the clinical trials for 8, 52 and 54 weeks of treatment. In addition, the NNT for sustained clinical remission was calculated for adalimumab and infliximab. If the proportion of treatment successes in the treatment group is denoted by p_a, and that in the control by p_b, NNT is calculated as: NNT = 1/(p_a − p_b).

In order to calculate the NNT costs for clinical remission, the NNT value at weeks 8, 52, and 54 for adalimumab and infliximab was multiplied by the total cost of therapy at weeks 8, 52, and 54. In order to calculate the NNT costs for sustained clinical remission, the NNT value for sustained clinical remission for adalimumab and infliximab was multiplied by the total cost of therapy at week 52 for adalimumab and at week 54 for infliximab.

Results

Table 3 shows the results of the base-case analyses for cost per clinical remission at weeks 8, 52, and 54 for the bio-naïve as well as all patients. Cost per clinical remission for bio-naïve patients for infliximab and adalimumab was $42,086 vs. $79,558 at week 8, $147,379 vs. $320,097 at week 52, and $147,379 vs. $330,767 at week 54 (Table 3). The cost per clinical remission for all patients for infliximab and adalimumab was $42,086 vs.$113,812 at week 8, $147,379 vs. $349,197 at week 52, and $147,379 vs. $360,836 at week 54 (Table 3). Table 3 shows the results of the analysis for the cost per sustained clinical remission for the bio-naïve as well as all patients. Cost per sustained clinical remission for bio-naïve patients for infliximab and adalimumab was $203,205 vs. $682,873, while cost per sustained clinical remission for all patients for infliximab and adalimumab was $203,205 vs. $698,393 (Table 3).

Table 3. Base case model results for cost per clinical remission and cost per sustained clinical remission analyses.

	8 weeks		52 weeks		54 weeks
	Adalimumab	Infliximab	Adalimumab	Infliximab	Adalimumab	Infliximab
Cost per clinical remission of bio-naïve patients	$79,558	$42,086	$320,097	$147,379	$330,767	$147,379
Cost per clinical remission of all patients	$113,812	$42,086	$349,197	$147,379	$360,836	$147,379
Cost per sustained clinical remission of bio-naïve patients					$682,873	$203,205
Cost per sustained clinical remission of all patients					$698,393	$203,205

For the cost per clinical remission analysis, the results are the same for infliximab at weeks 52 and 54 because ACT 1 patients only received drug through week 46; therefore costs do not differ and assumption was made that clinical effectiveness is the same in week 52 as in week 54. Results are the same for infliximab for bio-naïve and all patients because ACT 1 patients were only bio-naïve.

Sensitivity analysis of the lower limit of infusion costs demonstrated even lower cost per remission with infliximab. Cost per clinical remission for bio-naïve patients for infliximab and adalimumab was $40,984 vs. $79,558 at week 8; $143,518 vs. $320,097 at week 52; $143,518 vs. $330,767 at week 54 (Table 4). The cost per clinical remission for all patients for infliximab and adalimumab was $40,984 vs.$113,812 at week 8, $143,518 vs. $349,197 at week 52, and $143,518 vs. $360,836 at week 54 (Table 4). Table 4 shows the results of the analysis for the cost per sustained clinical remission for the bio-naïve as well as all patients. Cost per sustained clinical remission for bio-naïve patients for infliximab and adalimumab was $197,881 vs. $682,873, while cost per sustained clinical remission for all patients for infliximab and adalimumab was $197,881 vs. $698,393 (Table 4).

Table 4. Sensitivity analyses results.

	8 weeks		52 weeks		54 weeks
	Adalimumab	Infliximab	Adalimumab	Infliximab	Adalimumab	Infliximab
Lower limit for infusion costs18
Cost per clinical remission of bio-naïve patients	$79,558	$40,984	$320,097	$143,518	$330,767	$143,518
Cost per clinical remission of all patients	$113,812	$40,984	$349,197	$143,518	$360,836	$143,518
Cost per sustained clinical remission of  bio-naïve patients					$682,873	$197,881
Cost per sustained clinical remission of all patients					$698,393	$197,881
Upper limit for infusion costs19
Cost per clinical remission of bio-naïve patients	$79,558	$73,919	$320,097	$258,852	$330,767	$258,852
Cost per clinical remission of all patients	$113,812	$73,919	$349,197	$258,852	$360,836	$258,852
Cost per sustained clinical remission of  bio-naïve patients					$682,873	$356,902
Cost per sustained clinical remission of all patients					$698,393	$356,902

For the cost per clinical remission analysis, the results are the same for infliximab at weeks 52 and 54 because ACT 1 patients only received drug through week 46; therefore costs do not differ and assumption was made that clinical effectiveness is the same in week 52 as in week 54. Results are the same for infliximab for bio-naïve and all patients because ACT 1 patients were only bio-naïve.

Sensitivity analysis of the upper limit of infusion costs demonstrated lower cost per remission with infliximab. Cost per clinical remission for bio-naïve patients for infliximab and adalimumab was $73,919 vs. $79,558 at week 8; $258,852 vs. $320,097 at week 52; $258,852 vs. $330,767 at week 54 (Table 4). The cost per clinical remission for all patients for infliximab and adalimumab was $73,919 vs.$113,812 at week 8, $258,852 vs. $349,197 at week 52, and $258,852 vs. $360,836 at week 54 (Table 4). Table 4 shows the results of the analysis for the cost per sustained clinical remission for the bio-naïve as well as all patients. Cost per sustained clinical remission for bio-naïve patients for infliximab and adalimumab was $356,902 vs. $682,873, while cost per sustained clinical remission for all patients for infliximab and adalimumab was $356,902 vs. $698,393 (Table 4).

The NNT cost analysis revealed that infliximab has a lower NNT and NNT costs than adalimumab for clinical remission and sustained clinical remission (Table 5). The NNT and NNT costs for clinical remission for bio-naïve patients were lower for infliximab (4 vs.10, $40,235 vs. $81,945 at week 8; 5 vs.10, $134,115 vs. $307,293 at week 52; 5 vs. 10, $134,115 vs. $317,536 at week 54) than for adalimumab. The NNT and NNT costs for clinical remission for all patients were lower for infliximab (4 vs.14, $40,235 vs. $114,723 at week 8; 5 vs.11, $134,115 vs. $338,022 at week 52; 5 vs. 11, $134,115 vs. $349,290 at week 54) than for adalimumab. The NNT and NNT costs for sustained clinical remission for bio-naïve patients were lower for infliximab (8 vs.22, $214,584 vs. $676,045) than for adalimumab. The NNT and NNT costs for sustained clinical remission for all patients were lower for infliximab (8 vs. 23, $214,584 vs. $706,774) than for adalimumab.

Table 5. Number needed to treat (NNT) cost analysis.

	8 weeks				52 weeks				54 weeks
	NNT adalimumab	NNT costs of adalimumab	NNT infliximab	NNT costs of infliximab	NNT adalimumab	NNT costs of adalimumab	NNT infliximab	NNT costs of infliximab	NNT adalimumab	NNT costs of adalimumab	NNT infliximab	NNT costs of infliximab
Clinical remission for bio-naïve patients	10	$81,945	4	$40,235	10	$307,293	5	134,115	10	$317,536	5	134,115
Clinical remission for all patients	14	$114,723	4	$40,235	11	$338,022	5	134,115	11	$349,290	5	134,115
Sustained clinical remission for bio-naive patients									22	$676,045	8	$214,584
Sustained clinical remission for all patients									23	$706,774	8	$214,584

For clinical remission, the results are the same for infliximab at weeks 52 and 54 because ACT 1 patients only received drug through week 46; therefore costs do not differ and the assumption was made that clinical effectiveness is the same in week 52 as in week 54. Results are the same for infliximab for bio-naïve and all patients because ACT 1 patients were only bio-naïve.

Discussion

This study sought to model the cost per remission of infliximab and adalimumab in the treatment of moderate-to-severe ulcerative colitis. The results demonstrated that infliximab has a lower cost per remission than adalimumab for clinical remission and sustained clinical remission for bio-naïve as well as all patients. In addition, sensitivity analysis upheld the original study results. As costs of the two drugs were similar, the difference in cost per remission likely reflects the efficacy rates of infliximab reported in the clinical trials.

This study is a useful addition to the literature on the treatment of ulcerative colitis due to limited data on the cost per remission of anti-TNF therapies in this disease. While prior research has found that infliximab is cost effective for the treatment of ulcerative colitis in relation to standard therapy20, there are currently no published studies comparing the cost per remission of infliximab to adalimumab. Anti-TNF therapies provide an important treatment option for patients. Since the cost of these treatments is high, it is important that the cost per remission of the two treatments is considered in conjunction with clinical efficacy when making treatment choices for patients. This is the first study to examine the cost per remission of biologic therapies for ulcerative colitis.

However, this study has limitations that must be noted. First, this is a simulation model utilizing data from separate clinical trials, rather than a head-to-head trial. No head-to-head trial has been conducted comparing these two therapies. The two trials were selected for inclusion in this analysis because of their similarity in terms of patient population, methodology, and clinical endpoint definitions. Another limitation of this study revolves around the time points analyzed. Since the long-term outcomes were measured at slightly different time points between the two trials (week 52 and week 54), week 52 clinical outcomes for infliximab were assumed to be the same as those actually observed for infliximab at 54 weeks in the ACT 1 trial10. Similar assumptions were made for adalimumab; week 52 clinical remission for ADA was used for the week 54 model. However, since these two time points are similar, these assumptions are unlikely to have meaningful effects on the results. It is unclear whether the results would be consistent over a longer time horizon. Another limitation of the study is that for infliximab, clinical remission was the secondary clinical endpoint in the ACT 1 study10 while clinical remission was the primary clinical endpoint for adalimumab in the ULTRA 2 study11. However, as discussed earlier, given that the same definition of clinical remission was used in both clinical trials10,11, these studies provide comparable parameters to support a cost per remission analysis.

For the base case analysis, Wong et al. (2011)17 analyzed the costs of infliximab administered to rheumatoid arthritis patients in physician offices. Since infliximab is infused over a period of 2 hours, for both rheumatoid arthritis and ulcerative colitis, we felt it was appropriate to use infusion cost data from rheumatoid arthritis patients for our study. However, since infliximab may be infused in other settings such as in the hospital outpatient department, the administrative costs associated with infliximab may differ from one setting to another. Therefore, we included in the sensitivity analysis an upper limit evaluation of the infusion costs using data from Ollendorf and Lidksy19. This study determined infliximab infusion costs from a commercially-infused population of individuals with Crohn’s disease19. Infliximab is infused over 2 hours for Crohn’s disease as well.

Furthermore, the analysis only includes treatment costs associated with anti-TNF utilization. Other direct medical costs such as costs of hospitalization, costs of adverse events, emergency room visits, physician office visits, and other drug treatment are not included. Nor are indirect costs such as time lost from work due to receiving the infliximab infusion included in this study. Lastly, this study assumed that no dose adjustments occurred for infliximab or adalimumab. We assumed that each medication was administered according to the US FDA recommended dosing and frequency. Studies including the effect of infliximab and adalimumab on these costs would add further understanding to the cost per remission of the use of anti-TNF treatment for ulcerative colitis. Additionally, in order to have the analyses as comparable as possible, data from bio-naïve patients as well as bio-experienced patients were included in these analyses.

Conclusion

In summary, these analyses reveal that infliximab has a lower cost per remission and cost per sustained remission than adalimumab for the treatment of patients with moderate-to-severe ulcerative colitis based on standard costs and results from clinical trials of the two drugs. The study design may not be applicable to all patient populations. Therefore, further studies incorporating real-world data are needed to more fully understand the value of anti-TNF therapies in this patient group.

Transparency

Declaration of funding

This study was sponsored by Janssen Scientific Affairs, Inc.

Declaration of financial/other relationships

J.H.L. is an employee of Janssen Scientific Affairs, Inc. Her role included the study concept, study methodology, data analyses, manuscript preparation, manuscript writing, and manuscript finalization.

P.J.M. is an employee of Statistical Solutions which is a paid consultant to Janssen Scientific Affairs, LLC. J.A.R. is a paid consultant to Statistical Solutions which is a paid for consultancy by Janssen Scientific Affairs, LLC.

Acknowledgments

We would like to thank Rolli Greer and Dr. Divyesh Khetia for their review of the manuscript. Mr. Greer is an employee of Janssen Biotech, Inc. Dr. Khetia is an employee of Janssen Scientific Affairs, LLC.