Payer-Addressable Burden of Crohn’s Disease in Members Treated with Biologics in the United States: Actuarial Analysis Findings from RAINBOW

Payer-addressable burden (PAB) reflects how real-world disease-associated costs impact the per member per month (PMPM) budget of a health plan, and can help to delineate drivers of PMPM costs and inform cost-management strategies for diseases with a high cost burden, such as Crohn’s disease (CD). We aimed to evaluate the U.S. PAB of CD managed with biologics. Weighted mean costs per member with CD in the commercial health plan population between 2017 and 2019 were evaluated from a health plan actuarial perspective. In addition to the overall population of members with CD treated with adalimumab, infliximab, vedolizumab, or ustekinumab, the subpopulations of members who were naive to biologic therapies at treatment initiation and/or treatment-adherent members were also analyzed. Members treated with vedolizumab contributed the lowest PMPM costs. A similar number of members were treated with vedolizumab and ustekinumab, yet PMPM costs associated with ustekinumab were more than double those of vedolizumab. Biologic naivety and treatment adherence drove lower CD-related PMPM costs. The analyses we present here highlight that treatments and patient subgroups with lower PMPM costs are important focus areas for payers in terms of identifying strategies to manage the budget for CD in a U.S. plan population. Video Abstract Read the transcript Watch the video on Vimeo © 2022 The Author(s). Published with license by Taylor & Francis Group, LLC


INTRODUCTION
Inflammatory bowel disease (IBD), which includes Crohn's disease (CD) and ulcerative colitis (UC), was diagnosed in over 3 million adults in the United States-1% of the population-in 2015, according to Dahlhamer et al. (2016).It was estimated that about 200 per 100,000 adults had CD in 2016, following a steady increase since 2007 (Ye et al. 2020).
There are several therapies and treatment strategies for CD that aim to induce and subsequently maintain remission (Lichtenstein et al. 2018).Biologic treatments, which have greatly improved outcomes for many patients with IBD (Samaan et al. 2019), are generally reserved for patients with moderate to severe CD that has responded inadequately to conventional therapies used earlier in treatment pathways (Lichtenstein et al. 2018), although guidelines from the American Gastroenterological Association published in 2021 recommend the early introduction of a biologic, rather than delaying biologic use until specific prior therapies have failed (Feuerstein et al. 2021).Infliximab and adalimumab are tumor necrosis factor (TNF) antagonists, recommended for use in the induction and maintenance of remission in patients with moderate to severe CD (Lichtenstein et al. 2018;Feuerstein et al. 2021).Vedolizumab, an anti-integrin therapy, and ustekinumab, an anti-interleukin therapy, are also recommended for use in patients with moderate to severe CD (Lichtenstein et al. 2018;Feuerstein et al. 2021).
CD is associated with a high health care cost (Park et al. 2020;Rao et al. 2017;Ganz et al. 2016) and resource burden (Manceur et al. 2020); biologics used to treat CD may have a varying impact on overall health plan costs, depending on the Address correspondence to Jason Fehr, Pharmacy Advisory Services, Optum, 11000 Optum Circle, Eden Prairie, MN 55344.E-mail: jason.fehr@optum.com;Tao Fan, Takeda Pharmaceuticals U.S. A., Inc., Lexington, MA 02421. E-mail: tao.fan@takeda.comThis is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/ licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Ã This author was employed by Takeda Pharmaceuticals U.S.A., Inc., at the time of the study.
timing of their use in the course of disease (Pillai et al. 2020) and the treatment adherence of members with CD (Feagan et al. 2014).It is therefore pertinent for U.S. payers to understand the impact of different biologics on costs at a population level and to evaluate their real-world utilization in the management of budget for members with CD.Payer-addressable burden (PAB) is used to represent the impact of disease-associated costs of a national care plan, including both pharmacy and medical expenses, and aims to delineate key drivers of costs in the member population of a health plan to facilitate improved allocation of budgets (Schwark Pratt et al. 2019).PAB is estimated based on analysis of health care administrative claims; in this study, per member per month (PMPM) cost was used to represent PAB.Unlike other retrospective claims database analyses, PAB analyses consider the payer perspective, encompassing all real-world scenarios that have a combined effect on disease-related costs, which in turn drive PMPM costs at the population level.PAB analyses also differ from financial or economic modeling of PMPM costs because they use a single source of data to analyze both the health care resource utilization and costs that plan members generate in the real world, with different access and clinical choice dynamics.
The purpose of the RAINBOW (acronym drawn from actuaRiAl analysIs of payer burdeN of Biologic treated crOhn patients in real World) study was to elucidate the impact of costs incurred by members with CD who were treated with biologics on the U.S. payer cost burden of a health plan, in three successive years.

Study Design
This study was an actuarial retrospective claims analysis of disease-related direct costs based on payer-allowed resource utilizations over 2017, 2018, and 2019.

Member Identification
These analyses used data from medical and pharmacy claims of adult members (over 18 years of age) with commercial health plan coverage from Optum's proprietary deidentified Normative Health Information database.Administrative claims data for members with pharmacy and medical coverage were used to determine medical and pharmacy utilization and associated cost patterns for CD treatment.The overall study population included members with CD who had at least one claim for a biologic received in a year.Biologics included in the analysis were vedolizumab intravenous (IV), ustekinumab subcutaneous (SC; after an initial IV loading dose), infliximab IV, and adalimumab SC.
Biologic prescriptions were identified using CD diagnosis codes listed in the International Statistical Classification of Diseases and Related Health Problems, 10th Revision (ICD-10).Members with diagnosis codes for both CD and UC were included only if they had more claims for CD than for UC.Both biologic-experienced and biologic-naive members were included in the overall population.Biologic-naive members were defined as those who had not received any other biologic treatment within the current year and no biologic treatments in the 12-month period before the initial treatment date in the current year.

Data Analyses
The analyses, evaluating CD-specific annual allowed direct claims costs per member and PMPM costs, were conducted over three successive 12-month periods, from January 2017 through December 2019.Weighted mean annual allowed direct claims costs described the sum of all medical and pharmacy costs.Costs captured were the total paid by the health plan and the total paid by members for medical or pharmacy claims.The following were included in medical allowed costs: inpatient, outpatient, physician, and other costs; pharmacy costs included the cost of health care professional (HCP)-administered drugs and self-administered drugs.For HCP-administered drugs (i.e., infliximab and vedolizumab), administration costs were included within outpatient and physician costs.PMPM costs were calculated by dividing total annual costs of members with CD by the plan's entire population months of coverage (i.e., the number of individuals participating in the insurance plan each month) for that year.The analyses were performed from a health plan actuarial perspective.
Analyses were performed on the overall CD population and on subpopulations of treatment-adherent and/or biologic-naive members, to delineate the drivers of PMPM.Treatment-adherent members were defined as members with at least 80% of days covered by prescription for the respective biologic (including self-administered and HCP-administered drugs) within the coverage year.Demographics are also presented stratified by age group.

RESULTS
In total, 9180, 10,269, and 11,259 adult members with CD treated with one of four biologics-vedolizumab, ustekinumab, infliximab, or adalimumab-for 2017, 2018, and 2019, respectively, were included in the analyses.Table 1 displays the demographics for the population analyzed.The majority of members were aged 18-44 years.Overall, more members had previously received a biologic therapy at initiation of biologic treatment than had not (Table 1).
Between 2017 and 2019, there was an increase in the number of members treated with all biologics.The proportion of members treated with vedolizumab increased from 10.66% to 13.54% of total analyzed members.Similarly, during the same time period, the proportion of members treated with ustekinumab increased from 7.14% to 15.77%.The proportion of members treated with infliximab or adalimumab decreased over the same period.
The proportion of members who were classed as biologic naive and were treated with vedolizumab remained relatively stable between 2017 and 2019 (35.75%, 35.92%, and 34.58% in 2017, 2018, and 2019, respectively), while the proportion of members treated with ustekinumab, infliximab, or adalimumab who were biologic naive decreased by about 13%, 3%, and 7%, respectively, from 2017 to 2019.
Table 2 presents the treatment adherence of members with CD.The proportion of treatment-adherent members was greater than 60% for all of the four biologics across all years and was higher in the biologic-naive population than in the overall population.In the overall population, from 2017 to 2019, the proportion of treatment-adherent members increased for all the biologics analyzed; the greatest increase in adherence was observed for those treated with vedolizumab.Furthermore, a greater proportion of members treated with vedolizumab were treatment adherent than those treated with ustekinumab and adalimumab in all years.Adherence to infliximab was similar to that for vedolizumab.
The proportion of biologic-naive members who were treatment adherent slightly increased between 2017 and 2019 for vedolizumab (76.57% and 79.88%), infliximab (77.75% and 78.02%), and adalimumab (69.65% and 73.38%) but decreased for ustekinumab (72.12% and 68.00%).The proportion of adherent members within each age group was similar, although adherence was lower for those treated with infliximab who were aged 65-74 years than for those aged 18-64 years, and for members treated with adalimumab aged 18-44 years than for those aged 45-74 years, over all years analyzed.
Pharmacy costs were the main driver of total CD-related costs in all populations evaluated, primarily comprising prescription drug costs for members treated with ustekinumab or adalimumab and HCP-administered drug costs for members treated with vedolizumab or infliximab (Tables 3 and 4).Pharmacy costs per treated member were lower for those treated with vedolizumab and infliximab than for those using ustekinumab and adalimumab in the overall population (Table 3), with the highest pharmacy costs observed for ustekinumab.The same trend was observed for members who were treatment adherent and/or biologic naive (Tables 3 and 4).Overall, lower mean biologic drug costs were observed in the biologic-naive member population than in the overall population (Table 3).Among biologic-naive members who were treatment adherent, of the four biologics, mean total CD-related costs were lowest for those treated with vedolizumab in 2017, and for those treated with infliximab in 2018 and 2019 (Table 4).
Overall, the CD-related impact on PMPM costs, that is, the PAB, was lowest for vedolizumab out of the four biologics analyzed between 2017 and 2019 (Table 3).Similar mean numbers of members were treated with ustekinumab and vedolizumab (1215 and 1243 for ustekinumab and vedolizumab, respectively); however, PMPM costs for members treated with ustekinumab were more than double those of members managed with vedolizumab ($0.86 and $0.41 for ustekinumab and vedolizumab, respectively).This trend was similar between adalimumab and infliximab, whereby a comparable mean number of CD members were treated with adalimumab and infliximab overall, but the impact on PMPM cost for adalimumab was approximately one-third greater than for infliximab ($1.45 and $1.12 for adalimumab and infliximab, respectively).In the overall population, PMPM costs increased from 2017 to 2019 for all treatments, with the greatest increase observed for ustekinumab (Table 3).In  The portion of submitted charges covered under plan benefits.This is the amount after discounts and excluded expenses, and before employee and member responsibility (e.g., benefits limitations, co-pay amounts).Costs presented are before rebates.

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S. GHOSH ET AL.  f Costs not classified above as inpatient, outpatient, physician, or pharmacy (e.g., durable medical equipment and transportation). g The portion of submitted charges covered under plan benefits.This is the amount after discounts and excluded expenses, and before employee and member responsibility (e.g., benefits limitations, co-pay amounts).Costs presented are before rebates.
2019, there were about half the number of treated with ustekinumab than with infliximab; however, PMPM costs for ustekinumab were higher (Table 3).Adherent members (Table 4) had lower PMPM costs than the overall population (Table 3).A greater number of members were adherent to vedolizumab treatment than to ustekinumab in 2017-2019.Notably, members adherent to vedolizumab treatment had lower PMPM costs than ustekinumab-adherent members in 2018 and 2019, with the same PMPM costs observed for the two treatments in 2017 (Table 4).Similarly, overall, there were more treatment-adherent members receiving infliximab than adalimumab; however, PMPM costs were lower for the infliximab population (Table 4).
We observed about threefold lower PMPM costs for biologic-naive members compared with the overall population, with these costs appearing to be more stable for the biologic-naive than for the overall population between 2017 and 2019 (Table 3).These costs were further reduced by adherence to treatment (Table 4).In the subpopulation of biologic-naive, treatment-adherent members, PMPM costs were lower for vedolizumab than ustekinumab, despite a greater number of members being treated with vedolizumab (Table 4).

DISCUSSION
The impact of CD on PMPM costs, that is, the PAB, is important for payers in that it provides insights into areas for potential cost-saving assessments that may inform more effective strategies targeting biologic utilizations in the real world.The current actuarial analysis presented the combined effect of pharmacy and medical costs at the PMPM level, with an opportunity to delineate the scenarios of biologic naivety and treatment adherence that potentially have a positive impact on PMPM costs.
In our analyses, treatment costs contributed most to overall costs for members with CD, and were highest for ustekinumab; however, the PMPM reflects the combined impact of both medical and treatment costs.In a population of members with CD treated with one of four different biologics, those with relatively lower treatment costs, that is, those treated with HCP-administered vedolizumab or infliximab, had savings that potentially offset the incurred medical costs, resulting in a positive impact on PMPM costs.Given the high costs for members treated with ustekinumab, the PMPM cost is likely to increase if more members are treated with ustekinumab than with the other biologics evaluated in these analyses.Potentially, the impact on PMPM costs would be lower if more members were treated with vedolizumab than with adalimumab, ustekinumab, or infliximab.Consistent with our analyses, an analysis evaluating claims for IBD between 2007 and 2016 (Park et al. 2020), and a study using the Medical Expenditure Panel Survey (Ganz et al. 2016), demonstrated that costs for patients with IBD are driven largely by medication costs.Similar findings were also demonstrated in a retrospective claims study conducted from 1999 to 2017: A high proportion of health care costs was attributable to medication costs for patients with CD who were treated with biologics (Manceur et al. 2020).
Biologic-naive status and treatment adherence drove lower CD-related costs.In our study, a greater proportion of all members treated with vedolizumab were treatment adherent compared with those treated with ustekinumab or adalimumab, while proportions were lower than for infliximab in 2017 and 2018, and higher than for infliximab in 2019.The same trend was observed for those who were biologic naive.Our analyses included members treated with IV vedolizumab and infliximab, and SC adalimumab and ustekinumab.The greater adherence observed in our study for vedolizumab and infliximab may therefore be as a result of the need for physician visits for administration of the medication.Adherence to vedolizumab and infliximab likely had the most positive impact on PMPM costs.Adherence to a biologic potentially resulted in a greater medical benefit, thereby offsetting the higher pharmacy costs incurred.
In our analyses, lower PMPM costs were associated with treatment-adherent and biologic-naive members compared with the overall CD member population, suggesting that approaches to cost management should be focused in these areas.In a U.S. retrospective observational study, vedolizumab treatment was associated with better treatment persistence, lower rates of increased dosing frequency, and lower rates of a composite health care resource utilization endpoint than infliximab in patients with CD who were biologic naive (Patel et al. 2019), in support of our observations on overall treatment adherence and costs for vedolizumab compared with infliximab.In addition, a retrospective analysis of real-world claims data observed that patients who received an intervention to improve adherence to the anti-TNF agent certolizumab pegol had significantly fewer all-cause hospitalizations and lower total health care costs than those without (Wolf et al. 2018).A 2018 U.S. budget impact model evaluated the effect of including vedolizumab as a first-line biologic treatment option (i.e., along with the existing preferred first-line biologics infliximab and adalimumab) for patients with UC or CD in a hypothetical formulary, demonstrating large potential overall and PMPM cost savings over 3 years in comparison with its utilization as a second-line biologic (Wilson et al. 2018), which may align with our observation of lower PMPM costs in biologic-naive members.
The current actuarial analysis, unlike budget impact model analyses, includes a real-world assessment of biologic utilization, with an opportunity to assess the dynamics of formulary access and clinical choices that impact PMPM costs.These PAYER-ADDRESSABLE BURDEN OF CROHN'S DISEASE analyses therefore facilitate better understanding of different drivers of PMPM costs at the health plan level when members with CD are treated with biologics than with other types of real-world claims analyses.With varying formulary access, some biologics are used preferably to others early in the management of CD.Furthermore, a biologic that results in greater treatment adherence is likely to have a positive impact on medical costs, despite an incrementally higher pharmacy cost.
There are some limitations of this study.Our analyses did not include longitudinal follow-up of members for cost difference or adjustment of confounders.Additionally, these analyses represent costs before rebates, which may vary by health plan or pharmacy benefit manager and may affect formulary positioning.These analyses should therefore be considered from the perspective of a U.S. payer, regardless of plan-negotiated pharmacy rebates.Furthermore, our ability to measure treatment adherence was limited to the proportion of days covered as evaluated by prescriptions, and thus did not take into account the extent to which patients were actually taking the medication as prescribed.Finally, the definition of biologic-naive members differed from the clinical definition, in that members classed as biologic naive within our analyses may have previously received a biologic, but not within a certain time frame; however, data were limited to those available within the study period, so we cannot determine the full treatment history of members included within the analyses.

CONCLUSIONS
These analyses provide U.S. payers with a cross-sectional view of the financial burden at the health plan level when its members with CD are treated with biologics, and capture the real-world burden encompassing all forms of clinical practice and resource utilization for members with CD enrolled in a commercial national plan.
's disease; HCP, health care professional; PMPM, per member per month; Rx, prescription.The sum of inpatient, outpatient, physician, pharmacy, and other costs may not fully align with total allowed amount owing to rounding.a Costs associated with an inpatient facility, excluding HCP-administered drugs, durable medical equipment, transportation, and physician services; includes home health and hospice care.b Costs associated with an outpatient facility, excluding HCP-administered drugs, durable medical equipment, transportation, and physician services.c Costs associated with physician service both in and out of a facility setting.d Costs associated with HCP-administered drugs and prescription drugs.e Pharmacy costs associated with prescription drugs.

TABLE 1
Demographics of Overall and Biologic-Naive Members Note: NS, not enough sample; SD, standard deviation.a Low member count.

TABLE 2 Clinical
Characteristics of Overall and Biologic-Naive Members Note: NS, not enough sample; SD, standard deviation.a Low member count.

TABLE 3 CD
-Related Costs in Overall and Members Between 2017 and 2019Weighted mean costs per treated member per year (proportion of total allowed amount, %) Note:CD, Crohn's disease; HCP, health care professional; PMPM, per member per month; Rx, prescription.The sum of inpatient, outpatient, physician, pharmacy, and other costs may not fully align with total allowed amount owing to rounding.aCosts associated with an inpatient facility, excluding HCP-administered drugs, durable medical equipment, transportation, and physician services; includes home health and hospice care.bCosts associated with an outpatient facility, excluding HCP-administered drugs, durable medical equipment, transportation, and physician services.cCosts associated with physician service both in and out of a facility setting.dPharmacy costs associated with HCP-administered drugs.ePharmacy costs associated with prescription drugs.fCosts not classified above as inpatient, outpatient, physician, or pharmacy (e.g., durable medical equipment and transportation).g

TABLE 4 CD
-Related Costs in Overall and Biologic-Naive, Members Between 2017 and 2019 Weighted mean costs per treated member per year (proportion of total allowed amount, %)