Abstract
Background and Aims
Biologic therapy is indicated for patients with moderate to severe inflammatory bowel disease (IBD) and delays in access to these medications have been associated with higher health-care utilization. We examined whether patients who experienced insurance denials of biologics had worse outcomes, as indicated by disease activity and the number of emergency department (ED) visits and hospitalizations had following medication denial.
Methods
Our single-center retrospective cohort study included 169 patients with IBD who were seen at a tertiary care center (University of Maryland Medical Center) and had an insurance denial for biologic therapy between March 2021 and October 2021. Data were collected through chart review.
Results
At 6 months following denial, 58.0% of patients were in remission, 37.9% had active disease, and 4.1% had unknown status. Those who did not receive medication approval were significantly more likely to have active disease (Odds ratio = 0.16, 95% confidence interval = [0.04‒0.69] P = .042). Compared to patients in remission after delay in therapy initiation, those with active disease were likelier to receive steroids in the year following denial (38.5%, P < .001), trended toward higher likelihood of ED visits (P = .062), and had higher likelihood of hospitalization in that time (27.7% vs 8.2%, P = .002), with a higher number of average ED visits (P = .019) and hospitalizations (P = .003). Patients with active disease post denial had a nearly 80% increase in days between denial and final approval (P = .031).
Conclusion
Our study demonstrates an association between insurance denial of biologic therapy and lack of clinical remission with associated increased health-care utilization in IBD patients.
Keywords: Health-Care Utilization, Insurance Approval Policies, Inflammatory Bowel Disease, Outcomes of Medication Delays
Introduction
Biologics and small molecules are steroid-sparing therapies indicated for treatment of moderate to severe inflammatory bowel disease (IBD). In moderate to severe IBD, these medications have been found to induce and maintain remission, prevent disease progression, and avoid surgeries and hospitalizations.1, 2, 3, 4 Early intervention has been found to be especially beneficial for those with Crohn’s disease (CD), particularly in those with complicated disease.5 However, despite these proven benefits, and the decrease in health-care costs associated with biologic therapy,6, 7, 8, 9 access to biologics and small molecules due to insurance denial remains a barrier. Insurance companies often cite clinical guidelines when denying these medications; however, some formal guidelines have not been updated in years or companies will cite guidelines that are out-of-date with the new standards of care.10 In 2017, 98% of health insurance policies were found to be inconsistent with the American Gastroenterology Association guidelines on biologic use in ulcerative colitis (UC) and 90% of them were inconsistent with American Gastroenterology Association CD guidelines.11 Fail-first approaches were found to be especially responsible. Furthermore, companies similarly deny other interventions, such as therapeutic drug monitoring, that may help minimize need for therapy changes.11 Insurance denials of highly effective therapy initiation and continuation can lead to increased risk of adverse health outcomes in this population.12,13 In addition, delays in care for these patients are associated with higher health-care utilization with hospitalizations and emergency department (ED) visits, and higher overall costs as disease progression related costs outweigh initial savings from therapy denial.10,14,15 In this study, we sought to examine whether patients who experienced insurance denials of biologic therapies had worse health outcomes, as indicated by the patient’s disease activity and the number of steroid prescriptions, ED visits, and hospitalizations a patient had after having a delay in treatment. This included patients who were denied medication coverage but ultimately had it approved, as well as people who never received approval. We hypothesized that patients who experienced delays in insurance approval, would have an increase in adverse outcomes including steroid prescriptions, ED visits, and hospitalizations and that they would less likely be in clinical remission within 1 year following the denial of biologic treatment.
Materials & Methods
Patient Selection
This study was a single-center, retrospective analysis of 169 patients with IBD who were seen at the University of Maryland Medical Center and had an insurance denial for biologic therapy between March 2021 and October 2021.
Demographic and Clinical Data
Data collected through chart review of the electronic medical record (EMR), Epic, included demographics (age, sex, ethnicity, marital status, employment, zip code, insurance type), substance use (alcohol and tobacco), IBD phenotype, year of diagnosis, number of IBD-related surgeries, and number of biologic therapies the patient had been exposed to before therapy denial. The number of ED visits and hospitalizations within 1 year before and after insurance denial were also collected. The therapies denied in this cohort included Remicade (infliximab), Stelara (ustekinumab), Humira (adalimumab), Xeljanz (tofacitinib), and Entyvio (vedolizumab). Reasons for medication denial were primarily due to dose escalation, step therapy, site of care, or some combination thereof (Table A1). However, a large majority of denials were due to medication dosage with a low number of instances of alternative reasons for denial, thus we could not substratify based on reason for denial. No patients in this cohort had therapy denials at diagnosis. Information was obtained on the number of days it took for the medication to be approved postdenial (if at all), the number of IBD clinic visits the patient had within 1 year after medication denial, as well as the patient’s clinical status (active disease vs remission) between 6 months and 12 months after medication denial. Active disease was defined as any patient who had clinically active (uncontrolled symptoms), endoscopically active (inflammation seen on colonoscopy/sigmoidoscopy), or both clinically and endoscopically active disease, as documented by the gastroenterologist attending in the EMR. Patients with an “unknown” disease status were those without clear documentation of disease activity by a gastroenterologist 6–12 months following insurance denial of therapy. All patients without documented active disease were deemed in remission. Patients in this cohort who did not ultimately receive medication approval were followed for up to 12 months from the initial date of medication denial; however, additional data (eg alternative therapies used, ultimate medical management) were not collected.
Statistical Analysis
Two group differences for various factors were compared using Fisher’s exact test and Welch’s t-test for categorical and quantitative variables, respectively. Multiple logistic regression analysis was used to assess the relationships between several demographic and clinical factors, and the likelihood of patient’s being in remission after medication denial. Models were generated using generalized linear models with binomial distribution. Mixed generalized linear model with penalized quasi-likelihood (with participant ID as random error) were used to account for models predicting remission and controlling for race, as well as predicting remission in those who received approval, to account for smaller sample sizes. All tests were performed using the R “stats,” “MASS,” and “RVAideMemoire” packages, version 4.0.4.
Results
Demographic Characteristics and Clinical Outcomes
Our cohort included 169 individuals with IBD who were initially denied insurance coverage of either a new biologic therapy or an increased dose of their current therapy (Table 1). Patients were an average of 42.1 years old (interquartile range [IQR]: 31–50), with an average disease duration of 16.1 years (IQR: 7–22), and likelier to be female (53.3%), unmarried (50.9%), and employed (69.2%). Patients were predominantly White (76.9%) or Black (17.2%), with few patients falling into other race categories (6.5%). The majority of patients were current alcohol consumers (53.2%), with a significant minority never using (37.9%) or being former users (8.9%). In contrast, the majority of patients were never users of tobacco (65.7%) vs current (6.5%) or former (27.8%) users. The average income across all patients was $122,935 (IQR: $91,206–$149,453), and most patients had commercial insurance (85.2%), with fewer utilizing Medicaid (11.8%) or Medicare (3.0%). Patients were more likely to have CD (82.2%) vs UC (16.0%) or indeterminate colitis (1.8%), and most patients had previous biologic exposure (76.9%) with the remainder of patients having been on other non-biologic therapies before medication denial. The average number of previous biologic exposures was 1.7 (IQR: 1–3), and the average number of IBD-related surgeries was 1.2 (IQR: 1–3). In the year before denial, 18.9% of patients had an ED visit and 22.5% had a hospitalization, with an average of 0.35 (IQR: 0–0) and 0.36 (IQR: 0–0) ED visits or hospitalizations, respectively. Similarly, in the year following denial 18.3% and 16.0% had an ED visit or hospitalization, respectively, with an average of 0.30 (IQR: 0–0) ED visits and 0.22 (IQR: 0–0) hospitalizations. Patients had an average of 2.3 (IQR: 1–3) clinic visits in the year following denial, and 19.5% were prescribed a steroid in that time. It took an average of 34.7 days (IQR: 12–36.5, range: 0242) to receive medication approval for those who eventually were able to do so (73.4% of patients ultimately received approval). No differences were found across these factors between those who did and did not receive approval for their medication.
Table 1.
Cohort Demographic, Clinical, and Outcome-Related Information
| Factor | Cohort (n = 169) | Ultimately received approval (n = 124) | No approval received (n = 45) | P value |
|---|---|---|---|---|
| Age (mean, IQR, range) | 42.1 (31,50) (18,79) | 42.1 (31,51) (18,79) | 42.2 (34,48) (22,74) | .982 |
| Sex (female) | 90 (53.3%) | 62 (50.0%) | 28 (62.2%) | .168 |
| Race | ||||
| White | 130 (76.9%) | 100 (80.6%) | 30 (66.7%) | .161 |
| Black | 28 (17.2%) | 17 (13.7%) | 11 (24.4%) | |
| Other | 11 (6.5%) | 7 (5.6%) | 4 (8.9%) | |
| IBD Type | ||||
| CD | 139 (82.2%) | 104 (83.9%) | 35 (77.8%) | .368 |
| UC | 27 (16.0%) | 17 (13.7%) | 10 (22.2%) | |
| IC | 3 (1.8%) | 3 (2.4%) | 0 (0%) | |
| Average income based on zip code | $122,935 ($91,206, $149,453) ($46,185, $286,304) | $126,171 ($97,619, $154,207) ($46,185, $286,304) | $113,892 ($86,329, $127,072) ($54,242, $286,304) | .167 |
| Marital status | ||||
| Married | 83 (49.1%) | 62 (50%) | 21 (46.7%) | .731 |
| Unmarried | 86 (50.9%) | 62 (50%) | 24 (53.3%) | |
| Employed | 117 (69.2%) | 83 (66.9%) | 34 (75.6%) | .348 |
| Alcohol use | ||||
| Current | 90 (53.2%) | 69 (55.6%) | 21 (46.7%) | .357 |
| Never | 64 (37.9%) | 46 (37.1%) | 18 (40.0%) | |
| Former | 15 (8.9%) | 9 (7.3%) | 6 (13.3%) | |
| Tobacco use | ||||
| Current | 11 (6.5%) | 9 (7.3%) | 2 (4.4%) | .880 |
| Never | 111 (65.7%) | 80 (64.5%) | 31 (68.9%) | |
| Former | 47 (27.8%) | 35 (28.2%) | 12 (26.7%) | |
| Disease duration (y, mean, IQR, range) | 16.1 (7,22) (0,48) | 16.6 (7,23) (0,48) | 14.8 (7,21) (0,48) | .291 |
| Had a biologic exposure previously | 130 (76.9%) | 95 (76.6%) | 35 (77.8%) | ≥.999 |
| Number of prior biologic exposures | 1.7 (1,3) (0,6) | 1.7 (1,3) (0,6) | 1.7 (1,3) (0,4) | .998 |
| Had an ED visit in year before denial | 32 (18.9%) | 22 (17.7%) | 10 (22.2%) | .512 |
| Had a hospitalization in year before denial | 38 (22.5%) | 28 (22.6%) | 10 (22.2%) | ≥.999 |
| Number of ED visits in the year before denial | 0.35 (0,0) (0,7) | 0.27 (0,0) (0,4) | 0.56 (0,0) (0,7) | .227 |
| Number of hospitalizations in the year before denial | 0.36 (0,0) (0,5) | 0.31 (0,0) (0,5) | 0.47 (0,0) (0,5) | .405 |
| Prior IBD surgeries (mean, IQR, range) | 1.2 (0,2) (0,9) | 1.2 (0,2) (0,9) | 1.2 (0,2) (0,7) | .909 |
| Insurance type | ||||
| Commercial | 144 (85.2%) | 107 (86.3%) | 37 (82.2%) | .714 |
| Medicaid | 20 (11.8%) | 14 (11.3%) | 6 (13.3%) | |
| Medicare | 5 (3.0%) | 3 (2.4%) | 2 (4.4%) | |
| Steroid prescription following denial | 33 (19.5%) | 25 (20.2%) | 8 (17.8%) | .829 |
| Had an ED visit in the year following denial | 31 (18.3%) | 22 (17.7%) | 9 (20.0%) | .823 |
| Had a hospitalization in the year following denial | 27 (16.0%) | 17 (13.7%) | 10 (22.2%) | .234 |
| Number of ED visits in the the year following denial (mean, IQR, range) | 0.30 (0,0) (0,6) | 0.32 (0,0) (0,6) | 0.24 (0,0) (0,2) | .524 |
| Number of hospitalizations in the year following denial (mean, IQR, range) | 0.22 (0,0) (0,4) | 0.22 (0,0) (0,4) | 0.22 (0,0) (0,1) | .958 |
| Number of clinic visits in the year following denial (mean, IQR, range) | 2.3 (1,3) (0,8) | 2.3 (1,3) (0,8) | 2.2 (1,3) (0,5) | .493 |
| Remission status 6 mo following medication initiation | ||||
| Remission | 98 (58.0%) | 77 (62.1%) | 21 (46.7%) | .042 |
| Active disease | 64 (37.9%) | 44 (35.4%) | 20 (44.4%) | |
| Unknown | 7 (4.1%) | 3 (2.4%) | 4 (8.9%) |
IC, indeterminate colitis.
At 6 months following the denial, 58.0% of patients who experienced a delay in medication approval were in remission, 37.9% had active disease, and 4.1% of patients had unknown status. Those who did not receive medication approval were significantly more likely to have active disease (P = .042).
Differences in Patients in Remission vs With Active Disease Following Medication Denial
To identify potential confounding variables, demographic and outcome variables among those in remission vs those with active disease at 6 months following delay in initiation of the recommended biologic therapy due to insurance denial were characterized. There was no difference in marital or employment status, insurance type, tobacco use, IBD type, or likelihood of previous biologic exposure in those in remission vs with active disease at 6 months postdenial (Table 2). Those with active disease trended toward more IBD surgeries (P = .097), older age (P = .064), longer disease duration (P = .074), and female sex (P = .078). While race appeared to trend toward significance (P = .063), this was due to the “Other” category (Fisher’s multiple comparison for “Other” relative to Black and relative to White, P = .076 for both) and not a difference between the ratio of Black to White patients in each group (Fisher’s multiple comparison P = .526). Those with active disease after medication denial were more likely to be never drinkers (47.7% vs 32.0%, P = .002) and had a lower average income based on zip code ($111,032 vs $130,446, P = .004). Those with active disease post denial also had exposure to an average of 0.8 more biologics (P < .001), had more clinic visits following the denial (P < .001), and were likelier to have an ED visit (29.2% vs 11.3%, P = .007) or hospitalization (P = .011) in the year before denial, with a higher average number of both (P = .038 and .028, respectively). Those with active disease after delayed initiation of therapy were also likelier to receive a steroid prescription in the year following denial (38.5% vs 8.2%, P < .001), trended toward higher likelihood of ED visits (P = .062), and had higher likelihood of hospitalization in that time (27.7% vs 8.2%, P = .002), with a higher number of average ED visits (P = .019) and hospitalizations (P = .003). Patients with active disease 6 months after experiencing a delay in biologic initiation had a nearly 80% increase in days between denial and final approval for those who received medication approval (P = .031).
Table 2.
Demographic, Clinical, and Outcome-Related Information in IBD Patients With and Without Active Disease 6 Months Following Initial Denial
| Factor | Active disease (n = 65) | Disease in remission (n = 97) | P value |
|---|---|---|---|
| Age (mean, IQR, range) | 44.8 (36,53) (21,74) | 40.9 (31,49) (18,79) | .064 |
| Sex (female) | 41 (63.1%) | 47 (48.5%) | .078 |
| Race | |||
| White | 51 (78.5%) | 73 (75.3%) | .063 |
| Black | 13 (20.0%) | 14 (14.4%) | |
| Other | 1 (1.5%) | 10 (10.3%) | |
| IBD Type | |||
| CD | 54 (83.1%) | 80 (82.5%) | .702 |
| UC | 11 (16.9%) | 15 (15.5%) | |
| IC | 0 (0%) | 2 (2.1%) | |
| Average income based on zip code | $111,032 ($84,070, $127,046) ($54,242, $223,135) | $130,446 ($95,581, $155,652) ($46,185, $286,304) | .004 |
| Marital status | |||
| Married | 32 (49.2%) | 46 (47.4%) | ≥.999 |
| Unmarried | 33 (50.8%) | 51 (52.6%) | |
| Employed | 45 (69.2%) | 68 (70.1%) | .802 |
| Alcohol use | |||
| Current | 24 (36.7%) | 61 (62.9%) | .002 |
| Never | 31 (47.7%) | 31 (32.0%) | |
| Former | 10 (15.4%) | 5 (5.2%) | |
| Tobacco use | |||
| Current | 2 (3.1%) | 9 (9.3%) | .226 |
| Never | 42 (64.6%) | 63 (64.9%) | |
| Former | 21 (32.3%) | 25 (25.8%) | |
| Disease duration (y, mean, IQR, range) | 18 (8,25) (0,48) | 14.8 (7,20) (1,47) | .074 |
| Had a biologic exposure previously | 52 (80%) | 73 (76.8%) | .568 |
| Number of prior biologic exposures | 2.2 (1,3) (0,6) | 1.4 (1,2) (0,5) | <.001 |
| Had an ED visit in the year before denial | 19 (29.2%) | 11 (11.3%) | .007 |
| Had a hospitalization in the year before denial | 21 (32.3%) | 14 (14.4%) | .011 |
| Number of ED visits in the year before denial | 0.57 (0,1) (0,7) | 0.21 (0,0) (0,6) | .038 |
| Number of hospitalizations in the year before denial | 0.54 (0,1) (0,5) | 0.22 (0,0) (0,5) | .028 |
| Prior IBD surgeries (mean, IQR, range) | 1.4 (0,2) (0,7) | 1.0 (0,1) (0,9) | .097 |
| Insurance type | |||
| Commercial | 52 (80.0%) | 85 (87.6%) | .371 |
| Medicaid | 10 (15.4%) | 10 (10.3%) | |
| Medicare | 3 (4.6%) | 2 (2.1%) | |
| Days to approval (for those approved) | 48.6 (15.8,52.8) (0,242) | 27.1 (10.8,32) (1152) | .031 |
| Steroid prescription following denial | 25 (38.5%) | 8 (8.2%) | <.001 |
| Had an ED visit in the year following denial | 17 (26.2%) | 13 (13.4%) | .062 |
| Had a hospitalization in the year following denial | 18 (27.7%) | 8 (8.2%) | .002 |
| Number of ED visits in the year following denial (mean, IQR, range) | 0.51 (0,1) (0,6) | 0.16 (0,0) (0,2) | .019 |
| Number of hospitalizations in the year following denial (mean, IQR, range) | 0.42 (0,1) (0,4) | 0.09 (0,0) (0,2) | .003 |
| Number of clinic visits in the year following denial (mean, IQR, range) | 2.9 (2,4) (0,8) | 2.0 (1,3) (0,4) | <.001 |
IC, indeterminate colitis.
Patients that Receive Medication Approval are Likelier to Achieve Remission
A multivariate logistic regression was performed to assess medication approval as a predictor of remission status 6 months following the denial, while controlling for potentially confounding factors such as sex, age, alcohol use, disease duration, average income (based on zip code), and accounting for both number of prior biologic exposures and the interaction between number of biologic exposures and approval status (Table 3). Not receiving medication approval was found to be a predictor of active disease (OR = 0.16, 95% confidence interval [CI] = [0.04–0.69]), as was number of prior biologic exposures (Odds ratio = 0.57 for each additional biologic, 95% CI = [0.41–0.78]). The interaction between number of biologic exposures and approval was significant (2.29, 95% CI = [1.21–4.43]), indicating that those with more biologic exposures who received approval were more likely to achieve remission than those with more biologic exposures who did not receive approval.
Table 3.
Logistic Multiple Regression Assessing Predictors of Clinical Disease Remission
| Factor | OR | 95% confidence interval | P value |
|---|---|---|---|
| Not approved (relative to approved) | 0.16 | [0.04–0.69] | .014 |
| Number of prior biologic exposures | 0.57 | [0.41–0.78] | .001 |
| Male sex (relative to female) | 1.28 | [0.60–2.72] | .521 |
| Age | 0.99 | [0.96–1.02] | .423 |
| Alcohol use (none relative to current) | 0.37 | [0.16–0.80] | .012 |
| Alcohol use (prior relative to current) | 0.22 | [0.06–0.78] | .022 |
| Disease duration | 0.98 | [0.94–1.02] | .263 |
| Average income | 1.00 | [1.00–1.00] | .010 |
| Interaction between number of biologic exposures and approval (relative to no approval received) | 2.29 | [1.21–4.43] | .011 |
OR, Odds ratio.
An expanded version of this model was generated to include race (Table A2) and found no differences in these findings; race was not found to be a predictor of remission status when accounting for all other factors. However, this model was not used due to the inability to obtain an accurate confidence interval for the “Other” category. A separate multivariate logistic regression was performed to assess if the number of days from denial to approval was a predictor of remission status among the population of patients who eventually received approval (Table A3). Likely due to the lower sample size (n = 98), factors other than number of prior biologic exposures were not found to be significant predictors.
Discussion
Our study examined the impact of insurance denials of biologic therapy on the clinical outcomes of a cohort of IBD patients from a single institution in the state of Maryland. We found that patients who did not receive approval of biologic therapy after insurance denial were more likely to have active disease compared to patients whose medication was ultimately approved. Additionally, while we did not find a significant difference between the number of patient ED visits or hospitalizations in the year before medication denial and within 1 year after denial for our cohort, patients with active disease at least 6 months after medication denial, which led to either a delay in therapy initiation or lack of initiation of the biologic altogether, were found to have significantly more steroid prescriptions and a higher average number of ED visits and hospitalizations compared to patients in remission. We also found that for patients with active disease postdenial whose biologic therapy was ultimately approved, they had a nearly 80% increase in the number of days from medication denial to approval, compared to patients in remission.
In a study performed by Constant et al., looking at the association between prior authorization of biologic treatment, initiation time, and IBD-related health-care outcomes in pediatric patients, they found that prior authorizations were associated with delays in biologic treatment initiation and a 12.9% increased risk of IBD-related health-care utilization (hospitalizations, surgeries, and ED visits within 180 days of biologic recommendation).16 Our findings are similar to those of Constant et al., in that while we did not see a significant increase in hospitalizations and ED visits from the year before and within 1 year after biologic denial for our cohort as a whole, we did see that IBD patients with active disease 6 months after experiencing a delay in biologic therapy initiation due to insurance denial had a higher number of ED visits and a higher likelihood of hospitalization 1 year after denial. We also saw a significant increase in steroid prescriptions and more clinic visits after denial for patients with active disease compared to patients in remission. Given that these patients with active disease had longer delays in starting treatment compared to patients in remission, these findings support the notion that patients with IBD who experience a delay in initiation or continuation of biologic therapy due to insurance denials, are more likely to have poor disease control, worse health-care outcomes, and more complications.
We also found that patients with active disease 6 months after medication denial were, on average, exposed to a greater number of prior biologics, likely indicating that these patients had more severe disease at the time of medication denial compared to patients in remission postdenial. Thus, while there were overall more patients found to be in remission 6 months after denial, those with active disease trended toward having more severe outcomes, suggesting that patients with harder to control disease at baseline, were more negatively impacted by a delay in starting the appropriate treatment.
Physicians treating IBD have had to navigate a system in which insurance companies require prior authorizations for medical therapies, even when treatment decisions are accordant with evidence-based recommendations.14 These delays in care due to time-consuming processes of attaining medication approval and the subsequent risk of deleterious clinical outcomes for patients, raise the question of whether the current step therapy models of medication approval are appropriate, necessary, and causing negative outcomes for patients. Step therapy is the requirement of patients to try and fail one or more lower-cost medication, before the original prescribed medication can be approved.17 However, multiple studies have shown that in subsets of high-risk patients with IBD, the use of high-cost medications earlier in a patient’s disease course was more effective at inducing and maintaining remission for these patients, compared to patients who followed a step therapy approach.5,18, 19, 20, 21, 22 Thus, even though step therapy has long been the standard of care and can be a cost-saving approach for payers, updated treatment pathways and therapeutic advances now indicate a need for payers to recognize that changes need to be made to current policies to prevent patient suffering, disease progression, and ultimately increased health-care costs. Our study supports the notion that policies for UC and CD need to be updated to fall in line with current evidence-based treatment guidelines, as continuing to base approval of medications on outdated standard policies is now leading to poor patient outcomes and overall increased direct and indirect health care costs.11
Our findings demonstrate that the lack of approval of biologic therapy initiation or continuation for patients with IBD decreased the likelihood of patients achieving remission and directly correlated with an increase in poor outcomes for these patients and health-care utilization. We also uniquely found that patients with active disease were more likely to have a lower average income based on zip code, highlighting the impact of socioeconomic status on patient outcomes and potentially on medication approval. Social determinants of health have been shown to impact outcomes in patients with IBD, with lower socioeconomic status being associated with worse outcomes.23,24
This was a retrospective single-center study with a limited sample size and a cohort consisting of primarily Caucasians. As with all retrospective studies, this study is limited by misclassification bias and other unmeasured confounders. Larger prospective studies with more diverse populations are needed. Given our sample size, we were unable to characterize patients by IBD phenotype or by therapies, which should be considered in larger cohort studies. Additionally, determination of a patient’s disease status post medication denial was based on documentation of clinical symptoms or review of endoscopic data by their gastroenterologist in the EMR. Further studies using a validated scale to assess clinical remission would also help limit misclassification bias. For patients who received ultimate therapy approval, data regarding the date of first administration of the medication after approval was unavailable and would be important to include in future studies to more specifically evaluate patient outcomes based on time from denial date to actual medication administration. Given the nature of our cohort, it was also difficult to include a control group in this study, which would be beneficial in comparing outcomes for patients who receive initial approval of therapy compared to patients whose medication is initially denied. We were also unable to compare outcomes of patients with primary denials vs secondary denials because the vast majority of insurance denials in this cohort were primary (ie the first denial for a given biologic therapy or dose escalation). Lastly, our study did not include information regarding length of illness before medical evaluation, before the change in therapy type or dosage, as well as the length of time to medication prescription and time to denial after the medication was prescribed. These factors would be valuable information to include in future studies.
However, our study has several important strengths. The cohort in this study was receiving care at a tertiary referral center, many with comorbidities and more complicated and difficult-to-treat disease. Examining this cohort of patients allowed us to observe the impact of the insurance delays on the sickest IBD patients who are most vulnerable to delay in treatment. Although our cohort was predominantly White, we had a higher rate of diversity, particularly in Black participants, than is traditionally found in IBD studies. Finally, this cohort of patients was served by a dedicated team of pharmacy specialists, social workers, nurses, and IBD-trained physicians, thus optimizing care and allowing for thorough documentation of the outcomes we studied. Despite these resources targeted at the best possible outcomes, the number of days from denial to approval, if approval was obtained at all, remains unacceptably high.
Conclusion
Our results demonstrate an association between insurance denial of biologic therapy and lack of clinical remission associated with increased health-care utilization in patients with IBD. This research highlights the need for future multicenter prospective studies to further validate these findings and provide more insight into the potential clinical harm of continuing to adhere to current policies regarding insurance approval and prior authorization processes for biologic therapy, without adjusting to updated IBD treatment guidelines. Additionally, further study into the fiscal impact of current policies for patients, insurance companies, and health-care systems, should be done to address an additional, and highly weighed, factor in determining the need for policy change.
Acknowledgments
Authors’ Contributions
Erin Zisman: Study design and conception, writing – original draft, data collection. Madeline Alizadeh: Study design and conception, data collection, revision, statistical analysis. Uni Wong: Study design and conception, data collection, revision. Leah Rossmann: Data collection. Jennifer Grossman: Data collection. Cydney Nguyen: Data collection. Pinkle Paul: Data collection.
Footnotes
Conflicts of Interest: The authors disclose no conflicts.
Funding: This work was supported by grants from the National Institutes of Diabetes and Digestive and Kidney Diseases, of the National Institutes of Health [grant number T32DK067872] to M.A.
Ethical Statement: This cohort study was approved by the University of Maryland, Baltimore’s Institutional Review Board with a waiver of patient consent given the use of only electronic medical record data.
Data Transparency Statement: The data underlying this article will be shared on reasonable request to the corresponding author. This study was presented at the Digestive Disease Week, Chicago, Illinois, 2023.
Reporting Guidelines: STROBE.
Material associated with this article can be found in the online version at https://doi.org/10.1016/j.gastha.2025.100647.
Supplementary Materials
References
- 1.Hyams J., Crandall W., Kugathasan S., et al. REACH Study Group Induction and maintenance infliximab therapy for the treatment of moderate-to-severe Crohn's disease in children. Gastroenterology. 2007;132(3):863–873. doi: 10.1053/j.gastro.2006.12.003. quiz 1165-6. [DOI] [PubMed] [Google Scholar]
- 2.Sandborn W.J., Feagan B.G., Rutgeerts P., et al. GEMINI 2 Study Group Vedolizumab as induction and maintenance therapy for Crohn's disease. N Engl J Med. 2013;369(8):711–721. doi: 10.1056/NEJMoa1215739. [DOI] [PubMed] [Google Scholar]
- 3.Feagan B.G., Sandborn W.J., Gasink C., et al. UNITI–IM-UNITI Study Group Ustekinumab as induction and maintenance therapy for Crohn's disease. N Engl J Med. 2016;375(20):1946–1960. doi: 10.1056/NEJMoa1602773. [DOI] [PubMed] [Google Scholar]
- 4.Costa J., Magro F., Caldeira D., et al. Infliximab reduces hospitalizations and surgery interventions in patients with inflammatory bowel disease: a systematic review and meta-analysis. Inflamm Bowel Dis. 2013;19(10):2098–2110. doi: 10.1097/MIB.0b013e31829936c2. [DOI] [PubMed] [Google Scholar]
- 5.Berg D.R., Colombel J.F., Ungaro R. The role of early biologic therapy in inflammatory bowel disease. Inflamm Bowel Dis. 2019;25(12):1896–1905. doi: 10.1093/ibd/izz059. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Dretzke J., Edlin R., Round J., et al. A systematic review and economic evaluation of the use of tumour necrosis factor-alpha (TNF-α) inhibitors, adalimumab, and infliximab, for Crohn's disease. Health Technol Assess. 2011;15(6):1–244. doi: 10.3310/hta15060. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Wilson M.R., Azzabi Zouraq I., Chevrou-Severac H., et al. Cost-effectiveness of vedolizumab compared with conventional therapy for ulcerative colitis patients in the UK. Clinicoecon Outcomes Res. 2017;9:641–652. doi: 10.2147/CEOR.S135609. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Burisch J., Vardi H., Schwartz D., et al. Epi-IBD Group Health-care costs of inflammatory bowel disease in a pan-European, community-based, inception cohort during 5 years of follow-up: a population-based study. Lancet Gastroenterol Hepatol. 2020;5(5):454–464. doi: 10.1016/S2468-1253(20)30012-1. [DOI] [PubMed] [Google Scholar]
- 9.Beilman C.L., Kirwin E., Ma C., et al. Early initiation of tumor necrosis factor antagonist-based therapy for patients with Crohn's disease reduces costs compared with late initiation. Clin Gastroenterol Hepatol. 2019;17(8):1515–1524.e4. doi: 10.1016/j.cgh.2018.07.032. [DOI] [PubMed] [Google Scholar]
- 10.Spencer E.A., Abbasi S., Kayal M. Barriers to optimizing inflammatory bowel disease care in the United States. Therap Adv Gastroenterol. 2023;16 doi: 10.1177/17562848231169652. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Yadav A., Foromera J., Feuerstein I., et al. Variations in health insurance policies regarding biologic therapy use in inflammatory bowel disease. Inflamm Bowel Dis. 2017;23(6):853–857. doi: 10.1097/MIB.0000000000001153. [DOI] [PubMed] [Google Scholar]
- 12.Schoepfer A.M., Dehlavi M.A., Fournier N., et al. IBD Cohort Study Group Diagnostic delay in Crohn's disease is associated with a complicated disease course and increased operation rate. Am J Gastroenterol. 2013;108(11):1744–1753. doi: 10.1038/ajg.2013.248. quiz 1754. [DOI] [PubMed] [Google Scholar]
- 13.González-Lama Y., Suárez C., González-Partida I., et al. Timing of thiopurine or anti-TNF initiation is associated with the risk of major abdominal surgery in Crohn's disease: a retrospective cohort study. J Crohns Colitis. 2016;10(1):55–60. doi: 10.1093/ecco-jcc/jjv187. [DOI] [PubMed] [Google Scholar]
- 14.Bhat S., Zahorian T., Robert R., et al. Advocating for patients with inflammatory bowel disease: how to navigate the prior authorization process. Inflamm Bowel Dis. 2019;25(10):1621–1628. doi: 10.1093/ibd/izz013. [DOI] [PubMed] [Google Scholar]
- 15.Rumman A., Candia R., Sam J.J., et al. Public versus private drug insurance and outcomes of patients requiring biologic therapies for inflammatory bowel disease. Can J Gastroenterol Hepatol. 2017;2017 doi: 10.1155/2017/7365937. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Constant B.D., de Zoeten E.F., Stahl M.G., et al. Delays related to prior authorization in inflammatory bowel disease. Pediatrics. 2022;149(3) doi: 10.1542/peds.2021-052501. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Crohn’s and Colitis Foundation Step therapy: how does step therapy work? https://www.crohnscolitisfoundation.org/sites/default/files/2020- 06/infographic2%20%281%29.pdf
- 18.American Gastroenterological Association Ulcerative colitis clinical care pathway. https://www.gastro.org/guidelines/ibd-and-bowel-disorders
- 19.American Gastroenterological Association Crohn's disease clinical care pathway. https://www.gastro.org/guidelines/ibd-and-bowel-disorders
- 20.Schreiber S., Reinisch W., Colombel J.F., et al. Subgroup analysis of the placebo-controlled CHARM trial: increased remission rates through 3 years for adalimumab-treated patients with early Crohn's disease. J Crohns Colitis. 2013;7:213–221. doi: 10.1016/j.crohns.2012.05.015. [DOI] [PubMed] [Google Scholar]
- 21.D'Haens G., Baert F., van Assche G., et al. Belgian Inflammatory Bowel Disease Research Group. North-Holland Gut Club Early combined immunosuppression or conventional management in patients with newly diagnosed Crohn's disease: an open randomised trial. Lancet. 2008;371:660–667. doi: 10.1016/S0140-6736(08)60304-9. [DOI] [PubMed] [Google Scholar]
- 22.Lichtenstein G.R., Loftus E.V., Isaacs K.L., et al. ACG clinical guideline: management of Crohn's disease in adults. Am J Gastroenterol. 2018;113:481–517. doi: 10.1038/ajg.2018.27. [DOI] [PubMed] [Google Scholar]
- 23.Bernstein C.N., Walld R., Marrie R.A. Social determinants of outcomes in inflammatory bowel disease. Am J Gastroenterol. 2020;115(12):2036–2046. doi: 10.14309/ajg.0000000000000794. [DOI] [PubMed] [Google Scholar]
- 24.Sewell J.L., Velayos F.S. Systematic review: the role of race and socioeconomic factors on IBD healthcare delivery and effectiveness. Inflamm Bowel Dis. 2013;19(3):627–643. doi: 10.1002/ibd.22986. [DOI] [PMC free article] [PubMed] [Google Scholar]
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