Liisa Palmer, PhD

: Disease relapse with antitumor necrosis factor-α (TNFα) agents is common; up to 40% of patients initially responding to anti-TNF therapy will lose response in the first treatment year, which has important implications regarding clinical, cost, and resource utilization. We evaluated rates of dose escalation in patients with Crohn’s disease who were newly prescribed adalimumab, certolizumab pegol, or infliximab, using data from 2 databases.

: US patient data were obtained from OptumInsight’s Clinformatics Data Mart and Truven Health Analytics’ MarketScan Research databases. 

: Eligible patients were 18 years or older, diagnosed with Crohn’s disease, naïve to therapy with an anti-TNF 6 months pre-index, and received a new prescription for an anti-TNF agent (adalimumab, certolizumab pegol, or infliximab) after April 2008 (OptumInsight) or January 2008 (Truven). 

: Similar results were obtained from both data sets. From the OptumInsight analyses, 56 (9%; P = .0686 vs certolizumab pegol), 13 (5%), and 156 (28%; P <.0001 vs certolizumab pegol) patients who initiated treatment on adalimumab, certolizumab pegol, or infliximab, respectively, had an increase from their initial maintenance dose as a first treatment change over 12 months. 

: Fewer patients prescribed certolizumab pegol for the treatment of Crohn’s disease had a dose increase as a first treatment change within 12 months compared with adalimumab or infliximab. Further studies are needed to explore pharmacokinetics and prescribing habits with anti-TNFs, such as choice for first anti-TNF, change of dose, third-party payer and on-label prescribing, and the impact of these changes from clinical and economic perspectives. 

Disease relapse occurs in up to 40% of patients with Crohn’s disease who initially respond to anti-tumor necrosis factor-α (TNFα) agents, which has important clinical, cost, and resource utilization implications. This study describes data from 2 health claims databases.

Rates of anti-TNFα dose escalation differ in patients with Crohn’s disease who were newly prescribed adalimumab, certolizumab pegol, or infliximab. 

We note the proportion of patients who received the labeled loading dose, and the occurrence of inadequate loading doses. 

Comparisons show that certolizumab pegol therapy in patients with Crohn’s disease is associated with lower rates of dose escalation relative to infliximab or adalimumab.

Crohn’s disease is a chronic, progressive, and disabling disease that requires long-term management. It affects approximately 244 per 100,000 people in the United States

 and may be characterized by progressive structural damage and/or by episodes of acute inflammation of the gut alternating with periods of remission.

Patients with Crohn’s disease consume substantial healthcare resources. From 2003 to 2004, the mean number of annual excess healthcare utilization (control visits minus Crohn’s disease case visits) per 100 patients was estimated to be 21.7, 20.1, and 493 for hospitalizations, emergency department visits, and office visits, respectively.

 In the United States, the mean total costs for patients with Crohn’s disease are estimated at $10,952 per year, compared with $2898 for matched controls (ie, individuals with no inflammatory bowel disease, matched for age, sex, health plan, and geographic region). The mean annual Crohn’s disease associated treatment costs were $8265 per patient-year, with pharmaceutical claims accounting for the largest proportion of direct costs (35%).

Due to the high cost of Crohn’s disease, treatment goals with therapy are to modify the course of the disease and prevent long-term complications. Tumor necrosis factor-α (TNFα), a pro-inflammatory cytokine, is expressed in high levels in the blood, intestinal mucosa, colonic tissue, and feces of patients with Crohn’s disease, and may play an integral role in the pathogenesis of Crohn’s disease.

 As such, anti-TNFα therapies are widely used in the management of moderate to severe Crohn’s disease that is refractory to such conventional treatments as corticosteroids and oral immunosuppressants.

There are 3 anti-TNFα agents—adalimumab, certolizumab pegol, and infliximab&mdash;currently approved by the FDA in the United States for use in patients with moderate to severe Crohn’s disease, for whom conventional therapy has not achieved a satisfactory clinical response. However, disease relapse with all anti-TNFα agents is common: up to 40% of patients who initially respond to anti-TNFα therapy may lose response in the first year of treatment.

 In patients who lose response to firstline therapy with the anti-TNFα agents, the dose and/or dosing frequency are often increased to recapture response

; alternatively, clinicians may choose to switch treatments or add concomitant medications rather than increase doses or frequency. Previous analyses of health claims databases have shown that anti-TNFα dose escalation occurs in approximately 24%, 2%, and 28% of patients with Crohn’s disease receiving adalimumab, certolizumab pegol, and infliximab, respectively.

 (Note that the statistics for loss of response to treatment and for dose escalation were 2 different measurements; physicians may or may not decide that dose escalation is the proper course of action when a patient loses response.)

The FDA-approved loading dose for adalimumab is 160 mg administered by subcutaneous injection (given as 40 mg injections 4 times in 1 day, or 40 mg injections twice a day for 2 consecutive days), with a second 80 mg dose 2 weeks later. Following clinical response, 2 weeks after the 80 mg dose, adalimumab is administered at a maintenance dose of 40 mg every other week.

 Certolizumab pegol is also administered by subcutaneous injection, an initial dose of 400 mg every 2 weeks for 3 doses (at weeks 0, 2, and 4). If a clinical response occurs, certolizumab pegol is then given at a maintenance dose of 400 mg subcutaneously every 4 weeks.

 (Dose increase is not FDA-approved for either certolizumab pegol or adalimumab.) Infliximab is administered by intravenous infusion at a dose of 5 mg/kg at 0, 2, and 6 weeks, followed by a maintenance regimen of 5 mg/kg every 8 weeks.

 Some adult patients who initially respond to infliximab treatment may benefit from increasing the dose to 10 mg/kg if they later lose their response.

For the present study, we evaluated rates of anti-TNFα dose escalation in patients with Crohn’s disease who were newly prescribed adalimumab, certolizumab pegol, or infliximab, as well as the proportion of patients who received the labeled loading dose, using data from 2 health claims databases.

Anonymous patient data from the United States were obtained from 2 sources:

OptumInsight’s Clinformatics Data Mart.

 This is a single-payer health claims database from a large national health insurer that covers approximately 32 million lives. Patients who were 18 years or older with a diagnosis of Crohn’s disease (

International Classification of Diseases, Ninth Revision, Clinical Modification

 code 555.xx), were naïve to therapy with an anti-TNFα in the 6-month pre-index period, received a prescription for an anti-TNFα (ie, adalimumab, certolizumab pegol, or infliximab) after April 2008, and had continuous enrollment in the database and pharmacy data available for 12 months after the index date, were eligible. The qualifying time period for initiating the drug of interest was January 2009 to May 2011. Eligible patients also had no diagnosis of ulcerative colitis, psoriasis, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, celiac disease, irritable bowel syndrome, or Clostridium difficile infection during the 6 months prior to the index date, and had both medical and prescription coverage. OptumInsight data were used in the analysis of dose escalation and to determine the proportion of patients who received an appropriate loading dose of each anti-TNFα.

Truven Health Analytics MarketScan Research Databases.

 A retrospective claims analysis was conducted in 2011 by Truven Health Analytics Inc using the Truven Health MarketScan Research Databases, an administrative claims database that is fully compliant with the Health Insurance Portability and Accountability Act, and includes more than 150 contributing employers and 21 health plans throughout the United States. The database includes approximately 37 million covered lives per year, and health insurance claims across the continuum of care (eg, inpatient and outpatient, and mail order and outpatient pharmacy). Adult patients (aged ≥18 years) were eligible if they had a diagnosis of Crohn’s disease and were naïve to therapy with both an anti-TNFα in the 6-month pre-index period and received a new prescription for an anti-TNFα agent (ie, adalimumab, certolizumab pegol, or infliximab) after January 2008. The qualifying time period for initiating the drug of interest was January 2008 to October 2011. For inclusion, patients must have had at least 1 prescription on or after day 29 for adalimumab or day 56 for certolizumab pegol, while infliximab patients must have had at least 2 infusions. Infliximab-treated patients with doses that did not fall between 180 mg and 1360 mg, or who did not have a valid payment field (ie, it was missing or negative) at infusion 1, infusion 2, and all subsequent infusions, were excluded.

Both databases were used in the analysis of dose escalation and to determine the proportion of patients who received an appropriate loading dose of each anti-TNFα.

 OptumInsight defined the proper loading dose for adalimumab and certolizumab pegol as ≥240 mg and ≥1200 mg, respectively, within the first 35 days. Infliximab was administered by 3 or more intravenous infusions within the first 60 days (and no previous infliximab during the previous 12 months). For the Truven Health databases, the loading dose for adalimumab and certolizumab pegol (assessed on prescription drug claims) was based on the presence of the appropriate amount of product during the induction phase; for infliximab, the loading dose was based on the initial dose, and was deemed as a “proper” loading dose if it was within the dosing parameters.

 OptumInsight analyzed US patient claims and reported the number of patients with a dose increase above the approved and initially prescribed maintenance dose of adalimumab, certolizumab pegol, or infliximab as a first treatment change at any point during the 12-month analysis period. Dose escalation was defined as the following: adalimumab, an increase above an average of 40 mg every 2 weeks; certolizumab pegol, an increase above an average of 400 mg every 4 weeks; and infliximab, any increase in the number of vials per week above that initially dispensed during the maintenance phase of dosing. The time to dose escalation was the average number of days until dose increase for all eligible patients.

Truven Health analyzed dose escalation for adalimumab, certolizumab pegol, or infliximab during 12 months of follow-up. Dose escalation was defined as the following: adalimumab, ≥160 mg every 4 weeks; certolizumab pegol, ≥800 mg every 4 weeks; infliximab, any infusion greater than the first infusion or 6 weeks or less between 2 infusions beginning with infusion number 4.

For OptumInsight data, the mean time on therapy of dose-escalated patients was based on their actual claim-level activity. For the Truven analysis, univariate analyses were performed (χ

The patient demographics from both databases are shown in the 

. In the OptumInsight database, 1463 patients met the criteria for inclusion and had 12 months of available data. Of these eligible patients, 44% (n = 650) were newly initiated to adalimumab, 18% (n = 257) to certolizumab pegol, and 38% (n = 556) to infliximab.

In the Truven Health databases, 1023 patients were eligible for inclusion: 379 (37%) were newly initiated to adalimumab, 361 (35%) to certolizumab pegol, and 283 (28%) to infliximab.

The proportion of patients who received a loading dose of each anti-TNFα agent (range = 47%-85%) is shown in 

. Similar results were seen in both databases. The proportion of adalimumab patients receiving a loading dose was 80% (OptumInsight) and 86% (Truven Health) (

 <.0001 vs certolizumab pegol). This number decreased in the certolizumab groups to 62% and 74%, respectively. For infliximab, only approximately 50% of patients received a loading dose (

From the OptumInsight database analyses, 9% (n = 59), 5% (n = 13), and 28% (n = 156) of patients who initiated treatment on adalimumab, certolizumab pegol, or infliximab, respectively, had an increase from their initial maintenance dose as a first treatment change over 12 months (

 [A]). Similar results were obtained from dose escalation analyses on the Truven Health databases (Figure 2 [A]); 16% (n = 58; 

 = .0055 vs certolizumab pegol), 9% (n = 29), and 28% (n = 70; 

 <.0001 vs certolizumab pegol) of patients receiving adalimumab, certolizumab pegol, or infliximab, respectively, dose-escalated over 12 months. Significantly more patients receiving infliximab had a dose increase compared with certolizumab pegol (

 <.0001 in both databases). It is worth noting that some patients who lose response will undergo treatment switching or other adjustments rather than dose escalation.

The mean length of time to dose escalation, as a first treatment change over 12 months in the OptumInsight and Truven Health databases, was 163 and 132 days (

 = .02 vs certolizumab pegol), respectively, for adalimumab, 197 and 190 days for certolizumab pegol, and 178 and 179 days (

 = .58 vs certolizumab pegol) for infliximab (Figure 2 [B]).

When comparing rates of dose escalation between anti-TNFα agents from 2 data sources, fewer patients prescribed certolizumab pegol for the treatment of Crohn’s disease had a detectable dose increase as a first treatment change within the 12-month period, compared with adalimumab or with infliximab (

 <.0001). Most patients in the adalimumab and certolizumab pegol groups received the labeled loading dose, while only half of patients in the infliximab group received the appropriate loading dose of therapy.

Dose escalation, in terms of actual administered dose or an increase in dosing frequency, can be in response to a disease flare or attenuation and loss of response to therapy. In the present study, dose escalation ranged from 5% to 28%, depending on the data and analysis type and medication administered. These claims data consistently showed a lower rate of dose escalation for certolizumab pegol patients at 5% and 8%, inclusive of varying escalation definitions.

Additionally, rates of dose escalation may be impacted by a lack of flexibility in dosing recommendations or denial of insurance coverage; however, physician-determined need for maximizing therapeutic response prior to treatment changes is an accepted treatment paradigm among most gastroenterologists, and previous studies of patients with Crohn’s disease receiving biologic therapy have found that dose escalation is common. As this issue has significant clinical and cost implications,

 prospective studies are needed to further investigate the extent of the impact of this issue.

In this study, the mean length of time to dose escalation among patients prescribed adalimumab, certolizumab pegol, or infliximab over 12 months was also different between anti-TNFαs. Overall, there were differences in duration of therapy before dose escalation. The mean length of time to dose escalation as a first treatment change over 12 months for patients receiving adalimumab, certolizumab pegol, and infliximab, ranged from 129 to 163, 190 to 197, and 178 to 180 days, respectively. These results may suggest that patients receiving infliximab and certolizumab pegol had a longer duration of efficacy before dose escalation was required, although it is also possible that the aforementioned unavailability of flexible dosing or denial of coverage from the insurance carrier may have influenced this outcome.

An additional aspect to consider as a potential factor in both rate and time to dose escalation in patients with Crohn’s disease is the proper medication utilization. All 3 agents approved for treating patients with Crohn’s disease include use of a loading dose prior to maintenance therapy. In a retrospective claims study of certolizumab pegol, patients receiving initiation of therapy with a loading dose showed increased persistence versus those who did not.

Loading dose is also associated with improved rates of clinical remission in controlled clinical trials.

 Thus, presence or absence of a loading dose in patients with Crohn’s disease potentially impacts overall maintenance of disease. In this study, the use of the labeled loading dose was variable. It is postulated that inappropriate dosing strategies and issues with patient compliance to medication can contribute to the development of suboptimal drug levels and to a subsequent loss of response to anti-TNFα therapy.

 Our results provide further evidence of these findings in the literature, most prominently in the infliximab group.

Only 50% of patients received a loading dose in the infliximab group and this group also demonstrated the highest rates of dose escalation. These observations support the hypothesis that adherence to the prescribed dosing regimen may improve clinical outcomes for patients over the long term. Additional research is needed to confirm the benefit of induction and prescriber usage patterns of loading doses in the real-world clinical setting.

There are a number of limitations to this analysis. As this was a retrospective study, it was not possible to consider patient diaries or assess returned drugs. We were also unable to assess the proportion of patients who received 200 mg certolizumab pegol every 2 weeks, which is a type of pharmacokinetic dose increase. A further limitation was the difficulty in directly comparing the incidence of dose escalation between the different anti-TNFα agents, as well as the absence of drug level data to further understand pharmacokinetic changes and differences. The metric and threshold for detecting a dose increase differed between treatments (ie, milligrams vs vials), and different definitions for dose escalation were necessary for each treatment.

Moreover, dose increase is not approved for adalimumab or certolizumab pegol, and this may impact the number of patients having an increase from their maintenance dose over 12 months. There is also the possibility of an overlap between the OptumInsight and Truven Health MarketScan Research databases, since Truven includes some claims that fall within the OptumInsight database. However, this potential overlap of a small number of patient claims is not anticipated to affect the overall results. Another limitation to this study is that, as a claims data analysis, the incorrect use of treatment doses may be an artifact of the data source; additional studies with alternative data sources (eg, chart audit data) need to be conducted to validate the current findings.

Articles

This study evaluated the rates of dose escalation in patients with Crohn's disease.

Web Exclusive: Real-World Anti-TNF Dose Escalation in Patients With Crohn's Disease

Multiple sclerosis (MS), a chronic, disabling autoimmune disease of the central nervous system, affects approximately 400,000 people—mostly young adults from 20 to 40 years old in the United States.

 Currently the predominant treatment for MS is disease-modifying therapies (DMTs), which slow down disease progression and reduce relapses. Since 1993, 7 DMTs have been approved by the US Food and Drug Administration (FDA) to treat relapsing forms of MS. The 2008 Expert Opinion Paper issued by the National Multiple Sclerosis Society recommends treatment with a DMT once a definite diagnosis of MS is reached. Experts agree that except for certain circumstances (such as lack of benefits, serious side effects, or better treatment options), treatment should continue indefi nitely to avoid increased risk for recurrent disease activity; however, 43% of patients with relapsing-remitting MS (RRMS) are not receiving DMTs.

Suboptimal treatment adherence is common and associated with a higher risk of relapse, emergency department (ED) visits, hospitalizations, and medical costs.

 found that only 59.6% of the study patients had a medication possession ratio (MPR) of 80% or greater for DMTs. In another study examining treatment adherence, average MPR for patients on interferon-beta therapy varied from 72% to 76%, with fewer than 41% of patients with an MPR of 85% or greater.

Although many factors such as patient medical history, disease stage, physician and patient preference, and access to treatment can infl uence the likelihood of receiving DMTs and achieving treatment adherence, the role of patient out-of-pocket (OOP) costs on medication adherence has garnered interest in recent years. Against the national backdrop of rising healthcare costs, patients are facing increased financial burden for medications because of higher copayments, multitier drug formularies, and the adoption of pharmacy coinsurance. Unlike other chronic maintenance medications, which may have cheaper generic substitutes, DMTs are included under the more expensive specialty drug category; this leaves patients with MS few alternatives. Campbell et al

 examined the annual patient OOP spending on MS medications and found that the median cost increased from $832 in 2002 to $1042 in 2005, with the top 10% of patients incurring a 20% increase from $2598 in 2002 to $3230 in 2005. An evaluation of DMT use among privately insured patients with MS estimated through simulation that increasing drug copayment by 50% would lower the probability of receiving DMTs by 32.9%.

 Recently published studies have shed more light on the impact of cost sharing on treatment abandonment rate, MPR, and persistence with DMTs, finding a negative association between high cost sharing and treatment outcome.

 In these studies, patient cost sharing was measured based on either copayment of the first prescription,

total OOP amount during 6 months preceding the evaluation period,

 or mean copayment per 30 days during the evaluation period.

 Although these approaches refl ect the actual OOP costs, they do not include evaluation of patients who chose not to receive treatment because of cost-sharing burden.

Using a method developed and employed for other conditions and therapeutic agents,

 the present study used expected patient cost sharing to characterize the patient’s financial burden with regard to DMTs. Cost sharing for DMTs was measured using a price index calculated at the healthplan level, based on DMT prescriptions filled by all members enrolled in the same plan during the same calendar year. This amount represents the costs that patients would face when deciding on DMT and compliance. This method has the advantage of placing a price tag on DMTs even if the patient declines treatment, thereby allowing analysis of how cost sharing infl uences a patient’s decision on whether to receive DMTs and subsequently adhere to the regimen.

This retrospective observational study identifi ed patients from the Truven Health Analytics MarketScan Commercial and Medicare Supplemental and Coordination of Benefits (COB) Databases. These databases contain enrollment details (eligibility, health plan type) as well as medical and pharmacy claims with fi nancial information (provider reimbursement, member copayment, coinsurance, and deductible). Patient data used in this analysis were deidentified in compliance with the Health Insurance Portability and Accountability Act regulations. Institutional Review Board review and approval were not required.

Patients diagnosed with MS between January 1, 2004, and December 31, 2009, were identifi ed based on either 1 inpatient or ED MS diagnosis (

] code 340) or 2 or more outpatient MS diagnoses that were at least 30 days apart. Diagnostic claims were not considered for study inclusion. Patients were classified as treated or untreated based on evidence of nonintravenous DMTs (interferon beta-1a, interferon beta-1b, glatiramer acetate) during 2004 to 2009. For treated patients, the fill date for the first DMT was the index date. For untreated patients, the index date was randomly assigned to mimic the distribution of time between the first observed MS diagnosis and the DMTs among the treated cohort. To remain eligible for analysis, patients were required to be 18 years or older at index and have 12 months of continuous enrollment with pharmacy data availability before (preperiod) and after (postperiod) the index date. Patients with any claim for intravenous DMTs or with only medical claims for DMTs during the postperiod were excluded from analysis. Given that plan-level cost sharing is the key independent variable in this study, only patients enrolled in plans with valid (nonmissing, nonzero) cost-sharing data for DMTs were included in the analysis (

We hypothesized that patients with MS facing high cost sharing would be less likely to receive DMTs than those facing low cost sharing and that treated patients with high cost sharing would have lower medication adherence and persistence relative to those with low cost sharing. We assessed the probability of receiving DMTs, the probability of treatment adherence, and the risk of treatment discontinuation for patients in the high cost-sharing plans compared with those in the low costsharing plans. 

 was measured using MPR during the 12-month postperiod, calculated as the total number of days with DMTs on hand divided by 365 days. Treatment adherence was defi ned as an MPR 

80%, which was also used in the Tan et al

 study to examine the relationship between MPR and risk of relapse, healthcare utilization, and medical expenditures among MS patients. 

 was measured by the number of days between treatment initiation and treatment discontinuation. 

was identifi ed based on a gap in DMT treatment of 30 days or more. Patients were characterized as nonpersistent with treatment based on the first observation of treatment discontinuation.

The primary explanatory variable—patient costsharing&mdash;was characterized as the cost burden that patients would face if they received DMTs. Cost sharing was estimated for each patient based on the health plan in which they were enrolled. Plan-level cost sharing for DMTs was assessed by calendar year (2004-2009) and payer (commercial and Medicare) for all study plans in the MarketScan Commercial and Medicare Databases. Copayment and coinsurance were standardized to costs per 30-day supply in 2010 dollars. Plan-level cost sharing was determined by: (1) copayment if a plan had a nonzero copayment value, or (2) coinsurance if a plan had a $0 copayment but a nonzero coinsurance value. Study patients received their plan-level cost-sharing value based on the unique plan identifier, the calendar year of their index date, and the payer. Patients who did not receive a cost-sharing value were excluded. The median DMT copayment amount for plans associated with study patients was $29; this value was used as the threshold to classify low versus high cost-sharing plans.

Demographic variables including age, gender, US Census region, urbanicity, insurance plan type, and payer were measured at the index date. Charlson Comorbidity Index (CCI) and medical conditions known to be associated or commonly reported among patients with MS were evaluated during the preperiod as proxies for disease severity. These conditions included: vascular disease, endocrine disease, musculoskeletal disease, urogenital dysfunction, visual loss, neurologic conditions, depression, pain, sleep disorders, and fatigue. Use of systemic corticosteroids, symptomatic therapies for MS (antilymphocyte globulin, methotrexate, and intravenous immune globulin), and MS-related hospitalization and ED visits were also assessed during the preperiod. We created a variable that characterized the patient’s MS and DMT status in the preperiod. This variable classified patients as: previously treated; treatment naïve/previously diagnosed; treatment naïve/newly diagnosed; or treatment naïve/previous diagnosis status unknown. Multivariate Analysis Because study outcomes can be confounded by differences in patients’ demographic and clinical characteristics, multivariate analysis was employed to adjust for imbalances between low and high cost-sharing groups. Specifically, logistic regression was conducted to assess: (1) probability of receiving DMTs in the high cost-sharing cohort compared with the low cost-sharing cohort, and (2) probability of having treatment adherence in the postperiod among treated patients with high cost sharing compared with those with low cost sharing. A Cox proportional hazards model was employed to analyze the relationship between treatment persistence and costsharing level. Demographic and clinical variables were included in these models. Newly diagnosed status was included in the model that analyzed the probability of receiving DMTs; the composite variable that characterized preperiod MS diagnosis and DMTs status was included in treatment adherence and persistence models. The proportional hazards assumption for the model covariates was assessed graphically by plotting the log of the negative log of the estimated survival function versus time. The presence of influential patients on the parameters estimates was verifi ed by plotting the score residuals versus the covariate values.

Patient Demographic and Clinical Characteristics

A total of 110,356 patients were identifi ed as having MS, with 53% characterized as treated and 47% as untreated with DMTs. After applying the study exclusion criteria, 14,497 treated patients and 10,200 untreated patients with a valid nonzero plan-level cost-sharing amount for DMTs were included in the study (Figure 1).

Patients in the high cost-sharing cohorts were generally 3 to 4 years younger than those in the low cost-sharing cohort. The majority of study patients were commercially insured; a larger number of patients with low cost sharing than high cost sharing had indemnity plans. Patients in low cost-sharing plans were more concentrated in the North Central region than those in high cost-sharing plans. The low and high cost-sharing cohorts shared similar clinical profiles, as shown in 

Compared with treated patients, untreated patients were 6.8 years older and more likely to be Medicare enrollees. A total of 42% of treated patients had DMTs during the preperiod; 39% were newly diagnosed treatment- naïve patients. Only 6% of treated patients were previously diagnosed with MS and did not receive DMTs in the preperiod. By design, all untreated patients were treatment-naïve in the preperiod; 67% of these patients were newly diagnosed.

The majority of patients—83% and 95% of low and high cost-sharing plans, respectively&mdash;had copayment as the only cost-sharing arrangement for DMTs. Approximately 15% of the low cost-sharing cohort and 3% of the high cost-sharing cohort paid coinsurance only. Fewer than 3% of patients had both copayment and coinsurance. Seventy-nine percent of study patients enrolled in plans with monthly cost sharing <$50; 91% were in plans with cost sharing 

$100. Only 6% and 2% of patients faced cost-sharing burdens ranging from $100 to $200 and $200 to $300, respectively. And 1% of patients were in plans with cost-sharing arrangements for DMT in excess of $300.

The unadjusted probability of receiving DMTs was similar between patients with MS in the low and high cost-sharing plans (odds ratio [OR] = 1.03, 95% confi dence interval [CI] 0.98-1.08, 

= .3297). Although patients in the low and high cost-sharing plans were similar clinically, there were substantial imbalances in age, region, and health plan type. As shown in 

, these variables were significant predictors of receiving DMTs: (1) the probability of receiving treatment decreased with increasing age, (2) the probability of receiving treatment was lower for patients with indemnity health plans relative to those with POS plans, and (3) the probability of receiving treatment was higher for patients in the South relative to those in the West region. After multivariate adjustment for the aforementioned imbalances, the odds of receiving a DMT in the high cost-sharing group were 21% lower than for the low cost-sharing cohort (OR = 0.79, 95% CI: 0.74- 0.84, 

Compared with treated patients with MS in the high cost-sharing plans, patients in the low cost-sharing plans had a significantly higher unadjusted MPR for DMTs (0.82 vs 0.79; 

 <.0001), a lower unadjusted discontinuation rate (35% vs 37%; 

 = .0002), and a higher unadjusted mean number of days on persistent treatment (268 ± 141 vs 256 ± 148; 

<.0001). Results of the multivariate analysis, presented in 

, found that the odds of treatment adherence for the high cost-sharing cohort were 13% lower than for the low cost-sharing cohort (OR = 0.87, 95% CI: 0.81-0.94, 

 = .0006). The risk of treatment discontinuation was 8% higher for patients in the high cost-sharing plans than patients in the low cost-sharing plans (hazard ratio [HR] = 1.08, 95% CI: 1.02-1.15, 

To better understand the impact of the upper end of the cost-sharing ranges among our study patients, we performed a multivariate sensitivity analysis by creating 3 plan-level cost-sharing categories: 

$100, $101 to $200, and >$200. Compared with patients with plan-level costsharing

$100, the odds of receiving DMTs were 37% lower for patients in plans of cost sharing >$200 and 14% lower for patients with cost sharing of $101-$200 (OR = 0.63, 95% CI: 0.54-0.74, 

 <.0001 and OR = 0.86, 95% CI: 0.76-0.97, 

). The odds of treatment adherence were 39% lower among patients with >$200 cost sharing relative to those with 

 <.0001). The risk of treatment discontinuation was 27% higher for the >$200 cohort than the 

$100 cohort (HR = 1.27, 95% CI: 1.10-1.47, 

$100 plans, patients in plans of $101 to $200 had less favorable adherence and persistence outcomes, but no statistically significant differences were detected.

Using pharmacy and medical claims data from 2003 to 2010, this study evaluated how patients’ expected financial burden for DMTs would influence the likelihood of receiving treatment and subsequent treatment compliance. We used the median value of plan-level copayment for DMTs to classify 14,497 treated patients and 10,200 untreated patients into plans with low and high cost sharing. Patients in high costsharing plans had lower odds of receiving DMTs than patients in low cost-sharing plans; treatment adherence was lower, and discontinuation was higher among patients in high cost-sharing plans relative to their low cost-sharing counterparts.

Negative associations between high cost sharing and treatment compliance among patients with MS have been documented in several published studies. Despite different methods of defining cost sharing and classifying cost-sharing groups, previous studies consistently suggest that the negative impact of cost sharing on treatment compliance with DMTs is most likely at the higher end of the patient OOP cost spectrum. Express Scripts, a pharmacy benefit manager, evaluated factors predicting patient compliance with specialty drug therapy including DMTs.

 Patients were classified into 5 copayment categories. Results showed that patients with the highest copayment level (>$150) had 19% higher odds of being nonpersistent than those with copayment values <$20. However, the odds were not signifi cantly different between the $51 to $150 copayment groups and the <$20 group. Dor et al9 examined MPR among patients with MS who paid copayment only (n = 987) and coinsurance only (n = 987) for DMTs. Copayment was not significantly associated with MPR because the differences in copayment across alternative adherence thresholds were small, ranging from $31 to $42 per month. However, a 10% increase in cost sharing resulted in a 9% decline in adherence in the coinsurance cohort (patients with a mean OOP of $284). Gleason et al8 analyzed the relationship between OOP for the first filled DMT prescription and the treatment abandonment rate, which was found to be significantly higher for OOP expense >$200 when compared with an OOP expense of

$100. Results from the sensitivity analyses examining the impact of the upper end of the cost sharing on treatment compliance in the present study were consistent with these findings.

Our sensitivity analyses further confirmed that higher cost sharing signifi cantly lowered the likelihood of receiving DMTs. As noted, the average age for the untreated patients was nearly 7 years older than the treated patients. In part, these large imbalances are because DMTs are only indicated for RRMS, which is more prevalent among younger patients. In addition, MS is a highly heterogeneous disease, and patients with milder disease may be less likely to receive DMT treatment, given its cost and inconvenience. Because diagnosis codes do not specify MS type, we were unable to directly assess treatment availability with respect to disease progression. However, because older people are more likely to have progressive forms of MS than young people, age as a covariate in the multivariate models served as a proxy for disease status.

Previous research indicates that poor DMT adherence is associated with a higher risk of MS-related hospitalization, ED visits, relapse, and MS-related medical costs.

The consequences of delayed DMT initiation, low adherence, and poor persistence because of patient cost sharing were not assessed in this study, but it is possible that any revenue obtained through cost-sharing arrangements may be partially offset by increases in medical services and costs.

Results of this analysis should be interpreted in light of several limitations. Manufacturers offer patient assistance and copayment programs to reduce patient fi nancial burden, but these subsidized payments were not distinguishable from the actual patient OOP costs on the prescription claims. Although patient assistance programs are typically offered to patients with low income and/or those without insurance, copayment programs are offered to a broader patient population. Patients in the current analysis have commercial insurance, which often makes them ineligible for patient assistance programs. Very few study patients (0.1%) were enrolled in a high-deductible health plan, which is often considered a proxy for low income. Nonetheless, the study may underestimate the effects of benefit design on the outcomes, because the impact of copayment program enrollment cannot be assessed with available data. A multivariate technique was employed to adjust for imbalances in patient demographic and clinical characteristics using available data elements from the MarketScan databases. However, there are unobservable factors that may impact patients’ enrollment in high versus low cost-sharing plans, the choice to initiate treatment with DMTs, or treatment adherence. Some of the factors that could not be assessed include patient income, type/stage of MS, physician preferences, and distance to providers. Study results should be interpreted accordingly. This study relied on prescription claims and assumed that dispensing was equivalent to utilization of the prescription. Previous research suggests that claims-based evaluation of medication compliance is a reliable assessment method.

The choice of using 80% MPR to define treatment adherence was somewhat arbitrary. We evaluated the relationship between cost sharing and adherence using a 70% and a 90% threshold. The relationship between copay amount and adherence was modestly sensitive to the way adherence was defi ned; however, the study conclusions were unaffected. For example, the odds ratio for adherence, comparing copay amount greater than the median versus less than the median, fluctuated from 0.835 to 0.874 to 0.905 when adherence was defi ned as MPR

80%, and MPR >90%, respectively. All odds ratios were highly statistically signifi cant. A large percent of patients were excluded from the study because they did not meet the continuous enrollment criteria. The magnitude of this criterion was larger for the untreated cohort than for the treated cohort. Disenrollment from MarketScan databases is typically related to termination in employment or data contribution thresholds of MarketScan contributors. Consequently, we believe that patients excluded because of continuous enrollment were not markedly different, from a clinical perspective, from those who remained eligible for analysis.

Finally, our findings were limited to patients with commercial insurance and employer-sponsored Medicare supplemental coverage and cannot be generalized to the US population.

Our findings suggest that patients with MS are sensitive to the financial costs associated with DMTs and may forgo treatment or end treatment prematurely when facing a high cost-sharing burden. Benefit plan designs that negatively impact treatment initiation and/or adherence may increase the risk of relapse, health resource use, and disease progression. Future studies are desired to quantify clinical and economic consequence of undertreatment among patients facing high cost sharing.

This study evaluates the impact of patient cost sharing on the probability of receiving disease-modifying therapies and treatment compliance among patients with multiple sclerosis.