Abstract
Background
In multiple sclerosis (MS), delays in initiation of disease-modifying therapy (DMT) are associated with worse clinical outcomes.
Methods
This single-center retrospective chart review study included treatment-naive and previously treated people with MS (PwMS) initiated on DMT between 01 September 2021 and 01 September 2023. A generalized linear model was utilized to evaluate associations between start-up times (initial treatment decision to completion of first dose) and distance to the clinic, utilization of the center's infusion center and specialty pharmacy, insurance and educational status, route of administration, race/ethnicity, and household income.
Results
A total of 116 PwMS were included (median age 41 [15–74] years; 87.9% female). Increased geographic distance from the MS center correlated with longer start-up times (>100 km: 76.5 [0–393] days vs. ≤100 km: 53.5 [2–524] days); p = 0.04). People with MS with private insurers had longer start-up times (66 [0–524] vs. 50.5 [0–201] days; p = 0.016). The utilization of outside infusion centers and specialty pharmacies delayed initiation (82.5 [0–524] vs. 39.5 [0–372] days; p = 0.024).
Conclusions
This small retrospective study demonstrates an association between longer start-up times and greater geographic distance, private insurance status, and use of outside infusion centers and specialty pharmacies.
Introduction
Multiple sclerosis (MS) is an autoimmune central nervous system demyelinating disease affecting approximately 2.8 million people worldwide. 1 Multiple sclerosis predominantly affects young to middle-aged women and is considered the leading neurological cause of nontraumatic disability in young adults in the Western hemisphere due to a variety of disabling symptoms, including weakness, sensory disturbance, mood disorders, urologic dysfunction, cognitive deficits, and gait changes. 2
Over the past decades, significant scientific advances have been made leading to regulatory approval of disease-modifying therapies (DMTs) that aim to prevent disease progression and have made a significant impact on the accrual of MS-related disability. 3 These medications are most effective when initiated early in the disease, ideally at the time of diagnosis, 4 and delayed initiation of DMT is linked to unfavorable outcomes, including increased relapse rates and disability progression in people with MS (PwMS). 5
Initiating DMT therapy (henceforth termed “start-up”) is a complicated process that involves multiple steps including (1) establishing care with a neurologist, (2) completion of required safety laboratory work-up, (3) the prescription of the medication, (4) the insurance authorization process including peer-to-peer discussions and appeals (if required), (5) potential approval by financial assistance programs, and (6) delivery of the medication. Delays in any of these components can significantly prolong the duration until a DMT is initiated. As MS DMTs are specialty medications that are expensive and often have specific storage and handling requirements, they are frequently distributed by specialty pharmacies, which typically mail the medication to the patient's home 6 with third-party payors often mandating the use of national payor-owned specialty pharmacies. Additionally, intravenous DMT requires coordination with an infusion center/service. Scheduling and communication with specialty pharmacies and infusion centers can also be potential cause of delay. Accordingly, the establishment of institutional specialty pharmacies has been tied to improved outcomes in MS previously.7,8 The identification of barriers to health care is important, given the urgency needed to start MS DMT. In MS, there is concern for health inequities due to race, ethnicity, socioeconomic status, income, education, and health literacy. 9 Geographic distance and travel times have also been previously reported to be possibly associated with worse health outcomes. 10 This is especially important as there are large areas within the United States and worldwide that do not have adequate access to MS specialists, and commonly correspond with low-income regions.11,12
The objective of this study is to analyze the influence of geographic location, the utilization of outside specialty pharmacies and infusion centers, insurance status, route of administration, race/ethnicity, and household income on MS DMT start-up times at the University of Florida (UF).
Methods
In this single-center retrospective study, we included PwMS treated at the UF Health Multiple Sclerosis Program that were initiated on an MS DMT between 01 September 2021 and 01 September 2023. Patients were identified via a specific DMT start-up list that is utilized in our center to monitor the DMT start-up process. Both treatment-naive and previously treated PwMS were included, if they (1) were started or changed to an MS DMT (United States Food and Drug Administration-approved medications and rituximab) by one of our center's providers and (2) received at least one dose of the medication. People with MS without start-up information due to loss to follow-up were excluded. The study was approved by the UF Institutional Review Board.
The demographic, socioeconomic, and DMT variables were obtained via review of patient electronic medical records (EHRs; Epic Systems Corporation, Verona, WI, USA). Demographic patient characteristics, including patient age, sex, race, and ethnicity, were obtained. The DMT that was initiated was identified, and its route of administration (infusion, oral tablet, injection) documented. The DMT start-up time was defined as the duration (days) between the initial decision to initiate the specific DMT and the actual start date of the medication (completion of first dose). For this, the date of the initial decision to start the DMT and the actual subsequent start date were determined by reviewing clinic notes and medication orders. The center's clinic note template includes specific start dates for medication. If this information was missing in our documentation, fill/infusion dates of the medication were used. Clinical documentation was reviewed to identify causes for potential delays. Additionally, the date of prior authorization (PA) determination was obtained via chart review, and the duration (days) between initial treatment decision and PA determination was calculated. Documentation of peer-to-peer discussions with insurance companies was extracted from the EHR. Start forms from pharmaceutical companies were reviewed to assess the selection for financial assistance or fast start programs. The geographic distance between the MS clinic and the patient's residential address was calculated (driving distance in km). Clinic notes and medication orders were used to identify the utilized infusion centers and specialty pharmacies. Insurance status was determined as documented in the EHR and grouped into private and nonprivate (government insurances including Medicare and Medicaid) insurers. Educational status and approximate annual household income were determined through chart review.
Descriptive statistics were used to characterize the cohort and DMT start-up times. Categorical variables are displayed as percentages of participants, and continuous variables are displayed as medians (range). A multivariate generalized linear model was applied to evaluate differences in the total time from initial decision to completion of the first dose due to distance to the MS clinic, the utilization of the center's infusion center and specialty pharmacy, insurance status (private vs. nonprivate), educational status, route of DMT administration (infusion vs. oral or injection), race or ethnicity, and household income, corrected for age, sex, race/ethnicity, and insurance status (IBM® SPSS Statistics). A p-value of <0.05 was considered statistically significant.
Results
A total of 116 PwMS were included, and demographic, socioeconomic, and clinical patient characteristics are displayed in Table 1. Data for the analyzed variables were available for all participants besides education status and annual household income, which were available in 97 (82.8%) and 68 (58.6%) included PwMS, respectively. The participants’ median age was 41 (range 15–74) years and 87.9% were female. The majority (65.7%) were non-Hispanic Caucasian PwMS with smaller proportions of African-American (15.5%) and Hispanic (14.7%) participants. The participants’ median Expanded Disability Status Scale was 2.5 (range 0–9.0) with 19.1% receiving social security disability; 62.9% of participants had higher education and 49% were unemployed; 81.9% of participants had an estimated household income of <$100,000 and 60.3% of included PwMS were privately insured. The median distance from the participants’ residence to the MS clinic was 73 (0–761) km.
Demographic, socioeconomic, and clinical characteristics of included patients.
DMT: disease-modifying therapy; EDSS: Expanded Disability Status Scale; MS: multiple sclerosis.
Median DMT start-up time was 59 (range 0–524) days. One participant had a severely prolonged start-up time of 524 days, which was related to difficulties obtaining insurance approval; 50% of participants received infusion therapies (start-up time: 75.5 [range 0–393] days), 39.7% injections (start-up time: 42 [range 0–524] days), and 10.3% oral tablets (start-up time: 58 [range 0–276] days); 12.1% of participants had a clinical relapse during the start-up process. The characteristics of the subgroup with clinical relapses during the start-up process were overall similar to the total cohort (median age 36.5 years, 78.6% female, 50% with higher education, median DMT start-up time of 71 [range 16–132] days). The median time from treatment decision to the initial PA insurance determination was 22 (range 0–496) days. A peer-to-peer discussion with the insurance company was only documented in a small number of cases (n = 4). Financial assistance and fast start options were selected in 52.3% of participants. Numerically, start-up times were longer for patients with a selected fast start option (61 [range 0–393] days vs. 41 [range 0–393] days). Of note, coordination, communication, or scheduling with an outside specialty pharmacy and/or infusion center was determined as a cause of delay in 61.4% of participants.
The multivariate generalized linear model demonstrated that geographical distance, the use of outside specialty pharmacies and infusion centers, as well as insurance status significantly affected DMT start-up times. Start-up times increased for PwMS with a higher geographic distance from the MS center (>100 km: 76.5 [range 0–393] days vs. ≤100 km: 53.5 [range 2–524] days; p = 0.04 [CI 0.006–0.238]). The utilization of outside infusion centers and specialty pharmacies was associated with longer DMT start-up times (non-UF: 82.5 [0–524] days vs. UF: 39.5 [range 0–372] days; p = 0.024 [CI 4.6–65.2]). Similarly, PwMS with private insurers had longer DMT start-up times (private insurance: 66 [range 0–524] days vs. nonprivate: 50.5 [range 0–201] days; p = 0.016 [CI −73.4 – −7.7]; Figure 1). There was a nominal difference in median DMT start-up times for participants with a lower level of education (≤ secondary education: 77 [range 0–372] days vs. higher education: 54 [range 0–524] days) that did not reach statistical significance. Similarly, there was a nominal difference for the utilization of infusion DMT (75.5[range 0–393] days] vs. 50.5 [range 0–524] days) that was not statistically significant (Figure 2). The DMT start-up times were comparable for Caucasian (63 [range 2–524] days) and non-Caucasian (52.5 [range 12–252] days) PwMS. There was no significant difference in DMT start-up times associated with the participants’ household income (<$100,000: 56.5 [range 0–372] days vs. ≥$100,000: 72 [range 5–226] days) (Table 2).
Kaplan–Meier curves depicting differences in MS DMT start-up times due to insurance status (a; blue: non-private; red: private), geographic distance to the multiple sclerosis clinic (b; blue: <100 km; red: ≥100 km), and utilized specialty pharmacy/infusion center (c; blue: non-institutional; red: institutional). MS: multiple sclerosis; DMT: disease-modifying therapy; Cum Survival: cumulative survival.
Median multiple sclerosis disease-modifying therapy start-up times for the different analyzed factors.
Results of the multivariate generalized linear model to characterize differences in the total time from initial decision to start the disease-modifying therapy to completion of the first dose, corrected for age, sex, race/ethnicity, and insurance status. Statistically significant (p < 0.05) differences (*) are marked in bold.
Discussion
This small, single-center retrospective study demonstrates delays to DMT initiation associated with (1) increased distance from the MS Center, (2) the utilization of an outside specialty pharmacy or infusion center, and (3) private health insurance.
The median DMT start-up time of 59 days, nearly 2 months, was alarmingly high. This is especially concerning given that we are a specialty clinic with experience in managing the start-up process of MS DMT. It is also important to note that total start-up times were even longer, as the wait times to be seen in our specialist clinic were not included in our analysis. The occurrence of multiple clinical relapses during the start-up process further emphasizes the need to more thoroughly investigate factors that lead to delays in DMT initiation. This is also supported by a prior survey study, with almost half of PwMS reporting relapses due to difficulties and delays associated with gaining access to DMT. 13 Data from multiple international registries indicate that the time to initiation of DMT varies substantially across settings, with reported ranges from 2 to 9 months14,15 which is very high for a disease in which we can prevent neurological deterioration by preventing attacks. Of note, a 2-week time frame from decision to beginning of treatment has been previously proposed as a good standard of care by an international consensus paper on quality standards in MS. 16
A negative association between health outcomes and longer geographic distances or travel times has been reported in a variety of studies in the medical field previously 10 and similarly we identified increasing geographic distance from our MS specialty clinic adversely impacting DMT start-up times. This is concerning as there are large areas in the United States that do not have adequate access to MS specialists11,12 and highlights the need to establish better specialty care in rural areas.
The results of this study highlight the benefit of access to specialty pharmacy staff. Integrated health-system specialty pharmacies can alleviate burden from saturated neurology clinics by aiding with PAs, acting as an intermediary between the insurance company and patient, and overall expediting the time for patients to receive their medication. Accordingly, the integration of a specialty pharmacy team in neurology clinics has been previously reported to improve start-up of specialty medications in MS8,17 and Parkinson disease. 18 Additionally, previous studies suggest that including specialty pharmacists into clinics can improve medication adherence and monitoring.7,19
Patients with private insurance had significantly longer DMT start-up times. This may be explained by the taxing and inconsistent process implemented by private insurance companies entailing PAs, peer-to-peer discussions, and frequent initial denials with subsequent complicated and often lengthy appeal processes.20,21 Accordingly, authorization documentation required by insurance companies is a frequently reported (21.4–42.9%) cause of DMT access difficulties. 13 Of note, specific “quick start” programs offered by pharmaceutical companies for privately insured patients were frequently requested in our study, and accordingly, start-up times for privately insured PwMS may even be higher without such assistance options. Interestingly, DMT start-up times for patients with selected fast start options were numerically longer, which may reflect the additional challenges associated with DMT initiation in these patients (i.e., the fast start option may be more likely selected in patients where DMT start-up difficulties are already expected).
While not statistically significant, the nominal difference between start times with infusion therapies versus other medications may be associated with challenges accessing infusion centers and the complexity of that multistep process for patients, which includes investigation of benefits, PAs, potential payor-mandated site of care restrictions, and scheduling. 22 Accordingly, a previous study has shown that PAs are associated with treatment delays for infusible medications 23 as infusion centers will often not schedule patients until insurance authorization is obtained. Geographic distance to the infusion center could be a possible additional access-limiting step, which has been previously reported in oncological patients. 24
Health literacy likely plays an important role in achieving timely DMT start-up as it aids in understanding the medication's importance and navigating the complicated health care system. A strong association between lower educational status, a surrogate marker of health literacy, and higher rate of disability progression has been previously described in MS. 25 Accordingly, we observed nominally higher DMT start-up times for PwMS with lower educational status, even though this difference did not reach statistical difference. Similarly, lower socioeconomic status has also been reported to be associated with an increased disability risk in PwMS, 26 but we did not see a significant difference in DMT start-up times associated with the participants’ household income.
There are known disparities in MS affecting minorities such as African-American and Hispanic PwMS.11,12 Our findings did not demonstrate a statistically significant difference when comparing time to start DMT in Caucasian versus non-Caucasian populations. The low number of racial and ethnic minority members in our study population hindered further subgroup analysis.
The main limitation of this study is the small sample size. As our center's DMT start-up list was utilized to identify patients, PwMS that were not included on the list may not have been identified. Furthermore, data on education and household income were not available for all participants. A potential limitation of this study is also the generalizability of the data since this cohort was restricted to MS patients started on DMT at a single academic MS Center. Additionally, individual demographic characteristics, education level, and other socioeconomic variables were collected via patient questionnaire responses, which can be subject to self-reporting bias. Furthermore, some of the reported variables (utilized specialty pharmacies and infusion centers as well as insurance status) are directly linked to the US healthcare system and likely do not apply in other countries.
Our study's strength is the detailed information regarding different socioeconomic and demographic characteristics that was available for the included PwMS. To our knowledge, no previous studies have explored potential links between social determinants of health and DMT access/initiation in PwMS. This lack of data justifies the need for future investigation so that barriers to care are identified and swiftly managed.
In conclusion, we identified several important factors that may impact timely DMT initiation. While it is important to confirm these findings in larger prospective studies, they may aid in identifying pathways to address them. One possible solution includes adding a dedicated Multiple Sclerosis Care Coordinator to the care team whose primary role is to oversee the complicated DMT start-up process and help PwMS navigate and overcome obstacles of the healthcare system.
Data availability statement
The data sets generated and analyzed during this study are available from the corresponding author on reasonable request and with necessary approvals.
Declaration of conflicting interests
The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: This work was performed during the EMD Serono I’M IN Neurodisparity Fellowship. EMD Serono was not involved in study-related activities and did not influence study design, data collection, or interpretation of the results. Dr Snider has served on scientific advisory boards for Amgen. Dr Rodriguez has served on scientific advisory boards for Sanofi and Amgen. Dr Montalvo served on an advisory board for Horizon and Amgen Therapeutics, she has been a consultant for TG Therapeutics. Dr Rempe received grant funding from the National Multiple Sclerosis Society. He served on advisory boards for Genentech, Sanofi-Genzyme, Amgen, TG Therapeutics, and Alexion. He receives contract research support from Genentech, Sanofi-Genzyme, Celgene, and Novartis.
