Agashivala et al.

BMC Neurology 2013, 13:138

http://www.biomedcentral.com/1471-2377/13/138

RESEARCH ARTICLE Open Access

Compliance to fingolimod and other disease

modifying treatments in multiple sclerosis
patients, a retrospective cohort study
Neetu Agashivala1*†, Ning Wu2†, Safiya Abouzaid1†, You Wu2†, Edward Kim1†, Luke Boulanger2†
and David W Brandes3†

Abstract
Background: Adherence to disease-modifying therapies (DMTs) results in the reduction of the number and severity of
relapses and delays the progression of multiple sclerosis (MS). Patients with lower adherence rates experience more
inpatient visits and higher MS-related medical costs. Fingolimod, the first oral DMT approved by the US Food and Drug
Administration, may improve the access and compliance to MS treatment when compared to injectable DMTs.
Methods: This retrospective cohort study used pharmacy claims from Medco Health Solutions, Inc., of patients who
initiated DMTs between October 2010 and February 2011. Initiation was defined as no prescription fills for the same
DMT in the prior 12 months. Patients without a DMT prescription fill 12 months before the index date were considered
naïve users. Compliance was measured via proportion of days covered (PDC) and medication possession ratio (MPR)
for 12 months post-index. Discontinuation was defined as a ≥60-day gap of index DMT supply. Cox proportional
hazard models compared time to discontinuation between cohorts.
Results: Of 1,891 MS patients (mean age: 45.7; female: 76.4%), 13.1% initiated fingolimod, 10.7% interferon beta-1b,
20.0% intramuscular interferon beta-1a, 18.8% subcutaneous interferon beta-1a, and 37.4% glatiramer acetate. Patients
initiating fingolimod had highest average PDC and MPR in both experienced (fingolimod: mean PDC=0.83, 73.7% with
PDC≥0.8; mean MPR=0.92, 90.5% with MPR≥0.8) and naïve DMT users (fingolimod: mean PDC=0.80, 66.7% with
PDC≥0.8; mean MPR=0.90, 87.4% with MPR≥0.8). The proportion of patients discontinuing index DMT within
12 months was significantly lower for the fingolimod cohort (naïve: 31.3%; experienced: 25.7%). Adjusted results found
that patients receiving self-injected DMTs discontinued significantly sooner than fingolimod users. This association was
generally stronger in experienced DMT users.
Conclusions: Fingolimod initiators were more compliant, less likely to discontinue treatment, and discontinued later
than patients who initiated self-injected DMT.
Keywords: Multiple sclerosis, Compliance, Patient adherence, Medication persistence, Discontinuation, Fingolimod

Background or worsening neurological symptoms. Age of onset is typ-

Multiple sclerosis (MS), a chronic inflammatory disease of ically between 20 and 40 years, but diagnosis is often de-
the central nervous system, is the most common disabling layed due to its transitory nature and lack of specific
neurological condition in young people, affecting more diagnostic tests [1]. About 85 percent of those who are
than 400,000 individuals in the U.S [1,2]. MS is commonly newly diagnosed have relapsing MS [2]. Because MS is a
characterized by intermittent relapses associated with new lifelong disease with a relatively early onset, lifetime med-
ical costs associated with the disease are substantial [1].
Although there is no known cure for multiple sclerosis,
* Correspondence: [email protected]
†
Equal contributors
the primary aims of therapy are preventing new relapses,
1
Novartis Pharmaceuticals Corporation, One Health Plaza, 07936, East returning function after a relapse, and preventing disability
Hanover, NJ, USA [3]. There are multiple Food and Drug Administration
Full list of author information is available at the end of the article

© 2013 Agashivala et al.; licensee BioMed Central Ltd. This is an open access article distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly cited.
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(FDA) approved disease-modifying therapies (DMTs), which retrospective study analyzing de-identified administrative
are efficacious in reducing the frequency of relapses and/or claims database, so it is exempted from Institutional Re-
delaying disability progression [4]. In order to fully benefit view Board (IRB) review.
from their treatments, patients must follow their prescribed Patients who initiated one of the first-line DMTs be-
regimen, which may require frequent injections. tween October 2010 and February 2011 were selected:
Existing studies suggest that compliance to self-injected fingolimod, interferon beta-1b subcutaneous, interferon
DMTs is not optimal [5,6]. Portaccio et al. reported 14-44% beta-1a intramuscular, interferon beta-1a subcutaneous,
discontinuation rate of patients who started interferon or glatiramer acetate. Medication initiation was defined as
beta. Common reasons for discontinuation included flu no pharmacy claims for the same DMT in the 12 months
like symptoms and injection site reactions [6]. Needle before the first use dated between October 2010 and
phobia is another common tolerability issue of injectable February 2011. Patients were then assigned to one of
medications that may affect treatment continuation. Other the five DMT cohorts. Fingolimod was the most recently
factors that may lead to low adherence include depression Food and Drug Administration-approved first-line DMT,
and anxiety, cognitive impairment, disease progression, or available in US market since late September, 2010. To ob-
high patient out of pocket copayments [7]. Furthermore, tain sufficient sample size for the fingolimod cohort,
patients may not readily perceive the benefits of such patients who initiated fingolimod were included in the
costly, inconvenient, and at times painful treatments since fingolimod cohort regardless of prior DMT use. The
DMTs are prescribed to prevent relatively uncommon but remaining patients were assigned to one of the four
disruptive relapse events and disability progression, which self-injected DMT cohorts based on the first DMT
occurs over years. they initiated. The date of the second prescription fill
Fingolimod is the first oral DMT approved by the US of the index DMT was set as the index date. The ra-
Food and Drug Administration. Studies in other disease tionale for using the second fill date as the index date
areas suggest a higher compliance to oral medications was that, per FDA recommendation, the first dose of
than injectable medications [8]. In the absence of the fingolimod is to be administered under physician supervi-
tolerability issues that are known to affect adherence sion and with observation for at least six hours following
and persistence to the self-injected DMTs, we hypothe- ingestion. Because patients could receive a supply of medi-
sized that patients receiving oral fingolimod have a bet- cation but not start consuming fingolimod until their su-
ter compliance and a lower discontinuation rate than pervised first dose, any lag in first dose observation would
patients receiving first-line self-injected DMTs. lead to an underestimate of both adherence and persist-
ence measures for fingolimod. Patients who were less than
Methods 18 years old and who did not have continuous pharmacy
To test our hypothesis, we conducted a retrospective co- plan enrollment during the 12 months prior to index
hort study using pharmacy claims dated between October medication initiation and 12 months following the index
2009 and February 2012 from Medco Health Solutions, date were also excluded.
Inc (Medco). With over 60 million covered lives, Medco is
the largest pharmacy benefits management company in Study measures
the U.S. and has pharmacy claims data for nearly 1 in 5 Demographic characteristics of the selected patients were
Americans. The pharmacy claims data from Medco con- determined as of the index date including patient age,
tain national drug codes, prescription details such as days gender, and geographic region of residence. Patients were
of supply, fill date, and copayment amount, and the char- classified as DMT naïve patients if they did not have phar-
acteristics of prescribing physicians as well as dispensing macy claims for any DMT during the year prior to the ini-
pharmacies. An enrollment file also provides the gender, tiation of the index medication and experienced DMT
birth year, start and end dates of pharmacy plan enroll- users if otherwise. Characteristics of the index prescription
ment, and three digit postal zip codes of patient residence. were also examined. These include the specialty of the
This study complied with all applicable laws, regula- prescribing physicians, dosage of the index prescription,
tions, and guidance regarding patient protection includ- copayment amount standardized to a 30-day supply,
ing patient privacy. All data are compliant to Health whether physician needed to obtain prior authorization to
Insurance Portability and Accountability Act (HIPPA) prescribe the DMT, whether the DMT was on insurance
and all patient identification is replaced with encrypted plan’s formulary, whether the index prescription was filled
random patient identifiers, which can be used to cross via mail-in order, and type of pharmacy that dispensed the
link the medical, pharmacy and enrollment files. All the DMT. Dispensing pharmacies were classified into three
data are stored in a secure server. Only members in the types: Accredo Health Group, Inc, other specialty pharma-
research teams were granted permission by Medco and cies, and retail pharmacies. Accredo Health Group, Inc is
had access server using assigned credentials. This is a a specialty pharmacy that distributes medications and
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provides associated services to patients with complex and were plotted for DMT naïve and experienced users, re-
chronic diseases through Therapeutic Resource Centers. spectively. Cox proportional hazard models were esti-
Adherence to index DMT was assessed based on the mated to identify factors associated with time to index
pharmacy claims dated within 12 months following the DMT discontinuation using demographic and index pre-
index date (Figure 1). Proportion of days covered (PDC) scription characteristics as covariates. Separate Cox pro-
was measured as the total number of days with medica- portional hazard models were estimated for naïve and
tion supply in the 12-months follow-up period divided experienced DMT users.
by 365 days (Equation 1). Medication possession ratio
(MPR) was estimated as total days with medication sup- Results
ply within the refill interval divided by number of days Of the 1,891 DMT initiators identified, 13.1% initiated
in the refill interval (Equation 2). Extra days of medica- fingolimod, 10.7% interferon beta-1b, 20.0% intramuscu-
tion supply that covered the periods after the end of lar interferon beta-1a, 18.8% subcutaneous interferon
12-month follow-up were deducted from the numer- beta-1a, and 37.4% glatiramer acetate (Table 1). Mean
ator of both PDC and MPR measures. Time to dis- (SD) age was 45.6 (11.1) years, and 76.4% were females.
continuation was defined as the number of days to Overall, 75.4% of DMT initiators were naïve users. A sig-
the beginning of the first 60-day gap in supply of nificantly lower percentage of users of fingolimod
index medication. The 12-month persistence rate was (38.7%) were naïve to DMT treatment than the other co-
measured as the proportion of patients who did not horts (72.4-83.7%, Table 1).
discontinue the index DMT during the 12 months A higher percentage of fingolimod was prescribed by
since their initiation. We assessed the distribution of neurologists compared to other DMT cohorts (Table 1).
PDC, MPR and persistence measures as continuous While no users of fingolimod received an index medica-
measures, and created ordinal categorical measures tion supply for 90 days or more, 13.6% of glatiramer
(e.g., 0≤PDC<0.2, 0.2≤PDC<0.4, 0.4≤PDC<0.6, 0.6≤PDC<0.8 acetate users did receive at least a 90-day of supply
and 0.8≤PDC≤1) and reported the proportion of patients in (p<0.0001). Mail order prescriptions were utilized signifi-
each category. cantly more frequently for fingolimod users (74.6%) than
all other DMT users (all p<0.0001). The mean co-payment
Data analysis for a 30-day supply of fingolimod was $98.5 (SD: $315.5),
The distribution of baseline characteristics and out- which was not significantly different from other DMT
comes was assessed for each of the DMT cohort using cohorts.
percentages for categorical variables, and mean and Among naïve DMT users, the fingolimod cohort had a
standard deviation (SD) for continuous measures. Using significantly higher PDC (mean: 0.80, SD: 0.23) and MPR
the fingolimod cohort as the reference group, unadjusted (mean: 0.90, SD: 0.09) than the other four DMT cohorts
comparisons were conducted between the fingolimod co- (Table 2). Similarly, fingolimod users had a significantly
hort and each of the remaining cohorts using Chi-square higher proportion of patients included in the most com-
tests for categorical variables and Student t-tests for pliant category range. For example, 87.4% of fingolimod
continuous variables. Non-parametric Wilcoxon rank- cohort had MPR≥0.8, higher than the four injectable
sum tests were used for count variables and copayment DMT cohorts (range 72.8% to 81.5%). A significantly
amount. The assessment of the distribution of compli- higher percentage of fingolimod users (68.8%) were per-
ance measures were further stratified by patients’ prior sistent at 12 months compared to other cohorts (range
experience with DMT (i.e., naïve vs. experienced). 46.1% to 56.3%, all p<0.05). Similar patterns were ob-
Time to discontinuing index DMT was estimated and served in experienced DMT users, but the between-
compared between cohorts. Kaplan-Meier survival curves cohort difference favoring fingolimod was larger (Table 3).

Figure 1 Adherence Equations.

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Table 1 Demographic and index prescription characteristics

Fingolimod Interferon beta-1b Intramuscular Subcutaneous Glatiramer acetate
interferon beta-1a interferon beta-1a
N=248 N=202 N=379 N=355 N=707
p-value p-value p-value p-value
Age Categories (%) 0.3112 0.1516 0.0001 0.1733
18-24 3.2 2.5 3.4 2.0 1.8
25-34 10.5 17.8 13.5 19.2 15.6
35-44 24.6 23.3 28.0 33.2 27.4
45-54 37.5 33.7 27.2 31.6 33.1
55-64 21.0 18.3 22.4 10.1 17.8
65-74 3.2 4.5 5.0 3.9 3.7
75-84 0 0 0 0 0.6
Age: mean (SD) 46.4 (10.7) 45.5 (11.2) 0.4107 46.5 (11.5) 0.9349 43.5 (10.7) 0.0012 45.9 (11.1) 0.5079
Female (%) 79.0 70.3 0.0330 79.7 0.8437 74.4 0.1850 76.4 0.3925
Region (%) 0.2046 0.0008 0.0984 0.0126
Northeast 18.2 17.3 31.4 23.7 29.1
Midwest 29.4 27.7 28.2 33.0 27.2
South 32.7 41.1 28.2 26.8 27.3
West 19.8 13.9 12.1 15.8 16.1
Other/missing 0.0 0.0 0.0 0.9 0.3
Naïve to DMT treatment (%) 38.7 82.7 <0.0001 82.6 <0.0001 72.4 <0.0001 83.7 <0.0001
Specialty of prescriber: Neurologist (%) 82.3 78.2 0.2825 74.7 0.0257 74.7 0.0270 77.5 0.1159
Index medication days 0.0 0.5 0.2673 0.0 NA 0.6 0.2364 13.6 <0.0001
supply >= 90 days (%)
Prior authorization (yes) (%) 56.1 60.4 0.3527 48.6 0.0662 46.2 0.0173 47.4 0.0189
DMT on formulary (yes) (%) 15.3 71.8 <0.0001 97.9 <0.0001 85.1 <0.0001 96.2 <0.0001
Mail order (%) 74.6 51.5 <0.0001 47.0 <0.0001 54.1 <0.0001 54.0 <0.0001
Days’ Supply: mean (SD) 33.3 (16.3) 35.7 (19.5) 0.1709 35.2 (18.2) 0.2040 35.0 (18.4) 0.2302 38.8 (21.4) <0.0001
30 day Co-pay: mean (SD) 98.5 (315.5) 101.9 (291.0) 0.9063 124.1 (376.1) 0.3588 88.4 (255.6) 0.6768 119.2 (333.5) 0.3944
P-values based on comparison with fingolimod cohort using Chi-square tests for categorical variables and Student's t-test for age, and Wilcoxon rank-sum tests
were used for days' supply and copayment amount.
DMT: disease-modifying therapy. SD: standard deviation.

Figures 2a and 2b depict the unadjusted time to dis- patients with multiple sclerosis [6,9,10]. Using pharmacy
continuation of initiated disease-modifying agents for claims, our study assessed the adherence and persistence
naïve and experienced DMT users. In both cases the to first-line DMT treatments shortly after the approval
fingolimod cohort had higher medication persistence of the first oral DMT in the US. Similar to other recent
over the observation period. studies of individuals with MS, the patients included in
Results from the Cox proportional hazard models dem- our study were predominantly female with a mean age
onstrated that patients who initiated self-injected DMTs in the 40s [9,10]. About three quarters of the MS pa-
had a higher hazard of discontinuing index medication tients in our study were naïve to DMT treatment,
than patients who initiated fingolimod in both experi- though a significantly lower proportion of fingolimod
enced and naïve DMT users (Table 4). The association users (38.7%) were naïve to DMT treatment than the
was stronger in experienced users than in naive users. self-injected DMT users. A likely reason for this obser-
vation is that fingolimod’s recent availability prompted
Discussion patients to switch from their existing DMTs, potentially
To date, there have been limited publications comparing seeking a more efficacious or tolerable treatment alter-
compliance and persistence to DMT treatments among native. Compared to the compliance and persistence
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Table 2 Compliance and persistence measures of users naïve to disease-modifying agents

Fingolimod Interferon Intramuscular Subcutaneous Glatiramer
beta-1b interferon beta-1a interferon beta-1a acetate
N=96 N=167 N=313 N=257 N=592
p-value p-value p-value p-value
PDC: mean (SD) 0.80 (0.23) 0.65 (0.31) <0.0001 0.72 (0.30) 0.0027 0.67 (0.31) <0.0001 0.72 (0.29) 0.0017
PDC Categories (%) 0.0003 0.0347 0.0043 0.0127
0-<0.2 3.13 11.38 8.63 13.62 6.93
0.2-<0.4 7.29 16.77 10.86 12.45 11.49
0.4-<0.6 4.17 12.57 10.54 8.95 13.51
0.6-<0.8 18.75 17.37 18.53 15.56 14.02
0.8-1 66.67 41.92 51.44 49.42 54.05
MPR: mean (SD) 0.90 (0.09) 0.86 (0.17) 0.0055 0.88 (0.16) 0.0502 0.88 (0.15) 0.0551 0.89 (0.15) 0.1769
MPR Categories (%) 0.0349 0.1255 0.3037 0.2619
0-<0.2 0.00 0.62 0.68 0.41 0.36
0.2-<0.4 0.00 1.85 1.69 1.24 1.79
0.4-<0.6 1.05 8.02 6.78 4.96 5.02
0.6-<0.8 11.58 16.67 11.53 13.22 11.29
0.8-1 87.37 72.84 79.32 80.17 81.54
Persistence (<60 day gap) (%) 68.75 46.11 0.0004 53.67 0.0090 55.25 0.0218 56.25 0.0213
Persistent days (days till first 60-day gap) (%)
No gap 68.75 46.11 53.67 55.25 56.25
1-90 6.25 16.77 14.38 18.68 13.68
91-180 9.38 14.37 10.22 12.06 11.82
181-270 8.33 14.37 13.74 8.56 10.98
270+ 7.29 8.38 7.99 5.45 7.26
Switched to other DMTs after discontinuation (%) 1.04 13.17 0.0008 7.99 0.0147 11.67 0.0017 7.77 0.0153
P-values based on comparison with fingolimod cohort, using Chi-square tests for categorical variables and Student’s t-tests for continuous variables.
DMT: disease-modifying therapy. SD: standard deviation. PDC: proportion of days covered. MPR: medication procession ratio.

measures of patients who had failed at least one DMT injection site reactions were among the top reasons for
reported by Halpern et al [9], the MPR and proportion discontinuing the treatment with interferon beta in pre-
of persistent users among the experienced DMT users in vious studies [11]. Other commonly cited reasons in-
our study was generally higher. The differences in MPR cluded forgetting to take the medication and depression.
values may be because that Halpern followed patients Based on an online survey of patients using self-injected
for a longer period (averaged between 1.1-1.3 years across DMTs, Treadaway et al also found that, among patients
DMT cohorts) and used a slightly different method for es- who missed at least one dose, 32% reported injection-
timating MPR. Halpern et al defined MPR as “… days sup- related reasons, such as not feeling like taking injections
ply of the second-line DMT divided by days on second (22%), tired of taking injection (17%), pain at injection
line DMT” which did not contain sufficient details for site (7%), and the absence of someone to help administer
comparing results across studies. The method used for the medication (4%) [12]. Patients who missed >25% of
this study deducts the excess supply of the DMT at the their doses were more likely to report injection anxiety
end of the follow-up period. (11% vs. 1%) and not feeling like taking injections (29%
Our study found that patients initiating fingolimod vs. 20%) than those who missed less doses [12]. This
were more compliant and persistent to their treatment suggests that intolerance of self-injected DMTs, among
than patients initiating self-injected DMTs. One prob- all the factors that affect patient treatment adherence,
able explanation is that patients may find it easier to ad- plays an important role in “true” non-adherent users.
here to oral treatments with fewer side effects than The association between poor compliance and treat-
injectable DMTs associated with flu-like symptoms and ment intolerance and side effects is not unique in pa-
injection site reactions. Both flu-like symptoms and tients with multiple sclerosis. Such association has been
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Table 3 Compliance and persistence measures of users experienced to disease-modifying agents

Fingolimod Interferon Intramuscular Subcutaneous Glatiramer
beta-1b interferon beta-1a interferon beta-1a acetate
N=152 N=35 N=66 N=98 N=115
p-value p-value p-value p-value
PDC: mean (SD) 0.83 (0.23) 0.61 (0.30) 0.0002 0.67 (0.32) 0.0004 0.68 (0.31) 0.0001 0.73 (0.30) 0.0040
PDC Categories (%)
0-<0.2 4.61 17.14 0.0009 9.09 0.0002 10.20 0.0002 6.09 0.0003
0.2-<0.4 3.95 8.57 22.73 11.22 11.30
0.4-<0.6 2.63 11.43 4.55 12.24 13.91
0.6-<0.8 15.13 22.86 10.61 18.37 7.83
0.8-1 73.68 40.00 53.03 47.96 60.87
MPR: mean (SD) 0.92 (0.08) 0.82 (0.18) 0.0066 0.88 (0.13) 0.0287 0.84 (0.19) 0.0004 0.89 (0.16) 0.0602
MPR Categories (%) 0.0001 0.0069 0.0004 0.0106
0-<0.2 0.00 0.00 0.00 1.10 0.93
0.2-<0.4 0.00 3.33 0.00 3.30 1.85
0.4-<0.6 0.00 10.00 5.00 5.49 5.56
0.6-<0.8 9.52 16.67 16.67 18.68 6.48
0.8-1 90.48 70.00 78.33 71.43 85.19
Persistence (<60 day gap) (%) 74.34 42.86 0.0003 53.03 0.0020 54.08 0.0009 62.61 0.0396
Persistent days (days till first 60-day gap) (%)
No gap 74.34 42.86 53.03 54.08 62.61
1-90 6.58 22.86 15.15 19.39 12.17
91-180 4.61 5.71 21.21 10.20 13.91
181-270 9.21 17.14 6.06 10.20 6.96
270+ 5.26 11.43 4.55 6.12 4.35
Switched to other DMTs after discontinuation (%) 4.61 11.43 0.1219 13.64 0.0188 9.18 0.1488 13.04 0.0130
P-values based on comparison with fingolimod cohort, using Chi-square tests for categorical variables and Student’s t-tests for continuous variables.
DMT: disease-modifying therapy. SD: standard deviation. PDC: proportion of days covered. MPR: medication procession ratio.

identified in various chronic disease areas which require further improve the treatment adherence for patients with
long-term treatments, such as HIV antiretroviral ther- chronic illness.
apy, as well as in oral treatments with gastrointestinal Early treatment and adherence to DMT treatment are
tolerability issues shown among cancer patients [13-15]. two key factors for the effective prevention of relapses
In addition to tolerability issues and side effects of the and disability. Sormani et al reported that treatments
treatments, self-injection is often associated with add- that reduce relapses during the first two years of having the
itional barriers to compliance and persistence, including disease are associated with a lower accumulation of neuro-
storage issues and priming needles [13]. The availability logical disability [16]. Using real-world data, Tan et al dem-
of new oral DMTs will provide an alternative for MS pa- onstrated the association between DMT adherence and
tients who cannot tolerate the self-injected DMTs and patient clinical and economic outcomes. Tan et al found
improve adherence to DMT treatment. that being adherent to DMTs (defined as MPR≥80%) was
Despite the better treatment compliance observed in associated with a 37% lower risk of having an MS-related
patients initiating fingolimod than other DMT cohorts, hospital admission, a 29% lower risk of having an MS re-
27.8% of fingolimod users discontinued the medication lapse, and about $1,000 less in healthcare costs during the
within 1 year since the treatment initiation (25.7% among 12-month follow-up period [17]. Steinberg’s research found
experienced DMT users and 31.3% among naïve DMT similar results with adherent patients tending to have a
users). While oral medications may offer an improvement lower risk of inpatient admission over a 3 year period
in patient compliance to DMT treatment, other strategies [7,17]. With fewer relapses and hospitalizations, patients
or programs may need to be tested and implemented to are more able to experience an improved quality of life as
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a. Naïve disease modifying therapy users

1.0

Probabilit y of staying on index medication

0.9

0.8

0.7

0.6

0.5

0.4
5 25 45 65 85 105 125 145 165 185 205 225 245 265 285 305 325 345 365
Days
fingolimod interferon beta-1b intramuscular interferon beta-1a
subcutaneous interferon beta-1a glatiramer acetate

b. Experienced disease modifying therapy users

1.0
Probabilit y of staying on index medication

0.9

0.8

0.7

0.6

0.5

0.4
1 31 61 91 121 151 181 211 241 271 301 331 361
Days
fingolimod interferon beta-1b intramuscular interferon beta-1a
subcutaneous interferon beta-1a glatiramer acetate

Figure 2 Time to discontinuation of initiated desease-modifying agent.

well as reduced adverse effects. For this reason, selecting may have been misclassified as naïve DMT uses if they
treatments that are highly efficacious and tolerable will stopped DMTs for 1 year or longer prior to the index date
maximize the likelihood of optimal management of MS re- for different reasons such as pregnancy, breast feeding,
lapse activity and long-term outcomes. non-compliance, or enrolled in clinical trials of DMT. The
This study has several limitations. We might not have association between fingolimod use and treatment compli-
captured all the eligible patients from the Medco database ance was in the same direction among both experienced
because only pharmacy claims were used to identify MS and naïve DMT users, therefore, it is unlikely that the
patients. In addition, we did not measure the outcomes misclassification has affected the study conclusion. The
associated with different DMTs, or the clinical and eco- analyses were also limited by the variables in the database.
nomic consequences of differences in medication adher- For the majority of the patients, we used pharmacy claims
ence and persistence. Such a study would require a longer only to infer that patients were taking oral medications to
follow-up time and a larger sample size, neither of which treat MS; Compliance to DMT was assessed based on dis-
were possible due to the recent availability of fingolimod. pensed medications rather than medications consumed by
Additionally, patients were considered DMT naïve if they the patients. Further studies using patient-reported com-
did not have DMT prescription fill during 12 months pliance may provide a more accurate estimate of patient
prior to the index date. Some experienced DMT users compliance. Further event-based studies are warranted as
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Table 4 Time to index DMT discontinuation: cox proportional hazard models for experienced and naïve DMT users
Experienced DMT Users Naïve DMT Users
Hazard ratio 95% Confidence interval Hazard ratio 95% Confidence interval
DMT initiated
Fingolimod Reference Reference
Interferon beta-1b 2.83 (1.62-4.93) 1.90 (1.25-2.89)
Intramuscular interferon beta-1a 2.43 (1.49-3.97) 1.53 (1.03-2.28)
Subcutaneous interferon beta-1a 2.42 (1.54-3.82) 1.58 (1.05-2.38)
Glatiramer acetate 1.73 (1.11-2.69) 1.53 (1.04-2.24)
Gender
Male Reference Reference
Female 1.45 (0.99-2.11) 1.07 (0.89-1.29)
Age categories
18-44 Reference Reference
45-54 0.78 (0.55-1.11) 0.81 (0.68-0.98)
55-64 0.97 (0.65-1.46) 0.75 (0.60-0.94)
65+ 0.80 (0.38-1.69) 0.67 (0.44-1.01)
Region
West Reference Reference
Northeast 0.68 (0.40-1.15) 0.78 (0.60-1.01)
Midwest 0.99 (0.62-1.59) 0.88 (0.69-1.13)
South 1.19 (0.75 -1.87) 0.88 (0.69-1.12)
Prior authorization for index prescription 1.21 (0.88-1.65) 1.25 (1.06-1.48)
Copayment for index prescription
0-<30 Reference Reference
30-100 0.93 (0.65-1.32) 0.95 (0.78-1.15)
100+ 0.92 (0.59-1.45) 0.88 (0.70-1.09)
Mail order for index prescription 1.10 (0.59-2.07) 0.57 (0.42-0.78)
Pharmacy type for index prescription
Retail Reference Reference
Accredo 1.03 (0.54 -1.97) 1.05 (0.77-1.43)
Other specialty pharmacy 1.69 (0.86-3.31) 0.78 (0.56-1.07)
Bold numbers indicate that the hazard ratios are significantly different from 1 at p<0.05.

data become available. Finally, while we adjusted for avail- Abbreviations

able demographic and other covariates in our models, un- FDA: Food and drug administration; DMTs: Disease-modifying therapies;
MPR: Medication possession ratio; MS: Multiple sclerosis; PDC: Proportion of
observed factors may have contributed to differences in days covered; SD: Standard deviation.
adherence and persistence.
Competing interests
The authors declare that they have no competing interests.
Conclusion
The oral MS treatment fingolimod is associated with Authors’ contributions
lower rates of discontinuation and higher rates of adher- NA, SA and EK developed study concept and collaborated in development
ence in comparison to self-injected DMTs. One poten- of study design, and manuscript, and conducted a critical review. NW, YW,
LB developed study design, conducted analysis, and wrote manuscript. DB
tial rationale is the improved tolerability of fingolimod. completed interpretation and conducted critical review of manuscript. All
The emergence of other oral DMTs with differing toler- authors read and approved the final manuscript.
ability profiles will help clarify this issue of tolerability
Acknowledgements
versus formulation as a mediator of adherence and This study was sponsored by Novartis Pharmaceuticals Corporation. This work
persistence. was supported by Novartis Pharmaceuticals Corporation. Ning Wu, and Luke
Agashivala et al. BMC Neurology 2013, 13:138 Page 9 of 9
http://www.biomedcentral.com/1471-2377/13/138

Boulanger, who are employees of Evidera, You Wu was employed by Evidera at

the time of the study, and David W. Brandes, who is an employee of Sweetwater
Neurology, were contracted by Novartis to work in collaboration on this study.
Neetu Agashivala, and Edward Kim are employees of Novartis. Safiya Abouzaid
was an employee of Novartis at the time of the study.

Author details
1
Novartis Pharmaceuticals Corporation, One Health Plaza, 07936, East
Hanover, NJ, USA. 2Evidera, 430 Bedford Street, Suite 300, 02420, Lexington,
MA, USA. 3Sweetwater Neurology, 10800 Parkside Drive Suite 202, 37934,
Knoxville, TN, USA.

Received: 14 January 2013 Accepted: 26 September 2013

Published: 4 October 2013

References
1. Tullman MJ: Overview of the epidemiology, diagnosis, and disease
progression associated with multiple sclerosis. Am J Manag Care 2013,
19:S15–20.
2. Loma I, Heyman R: Multiple sclerosis: pathogenesis and treatment. Curr
Neuropharmacol 2011, 9:409–16.
3. Compston A, Coles A: Multiple sclerosis. Lancet 2002, 359:1221–1231.
4. Martinelli Boneschi F, Rovaris M, Capra R, Comi G: Mitoxantrone for
multiple sclerosis. Cochrane Database Syst Rev 2005, 4:CD002127.
5. Girouard N, Soucy N: Patient considerations in the management of
multiple sclerosis: development and clinical utility of oral agents. Patient
Prefer Adherence 2011, 5:101–108.
6. Portaccio E, Amato MP: Improving compliance with interferon-beta therapy in
patients with multiple sclerosis. CNS Drugs 2009, 23:453–462.
7. Steinberg SC, Faris RJ, Chang CF, Chan A, Tankersley MA: Impact of adherence
to interferons in the treatment of multiple sclerosis: a non-experimental,
retrospective, cohort study. Clin Drug Investig 2010, 30:89–100.
8. Jordan LB, Vekeman F, Sengupta A, Corral M, Guo A, Duh MS: Persistence
and compliance of deferoxamine versus deferasirox in medicaid patients
with sickle-cell disease. J Clin Pharm Ther 2012, 37:173–181.
9. Halpern R, Agarwal S, Borton L, Oneacre K, Lopez-Bresnahan MV:
Adherence and persistence among multiple sclerosis patients after one
immunomodulatory therapy failure: retrospective claims analysis. Adv
Ther 2011, 28:761–775.
10. Devonshire V, Lapierre Y, Macdonell R, Ramo-Tello C, Patti F, Fontoura P,
Suchet L, Hyde R, Balla I, Frohman EM, et al: The global adherence project
(GAP): a multicenter observational study on adherence to disease-
modifying therapies in patients with relapsing-remitting multiple
sclerosis. Eur J Neurol 2011, 18:69–77.
11. O’Rourke KE, Hutchinson M: Stopping beta-interferon therapy in multiple
sclerosis: an analysis of stopping patterns. Mult Scler 2005, 11:46–50.
12. Treadaway K, Cutter G, Salter A, Lynch S, Simsarian J, Corboy J, Jeffery D,
Cohen B, Mankowski K, Guarnaccia J, et al: Factors that influence adherence
with disease-modifying therapy in MS. J Neurol 2009, 256:568–576.
13. Brod M, Rousculp M, Cameron A: Understanding compliance issues for
daily self-injectable treatment in ambulatory care settings. Patient Prefer
Adherence 2008, 2:129–136.
14. Braithwaite RS, Kozal MJ, Chang CC, Roberts MS, Fultz SL, Goetz MB, Gibert C,
Rodriguez-Barradas M, Mole L, Justice AC: Adherence, virological and
immunological outcomes for HIV-infected veterans starting combination
antiretroviral therapies. AIDS 2007, 21:1579–1589.
15. Conte P, Guarneri V: Safety of intravenous and oral bisphosphonates and
compliance with dosing regimens. Oncologist 2004, 9(Suppl 4):28–37.
16. Sormani MP, Li DK, Bruzzi P, Stubinski B, Cornelisse P, Rocak S, De Stefano N: Submit your next manuscript to BioMed Central
Combined MRI lesions and relapses as a surrogate for disability in and take full advantage of:
multiple sclerosis. Neurology 2011, 77:1684–1690.
17. Tan H, Cai Q, Agarwal S, Stephenson JJ, Kamat S: Impact of adherence to • Convenient online submission
disease-modifying therapies on clinical and economic outcomes among
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patients with multiple sclerosis. Adv Ther 2011, 28:51–61.
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