Background: Nonadherence to disease-modifying drugs (DMDs) for multiple sclerosis (MS) is associated with poorer clinical outcomes, including higher rates of relapse and disease progression, and higher medical resource use. A systematic review and quantification of adherence and persistence with oral DMDs would help clarify the extent of nonadherence and nonpersistence in patients with MS to help prescribers make informed treatment plans and optimize patient care. The objectives were to: 1) conduct a systematic literature review to assess the availability and variability of oral DMD adherence and/or persistence rates across 'real-world' data sources; and 2) conduct meta-analyses of the rates of adherence and persistence for once- and twice-daily oral DMDs in patients with MS using real-world data. Methods: A systematic review of studies published between January 2010 and April 2018 in the PubMed database was performed. Only studies assessing once- and twice-daily oral DMDs were available for inclusion in the analysis. Study quality was evaluated using a modified version of the Newcastle-Ottawa Scale, a tool for assessing quality of observational studies. The random effects model evaluated pooled summary estimates of nonadherence. Results: From 510 abstracts, 31 studies comprising 16,398 patients with MS treated with daily oral DMDs were included. Overall 1-year mean medication possession ratio (MPR; n = 4 studies) was 83.3% (95% confidence interval [CI] 74.5–92.1%) and proportion of days covered (PDC; n = 4 studies) was 76.5% (95% CI 72.0–81.1%). Pooled 1-year MPR ≥80% adherence (n = 6) was 78.5% (95% CI 63.5–88.5%) and PDC ≥80% (n = 5 studies) was 71.8% (95% CI 59.1–81.9%). Pooled 1-year discontinuation (n = 20) was 25.4% (95% CI 21.6–29.7%). Conclusions: Approximately one in five patients with MS do not adhere to, and one in four discontinue, daily oral DMDs before 1 year. Opportunities to improve adherence and ultimately patient outcomes, such as patient education, medication support/reminders, simplified dosing regimens, and reducing administration or monitoring requirements, remain. Implementation of efforts to improve adherence are essential to improving care of patients with MS.
Keywords: Adherence; Dimethyl fumarate; Discontinuation; Fingolimod; Meta-analysis; Persistence; Real-world; Teriflunomide
Multiple sclerosis (MS) is a progressive, inflammatory, autoimmune, neurodegenerative disease of the central nervous system that often begins in early adult life. Guidelines recommend that clinicians should offer disease-modifying drugs (DMDs) to people diagnosed with relapsing forms of MS (RMS) [[
Medication adherence and persistence are challenging for patients with MS [[
A systematic review and quantification of the real-world adherence to and persistence with oral DMDs would help clarify the extent of nonadherence and nonpersistence in patients with MS. Kantor et al. 2018 conducted a systematic review and meta-analysis of real-world persistence with fingolimod in patients with relapsing-remitting MS (RRMS) and reported a consensus 1-year persistence rate of 82% (95% confidence interval [CI] 79–85%) [[
A systematic literature search was performed of all studies published between January 2010 and April 2018 in the PubMed database that evaluated adherence or persistence to oral DMDs. The search strategy used the following terms: (Aubagio OR cladribine OR dimethyl fumarate OR fingolimod OR Gilenya OR Tecfidera OR teriflunomide OR oral OR disease modifying drug OR DMD OR disease modifying therapy OR DMT) AND multiple sclerosis AND (adherence OR compliance OR persistence OR discontinuation). A priori exclusion criteria were: lack of primary data; lack of primary real-world DMD adherence/persistence data; lack of oral DMD adherence/persistence data; pediatric studies; non-English studies; and abstract-only available. Two reviewers independently reviewed the search results and reference lists of selected articles to identify additional appropriate studies and carried out data extraction. Full search strategy and search results are provided in Additional File 1.
Information extracted from the screened articles included the type of study/data source; study population (baseline demographic and clinical characteristics); treatment arms; duration of follow-up after DMD initiation; sample size; outcomes evaluated (including definition of adherence and method of measurement); clinical results; secondary results; and strengths and limitations of the studies.
The quality of selected studies was evaluated using a modified version of the Newcastle-Ottawa Scale (NOS), a tool for assessing the quality of observational studies [[
Study quality as evaluated using a modified version of the Newcastle-Ottawa Scale
Reference Study design and patient selection Outcome evaluation Ascertainment of intervention/validity of study design Patient selection Outcome not present at start Appropriate measure of adherence/persistence Adequate/appropriate duration of follow-up All patients accounted for followed up Lanzillo R, et al. ◉ ● ● ● ● ● Ferraro D, et al. ◉ ● ● ● ● ● Granqvist M, et al. ● ● ● ● ● ● Hua LH, et al. ◉ ◉ ● ● ◉ ● Eriksson I, et al. ● ● ● ● ● ● Williams MJ, et al. ● ◉ ○ ● ● ● Ernst FR, et al. ◉ ● ● ● ◉ ● Lattanzi S, et al. ◉ ● ● ● ● ● Gerber B, et al. ● ◉ ○ ● ● ● Zimmer A, et al. ◉ ● ◉ ◉ ◉ ● Hersh CM, et al. ◉ ● ● ● ● ● Vollmer B, et al. ◉ ◉ ◉ ● ◉ ● Johnson KM, et al. ● ◉ ● ● ● ● Smoot K, et al. ● ● ● ● ● ● Burks J, et al. ● ◉ ○ ● ● ● Munsell M, et al. ● ◉ ○ ● ● ● Hersh CM, et al. ◉ ◉ ● ● ● ● Zhovtis L, et al. ◉ ● ● ● ● ● Nazareth T, et al. ● ● ● ◉ ● ● Wicks P, et al. ◉ ● ● ● ○ ◉ Warrender-Sparkes M, et al. ● ◉ ● ● ◉ ● Lapierre Y, et al. ◉ ○ ◉ ● ● ● Braune S, et al. ● ● ● ● ● ◉ Frisell T, et al. ● ◉ ● ● ● ● Longbrake EE, et al. ◉ ◉ ● ● ◉ ● He A, et al. ● ● ● ◉ ● ● Hersh CM, et al. ◉ ● ● ● ◉ ● Bergvall N, et al. ● ◉ ○ ● ● ● Al-Hashel J, et al. ◉ ● ● ◉ ◉ ● Agashivala N, et al. ● ◉ ○ ● ● ● Ontaneda D, et al. ◉ ◉ ● ● ○ ●
Abbreviations: RRMS relapsing-remitting multiple sclerosis, ● full-quality score, ◉ partial-quality score, ○ poor-quality score For the ascertainment of the intervention/validity of study design criterion, if the study was a medical chart review, evidence that there was an effort made to validate reported data resulted in a full-quality score. Otherwise, the medical chart review or registry study was assigned a partial-quality score. Prospective cohort studies and administrative claims database evaluations were given a full-quality score for this criterion For the patient selection criterion, studies were given a full-quality score if the patients were well characterized (i.e., age, sex, region, duration of MS diagnosis, MS severity, prior treatments, current treatment) and were representative of patients with RRMS. Studies were not penalized for including selected populations or for only evaluating a single center because it was felt that these studies were still valid cohort studies. Studies were given a poor-quality score if the patient population was not well-characterized and was not representative of patients with RRMS For the outcome of interest not present at the start of the study criterion, studies were given a full-quality score if they attempted to capture patient prescription abandonment and thoroughly described how it was ascertained. Administrative claims database analyses were not able to ascertain this, and were therefore given a poor-quality score for this criterion For the appropriate measurement of adherence/persistence criterion, studies with a full-quality score had to appropriately define and measure adherence and persistence and include and/or delineate switching for discontinuation The adequate/appropriate duration of follow-up criterion required full-quality studies to measure adherence/persistence over 1 year as this was the most common time horizon used and enabled comparability The all patients accounted at follow-up criterion required that all patients evaluated were followed up throughout the study and did not have missing data
The selection of endpoints was driven by the availability of data in the published, peer-reviewed literature. Adherence was evaluated using either the medication possession ratio (MPR) or the proportion of days covered (PDC). MPR was calculated as the total number of days of medication supply between the first prescription claim and the last prescription claim issued during the follow-up period divided by the total number of days in the follow-up period. A variable follow-up period was used for the MPR denominator (number of days between the index date and the last prescription dispensed inclusive of supply) [[
In line with published recommendations regarding the use of real-world data in meta-analyses, [[
From a total of 510 abstracts identified, 31 studies comprising 16,398 patients were included in the systematic review after applying exclusion criteria (Fig. 1). Table 2 provides information about the individual studies. No studies evaluating cladribine tablets were identified due to its recent approval, therefore the analyses focused on once- and twice-daily oral maintenance DMDs. Siponimod was not available at the time of the study and is not included in the analyses.
Graph: Fig. 1 Study selection flowchart. Abbreviations:DMD disease-modifying drug
Studies included in the systematic review (n = 31) [[
Reference Study design Geographical area Sample size for oral DMD(s) studied Study population Outcomes evaluated Agashivala N, et al. Retrospective administrative claims database evaluation USA Fingolimod ( Patients with MS Mean MPR and PDC; MPR ≥80%; PDC ≥80%; discontinuation rate mean age 46.4 (10.7) years; 79.0% female; Al-Hashel J, et al. Retrospective evaluation of patient MS registry Kuwait Fingolimod ( Patients with RRMS % discontinuation mean age 33.3 ± 9.2 years; 75.4% female Bergvall N, et al. Retrospective administrative claims database evaluation USA Fingolimod ( 889 patients (age range NS) with MS initiating fingolimod MPR ≥80%; PDC ≥80%; discontinuation rate Braune S, et al. Prospective, observational, multi-center cohort study Germany Fingolimod ( Patients with RRMS (age range NS) with failure of earlier therapy with injectable DMT initiating fingolimod Discontinuation rate Burks J, et al. Retrospective administrative claims database study USA Patients with MS (aged 18–65 years) initiating an oral DMD Mean PDC; proportion of patients with PDC ≥80%; discontinuation rate Teriflunomide, fingolimod, DMF mean age 44.41 (10.52); 72.1% female Eriksson I, et al. Prospective cohort which includes retrospective claims and other health-related data analysis Stockholm county, Sweden DMF ( 400 patients with RRMS (age range NS) initiating DMF Discontinuation rate Mean age ranged from 35.3–40.5 years 61% previously treated. Ernst FR, et al. Retrospective medical chart review USA DMF ( 307 patients (aged ≥18 years) with RRMS initiating DMF Discontinuation rate Mean age 46.6 ± 11.8 years; 77.9% female; Ferraro D, et al. Prospective observational cohort study Italy Patients with RRMS (age range NS) initiating oral DMD Discontinuation rate Teriflunomide, DMF mean age 43 years, 29.8% female Frisell T, et al. Prospective, observational, multi-center cohort study Sweden Fingolimod ( Patients with RRMS initiating fingolimod tx Discontinuation rate mean (SD) age 38 (10) years; 67% females Gerber B, et al. Retrospective administrative database evaluation Alberta, Canada 72 patients with MS (aged < 35–≥65 years) initiating an oral DMD MPR ≥80%; discontinuation rate Fingolimod, teriflunomide, DMF 61.7% aged 35–55 years; 73.8% female Granqvist M, et al. Retrospective medical chart review from MS registry Sweden Patients with RRMS initiating DMD tx Discontinuation rate DMF ( The median (interquartile) age 34.4 (27.4–43.4) years; 68% female He A, et al. Matched retrospective analysis of data collected prospectively from an international, observational cohort study International Fingolimod ( Patients with MS (age range NS) switching to fingolimod tx Discontinuation rate Hersh CM, et al. Retrospective, single-center medical chart review Cleveland, OH, USA Fingolimod ( Patients with MS (age range NS) initiating fingolimod Discontinuation rate 3.5% treatment naïve and 24.0% had remote DMT use prior to fingolimod Hersh CM, et al. Retrospective, single-center medical chart review Cleveland, OH, USA Fingolimod ( Patients with MS (age range NS) being treated with DMD for ≥1 year Discontinuation rate Hersh CM, et al. Retrospective, single-center medical chart review Cleveland, USA Fingolimod ( Patients with MS initiating DMD tx Discontinuation rate mean age DMF 47.1 ± 11.2 years fingolimod 43.9 ± 9.2 years; RRMS DMF 73.5% fingolimod 81.7% Hua LH, et al. Retrospective medical chart review Cleveland, OH; Las Vegas, NV; Weston, FL, USA Fingolimod (n = 10), DMF ( Patients (aged over 60 years) with MS on DMD for ≥2 years Discontinuation rate Johnson KM, et al. Retrospective administrative claims database evaluation USA Fingolimod ( Patients with MS (aged ≥18 years) initiating DMD tx MPR, MPR ≥80%, mean PDC, PDC ≥80%, discontinuation rate Mean age range 44.4–53.2 years; 75.5–83.6% female Lanzillo R, et al. Retrospective medical chart review Italy Patients with RRMS (age range NS) initiating oral DMD Discontinuation rate Teriflunomide, DMF mean age 40.0 (11.2) year Lapierre Y, et al. Prospective, observational, multi-center cohort study Canada Fingolimod ( Patients with RRMS (age range NS) receiving fingolimod and participating in an education and support program Discontinuation rate Mean age was 41.2 years (range 18–75.5); 75.2% were female. Lattanzi S, et al. Retrospective medical chart review Italy Fingolimod ( Patients with RRMS; Discontinuation rate mean age was 41.2 (10.3) years, 66.5% female Longbrake EE, et al. Retrospective, single-center medical chart review USA Teriflunomide ( Patients (age range NS) with relapsing forms of MS initiating oral DMD tx Discontinuation rate mean age 39.8–49.4 years; 72.0–81.9% female Munsell M, et al. Retrospective administrative claims database evaluation USA Patients with MS (aged 18–64 years) initiating an oral DMD; mean age 44.9 years; 76.2% female Mean MPR; proportion of patients with MPR ≥80%; discontinuation rate Teriflunomide, fingolimod, DMF Nazareth T, et al. Retrospective medical chart review USA Teriflunomide (n = 31), fingolimod ( Patients with MS (aged ≥18 years) initiating DMF; Discontinuation rate Age range (mean ± SD); 44.2 ± 10.7 to 50.6 ± 9.6 years. Ontaneda D, et al. Retrospective, single-center medical chart review Cleveland, OH, USA Fingolimod (n = 317) Patients with MS (age group NS) prescribed fingolimod Discontinuation rate Smoot K, et al. Prospective registry at a single site Oregon, USA DMF ( Patients (aged ≥18 years) with RMS initiating DMF tx; Discontinuation rate mean age 49.4 ± 12.0 years Vollmer B, et al. Retrospective, single-center medical chart review Colorado, USA Fingolimod ( Patients with MS (age range NS) initiating DMD tx; Discontinuation rate mean age range 42.5–45.8 years; 69.6–72.0% female Warrender-Sparkes M, et al. Prospective, observational multi-center cohort study International Fingolimod ( Patients with CIS or early RRMS (age range NS) initiating fingolimod tx Discontinuation rate Wicks P, et al. Online community patient survey USA Fingolimod ( Patients (aged ≥18 years) with RRMS with current or past experience of fingolimod or DMF tx Discontinuation rate mean age 46.2–51.8 years; % female 77.0–93.8%; Williams MJ, et al. Retrospective administrative claims database evaluation USA DMF ( Patients (aged ≥18 years) with MS initiating DMD tx Mean MPR; MPR ≥80%; mean PDC; PDC ≥80%; discontinuation rate Zhovtis Ryerson L, et al. Retrospective medical chart review in 2 tertiary MS clinics New York/New Jersey, USA DMF ( Patients (aged ≥18 years) with RRMS initiating DMF Discontinuation rate range across subgroups: mean age 42.5–47.4 years, 71–83% female Zimmer A, et al. Prospective, observational, single-center cohort study Basel, Switzerland Fingolimod ( Patients with relapsing MS (aged ≥18 years) initiating fingolimod; Discontinuation rate; % nonadherent (pill count) 80% female
Note:
Most studies (n = 18; 58.1%) were conducted in the US, one-quarter (25.8%; n = 8) were from Europe, two (6.5%) were multinational, two (6.5%) were from Canada, and one (3.2%) was from Kuwait (Table 2). Twelve studies (38.7%) were retrospective analyses of chart/electronic medical records; eight (25.8%) analyzed administrative claims databases; seven (22.6%) were prospective observational cohort studies; three (9.7%) used patient registries; and one (3.2%) was a patient survey (Table 2). The duration of follow-up for the studies ranged from 3 months to 3 years, with 21 studies (67.7%) reporting data at 1-year follow-up. All 31 studies evaluated treatment discontinuation for various follow-up periods. The 1-year treatment discontinuation range was 5.1–42.3% (n = 20 studies). For 1-year adherence, 4 studies reported the mean MPR, 6 studies reported MPR ≥80%, 4 studies reported the mean PDC, and 5 studies reported PDC ≥80%.
Quality assessments of the selected studies are presented in Table 1. For the ascertainment of the intervention/validity of study design criteria in the study design and patient selection perspective, approximately half of the studies had a full-quality score and half had a partial-quality score. One study (Lapierre et al. 2016) was assigned a poor-quality score for patient selection because the patient population was neither well-characterized nor representative of patients with RRMS [[
A significant Cochran's Q statistic and an I
The overall mean MPR during the 1-year follow-up period for once- and twice-daily oral maintenance DMDs (4 studies) was 83.3% (95% CI 74.5–92.1%) (Fig. 2a) whereas the overall 1-year mean PDC (4 studies) was 76.5% (95% CI 72.0–81.1%) (Fig. 2b). The pooled MPR ≥80% adherence rate during the 1-year follow-up period across 6 studies was 78.5% (95% CI 63.5–88.5%) (Fig. 3a) and 1-year pooled PDC ≥80% adherence rate (5 studies) was 71.8% (95% CI 59.1–81.9%) (Fig. 3b). All 31 studies evaluated treatment discontinuation using various follow-up periods; the 1-year pooled discontinuation rate across 20 studies for oral maintenance DMDs was 25.4% (95% CI 21.6–29.7%) (Fig. 4).
Graph: Fig. 2 Meta-analysis of mean adherence rate as determined by a) MPR or b) PDC. Note: For studies for which results for treatment-naive and treatment-experienced patients were reported separately (combined data were not available), data were combined; for studies reporting data for more than 1 oral DMD (combined data were not reported), data were combined; for studies reporting data for subgroups (combined data were not reported), data were combined. The area of each grey square is proportional to the study's weight in the meta-analysis. Weight values are rounded. Abbreviations: CI, confidence interval; DMD, disease-modifying drug; MPR, medication possession ratio; MRAW, raw mean; PDC, proportion of days covered
Graph: Fig. 3 Meta-analysis of proportion of patients adherent to a DMD as determined by MPR or PDC. Note: For studies for which results for treatment-naive and treatment-experienced patients were reported separately (combined data were not available), data were combined; for studies reporting data for more than 1 oral DMD (combined data were not reported), data were combined; for studies reporting data for subgroups (combined data were not reported), data were combined. The area of each grey square is proportional to the study's weight in the meta-analysis. Weight values are rounded. Abbreviations: CI: confidence interval; DMD: disease-modifying drug; MPR: medication possession ratio; PDC: proportion of days covered
Graph: Fig. 4 Meta-analysis of proportion of patients discontinuing a DMD. Note: For studies for which results for treatment-naive and treatment-experienced patients were reported separately (combined data were not available), data were combined; for studies reporting data for more than 1 oral DMD (combined data were not reported), data were combined; for studies reporting data for subgroups (combined data were not reported), data were combined; for Lattanzi et al., number of patients discontinuing at 12 months included patients for whom data were not available at 12 months because they stopped taking medications (n = 34); 34 + 46 = 80 of 307 or 26.05%; for Vollmer et al. and He et al., for which data were reported in Kaplan–Meier curves only, 1-year persistence rates were extracted from the curves using a digitizer (Guyot P et al. 2012); for Zhovtis et al. 2016, number of patients discontinuing at 12 months was derived from the reported 14-month rate (n = 76.4). The area of each grey square is proportional to the study's weight in the meta-analysis. Weight values are rounded. Abbreviations: CI, confidence interval; DMD, disease-modifying drug
Subgroup analyses were only conducted for the outcome of discontinuation due to the small number of studies reporting MPR and PDC oral DMD adherence. When studies were analyzed by US and ex-US groupings, similar proportions of patients were found to discontinue DMD therapy (25.6% [95% CI 20.7–31.1%] vs. 25.3% [95% CI 19.6–31.9%], respectively) (Fig. 5a). The proportion of patients discontinuing DMD therapy was greatest for studies evaluating administrative claims databases (29.0, 95% CI 22.0–37.2%), followed by prospective cohort studies (24.7, 95% CI 18.7–31.9%) and medical chart reviews (22.9, 95% CI 18.4–28.1%) (Fig. 5b), though some overlapping of CIs was apparent. The results of the leave-one-out sensitivity analysis confirmed that removal of individual studies did not affect the results (Supplementary Figs. 1, 2a, and 2b).
Graph: Fig. 5 Subgroup meta-analyses of proportion of patients discontinuing a DMD. Note: For studies for which results for treatment naive and treatment-experienced patients were reported separately (combined data were not available), data were combined; for studies reporting data for more than 1 oral DMD (combined data were not reported), data were combined; for studies reporting data for subgroups (combined data were not reported), data were combined. The area of each grey square is proportional to the study's weight in the meta-analysis. Weight values are rounded. Abbreviations: ACD, administrative claims database; CI, confidence interval; MCR, medical chart review; PC, prospective cohort
This is the first meta-analysis to assess real-world adherence to and persistence with multiple oral maintenance DMDs in patients with MS. Results showed that one in five patients do not adhere to once- or twice-daily oral maintenance DMDs, and one in four patients discontinue the initially-prescribed oral DMDs before 1 year. Ninety-five percent CIs for the estimates of adherence and persistence were wide, reflecting the heterogeneity in rates of adherence and discontinuation.
Adherence to DMDs is an important aspect of optimizing patient care in MS as greater adherence has been shown to be associated with improvements in relapse outcomes and quality of life, fewer hospitalizations and emergency room visits, decrease in neuropsychological issues, fewer days of work lost, and lower MS-related medical costs [[
An increased understanding of barriers to DMD adherence and persistence and the implementation of efforts to improve adherence and persistence are important. Real-world data on adherence to DMDs in patients with MS can help inform therapeutic decision making [[
Depression has also been shown to be associated with decreased DMD adherence and persistence in patients with MS. Gerber, et al. and Munsell, et al. both reported a significant relationship between comorbid depression and nonadherence, [[
The rates of adherence and discontinuation may differ among oral DMDs due to several potential factors such as the dosing regimen (e.g. once- versus twice-daily), efficacy, tolerability, and adverse events [[
This study was conducted in line with recommendations available in the literature for the use of real-world evidence in meta-analyses [[
The I
Subgroup analyses demonstrated that there were essentially no differences between US- and ex-US-based studies and support the need for a better understanding of why patients worldwide discontinue oral DMD treatment. The study design subgroup analyses showed overlapping CIs, indicating a lack of significant differences. However, numerical differences suggested that administrative claims data analyses may more fully capture discontinuation than prospective cohort studies and medical chart reviews. With prospective cohort studies and medical chart reviews, bias may arise from patient or investigator report, whereas administrative claims database analyses provide objective billing information for medication dispensed. Also, cohort studies may also inherently encourage patients to remain in the study and continue treatment. Chart reviews may not capture all discontinuations, depending upon the availability and quality of follow-up data. Further subgroup analyses were limited by the small number of real-world/observational studies, suggesting that more real-world research is needed.
This is the second published meta-analysis of real-world adherence to or persistence with oral DMDs in patients with MS. Kantor et al. 2018 conducted a systematic review and meta-analysis focusing on the real-world persistence with fingolimod in patients with RRMS [[
There are limitations to this study. Although nonrandomized cohort studies or observational studies may provide a more 'real-world' representation of outcomes, costs, and utilization, differences in baseline characteristics can introduce biases, and the influence of unmeasured factors cannot be ruled out. As described, the substantial proportion of heterogeneity found across the studies is also a limitation. The use of a variable follow-up period for the MPR denominator potentially contributed to an inflated mean MPR [[
Adherence to treatment is an important issue for the management of patients with MS. This meta-analysis of real-world studies showed that approximately one in five patients with MS do not adhere to once- or twice-daily oral maintenance DMD treatment regimens, and one in four patients with MS discontinue once- or twice-daily oral maintenance DMDs before 1 year. Wide 95% CIs for the estimates of adherence and discontinuation reflect the heterogeneity in the rates that was observed. Opportunities to address barriers to DMD adherence in patients with MS remain, such as patient education efforts to manage expectations and to emphasize the importance of adherence, implementation of medication support/reminder techniques, simplification of dosing regimens, and reducing the need for specialized administration or monitoring requirements [[
The design of this study, the collection and analysis of data, and medical writing and editorial support in development of this manuscript were sponsored by EMD Serono, Inc., Rockland, MA, USA, an affiliate of Merck KGaA, Darmstadt, Germany.
Writing and editorial support for the preparation of this manuscript was provided by Jenna Steere, PhD and Nick White of Ashfield Healthcare (New York, NY); funding was provided by EMD Serono, Inc., Rockland, MA, USA, an affiliate of Merck KGaA, Darmstadt, Germany. The authors had full editorial control, and provided their final approval of all content.
JN, NE, RE, AD, MG, and AP were involved in the study design, interpretation of the data, writing and reviewing the manuscript, and the final approval of the version of the manuscript to be published. AD, NE, and RE conducted the data analyses.
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Not applicable.
Not applicable.
JN has received consulting fees for speaking, advising, and consulting from: Biogen Idec, EMD Serono, Inc., Rockland, MA, USA, an affiliate of Merck KGaA, Darmstadt, Germany, Genzyme, Genentech, MSAA, MS World, and Novartis. She has received research grants from Genzyme, Biogen, and Novartis. NCE and RAE are employees of Health Services Consulting Corporation. AD is an employee of Fair Dynamics Consulting and worked on behalf of Health Services Consulting Corporation. Health Services Consulting Corporation received funding from EMD Serono, Inc., Rockland, MA, USA, an affiliate of Merck KGaA, Darmstadt, Germany, to run the analysis. MG and ALP are employees of EMD Serono, Inc., Rockland, MA, USA, an affiliate of Merck KGaA, Darmstadt, Germany.
Graph: Additional file 1: Supplementary Methods: Electronic Search Strategy. Details of electronic literature search strategy, exclusion criteria and full list of search results (including abstract citation, title, text, digital objective identifier [DOI], PubMed ID [PMID], and author names and information).
Graph: Additional file 2: Supplementary Figure 1. Leave-one-out sensitivity analysis for the proportion of patients discontinuing a DMD. For studies for which results for treatment naive and treatment-experienced patients were reported separately (combined data were not available), data were combined; for studies reporting data for more than 1 oral DMD (combined data were not reported), data were combined; for studies reporting data for subgroups (combined data were not reported), data were combined. Abbreviations : DMD, disease-modifying drug.
Graph: Additional file 3: Supplementary Figure 2. Leave-one-out sensitivity analysis for subgroup analyses for the proportion of patients discontinuing a DMD. For studies for which results for treatment naive and treatment-experienced patients were reported separately (combined data were not available), data were combined; for studies reporting data for more than 1 oral DMD (combined data were not reported), data were combined; for studies reporting data for subgroups (combined data were not reported), data were combined. Abbreviations : DMD: disease-modifying drug.
• CI
- Confidence interval
• DMD
- Disease-modifying drug
• MPR
- Medication possession ratio
• MS
- Multiple sclerosis
• NOS
- Newcastle-Ottawa Scale
• PDC
- Proportion of days covered
• REM
- Random-effects model
• RMS
- Relapsing MS
• RRMS
- Relapsing-remitting MS
Supplementary information accompanies this paper at 10.1186/s12883-020-01830-0.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
By Jacqueline A. Nicholas; Natalie C. Edwards; Roger A. Edwards; Anna Dellarole; Megan Grosso and Amy L. Phillips
Reported by Author; Author; Author; Author; Author; Author