Observational Studies in MS Therapeutics: Harnessing Insights from Real-World Data

By Carrie M. Hersh, DO; Devon Conway, MD; and Daniel Ontaneda, MD

Clinical trial data, while valuable from a regulatory standpoint for the approval of new medications, has limited applications in clinical settings. At Cleveland Clinic’s Mellen Center for Multiple Sclerosis Treatment and Research, we are using our large patient experience to derive real-world evidence for multiple sclerosis (MS) patients and providers. These studies use data from our clinical practice and do not have the rigid constraints of clinical trials. As such, the results are more generalizable for the neurologist in clinic and provide patients more realistic insights into the efficacy and safety of medications and interventions.

Here we highlight two such observational real-world studies: a comparison of two commonly prescribed MS disease-modifying treatments (DMTs), and an evaluation of the use of MRI in clinical practice to ascertain treatment response.

Comparative efficacy of two disease-modifying therapies

In the rapidly advancing landscape of novel neurotherapeutics for MS, it has become increasingly challenging and important to compare the effectiveness and safety of DMTs. While randomized controlled trials are the standard for regulatory approval of DMTs, the cost and time involved makes such trials impractical for providing these comparisons. Observational studies are thus valuable for comparing the effectiveness and safety of DMTs to inform decision-making in routine practice.

Despite the pragmatic utility of observational studies, they are often prone to confounding and bias, making it necessary to limit baseline imbalances in demographic and disease characteristics before direct comparisons are made. Propensity score (PS) analysis is a unique statistical method that reduces the impact of confounding and certain biases, thereby approximating a randomized study design. Propensity studies commonly use standardized difference plots (Figure 1) to show how adjustments improve covariate balance and make study groups more comparable.

Figure 1. Covariate balance before (green) and after (orange) propensity score adjustment. Improved balance (i.e., reduced standardized differences) was obtained after propensity adjustment. Reprinted from Hersh et al. in Multiple Sclerosis Journal — Experimental, Translational and Clinical, SAGE Publishing.1 DMT: disease-modifying therapy; EQ5D: European Quality of Life-5 Dimensions; GA: glatiramer acetate; GdE: gadolinium-enhancing; IFN: interferon; intol: intolerability; IS: immunosuppressive therapy; IVMP: intravenous methylprednisolone; linps: linear propensity score; MRI: magnetic resonance imaging; MS: multiple sclerosis; MSPS: Multiple Sclerosis Performance Scale; NTZ: natalizumab; PHQ9: Patient Health Questionnaire-9; PS: propensity score; T25FW: timed 25-foot walk.

In this context, we conducted a retrospective observational study using PS analysis to investigate the comparative effectiveness and discontinuation rates of fingolimod (FTY) and dimethyl fumarate (DMF), two commonly used oral DMTs for relapsing MS.1 In total, 395 DMF-treated and 264 FTY-treated patients had 24-month follow-up data available for analysis.

At 24 months, patients treated with DMF and FTY showed comparable effectiveness on multiple outcome measures, including the following:

• Annualized relapse rate (OR = 1.45; 95% CI, 0.53-3.99)
• Time to first relapse (HR = 1.26; 95% CI, 0.87-1.81) (Figure 2)
• Proportion of patients with new T2-weighted brain MRI lesions (OR = 1.60; 95% CI, 0.80-5.12)
• New gadolinium-enhancing brain MRI lesions (OR = 1.64; 95% CI, 0.82-5.63)
• Proportion of patients with disability progression, measured as 20-percent worsening on the timed 25-foot walk (OR = 1.23; 95% CI, 0.72-2.13) and 20-percent worsening on the 9-hole peg test (OR = 0.79; 95% CI, 0.34-1.80)

At 24 months, DMF-treated patients discontinued DMT earlier than did FTY-treated patients, with the difference mostly driven by early mild-moderate side effects (HR = 1.40; 95% CI, 1.11-1.77) (Figure 2). The primary reasons for discontinuation due to intolerability were gastrointestinal side effects for DMF and headaches for FTY.

Figure 2. Kaplan-Meier plots of relapse-free status and discontinuation with dimethyl fumarate (DMF) and fingolimod (FTY) therapy through 24-month follow-up. Reprinted from Hersh et al. in Multiple Sclerosis Journal — Experimental, Translational and Clinical, SAGE Publishing.1

Our results showed clinical and radiologic outcomes similar to those observed in the pivotal clinical trials of each DMT (CONFIRM2 and DEFINE3 for DMF, and TRANSFORMS4 and FREEDOMS5 for FTY), confirming treatment effects in clinical practice.

This real-world comparative effectiveness data should assist clinicians in treatment decisions regarding DMF and FTY in the management of MS. Our investigation also highlights the utility of PS-adjusted observational studies that reflect treatment effects in real-world settings while minimizing confounding and bias.

MRI as treatment target

In a separate study, we used an observational design to investigate MRI stability as a treatment target in MS.6 A treat-to-target approach to MS management has gained increased acceptance, with “no evidence of disease activity” (NEDA) — in which patients are free of relapses, disability progression and MRI activity — as the preferred target.7 While NEDA seems a sensible goal, there is limited evidence that it leads to better long-term outcomes.

Our study utilized the Knowledge Program, a Cleveland Clinic-developed database used to electronically collect patient- and clinician-reported outcomes longitudinally.8 We identified 417 patients who had activity on their MRIs and then determined if they remained on the same DMT or were switched to an alternative therapy. After PS matching, we compared clinical and radiologic outcomes after 18 months in 78 switchers and 91 nonswitchers. No significant differences were observed between the groups.

Our study did not show a short-term benefit of switching treatment, but it is possible that efficacy differences are apparent only after longer follow-up. It is also worth considering the possibility that zero tolerance of new MRI lesions, which is required to achieve NEDA, may be too stringent a goal. To reach such a target, most patients will require escalation to treatments with more safety concerns,9 so it will be important to justify that risk by demonstrating that achieving NEDA leads to better long-term outcomes.

Conclusions

Observational studies based on real-world data from clinical practice can answer clinically relevant questions that have broad applicability and may not be addressed by randomized trials. Structured collection of clinical data, such as through our Knowledge Program tool, enables implementation of this type of research.

References

1. Hersh CM, Love TE, Bandyopadhyay, A, et al. Comparative efficacy and discontinuation of dimethyl fumarate and fingolimod in clinical practice at 24-month follow-up. Mult Scler J Exp Transl Clin. 2017 Jul-Sep;3(3):2055217317715485.
2. Fox RJ, Miller DH, Phillips JT, et al, for CONFIRM study investigators. Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis. N Engl J Med. 2012;367:1087-1097.
3. Gold R, Kappos L, Arnold DL, et al, for DEFINE study investigators. Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. N Engl J Med. 2012;367:1098-1107.
4. Cohen JA, Barkhof F, Comi G, et al, for TRANSFORMS study group. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Engl J Med. 2010;362:402-415.
5. Kappos L, Radue EW, OʼConnor P, et al, for FREEDOMS study group. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med. 2010;362:387-401.
6. Conway DS, Thompson NR, Cohen JA. Lack of magnetic resonance imaging lesion activity as a treatment target in multiple sclerosis: an evaluation using electronically collected outcomes. Mult Scler Relat Disord. 2016;9:129-134.
7. Giovannoni G, Turner B, Gnanapavan S, et al. Is it time to target no evident disease activity (NEDA) in multiple sclerosis? Mult Scler Relat Disord. 2015;4:329-333.
8. Katzan I, Speck M, Dopler C, et al. The Knowledge Program: an innovative, comprehensive electronic data capture system and warehouse. AMIA Annu Symp Proc. 2011;2011:683-692.
9. Moll NM, Rietsch AM, Thomas S, et al. Multiple sclerosis normal-appearing white matter: pathology-imaging correlations. Ann Neurol. 2011;70:764-773.

Dr. Hersh (hershc@ccf.org) is a neurologist at Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas.

Drs. Conway (conwayd2@ccf.org) and Ontaneda (ontaned@ccf.org) are neurologists with Cleveland Clinic’s Mellen Center for Multiple Sclerosis Treatment and Research.