The importance of collecting structured clinical information on multiple sclerosis

Ziemssen et al. BMC Medicine (2016) 14:81 DOI 10.1186/s12916-016-0627-1 OPINION Open Access The importance of collecting structured clinical information on multiple sclerosis Tjalf Ziemssen1*, Jan Hillert2 and Helmut Butzkueven3 Abstract Background: Randomized controlled trials (RCTs) are the ‘gold standard’ in the generation of drug efficacy and safety evidence. However, enrolment criteria, timelines and atypical comparators of RCTs limit their relevance to standard clinical practice. Discussion: Real-world data (RWD) provide longitudinal information on the comparative effectiveness and tolerability of drugs, as well as their impact on resource use, medical costs, and pharmacoeconomic and patient-reported outcomes. This is particularly important in multiple sclerosis (MS), where economic treatment benefits of long-term disability reduction are a cornerstone of payer drug approvals – these are typically not examined in the RCT itself but modelled using real-world datasets. Importantly, surrogate markers used in RCTs to predict the prevention of long-term disability progression can only truly be assessed through RWD methodologies. Summary: We discuss the differences between RCTs and RWD studies, describe how RWD complements the evidence base from RCTs in MS, summarize the different methods of RWD collection, and explain the importance of structuring data analysis to avoid bias. Guidance on performing and identifying high-quality real-world evidence studies is also provided. Keywords: Multiple sclerosis, Real-world evidence, Real-world data, Randomised controlled trials, Registries, Pharmacoeconomics An introduction to real-world evidence (RWE) in multiple sclerosis (MS) In general, randomised controlled trials (RCTs) and RWE studies are important for improving our understanding of disease outcomes and treatment effects, with the two methodologies being increasingly viewed as complementary by clinicians, the pharmaceutical industry, drug regulatory and reimbursement agencies, and patients [1]. The prominence and value of RWE studies (Box 1) have made them mandatory in many settings; however, inherent variability in patient care means that their analysis requires particular care. Figure 1 summarises the key differences between RCTs and RWE studies. In MS, there is a current and growing emphasis on obtaining data beyond phase 3 RCTs. In 2014, the * Correspondence: 1 Center of Clinical Neuroscience, Department of Neurology, MS Center Dresden, Center of Clinical Neuroscience, University Hospital Carl Gustav Carus, Dresden University of Technology, Fetscherstr. 74, 01307 Dresden, Germany Full list of author information is available at the end of the article number of published RWE studies in MS exceeded that of published phase 2 and 3 studies by more than twofold (Fig. 2). This has been driven by increasing demand from payers and healthcare decision-makers for postapproval evidence to inform reviews of pricing, reimbursement, licences for new therapies, and formulation and indication changes [2]. Post-approval RWE studies are important for providing information on compliance with current treatment guidelines, identifying suboptimal therapies, defining treatment responder subgroups, optimizing treatment sequencing, and monitoring rare serious adverse events. This information can support licence extensions and treatment sequencing [3]. RWE studies can also provide valuable insights prior to product development. Pre-launch RWE studies, for example, are useful for mapping out the natural and drug-modified history of disease, current practice patterns and service structures [3]. In MS, this can go some way to meeting the need for information on disease characteristics, treatment behaviours, and healthcare availability for ‘real’ patients with the disease. Closer to © 2016 The Author(s). Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Ziemssen et al. BMC Medicine (2016) 14:81 Page 2 of 9 Box 1. About real-world evidence (RWE) studies [1, 5] Randomised controlled trials (RCTs) are the ‘gold standard’ in the generation of efficacy and safety evidence of a product in restricted trial settings. Advantages 1. Can mimic RCTs in the real world to allow assessment of a drug in the clinical setting 2. Complement the evidence base from RCTs by assessing a diverse range of outcome measures to provide information that may not be captured by other means, including: • comparative effectiveness data between multiple therapies • information on long-term disability outcomes • better characterization of long-term exposure risks and benefit–risk profiles • patient-reported outcomes • economic outcomes Challenges 1. They cannot address the potential benefits and risks of a product in the real world [1, 5] because enrolment is restricted by disease-activity criteria, and subjects with comorbid conditions are typically excluded 2. Active comparator arms may not reflect the usual standard of care and selected endpoints can be artificial or chosen to maximize statistical power, thereby limiting the real-world relevance of study conclusions 3. There are significant ethical concerns about conducting placebo-controlled trials in countries where disease-modifying therapies are approved and reimbursed [2]; these pivotal trials are therefore conducted in countries without these approvals, and thus in populations different to potential target markets 4. There are many potential biases in real-world treatment Fig. 1 The key differences between randomized controlled trials and real-world evidence studies [1, 3, 4] and 3 MS studies, such as inflammatory lesions and relapse rates, are important surrogate markers for predicting the anticipated long-term prevention of disability, and these can only be validated via RWE methodologies. comparisons and variations in data quality caused by acquisition in busy clinics product launch, RWE can provide further insights into early clinical experience, safety, resource use, patient tolerability, and identification of untreated patients [3]. MS is a lifelong disease that can span more than 40 years. The short duration of RCTs provides limited information on MS disease course and long-term treatment effects. RCTs alone may be acceptable in acute neurological diseases like meningitis and stroke, where discrete endpoints, such as survival or post-acute fixed disability, can be swiftly measured. Conversely, for MS, the potential effects (...truncated)