BNAC Director Robert Zivadinov, MD, PhD, is lead author of “Population Health Guide to the Evolution of Endpoints in Multiple Sclerosis.” The AJMC whitepaper, sponsored by Janssen Pharmaceuticals, addresses the challenge to formulary and clinical decision makers in comparing the efficacy of disease-modifying therapies (DMTs) for people with Multiple Sclerosis.

Zivadinov, along with Michael J. Fine, MD, Krishna R. Patel, PharmD, RPh, and Neil Minkoff, MD, have provided a framework for providers and payers to better understand the methodologies employed in clinical trials on the increasing number of MS DMTs.

The rapid rise in DMT alternatives—relatively few of which have been studied in head-to-head trials—has made it difficult for payers to settle on formulary guidelines and utilization management criteria. This has contributed to disputes between payers and providers. With more evidence-based, scientific understanding of the DMT trials and their increasing number of endpoints, decisions can be made based on efficacy rather than cost.

“Our understanding of MS pathophysiology is continuously evolving,” the authors argue. “The disease has variable clinical presentations, an array of factors affect its pathophysiology at the individual level, and there is a long time delay between DMT intervention and outcome. As such, measuring the impact of DMTs is far from the straightforward use of a single biomarker; it instead requires a complex duet between what patients can report and what providers can assess.”

Four major outcome measures are used to assess DMTs in clinical trials:

1. Clinical outcomes (e.g., measures for relapses and disability),
2. Biological markers (e.g., magnetic resonance imaging scans, neurofilament light chain, and cerebrospinal fluid oligoclonal bands),
3. Composite measures that consist of some combination of clinical outcomes and biological markers, and
4. Patient-reported outcomes (PROs) measure quality of life.

New trials bring new options within and across each category.

Because a given DMT does not always achieve similar results in relapsing-remitting MS (RRMS) compared to progressive forms of MS such as primary progressive MS (PPMS) and secondary progressive MS (SPMS), DMTs can only be assessed using different endpoints. For example, because relapses do not occur frequently in progressive forms of MS, this subtype requires alternative endpoints.

The whitepaper compares the four types of endpoints describing some of the distinct pathophysiologic processes of MS they capture as well as some of their limitations.

Relapse is believed to be predictive of disease progression in short-term trials for relapsing MS and is defined as the “acute worsening of function” that lasts at least 24 hours, usually lasting for several days or weeks, followed by an improvement that lasts for at least 1 month. Relapse endpoints can be readily adapted in the clinical setting as their measurement is a matter of accurate and objective identification of such events.

Disability, typically assessed in a physical examination, is an important measure to track physical and cognitive impairment over time. One of the most widely used neurologic examinations, the Expanded Disability Status Scale (EDSS) is expected to remain the most accepted clinical outcome measure for the near future. However, it is limited by inter-rater variability, heavy emphasis on walking, limited assessment of cognitive impairment, and nonlinear scale. These constraints have led to the development of a multidimensional test battery that integrates various individual performance measures from walking and dexterity to acuity and cognitive processing.

Biological markers include MRI lesions, Brain Volume Loss (BVL), and Fluid Biomarkers.

MRI lesions, which are objective, quantifiable, and highly sensitive in detecting subclinical disease activity, have become critical in the development of new DMTs because new lesions appear more frequently than clinical relapses and are thought to strongly predict rates of relapse. Perhaps the biggest disadvantage of MRI lesions is that they do not accurately reflect the degree of clinical disability.

Brain Volume Loss (BVL), also known as brain atrophy, is thought to predict disability progression as well as cognitive impairment and neurodegeneration, however it can be challenging to manage technical errors that are common in a clinical setting. BVL is now often used in clinical trials and may soon provide more granular detail on cortical pathology with the detection of white matter, deep central gray matter, and other lesions not visible using older methodologies.

Clinical and neuroimaging measures remain the cornerstone of assessing DMT efficacy as the search for fluid biomarkers obtained from serum has not yielded promising results. Although there are currently no established fluid biomarkers in use in clinical trials, neurofilament light chain protein (NfL) is among the most promising potential options.

Measurement of cerebrospinal fluid (CSF) oligoclonal bands holds promise as a biomarker. However, its use is currently limited because it requires measuring levels in the CSF rather than in the blood.

Composite measures offer more holistic endpoints for studying a disease which touches individuals in a broad variety of ways. One such measure is No Evidence of Disease Activity (NEDA). If, over a certain period, patients do not experience relapses or changes in disability or MRI activity, they can be classified as having achieved NEDA—a simple “yes/no” endpoint for clinical trials. The challenge, of course, is determining which specific outcomes should be included. Moreover, some patients correctly classified as NEDA later experience disability.

The most frequent Patient-Reported Outcomes tools are MS Quality of Life-54 (MSQOL-54) and Quality of Life in Neurological Disorders (Neuro-QoL). These may play a bigger role in MS care in the future.

A Challenge for All Stakeholders

As MS patients live longer, the science of DMTs advances while demand increases. Understanding clinical trial methodologies along with their implications for new science as well as patient care becomes both more important and more complex. It is incumbent upon all stakeholders—from researchers and review boards to pharmaceutical manufacturers and clinicians, and even patients—to remain current on a complex web of developments.

Click here for the full whitepaper including a payer point of view on assessing clinical trials in MS with Michael J. Fine, MD, Medical Director At Health Net.

 

Building on BNAC Research

More about MS-related and other studies performed by Zivadinov and his colleagues at the University of Buffalo’s 21-year-old Buffalo Neuroimaging Analysis Center, including a list of published papers can be found elsewhere on our website.

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Find information about BNAC’s neuroimaging clinical trial capabilities.

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