The National MS Society-funded MS Outcome Assessments Consortium (MSOAC) held its first annual meeting with the U.S. Food and Drug Administration on April 1-2 to discuss steps needed to “qualify” a new measure of MS disability that will be recognized by the FDA and the European Medicines Agency to speed new therapies for MS, particularly progressive forms of the disease. This consortium of industry, academia, patient representatives, regulatory and other government agencies, the National MS Society, and the Critical Path Institute
agreed to next steps for collecting, standardizing and analyzing data from clinical trials of MS therapies and other related research to develop a new “clinician-reported outcome measure.”
We Need Better Ways to Track MS Progression
There is a critical need for more sensitive and accurate ways to detect the benefit of potential treatments that slow or reverse worsening disability in people with MS. There has been some progress in developing improved imaging tools as windows to MS nervous tissue damage, but progress in developing a clinical outcome measure that can accurately track a person’s clinical condition has been slow.
A National MS Society-supported task force met in late 2011 to determine whether one currently used outcome measure, called the MSFC (Multiple Sclerosis Functional Composite) could be enhanced to improve its ability to track changes in disability. The task force determined that a key aspect of the project would be to analyze data from completed clinical trials that have used parts of the MSFC as well as other measuring tools.
It became clear through discussions that a collaboration with the Critical Path Institute (C-Path) would be of great value to the goals of the project. C-Path is a nonprofit partnership with the FDA, whose aim is to accelerate the pace and reduce the costs of medical product development by creating new standards for evaluating the safety and effectiveness of therapies. A roadmap for the project was published in August 2012
, and the Multiple Sclerosis Outcome Assessments Consortium
was launched that fall
with funding from the National MS Society.
The consortium is co-directed by Richard Rudick, MD (Vice Chairman, R&D, Neurological Institute and Director, Mellen Center, Cleveland Clinic Foundation), Nicholas LaRocca, PhD (Vice President, Health Care Delivery and Policy Research, National MS Society), and Lynn Hudson, PhD (Chief Science Officer, Critical Path Institute).
April 2013 Meeting
The meeting had strong international participation from consortium members, with a total of sixteen academic institutions and nine pharmaceutical companies represented. Highlights include:
Regulators Weigh In:
The first day was a meeting with regulatory agencies including key members of the FDA’s Center for Drug Evaluation and Research (CDER) and the European Medicines Ageny (EMA), including Janet Woodcock, MD (Director of the CDER), Laurie Beth Burke, RPh, MPH, (Director, Study Endpoints and Labeling Development, Office of New Drugs), Marc Walton (MD, PhD, Associate Director for Translational Medicine, Office of Translational Sciences) and Maria Isaac, MASc, MD, PhD (Scientific Administrator, Science Advice & Orphan Drugs Sector, EMA). The teams expressed strong support for the goals of this undertaking, and provided important insights into steps needed to qualify a new measure for use in clinical trials.
Weyman Johnson (Chair of the Multiple Sclerosis International Federation, former Chair of the National MS Society’s National Board of Directors, and member of its National Advisory Council), shared his family’s history of having several members, including himself, who have MS, and the stark variability in disease severity and progression they each have experienced.
What Do People with MS Think?
Elizabeth Morrison, MD (University of Southern California) is a former family physician who shifted gears when she developed MS, and is now in the process of becoming a neurologist. She has done research with people with MS to determine what abilities impacted by MS matter most to people who have the disease, which would ideally be among those tracked by a new outcome measure. Her research identified symptoms related to walking and vision as those most often named as important to people living with MS. Problems with cognition, hand function, pain, and fatigue were also noted.
What’s Not Working Now:
Dr. LaRocca noted progress related to the development of disease-modifying therapies, largely for relapsing MS, emphasizing that our ability to develop therapies that slow or halt the progression of disability is limited by the measurement tools available. He reviewed the history of clinical outcome assessment tools in MS, including the Expanded Disability Status Scale (EDSS), which has various limitations (for example, the meaning of change in the low-disability range is often not clear, and the scale is completely dependent on walking ability at the higher-disability range). The MSFC was developed as a more objective tool with the intention of expanding on the EDSS approach by tracking several disease dimensions, such as cognitive changes and hand dexterity. It, too, has limitations (for example, the initial version lacked a visual measure, and contained a less than optimal measure of cognition). New components and new approaches to using an MSFC-like instrument may enhance its usefulness in detecting change in disability.
Tools to Consider:
Discussion occurred related to newly emerging tools and information that may be incorporated into designing a new outcome measure. For example, Gary Cutter, PhD (University of Alabama at Birmingham) noted that mobile devices such as smartphones offer the opportunity to collect real-time activity readouts from people in their own environment. He also cautioned about the need to consider other aspects of a person’s health, such as other disorders (called co-morbidities) which may complicate the interpretation of outcomes.
MS can impair a person’s vision, even early on. Laura Balcer, MD (New York University) described progress in being able to detect vision changes using low-contrast visual acuity testing, which has been successfully tested in MS clinical trials. Ralph Benedict, PhD (University of Buffalo) described difficulties in testing cognition, and how depression can change results. He described the Symbol Digit Modalities Test as a possible candidate for testing processing speed and memory in MS. Tanuja Chitnis, MD (Harvard Medical School) informed the group that pediatric MS involves more relapses than adult MS, and early cognitive deficits. These differences need to be considered in any new outcome measure to be developed.
A Wealth of Information:
The second day focused on next steps. The group reviewed dozens of clinical trials and other studies in MS and the outcome measures that were used in those studies. Jeremy Hobart, MD, PhD (Universities of Exeter and Plymouth) and others discussed the need to clearly define the dimensions of MS disability and progression to be tracked by the new tool along with its anticipated uses. The plan is to obtain the data from trials that used elements of the MSFC, EDSS and other disability measures such as low contrast visual acuity so that they can be analyzed to determine how sensitive each measure is. Ideally, the existing data may be sufficient to qualify a new measure, but some additional research may also be needed during the analysis process.
One important bonus of this project is that in addition to developing a new outcome measure, the project will also develop new MS data standards and generate a database of pooled, standardized data from MS clinical trials. The data standards will be used by regulatory authorities to provide guidelines for the conduct of future MS clinical trials.
Consortium members from industry and academic institutions are in the process of providing data from clinical trials. Working groups are forming to establish the new MS data standard, identify key data available for analysis, and further define aspects of MS progression to be tracked. Regular teleconferences are helping to keep this project moving. In addition, a report is being written for publication. As part of the project, an annual meeting will be held with the FDA. As progress is made in gathering and analyzing data from studies, developing components of the modified outcome measure, and submitting the proposed outcome measure to regulatory authorities for qualification, the Society will provide periodic updates.