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Group Medical Director, Neuroscience, U.S. Medical Affairs, Genentech
Over the past decade I’ve worked in clinical development to advance new medicines to treat multiple sclerosis (MS). My job has been to design clinical trials and monitor the data they generate to determine a potential medicine’s safety and efficacy. One question we aim to answer is whether the new medicine is more effective than what’s already available. Answering this question of efficacy requires tools for measuring and comparing both the state and progression of the disease.
Measuring the impact of MS isn’t as simple as unspooling a tape measure – we’re limited both by what a patient can report and what a neurologist can assess. The biology of MS is not fully understood, symptoms of MS vary from person to person, and the biological markers of MS don’t always correlate with a patient’s clinical signs and symptoms. MS usually appears early in life and it is a chronic, lifelong disease, where symptoms typically evolve over time. Furthermore, there are different subtypes of MS.
Most people living with MS have the relapsing form, in which new symptoms abruptly appear or old symptoms worsen for a limited period of time and are followed by either full or partial recovery, in episodes known as relapses or MS attacks. Others have progressive MS, in which the disease steadily worsens over time. Thus, demonstrating the efficacy of treatments for MS is complicated and the science around this continuously evolves.
In designing a therapeutic clinical trial, patients are randomly assigned into two or more treatment groups, those receiving the new medicine and those receiving an existing treatment or placebo (also known as the control group). Then we identify patient outcomes that are important in that disease and use them to define the trial’s endpoints, which are quantified outcome measures used to formally compare results between the two groups. We assess all of the patients over time, record their outcomes during the trial, and compare the two groups at the end of the trial using the pre-defined endpoints.
At present, neurologists use three major types of outcome measures to assess the state of one’s MS disease: frequency of relapses; physical disability status; and biological markers, including brain scans using MRI. In MS clinical trials, these same types of outcomes are used to define the specific endpoints to be statistically analyzed.
Relapses are meaningful as they reflect how individuals experience fluctuations in symptoms that are central to relapsing MS. In many clinical trials, the relapse frequency, measured by the Annualized Relapse Rate, is a primary endpoint. For progressive MS, where relapses don’t occur frequently, other endpoints are used.
Physical disability is an important measure to track because MS is a chronic condition where a person’s functional disability worsens over time. A neurologist’s physical examination is still the gold standard for its measurement. That examination is a remarkable process and reflects the foundation of what a neurologist does. We use our eyes, ears and hands to assess a patient’s problems with cognition, vision, strength, coordination, sensation, walking and agility. In order to compare one patient to another (or one patient to himself or herself over time), we’ve developed ways to rate the individual symptom assessments numerically and then combine them into a single score. The most widely used neurologic exam in MS is called the Expanded Disability Status Scale (or EDSS), which is often used as an endpoint in clinical trials. The goal is to find medicines that stabilize or potentially even improve disability scores.
In the early 1980s, a new assessment tool became available – MRI brain scans. For the first time, we could actually see lesions or damaged areas in the brain, and we could count new lesions by comparing MRI scans over time. When drug approval agencies evaluate new medicines, however, they prefer to rely on clinical outcomes that more closely reflect the patient’s symptomology – relapses and disability scores. Nonetheless, MRI is a valuable secondary tool in both clinical trials and in individual patient care. MRI can highlight the presence of MS disease activity in the brain, whether or not this activity directly results in physical, cognitive or visual symptoms a person may experience.
There’s no single measure that captures the entire MS experience. As more becomes known about the biology of disease and treatment, the field develops newer ways to integrate relapse records, disability scores and biological markers. One example of progress in MS outcomes measurement is NEDA, an acronym for No Evidence of Disease Activity. If, over a certain period, a patient experiences no relapses, if his or her disability score remains stable and if no new or enlarged brain lesions appear in MRI scans, then that patient can be classified as having achieved NEDA. It provides a simple “yes/no” endpoint for a clinical trial, investigating whether a new medicine increases the percentage of patients with NEDA compared to an existing medicine. Emerging combination endpoints that give us a fuller, more comprehensive picture of the disease in clinical trials may find their way into clinical practice to help doctors make treatment decisions.