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.
Annualized Relapse Rate (ARR):
The average number of relapses a group of patients in a clinical study have in one year.1
Brain Volume Loss:
The overall decline in brain volume due to MS disease activity, which can be measured with MRI. Also referred to as “atrophy,” brain volume loss is associated with permanent disability.2
Composite Confirmed Disability Progression:
Measures the risk of a patient’s disability getting worse based on any one of three disability endpoints – confirmed disability progression (CDP), walking ability (T25-FW) and hand function (9-HPT).
Confirmed Disability Progression (CDP):
Measures the increase in a patient’s EDSS score that is sustained over a pre-determined time period, which means a patient’s physical disability has increased.3
The loss of abilities that results from damage to the central nervous system (CNS) and may be irreversible.4
Expanded Disability Status Scale (EDSS):
Measures the degree of physical disability based on a neurological exam of seven functional systems throughout the body, plus a patient’s walking ability. The EDSS and its predecessor DSS have been used in nearly every MS clinical trial in the last 40 years.5
MRI Brain Scan – Gadolinium-enhanced T1-weighted Image:
Shows active lesions that appear bright white on an MRI scan after administration of an intravenous imaging contrast agent (gadolinium).6
MRI Brain Scan – Hyperintense T2-weighted Image:
Shows all lesions, both active and chronic. These appear bright white and can be tracked over time to measure MS progression.6
MRI Brain Scan – Hypointense T1-weighted Image:
Shows sites of significant tissue injury and nerve cell death, referred to as “black holes” due to their appearance on an MRI scan.1,6
Multiple Sclerosis Functional Composite (MSFC):
A combined measure of three separate disability assessments that was first introduced in the late 1990s. The MSFC is calculated based on leg, hand and cognitive function (T25-FW, 9-HPT, PASAT).7
Nine-Hole Peg Test (9-HPT):
Measures arm, wrist and hand function by timing the speed in which a patient can move nine pegs into nine holes and then remove them, using one hand at a time.9
No Evidence of Disease Activity (NEDA):
A combined measure of disease activity based on relapses, disability progression and MRI results. If someone meets NEDA criteria, they are free from measurable disease activity over a defined period of time.8
No Evidence of Progression (NEP):
A novel composite endpoint that measures the proportion of patients with no confirmed progression of disability status (EDSS), walking speed (T25-FW) and upper extremity function (9-HPT) and may represent a new outcome for people with PPMS.
No Evidence of Progression or Active Disease (NEPAD):
A novel composite endpoint that measures the combined absence of disease activity (relapses and MRI activity) and progression (disability). NEPAD is similar to NEDA, but uses a composite endpoint (no confirmed disability progression by EDSS, 20% progression on T25-FW, and 20% progression on 9-HPT) to measure disability. This may represent a more comprehensive measurement of overall disease activity and progression for people with PPMS.
Paced Auditory Serial Addition (PASAT):
Measures cognitive function by testing thinking speed and calculation ability.10
Progression Independent of Relapse Activity (PIRA):
Measures a person’s disability getting worse independently of a relapse and based on a composite disability score of confirmed disability progression (CDP), walking speed (T25-FW) and upper extremity (hand and arm) function (9-HPT). This may be an indicator of underlying disease progression.
New or worsening signs and symptoms caused by inflammation in the central nervous system (CNS). These episodes develop quickly, last at least 24 hours and can continue for several days to weeks. Relapses can be followed by a full recovery or some continuing disability.11
Slowly Evolving Lesion (SEL):
Chronic inflammation in the brain is present in lesions and normal-appearing tissue and is more likely to occur in people with progressive MS. Recent scientific advances have suggested that SELs may be measured with conventional brain MRI. SELs may represent a measure of ongoing chronic tissue damage in pre-existing lesions of the brain.
Timed 25-Foot Walk (T25-FW):
Determines walking speed by measuring how fast a patient can walk 25 feet.12
1 Multiple Sclerosis Coalition. The Use Of Disease – Modifying Therapies In Multiple Sclerosis: Principles and Current Evidence Summary. Available at http://www.nationalmssociety.org/getmedia/1e64b96c-9e55-400e-9a64-0cdf5e2d60fe/summaryDMTpaper_-final. Accessed September 2016.
2 Bermel, RA, et al. The measurement and clinical relevance of brain atrophy in multiple sclerosis. The Lancet Neurology. 2006; 5(2):158 – 170.
3 Wiendl H, Meuth SG. Pharmacological Approaches to Delaying Disability Progression in Patients with Multiple Sclerosis. Drugs. 2015;75(9):947-977.
4 Giovannoni, G, et al. Brain Health: Time Matters in Multiple Sclerosis. 2015; pp 14.
5 National MS Society. Functional Systems Score (FSS) and Expanded Disability Status Scale. Available at http://www.nationalmssociety.org/For-Professionals/Researchers/Resources-for-Researchers/Clinical-Study-Measures/Functional-Systems-Scores-(FSS)-and-Expanded-Disab. Accessed September 2016.
6 National MS Society. Magnetic Resonance Imaging (MRI). Available at http://www.nationalmssociety.org/Symptoms-Diagnosis/Diagnosing-Tools/MRI. Accessed September 2016.
7 National MS Society. Multiple Sclerosis Functional Composite (MSFC). Available at http://www.nationalmssociety.org/For-Professionals/Researchers/Resources-for-Researchers/Clinical-Study-Measures/Multiple-Sclerosis-Functional-Composite-(MSFC). Accessed September 2016.
8 MS Society UK. NEDA (no evidence of disease activity). Available at https://www.mstrust.org.uk/a-z/neda-no-evidence-disease-activity. Accessed September 2016.
9 National MS Society. 9-Hole Peg Test (9-HPT). Available at http://www.nationalmssociety.org/For-Professionals/Researchers/Resources-for-Researchers/Clinical-Study-Measures/9-Hole-Peg-Test-(9-HPT). Accessed September 2016.
10 National MS Society. Paced Auditory Serial Addition Test (PASAT). Available at http://www.nationalmssociety.org/For-Professionals/Researchers/Resources-for-Researchers/Clinical-Study-Measures/Paced-Auditory-Serial-Addition-Test-(PASAT). Accessed September 2016.
11 National MS Society. Managing Relapses. Available at http://www.nationalmssociety.org/Treating-MS/Managing-Relapses. Accessed September 2016.
12 National MS Society. Timed 25-Foot Walk (T25-FW). Available at http://www.nationalmssociety.org/For-Professionals/Researchers/Resources-for-Researchers/Clinical-Study-Measures/Timed-25-Foot-Walk-(T25-FW). Accessed September 2016.
Where is MS measurement headed?
Our measurements have improved, but there’s more to be done. There’s a symbiotic relationship between our understanding of MS and our tools for measuring it – better understanding leads to better tools, and better tools lead to better understanding. But it’s perhaps overly optimistic to expect an exact measurement tool, as the disease is very complex.
John Tukey, a mathematician who developed an algorithm that is fundamental to investigating MS with MRI, said it well: “Far better an approximate answer to the right question, which is often vague, than an exact answer to the wrong question, which can always be made precise.”
We learn as we go, both in science and in measurement of outcomes. At Genentech, we’re committed to advancing on both fronts.