Trials testing new immunotherapies for multiple sclerosis (MS) should focus more on patients’ experiences and on symptoms relevant for them such as fatigue, depression, and cognitive difficulties, a German working group recommends.
According to the team, which is working on developing new standards for planning MS trials, clinical studies should also implement predictive markers of individual treatment responses, which are an “indispensable prerequisite” to maximize benefits for trial participants.
In addition, patients on new treatments should be studied for longer periods of time to gather long-term data on the safety and benefits of therapies, which is still scarce.
The group’s analysis and recommendations, “Suggestions for improving the design of clinical trials in multiple sclerosis—results of a systematic analysis of completed phase III trials,” were published in the EPMA Journal.
“Given the increasing number of available immunotherapies, the therapeutic strategy in MS has shifted from a mere ‘relapse-prevention’ approach to a personalized provision of medical care as to the choice of the appropriate drugs and their sequential application over the course of the disease,” the group wrote.
But how can clinical trials addressing new treatments for MS align more with personalized care and take into account patient preferences? This question was investigated by a working group in Germany, made up of members from the Drug Commission of the German Medical Association (AkdÄ), the Charité University Hospital Berlin, and the Institute for Quality and Efficiency in Health Care (IQWiG).
They reviewed 29 pivotal Phase 3 trials, that is, trials conducted to provide evidence for the marketing approval of new disease-modifying (immunomodulatory) treatments for MS. All the treatments tested in these studies are now approved and used for relapsing-remitting MS, secondary progressive MS, primary progressive MS, or clinically isolated syndrome.
Several aspects of each trial were analyzed, including trial duration, sample size, comparator treatments (placebo or other immunomodulatory treatments), and magnetic resonance imaging outcomes, as well as patient-reported outcome measures.
The analysis showed that patients’ perspectives — namely outcomes that are highly relevant for patients such as symptoms of fatigue (tiredness and increased exhaustibility), depression, cognitive impairment, pain, spasticity, sleep disorders, and loss of vision — were often overlooked in trials. When accounted for, they only served as secondary or explorative objectives.
In contrast, biomarkers and surrogate imaging measures of “dubious clinical importance” were frequently investigated, according to the group.
“If in [the] future we design the studies in such a way that they are more closely orientated to the needs of patients, we will obtain study results that are more likely to enable us to provide patients with more targeted and individualized medical care,” Friedemann Paul, scientific director of the Experimental and Clinical Research Center (ECRC), which is part of Charité, said in a press release.
The team also noted another important shortcoming in pivotal MS trials in that, beyond the trial period, high-quality data on the benefits or side effects of these treatments are almost non-existent.
“Understanding of long-term benefits and risks of disease-modifying MS therapy is largely lacking,” the team wrote.
“Due to their duration and usually short follow-up, drug approval studies are not suitable for collecting data on the sometimes very serious side effects that only occur after long-term treatment,” said Wolf-Dieter Ludwig, chairman of the AkdÄ.
To overcome these deficits, the group made specific recommendations, namely that future trials in MS should be directed more toward individualized treatment and patients’ experiences.
On top of the clinical and radiological findings needed to demonstrated efficacy, they should also focus on patient-reported outcomes that address symptoms important for patients such as fatigue, pain, depression, and cognitive impairment, and their impact on quality of life.
“If no data on symptoms and quality of life are collected in studies, then these studies do not provide a complete picture of the benefit of a drug,” said Thomas Kaiser, head of IQWiG’s Drug Assessment department. “Many of these symptoms could and should in the future be documented with the help of internationally established and validated patient questionnaires.”
In addition, considering the often required long-term treatment with immunomodulating therapies, study participants should be observed for longer periods to gain more insight into significant complications and side effects.
According to the team, studies should also set better enrollment criteria, adjusted to the treatment’s mode of action. This will improve the selection of patients who are likely to benefit from treatment, while limiting safety risks.
Prior to enrollment, there must be “utmost accuracy when diagnosing MS and ruling out relevant differential diagnoses,” the team emphasized, as newer and high-efficacy immunotherapies for MS may harm people with related disorders such as neuromyelitis optica spectrum disorders or others.
“With our recommendations, we want to make a contribution to improving the care of patients with MS,” said Sinje Gehr, project head of the Charité MS Initiative.