Measuring treatment effects based on patient preference

To evaluate the effect of an investigational drug in ALS clinical trials, we use measuring scales such as the ALSFRS-R or readouts of muscle strength. This is to objectively determine whether a drug can slow disease progression. However, this strategy may not consider the concerns most important to people living with ALS. A crucial question therefore remains often unanswered: does the benefit of a new drug outweigh the possible risks and side effects for people living with ALS?

TRICALS researchers from the University Medical Centre Utrecht (UMC Utrecht), and in close collaboration with the Center for Innovative Study Design (Stanford University) have now developed a new endpoint (principal outcome that is measured in a clinical trial) to better assess treatment benefits for people with ALS. For the first time, this method takes the views of people living with ALS into account.

A variable disease course

Regulatory agencies such as the European EMA and the American FDA weigh up the potential risks and the intended benefit when evaluating new drugs. This consideration is not very easy to make for ALS. After all, the course and symptoms of the disease vary greatly from one person to the other. As a result, a treatment to improve speech may not be very helpful for people who mainly suffer from weakness in their legs. Unfortunately, these differences in the manifestation and disease course of ALS are not taken into account in clinical trials for ALS. Therefore, it may be that a drug seems ineffective on paper, but in reality actually benefits people living with ALS.

“This is a topical issue, especially with recent advances in treatments such as AMX0035, NurOwn and edaravone,” says Dr. Ruben van Eijk, first author of the study and assistant professor at the UMC Utrecht. “How do we decide if a medicine is helpful for patients? This is relevant not only for healthcare practitioners and regulatory agencies, but also for people living with ALS and their loved ones.”

“How do we decide if a medicine is helpful for patients? This is relevant not only for healthcare practitioners and regulatory agencies, but also for people living with ALS and their loved ones.”

New method to assess treatment effects

Together with Stanford University (United States), TRICALS researchers from the UMC Utrecht have devised a new way to better evaluate the results of ALS Clinical trials. Dr. Ruben van Eijk: “Our new method allows us to determine more quickly whether a drug meets the needs of individual patients and is suitable for the treatment of ALS in general. We do this by weighing treatment effects on measurement scales such as the ALSFRS-R or muscle strength with the preferences of people with ALS. For example, if someone considers speaking to be more important than walking, then ALSFRS-R questions about speaking should be prioritised over questions about walking. By applying this principle to each individual patient, we can determine if the patient population actually benefits from a treatment on domains that are most important to them. Treatments that improve the domains considered very important by patients receive higher scores than treatments affecting lesser important domains.”

Preferences of people living with ALS

In the present study, 433 people living with ALS in the Netherlands completed an online questionnaire. They were asked which symptoms they would like most to improve. This included problems with speech, use of arms and hands, walking and breathing. “Overall, people felt that speaking and breathing were most important. However, this was influenced by the domain where the first symptoms appeared and how long someone had experienced symptoms. Our method turned out to provide a more accurate picture of the effect of investigational treatments. This has important implications for ALS clinical trials, in which the perspectives of people with ALS should be given a central place.”

“Our method turned out to provide a more accurate picture of the effect of investigational treatments. This has important implications for ALS clinical trials, in which the perspectives of people with ALS should be given a central place.”

The researchers are currently preparing to apply their method in future clinical trials to further validate their method. This is important to convince regulatory authorities such as the EMA and FDA. The scientific results of the study have been published in the scientific journal Journal of Neurology, Neurosurgery and Psychiatry. An accompanying commentary has also been written by independent researchers.

For Researchers: The method is available for free as an online calculator with access to study participants’ anonymised data (https://tricals.shinyapps.io/PROOF/).

This study was funded by the Dutch ALS Foundation