Full citation: Servais L, Strijbos P, Poleur M, et al. Evidentiary basis of the first regulatory qualification of a digital primary efficacy endpoint. Sci Rep. 2024 Nov 29;14(1):29681.
Stride velocity 95th centile (SV95C) has been approved to be used as a primary endpoint to evaluate the impact of investigational treatments on people with Duchenne muscular dystrophy (DMD) in clinical trials in the European Union. This is the first time a digital outcome measure has been approved as a primary endpoint by any regulatory agency for any disease. The SV95C is a measure of the top ambulation or walking speed of a patient in a real-world setting based on the measurement of ambulation or walking speed measured from a digital health tool (DHT) that the person wears throughout the day. Endpoints, which are measurable events or outcomes that may prove or disprove if an investigational product works well enough to treat the disease being studied in a clinical trial, can be “primary,” which are the main endpoints needed to prove or disprove if the investigational product works and “secondary” or “exploratory”, which are endpoints that can support the primary endpoint.
Primary endpoints need to be objective, or not open to interpretation by different people evaluating it. A single dystrophin level is an objective measure. Often clinical trials for DMD include endpoints that measure the person’s ability to achieve a physical task. An example of this type of endpoint is the North Star Ambulatory Assessment (NSAA), a 17-item rating scale is used to evaluate how well a person with DMD can achieve tasks such as standing, walking, standing from a chair, stepping up on a step, and other tasks that may become progressively more difficult for a person with DMD. The goal of the study is for the person with DMD to improve or at least maintain their ability to perform the tasks in the NSAA during the treatment with the investigational product. The problem with measures such as the NSAA is that there are other factors that can influence the results for the test. For example, a young child might be in a bad mood and refuse to the assessment or not put in a consistent level of effort. Other issues that may influence these types of assessments is whether the test is being done in the same location or by the same practitioner. If not, the results may vary enough to make the assessment inappropriate as a primary endpoint.
Regulatory agencies like the United States Food and Drug Agency (FDA), Health Canada (HC), or the European Medicines Agency (EMA) approve assessments for clinical trials. Previously, SV95C had only been approved to be a secondary endpoint by the EMA. A lot of work and analyses went into having it approved as a primary endpoint in clinical trials. First, the SV96C had to be validated, which means it had to be confirmed as sensitive enough to detect differences. To do this, 8 healthy participants who did not have DMD and 23 participants with DMD wore the device. When comparing the results from the device to results from trained physiotherapists assessing the 6-minute walking distance (6MWD) test, the results were similar enough to confirm that the data from the device was accurate. The results of the SV95C correlated (was very similar) to the results of other tests of ambulation speed such as the NSAA, and the 4-stair Climb (4SC), and quality of life measures. The results were repeated and reliable, meaning that the results could be duplicated several times. The SV95C could also detect the results from someone with or without DMD, similar to the 6MWD and NSAA.
The data indicates that SV95C is more sensitive than other assessments, detecting the progressive loss of speed of walking in a shorter time than with other assessments. This is important as it can evaluate both disease progression and impact of treatment more quickly than other assessments. This could mean that clinical trials could be done more quickly using the SV95C than with other assessments as the effect of the investigational product may be seen more quickly.
The use of SV95C as a reliable primary endpoint for studying the impact of investigational treatments for DMD has the potential to change the development process for treatments for DMD, and other neuromuscular and neurodevelopmental diseases. The use of wearable devices in clinical trials may provide other advantages, such as:
- Reducing the burden for participants having to do all assessments in clinic
- Measuring other real-world variables such as stair climbing at the same time
However, there may be disadvantages, such as technical difficulties that could occur, data privacy, and the reliability of the participant to always wear the device.
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