In April 2019, the Committee for Medicinal Products for Human Use (CHMP) issued a qualification opinion on stride velocity as an endpoint in clinical studies of medicines for the treatment of Duchenne Muscular Dystrophy (DMD).[1] Mutations in the dystrophin gene cause this inherited, x-linked disorder which causes progressive muscle weakness starting in early childhood. Wheelchair use begins around age 12; death from respiratory insufficiency or cardiomyopathy often occurs in the late teens or 20s; few patients survive beyond the third decade.[2]

Approved therapies targeting specific mutations in the dystrophin genes are available in the EU and US with additional therapeutic approaches in development. In clinical trials of therapies aimed at preserving ambulation, the 6MWT (maximum walking distance covered by the patient in six minutes) is a commonly used endpoint assessing motor function and considered a gold standard. However, this assessment has limitations: it has high variability, a learning effect, cannot be applied to non-ambulant patients, and may have limited sensitivity in ambulant patients depending on their disease stage and progression.[3] Regulators recommend that if the 6MWT is used as a primary endpoint, it should be supported by secondary clinical outcomes such as tests of motor strength, motor function, cardio-pulmonary function, and activities of daily living.

Qualification request for gait parameters If qualified, the novel ways of assessing patients’ gait could support efficacy assessments in DMD clinical trials. Five gait parameters were assessed for validity as a part of the initial qualification request filed with the EMA in 2017: the 95th centile of the stride velocity (SV95C), the median stride velocity, the 95th centile of the stride length the median stride length and the distance walked/recorded per hour. [1]The gait parameters are measured through a valid and suitable wearable device system to quantify patients’ ambulation ability through continuous monitoring, ie, real-world measurements. The system comprises two battery-operated sensors placed on the wrist and ankle (or wheelchair arm) and a docking station. Data are gathered in the sensors during the day and transferred to the docking station that charges the sensors at night and sends anonymised data to a secure database. Variables are computed for each patient using the transmitted data.

Data supporting the validation of the gait parameters came from ambulant DMD patients aged five to 14 years.[1] Analytical validation included:

  • Analysis showing the distance measured by reconstructing the ankle trajectory of ambulant patients wearing the sensor was within 5% of the actual distance measured manually during the 6MWT in 31 tests by 23 different patients in different clinical conditions.
  • Measurement of variability for the gait parameters, including studying the influence of poor compliance and missing data to generate recommended minimal use. For SV95C, variability was 4.41% during 180 hours of sensor use in 28 patients in a non-controlled setting.

Clinical validation included:

  • Cross validation of the gait parameters with two clinical assessments, the 6MWT and the North Star Ambulation Assessment. For SV95C, correlation was 0.54 with the 6MWT and 0.64 with the North Star Ambulation Assessment at baseline.

  • Study of sensitivity to changes in ambulation over six months and one year in patients with DMD. For SV95C, a significant decline over six months (8.5%) was observed in 20 patients older than six years of age with a baseline 6MWT of less than 40 meters.

Regulatory review

The Scientific Advice Working Party (SAWP) raised queries for clarification with the applicant and discussed them during an initial teleconference in November 2017.[5] Additional rounds of queries were raised and addressed culminating in the SAWP meeting in March 2018 after which a draft opinion was agreed to and adopted by the CHMP for public consultation in April 2018.23 Following the public consultation period, the CHMP adopted the qualification opinion in April 2019.

Context of use

The qualification opinion’s context of use states that in DMD patients ages five and older SV95C is an acceptable secondary endpoint in pivotal or exploratory drug therapeutic studies for regulatory purposes when measured by a valid and suitable wearable device to quantify a patient’s ambulation ability directly and reliably in a continuous manner in a home environment and as an indicator of maximal performance, or to collect a patient’s baseline performance in such studies.[1] To be used as a primary endpoint, additional data from more patients over a longer time period are needed. When using SV95C in clinical trials, education and training for staff, patients, and their caregivers should be provided to increase user acceptance and reduce missing data.

 

Conclusions

From the SV95C qualification process, key issues raised by the CHMP included the need for a detailed context of use as well as a best practice document, which were supplied by the applicant. The supporting data did not include interventional data gathered from a large study over an extended period, which ultimately limited the context of use to include SV95C as a secondary rather than primary endpoint. At the time of writing, the publicly available US information does not allow for any definitive comparisons across the regions.

 

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[1] Qualification opinion on stride velocity 95th centile as a secondary endpoint in Duchenne Muscular Dystrophy measured by a valid and suitable wearable device. April 2019. EMA. Available at: https://www. ema.europa.eu/en/documents/scientific-guideline/qualificationopinion-stride-velocity-95th-centile-secondary-endpoint-duchennemuscular-dystrophy_en.pdf

[2] Duchenne Muscular Dystrophy Signs and Symptoms. Muscular Dystrophy Association. Available at: https://www.mda.org/disease/ duchenne-muscular-dystrophy (accessed 5 February 2021).

[3] Haberkamp M, Moseley J, Athanasiou D et al. European regulators’ views on a wearable-derived performance measurement of ambulation for Duchenne muscular dystrophy regulatory trials. Neuromuscular Disorders. July 2019;29(7):514–516. https://doi. org/10.1016/j.nmd.2019.06.003

[4] Foschini L, Furlong P, Servais L et al. Stride Velocity 95th centile as a Secondary Endpoint in Duchenne Muscular Dystrophy Measured by a Valid and Suitable Wearable Device. Presented February 2020 at the Remote Digital Monitoring Workshop. Available at: https://fnih.org/ sites/default/files/final/pdf/CS4_SV95C%20DMD.pdf (accessed 25 February 2021).

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