Redefining physical activity measurement in clinical trials

Physical activity is important for maintaining health in virtually all therapeutic areas and is often recognised as a sixth functional vital sign. With more than one in five US adults already using wearable technologies, there is an opportunity to leverage digital measures for physical activity in clinical trials and finally move away from relying solely on clinic-based assessments.

Through collaboration, the field can begin to realise the full potential of digital health technologies (DHTs) to capture physical activity in novel ways, improving measurements of how patients function and feel and ultimately supporting quicker drug development and access to needed treatment.

Questioning the ‘gold standard’

Industry pioneers are already seeing how digital technologies can enhance how disease progression and quality of life are measured, especially with diseases that impact physical activity. For example, Duchenne’s Muscular Dystrophy (DMD), a genetic condition leading to progressive muscle degeneration, makes it difficult for boys to walk or move from an early age. Currently, the assessments for physical function in DMD are clinic-based tests measured at discrete intervals, which can be influenced by the patient’s motivation, level of tiredness during the day of the test, or even encouragement from test facilitators. The 6-minute walk test (6MWT) is often considered a ‘gold standard’ used to assess physical activity in DMD and, more ubiquitously, in conditions of the lungs, heart, neuromuscular system, osteoarthritis, and ageing.

But does it deserve ‘gold standard’ status? Industry leaders are actively considering whether the 6MWT and other functional assessments truly capture what it means to be physically active - not just in a clinical setting - but in contexts that are most meaningful to patients. Jerrod Kerr, a patient partner engaged in the physical activity project, lives with a spinal cord injury and shares that his physical function – specifically, upper body mobility and strength - is essential for his independence and carrying out of daily activities:

• “[For me], the priority is hand function and arms. If you think about it, you can live by yourself independently: if you can feed yourself, you can bathe, get in and out of bed, get in and out of the shower, go to the toilet. All those things are paramount to being independent. Being able to do activities outside is a big deal; it’s a huge part of quality of life – [of] independence.”

Here, wearable technologies could better measure aspects of physical function needed for independence over the course of day, week, or even month, providing a clearer picture of a patient’s true behaviour in real life.

Beyond moving towards a more patient-centric measurement approach, there is tremendous potential for the use of digital physical activity measurement in clinical trials in the rare disease space.

Treatments and clinical studies for rare diseases

There are more than 7,000 known rare diseases for which less than 10% have treatments, let alone validated measures of disease progression and treatment effect. Instead, measures validated in more populous diseases with similar phenotypes are often used, with little or no evidence at first. Many rare diseases are also genetic and, therefore, systemic – meaning that a single symptomatic measure like the 6MWT may not capture the full burden of disease or treatment effect.

Further, 39% of rare disease patients travel at least 60 minutes to receive medical care, and likely longer to participate in a clinical study. Travel can be physically and mentally stressful, possibly impacting performance on activity-based tests. Given that rare disease patients are few in number, clinical studies are often small. Conducting infrequent, in-clinic 6MWT assessments limits the data available for clinical studies.

The field is making progress, however. In 2019, the European Medicines Agency (EMA) qualified the first digital endpoint, walking speed (i.e., SV95C) measured using a wearable device, for DMD. As a result, the clinical trial designers were able to significantly reduce the required sample size needed, decrease patient burden, and capture real-world ambulation in contexts that matter to patients.

At the same time, there is a risk of siloed innovation in digital medicine. More than 70 unique digital physical activity endpoints are currently being used in clinical trials by around 44 organisations, indicating a clear need for industry consensus. With outcomes ranging from step count to digitally recorded physical activity diaries, the field would benefit from efficiencies created by focusing on digital clinical measures where the evidence supports their meaningfulness to patients.

The need to progress rare disease treatments, collaboratively

Validating novel endpoints, especially digital measures, requires a significant investment of time, funds, and patients. For rare diseases with small patient populations, it can be even more challenging to validate disease-specific measures. Thus, it’s vital that industry stakeholders work together instead of duplicating efforts. This will allow innovators to leverage an evidence base that will quicken endpoint development and innovative treatment.

To address these challenges and facilitate cross-industry collaboration, the Digital Medicine Society (DiMe) is leading a pre-competitive collaboration to define a core set of digital clinical measures for physical activity that are centred on the patient. Stakeholders across academia, pharma, digital health technology companies, and patient groups are working together to drive consensus on the measures for physical activity that can meet the needs of patients, regulators, and clinical researchers, and to identify pathways forward to developing relevant digital physical activity measures across multiple therapeutic areas. Consistent with the US Food and Drug Administration’s (FDA) patient-focused drug development framework, the group has been exploring what aspects of patients’ physical activity they want to improve, maintain, or prevent from becoming worse.

Aligned, but small steps forward now

At a recent workshop, the group heard from patients who shared that the ability to maintain physical function for independence - like bending, walking, upper body mobility, and balance - were important to participate in work, household chores, and social activities they enjoyed.

While experts during the workshop also identified downstream considerations of validating measures across heterogeneous populations and challenges related to analysing continuous longitudinal data, the consensus was that aligned, but small steps forward now can have a big impact in the near term. There also was a clear recognition that current clinic-based assessments were inadequate to measure the important nuances of physical activity in everyday life and that collaboration is needed to move the field forward.

There is no time to delay. Episodic clinic-based assessments are not meeting the needs of patients, and improvements can be made by understanding the aspects of physical activity that are truly meaningful to patients and then defining a core set of digital measures capturing those health concepts.

By collaborating as a field to set the roadmap of what good looks like in digital measurement, industry leaders can be confident about evidence-based measures for better decision-making, enabling the field to focus on innovation and getting needed medicines to patients more quickly.

About the authors

Candice Taguibao is program lead at the Digital Medicine Society. She leads the physical activity project. Her background in public health and experiences working in the health tech start-up, clinical care, and academic research spaces have supported her current role in facilitating collaboration among diverse stakeholders to define digital measures for physical activity which are meaningful to patients.

Ankita Deshpande is head of digital health and experience innovation at Alexion, AstraZeneca Rare Disease. After seven years of biopharma-focused strategy consulting, Deshpande has since held roles in small- and medium-sized companies and nonprofits spanning commercial, market access, pricing, business development, corporate strategy, and strategic partnerships and experienced implementing human centred design, agile, and scrum in the biopharma context.