Developing a Novel Measurement of Sleep in Rheumatoid Arthritis: Study Proposal for Approach and Considerations

Abstract

The development of novel digital endpoints (NDEs) using digital health technologies (DHTs) may provide opportunities to transform drug development. It requires a multidisciplinary, multi-study approach with strategic planning and a regulatory-guided pathway to achieve regulatory and clinical acceptance. Many NDEs have been explored; however, success has been limited. To advance industry use of NDEs to support drug development, we outline a theoretical, methodological study as a use-case proposal to describe the process and considerations when developing and obtaining regulatory acceptance for an NDE to assess sleep in patients with rheumatoid arthritis (RA). RA patients often suffer joint pain, fatigue, and sleep disturbances (SDs). Although many researchers have investigated the mobility of joint functions using wearable technologies, the research of SD in RA has been limited due to the availability of suitable technologies. We proposed measuring the improvement of sleep as the novel endpoint for an anti-TNF therapy and described the meaningfulness of the measure, considerations of tool selection, and the design of clinical validation. The recommendations from the FDA patient-focused drug development guidance, the Clinical Trials Transformation Initiative (CTTI) pathway for developing novel endpoints from DHTs, and the V3 framework developed by the Digital Medicine Society (DiMe) have been incorporated in the proposal. Regulatory strategy and engagement pathways are also discussed.

Keywords: Hypothetical study; Novel digital endpoint; Validation framework.

Fig. 1

Conceptual framework for measuring sleep in RA. The COI for measuring sleep in RA patients will monitor treatment effect via the actigraphy device and algorithms. The measurement of the variables of sleep in a defined patient population provides information about a meaningful aspect of the patients' condition affected by RA and the effectiveness of treatment, thus defining the conceptual framework for validation of the NDE. TNF-α, tumor necrosis factor-alpha; COI, concept of interest; RA, rheumatoid arthritis; NDE, novel digital endpoint.

Fig. 2

Studies and objectives for validation. Based on our hypothetical NDE for sleep parameters in patients with RA. ∆, change; ClinRO, clinician-reported outcome; DHT, digital health technology; HV, healthy volunteer; PRO, patient-reported outcome; PSG, polysomnography; RA, rheumatoid arthritis; SE, sleep efficiency; TNF, tumor necrosis factor; TST, total sleep time; WASO, wake-after-sleep onset.

Fig. 3

HA interactions to discuss the development and validation of the NDE when developed in parallel to a molecule. These interactions are mapped against the following: phases of drug development, phases of digital endpoint development and validation, and the NDE qualification pathways available at the EMA and the US FDA. This figure illustrates how developers can present the evidence needed at each stage of the NDE qualification pathways through the interactions of the drug development program to obtain HA acceptance on the use of the endpoint in the pivotal clinical trial. COA, clinical outcome assessments; COI, concept of interest; COU, concept of use; CPIM, Critical Path Innovation Meeting; DHT, digital health technology; FQP, full qualification package; GxP, Good X Practices, where X refers to Laboratory, Manufacturing, Clinical, etc.; IND, Investigational New Drug; ITF, Innovation Task Force; LOI, letter of intent; QP, qualification plan; HA, health authority; US FDA, United States Food and Drug Administration; NDE, novel digital endpoint; EMA, European Medicines Agency.