Findings
Cytokine Release Syndrome (CRS) is a common and potentially life-threatening adverse event of immunotherapies, particularly in Oncology, complicating patient care and increasing healthcare costs. Standard-of-care inpatient monitoring for CRS is manual, intermittent, costly, and restrictive, providing an incomplete view of the syndrome’s development and progression. The use of Digital Health Technologies (DHTs) for continuous, remote monitoring of vital signs (like heart rate, respiratory rate, skin temperature, SpO2, and activity) can capture early indicators of CRS up to two hours earlier than standard episodic monitoring. This ability to collect multivariate continuous data is valuable for informing robust model development for CRS risk prediction.

Recommendations
Investigators should deploy DHTs available today to monitor vital signs and symptoms currently observed in the hospital setting, but in an outpatient or home environment. The goal is to develop Early Warning Products that assess the probability of developing CRS, providing clinical decision support. Product developers should follow a strategic roadmap that outlines milestones for building products that are clinically relevant and commercially viable. Researchers should use a common set of digital clinical measures to gather high-quality datasets and ensure comparability across studies to build more robust predictive models. Predictive algorithms should be built on a robust reference measure for analytical validation and be clinically validated with sufficient data.

Regulatory Considerations
The resources are designed to help developers build products that are clinically appropriate, regulatory-acceptable, and commercially viable. Future regulatory submissions for CRS de-risking products will benefit from aligning with this industry-wide dialogue that is being built in collaboration with the FDA. Developing a robust CRS safety biomarker could enhance the safety profile of clinical trials, increase trial access, and streamline regulatory decision-making, possibly through a qualification pathway. Products that aim for a higher level of autonomy, such as a Diagnostic that redefines current CRS grading classes, may require very high clinical evidence and likely stringent regulatory review.

Findings
There are gaps in assessing aspects of physical function that matter to patients.
Existing assessment methods have limitations, including their episodic nature and burden to patients.
There are currently no approved drugs in the United States for the treatment of cancer cachexia.

Recommendations
Develop and validate digital measures of health.
Ensure digital measures are meaningful to patients.
Qualify digital measures for use in clinical development and regulatory decision-making.

Regulatory Considerations
Qualification of digital measures as drug development tools is necessary.
Digital measures are gaining traction in regulatory decision-making.
The FDA recommends qualification of digital measures in their PFDD guidelines."

Findings
There is a lack of consensus on outcome measures and adherence definitions across studies using wearables in oncology.
There is significant heterogeneity in study designs and outcomes, making comparisons difficult.
Limited guidelines exist for designing or reporting trials using wearables in oncology.

Recommendations
Establish standardized definitions for wearable outcomes and adherence to improve study comparisons.
Encourage research using advanced wearable devices and active data use.
Conduct more randomized clinical trials to create consensus on implementing wearables in oncological practice.
Develop guidelines for designing and reporting trials using wearables.

Regulatory Considerations
The Clinical Transformation Initiative (CTTI) provides recommendations for the use of mobile technology in clinical trials, which could inform regulatory frameworks.

Findings
Concerns about data accuracy, particularly variability in measurements across different age groups and devices.
Issues with data provenance, as raw data from wearables are often transformed and filtered before storage, making comprehensive analysis difficult.
Regulatory challenges due to lack of specific FDA guidance for clinical trials using wearables and mobile devices.

Recommendations
Improve data accuracy through standardized approaches and expert recommendations.
Enhance data provenance by developing methods to trace data lineage and ensure transparency in data processing.
Develop specific FDA guidance for the use of wearables and mobile devices in clinical trials.
Implement robust security measures to protect data integrity and privacy.
Follow the ePRO Consortium's recommendations for device suitability in clinical trials.

Regulatory Considerations
The need for FDA guidance specific to clinical trials using mHealth technologies.
Sponsors' responsibility to validate the reliability of mHealth technology in capturing and transmitting data.
Security vulnerabilities in devices, necessitating adherence to privacy standards and robust security protocols.