5.4 Risk mitigation
Responding to risks identified through monitoring
Risk mitigation encompasses both advance planning and the actions taken when risks materialize.
This section focuses on how predefined mitigation strategies are applied in practice when monitoring activities identify signals that may affect participant safety, data integrity, or trial conduct.
OVERVIEW
Responding to real-time trial signals
Risk mitigation encompasses the predefined controls and response pathways that enable study teams to act when monitoring identifies potential risks. Many mitigation elements are established before the trial begins, including escalation criteria, adjudication processes, and documentation expectations. Their purpose is to ensure that responses are timely, consistent, and proportionate to the risk identified.
Building on the monitoring principles described in Section 5.3: Trial monitoring, this section focuses on how those mitigation plans are applied during trial execution. It describes how signals are investigated, how decisions are made and documented, and how appropriate follow-up actions are taken to protect participant safety and maintain trial integrity.
IN PRACTICE
Systematic risk response: Ensuring proportional and documented action
Risk mitigation is about translating monitoring signals into informed decisions and appropriate action. When a signal is identified, study teams must determine what it means, who should review it, and what response is warranted. Clear processes help avoid overreaction to benign variation while ensuring that meaningful risks are addressed promptly and consistently.
The subsections below walk through the core components of risk mitigation during trial execution, focusing on how signals are reviewed, escalated, and resolved once they are identified through monitoring activities.
Managing clinically actionable signals
Whether the detected signal is related to a target endpoint or not, an sDHT may capture signs that a participant requires medical assessment. Your risk mitigation strategy should be formalized into a single, cohesive Adjudication Protocol that aligns clinical, legal, and ethical requirements before the first participant is enrolled. This protocol is the definitive source for handling any actionable signal.
While adjudication protocols and escalation pathways are established before the trial begins, their value is realized during trial execution.
Liability containment and data flow integrity are mutually dependent goals that rely on explicit contractual agreements and defined Standard Operating Procedures (SOPs). Both the developer and the adopter must establish clear boundaries and rigorous documentation practices to protect the trial once a safety signal is detected.
Such a protocol includes:
Risk mitigation plans should be aligned with your Institutional Review Board (IRB) and clearly communicated to participants.
- Define “off-target”: Explicitly describe to the IRB which signals the sDHT is intended to detect (on-target) and which may emerge unexpectedly (off-target). Share with the IRB your signal confirmation processes including adjudication and communication workflows. Acknowledge the possibility or probability of false positives and describe how participant distress or unnecessary clinical referrals will be minimized.
- Transparent consent: The Informed Consent Form (ICF) must clearly state how off-target findings will be handled—including when participants will or will not be notified. This includes acknowledging the possibility of false positives and describing how unnecessary clinical referrals will be minimized.
PRO TIP
Example phrasing for consent:
“Although the [sDHT; label by name and type] is being used to measure [endpoint], it may also capture signals not directly related to this study. If such a signal appears to represent a potential health concern, the research team will review the data and may contact you or your healthcare provider. Not all incidental findings will be reported, and not all such findings are clinically meaningful.”
Adjudication protocols are typically established during trial planning to ensure that clinically actionable signals can be managed consistently once a trial is underway. In practice, the adjudication protocol serves as the operational framework used when monitoring identifies a signal that requires clinical review.
During trial execution, the adjudication protocol guides how signals are assessed, who participates in decision-making, what evidence is considered, and what follow-up actions are permitted. It helps distinguish true clinical findings from artifacts, expected variability, or operational issues, and supports timely, proportionate responses aligned with the study protocol, informed consent materials, and safety monitoring plan.
A well-functioning adjudication protocol also clarifies documentation expectations, ensuring that decisions and actions taken in response to signals are traceable and auditable. This enables consistent application across sites and provides a clear record for trial oversight and regulatory review.
Example: Adjudication protocol for sDHT data in a drug trial
| Step | Action | Owner | Purpose |
|---|---|---|---|
| 1. Automated detection | System flags a critical or abnormal reading (e.g., severe arrhythmia) | Developer | Detection and Triage |
| 2. Signal confirmation | Developer/Data Science verifies the signal is real (not a false positive, technical error, or data artifact) | Developer | Ensure technical integrity and minimize false positives |
| 3. Clinical adjudication | Confirmed signals are routed to the Principal Investigator (PI) or Medical Monitor for immediate review and clinical judgment | Adopter / PI | Determine clinical significance and necessary action |
| 4. Participant notification | If deemed actionable, the PI/site staff notifies the participant using an IRB-approved script and refers them to standard local care | Adopter / Site PI | Fulfill duty of care; protect participant welfare and safety |
| 5. Regulatory & ethics reporting | Adjudicated signals are mapped to adverse event reporting timelines (e.g., within 24 hours for critical signals) | Adopter pharmacovigilance lead | Mandatory regulatory/safety reporting |
Developers: Technical integrity
Developers are the first line of defense; they are accountable for the technical design that minimizes errors and maximizes security, thereby limiting unnecessary clinical intervention.
- Minimize false positives: Excessive or poorly calibrated alerts can create unnecessary participant anxiety and place avoidable burden on clinical sites. Developers should support trial operations by providing clear documentation describing how false positives are minimized, how alert thresholds are set, and how known limitations should be interpreted when signals are reviewed.
- Cybersecurity and provenance: Developers are responsible for maintaining the security and integrity of the data pipeline throughout the trial. This includes providing an up-to-date Software Bill of Materials (SBOM), maintaining documented vulnerability management and patching procedures, and ensuring data provenance is preserved to support incident response, audits, and regulatory review.
Adopter: Legal and operational firewall
Once a signal requires action beyond the study protocol, adopters are responsible for ensuring that legal, operational, and clinical boundaries are applied consistently during trial execution.
- Liability containment: Adopters should ensure contractual language clearly defines sponsor responsibilities when a participant is referred for standard medical care following a signal. This typically includes provisions clarifying when sponsor responsibility ends and may involve indemnification language reviewed by legal counsel.
- Documentation discipline: Comprehensive documentation supports both trial oversight and regulatory inspection. All actions related to a signal, from initial detection through Principal Investigator adjudication and follow-up, should be traceable and auditable. This includes maintaining records in the electronic Trial Master File (eTMF), preserving audit logs, and completing required documentation to support case report forms (CRFs).
Pre-Launch Checklist:
Once your trial is underway—or wrapping up—pause to confirm that Section 5 objectives have truly been met. This checklist focuses on monitoring fidelity, risk mitigation, documentation discipline, and early learnings. Completing these steps sets you up for effective reflection, iteration, and field-wide contribution in Section 6: Refine your strategy.
KEY TAKEAWAYS
Putting risk mitigation into practice
Risk mitigation in sDHT-enabled trials focuses on how predefined plans are applied once monitoring identifies a signal that may require action. Clear processes for triage, adjudication, escalation, and documentation enable study teams to respond consistently and proportionately during trial execution.
By establishing roles, decision pathways, and documentation expectations in advance, study teams can manage unexpected or off-target signals without unnecessary disruption, while protecting participant safety and maintaining trial integrity.
5.4 Risk mitigation
Library resources to guide you
The sDHT roadmap library gathers 200+ external resources to support the adoption of sensor-based digital health technologies. To help you apply the concepts in this section, we’ve curated specific spotlights that provide direct access to critical guidance and real-world examples, helping you move from strategy to implementation.
Features essential guidance, publications, and communications from regulatory bodies relevant to this section. Use these resources to inform your regulatory strategy and ensure compliance.
Gathers real-world examples, case studies, best practices, and lessons learned from peers and leaders in the field relevant to this section. Use these insights to accelerate your work and avoid common pitfalls.