By: Cindy Howry, VP, eCOA Science
On December 23, 2023, the FDA released guidance for the industry on how digital health technologies (DHTs) should be used in clinical trials.
DHTs, which the FDA defined in their “Framework for the Use of DHTs in Clinical Trials,” are “technologies such as wearable, implantable, ingestible, and environmental sensors and software applications on mobile phones, among others.”
DHTs can be used to collect data from clinical trial participants more efficiently and objectively than traditional methods. For example, DHTs can collect data on participants' activity levels, sleep patterns, and medication adherence. This data can be collected electronically, which can reduce the burden on participants and improve the accuracy of the data.
The FDA Guidance touches on several key areas:
- Considerations for DHT Selection
- Design and operation of DHTs
- Use of participant's own DHT and/or technologies
- DHT submissions
- Verification, Validation, and Usability
- Evaluation of endpoints involving DHT data
- Record protection and retention
- Other considerations for sponsors and investigators
Below is a summary of each section contained above, to read through the FDA’s full text, click here.
1. Considerations for selecting DHTs
Clinical trial population
Organizations must take into account the diverse characteristics of the trial participants. Education levels, language preferences, age groups, and the physical condition of participants are essential considerations. Additionally, assessing the technical aptitude of the trial population is crucial to ensure that participants can effectively use the chosen DHT for the trial's intended purposes.
Technical and performance specifications
Identifying the minimum technical and performance specifications is fundamental. This includes aspects such as the operating system, storage capacity, and sensors to be used in the clinical investigation.
Flexibility is key; sponsors should remain open to incorporating new models or versions of the DHT during the trial, provided they meet the established technical and performance specifications.
2. Design and operation of DHTs
DHT design
The design of the DHT plays a pivotal role in participant engagement. Factors such as material, size, weight, appearance, and portability can significantly influence whether participants use the device as intended.
For wearable technologies, comfort and convenience become paramount considerations for sustained participant compliance throughout the clinical investigation.
User feedback
DHTs often provide users with real-time feedback on measurements. Understanding how this feedback may impact participant behavior and the evaluation of the investigational product is crucial. Additionally, the ability to maintain blinding or masking of data becomes essential, especially when data can be transmitted directly to investigators, sponsors, or other authorized parties.
Power needs
The practicality of a DHT is closely tied to its power requirements. Battery life and charging recommendations can significantly impact the feasibility of using the DHT for data capture throughout the specified duration of the clinical trial. Addressing these power-related considerations ensures uninterrupted data collection.
Operational specifications
Operational specifications, including data storage capacity and the frequency of data transmission, should align with the trial's requirements. Adequate operational specifications minimize the risk of missing data, ensuring a comprehensive dataset for analysis.
Alerts and environmental factors
Implementing alerts for low battery, poor signal, or data recording/transmission issues is a proactive measure to prevent data loss. Additionally, environmental factors such as temperature and humidity must be considered to assess their potential impact on DHT performance during the clinical investigation.
Network systems and cybersecurity
The availability and capacity of participant and sponsor network systems are critical factors, especially for trials involving frequent or continuous data recordings. Rigorous safeguards should be in place to manage cybersecurity risks, prevent unauthorized access, and guarantee the privacy and security of sensitive health data.
3. Use of participant's own DHT and/or technologies
Advantages and disadvantages
Allowing trial participants to use their own DHTs or other technologies introduces a dynamic element into the trial design. Evaluating the advantages and disadvantages of this approach is necessary. While it may reduce participant burden, certain considerations, such as the specificity of the DHT for the trial's purpose, must be taken into account.
Sponsor-provided options
To ensure inclusivity and mitigate potential exclusions based on participants' technology preferences, sponsors should make sponsor-provided DHTs or technologies available as an option. Additionally, providing telecommunication services is crucial for participants with limited access, ensuring equitable participation in the clinical investigation.
4. DHT submissions
Fit-for-purpose explanation
Sponsors are tasked with elucidating how the chosen DHT aligns with the goals of the
clinical investigation. This entails detailing the design, technological characteristics, data output, and methodology employed by the DHT to measure the clinical event or characteristic of interest. A crucial aspect is explaining how data flows from the DHT to the first durable electronic data repository.
Usability features
To foster a comprehensive understanding of data collection plans, sponsors should
articulate features influencing usability. This includes insights into the user interface, how the DHT is worn, operated, and maintained, as well as the control measures in place for ensuring data privacy and security.
Participant engagement
To enhance participant engagement, sponsors must consider features that impact how
participants interact with the DHT. This includes the user interface design and details on charging, calibration, and overall maintenance of the DHT.
Access control and reporting options
Maintaining control over access to the DHT and its collected data is imperative for privacy
and security. Additionally, sponsors should outline mechanisms for users to report supplementary information, such as symptoms or activities, to enrich data recordings and aid in their interpretation.
Data management
A critical aspect of the submission is detailing how data integrity is preserved.
This involves comprehensive information on data management, covering aspects
such as collection, storage, transmission, and archiving.
5. Verification, Validation, and Usability
Verification and validation defined
Verification and validation are key components regardless of whether the DHT qualifies as a
device under regulatory definitions. Verification involves confirming the accurate and precise measurement of parameters, while validation ensures that the DHT appropriately assesses the clinical event or characteristic in the proposed participant population.
Gradual testing progression
The verification and validation process may progress from benchtop studies to
testing in healthy volunteers and individuals representing the target patient population. This ensures that the DHT functions consistently and appropriately across different contexts.
Calibration and measurement evaluation
Validation studies include evaluating calibration processes, comparing measurements with
reference measurements, and assessing factors influencing measurement accuracy.
Usability evaluations are crucial to identify and address potential use errors or difficulties faced by trial participants.
Interoperability
Sponsors are encouraged to ensure interoperability, facilitating the effective and
secure exchange of information between connected systems in the clinical
investigation. Public data exchange standards are recommended for seamless
interactions.
Usability evaluations
Usability evaluations play a critical role in confirming that the DHT can be used as
intended, without errors or problems. These evaluations should be tailored to
the risks and complexities associated with each DHT and should assess the
ability of participants to efficiently use the technology in a remote setting.
Continuous improvement
Findings from usability evaluations contribute to ongoing improvement in DHT design and
functionality. They also should inform instructions for use and the training provided to
trial participants and personnel, ensuring sustained participant engagement
throughout the clinical investigation.
6. Evaluation of endpoints involving DHT data
Justifying endpoints
When selecting endpoints involving DHT data, sponsors should provide a well-defined and reliable methodology for assessing participants' responses to a medical product. This involves a comprehensive description of the endpoint, its clinical relevance, and a collaborative approach involving stakeholders such as patients, caregivers, clinicians, engineers, statisticians, and regulators.
Defining the endpoint
Precision in defining the endpoint is crucial. This entails specifying the type of assessment, timing, tools used, and details on combining multiple assessments if applicable. The clarity in this definition ensures consistency and reliability in data collection.
Established vs. novel endpoints
DHTs might replicate existing measurements or introduce novel endpoints offering unique insights. While established endpoints may not require new justifications, novel endpoints demand careful consideration. Sponsors must address factors such as clinical relevance, biomarker utility, meaningfulness to the target population, and reliability in assessing disease severity or health status.
Statistical analysis plan
To ensure a robust evaluation, a detailed statistical analysis plan is imperative. It should delineate the method for data collection, define endpoints and their source data, adhere to the estimand framework, and account for potential events that may affect data collection or interpretation.
Non-inferiority trial designs
Non-inferiority trials may pose challenges if the effect size of the comparator using similar DHT measurements is undefined. This necessitates careful consideration of trial design based on established standards.
Handling missing data
The use of DHTs may impact data collection, leading to potential missing data issues. Sponsors should implement proactive strategies like automated data monitoring, participant reminders, and investigator outreach to mitigate these challenges and ensure data quality.
Protocol and statistical analysis plan alignment
The study design should align with the statistical analysis plan, addressing relevant events and technology changes during the study. Strategies for identifying and handling these events, ensuring DHT adherence, and minimizing data collection issues should be clearly outlined.
Physical features and safety
Evaluation of DHT physical features is crucial to identify potential discomfort or injury risks (e.g., skin irritation or occlusion of blood supply). Safety testing and usability evaluations by manufacturers or sponsors are essential for minimizing participant risks. Clear instructions on DHT reuse and cleaning processes should also be provided.
Impact on treatment
When DHT measurements influence investigational product administration or participant treatment, the risk of erroneous measurements leading to inappropriate or inadequate treatment must be carefully assessed.
Cybersecurity threats
Sponsors should consider cybersecurity threats that could compromise DHT functionality, posing clinical risks to participants. Adhering to FDA guidelines on cybersecurity is essential to securely store and transmit data.
Data disclosure and sharing
Unique privacy risks may arise, including the potential disclosure of personally identifiable information. End-user license agreements or terms of service may allow data sharing. Sponsors should work with manufacturers to modify agreements, ensuring participant privacy.
Security safeguards
Appropriate security safeguards must be in place to secure data at rest and in transit, protecting against unauthorized access or malicious activities.
Informed consent process
Informed consent processes should comprehensively outline foreseeable risks related to DHT use, potential actions to mitigate risks, and the type of information collected. Participants should be informed of who may access their data and the measures in
place to protect privacy.
Data sharing and additional costs
The consent process should clarify potential data sharing as per end-user agreements and any additional costs participants might incur due to DHT use.
7. Record protection and retention
Durable electronic data repository
Data captured by DHTs, along with associated metadata, should be securely transferred to a durable electronic data repository. Sponsors should discuss data formats and transmission specifics with review divisions.
Source data and inspection
DHT data in the durable electronic repository is considered source data, available for inspection. Clinical investigators should review and maintain source data while also ensuring the FDA can access it.
By addressing these critical aspects, sponsors, investigators, and IRBs can navigate the ethical landscape of DHT usage in clinical trials, ensuring participant safety, data privacy, and compliance with regulatory standards.
8. Other considerations for sponsors and investigators
Physical features and safety
Evaluation of DHT physical features is crucial to identify potential discomfort or injury risks (e.g., skin irritation or occlusion of blood supply). Safety testing and usability evaluations by manufacturers or sponsors are essential for minimizing participant risks. Clear instructions on DHT reuse and cleaning processes should also be provided.
Impact on treatment
When DHT measurements influence investigational product administration or participant treatment, the risk of erroneous measurements leading to inappropriate or inadequate treatment must be carefully assessed.
Cybersecurity threats
Sponsors should consider cybersecurity threats that could compromise DHT functionality, posing clinical risks to participants. Adhering to FDA guidelines on cybersecurity is essential to securely store and transmit data.
Data disclosure and sharing
Unique privacy risks may arise, including the potential disclosure of personally identifiable information. End-user license agreements or terms of service may allow data sharing. Sponsors should work with manufacturers to modify agreements, ensuring participant privacy.
Security safeguards
Appropriate security safeguards must be in place to secure data at rest and in transit, protecting against unauthorized access or malicious activities.
Informed consent process
Informed consent processes should comprehensively outline foreseeable risks related to DHT use, potential actions to mitigate risks, and the type of information collected. Participants should be informed of who may access their data and the measures in place to protect privacy.
Data sharing and additional costs
The consent process should clarify potential data sharing as per end-user agreements and any additional costs participants might incur due to DHT use.
Durable electronic data repository
Data captured by DHTs, along with associated metadata, should be securely transferred to a durable electronic data repository. Sponsors should discuss data formats and transmission specifics with review divisions.
Source data and inspection
DHT data in the durable electronic repository is considered source data, available for inspection. Clinical investigators should review and maintain source data, permitting FDA access under regulations.
Conclusion
In conclusion, the FDA's guidance on the use of digital health technologies (DHTs) in clinical trials marks a significant step forward, offering guidelines for sponsors and investigators to follow when using these innovative tools.
By providing clarity on the selection, design, and operation of DHTs, the FDA is helping facilitate their integration into clinical trials, promising more efficient and objective data collection and offering the potential to enhance participant experiences and improve data accuracy.
