As an end of the year gift, FDA finalized its guidance document, Digital Health Technologies for Remote Data Acquisition in Clinical Investigations, in late December. We previously blogged on the draft guidance (here) and on FDA’s broader framework for Digital Health Technologies (DHT) (here and here). A DHT is a system that uses computing platforms, connectivity, software, and/or sensors, for health care and related uses. The guidance addresses the use of DHTs in clinical investigations of drugs, biologics, and medical devices.
Overall, the final guidance provides many editorial clarifications as well as some noteworthy updates, including discussions on DHTs that meet the definition of a device, selection of a DHT and rationale for use in a clinical investigation, retention and protection of data collected by DHTs, and DHT updates.
The final guidance provides additional discussion with respect to DHTs that meet the definition of a device. Just like other devices used in a clinical investigation are exempt from most regulatory requirements, the same goes for DHTs. The table below, consistent with FDA’s DHT Guidance, illustrates what regulatory requirements apply to medical device DHTs used in clinical investigations, whether the DHTs are the object of the investigation (i.e., investigational device as defined in 21 C.F.R. § 812.3(g)), or simply used to collect data as part of a clinical investigation of a drug, biologic, or different medical device. It is interesting to note that even when the DHT is not the subject of the investigation and therefore not an investigational device as defined in 21 C.F.R. Part 812, the requirements under 21 C.F.R. Part 812 are applied for the use of the DHT in the clinical study.
|If DHT is a medical device and…
|is cleared or approved and used in a clinical investigation in accordance with its approved or cleared indications for use
|a submission of an IDE to the FDA is not required.
|falls into one of the categories of exempt investigations under 21 C.F.R. § 812.2(c)
|a submission of an IDE to the FDA is not required.
|is used in a clinical investigation of a drug or biologic under IND and the DHT meets the definition of a nonsignificant risk device
|a submission of an IDE to FDA is not required as long as the investigation complies with abbreviated IDE requirements under 21 C.F.R. § 812.2(b).
|is used in a clinical investigation of a drug or biologic under IND and the DHT meets the definition of a significant risk device
|a submission of an IDE to the FDA is required unless all the information required for the IDE is contained in the IND.
Another noteworthy update in the final version of the guidance relates to the selection of a DHT or other technologies (e.g., smartphones and tablets) for remote data acquisition in a clinical investigation. For these devices that do not have market authorization and are only used for remote data collection in a clinical investigation, if the sponsor conducts verification and validation activities consistent with the guidance to demonstrate the DHT is “fit-for-purpose,” FDA does not intend to assess sponsors’ compliance with design controls. Drug or biologic sponsors should engage with manufacturers of DHTs to ensure appropriate evidence has been established for the DHTs before use in a clinical study. Whereas if the DHT meets the device definition and is used outside of a clinical investigation, full compliance with design controls requirements is applicable.
The final guidance also revised sections on verification, validation, and usability evaluation of DHTs, clarifying that verification and validation should be addressed regardless of whether the DHT meets the definition of a device and should consider all relevant functions of the DHT in the context of use in the clinical investigation. An important footnote is added stating that when DHTs include device software functions that sponsors should address the documentation recommendations in the FDA’s guidance on Content of Premarket Submissions for Device Software Functions. Considerations for design of usability evaluation are provided as well as a statement that the principles in the FDA’s guidance on Applying Human Factors and Usability Engineering to Medical Devices may be helpful in designing appropriate usability evaluations for DHTs.
The final guidance also expands the discussion of analysis of data collected from DHTs which should be defined in a clinical study’s statistical analysis plan. New content in this section relates to late phase trials and reduction and handling of missing data. Use of automated data monitoring and alerts, participant reminders, a “run-in” period for participants, and investigator outreach are provided as examples that may reduce missing data.
With respect to DHT record protection and retention, the final guidance clarifies how DHT data will be reviewed in an inspection, noting that data may be requested in various formats and that data must be maintained according to sponsor or investigator’s record retention requirements and should be in human readable form. However, in general, FDA does not intend to request machine or raw data that require electronic processing to be understood in an inspection. This section of the guidance further clarifies that source data are considered the first durable electronic data repository which the data are transferred to, and that FDA does not intend to inspect individual DHTs for source data.
With respect to DHT updates and other changes during clinical investigations, the final guidance notes significant changes in the measurement after updates may invalidate the results from a clinical investigation. As such, careful evaluation of changes and validation of changes where measurements may be affected by a change are important. If changes to the measurement have occurred after the update, sponsors should compare data from DHTs before and after the update, conducting sensitivity analyses as necessary, and taking steps to mitigate any resulting differences.
If a sponsor is considering the use of a DHT in a clinical investigation, this guidance will help ensure they have the required documentation to demonstrate the DHT is “fit-for-purpose” to include in a final submission. The sponsor should be able to describe the DHT design and technological characteristics, data output provided, and how the DHT measures the event of interest. Details such as this might be publicly available or provided by the DHT manufacturer to the sponsor or, depending on the technology, could require the DHT manufacturer to provide the sponsor a right to reference to the DHT master file. If sponsors are considering the use of DHT to capture novel endpoints, rather than simply using the DHT to replace manual capture of established endpoints, sponsors should be prepared to provide additional justifications regarding the use of the DHT, its impact on the participants, effect on interventions, how it relates to other endpoints, the reliability of the data, and how the positive control can be detected using the novel endpoint.
Any sponsor considering the use of DHT in a clinical investigation will benefit from careful consideration of the recommendations contained in the guidance to facilitate a successful future marketing authorization submission to the FDA.