Digital Tech for Clinical Trials May Carry Hefty Compliance Requirements

January 1, 2022

The FDA’s new draft guidance for the use of digital health technologies (DHTs) for remote data acquisition in clinical trials promises to help advance the market for a wide range of products in the digital health space. However, developers of these products should be aware that their products will be subject to a substantial amount of verification and validation work, along with a considerable load of usability studies.

The draft is a continuation of a 2015 docket regarding the use of technologies and innovative methods for the conduct of FDA-regulated clinical investigational drugs. That docket was directed toward DHTs used to aid in trials of investigational drugs, a scope that has been expanded upon in this new draft guidance to include trials of medical devices and biotech products.

Among the concerns cited in comments to the 2015 docket was that any unique validation requirements imposed to ensure data integrity could impede development of these technologies. There were also concerns about whether patients may need assistance to reliably make use of these data acquisition technologies, as well as concerns about the cost of providing the required electronic devices to patients/enrollees. Because of these and other issues, some stakeholders recommended that any regulatory requirements be developed on a case-by-case basis until the FDA and industry had developed a stronger sense of how a guidance should be drafted.

For the purposes of this draft, a DHT is a system that uses computing platforms, connectivity, software and/or sensors for healthcare and related uses. Firmware is included in the definition of hardware, and general-purpose computing platforms are within the scope of the draft. The draft states that software that meets the definition of a DHT might also meet the definition of a device as modified by the 21st Century Cures Act. Any DHT products used in clinical investigations are generally exempt from typical premarket requirements so long as the sponsor is in compliance with the regulations for investigational device exemptions (Part 812).

User Calibration a Key Validation Point

The section on verification and validation covers several different product and component types, such as sensor-based DHTs. Among the verification and validation activities the draft would require for sensor-based products are:

  • Comparisons of DHT measurements with reference measurements of the clinical event or characteristic(s);
  • An evaluation of any factors that could affect the precision and accuracy of the measurement (such as anatomical location) and any potentially interfering physical activities; and
  • An evaluation of the calibration process for the sensor, where applicable (some DHTs may require calibration by the user and/or clinical trial staff, and any associated calibration procedures must themselves be validated).

The FDA stated that validation studies can be conducted with patients suffering from varying degrees of disease severity. These studies can also be conducted with healthy volunteers, assuming the measurement of interest is unaffected by the condition or disease of interest. As an example, validation of an instrument for measurement of heart rate in patients with Parkinson’s disease may be conducted with healthy volunteers, but a sensor that tracks step counts cannot be validated with healthy controls due to the gait disturbances common to this disease.

There are brief discussions of validation for DHT software and the implications of the use of general-purpose computing platforms, but the draft also raises the question of data interoperability. There are two resources of interest regarding interoperability, including IEEE ISO 11073, which addresses interoperability of personal health devices. The agency also made reference to a September 2017 guidance for device interoperability, the terms of which would apparently apply to DHTs.

Usability studies should enroll patients/users that are similar to the intended study participants and should check to ensure that users can enter all their data before the software automatically logs the user out. The draft states that sponsors can refer to published studies as part of the data for a usability study, assuming those studies address similar populations.

For sponsors considering bringing these devices to market under a conventional premarket filing, we would point out that the usability requirements in this draft are less stringent than are found in the FDA’s February 2016 final guidance for the application of human factors and usability engineering to medical devices. While software devices and sensors as described in this new draft guidance do not appear on the associated human factors priority list, developers should nonetheless be aware that these requirements are likely to be applicable once these products are used outside the bounds of a clinical study.

The section on risk considerations is divided into discussions of clinical risks and privacy-related risks. Privacy-related risks fall into three areas, including:

  • The risk of disclosure of identifiable information via a breach of the DHT;
  • Data sharing as a result of an agreement between the vendor of a general-purpose platform and third parties; and
  • Security safeguards to ensure that data, both at rest and in transit, cannot be accessed by intervening or malicious parties.

The FDA recommended that sponsors and vendors of general-purpose computing platforms revisit these data-sharing agreements for the study, the terms of which may have to be disclosed to study participants as part of informed consent.

Part 11 Requirements Also Apply

Under the terms of the draft, there will also be a requirement for a durable electronic data repository, which will serve as part of the record for the clinical investigation. This repository will include all data captured from the DHT along with any metadata, and as might be expected, Part 11 requirements apply here. These requirements are described in the June 2017 Part 11 Questions and Answers draft guidance for the use of electronic records and electronic signatures in clinical trials.

The Part 11 Q&A draft builds on a final guidance from 2003, but the preamble to the 2017 draft states that the FDA intends to exercise enforcement discretion regarding some Part 11 requirements, such as validation, audit trails and record retention. However, the agency also said that sponsors should nonetheless maintain records and comply with the predicate rule for Part 11.

The 2017 Part 11 draft seems to offer some leeway with regard to some validation requirements, given that the draft takes a risk-based approach. Validation is virtually compulsory when an electronic system serves to process any records deemed critical to the clinical study, but the sponsor has some discretion when it comes to validating the use of commercial off-the-shelf software (COTS) used to process non-critical procedural records. In this scenario, the agency states that any validation activities should be guided by the organization’s internal practices and needs.

There are other provisions in the 2017 Part 11 Q&A draft that sponsors should take careful note of, such as a discussion of the use of COTS in electronic data capture. Any validation by the vendor of that COTS should be retained by the sponsor of the clinical study, but the sponsor may also be required to develop a unique validation plan for when COTS are integrated with other computer systems or are part of a system developed specifically for the needs of the user. These systems will be examined during FDA inspections, and so we would advise our clients to pay heed to these Part 11 requirements when developing DHTs for use in clinical trials. This includes instances in which the developer of the DHT is uncertain as to whether they intend to bring that product to market outside the clinical trial.

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