The FDA has released a framework for the use of digital health technologies (DHTs) in the development of pharmaceuticals and biologics, but the FDA’s Center for Devices and Radiological Health (CDRH) will be intimately involved in this project. For now, the FDA seems to have more questions than answers regarding this concept, a state of affairs that will require input from a range of disciplines and participants to overcome.
The Prescription Drug User Fee Act VII (PDUFA VII) commitment letter calls on the FDA to develop policies related to DHTs used for drug product development and review (the document includes biologics in defining a drug), but the principal focus is on clinical trials. The FDA has some experience in this use of technology, such as a program for the use of mobile health technology for real-world use of psychotropics, but the DHT framework is the most comprehensive program of this type to date.
Framework Requires New Statistical Methods, New IT Capabilities
While there is some discussion of artificial intelligence (AI), the scope of this program is exclusive of basic research directed toward the identification of potential new molecular entities regulated by the Center for Drug Evaluation and Research (CDER) or the Center for Biologics Evaluation and Research (CBER). Interestingly, the DHT framework refers to several FDA initiatives regarding AI and machine learning (ML), including the January 2021 AI/ML action plan for software as a medical device (SaMD), which promised draft guidance on predetermined change control by the end of 2021. That promise has not been fulfilled.
This framework includes a list of goals and objectives, such as establishing internal FDA capabilities. The list is extensive and demanding and includes the following:
- Formation of a DHT steering committee;
- Programs for the development of technical expertise and training, which would help manage regulatory questions such as verification and validation of DHTs;
- Establishment of internal processes to ensure that DHTs are reviewed consistently across the agency;
- Development of new statistical methods for the analysis of data derived from DHTs; and
- Improvements in the FDA’s internal IT systems, including cloud-based systems, which will be funded by fees collected under PDUFA VII.
Framework-Related Guidances Likely to Prove Time-Consuming
The PDUFA VII commitment letter states that the FDA was required to release at least a draft guidance on using DHTs in both traditional and decentralized clinical trials by the end of the first quarter of the fiscal year 2023. This guidance would review matters such as the validation of measurements obtained by DHTs, which seems to have been fulfilled by the release of the December 2021 draft guidance for using DHTs for remote data acquisition in clinical investigations. As our clients know, this draft guidance suggests that developers of these DHTs will face significant regulatory hurdles before their products make it to market.
Several other draft and final guidances will play a vital role in this new program, such as draft guidance for decentralized clinical trials for biologics, devices, and drugs, which will likely be a complex regulatory consideration. Another draft guidance that will be critical for this framework is one that will take up regulatory considerations for prescription drug use-related software. Both draft guidances are due by the end of the fiscal year 2023, and it is reasonable to assume that the agency and industry may need as much as a year, potentially longer, to work through the process of converting them to final guidance.
Interlocking Guidance Requirements Will Create Complexity
The most significant task in connection with the DHT/drug development framework may be the sheer number of existing guidances that are directly or indirectly implicated. The following is a small selection of the CDRH guidance listed applying to this framework. We would emphasize that the volume of interacting guidances and policies suggests that the FDA will need several years to accomplish everything listed in this framework. Among the draft and final guidances cited in the framework are:
- The October 2017 guidance for deciding when to submit a new 510(k) for a software change to an existing device;
- The December 2017 guidance for clinical evaluation of SaMD;
- The July 2020 guidance for multiple function device products; and
- The November 2021 draft guidance for the content of premarket submissions for device software functions.
This list is far from exhaustive, but many in the pharmaceutical industry are only peripherally aware, at best, of these guidances and the work needed to fulfill the related requirements. This would seem to confirm that CDER- and CBER-regulated entities will seek out partnerships with companies familiar with the regulated software space, but the supply of this sort of expertise may not suffice to meet the demand.
CDRH-regulated entities will find most of the content of the DHT framework familiar. However, the process of applying existing wearable and other digital technologies to the task of collecting clinical trial data might not be as straightforward as hoped. Conversely, while there is a context-specific definition of both verification and validation in this framework, neither of them deviates much from the standard definition. For instance, the framework’s definition of verification is confirmation by examination and provision of objective evidence that the physical parameters measured by a DHT are measured accurately and precisely. The commonly accepted, broad definition of verification is confirmation by examination and provision of objective evidence that specified requirements have been fulfilled, according to a learning module provided by CDRH staff.
The key takeaway from this framework may be that it represents an ambition as much as a schedule of developments.
At least three demonstration projects are also part of the DHT/drug development framework, which can aid in the process of sorting through questions such as analytical approaches to missing data and the respective merits of continuous streams of data and data derived from discrete measurements. The key takeaway from this framework may be that it represents an ambition as much as a schedule of developments. For context, the FDA Digital Health Innovation Action Plan was released in 2017. While it is essential to acknowledge the potential impact of the COVID-19 pandemic on the plan, several elements of that plan have not gone as planned. That plan lists final guidance for clinical decision support (CDS) tools, which is now the target of a citizen’s petition, as we explained here.
The CDRH digital health plan also included the precertification pilot for the software SaMD, which has ended without producing the promised insights into the regulation of SaMD because of profound structural, legal, and regulatory issues. As an aspirational document, this new DHT framework is useful, but it may be prudent to view it as a series of goals rather than a set of commitments that will arrive on a fixed timeline. This framework certainly bears watching, but developers of these technologies should not expect a near-term avalanche of demand for their products or expertise based on any progress toward the goals described in the framework.
