Clinical trial monitoring for FDA-regulated products can be expensive and troublesome, but digital health technologies (DHTs) can make the process less painful and more cost-efficient. However, in order for clinical trial sponsors to enjoy these benefits, proper planning and execution will be necessary, according to a new FDA guidance for clinical trial monitoring.
This new Q&A guidance is complementary to a 2013 guidance on risk-based monitoring (RBM) of clinical trials, but this new guidance offers more clarity on several key details than the 2013 RBM guidance. As is typically the case, there is quite a bit of context for this new guidance, including a report by the Government Accountability Office on federal government oversight of institutional review boards (IRBs). There is also the recent emphasis on the use of DHTs in these trials, for which the FDA has developed this guidance.
Significant Market Opportunities in Decentralized Clinical Trials
The already-growing willingness of payers to cover telehealth services was greatly amplified by the COVID-19 pandemic, which in turn has expanded the bandwidth for overlapping activities. This includes the use of telehealth in decentralized clinical trials, a theme that was explored here. When combined with FDA policies that enable remote monitoring of clinical trial sites, this increased interest in telehealth and DHTs is quickly expanding the market for third-party software developers with the right products for their clients. For in-house software development teams, this is a responsibility that must be addressed as rapidly as possible if a manufacturer is to capitalize on its investment in that technology.
This new Q&A guidance lists several factors that help determine the timing, frequency, and type of a clinical site monitoring exercise, including:
- How well-established the clinical study infrastructure is at an investigational site;
- The experience of the clinical investigators and the sponsor’s experience with those investigators; and
- Whether electronic data capture (EDC) technologies will be used for the study.
Source Data Verification a Key Ingredient
We should emphasize that the FDA is not promoting remote monitoring as a method of eliminating the need for on-site clinical trial audits and inspections. Even with a combination of on-site inspections and remote monitoring, however, source data verification (SDV) promises to be one of the more challenging elements related to the use of EDC technologies in electronic clinical trial oversight.
A lack of protocols that ensure the accuracy and reliability of source data could lead to failures to recognize when the data from a study site suggest that the site is deviating from the protocol, which can endanger the clinical study. As complicated as SDV can be, it may be particularly challenging for decentralized clinical trials, which the FDA has been emphasizing recently.
Predictably, there are several overlapping guidances, in both draft and final form, that are related to this Q&A guidance, such as the March 2023 Q&A draft guidance for electronic records and electronic signatures for clinical investigations. This draft makes reference to a number of elements in Part 11, but also revises a draft guidance issued in June 2017 that was intended to replace a guidance from 2003. The electronic records and signatures draft highlights several points of importance from the FDA’s perspective, such as the fact that a legacy data system for collection of real-world data (RWD) that was not designed with Part 11 compliance in mind must nonetheless be brought into compliance with Part 11.
Definition of ‘Processing’ is Expansive
The electronic records Q&A draft describes a risk-based system for Part 11 validation, citing several factors that would seem to suggest a need for validation. Any system used to generate or process data that will be used to support a marketing application may require validation under Part 11, as is the case for any software used to ensure patient safety. In a footnote, the FDA describes the function of “processing” as including creation, modification, maintenance, archiving, retrieval, or transmission of records, an exhaustive list.
This electronic records draft guidance does not offer specifics about the process of validating under Part 11, however, nor does it offer insight into the agency’s thinking about the risk assessment process for Part 11 considerations, both being subjects of separate guidance and/or international standards. There is one point in this electronic records draft that could be easily overlooked, which is that the individual tasked with manually entering data into the DHT should be identified even when that individual is not the clinical investigator.
The sponsor will have to provide written justification for the manual entry of data by anyone other than a member of the clinical trial team, but in any event, the sponsor is required to develop and maintain a list of authorized data originators, which should be readily available for any FDA field investigators.
2013 RBM Guidance Lists Several Red Flags
The 2013 RBM guidance offers several examples of instances in which data obtained from remote clinical trial monitoring should prompt an on-site visit by the sponsor, such as a conspicuous difference in the rate of missing case report forms, the rate of enrollment, or the number of study protocol deviations. There are several standards highlighted in the 2013 RBM guidance, but the most recent version of ISO 14155 is perhaps the most useful. ISO 14155 provides a framework for good clinical practice for the design, conduct, and reporting of clinical trials for medical devices, but for the most part is exclusive of in vitro diagnostics. The use of this standard for studies of software as a medical device (SaMD) is perhaps not as linear as the case is for a hardware device because of the lack of direct contact between the study subject and the SaMD, however.
…the growing demand for both decentralized clinical trials and more routine use of remote patient monitoring will continue to drive demand for technologies that enable this method of clinical trial oversight.
Makers of hardware medical devices may not be especially keen to develop their own software solutions for remote clinical trial monitoring, but software developers that are not familiar with remote monitoring of clinical trials may also find entry into this market a daunting prospect. It is quite clear, however, that the growing demand for both decentralized clinical trials and more routine use of remote patient monitoring will continue to drive demand for technologies that enable this method of clinical trial oversight. Regardless of whether you are a device manufacturer or a developer of software solutions for this purpose, there is a significant opportunity for technologies for remote clinical trial monitoring, even if the task of setting up such a system is not for the faint of heart.