he pandemic, the war in Ukraine, and other factors have highlighted the need to provide new modern solutions to the way we run clinical trials for the benefit of both patients and healthcare professionals. With the decrease of COVID cases and the possibility for regulators and industry to allocate time and human resources to other topics, now is the time to drive awareness and actively advance the use and acceptance of decentralized clinical trial (DCT) approaches.
When implementing a DCT strategy with digital elements, four key global regulatory considerations and one US-specific consideration apply:
- The use of digital health technologies and digital endpoints in clinical development programs.
- Mixed modalities data equivalency.
- ICH E6 Good Clinical Practices considerations for virtual sites.
- Global regulatory acceptance to advance digital elements as a key enabler of DCT approaches.
- Digital recruitment of patients in the US.
We will examine the current regulatory state, challenges ahead of us, and how stakeholders, including regulatory health authorities, can support and advance DCT use, for each of these considerations.
Use of Digital Health Technology (DHT) and Digital Endpoints in Clinical Development Programs
It is important that regulators apply flexibility in approaching verification and validation depending on how the data from a DHT is being used (e.g., exploratory use, registration trial), while emphasizing the need for scientific rigor and risk-based approaches. Data collected via a DHT to support exploratory endpoints would not be expected to first have complete evidence of verification and validation. Data collected via a DHT to support primary endpoints would receive the highest appropriate level of verification and validation.
To avoid duplication of efforts and increase efficiency, regulators should state that it is acceptable to leverage available prior work from a DHT developer and other parties (e.g., pharmaceutical industry, consortium, academia, private-public partnerships, technology suppliers) to show that a DHT is fit for purpose for use in a clinical trial. Available prior work could include information such as published data, regulatory status, data sets, concept of interest data, and usability data. FDA mentions leveraging prior work in the Digital Health Technologies for Remote Data Acquisition in Clinical Investigations Guidance. Support from other regulators in this direction will assist in advancing the field.
The current lack of “digital endpoints” to be measured by DHTs and the acceptance of such endpoints by regulatory health authorities is an area for growth. Multiple workstreams can be considered to advance the development of such digital measures such as the work of the Innovative Medicines Initiative/Innovative Health Initiative (IMI/IHI) and other consortia, the Digital Medicine Society (DIME), and the Digital Endpoints Ecosystem and Protocols (DEEP) initiative. One specific example is the IMI MOBILISE-D project, which aims to develop a comprehensive system to analyze people’s gait based on digital technologies, including sensors worn on the body. Another example is the development of the DEEP cloud-based platform that provides for stakeholder collaboration and enables the development, validation, adoption, and use of digital measures. By working closely with regulators and other stakeholders to ensure that the solutions are accepted, such initiatives will be key to advance DHT and related digital endpoints acceptance.
Mixed Modalities Data Equivalency
ICH E6 Good Clinical Practice (GCP) Considerations for Virtual Sites
But in a decentralized clinical trial scenario, there is a virtual (or meta) site. A patient may never set foot in a physical site and may participate in a trial completely digitally. The principal investigator and sponsor must still adhere to their GCP responsibilities when the site is virtual.
However, a DCT that utilizes a virtual site and employs digital elements raises interesting considerations. What kind of documentation is expected to be maintained and where, when the site is virtual and the documents are digital? What site-monitoring approaches work best when the site is virtual and the documents are digital? As ICH E6 revisions are underway, it is important that ICH GCP requirements remain flexible and applicable to a virtual site.
Global Regulatory Acceptance of DCT
Digital Recruitment of Patients in the US
In the US, medical licensure is regulated at the state level, but investigational clinical trials and their conduct are regulated at the federal level. State licensure requirements could construct a barrier on DCTs if a virtual site would need to have investigators on staff who are licensed in all 50 states. In response to the COVID-19 crisis, many states modified the licensure requirements for healthcare providers, including out-of-state requirements for telehealth. Flexible reciprocity schemes, such as the Interstate Medical Licensure Compact, can facilitate running trials across multiple states. Federal and state legislation that would ease or remove these licensure barriers and/or differentiate the practice of medicine and clinical trials (e.g., limited waivers for clinical trials) would also have a positive impact.
The accelerated modernization of clinical trials driven by recent crises has impacted all stakeholders (sponsors, sites, patients, regulators) in the clinical trial ecosystem. Deploying DCTs with digital elements is an important tool in the clinical trial sponsor toolkit. Not every clinical trial is appropriate for a DCT approach, and not every digital element is appropriate for each clinical trial. Selection and implementation of each of these elements must be assessed to determine what is the best option for the patient population, the indication studied, and the investigational product.
All stakeholders in the clinical trial ecosystem have a role and responsibility in advancing the digitalization of clinical trials. Collaboration across regulatory health authorities, sponsors, consortia, patients, vendors, and other stakeholders will be key to advancing the overall use and acceptance of DCT approaches.