Advancing Use and Acceptance of Decentralized Clinical Trials with Digital Elements
Amy Bertha
Patrick Brady
Antoine Manson
Max Wegner
Aneta Woroniecka-Osio
Bayer AG

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.

Importantly, DCTs have the potential to reduce clinical trial timelines and ultimately bring a new drug to market faster for patients. Digitizing DCTs may help, but there are challenges ahead of us: How can the clinical trial ecosystem support increasing use and acceptance of digital elements as a key enabler of 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

The use of DHTs in clinical development programs is part of a modern innovative drug development paradigm that enables remote data collection, supports a patient-centric approach, and is a key enabler of decentralized clinical trials. The development of DHTs should be supported by a collaborative approach across a broad range of stakeholders, including regulatory health authorities, drug and biologic developers, consortia, and DHT developers.

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

Today, DCTs are often run in a hybrid version, with some study procedures performed at the clinical site and some at the study participant’s home. This raises questions around the collection of data from mixed modalities to support regulatory decision-making. Some participants may use a DHT for remote data collection, while other participants may visit a clinic for an in-person assessment. Data generated “digitally,” and data generated via “traditional” means, would need to be seen as comparable through application of the appropriate verification, validation, and statistical analysis plan. Regulators should confirm or specify conditions under which it would be acceptable to obtain and pool data using different modalities and approaches within a clinical trial or within a clinical development program with appropriate validation and verification.

ICH E6 Good Clinical Practice (GCP) Considerations for Virtual Sites

Traditional clinical trials are conducted at physical sites. Principal investigator GCP responsibilities include coordinating implementation and advancement of the clinical trial as well as ensuring appropriate documentation of a physical site’s activities and maintaining source documents. The sponsor’s GCP responsibilities include monitoring the conduct and progress of their clinical investigations. Traditionally, a sponsor’s site monitor would conduct on-site monitoring that includes review of source documents and medical records, among others. As part of a health authority review of a marketing authorization application, they may conduct an appropriate on-site GCP inspection.

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

Today’s clinical trials are commonly international and run simultaneously across many countries, on different continents. However, different countries oversee clinical research and trials under varying sets of regulations. Convergence and harmonization of DCT requirements is crucially important to advance the use and acceptance of DCT approaches. To mitigate potential regulatory challenges in the future, regulatory health authorities, especially those with the most DCT review experience, should publish guidance in this space and such guidance should be used at the international level for convergence and harmonization. We have seen publications on DCT approaches by Denmark and Switzerland that outline the challenges and conditions under which such trials may be conducted in those countries. We could expect publications by EMA and FDA soon. Such publications could help pave the way for a future regulatory landscape that allows for safe and efficient DCT approaches with common requirements across borders.

Digital Recruitment of Patients in the US

In the US, state medical licensure disparities can limit the ability to recruit patients from different states. In full expression of a DCT approach, sponsors would be able to reach a potential patient anywhere utilizing a digital campaign and enroll them into a virtual trial. However, there could be a case where a patient resides in a different state from where the investigator is medically licensed, thereby posing a challenge to full implementation of a DCT approach.

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.