Context for IMPORTANT

The concept of Decentralized Clinical Trials (DCTs) has been evolving for several years and is one of the main innovations within IMPORTANT. This section aims to provide background information and context for DCTs, discuss their main characteristics, explore benefits and challenges, and outline key ethical considerations.

High-level description

The European Medicines Agency describes Decentralized Clinical Trials as follows: “Traditionally, clinical trials have been conducted at specific clinical trial sites, to which patients had to travel to. The aim of DCTs is to make it easier for patients to participate in clinical trials by reducing the need to travel to central trial sites. This approach has the potential to make clinical trials available to a wider demographic of participants and reduce drop-out rates”.

The FDA, in its draft guidance, describes a DCT as “a clinical trial where some or all of the trial-related activities occur at locations other than traditional clinical trial sites”.

History of DCTs

It is not easy to pinpoint exactly when a clinical trial was first conducted in a “Decentralized” manner. A feasibility study conducted in 2003 on a trial in patients with knee osteoarthritis. A few small studies were conducted in the subsequent years, driven by academic and commercial interests. There was even an patent awarded to Boston University in 2007, which was originally filed in 2000, with the same key owner as the author of the subsequent, aforementioned, feasibility study.

It is generally considered that the first fully remote study was conducted in 2011.

The evolution of DCTs continued, and a key inflection point was formed by the forces of COVID-19 in 2020 and later, which made hospital visits extremely complicated, and forced several traditional trials to shift towards the DCT model and include several decentralized elements.

Defining DCTs

The descriptions and definitions mentioned above are relatively vague, and this is not unintentional in a very diverse and broad ecosystem of clinical research. Below we attempt to capture the main elements of DCTs.

In a DCT, some parts of the trial are conducted outside of the strictly defined clinical physical settings (e.g., a hospital).

This often starts with the patient information and education about the trial; more importantly, it can encompass the entire recruitment and enrollment journey and experience, including the Informed Consent of the patient towards the trial’s protocol details and requirements.

Similarly, and beyond enrollment, a very common component of these trials’ decentralized parts includes patients’ travel: although it is not always possible to receive medical treatment (if this is part of the trial) away from a hospital, there are often other engagement paradigms which, in a DCT, are shifted elsewhere. For example, patient consent, data collection, monitoring of vital signs, and other activities, can be conducted from a distance, and often from the patient’s home.

The data collection can take place in several ways, including:

  • Traditional phone calls
  • Smartphones and applications
  • Wearable devices
  • Internet-of-Things (IoT) devices.

Similarly, patient visits which do not require an administration of a medication or treatment (which would not be possible elsewhere) can often be conducted via telehealth.

At the same time, if a physical appointment is necessary, it can be done with a local healthcare professional via home visit or otherwise.

In the case of treatments that are normally administered in a clinical setting, they, too, are often redesigned to be administered elsewhere. For example, oral medications can be shipped in a controlled manner to a patient’s home, or can even be distributed locally to the patient’s home and, in collaboration with local healthcare professionals, administered outside of the main clinical site.

This is why Decentralized Clinical Trials (DCTs) are often called remote, siteless, virtual, or even digital – to capture the modality of interaction. In the majority of cases, though, they are “hybrid” in reality, because they encompass a combination of “traditional” and “decentralized” modalities.

Benefits of DCTs

The benefits of Decentralized Clinical Trials (DCTs) span all stakeholders; this section outlines the key ones.

Benefits for the Patient

The patient gets to stay at home longer and may require fewer interactions with the bureaucratic aspects of the healthcare system. Moreover, the framework of a DCT can allow more flexibility as it depends less on the physical colocation and synchronous exchange of information. This also means fewer costs for the patients, and less time spent commuting. For many patients, a DCT means more convenience and improved ability to continue living as normal despite having been diagnosed with a serious health condition.

Benefits for the Sponsor

Significant part of the complexity of the clinical trials is absorbed and streamlined in a DCT setting; from information, enrollment, engagement to overall communications, the sponsor can focus more on the actual study objectives. In some cases, a DCT can have a more favorable cost structure as well. Moreover, the additional data points can be quite valuable when further analyses are required (always in alignment with the Protocol and Informed Consent).

Benefits for the Clinical Research Organization (CRO)

The CRO of a well-designed DCT can benefit from better structured data collection and more aligned data processes, given the flexibility of digitalized procedures and methodologies. Although this may come at a “cost” of reduced visibility into some of the patient-centric data input processes, the corresponding technologies and tools often provide several options as alternatives.

Benefits for the Clinical Trial Site

A clinic is a complicated operation. Many of its activities are beyond the medical or clinical scope, and include data capture and exchange, as well as procedural components that are not necessarily executed at the most appropriate time and place. A DCT can help the Sites improve their efficiencies and reduce the duplication of processes, while capturing more specific and structured data that can also help them deliver internal operational improvements.

DCTs: Challenges and barriers

Despite the several benefits, some of which have been outlined here, many challenges remain. The below bullet points identify a few generic ones, although additional ones can emerge depending on the specifics of each DCT.

  • Stakeholders (including clinics, clinicians, CROs and patients) should be familiar with some technical tools and have access to sufficient and appropriate technologies and network resources in order to be able to participate in their own capacity.
  • The design of a DCT requires significant focus on the technologies and tools, and experience with their integration in a clinical setting.
  • In healthcare, clinical examination is the gold standard for many processes, and physical proximity is required.
  • Clinical Trials are very lengthy and complex processes; this means that their evolution and maturity into DCTs is prolonged further, delaying their institutionalized adoption.
  • In hybrid DCTs (which constitute the majority), the transition between physical and remote/virtual settings is continuous and often very complicated.
  • The software and technological elements involved in DCTs may invertently become influencers of its design, endpoints, and outcome.
  • Managing more data from various sources can be a burden for all stakeholders, and the impact and importance of each data set or point is often under scrutiny (EU Recommendations on Decentralised Elements in Clinical Trials, PCWP/HCPWP joint meeting, 28 June 2023, EMA Amsterdam)

Ethical considerations for DCTs

In general, clinical trials overall implicate substantial ethical considerations. Their Decentralized versions have even further complications to consider. The growing maturity of DCTs has led some researchers to analyse towards initial analysis of considerations.

Starting with the recruitment and enrolment paths, is the information patients receive sufficient, if it is equivalent to that of a “traditional” clinical trial? Are they expected to be familiar with the technologies? Is the e-Consent variety of Informed Consent equivalent and always sufficient?

Furthermore, a fundamental ethical consideration is related to the access to, and familiarization with, these technologies: is there a bias introduced when any element of a trial is shifted to a Decentralized version? How does this affect the applicability of the trial, and the generalizability of its results?

A key set of consideration arises from the increasing breadth and variety of data collection modalities, especially when it is originated from the patient (for instance, directly via ePROMs, or indirectly via devices): what is the significance of these datapoints, and what impact can they have on the patient’s participation, health-related decisions, and trial outcomes? Also, how does the submission of ePROM datasets affect adverse event reporting – for instance, are these equivalent to clinician-reported for pharmacovigilance and other purposes?

Furthermore, what are the Data Protection and Privacy preservation requirements when it comes to DCTs? Since clinicians have unique access to the patient records and have a duty and obligation to include them in their decision making, how does the GDPR affect these processes, especially when it comes to non-clinical level data? What are the legal and security implications? How do the technical details of the implementation affect the trial design and its impact (e.g. around cloud computing, specific device types, data input requirements etc)?

Another set of concerns is related to the relationship between the patients and their healthcare professionals: does the natural distance between them, combined with the use of technology, alienate them, and thus deviate from the expected and necessary collaborative elements? Are asynchronous and virtual tools sufficient?

Similar to the above, what are the expectations of patients when they report anything directly or indirectly? Should clinicians be made aware of these reports, and if so, should their awareness be immediate and require prompt action? How can the proper prioritization and triaging take place?

Clearly, therefore, Decentralized Clinical Trials are not without their own, unique ethical complications. As more institutions become part of the conversation (including the European Commission and the European Medicines Association) there will be more guidelines and improved alignment for the benefit of patients and all other stakeholders.