Bringing a new therapeutic solution through the length of research and development can take well over a decade, and can cost an average of $2.6 billion when accounting for the shared cost of failed compounds. Clinical testing takes up a substantial amount of these time-based and financial resources, with monitoring alone representing around ten percent of the overall expenditures.
On top of this, retention is an issue. Patient participation is hindered and engagement often leaves a lot to be desired; ultimately, almost half of all enrolled patients fail to see it through. An increase in interest in the benefits of virtual clinical trials, or “siteless trials” in response to many of these challenges suggests the potential for the adoption of new technological systems that may provide some solutions, but these systems come with their own shortcomings too, and many of the challenges with clinical trials cannot be remedied remotely.
In this article, we’ll look at some of these benefits and challenges, and suggest, with some examples, ways in which it’s possible to implement siteless trials more commonly. First, some context.
The Rise of Siteless Trials
The clinical trial environment is increasingly complex and challenging, with costs and cycle times on the rise, and regulatory influences growing in volume and detail. As such, there has been a growing response towards more efficient, cost-effective ways of collecting and managing patient data in the last decade.
Some of the major barriers to effective clinical research come from the lack of proximity to medical centers and/or the lack of personal commitment of participants to follow-up visits to locations that are too far away. This is a major struggle due to the need for trials to access large demographics not only for larger sample sizes, but also to ensure that drugs are efficacious across multiple age groups and ethnicities.
The first FDA-approved pharmaceutical trial that made use of web-based and remote technology was conducted by Pfizer in 2011. Smartphones and web forms were utilized to recruit and manage participants from a distance. This was a feasibility study, aptly (though perhaps clumsily) given the ‘bacronym’ for Research On Electronic Monitoring of Overactive Bladder Treatment Experience (REMOTE).
From this early experiment, various advantages and shortcomings relating to its web-based components became obvious and spurred curiosity from all stakeholders for the potential to facilitate more technologically-driven research protocols and methodologies.
Until recently most clinical trials relied almost entirely on paper-based processes; a system that is both time and labor-intensive, and represents a higher security risk. While these systems are still common, there is a growing shift towards leveraging the available telemedicine technology options to keep up with the growing demand for complexity and provide time-sensitive results without jeopardizing data or patient security.
The concept of using “telehealth” technologies to improve the efficiency or research was reinforced in 2015 when the FDA requested feedback on their use. Multiple feasibility studies have been launched in the US and Europe to assess the use of web-based methods.
Early investigations suggested that the time needed for the coordination of a study can be reduced by 66% when participants can consent and register themselves remotely, and patient information can be reviewed electronically. On top of this, there have been promising improvements in compliance and retention. Enrollment through a virtual site for one study was conducted more than 20 times faster than projected for non-remote sites.
Using videoconferencing and messaging platforms has allowed rare diseases to benefit from larger samples, and these benefits have not gone unnoticed. The first siteless clinical research organization was set up to use certified clinical trial research pharmacists to access live patient data from the homes of participants.
To date, they have supported over five thousand participants in more than 27 studies. So, there is a growing interest in incorporating remote research practices into clinical trials, despite the challenges that we will discuss later. First, let’s take a look at some examples of how technology is helping investigators and patients.
Siteless Trials: Some Examples
Some clinical research companies are now working with pharma companies to help transform the way research is conducted. Companies like UCB, Novartis, Sanofi, and Otsuka have begun working with the research company to implement telemedicine-based platforms in their trials so that siteless trials can become more involved and wider-reaching.
A platform known as the Network-Oriented Research Assistant (NORA) is now being used for numerous studies and is run by physicians who have been trained to work on the software across multiple therapeutic areas. It’s essentially an all-in-one EMR and data collection tool, which makes the collection and monitoring of patient data possible remotely.
This platform has enabled recruiters to gather patient data from up to ten states in a single trial, greatly reducing the difficulties that arise from lack of proximity to test sites. As we’ll discuss, this is one of the key benefits of remote management in trials and has promising implications for rare diseases, among other cases.
Another tool that has helped decentralize trials is the Fox Trial Finder: an online clinical trial matching tool that encourages Parkinson’s Disease-sufferers and their carers to contribute to clinical research. From a large database, researchers were able to use the tool to encourage volunteers from all over the US to make use of videoconferencing tools. This was intended to serve four purposes:
- To act as a feasibility study for virtual research visits for these patient demographics,
- To collect specific, phenotypic data of the participants,
- To validate self-reported diagnoses remotely
- Evaluate the level of interest in virtual research visits
166 virtual visits were conducted in this manner, and neurologists were able to confirm and validate the self-diagnoses for 97% of cases, as well as add to the wealth of data stored in the database. There were, however, some roadblocks to using the system, which we will cover in the next section.
Home studies are also very effective in meeting the need for early detection of cognitive decline, as well as providing monitoring of real-world function in patients with Alzheimer’s. The Oregon Center for Aging and Technology (ORCATECH) has come up with a prototype system of sensors placed inside over 480 homes that have been collecting data for over a decade.
These sensors help measure mobility, sleep, and activity patterns as well as things like medication adherence and computer use. The measurements aim to provide valuable data for refining detection techniques and monitoring key cognitive changes.
Common Challenges with Clinical Trials: Can Siteless Trials be the Solution?
One talking point to consider is that virtual aspects of a trial can be implemented as part of a hybrid approach to research, without the need for going 100% siteless in trials. Secondly, certain components of trials are impossible to conduct remotely. MRIs, biopsies, and other procedures necessitate a visit to a test site – at least for now; however, even within these trials, there are components that can be improved with remote management technologies.
With this in mind, it’s possible to focus on challenges as they arise specifically in research that is otherwise eligible for siteless or hybrid trials, but this doesn’t rule out speculative technological advancements in the future that may bring solutions into the homes of patients one day.
Staying current, the use of siteless CRO practices stands to impact large sample trials in particular. As mentioned, one of the key challenges with clinical trials of this nature is reaching a wide enough base of participants, and remote recruitment and data collection promise to negate this challenge entirely in many cases.
Another challenge that we have touched upon is the early detection of conditions such as the development of adverse effects or the early symptoms of diseases, which can be accomplished with remote monitoring. Communication is one of the key contributors to this, too. Coordination of communication between and among sponsors, investigators, patients, and regulators can be streamlined to these and many other ends.
So, it seems that the virtual elements needed to make trials entirely siteless are coming together, however, there are some inherent challenges to virtual trials too.
In the initial REMOTE study that we covered, only 18 of the 118 eligible participants were randomly assigned to treatment. The study illuminated two points at which there was a significant drop-out. They were:
- The online identity-verification procedure
- The use of a sponsor-supplied mobile phone to enter bladder e-diary information
These areas suggest weak points in the process, and the investigators themselves suggested that the devices and the processes could have been more user-friendly and simpler in both cases.
Challenges also arose in the ORCATECH trial with Alzheimer’s patients. Sensors struggled to differentiate between residents, suggesting that wearable devices might be an improvement.
These challenges represent a few of the issues along the learning curve for all stakeholders in the move to siteless trials and suggest that a focus on simplicity and ease of use is needed to improve patient engagement.
While remote management reaches more people in diverse demographics across the country, it comes at a loss of personal interaction between patients and investigators that must be compensated for with engagement-promoting communications channels and policies.
The cost factor cannot be ignored, either. As with any new technologies, the relevant hardware, and software needed to run trials entirely remotely often come with a hefty price tag. While some devices and systems are generalized and multi-purpose, like communications systems, others are particularly specialized, such as wearable implants. For every monitored patient who is recruited as a result of the extended range of siteless clinical trial technology, there is another person whose device needs to be bought, calibrated, and maintained.
Another challenge that remains unresolved is the lack of clear and standardized regulatory guidance relating to the use of various components of the siteless prototypes. While the FDA previously issued regulations relating to the receipt of electronic data, and there are concerns about accidental protocol deviations as a result of loose or absent guidance in remote management systems.
So, as siteless trials stand today, are they worth the shortcomings?
Do the Benefits of Virtual Clinical Trials Outweigh the Challenges?
There is a continued push for methods that eliminate the need for additional equipment or complicated procedures for participants to follow, but for now, there is still room for improvement. Still, in the ORCATECH approach, participants responded favorably, with a dropout rate of only 2.6% each year. The positive attitude was evidenced further by the fact that all but one of the 24 participants who moved to a new home chose to have the system reinstalled.
It’s hard to suggest that the tremendous boost to recruitment and retention that’s available from decentralized and siteless clinical trials isn’t worth the trade-offs, especially since many of the challenges that arise are teething problems that come with the adoption of any new systems.
While of course, there are economic challenges that will arise in the adoption of new technologies, the hope is that these are quickly offset by the return in terms of sample sizes and efficiency of research.
In the cases where the strengths of remote technologies can be leveraged, all stakeholders benefit. Faster recruitment means that design decisions can be made sooner; pharma companies are attracted to the efficiency and security of data collection across a wide scope; participants are happy to contribute in a way that involves little to no traveling to test sites; and many others benefit from the accessibility of trial information that’s stored and shared from a single repository online.
On the significant issue of regulatory guidance, there are some bright prospects. The European Guidance on Good Clinical Practice now clearly describes the requirements for the use of electronic trial data and remote data systems. This is considered a more manageable focus that could pave the way for the necessary transformation to decentralized, hybrid, or siteless trials.
Best Ways to Incorporate Siteless Trials into Clinical Trial Research
There is more than just hope to refer to when it comes to implementing siteless systems into clinical trial research. An ever-increasing number of public-private partnerships are collaborating on frameworks to accelerate this shift with the intention of shaping strategies for its adoption and selecting champion cases to affect widespread attitude changes.
Further, there are some specific approaches being tested to compensate for the potential loss in engagement. Virtual gaming is one strategy that has been employed to promote deeper participation in patients. Rather than money, it’s been demonstrated that offering points for every aspect of participation show a lot of promise in keeping patients engaged remotely.
The purpose is to introduce a level of fun to the process of recording and reporting patient-reported data by prioritizing the patient perspective. However, even introducing games to the participant experience will not compensate for a lack of humanity in investigators’ approach to their participants. If siteless trials are to go ahead successfully, patients need to be inspired to contribute. The traditional approach to doing business will always be one of the single most significant contributors to dropout.
It could be said that there are two approaches to implementing siteless trials successfully. First, there are the elements of remote monitoring and recruitment that are already particularly effective. These can be pushed and made commonplace without much need to change anything. Secondly, the bumps in the road relating to regulations, standardization, and user access can be a major point of focus along the way.
For now, it’s already a significant step to simply leverage the technology to focus on so-called “low-hanging fruit”; the early warning signs of adverse effects, or informed e-consent. As more trials adopt the technologies, the champions will present themselves, and the research community will overcome both the economic and organizational challenges inherent to any new system.
The benefits of virtual clinical trials or at least the virtual components of hybrid trials cannot be ignored. Further, many of their limitations come from the early stages of adoption and relate to the immediate overheads, the learning curve that comes with new technologies, and how the patient experience is affected by them.
This suggests that given a more widespread adoption, many of these challenges will dissipate and the benefits will certainly outweigh the shortcomings if they don’t already. Still, it stands to reason that truly remote trials will not be applicable to every case. There is still a need for expensive and on-site imaging, for example, as well as most lab-based procedures that can’t be brought into the patient’s home.
Still, if these decentralized trials become more commonplace, there will likely be a significant boost to research involving rare diseases, as well as others that have previously suffered from low sample sizes. In all, remote management in trials represents a promising new leap in cost and time savings, as well as a tremendous boost to the power of clinical research trials.