By Nov 17, 2016 on
Clinical trials are moving out of the clinic and into patients’ own homes.
In common with many areas in pharma, drug development is in a state of constant change. The emergence of disruptive technologies combined with the powerful push towards patient-centricity are forcing companies to shake off inertia and consider radical new models.
One such model would have been unthinkable a decade ago but now, interest in clinical trials taking place outside the clinic is growing exponentially. With a focus on remote monitoring and patient engagement, ‘siteless’ or direct-to-patient clinical trials have the potential to impact the most perennial of problems – patient recruitment and retention. In addition to the sheer convenience for patients, siteless trials tear down geographic barriers, opening up trials to a much wider – and potentially more diverse and representative – patient population.
By harnessing wearable technologies and mHealth, such trials offer the allure of not just enhanced data quality but better data volume through continuous monitoring. Siteless also has the potential to remove some of the well-documented inefficiencies of site-centric trials, where investigator payments account for 48 percent of the cost of a phase III trial (Clin Trials February 2008 vol 5 no 1 75-84) and two-thirds of investigator sites fail to meet the patient enrollment requirements, according to the Tufts Center for the Study of Drug Development.
With 55 percent of people citing the location of the site as the most important factor in deciding whether to participate in a clinical trial (CISCRP 2015 Perceptions & Insights Study), fewer site visits (or none) address some of the inherent inefficiencies of the traditional trial model. Yet, as with any radical innovation, challenges abound – concerns about data quality and security, worries about meeting regulatory requirements and gaining the buy-in of an industry resistant to change, not to mention simply finding the right patients to participate.
Siteless trials build on two already well-established trends, says Tom O’Leary, Chief Information Officer at drug development services company, ICON. “Place-shifting means enabling activities to be performed in a different location; for example, remote assessment of patients by video. Time-shifting means enabling activities to be carried out at a time convenient to the patient,” he says. “The latter is more critical because it dramatically reduces one of the major barriers to recruitment and retention – the time invested by a patient in a trial.” Electronic patient recruitment, patient training, and consent have transformed the cumbersome process of trial start-up, says O’Leary. With such capabilities already available from patient portals, pharma is making far more information about a clinical trial available to those who may participate, a major shift from the old model of a physician having to explain the minutiae of a trial to each patient. “Previously you were dependent on that interaction,” he says. “Now we are in an era where the patient can inform him or herself. Patients are seeking to be more empowered.”
Another shortcoming with the traditional process is that patients receive a potentially overwhelming amount of information about the trial in a relatively short time frame. In contrast, electronic training – delivered via investigator and site portals – can be delivered in more accessible formats, such as animated video, and in more digestible modules. “Gone are the days when investigators and site staff have to get through 80-page instruction manuals in order to understand the protocol,” says O’Leary. “We can track directly who has taken the training, allowing for enhanced compliance.” Similarly, electronic patient consent is not just a more efficient but also a more consistent process, with remote technology allowing subjects to interact with site nurses and investigators. Another recent development that is feeding into the growth in ever-more siteless trials is at-home dispensing, which permits the sponsor to use RFID tags or chips to track whether the patient has received the correct medication and is taking the correct dose. Such streamlining has not affected quality, says O’Leary. “I don’t believe that anything is lost. In fact, we have seen a reduction in queries at sites [because] we are delivering it in a way that meets the expectations of those involved in clinical trials.”
We need to make sure participation is fit for the patient rather than fit for the protocol; that convenience for the participant is put before convenience for the study team.
Wearables and sensors lie at the fulcrum of the shift towards siteless trials; without them, remote, unobtrusive and real-time capture of patient data – activity levels, sleep, blood pressure, heart rate, etc. – would be impossible. “We are seeing a significant reduction, if not elimination, of paper patient diaries, and a reduction in electronic diaries. When subjected to high-level analysis, sponsors can see more closely what is happening during a clinical trial,” says O’Leary.
Craig Lipset, Head of Clinical Innovation at Pfizer Global Product Development, prefers the term ‘remote’ because the investigator site cannot be eliminated entirely. “From a legal, medical and ethical accountability perspective, there has to be a site. However, it means the investigator can be centralized somewhere and, in today’s world, the patient may not physically need to go in and out.”
Not all patients are happy to “go it alone”, he says, emphasizing the importance of offering patients greater choice in how they participate in a trial. “We need to make sure participation is fit for the patient rather than fit for the protocol; that convenience for the participant is put before convenience for the study team,” he says. Patients who happen to be local to a site or are happy to attend appointments should be able to continue to do so, while those who prefer not to travel or are comfortable with enabling technology can take part remotely.
Such ‘hybrid’ studies can take two forms, says Lipset. The first was used by Roche with their biologic therapy rituximab for patients with the skin disease pemphigus, where brick-and-mortar investigator sites were complemented by a centralized virtual site, reducing risk and giving study teams and patients a choice.
The second form involves a more conventional trial site with some procedures or visits carried out remotely. “This form of hybrid trial removes some of the burden of a conventional trial by incorporating home visits or using remote monitoring technologies. However, both types can make sense and there may be different options based on the study protocol, phase of development, indication and so on,” he says.
Barriers to change include concerns around device selection, battery life, wear position and endpoint selection, while some clinical experts point to parameters such as the quality and value of the data generated.
Many of these concerns are being addressed, says ICON’s O’Leary. While the majority of devices are still consumer grade, medical-grade devices are being furiously worked on, plus significant work is underway around data security, ensuring that patient data is transmitted securely and in a way that does not impact confidentiality.
Most of all, regulators want to know that the data is good data, he says. “How do they know the data came from that particular patient and whether the device was recording that particular activity? How do they know the patient did 12,000 steps yesterday or the device was put into a tumble dryer?”
Pfizer’s Lipset sees other, more pragmatic obstacles to virtual trials, including the removal of financial incentives for study investigators. “You can’t simply tell investigators that visits two, four and six can be done from the home, and we are going to take the money [from] the investigator and give it to the visiting nurse. If the investigator is then tasked with offering patients the option of home visits, I guarantee you that you’ll get zero patients opting for home visits.”
People often ask why there aren’t more remote trials carried out, he says. “People ask, what are the barriers? Is it technology, regulations?” The answer to that question is clear; culture remains the final frontier to cross to reach truly siteless trials. “The tools exist, the regulations do not have to be amended, so it is down to the willingness of our organizations to try new things.”
Lipset was involved in Pfizer’s first remote trial some years ago; REMOTE (Research on Electronic Monitoring of OAB Treatment Experience) used mobile and web-based technology to collect data on the safety and efficacy of Detrol LA (tolterodine tartrate), its extended-release treatment for overactive bladder. “Prior to that there had been similar efforts that were not interventional, for example purely observational trials, or interventional but not with a medicine, for example with a neutraceutical or a dietary supplement.”
With REMOTE, Pfizer found that any regulatory issues were easily overcome, he says. “The only waiver we required from the FDA to do the remote study was shipping blinded investigational medicine to patients through the mail instead of distributing it to the patient through a research pharmacy.”
Lipset also points to the work of the Clinical Trials Transformation Initiative (CTTI) in trying to increase the use of mobile technologies in trials by focusing on regulatory and legal barriers.
Siteless in action
Lipset and O’Leary cite a host of examples where mobile technologies and remote data capture are being used in clinical trials, from AstraZeneca’s mHealth initiative – that saw the company team up with Adherium on a ‘connected’ inhaler trial to explore adherence in COPD – to Roche’s app to test the unified Parkinson’s disease ratings scale using data captured from patients not physicians, and Novartis’ collaboration with Walgreen’s Clinical Trials of the Future.
“This isn’t new territory; steps have been taken incrementally in many different studies in the past, showing that they are both realistic and feasible,” says Lipset. “Nobody that did this went to jail.”
Whether you call them DTP, remote, virtual, siteless or simply patient-centric trials, they are here to stay. Kai Langel, cofounder and Director of Patient Solutions at eClinicalHealth (see right, Breaking New Ground) predicts that siteless trials will continue to grow in popularity as the industry invests more widely in patient-centricity. “In a recent webinar, we asked companies whether they were planning to do a remote trial in the near future – around 40 per cent said ‘yes’. There will be more of these trials,” says Langel.
The ultimate winner is the patient, says O’Leary. “[Remote trials] have opened up a host of convenience for the patient, expanding the number of patients prepared to consider entering a trial. Plus patients in a clinical trial perform better than those not in a trial, so getting patients to look at clinical trials as a care option is a big focus for industry.”
The momentum will continue until all clinical trials are performed this way in the future, he predicts, although generational differences will remain a barrier. “There is a significant proportion of patients who want to put their care in the hands of a physician and you’ve got to respect that they still want to go to their physician and have that conversation. But these people are juxtaposed with empowered patients who want to take ownership, who want the information in their own hands and to take control of their care. They want to know how they are progressing relative to their peers and what the road ahead looks like. These two classes of patients exist and you have to allow for that.”
Lipset agrees, citing a “marketplace of organizations” that have positioned themselves to support remote or virtual trials. He forecasts that the industry will continue its deliberate approach. “I don’t expect to see entirely siteless trials flourishing but I do expect to see far more hybrid studies. Companies will look at a particular indication and say, let’s try one virtual site in this multicenter trial and see how it performs, or they will spare patients certain visits. As these experiences grow and the impact is realized, more opportunities to go remote will emerge.”” he says.
Reflecting on REMOTE, he adds: “When we drew up the map of what the study looked like, it revolved around the patient. For remote trials to go backwards now, the entire concept of patient-centricity would need to go backwards. The two are intimately connected.” Everything comes down to choice, he adds. “Maybe siteless isn’t the solution, rather simply giving people the choice to participate on their own terms. It can seem daunting and takes a lot of vision to redesign everything from the bottom up, but for those that don’t have the capacity or the time, they can still make their trial more accessible and engaging for patients,” says Lipset.