The idea of conducting “site-less” or “virtual” clinical trials has been around for some time, and like many new insights, has collected discrete scepticism. However, the industry has recently begun to see the possibility of realizing this approach and the benefits it can bring to patients and sponsors. The columns of Nature Drug Discovery of the month of May have dedicated two pages to the topic of virtual trials, ie clinical trials conducted limiting or eliminating the need to make patients recruited at research Centres. The attention is also high from a Regulatory point of view: companies must be sure to completely adhere to laws and guidelines requests; in this sense, both the GCPs in the second revision (validation of computerized systems, risk analysis) and FDA guidelines were implemented. The American agency seems to be ahead of EMA on this point to date.
Virtual trial
Virtual clinical trials are a relatively new method of conducting a clinical trial to collect data on the safety and efficacy of a molecule or medical device. These trials take full advantage of technology (apps, monitoring devices, etc.) and inclusion platforms (recruitment, informed consent, counselling, measurement of endpoints and any adverse reactions) to allow the patient to be homebased at every stage of clinical trial. By relying on the new possibilities offered by technology, many argue that virtually conducted clinical trials offer an opportunity for a more patient-centered approach.
Pioneeristic virtual studies
The first partially virtual study dates back to 2001, when Eli Lilly tested his drug tadalafil to combat erectile dysfunction with asking men, in addition to participating in visits to the centers of reference, to fill out an online questionnaire. After 10 years it is Pfizer’s time, which paved the way for the first totally virtual clinical trial model with the REMOTE (Research On Electronic Monitoring of Overactive Bladder Treatment Experience) hyperactive bladder study. The study was the first randomized clinical trial with recruitment and collection of patient data included via web and smartphones. One of the main objectives was to compare the virtual approach with a conventional Phase IV clinical study to determine if the virtual experimentation project could be a useful model for future studies. Unfortunately, the REMOTE study by Pfizer has faced a number of challenges, not least the problem of recruiting patients (most of the members of the target group were elderly, so with limited skill in the use of technology).
Probably, as long as the use of technology and this new way of conducting clinical trials will not capture the trust of patients, the right approach is a step by step one, in which virtual study is not the only possibility offered, but starts to be presented among the possible options. A so-called hybrid approach, as Genentech has carried out with its head to head trial on rituximab and mycophenolate mofetil in patients with pemphigus vulgaris, a rare autoimmune skin disease. Recruitment through the “virtual” channel (especially through Facebook and Google AdWords) was faster than the standard one that included 21 research centers involved. This speed was again on display last year when Science 37 completed a 372-person, placebo-controlled trial of a topical probiotic spray for mild-to-moderate acne on behalf of AOBiome. Todd Krueger, AOBiome’s CEO, says that the study lasted less than 12 months, much faster than anticipated. In March of this year, Novartis announced that, with an agreement with Science 37, it will launch up to 10 virtual clinical trials in the next three years.
Benefits
The number of recruited patients increases considerably if the barriers linked to travel distances are broken down to reach the research centers. Furthermore, by reducing the discomfort associated with travel and simplifying the collection of information, it is hypothesized that virtual trials can reduce the current high drop-out rate of patients involved in phase III studies (equal to 40% today). «This is a very important and interesting point – confirms Lorenzo Cottini, vice-coordinator of the AFI (Associazione Farmaceutici industriali) Clinical Trials study group, and President of High Research CRO. There is already enough technology to avoid as much as possible the patients’ movement and therefore increase the compliance in the study. You could make “remote” visitis for those patients who are not able to move but have a minimum of technology (sometimes even just a tablet) or caregivers who can help them. In order not to select patients and enlist only the most “technological” ones, this type of view could be added to the traditional ones – as said the hybrid approach». About the use of technology, electronic medical records can help to identify subjects with specific targeted characteristics and to increase awareness of experimentations and recruit subjects directly. From an economic point of view, although this new approach requires strong technological support and the movement of health personnel, it is believed that savings can be achieved both because time is reduced and because the traditional set-up of multiple study sites is eliminated. Virtual testing also offers the possibility of reducing risks in the drug development process. The “live” collection of data thanks to the monitoring devices allows the investigators to calibrate, modify, and possibly even interrupt the study more easily. This is to the benefit of patient safety, allowing a more specific study design and limiting costs in case of study failure. Finally, the virtual experimental design could allow groups with an interest (investors, doctors, government agencies, patient advocacy groups and even patients themselves) to have more opportunities to play an active role in the study.
Scepticisms
The virtual trials scare, as we read in Nature Drug Discovery, from a legal point of view. On the one hand we must guarantee the privacy of the recruited patients, on the other we must be sure of the truthfulness of the collected data, otherwise the results of the study would be compromised. This is perhaps the main reticence of the industries in the sector. Another perplexity concerns the small number of clinicians interfacing with patients: virtual studies must guarantee the same quality standards as standard ones. To increase enrolment and limit the abandonment of virtual trials, as had happened in the REMOTE study, the idea of rewarding the participants was carried forward. The so-called virtual gaming, tested for example by EmpiraMed, in which, in the specific case proposed, the patient received points for each goal achieved (registration, recruitment, etc) to be used for gift cards or to make a donation to an association. «This approach – said Cottini – could introduce ethical evaluations, but it is a point to be taken into consideration: our legislation, in Italy, would not allow it at the moment». According to Jason Bobe, who studies patient engagement at the Icahn School of Medicine at Mount Sinai, the main problem is that «industry still tends to see individual patients as case studies and not as active participants».
FDA point of view
Though the FDA has stated that they see benefits in the appropriate use of technology in clinical trials, they are still in the process of learning about virtual clinical trials, the bring-your-own-device (BYOD) model of provisioning and other aspects of today’s tech-enabled research environment. In particular, the agency is looking for input on four specific issues: how the FDA could encourage the adoption of technological tools in clinical trials; what are the barriers; how the new research models will influence patients and the eventual limiting action of regulatory requirements. Not surprisingly, the FDA is looking for input, as supporting and encouraging innovation is the agency’s job. To this end, the guidance document issued by the FDA “Use of electronic informed consent in clinical investigations” explains how federal regulators allow companies to use electronic media (such as interactive websites) to facilitate the informed consent process. This will certainly help companies to conduct virtual clinical trials. The FDA has been in favor of virtual testing Transparency Life Sciences, a Boston-based biotechnology start-up, for example, recently received FDA approval for a fully tele-monitored test protocol in just 30 days, and was encouraged to make more innovation in the direction of virtual experimentation.
Future
Looking to the future, different scenarios seem plausible. Perhaps virtual studies will increase instead of replacing traditional study practices and workflows. The study’s virtualization aspects can be exploited when circumstances require it – similar to how remote monitoring streams are being adopted by the study supervision teams today. On-site monitoring is still a pillar of the study, for example, but much of the data is monitored remotely, depending on the case «CRO, emphasizes Cottini, and companies are already equipped to reduce (maybe not to zero) the monitoring at the experimental centers for a “physical” check of the folders, reports and consents (the so-called “source data” for the GCPs)». Maybe virtual clinical trials will be used in areas where traditional models have failed (eg for geographically dispersed groups or rare disease populations). Interestingly, the Sanofi VERKKO study does not test a drug but instead focuses on a wireless glucometer. Perhaps virtual studios will lend themselves well to the evaluation of medical devices such as sensors and diagnostics, which will continue to increase in importance as technology evolves. As Pfizer’s experience has shown us, it is not an easy road, but it is likely to offer significant benefits for some studies and selected patient populations.