The Virtual World of Digital Clinical Trials

Emerging technologies have the potential to fundamentally alter how patients engage with and participate in clinical trials. Creating a digital strategy for drug development has become a critical focus area for pharmaceutical companies. Virtual / digital clinical trials minimise the burden on clinical sites, typically retaining a central coordinating site for the study. Patient enrolment is usually done remotely using social media and e-consenting tools, drugs and assessment tools such as sensors, are home delivered and conduct most trial procedures can be performed at home.

With leading pharma companies such as Novartis rebranding themselves as a ‘Medicine and Data Sciences’ companies (Narasimhan, V, 2018), it is time to sit up and think. Vas Narasimhan, the CEO of Novartis, believed that digital technology could save up to 10 to 25 per cent of the cost of clinical trials (Neville and Atkins, 2017). There are currently 294,244 research studies ongoing in 50 states and in 207 countries (clinical.trials. gov, as of 12th Jan, 2019). A very small percentage of these are virtual clinical trials. While hybrid clinical trials (using at least some components of digital technology) are the accepted norm today, Anthony Costello, VP, Mobile Health, Medidata has predicted that one-fourth of clinical trials in the US could be completely ‘virtualised’ (Baum, 2018).

Spiralling drug development costs and an increased focus on ‘patient centricity’ are driving change in the conventional model of clinical trials. To put it simply, as Dr. Eric Topol’s book states ‘The Patient Will See You Now’ and dwells upon how the technology is enabling the ‘democratisation of medicine and empowering the patient (Parish, 2015). The pharma industry is increasingly trying to minimise the need of the subject to visit the site. Technology cycles are shorter than pharma product lifecycles, thus driving the need for agility and speed of adoption, in what is per se, a highly regulated industry, where a culture of risk taking has not been the norm.

The Virtual Clinical Trial Revolution

This decade rang in the digital clinical trial initiative, with the first ‘virtual’ trial being approved by the FDA in 2012. This was Pfizer’s Research On Electronic Monitoring of Overactive Bladder Treatment Experience (REMOTE) trial. It used e-consenting, web and smartphone-based recruitment, the study drug was delivered to patient’s and patient data and patient safety were monitored remotely by physicians throughout the trial. The objective was to enrol 600 patients from about 10 states across the USA. However, the trial failed, primarily as recruitment targets were not met, owing to the fact that technology proved to be challenging for an elderly patient population (Applied Clinical Trials Editors, 2011).

Sanofi, in 2015, ran an entirely remote online Phase IV clinical trial for diabetes. This was Europe’s first remote clinical study to use only e-consenting. It used eClinical Health’s online clinical trial platform and tested Mendor’s 3G-enabled wireless blood glucose meter. 60 patients were recruited through Facebook and the conversion ratio was 81 per cent. There were no site visits and study materials were delivered directly to patients. The patients and the site could review the glucose measurements real-time review. Interestingly the average age of patients was 56, with several over 70: thus, the technology barrier related to age that had been reported to be the cause of failure of the REMOTE trial was overruled. Even more significant were the high patient satisfaction scores of 4.52 out of 5, with a drop-out rate of 9 per cent, which was the same as a comparator study. Notably, the site spent 66 per cent less time in study coordination (Adams, 2016). Thus, one drug trial (REMOTE) in the US and one device trial (VERKKO) in the EU setting the stage for virtual clinical trials, many more organisations are following suit.

Science 37 is a Los Angeles-based company which uses a blend of a proprietary cloud-based mobile platform called the Network Oriented Research Assistant (NORA), telemedicine technology, wireless devices, decentralized physician networks, and in-house experienced clinical study staff to conduct virtual clinical trials. It is running virtual trials in partnership with Novartis (with plans to launch up to 10 virtual trials in the next three years) and has also partnered with UCB for the same (Adams, 2018; Tyer, 2018). It also partnered with AOBiome Therapeutics to conduct a phase 2b clinical trial on an experimental acne drug and the study was completed much faster than planned. Eleven physicians across 10 states, enrolled patients through Facebook and Google. More than 8,000 subjects were screened; finally, 372 participants received the drug or a placebo via mail. Companyissued iPhones were used to take selfies of their acne and photos were sent to the investigators via a phone app for evaluation, and video conferencing was used to communicate with study staff. No CROs were involved (Muoio, 2017).

Novartis’ ‘Trials of the Future’ initiative attempts to digitally connect and aggregate medical device data during clinical trials. It follows a twopronged strategy — “around the pill” and “beyond the pill” (Alsumidaie, 2017). The “around the pill applications” support or enable the efficacy of drugs, by using adherence tools and applications (such as mobile patient engagement apps), intelligent drug delivery systems, remote monitoring tools and precision diagnostic tools. The “beyond the pill” involves things such as digital therapeutics. While many have still not even heard of ‘a chip in a pill’, Proteus has used Ingestible Event Marker (IEM) technology which was approved by the FDA in 2012 to develop it. The IEM is a tiny IC on which an anode and a cathode are placed and serves as a sensor. The gastric juices in the stomach activate the sensor and the electric signal that is generated creates unique signatures which are detected by a wearable patch applied to the skin of the patient. communicate information After about seven minutes, the sensors which have transmitted information about the body become inactive and are eliminated in the faeces or are absorbed in the body (Limaye, 2018). The first ‘chip in a pill’ to receive FDA approval in 2017, was Otsuka’s ‘Abilify’ used for the treatment of schizophrenia and bipolar disorder (FDA, 2017). Earlier on in 2015, Aprecia’s Spritam for the treatment of seizures became the first 3-D printed prescription drug to receive FDA approval (Scott, 2016). With 3D – printing reaction ware that can actually custom-print drugs in the making, one may not only be able to increase the access to drugs in remote settings, but distributed chemical manufacturing may also help curtail the counterfeiting of drugs (Service, 2018). Janssen partnered with Scripps Translational Science Institute, Aetna, and iRhythm Technologies to run a home-based trial on 2,659 subjects, called mSToPS (short for mHealth Screening To Prevent Strokes). It assesses a wearable ECG patch as a new way to remotely detect a trial fibrillation. Results showed earlier diagnosis as compared to routine medical care. Since untreated a trial fibrillation is associated with a fivefold increased risk for stroke this could be of considerable value and a similar approach is now being tested for rheumatoid arthritis using real-world data to identify subjects, including data from Aetna’s Healthagen insurance databases. Janssen is running this as a part of part of an umbrella project called Global Trial Community, which aims to keep patients engaged, by sharing some patient data during the trial sharing the outcome of the trial as well. The objective was to expand this platform to 26 countries by the end of 2018 (Koester, 2018).

IBM is using a fingernail sensor prototype and machine learning to diagnose Parkinson’s disease based on fluctuating changes in a patient’s speech. It has received a grant from the Michael J. Fox Foundation for Parkinson’s Research for the conduct of Parkinson’s Progression Markers Initiative (PPMI), an observational PD study that has collected a vast amount of anonymous longitudinal data (Ghosh, 2019).

Novartis recently launched the FocalView app which will be used to remotely collect electronic device reported outcomes (eDROs) from 150,000 patients to track ophthalmic disease progression and will also use electronic informed consent and electronic patient reported outcomes (ePROs) (Gruber, 2018).

Challenges Associated with Digital Clinical Trials

While digital clinical trials seem to be the way ahead, there do exist diverse challenges related to digital clinical trials. These include challenges related to:

• Data privacy and security
• Dealing with populations with very low levels of computer literacy
• Complex trials involving invasive procedures for which site visits would be essential
• Dealing with an elderly population which may not very social media savvy – this may directly impact patient recruitment
• The lack of in-patient support
• Technology costs associated with running virtual trials
• Interventional studies that need to be conducted in a structured setting, such as an intensive care unit or phase I unit – along with early-phase oncology and first-in-human studies
• Patient engagement – as the interaction with clinicians decrease, companies have evaluated different options to keep patients engaged. EmpiraMed tested virtual gaming, wherein patient were rewarded by points for each goal that they achieved (registration, recruitment, etc) and these points could be used for gift cards, etc. However, such approaches could raise ethical issues (Luchhini, 2018).

Advantage, Digital

Digital clinical trials have their own unique advantages:

• The costs of patient visits range from US$3000 - US$7000 per visit. For a large multi-centric trial, running over 1-2 years, this could account for close to 60 per cent of the budget. Some of these costs could be offset through the virtual clinical trial model (Mantel, 2018).
• For indications where patients are incapacitated, or they may have challenges traveling to a distant site, the virtual model poses significant advantages in terms of retention.
• The virtual model may in fact be more representative of a patients’ real-life experience, and the latency of actionable insights associated with the conventional ‘brick and mortar’ model is significantly reduced. Companies like TriNextX partner with over 80 healthcare organisations across 16 countries, providing access to data of over 135 million patients through a cloud-based federated health research platform called TNX, which can use data from EHRs and run analytics to support the real-time modelling of proposed clinical trial protocols, feasibility studies and patient recruitment (Lynch, 2018 Yeates, 2018). Sanofi also partnered with Evidation to monitor ‘digital biomarkers‘ in patients to analyse real-world behavioural data to bridge the gap between drug efficacy and effectiveness bey analysing patient behaviour, since 50 per cent of health outcomes are determined by patient behaviour (Staines, R, 2019; Bulik, BS, 2018).
• Subjects evolve from being only data producers to being both data producers and data consumers, enabling them to take more informed decisions regarding their health.
• Social media and mobile apps have literally transformed patient recruitment. Stanford University ran a cardiovascular trial using Apple’s MyHeart Counts App (from the Apple Research Kit - ARK) attracted 11,000 volunteers within one day. Similarly, the mPower app enabled the enrolment of 7,406 people in a Parkinson’s study within six hours: prior to that, the largest study group has been 1,700 (Landman, 2018). Biogen, which used to recruit an average of six patients per week partnered with the My Health Team, resulting in an upward spike in subject recruitment to 800 patients within 2 weeks 37 per cent of sites fail to meet recruitment criteria and up to 10 per cent do not recruit a single patient during a trial. Hence, the use of social media to enhance recruitment has becomes key (Limaye N. and Saraogi, V, 2018).

The FDA Perspective

FDA Commissioner, Scott Gottlieb, has strongly advocated the use of digital technology in clinical trials (ACRP, 2018) and has proposed a Centre of Excellence for Digital Health in 2019 (Fassbender, 2018). It also launched the Digital Health Innovation Action Plan in 2018 to enable timely access to high-quality, safe and effective digital health products and the FDA Pre-Cert program, a pre-certification program to work with companies to develop a new approach to digital health technology oversight. The FDA in Dec 18, also as a measure of caution, published a report on the benefits and risks of digital health tools that are not regulated by the FDA as medical devices., since the Cures Act amended the Federal Food, Drug, and Cosmetic Act to exclude certain software functions (such as those software intended for use as general wellness software products, certain types of electronic patient records etc) from the definition of a medical device and thereby FDA regulation (Caccomo, 2018).

There is an important need to create a digital clinical trial ecosystem or a continuum, clearly identifying the data flows between all the key stakeholders. Compliance with guidance and regulations such as ICHE6 R2, 21 CFR part 11, HIPAA and the FDA’s draft guidance on ‘Content of Premarket Submissions for Management of Cybersecurity in Medical Devices’, released in October 2018, GDPR is important. Blockchain technology, though still in a nascent stage, is being increasingly evaluated to facilitate interoperability between data contributors enabling all participants to securely maintain their own copies of the data, as per Deloitte (Kent, 2018).

With the cost of managing a study site ranging from $1,500 and $2,500 per month, the potential benefits of moving to a ‘siteless’ virtual clinical trials are significant (Petersen, M, 2018). Virtual trials and the concept of ‘quantified health’ as described by Dr. Daniel Kraft, Executive Director, Exponential Medicine will probably define the future (Oymaci, 2018). ‘Virtual clinical trials’ or ‘digital clinical trials’ are clearly the destination of the future. Yes, it is of utmost importance to truly focus upon ‘patient centricity’ and ethics.

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