Tim Davis

While pharma companies and specialist vendors used to be the drivers of technical innovation, it is now the consumer world which is providing us with the most exciting and potentially valuable advances. Although today’s clinical trials industry faces long-standing challenges, there is now a fast-growing collection of technologies that have the capability to address these obstacles, potentially determining the shape of clinical studies for many years ahead.	 	The use of digital technologies in clinical studies is already well established. If we look as far back as 1966, researchers were testing the use of “a small, general-purpose, high-speed digital computer” for patient questionnaires.

 And by the mid 1990’s we saw the emergence of touch-screen technology. However, it is only relatively recent technological advances that have proved to be much more significant for the pharmaceutical industry. Apple’s iPhone in 2007, for example, enabled touch-screen technology to advance into the mainstream.	 	In addition, the adoption of smartphones has supported the development of other wireless technologies, with wearable activity trackers being the most obvious example. These devices can collect an ever-increasing variety of data, including sleep metrics and heart rate readouts. The advent of wearables is undoubtedly forming the first step towards the “Internet of Medical Things” - a network of biomedical sensors that continually track an individual’s physiological status.	 	Understanding what sponsors value is key and innovators should be looking to improve data quality, shorten time to market and reduce costs. Simplicity and regulatory acceptance of the technology are similarly vital. Over-complex approaches are unlikely to be implemented widely, while those that carry a risk of regulatory rejection are typically seen as too much of a gamble.	 	It is also important for sponsors to understand how such consumer technologies can be adapted for different purposes within the clinical trial environment. Whereas consumer devices are relatively cheap and easy to use compared to specialist devices, they are limited to the generation of data for exploratory endpoints only and not designed to generate validated data. When validated data is needed, sponsors are still required to use specialist clinical trial wearables such as ActiGraphs which meet the demands of regulators. Therefore knowing which technologies to use and in what context will undoubtedly lead to improvements in clinical trials by enabling a shift towards continual data collection.	 	It’s clear that, for the full potential of digital health to be realized, the support of regulators is paramount. With drug developers being traditionally risk averse, the onus is therefore on regulators to provide guidance on the regulatory-compliant nature of integrating such innovations into clinical trials. They must provide clarity on when and how new products can meet the requirements of clinical studies, thus providing sponsors with the confidence they need to begin wide-scale adoption. For example, while the FDA has decided against regulating “low-risk general wellness products”, it is interested in devices used to gather data against the primary endpoint of a trial.	 	If we take a look at the early days of electronic data capture systems (EDCs), many sponsors understandably had concerns over its use and the validity of the data it would produce, opting instead to continue using paper. However, the experiences of early adopters and regulatory support for EDC systems helped to tip the risk-benefit balance in favor of this technology. Digital health providers now need to engineer their own tipping point by helping regulators to support the adoption of trial technologies.	 	Once this level of confidence can be provided, pharma companies will embrace new technologies and novel ways of working. Indeed, in recent years we have even seen drug developers engaging in pre-competitive collaborations and data sharing initiatives – a trend that is typified by TransCelerate BioPharma. This indicates that there are shared problems too big for any one company to address and we are now observing companies working together on qualifying trial sites, training investigators and establishing a model approach for the anonymization of clinical trial data.	 	Another great example of this is the anonymization initiative which has the potential to enable greater sharing of clinical study data. Previously it had been difficult for third parties to analyze and learn from results. However, in 2014 the European Parliament passed regulations that necessitated the publication of clinical trial results, which compelled drug developers to begin data sharing initiatives, such as Johnson & Johnson's collaboration with Yale University.	 	It is predicted that data sharing initiatives will speed up the process of bringing innovative drugs to market. Yet, as with the adoption of digital devices, it is imperative that their advocates continue to demonstrate that sharing data is a price well worth paying to bring about the spread of knowledge.	 	A final challenge facing the industry has been brought about by the introduction of digital technology itself. Wearables, for example, are already allowing sponsors of clinical trials to capture unprecedented amounts of data. While this should be a boom for pharma, it is, in actual fact, also creating a fresh set of challenges in terms of how to take advantage of the huge potential insights they may hold. Nevertheless, systems now exist which can process and analyze the information in a way that yields meaningful insights and easy-to-understand reporting.	 	Implementing changes can be difficult for the typically risk averse pharma industry, but equally inaction carries its own dangers. Companies that take the initiative to leverage new technologies will undoubtedly benefit from clinical trials that generate broader, more continual and insightful data sets while, at the same time, seeing the burden that trial participation places on patients and investigators significantly reduce.	 	There is obviously a tension between the potential to derive benefits from a new approach and the security of established methods. How sponsors, vendors, regulators and new entrants to the sector manage this transition will determine how effectively the industry adopts new tools and ways of working.	 	

		Slack, W. V., Hicks, G. P., Reed, C. E. & Van Cura, L. J. A computer-based medical-history system. N. Engl. J. Med. 274, 194–198 (1966).

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Technology now provides many advances that can determine the future of clinical trials. How sponsors, vendors, regulators and new entrants to the sector manage this transition will determine how effectively the industry adopts these tools.

The Drive for Technical Innovation – Addressing Clinical Study Challenges

	Trigemina’s TI-001 is a patented application of a formulation including oxytocin with a novel mode of action as a therapy for high frequency migraine. Open label data suggests that TI-001 holds the promise to be safe and effective in reducing moderate and severe headache day frequency among this population by more than 50%, with corresponding decreases in secondary migraine symptoms (nausea, vomiting etc.) and use of acute medications, a significant improvement compared to current drugs.

	Following several single-dose trials in which TI-001 demonstrated promising analgesic effects, a Phase II trial was initiated in mid-2013 to seek analgesic effects and reduction in frequency of migraine headache days in a chronic and high frequency episodic migraine population.

	The decision to use electronic patient reported outcomes (ePRO) data was an important part of Trigemina’s clinical strategy. Trigemina were concerned with data integrity and ePRO provided the necessary assurance that data was entered by the patient at the time the migraine episode occurred. In a multi-month trial such as Trigemina’s in which patients record their headaches round the clock, ePROs were considered a critical component of the study protocol.

	There were a number of considerations for Trigemina when selecting the best approach to incorporate ePRO into the TI-001 study. Given the wide range of mobile devices available, the first was to select the most appropriate device for the planned study population. Since PROs had to be collected throughout the day, it was important to ensure that patients carried the device when they left their homes, so a smartphone was selected. Additionally using a smartphone to collect ePRO data allowed Trigemina to build SMS-based engagement into the ePRO design, which assists patients to remain engaged in the study until it is complete. The study required provisioning of smartphones to all patients to preserve psychometric validity and to provide a consistent user experience across the patient population for the collection of primary endpoint data. Exco InTouch provided the technology and services for the mobile ePRO implementation.

Impact of mobile ePRO on study progression

	The selection of mobile ePRO had a positive impact on the conduct of the TI-001 study. Most notably through the immediate access to data it has provided for review and progression. For Trigemina this was not only important to monitor the progression of the study itself, the information they were able to glean from the ePRO data showed positive results to date and was a pivotal factor in securing further funding from investors. Additionally, the early results have enabled Trigemina to expand the study. The trial population has been increased almost threefold and sites in Australia and New Zealand have now been introduced to meet their desire to garner data from multiple ethnic populations.

	Implementation of the ePRO solution within multi-country sites has also been a successful process. When it comes to the experience for sites, for Trigemina the key measure is the low level of technical support required from sites (and therefore patients). They have not received any concerns from sites regarding any aspect of implementation, including the complexity, size or weight of the provisioned devices that can be common with some ePRO solutions. During a recent visit to a site in New Zealand, which specializes in chronic conditions and manages a wide variety of ePRO solutions, Trigemina received feedback that they valued the small, simple phones provided because that’s what patients value. The sites were pleased that Trigemina and their vendor focused on simplicity and ease of use.

Case Study, Trigemina TI-001 for high frequency migraine

Tim Davis

Articles

The Drive for Technical Innovation – Addressing Clinical Study Challenges

Incorporating Mobile ePRO to Capture Patient Data