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Right-Sizing Technologies for Early Clinical Development

We all love technology...right? Some of us will camp outside the Apple store for the next iPhone or rapidly adapt to the next gaming device or streaming capability. It is exciting to embrace new technology, be current in the field and incorporate new capabilities rapidly into your life and work. It is easy to forget that with evolving technologies there are winners and losers (for anyone old enough to recall the Beta and VHS wars, or MySpace versus FaceBook, and others).

Similarly, as drug development executives, we are heavily invested in moving faster to obtain more meaningful results earlier in clinical trials to bring novel therapeutics to market sooner. Superficially it is compelling to incorporate tools that will support that ever shortening runway to drug approval for both altruistic and business reasons. Here we dive a little deeper to examine what "meaningful technology" is in early clinical trials where obtaining faster Proof of Concept drives faster drug development decisions, higher business valuations and (hopefully) earlier drug approval.

Clinical pharmacology studies where new drugs are tested for the first time in humans and then in patients (Phase I/IIa) to understand safety, tolerability and potentially efficacy is an area where new technologies to speed the clinical operations, exploratory endpoint evaluation and efficacy data can be highly useful on one hand, but also challenging in other ways. Technology is rapidly evolving in this early clinical space to replace paper data collection around source documents, safety parameters, and efficacy measures with more robust and timesaving electronic capabilities. Caveat emptor, however. Individual emerging technologies may not win the Beta versus VHS War, may have validation questions and ultimately may not be ready for prime-time industry use.

We examine a few emerging technologies and their impact on early clinical research here.

Electronic Source in the Clinical Phase I/II Research Facility

The emerging field of electronic, tablet-based source will be the future means to maximize data quality and efficiency in the clinical research environment. "Source" refers to the first-hand, original collection of raw data generated in the clinical research facilities. This "source" has traditionally included all patient demographics, lab results, medical observations and operational parameters completed during the execution of the study collected on paper and later transcribed into databases for analysis. This analysis becomes the bedrock for the conclusions drawn in the final product of all clinical trials, the clinical study report (CSR).

Frankly the evolution of true data capture in the clinical setting has been painfully slow compared to animal toxicology "online" data collection via VAX/VMS systems as early as the 1990s and only in the recent years have comparable technologies for clinical applications made a commercial entrance. Most of this early electronic source truly amounted to hand translation from paper documents into electronic case report forms (eCRF) which then allowed for data fields to be filled in the corresponding database - not "true" electronic data capture at all. These products were add-on components created by data management services to expand offerings and potentially lock clients into technology applications for entire drug development programs. Additionally, the actual products were reverse engineered from late phase offerings with little or no flexibility for earlier adaptive studies which did not have the same needs; indeed, they were priced for late stage multi-site global studies and as such were complete overkill for early clinical development.

Lately smaller companies have emerged with true end-to-end services for early clinical development as well as clinical pharmacology providers who have created their own versions of electronic data capture designed for the Phase I/II environment.

One example is the source product from Clinical Research IO (CRIO), a scalable source technology created by and for researchers who come from the actual site perspective in early development and understand the abbreviated set up, speed and data collection needs of a study that initiates, executes and ends in less than six months. Up and going in two weeks it directly captures data without intensive staff training, multiple modules to maintain or high costs to the clinic or clients. CRIO's approach to working directly and rapidly with sites and biopharma customers to hone the product offering at the ground level is a unique business model approach gleaned from its Boston biotech environs.

Another early phase CRO, Celerion, has revolutionized its original data capture system ClinQuickTM into a sophisticated data trending and reporting tool, CelexusTM, which impressively shows immediate custom reporting of all related patient data captured in real time for adaptive design edits to protocols and a rapid understanding of emerging adverse events, critical for First in Human data escalation decisions.

Apps and Wearables

The emerging array of wearables and digital devices offers a new world of data collection for all clinical trials' point of care devices, wearable devices, and apps controlled via phones and watches are the future means to gain insight into the patient experience outside of the clinic and protocol-preconceived timepoints. This flexibility significantly increases the data pool to inform disease progression but raises the question of how to manage and select the most compelling data to avoid being overwhelmed by a tidal surge of nonspecific and potentially conflicting, unvalidated exploratory effects. This influx of data requires a different mindset and skill base to integrate and benefit from this knowledge. Actualizing this therapeutic benefit approach requires a more scientific and thoughtful approach around mechanistic understanding than the normal First-in-Man protocol design with its very heavy and singular focus on safety and tolerability with only a slight emphasis on efficacy. Moving forward earlier understanding of effect will be included to clarify and add to safety, tolerability and efficacy. Such endpoints around respiratory patterns, glucose metabolism, and cardiac safety are currently being incorporated for measure now in diseases and safety assessments including Chronic Obstructive Pulmonary Disease (COPD), metabolic syndrome and QT prolongation potential, respectively. These digital biomarkers will contribute to the understanding of efficacy and mechanism via quantitative assessment of physiological outcomes during early exploratory clinical trials.

Electronic Visual Analog Scales and other Tablet-Based Technologies

Cognitive assessments are crucial tools for the clinical development of CNS-focused therapies. The traditional approach on paper has been to utilize a uni-or bi-polar 10 cm line scale where a patient provides a subjective response to predetermined queries regarding a specific product experience. These measurements can range from subjective pain/pain relief measurements, to how much the subject "likes" a product to how much a subject would pay for a product.

These scales yield valuable insights into the characteristics of novel therapeutics in development. Some scales have been validated in the research world and trademarked (i.e., Columbia Suicidality Scale) versus scales that may be developed for specific subject responses in commercial settings.

Research conducted in our clinic demonstrated the effectiveness of new tablet based technologies to gather this information quickly (Austin et al 2017, attached). On one study, paper forms were used to capture this data, and on the other, an electronic tablet (iPad) with software containing the questionnaires was employed (Cambridge Cognition, LTD, Cambridge UK). Both studies had similar protocol design, inclusion/exclusion criteria, and patient demographics.

Obtaining accurate clinical trial data in a timely fashion is vital to ensure top quality data for trustworthy conclusions; obtaining it faster in a less resource-intense manner is imperative from a business perspective. While both methods can capture subject responses in nearly the same amount of time, the e-tablet based collection method was found to reduce queries from entry error significantly and the total query time by 30 minutes per subject, or 12 hours for 24 subjects. Even in this relatively small study, the time comes at the cost of professional clinical researcher's hourly rate and rapidly increases with the size of the study or the addition of more VAS scales. As some study designs can include multiple scales the time costs become prohibitive if performed manually. The emergence of electronic applications are increasingly common in clinical research trials and offer a means to collect data accurately and in a time efficient manner.

Caveat emptor

The options are dizzying and the potential impact on driving drug development decisions is immense. From faster insights into the physiological effects of novel drugs to increased safety monitoring and improved business practices the benefits of the emerging technologies is compelling. One almost overlooks the challenges of incorporating new technologies in the quest to be an early adopter and reap the rewards of the digital era of wearables, apps and implantable devices.

In a very real sense these tools all come with specific challenges to the sponsor, the contractor and let's not forget, the patient.

The Research Facility

In the early development space where many trials are executed in a clinical pharmacology facility where patients are domiciled for a specific period to observe safety and monitor compliance the environment is heavily controlled. This yields itself ideally to the usage of digital and tablet-based technologies in theory. However, there are considerations to be made. For example, the physical footprint of the facility must be amenable to heavy and secure internet usage throughout all areas of patient access. This of course requires significant internet coverage and technology security capability from research sites that traditionally have not created such an environment in the past.

Additionally, and perhaps even greater concern arises around the actual validity and testing of emerging technologies. Depending on the actual claims, technologies can range from completely exploratory to qualified testing to fully validated testing complete with User Acceptance Testing (UAT) documentation. Again, the site is responsible for ensuring that the appropriate level of training and documentation accompanies these tools. This responsibility ultimately lies with the site executing the trial, up to and including Good Clinical Practice (GCP) compliance, which adds to the complexity and cost of executing studies which include such technologies.

Finally, though many of the wearables and apps may have undergone UAT at the source of technical creation, much like the drugs we develop, the real-world application of these technologies may bring forward unexpected outcomes when used broadly. For example, touch screens used in electronic sources (i.e., VAS, product dispensation, etc.) may occasionally not record sensitive touches. This may create double entries, missing entries, etc. which in turn create reconciliation issues and ultimately potentially false levels of queries to be addressed at the site, as well as inaccurate refection of site quality.

The Patient

Ultimately our focus should be the effect of technologies on our patients. These patients entrust us as drug development and clinical professionals with their time, energy, compliance and indeed their lives. This trust obligates us to ensure that technologies are used to their purpose and limited to the extent where they benefit the patient, as opposed to simply for the gathering of data for undefined purposes.

Patient fatigue is a real and present concern where overuse of a variety of technologies are employed in early clinical protocols. One example of such an issue includes the overuse of timepoints for assessment of a variety of subjective analysis. In product "liking" studies too many timepoint assessments lead to inaccurate self-reporting. Indeed, Human Abuse Liability (HAL) studies may have such high statistical variability in response during impairment that additional staff is required to aid them in completing these questionnaires. Another example of fatigue can occur in the usage of electronic patient diaries. The requisite tools required to actualize the use of diaries can be challenging to the patient as well. Their possession of a technically suitable cell phone, the wireless bandwidth to support such data requirements and the capability or time to be educated on the download, usage and troubleshooting involved. Indeed, sites have long experience in the time and trouble taken to support the patients' ability to utilize these technologies in their homes.

So?

As we all camp out for "the next Big Thing" we would benefit from a thought exercise that includes all stakeholders in the early clinical development space. As opposed to turning a fully formed protocol out into the world, sponsors would benefit from live feedback on technologies under consideration. Sites are robust sources of this information ranging from basic small facilities to commercial research destinations with a swath of experience to share from both the compliance, user and patient perspective.

Additionally, some sponsors have statistical and medical capabilities which are heavily engaged in the conceptualization of data flow and ultimately drug development design. Smaller organizations may wish to consider the addition of resources or consultants to truly roadmap the use of technologies and the amalgamation of data for their desired endpoints.

This thought exercise will create better more feasible protocols with responsible budgets and data that has a higher likelihood of being used productively rather than shelved in a warehouse. Even more importantly, planning what technologies are used in moderation embraces the need for patients to continue contributing their time and lives into these clinical trials by reducing the technology burden to a level that is reasonable. Reasonable requirements for patients will keep them engaged and excited that they may contribute to the cure, not simply be considered a data point.

The thoughtful use of technology will allow us to embrace the best tools for novel drug development while not overwhelming potential patients, overworking research facilities, and generating undefined data sets.