Risk Based Monitoring, mHealth and ePROs in this new era of App Darwinism

24th June 2016 (Last Updated July 18th, 2018 11:34)

Aldir Medeiros Filho, Senior Reviewer, MTPE, reviews the logistical challenges of ePROs in clinical program development

Risk Based Monitoring, mHealth and ePROs in this new era of App Darwinism

Over the last few years, Mobile health or "mHealth" has risen to prominence in the clinical research space. mHealth is an enveloping term that covers "medical and public health practice supported by mobile devices, such as mobile phones, patient monitoring devices, personal digital assistants (PDAs) and other wireless services".

It also includes mobile applications ("apps"), such as lifestyle and wellbeing apps that can connect to medical devices or sensors (e.g. bracelets or watches), as well as personal guidance systems, and much more.

Alongside the rise of mHealth tools, electronic patient-reported outcomes (ePROs) have grown in popularity. Whereas Wikipedia provides a comprehensive summary on the use of ePROs, a careful reading of the references show that all of them date back to before 2011. It's fair to say the ePRO ecosystem has evolved significantly since then.

Furthermore, according to a European Committee, about 100,000 mHealth apps were currently available back in 2014 when the report was published. 70 percent of the apps targeted consumers whereas 30 percent targeted health professionals.

Considering the first mobile apps started to appear in 2008 that gives an idea of the explosive growth of this industry segment. Back in 2014, it was projected that by 2017, 3.4 billion people worldwide would own a Smartphone, with half of them using health apps.

The rapid technological evolution of smartphone and sensory devices over the last few years are significantly improving the sophistication of mobile apps, and are expanding the range and potential of ePROs.

Some mobile apps and/or sensors can be adapted and used as ePRO tools to collect Vital Signs (VS) data, Quality of Life Questionnaires, or disease specific patient diaries, all of which can be completed by the patient.

Additionally, the RBM model could significantly be enhanced by the use of mobile Apps as they became a pivotal part of modern ePRO models.

ePRO apps are very tempting for clinical trial sponsors, as at first sight, it could set up more cost-effective RBM strategies. For example, some ePROs may potentially reduce the number of patient journeys to a hospital for a protocol visit.

Nevertheless, before we get overexcited by these fascinating new tools, we must keep in mind the efficiency and cost-effectiveness of mHealth tools may be heavily dependent on:

  • A complex infrastructure supporting inter-dependent, computational related tools (Smartphone, tablets, sensor devices), their operating systems (software and mobile Apps), web browsers (Google Chrome, Explorer, Mozilla) and;
  • High capacity, ubiquitous and flexible network services (broadband, 3G, 4G).

However, we should take into consideration the speed with which these new tools, devices, software, and applications are evolving and disappearing.

It remains unclear if the computational era is helping to significantly reduce the duration of the clinical phase of a successful program development. I believe the ballpark of about 10 years is still a reality that we need to deal with.

In this era of high speed App Darwinism, sponsors and clinical trial professions who decide to use ePRO apps as their primary, secondary or key or surrogate exploratory endpoints must carefully assess the longitudinal reliability and survival of their raw data.

I would like to focus attention on two aspects in this fast moving App ecosystem.

  • Reproducibility
  • CONSORT PRO Extension

 

Reproducibility

Nowadays most compounds in development are part of a partnership effort across several sponsors. The results of some clinical trials (i.e. phase I and/or POCs studies) may be used by different sponsors across the globe for different indications. Ensure the reproducibility throughout the lifecycle requires careful risk assessment to secure data integrity for the duration of the Clinical Development Program.

For example, Vital Signs (VS) are a constant safety and/or efficacy parameter for all clinical trials, whatever the indication. In case a sponsor decides to use an ePRO app for VS measurement it is important to perform a risk assessment on the sensitivity of the data for the clinical program(s) as well as compatibility, reproducibility and reliability of such tools across clinical trial projects.

Heart Rate, for example, can be collected using different tools and/or combinations: directly from a smartphone or wearable (wrist bracelet or around the chest) or chest transferring to a watch via Bluetooth then transferred to a computer. Each system will use different algorithms that need to be checked and the data collected will have different definitions according the immigration process and transformation across devices (i.e. native or raw data).

It would be very annoying if a new ePRO device and app used in a Phase III study delivered results that were inconsistent with previous studies due to a technological evolution.

A sponsor, or different sponsors spread around the world, may be asked by Regulatory Agencies to provide documentation and proof of validation of intended purpose of the raw data produced by ePROs and the supports devices (smartphone or sensor) used on their clinical program.

As mentioned earlier, a successful clinical program covers a long period of time and involves a vast range of heterogeneous datasets. Regulatory agencies around the world have different policies about how clinical research data be presented in a regulatory package submission. For example, the FDA usually requests to receive the "raw data" for review.

The Medicines and Healthcare products Regulatory Agency's (MHRA) definition of "Raw Data" are "Original records and documentation, retained in the format in which they were originally generated (i.e. paper or electronic), or as a 'true copy'. Raw data must be contemporaneously and accurately recorded by permanent means. It must also:

  • Be legible and accessible throughout the data lifecycle, as well as;
  • Permit the full reconstruction of the activities resulting in the generation of the data."

 

CONSORT PRO

Pressure is intensifying on sponsors to publish the results of their clinical trials. One point that will most likely become a criterion for the quality of a clinical trial will be the reliability of ePRO apps used to obtain their primary or secondary endpoints.

The CONSORT 2010 lacked guidance on Patient-Reported-Outcomes (PROs), which are often inadequately reported in trials, thus limiting the value of the data.

The 2013 CONSORT-PRO extension provides guidance for authors of trials describing patient-reported outcomes. Specifically, it extends five items of the CONSORT 2010 checklist to facilitate optimal reporting of RCTs (Randomized Clinical Trials) in which PROs are primary or secondary endpoints.

However, CONSORT-PRO was last published on 2013, largely considered the nascent stage of modern mobile apps. The absence of the "e" prefix is telling in that it suggests the use of ePRO apps is not yet mature enough to require an amendment of the CONSORT PRO statement.

 

Conclusion:

A recent report about reproducibility and reliability on biomedical research suggested that the biomedical research community could improve their records by using well established procedures for randomized controlled trials (RCTs).

I am confident that the clinical research community will keep a step ahead in this fast moving era of App Darwinism to deliver reproducible, robust, but also therapeutically relevant products that can be used clinically for the benefit of patients.

 

Aldir Medeiros Filho

 

*The views expressed in this article are solely those of the author's and do not represent Mitsubishi Tanabe Pharma Europe Ltd (MTPE)