It took a pandemic to eventually shift the focus to long-overdue regulatory changes

The worldwide COVID-19 pandemic has slowed down growth across all domains, and the clinical trial industry is not an exception. However, this impediment to critical medical research across the globe has pushed sponsors, and contract research organizations (CROs), to reevaluate ways to keep existing trials on track while also trying to find a way to initiate novel coronavirus related trials. While the industry is now moving from traditional to central and remote monitoring of trials, it is important to note that regulators have been driving this shift towards the ‘new normal’ by providing formal guidance for this purpose. In this article, we explore the concept of risk-based eCOA and how it has evolved over time to befit this ‘new normal’ phase.

What is eCOA and what does it entail?

The usage of electronic Clinical Outcome Assessment (eCOA) is a push towards adapting to the ‘new normal’ as it is a method to gather patient data electronically through the use of technology such as smart home devices, handheld monitors, wearables, e-diaries, tablets and web servers to allow the stakeholders in the trials (patients, healthy volunteers, investigators and caregivers) to report outcomes directly and digitally. Although historically COA was only related to the evaluation of Patient-Related Outcomes (PRO), the FDA has now broadened the definition to include PerfO, ClinRO and ObsRO along with PRO. In simple terms, when the above parameters are reported electronically, they fit under the eCOA spectrum.

How has COA changed from paper diaries to digital devices?

Meantime COA has evolved from paper-based reporting through patient diaries and questionnaires to eCOA wherein the outcomes are reported on handheld devices such as PDAs, tablets and smartphones, wearable sensors, Google web servers and also through apps on the patient’s bring-your-own-devices (BYOD). This is achieved in several ways such as the pairing of smartphones with devices such as glucometers, blood pressure meters or usage of wearables.

The move from paper to digital now facilitates outcomes to be recorded through the use of specific apps installed on the patient’s smartphone that comply with the important endpoints to be gathered. As smartphones have become an integral part of our daily lives, allowing patients to use their BYODs has proven to increase not only patient satisfaction but also patient retention. 

Modern world interconnectivity enables remote and real-time tracking of important parameters related to e.g. physical activity and even body temperature and fluids to gather vital information, while simultaneously uploading and assessing data

How does eCOA contribute to data quality and data integrity?

As the landscape of clinical trials is constantly changing, it is of utmost importance to adapt to ways of gathering data which is reliable, integral without a compromise on patient safety while ensuring compliance and patient retention. Through eCOA, data is captured using electronic reminders and alerts. The in real-time captured data, which must be be accurate and reliable, allow the site staff and sponsor (monitors, etc.) to respond promptly while working with the patient and to stay up to date in diary submissions. For example, algorithms are being integrated which can measure if there is worsening of symptoms in the patient. This direct feedback enables study teams to stay on top of the patient data and visit status, site status and eventually the trial status. 

eCOA technologies also include audit trail information such as a timestamp associated with each data entry, which helps in assessing the reliability of the data. In other words, eCOA facilitates checking whether the data has truly been entered in real-time or later. eCOA also helps keep a check on the integrity of the data, through detection of fraud/misconduct which was almost impossible in case of paper diaries. For instance, in the past patients completed the forms while waiting in the parking lot next to the doctor’s office. It was difficult to detect whether the data had been entered the same day. The data was also not reliable, since the patient had the ‘recall bias’, i.e. they could not remember an event for e.g. the grade of pain from about a week ago. This phenomenon has been called the ‘parking lot syndrome’.

Maintaining data quality and integrity is extremely important throughout the lifecycle of a clinical trial and even more so from a regulatory perspective. The eCOA data therefore need to meet regulatory guidelines as they are Attributable, Legible, Contemporaneous, Original and Accurate (ALCOA). Furthermore, due to the automation of data entry into EDC systems chances of human/transcription errors are being eliminated. And because of real-time at data capture, data quality issues such as inconsistencies or missing information can be detected instantly.

Why should eCOA be part of an RBQM system?

eClinical systems, and in particular eCOA, are intricately linked with the concept of holistic Risk-Based Quality Management (RBQM). The holistic RBQM methodology brings all risks in scope, from start to finish. Once eCOA is incorporated into the ‘RBQM neuronetwork’, it will feed the RBQM ‘brain’ with the data it needs for its predictive, anticipatory risk analytics. This is supplemented by the fact that eCOA has options to send reminders to patients to complete diary entries/questionnaires, making the data gathered reliable and its collection possible in real-time. Being an integral part of the RBQM neuronetwork also permits regular analyses of the data through its audit trail feature. This is a huge benefit, as it ensures that data quality is maintained right from the source and the risks associated with it can be mitigated proactively.

eClinical systems, and in particular eCOA, are intricately linked with the concept of holistic Risk-Based Quality Management (RBQM).

Cyntegrity’s MyRBQM® Portal expedites the principles of holistic RBQM. MyRBQM® Portal not only integrates eCOA devices but also clinical data recording platforms such as EDC, CTMS, IxRS, LabData and PV systems in its all-embracing neuronetwork. Using features such as digital time-stamped audit trail and proprietary risk detection algorithms, data integrity and reliability are proactively maintained. For instance, using the eCOA data, MyRBQM® Portal can detect various types of misconduct and fraud in clinical research. Study administrators can preconfigure key risk indicators (KRIs) and set data thresholds that enable them to proactively mitigate risks throughout a trial.

Whilst the fundamental hazards of eCOA data quality, e.g. “parking-lot syndrome” or cheating with a time of the data entry, are solved (since the ePRO system checks the time and date of the entry) the remaining set of risks, e.g. false-person entry fraud (whether the patient entered the data or someone else did) or duplication of patient data by site staff or patient answering the questions randomly clicking around without considering the sense of questions, remains still unsolved. MyRBQM® Portal utilizing its proprietary mathematical models can in response to the unsolved data quality hazards offer the next level of risk-detection dealing with previously-mentioned complicated high-level risks.

MyRBQM® Portal technology extends beyond the limitations of eCOA by facilitating the next level of AI-enabled risk analytics. eCOA as part of a holistic RBQM system enables more effective risk detection and fraud prevention.

What are the drawbacks of eCOA as an isolated technology?

As any technological adaptation eCOA also has its drawbacks. As it is an electronic form of data capture, the devices used are prone to similar issues such as other gadgets i.e. malfunctions, device damage/loss or connectivity problems. This may lead to data being incomplete, corrupted or entirely missing. If the eCOA solution resorts to paper backup, this will obviously lead to degradation of data quality and eventually result in dirty data. Additionally, a measurement of equivalency of paper data versus electronically captured data may have to be demonstrated to the regulators depending on factors such as the phase of the trial, the ratio of paper versus electronically captured data, etc.

Hence a good contingency plan for such situations is patients and sites being given access to a backup electronic data collection system (e.g. web-based backup) till the device is fixed/replaced. However, this could also pose problems in terms of cybersecurity which need to be addressed. Another shortcoming is the non-existence of data integrity plans in place. They basically involve having scheduled review cycles integrated into the eCOA platform to ensure potential risks are addressed proactively. This would go hand in hand with eCOA features such as customizable alerts and would ensure that site personnel not only stay appraised of patient compliance but regularly follow up on issues. 

Risk-based eCOA: The way forward in the drug development process

In summary, Combined with an effective risk-based quality management process which considers the risks associated with eCOA technologies, ‘risk-based eCOA’ is paving the way forward for complete transparency in clinical trials whilst ensuring compliance. This has been a problem which has plagued regulators and researchers for several years. If clinical outcomes can be measured with ‘clean data’ which is not only reliable but accurate, it will be much more useful while developing a new compound/drug.

With the support of regulatory bodies such as the FDA which requires eCOA to be used instead of paper diaries, technological advancements supporting timely collection and storage of data, risk-based eCOA is definitely the best way to ensure seamless transfer of patient data for evaluation and assessment. Thus, ensuring a life-threatening pandemic does not come in the way of the fight against this life-threatening pandemic and other diseases alike.