Advancing Electronic Clinical Outcome Assessments
Through recent EU, EMA, and FDA draft regulations
Bryan McDowell, M.Sc., M.B.A. – VP, eCOA Science and Consulting at Clario
Kelly Dumais, Ph.D. – Director, eCOA Science and Consulting at Clario
Valdo Arnera, M.D. – Medical Scientific Advisor, eCOA Science and Consulting at Clario
Pierre-Frederic Omnes – Executive Director at TransPerfect Life Sciences
Editor’s note: The following article is adapted from the recent webinar “How the Recent FDA & EMA Regulations are Helping Advance and Enhance Electronic Clinical Outcome Assessments (eCOA-ePRO).” Responses have been edited for clarity. You can watch the full webinar recording here.
The Evolution of eCOA
eCOA is not a new principle. Over the 25 years of its existence, the scientific community has learned a lot about how to improve clinical trials by listening to patients and reducing patient burden. This means asking the right questions to ensure the right data is captured at the right time, frequency, and location. Striking the right balance is key and will ensure a more successful program.
The most recent EU, EMA, and FDA guidelines were created to help advance and enhance the use of eCOA by maintaining data quality in decentralized trials and electronic submissions to ethics committees. By having clear definitions of the processes, you can ensure lessening of patient burden by only collecting the most pertinent data while maintaining data integrity in a flexible trial environment.
A Changing Regulatory Landscape
New regulations are focused on advancing the accessibility and the inclusivity of patients to ensure that all trials are open and accessible to all patients who would like to be involved. With the advent of decentralized trials (flexible trial design), there are more opportunities than ever to have a diverse patient mix. Accessibility also includes having functionalities in place to ensure that patients who may have various impairments, whether they’re associated or non-associated, can comfortably take part in trials and be able to use the technology that is in place to capture their important responses.
It is also important to ensure that accessibility goes hand in hand with data integrity. They should not be two separate entities. For example, when adding accessibility features such as zoom functionality, data integrity shouldn’t be jeopardized in the process.
New EU Regulations
Clinical trial stakeholders worldwide have felt the impact of the new EU Clinical Trials Regulation (CTR) since it became mandatory in January of this year, but draft text has actually been in place for quite some time.
First approved in 2014, the rollout was prolonged due to the inadequate IT infrastructure that supports the EU Clinical Trial information systems, portals, and corresponding databases. There was a lot of work that needed to be done to have these systems complete a successful external audit.
This regulation took effect at the beginning of 2022 with a transitional period of one year where both the old (EU CTD) or the new (EU CTR) system could be applied
As of January of 2023, all new trials need to be submitted under this regulation. This regulation oversees all aspects of clinical trial conduct; from preparation, submission conduct, and trial publication of result transparency disclosure.
The use of EU CTR is mandatory for any new clinical trial application, but those trials that were approved under the old regulation can continue to be executed under the clinical high-end directive and the corresponding national approvals, until the beginning of 2025.
While this new regulation is extremely wide and impactful in many domains, it does not change the science of eCOA. The way that COA and eCOAs are developed does not change, but submission requirements do. The biggest shift patient-facing documents must now be submitted via portal instead of paper submission. This requires a bit of advanced planning on all the components that need to be ready in order to have a complete submission since it is not limited to one country, but for all countries you want to include in your first wave of submission. This involves coordinating aspects like translations, vendor readiness, and all of the documents that are relevant to the clinical trial application.
Overall, this new CTR can be seen as an opportunity to simplify processes. For example, it’s not efficient to wait for a translation and delay a clinical trial. With CTR, you know what is needed upfront for submission in each country, making clinical trials in Europe more efficient.
The new EMA guidance is specific to computerized systems and electronic data management in clinical trials. One of the biggest items this guideline addresses is the longstanding discussion with the regulatory authority to know what is considered source data. With the new EMA guidelines, we are finally all in agreement that when the subject enters the data into the device, the device is the source until the data has been transmitted to the database. This is because the data transfers are a true copy, and therefore the database becomes the source, and then the data is erased from the device because the device is not intended to keep all the data on the device.
The EMA also provides guidelines, definition, and best practices on bringing your own device (BYOD). It is also necessary to provide alternative ways of data collection, as trial participants shouldn’t be excluded from a trial if they’re not capable of or willing to use BYOD.
FDA Decentralized Trials Draft Guidance
The FDA released draft guidance in May providing recommendations for implementing decentralized clinical trials for drugs, biological products, and devices. The guidance was in response to the need for FDA to address the changing nature of clinical trials in today’s modern world. This includes the use of more remote data collection technologies, decentralized elements, digital health technologies, and flexible trial designs needed for increasing clinical trial diversity. This draft acknowledges that many clinical trials already include some decentralized elements and clearly defines what a decentralized clinical trial is: “a clinical trial where some or all of the trial- related activities occur at locations other than the traditional clinical trial sites.” This classification includes fully decentralized trials and hybrid trials.
Most importantly, it references the reason why one might want to adopt more decentralized clinical trials, as it has the potential to expand access to more diverse patient populations and improve trial efficiencies. Under the flexible trial design approach, ePRO — or eCOA — is part of the DCT and should be available and suitable for the populations under study, which aligns with the FDA Patient Focused Drug Development (PFDD) Guidance.
FDA Patient-Focused Drug Development (PFDD) Guidance
The PFDD Guidance is a series of recommendations that describe how stakeholders can collect and submit patient experience data. The guidance is divided into four separate focus areas:
- Methodology to collect data that is accurate and representative of the patient population
- Approaches to identifying what is most important to a patient for their disease/condition and burden of treatment
- Approaches to selecting, modifying, developing, and validating clinical outcome assessments (COAs) to measure outcomes of importance to patients in clinical trials
- Methods, standards, and technologies for collecting and analyzing COA data for regulatory decision making, including selecting the COA-based endpoint and determining clinically meaningful change in that endpoint
The recurring theme throughout the PFDD guidance is that the COAs selected or built should be fit for purpose. It should be focused on all the patients that are under study and be meaningful to capture the right outcomes that are important to that population without being a burden. This is why training is so important to ensure that patients understand the questions at hand. In the real world, 100% compliance is very hard to achieve, but there are higher compliance rates with ePRO than with paper.
Evolving trials for an ever-changing world
Just as the science of eCOA has advanced over the course of two and a half decades, so have the regulations to keep up with technological compliance. What’s clear from these recent regulations and draft regulations is that CTR is a moving field. There will be more to learn as time passes and expectations from regulators become clearer.
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