New Compliance Issues Emerge Amidst COVID Clinical Operations

There has been much discussion on the move towards decentralized clinical trials (DCTs) amidst the wake of COVID-19, and a new movement (#NOGOINGBACK) is emerging to push clinical operations personnel and biopharmaceutical enterprises to continue with DCT approaches in clinical trials. COVID has forced biopharmaceutical enterprises to move at breakneck speed to implement DCT approaches. However, many biopharmaceutical sponsors with little or no clinical innovation experience and limited resources have implemented poorly designed DCTs in a rush to sustain clinical operations during COVID. This poor implementation manifested in poor clinical quality, non-compliance, and good clinical practice (GCP) related deviations at study sites. In this article, I’ll discuss some of the significant forces currently impacting global operations, FDA foresight on operating clinical studies during COVID, and the subsequent compliance issues manifesting from poorly executed DCT operations.

The #NOGOINGBACK movement

The #NOGOINGBACK Movement recently emerged to continue the innovation spurred during the COVID pandemic. This movement’s approach suggests that the clinical trials industry has gotten a glimpse of the future of clinical trials, where clinical operations can run seamlessly, efficiently, and reliably by using future technologies and methodologies that support DCT execution. For example, many sponsors have implemented eClinical and decentralized technologies to keep the patient at home. Examples include eConsent, eSource, telehealth visits, home-nursing visits, and remote monitoring, to name a few.

One of the risks that this movement emphasizes is that the industry will go back to its old ways after the pandemic is over; The reality is that the pandemic is not going away anytime soon, and the world has radically transformed to a point where it is unfathomable to go back to the old ways of clinical trial execution. However, this risk is valid, as the clinical trials industry is very comfortable with implementing tried and true traditional methodologies of clinical trial execution, no matter the cost or impact on clinical trial efficiency.

FDA guidance during COVID-19 public health emergency

The new FDA guidance on operating clinical trials during the COVID pandemic has pushed sponsors to move towards DCTs. FDA specified in its guidance that “ensuring the safety of trial participants is paramount,” and that sponsors should do whatever it takes to ensure that patients are protected. Recommended strategies branch out to alternative methods of safety assessments (i.e., virtual and decentralized visits) whenever possible, home-nursing visits, shipping investigational medical products to the patients’ homes, modifying protocols to include any changes to visit procedures, and virtual monitoring visits.

The FDA also forewarned sponsors of the potential issues that may come from rapid decentralization, such as missing endpoint data (due to patient discontinuation, changes in study visit schedules, and missed visits), delayed data collection due to healthcare disruptions, and additional safety monitoring for patients who cannot access investigational medical product.

One of the most prominent sections and emphasis in this guidance document includes conducting informed consent remotely; it is clear FDA expected that there would be a significant influx of consent amendments, as they expected many sponsors to amend the protocols to incorporate changes related to operating their clinical studies during the COVID pandemic. The FDA outlines a complicated and convoluted process in its guidance if an eConsent is not available to the patient. For example, study sites are required to send the ICF to the patient electronically, conduct a telephone/video conference call with the patient, and provide sufficient documentation (i.e., identification of personnel on the call, review of the ICF and any questions patients may have, and obtaining verbal confirmation from patients of trial participation). Subsequently, the patient is required to sign a blank piece of paper with a written statement about their voluntary agreement to partake in a specified study and send a photo of that document to the site or mails it. Once received at the site, the study staff are to attach this document to the consent form and generate a note to file explaining the consenting circumstances with this method.

The FDA also expected that major deviations and GCP non-compliance issues would arise due to COVID control measures and monitoring changes. In its document, FDA specified that sponsors should implement alternative and decentralized approaches to monitoring to maintain trial participants’ safety and data integrity, such as enhanced centralized monitoring, phone calls with study sites to review updated study procedures, evaluate trial participants’ status, study progress, and conduct remote monitoring. However, FDA also recognizes that decentralized monitoring could result in missed findings, which would later be identified in on-site monitoring visits. Any missed findings and deviations are to be documented, and the cause for missing the deviations/non-compliance issues should expressly point to the modified monitoring procedures during COVID.

The risks are now becoming realities

Some large biopharmaceutical sponsors were prepared and had the budgets to implement DCT measures, such as rolling out eConsent using established technology systems, adjusting their centralized monitoring practices, and implementing remote monitoring using specific technologies. These methods protected sites from non-compliance because these methods have been tested in clinical innovation pilots, have less room for human error, and could rapidly be verified by monitors. However, many other sponsors with minimal or no DCT or clinical innovation experience were left to scramble to put poorly designed methodologies together, which exposed study sites to GCP non-compliance and major protocol deviations.

For example, some sponsors have followed FDA guidance on conducting consent remotely and have not relied on eConsent technology. The implementation of such methodologies has resulted in poorly designed consenting case report forms (CRFs), a lack of proper consenting documentation, missed consent form signatures, and sometimes consenting couldn’t be verified due to staff turnover. Furthermore, monitors could not identify these deviations for several months, as sponsors did not equip their monitors with the appropriate technologies to properly perform remote monitoring visits. Now that new COVID safety procedures are implemented, and monitors can physically access sites, they discover a slew of major protocol deviations and GCP non-compliance issues.

How to make clinical innovation and DCTs work

Some large biopharmaceutical sponsors have enjoyed stepping into the future by implementing novel technologies that support DCT execution and seeing them work. Nevertheless, many sponsors who could not afford DCT technologies (do not know the return on hiring DCT vendors) and lack clinical innovation experience are left behind with major non-compliance issues and protocol deviations amidst the pandemic. Implementing DCTs must be done with the latest technologies and clinical operational design expertise to minimize human error. The examples I see first-hand prove that implementing DCTs using traditional methodologies will result in significant issues. Biopharmaceutical sponsors who have had a good experience with DCTs will likely support moving forward and #NOGOINGBACK, whereas sponsors who did not risk going back to traditional methodologies.

Moe Alsumidaie, MBA, MSF, is a thought leader and expert in the application of business analytics toward clinical trials, and Editorial Advisory Board member for and regular contributor to Applied Clinical Trials.