ver the past year, the Coronavirus Disease 2019 (COVID-19) pandemic has impacted the pharmaceutical industry, particularly clinical trials. Safety of subjects and clinical study staff safety is a major concern, resulting in modifications to study operations, including enrollment/recruitment delays, subject retention, protocol amendments/modifications, subject diversity and budgets, statistical analyses and validity of results, and regulatory interactions.

Addressing these issues requires real-time revisions and updates to clinical study protocols and clinical study reports (CSRs). As a result, there is an increasingly important role in thoughtfully updating these documents to enable study continuation, subject safety, data integrity, and regulatory compliance. This article provides an overview of the impact of the COVID-19 pandemic on clinical trial operations, required protocol adjustments, and steps taken to address some of the most pertinent issues resulting from the pandemic.

Clinical Trial Operations

Enrollment, Recruitment, and Retention

Due to concerns about the spread of the SARS-CoV-2 virus, subject enrollment, recruitment, and retention are challenging. Consequently, many sponsors have suspended or delayed enrollment in their clinical trials, leading to downstream impacts on statistical analysis and validity of results.

To protect study subjects and staff, safety practices such as physical distancing and lockdown procedures have been enacted. The challenge of maintaining onsite activities has resulted in thousands (80 percent) of clinical trial delays, suspensions, and terminations. Despite a recent downward trend in trial disruptions, as of September 2020, 1,036 trials remain affected by the COVID-19 pandemic according to GlobalData’s Covid-19 Executive Briefing, significantly influencing subject enrollment and retention. A Clinical SCORE survey queried clinical trial sites (n=363) and found that that 48 percent of actively enrolling sites were struggling to get subjects to come in for study visits.

These study disruptions, safety concerns, and associated budget strain can produce protocol deviations that lead to amendments and revisions, increased data integrity issues and interactions with Investigational Review Boards and Independent Ethics Committees as stated within FDA’s September 2020 Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 Public Health Emergency. Additionally, limited patient access reduces subject diversity given subjects’ hesitancy to come onsite and the fact that traditional sites already have limited geographical reach.

Decentralized Trials: Virtual and Offsite Approaches

While pandemic-initiated trial disruptions may result in increased oversight burden, they can also lead to greater flexibility on the part of sponsors and regulatory bodies, enabling tests to be done locally and less frequently.

This has provided an opportunity for sponsors to transition to decentralized or virtual clinical trial models sooner than projected given that they enable a safer environment for study subjects and staff. According to a GlobalData survey that queried healthcare experts (n=150), 34 percent were already utilizing decentralized clinical trial models, and 67 percent were planning to transition to decentralized models due to the COVID-19 pandemic.

Virtual trial models enable more timely reporting of adverse events, diverse patient recruitment across geographic areas, improved subject engagement and data collection, and lower dropout rates, all of which bolster enrollment and retention.

While there are potential barriers to implementation, such as lack of sponsor expertise, budget or external challenges, the virtual trial model offers a timely and effective solution.

Impact on Regulatory and Clinical Documents

Clinical and regulatory development teams play a critical role in updating protocols, CSRs, and other clinical documents to address pandemic-related modifications, enabling clinical trial continuation, subject safety, data integrity, and regulatory compliance.

A recent American Medical Writers Association survey queried members including regulatory writers (n=252). The most common impact of the pandemic on regulatory writing is on clinical trials operations, including changes to the dosing schedule, visit windows, and monitoring frequency. Notably, almost half of regulatory writers surveyed reported temporary stops or interruptions to ongoing clinical trials.

Protocol Revisions

Often, protocol revisions or amendments occurring in response to COVID-19 address the need for virtual visits or a hybrid virtual and in-person visit combination. Additionally, because disruptions may lead to potential bias, trials may be amended to enable extended visit windows, enrollment increases, and endpoint modifications.

In the US, not every regulatory document must be amended to accommodate these updates. For example, as outlined within the September 2020 FDA guidance, if the healthcare system conducting the clinical trial mandates COVID-19 screening procedures, reporting these procedures as protocol amendments isn’t required unless the sponsor is incorporating the data as part of a new research objective.

EMA Guidance on the Management of Clinical Trials During the COVID-19 Pandemic released in April 2020 obliges sponsors to consider implementing virtual visits as well as trial suspension, relocation, postponement and/or extension. An amendment is required based on whether it is “substantial,” meaning whether it has an impact on subject safety or mental integrity or on the scientific value of the trial. EMA gives priority to COVID-19 related amendments to existing clinical trials.

Clinical Study Reports

For all US trials impacted by the COVID-19 public health emergency, sponsors are required to describe specific CSR modifications. sponsors must implement contingency measures to manage study conduct and how subjects’ participation was altered as a result of COVID-19 and report the impact of these measures according to the September 2020 FDA guidance.

In Europe, sponsors are advised to preplan for systematic deviations, consider alternative data collection methods, evaluate impacts on retention, risk assessment, blinded review, include a DMC, and address biases/sample size adjustment according to EMA’s June 2020 Guidance on points to consider on implications of COVID-19 on methodological aspects of ongoing clinical trials.

Statistical biases resulting from disruptions that would not otherwise exist may compromise the validity and interpretation of study results as stated in the FDA’s June 2020 Statistical Considerations for Clinical Trials During the COVID-19 Public Health Emergency. Disruptions can include subjects lost to follow-up, early withdrawal, incorrect dosing, and missed assessments/doses; therefore, subgroup analyses (pre-, during, and post-pandemic), interim analysis plans, and pooled data summaries may partially address potential bias as recommended by the June 2020 FDA guidance. The CSR should identify instances of bias, discuss rationale for acceptability and measures taken to minimize bias.

Conclusion

The COVID-19 pandemic continues to impact clinical trial retention, enrollment, and operations. In particular, the pandemic has catalyzed the advent of decentralized, hybrid, or virtual trial models. Industry professionals in clinical development, regulatory, medical writing, and biostatistics, play a critical role in clearly and accurately communicating COVID-19-related updates to protocols and CSRs to ensure clinical trial continuation, subject safety, data integrity, and regulatory compliance.