Data Management & Biostatistics

Managing Pandemic-Related Protocol Deviations: Tips for Clinical Trial Conduct

Conducting clinical trials of therapeutics and devices can be daunting, and COVID-19 has made this endeavor even more challenging. With the emergence of this pandemic, sponsors and CROs have been tasked with adapting processes, technologies, and training to move studies forward in a dynamic, demanding environment where regulations continue to evolve.

For global studies, this requires practical, flexible approaches that comply with the regulatory guidance in each region or country where participants are enrolled. At Premier Research, our COVID-19 Task Force combed through the relevant regulations to create a consolidated overview of the guidance that is common to all countries, offering a framework for clinical trial conduct that maintains patient safety while optimizing data integrity and minimizing site burden. In this blog post, we share some of our tips for managing pandemic-related disruptions while collecting the information regulatory agencies will require regarding protocol deviations going forward:

  1. Understand the regulatory requirements on protocol deviations. Collectively, regulatory agencies have acknowledged that an increase in protocol deviations due to COVID-19 is inevitable. Unavoidable protocol deviations will not constitute a serious breach, and the agencies have agreed that prospective protocol waivers will not be allowed.

    Any deviation from current practice must be proportionate, justifiable, and clearly documented. If the deviation does not impact the safety of the subject, there is no need for review by the Institutional Review Board, Ethics Committee, or Competent Authority. However, sponsors should keep in mind that all protocol deviations must be documented, and a compilation of these deviations must be submitted as part of the Yearly Status Reports and Clinical Study Report.

  2. Differentiate and document COVID-19 impacts. Protocol deviations may result from a variety of pandemic-related factors, ranging from site closures and travel restrictions to COVID-19 infection in a study participant. Until the public emergency has ended, site and study staff should carefully document:

  • Whether the protocol deviation was related to the circumstances surrounding COVID-19
  • Whether the participant has been diagnosed with COVID-19

  1. Count deviations. Keeping track of deviations can be complex. Site and study staff should be trained on the requirement to document a protocol deviation every single time a process that was established by the protocol is not met. For instance, if a remote visit is performed instead of the onsite visit and onsite assessment(s) described in the original study protocol, at least two protocol deviations must be recorded: one for the missed/changed visit and at least one other for the missed assessment(s).

    In addition, the regulatory agencies recognize that delays in monitoring visits may result in delayed identification of protocol deviations. If this is the case, documentation of the deviation should capture the date when the deviation became known as well as details describing when the deviation occurred and why knowledge of its occurrence was delayed. Of note, if a protocol amendment has been submitted to and approved by the appropriate regulatory body, that amended protocol becomes the new reference point for deviations from that point forward.

  2. Double-check that data collection is consistent and data is usable for analysis. Most clinical trials depend upon an interaction at a physical site to produce the data necessary for analysis. If alternative data collection methods are required – for example, switching a paper patient reported outcome (PRO) to an electronic PRO (ePRO) (or vice versa) – sponsors should consider collecting quantitative data, i.e., numeric data, or establishing well-defined categories of responses. This will make data collection more consistent and easier to input for analysis.

  3. Minimize site burden. COVID-19-related disruptions, and the documentation requirements that come along with them, can significantly increase the burden on site and study staff. As sponsors consider trial modifications, it’s important to minimize the extra work required. Updated template Case Report Forms (CRFs), alternative monitoring strategies, and adaptations to the informed consent or re-consent process may help to minimize site burden, both during the pandemic and after the end of the public health emergency.

As part of our response to the COVID-19 pandemic, we at Premier Research are working diligently to understand all the potential impacts on clinical trial conduct and to standardize alternatives that help keep critical research moving forward. Our goal is to help sponsors understand and meet their oversight and monitoring obligations while supporting study staff and limiting additional burden on site personnel. To learn more about how we can help you navigate this fluid environment, contact us today.

Related Resources:

PREMIER VOICES #11: Statistical Considerations in the Wake of COVID-19

Data Driven: How Electronic Patient-Reported Outcomes Provide a Vital Opportunity to Capture Key Data Beyond the COVID-19 Crisis

COVID-19 & Clinical Trials: Direct-to-Patient Model Keeps Research Moving and Patients Safe