Clinical Trials: Adaptations to Risk Management in Response to COVID-19
Khan Lau OD, MBA and Mei Tran, BA
On 20 Mar 2020 the FDA released an amended guidance on the conduct of clinical trials due to the impact caused by the COVID 19 pandemic. Some key points outlined in the guidance included patient safety, clinical patient care, out-of-window study visits, and protocol deviations.
While the guidance may not be applicable for every trial or all instances in the clinical trial landscape, it does highlight steps sponsors, IRBs, Investigators, clinical teams, and subjects should consider in order to maintain subject safety, assure compliance with regulatory requirements and good clinical practices (GCP), and minimize risks to study data. Overcoming the challenges presented by COVID-19 will involve cooperation, communication, and coordination of the stakeholders, as well as creative thinking.
The primary issues from a high-level perspective is the delay or displacement of subject visits, delayed timelines, and management of the out-of-window visits. Keeping the integrity of the trial intact while focusing on patient care and safety will be the most crucial challenges for all of the stakeholders. As such, an organized modification to the risk management plan is necessary to adapt to the evolving changes during this unprecedented time.
This paper provides an overview of items related to trial integrity and promote elements to the patient centric changes. While it is not intended as an all-inclusive list of key elements, the focus will be on risk evaluation, subject safety, and remote monitoring of clinical sites.
The risk management plan for a multi-site clinical trial is created in anticipation of potential risks and the severity of their impact on the study. A risk is typically identified by an expected trigger of the anticipated problem. With each clinical trial there is an expectation for risks involving subject recruitment/enrollment challenges, site performance, subject safety, investigational product accountability, monitoring activities, and data management to name a few. However, the cascading effects of the COVID-19 pandemic and social distancing were unforeseen, resulting in unexpected clinical site closures and monumental study disruptions. Consequently, most study teams have had to react to risks as they occurred. The below tables outline how risks can be categorized in the order of likelihood and severity so that appropriate mitigation plans can be developed to address challenges and priorities developed.
A risk matrix created for the risk management plan should include: the category (what aspect of the clinical trial is impacted), the risk (what the issue is and how it affects the trial), the likelihood/detectability (how likely the risk will occur and how easily it is identified), and finally the impact in terms of severity.
|High||An event that is extremely or very likely to occur and whose occurrence will have immediate impact on the subject’s safety, privacy and well-being, or trial compliance, quality, and integrity of the data, (and/or timeline) so severe that the project will be terminated or will cause significant cost (and/or timeline) increases on the project; this risk should be escalated (where possible) and reviewed frequently|
|Medium||An event that has a 50-50 chance of occurring and, if it occurs, may have an impact on subject safety or trial compliance, data quality and integrity; will cause noticeable cost (and/or timeline) increases on the project; this risk should be reviewed regularly|
|Low||An event that is unlikely or very unlikely to occur and, if it occurs, will cause small or no impact on subject safety or trial compliance, or cost (and/or timeline) increase, and in most cases can be absorbed by the project|
Some of the immediate risks of COVID-19 are on enrollment and study visits. Whether the cause is due to site closure, social distancing, or staff/subject illness, the impact is ceased enrollment, missed visits, or out-of-window visits. Depending on the study status at the time of COVID-19 disruptions, mitigation activities may involve enrollment suspension, remote follow-up calls with subjects, discontinuation of subject participation, or other approaches.
For sites with enrolled subjects involving medical intervention, subject safety is paramount; therefore, it is critical to examine remote monitoring opportunities to insure subject safety and data integrity are not compromised. During the quarantine/social distancing period, some possible solutions could involve the remote review of scanned study documents or video conferences with clinical sites to review pertinent study materials and source data. In the long term, a more robust remote monitoring plan is needed to address the new norm. As much as we would like to believe clinical trial activities will normalize once the COVID-19 threat dissipates, realistically, the traditional clinical care patterns we have seen in the past will unlikely exist in the near future and will need to be modified to reinforce new safety standards. With the paradigm shift in how subject visits will be handled to minimize contact, the same principles will apply to monitoring visits, with the adaptation or modification of remote monitoring becoming the new ideal method.
A more in-depth look at remote monitoring may involve the use to technology to overcome the shortcomings. It may be necessary to explore creative approaches to perform site feasibility and qualification visits remotely, and the dynamic in which facility tours and equipment calibration confirmations are accomplished. Rather than on-site visits, the adapted process may involve video conferences and virtual tours of the facility and remote verification of equipment. Routine monitoring of clinical source data may be conducted under a different scenario as well. Sites may be required to fax or email scanned source documents, provide monitors with remote access to databases, or participate in web meetings to satisfy the delivery of study documents and maintain the validity of source data verification.
It is necessary to evaluate each line item of a risk management plan and develop the appropriate contingency plan to assure subject safety, compliance with GCP and regulatory requirements, and maintenance of the integrity of study data. On a global scale, various aspects of a clinical study are negatively impacted and the result is delayed study timelines. While it is important to acknowledge the impact on delayed timelines, it is more relevant to accept that the COVID-19 pandemic will change how we conduct clinical trials moving forward. Given the new safety precautions, we all need to proactively identify potential risks and develop plans so we may navigate through change. The lessons learned from this recent threat is that it is critical to routinely review the risk management plan, be prepared for the unexpected, and have tools in place to allow flexibility in how we manage trials.
The FDA guidance is a good first step in reformatting your clinical trial operation due to the problems caused by the pandemic. But again it will involve cooperation, communication, and coordination of sponsors, IRBs, Investigators, clinical teams, and subjects as well as good common sense. In addition, no matter the short term outcome, planning to adapt will be the key to maintaining integrity of study data and minimize risks to subject safety.