By Laurie Halloran, CEO and Chairwoman of the Board, Halloran Consulting Group, Inc.
While COVID-19 has proven to be an extremely trying obstacle for the life science community, it is crucial for organizations to not only focus on the short-term impacts of COVID-19 but on developing a long-term plan of action for how we return to business once the pandemic subsides.
On March 27, Halloran Consulting Group held a Virtual Town Hall, which brought together industry colleagues came together to discuss issues specifically related to identifying and managing clinical trial risk during the COVID-19 crisis. The overwhelming influx of potential risks and new issues has continued to pour in daily, requiring clinical trial professionals to adapt quickly. As we begin to adjust to our new normal, it is extremely important to lean on each other and share ideas to help us move from a reactive to a proactive state of identifying and managing risks.
This article captures, in Q&A format, some key learnings and information shared during last week’s Virtual Town Hall. (For my previous articles on the impact of COVID-19, see “8 Significant Risks COVID-19 Poses To Clinical Trials — And How To Mitigate Them”, “Assessing The Impact Of COVID-19 On Regulatory Interactions, Inspections, & Audits”, and “Clinical Study Conduct During The COVID-19 Pandemic — Challenges & Solutions”.)
How should an organization determine if it should proceed with a clinical study?
Sponsor organizations must make an initial assessment of whether their studies are essential or non-essential. Johns Hopkins has a tiered breakdown that the institution uses to identify what studies and related activities are considered essential and can continue at various phases of emergency preparedness. Since Johns Hopkins has reached the highest level of emergency now, as a significant percentage of the country has, the limitations on clinical trial conduct are severe. Many organizations have already decided whether they can proceed with an active trial or if a pause is necessary. For those that continue to stay active, numerous mitigations are now being put into place due to COVID-19. For those who have not yet decided what to do with an existing study, this needs to be done as quickly as possible.
What are organizations struggling with the most when it comes to identifying risks?
Risk by definition is the potential for an event to occur that will cause a negative impact. Now that the negative event has occurred (in the form of COVID-19), sponsors are being called to evaluate their ability to identify, assess, mitigate, document, and manage risk.
Organizations continue to feel overwhelmed and bombarded with information daily. As stated in the FDA guidance, sponsors are required to perform a risk assessment of the trial, the investigational sites, and the participants so that measures can be taken to prioritize patient safety first while maintaining data integrity. Patient safety must be your overriding guide to navigate these uncharted waters. Upheavals to daily routines will continue so it will be crucial for organizations to systematically assess the impact and quickly tackle any potential areas of concern while documenting decision making continuously.
Organizations are still operating in a reactive mindset, but as this current state becomes our new normal, it is vital for organizations to begin to shift into a proactive state. To be clear, sponsors will need to be comfortable with their existing process of identifying risks in real-time as well as measures to mitigate those risks that have now become real issues.
Many organizations have leveraged their existing risk management processes, while others have tried different techniques to ensure appropriate documentation. The overarching issue is that organizations must review their protocol(s) to identify those critical data and processes that have been affected by COVID-19 through the lens of protecting patient safety and ensuring data integrity, not only in the interim but for the long term.
For organizations with clinical risk management plans currently in place, COVID-19 should have triggered an immediate risk reassessment. The key characteristic of a robust risk management plan is that it serves as a framework that can be applied to unexpected situations. It is important to focus closely on the likelihood, impact, and detectability (LID) criteria in your reassessment.
For those organizations that are outsourcing clinical trial activities to a CRO, it is essential to ensure close communication and partnership when approaching clinical study/site risks. There needs to be constant communication occurring on documentation of risks related to COVID-19, as well as appropriate mitigations that need to be put in place. Otherwise, CROs become extremely overwhelmed due to the industry-wide need for these activities to occur, so engagement early in this process may alleviate difficulties in the long run.
What types of tools are organizations using to document risks pertaining to COVID-19?
As we are in the thick of handling the impacts of COVID-19, the method of documentation may seem like a low priority. However, it has never been more important, given the unprecedented interruptions that have occurred as a result of the pandemic. Using even a simple risk assessment tool allows sponsors to document real-time assessment and mitigation efforts as the sequence of events unfolds. The key to your clinical trials’ future success will be the ability to recreate a clear narrative of your organization’s actions and changes during COVID-19 so that there is little guesswork when things get back to normal.
Many organizations are using a modified version of the TransCelerate Risk Assessment Categorization Tool (RACT) when performing risk assessments. Additional industry tools are available from organizations such as Metrics Champion Consortium (MCC) and the Avoca Group; however, access to these tools does require membership. As the TransCelerate RACT is a comprehensive tool, many smaller organizations are instead using a simple Excel risk log to capture risks, actions, and mitigations.
Some organizations are creating chronological trackers to narrate study risks in real-time since there may be several trackers utilized to document risks in a heavily outsourced clinical trial. This approach is similar to a storyboard describing events that are occurring on a daily or even hourly basis. Other organizations are providing a weekly slide deck in a dashboard format for each study; these include a site-by-site breakdown of emerging risks/issues that have been identified, assessed, and mitigated.
Sponsors are using a mix of COVID-19-specific risk assessment trackers as well as leveraging existing study-specific risk assessment tools and adding on to what has already been identified (pre-COVID-19). The important thing to remember is that identifying, assessing, and mitigating risks and documenting your actions in whatever way works for your organization is the most important action you can take, both now to ensure patient safety and for the future as your clinical trial resumes.
Are organizations using a “point-person” to manage the documentation and transcendence of information to key stakeholders?
Some organizations are establishing a COVID-19 project manager to monitor the large amounts of information coming in daily. Others are using individual trackers managed by a representative from clinical operations. However, the majority of organizations are taking a collaborative approach to information gathering and dissemination across the organization, as available centralized resources are limited.
Once risks are identified and mitigations put in place, what other tools can people use to continue to assess and monitor those risks and mitigations?
Organizations should already be using key risk indicators (KRIs) and quality tolerance limits (QTLs) to monitor risk thresholds and critical key-to-quality factors during their studies. However, the documentation needs to include how your QTLs and KRIs are affected by COVID-19.
Chances are, almost all of your current risks and KRIs will be impacted by COVID-19, since they are typically fueled by data collection methods that are now compromised by several factors (i.e., patients not coming in for visits, data entry staff either not on site or prioritizing COVID-19 activities, monitors not allowed on site, etc.). Common KRIs such as protocol deviation rate, adverse event/serious adverse event rates (underreporting), premature discontinuation, and loss to follow up rates (higher) will likely exceed established thresholds. It will be important to continue collecting this information to ensure strong documentation (including dates), so you can appropriately evaluate and assess the long term COVID-19 impacts.
Subject safety needs to be the highest priority, and a KRI for key safety visit completion should be added to your RACT/risk log and closely evaluated. QTLs will need to be reassessed and closely monitored since their main purpose is to assess endemic subject safety or trial result reliability. Most companies tend to have QTLs built around patient discontinuation and key efficacy parameter completion. Organizations should be discussing QTL assessments with their statisticians and medical stakeholders.
How have risk categories been used to assess the appropriate impact? How can sponsors leverage their site relationships to assess site and patient risks?
Some organizations are trying to work with CROs to include the CROs’ assessment of site-level risks related to COVID-19 into the algorithm with their centralized monitoring tools, so these risks may be assessed centrally. Sponsors are starting to see how complicated risk management can be when you have many vendors engaged and haven’t had a coordinated approach to managing risks to date. It is important to align your CROs’ risk categorizations across your clinical trial to ensure a consistent approach. This goes back to keeping lines of communication open with the CROs and being heavily engaged in this risk assessment process.
Also, Virtual Town Hall participants shared that communication with principal investigators (PIs) has been crucial during this process. Some organizations have found that there are PIs whose caseload had significantly decreased due to COVID-19, so there is an opportunity for communication to happen more easily. The local reports on the ground (at sites) have been extremely helpful to understand the full picture of patient/site/study risk in real time.
What types of risks are organizations currently seeing at the subject level?
The approach to subject-level risk will differ based on whether the study will continue during COVID-19 or be put on hold. For those that are put on hold, it is important to keep the subject engaged and ensure that information disseminated from the sponsor to the CROs and sites also trickles down to the subjects. For studies that will continue, assessing subject access to sites is critical. If telehealth visits are occurring, you must understand the risks associated with home health with respect to COVID-19 exposure and protected health information (especially in Europe due to GDPR requirements). Subjects may also have limited access to public transportation depending on where they are located. Sponsors need to provide patients with information on how they will ensure their safety during this pandemic. Keeping the lines of communication open with the site and subject and providing reassurance through sponsor-level efforts will go a long way for subjects.
Does the approval of home healthcare professionals need to go through the IRB if it is not in the protocol?
Based on the FDA guidance, you can implement the change immediately, due to patient safety issues, and inform IRB as soon as possible. Organizations are heavily leveraging urgent safety measures to implement clinical trial protocol/process changes quickly while ensuring subject consent. Therefore, it will be important to handle the use of home healthcare visits on a case-by-case basis.
How are sites being affected by COVID-19? How can sponsors work with sites to alleviate some of their issues?
One of the risks sponsors are seeing at the site level is constrained resources, as many site staff members have been pulled in to help with other COVID-19 efforts. In some instances, clinical research at sites has been “shut down” and limited only to treating patients. Institutional review boards (IRBs) have been stretched extremely thin with the increase in and priority of COVID-19 research. Some IRBs aren’t able to reach quorum when physicians sitting on the IRB are pulled to help with COVID-19 efforts. Site accessibility has been limited, with staff working remotely. Depending on the institution, there has also been some confusion as to whether or not sites are considered essential businesses.
Sponsors must provide guidance to sites on how to stay engaged with clinical trials and help them prioritize the key areas to focus on during this time. The lines of communication need to remain open so that sites continue to see sponsor support and guidance in working through issues. This is where your site relationships become important — if they have not been test before, they will be, and they can still be strengthened.
How are organizations handling protocol amendments and other study-specific documentation?
We must take the lessons learned during this period and apply them as we make updates to applicable study-specific documents such as protocols. It is not only crucial for our current state but in the event of a second wave of COVID-19. It is important to evaluate our timeline and goals based on the issues we have seen and to ensure flexibility is built into future protocols.
Another issue that was brought up during the Town Hall was updating informed consents and the potential impact on liability clauses should a subject be exposed to COVID-19 during the study, especially with home health nurses adding a new level of risk for COVID-19 exposure. These new issues should be brought up with your legal department.
Each organization must reference guidance from the various regulatory authorities to address any protocol changes. Each country has nuances that need to be followed, so sponsors should be aware of the specific guidance in effect for their study and their sites.
What will happen when we go back to a “normal” state?
EMA has released a guidance document that discusses the need to consider how you will view data and perform analyses of affected/non-affected populations. It is important to start thinking about how you are going to analyze the efficacy of your study as well as how COVID-19 impacted your study design.
One Town Hall participant suggested using a data monitoring committee (DMC) to assure the safety of trial participants and assist in a risk-based analysis of the impact COVID-19 may be having on your trial participants directly. The DMC can also assess the impact of protocol and oversight modifications and how clinical study conduct may be compromised. If your study does not have a DMC, you should consider putting one in place.
It will be necessary to track COVID related deviations so that information can be easily highlighted within the clinical study report (CSR). As discussed, missed visits and protocol deviations will occur, but the documentation should still make sense chronologically. Begin having discussions around how many consecutive missed visits could impact patients’ evaluability in the analysis and whether the sample size may need to be amended. The FDA’s guidance document discusses the impact at a subject level, along with the need to document it within the CSR. This is also an opportunity to leverage a DMC to help in making and documenting decisions on subject disposition and data analysis based on the impact COVID-19 has had on the study.
Do we go back to “normal,” or has COVID-19 provided the industry with hope for a “new normal”?
From an industry perspective, we must think about how we move forward from this in a broader sense and what future improvements in clinical trial conduct we can make to get our products to market. We are proving now that we can do what we always thought was unachievable. Who would have thought that, in a matter of weeks (not months), we could change course in the way we conduct clinical trials? We have altered how we monitor study data, have quickly processed protocol amendments, have changed the way we perform subject study visits, and have determined that only certain data is critical in our studies. It is the perfect time to start thinking about technology we can implement and the changes we can make to how we conduct our studies — and prioritize our resources once we get past this pandemic and look to the future.
It may also be time to reevaluate your risk management methodologies, your risk management tools, and how you are collecting key data points so you can easily look at KRIs and/or QTLs to make rapid changes in your approach.
Are sites beginning to test for COVID-19 before any procedures are happening in studies?
Major institutions have implemented testing before procedures happen in studies. Lack of access to tests has prevented many sites from performing testing before participation, but sites are beginning to think about it.
Where can readers turn for additional guidance?
Links to valuable guidance document links are listed below, though we recommend visiting health authority websites often, as guidances have been updated frequently as new information becomes available:
If you would like to be included in future Halloran Virtual Town Halls on COVID-19, please send an email request to firstname.lastname@example.org.
About The Author:
Laurie Halloran, BSN, MS, founded Halloran Consulting Group in 1998. Her time as a pediatric ICU nurse had inspired her to start a company that helps move new therapies through FDA processes to get them into the hands of patients desperately in need. Halloran has been named 2018 Women’s Business Enterprise Star by the Women's Business Enterprise National Council (WBENC) and has won a 2017 Enterprising Women of the Year Award from Enterprising Women magazine. Halloran Consulting Group was also named an Inc. 5000 Fastest Growing Company for the past three years in a row.