Global clinical guidelines have shifted the industry toward risk-based approaches for the planning and execution of clinical trials. The ICH’s guidelines for Good Clinical Practice state that sponsors should evaluate identified risks against existing risk controls by considering “the likelihood of errors occurring, the extent to which such errors would be detectable, and the impact of such errors on human subject protection and reliability of trial results” (ICH E6 R2).

If a study team was brainstorming risks (prior to a few weeks ago) and one of the members asked about the risk of a global pandemic, the exercise to score the risk would have probably looked like this (assuming a 1, 4, 7, 10 scaled approach):

• Impact: 10 (Really bad, severe GCP issue)
• Detectability: 4 (Would probably detect it)
• Likelihood: 1 (Not going to happen)

The team would have then moved on, thinking that there was no reason to mitigate that risk.

The New Reality With COVID-19

However, today that risk is a very real and very significant global GCP issue impacting clinical trials. It’s no surprise that information coming from our clients point to trial impact on a global scale. Concerns about whether to begin trials are significant but perhaps pale in comparison to what to do about ongoing studies.

ICH E6 R2 requires the establishment of Quality Tolerance Limits (QTLs) to identify systematic issues that can impact subject safety or reliability of trial results. A QTL is a value (data point) associated with a parameter and, if crossed, there will be a severe impact to subject safety and reliability of trial results. Examples of QTL parameters include such events as the percentage or number of study participants with premature discontinuation of a study drug; who withdrew informed consent; who are lost to follow-up; whom study endpoint data was not collected; with important protocol deviations other than eligibility; or who are non-compliant with study drug administration as defined in the protocol.

Safety QTLs can include the percent or number of immediately reportable events that have been reported late (that is, serious adverse events and other critical GCP information).

Unfortunately, during this pandemic, QTLs will accumulate in ongoing clinical trials. With this accumulation, there’s a view that if enough QTLs occur, there might be an impact on the ability to draw a conclusion from the data due to loss of statistical power. 

The industry is working feverishly to ensure that data can be safely collected, with a primary focus on the safety of trial participants, trial sites, employees and society. Pharmaceutical clinical development leaders have stated:

• “The organization in general is feeling stressed”
• There have been “nightmares on corona with global logistics (monitoring, patient visits, etc.)”
• “Unprecedented”

In addition to the concern about the reliability of trial results, if trial subjects contract COVID-19, all of the comorbidities would be adverse events or serious adverse events. Furthermore, if treatment is needed, concomitant medications would be added into the mix of potentially confounding factors.

What’s Next?

Will COVID-19 be the event that transforms how the industry executes clinical trials? Will our current abilities with remote and centralized monitoring save the day? Will decentralized, site-less trials pull through unscathed? Will telemedicine prevail? These are some potential solutions currently being debated.

As a co-author on the paper “Quality Risk Management Framework: Guidance for Successful Implementation of Risk Management in Clinical Development,” I would advocate that the new state of affairs when considering clinical trial risk management should be this: If there is anything with an impact of 10 to GCP, regardless of the likelihood of occurrence, that risk requires a mitigation plan.