Pre, During, and Post Pandemic: what are the cut points for defining pandemic start/end?

The Covid-19 pandemic will have a lasting impact on clinical trials. The way how the clinical trials are conducted will forever be changed. For ongoing clinical trials that are impacted by the Covid-19, the regulatory agencies have rushed to publish the guidance/guidelines. Many countries have published their own guidance/guidelines for clinical trials in the middle of Covid-19 pandemic. The most significant ones are those by US FDA and EMA: 

• FDA Guidance on Conduct of ClinicalTrials of Medical Products duringCOVID-19 Public Health Emergency
• Guidance on the Management of Clinical Trials during the COVID-19 (Coronavirus) pandemic

The impact of Covid-19 on the ongoing clinical trials is multi-front. I listened to a webinar organized by DIA "Study and Data Integrity Considerations for Clinical Trials Impacted by COVID-19" and the potential impacts of Covid-19 on clinical trials were listed as the following: 

 The impact of Covid-19 on clinical trials is beyond what the table above can summarize. For example, the psychological impact could change the behavior of subjects who participate in the clinical trials - patients may be less compliant with the study protocol and more difficult to retain in the study - healthy volunteers may be less willing to participate in clinical trials. 

One thing for sure is that the Covid-19 will have impact on the study quality, efficacy evaluation, and safety evaluation of the ongoing clinical trials. How to assess the impact is not an easy task. For the statistical analysis plan (SAP), additional sections will need to be included to describe the impact of the Covid-19 on study quality, efficacy, and safety evaluations.  

EMA also issued guidance (Points to consider) for methodological aspects / statistical analyses.

Points to consider on implications of Coronavirus disease (COVID-19) on methodological aspects of ongoing clinical trials

The Points to consider suggested:

"Sponsors are advised to contemplate an analysis of the accumulating trial data in order to evaluate the implications on recruitment, loss of patients during the trial, ability to record data and ability to interpret the treatment effect in light of the pre-, during and post-pandemic measures phases. "

The suggested approach seems to be reasonable. The subjects in the whole study can be grouped into three categories: subjects who were enrolled into the study and completed the study prior to the pandemic start; subjects who were enrolled into the study and ongoing in the study during the pandemic; and subjects who are enrolled into the study after the pandemic. Statistical comparisons can be performed to compare the differences between these groups regarding the subject characteristics, compliance, efficacy, and safety endpoints. The findings from these comparisons may trigger further actions on how the final analyses should be performed. 

The analysis by pre, during, and post pandemic has been discussed in several webinars - it seems to be an approach that people will adopt in handling the statistical analyses for studies that are impacted by Covid-19 pandemic - until the following question is being asked:

How to define the cut points for deciding pre, during, and post pandemic? 

We know that the Covid-19 outbreak started in Wuhan, China, and then spread to other countries (China -> Neighboring countries of China -> European Countries -> United States -> all over the world). The exact date of the Covid-19 outbreak is still in debate and may not be known forever. 

For clinical trials involving multiple countries, are we going to define a cut point for a pandemic start for each country?   

Officially, WHO declared the Covid-19 as a pandemic on March 11, 2020. But we know that by then, Covid-19 had already spread in so many countries.

If the pandemic start is difficult to define, the cut point for the pandemic end will be even more challenging. Covid-19 may stay with us for a long time (until there is an effective and safe vaccine available).