Clinical trials conducted during the COVID-19 pandemic have been impacted by public health measures to control the virus. Impacts may include delayed protocol start, trial participants not able to visit clinical sites for assessments, interruptions in supply chain, and entire site closures, to name a few. In June, the FDA released a guidance on Statistical Considerations for Clinical Trials During the COVID-19 Public Health Emergency. Below is a brief summary of the FDA guidance and some examples of activities Rho has undertaken to maintain trial integrity and patient safety in ongoing and upcoming clinical trials.
The main focus points for trial integrity in the guidance document are as follows:
- The statistical analysis plan (SAP) should be updated to reflect any modifications to the analysis of the primary and key secondary endpoints prior to database lock.
- For studies requiring protocol modifications, clinical sponsors must ensure they do not introduce bias by making modifications based on information that reveals the magnitude of the treatment effect. To maintain appropriate safeguards to both trial integrity and patient safety, the FDA recommends the use of Data Monitoring Committees who can assess if a trial may be stopped based on unblinded data.
- Pooled summaries over treatment arms for data such as missing endpoint data, treatment discontinuation, and trial withdrawal should be considered when planning protocol modifications.
The main focus points for trial mitigation and analysis are as follows:
- Data capture should be updated to note if post-baseline events were related to COVID-19 to be incorporated into analysis strategies as needed. This includes discontinuation of treatment, withdrawal from trial, alternative treatments, missing endpoint ascertainment, or alternative methods to endpoint ascertainment.
- Blinded power assessments should be conducted for trials considering stopping early to understand the loss of statistical power from a smaller sample size or less follow-up time.
Highlighted below are a few activities Rho has undertaken to address concerns regarding the impact of COVID-19.
- The statistician identified potential new risks requiring monitoring. For one study, no endpoint data were missing during the Phase 2 study and endpoint ascertainment was originally not an identified risk. However, there are concerns about participants coming to the clinic during the pandemic so an additional Quality Tolerance Limit (QTL) will be measured to monitor endpoint ascertainment.
- Rho conducted blinded power calculations to estimate the level of power to be expected under different scenarios for a trial considering stopping early. This information allowed the Sponsor to make an informed decision regarding the stopping of the trial.
- Rho has worked with Sponsors to review statistical analysis plans (SAPs) to ensure the estimand is appropriately defined with respect to the occurrence of the pandemic and implement updates as appropriate to either modify current analyses or define additional sensitivity analyses.
- Case Report Forms (CRFs) were updated to identify which assessments and visits were missed due to COVID-19 or were collected via an alternative method. CRF updates were also needed to allow for alternative collection methods (e.g. use of a local laboratory versus a central laboratory). These updates are critical to ensure the biostatistician has the appropriate detail to inform analyses.
- Statistical programmers quickly learned new methods for appropriately incorporating flags for missing data due to COVID-19 into SDTM datasets so they would be available for incorporation into ADaM datasets for analyses. CDISC and PHUSE released guidelines with proposed changes and the FDA released an updated conformance guide.
Heather Kopetskie, Director of Biostatistics, has over 16 years of experience in statistical planning, analysis, and reporting. She brings an extensive background of statistical and project leadership experience working on NIH and industry funded clinical trials in all phases of clinical development. Ms. Kopetskie has contributed to the publication of peer reviewed manuscripts and industry publications.