Cytel's Response: FDA Guidance on Conduct of Clinical Trials during the COVID-19 Pandemic

March 19, 2020

The FDA issued a guidance yesterday on how the COVID-19 Pandemic may affect the conduct of clinical trials. Below are some key messages from the guidance along with some interpretations and recommendations.

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Link to the full FDA Guidance.

Completing Data Collection

Selected FDA Guidance

Since trial participants may not be able to come to the investigational site for protocol-specified visits, sponsors should evaluate whether alternative methods for safety assessments (e.g., phone contact, virtual visit, alternative location for assessment, including local labs or imaging centers) could be implemented when necessary and feasible, and would be sufficient to assure the safety of trial participants.

Interpretations and Recommendations

Consider alternative endpoints for evaluation.

Use blinded forecasting techniques to predict delays to enrolment, and subsequent impact on trial timelines.

Evaluate the comparability of data obtained digitally or virtually vs with “traditional” approaches.

Implement secure digital data elicitation methods.

Amend data management plans for new data sources.

Evaluate the impact of modification on safety analyses and amend protocol and SAP for the discussion with FDA.

Plan for regulatory interactions in the context of the updated methods.

Handling Missing Information

Changes in study visit schedules, missed visits, or patient discontinuations may lead to missing information (e.g., for protocol-specified procedures). It will be important to capture specific information in the case report form that explains the reasons for the missing data, including the relationship to COVID-19 for missing protocol-specified visits/procedures. This information, summarized in the clinical study report, will be helpful to the sponsor and FDA.


Develop procedures to capture additional COVID-19 information to help interpret missing data case.

In accordance with ICH E9 (R1) assess whether any impact due to COVID-19 needs to be considered as an intercurrent event, and what strategies should be used to handle it in order to estimate the treatment effects of interest.

If appropriate, assess alternative ways of obtaining elements of missing data e.g., surveys, ‘virtual’ visits, e-health data).

Amend statistical section of the protocol to specify handling of missing data and update statistical analysis plan appropriately.

Consider supplementary analyses using historical clinical trial data or real-world data to support assessment of the impact of missing data elements.

Amend data management plans for new data and new data sources.

Run simulations to prepare for regulatory interactions regarding missing data management with FDA.

Protocol Modifications for Efficacy Assessments

With respect to efficacy assessments, FDA recommends consultation with the appropriate review division regarding protocol modifications for the collection of efficacy endpoints, such as use of virtual assessments, delays in assessments, and alternative collection of research-specific specimens, if feasible.

Evaluate the impact of modifications on efficacy analysis and amend the protocol and SAP for discussion with FDA.


Propose strategies to preserve statistical rigor of the trial.


Implement secure digital data elicitation methods.


Amend data management plans for new data sources.


Consider supplementary analyses exploring the consistency of trial results pre and post any study changes (known or otherwise) due to COVID-19.


Consider design strategies which can help overcome the issue of missing visits and discuss with the appropriate review division.

Amendments to Data Management and Statistical Analysis Plan

If changes in the protocol will lead to amending data management and/or statistical analysis plans, the sponsor should consider doing so in consultation with the applicable FDA review division. Prior to locking the database, sponsors should address in the statistical analysis plan how protocol deviations related to COVID-19 will be handled for the prespecified analyses.


Consult FDA to agree on amendments and revise the statistical analysis plan accordingly.


Consider supplementary analyses using historical clinical trial data or real-world data to support assessment of the impact of missing data elements.


Consider unplanned Interim Analysis and Adaptations for trials with advanced recruitment to evaluate predictive power and whether the trial should be stopped early rather than modified or prolonged.


Consider Bayesian borrowing from historical data to counter trial delays, dropouts and missing data.

 

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Link to the full FDA Guidance.

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