COVID-19 FDA Response: Guidance on Protocol Amendments and Clinical Study Reports in Affected Ongoing Trials
April 10, 2020
Patricia Edkins, MD, Research Scientist at Rho, has 19 years of experience writing and editing clinical documents for the pharmaceutical industry, including documents supporting submissions, individual clinical studies, and product launches. In addition to her writing background, Dr. Edkins has 17 years of clinical practice experience at an academic medical center and NCI-Designated Comprehensive Cancer Center.
One of the impacts of the COVID-19 pandemic on the conduct of ongoing and planned clinical trials will be the need for protocol modifications to adjust for COVID-19 control measures and COVID-19 illness. The recent FDA Guidance on Conduct of Clinical Trials of Medical Products during the COVID-19 Pandemic offers advice on managing protocol amendments and deviations and documenting changes to the trial.
The FDA recommends that sponsors document all changes to the protocol and the reasons for such changes, in particular, the extent of the changes (duration, subjects affected) and how the changes were related to COVID-19. Subject and staff screening for COVID-19 as required by the local health care authorities does not require a protocol amendment, except when these assessments will be a new part of the research. While institutional review board approval is generally required for protocol amendments, changes to immediately eliminate or reduce subject risk associated with COVID-19 can be made prior to IRB approval, but should be followed as soon as possible by filing of an amendment. The rationale for any changes to the protocol should be documented in all amendments. If an amendment to a study intended to provide efficacy data to support registration requires amending the data management and/or statistical analysis plans, FDA recommends consulting the appropriate review division.
Changes to the trial resulting from the COVID-19 pandemic and the impact on study results should be clearly documented in an ongoing manner and summarized in the clinical study report. Examples of such impacts include subject discontinuations, missing data due to missed visits, changes to the study schedule, and modification of the assessment methods (eg, replacing face-to-face encounters with virtual interactions). Many of these impacts, such as missed visits, may be captured as protocol deviations, whereas others may be documented as changes to the monitoring plan, findings in site visit monitoring reports, or data within the electronic data capture system. If the collection of efficacy assessments for a study intended to provide efficacy support for registration is modified, the FDA recommends consulting the appropriate review division. The clinical study report author should be involved early during the study, eg, writing, or reviewing the protocol and protocol amendments, so that he/she is familiar with the course of events. Following ICH E3 format for clinical study reports, most of the changes incurred by COVID-19 modifications would typically be reported in Section 9.8 (Changes in the Conduct of the Study or Planned Analyses) of the report. For clarity, however, an overview of such changes may be appropriate as a dedicated subsection of Section 9.1 (Overall Study Design and Plan – Description), with more focused comments about changes in specific methodology in the applicable section(s). The impact of changes on reported study results should also be addressed in Sections 10 (Study Patients), 11 (Efficacy Evaluation), and 12 (Safety Evaluation).