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The US Food & Drug Administration (FDA) Guidance on Conduct of Clinical Trials of Medical Products during the COVID-19 Pandemic[2] lists various requirements for COVID-19-related information to be included in the clinical study report (CSR) for clinical trials ongoing at the time of the pandemic. One such requirement is a listing of all of the impacts on study subjects resulting from the pandemic. This section lists discussion points from the guidance that provide insight into those requirements, and recommended approaches to acquiring and representing the associated data. Because each sponsor collects and manages data differently, it is impossible to specify how to gather all possible data; rather, it outlines data that may need to be gathered. For example, some sponsors may have a flag in the electronic data collection (EDC) system to indicate when a visit did not occur, whereas others may include this on a CRF and still others may derive it from monitoring information. Regardless of how the information is obtained, the COVID-19-related listing(s) must include what visits were missed and why.

FDA GuidanceCDISC COVID-19 Interim User GuideAssociated Domains
The Introduction of the guidance discusses how restrictions related to COVID-19 may lead to changes in study conduct, and states the need to document the changes, their durations, and which trial participants were affected.The Introduction to the guidance does not provide specifics on how or where the documentation should happen (e.g., documentation could reside in the site's files and not necessarily appear in collected data).  n/a

The Discussion section provides an overview of process, data, and analysis changes that may be needed for ongoing studies. 

Per Section III.B, when data are missing due to COVID-19-related reasons, both the data that was missed and the pandemic-associated reason must be clearly noted on the CRF.

Section III.B provides context for the specifics listed in Section III.C.

For missing protocol-specified information, the preference is to capture subject-level data on a CRF. If this is not possible, data can be captured systematically across sites in a way that allows the regulatory body to analyze its impact. See the Protocol Deviations, Missed Visits, and Missed Assessments sections for direction.

The domain-specific information on missing data will primarily appear in the domains, using standard variables such as --STAT and --REASND, and non-standard variables such as --REASOC and others proposed in this guide (see Appendix A, Non-standard Variables (NSVs)). 

When visits are missed, a different solution is needed. Advantages and disadvantages of these approaches are discussed in Missed Visits. How data are acquired to populate each of these depends upon how the sponsor's data capture is set up. Extending the Subject Visits (SV) domain was considered, but this approach was rejected because the model does not allow additional standard or NSVs in that domain.

If data on site-level reasons for missing information are captured in such a way that individual subjects affected could be identified, the effects of site-level disruptions on individual subjects can be represented in SDTM-based datasets.

VE (Visit Events; interim custom)

DV (Protocol Deviations)

Section III.C describes specific information to be included in the CSR, including

  • the contingency measures implemented during study disruption,
  • a listing of all participants affected by COVID-19-related study disruptions and specifics about how participation was disrupted,
  • analyses and discussions addressing the impact of implemented contingency measures on safety and efficacy, and
  • protocol deviations and specific reasons for them.

For the information required in Section III.C:

  • Contingency measures would be derived from protocol amendments, addenda to monitoring guidelines, data management plans, and documentation in the trial master file. Because some of this may come from the sponsor's administrative database content, it is probably not related to CDISC standards.
  • The listing of participants affected by COVID-19-related disruptions will probably be a highly derived compilation of data from many different domains, the specific content of which will depend on the data in the study. The domains that are most likely to be impacted by the COVID-19 pandemic are addressed in this interim guide.
  • A significant concern when processes or data are changed during a study is the potential impact on the primary outcome. Impacts will vary greatly from study to study, and analyses to address these impacts are beyond the scope of this interim guide.
  • COVID-19-related reasons for protocol deviations are modeled in Protocol Deviations. The FDA guidance[2] states that reasons must be specific. This is interpreted to mean that "Visit missed due to pandemic" is not sufficient, but rather "Visit missed due to patient's lack of transportation related to pandemic." An NSV has been added to make it easier to identify records that are related to the pandemic.

DV (Protocol Deviations)

DS (Disposition)

DA (Product Accountability)

PR (Procedures)

AE (Adverse Events)

EC/EX (Exposure as Collected/ Exposure)

ST (Site Transfer; custom domain)

Any/all domains holding data which may be missed due to the pandemic

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