The clinical study report (CSR) is a crucial document in the drug development and regulatory submission process that describes the background, methods, analysis, and results of a clinical trial. CSRs are vital to the regulatory assessment of a drug and form an integral part of any marketing application.
The COVID-19 pandemic has led to substantial, wide‑ranging disruptions to clinical trials. CSRs for clinical trials conducted during the pandemic need to describe how the trial was impacted. This description should cover both the direct effects of the pandemic on study conduct (eg, missed study visits due to COVID‑19 illness or pandemic-related restrictions) and any contingency measures introduced. In addition, any changes in planned statistical analyses should be summarized and discussed in the CSR, and sufficient details need to be provided to enable a reviewer to determine whether any conclusions drawn from the study are valid. It is undeniable that individual trials will have been impacted in many ways, with some trials initiated before the pandemic unable to provide complete results. However, the CSR will still need to describe the course of events and data that are available at the end of the trial. Emerging industry guidance from the FDA, EMA, TransCelerate, and others provide a framework to support reporting results in a clear and robust manner (see recommended reading at end of article for more information). As such, we have compiled below some recommendations that we feel are important when developing CSRs for studies impacted by the pandemic.
Gather Information Sources.
As with all CSRs, the original protocol, protocol amendments, the statistical analysis plan, any notes to file, and study data are key sources for CSRs. A gap analysis for information provided by these sources may help to identify any additional sources required for CSR writing according to the regulatory guidance.
The timeframe and impact of the COVID‑19 pandemic on a single clinical trial will likely vary on regional‑, country‑, site‑, and patient‑levels. Understanding the trial status at the onset of the pandemic, the extent to which contingency measures introduced were implemented, and the quantity and nature of protocol deviations are imperative before the potential impact of the pandemic on the study can be assessed. CSR authors should liaise with study teams at the earliest opportunity to verify that such information will be available in an accessible format to support CSR writing.
For example, a log of trial processes (storyboard) impacted by the pandemic in each country with key dates and links to the corresponding documents in the Trial Master File may be developed. This will be a valuable tool to assess the impact of the pandemic on the study and to prepare the CSR. CSR authors should review any protocol amendments with the statisticians and other study team members to understand how data will be impacted and summarized. Similarly, CSR authors should also review the statistical analysis plan (and any revisions) to ensure any required COVID‑19 listings are planned, including protocol deviation listings. During this review, any additional data tables that are needed to understand the impact of the pandemic on the study should be identified.
Discuss the Approach to CSR Writing.
As the COVID‑19 pandemic may affect almost every aspect of a study, describing its impact could affect every section of a CSR. A balance should be sought to provide sufficient detail that allows a reviewer to assess the impact, without providing so much information that it distracts from the purpose of the study.
Prior to the start of CSR writing, CSR authors should facilitate discussions with the study team (including the study statistician) on the approach to CSR writing. The outcome of these discussions will be driven by the extent to which the pandemic, or the contingency measures implemented, are deemed to have affected the study. For studies where the impact of the pandemic and contingency measures is considered minimal, we suggest including a concise, consolidated account of the impact in ICH E3 Section 9.8 Changes in the Conduct of the Study or in the Planned Analyses. Further detailed information can be included in other study‑specific documents, such as protocol amendments and a revised statistical analysis plan, which should be included in appendices and cross‑referenced from the CSR body. However, for studies significantly impacted by the pandemic (requiring extensive changes to the analyses or interventions in study conduct), it may be appropriate to include detailed descriptions throughout the CSR body. In general, the greater the impact of the pandemic on the study, the greater the detail to be included in the CSR body.
The potential contingency measures implemented due to the COVID‑19 pandemic are wide‑ranging. They may include changes relating to treatment administration, study visit location and schedule, and assessments and procedures to collect and verify data. These changes need to be summarized in the CSR, whether or not they were introduced in a protocol amendment.
Describe, Justify, and Assess the Study Contingency Measures Introduced due to the Pandemic.
The contingency measures introduced need to be summarized and justified. An assessment regarding the extent to which each contingency measure was implemented is fundamental to determining any potential impact of these measures on study outcomes.
Given the varied impact of COVID‑19 on clinical studies across different countries, the likelihood of local contingency measures is high. Thus, subsets of the total trial population—or individual trial participants—may be affected by a particular measure and for different durations at different stages of study participation. If applicable, data summaries visualizing the extent to which trial participants were impacted by the contingency measures may be included in the CSR body or appendix. For example:
- Contingency measures impacting the greatest proportion of trial participants overall and by country
- Proportion of trial participants impacted by the contingency measures deemed to have the greatest potential to bias or confound the study results
- Proportion of trial participants affected by the various contingency measures at the time of data collection for the primary endpoint
These summaries will help to define any potential impact of the contingency measures on study outcomes.
Assess the Data Quality and Protocol Deviations.
The protocol deviations that occurred due to the COVID‑19 pandemic need to be described. This may include a description of any quality tolerance limits (QTLs) exceeded due to the pandemic, along with any remedial actions undertaken.
It is well acknowledged that an increase in protocol deviations is expected due to the COVID‑19 pandemic. The increased incidence of protocol deviations may exceed certain QTLs that were pre-specified as part of the risk assessment and quality management approach prior to study start. However, this increase does not necessarily mean that the study did not adhere to Good Clinical Practice (GCP). For example, certain protocol deviations may have been necessary to immediately minimize or eliminate exposure of research participants to SARS‑CoV‑2. A clear description of the protocol deviations in the CSR will facilitate both an assessment of GCP compliance and the impact of the COVID‑19 pandemic on the study.
Assess and Discuss the Impact of COVID-19 Illness and Contingency Measures on Study Outcomes.
A consolidated summary of the changes made to the analyses due to the COVID‑19 pandemic should be provided, along with a brief description of the changes’ impact.
The changes made to the analyses due to the COVID‑19 pandemic should be summarized and justified in the CSR. This is particularly important for any changes made to the study endpoints and/or estimand framework. Missing data may pose significant challenges for many studies due to missed study visits or discontinuations. The handling of missing data in the primary and secondary analyses should be described and any sensitivity analyses should be presented. For example, analyses assessing the impact of missing data or sources of potential bias. Other relevant analyses may assess the impact of treatment on study outcomes for the pre-, during-, and post-pandemic contingency measure phases. It is important to consider that data summarizing the incidence of COVID-19 illness in trial participants are relevant for inclusion in the CSR body; for example, adverse events and serious adverse events would capture COVID‑19 infection. The discussion and conclusions of the CSR should be concise and address whether the study objectives have been met. Only a brief discussion of the potential impact of the COVID‑19 pandemic on study outcomes may be appropriate so as to avoid over interpreting the data and drawing premature conclusions.
Recommended reading for further guidance.
We recommend visiting these sites (links to the most recent versions at the time of writing this article):
Note: This article describes our current recommendations. These need to be considered together with the current regulations and any advice from regulators and scientific bodies.
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