How to report clinical trials affected by the COVID-19 pandemic: Dealing with extraordinary circumstances

Based on our experience, common issues and causes of uncertainties include situations where:

• participants could not come to the sites for their visits
• planned assessments were not performed leading to missing data
• participants did not get the trial drug
• participants or trial staff fell ill with COVID-19

But what level of detail do the regulatory authorities expect in the CSR? Where in the report should the information be placed? And which topics are most important to focus on? This article will explore these important areas and provide best practices for a sequential and efficient approach.

The US Food and Drug Administration (FDA) (2) offer high-level recommendations specific to the reporting of data from affected trials in the CSR, recommending that sponsors should describe the following in appropriate sections of the CSR (or in a separate study-specific document):

1. Contingency measures implemented to manage study conduct during disruption of the study as a result of COVID-19 control measures.
2. A listing of all participants affected by the COVID-19 related study disruption by unique trial participant number identifier and by investigational site, and a description of how the individual’s participation was altered.
3. Analyses and corresponding discussions that address the impact of implemented contingency measures (e.g., trial participant discontinuation from investigational product and/or study, alternative procedures used to collect critical safety and/or efficacy data) on the safety and efficacy results reported for the study.

Robust efforts by sponsors, investigators, and IRBs/IECs to maintain the safety of trial participants and study data integrity are expected, and such efforts should be documented.

In addition, TransCelerate BioPharma Inc. have proposed a set of guiding principles published together with comprehensive considerations for reporting clinical studies that have been impacted by COVID-19 (3,4). While additional detail supplementing the FDA guidance is welcome, we acknowledge that this impressive 27-page document can seem overwhelming at first.

Thus, by integrating the high-level FDA guidance with the key points from the detailed TransCelerate BioPharma Inc. principles, we seek to draw out some of the key considerations for what kind of information to include in the CSR for a trial disrupted by the COVID-19 pandemic. We hope this overview can serve as a starting point for CSR authors seeking guidance on how to describe the effect of the COVID-19 pandemic on a clinical trial.

The degree of COVID-19 impact determines the extent of reporting

First and foremost, it is important to evaluate the extent of impact COVID-19 had on the trial. While some trials are only mildly impacted, others may be subject to trial failure or premature termination. The extent of impact will determine the extent of reporting needed.

If a trial was minimally impacted, then the description of the COVID-19 impact should not overshadow the results and conclusions of the trial. This also applies in cases where the impact was more extensive, but could be sufficiently mitigated (e.g., by adjustments of trial conduct) to ensure trial continuity, data integrity and participant safety. In these cases, the description of COVID-19 impact could be confined to a single section or appendix of the CSR. In all cases, best practice will be to present information only in one place, and cross-link to relevant sections or appendices to avoid duplicate descriptions.

In contrast, if the pandemic significantly impacted the trial, leading to trial failure or early termination, the discussion of COVID-19 impact would constitute the main discussion in the CSR, and information about the effects on the pandemic on the trial should be described in all relevant sections throughout the CSR.

Focus CSR on trial conduct, participant safety, and data integrity
Once the extent of reporting has been determined, the next question will be what type of information is required?

The public health measures implemented to control the pandemic have impacted the conduct of clinical trials in numerous ways. Delayed participant enrolment, obstruction of planned assessments, missing data for key endpoints, and disruption of supply chains for investigational medicinal drug (IMP) distribution are just some of the disruptions that could lead to potential new biases in trial data. In addition, COVID-19 illness among participants, and its treatment, could not only put the patients at risk but also potentially introduce bias in the data.

The description of COVID-19 impact in the CSR should cover three key topics:

1. How did the pandemic impact trial conduct, and what was done to mitigate the effect of the pandemic to ensure that the trial could continue?
   – E.g., site closures and conversions of clinic visits to phone visits, remote monitoring, remote source data verification
2. What was done to ensure that it was safe for the participants to continue in the trial?
   – E.g., remote visits instead of clinic visits, requirements for COVID-19 testing
3. How did the implemented emergency procedures affect data quality and trial results?
   – E.g., the extent of missing data and sensitivity analyses performed to analyze the effects of the missing data

Trial conduct

When it comes to describing pandemic-related changes to trial conduct, TransCelerate BioPharma’s prime recommendation is to “tell the story”, that is, provide a narrative description of how COVID-19 impacted the trial, and how the impact was mitigated to ensure that the trial could safely continue

During a major disruption such as a global pandemic, deviations from the original trial plans are inevitable. The description should be forthcoming and transparent, focusing on events and actions that differed from established plans and procedures due to the pandemic. A few examples of pandemic-related disruptions and corresponding considerations for the CSR are summarized below:

For trials that were minimally impacted, or where adjustments and mitigations enabled the trial to continue and conclusions to be drawn, these descriptions could be confined to a self-contained summary in the CSR or an appendix. However, for severely impacted trials, the descriptions of changes to trial conduct may need to be included in the relevant methods sections of the CSR.

COVID-19 related changes to trial conduct will lead to protocol deviations (PDs), and this is expected and acknowledged by health authorities. PDs that impact participant safety and the reliability of results should be identified, documented, and considered when the data are analyzed. PDs may reveal trends in the impact on trial conduct, e.g., in terms of regional differences in COVID-19 impact, differences related to timing of events, and differences between treatment arms. Marking PDs related to COVID-19 will be helpful when summarizing and analyzing the PDs in the CSR.

Participants safety

The efforts to maintain the safety of trial participants during the trial should also be mentioned in the CSR, along with an evaluation of whether these efforts were effective in keeping participants safe. Note that this evaluation is different from the impact of COVID-19 on the safety results of the trial, which should be described as part of the safety evaluation, if relevant (although some overlap may be unavoidable). A few examples of pandemic-related disruptions in relation to patient safety and corresponding considerations for the CSR are outlined below:

Impact	Example – what to consider in the CSR
Reporting timelines	·     Was reporting of serious adverse events delayed or incomplete, and did this have any consequences for the safety of the participants?
Changes to safety assessments	·     How was safety information collected if physical visits were reduced or postponed? ·     Did changes or delays in safety assessments jeopardize the safety of the participants? ·     Did missing safety assessments impair the signal detection in the trial?
Treatment interruptions	·     Did treatment interruptions or discontinuations due to lack of IMP impact the safety of the participants?
COVID-19 illness	·     Were many participants infected with SARS-CoV-2, despite efforts to maintain participant safety?

Data integrity

Trial adjustments and PDs due to the COVID-19 pandemic will inevitably affect the trial data. In the worst cases, the effects of the pandemic could limit the interpretability of the results or lead to objectives not being met. In trials with less severe impact, planned statistical analyses may need to be revised, or additional sensitivity analyses added. In addition, data might be collected from alternative sources such as samples analyzed at local laboratories or assessments done at home or via phone or video.

FDA recommends including a discussion and analysis of the effects of such changes on the efficacy and safety results. But where in the CSR should these analyses and discussions be placed? And what level of detail should be aimed for in the analyzes?

High-level statements related to the trial conclusions can be introduced in a chronological summary of events at the beginning of the CSR, while more detailed analyses should be placed in appropriate sections of the CSR, or in an appendix. The primary and key secondary endpoints should receive the most focus, along with any key safety results that are important for characterizing the study drug.

Changes to objectives, estimands or statistical analyses, and any added sensitivity analyses related to COVID-19 impact should be described in the statistical section of the CSR, addressing whether the changes were defined before or after unblinding.

The extent of missing data due to COVID-19 should also be described in the CSR, along with reasons for why the data is missing. In severely impacted trials, such descriptions could be placed e.g. in the results section, under the endpoint(s) for which the data are missing. Stratifying the information by treatment arm will help in detecting any imbalances across treatment groups in the extent and nature of missing data. If imbalances in missing data have affected aspects of the estimands (i.e., population, treatment, variable, or summary measures), this should be described as well.

COVID-19 illness in trial participants may impact the safety results of a trial, for instance if the distribution of COVID-19 related adverse events (AEs) differ between treatment groups, if a subgroup of the population is more susceptible to severe COVID-19 illness, or if vaccines or treatments for COVID‑19 illness interact with the trial drug. COVID-19 illness can be described in the safety section, along with the other adverse events of the trial. If the adverse event profile of the IMP differs from what is expected due to COVID-19, this should be discussed in the CSR.

In addition to the brief guidance included here, the literature offers further support with strategies to solve statistical issues (5,6). These may be useful for both the CSR author and the trial statistician when reporting a COVID-19 affected trial.

Provide a list of impacted participants
The FDA guidance recommends including a list of all participants affected by pandemic-related trial disruption – including how they were affected – by participant and by site. Producing such a listing may seem like a daunting task, especially for a large trial with many participants.

If records of pandemic-related deviations for each participant have not been kept via dedicated fields in the case report form (CRF), protocol deviations can serve as the source for the participant listing. For instance, a list of all subjects who had one or more on-site visits converted to remote visits can give an indirect overview of missing assessments (and thereby missing data) due to the pandemic. Listings of subjects who discontinued the treatment or the trial due to COVID-19 (whether it be operational reasons or COVID-19 illness) will also be relevant to include.

In Conclusion, the COVID-19 pandemic has created unprecedented challenges in clinical research activities. We have yet to see the full impact of the pandemic on the clinical trials, since many affected trials are now in the reporting phase.

In this article, we have focused on the challenges faced by authors when writing a CSR for an impacted trial. Guidance is also available for how to transparently communicate changes to trials affected by COVID-19 in scientific publications (7).

No two trials are alike, and guidance can never cover every potential issue that might occur. Eventually, it will be up to the individual trial team to identify the most important issues to describe and the level of detail necessary.

The referenced guidelines were developed to manage changes imposed by the COVID-19 pandemic. However, even as the threat of COVID-19 eases, the mitigations for ensuring participant safety and securing trial results will continue to apply – also for clinical trials conducted during other difficult circumstances, such as natural disasters or other major societal disruptions.

How our Medical Writing team can support your needs
We hope this article has been helpful in identifying key points to consider when reporting trials conducted under extraordinary circumstances. If you have questions or need our help reporting your next trial, our experienced medical writing team are at the ready.

Please reach out to us at info@aixial.com

References
1. EMA: Guidance on the management of clinical trials during the covid-19 (coronavirus) pandemic, Version 5 (10/02/2022) https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-10/guidanceclinicaltrials_covid19_en.pdf
2. FDA: Guidance on Conduct of Clinical Trials of Medical Products During the COVID-19 Public Health Emergency. Guidance for Industry, Investigators, and Institutional Review Boards (august 2021). https://www.fda.gov/regulatory-information/search-fda-guidance-documents/fda-guidance-conduct-clinical-trials-medical-products-during-covid-19-public-health-emergency
3. TransCelerate Biopharma Inc: Clinical Study Report Considerations for Studies Disrupted by the COVID-19 Pandemic. https://www.transceleratebiopharmainc.com/wp-content/uploads/2020/06/CTS_ITK-CSR-Considerations-COVID-19-Pandemic-Disrupted-Studies_v002.docx
4. TransCelerate Biopharma Inc.: Clinical Study Report Considerations for Studies Disrupted by the COVID-19 Pandemic – YouTube (webinar)
5. Meyer, D.R., Ratitch, B., Wolbers, M., Marchenko, O., Quan, H., Li, D. Fletcher, C., Li, X., Wright, D., Shentu, Y., Englert, S., Shen, W., Dey, J., Liu, T., Zhou, M., Bohidar, N., Zhao, P-L, & Hale, M.: Statistical Issues and Recommendations for Clinical Trials Conducted During the COVID-19. Statistics in Biopharmaceutical Research, 2020, VOL. 12, NO. 4, 399–411. https://doi.org/10.1080/19466315.2020.1779122
6. FDA: Statistical Considerations for Clinical Trials During the COVID-19 Public Health Emergency Guidance for Industry June 2020. https://www.fda.gov/media/139145/download
7. Perlis, R.H., Haneuse, S.J.P.A., Rubenfeld, G.D., Fihn, S.D., Rivara, F.P.: Reporting Clinical Studies Affected by the COVID-19 Pandemic: Guidelines for Authors. JAMA Netw Open. 2021;4(1). https://doi.org/10.1001/jamanetworkopen.2020.36155

Note that this article is based on the currently available guidance. The text provides points for consideration but is not to be viewed as an exhaustive list or a set of mandatory requirements. The strategy for reporting will depend on the circumstances surrounding the trial in question and should be adapted to the specific situation.