Clinical Trials Impacted by the COVID-19 Pandemic: Adaptive Designs to the Rescue?

Kunz, Cornelia Ursula; Jörgens, Silke; Bretz, Frank; Stallard, Nigel; Lancker, Kelly Van; Xi, Dong; Zohar, Sarah; Gerlinger, Christoph; Friede, Tim

doi:10.1080/19466315.2020.1799857

Cited by 41 publications

(45 citation statements)

References 58 publications

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“…However, DMCs have of course an important role to play in trials in non-COVID-19 diseases that are impacted by the SARS-CoV-2 pandemic. However, they should not be involved in decisions on any design changes if they have been exposed to unblinded (comparative) data [ 76 , 77 ].…”

Section: Discussionmentioning

confidence: 99%

Data monitoring committees for clinical trials evaluating treatments of COVID-19

Mütze

Friede

2020

Contemporary Clinical Trials

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The first cases of coronavirus disease 2019 (COVID-19) were reported in December 2019 and the outbreak of SARS-CoV-2 was declared a pandemic in March 2020 by the World Health Organization. This sparked a plethora of investigations into diagnostics and vaccination for SARS-CoV-2, as well as treatments for COVID-19. Since COVID-19 is a severe disease associated with a high mortality, clinical trials in this disease should be monitored by a data monitoring committee (DMC), also known as data safety monitoring board (DSMB). DMCs in this indication face a number of challenges including fast recruitment requiring an unusually high frequency of safety reviews, more frequent use of complex designs and virtually no prior experience with the disease. In this paper, we provide a perspective on the work of DMCs for clinical trials of treatments for COVID-19. More specifically, we discuss organizational aspects of setting up and running DMCs for COVID-19 trials, in particular for trials with more complex designs such as platform trials or adaptive designs. Furthermore, statistical aspects of monitoring clinical trials of treatments for COVID-19 are considered. Some recommendations are made regarding the presentation of the data, stopping rules for safety monitoring and the use of external data. The proposed stopping boundaries are assessed in a simulation study motivated by clinical trials in COVID-19.

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Section: Discussionmentioning

confidence: 99%

Data monitoring committees for clinical trials evaluating treatments of COVID-19

Mütze

Friede

2020

Contemporary Clinical Trials

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“…Also, Kunz et al. ( 2020 ) discussed the use adaptive designs to combine information across stages (e.g., pre-/during/post-pandemic) and/or to allow for unplanned mid-trial modifications to respond to the pandemic. The use of these and other methods will benefit from additional scientific discussions and regulatory guidance.…”

Section: Additional Statistical Considerationsmentioning

confidence: 99%

“…This power calculation was independently also developed by Kunz et al. ( 2020 ). With our agreement, the app now also incorporates various extensions, for example, to group sequential designs as described in Friede and Henderson ( 2009 ).…”

Section: Additional Statistical Considerationsmentioning

confidence: 99%

Challenges in Assessing the Impact of the COVID-19 Pandemic on the Integrity and Interpretability of Clinical Trials

Akacha

Branson

Bretz

et al. 2020

Statistics in Biopharmaceutical Research

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The COVID-19 pandemic has a global impact on the conduct of clinical trials of medical products. This article discusses implications of the COVID-19 pandemic on clinical research methodology aspects and provides points to consider to assess and mitigate the risk of seriously compromising the integrity and interpretability of clinical trials. The information in this article will support discussions that need to occur cross-functionally on an ongoing basis to "integrate all available knowledge from the ethical, the medical, and the methodological perspective into decision making. " This article aims at facilitating: (i) risk assessments of the impact of the pandemic on trial integrity and interpretability; (ii) identification of the relevant data and information related to the impact of the pandemic on the trial that needs to be collected; (iii) short-term decision making impacting ongoing trial operations; (iv) ongoing monitoring of the trial conduct until completion, including the possible involvement of data monitoring committees, and adequately documenting all measures taken to secure trial integrity throughout and after the pandemic, and (v) proper analysis and interpretation of the eventual interim or final trial data.

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“…Kunz et al. ( 2020 ) provide a detailed discussion of these considerations and methods for resizing trials along with an R Shiny tool that implements the methods in the context of COVID-19.…”

Section: Data Collection and Assessing Covid-19 Impactmentioning

confidence: 99%

Clinical Trial Drug Safety Assessment for Studies and Submissions Impacted by COVID-19

Nilsson

Crowe

Anglin

et al. 2020

Statistics in Biopharmaceutical Research

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– In this article, we provide guidance on how safety analyses and reporting of clinical trial safety data may need to be modified, given potential impact from the COVID-19 pandemic. Impact could include missed visits, alternative methods for assessments (such as virtual visits), alternative locations for assessments (such as local labs), and study drug interruptions. Starting from the safety analyses typically included in Clinical Study Reports for Phase 2-4 clinical trials and integrated submission documents, we assess what modifications might be needed. If the impact from COVID-19 affects treatment arms equally, analyses of adverse events from controlled data can, to a large extent, remain unchanged. However, interpretation of summaries from uncontrolled data (summaries that include open-label extension data) will require even more caution than usual. Special consideration will be needed for safety topics of interest, especially events expected to have a higher incidence due to a COVID-19 infection or due to quarantine or travel restrictions (e.g., depression). Analyses of laboratory measurements may need to be modified to account for the combination of measurements from local and central laboratories.

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Clinical Trials Impacted by the COVID-19 Pandemic: Adaptive Designs to the Rescue?

Cited by 41 publications

References 58 publications

Data monitoring committees for clinical trials evaluating treatments of COVID-19

Data monitoring committees for clinical trials evaluating treatments of COVID-19

Challenges in Assessing the Impact of the COVID-19 Pandemic on the Integrity and Interpretability of Clinical Trials

Clinical Trial Drug Safety Assessment for Studies and Submissions Impacted by COVID-19

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