Under a Black Cloud Glimpsing a Silver Lining: Comment on Statistical Issues and Recommendations for Clinical Trials Conducted During the COVID-19 Pandemic

Hemmings, Rob

doi:10.1080/19466315.2020.1785931

Cited by 10 publications

(13 citation statements)

References 1 publication

(7 reference statements)

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“…An alternative approach is to treat beyond the primary time point so that assessments can be made once site visits are again possible to validate assessments made remotely at the primary time point, or to facilitate modeling of outcomes that would have been observed had it been possible to take a measurement at the primary time point. Other approaches to compensate for lost information can be considered as well, such as leveraging data on short-term endpoint(s) that are correlated with the primary response or to integrate data from external sources, to augment the control arm, or pool trial data (Hemmings 2020 ).…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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 best estimate to use for an event in a label may depend on the event and how it may have been impacted by COVID-19. As noted by Hemmings ( 2020 ), we surely do need to be attentive to the summary metrics used to quantify risks.…”

Section: Quantification Of Risk and Product Labelingmentioning

confidence: 99%

“…We focus on analyzing the observed data. As noted by Hemmings ( 2020 ), with respect to missing safety data, making predictions for toxicities from a statistical model seems difficult and conceptually undesirable.…”

Section: Introductionmentioning

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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“…Another small number of patients were planned to be recruited during (or after) the pandemic. As recommended by Meyer et al, 4 Degtyarev et al, 8 and Hemmings, 9 we will use the estimands framework as outlined in the ICH E9 addendum on estimands and sensitivity analyses 10 to describe and investigate the impact of the COVID-19 pandemic. In the ICH E9 addendum, estimands are defined as a "precise description of the treatment effect reflecting the clinical question posed by a given clinical trial objective," and characterized by the attributes treatment, population, variable of interest, (strategies for handling) intercurrent events and the population-level summary.…”

Section: Introductionmentioning

confidence: 99%

Potential impact of COVID‐19 on ongoing clinical trials: a simulation study with the neurological Yale Global Tic Severity Scale based on the CANNA‐TICS study

Lasch

Guizzaro

Dávila

et al. 2021

Pharmaceutical Statistics

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The COVID‐19 pandemic has manifold impacts on clinical trials. In response, drug regulatory agencies and public health bodies have issued guidance on how to assess potential impacts on ongoing clinical trials and stress the importance of a risk‐assessment as a pre‐requisite for modifications to the clinical trial conduct. This article presents a simulation study to assess the impact on the power of an ongoing clinical trial without the need to unblind trial data and compromise trial integrity. In the context of the CANNA‐TICS trial, investigating the effect of nabiximols on reducing the total tic score of the Yale Global Tic Severity Scale (YGTSS‐TTS) in patients with chronic tic disorders and Tourette syndrome, the impact of the two COVID‐19 related intercurrent events handled by a treatment policy strategy is investigated using a multiplicative and additive data generating model. The empirical power is examined for the analysis of the YGTSS‐TTS as a continuous and dichotomized endpoint using analysis techniques adjusted and unadjusted for the occurrence of the intercurrent event. In the investigated scenarios, the simulation studies showed that substantial power losses are possible, potentially making sample size increases necessary to retain sufficient power. However, we were also able to identify scenarios with only limited loss of power. By adjusting for the occurrence of the intercurrent event, the power loss could be diminished to different degrees in most scenarios. In summary, the presented risk assessment approach may support decisions on trial modifications like sample size increases, while maintaining trial integrity.

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Under a Black Cloud Glimpsing a Silver Lining: Comment on Statistical Issues and Recommendations for Clinical Trials Conducted During the COVID-19 Pandemic

Cited by 10 publications

References 1 publication

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

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

Potential impact of COVID‐19 on ongoing clinical trials: a simulation study with the neurological Yale Global Tic Severity Scale based on the CANNA‐TICS study

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