Missing Clinical Trials Data During a Pandemic

Registrations have now closed. A recording will be made available soon!

Featuring: Professor James Carpenter,
Programme Leader in Methodology (MRC Clinical Trials Unit, LSHTM)

PHASTAR are recognized as world-leaders in clinical study design and analysis, and their expertise has been much sought after during the current COVID-19 global pandemic.

Due to the unprecedented impact of the COVID-19 pandemic on clinical activities, many randomized clinical trials have been affected. This is a result of the pandemic’s high infection and morbidity rates causing patients to drop out of the trial or not being evaluated on time, the immense strain being put on healthcare services limiting their ability to collect study data, and the concern of the spread of infection during patient testing and evaluation.

The resulting large amount of missing data must be addressed in ongoing clinical trials and now needs to be considered in the design of any new studies.

To investigate this hot issue, PHASTAR held a webinar on Thursday December 16th to review a four step-strategy for handling outcome data in randomised trials affected by a pandemic presented by Professor James Carpenter, Programme Leader in Methodology, MRC Clinical Trials Unit, at the London School of Hygiene and Tropical Medicine.

Thanks to all those who attended. A recording has been made available here!

Blog series

How the COVID-19 Pandemic has Affected Clinical Trials

The World Health Organisation (WHO) declared COVID-19 a global pandemic on 11th March 2020 and the subsequent restrictions on everyday life caused significant disruption to clinical trials. The full extent of the impact of COVID-19 will not be known for some time but the effect on clinical trials will most certainly be significant. Although sponsors have been quick to make changes to clinical trials there will undoubtably still be many issues to address. The range of disruptions of COVID-19 to clinical trials are expected to be so diverse that no single solution will be appropriate for all trials. It is likely that each trial will need to be assessed on a case-by-case basis, although there will be many common issues. It is critical for sponsors and regulators to work together and make the best use of clinical trials affected by COVID-19. Collaboration and sharing of learnings during the pandemic are going to be vitally important for a long time to come.

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The Effect of COVID-19 on the Estimands of Clinical Trials

If it is safe for a trial to continue, it is important to understand and mitigate against the impact of the pandemic. For all clinical trials affected by the COVID-19 pandemic, the first step should be to perform a risk assessment to assess the impact to the trial and the ability of the trial to still meet its planned objectives. In blinded trials, the risk assessment should be performed on blinded data. This is an ongoing process and should be conducted on a regular basis throughout the duration of the trial. Once the risks are understood, contingency measures/mitigation can then be looked at. It will be necessary to document any changes made to the trial in the protocol and the statistical analysis plan (SAP) and the impact of COVID-19 will need to be addressed in the clinical study report (CSR). It is recommended to discuss and interact with regulatory agencies as early as possible.

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Assessing The Impact of COVID-19 on a Clinical Trial

The safety of trial participants and all staff involved remains the primary concern in all clinical trials. The key message has always been (and remains) that clinical trials are critical and should continue during the COVID-19 pandemic, if it was safe to do so.

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Missing Data Caused by the COVID-19 Pandemic on Clinical Trials – Overall Approach

It is generally accepted that there will be an increased amount of missing data in most clinical trials due to the COVID-19 pandemic. Missing data should be anticipated and the appropriate methods of dealing with it need to be in place. Missing data and premature termination are not new to statisticians and well-established methods exist on how to deal with these issues, but the disruptions of the COVID-19 pandemic to clinical trials are expected to be so diverse that no single solution will be appropriate for all trials.

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Case study

Missing Data in COVID Adverse Events

Much of the discussion around adverse events (AEs) and serious adverse events (SAEs) in clinical trials through the COVID-19 pandemic has been focussed AEs associated with new therapies and vaccines for COVID-19 itself. But what about other clinical trials that have been impacted by COVID-19? We have already explored the many ways in which the COVID-19 pandemic has affected the conduct, analysis, and interpretation of clinical trials with respect to efficacy data. We have discussed how global quarantines and travel restrictions have resulted in site closures and interruptions to investigational product supply, which have subsequently resulted in issues such as missed assessments and treatment interruptions. But how might these issues also affect safety data?

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Webinar: A four-step strategy for handling missing outcome data in randomised trials affected by a pandemic

Featuring: Professor James Carpenter,
Programme Leader in Methodology (MRC Clinical Trials Unit, LSHTM)

Professor Jennifer Rogers,
VP, Statistical Research & Consultancy (PHASTAR)

Thursday 16th December
16:00 GMT | 11:00 EST | 08:00 PST

Image of Professor James Carpenter

Professor James Carpenter

Image of Professor Jennifer Rogers - VP, Statistical Research & Consultancy

Professor Jennifer Rogers

The coronavirus pandemic (Covid-19) presents a variety of challenges for ongoing clinical trials, including an inevitably higher rate of missing outcome data, with new and non-standard reasons for missingness. International drug trial guidelines recommend trialists review plans for handling missing data in the conduct and statistical analysis, but clear recommendations are lacking.

We present a four-step strategy for handling missing outcome data in the analysis of randomised trials that are ongoing during a pandemic. We consider handling missing data arising due to (i) participant infection, (ii) treatment disruptions and (iii) loss to follow-up. We consider both settings where treatment effects for a ‘pandemic-free world’ and ‘world including a pandemic’ are of interest.

In any trial, investigators should; (1) Clarify the treatment estimand of interest with respect to the occurrence of the pandemic; (2) Establish what data are missing for the chosen estimand; (3) Perform primary analysis under the most plausible missing data assumptions followed by; (4) Sensitivity analysis under alternative plausible assumptions. To obtain an estimate of the treatment effect in a ‘pandemic-free world’, participant data that are clinically affected by the pandemic (directly due to infection or indirectly via treatment disruptions) are not relevant and can be set to missing. For primary analysis, a missing-at-random assumption that conditions on all observed data that are expected to be associated with both the outcome and missingness may be most plausible. For the treatment effect in the ‘world including a pandemic’, all participant data is relevant and should be included in the analysis. For primary analysis, a missing-at-random assumption – potentially incorporating a pandemic time-period indicator and participant infection status – or a missing-not-at-random assumption with a poorer response may be most relevant, depending on the setting. In all scenarios, sensitivity analysis under credible missing-not-at-random assumptions should be used to evaluate the robustness of results. We highlight controlled multiple imputation as an accessible tool for conducting sensitivity analyses.

Missing data problems will be exacerbated for trials active during the Covid-19 pandemic. This four-step strategy will facilitate clear thinking about the appropriate analysis for relevant questions of interest.

For more information see Professor Carpenter's paper here.

To sign up for the webinar click here.

Meet the speakers

Professor James Carpenter
Programme Leader in Methodology (MRC Clinical Trials Unit, LSHTM)

A Professor of Medical Statistics, James leads the Methodology Analysis programme at the MRC Clinical Trials Unit, London School of Hygiene & Tropical Medicine, and has interests across the Methodology theme. The motivation for his research is finding practical methodological solutions to challenges in Phase III clinical trials and observational research, principally: choosing the appropriate estimand for a trial, practical approaches for exploring and communicating the sensitivity of trial results to a range of appropriate assumptions about the missing outcome data, statistical methods in meta-analysis, and using routinely collected health care data to inform trial outcome measures.

Professor Jennifer Rogers
VP, Statistical Research & Consultancy (PHASTAR)

Jen joined PHASTAR as Head of Statistical Research in August 2019, following a move from the University of Oxford where she was Director of Statistical Consultancy Services and an Associate Professor in the Department of Statistics. She had previously worked as a Post-Doctoral Research Fellow in the Department of Statistics funded by the National Institute of Health Research. Formerly Vice President for External Affairs at the RSS and now a member of its COVID-19 task force, Jen directs the statistical research strategy helping the company stay at the cutting edge of new methodological advances.

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