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14 June 2022

Khadija Rantell (MHRA), Asa Hellqvist (AstraZeneca), Nicola Scott (GSK)

COVID 19 presented a variety of challenges in the conduct and analysis of ongoing clinical trials, including additional protocol deviations that lead to increased missing data and the occurrence of unforeseen intercurrent events. This session includes 3 talks covering the following aspects: 1) How regulators approached the acceptability of changes in conduct and handling of missing data or intercurrent event; 2) A case study of a Phase 3 trial where the collection of the primary endpoint was impacted, as well reconsideration being needed of dosing, analyses, data collection and site monitoring; 3) A case study of the development of a treatment for COVID-19, navigating emerging scientific information and evolving regulatory pathways.

Interpretation and translation of clinical trial outcome impacted by COVID-19 pandemic:
COVID 19 presents a variety of challenges in the conduct and analysis of ongoing clinical trials, including additional protocol deviations that lead to increased missing data and the occurrence of unforeseen intercurrent events. In response to these difficulties, regulatory agencies issued guidance on how to assess potential impacts on ongoing clinical trials. This stressed the importance of collecting additional pandemic related data in order to distinguish between pandemic and non-pandemic related intercurrent events and to select an appropriate strategy for handling them. Selecting appropriate statistical analyses, with justifiable and plausible assumptions, is also critical to the delivery of reliable interpretable results targeting an agreed estimand that can be reliably translated into a clinically meaningful and interpretable treatment effect for decision making. In this talk, I will provide examples of trial results impacted by COVID-19 pandemic, describe their approaches to handling intercurrent events and missing data, and provide regulatory feedback on their acceptability.

Delivering a clinical study during a global pandemic: Experiences from the OSTRO nasal polyps study:
The phase III OSTRO trial of Benralizumab in Nasal Polyps was ongoing at the beginning of the COVID pandemic in early 2020. The pandemic restricted the ability of subjects to travel and attend scheduled visits, and it prevented the collection of data. The nasal endoscopy procedures required to collect the co-primary endpoint Nasal Polyp Score (NPS) were put on hold by the sponsor because of the high risk, to both subjects and site staff, of exposure to COVID-19. More than 25% of subjects would miss their primary endpoint due to inability to collect the Week 56 endoscopy. The effort to overcome the difficulties introduced by the pandemic involved reconsidering dosing procedures, statistical analyses, and planned approaches to data collection and site monitoring. We introduced flexibility in dosing and data collection to allow subjects to remain at home. We allowed flexibility for data monitoring without sacrificing study integrity. The statistical testing hierarchy was updated to consider an earlier timepoint for primary testing, which allowed for nearly 100% pre-pandemic contribution from subjects. We also considered other sensitivity analyses to assess the impact of COVID by determining on a subject level when the pandemic first had an impact on their data. While a global pandemic cannot be anticipated, we can still learn lessons from these challenges and solutions. In other trials we have introduced flexibility in operations and planned for statistical sensitivity analyses. In this presentation we will discuss the OSTRO experience and how we learn from it.

Statistical and operational challenges of developing a treatment for COVID-19:
A case study of the development of treatment for COVID-19. A story of navigating the ever changing nature of the COVID-19 pandemic while focusing on the target of delivering a drug to patients as soon as possible; fluctuating background rates of infection, evolving disease knowledge, emerging variants, changing competitive landscape and new regulatory procedures.

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