The South Australian Branch of the Statistical Society would like to invite you to the October meeting of the 2024 program. This is an online-only presentation regarding Estimands in Clinical Trials from Anneke Grobler & Francesca Orsini from the Murdoch Children’s Research Institute.
Date: 31st October (Thursday) 2024
Time: 6:00 – 7:00 pm (Adelaide time) - Zoom access from 5:45 pm
Venue: Online via the following Zoom link:
https://adelaide.zoom.us/j/85988096449?pwd=cY06ggLbZ87NUQy5ssCeeOa002FD4e.1
Join from a PC, Mac, iPad, iPhone or Android device:
Speakers
- Anneke Grobler (Team Leader Clinical Epidemiology & Biostatistics Unit)
- Francesca Orsini (Senior Biostatistician Clinical Epidemiology and Biostatistics Unit)
Topic
Estimands in clinical trials
The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) updated statistical guidance for trials and introduced the estimand framework to align objectives, trial conduct, statistical analysis, and interpretation in randomised clinical trials. An estimand is defined as “the target of estimation to address the scientific question of interest posed by the trial objective”. New to this guidance is the explicit need to consider how intercurrent events will be handled. Intercurrent events are defined as events after randomisation, such as discontinuation of treatment, use of rescue medication or death that may interfere with the estimation of treatment effects.
The guidance provide five strategies to handle intercurrent events, these are the treatment policy, hypothetical, composite, principal component and while on treatment strategies.
In this talk we will give a short introduction to the estimand framework, highlighting what is new. We will then illustrate the use of the estimand framework with a trial recently done in our unit. This was the BRACE trial, that was the winner of the 2024 ACTA STInG Excellence in Trial Statistics Award.
The BRACE (BCG vaccination to Reduce the impact of COVID-19 in healthcare workers following Coronavirus Exposure, by Pittet [BMJ Open 2021;11:e052101]) trial was a phase III, two arm, multicentre, randomised placebo-controlled trial of BCG vaccine to reduce the incidence of COVID-19 in healthcare workers during the coronavirus pandemic. BRACE was stopped prematurely due to the rollout of COVID-19-specific vaccines, affecting the ability of the trial to determine the effectiveness of BCG vaccination in protecting against COVID-19. The aim of this work is to describe potential estimands of interest within the BRACE trial and the effect this has on the estimated efficacy of the BCG vaccination.
The estimand of interest was the difference in the proportion of participants with symptomatic COVID-19 by 6 months between the BCG and placebo arms, estimated using a time-to-event analysis via a flexible parametric survival model (Royston-Parmar model). In the primary analysis, the ICE of receiving a COVID-19 vaccine was handled using a Hypothetical Strategy, to assess the efficacy of BCG if a COVID-19 vaccine had not been found. Under this strategy, participants who received a COVID-19 vaccine had their data censored at the date of their first dose of a COVID-19 vaccine. As supplementary analysis, the same ICE was handled using a Treatment Policy Strategy, including follow-up after COVID-19-specific vaccine.
The estimated treatment effects under the two strategies were similar, but the 95% confidence intervals (CI) were narrower in the supplementary analysis as expected given the additional follow-up information.
The results of this study suggested that the ICE of receiving a COVID-19 vaccine did not alter the efficacy of the BCG vaccine. This case study highlights the importance of the estimand framework in guiding analysis planning, as it helps to specify the research question that the trial is designed to answer, leading to a better understanding of the treatment effect being estimated.
Biographical information
Anneke Grobler has more than 26 years’ experience as a biostatistician, at a contract research organisation, at the Centre for the AIDS Programme of Research in South Africa (CAPRISA), Melbourne University, Murdoch Childrens Research Institute (MCRI) and Victorian Comprehensive Cancer Centre (VCCC). In this capacity she has been involved in study design, manuscript writing, protocol writing, grant application, analysis of randomised clinical trials and epidemiological data and database set-up and management as well as the management of staff members.
Francesca Orsini is a senior biostatistician at the Clinical Epidemiology and Biostatistics Unit (CEBU) at the MCRI, where she has worked since 2011, and a member of the Melbourne Children’s Trials Centre (MCTC). She is involved in the design, planning, conduct, and statistical analysis of clinical trials in fields such as allergy, neonatology, and public health. She provides statistical consultancy, training in clinical research, and mentors students and team members. She collaborates with various research groups at the RCH and MCRI and supervises two junior statisticians within CEBU. Her primary interest is in the design and analysis of clinical trials.
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