Group sequential designs in pragmatic trials: feasibility and assessment of utility using data from a number of recent surgical RCTs

Nick R Parsons* (Corresponding Author), Nigel Stallard, Helen Parsons, Aminul Haque, Martin Underwood, James Mason, Iftekhar Khan, Matthew L Costa, Damian R Griffin, James Griffin, David J Beard, Jonathan A Cook, Loretta Davies, Jemma Hudson, Andrew Metcalfe

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)
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Abstract

BACKGROUND: Assessing the long term effects of many surgical interventions tested in pragmatic RCTs may require extended periods of participant follow-up to assess effectiveness and use patient-reported outcomes that require large sample sizes. Consequently the RCTs are often perceived as being expensive and time-consuming, particularly if the results show the test intervention is not effective. Adaptive, and particularly group sequential, designs have great potential to improve the efficiency and cost of testing new and existing surgical interventions. As a means to assess the potential utility of group sequential designs, we re-analyse data from a number of recent high-profile RCTs and assess whether using such a design would have caused the trial to stop early.

METHODS: Many pragmatic RCTs monitor participants at a number of occasions (e.g. at 6, 12 and 24 months after surgery) during follow-up as a means to assess recovery and also to keep participants engaged with the trial process. Conventionally one of the outcomes is selected as the primary (final) outcome, for clinical reasons, with others designated as either early or late outcomes. In such settings, novel group sequential designs that use data from not only the final outcome but also from early outcomes at interim analyses can be used to inform stopping decisions. We describe data from seven recent surgical RCTs (WAT, DRAFFT, WOLLF, FASHION, CSAW, FIXDT, TOPKAT), and outline possible group sequential designs that could plausibly have been proposed at the design stage. We then simulate how these group sequential designs could have proceeded, by using the observed data and dates to replicate how information could have accumulated and decisions been made for each RCT.

RESULTS: The results of the simulated group sequential designs showed that for two of the RCTs it was highly likely that they would have stopped for futility at interim analyses, potentially saving considerable time (15 and 23 months) and costs and avoiding patients being exposed to interventions that were either ineffective or no better than standard care. We discuss the characteristics of RCTs that are important in order to use the methodology we describe, particularly the value of early outcomes and the window of opportunity when early stopping decisions can be made and how it is related to the length of recruitment period and follow-up.

CONCLUSIONS: The results for five of the RCTs tested showed that group sequential designs using early outcome data would have been feasible and likely to provide designs that were at least as efficient, and possibly more efficient, than the original fixed sample size designs. In general, the amount of information provided by the early outcomes was surprisingly large, due to the strength of correlations with the primary outcome. This suggests that the methods described here are likely to provide benefits more generally across the range of surgical trials and more widely in other application areas where trial designs, outcomes and follow-up patterns are structured and behave similarly.

Original languageEnglish
Article number256
Number of pages18
JournalBMC Medical Research Methodology
Volume22
Issue number1
DOIs
Publication statusPublished - 1 Oct 2022

Bibliographical note

Funding
The work reported here is funded by the Efficacy and Mechanism Evaluation (EME) Programme, an MRC and NIHR partnership. The funding body had no other role in the work reported here and played no part in writing the manu- script. The views expressed in this publication are those of the authors and not necessarily those of the funding body or the MRC, NIHR or the UK Department of Health and Social Care.

Data Availability Statement

The data summaries and code written as part of this study are available from the corresponding author on reasonable request.

Keywords

  • Data Collection
  • Feasibility Studies
  • Humans
  • Medical Futility
  • Records
  • Sample Size

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