Question 27

College answer

Not available.

Discussion

a)

• Platform trials are an example of adaptive multiarm multistage trials:
  • Adaptive trials undego regular interim analysis and can change the sample size of the treatment group
  • Multiarm multistage trials are adaptive trials with multiple treatment arms compared against the same control group, with the option of dropping an underperforming arm
  • Platform trials are the same design, but with the option of adding arms and adjusting the size of the control group
• Advantages:
  • "Disease-focused" instead of "intervention-focused
  • Efficient use of study resources (as compared to running an individual trial for each of the interventions in each arm)
  • Avoids redundant duplication of design and infrastructure
  • Easier to compare interventions (instead of comparing between different trials with different methodologies)
  • Resistant to obsolescence: novel developments can be incorporated into the study protocol, maintaining currency 
  • Perpetual: the trial never actually needs to finish; new arms can be added and old arms removed under the same master protocol
  • Minimises the size of the control group: this is ethically better, as trial treatment is being provided to the maximum number of potential beneficiaries
  • A platform trial can declare one treatment superior to the others
  • Interim sample size adjustment can prevent underpowered results
  • Decreased risk of participation: for the patients enrolled, the trial decreases the risk that they will be allocated to a control group (which is smaller) or to an ineffective treatment (which would be dropped from the study). 
• Disadvantages:
  • Data complexity: the added care that is required to manage the responsive randomisation, multiple stages of interim analysis, multiple arms,  the design of a master protocol with longevity - all of these are extremely labour-intensive from a statistical  perspective
  • Administrative complexity: each intervention may have its own corporate sponsor, its own additional consent requirements, and follow-up might be different, making the process of running a platform trial more complex. 
  • No fixed end date: harder to secure funding
  • More difficult to togansie and plan: unsuited for interventions that need to be investigated immediately
  • Nonconcurrent control group could bias the results, for example where the standard of care changes over time

b) Examples from ICU literature are far fewer than the examples from oncology, where these trials are really popular. It is almost certain that most trainees would have put REMAP-CAP down for one of these, but there are a couple of others as well:

• REMAP-CAP
• ASCOT
• RECOVERY
• I-SPY COVID

"Adaptive platform trials: definition, design, conduct and reporting considerations." Nature Reviews Drug Discovery 18, no. 10 (2019): 797-807.

Park, Jay JH, et al. "An overview of platform trials with a checklist for clinical readers." Journal of Clinical Epidemiology 125 (2020): 1-8.

Berry, Scott M., Jason T. Connor, and Roger J. Lewis. "The platform trial: an efficient strategy for evaluating multiple treatments." Jama 313.16 (2015): 1619-1620.

Antonijevic, Zoran, and Robert A. Beckman, eds. Platform trial designs in drug development: umbrella trials and basket trials. CRC Press, 2018.

Pallmann, Philip, et al. "Adaptive designs in clinical trials: why use them, and how to run and report them." BMC medicine 16.1 (2018): 1-15.

Mahajan, Rajiv, and Kapil Gupta. "Adaptive design clinical trials: Methodology, challenges and prospect." Indian journal of pharmacology 42.4 (2010): 201.

Sampson, Allan R., and Michael W. Sill. "Drop‐the‐losers design: normal case." Biometrical Journal: Journal of Mathematical Methods in Biosciences 47.3 (2005): 257-268.

Lee, Kim May, et al. "Statistical consideration when adding new arms to ongoing clinical trials: the potentials and the caveats." Trials 22.1 (2021): 1-10.