General considerations about adaptive trials

Resources

Tutorial papers

There are some easy-to-read papers discussing the concept of adaptive designs and real-life case studies as well as general practical considerations:

  • Burnett et al.   Adding flexibility to clinical trial designs: an example-based guide to the practical use of adaptive designs. BMC Med. 2020;18(1):352. 
  • Pallmann et al. Adaptive designs in clinical trials: why use them, and how to run and report them. BMC Med. 2018;16:29.
  • Park et al. Critical concepts in adaptive clinical trials. Clin Epidemiol. 2018;10:343–51. 
  • Thorlund et al. Key design considerations for adaptive clinical trials: A primer for clinicians. BMJ. 2018;p. k698 
  • Stallard et al. Efficient adaptive designs for clinical trials of interventions for COVID-19. Stat Biopharm Res. 2020;1–26. 
  • Porcher et al. Adaptive methods: when and how should they be used in clinical trials? Therapie. 2011;66:319–26.
  • Crawford et al. Adaptive clinical trials in stroke. Stroke. 2024.
  • Ciolino et al. Guidance on interim analysis methods in clinical trials. J Clin Transl Sci. 2023.

Easy-to-read books with case studies

These are some of non-technical and practical oriented books suitable for multidisciplinary audience. They also cover useful real-life case studies and considerations when using adaptive designs:

  • Rosenberg. The agile approach to adaptive research: optimizing efficiency in clinical development. John Wiley & Sons, Inc. 2010 
  • He et al. Practical considerations for adaptive trial design and implementation. Springer. 2014

Statistical books

These are some of the available books for statisticians who may want to know about about statistical issues around adaptive methods:

  • Proschan et al. Statistical monitoring of clinical trials - A unified approach. Springer. 2006
  • Wassmer et al. Group sequential and confirmatory adaptive design in clinical trials. Springer. 2016
  • Whitehead. The design and analysis of sequential clinical trials. John Wiley & Sons Ltd. 2000

Guidance for adequate costing of adaptive trials

Wason et al. Practical guidance for planning resources required to support publicly-funded adaptive clinical trials. BMC Med. 2022.

Guidance on statistical simulation

Mayer et al. Simulation practices for adaptive trial designs in drug and device development. Stat Biopharm Res. 2019;11(4):325–35.

Guidance for developing trial protocols

The SPIRIT-DEFINE 1 provides a consensus-driven guidance for researchers when developing a protocol for early phase dose-finding trials with dose escalation or/and de-escalation strategies (trial adaptations) which may or may not be randomised.  Another methods guidance was developed in the context of early phase trials 2,  but the guiding principles are similar so it can be easily adapted and used to inform the development of protocols in late phase adaptive trials.

Finally, although in principle, the ACE guidance 3 is intended for reporting trial results, it can be used to mirror the development of a robust adaptive trial protocol. That is, if researchers know what to expect when reporting results, then they can use that knowledge to pre-plan robust methods in protocols to address reporting expectations in the future.

References

1. Yap et al. Enhancing quality and impact of early phase dose-finding clinical trial protocols: SPIRIT Dose-finding Extension (SPIRIT-DEFINE) guidance. BMJ. 2023 Oct 20;383:e076386.
2. Lorch et al. Three steps to writing adaptive study protocols in the early phase clinical development of new medicines. BMC Med Res Methodol. 2014;14:1–9. 
3. Dimairo et al. The Adaptive designs CONSORT Extension (ACE) statement: a checklist with explanation and elaboration guideline for reporting randomised trials that use an adaptive design. BMJ. 2020;369:m115.

Guidance for conducting timely and robust interim analyses

Coming soon ...!

Guidance for reporting results from an adaptive trial

Researchers are encouraged to use the official CONSORT extension for randomised adaptive trials 1, 2. This Adaptive designs CONSORT Extension (ACE) is publicly accessible via several platforms:

A related reporting guidance for early phase dose-finding trials with dose escalation or/and de-escalation strategies (trial adaptations), which may or may not be randomised exists 3.

References

1. Dimairo et al. The Adaptive designs CONSORT Extension (ACE) statement: a checklist with explanation and elaboration guideline for reporting randomised trials that use an adaptive design. BMJ. 2020;369:m115.
2. Dimairo et al. The adaptive designs CONSORT extension (ACE) statement: a checklist with explanation and elaboration guideline for reporting randomised trials that use an adaptive design. Trials. 2020;21(1):528.
3. Yap et al. Enhancing reporting quality and impact of early phase dose-finding clinical trials: CONSORT Dose-finding Extension (CONSORT-DEFINE) guidance. BMJ. 2023;383:e076387.

Regulatory guidance

FDA. Adaptive designs for clinical trials of drugs and biologics. Guidance for Industry. 2019. 

Online resources


ACTA Innovative Trial Design



Open access statistical resources

Anderson statistical software resources

Offers a very useful list of statistical software (and access to that software) that can be used to design and conduct adaptive clinical trials in various trial phases.
 

MEDIANA Adaptive Designs Toolkit

The R package (MedianaDesigner) supports simulation-based power and sample size calculations for a broad class of late-stage clinical trials, including adaptive dose-finding phase II and confirmatory phase III trials. The following adaptive designs are currently supported: 

  • phase II trials with response-adaptive randomisation, 
  • phase III trials with data-driven sample size or event count re-estimation, 
  • phase III trials with data-driven treatment selection, 
  • phase III trials with data-driven population selection. 
The package enables efficient clinical trial simulations for most commonly used types of trial designs; e.g., phase III designs with one or two interim analyses, and emphasizes user-friendly features such as the availability of a graphical user interface (shiny-based applications) and comprehensive simulation reports (Microsoft Word documents).
 
 For more information about the package, as well as the online manual with case studies and technical documentation. A ten-part online training course with a general introduction to adaptive designs, a review of relevant statistical and regulatory considerations, case studies, and instructional videos for the software is available at Mediana’s YouTube channel.