In the rapidly evolving field of clinical research, adaptive trials have been heralded as a significant innovation, with the potential to make the development of desperately needed treatments more efficient. However, a new systematic survey published in the Journal of Clinical Epidemiology highlights the current shortcomings of these trials and underscores the need for methodological improvements.

DOI: 10.1016/j.jclinepi.2024.111257

The study, led by a team at the West China Hospital’s Institute of Integrated Traditional Chinese and Western Medicine, examined the design, conduct, and analysis of adaptive trials to provide a comprehensive review and guidelines for future research. Adaptive trials are characterized by a pre-planned, dynamic structure that allows for modifications to the trial after commencement without undermining its integrity or validity. These modifications can include dosage changes, sample size adjustments, or a switch in the primary outcome based on interim results.

The survey, spearheaded by researchers Yuning Wang, Minghong Yao, and their colleagues, included 128 trials from databases including MEDLINE, EMBASE, and ClinicalTrials.gov up until January 2020. Wang and her co-authors identified the primary motivation for using an adaptive design: to speed up the trial process and aid in decision-making.

Three methods, in particular, were prevalent: group sequential design (GSD), adaptive dose-finding design (ADFD), and adaptive randomization design (ARD). However, the study found that while these designs are widely used, many trials failed to follow best practices, particularly regarding appropriate documentation and protocol adherence.

Key Findings

Gap in Documentation: Over half of the trials did not state the accessibility of key supporting documents.
Lack of Independent Oversight: Two-thirds of the trials did not mention the existence of independent data monitoring committees (IDMCs).
Issues with Interim Analysis: Details on interim analysis were infrequently reported, and many trials didn’t provide explicit reasons for selecting different outcomes to those originally planned for these analyses.
Unplanned Adjustments: One-sixth of the trials made unplanned changes during their execution.

To address these challenges, the study offered 14 recommendations for enhancing the design, conduct, and analysis of adaptive trials. Among these, the authors underscore the establishment of IDMCs, improved transparency and documentation, and rigorous pre-trial planning to minimize unplanned adjustments.

The ramifications of these suggestions may extend far beyond the sphere of clinical methodology. For patients and stakeholders, improvements in the adaptive trial process potentially mean quicker access to new therapies and greater confidence in the results of such trials.

As per the authors, the recommendations aim to serve as a resource for clinical trialists, offering both general advice and specific guidance. They urge researchers to heed these insights to carefully design, conduct, and analyze adaptive trials.

Implications for the Clinical Research Community

The findings call attention to a significant gap that exists between the potential efficiencies offered by adaptive trials and the sometimes lax adherence to methodological rigour in their execution. With numerous new drugs and therapies entering trials annually, the need to refine these processes is urgent. Improving the design and oversight of adaptive trials can reduce costs, enhance patient safety, and potentially bring life-saving treatments to market faster.

References

1. Yuning Wang, Minghong Yao, Jiali Liu, Yanmei Liu, Yu Ma, Xiaochao Luo, Fan Mei, Hunong Xiang, Kang Zou, Xin Sun, and Ling Li. “A systematic survey of adaptive trials shows substantial improvement in methods is needed.” Journal of Clinical Epidemiology, 2024 Jan 11. DOI: 10.1016/j.jclinepi.2024.111257

The cornerstone article reporting the systematic survey.

2. Chow, S.-C., Chang, M. (2008). “Adaptive Design Methods in Clinical Trials – A Review.” Orphanet Journal of Rare Diseases. DOI: 10.1186/1750-1172-3-11

A previous review on adaptive design methods in clinical trials.

3. Pallmann, P., Bedding, A.W., Choodari-Oskooei, B., Dimairo, M., Flight, L., Hampson, L.V., Holmes, J., Mander, A.P., Sydes, M.R., Villar, S.S., Wason, J.M.S., Weir, C.J., Wheeler, G.M., Yap, C., Jaki, T. (2018). “Adaptive designs in clinical trials: why use them, and how to run and report them.” BMC Medicine. DOI: 10.1186/s12916-018-1017-7

An informative resource on why and how to run and report adaptive designs in clinical trials.

4. Meurer, W. J., Lewis, R. J., Tagle, D., & Berry, S. M. (2012). “An overview of the adaptive designs accelerating promising trials into treatments (ADAPT-IT) project.” Annals of Emergency Medicine. DOI: 10.1016/j.annemergmed.2011.12.009

Discusses an initiative to accelerate adaptive clinical trials.

5. Berry, S. M., Connor, J. T., & Lewis, R. J. (2015). “The platform trial: an efficient strategy for evaluating multiple treatments.” JAMA. DOI: 10.1001/jama.2015.2316

Explores platform trials, a type of adaptive clinical trial.

Keywords

1. Adaptive Clinical Trials
2. Clinical Trial Methodology
3. Group Sequential Design
4. Clinical Research Innovations
5. Interim Analysis in Trials

The research presented in this article is not merely an academic exercise; it represents an essential step towards ensuring the integrity and efficiency of clinical trials. As adaptive trial methods continue to evolve, these findings and recommendations could help shape better protocols and outcomes for trials across the globe, ultimately improving patient care and accelerating medical progress.