Adaptive Design Clinical Trials

  Adaptive Design Clinical Trials

An adaptive design is defined as a clinical trial design that allows for prospectively planned modifications to one or more aspects of the design based on accumulating data from subjects in the trial. The modifications may include the eligibility criteria, study dose, treatment duration, study endpoints, laboratory testing procedures, diagnostic procedures, criteria for evaluation, and assessment of clinical responses. Statistical procedures include randomization, study design, study hypotheses, sample size, data monitoring, and interim analysis, statistical analysis plan, and/or methods for data analysis. 

The adaptive clinical trial design are categorized into
Prospective adaptations
Prospective adaptations include, but are not limited to, adaptive randomization, stopping a trial early due to safety, futility or efficacy at interim analysis, dropping the losers (or inferior treatment groups), sample size re-estimation, and etc. Thus, prospective adaptations are usually referred to as by design adaptations. 
Concurrent adaptations
Concurrent adaptations are usually referred to as any ad hoc modifications or changes made as the trial continues. Concurrent adaptations include, but are not limited to, modifications in inclusion/exclusion criteria, evaluability criteria, dose/regimen and treatment duration, changes in hypotheses and/or study endpoints, and etc. 
Retrospective adaptations
Retrospective adaptations are usually referred to as modifications and/or changes made to statistical analysis plan prior to database lock or unblinding of treatment codes. In practice, prospective, ad hoc, and retrospective adaptations are implemented by study protocol, protocol amendments, and regulatory reviewer's consensus, respectively.

Types of Adaptive Clinical Design

• Adaptive randomization design
• Adaptive group sequential design
• N-adjustable design
• Drop-the-loser design
• Adaptive dose-escalation design
• Biomarker-adaptive design
• Adaptive treatment-switching design
• Adaptive-hypotheses design
• Adaptive seamless phase II/III trial design
• Any combinations of the above (multiple adaptive designs)

Four Principal of Adaptive Clinical Design 

• Controlling the Chance of Erroneous Conclusions
• Estimating Treatment Effects
• Trial Planning
• Maintaining Trial Conduct and Integrity

Advantages of Adaptive Clinical Design

• Provide statistical efficiency
• Enables ethical consideration
• Allow improved understanding of drug effects
• Considerably higher acceptability to stakeholders

Limitation of Adaptive Clinical Design

• Adaptive designs require specific analytical methods to avoid increasing the chance of erroneous conclusions and introducing bias in estimates.
• The use of an adaptive design adds logistical challenges to ensuring appropriate trial conduct and trial integrity.
• The opportunity for efficiency gains through adaptation may be limited by important scientific constraints or in certain clinical settings.
• An adaptive change to a trial design may lead to results after the adaptation that are different from those before the adaptation. This may lead to challenges in the interpretability of results.

Reference

Adaptive Designs for Clinical Trials of Drugs and Biologics (FDA Guidance)
Chow et al 2008. Adaptive design methods in clinical trials – a review, Orphanet J Rare Disease