Guidance on Adaptive Design for Clinical Trials Released for Comments!

12/04/2019

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The Food and Drug Administration (FDA) released a final guidance “Adaptive Designs for Clinical Trials of Drugs and Biologics” for comments. An adaptive designed clinical trial means that during the trial, the design can be changed based on an interim analysis of the data collected from subjects already enrolled. This means that the trial design could be altered during enrollment to increase the type of subjects that are more likely to benefit or reduce those who may be at greater risk for adverse effect. This could reduce the time needed to determine if the investigational product is safe and effective and reduce risks to subjects. The final guidance clarifies principles for the design, conduct, and reporting of adaptive clinical trials for evaluation of safety and effectiveness of drugs and biologics and is part of FDA’s modernization efforts.

Before initiating an adaptive design trial, the FDA recommends the sponsor include in the protocol:

  • the rationale for the selection of the design,

  • a detailed description of the adaptive plan,

  • information about the DMC or independent adaptation body,

  • the statistical methods to be used, and

  • the data access plan.

The guidance provides four principles for considerations specific to adaptive trials:

  • Control the chance for incorrect determination for or against the safety and effectiveness of the investigational product, or the assessment for benefit-risk

  • Ensure the estimation of treatment effects are reliable to support the appropriate evaluation of benefit-risk

  • Although the trial design is adaptive, it should be thoroughly planned and documented in advance, including the interval for interim data analyses and the types of adaptations that may be considered, including the level of flexibility

  • Plans to describe how to limit access to interim data analysis to reduce bias and plans to reduce potential issues related to interpretation of design changes (e.g., assumptions about the treatment effect if a sample size is increased or decreased)

In an adaptive trial design, it can be more challenging to maintain trial integrity, and it can introduce an increased possibility for error or bias if not designed or conducted properly. Interim results should be restricted to those who need to know so that unplanned design changes are not due to knowledge of the results. Also, knowing the interim analysis results could adversely affect subject recruitment or retention.

A well-designed adaptive design trial should be carefully planned before starting the trial and implemented to ensure confidentiality of interim trial data and integrity of the trial. In addition to a Data Monitoring Committee (DMC), an independent adaptation body can assist with recommendations. In any case, the preparation and analysis of interim data should be done independently of those conducting the day to day activities of the clinical trial.

Adaptive design clinical trials introduce additional complexities compared to traditional clinical trials. By following the recommendations in the guidance, the adaptive clinical trial is more likely have a successful outcome and could potentially reduce the time needed to obtain enough data to determine safety and effectiveness. Comment now through January 2, 2020 here.

 

- The Clinical Pathways Team

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