FDA´s Advice for Sponsors of Adaptive Design Clinical Trials

The FDA published a new guideline on Adaptive Design Clinical Trials for Drugs and Biologics. The document provides guidance to sponsors on the appropriate use of adaptive designs for clinical trials (CTs) to provide evidence of the effectiveness and safety of a drug or biologic. The guidance describes important principles for designing, conducting, and reporting the results from an adaptive CT. In addition, it advises sponsors on the types of information to submit to facilitate FDA evaluation. According to the agency, the concepts provided are also useful for early-phase or exploratory CTs as well as trials conducted to satisfy post-marketing requirements.

What is an Adaptive Design Clinical Trial?

The guidance defines an adaptive design as a CT design that allows for prospectively planned modifications to one or more aspects of the design based on accumulating data from subjects in the trial.

Potential Advantages

According to FDA, adaptive designs can provide a variety of advantages. These advantages arise from the fundamental property of CTs with an adaptive design: they allow to adjust the trial to information that was not available when the trial began. The specific nature of the advantages depends on the scientific context and type of adaptation considered, with the following potential advantages:

• Statistical efficiency (i.e., greater statistical power),
• Ethical advantages (e.g. the ability to stop a trial early if it becomes clear that the trial is unlikely to demonstrate effectiveness),
• Improved understanding of drug effects,
• Acceptability to stakeholders.

Data and Study Integrity

The FDA strongly recommends that access to comparative interim results be limited to individuals with relevant expertise who are independent of the personnel involved in conducting or managing the trial and have a need to know. It has to be ensured that patients, investigators and their staff as well as sponsors do not have access to comparative interim results. Knowledge of accumulating data by trial investigators can adversely affect patient accrual, adherence, retention, or endpoint assessment, compromising the ability of the trial to reliably achieve its objective in a timely manner. According to FDA, a clinical trial with an adaptive design should include the following:

• A Data access plan that identifies who has access to confidential data, when that access occurs, and what types of data and results are involved.
• Safeguards to ensure that the persons responsible for preparing and reporting interim analysis results are physically and logistically separated from the personnel tasked with managing and conducting the trial.
• Limitation of access. In situations (such as dose selection) where limited access for specific sponsor personnel can be necessary, this limited access might be justifiable under certain circumstances. However, risks to trial integrity are most easily minimized by completely restricting sponsor access to comparative interim results.
• Procedures to maintain and verify confidentiality, as well as documentation of monitoring and adherence to the operating procedures. Approaches typically include the use of confidentiality agreements for persons with access to interim data and the use of logistical or physical firewalls that prevent access by trial personnel to any data that include information that might allow one to infer treatment assignment.
• Steps to minimize information that can be inferred by observers. Investigators and trial participants should be shielded as much as possible from knowledge of adaptive changes. For example, if the sample size is increased after an interim analysis, trial sites could be informed that the targeted enrollment number has not been reached rather than being notified of the specific targeted final sample size.

More information can be found in FDA´s Guidance for Industry: Adaptive Designs for Clinical Trials of Drugs and Biologics.