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This is the third installment of a three-part blog series on Complex Innovative Trial Designs.  As we’ve discussed previously, clinical trials are evolving rapidly, with new data sources and medical innovation increasing the complexity of study designs. The FDA has demonstrated support of these trends, providing resources to guide research organizations in designing and executing innovative clinical trials. The industry should be encouraged by the support, which will facilitate greater medical innovation, and ultimately, more effective treatments and better patient care. In this blog, we’ll discuss the recently published guidance from the FDA, “Guidance for Industry: Adaptive Designs for Clinical Trials of Drugs and Biologics”.

Part 1: Complex Innovative Trial Design (CID) to Facilitate Innovation

Part 2: Understanding the FDA’s Guidance on Complex Innovative Trial Designs

This guidance addresses the appropriate use of adaptive designs for clinical trials and replaces the draft guidance that was published in September 2018, which replaced a 2010 draft. The commenting period for the September 2018 draft closed on November 30, 2018 and this resulting 37-page guidance representing the FDA’s current thinking on adaptive clinical trials was published in November 2019.

This new guidance from the FDA could almost be considered a ‘user guide’ for adaptive design trials and addresses key considerations and practices that span the design, execution and reporting of adaptive trials. It thoroughly describes adaptive clinical designs, along with the value of such designs and key examples of trials that have used this approach effectively. The document also provides an overview of the potential advantages of adaptive design trials, including statistical efficiency, ethical advantages, improved understanding of drug effects, and greater perceived acceptability to stakeholders. While discussing potential limitations, the FDA provides specific guidance on the requirements for specific analytical methods to avoid bias, effort required to pre-plan design modifications, logistical challenges of managing access to comparative interim results, limitation of certain scientific constraints, and challenges in the interpretability of the results.

The FDA outlines four key principles that adaptive trial designs should satisfy:

  1. The chance of erroneous conclusions should be controlled: Trial designers must consider the probability of incorrect conclusions that would impact the benefit risk assessment.
  2. The estimation of treatment effects should be reliable:  The design should not introduce statistical bias in calculation of the treatment effect as this will ultimately impact the accuracy of the new drug label.
  3. The details of the design should be prespecified: All trial details, including planned modifications, must be prospectively specified. This ensures that adaptation decisions aren’t based on ongoing results in an unplanned manner.
  4. The trial integrity should be maintained. Knowledge of ongoing data can impact sponsor, investigator, patient and other stakeholder behaviors. It is critical that access to this data be limited to relevant experts outside of the team conducting and managing the trial.

These overarching principles guide specific recommendations and considerations about how to design and conduct adaptive clinical trials. This includes considerations relative to the different types of clinical trial designs, based on both non-comparative (blinded) or comparative (unblinded) analyses of data. 

The final section in the guidance reviews regulatory considerations relative to adaptive clinical trial designs and recommends early interactions with the FDA through existing mechanisms including Type C meeting requests and End-of-Phase II meetings. (Sponsors should also consider participating in the agency’s Complex Innovation Design Pilot Program which we covered in a previous blog.) The guidance follows the typical clinical trial lifecycle and outlines recommended documentation to submit so that substantive conversations can take place with the agency prior to conducting an adaptive design trial. In addition, the FDA also recommends reporting documentation that should be included in addition to standard NDA or BLA requirements, once the trial is completed. Combined, the guidance indicates the documentation should be sufficient for the agency to review the results and to inform a regulatory decision.

The use of adaptive design trials opens up exciting possibilities in scientific innovation. Yet these complex programs demand careful planning, flexible technology and detailed documentation. The mounting complexity can only be addressed with creative technologies that provide flexibility, enable innovation, and are informed by significant trial expertise. Mednet’s unified platform is designed to support clinical trials of any size, type or phase, while also delivering a highly flexible solution that enables users to easily adapt to new and innovative study designs and requirements. For more information, contact us.