How to Ensure Your Adaptive Trial Is Appropriate for Regulatory Submission

Adaptive clinical trial designs have become increasingly popular among developers and investors due to the many advantages they offer over traditional designs, but how can you ensure your adaptive trial is appropriate for regulatory submission?

First, what are adaptive trials?

Adaptive clinical trial designs are a type of study design that allows pre-specified modifications to be made to the trial protocol based on interim looks at accumulating data. Due in part to their greater flexibility, adaptive trial designs offer several scientific, financial, strategic, and ethical advantages over traditional clinical trial designs, such as increased efficiency and reduced cost.

Once a developer has determined that an adaptive trial is right for their drug, they may still be wondering about the investor perspective on adaptive trials and how to ensure their design is appropriate for regulatory submission.

What makes adaptive trials attractive to investors?

Since adaptive trials are trials that not only include interim looks, but that can be modified based on those interim looks, this offers several benefits from the investor perspective.

By taking interim looks while the trial is progressing, there is a flow of information from the trial throughout, rather than just one result at the end, and there is often an early “off-ramp” for cost and time in the form of stopping early for futility.

By adapting the design to the accumulating data, the design has the best chance of success as it mitigates the risk of the trial failing.

Ultimately, by using adaptive trial designs, investors will see that the sponsor has already thought about how to optimize the quickest route to approval and has shown proactivity in managing the unknowns in the trial design.

But of course, a clever design only goes so far if not approved by authorities, so what do developers need to consider from a regulatory perspective?

What do regulators look for when evaluating an adaptive trial?

When evaluating a clinical trial design, regulators will be considering a variety of questions, including:

1. 1. Has there been an opportunity to comment on the adaptive trial design before it started?
      
      
   2. Is the adaptive trial design appropriate given the clinical setting?
      
      
   3. Has the adaptive trial design and its analysis been completely pre-defined and documented?
      
      
   4. Does the adaptive trial design strongly control the Type I error, have a good plan for multiplicity, and state the Estimand Strategy precisely?
      
      
   5. Have the operating characteristics of the adaptive trial design been sufficiently explored?
      
      
   6. Is any stopping for early efficacy appropriate and would it provide enough data to assess benefit and risk?
      
      
   7. Is there any opportunity for operational bias?
      
      
   8. Has the trial integrity been preserved? Is an iDMC planned? Is there a trial integrity document?
      
      
   9. Does the proposed analysis take into account the adaptations?

Knowing what regulators are looking for, there are several steps developers can take when planning their trial.

Steps developers can take to ensure their trial is appropriate for regulatory submission

1. 1. Get expert advice on whether an adaptive design is right for your trial.
      
      
   2. In the design stage, ensure that you expect to see reductions in time and resources compared to a standard design trial.
      
      
   3. Consider your plan for multiplicity adjustment and preserving the Type 1 error rate (or the probability of a false-positive for Bayesian designs), and that your Estimand strategy is well thought out.
      
      
   4. Plan thorough trial simulations — the Trial Simulation Report will be necessary as you decide on the design and communicate the design to regulators.
      
      
   5. Pre-define and document your plans.
      
      
   6. Protect the trial integrity.
      
      
   7. Engage with regulators early to get their comments and approval before initiating the study.

Key takeaways

Adaptive trial designs provide many benefits, but to help ensure your trial is successful, it’s important to start planning your regulatory strategy and engaging with regulators early on; use trial simulation to help guide your design choices; and get expert advice to help define your regulatory strategy.

Interested in learning more? Watch our webinar “Balancing Priorities in Therapeutics Development: Simulation-Guided Decision-Making”:

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