FDA Guidance Sheds Light on Complex Innovative Trial Design Proposals

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A new guidance from the U.S. Food and Drug Administration (FDA) aims to help sponsors and applicants when interacting with the agency on complex innovative trial design (CID) proposals for drugs or biological products.

“Although CID has been referred to as complex adaptive, Bayesian, and other novel clinical trial designs, there is no fixed definition of CID because what is considered innovative or novel can change over time,” FDA notes in the guidance issued this week. FDA says its focus is on trial designs that have rarely or never been used to provide substantial evidence of effectiveness in new drug applications or biologics license applications.

A common feature of many CIDs is the need for simulations rather than mathematical formulae to estimate trial operating characteristics. Some examples of trial designs that might be considered novel or CID are those that formally borrow external or historical information or borrow control arm data from previous studies to expand upon concurrent controls, Sequential Multiple Assignment Randomized Trials, or master protocols.

In most cases, sponsor/FDA interactions related to CID proposals will occur in the context of investigational new drug applications (INDs) or pre-IND meetings. Novel clinical trial designs call for clear communication between sponsors and FDA on aspects of the design, including the purpose, execution, and operating characteristics (such as the chance of producing erroneous conclusions) of the design, and how the trial data will be analyzed and presented, FDA says in the guidance.

The agency also provides examples of clinical trial designs it would consider to be CID and describes the type of information sponsors should submit to the agency “to facilitate a productive discussion” between the parties. Additionally, the guidance addresses the role of simulations in clinical trial design and planning.

Because CID proposals may involve novel scientific review considerations, FDA encourages sponsors of CID proposals to seek early interaction with FDA regarding details of their CID plans. In general, sponsors should use existing pathways for interacting with FDA during the course of the clinical development program, including Type A, Type B, Type B end-of-phase, and Type C meetings, as well as IND amendment review and possibly pre-IND meetings for early-phase studies with novel design elements.

Detailed documentation is necessary for FDA to review novel design proposals thoroughly and provide feedback. Documentation should include the novel features that are planned to be incorporated, the timing and details of the planned implementation, and how the design addresses the underlying scientific objectives.

Bayesian approaches may be well-suited for some CID settings because they can provide flexibility in the design and analysis of a trial, particularly when complex adaptations and predictive models are used, FDA says. In addition, Bayesian inference may be used in settings where it is advantageous to combine multiple sources of evidence, such as extrapolation from adult data to pediatric populations, or to borrow control data from Phase II trials to augment a Phase III trial.

If a sponsor chooses to submit a Bayesian CID proposal, FDA’s evaluation of the proposal will rely on clear communication between the sponsor and agency regarding two areas: the prior distribution and the study decision criteria for primary and key secondary endpoints.

Author: Michael Causey