Thank you for joining us for another episode of the Guidance Recap Podcast. The Guidance Recap Podcast provides highlights for FDA guidance documents straight from the authors. My name is Kylie Haskins, and I am the host for today’s podcast. I am a member of the Guidance, Policy, and Communications Team in the Office of Translational Sciences here at the FDA. In today’s episode, I am excited to be talking with Dr. Greg Levin, who is the Deputy Director of the Division of Biometrics III in CDER’s Office of Biostatistics. Dr. Levin will be sharing some thoughts with us on the newly published final guidance titled, “Interacting with the FDA on Complex Innovative Trial Designs for Drugs and Biological Products.” Welcome, Dr. Levin! Thank you for speaking with us today.
Dr. Levin, can you explain what a complex innovative trial design is for listeners who may not be familiar with this area?
Sure, there is no fixed definition of complex innovative trial design (also called CID) because what is considered innovative or novel can change over time. The guidance describes CID as trial designs that have rarely or never been used to date, and these may include some types of adaptive designs, Bayesian designs, and designs that are so complex that they require simulations to estimate trial operating characteristics. CID can also include the novel application of complex trial design features to a given indication, even when those design features have been used in other indications. Some examples of trial designs that might be considered CID are trials that formally borrow external or historical information, such as adult data to support a pediatric trial or control arm data from Phase 2 to support a Phase 3 trial; Sequential Multiple Assignment Randomized Trials (also known as SMART trials); and master protocols that assess multiple interventions or diseases.
Can you explain to the audience the potential value of complex innovative trial designs and provide some of the reasons that FDA issued this guidance?
These trial designs have the potential to improve trial efficiency, for example making trials smaller and more affordable. They also may have ethical advantages by minimizing patient exposure to ineffective therapies and accelerating the approval and adoption of effective therapies. They are also appealing to stakeholders such as sponsors because of the potential to add flexibility and can be particularly helpful for dealing with the statistical challenges posed by a small patient population in situations such as rare disease drug development.
However, with these potential advantages also comes additional challenges, in part, because we don’t have experience with using these trial designs in regulatory decision making. We also may not understand the operating characteristics of the design, making results from such trials difficult to interpret. To address this unfamiliarity and uncertainty, CID submissions often necessitate additional documentation, which require additional resources for industry to generate and additional resources for FDA staff to review. For example, these trial designs may require simulations to understand the operating characteristics, and these advanced techniques may require additional training for stakeholders and additional time and effort at the planning stage. In some cases, the potential advantages of these designs may not outweigh the limitations and challenges, and it may be more appropriate for sponsors to use a more traditional design.
FDA is issuing this guidance to help ensure successful interactions between sponsors and the FDA that support the regulatory review of CID proposals for trials intended to provide substantial evidence of effectiveness for drugs and biologics. The guidance provides clarity on the type of information needed to determine if a specific design proposal is appropriate for a specific therapeutic setting to facilitate a productive discussion between sponsors and FDA. The guidance doesn’t determine whether a specific type of CID is appropriate, but instead provides the types of information and the types of interactions that are critical to help determine if a specific design proposal is appropriate for a sponsor’s drug development program. FDA issued this guidance as part of an ongoing effort to support innovation in medical product development and to satisfy a mandate under the 21st Century Cures Act.
Can you provide a little background about the Complex Innovative Trial Design (CID) Pilot Meeting Program? How does this guidance relate to the CID Pilot Meeting Program?
The CID Pilot Program launched in August 2018 and offers sponsors an opportunity for increased engagement with FDA to discuss CID proposals in drug and biologic development programs. The CID pilot program is a joint CDER/CBER program that accepts up to two submissions every three months. The program provides sponsors of CID proposals two additional face to face meetings with FDA to allow for a more substantive and interactive regulatory discussion and the opportunity to focus on challenging statistical issues. Participants in the program agree to unique disclosure agreements that allow FDA to publicly share certain information about the trial design and the interactions to help educate stakeholders on CID. Before FDA grants the initial meeting under the CID pilot meeting program, FDA and the sponsor must discuss and agree on the information that FDA will share publicly. FDA intends to request public disclosure of information that is beneficial to advancing the use of CIDs, such as the important components of a simulation report to help understand a CID and the potential value of certain designs for clinical trials intended to support regulatory approval.
The CID guidance discusses methods for interacting with FDA on CID proposals. These discussions can occur through existing pathways for interacting with FDA during the course of drug development but also may occur through the recently initiated CID Pilot Program. The final version of the CID guidance also includes a brief discussion of some submissions reviewed in the CID Pilot Program.
That segues nicely to our next question, what has changed from the draft version to the final version of the guidance?
There a few changes between the draft version and the final version of the CID guidance, but none of them are major.
The draft version of the CID guidance published in September of 2019. As I mentioned earlier, FDA issued this guidance to promote the appropriate use of complex innovative trial designs and to satisfy a mandate under the 21st Century Cures Act. The public comments we received for the draft version of the guidance were overall very positive. Most of the comments expressed appreciation for the recommendations provided in the guidance and many requested additional examples. However, we did receive a few technical comments related to the choice of operating characteristics for clinical trials with Bayesian inference.
Because of the positive feedback received for the draft guidance, not many changes were made in the final version. The two biggest changes are the following:
- First, we added case studies from the CID pilot review program, including one involving a master protocol design, to provide additional examples that were requested in the public comments.
- And second, we eliminated one specific technical statement on operating characteristics of trials with Bayesian inference that received critical feedback in the public comments.
How do you anticipate this guidance will affect external and internal stakeholders?
We anticipate that the final guidance will be welcomed by both FDA and industry as it provides additional clarity on interactions and information needed to determine appropriateness of CID proposals in drug and biologic development programs. The public comments for the draft guidance were positive, and the requests for additional information and clarification were addressed. This guidance also publicly shows FDA’s commitment to innovation and encourages sponsors to consider CID approaches in settings where they may add value.
The guidance contains an incredible amount of useful and important information. What are a couple of key items that you especially want listeners to remember?
That is a great question. First, I would like listeners to remember that the information and discussions necessary to support CID proposals are going to be complex, and applications will thus benefit from earlier and potentially more frequent interactions, and that CIDs may not be appropriate for all settings but may add value in certain cases.
Second, to facilitate productive interactions on CID proposals, stakeholders should review the content elements recommended in the guidance for a CID proposal. For example, documentation to facilitate discussions may need to include the statistical analysis considerations related to the complex innovative design features, how any prior information is used, a simulation report containing details about operating characteristics if simulations are used, and a comprehensive data access plan defining how trial integrity will be maintained, among other things.
Lastly, if a CID proposal contains Bayesian features, especially if the design proposes to utilize external information in the form of an informative prior that will be combined with data in the trial to evaluate the effectiveness of a drug, the guidance emphasizes that the submission should address the choice and justification of the prior distribution and the efficacy criteria for primary and secondary endpoints.
Dr. Levin, thank you for taking the time to share your thoughts on the CID final guidance. We have learned so much from your experience and insights in this area, and we appreciate the hard work that you do to ensure the safe and effective use of the drugs and biologics we regulate. We would also like to thank the guidance working group for writing and publishing this final guidance.
To the listeners, we hope you found this podcast useful. We encourage you to take a look at the snapshot and to read the final guidance.