Webinar Q&A: How to Advance New Cancer Therapies in Alignment with FDA Project FrontRunner

Last month, in partnership with Clinical Leader, Veristat consulting, regulatory, and clinical experts gave a live webinar outlining how to better advance new cancer therapies in alignment with FDA’s Project FrontRunner. The webinar covered the following:

• What is Project FrontRunner, and why now?
• When does it make sense to offer patients earlier investigational therapy options?
• What are the trial design considerations/implications?
• How does it impact patient safety and site participation?

The full replay of the presentation can be found here. After an engaging Q&A session was cut short due to time restraints, we gathered all the questions and had our speakers answer each in detail below.

1. How can I evaluate whether Project Frontrunner applies to my projects?
   

   In principle, Project FrontRunner (PFR) applies to projects that rely on a biomarker/surrogate endpoint for accelerated approval. The initiative was established in the oncology therapeutic area where 1) the unmet needs are high, 2) measures of disease progression (e.g., ORR and PFS), and 3) measures of clinical benefit tend to require long treatment periods to read out. The key features of PFR are dose optimization, randomized study designs, and the seamless conduct of biomarker-based studies for accelerated approval, with confirmatory studies for conversion to full approval. Theoretically, these elements of Project Front Runner are expected to be applicable outside of oncology.

   To determine whether your program may benefit from Project FrontRunner, consider whether there are benefits for treating patients with your product in earlier metastatic disease. Are there standards of care that you might need to compare against? How might your product compete against the already available early lines of treatment? Is there a benefit your product could offer patients with early metastatic disease?

   We strongly recommend discussing the planned development program with the FDA early and often to obtain their recommendations for the best approach to development.

2. How can DCT contribute to the new rule?
   

   Project FrontRunner focuses on establishing benefits for novel products within earlier lines of metastatic disease. Decentralized clinical trials can be used within Project FrontRunner in the same capacity as other oncology programs.

3. How do we accelerate our development timeline and reflect the latest regulatory trend?
   

   Veristat advises proactive planning to achieve the most efficient clinical development program, considering whether accelerated approval (and later conversion to full approval) may be appropriate. In the context of Project FrontRunner and related FDA Oncology Center of Excellence initiatives, this involves executing nonclinical safety studies earlier in development program, enabling dose optimization within the targeted indication early within the development program (Project Optimus), considering whether the product may be effective against early metastatic disease (Project FrontRunner), and discussing the development program with the FDA review team to align on the strategy for approach and enable an efficient pathway to market. Consideration should be given to GMP manufacturing at a suitable scale for use in clinical trials, leading to accelerated approval.

4. Are immunotherapies included?
   

   Yes, all oncology programs may be impacted by the paradigm of Project FrontRunner. As noted in the webinar, Project FrontRunner is not a requirement but a structure to engage more research in early metastatic disease.

5. What are the new guidelines for drug development for early advanced metastatic cancer?
   

   In addition to our answer to question 1 above, Veristat recommends that sponsors become familiar with the set of FDA oncology guidelines on RTOR, Project FrontRunner on accelerated approval, Project Optimus on dose identification, and the new FDA authority per FDOR 2023. Please see the references at the end of the webinar slide set.

6. What relevance of the target used in the earlier access setting?
   

   It is possible to use different endpoints in studies for accelerated approval versus conversion to full approval; however, the differences are usually related to enrolling patients in earlier lines of treatment. Sponsors should remember that these programs aim to establish the predictive value of the endpoint used for accelerated approval, so there should be an inherent relationship between the endpoints.

7. What regulatory strategy and FDA collaboration should be taken on IND applications for new cancer treatments?
   

   In addition to our answer to question 1 above, Veristat recommends that sponsors become familiar with the set of FDA oncology guidelines on RTOR, Project FrontRunner on accelerated approval, Project Optimus on dose identification, and the new FDA authority per FDOR 2023. Please see the references at the end of the webinar slide set.

8. What are the requirements of a confirmatory trial to support accelerated approval?
   

   The protocol for a confirmatory trial to support conversion to full approval following an accelerated approval should be reviewed by the FDA in the planning stages of the Phase 3 portion of the program. Any modifications to the study design can be communicated to the FDA before study initiation.

   The details of the confirmatory study will be program-specific; however, we can comment that typically randomized confirmatory studies that have a primary time-to-event endpoint (i.e., overall survival, progression-free survival, or similar acceptable outcome) to establish the clinical benefit of the novel product in comparison to a standard of care or placebo control. The confirmatory study is typically expected to have been initiated, with enrollment ongoing, by the time of application for accelerated approval.

9. What does the FDA consider as the new oncology therapies and in which oncology area are these in?
   

   Project FrontRunner applies to any newly developed therapies where there may be a benefit to treating patients with early metastatic disease. The concepts are applicable across oncology therapies and indications; however, for rare tumor types and unserved populations (i.e., where no standard of care exists), single-arm approaches to clinical development programs may still be appropriate.

10. When and how should I engage with the FDA and Project FrontRunner?
    

    While not required, Project FrontRunner provides a structured paradigm for developing novel oncology treatments. Veristat recommends that sponsors correspond regularly with the FDA to discuss the ongoing clinical development program, which will be impacted by the Project FrontRunner paradigm.

    In the context of Project FrontRunner and related FDA Oncology Center of Excellence initiatives, this involves executing dose optimization within the targeted indication early within the development program (Project Optimus), considering whether the product may be effective against early metastatic disease (Project FrontRunner), and discussing the development program with the FDA review team to align on the strategy for approach and enable an efficient pathway to market.

    An early determination of accessing Project FrontRunner is whether the new intervention qualifies for Breakthrough Therapy Designation. Oncology projects in the PFR program usually present a significant therapeutic gain

Would you like insight into how to plan for your next oncology trial? Our experts are on hand to help. Let’s talk