Oncology Drug Development: A Regulatory Perspective

Tatiana Prowell, MD, US Food and Drug Administration, Silver Spring, Maryland

Fellow summary authored by Christopher Devine, MD, MBA

Dr. Prowell provided an excellent overview of the FDA’s programs that expedite the regulatory review of novel drugs:

1. Fast Track Designation offers the lowest threshold for a drug company to clear and is based on preclinical or clinical data that demonstrate the potential to address an unmet need. It can enable rolling submission of an NDA/BLA but does not provide any major advantage since the Prescription Drug User Fee Act (PDUFA) goal date is set by the final submission date of the data package.
2. Breakthrough Therapy Designation (BTD) is very impactful to the review process and is based on early clinical data demonstrating a meaningful advancement over standard of care. The application for BTD is ideally submitted no later than the end of Phase 2 meeting, and sponsors receive intensive guidance from FDA throughout the review process. Notably, BTD may be withdrawn if standard of care improves and the drug is no longer a meaningful advance, or if the drug’s clinical efficacy/safety data degrades during development.
3. Priority Review enables a six-month PDUFA clock (vs. the typical Standard Review of 10 months). This designation is available for drugs that would demonstrate a significant improvement in safety/efficacy over standard of care. Marketing the drug four months earlier than usual has important financial implications for sponsors.
4. Accelerated Approval is the approval pathway that is arguably the most complex among the four programs. This pathway allows for approval based on surrogate endpoints reasonably likely to predict clinical benefit. In oncology, for example, drugs may be approved based on single-arm trials with an overall response rate as the primary endpoint. This is much faster than running a randomized controlled trial with a primary endpoint of progression-free and/or overall survival.

There was an extensive discussion on the nuances of accelerated approval. Importantly, the clinical benefit must be confirmed in a subsequent trial, which can present enrollment challenges for randomized studies if the drug is already commercially available and known to be effective. To mitigate these challenges, companies may confirm benefit by (1) an interim analysis of a surrogate endpoint for accelerated approval in a randomized trial with confirmation of benefit at the completion of the same trial, or (2) evaluation of the drug in earlier lines of treatment to confirm accelerated approval in later lines of disease. It is also worth noting that accelerated approval must demonstrate benefit over the current standard of care, which can change during the review process. Dr. Prowell cited the example of the EMBRACE trial of eribulin in HER2+ breast cancer, the approval of which blocked the accelerated approval of T-DM1 in the same indication. Drug development is challenging because sponsors must “play to where the puck is going, not where it currently is” and this competitive intelligence is particularly relevant for accelerated approval.

The talk also focused on the role of precision medicine at the FDA, and how biomarkers are incorporated into drug development. Dr. Prowell urges sponsors to include biomarker-negative patients in trials, given sometimes unexpected findings in prior trials and the heterogeneity of biomarkers. She illustrated these points with a number of case studies and did a very nice job covering the FDA’s role in the drug development process.