Breakthrough Therapy: FDA Highlights Lessons Learned During First Two-and-a-Half Years

Quality of Data is Key, and the Bar is Always Moving for Innovators

By: Nancy Bradish Myers, President, Catalyst Healthcare Consulting, Inc.

Twitter: FDAInsightGuru

FDA started implementing the Breakthrough Therapy Designation (BTD) in July 2012, as mandated by Food and Drug Administration Safety and Innovation Act (FDASIA), Section 902. From the start, FDA and CDER leadership responded enthusiastically by throwing their doors wide open.

At a recent Brookings/FDA conference, the agency offered some lessons learned with the BTD program from the first two-and-a-half years. Here are a few of the new insights I heard:

• Lesson #1: In the words of Dr. Rick Pazdur, a BT-designated drug must be “transformative.” Sponsors must attempt to be objective and try to avoid “unrealistic optimism.”
• Lesson #2:  Quality of data wins the day. Quality of data in a one-arm trial tends to be more convincing to FDA than 2 trials with lower-quality data.
  • Trials must be well-designed, and FDA wants sponsors to think through endpoints early. With multiple endpoints, if it is not obvious which is the most important, try to get FDA agreement.
  • BTD requests that are approved tend to have prospective study designs, larger numbers of patients, and longer follow-up than the requests that are denied.
  • FDA looks at the “totality of the data” when determining “substantial improvement” over existing therapies; there is no “bright line” or threshold one can point to.
  • Consistency of findings is key.
  • If a PRO is good enough, do it early and commit to it.
• Lesson #3:  To be even considered for the designation, the drug must have clinical data (humans). Animal data does not cut it.
• Lesson #4: Data analysis is a big part of the decision to grant or deny a BTDR. Generally, FDA does not trust post hoc analysis or subgroup analysis in a failed trial. On post hoc subgroup analysis, Dr. Ron Farkas, a clinical team leader in FDA’s neurology division said: “There is always a way to find a group that does better. But this is a hypothesis, not a reason to support Breakthrough Drug designation.” He focused on the fact that it is hard to distinguish if it is real or just chance.
• Lesson #5: If there is not a dramatic improvement and there is a not substantial benefit over available therapy, looking at safety signals becomes a more significant factor for FDA.
• Lesson #6:  Make sure any biomarker assay used is reliable!
• Lesson #7:  If it does not look like a slam dunk, too many smaller issues can sink the ship.
• Lesson #8: Phase II or earlier data is better than Phase III:  As safety concerns rise, so does the change of a denial.
• Lesson #9:  A sponsor can resubmit a request for a BT designation. For example, thus far, CDER has received 10 resubmissions of previously denied or withdrawn requests. Of those 10, four were granted.
• Lesson #10:  Available therapies change over time, so the bar is moving for BTD applicants. When determining standard of care and defining substantial improvement over existing therapies, officially FDA looks at marketed products at the time the request is filed. FDA does not consider an Accelerated Approval to be an available therapy; it must be a regular approval.  However, one senior CDER person admitted that the Medical Policy Council view of what is substantial could be affected by knowing what else is in the pipeline.
• Lesson #11:  A negative biomarker increases concern that the drug may not have the intended pharmacodynamic effect.
• Lesson #12:  Before jumping to the conclusion that some offices grant more BTDs than others, CDER leadership would advise us to understand that successes in disease areas like oncology may reflect the state of the science.  Some disease states may not be well understood scientifically.
• Lesson #13:  Evidence needs to be in the context of understanding the natural history; in a disease with very limited clinical trial precedent, natural history data is key to demonstrate “substantial improvement.”
• LAST LESSON: FDA encourages sponsors to reach out to your FDA Project Manager and have preliminary talks about whether applying for the BTD makes sense. Though the conversation is not binding, it may save time and resources knowing how FDA may view your innovation.

Insight into the internal FDA review process:

Within 60 days of a request for designation, a great deal of work happens at FDA. Here is a high-level stepwise chart of actions to help visualize the process: