By Michelle Rohrer, Vice President, U.S. Regulatory Affairs, Genentech
In August I had the pleasure of participating in Fierce's "Understanding Major Regulatory Change" webinar. This session was about the FDA's new "Breakthrough Therapy" designation, and I was joined by Dr. Jay Siegel from Johnson & Johnson ($JNJ) and James Pierce from Appian Corporation for a lively discussion. In case you missed it, you can replay the full webinar on-demand here. We didn't have time to address all the great questions submitted to Fierce during the live session, so as a follow up I'd like to answer some of them here. I've also provided a few helpful links at the end for more information.
Most of the questions, submitted by a mix of people from various companies as well as academic and government institutions, fit into three major themes: The logistics of submission/review, criteria for acceptance and broader implications of the new designation.
Who at the FDA makes the decision to grant Breakthrough Therapy designation and when?
Applications are reviewed by an FDA Medical Policy Committee. Importantly, that committee is separate and independent from the review divisions within the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER). Companies can apply at any stage of development, but the FDA can also withdraw the designation at any time if the early clinical evidence of a substantial improvement changes.
How much time does breakthrough designation shave off of the standard FDA review process? Does it change any of the official deadlines or action dates?
The official FDA review timelines or action dates don't change. For example, from the time of a new drug or biologic submission, the FDA has 60 days to respond, and for new molecular entities an action date is set at 12 months from the time of submission (or 8 months if priority review is also granted--which seems likely but is not guaranteed).
As for the overall development time, it's hard to say. Factors like enrollment and the event-driven nature of certain trials can have a significant impact on timing and are not influenced by FDA legislation. However, many analysts are speculating that breakthrough designation will speed up the total time from IND submission to approval by months or even years.
Is there a guideline for how much data is required (e.g. minimum number of patients treated)?
There isn't an exact requirement for the data necessary, but it has to be exceptional. Specifically, the FDA legislation requires that "preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints."
What are the key criteria a drug sponsor should use to decide if or when to apply for breakthrough designation?
Each sponsor obviously will have to develop its own criteria, but the primary consideration should be simply whether or not the requirements (serious disease, early clinical evidence, substantial improvement) are met.
Does the FDA only base its decision on disease management and efficacy, or would drug safety and other factors be considered?
Breakthrough designation is about recognizing the potential benefit for people with serious or life-threatening diseases. Usually that means evidence of substantially improved efficacy over existing therapies. However, per the FDA's draft guidance (see below), substantial improvement could also come from a significantly better safety profile. So while efficacy is the primary criteria, it isn't the only one the FDA considers.
How many applications for breakthrough designation have been accepted? What are some common reasons for rejection?
So far, roughly two dozen investigational medicines have received breakthrough designation (and this number will probably be outdated by the time you're reading this!). That's about a 30% acceptance rate, at least for now.
The FDA tracks the number of submissions, acceptances, and denials, but they don't disclose specifics. Only sponsors can choose to announce the decisions. So it's very tough to conclude anything about rejections.
Having said that, it's important to remember that just because a medicine is rejected doesn't mean it isn't important for patients. On the flip side, just because a medicine does receive breakthrough designation doesn't guarantee it'll be a success, and it's important to note that the FDA can withdraw the designation if clinical evidence doesn't continue to support breakthrough status.
How will the FDA ensure safety as development time is shortened? Will there be additional/stricter postmarketing requirements for breakthrough therapies after approval?
While the specifics have yet to be ironed out, if approvals are based on Phase I or Phase II data there will almost certainly be additional postmarketing requirements and commitments (PMRs and PMCs). In theory, we could also see more accelerated approvals as a result of breakthrough designation.
Would a new drug combined with a companion diagnostic be more likely to receive breakthrough designation?
Many new medicines are being developed in parallel with companion diagnostics, and some of these will probably be granted breakthrough status. However, it's hard to say if drugs with companion diagnostics will be more likely to receive the designation. Undoubtedly there will be drugs with and without companion diagnostics. The specifics of how the diagnostic is developed and reviewed under breakthrough designation (which currently does not apply to diagnostics) are under active discussion.
Will this put small companies at a disadvantage because it's harder for them to compress development timelines and prepare for immediate product launch?
The current list of publicly disclosed breakthrough designations reflects a mix of both large and small companies. So at least in terms of the designation itself, there doesn't seem to be an imbalance.
As for what comes next, there's no doubt that companies of all sizes will face challenges. Breakthrough designation comes with a commitment for an "all hands on deck" approach from both the sponsor and the FDA. Drug sponsors have to step up and take on increased personnel demands, earlier manufacturing deadlines and tighter timelines in every aspect of development. This will require advanced planning and flexibility from everyone involved. My colleague Sandra Horning wrote a great article in Clinical Cancer Research addressing some of these challenges.
Breakthrough designation is in its infancy and we're all learning as we go. Though the situation is very fluid, I am most impressed by the level of commitment from all the involved parties who are dedicated to making this program work as best as it can.
Links for more information
FDA's official draft guidance for breakthrough designation
FDA summaries of the number of breakthrough applications submitted, denied, and rejected
Horning SR, et al. (2013). Developing Standards for Breakthrough Therapy Designation in Oncology. Clin Cancer Res 19(16):1-8.
Michelle Rohrer received her Ph.D. in Nutrition Science with a minor in Physiological Biochemistry from the University of California, Davis. She joined Genentech as a post-doctoral fellow in 1993 and later became a Clinical Scientist in Genentech's Development organization. In 1999, Rohrer joined Genentech's Regulatory organization holding positions of increasing responsibility, including head of both the Commercial and Clinical Regulatory groups with responsibilities overseeing the development and commercial regulatory strategies for Genentech's entire product portfolio. In the now-merged Genentech Roche organization, Rohrer is Vice President of U.S. Regulatory Affairs. In this capacity, Rohrer oversees Genentech Roche's regulatory development strategies, commercial aspects and policy efforts in the US. In addition, Rohrer is also the South San Francisco Site Head for Roche's Global Product Development organization.