Cut the Cycle, Not the Science: Breakthrough Therapy Designation

Reproduced with permission from DIA North America.  You can see the original here.

By Sarah DeMare

Signed into law in July 2012, the US Food and Drug Administration Safety and Innovation Act (FDASIA) included a new expedited drug development pathway known as the Breakthrough Therapy Designation. This program provides the FDA and sponsors an avenue for expedited drug development with one main requirement: the submitted application must contain preliminary clinical data indicating the drug may “offer a substantial improvement over available therapies for patients with serious or life-threatening diseases”1. As of 1 May 2015, 14 new drugs have been approved by CDER, and two by CBER, under the Breakthrough Therapy Designation program2.

The recent 2075 DIA CMC Workshop featured one session specifically focused on the chemistry, manufacturing and control (CMC) challenges related to Breakthrough Therapy Designation; panelists Brian Kelley (Genentech) and John Groskoph (Pfizer) represented industry, and Dorota Matecka and Robert Wittorf represented FDA’s Office of Pharmaceutical Quality. While the two industry panelists presented different case studies, the overall message from all participants was similar and very clear: Accelerating product development for critical new therapies along the condensed timelines of the Breakthrough Therapy Designation program will pose significant challenges for CMC professionals.

Sponsors certainly benefit from many aspects of the Breakthrough Therapy Designation, including a rolling submission; more intensive FDA guidance on their development program; more frequent communication with FDA during the review cycle; and more senior FDA managers and reviewers involved in review of their application.

It is important to note that the Breakthrough Therapy Designation does not excuse a sponsor from fulfilling their regulatory requirements for that product. Sponsors must still meet all submission requirements for safety, efficacy and quality. This designation simply allows for development on a condensed timeline with some activities potentially pushed to a post-approval commitment or requirement.


Reducing time in the normal development schedule can significantly cut into time allocated for CMC development. For example, there is less time for method development and process optimization, and specifications will be set with limited data because of the reduced number of batches produced. Shelf life may be difficult to assign from the available stability data. Simultaneously preparing for both pre-approval inspection (PAI) and launch, along with simultaneously manufacturing clinical supplies and commercial product, poses particularly daunting resource challenges for most companies. All these factors often combine to place CMC activities on the project critical path.

The limited available data also poses regulatory challenges. FDA must perform its benefit-risk analysis based on the decreased available amount of quality information. In response, FDA has been evaluating new approaches to ascertain the quality of breakthrough therapy products that will mitigate the risks associated with basing such determinations on less data.

These speakers identified areas of opportunity to improve the Breakthrough Therapy Designation process. Brian Kelley suggested adaptions to the sponsor’s pharmaceutical quality system, control strategy, and PAI readiness preparation. John Groskoph proposed opportunities for leveraging the sponsor’s previous PAI inspection history, more real-time sponsor-agency communication (potentially by adjusting meeting procedural timelines), and establishing provisional specifications based upon the limited data; he further recommended that sponsors leverage comparability protocols to handle areas of process improvement that the sponsor has identified but did not have enough time to fully investigate. Comparability protocols could also be used to extend shelf life; the initial shelf life may be shorter than optimal since it will be based upon limited stability data.

While the Breakthrough Therapy Designation poses many CMC challenges for FDA and sponsors, all speakers made it clear that both FDA and sponsors are committed to getting important medications to patients quickly. Every speaker underscored that one clear way to help mitigate these challenges is open communication between the sponsor and FDA.

The Breakthrough Therapy Designation does not give sponsors a free pass from fulfilling any regulatory requirements. These products must still meet the same efficacy, safety, and CMC requirements, as any other drug. However, FDA gives these applications the highest priority, and FDA recommends that sponsors submitting these applications engage with them as soon as possible because active and timely communication is paramount during the approval process2 As more experience is gained with breakthrough therapy products, and more products are approved under this pathway, I anticipate the development of further guidance documents that incorporate some of our lessons learned and opportunities identified for improvement.