FDA Provides Update on Breakthrough Product Designation Program, Showing Industry Interest

Posted 12 December 2013 | By Alexander Gaffney, RAC 

More than one year has passed since the US Food and Drug Administration (FDA) was first given the authority to give products "breakthrough" designation under the Food and Drug Administration Safety and Innovation Act (FDASIA), granting companies a range of tools to accelerate the review of a product.

But despite not having much in the way of information about the designation until June 2013, sponsors have been nothing but eager to obtain it, according to data released this week by FDA.


As defined by FDA, breakthrough products are those intended to treat a serious condition based on preliminary clinical evidence that indicates the drug may demonstrate substantial improvement on clinically significant endpoints over available therapies.

Unlike the other designations or pathways (fast-track designation, priority review designation, or accelerated approval), breakthrough product designation isn't meant to expedite development based on shortened timelines or surrogate markers, but rather grant access to enhanced review tools such as all of the features of the fast track designation, as well as "intensive guidance" from FDA regarding the development of the product.

In June 2013, FDA released a new guidance document, Expedited Programs for Serious Conditions - Drugs and Biologics, intended to establish its expectations for the program and illustrate how sponsors could obtain the designation.

The guidance, however, came months after the first breakthrough product application was accepted by FDA. In January 2013, FDA accepted two applications from Vertex Pharmaceuticals, one for an expanded indication for Kalydeco (ivacaftor) (already approved to treat a specific genetic variant of cystic fibrosis) and the second a combination of Kalydeco and an experimental compound (VX-809).

By November 2013, FDA had approved its first-ever product under the pathway, Roche's Gazyva (obinutuzumab), a biologic intended to treat chronic lymphocytic leukemia (CLL) in combination with chlorambucil. Some critics noted that the approval took more than six months to complete-hardly unprecedented speed for an oncology product intended for an orphan drug population.

Industry Interest

But if the pathway has been slow to take shape and illustrate its benefits, companies don't seem to mind much.

In presentations delivered on 11 December 2013 at the FDA/CMS Summit in Washington, DC, two officials within FDA's Center for Drug Evaluation and Research (CDER) presented data showing that demand for the program is strong.

Richard Moscicki, deputy center director for science operations, said that to date, FDA has received 113 requests for breakthrough designation, of which 34 have been granted and three already approved.

Of those designations that were granted, 26% were for antiviral drugs, 24% for hematology, 18% for oncology and 9% for gastroenterology and neurology, respectively.

John K. Jenkins, director of CDER's Office of New Drugs, elaborated further, noting that despite the guidance, the breakthrough product designation is very much a subjective criteria requiring judgment by FDA reviewers. All designation requests are reviewed by CDER's Medical Policy Council to "ensure consistency of standards and approach," Jenkins explained.

Jenkins' data showed that of the 113 requests received so far, 49% have been denied, 30% granted, 9% withdrawn and 12% remain pending.

Observations and Errors

The applications received have also reflected a range of development states, perhaps due in part due to the rollout of the program.

"Some designated drugs have been late in development," Jenkins added. "In some cases, the marketing application [was] already submitted."

This stands in contrast with the intent of the program, which is to identify drugs very early on in development, such as after Phase I clinical data has been obtained.

Jenkins, as other FDA reviewers have noted in the past, also called attention to a rarely discussed topic: rate limiting. The review process was not the sole limiter of reviews, he said. Without ways of speeding up manufacturing and scale-up processes, additional review efficiencies will be for naught.

Jenkins also provided a helpful list of common reasons requests for breakthrough designation are denied:

  • evidence does not include clinical data
  • evidence is too preliminary to be considered reliable
  • failure to demonstrate "substantial" improvement over available therapy
  • reliance on a novel biomarker or surrogate endpoint without sufficient evidence
  • post‐hoc analyses of failed studies that identify a subset that may benefit

Jenkins Slide Deck

Mosckicki Slide Deck

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