Regulatory Focus™ > News Articles > FDA Releases Long-Awaited Guidance on Breakthrough Product Designation

FDA Releases Long-Awaited Guidance on Breakthrough Product Designation

Posted 25 June 2013 | By Alexander Gaffney, RAC

The US Food and Drug Administration (FDA) has released a new guidance document pertaining to the use of so-called "expedited programs" for serious conditions by the pharmaceutical and biotechnology industries, including a new designation known as breakthrough product designation.


At FDA, fast track development is meant to focus agency resources on an application for a promising drug or biological product intended for a serious or life-threatening condition for which there is no adequate treatment or cure.

There are currently three main programs used by FDA to expedite the process of approving a drug intended to treat a serious or life-threatening condition:

  • Fast track designation - A designation given to a drug application for which there is evidence that it has the potential to address an unmet medical need or one that has been designated as a qualified infectious disease product. Allows for a rolling review of an application by FDA and the ability to expedite certain aspects of development and review.
  • Priority review designation - A designation given to applications (either new or supplemental applications) for which there is evidence that a treatment would provide a significant improvement in the standard of care for a patient. The designation shortens FDA's timeline for reviewing the application from 10 months to six.
  • Accelerated approval - An approval pathway through which a drug that provides a "meaningful advantage over available therapies" can obtain approval based on data in support of a surrogate endpoint. No change in the review timeline.

Breakthrough Product Designation

Since the 2012 passage of the FDA Safety and Innovation Act (FDASIA), FDA has also been able to use a fourth expedited program known as breakthrough product designation.

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

In other words, no "me-too" drugs - the breakthrough designation is meant for first-in-class treatments or ones targeting diseases in ways that no other drug has before.

Unlike the other designations or pathways, 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.

As with the other two types of designations, FDA may withdraw breakthrough status if the product no longer meets the qualifying criteria for the designation.

Definitional Details of Evidence

FDA's new guidance explains that to qualify for breakthrough status, a company must be able to show preliminary clinical evidence of an effect, as well as a rationalization that the effect would mark a "substantial improvement" over the current standard of care.

Evidence provided to FDA could include early clinical evidence, the use of mechanistic biomarkers, and nonclinical information on drug activity. However, explained FDA, "In all cases, preliminary clinical evidence demonstrating that the drug may represent a substantial improvement over available therapy should involve a sufficient number of patients to be considered credible."

Regulators added that they realized preclinical data "cannot be expected to be definitive at the time of designation." However, on an ideal basis, sponsors would provide clinical evidence from a clinical trial comparing the investigational drug to either a standard therapy or a placebo. Other clinical data would only be found to be "persuasive" if there was a "large difference" between the new treatment and the historical experience.

The guidance also goes on to define "clinically significant endpoints" as well, explaining that sponsors may support designation using surrogate endpoints, intermediate clinical endpoints that are likely to predict clinical benefit (similar to the accelerated approval standard), pharmacodynamics biomarkers, or an improved safety profile relative to available therapies.

Substantial Improvement

Even beyond standards of acceptable data, FDA reiterates that companies must be able to show evidence of "substantial improvement," which it notes is something of a subjective standard taking into account the "magnitude" and duration of an effect, as well as the effect's importance.

"In general, the preliminary clinical evidence should show a clear advantage over available therapy," it added. "Such improvement will be clear when there is no available therapy or when available therapy shows only a modest response and the new therapy shows an effect on an important outcome. Where there is an effective available therapy, showing substantial improvement is more challenging."

In addition to the two obvious comparison methods - to available therapy or to an available treatment - FDA also said it hopes to see the introduction of drugs that treat the underlying cause of a disease. The first two drugs designated as breakthrough products, Vertex Pharmaceuticals' Kalydeco (ivacaftor) and a combination of Kalydeco and another compound (VX-809), are meant to treat cystic fibrosis by treating its underlying cause. "In this case, the treatment effect is entirely new," FDA noted.

Drugs may also be eligible if they reverse disease progression or demonstrate important safety advantages over existing standards of treatment.

The draft guidance, Expedited Programs for Serious Conditions - Drugs and Biologics, may be found here.

Expedited Programs for Serious Conditions - Drugs and Biologics

Federal Register

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