Break On Through to the Other Side, Part 2: FDA Issues Draft Guidance About Breakthrough Therapy Designation Rescission

Footnotes for this article are available at the end of this page.

In September 2014, AGG prepared a Bulletin on the Food and Drug Administration’s Breakthrough Therapy Designation (BTD) program, referencing The Doors’ “Break On Through to the Other Side.”1 Time for Part 2. FDA issued a draft guidance in June titled, “Considerations for Rescinding Therapy Designation,” which explains when it might take away this treasured status.2


  • According to Section 506(a) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. § 356(a)), FDA may afford BTD status “if the drug is intended, alone or in combination with one or more other drugs, to treat a serious or life-threatening disease or condition and preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints, such as substantial treatment effects observed early in clinical development.”
  • Benefits include multidisciplinary meetings involving senior FDA personnel to promote frequent company/agency discussions and, if appropriate, expediting the review of marketing applications.
  • In its guidance, FDA noted that, while a drug may appear promising in early development, it may not be shown to be safe or effective in later trials, or the potential benefit of treatment effect suggested by early development may not be seen later; therefore, FDA may rescind the designation if it is no longer appropriate.
  • FDA may look to early clinical data, including evidence based upon robust pharmacodynamics endpoints, to support a BTD.
  • FDA provided examples of where it might rescind a BTD:
    • A different drug is approved to treat the unmet need that provided the rationale for granting BTD; therefore, the drug no longer meets the BTD criteria regarding substantial improvement over existing available therapies.
  • The agency added that another drug approved under the accelerated approval process would generally not be considered sufficient to lead to a BTD rescission.
    • Emerging data for the designated drug no longer support a finding that “preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies” (citing the statute).
    • The designated drug’s sponsor is no longer pursuing the drug’s development program for the use that was the basis for the BTD.
  • One specific example FDA provided is that it might rescind a BTD “if a phase 3 trial intended to definitively show the designated drug’s effect fails to meet its primary endpoint, or the extent of benefit is more modest such that the trial does not indicate that the drug may demonstrate a substantial improvement over available therapy.”
    • Additional safety information that affects the benefit-risk assessment of the designated product may also be the basis to rescind a BTD.
    • The agency stated that it will generally afford “greater weight to trials that are conducted in larger populations, use a well-understood and widely accepted, well-constructed clinical endpoint, and incorporate certain design features (e.g., randomization, blinding)” when reviewing whether BTD criteria remains intact, “the quality of evidence available may impact FDA’s decision-making.”
  • FDA might choose not to rescind a BTD, even if it otherwise appears it should be done (e.g., there are issues with the design and conduct of a subsequent study, but the initial data was favorable). “The decision whether to maintain or revoke BTD in such cases will depend on the facts specific to that drug development program.”

AGG Observations

  • FDA can giveth and taketh away. A BTD is not absolute.
  • It is important that companies that receive a BTD appreciate that, if certain conditions apply, the BTD prize can be lost, which can have significant product review and, possibly, commercial and financial implications.
  • If a company has concerns about a particular BTD and its viability, depending on the facts, it should discuss them with FDA sooner rather than later. To paraphrase Jim Morrison, you don’t want to cry when your chased pleasures and dug treasures no longer remain.


[1] See Nduom/Minsk Bulletin –

[2] The guidance document can be assessed at