FDA’s Breakthrough Therapy Designation program helps to expedite the development and review of new drugs and biological products that may demonstrate “substantial improvement” over existing therapies on one or more “clinically significant endpoints” that measure an effect on irreversible morbidity or mortality (IMM), or on symptoms that are serious consequences of the disease. If a therapy is granted breakthrough designation, it receives all the benefits of fast track designation (FTD) – which include more frequent meetings and written communication with FDA, rolling review, and eligibility for Accelerated Approval and priority review. In addition, drugs granted BTD are eligible for intensive guidance on an efficient drug development program, as well as involvement of FDA senior managers to expedite drug development. FDA recently indicated in its “PDUFA Reauthorization Performance Goals and Procedures” document that the agency is “committed to ensuring the expedited development and review of innovative therapies for serious or life-threatening diseases or conditions by investing additional resources into the breakthrough therapy program.”

FDA may periodically assess whether breakthrough-designated products continue to meet the criteria for BTD, as the information supporting FDA’s grant of BTD for a particular drug or biological product may change over time. For example, some drugs or biologics that appear promising in early development may no longer appear to meet the BTD criteria after later-stage clinical trials. If the BTD designation is no longer supported by subsequent data, FDA may rescind the designation.  According to CDER, one BTD has been withdrawn after granting in FY 2022, with none being rescinded, and in fiscal years 2012-2021, 10 BTDs have withdrawn after granting and 35 separately rescinded in total.

To help stakeholders better understand FDA’s criteria for rescission of a BTD, the agency published a six-page draft guidance last week. Most notably, the draft guidance says a BTD may be rescinded for reasons such as:

1. A different drug is approved to treat the unmet need that informed the rationale for granting BTD. As a result of this new therapy, the BTD drug no longer meets the BTD criteria regarding substantial improvement over existing available therapies. FDA notes in the draft guidance, however, that another drug approved under accelerated approval generally will not be considered sufficient to lead to rescinding BTD.
2. 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.”
3. The designated drug’s sponsor is no longer pursuing the drug’s development program for the use that was the basis for BTD.

The draft guidance spotlights how rescinding a BTD may be warranted “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.” The draft guidance continues, “[t]he emergence of additional safety information that alters the benefit-risk assessment of the designated product may also support a decision to rescind BTD.” The draft guidance emphasizes that FDA will generally apply greater weight to larger trials and those that “use a well-understood and widely accepted, well-constructed clinical endpoint, and incorporate certain design features,” such as randomization or blinding, noting that the quality of available evidence can play a role in FDA’s decision-making.

FDA also explains when it may decide to not rescind BTD designation, even if subsequent clinical trial results appear not to support the evidence on which BTD was based. For example, “if initial data were promising, and there are significant issues with the conduct and design of a subsequent study, the subsequent study may be given less weight in assessing whether the criteria for BTD are still met.” However, “if the evidence available from multiple well-designed studies reflect an inconsistent picture of clinical benefit, the assessment of whether the criteria for BTD continue to be met may become more challenging.” As such, FDA emphasizes that decisions will be made on a case-by-case basis, depending “on the facts specific to that drug development program.”

Before FDA rescinds a grant of BTD, CDER will notify the sponsor in writing of its intent to rescind, providing its rationale for this decision in the letter, pursuant to MAPP 6025.6. The letter will provide the sponsor with an opportunity to submit additional data and justification to support the continuing BTD and to request a meeting with the division to discuss the BTD for the drug. If, after any additional information is presented, the reviewing division’s determination that the criteria for BTD are no longer being met remains unchanged,  the agency will notify the sponsor in writing of the decision to rescind the BTD. However, the sponsor may have the option to appeal the decision through  Formal Dispute Resolution to the next higher management level, according to the agency guidance “Formal Dispute Resolution: Sponsor Appeals Above the Division Level,” revised November 2017.

Next steps

The timing of this draft guidance may signal that the agency is preparing to institute routine reviews of  BTDs, which may lead to more rescissions.

If you have any questions about BTDs, the information necessary to continue to support a BTD, or FDA’s expedited approval programs more generally, you may contact any of the authors of this alert or the Hogan Lovells attorney with whom you generally work.

Authored by Robert Church, Lynn Mehler, and Dave Fox