Through with Breakthrough? FDA’s New Draft Guidance Reflects an Uptick in Notices of Intent to Rescind

June 29, 2022By Mark A. Tobolowsky & Deborah L. Livornese

Last week, FDA issued a draft guidance entitled “Considerations for Rescinding Breakthrough Therapy Designation” (the Draft Guidance), authored by CDER, CBER, and the Oncology Center of Excellence (it is interesting, though not surprising, to see the OCE as an author on this document, given the popularity of the program in oncology). Prior to issuance of this Draft Guidance, information about this previously little-used process was included in a variety of sources we describe below. Indeed, the Draft Guidance appears intended largely to capture these policies in one single document.

Breakthrough Therapy Designation (BTD) was created in 2012 as part of the FDA Safety & Innovation Act (FDASIA). Section 506 of the Food, Drug, & Cosmetic Act describes the qualifications for a designation, the procedures for both the applicant and FDA to take to result in a BTD, and the implications of a designation. Notably, nothing in the statutory language describes grounds or a process for the rescission of a BTD.

In May 2014, FDA finalized a guidance document entitled “Expedited Programs for Serious Conditions – Drugs and Biologics,” (the Expedited Programs Guidance) This guidance noted that a “[d]esignation may be rescinded if it no longer meets the qualifying criteria for breakthrough therapy.” It added the justification that “FDA commits significant resources to work particularly closely with sponsors of breakthrough therapy products,” and, thus, “needs to focus its resources on breakthrough therapy drug development programs that continue to meet the program’s qualifying criteria.” The Expedited Programs Guidance describes situations warranting rescission as when emerging data no longer support the BTD, another product gains traditional approval and evidence is not provided that the designated drug may demonstrate substantial approval over the approved product, or when the program is no longer being pursued. In such an instance, the guidance elaborated, “FDA will notify the sponsor of its intent to rescind and will offer the sponsor an opportunity to justify its product’s continued designation.”

Subsequently, CDER, in MAPP 6025.6, and CBER, in SOPP 8212, provided more granularity as to how this process would work with step-by-step instructions for FDA staff. Both documents describe the process in two steps: the intent to rescind step and the rescinding step. The review division notifies the sponsor of its intent to rescind the BTD with supporting justification (CDER’s MAPP explicitly cites the three justifications cited in the Expedited Programs Guidance) and provides the sponsor with an opportunity to submit additional data and justification to support the continuing BTD and/or to request a meeting. If the sponsor fails to convince the division that the BTD should be continued, the division then notifies the sponsor that BTD has been rescinded. For CDER specifically, the division must discuss the proposed rescission with CDER’s Medical Policy Council prior to notifying the sponsor. The Medical Policy Council’s role, as described in the MAPP, is to discuss decisions to rescind to ensure consistency in policy implementation across review divisions. For both CDER and CBER, the Division Director’s concurrence on the decision is required. If the sponsor succeeds in persuading FDA to maintain the BTD, the Medical Policy Council is not explicitly involved, and plans for a path forward under the BTD should be discussed.

Until last week, these documents constituted the official descriptions of the process for rescinding a BTD.

This bring us to the publication of the recent Draft Guidance which begins by noting that the breakthrough therapy program involves a significant resource commitment, and as such, “it is important that available evidence continues to fulfill the standard for BTD.” FDA goes on to say that the information that originally supported the BTD, often preliminary or early data, “may change over time,” and, thus, FDA has determined its BTD determination must also change. The Draft Guidance specifically lists the three reasons originally cited in the Expedited Programs Guidance as examples justifying rescission:

  1. A different drug is approved to treat the unmet need and the BTD drug no longer meets the criteria regarding substantial improvement over available therapies. In accord with FDA’s definition of “available therapy,” the Draft Guidance notes that drugs approved under accelerated approval will not generally be considered available therapy unless and until it is granted traditional approval.
  2. Emerging data no longer support the BTD.
  3. The sponsor is no longer pursuing the development program.

The Draft Guidance also includes a few interesting new pieces of information that are part of the rescission determination. It explains that “FDA typically gives 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).” If there are “significant issues with the conduct and design of a subsequent study,” FDA may decide not to rescind the BTD, even if the trial’s results appear to support such an action.  More on this point below.

Additionally, if trial results from multiple well-designed studies “reflect an inconsistent picture of clinical benefit,” the determination may also be “more challenging”. The Draft Guidance describes a scenario where the primary endpoint does not demonstrate statistical significance, but a secondary clinical endpoint of interest shows a favorable trend; in such a situation, the trial might still demonstrate “preliminary clinical evidence” to support the BTD. However, the determination “will depend on the facts specific to that drug development program.”

Historically, FDA has not rescinded many BTDs. As of March 31, 2022, CBER had never rescinded a BTD.  As for CDER, although rescission of a BTD has not been a particularly common occurrence, we have seen what seems to be an uptick in FDA’s issuing Notices of Intent to Rescind, even as requests and grants have slightly declined from the 2019 highs.

Fiscal YearTotal Requests ReceivedGranted              Rescinded                 

Sources: CDER BTD Requests and CDER BTD Rescissions.

Perhaps the decision to publish this Draft Guidance reflects what may be a trend toward issuing notices, and maybe that trend, if there is one, is yet another consequence of the pandemic and its unprecedented strain on FDA staff.

Regardless, the Draft Guidance leaves us with some questions. It describes how studies with “significant issues with the conduct and design,” are less likely to result in rescission. We assume this refers to the challenges of rare disease development, and how it may be more difficult for rare disease sponsors to design trials with the features outlined in this section (randomization, well-understood endpoints, etc.). Further clarification in the Final Guidance that this section is intended to reflect the need to evaluate these programs with more flexibility would be welcome.

Additionally, while the Draft Guidance is entirely silent as to how a sponsor may challenge the proposed action, the referenced MAPP and SOPP include direction to FDA staff about providing an opportunity for a sponsor to submit more information and/or request a meeting. The Draft Guidance is silent on whether FDA intends to maintain the opportunity to justify the continued designation prior to rescission as described in those other documents. The intent may be to leave that to the individual Centers to describe as they now do, but it would be helpful to include a statement to that effect in the Draft Guidance.