Parexel introduces FDA expedited designation trends for advanced therapies

FDA expedited designation trends are a marker of innovation, promise, and momentum in the R&D pipeline, particularly for cutting-edge therapies.

In this quarterly analysis, Parexel’s Cell & Gene Therapy Center of Excellence explores the latest trends in FDA expedited development designations for advanced therapies regulated by the Center for Biologics Evaluation and Research (CBER), with a focus on the three most recognizable regulatory designations available to innovative and novel products: breakthrough therapy designation (BTD), regenerative medicine advanced therapy (RMAT), and fast track (FT) designations. To inform the regulatory strategies for innovator organizations, our compendium provides unprecedented regulatory insights that include:

• The latest trend data on industry regulatory designation requests and FDA designation grants to highlight the degree to which other advanced therapy companies are pursuing these designations and the extent to which CBER is granting them.
• Detailed listings and analyses of the latest advanced therapy designations to identify the basis for each individual therapy designation, including the phase and size of each clinical study used to support the request/grant and, where applicable, the patient response rates believed to justify the basis for each designation.
• Commentary and analysis from recognized Parexel experts that offer additional context and analysis on data and findings.

Breakthrough designation: still the apex FDA expedited designation?

Since its creation in 2012, the BTD has been considered as the FDA’s apex regulatory designation for drugs, biologics, and vaccines. Although RMAT designation provides the same tangible regulatory benefits for cell and gene therapies (CGT) which are eligible for both designations; these products must fulfill a higher standard to qualify for BTD status than for RMAT.

The BTD has had an interesting decade-plus history for advanced therapies. Like FT designation and unlike RMAT designation, BTD’s eligibility cuts across all key categories of CBER-regulated products, including vaccines, CGT, and others. 

As the CBER designation with the highest qualifying bar, BTD has a grant success rate of only 33% for the life of the program (2012-2023).  Measured by industry requests, BTD’s popularity grew quickly for biological and related products, before RMAT’s rapid ascent began with its creation in 2016, enabling a competitive pathway for CGTs to gain BTD-like benefits at a lower qualifying bar. Then, following a similar trend to other higher-order designations such as RMAT, industry BTD requests to CBER dropped substantially during the pandemic to a record low of 10 in 2021. However, industry requests for BTD and RMAT rebounded strongly, reaching record highs in FY2023. While BTD success rates reached a high point in 2022, only 29% of BTD requests were granted in 2023. Midway through 2024, BTD grant success rate remains among the lowest levels since 2013.

CBER BT submission/grant trends 2012-2024*

RMAT designation: CBER’s most requested high-order designation

Although only a subset of products qualify for it, RMAT quickly became CBER’s more requested high-order designation shortly upon its creation in late 2016.  Since that time, developers of eligible CGTs have been able to request either RMAT status, BTD, or even both, to access a possible bounty of advantages, including higher program visibility within and streamlined access to CBER meetings. 

While BTD and RMAT offer access to an identical set of tangible benefits, CGT developers have favored RMAT, due to a perceivedlower qualifying bar. Although the lower bar has not always been acknowledged by CBER, FDA officials have discussed it in recent years:

When it was first passed, I would have been very skeptical about the difference between BT and RMAT. But as it’s come to evolve, the fact that the standard is a little bit lower to receive this designation—one simply has to show that you have possible clinical benefit, not that you are better than existing standard of care—it allows us to designate products that might not have quite the same amount of clinical information. [The lower evidentiary standard for RMAT] is somewhat helpful for some of these regenerative medicine products, which are a little bit earlier on and are a little bit harder to study early on in their development.

CBER Director Peter Marks, MD, PhD
@ FDLI Annual Meeting,
May 20, 2021

CGT developers’ preference for RMAT might also be a function of a second perceived advantage, and one that could elevate RMAT to the next apex designation—in terms of regulatory value. “One thing that I’ve noticed is that some sponsors view an RMAT designation request as a way to gain earlier insight than would be possible with a BTD request as to whether the company and the FDA are seeing eye-to-eye on the potential for the product to fulfill unmet needs,” observes Winitsky. “The earlier in development that this touchpoint occurs, if there is a disparity in sponsor/agency perspectives, the more potential there is for further discussion with FDA on mutually agreed upon changes to key elements of the clinical development program.”

While RMAT grant success rates for CGTs have generally been higher than those for BTD across all CBER-regulated products, the rates have been largely comparable. In certain years, the BTD success rate has even been notably higher. It is possible that many companies, encouraged by perceptions of a lower qualifying bar that can be met with less evidence and earlier-stage clinical data, have been more aggressive in testing the lower limits of RMAT designation. RMAT designation requests have outpaced BTD requests in many years by more than double. In 2023 and so far in 2024, CBER’s RMAT grant success rates have significantly bettered BTD grant rates.

RMAT vs. breakthrough designations requests to CBER 2017-2024
 

Contributing Experts