Executive Summary

Agency staff, stakeholders see advantages to bundling requirements for fast-track and RMAT designations into a single, pre-breakthrough therapy pathway, and codifying processes and interactions that take place following award of breakthrough designation; proposal is aimed at reducing current programs’ redundancies and maximizing benefit of frequent, early interactions with the FDA.

US Food and Drug Administration staff and stakeholders are discussing a potential redesign and simplification of the agency’s expedited regulatory programs to eliminate redundancy, better facilitate development of promising therapies, and address emerging drug development challenges.

One idea for reconfiguring the expedited development programs – fast track, breakthrough therapy and regenerative medicine advanced therapy – is to create a common entry point for drugs intended to treat a serious or life-threatening condition and with the potential to address an unmet need.

Under this approach, the requirements associated with fast track and RMAT designations could be bundled into a single, pre-breakthrough therapy designation pathway, while the processes and interactions that take place after breakthrough therapy designation is awarded would be better spelled out.

Modernizing the FDA’s expedited development programs was the focus of the first part of the Friends of Cancer Research’s virtual annual meeting in November. The user fee reauthorization, which must be completed by the end of September next year, seems a ready vehicle for making the changes.

“We spend a lot of time at the FDA designating all of these different programs, what drugs should go into them, and to be honest there’s a lot of overlap that exists.” – FDA’s Richard Pazdur

“Streamlining expedited programs where less redundancy exists can lead to more optimal and successful use within the lifecycle of a drug to avoid confusion as to when they can be used during a development program,” a multi-stakeholder working group said in a white paper prepared for the FOCR meeting.

“We spend a lot of time at the FDA designating all of these different programs, what drugs should go into them, and to be honest there’s a lot of overlap that exists,” Oncology Center of Excellence director Richard Pazdur said during the FOCR meeting. “I really want to challenge people to kind of take a look at all of these programs and how we could actually simplify them.”

An important consideration in the early discussions around reimagining the existing presubmission expedited programs is the “need to critically look at what goes on after we make these designations,” Pazdur said. “The designation means nothing unless one actually executes it.”

Getting Rid Of Redundancies

The FDA’s expedited pathways, which also encompass the postsubmission programs accelerated approval and priority review, are popular among sponsors, particularly in the oncology space.

According to a landscape analysis included in the white paper, 90% of initial oncology drug approvals from 2012-2019 used an expedited program, versus 55% of new non-oncology drug approvals. Priority review and fast track were the most frequently used programs, followed by breakthrough therapy.

The agency’s presubmission expedited programs have evolved in piece-meal fashion over the past 30 years through passage of various legislative measures. This has resulted in redundancies in qualifying criteria and benefits among the pathways.

Sponsors spend extensive amounts of time preparing designations requests; the FDA, in turn, spends a lot of time reviewing those requests.

“It would certainly be more efficient for us as a sponsor, and I imagine for the FDA as well, if we were to apply for one early designation rather than prepare multiple requests over time for various different designations that give us a similar benefit,” said Scott Korn, VP-global regulatory affairs at Merck & Co., Inc.

While the benefits of the various designations can vary depending upon how far along a development program is, the timing for use of the expedited pathways often is less than optimal.

In a cohort of nine oncology drugs that used fast track, breakthrough, priority review and accelerated approval, fast track and breakthrough designation often occurred later in the lifecycle of the development program, several years after IND submission and close to the time of NDA/BLA submission. This is “likely indicative of having greater confidence in the clinical data,” the white paper states.

“However, the benefit of these expedited development programs may be most realized earlier in development and could enable more meaningful interactions on other key aspects of a development program (e.g., chemistry, manufacturing, and controls [CMC], co-development of a diagnostic assay).”

Harpreet Singh, director of the FDA’s Division of Oncology 2, said redundancy in the programs creates confusion for both the FDA and industry.

“We would encourage the agency to have a more holistic approach to advise sponsors in these expedited pathways to synchronize their clinical and CMC development or link other complex parts of their development to ensure that they are tracking together.” – bluebird bio’s Anne-Virginie Eggimann

For some oncology therapeutics, fast track and breakthrough designation have been granted in close proximity, Singh said. “You have to wonder about the effort that goes behind reviewing these and all the documentation and what the value is there.”

The need to better align the chemistry, manufacturing and controls processes with clinical development continues to be a challenge, despite the availability of the expedited programs.

Anne-Virginie Eggimann, SVP-regulatory science at gene therapy company bluebird bio, said breakthrough and RMAT have been helpful in increasing interactions with FDA staff and accelerating clinical development. However, they have been less useful in accelerating CMC development, particularly for the emerging and complex field of cell and gene therapies.

This is an area that should be further explored in any redesign of the presubmission expedited programs, Eggimann said. “We would encourage the agency to have a more holistic approach to advise sponsors in these expedited pathways to synchronize their clinical and CMC development or link other complex parts of their development to ensure that they are tracking together.”

Before And After Breakthrough

A proposal for revamping the presubmission expedited programs into pre- and postbreakthrough designations is laid out in the white paper.

Bundling the requirements for fast track and RMT into a prebreakthrough pathway “may help efficiently usher drugs through key development stages as clinical evidence is generated to support qualifying for breakthrough therapy designation,” the white paper states. “This can help maximize earlier interaction and iterative rapid feedback between sponsors and FDA.”

“This simplistic approach should be centered around the conversations or interactions that ought to occur when a development program sees early, promising data and when it sees clear, confirmatory data to transition from prebreakthrough therapy designation to qualifying for breakthrough therapy designation and eventually approval,” the paper states.

The white paper also recommends codifying the pre- and postbreakthrough designation processes that would be most helpful in expediting drug development.

Although much attention is paid to whether a product receives breakthrough designation, much less attention is given to the processes that actually follow that designation, the working group said.

“A structured process should be defined that enables early and frequent feedback/dialogue in a more standardized way with shorter timelines than currently available with formal interactions to address early stage questions in a development program.” – FOCR white paper

“Identifying scenarios where earlier and more frequent interaction would have benefited a program … could help elucidate best practices,” the paper states. “A comprehensive effort to assess what happens ‘Beyond Breakthrough,’ following a designation, is needed to delineate the obligations and deliverables for sponsors and the FDA once a program qualifies for an expedited program.”

For a product in early-stage (prebreakthrough) development, sponsor/FDA interactions can be extremely valuable.

“A structured process should be defined that enables early and frequent feedback/dialogue in a more standardized way with shorter timelines than currently available with formal interactions to address early stage questions in a development program, such as optimal analytical tools, discussion on planned manufacturing changes (improved processes, scale up), design of any additional nonclinical studies, dose finding, proof of concept, design of pivotal studies, and approval pathway,” the white paper states.

After a product receives breakthrough designation (postbreakthrough), a cross-disciplinary project lead should use a holistic multidisciplinary approach to begin to map out various processes and the necessary interactions that should occur with different groups within the FDA. These could involve manufacturing site inspections, strategies for diagnostic test development, and design of potential postmarketing commitments, among other issues.

Emerging Therapies

The white paper also contains recommendations on synchronizing key components of drug development for emerging therapies.

“Dedicated and more frequent meetings for emerging therapies, such as cell and gene therapies and next generation immunotherapies, in a prebreakthrough therapy designation setting may be necessary to keep key development components in sync to get these potentially transformative therapies to patients quickly and safely,” the paper states.

For example, the working group suggested sponsors and the agency could initiate manufacturing meetings in a prebreakthrough therapy space when clinical data are indicative of a product potentially worthy of breakthrough designation, but duration of follow-up is not yet sufficiently long.

Accelerating CMC

FDA guidance on expedited programs and RMAT should be revised to provide additional recommendations for accelerating CMC development and formalizing extended CMC discussions at key development milestones.

The working group also suggested establishing a pilot program to accelerate CMC for products with complex innovative manufacturing processes. This pilot could test the concept of real-time review of manufacturing information for these emerging and complex products.

“While ‘rolling review’ allows for submission of individual completed modules one at a time rather than at once all together, ‘real time review’ takes this concept a step further and allows the agency to start the review of a module before the application is complete and may allow submission of pre-agreed CMC data during the NDA/BLA review,” the paper states

The Oncology Center of Excellence’s Real-Time Oncology Review pilot facilitates earlier submission of top-line clinical trial results and datasets for agency review ahead of a full application. (Also see “Taking The ‘O’ Out Of RTOR: US FDA’s Real-Time Review Primed For Expansion Beyond Oncology” – Pink Sheet, 27 Sep, 2020.)

The program’s success has spurred talk of expanding the RTOR concept beyond the cancer setting. (Also see “US FDA Drug Review Goals Should Be Faster In PDUFA VII, Industry Negotiators Propose” – Pink Sheet, 3 Feb, 2021.)

The working paper also suggests defining a structured process for cross-disciplinary interactions, as early as pre-IND, for complex development programs that may try to use innovative trial designs or require earlier advice on complicated manufacturing issues to generate the early clinical evidence needed to qualify for an expedited pathway.

https://pink.pharmaintelligence.informa.com/PS143313/US-FDAs-Presubmiss…