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FDA and Sponsors Discuss Quality Challenges in the Breakthrough Therapy Pathway

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Need to Know: On June 10, Friends of Cancer Research held a public meeting to discuss how sponsors and FDA may be able to expedite rate-limiting steps in Chemistry, Manufacturing, and Controls (CMC) and current Good Manufacturing Practices (cGMPs) for breakthrough therapy designated products, while ensuring an adequate supply of safe and efficacious product at the time of approval.

The meeting featured case studies from the biopharmaceutical industry regarding expedited development of drugs and biologics, as well as panel discussions comprised of members from both the Food and Drug Administration (FDA) and sponsors.

Meeting Highlights. Panelists highlighted the overwhelming success of the breakthrough therapy designation (BTD) program in delivering treatments to patients with unmet medical needs, but that it has also challenged and strained manufacturing readiness both for FDA and manufacturers. Topics that were prevalent and reiterated in both panels are discussed below.

FDA’s Resource Challenges.One discussion point in particular focused on FDA’s resource challenges in assessing and reviewing the quality aspects of a BTD application. An agency member stated that with the “all hands on deck” approach, CMC reviewers who typically are handling five to seven applications at a given time are left to prioritize the breakthrough therapy applications while trying to meet the mandated Prescription Drug User Fee Act (PDUFA) action dates for the others. In addition, reviewers and staff on other projects are often shifted around to complete the review expeditiously and grant an FDA approval in order to get the product to patients faster. A question from the audience asked the FDA panelists if more resources are needed, and both answered “yes,” and that FDA needs more people.

Patient-Focused Drug Development and Patient Access. Both at FDA and in industry, there is often a perception that quality is seen as the rate-limiting step in getting products to patients. FDA stated that at the Office of Pharmaceutical Quality (OPQ), they always talk about the patient, what the patient needs and how they can serve patients best. By doing so, the technical requirements are tied to the risk/benefit profile of the patients.

FDA’s Advice to Sponsors.Transparency and communication from the sponsor were highlighted by agency officials as keys to success of a sponsor’s breakthrough therapy program. Suggestions included letting FDA know they were applying for a BTD request prior to receiving the designation, as well as when FDA officials can anticipate the submission of a BTD application or the quality sections of a rolling review. Agency officials also noted that industry should not be shy in contacting OPQ senior management, preferring phone calls over emails, on BTD programs as they can get the ball rolling faster on any issues or concerns. In addition, they advised that sponsors should assess areas of variability in their quality program and anticipate what challenges may come.

Sponsor Takeaways. Sponsors noted that to achieve success, the program not only needed an all-hands-on-deck approach, but also management’s full support. Frequent informal and formal communications with FDA was also critical in receiving a timely approval and succeeding in a same-day launch. In addition, sponsors should discuss life cycle management plans with the agency as several quality attributes (e.g., formulation, process, and validation) may not be optimized at the time the application is filed.

More details on the topics discussed at the meeting, as well as the case studies, can be found in the issue brief released prior to the meeting.

Avalere’s Take. When Congress passed the Advancing Breakthrough Therapies for Patients Act as part of the Food and Drug Administration Safety and Innovation Act (FDASIA) in July 2012, no one could have anticipated the success of the program. It is clear from comments made at the meeting, as well as comments made at previous meetings on breakthrough therapies, that the agency is in dire need of additional resources. These resources are strained not only in FDA’s therapeutic divisions, but OPQ as well. And with an increased number of companion diagnostics being submitted on a number of these indications as a part of the drug/biological product therapy, the agency is starting to see resource constraints spillover to the Center for Devices and Radiological Health (CDRH).

As seen earlier this year in the OPQ white paper that was released by FDA and echoed at this meeting, the quality arm of the agency is also putting the patients first by balancing the nice to have requirements with the must-haves without compromising patient safety or product efficacy. In this accelerated drug development program, sponsors may potentially launch with processes or products that have not been optimized as long there is no harm to patients.

A decade ago, it was unheard of for sponsors to contact anyone but their regulatory project managers and infrequently at that or only through the established communications channels. Acknowledged by both FDA and industry at the meeting, it is apparent that there has been a shift towards greater and earlier collaboration, with the agency willing to accept, in fact wanting, frequent and informal communications. An FDA official stated that the agency will soon be issuing a guidance on best communication practices, outlining example cases and procedures for sponsors to contact regulatory project managers, reviewers and senior FDA officials.

With PDUFA reauthorization on the horizon (the first public meeting will occur on July 15th), we can expect a call for increased funding to hire additional staff to support the overwhelmingly successful breakthrough therapy program. And should user fees increase, by how much remains to be seen. In addition, will all manufacturers support an increase in user fees that would be meant to support additional FDA staff for BTD applications, particularly if only a select number of sponsors anticipate using the breakthrough pathway? Or perhaps a breakthrough therapy application review user fee in addition to any fee required by PDUFA for these application will be structured similar to that of the fee for the use of a priority review voucher, allowing a lesser increase in the application user and the cost of the BTD application review to be picked up by those utilizing the pathway. What is evident is that should the breakthrough program remain as popular as it is today, without additional funding, either BTD applications will no longer be able to be prioritized or other applications will miss their PDUFA action dates, as the impact on FDA’s time and resources will become unsustainable.

Debleena will be attending the 51st DIA annual conference in Washington D.C., June 14 -18.

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