As we noted in a separate blog post, the forthcoming reauthorization of the FDA’s Prescription Drug User Fee Act (PDUFA VII) includes several provisions that are expected to help advance cell and gene therapy products, as well as therapies designed to treat rare diseases. However, the anticipated impact of PDUFA VII will extend well beyond those industry segments. This post examines elements of PDUFA VII that have broad implications for the industry as a whole.

New timelines for PMR reviews

PDUFA VII will establish a new process, timelines, and associated performance goals for post-marketing requirements (PMRs) during pre-approval and a new process for the review of existing PMRs post-approval. For a standard new drug application (NDA) for a new molecular entity (NME) or original biologic license application (BLA) pre-approval, the FDA will communicate details on anticipated PMRs to the applicant no later than eight weeks prior to the PDUFA action date. For priority NDAs and original BLAs pre-approval, the PMR communication deadline will be no later than six weeks prior to the action date.

For post-approval review of an existing PMR, the applicant will submit a request summarizing why it believes the PMR is no longer needed. Within 45 days of its receipt of that request, the FDA will notify the applicant if any additional information is necessary to make its evaluation. The Agency will then communicate its decision within 60 days of its receipt of the original request or within 60 days of its receipt of the additional requested information, whichever is later.

Notably, there will be no change to the review timelines for initial NDA or BLA submissions.

STAR pilot program

Another key PDUFA VII provision is the establishment of a Split Real-Time Application Review (STAR) Pilot Program, which is intended to shorten the time from the date of complete submission of an efficacy supplement to its PDUFA action date, thereby enabling earlier patient access to therapies that address an unmet medical need. Inspired by the Oncology Center of Excellence’s Real-time Oncology Review (RTOR) program, the pilot program will focus on efficacy supplements for novel uses of existing therapies across all therapeutic areas and review disciplines that meet specific criteria. Accepted STAR applications will be submitted in a “split” fashion: the initial submission must include all datasets, protocols, statistical analysis plans, and other elements deemed essential for the FDA to initiate its review; completed clinical study reports and integrated summaries will be submitted approximately two months later.

The FDA has announced plans for a public workshop to discuss the STAR Pilot Program. The workshop, as yet unscheduled, will discuss feedback and experiences from the pilot program with industry stakeholders.

Additions to PDUFA meeting types

Two new formal PDUFA meeting types will be added: Type D meetings and INitial Targeted Engagement for Regulatory Advice on CBER/CDER ProducTs (INTERACT) meetings. The latter are intended to facilitate early discussions of novel questions and unique challenges in early development (i.e., prior to filing an Investigational New Drug [IND] application). INTERACT meeting discussions may focus on topics such as the design of IND-enabling toxicity studies, complex manufacturing technologies or processes, and the development of innovative devices to be used with drug or biologic products. While this type of meeting was previously limited to discussions of products regulated by the Center for Biologics Evaluation and Research (CBER), INTERACT meetings will also encompass those regulated by the Center for Drugs Evaluation and Research (CDER) under PDUFA VII.

A Type D meeting, unlike Type C meetings, will facilitate a discussion between the FDA and a sponsor on one or two defined topics. Due to the narrow focus of the Type D meeting, the overall meeting timelines are more expeditious than those for a Type C meeting.

The PDUFA VII Commitment Letter outlines the proposed timelines for the various meeting types as follows:

Meeting Type	Response Time (calendar days)	Receipt of Background Package	Meeting Scheduling or Written Response Time
A	14	At the time of the meeting request	30 calendar days from the receipt of the meeting request
B	21	30 calendar days before the date of the meeting or expected written response	60 calendar days from the receipt of the meeting request
B(EOP)	14	50 calendar days before the date of the meeting or expected written response*	70 calendar days from the receipt of the meeting request
C	21	47 calendar days before the date of the meeting or expected written response*	75 calendar days from the receipt of the meeting request
D	14	At the time of the meeting request	50 calendar days from the receipt of the meeting request
INTERACT	21	At the time of the meeting request	75 calendar days from the receipt of the meeting request

*If the scheduled date of a Type B(EOP) or C meeting is earlier than the timeframes specified above, the meeting background package will be due no sooner than six calendar days following the response time for Type B(EOP) meetings and seven calendar days for Type C meetings.
EOP =  end of phase.

New performance goal for URRA review

PDUFA VII will also establish a new performance goal for the review of use-related risk analyses (URRAs) for the development of drug-device and biologic-device combinations (regulated by CDER and CBER, respectively). URRAs are a tool sponsors may use to identify the need for risk mitigation strategies and to design a human factors (HF) validation study. Based on a URRA, a sponsor may propose that a HF validation study is not needed to support the safe and effective use of a combination product. Per the new performance goal, a URRA is to be reviewed within 60 days of submission to the IND.

Other notable PDUFA VII provisions

In addition to the above, PDUFA VII will institute several other notable changes, including:

• Real-World Evidence (RWE) Program Advancement: This program is designed to improve the quality and acceptability of RWE-based approaches sponsors may take to support new labeling claims. The program will encompass the use of RWE both to support new indications for approved products and to address post-approval study requirements. The FDA has announced plans to hold a public workshop and to issue updated and/or draft guidance documents based on the pilot program.
• REMS Assessment Modernization and Improvement: Acknowledging the need to optimize risk evaluation and mitigation strategy (REMS) assessments, the FDA aims to modernize these assessments with new review performance goals and plans for updated and/or draft guidance documents.
• New Allergenic Extract Products: These products have not previously been part of the PDUFA program but henceforth will be.

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In summary, PDUFA VII will increase support for CDER and CBER and usher in a series of changes designed to continue to enhance the review of NDAs, BLAs, and related submissions in an era of rapid innovation. Many of the proposed provisions of PDUFA VII are prompted by input from the industry and patient advocacy groups, reflecting the FDA’s responsiveness and willingness to work with these key constituencies. The nature and scope of these provisions are thus an apt reflection of the issues sponsors can expect to face in the continually evolving U.S. regulatory environment.

For insights on aspects of PDUFA VII pertaining specifically to cell and gene therapy products, please see this accompanying blog post.

Author:

Laura Kilgore, RAC
VP, Regulatory Affairs, CMC