The Center for Drug Evaluation and Research will try to shave at least one month off the review period for certain “breakthrough therapy” applications that warrant an expedited examination.

CDER explains the one-month goal, and the criteria for products that qualify for the compressed review timeframe, in a new Manual of Policies and Procedures.

In the process, the agency appears to be establishing a new regulatory paradigm known as “expedited review” – albeit one that is not laid out in statute officially.

FDA review staffers have been formally working under the concept of expedited review for the past five months.

FDA’s oncology review division often sets more ambitious review targets for promising agents that address unmet medical needs than the goal dates provided under the Prescription Drug User Fee Act. For example, the division might set a four-month target date for a new molecular entity undergoing priority review that otherwise would carry an eight-month PDUFA goal date.

It now appears this type of approach, on a less ambitious scale, is being encouraged across review divisions at least with regard to a subset of breakthrough therapy applications: those that are designated for priority review but also meet the criteria for an expedited review.

In response to questions from “The Pink Sheet” DAILY, FDA suggested that agency staffers have been formally working under the concept of expedited review for the past five months.

Modifications to the 21st Century Review Process Desk Reference Guide and other reviewer tools and templates to accommodate expedited review of applications in the PDUFA V review program for NMEs and novel biologics occurred as of October 2014, the agency said.

Furthermore, the MaPP released March 9 “is based on CDER staff experience to date with breakthrough-designated drugs” and may be updated as additional experience is acquired.

Quantifying The Meaning Of ‘Expedite’

MaPP 6025.7 , “Good Review Practice: Review of Marketing Applications for Breakthrough Therapy-Designated Drugs and Biologics That Are Receiving an Expedited Review,” has its origins in the FDA Safety and Innovation Act provisions that created the breakthrough therapy program.

FDASIA required that the agency “expedite the development and review” of a drug intended to treat a serious or life-threatening disease or condition when preliminary clinical evidence indicates it may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints.

However, FDASIA did not quantify the extent to which FDA should expedite development or review activities.

FDA confirmed that the concept of an expedited review was not required by legislation.

Under the MaPP, if an application with breakthrough status is designated for priority review, “CDER review staff and managers will consider whether the marketing application qualifies for an expedited review. CDER staff will consider an expedited review of a marketing application for a breakthrough therapy-designated drug whenever possible.”

The MaPP defines an expedited review as “one where the review team plans to act at least one month before the Prescription Drug User Fee Act goal date, provided that no unexpected review issues arise and/or the review team does not experience an unexpected shift in work priorities or team staffing.”

A breakthrough application must meet three criteria to be considered for expedited review (see box).

Criteria For Expedited Review

Preliminary review of results from clinical trials must indicate that the drug has demonstrated substantial improvement over existing therapies
Marketing application must be designated as a priority review
Review team must have determined that a first-cycle approval is likely

The MaPP notes that not every breakthrough product will receive expedited review, and each application is evaluated on a case-by-case basis to determine if the abbreviated review period is warranted.

The agency gives four examples of factors that may influence a decision to grant an expedited review, even if the threshold criteria are met:

Resources to expedite the review are not available because of competing public health priorities (e.g., anthrax, Ebola, influenza)
An advisory committee meeting is needed for reasons such as clinical trial results or safety issues
An unanticipated safety issue is identified that requires a Risk Evaluation and Mitigation Strategy
Manufacturing issues are identified

The MaPP also makes clear that the expedited review designation is an informal one in that it “will not change the PDUFA review performance goals.”

Earlier PDUFA V Meetings

Agency staff and some sponsors have spoken to the challenge of trying to shoehorn the meetings required under the PDUFA V review program into the sometimes-compressed review timelines for breakthrough-designated products Also see "FDA Strains Under New NDA Review Model; Will Industry Want To Retain It?" - Pink Sheet, 16 December, 2013..

Some in industry have even suggested that the PDUFA V review program mid-cycle and late-cycle meetings should be made optional so as not to hold up the review process. However, FDA has noted that it remains subject to the PDUFA V performance goal metrics under the review program Also see "“Breakthrough” Review: FDA And Sponsors Discuss Ways To Improve Efficiency" - Pink Sheet, 12 May, 2014..

The MaPP makes clear that breakthrough-designated NMEs and novel biologics must follow the PDUFA V program-review requirements. However, program-related meetings “will occur earlier in the review cycle for applications undergoing expedited reviews,” the agency said.

The MaPP also lays out specific procedures for agency staff relative to the expedited review process.

“Early internal discussions about the appropriateness of an expedited review are critical because an expedited review demands substantial logistical planning from the review team and the sponsor,” the document states. “These internal discussions should occur after granting breakthrough therapy designation and no later than the internal premeeting before the presubmission meeting” with a sponsor.

Although the MaPP says that a decision to conduct an expedited review should be made before the internal premeeting, the expedited designation must be conditioned upon FDA’s determination that an application qualifies for priority review, and the agency generally does not make such a formal designation until after receipt of the application.

However, agency staff will provide guidance for sponsors ahead of submission as to whether a priority review is likely.

The policy manual also recognizes the challenge of ensuring that manufacturing operations can keep pace with a breakthrough product’s compressed development timeline Also see "“Breakthrough Therapy” Development Speed May Be Tempered By Manufacturing Hurdles" - Pink Sheet, 26 November, 2012..

The Office of New Drugs’ regulatory project manager for a given application should have frequent discussions with representatives from other agency offices to promote information-sharing on an application, the MaPP states. “Discussions could include such topics as identified issues and plans for resolution, the status of targeted internal goals, and the sponsor’s readiness to have the commercial drug product available for distribution by the targeted action date.”

Reversing Course On Expedited Review

The document leaves room for the agency to reverse course if it determines that an expedited review is no longer appropriate. This could occur for a variety of reasons, such as when unexpected application deficiencies are found, the marketing application is of poor quality or the sponsor fails to timely respond to information requests.

Unanticipated review issues or the need to hold an advisory committee also could derail an expedited review, as could an unexpected shift in work priorities or staffing for the review team.

“If the CDER review team determines that an expedited review is no longer appropriate, the review timeline will default to the priority review timeline.” This change, and the rationale underlying it, must be communicated to the sponsor within three business days.

FDA ‘Expedited Review’ Would Shave Off Additional Month For Some ‘Breakthrough’ Products

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