A Mighty Minyan and the Lords of Discipline (Letters)

Terrific review of PDUFA V (via BioCentury’s always insightful Washington Editor, Steve Usdin), “PDUFA:  A lot of talk.”

The selected verbiage below is from Mr. Usdin’s article – the subheads are not.

Thy rod and thy staff, they comfort me

High quality reviews performed on a predictable timetable has been the industry’s primary objective for PDUFA since the program’s inception in 1992. But as user fees have exploded over the decades and have been allocated to a widening range of activities, success in achieving their principal goal has been elusive. FDA has consistently managed to approve about 60% of priority NDAs for new molecular entities (NMEs) and original BLAs within a single review cycle, but has done so only by pulling staff away from standard reviews.

The 33 1/3^rd % Solution

Although about 80% of all NDAs and BLAs are eventually approved, there has never been much more than a one-in-three chance that a standard NME or BLA would be approved in the first cycle.

Subjective Meeting Objectives Meetings

To increase first-cycle approval performance, the PDUFA V agreement adds a two-month “filing period” to the start of the review process for NME NDAs and original BLAs, establishes a mid-cycle meeting to allow sponsors to attempt to get errant reviews back on track, and sets up a late-cycle meeting to smooth any advisory committee meetings or negotiations over labels or risk evaluation and management strategies (REMS).

In addition to improving communications with sponsors, the agency plans to create new fora for patients, along with formal procedures for integrating patient perspectives into review criteria.

According to CDER Director Janet Woodcock, “I would like to pursue patient-centered drug development where the regulators and the developers really understand where the patients are coming from in that disease,” She said that “no one, the medical profession or the FDA, has done a good enough job listening from the patients how drugs feel to them and how they feel about benefits and risks.

The BRAT Pack

Woodcock added that FDA is developing a semi-quantitative benefit-risk framework that will “standardize how we think and talk about benefits and risks and residual uncertainty,” and that the agency plans to make it part of the review process during PDUFA V.

Begging the question – or just begging?

The industry also has agreed that FDA can use PDUFA money to hire over 10 staff to bring new scientific expertise into the agency. Nevertheless, the total tab for PDUFA V over five years is expected be about $3 billion, compared to $2.9 billion for PDUFA IV. Thus the begging question will be whether the added review time and communications commitments, rather than money, will achieve the kind of agency performance that has not been reached in prior user fee agreements.

Unpresent Danger

Moreover, the agency’s Office of Surveillance and Epidemiology (OSE) has not been present in the negotiations, which could be a sign the agreement will not resolve poor coordination and bureaucratic in-fighting.

A Mighty Minyan

Industry agreed to pay for 10 FTEs to implement the enhanced communications program, as well as $100,000 annually for internal training and industry outreach. FDA has agreed that the “liaison staff. The new liaison staff will “serve as a point of contact for sponsors who have general questions about drug development or who need clarification on which review division to contact with their questions,” according to the goals letter.

Better Late Than Never

PDUFA V also will add a late-cycle meeting for new molecular entity NDAs and new BLAs that is intended to be a comprehensive assessment of the agency’s review, including descriptions of issues that might be raised at an advisory committee meeting.

The late-cycle meeting addresses complaints from sponsors that they have learned about critical issues FDA will raise with an advisory committee only a few days before the meeting, and that often companies learn about agency concerns for the first time in a complete response letter.

For applications that will be discussed by an advisory committee, the late-cycle meeting will occur at least 12 calendar days before the panel meets. FDA will provide the sponsor with a draft of the questions the agency plans to ask the committee.

The Lords of Discipline (Letters)

FDA has stated it will provide the briefing package at least 20 calendar days prior to a scheduled advisory committee meeting and at least 12 calendar days prior to the late-cycle meeting if a panel meeting is not planned. FDA told industry it aims to have “discipline review” letters ready in advance of the late-cycle meeting. Discipline review letters note any deficiencies in specific sections of applications, such as the clinical, chemistry, manufacturing and controls, non-clinical pharmacology and toxicology, and the human pharmacokinetics and bioavailability sections.

A New Broom?

In the end, FDA and the industry groups agreed on a sweeping policy that applies to all companies and is intended to make the drug review culture more interactive and collaborative.

Amen.