FDA Review “Program” Tweaks May Include Smaller Mid-Cycle Meetings

Mid-cycle meetings under FDA’s review “Program” have ballooned into 30- to 40-person affairs – far larger than originally envisioned under PDUFA V. Those numbers – which can sometimes include the entire FDA review team – have made mid-cycle conference calls difficult to schedule, especially for expedited products with tight review timeframes. It is one lesson learned from the first 18 months of the Program.

WhenTakeda Pharmaceutical Co. Ltd. executives called into a mid-cycle communication teleconference with the Food & Drug Administration to discuss the status of the Entyvio (vedolizumab) BLA for ulcerative colitis and Crohn’s disease, they found quite an audience on the other end of the line: no fewer than 24 representatives from FDA, including three high-ranking agency officials.

That isn’t what FDA or industry had in mind when a requirement for a “mid-cycle communication” was included in the new “Program” review of new molecular entities and novel biologics under the Prescription Drug User Fee Act reauthorization in 2012. Rather, the mid-cycle communication was intended to be an opportunity for a relatively small group of FDA representatives to update a sponsor on the status of an application. As the name suggests, they are held roughly halfway through a review cycle.

But mid-cycle meetings have “mushroomed” to the point where they now can involve 30 or 40 different individuals – and often high-ranking FDA officials at the office and division level, Center for Drug Evaluation & Research Associate Director for Regulatory Affairs Beth Duvall acknowledged during a panel discussion at the Drug Information Association annual meeting in San Diego on June 17. (Technically, FDA refers to its own internal review team meeting as the mid-cycle meeting; the follow-up briefing for sponsors is known as the “mid-cycle communication” within the agency.)

The sheer number of people invited to be on the mid-cycle calls under the PDUFA V Program is one factor that is making it difficult to schedule the communications – especially for applications under expedited review, when the timeframes are especially tight, Duvall said. Schedules are further complicated when higher-ranking FDA officials are invited, as those individuals tend to have especially busy calendars.

The need to adjust the way mid-cycle communications are being implemented is one “lesson learned” from the first 18 months of the Program. Overall, the Program has been well received by both FDA and sponsors; the agreement under PDUFA V offered additional transparency from the agency during the review of novel products in exchange for the addition of a two-month “filing period” to give FDA more time to complete the review. (Also see "Time for Transparency: PDUFA V’s Big “Experiment”" - Pink Sheet, 19 Jan, 2012.)

FDA says none of the Program elements – including the larger-than-anticipated mid-cycle meetings – have caused the agency to miss any user fee deadlines. But according to preliminary findings from FDA’s outside assessor of the Program, Eastern Research Group, the number of participants invited to mid-cycle communication calls has made them challenging to schedule during what is already a busy part of the review.

The issue is vexing enough to FDA to prompt another senior CDER official, Office of New Drugs Director Sandra Kweder, MD, to raise it from the audience during Duvall’s DIA panel session on the Program.

Speaking during the question-and-answer session, Kweder noted that the mid-cycle communication calls now regularly involve “30 to 40 individuals.” Duvall agreed that the size of the meetings with sponsors have grown significantly, but stressed that so far, neither those calls nor other Program requirements have caused FDA to miss any review deadlines.

But while FDA has issued review decisions under the Program on time so far, the difficulty of meeting all the PDUFA requirements under the Program may have lead to longer-than-necessary reviews in some cases – especially for expedited applications. And as FDA continues to tweak the Program as it implements the new review process for novel drugs and biologics, it’s an issue that is on the table at FDA for discussion.

A New Milestone For Sponsors

There are few specifics in the PDUFA V goals letter about exactly who at FDA is supposed to be involved in mid-cycle communications with sponsors. The letter notes that the regulatory project manager “and other appropriate members of the FDA review team” will call the sponsor within two weeks of FDA’s internal mid-cycle review meeting “to provide the applicant with an update on the status of the review of their application.”

That would seem to suggest, in most cases, a handful of representatives each from FDA and the sponsor. Instead, mid-cycle calls for drugs approved under the Program in 2014 are regularly involving dozens of people on a conference call; in extreme cases like Merck & Co. Inc.’s anti-platelet agent Zontivity (vorapaxar) there were more than 50 individuals. (See Exhibit 1.)

And looking back at the early Program reviews, one can see that the number of meeting participants has greatly expanded – especially on FDA’s side – since the beginning of PDUFA V.

For example, the first Program approval, Bayer AG’s Xofigo (radium-223 dichloride) had just seven FDA officials on the mid-cycle conference call, and the most senior official was the deputy director of the Division of Oncology Products. (Patrick Frey, Director of the Office of Planning and Analysis, was also present; his involvement in Program meetings is to ensure a smooth implementation.)

Mid-Cycle Communications: Very Large Conference Calls

Exhibit 1

FDA mid-cycle communications with sponsors during the review of “Program” applications can involve 30-40 individuals – far more participants than originally envisioned during PDUFA V negotiations. Below is a list of recent Program approvals and the number of participants from FDA and the sponsor.

Drug Under Review	Approval Date	Date of Mid-Cycle Communication	FDA	Sponsor
Takeda’s Entyvio vedolizumab	May 20, 2014	October 14, 2013	24	20
Merck’s Zontivity (vorapaxar)	May 8, 2014	October 31, 2013	20	31
Novartis’ Zykadia (ceritinib)	April 29, 2014	March 7, 2014	18	12
Janssen’s Sylvant (siltuximab)	April 22, 2014	December 13, 2013	16	17
Eli Lilly’s Cyramza (ramucirumab)	April 21, 2014	December 9, 2013	14	9
GlaxoSmithKline’s Tanzeum (albiglutide)	April 15, 2014	June 26, 2013	16	16
Celgene’s Otezla (apremilast)	March 21, 2014	August 20, 2013	9	18
Paladin Therapeutics’ Impavido (miltefosine)	March 19, 2014	July 31, 2013	16	5
Amylin’s Myalept (metreleptin for injection)	February 24, 2014	September 30, 2013	23	21
Chelsea Therapeutics’ Northera (droxidopa)	February 18, 2014	September 29, 2014	N/A	N/A
BioMarin’s Vimizim (elosulfase alfa)	February 14, 2014	July 31, 2014	19	22
Vanda’s Hetlioz (tasimelteon)	January 31, 2014	September 26, 2014	13	9

The Food & Drug Administration, BLA/NDA review documents

Despite being held only partway through a review, mid-cycle meetings are key events for drug sponsors. During the calls, FDA communicates significant issues with an application, major safety concerns and potential risk management plans. Sponsors also receive an update on whether an advisory committee meeting will be needed, and the timing of the late-cycle meeting, as well as other projected milestones.

Of the mid-cycle communication calls held to date, most of the significant issues communicated to the sponsor by FDA relate to product quality (32%) and clinical development (29%), Duvall reported during her presentation at DIA. Of the information requests made to sponsors from FDA, the majority are associated with product quality (29%) and statistics (36%).

Given the breadth of potential issues discussed at the mid-cycle communications, it’s understandable that the calls have evolved to involve so many participants – better to invite everyone than for a sponsor or FDA to put an issue on the table without the expertise available to address it.

Takeda’s Entyvio Mid-CycleExperience

Takeda’s mid-cycle communication call for Entyvio is just one example of how large the roster of participants can get.

The Entyvio meeting was held as a 90-minute conference call on October 14, 2013. FDA’s 24 representatives included three high-level agency officials: Office of Drug Evaluation III Director Julie Beitz, MD, Division of Gastroenterology and Inborn Errors Director Donna Griebel, MD, and CDER Deputy Director for Operations Richard Moscicki, MD. The participation of Moscicki in particular is unusual for mid-cycle meetings.

Takeda had 20 people on the teleconference for Entyvio, including four corporate vice presidents: VP-Gastroenterology and General Medicines R&D Asit Parikh, MD, PhD; VP-Global Risk Management and Pharmacoepidemiology Leslie Wise, PhD; VP-Drug Safety Evaluation Vivek Kadambi, PhD; and VP-Global Regulatory Affairs Melody Brown.

That is a lot of people on the line.

It is worth noting that the Entyvio application was unusual in two respects. First, the two indications were treated as separate applications and were placed by FDA on different tracks, with the ulcerative colitis indication granted Priority Review status and the Crohn’s indication on a standard review timeline.

However, FDA moved the two indications along at the same pace, bringing both applications to advisory committee at the same time, discussing both indications during the mid-cycle communication and granting approval to both on the same day (after a three-month extension for the priority ulcerative colitis indication).

In addition, the safety profile may have prompted FDA to involve more high-level officials than normal. Entyvio has a mechanism of action similar to Biogen Inc.’s Tysabri, which was briefly withdrawn from the market due to an increased risk of progressive multifocal leukoencephalopathy. Entyvio had already been the subject of a closed-door advisory committee meeting in 2011, and the safety profile was the focus of the second, open advisory committee after the BLA was submitted. (Also see "Mystery Adcomm Revealed" - Pink Sheet, 10 Dec, 2013.)

Indeed, the potential for a Risk Evaluation & Mitigation Strategy was discussed during the mid-cycle conference call, but FDA declined to commit either way until after the advisory committee meeting. In the end, Entyvio was approved with a clean label and, somewhat surprisingly, without a REMS, although Takeda has committed to a post-marketing observational study to monitor PML cases. (Also see "The End of the REMS Era? Entyvio Approval Is Another Marker" - Pink Sheet, 3 Jun, 2014.)

Preliminary Feedback on the “Program”

Overall, FDA and sponsors alike are finding the more open communication under the Program to be a real benefit. Duvall used part of her DIA presentation to share preliminary feedback from FDA and sponsors based on interviews conducted by the Eastern Research Group. (See Exhibit 2.)

Duvall’s presentation represented only summary analyses; ERG’s preliminary report is due in March 2015, to be followed by a public meeting by the end of June 2015. A final assessment from ERG is due by the end of December 2016, and will be discussed in a public meeting by the end of March 2017. However, any decisions about modifications to the Program will likely be based on the interim report, given the timeline for the FDA/industry negotiation process. (Also see "The “Program’s” Outside Contractor: Eastern Research Group" - Pink Sheet, 25 Sep, 2013.)

Positive on the “Program”

Exhibit 2

Preliminary findings from Eastern Research Group’s assessment of FDA’s new review “Program” indicate that both FDA and drug sponsors appreciate the additional opportunities for transparency during the review. However, FDA has found that some meetings are difficult to squeeze in; the concern is that they might slow down the review of expedited applications.

	FDA Feedback	Sponsor Feedback
Pre-Submission Meetings	Pro: Useful for developing shared understanding of expectations for complete applications	Pro: Useful for obtaining FDA feedback on top-line results Pro: Useful for understanding FDA’s expectations for complete applications
Mid-Cycle Communications	Pro: Allow for discussion of issues and possible paths forward Con: Challenging to schedule during a busy part of the review	Pro: Allow for discussion of application as a whole rather than piecemeal communications
Late-Cycle Meetings	Pro: Provide clarity and prioritization of key issues with possible paths forward Con: Additional work that sometimes slows down priority reviews	Pro: Provide helpful information (e.g. FDA background package) Pro: Anchor the review process with a predictable milestone

CDER Associate Director for Regulatory Affairs Beth Duvall, DIA annual meeting 2014

In general, the open, collaborative communications under the Program have reduced “surprises” during the review cycle, drug sponsors have reported to Eastern Research Group, Duvall said. For FDA, the meetings have helped to “identify mutually agreeable solutions to issues.”

ERG has also found that most applicants are satisfied with the timing and nature of FDA’s communications regarding the need for risk management programs, Duvall reported. Sponsors are also finding that earlier discussion of labeling is helpful in understanding FDA’s rationale when proposing changes. One area for improvement that has been flagged by both sides is communication on the status of inspections.

FDA Seeking Flexibility for Expedited Reviews

FDA is also paying special attention to expedited reviews to ensure that the requirements under the Program aren’t delaying the approval of new treatments. (Also see "FDA “Program” Reviews Are Positive So Far, But Are They Sustainable?" - Pink Sheet, 15 Jan, 2014.) The agency established a working group in December 2013 to “develop approaches to addressing the logistical challenges of applying PDUFA V Program requirements to applications identified for expedited review,” FDA said in an email.

Duvall reviewed ways that FDA will exercise flexibility in how the Program is executed while still meeting the requirements laid out in the PDUFA V goals letter:

1. Identifying applications for expedited review prior to submission, whenever possible;
2. Providing incremental communication of expedited timelines as the review proceeds – a specific early action date will not be communicated at onset; and
3. Updating the 21^st Century Review Desk Reference Guide to reflect FDA’s ability to apply flexible Program timelines for expedited reviews.

That is an issue that Office of New Drugs Director John Jenkins, MD, had first commented on during the RPM Report’s FDA/CMS Summit for Biopharmaceutical Executives in December 2013 – right around the time the working group was established. The group, which is still meeting periodically, includes staff from the Office of New Drugs and the Office of Program and Strategic Analysis in CDER, as well as staff from the Center for Biologics Evaluation & Research, FDA said.

It’s clear that the Program is still a work in progress as FDA reviews novel drugs and biologics under PDUFA V. For sponsors, that’s good news: The agency is carefully tracking implementation of the Program and instituting changes to prevent missed deadlines – especially for expedited applications. As far as the mid-cycle conference calls are concerned, that means sponsors might start hearing fewer FDA staff on the line.