Prescription Drug User Fee Act negotiations should address the discrepancy in FDA performance on approval times for standard and priority review applications, Biotechnology Industry Organization's Amit Sachdev said.

"The FDA's emphasis on the continued consistent performance of the priority review applications and the review times...downplay[s] the fact that on standard reviews...there hasn't been progress," BIO Exec VP-Health Amit Sachdev observed during the BIO CEO & Investor Conference Feb. 14-15.

While BIO wants to see the agency continue to maintain its performance in priority review, the organization is concerned by the lack of emphasis on similar improvement for standard review applications.

This "puts a lot of pressure on us and industry to decide: 'where do we put our eggs,'" Sachdev said. Sachdev previously served as deputy commissioner for policy at FDA.

"As you do PDUFA IV, if you think about pathways for increasing the utilization of accelerated approval of the fast track program, where does that leave us?" Sachdev asked.

"What have you done to the standard review? What does it mean for PDUFA V, if we ever get there?"

Over the past few years, FDA has highlighted lower priority review times to justify increases in user fees. Comparatively, standard review times have not improved as much, Sachdev noted.

From 2004 to 2005, average priority approval times decreased by 3.8 months for new molecular entities, while average standard approvals increased by 2.6 months.

The lag between standard and priority reviews also increased from 2004 to 2005.

In 2004, the standard NME applications took an average 8.2 months longer to be approved than priority applications (22.3 months vs. 14.1 months).

The lag between NME standard and priority approval times increased in 2005 to 14.6 months (24.9 months vs. 10.3 months).

While standard approval times have drifted upwards for new drugs, the same is not true for biologics, which saw significant decreases in standard approval times.

From 2004 to 2005, standard approval times for biologics decreased more than priority reviews. FDA reduced its average standard approval times by 21 months (31.6 months vs. 10.6 months). Priority review times were reduced by four months (11.2 months vs. about 7.2 months). In 2004, the standard approval time was skewed by a 56-month approval for Palatin's NeutroSpec .

The gap between standard and priority approvals also decreased for biologics from 2004 to 2005. Standard approval were on average 3.4 months longer than priority approvals in 2005; whereas, in 2004, standard reviews took 20.4 months longer on average than priority applications.

Although primarily focused on biologic applications, BIO's constituency wants the overall lag in standard approval times to be addressed at FDA, Sachdev said.

Responding to Sachdev, FDA Deputy Commissioner for Medical & Scientific Affairs Scott Gottlieb explained that "the difference between standard and priority applications is a bit more complicated than it is being set out here."

"It includes a lot of factors, including a small number of applications from which you are extrapolating to make the conclusions," he said.

Last year, FDA approved significantly fewer NMEs, but slightly more biologics than in 2004. The 2005 class of NMEs had a high proportion of priority reviews, constituting 72% of the 18 approvals. In 2004, 16 of the 31 approved NMEs, or 52%, received priority reviews (¹ Also see "Oncology, CNS Agents May Dominate 2006 NME Approvals; 2005 Total Is 18" - Pink Sheet, 9 January, 2006., p. 28).

Of the 10 biologics approved in 2005, 50% received priority reviews, down from the year-ago period when four of the seven approved biologics, or 57%, received priority reviews (² [A#00680020013], p. 23).

Gottlieb said that other factors play into the speed of approval for drugs and biologics, including the importance of the application to the company and the public health benefit of a therapeutic.

"There is no question that if there is a blockbuster drug that holds a lot of potential for a public health impact that we are going to marshal resources internally to work on that," Gottlieb said.

"You see that time and time again, particularly in the cancer division where they get their reviews done very quickly, sometimes in less than four months for some of the very significant cancer therapies," he added.

FDA approved Lilly's Alimta (premetrexed) in 2004 in a little over four months for treatment of refractory lung cancer and malignant pleural mesothelioma (³ Also see "Lilly Alimta For Lung Cancer “Reasonably Likely” To Improve Survival" - Pink Sheet, 23 August, 2004., p. 25).

The fastest approval in 2005 was GSK's vaccine Fluarix , which cleared FDA in three months to avoid a vaccine shortage during the 2005-2006 flu season.

One factor that could increase the number of first-cycle approvals, especially among standard review applications, is a greater use of end-of-Phase II meetings.

A Booz Allen Hamilton report on FDA's First Cycle Review Performance released in early February found that greater funding for "milestone" meetings, particularly end-of-Phase II (EOP2) meetings, could have a positive impact on reducing the number of review cycles (⁴ Also see "Key To First-Cycle Approval Is To Meet Early And Often, Consultants Tell FDA" - Pink Sheet, 13 February, 2006., p.3).

According to the study, of 46 products with EOP2 meetings, 52% received first-cycle approval, versus only 29% for products that did not have such meetings.

Gottlieb lauded the report, saying, "I think there are ways to help create more opportunities for FDA to bring that dialogue back to sponsors, particularly in the critical junctures of the development process."

FDA is calling for additional user fee funding for industry-requested meetings to be included in the reauthorization of PDUFA (⁵ Also see "PDUFA IV: FDA Stresses Burden Of Industry Meetings In User Fee Discussions" - Pink Sheet, 21 November, 2005., p. 3).

The current user fee adjustment structure of PDUFA III is based on a weighted average of the change in the total number of human drug applications, efficacy supplements, manufacturing supplements and commercial investigational new drug applications.

"When we look at the growth of the workload at FDA, the most substantial growth has been in the number of meeting requests that we get and the number of meetings that we have with sponsors," Gottlieb said. The fee adjustment structure in PDUFA III did not account for meetings, he noted.

According to an FDA ⁶ white paper on the user fee program released Nov. 11, the agency held 2,131 industry-requested meetings in fiscal year 2004, up from 1,555 meetings held in FY 1999.

Sachdev noted, however, that if FDA wants additional funding for industry-requested meetings, the agency should develop more consistent criteria for documenting meeting minutes.

Also, PDUFA, as legislation, will not help address the inherent cultural issues affecting FDA, Sachdev said.

PDUFA IV "is not a bill to make fundamental statutory changes to FDA beyond performance in terms of criteria of standards and units of performance for safety and efficacy," Sachdev noted. "I think it is important for us to not overlook if there are cultural issues that just aren't being addressed at FDA."

Other participants at the BIO meeting agreed that cultural issues regarding FDA must be addressed.

"It would be wise for companies, if they really wanted to get things done....to address some of the long-standing cultural problems with FDA," Manhattan Institute Center for Medical Progress Director Robert Goldberg said.

Participants also cautioned that with congressional and patient groups' growing interest in FDA regulatory matters, industry needs to come up with creative proposals to set the stage for PDUFA negotiations.

Without industry input, PDUFA reauthorization is going to be a "train wreck" and "a platform for guerilla theater on why drug companies are so awful," Goldberg warned.

PDUFA "has got a constituency of a lot people....Let me be very blunt, it has got the constituency with one of the biggest pains in the asses, [Senate Finance Committee Chairman] Chuck Grassley [R-Iowa] who has got the media trained on him," Goldberg said.

"The companies actually try to invent new medicines that improve lives as opposed to what Charles Grassley does, which is nothing," Goldberg goaded.

Grassley and others have expressed interest in using user fees to support drug safety activities. The idea was widely discussed at a November FDA public meeting on reauthorization of PDUFA (⁷ Also see "PDUFA Provides Opportunity For Conditional Approvals, Consumer Groups Say" - Pink Sheet, 28 November, 2005., p. 11).

PDUFA IV Fix For FDA Performance On Standard Reviews Advocated By BIO

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