Phase IV Studies Need Greater Input From FDA, Industry Tells IoM Panel

Drug manufacturers need more clarity from FDA regarding post-marketing studies, industry representatives told the Institute of Medicine's Committee on the Assessment of the U.S. Drug Safety System.

"FDA can communicate a lot more effectively in certain cases with sponsors about the need to approach post-marketing commitments in a prompt and effective way," Wyeth Regulatory & Research Chief Counsel Geoffrey Levitt said during the IoM meeting Jan. 17-19.

Levitt was part of a panel that included Lilly Global Product Safety Director James Kotsonas, Pfizer Clinical R&D Senior VP Steven Ryder and Genentech Senior Director-Development James Nickas.

During the meeting, IoM committee members expressed concern about the number of incomplete post-marketing studies.

"We've seen literature about a large backlog of uncompleted Phase IV post-marketing trial commitments, a very large back log, an extraordinarily high percentage," committee member David Korn (Association of American Medical Colleges) said.

According to FDA's fiscal year 2004 report on the status of Phase IV commitments, 812 (68%) of 1,191 commitments for NDAs and ANDAs were classified as "pending" (¹ (Also see "FDA May Seek More Authority To Require Post-Marketing Safety Studies" - Pink Sheet, 1 Aug, 2005.), p. 4).

Genentech's Nickas pointed to the design of studies as a central difficulty with fulfilling Phase IV commitments. "When post-marketing commitments aren't scientifically designed," sponsors encounter hurdles that hamper the progress of post-approval studies, Nickas said.

"We often find afterwards, we didn't think about this population, it's hard to enroll, and we just don't tease out the challenge of doing that."

Phase IV studies are "a major area...where the science and standards need to be raised....If we do that, I think the post-marketing commitments that are conceived moving forward will have a much better chance of being completed," Nickas said.

He suggested FDA involve independent therapeutic experts earlier in the drug development process to identify important safety questions that would need to be addressed following a product's approval.

"The worst thing for a company is to go through a whole development process and get deep into it, a lot of money spent, and identify things later on that can kill the drug. We want to exercise this process as early as possible so that hopefully we have success," Nickas said.

"It would be a good thing to ask the companies when they are ready to submit the data: what are the most important risks...and the most important missing information, given the context of what this drug is used for and its toxicities," he said. "I believe that if we continue with advisory committees, those questions need to be a part of the process."

Although post-marketing commitments are discussed by advisory committees, Nickas maintained that committees only "hastily consider" questions on Phase IV studies.

"The questions put forth to advisory committees about what are the specific safety questions that need to be answered in post-marketing studies, that discussion has not been as sophisticated as...it should be moving forward," Nickas said.

Nickas said he agreed with Steve Nissen (Cleveland Clinic Foundation) who told the IoM committee that FDA needed to bolster its advisory committees with experts who can better scrutinize safety data.

"I think that independent review should be factored into the review process but with the right people so that the right questions can be asked," Nickas said. "If we raised the bar in this area and initiate this kind of expert review...I think over time, this will correct itself," he said.

Pfizer's Ryder held up the proposed post-marketing safety program for the company's inhaled insulin Exubera , which includes timeframes for completion of the studies, as a model for industry. Ryder said sponsors of Phase IV studies should not "walk away from the fact some of it has to be expensive and comprehensive" (² (Also see "Exubera’s Post-Marketing Safety Program Is Industry Model – Pfizer’s Ryder" - Pink Sheet, 23 Jan, 2006.), p. 12).