Recent improvements to FDA's screening process for intellectual conflicts of interest among advisory committee members are likely to be part of the agency's response to a congressional inquiry into the review of Lilly's prasugrel ( Effient ).

FDA has faced criticism for its handling of the Feb. 3 Cardiovascular & Renal Drugs Advisory Committee review of the prasugrel NDA - especially the last-minute decision to "disinvite" a committee member from participating due to a potential intellectual bias (¹ Also see "Prasugrel Advisory Committee Highlights FDA’s Continued Credibility Gap" - Pink Sheet, 9 February, 2009., p. 5).

That criticism has prompted House Energy & Commerce Committee Chairman Henry Waxman, D-Calif., and Oversight & Investigations Subcommittee Chairman Bart Stupak, D-Mich., to launch an investigation into the dismissal of the member, Cedars-Sinai Medical Center cardiologist Sanjay Kaul.

"We request that FDA provide a briefing to committee staff on this matter by March 12," Reps. Waxman and Stupak say in a Feb. 27 letter to acting FDA Commissioner Frank Torti.

Agency staff should be "prepared to describe in detail how FDA decided to disinvite Dr. Kaul from [the] advisory committee meeting, including who made or was informed of the decision, the basis for the decision, and any communications with Eli Lilly or others regarding Dr. Kaul."

FDA Reviewing Screening Standards

In response to the inquiry, FDA will be able to point to recent changes in its screening practices for intellectual bias - which both reinforce the agency's existing process and establish new procedures to ensure that screening is conducted properly in the future.

Two weeks after the prasugrel meeting, on Feb. 17, FDA "tightened the process for determining whether participation of SGEs designated to serve on FDA advisory committees should be restricted for reasons of intellectual bias," the agency said.

The decision to disinvite Kaul from the prasugrel discussion was not properly vetted by high-level agency officials, FDA said. Going forward, decisions on a potential conflict will be proposed by the advisory committee staff, and finalized only after written concurrence by the center director and by the assistant commissioner for accountability and integrity, the agency said in an e-mailed response to questions.

"Moreover, such decisions should be made only after explicit consideration of ways of ensuring that scientific data supporting the views of such [special government employees] are fully available to the committee during its deliberations."

FDA has also initiated an internal review of the standards for determining intellectual bias; the ² current criteria have been in place since the early 1990s.

"As soon as we realized what had happened ... we put in place procedures along every step of the way that all the individuals at different checkpoints are aware of now," Center for Drug Evaluation & Research Director Janet Woodcock said on a Feb. 23 media call.

"It would have to break down at every single step for this to happen again," she said. "So I can pretty confidently say that this is not going to happen again."

No Review For Intellectual Bias

FDA characterized Kaul's review of potential conflicts as a series of breaches in protocol that led to an erroneous decision to disinvite him from the meeting. "What happened was a series of small errors, and as often is the case when those small errors line up, they led to a mistake," Woodcock acknowledged.

The first mistake was that while Kaul was fully screened for financial conflicts of interest, he was not vetted for intellectual conflicts of interest. FDA has general criteria for what constitutes intellectual bias, but admits the document is vague and requires a case-by-case assessment.

It is rare for FDA to excuse a committee member for intellectual bias. One recent - and extreme - example was the recusal of Drug Safety & Risk Management Advisory Committee member Sidney Wolfe from a meeting regarding the safety of propoxyphene drugs. In that case, Wolfe and his organization (Public Citizen) had petitioned FDA to remove the products from the market (³ Also see "Collaring Wolfe: Propoxyphene Moves Activist Back To Public Supplicant Role" - Pink Sheet, 9 February, 2009., p. 11).

In Kaul's financial review, FDA flagged five abstracts that re-analyzed data from the pivotal TRITON study. TRITON compared prasugrel to GlaxoSmithKline's Plavix (clopidogrel), and found a 19 percent reduction in the relative risk for the composite endpoint of cardiovascular death, non-fatal heart attack and non-fatal stroke (⁴ Also see "Lilly’s Prasugrel Superior To Bristol’s Plavix In Reducing CV Events In Pivotal TRITON Trial" - Pink Sheet, 4 November, 2007.).

In the abstracts, presented at an American Heart Association November meeting, Kaul and co-authors George Diamond and Prediman Shah (Cedars-Sinai), concluded that prasugrel's efficacy advantage over Plavix was less than demonstrated by TRITON.

FDA asked Kaul whether he received financial support from drug sponsors or "anything related to him conducting those re-analyses and submitting them as abstracts," Office of New Drugs Director John Jenkins said in an interview.

Kaul responded to FDA in an e-mail stating that he had no financial ties to the companies involved, and noted that he has re-analyzed data on other cardiovascular products and published his own analyses to raise questions or use different statistical methods.

With that, the advisory committee staff was satisfied that Kaul did not have a financial conflict, but made the mistake of not questioning whether that same information might represent an intellectual bias. That possibility was not relayed to the cardio-renal review division before the meeting, and Kaul was cleared to participate as a full voting member.

TRITON Abstracts Called Into Question

FDA posted the prasugrel advisory committee briefing documents to its Web site two working days before a meeting date, as is now standard practice. Since the meeting fell on a Tuesday, the briefing documents went up on the FDA Web site Friday morning.

Once the documents were made public, Lilly called FDA to question whether the TRITON abstracts constituted an intellectual bias and could disqualify Kaul from participating in the meeting.

Discussions were held over the weekend, and it was then that the staff made a second crucial mistake. While the advisory committee staff consulted with their counterparts in the center and the commissioner's office, they did not consult with their superiors.

"Instead, all those people got together and decided that it was too late to make a formal determination of whether there was ... an intellectual bias," Woodcock said. Instead, the staff recommended to Kaul that he not make the Los Angeles-to-Maryland trip to avoid the possibility that he arrive only to discover that he had been recused from the meeting. "That is not the correct procedure," she said.

As a result, FDA made no formal evaluation of Kaul's eligibility from a standpoint of intellectual bias. But Jenkins concluded from his own after-the-fact review that the TRITON abstracts alone were not enough to prohibit Kaul's participation from the meeting.

"He was critically analyzing the data, and I didn't see any evidence that he had formed in his mind an opinion of the products that would allow someone to say in advance, well, we already know how he's going to vote," Jenkins said in an interview.

"We want our advisers to come to the table with an open mind to look at the data, hear the presentations, hear the discussion, and then give us their perspective based on all of that information, and not come to the table with pre-formed judgments."

Kaul has also made comments in the media about TRITON, including some that questioned whether the data demonstrate that prasugrel's benefits outweigh its risks. But under FDA's guidelines, even those statements would require an individual assessment of whether they represented an intellectual bias.

Despite the mistakes made regarding Kaul's eligibility, Woodcock stressed that his absence did not change the outcome of the meeting. The committee voted 9-0 to recommend approving prasugrel despite an increased risk of bleeding and a potential risk of cancer (⁵ Also see "The Return Of The Blockbuster? Stage Is Set For Prasugrel Approval" - Pink Sheet, 9 February, 2009., p. 3).

"We had nine extremely competent individuals who were able to give us advice. We believe that it was a ... mistake that Dr. Kaul was not included amongst the advisors at this meeting, but we do not believe that invalidates the results of the panel," Woodcock said.

The prasugrel meeting was to be Kaul's first as a standing member of the Cardiovascular & Renal Drugs Advisory Committee, and Jenkins expressed hope that the incident would not dissuade him from returning: "We hope that he will continue to serve and will be a productive member of the committee going forward."

The prasugrel incident comes at a time when qualified advisory committee members are increasingly hard to come by. Prasugrel represents one of FDA's challenges: some candidates are reluctant to take a position that can be cast in a harsh light ("⁶ FDA Advisory Committees on the Brink," The RPM Report, October 2008).

- Kate Rawson (k.rawson@elsevier.com)

Prasugrel Intellectual Bias: FDA Makes Changes, Congress Demands Answers

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