"Mistakes" Made: FDA Acknowledges Lilly Phoned to Question Sanjay Kaul's Inclusion on Prasugrel Panel

Michael O'Riordan

February 20, 2009

February 20, 2009 (Rockville, Maryland) — Prior to the February 3, 2009 Food and Drug Administration advisory panel hearing on prasugrel (Lilly/Daiichi Sankyo), the drug's sponsor called the agency to question the inclusion of Dr Sanjay Kaul (Cedars-Sinai Medical Center, Los Angeles, CA) on the Cardiovascular and Renal Drugs Advisory Committee, heartwire has learned.

In an interview today, FDA officials insisted that the call from Lilly had no bearing on their decision to exclude Kaul but acknowledged "mistakes" were made.

The agency received a phone call from Lilly on January 30, 2009, just four days before the advisory panel was scheduled to meet to discuss the risks and benefits of the new antiplatelet agent. The call was made by Lilly to staff members in the cardiovascular and renal division at the Center for Drug Evaluation and Research.

According to Dr John Jenkins, FDA director of the Office of New Drugs, who was not involved in the decision to exclude Kaul, Lilly specifically questioned whether Kaul had already made up his mind on the drug. "I've reviewed some of the paperwork that went back and forth, and they [Lilly] were raising questions about whether he had an intellectual bias that would preclude him from being a fair member of the committee," said Jenkins.

Days later, Kaul, an expert in vascular physiology and an outspoken critic of prasugrel, was dropped from the committee. The panel subsequently went on to unanimously recommend approval of prasugrel for the treatment of acute coronary syndromes.

Explaining the chronology of events to heartwire , Dr Janet Woodcock, director of the Center for Drug Evaluation and Research, said that staff at the cardiovascular and renal division only became aware of Kaul's past research with the phone call from Lilly, when the roster for the FDA panel was released. This phone call precipitated weekend discussions among the cardiovascular and renal division staff, as well as among the advisory committee staff, over whether or not Kaul's research, particularly his independent analyses of the TRITON-TIMI-38 study and his interpretation of those findings, constituted an intellectual bias.

However, according to the FDA, neither Jenkins, Woodcock, nor any supervisors at the different divisions were alerted to this potential bias, because division staff failed to report the issue. Instead, the division decided it was easier to have Kaul not travel rather than make a decision about whether or not his position on prasugrel was compromised.

"Basically, this was a mistake," said Woodcock. "And like many other errors, there were a series of small errors that led up to this happening."

Woodcock said the division staff failed to follow procedure, one that would involve discussing the possibility of intellectual conflict of interest with the Office of New Drugs, the Center for Drug Evaluation and Research, and the commissioner's office. According to Jenkins, who became aware of the division staff's decision to disinvite Kaul only on Tuesday morning, division staff did not alert their supervisors about these analyses, and as a result, this "late-breaking issue" was not discussed outside the cardiovascular and renal division and advisors and consultant staff.

"They decided there wasn't enough time to do this, and therefore, they didn't recuse him because of intellectual bias but disinvited him," added Woodcock. "We didn't go through our ordinary procedures. . . . They consulted with the advisory staff, but after that the process fell apart."

The fact that Lilly called to question Kaul's inclusion on the panel is "not unusual," given that the agency receives lots of calls from companies and others about who is included on the panel. However, the FDA has been publicly criticized by experts who said itwas not "good science" to exclude a panel member who was likely to inject healthy debate into the daylong hearing. Others have since speculated whether the sponsor played any role in Kaul's exclusion from the committee.

Five Abstracts in Question

Last week, the agency explained that Kaul was asked not to fly to Maryland for the FDA hearing because of an incomplete vetting process that left unanswered questions about a possible "intellectual bias." The FDA previously told heartwire that in the course of its own review, the conflict-of-interest screeners failed to alert the advisory panel staff and the division of cardiovascular and renal drugs in a timely manner about five abstracts presented by Kaul last year at the American Heart Association Scientific Sessions [1,2,3,4,5].

In these abstracts, Kaul, along with coauthors Drs George Diamond and Prediman Shah (Cedars-Sinai Medical Center, Los Angeles, CA), reached numerous conclusions, among them that the clinical benefit associated with prasugrel was less than implied by conventional analyses of the TRITON-TIMI-38 trial, the pivotal prasugrel study before the FDA panel.

In addition, Kaul has commented publicly on the TRITON study, including in interviews with heartwire , and suggested that prasugrel fell short in its goal of balancing improved efficacy against the risk of bleeding.

Speaking with heartwire , Woodcock said that Kaul submitted all necessary information to the agency on time, including his TRITON analyses that he presented at the AHA last November. However, the conflict-of-interest screeners at the FDA focused on financial conflicts of interest and did not pursue the possibility of an intellectual bias that might preclude him from sitting on the FDA advisory panel. As a result, division staff was not alerted to his research.

Woodcock and Jenkins denied that pressure from Lilly resulted in Kaul not being included on the FDA panel, despite the phone call to the cardiovascular and renal division.

Intellectual Bias?

Within the Center for Drug Evaluation and Research, there are provisions stating that members participating on advisory panels should be free from intellectual bias. According to the FDA document, the appearance of intellectual bias is an issue if the member is identified as a "primary advocate" or is "so strongly associated with a position on a matter" that concerns could be raised about his or her impartiality and objectivity.

Also, intellectual bias may exist if "statements of record have been made by that member concerning an issue to be considered by the committee that draw conclusions or strongly appear to draw conclusions to a degree that would appear, to informed experts, to preclude an impartial and objective evaluation of information on that matter presented to the committee." These statements could be taken from legal cases, other regulatory agencies, or even from the media.

As Jenkins told heartwire last week, members are welcome to bring differing perspectives and to ask tough questions, "But at the same time, we want the committee members to come to the table with an open mind, so they can give us advice based on the data, the presentations, and the discussions that are held at the committee meeting itself."

All the Players Not Involved

When the FDA has concerns about intellectual bias, it may take "additional action," including excluding a committee member from participating on the panel. However, it states clearly that the decision-making process will include discussions with the appropriate FDA officials, the chair of the committee, and the panel member.

Speaking with heartwire last week, advisory panel chair Dr Marvin Konstam (Tufts University School of Medicine, Boston, MA) said committee members were told that morning that Kaul would not be on the panel and the decision was made by the agency without his involvement. Konstam referred all questions about Kaul to the FDA. Kaul declined to comment on the FDA's decision.

Woodcock said that Konstam and Kaul were not involved in discussions because no final decision was made on his intellectual conflicts of interest. Dr Anthony Ware, a vice president at Lilly, said the company became aware that Kaul would be on the panel when the roster became public on Friday, January 30, 2009. He said the company does not comment on discussions with the FDA, including whether or not it called to complain about Kaul, and referred questions concerning the exclusion to the agency.

Speaking with heartwire , Jenkins reiterated that, from a personal standpoint, a cursory look revealed nothing in Kaul's research or in his comments to the media that rose to the level of intellectual bias. "I think he should have participated," he said. "He would have been a very good participant because he would have raised many of the issues that we have been raising internally as we reviewed the application." Jenkins said, however, that what constitutes "intellectual bias" is somewhat murky and subject to interpretation. Had the issue been elevated within the different departments, another decision might have been reached, he said.

Woodcock noted that Dr Sidney Wolfe has been previously released from a recent advisory panel, although he was also presenting to the panel on behalf of the advocacy group Public Citizen. Interestingly, Wolfe has written Woodcock and the FDA to raise concerns about the safety and efficacy of prasugrel, as well as to question the exclusion of Kaul from the advisory panel.

Lilly and Daiichi Sankyo supported TRITON-TIMI-38.

  1. Kaul S, Diamond GA, and Shah PK. Abstract 988: Do high-risk characteristics (history of stroke or TIA, age >75 years, weight <60 kg) reliably predict bleeding in TRITON-TIMI 38? Circulation 2008; 118:S638-S639.

  2. Kaul S, Shah PK, and Diamond GA. Abstract 4014: Timing of benefit with prasugrel in patients with acute coronary syndromes undergoing percutaneous coronary intervention: reanalysis of TRITON-TIMI 38 results. Circulation 2008; 118:S818-S819.

  3. Kaul S, Shah PK, and Diamond GA. Abstract 4015: Validity of the combined efficacy plus safety composite endpoint (net clinical benefit) in TRITON-TIMI 38. Circulation 2008; 118:S819.

  4. Kaul S, Shah PK, and Diamond GA. Abstract 4016: Does prasugrel provide a clinically important treatment benefit compared with clopidogrel? A Bayesian analysis of TRITON-TIMI 38. Circulation 2008; 118:S819.

  5. Kaul S, Shah PK, and Diamond GA. Abstract 4587: Weighted composite endpoint analysis of TRITON-TIMI 38: Disconnect between analytical equivalence and clinical importance. Circulation 2008; 118:S916.

face="Verdana" size="1">The complete contents of Heartwire , a professional news service of WebMD, can be found at www.theheart.org, a Web site for cardiovascular healthcare professionals.


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