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Trasylol Fiasco - FDA Fails To Protect Americans Again - Part II

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Washington, DCIn reading the report issued by the Zuckerman Spaeder law firm, one thing is perfectly clear. Bayer was willing to pay $700,000 to get a Trasylol study done in time for the September 21, 2006 advisory committee meeting, if it could refute the findings of the New England Journal of Medicine study.

However, unbeknownst to the contract research firm, i3 Drug Safety, it was decided early on that the study would not be mentioned to the FDA or the advisory panel unless and until Bayer was certain that it would achieve that goal.

In the NEJM study, Trasylol was found to be associated with a 109% increase in heart failure, a 48% increase in myocardial infarction, a 181% increase in strokes, and a risk of kidney failure 259% greater than patients who received no drugs.

Medical ResearchAs soon as the advisory panel voted against adding new warnings to the Trasylol label, Bayer issued a press release stating, "the committee overwhelmingly affirmed (18 yes votes and one abstention) that the totality of clinical data presented in today's meeting supports acceptable safety and efficacy for Trasylol among coronary artery bypass graft (CABG) surgery patients."

The committee agreed that the data were consistent with an association with Trasylol use and renal impairment, however, most members said they were not convinced that there was a definite increased risk of renal failure requiring dialysis.

Less than a year later, Dr Sebastian Schneeweiss told the September 12, 2007 advisory committee that the i3 study found a 60% increased risk for renal failure requiring dialysis and a 64% increase in the risk of in-hospital death with Trayslol.

The "Report on Computerized Inpatient Data from the Premier Perspective Comparative Database," was sent to Bayer a week before the hearing and the preliminary results showed that in addition to serous kidney damage, Trasylol increased the risk of death, congestive heart failure, and stroke.

When Dr Alexander Walker, who led the study, learned that Bayer had not made the FDA or the committee aware of the negative findings that basically verified the findings of the studies discussed at the hearing, he revealed that Bayer had commissioned the study and that the results were sent in the time for the hearing.

The Zuckerman law firm took over the investigation of the Trasylol matter from the Wiley Rein & Fielding law firm after the original attorney hired for the job, Fred Fielding was appointed White House counsel by President Bush less than 3 months after the investigation began.

The Zuckerman report blames the whole mess on Dr Kuno Sprenger, a Risk Manager and Drug Safety Advisor, and Dr Ernst Weidmann, a Vice President for GDS. "Bayer did not disclose the findings and conclusions from the Preliminary Report on or before September 21, 2006, because Drs. Weidmann and Sprenger did not advise BPC, FDA, or the Advisory Committee that they had received the Preliminary Report," the report concludes.

The fact is, this was not a 2-man job. Bayer received a pre-publication copy of the January 26, 2006 NEJM article by Dr Dennis Mangano and immediately mobilized to respond, according to the report. Bayer also created a separate Advisory Committee Steering Committee to coordinate preparation for the FDA advisory meeting.

The report answers the question: "Who at Bayer knew of the existence of the i3 study and which of those persons, if any, were functionally responsible for informing FDA of its existence?"

A list of all the names in the answer are included here only to show how absurd it is to try to blame the non-disclosure of the study on 2 lone employees.

Bayer personnel who knew about it include: Conny Berlin, Department of Integrated Analysis; Pam Cyrus, Vice President for Trasylol and Non-Specialty Products, US Medical Affairs; Howard Dorfman, Head of Patents, BPC Legal; Tomasz Dyszynski, International Drug Safety Manager for Aprotinin; Allen Heller, Vice President of Medical Science, US Pharma Division; Hans-Peter Kraemer, Head Systems and Operations, GDS; Paul MacCarthy, Vice President, Head of Medical & Scientific Affairs (North America); Kemal Malik, Global Head of Development and Chief Medical Officer; Andrea Nadel, Deputy Director of Statistics, BPC; Michael Rozycki, Director of US Regulatory Affairs; Joseph Scheeren, Senior Vice President of Global Regulatory Affairs; Anita Shah, Global Project Leader, BPC; Kuno Sprenger, Risk Manager and Drug Safety Advisor for GDS; Ed Tucker, Vice President, US Drug Safety Assurance; Terry Taylor, Vice President, Global Clinical Development; David van Veenhuyzen, Global Clinical Leader, Trasylol; and Ernst Weidmann, Vice President for GDS.

Another question asks: "Why was the existence of the i3 study not communicated to FDA in advance of the Advisory Committee meeting on September 21, 2006?"

"The highest levels of Bayer management responsible for preparing for the Advisory Committee meeting agreed that Bayer should and would disclose the ongoing study before the meeting," the report states.

"The managers responsible for making that disclosure ultimately failed to do so," it concludes.

Dr Scheeren and Dr Rozycki were responsible for communicating with the FDA about any Trasylol study, not Dr Weidmann and Dr Sprenger, and Dr Rozycki was the Trasylol liaison with the FDA during 2006, including all matters pertaining to the advisory committee meeting.

"Dr. Rozycki, the person responsible for actually making the regulatory contact with FDA, also had primary responsibility for overall coordination of Bayer's preparation," the reports states.

"Dr. Rozycki freely acknowledges having neglected certain outstanding "action items" - including disclosure of the i3 study to FDA," it says.

Yet at the September 12, 2007 advisory committee meeting, Dr Malik also placed all the blame on Dr Weidmann and Dr Sprenger for not revealing the study stating:

"Unfortunately, shortly after last year's advisory committee, Bayer became aware that two individuals within our organization had received preliminary results of this study prior to the advisory committee. They chose not to share these data more widely within Bayer or with the advisory committee.

On behalf of Bayer, I would like to personally apologize for this error. As was publicly stated when we published the results of an independent investigation conducted by William Taylor, no other individuals other than these two people knew of the results of this study prior to the advisory committee meeting.

I would like to emphasize that those consultants who are with us at the meeting did not know about the existence of these data prior to the advisory committee meeting."

Dr Malik fails to mention the fact that neither he nor anyone else at Bayer informed the FDA of the i3 study after the meeting either until Dr Walker did.

It's highly unlikely that the advisory panel was impressed by these comments because many members had already expressed in the press how appalled they were to learn that Bayer had failed to reveal the existence of the study a year earlier.

"For them not to mention that it was under way, that it was being analyzed or that results were available is appalling and will do significant harm to their reputation for transparency," Dr John Teerlink, a professor at the University of California told the New York Times on September 29, 2006.

He also told Bloomberg on October 6, 2006, that Bayer's failure to tell the FDA about the study before the meeting "calls into question the honesty of Bayer and the honesty of the pharmaceutical industry in general."

On October 6, 2006, committee chairman, Dr Bob Harrington, from Duke University, told Heartwire: "Bayer's failure to even disclose that these data were available and under preliminary analysis is very disturbing to me."

"It is ironic that we spent part of the panel meeting criticizing Dr Mangano for failing to allow the FDA to perform an independent review of his database," he noted, "yet Bayer failed to even acknowledge the existence of these data."

"It is especially troubling," Dr Harrington said, "when several panel members, including me, commented that more data and more analyses were needed to fully understand the risks and benefits of the drug."

Panel member, Dr Michael Lincoff, from the Cleveland Clinic, told Heartwire: "It was astounding to me that they did not disclose the information that the study had been conducted even if the findings were considered preliminary."

"It is inconceivable that the representatives from Bayer did not know about the existence of the study or its potential relevance to the committee," he added.

"They were in the midst of an entire day's discussions at the FDA on that precise topic where there was substantial comment regarding the desirability of more contemporary data than their older trials," Dr Lincoff pointed out.

At the hearing itself, Dr Valluvan Jeevanandam, a cardiac surgeon, specifically asked Bayer officials about other studies. "Could you comment on other trials other than CABG trials where there might have been an effect on renal function," he asked, "because a lot of the questions we had in our first presentation by Dr. Mangano was perhaps concomitant procedures with higher incidence of renal dysfunction, so do you have other trials other than just CABG trials looking at renal function?"

"Probably the most recent study where you could just remove the effect of bypass totally is a study that was just conducted by Bayer in hip surgery," Dr Cyrus responded.

Committee member, Dr Susan Heckbert also asked about other studies. "It looks to me like the U.S. studies in that database," she said, "most of them are from the early nineties and they would reflect the kind of patient that would present and might be considered for a clinical trial in those days."

"You don't have anything beyond the early nineties in the United States in that database?" she asked.

"The bulk of our clinical trial experience that I shared with you in the safety database was between the late eighties and late nineties," Dr Cyrus answered. "There were a few studies that went to 2001."

However, the dates in the Zuckerman report reveal that the study that Bayer officials conveniently forgot to mention was initiated 8 months earlier. Four days after the NEJM study was published, on February 1, 2006, Dr Sprenger and Dr Weidmann, contacted Dr Walker at i3 Drug Safety by email about performing an observational study for Bayer to compare Trasylol (aprotinin), aminocaproic acid and tranexamic acid.

On February 23, 2006, Dr Sprenger emailed Dr Walker and said Bayer was expecting an advisory committee meeting in late summer and asked Dr Walker to present the results of the study at the meeting.

On June 2, 2006, Dr Sprenger informed Dr Walker of Bayer's approval of the study and that Bayer would like him to finish the study in time to meet the deadline of the September 21 advisory meeting.

On June 28, 2006, Bayer and the FDA held a conference call regarding the advisory meeting and Dr Scheeren recalled that a Bayer agenda item was to inform FDA about the study on that call. But according to Dr Scheeren, the conference call ended before Bayer could discuss the study.

On July 13, 2006, Dr Sprenger again asked Dr Walker whether he would be willing to present the study at the meeting and informed him that the briefing packet for the FDA was due by August 18.

On July 17, 2006, Dr Walker told Dr Sprenger in an email that he and Dr Seeger would be happy to present the results at the meeting. On the same day, Dr Seeger emailed Dr Sprenger and Dr Walker and explained that the results would not be ready in time for the briefing deadline on August 18, but said Dr Sprenger should provide a description of the study in the briefing package.

On July 16, 2006, Bayer held a meeting to prepare for a July 17 face-to-face meeting with the FDA and among the attendees were Dr Cyrus, Dr Heller, Dr MacCarthy, Dr Nadel, Dr Rozycki, Dr Scheeren, Dr Shah, Dr Sprenger, Dr Taylor, and Dr Van Veenhuyzen.

At this meeting, Dr Sprenger said that he gave the group a verbal overview of the study and he also told Dr Scheeren and Dr MacCarthy that preliminary results would be ready for the advisory committee meeting.

According to the report, Dr MacCarthy said the group decided to inform the FDA about the study at the July 17, 2006 meeting and Dr Scheeren told Dr Sprenger to be prepared to discuss the study when it came up.

On July 17, several Bayer scientists, regulatory leaders, and external consultants met at a hotel in Maryland to prepare prior to the meeting and the group agreed that Bayer should inform the FDA of the study during the meeting. Dr MacCarthy, Dr Scheeren, and Dr Rozycki were responsible for doing so, according to the report.

Dr Sprenger said he informed at least Dr Scheeren and Dr MacCarthy that the study results would be in before the advisory committee meeting.

However, once again, no one informed the FDA about the study at the July 17, meeting.

On August 17, 2006, Dr Seeger informed Dr Sprenger in an email that i3 was on track to meet the schedule for delivering the preliminary results of the study and the same day, Bayer submitted the briefing document to the FDA with no mention of the study.

On August 19, Bayer conducted a mock panel to rehearse for the advisory meeting and according to the report, Dr Sprenger remembered mentioning the status of the study to people during a pre-meeting to the mock panel, including Dr Scheeren and Dr MacCarthy.

Dr Weidmann said that several times between July 2006 and the advisory meeting, he asked Dr Scheeren why he had not yet told the FDA about the study and Dr Scheeren claimed that regulations did not require disclosure.

He also said that he told Dr Scheeren that the timelines for the study had been shortened to produce the preliminary results before the advisory meeting. Dr Sprenger also said he told Bayer colleagues on more than one occasion that the study results would be available before the meeting.

"Notwithstanding these discussions of the i3 study, however, they did not cause Dr. Rozycki or anyone else to take affirmative steps to tell FDA about it," the report states.

On August 23, 2006 Dr Sprenger emailed Dr Seeger and proposed that i3 meet with Dr Tomasz Dyszynski, the International Drug Safety Manager for Trayslol, and the report shows that Dr Dyszynski and Dr Conny Berlin did meet with i3 on August 26.

As far as nobody else knowing that the findings would be in before the meeting, the report specifically states that on September 6, 2006, "After hearing from Dyszynski that preliminary results will be available from the i3 study the first week in September, Sprenger emails Walker (copying Weidmann) proposing a meeting or conference call to discuss preliminary results."

In response, on September 7, 2006, Dr Walker emailed Dr Sprenger and Dr Weidmann and said i3 was ready to give Dr Sprenger a summary of findings.

The same day, Dr Weidmann sent an email containing the March 3, 2006, i3 proposal to Dr MacCarthy, Dr Scheeren, and Dr Tucker, and Dr Sprenger separately re-forwarded his July 21 email with the i3 proposal to Dr MacCarthy, Dr Scheeren, and Dr Tucker.

Dr Sprenger said that he sent the email to remind the others about the i3 study and the report says, "Nothing about the email would have led its recipients to understand that results would soon be forthcoming."

However, the report also notes that "within minutes" after receiving the i3 study proposal, Dr Scheeren forwarded the email to Dr Rozycki with the note, "Mike - We need to discuss this as well."

Dr Scheeren admitted speaking to Dr Rozycki after this email. "Although Dr. Scheeren denied a detailed recollection of the conversation, he said that an "unconscious decision" "could have" been made to delay disclosure until after the Advisory Committee meeting," the report states.

"He thought Dr. Rozycki "could have" left that meeting with a sense that the timing of the disclosure was "in the air" (i.e., undecided), and "maybe" Dr. Rozycki thought disclosure could occur after the September 21 Advisory Committee meeting," the report notes.

One question in the report asks, "Which employees of Bayer received, or otherwise knew about, the findings and conclusions of the i3 study in advance of the Advisory Committee meeting on September 21, 2006?"

The report answers: "Only two people at Bayer received or otherwise knew about
the findings and conclusions of the i3 study in advance of the Advisory Committee meeting: Dr. Ernst Weidmann, the Vice President for GDS; and his associate Dr. Kuno Sprenger, Bayer's Risk Manager and Drug Safety Advisory for GDS."

"They received the Preliminary Report for the i3 study no later than September 14, 2006," the report notes.

Those statements are totally false. The Zuckerman report itself shows that close to a month before September 21, Dr Dyszynski and Dr Berlin met with i3 on August 26, and the notes taken by Dr Dyszynski at the meeting identify some of the same problems with the study that were highlighted in Dr Sprenger's questions sent to i3 on September 14.

If he was not made aware of the preliminary findings at the meeting with i3, common sense says Dr Dyszynski would not have been able to identify any problems, much less the exact same ones that Dr Sprenger highlighted close to 3 weeks later.

The report goes on to say that neither Dr Weidmann nor Dr Sprenger recalled Dr Dyszynski discussing these issues in detail but they acknowledged that Dr Dyszynski briefed them on the August 26, meeting with i3.

On September 21, the advisory meeting took place and no one from Bayer mentioned the study. On September 22, 2006, Dr Seeger emailed Dr Sprenger asking for confirmation that Dr Sprenger had received i3's September 19 responses to Bayer's questions.

On the same day, Dr Walker emailed Dr Sprenger, and copied Dr Weidmann, asking why the study had not been mentioned. On September 26, Dr Weidmann emailed Dr Walker and claimed that due to email problems, Bayer had not received i3's responses until September 22, and that they wanted to review the study before any disclosure was made.

Dr Walker responded by email and said the preliminary report had public health implications and had to be communicated to the FDA and requested that Bayer submit the report to the FDA by September 28. The rest is history, because Dr Walker decided to reveal the existence of the study himself and the New York Times reported the story on November 29, 2006.

On January 23, 2007, the South Florida Business Journal reported that Florida and 29 other states had reached an $8 million settlement with Bayer resolving an investigation into the marketing of a drug to lower cholesterol.

As it turns out, at the exact same time that Bayer was concealing the existence and the results of the Trasylol study, the company was in negotiations to settle Medicaid fraud charges that included hiding studies that revealed the adverse effects of Baycol that was pulled off the market in 2001 after 100 deaths were reported.

As part of this settlement, Bayer agreed to post information on new clinical studies online in a trial registry. This registry was supposed to give physicians, consumers and researchers access to information on the efficacy of the drugs, type and severity of side effects, goals of treatment, and timing and reasons for termination of studies.

Bayer specifically agreed to register all Non-Exploratory Phase II trials and all Phase III and IV trials on at the time the studies were initiated and post the results of all trials on

A press release by the Illinois attorney general, Lisa Madigan, noted that, "Phase IV trials are performed after a drug or treatment is on the market to gain additional information about risks, benefits, and optimal use."

Which obviously means that the initiation and the results of the i3 Trasylol study should have been posted online and Bayer should have been thrown out of the Medicaid program a year ago for violating the agreement.


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