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The Tragedy of Trasylol: Did the FDA Stonewall Mangano?

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Washington, DCThe debacle over the handling of Trasylol and the tragedy of thousands of lives lost during the ensuing delay in getting the blood-clotting drug removed from the market, gets more interesting by the day.

And once again, the focus turns to a pivotal day in September 2006, during which an advisory committee convened by the US Food and Drug Administration (FDA) discussed the safety of Trasylol.

That's the same meeting at which representatives of Bayer AG, the makers of Trasylol, appeared to defend their product and promote the continuation of Trasylol on the market, all the while knowing the results of a study that raised serious concerns about the drug. Bayer claimed later that the study was withheld in error and the individuals involved reprimanded. At least one panel participant that day observed that, had the Bayer study been available, it may have changed the outcome of the vote to stand behind Trasylol.

Arteries and VeinsHowever, this appears to fly in the face of two existing studies, which had already been released, and published well before the September 21st 2006 advisory panel meeting.

And the author of one of those studies, noted researcher Dr. Dennis Mangano of the not-for-profit Ischemia Research and Education Foundation (IREF) and the Multicenter Study of Perioperative Ischemia (McSPI), has since gone on record as saying thousands of lives could have been saved since that day when the FDA panel allowed Trasylol to continue, and this past fall when the drug was finally pulled from the market, partly motivated by the halt of a Canadian investigative study made necessary by a spike in deaths associated with Trasylol participants.

The findings of the Canadian BART study, up to the point at which it was halted, mirrored the findings of Mangano's, which were not only available for presentation at the advisory panel hearing, but appears to have been offered to the FDA some months before.

His exhaustive study, taking over a decade to complete and costing $45 million dollars in total, was summarily dismissed by the panel called, in part, as a direct response to his study and an accompanying, but separate investigation concerning a link connecting aprotinin (which is what Trasylol is) to renal dysfunction. Mangano's research identified not only concern over kidney reactions to Trasylol, but also cardiac, and cardiovascular concern leading to death.

However, his findings were dismissed even though, according to Dr. Mangano in a letter appearing in the New England Journal of Medicine (NEJM), he had made his methodology, database and findings available to the FDA for corroboration, and independent analysis. Indeed, he claims to have fully and completely complied with an FDA request, only to be stonewalled.

Dr. Mangano, who was recently profiled on the CBS News magazine '60 Minutes' relative to the tragedy of Trasylol, writes that in February of 2006 following the publication of Mangano's findings, the FDA asked to see the data.

"We agreed," Dr. Mangano writes in his letter, which appears on the NEJM website, "and sent a team of IREF scientists to the FDA. The FDA and Bayer then asked that we send them our database, because they each wanted to combine our data with Bayer's data and then perform a number of unspecified analyses. We agreed to the FDA proposal..."

However, a letter written by to two FDA doctors, also published in the NEJM, appears to dispute this. They claim that while the authors of the other trial, Karkouti et al complied fully and completely with the FDA request, the same could not be said for Mangano who, the letter writers' claim, imposed restrictions and limitations that in the FDA's view prevented the agency from successfully performing a substantive, and independent evaluation of his statistical methods.

Because his methods and conclusions could not be substantiated and verified in this way, and because it was not a 'gold standard' clinical trial, Mangano's study was dismissed at the pivotal meeting.

However, Dr. Mangano tells an entirely different story.

He made just "three requests," he writes: "that patient privacy and legal trust be preserved, that the methods used to mix our patient data with the Bayer patient data be specified, and that in addition to their analyses, the FDA independently analyze our data, comment on each finding of our study published in the Journal, and make the results known to the public.

"In May (four months before the Advisory Committee meeting), frustrated by the delay and concerned that our data would not be reviewed, I abandoned all three requests and informed the FDA that we would provide our database and any and all source data for its review.

"Hearing no response, after several weeks, I wrote to the FDA and again asked for a review of our data. However, the FDA refused, and we were told that a review was not necessary.

"As I publicly stated to the Advisory Committee on September 21, 2006, we stand by our offer to the FDA to provide for review any and all data regarding our publication without constraint or condition."

It has been reported that Mangano's exhaustive observational study sampled 5,065 patients in 17 countries, and collected over 7,500 data points for each participant. And yet, in spite of Mangano's presentation and findings the FDA panel voted to retain the status quo.

Bayer's own study, which mirrored Mangano's findings and brought to the attention of the FDA by a whistleblower mere days after the panel vote, was the first in a series of events that further proved the value, and accuracy of Mangano's research. A subsequent FDA expert panel convened in September of 2007 further discussed Mangano's research, together with the now-public Bayer study which appeared to further substantiate Mangano's concern over Trasylol.

And yet, incredibly the panel again approved Trasylol, finding that in spite of the risks, they could not determine--or at least be assured--that the risks outweighed the benefits.

It should be noted that the benefits had always been the subject of some debate from the beginning. Trasylol was formulated to reduce the need for transfusions during coronary artery bypass graft surgeries (CAGB). Trasylol could also reduce the number of patients requiring a second operation because the first hadn't properly healed. Yet another group, a small percentage of patients prone to adverse reaction to foreign blood factors, would benefit from the avoidance of a blood transfusion.

However, at the end of the day, it has been reported that there has never been any evidence showing that any of these benefits actually improve patient survival.

It should also be noted that in spite of three exhaustive studies, in addition to a concern over risk to the kidney that was revealed during the clinical trial prior to Trasylol's approval in 1993 (interpreted as a small risk, due to the small number of trial participants), the FDA panel in September of 2007 approved Trasylol yet again.

It wasn't until the Canadian study, a gold standard clinical trial that was demonstrating that aprotinin patients had an increased risk of death, did Bayer and the FDA finally pull the plug.

Interestingly, the original FDA advisory panel appeared to find fault with Mangano's study, given that it was an observational study and not a true, clinical trial. And yet it was an unfinished clinical trial, with incomplete data, that finally spurred the FDA and Bayer to act.

Bayer AG has said that it is not making any official pronouncement on the future of Trasylol until data from the halted Canadian BART study is analyzed, and therefore regards the market withdrawal of Trasylol as a temporary response pending further information. The FDA, meanwhile has said that while Trasylol is off the market, surgeons would have the wherewithal to use Trasylol on a case-by-case basis. However the complete phasing out of Trasylol would have to happen gradually, due to a lack of alternatives in the market.

That appears to be true, in the context of price. There is only one aprotinin (Trasylol), and only one that costs a reported $1000 per dose. However there are at least two other alternatives, which provide substantially the same benefit as Trasylol, without the risks, for a reported $50 per dose.

Given all of that, it makes you wonder just which side the FDA is really on?

In the meantime, it has been estimated that 20,000 lives or more have been lost needlessly, to Trasylol.

One can imagine the lawsuits stemming from this.



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