Sue Hughes
October 2, 2006
(updated October 6, 2006)
UPDATE: Harvard researcher
alerted FDA to Bayer study
A
Harvard researcher who helped to conduct the new Bayer study of aprotinin
told the FDA about its existence after noticing that it was not mentioned
at the advisory committee meeting, Bloomberg News reports [2].
Dr Alexander Walker, a professor at Harvard's School of Public
Health, helped run the study for i3 Drug Safety, a private clinical research
company. Walker, previously head of Harvard's department of epidemiology
and a former consultant to the New England Journal of Medicine, is quoted
by Bloomberg as saying that notifying the FDA "seemed like the right
thing to do.''
The Bloomberg
report also quotes advisory-committee member Dr. John Teerlink (University
of California, San Francisco) as saying that Bayer’s
failure to tell the FDA about the study before the advisory committee meeting "calls
into question the honesty of Bayer and the honesty of the pharmaceutical
industry in general. Teerlink adds: "I think the public health has been
harmed in two ways. One, we didn't have complete information to make our
decision. But second, it calls into question a process that all of us depend
on."
ORIGINAL POST:
(West Haven, CT) - Just days after an FDA advisory
committee effectively endorsed the safety of aprotinin (Trasylol, Bayer),
a new study conducted for Bayer has come to light that suggests that there
could be an increased risk of cardiovascular events with the drug after all.
A
September 29 letter to the panel members said the FDA may call for a second
meeting of the advisory panel to review the new data, the report notes.
Bayer is said to have started the study in June. It
received a preliminary copy of i3's report on September 14 and submitted
questions aimed at getting clarifications on the data on September 18, Bloomberg
notes. The company also claims that Bayer employees who presented information
to the FDA panel did not know the study results were available.
A front-page story in the
New York Times, headlined “FDA
says Bayer failed to reveal drug risk study,” reports that the FDA
only learned of the study because of a tip from a researcher involved in
it [1].
That Bayer chose not to reveal these results before or at the advisory-committee
meeting has angered some of the panel members. The company has now acknowledged
that not sharing the data before the meeting was a “mistake.”
The FDA’s
cardiovascular and renal advisory committee met on September 21 to discuss
two observational studies published earlier this year questioning the safety
of aprotinin, an antifibrinolytic drug used to reduce bleeding risk in CABG
patients. One study, by Mangano et al [3], suggested an increased risk of
cardiovascular events and renal insufficiency with aprotinin; the other study,
by Karkouti et al [4], suggested some renal toxicity but did not show any
increased cardiovascular risk.
Because
of concerns about methodology in the Mangano study, because Mangano did not
allow independent analysis of his data by the FDA, and because this was the
only study that suggested an increased cardiovascular risk with the drug,
the advisory committee concluded that there was not enough evidence to support
changing the cardiovascular-safety labeling of the drug.
But just
six days later, Bayer admitted to the FDA that it had commissioned an observational
study of its own to investigate the cardiovascular safety of aprotinin and
that preliminary results of that study suggested that the use of aprotinin
increases the chance of death, serious kidney damage, congestive heart failure,
and stroke.
FDA issues
new safety warning
On September 29, the FDA issued a statement
saying that it was not aware of these new data when the advisory-committee
meeting was held and that it is now evaluating the new study and its implications
forappropriate use of the drug [5].
In the meantime, the FDA offers the following advice:
Physicians who use
aprotinin should carefully monitor patients for the occurrence of toxicity,
particularly to the kidneys, heart, and brain, and promptly report observed
adverse-event information to Bayer or to the FDA MedWatch program.
Physicians should consider limiting aprotinin use to situations in which
the clinical benefit of reduced blood loss is essential to the medical management
of the patient and in which its benefits outweigh potential risks.
These recommendations
are similar to those provided in a February 8, 2006 FDA Public Health Advisory,
which was issued after the publication of the initial studies.
The FDA statement notes that, in the new Bayer study,
which was conducted by a contract research organization, hospital data
from 67 000 CABG
patients were examined. Of these, 30 000 patients were treated with
aprotinin and 37 000 were treated with other products. The report, which
used complex epidemiological and statistical methods, suggested that patients
receiving aprotinin were at increased risk for death, kidney failure, congestive
heart failure, and stroke.
Advisory committee angry
Members of the cardiorenal advisory committee were
understandably angry that Bayer had not revealed this information before
the meeting.
Dr. Robert Harrington
(Duke University, Durham, NC) commented to heartwire: “Bayer's
failure to even disclose that these data were available and under preliminary
analysis is very disturbing to me. The process of evaluation, comment, and
[the provision of] advice on important drug efficacy and safety data only
works when all of the involved parties are open and honest about their data.
It is ironic that wespent part of the panel meeting criticizing Dr. Mangano
for failing to allow the FDA to perform an independent review of his database,
yet Bayer failed to even acknowledge the existence of these data. It is especially
troubling 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. I'd like to know if the Bayer team... present that
day had knowledge of the existence of the data and why they chose not to
even mention it.”
Dr. Michael Lincoff (Cleveland Clinic, OH), also a
member of the advisory panel, had similar views. “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. 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. 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
told heartwire.
The chair of the committee, Dr. William Hiatt (University of
Colorado Health Sciences Center, Denver), confirmed that he was unaware of
these new data at the September 21 meeting. “While the new study does
not change things at the moment, after full review by the FDA, it possibly
could change our impression of the safety of aprotinin,” he said.
Teerlink is quoted
in the New York Times as saying of Bayer: “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.”
Bayer acknowledges "mistake"
Bayer issued a statement saying it
was a mistake not to have informed the FDA about the study before the advisory-committee
meeting. “This... was not shared immediately with the agency because
it was preliminary in nature and raised significant questions on the study
population, outcomes, and methodology. Bayer believes that despite the highly
preliminary nature of [these] data, the information should have been shared
with the FDA prior to the September 21 advisory-committee meeting held to
assess the safety and efficacy of Trasylol. This was a mistake on the company’s
part,” the
statement reads. It adds that the company will work with the investigators
and other experts to examine the underlying source data and fully understand
the results.
Harris G. FDA Says Bayer failed to reveal drug
risk study. New York Times, September 30, 2006. Available at: http://www.nytimes.com/2006/09/30/health/30fda.html?_r=1&oref=slogin.
Blum J and von Schaper E. Harvard researcher forced Bayer to disclose drug
toxicity study. Bloomberg News, October 6, 2006. Available at: http://www.bloomberg.com/apps/news?pid=20601103&sid=aLufHbinR8bI&refer=news.
Mangano DT, Tudor IC, Dietzel C, et al. The risk associated with aprotinin
in cardiac surgery. N Engl J Med 2006; 354:353-365.
Karkouti K, Beattie WS, Dattilo KM, et al. A propensity score case-control
comparison of aprotinin and tranexamic acid in high-transfusion-risk cardiac
surgery. Transfusion 2006; 46:327-338.
US Food and Drug Administration. FDA Public Health Advisory: Aprotinin Injection
(marketed as Trasylol). September 29, 2006. Available at: http://www.fda.gov/cder/drug/advisory/aprotinin20060929.htm.
Heartwire
2006
©2006 Medscape
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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