15th July 03:25
Drug-Safety Reviewer Says F.D.A. Delayed Vioxx Study (depression heart arthritis)
Thanks to one of our readers for sending the following. . .Myrl
Drug-Safety Reviewer Says F.D.A. Delayed Vioxx Study
By GARDINER HARRIS
Published: November 4, 2004
n a series of testy e-mail exchanges with his bosses, a federal
drug-safety reviewer contends that an effort to publish his study
demonstrating the dangers of Vioxx was delayed and demeaned by top
officials at the Food and Drug Administration.
The e-mail and meeting notes also show that Dr. David Graham, an
official in the F.D.A.'s Office of Drug Safety, is seeking to launch a
study of the safety of Bextra and Mobic, two arthritis pills that are
similar to Vioxx. Merck withdrew Vioxx in September after finding that
it caused an increase in the risk of heart attacks.
The proposed study of Bextra and Mobic would use data from the
Paul Seligman, director of the Office of Drug Safety.
The exchanges are part of a stream of e-mail suggesting a tense
environment in the F.D.A. office. In one note, Dr. Graham reports that
the atmosphere has gotten so bad that Dr. Seligman has said he was
going to resign.
In the note from the meeting of Oct. 29, Dr. Graham wrote that Dr.
Seligman said to him: "This only confirms what I suspected, that the
staff don't trust me. You can't lead if the staff don't trust you.
That's why I have a letter of resignation I am handing in next
Dr. Seligman could not be reached for comment.
In e-mail dated Oct. 25, 2004, Dr. Graham said one of his bosses, Dr.
Anne Trontell, referred to his Vioxx study's conclusions "as nothing
more than a scientific rumor."
Dr. Graham defended his study and chided Drs. Trontell and Seligman
for taking weeks to decide whether they would approve the study's
publication in the Lancet, a leading medical journal. Dr. Trontell is
the office's deputy director. Dr. Graham's study concluded that Vioxx,
also known as rofecoxib, had a dangerous effect on the heart. The
study has been submitted to the Lancet for peer review and possible
publication. Meanwhile, the F.D.A. posted a version of the study on
its Web site on Tuesday, after certain parts of the study were first
published in The Wall Street Journal.
"For all the center claims in its operating principles that respect
for others is a core value, my experience with rofecoxib was just the
opposite from management, once the results from this study and their
potential implications came to light in August," Dr. Graham wrote in
e-mail dated Oct. 26.
The e-mail and notes, which were made available to The New York Times,
come in the midst of a Congressional inquiry into whether the agency
has been slow to respond to findings that antidepressants may cause
children to become suicidal and that Vioxx may be harmful to the heart
in some cases. Senator Charles E. Grassley, Republican of Iowa, who is
chairman of the Senate Finance Committee, has criticized the agency
for failing to respond more quickly to these findings and for
suppressing the findings of its own drug safety reviewers that
concluded that the drugs were risky.
In the case of antidepressants, Dr. Andrew Mosholder, another reviewer
at the Office of Drug Safety, concluded last fall that depressed
children should not be prescribed most antidepressants because they
have failed to show any benefit against depression and may cause some
to become suicidal.
Top agency officials refused to allow Dr. Mosholder to testify about
his findings at a public meeting in February because they disagreed
with his conclusions. A second study conducted by researchers at
Columbia University confirmed Dr. Mosholder's conclusions in August,
and the agency has since decided to place a "black-box" warning on the
labels of antidepressants warning of the suicide risk.
In his notes on an Oct. 29 meeting with Dr. Seligman, Dr. Graham
writes that he, Dr. Mosholder and others in the Office of Drug Safety
feel that "the review and clearance process had been turned into a
battleground, full of contention and intimidation because our
managers, the people who fill out our performance evaluations, had
created a system where it was taking a great risk to stand firm in our
Indeed, according to the meeting note written by Dr. Graham, Dr.
Mosholder recently asked to have his name removed from a textbook
chapter on risk management "because under the current climate, he's
afraid to do anything that will set him up for retaliation or adverse
The e-mail responses from Drs. Seligman and Trontell are mostly brief
requests from seemingly harried bosses asking for more time to review
Dr. Graham's manuscript.
Top agency officials have said they have no convincing evidence that
either Bextra or its cousin Celebrex is unsafe, but independent
researchers have speculated that the entire class of medicines known
as Cox-2 inhibitors may be harmful to the heart. Bextra, Celebrex and
Vioxx are all Cox-2 inhibitors. The F.D.A. will hold an advisory panel
meeting in January to discuss these concerns.
Mobic is made by Boehringer Ingelheim Pharma. They could not be
reached. Officials at F.D.A. and Pfizer did not immediately have
Steve Galson, director of F.D.A.'s Center for Drug Evalution and
Research, said the back-and-forth between Dr. Graham and his bosses is
part of a scientific peer review that "is a totally normal process
that takes place all over the government dozens of times a day.''
He said he would consider Dr. Graham's request to perform studies on
the safety of Bextra and Mobic, but he said other studies are under
way into the safety of Bextra that might provide better evidence.
Andrew McCormick, a spokesman for Pfizer, said he could not comment on
e-mail that he had not seen.
Dr. David Campen, Dr. Graham's co-author on the Vioxx study and a top
medical director at Kaiser Permanente, which provided data for the
Vioxx study, supported Dr. Graham's view of events, including the
proposal for a new study.
"This has been a real challenge for us with respect to the support we
have received from F.D.A.,'' Dr. Campen said. "There were a number of
e-mails that were generated within F.D.A. that were really an effort
to delay publication of our study."