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Joined: 24 Mar 2005
|Posted: Sun Jul 16, 2006 9:08 pm Post subject:
That's just plain not true. Zerhouni and McSweegan.
From: Kathleen Dickson <firstname.lastname@example.org>
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Subject: NIH's Zerhouni is FOS
Date: Sunday, July 16, 2006 17:06:33 [View Source]
That's just plain not true. NIH "scientist" Edward
McSweegan was heavily involved in the Lyme/LYMErix
spin, as an approver of the bogus Dearborn Method to
diagnose Lyme, the intent of which was to come up with
a standard to qualify vaccines. There were 400
adverse neurological events to LYMErix, which the
public did not hear about.
LYMErix was actually Edward McSweegan's idea:
Wouldn't it be nice if the DHHS, NIH, FDA, and CDC
told the truth once in a while?
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Subject: [SpinLyme] Drug Trials With a Dose of Doubt
Date: Sunday, July 16, 2006 13:43:18 [View Source]
A TIMES INVESTIGATION
Drug Trials With a Dose of Doubt
An NIH scientist with ties to pharmaceutical firms
helped test their new drugs.
Some peers questioned the results of the studies.
By David Willman, Times Staff Writer
July 16, 2006
BETHESDA, Md. ? On Jan. 10, 2001, pharmaceutical
giant Merck & Co. gathered its
forces in a hotel conference room here with a
clear-cut mission: Win a favorable
vote for a new antifungal drug from a federal advisory
committee ? a victory
that would position the product for swift government
approval and for hundreds
of millions of dollars in sales.
But after hours of speeches and slides, the committee
members, appointed by the
U.S. Food and Drug Administration, had yet to vote.
The members were focused on
the quality of Merck's case for the new drug, which
rested on the treatment of
only 69 patients.
Merck summoned to the microphone one of its announced
consultants, a man whose
government job was nearby, at the National Institutes
of Health. Dr. Thomas J.
Walsh assured the committee that Merck's data
describing the patients was
"extremely robust and very, very rigorous." He said
his government staff had
assisted in vetting the company's data. About 30% of
the patients were helped by
the drug, he said.
The advisory committee voted unanimously to endorse
the drug, called Cancidas.
Sixteen days later, the FDA approved it. Doctors would
later prescribe it for
patients whose immune systems had been ravaged by
chemotherapy and who were
presumed to have a potentially deadly, invasive fungal
infection. In its first
five years on the U.S. market, Cancidas would generate
$859 million in sales for
U.S. law generally prohibits a federal employee from
representing an outside
party before a government agency.
In building a career as an influential government
scientist, Walsh has served as
both a paid and unpaid advisor to pharmaceutical
companies and has helped lead
clinical trials that tested the effectiveness of their
products. With his help,
the companies have brought new antifungal drugs to
market, but controversy has
flared over whether results from two of the studies
were misleading and whether
some of the participating patients received adequate
In written comments for this article, Walsh said his
advice to industry did not
conflict with his position at the NIH's National
Cancer Institute, or affect his
"I am not and have never been a representative of, or
advocate for, any
pharmaceutical company," Walsh said.
Two drug makers involved with his federal research,
Merck and Pfizer Inc., said
they have paid fees to Walsh. Merck and another
company, Fujisawa USA Inc., have
made financial or other donations to support Walsh's
federal research with the
approval of his NIH superiors, interviews and
government records show.
|From 1997 to 2003, Walsh appeared at meetings with FDA
committees or staff
alongside representatives of Pfizer, Fujisawa and
Merck, according to
videotapes, transcripts and other government records.
He also helped design,
oversee and interpret the results of major clinical
studies of four antifungal
drugs made by those companies. The studies helped win
FDA approvals for three of
In separate letters to a leading medical journal,
other researchers criticized
two of those studies. They questioned whether the
studies artificially boosted
the new products by comparing them to drugs that were
given at doses that were
More patients died who took the "comparator" drugs
than those who got the new
Walsh, in journal articles and in remarks to medical
leaders, noted the
disparities in deaths while describing the advantages
of the newer drugs. In
published responses to the scientific critics, he said
the doses of the
comparator drugs reflected the general standard of
care at the participating
What led to the higher death rates of the
control-group patients in the two
major studies may never be known: A limited number of
autopsies were performed,
and factors other than fungal infections, such as the
patients' cancer, could
have caused the deaths.
No published study has established that a higher dose
of an antifungal drug is
more effective in treating suspected infection, and
some studies have suggested
that lower dosing may provide similar benefits. But
the possibility that
patients did not receive adequate doses, combined with
Walsh's advisory role
with the drug companies, adds a new dimension to the
furor over NIH scientists'
ties to industry.
Earlier revelations of the agency scientists' outside
arrangements called into
question their impartiality and the independence of
the NIH, the nation's
largest agency for experimental medical research,
hearings, policy reforms and ethics investigations.
However, even as the NIH moved recently to ban some of
the activities with
industry, the agency's director said the arrangements
had apparently not
jeopardized patients in clinical studies.
"Thus far, we have not identified any situations where
patients were harmed as
the result of financial arrangements NIH employees had
with outside parties,"
NIH Director Elias A. Zerhouni told a Senate
subcommittee in 2004. "I will,
however, reserve final judgment until all internal and
external reviews are
In response to questions from The Times regarding
Walsh, Zerhouni responded
generally in a prepared statement. "We revamped our
rules last year, and
continue to carry out a vigorous program of education,
enforcement," he said, adding, "Violations of the
ethics rules are unacceptable,
and I remain determined to pursue any information
brought to my attention."
Walsh, 54, heads a medical research and treatment unit
within the pediatric
branch of the National Cancer Institute, where he
arrived in 1986. He said that
collaborating with companies has been fundamental to
his government work.
"My efforts are in service of the public interest in
sound, reliable science
concerning potentially effective agents for the
treatment of life-threatening
infections in children and adults with cancer," Walsh
said in a statement to The
Times. "This mission frequently includes collaboration
with companies that
research and develop new compounds in this area ?
for example, utilizing my
[staff's] expertise to ensure that clinical trials
relating to these compounds
are designed and implemented in a manner that elicits
reliable and useful
He said he has appeared before the FDA only "as a
government scientist providing
information and/or evaluation" regarding clinical
trials. Referring to studies
he helped lead, Walsh said, "There is no conflict of
interest, and the trials
were well and appropriately designed."
The full extent of Walsh's ties with industry is not
open to view by outsiders.
His yearly financial-activity reports at the NIH are
exempt from release under
the Freedom of Information Act, as are the reports for
most senior researchers
at the agency.
None of Walsh's outside arrangements were listed in
records that the NIH turned
over to a congressional committee that had sought
details of connections between
agency scientists and the drug industry.
Although Walsh declined to answer a number of
questions about his financial
arrangements with the drug companies for this article,
he said in a telephone
conversation on May 18: "On the personal issues, I've
Walsh also said he preferred to let colleagues address
questions regarding the
dosages selected for the two major studies he helped
design. Two private lawyers
representing him, H. Bradford Glassman and Jeffrey D.
Robinson, noted in a
letter to The Times that the dosages were chosen with
the assent of other
researchers, and not by Walsh, individually.
Walsh is well-known in his field, having written or
cowritten more than 230
medical journal articles over the last decade. A
medical graduate of Johns
Hopkins University in Baltimore, he has won honors
within the NIH as a mentor,
receiving the agency's Distinguished Clinical Teacher
Award. In 1996, he
received an Outstanding Service Medal from the U.S.
Public Health Service for
"sustained and outstanding advances in the treatment,
prevention and diagnosis
of invasive fungal infection in children with cancer
and HIV infection."
Three of Walsh's superiors at the National Cancer
Institute contacted The Times
by e-mail and defended as scientifically sound the two
major studies that he
helped lead. The officials noted that the designs of
both studies were reviewed
and approved by the FDA and by boards at the medical
sites where patients were
treated. Dosages for one of the studies, they wrote,
were selected based on a
consensus of participating researchers.
Eight doctors, including seven who participated in one
or the other major study
with Walsh and who are not employed by the NIH, also
contacted the newspaper and
said they stood behind the validity of the research.
The study designs, they
said, "were both scientifically and medically sound,
reflect the state of the
art in the field, and have advanced supportive care,
improving the management of
patients worldwide and saving lives."
Other researchers have said that doses of comparator
drugs that are inadequate
may endanger patients or make a new drug look more
effective than it is.
"I can see why the companies are eager to get an easy
comparison, a drug they
can beat," said Dr. Curt D. Furberg, who formerly
headed clinical research at
the NIH's National Heart, Lung, and Blood Institute.
"But for [scientific]
investigators to go along with that, it's just a bad
Picking the Patients
|From the late 1950s to today, the drug of choice for
many doctors treating
potentially lethal fungal infections has been a
powerful compound called
Nurses and doctors have long dubbed the drug, derived
from spores found in
Venezuela's Orinoco River region, "ampho-terrible."
Some patients tremble
violently as the solution, infused intravenously,
courses through their bodies.
Fever and vomiting also can result. In some cases, the
drug can cause fatal
Approved by the FDA in 1958, amphotericin gained
greater acceptance in the
United States in the 1980s after research conducted in
Europe and at the
National Cancer Institute suggested that the drug
vulnerability to an internal fungal infection.
For decades, amphotericin has been available worldwide
in relatively cheap,
generic formulations. By the early 1990s, several
firms were aiming to modify it
into their own brand-name products ? agents that
they hoped would be better and
that could fetch far higher prices. The new products
would deliver the
amphotericin in fatty mixtures, changing the
characteristics of the drug to
reduce the risk of kidney damage.
The modified amphotericin products would cost as much
as $800 a day, compared
with about $16 per day for the older drug.
In order to get their reformulated drugs approved by
the FDA, the companies had
to conduct human studies. The FDA held two public
meetings, in 1994 and 1995, to
hear experts' opinions regarding design standards for
The FDA was under pressure to cooperate more closely
with the pharmaceutical
industry. Amid complaints that existing standards had
stymied the development of
new drugs, the agency had been directed by Congress
and the White House to
streamline its medical reviews.
For makers of the new antifungal drugs, less
burdensome clinical-study standards
could make it easier to get the products approved. For
instance, some companies
wanted to enroll cancer patients with suspected ?
but unproven ? fungal
infections. These would be patients who had abnormally
low levels of
infection-fighting white blood cells and fevers
lasting at least four days,
despite treatment with a standard antibiotic.
Walsh has stressed the need for treating suspected
infections quickly, noting
that persistent fever may be the only sign and that
delaying treatment could
lead to increased deaths. As envisioned by Walsh and
others developing the new
products, the drugs would be assessed on several
factors, including whether the
patients' fevers abated.
Some cancer and infectious-disease specialists
questioned that approach. Every
enrolled patient would have a fever, but would its
disappearance mean that the
drug had defeated a fungal infection?
Noting that fever can have many causes, the
specialists stressed the importance
of studying patients with proven, as opposed to
Eliminating fever in the patients with proven
infections, they said, would
provide better evidence of effectiveness.
But at the 1995 FDA meeting, Walsh said enrolling and
treating more of the
patients with proven fungal infections would pose
"financial and logistical
limitations," meaning the major studies would take
longer and cost more. He
estimated that it would take years to identify and
enroll a sufficient number of
patients with proven infections.
"I think it is appropriate to have a relatively low
frequency of the proven
infections," Walsh said.
Walsh also told the FDA committee it was essential to
launch separate studies
that would more directly examine a drug's effect on
specific fungal infections.
The FDA accepted the approach of designing the major
studies to enroll and treat
patients with persistent fevers who had suspected but
unproven infections. An
FDA medical officer, Dr. Teresa Wu, said the approach
"largely was motivated by"
the ease of enrolling such patients.
Roughly half the patients would get new drugs, made by
companies that helped pay
for the research. The remaining "control" patients
would get dosages of an
older, comparator drug.
The choice of dose might determine patients' survival:
If the dose of the
comparator drug in the first study, amphotericin, was
could be left more vulnerable to an infection invading
the lungs or other
One of the fungal infections, aspergillus, typically
kills 50% or more of the
patients who develop it. And it is notoriously
difficult to diagnose: Because
the patients are so sick, doctors often are reluctant
to collect a sample of
lung tissue, which might confirm an underlying
infection. Aspergillus often
cannot be confirmed before autopsy.
Yet if the dose were set too high, patients, including
those who turned out not
to have a fungal infection, would be put at greater
risk of kidney damage.
Walsh did not commit to an exact dosage of
amphotericin at the 1995 FDA meeting.
He did, however, say that a drug used in the new
studies would need to be
powerful enough to treat aspergillus or other
devastating mold-type fungal
infections, not just yeast-type fungal infections,
such as candida, which are
lethal less often and are commonly treated with lower
doses. Since the early
1990s, experts in the U.S. and Europe had reported
increases in the frequency of
"If we are really trying to protect the high-risk
patients," he said, "we have
to appreciate that there are more than just yeasts
that we are trying to prevent
or to impact upon."
The first major study that Walsh helped lead compared
one of the new, modified
drugs, AmBisome, with conventional amphotericin.
The study was paid for by the developer of the new
drug, Fujisawa USA Inc., and
by a grant from the NIH. Walsh had conferred about the
study design with
Fujisawa and with a national network of other
physicians who would carry out the
The dosage for patients who would be given
amphotericin was 0.6 milligram per
kilogram of body weight, daily.
One expert invited by the FDA advisory committee, Dr.
John H. Rex of the
University of Texas Medical School at Houston, said in
April 1995 that the
dosage in such a study "probably, actually, should be
higher." Asked if he
favored the higher dosage even for the yeast-based
fungal infections, Rex added:
"The general feeling is ? somewhere between 0.6 and
1 is the correct dose."
Walsh had foreshadowed concern about using low-dose
amphotericin for suspected
aspergillus. In a 1990 article published by Seminars
in Oncology, Walsh and a
colleague wrote: "When Aspergillus pneumonia is
suspected or proven, higher
doses of amphotericin B (1 to 1.5 mg/kg/d as opposed
to the standard 0.5 mg/kg/d
used in other infections) are indicated to optimize
A dose of 0.6 milligram per kilogram of body weight,
daily, for patients with
suspected but unproven infections "obviously is not
aspergillus, Walsh and his co-authors wrote in a 1991
article published by
Reviews of Infectious Diseases.
In the AmBisome study, Walsh supported using the
0.6-milligram dosage. Walsh had
told the FDA committee in 1995, without referring to
the ongoing study with
Fujisawa, that he preferred "flexibility in dosage."
This would allow increases
if a patient faltered. He said that "some experimental
data" suggested that
higher doses of conventional amphotericin might be
The study treated 687 patients: 343 with AmBisome, at
3 milligrams per kilogram
of body weight, daily; and 344 with conventional
amphotericin, at 0.6 milligram.
The patients, treated at sites throughout the United
States and ranging in age
from 2 to 80, were enrolled within 16 months, at what
Walsh later called "a
remarkably rapid rate." He also would describe the
patients as a "very high-risk
population," vulnerable to fungal infections.
Of the patients given conventional amphotericin, 36,
or 10.5%, died. Of patients
given Fujisawa's drug, 25, or 7.3%, died.
Those who oversaw the treatments concluded that fungal
infection was the primary
or contributing cause of death for 11 who received
conventional amphotericin and
for four treated with the Fujisawa drug. The remaining
deaths were attributed to
On July 16, 1997, Walsh anchored Fujisawa's
presentation of AmBisome to the FDA
advisory committee, which met in Silver Spring, Md.
The FDA's agenda listed
Walsh as part of the "Fujisawa USA Presentation."
Fujisawa's vice president for regulatory affairs,
Jerry Johnson, told the FDA
committee: "Our presentation will conclude with Dr.
Walsh presenting the key
results from the U.S. study."
Walsh narrated a series of slides and told the
committee that AmBisome "was more
effective in preventing proven invasive fungal
fungal-infection-related deaths" than conventional
Within hours, the advisory committee voted unanimously
in support of the new
On Aug. 11, 1997, the FDA approved AmBisome for
treating presumed fungal
infections in children and adults. The dose approved
by the FDA ? 3 milligrams
per kilogram of body weight, daily ? was the same as
that used in the study.
The next month, Walsh told a conference of physicians
and research scientists in
Toronto that AmBisome was "the first agent shown to be
superior to amphotericin
B in reducing proven, invasive fungal infections in
cancer patients." AmBisome,
he said, was "a new standard" in treatment. Within
days, Fujisawa began
marketing AmBisome in the U.S.
In the FDA's final review of the new drug,
statistician Thomas Hammerstrom wrote
that although AmBisome was similar in effectiveness to
amphotericin, there were
"inadequate scientific grounds" to judge it superior.
In March 1999, Walsh appeared as the lead author of an
article in the New
England Journal of Medicine that reported detailed
results from the study that
had compared AmBisome with amphotericin. The article
said the drug dosages were
"deliberated upon and adopted by consensus of the
investigators" who conducted
Physician-researchers from Germany questioned the
design of the study in a
letter to the journal seven months later.
"We think that the design of this randomized trial was
not adequate because the
dose of conventional amphotericin B (0.6 mg per
kilogram of body weight per day)
that was used does not reflect widely used standards
of care," wrote Drs. Thomas
Fischer, Gudula Heussel and Christoph Huber of
Johannes Gutenberg University.
"Most institutions in Europe and the United States
would agree that treatment of
this patient population requires a dose of at least 1
The physicians said it seemed "very likely" that if
Walsh and his collaborators
had used a "normal," higher dose of conventional
amphotericin, fewer patients
who took that drug would have had fungal infections
emerge or progress. (Fischer
declined to be interviewed for this article; he said
by e-mail that AmBisome had
proved to be a useful drug.)
Skepticism about the dose of conventional amphotericin
used by Walsh also was
reflected in a 2001 medical reference book issued by
the British Society for
Haematology and other groups. The authors said that
had been given to similar patients in Europe at doses
up to twice as high as in
the study that Walsh helped lead.
The lower dose, the authors wrote, "may bias the
results in the favour of
AmBisome" and "could entirely explain the differences
Fujisawa had agreed to allow doctors conducting the
study to double the dose of
either drug, depending on patients' conditions. But
doctors ultimately increased
the dose for 17% of the patients who took amphotericin
? while doses were
increased for 34% of the patients who took AmBisome.
The New England Journal of
Medicine report cowritten by Walsh described the study
as "blinded," so that
neither the doctors nor their patients were supposed
to know which of the two
drugs was being administered.
Walsh and two colleagues, in a reply published by the
journal, said the dose of
amphotericin reflected "the standards of care" at the
centers. Walsh also suggested that the toxicity of
amphotericin had prevented
the administration of "appropriate doses" to some
The three officials who wrote to The Times on Walsh's
behalf, including Robert
H. Wiltrout, a research director at the National
Cancer Institute, defended the
dose of conventional amphotericin.
"There is no rational motivation for an investigator
or sponsoring company to
design a trial with a control arm that is not standard
of care," wrote Wiltrout,
along with Drs. Lee J. Helman and Frank Balis of the
National Cancer Institute.
As Walsh defended his study in the New England Journal
of Medicine, he was
helping write new medical-practice guidelines
suggesting far higher doses for
In a paper submitted for publication in October 1999,
Walsh and other authors
said that, following prompt and aggressive evaluations
of the patients, doctors
should consider "maximum tolerated doses" of
conventional amphotericin if
aspergillus infection, specifically, was suspected.
They defined those doses as
1 to 1.5 milligrams per kilogram of body weight,
Standing With Merck
By 1999, Walsh was collaborating with Merck & Co., on
its new antifungal drug,
Cancidas. One Wall Street firm predicted that Cancidas
could generate annual
sales of $330 million. But first Merck needed FDA
AmBisome, the same drug that Walsh had just helped
guide to FDA approval, was
picked as the comparator.
Merck paid for the study. Walsh designed it in
collaboration with Merck and one
other researcher, who received fees from Merck. The
initial dose selected for
AmBisome ? 3 milligrams per kilogram of body weight,
daily ? was the same as in
the earlier study.
In a statement delivered to The Times last week, Walsh
said "there was and is no
evidence" that higher dosages of AmBisome would offer
Previously, Walsh supported higher doses of AmBisome
for patients with
At the 1997 conference in Toronto, Walsh said that a
lower dose might suffice
for a yeast-type infection. But for aspergillus or for
other mold infections
that resist treatment, he said, "I would submit that
we probably should be using
more?. There are good experimental data to show that
more is better."
When choosing a dose, Walsh added, "I think it depends
on what disease one is
At a September 1999 conference in San Francisco,
Walsh, along with Fujisawa's
medical director and several other scientists,
described having used AmBisome
doses from 7.5 to 15 milligrams per kilogram of body
weight per day in patients
with possible, probable and proven infections.
A summary of their research said the high dosages "are
safe, well-tolerated, and
can provide effective therapy for aspergillosis" and
similar infections. (Two
years later, their full-length article on the study
repeated that conclusion but
also said the study did not have enough patients to
prove which dosages worked
At a symposium to discuss the treatment of aspergillus
infections last October
in San Francisco, Walsh was asked by a physician which
maximum dose of AmBisome
"Certainly, we want to think that more is better,"
Walsh replied, adding that
while results from clinical trials did not support
using more than 5 milligrams
per kilogram of body weight, daily, there were data,
based on safety and drug
concentration in the blood, suggesting a benefit at
7.5 to 10 milligrams.
|From January 2000 through August 2002, 116 hospitals
and clinics worldwide
carried out the study of Cancidas.
The 1,095 patients with suspected fungal infections
received either Cancidas or
AmBisome. The patients ranged in age from 16 to 83.
At around the same time, Merck persuaded the FDA to
conduct a fast-track review
of Cancidas for a more narrow use: treating
aspergillus in patients who had
either not tolerated or failed to improve while taking
another antifungal drug.
On Jan. 10, 2001, representatives of Merck ?
assisted by Walsh ? presented the
company's case for approval of the drug to the FDA
advisory committee in
Walsh, in his statement to The Times, said: "I did not
appear as a consultant to
But that is how Merck identified him to the FDA
committee, both orally and in a
Tamara Goodrow, a Merck regulatory affairs official,
said: "Merck has brought
several consultants to the meeting today so that they
are available to
facilitate the advisory committee's discussion and
deliberations." Goodrow then
named the consultants, including "Dr. Thomas Walsh."
Another Merck official said Walsh served as the head
of a company committee of
three researchers who assessed how patients with
aspergillus infections had
responded to treatment with Cancidas in the smaller
Several members of the FDA advisory committee voiced
concern about the validity
of the small study involving 69 patients. They pointed
out that it lacked a
"control" group of patients treated at the same time
to gauge the comparative
effectiveness of Merck's drug.
They questioned whether the study proved that Cancidas
provided patients with a
At that point, a videotape of the meeting shows,
Merck's senior director of
clinical research, Dr. Carole A. Sable, gestured to
the audience and said:
"Perhaps Dr. Walsh, who is actually the head of our
expert panel, would like to
make a comment."
Walsh strode to the podium, took the microphone and
assured the FDA committee
that Merck's case-by-case information for the 69
patients was reliable. "I think
this was really the largest and most robust set of
data that we've ever had on
individuals," Walsh said. He said his "whole section"
of NIH government
scientists had assisted him in reviewing Merck's data.
A member of the FDA committee, biostatistician William
Blackwelder, asked Walsh
if he was "confident" that the patients with worsening
had benefited from Merck's drug. "Yes, indeed," Walsh
The committee endorsed the approval of Cancidas for
treating patients with
aspergillus who had not responded to other drugs. On
Jan. 26, 2001, the FDA
approved Merck's application to market it for that
narrow use, although doctors
were at liberty to prescribe Cancidas as they saw fit.
A Merck spokesman said recently that Walsh was paid a
total of $3,000 in fees,
in 1999 and 2001, not related to his involvement with
the company's drug. Walsh
said in his statement to The Times that Merck had not
paid him for any
appearance before the FDA.
U.S. conflict of interest law generally prohibits a
federal employee from
representing anyone before a government agency,
regardless of whether outside
compensation is paid.
"Outwardly, it looks like it could be a problem," said
John M. Treacy, who
formerly directed operations of the FDA's advisory
Meanwhile, Merck's hopes for wider use of Cancidas ?
in patients with presumed
but unproven fungal infections ? rested with the
large international study that
continued through late 2002.
The results were published in the New England Journal
of Medicine on Sept. 30,
2004, with Walsh listed first among the authors.
Patients who were given
AmBisome as a comparator fared somewhat worse than
those who got Merck's
Cancidas: Of the 539 patients given AmBisome, 75, or
13.9%, died. Of 556
patients given Merck's drug, 61, or 11%, died.
A sharper contrast was reported among 24 patients
described as having an
aspergillus infection: 11 of the 12 given the older
drug died or were otherwise
not treated successfully, compared with seven of the
12 patients who got Merck's
Walsh and his co-authors, who included four Merck
employees, noted the
differences in their journal article: Among the
patients with "baseline" fungal
infections, "the rate of death during the study was
lower in the [Cancidas]
group." Overall, they said, Cancidas offered "improved
On Sept. 29, 2004, the FDA approved Merck's
application to market Cancidas for
treating patients with presumed fungal infections. On
Dec. 8, 2004, a Merck
executive told stock-fund managers that the approval
could "give us a great
opportunity to increase sales in 2005."
A month later, Dr. Francisco Marty, a specialist from
Brigham and Women's
Hospital in Boston who also is an instructor at
Harvard Medical School, voiced
concern about the Walsh-led study in a letter
published in the New England
Journal of Medicine.
Patients with early fungal infections who were given
AmBisome "may have received
suboptimal doses of that drug at a time when
frontloading of therapy is critical
to gain control of the infection," Marty and a
Although the initial dose selected for AmBisome was
the same as in the earlier
major study, Marty's letter pointed out a distinction:
In the newer study, the dose was not supposed to be
increased until a patient
had received treatment for five days on the original
dose ? and had continued to
deteriorate. (A patient also could be removed from the
study and treated
differently at the discretion of the physician.)
In an interview at his Boston office, Marty said that
the patients whose
infections were found early in the Merck study and who
were given the lower dose
of AmBisome may have been put at a disadvantage.
"You have a bad infection and you don't get enough
drug, you may be dead," Marty
said. He noted that the medical-practice guidelines
? cowritten by Walsh ?
suggested a dose of 5 milligrams per kilogram of body
weight for aspergillus.
For those patients, Marty said, "you're not doing a
good job with 3 milligrams."
Other doctors who wrote to the New England Journal of
Medicine raised questions.
An unusually low percentage of patients in the
AmBisome group responded
favorably to treatment, wrote Dr. Dimitrios P.
Kontoyiannis and a colleague from
the University of Texas M.D. Anderson Cancer Center in
In reply, Walsh wrote in the journal that various
groups had advocated both
higher and lower dosages of AmBisome. The use of 3
milligrams per kilogram of
body weight per day, he and two co-authors wrote in
January 2005, was "the most
tenable initial dosing strategy."
Walsh, responding to questions for this article, said
that the five-day
provision in the second study was intended to
standardize the conditions for
increasing the dosages. He said the provision was
approved by consensus of the
participating institutions on the belief that it would
not put patients at added
In his statement last week, Walsh pointed to results
from a recently completed
study, suggesting that a 3-milligram dosage of
AmBisome was about as effective
against aspergillus as was a 10-milligram dosage.
The points made on his behalf recently by his
superiors and by other letter
signers, Walsh said, "conclusively refute any possible
contention that the two
clinical trials violated a standard of care or
otherwise called for
inappropriate dosages of antifungal medications."
A 2005 book, "Fungal Infections in the
Immunocompromised Patient," written for
doctors caring for patients most at risk, concluded
that "much controversy still
surrounds the optimal timing, dosage and duration of
therapy" for patients with
the suspected infections.
Furberg, the former NIH clinical research specialist,
said the two major
antifungal studies fell short because they left
unanswered which drug or dose
was best against suspected infections.
"When you set up studies with controversial
comparisons, you risk misleading
everybody ? regulatory agencies, physicians and
patients," said Furberg, now a
professor at Wake Forest University.
Times researcher Janet Lundblad in Los Angeles
contributed to this report.
A deadly fungus
Dr. Thomas J. Walsh has led major studies that helped
bring new antifungal drugs
to market. One fungus, aspergillus, is widely found
indoors and outside. It can
cause deadly infections in people with compromised
immune systems, such as those
who have undergone cancer or AIDS treatment or bone
marrow or organ transplants.
Where found: Widely distributed in soil, household
dust and damp building
Structure: Microscopic stalks topped with spores
called conidia; as they grow
they form a mass of fungus fibers.
Aspergillus can spread rapidly through the lungs and
often to the brain and
Symptoms: Fever, chills, shock, delirium.
Results: Kidney and liver failure can occur, with
death resulting quickly.
Inside the body
The infections often appear in the lungs as a mass of
fungus fibers, blood clots
and white blood cells. The fungus grows, destroying
Sources: Centers for Disease Control and Prevention,
Merck & Co., Medline Plus
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