Drug Trials With a Dose of Doubt

[Guest guest]

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 Willman, Times Staff Writer

July 16, 2006

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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. 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 Merck.

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

treatment.

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 scientific judgment.

" 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 the drugs.

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 too low.

More patients died who took the " comparator " drugs than those who

got the new products.

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 hospitals.

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,

prompting congressional 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 completed. "

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, oversight and 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 results. "

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 made mistakes. "

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 D. , 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 s 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 practice. "

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 amphotericin B.

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 kidney damage.

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

decreased patients' 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 studies.

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

suspected, infections. 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. 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

insufficient, patients could be left more vulnerable to an infection

invading the lungs or other organs.

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 aspergillus.

" 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. "

Disputed Results

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 project.

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. 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 successful outcome. "

A dose of 0.6 milligram per kilogram of body weight, daily, for

patients with suspected but unproven infections " obviously is not

sufficient against " 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 more effective.

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 other causes.

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 ,

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

infections and fungal-infection-related deaths " than conventional

amphotericin.

Within hours, the advisory committee voted unanimously in support of

the new drug.

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

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 the study.

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. 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 mg. "

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 conventional amphotericin 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

observed. "

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

participating research centers. Walsh also suggested that the

toxicity of amphotericin had prevented the administration

of " appropriate doses " to some patients.

The three officials who wrote to The Times on Walsh's behalf,

including 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 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 some patients.

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, daily.

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 approval.

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

better effectiveness.

Previously, Walsh supported higher doses of AmBisome for patients

with aspergillus.

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 treating.''

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 best.)

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 he recommended.

" 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 Bethesda.

Walsh, in his statement to The Times, said: " I did not appear as a

consultant to Merck. "

But that is how Merck identified him to the FDA committee, both

orally and in a slide.

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.

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 company study.

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 measurable benefit.

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 Blackwelder,

asked Walsh if he was " confident " that the patients with worsening

aspergillus infections had benefited from Merck's drug. " Yes,

indeed, " Walsh concluded.

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 M.

Treacy, who formerly directed operations of the FDA's advisory

committees.

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 drug.

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 survival. "

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 colleague wrote.

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.

Cancer Center in Houston.

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 risk.

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.

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Times researcher Janet Lundblad in Los Angeles contributed to this

report.

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(INFOBOX BELOW)

A deadly fungus

Dr. 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.

Aspergillus

Where found: Widely distributed in soil, household dust and damp

building materials.

Structure: Microscopic stalks topped with spores called conidia; as

they grow they form a mass of fungus fibers.

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Infections

Aspergillus can spread rapidly through the lungs and often to the

brain and kidneys.

Symptoms: Fever, chills, shock, delirium.

Results: Kidney and liver failure can occur, with death resulting

quickly.

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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 lung

tissue.

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Sources: Centers for Disease Control and Prevention, Merck & Co.,

Medline Plus

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Drug studies

Dr. J. Walsh of the National Cancer Institute helped design

and lead major clinical studies of drugs that treat potentially

lethal fungal infections. The studies supported FDA approval of the

drugs, made by companies that helped pay for the research. When the

results of two of the studies were published, other doctors

questioned whether dosage levels were high enough for drugs used as

comparators.

AmBisome

(liposomal amphotericin

Company: Fujisawa USA Inc.

When patients were enrolled and treated: January 1995 to May 1996

Comparison drug: amphotericin B (conventional amphotericin)

Number of patients: AmBisome, 343; amphotericin, 344

Daily dosage: AmBisome,

3 milligrams per kilogram of body weight; amphotericin,

0.6 milligram

Deaths in each group: AmBisome 25; amphotericin 36

Cost per daily dose: AmBisome $800; amphotericin $16 *

FDA approval: Aug. 11, 1997

Total U.S. sales: Exceeded $665 million through 2005

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Cancidas

(caspofungin)

Company: Merck & Co.

When patients were enrolled and treated: January 2000 to

August 2002

Comparison drug: AmBisome (liposomal amphotericin

Number of patients: Cancidas, 556; AmBisome, 539

Daily dosage: Cancidas,

50 milligrams per kilogram of body weight; AmBisome, 3 milligrams

Deaths in each group: Cancidas 61; AmBisome 75

Cost per daily dose: Cancidas $395; AmBisome $800 *

FDA approval: Jan. 26, 2001; for expanded use, Sept. 29, 2004

Total U.S. sales: Exceeded $859 million through 2005

* Costs per daily dose are approximate and have varied by year.

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Sources: New England Journal of Medicine; IMS Health; Credit Suisse;

U.S. Food and Drug Administration; Times reporting