10/12/2000 – A Wonder Drug That Carried the Seeds of Death

I have been meaning to send this out to you for some time now as a reminder
of the terrible aftermaths that so often follow a so called “Wonder Drug.”
Note that this little wonder was distributed free of charge by the most noted
health agency in the country, the National Institutes of Health. We can add
one more terrible tragedy to the very long list of “wonder drugs” gone bad.
It makes one think back to the government admission several years ago that
they hired family practitioners to pick out several of their patients to
inject, without the patient’s knowledge of course, with plutonium to learn
the effects of this substance on humans. Ever so often the doctor would bring
the patient in for a “check up” to note any changes. The families learned of
this after the deaths of their loved ones and sued. The government settled
the suits and apologized on the evening news.

Funny, I thought true sorrow included stopping the thing you are doing that
is wrong. Obviously it has never stopped. Only the names of the drugs have
changed. The standard practice remains the same: deny the truth, then hide
the evidence, then deny you knew what the outcome would be when you did know,
then fight the victims in court to avoid having to pay for what you did to
them and badger them enough so that they will drop their suit against you.

This is also a wake up call to the dangers of mad cow disease in this
country. Any blood product, which human growth hormone is, can carry this
disease. (Of course now that it is synthetically produced we are to believe
it is now safe.) The last mad cow (CJD) death in Utah was a young man who got
it from eating Elk that he had hunted. The CDC came into Utah to investigate
as they have thought the wild animals did not yet have the disease. There was
great alarm generated by the fact that this young father had given blood over
the years. As CJD lies dormant for many years before manifesting the
symptoms, they were afraid that several years down the road we would see many
more cases of mad cow due to the blood transfusions that came from this man’s
blood. Blood products of any kind are suspect.

Ann Blake-Tracy, Executive Director,
International Coalition For Drug Awareness

Sunday, May 21, 2000 | L A Times

A Wonder Drug That Carried the Seeds of Death

Human growth hormone held promise for thousands, but contamination of early
samples has been linked to a fatal disease. A purification method was known
but not used.

By EMILY GREEN, Times Staff Writer

In 1958, an American scientist managed to do what nature had failed to.
He made a dwarf grow. For the first time, man had harnessed human growth

By 1963, while technically still an experimental drug, the hormone was
being supplied free of charge by the National Institutes of Health to
pediatricians across America. For the next 22 years, the drug was
administered to more than 8,000 stunted children.

It worked. The children grew–collectively, more than a mile. They went
on to become soldiers, doctors, journalists and secretaries. They married and
had children. But then, decades after taking the hormone, a small but steady
succession of recipients began to develop strange symptoms.

First they lost their balance. In the case of a 32-year-old foot surgeon
from Brooklyn, N.Y., Dr. Stacey Crair, she suddenly started toppling over. As
a child, Crair had received growth hormone treatment for 12 years.

Nearby on Long Island, a water safety engineer named Mike Nofi remembers
that his 30-year-old wife, Wendy, suddenly started feeling like “she was on a
boat.” She had received growth hormone for six years.

Soon they began to stagger and drool. Their personalities changed.
Within months they were in comas. Their brains were turning to sponge.

They had Creutzfeldt-Jakob disease, or CJD, a human variant of the
so-called mad cow disease. CJD is incurable. The agent that causes it is
unknown. How they got it, however, was clear. They had been infected by
contaminated hormone. Twenty other hormone recipients in the United States
have also died from CJD, and the toll continues to rise.

But the NIH has not apologized, or even helped with the care of victims.
Having investigated the debacle, the NIH has insisted for the last 15 years
that the deaths were unforeseeable.

“It was an experimental treatment, and people signed informed consents,”
NIH spokeswoman Jane Demouy said recently.

However, The Times has unearthed British court documents showing that
the deaths were not only foreseeable, they were foreseen. The NIH lab called
in to investigate the deaths in 1985 had been warned of the danger of
contamination seven years earlier.

Moreover, a body of research shows that a safer method for processing
the drug had been available from the inception of the program. But scientists
under contract to the NIH chose a cheaper, less labor-intensive method.

Shown the documents, Demouy said the NIH involvement was limited to
funding the program:

“Physicians around the country administered the hormone. Decisions
regarding the program were made more than 35 years ago, and the people
involved are deceased or retired. In 1985, when it was learned that three
patients who had received human growth hormone had contracted CJD,
distribution of human growth hormone [from cadavers] was ended.”

Plundering the Pituitary Gland

Today human growth hormone is synthetic, and safe. So it is easy to
forget how crude its early forms were–or that it was an important medicine.
A sign of how fast its development has been is that, at the turn of the 20th
century, the word “hormone” did not even exist. Endocrinology–the study of
the network of glands that produce hormones responsible for growth, sexual
maturation, reproduction and digestion–was a new science.

Early research was brutal but effective. Experimenting on animals,
mainly dogs, scientists in Europe and North America deduced what endocrine
glands did by surgically removing the organs and seeing what happened.
Usually the dogs died.

In 1921, a University of Toronto team found not only that removal of a
dog’s pancreas caused diabetes but also that injecting the dog with
pancreatic extract appeared to cure the disease. The extract contained the
lifesaving hormone insulin. Within a year, insulin from the pancreases of
cows was being injected into diabetic children. The first American recipient
went on to live to the age of 74
and came to describe the hormone as “unspeakably wonderful.”

Plundering the pituitary gland proved a good deal trickier. Located
behind the bridge of the nose, the bean-size organ was difficult to remove
without killing the test animal. By the 1950s, however, not only had
scientists managed this, but it had also become clear that the pituitary was
home to a complex cache of hormones governing growth, maturation and

The first pituitary hormone to receive the insulin-style extraction
treatment was human growth hormone. But unlike insulin from cattle, bovine
growth hormone had no effect on people. Scientists needed human pituitary
glands to make people grow. They would have to look to morgues.

In 1958, a Boston-based researcher named Maurice Raben at the Tufts
University School of Medicine produced another first. A 17-year-old boy, whom
Raben had experimentally injected with human growth hormone, grew 2.1 inches
in 10 months.

For parents of stunted children, this offered precious hope: Their
children might be spared lives as dwarfs.

But then they were asked to wait. Dwarfism wasn’t diabetes. It wasn’t
life-threatening. Unlike insulin, human growth hormone was not seen by drug
companies as commercially viable.

Almost immediately, the most enterprising parents enrolled their
children in small trials, very like the first Raben experiment. Even then
there were not enough pituitaries for steady production of the growth
hormone. Some parents turned organ scavengers, personally petitioning
hospitals and morgues for pituitary glands from cadavers.

By 1963, pressure from parents, pediatricians and endocrinologists had
become so intense that the NIH stepped in. It formed the National Pituitary
Agency out of Baltimore’s Johns Hopkins University. The agency would organize
collection and redistribution of the glands to three universities for
processing into growth hormone: Emory in Atlanta, Tufts in Boston and Cornell
in Ithaca, N.Y.

Soon, the NIH was guardian of a sweeping experimental drug trial. For 22
years, from 1963 to 1985, it supplied the hormone to 8,157 children
nationwide and to about 50 foreign-born children who came to America for

For the first 14 of these years, the largest seat of hormone production
was at Emory, supervised by Alfred E. Wilhelmi. A former Rhodes scholar, he
was at the peak of a charmed career. He had received a doctorate from Oxford
University in England and taught at Yale before moving to Emory. Soon to
become president of the Endocrine Society, he was the NIH expert of choice.

But more advanced work was going on in Sweden, at the University of
Uppsala, where chemists had observed problems with the human growth hormone
being extracted using Wilhelmi’s method; it caused immune responses and was
far from pure.

The Swedes, by contrast, had developed a method to produce hormone that
was 95% pure. It did not spark immune response and appeared to be more potent
in inducing growth. The difference was part effort–the Swedes took a much
more labor-intensive approach to gland collection and storage–and part
technology–they filtered their drug using a process called Sephadex gel

Wilhelmi chose not to use the filter.

“Wilhelmi’s philosophy was that the material was human protein, and
human protein cannot harm human beings,” said Albert Parlow, a
Harvard-educated biochemist who was at Emory at the time.

The result was that the NIH supplied thousands of American children with
a drug that could have been pure, but wasn’t. In 1969, Wilhelmi unveiled what
he described as an “improved method” for hormone extraction. But the
improvement was in yield, not purity. The resulting hormone was, Wilhelmi
wrote in the Journal for Clinical Endocrinology, “clinically useful and . . .
may be purified further for chemical use and immunochemical studies.”

Put more simply, this meant that Wilhelmi regarded the hormone as safe
for children but in need of further refinement for use in experiments.

Another believer in the acceptability of clinical grade hormone was Anne
Stockell Hartree, an American-born biochemist then on staff at Cambridge
University in England. She co-wrote the 1969 Wilhelmi paper announcing the
“improved” hormone and was using the method to process the hormone being
employed in an almost identical program in Britain.

By 1973, both Wilhelmi and Hartree were facing questions. A member of
the British hormone program’s steering committee raised concerns about the
safety of the drug.

Wilhelmi replied: “We have been preparing hGH since 1958 in increasing
quantities, and in all that time there has never been a complaint of that
kind of contamination. . . . We are presently going to modify our procedure
to include a step of filtration on Sephadex G-100, and this, I think, will
provide further assurance of removing virus from the system.”

The Times could find no record that Wilhelmi or Hartree ever used the
Swedish-style Sephadex filtering.

The method wasn’t officially adopted until after Wilhelmi’s retirement
in 1977. That year, the NIH put hormone production out to bid. The winner was
Parlow, by then a research professor of obstetrics and gynecology at the UCLA
School of Medicine. Written into his proposal was strict incorporation of
Swedish-style protocols.

The same year, British purification was moved from Hartree’s lab to one
that also began filtering the drug.

Even so, for the next seven years, Wilhelmi’s confidence in his method
seemed justified. As he had once observed to those questioning his methods,
nobody seemed to “have caught anything.”

Woman’s Death Sparks a Crisis

But in March 1984, in the English cathedral town of Winchester, that
changed. What began as an off day for a 22-year-old woman quickly escalated
into an international public health crisis.

Alison Lay, a secretary at a local Barclay’s bank, noticed that her
balance was unsteady. “She progressed from not being able to go to work,”
recalls her mother, Mavis Lay, “to not being able to feed herself and not
being able to walk without help.”

On Feb. 12, 1985, eight days short of her 23rd birthday, Alison Lay died
from CJD.

When she was 2, surgery to remove a brain tumor had also taken out her
pituitary gland. To compensate, between the ages of 10 and 14, she had
received more than 550 injections of human growth hormone.

Unbeknown to the Lays, CJD cases were also being recognized in young
people in the U.S.: a 22-year-old in Buffalo, a 34-year-old in Dallas, a
21-year-old in San Francisco. All had received human growth hormone.

CJD is among the rarest of diseases, striking about one in a million
people per year. It is rarer yet in the young. Of more than 3,000 cases
recorded in international literature, before 1985 only nine were in patients
younger than 30. The typical age was between 55 and 65.

But when autopsy results from the first four hormone recipients came in,
the average age was 25.

Alarms blared. After an urgent meeting on April 20, 1985, the NIH
suspended the National Pituitary Program. The anguished reaction of
University of Virginia pediatrician Robert Blizzard was typical. He wrote
British colleagues: “Just an hour ago I left a meeting at NIH and I am very
depressed. . . . I realize full well the implications of this worldwide–both
for investigators and for patients. The implications are tragic.”

By June, programs had been stopped in Belgium, Finland, Greece, the
Netherlands, Sweden, Britain and Australia. An estimated 27,000 children
worldwide had been given the drug. In the U.S., the Centers for Disease
Control and Prevention in Atlanta was brought in to track down the 8,157
American recipients.

Meanwhile, the NIH switched hats from overseer of the program to its own
accident investigator. Sponsor of the hormone program had been the National
Institute of Diabetes and Digestive and Kidney Diseases. Assessing the
disaster fell to a sister institute, the National Institute of Neurological
and Communicative Disorders.

A pediatrician there, Dr. Daniel Carleton Gajdusek, had received the
Nobel Prize for physiology or medicine in 1976 for his work on CJD. In 1968,
he had published in Science magazine an article showing that CJD was
transmissible through exposure to infected brain tissue.

However, the man who would lead the institute’s investigation was
Gajdusek’s colleague, Dr. Paul Brown, then establishing himself as a
world-class epidemiologist on the spread of CJD.

When the first CJD case appeared in a growth hormone recipient, Brown
thought it was a coincidence. Then, as other cases rolled in, he became
convinced that the hormone was the culprit. He began systematically testing
remaining stocks of the drug.

“One of the lots that was inoculated did in fact transmit disease to an
animal,” he told The Times.

It took Brown six years to publish an estimate of how many glands
infected with CJD might have entered the system. By 1991, the official
estimate was 140.

As shocking as this seems in retrospect, Brown takes pains to stress
that, at the time, too little was known about CJD. “Before 1985, nobody had
any idea it [the hormones] would be contaminated,” he said.

Veterinary Geneticist Raises the Alarm

That is where American knowledge stood for the next 15 years. It was
regrettable, but unavoidable. Nobody could have known.

Except, it emerges, someone did.

In reviewing the documents generated during the 1996 British human
growth hormone trial, The Times found a paper trail between the British
government and the NIH. Its existence had remained unknown in America and its
significance unrecognized in Britain.

The man who raised the alarm was not a Nobel laureate, not a
neurologist, but a specialist in an obscure disease of sheep: veterinary
geneticist Alan Dickinson, founder of the Neuropathogenesis Unit at the
University of Edinburgh in Scotland.

Dickinson specialized in the sheep form of CJD, called scrapie. In
decades of experimentally infecting mice with scrapie, he had observed that
the pituitary glands became both infected and infectious.

On Oct. 5, 1976, nine years before the first cases of CJD appeared,
Dickinson called to warn the British Medical Research Council of the danger
posed by its growth hormone program.

“My intrusion came after the sudden realization that they were using
human pituitaries,” he said.

But it was only four months later, after Gajdusek reported that CJD
could be spread by surgical instruments, that curiosity among the British
officials was roused. Even so, a member of the British pituitary program took
more than a year to write Gajdusek, seeking his opinion about Dickinson’s
warning. By then Gajdusek was traveling abroad.

On May 8, 1978, a visiting Australian pathologist named Colin Masters
answered on his behalf. Masters echoed Dickinson’s warning: “It would be
reasonable to expect that the pituitary gland and/or surrounding tissue taken
from a case of CJD disease would be contaminated with the virus.”

At Masters’ invitation, the British then forwarded the purification
protocols to the NIH for review. But there is no record that Masters ever
made good on his offer to evaluate either the Swedish or Wilhelmi methods for
their ability to remove CJD contamination.

And in spite of the now-acknowledged danger, neither the British nor the
Americans moved to exclude the use of glands from organ donors who had died
of CJD. Nor did Masters warn the NIH’s National Pituitary Program.

Masters subsequently returned to Australia, where he is now head of the
Australian National CJD Surveillance Unit at Melbourne University. Asked why
he did not relay the warning, he responded, “Presumably the people who were
running the pituitary programs should have been aware of the warnings that
were being sounded in the medical press.”

Both Brown and Masters were in Gajdusek’s lab at the NIH. But, while
Brown insists that the danger of CJD contamination was unforeseeable before
1985, to the mind of Masters, it was too obvious to mention.

By 1979, the British were worried enough to give Dickinson money to test
the Swedish protocol for its ability to eliminate CJD. Pituitaries were
deliberately infected, then purified and injected into test mice. The
Wilhelmi-Hartree method, however, was not tested. In 1982, Dickinson had his
answer: The Swedish method appeared to be safe.

The results were not published for three years. Both Dickinson and the
British hormone program sponsors were sensitive to the potential for a scare.
But in the wake of Alison Lay’s death in 1985, the results showing the
Swedish method’s safety were seen to have a calming effect. They were
published in the same issue of the Lancet as her case history.

The drug appeared safe for children, including 4,000 Americans, who had
received the drug after 1977, the year Parlow took over production and
insisted on the filtration.

The other roughly 4,000 American children treated before 1977 with
hormone from Emory, Tufts and Cornell no longer needed Dickinson to test the
drug on mice. They were the mice, and it was official: The drug was
potentially deadly.

After the Lancet report, in September 1985, Brown reported on the three
American deaths in the New England Journal of Medicine. America faced, Brown
wrote, the “ominous possibility of a burgeoning epidemic” of CJD.

Survivors Mired in Legal Battles

Public displays of concern about a potential epidemic of CJD were one
thing. Doing something to help the victims proved to be another. When Wendy
Nofi first descended into madness between July and November 1995, her
husband, Mike, sought assistance from the NIH. “I was in contact with the NIH
when she first got sick,” he said. “I told them I wanted to keep apprised. I
haven’t received one thing.”

The Crairs say they too were rebuffed. “We called the NIH to seek help,
but we received no counseling, no support whatsoever,” said Stacey’s sister,
Lisa Crair. “At first we couldn’t even get a doctor who would take Stacey

By 1996, Gajdusek’s lab was in turmoil. In March, as the laureate
addressed a scientific meeting in Europe, the mad cow crisis erupted in the
Britain. The next month, Gajdusek was arrested in Maryland on charges of
child molestation. Found guilty in April 1997, he served a year of an
18-month sentence and then left for France.

Mike Nofi had his wife placed on a feeding tube in a rest home. It took
her 2 1/2 years to die. The Crairs nursed Stacey at home for four years.

Both Lisa Crair and Mike Nofi are now lost in legal battles that they
say they neither relish nor understand. Crair’s lawsuit has been thrown out
of court over legal technicalities in three states where the hormone was
processed. Nofi has been given leave in New York state courts to sue numerous
doctors, technicians and every university that handled the hormone–even
Parlow’s UCLA lab, the very place that in 1977 cleaned up the hormone.

But Nofi is not suing the NIH. According to Pamela Liapakis, former
president of the Assn. of Trial Lawyers of America, the agency enjoys what
the legal profession calls “sovereign privilege” and is exceedingly difficult
to sue under federal tort law.

In Britain, however, outraged families did sue the government. In 1990,
an English lawyer named David Body tracked Dickinson down in a drafty stone
house outside Edinburgh, where he had been living in retirement for three
years. Body then represented three of what are now 34 families of British
hormone victims. He was going to try something nobody had ever done
successfully in Britain: sue the Department of Health in a personal injury

He needed an expert witness. After interviewing Dickinson, Body realized
that he could “never put him on the stand.”

The scientist was frail and prone to severe migraines. But he typed out
a statement that both outlined the state of knowledge about CJD 25 years ago
and recounted his 1976 warning about the risk of contamination. In July 1996,
the court decided against the British government to the tune of more than
$7.5 million. Anyone treated with the potentially contaminated hormone after
Dickinson’s warning was issued would be compensated. Damages are now even
going to the “worried well.”

Although Alison Lay’s death sparked the 1985 crisis in Britain, her
parents were excluded from the settlement, because their daughter was treated
before Dickinson sounded the warning.

“At least in this country we did have the trial,” said Mavis Lay. “And
the government admitted that it was at fault and caused the deaths.’

By the time of the trial, Hartree had returned home to Nashville. She
refuses all contacts with the media, lawyers and hormone recipients. In her
absence, the British judge concluded that Hartree’s failure to use Sephadex
was, by analogy, “a commercial decision: quantity before quality.”

The court stopped short of finding the government negligent in the
preparation of the hormone. “In the English claims, the issue of purification
became secondary to the policy failures,” said Body. “I’d like to see
purification explored further in the United States.”

The more time that passes, the more difficult this will be. In 1994, at
the age of 84, Wilhelmi died at his home in Atlanta.

However, Parlow, his former colleague who upgraded the purity of the NIH
hormone, said clear “warning bells” were ignored. Describing the early
hormone, he said, “It was painful on injection. This signaled impurities.”

That was confirmed by a second side effect. “Ten to 15% of the kids
treated developed antibody formation,” said Parlow. “Though this is not
life-threatening, it is not a good thing, and it means that there is
something wrong with the product.”

In addition to the 22 Americans who have died from Wilhelmi-era hormone,
CJD has killed five New Zealanders and one Brazilian who received pre-1977
American hormone. In Britain, 34 people have died, and the global toll stands
at more than 125. The Centers for Disease Control says the rate of CJD cases
among hormone recipients worldwide is increasing.

Tracing the Growth Hormone

* * *
1901-05: The word “hormone” coined

* * *
1921: Creutzfeldt-Jakob disease (CJD) discovered in Germany.

* * *
1925-45: Growth and reproductive hormones found in the pituitary glands
in the brains of animals

* * *
1958: Maurice Raben at Tufts University School of Medicine in Boston
spurs 2.1 inches of growth in a dwarf by injecting him with human growth
hormone extracted from pituitary glands taken from the brains of cadavers

* * *
1963: The National Institutes of Health takes up sponsorship of the
National Pituitary Program.

The largest seat of production is the lab of Alfred E. Wilhelmi, head of
the biochemistry department at Emory University in Atlanta. Swedish
scientists notice that American growth hormone causes immune reactions and
publish an alternative method for making the drug.

* * *
1968: NIH doctor Daniel C. Gajdusek writes in Science magazine that CJD
is transmissible via infected brain tissue. *

* * *
1976: Edinburgh-based veterinary geneticist Alan Dickinson warns the
British government that its pituitary program might spread CJD.

* * *
1977: Wilhelmi retires. The NIH moves production of human growth hormone
to the UCLA lab of Albert Parlow, who begins filtering the drug. The British
hormone program also switches from the Wilhelmi protocol to the Swedish
extraction method.

* * *
1978: Dickinson’s fears of CJD contamination in the hormone are passed
to Gajdusek’s lab at the NIH. In May, a visiting Australian pathologist
replies on NIH letterhead that pituitary glands could be contaminated with
CJD. But he does not pass the warning to the NIH’s own pituitary program. *

* * *
1985: Alison Lay, a hormone recipient, dies in Britain. Three
unidentified American recipients also die. The NIH suspends the human growth
hormone program. Paul Brown of Gajdusek’s lab is called in to investigate. He
warns of a potential “epidemic” of CJD.

* * *
1991: Brown and others report in the Journal of the American Medical
Assn. that 8,157 American children received the drug and that as many as 140
glands infected with CJD may have entered the system.

* * *
1996: A class-action lawsuit on behalf of hormone recipients is brought
against the British government. A London high court awards the plaintiffs
$7.5 million.

* * *
2000: The CJD death toll among American recipients of pre-1977
unfiltered hormone stands at 22. The Centers for Disease Control and
Prevention in Atlanta reports that the incidence of CJD in hormone recipients
is rising from one case a year to two.

* * *

Failed Warnings

NIH epidemiologist Paul Brown was called in by the human growth hormone
program to investigate CJD contamination in 1985. Since then, he has
insisted,”Before 1985, nobody had any idea it [the hormone] would be
contaminated.” But newly discovered letters show that in 1978, a colleague in
Brown’s own lab acknowledged the danger and failed to alert the hormone

* * *
Letter to British government acknowledging danger in 1978.

* * *
Robin Mayper in the Times library contributed to this story.

Search the archives of the Los Angeles Times for similar stories about:
National Institutes Of Health, Medical Research, Experiments, Drugs, Medical
Treatments, Human Growth Hormone, Creutzfeldt Jakob Disease, Health Hazards.
You will not be charged to look for stories, only to retrieve one.

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5/31/2000 – Profit Motive Creates Conflicts in Drug Trials

Here are another couple of articles on the close ties between the drug
industry and medicine have become even closer. From these articles we learn
what has gone wrong with the clinical trials that we thought were protecting
us from big profit motives. The overall general attitude now seems to be:
“Approve all drugs in exchange for profits and let the general population be
the true clinical trial.”

Please note that I have highlighted the statement about Dr. Angell leaving
the New England Journal of Medicine as a doctor with very close ties to the
pharmaceutical companies comes in to replace her as the journal’s editor. So
much for any honesty coming from the New England Journal of Medicine now. As
Dr. Angell leaves her prestigious post she is basically airing the industry’s
dirty laundry. The subject of her article that follows this e-mail is Dr.
Bodenheimer’s journal article mentioned below – a long needed followup to Dr.
Seymour Fisher’s classic article, “Hanky Panky in the Pharmaceutical
Industry.” (Dr. Fisher’s article has been posted at www.pssg.org if you would
like to read it.)

Free speech? Protection from conflicts of interest that could cost consumers
their lives? You will not fine either in this industry! Clearly patients need
to understand that medicine in America has become just another very big

Ann Blake-Tracy, Executive Director,
International Coalition for Drug Awareness


Profit Motive Creates Conflicts in Drug Trials

May 21, 2000

Reuters Health Information

NEW YORK — Pharmaceutical companies that pay researchers to design and
interpret drug trials sometimes spin or suppress unfavorable findings, The
New England Journal of Medicine reported on Wednesday.

The scathing new report discusses tactics used to mask negative results and
warns that the profit motive of commercial research outfits threatens to
further corrupt the high-stakes process of translating science into
marketable drugs.

The report, “Uneasy Alliance — Clinical Investigators and the
Pharmaceutical Industry,” was written by Dr. Thomas Bodenheimer of the
University of California at San Francisco (UCSF) School of Medicine.

Bodenheimer’s interviews with people involved in the drug trial process
highlight the conflicts that arise in the process of
testing new drugs and publishing those results.

An accompanying editorial by Dr. Marcia Angell, the journal’s editor,
picks apart the cozy relationship that has developed between clinical
researchers and industry.

“Academic institutions and their clinical faculty members must take care
not to be open to the charge that they are for sale,” she writes.

The articles come a week after the peer-reviewed journal’s publisher,
the Massachusetts Medical Society, announced that it had named Dr. Jeffrey M.
Drazen, a prominent asthma researcher with strong ties to the drug industry,
as its new editor. He replaces Angell, who will be retiring.

Jeffrey Trewhitt, a spokesperson for the drug industry’s lobbying
group, the Pharmaceutical Research and Manufacturers of America, told
Reuters that “the articles overlook many safeguards in the system, including
the fact that the FDA (US Food and Drug Administration) reviews all the study

Trewhitt said that the FDA issued financial disclosure rules 18 months
ago “and they help to avoid conflicts of interest.” But six investigators
interviewed by Bodenheimer cited cases in which a sponsor actually halted
publication or altered a report’s content.In one instance, Dr. Steven
Cummings, professor of medicine and epidemiology at University of California,
San Francisco, said that a company held up the prepublication review process
for more than 6 months, secretly penning a competing article that favored the
company’s point of view.

Another investigator who found adverse reactions while studying a drug
was told by the sponsor that it would never fund his research again. It
published a competing article that barely mentioned the adverse reactions.

Critics have long questioned the integrity of drug research funded by
the pharmaceutical industry. But Bodenheimer warns of a deepening conflict as
more and more of those studies are farmed out to commercial research outfits.

When academia conducts drug studies, there is at least the potential
that researchers’ scientific goals will offset the pharmaceutical industry’s
commercial interests, he notes. “In contrast, trials conducted in the
commercial sector are heavily tipped toward industry interests, since
for-profit CROs (contract-research organizations) and SMOs (site-management
organizations), contracting with industry in a competitive market, will fail
if they offend their funding sources,” he argues.

Bodenheimer’s article recalls the time Dr. Curt Furberg, a professor of
public health sciences at Wake Forest University School of Medicine, refused
to place his name on published results of a study because the sponsor was
“attempting to wield undue influence on the nature of the paper.” Furberg
describes the effort as “so oppressive that we felt it inhibited academic

Furberg noted, “Companies can play hardball, and many investigators
can’t play hardball back. You send the paper to the company for comments, and
that’s the danger. Can you handle the changes the company wants? Will you
give in a little, a little more, then capitulate? It’s tricky for those who
need money for more studies.”

SOURCE: The New England Journal of Medicine 2000;342:1539-1544, 1516-1518.

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4/16/2000 – More from Boston Globe on Drug Safety Issues

This story ran on page A10 of the Boston Globe on 5/15/2000.
© Copyright 2000 Globe Newspaper Company.


Better drug reporting deal with a wide range of conditions, from depression
to osteoporosis, doctors are reaching increasingly for their prescription
pads. Patients who consume these drugs have faith that any side effects other
patients have had are carefully reported by physicians and monitored by
officials so that, if need be, warnings can be issued.

That faith is misplaced.

While the drug companies and the US Food and Drug Administration have a
system for maintaining an adverse-event database, doctors are not required to
report the serious problems patients have with a drug. As a result, there are
distinct limitations in the system to track bad reactions and then add new
warnings on the drug’s label or withdraw it altogether. Public Citizen, a
watchdog group in Washington, D.C., reports that actual surveys of medical
records turn up 10 times as many drug reactions as are reported voluntarily
by doctors.

Under current practices, drug companies are required to alert the FDA within
15 days of any severe reactions to drugs and within a year of less serious
reactions, but without more mandatory reporting by practitioners (hospitals
and nursing homes are required to make such reports), companies’ own
awareness of problems will be stalled.

If reporting by doctors of bad reactions were mandatory, both the FDA and Eli
Lilly and Co. would know more than they do about some of the problems
connected with Lilly’s popular antidepressant, Prozac. While Prozac and
similarly acting drugs have been hailed by both doctors and patients for
relieving symptoms that can often presage suicide, there have long been
reports of extreme agitation and anxiety among a small percentage of users.

One argument against mandated reporting of adverse reactions from doctors is
the extra paperwork this would entail. But, for the past several years, the
FDA has maintained a Web site that permits doctors – and patients – to make
online reports with little fuss. Closer monitoring could give both health
professionals and the public a greater awareness of what to be alert for as
they make use of the drugs that are changing American medicine.

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5/7/2000 – Drugmaker: Breast Cancer Drug Linked to Death

Adverse Reaction
Drugmaker: Breast Cancer Drug Linked to Death

By Jessie Seyfer
The Associated Press

S A N F R A N C I S C O, May 5 — Pharmaceutical maker
Genentech Inc. has warned doctors that the breast cancer drug
Herceptin is linked to 15 deaths and 47 other adverse reactions
in patients.

In a letter to doctors sent Thursday, the company said the
adverse effects included allergic shock and extreme respiratory

“We sent the letter to oncologists to heighten their awareness
and educate them about infrequent adverse events that can
occur in certain patients,” Genentech spokesman Neil Cohen

An estimated 23,000 patients have been treated with Herceptin.

Severe Reactions
Severe reactions to Herceptin had not occurred in clinical trials
before the drug gained Food and Drug Administration approval
in 1998, Cohen said.

But sometimes reactions can’t be foreseen in trials, he said.

“A lot of times you might see some safety issues once the drug
gets put into a larger patient population,” Cohen said.

Cohen said he didn’t know when the company first heard of the
deaths and reactions, but analysis had confirmed the link to

Symptoms Seen Within 24 Hours
In nine of the 15 deaths, symptoms arose within 24 hours of the
time Herceptin was administered, according to the letter.

Genentech is working with the FDA to have the drug’s label
amended to reflect the new risks, Cohen said.

Herceptin is used to treat breast cancer patients that have too
many copies of the HER2 gene. A healthy version of this gene
produces a protein that signals cells to grow and multiply
normally. But in women with too much HER2, the breast cells
reproduce out of control and spread throughout the body.
Herceptin, an antibody, blocks excess HER2, shrinking and
eliminating tumors.

Copyright 2000 The Associated Press. All rights reserved. This
material may not be published, broadcast, rewritten or


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