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By Susan Levine
To this day, Patient #10 has no regrets.
Eight years ago this summer, he and six
other participants in a clinical trial at the National Institutes
of Health (NIH) became sick.
Extremely sick. Within days researchers realized
that an experimental drug the volunteers had been taking for
hepatitis B had killed more
than that virus.
In fact, it had poisoned and begun destroying
major organs throughout their bodies. By July 30, four people
were dead. Another was dying.
Patient #10 was poised perilously near
that edge, with a transplanted liver that no one was sure
would save his life. His kidneys were failing and a ventilator
was forcing air continually into his lungs. Feeding tubes
snaked down his nose into his stomach. He was comatose. Doctors
had little understanding why.
Never before has he talked publicly about
his experience in the clinical trial for the drug fialuridine,
which became an unprecedented catastrophe for NIH.
Then came news in mid-June that a young
woman had died during an asthma
study at Johns Hopkins University in Baltimore. In mid-July,
government regulators suspended all Hopkins medical trials
involving human subjects; while reversing that order last
week, they nonetheless maintained severe restrictions that
will hamper many studies for months.
The Hopkins tragedy again brought into
focus the tightrope on which
much medical research operates, and it persuaded
Patient #10, a retired educator, to finally recount what he
went through, to reflect aloud on the impact it had.
Perhaps the biggest surprise is not that
he survived, but that he remains committed to medical research
despite his near-death experience.
"Someone has to go out and do it,
and so you volunteer for these things," he says. "There
will be accidents, and there will be problems. . . . But when
there's nothing else [as treatment], are you just going to
sit there?"
The Volunteers
Fundamental differences distinguish the
NIH trial from the project that was underway at Hopkins until
24-year-old Ellen Roche fell ill in early May. She was one
of nine healthy volunteers on whom a chemical was being tested
for its ability to block neural signals involved in airway
constriction; that physiologic response, if better understood,
might lead to a cure for asthma.
Roche and the others stood to profit
little beyond researchers' appreciation and $365 for their
time.
By contrast, the drug known as fialuridine,
or FIAU, was being studied in 1993 for its possible therapeutic
value. While the NIH participants had no symptoms of hepatitis
B, they definitely carried the virus and it is easier to understand
why they agreed to serve as guinea pigs.
Their disease is maddeningly untreatable,
and chronic infection can linger for years before causing
severe liver damage, scarring, cancer or death. They would
have been among the millions
to gain had FIAU lived up to the tremendous optimism
that marked the trial's start.
"This was basically going to be the
answer to help 300 million people around the world,"
Patient #10 remembers.
Excepting the gold medical-alert bracelet
on his right wrist -- alerting strangers that he is a transplant
recipient -- Patient #10 bears no obvious sign of the events
that followed.
He is today a sturdy man of 71, deeply
tanned and constantly on the go. He lives in Arlington, not
far from his two grandchildren -- and that, he says, is all
strangers need to know about his current life, which is why
he remains identified as Patient #10 in this story's telling.
He does not know where or when he contracted
the hepatitis that eventually led him to the liver disease
researchers at NIH, but he readily acknowledges enthusiastically
enrolling as a study participant -- not once, not twice, but
five times between 1988 and 1993.
"I told them, if something comes
along that looks promising, sign me up," he explains.
"When you have a disease that's incurable and it's going
to progressively get worse, I just felt, hey, I'll jump in."
A Dramatic
Success
His first three trials with other drugs
produced a variety of bodily aches but made little research
headway against the disease. Then he heard that NIH needed
24 people for a 28-day trial of FIAU. He again enrolled. And
for just shy of a month, he squirted a cherry-flavored dropper
of liquid into his mouth once per day.
He washed it down with water. He suffered
no immediate side effects. But
the results were spectacular. Tests indicated that
the virus was being routed, dramatically so.
"We were so excited," his wife
recalls. "We talked about it all the time."
The results were so promising he feared
only that he might not be chosen for NIH's next phase of testing,
which began in the spring of 1993 and was to last six months.
Ten people were accepted. He was the tenth.
Like the others, he signed a consent form
that laid out in detail the potential adverse consequences
of FIAU, including nausea, upset stomach, seizures, and pain
and numbness in the arms and legs. The list went on for nearly
two pages. The arm and leg pains, it noted, "can be severe
and last for weeks to months. In some cases, a permanent decrease
in nerve function is found." Death
was not mentioned.
Despite the wording, he admits to having
had a false security that no significant problems would arise.
It's why he dismissed a passing comment from one NIH physician
that he'd already "given enough to science" and
should take a break.
He believes the NIH researchers were
completely upfront with him. He describes Jay Hoofnagle, the
study's principal investigator, as brilliant and compassionate.
What happened next was nobody's fault,
he insists: "I hold no grudges against anyone."
Sudden Reversal
What happened next became horribly clear
in a single weekend in late June after one of the volunteers
was hospitalized, critically ill, with liver failure. At that
point, the group had been on FIAU for as long as three months.
That was long enough for the drug's previously
unknown and unanticipated toxicity to emerge, damaging
-- or destroying -- mitochondrial cells that produce energy
for the body. The result was a massive buildup of lactic acid,
which caused multiple-organ collapse. Critics later would
say the warning signs had been overlooked or disregarded.
Patient #10 was feeling severely nauseated
and exhausted when Hoofnagle called him at home and told him
not to take any more medicine. The doctor's voice was urgent:
We want to see you Monday morning. Plan on staying overnight.
As it turned out, it would be nearly Halloween
before he and his wife returned home. "They told me every
cell in my body had stopped functioning," he says. He
thinks about that now, wondering what made the difference
in his case, why he survived. "How come I made it? I
should have been gone."
The scene that Monday morning at NIH was
quiet, desperate crisis. Some of the assembled families were
in shock, others venting anger. Over the next several days,
the patients began to be transferred out of town for transplants.
Two didn't even live long enough for those operations to give
them a chance.
Patient #10 was flown in early July to
the University of Virginia Health Sciences Center in Charlottesville.
By week's end, with no liver available, doctors were preparing
his wife for the worst. "They told me they didn't think
they could save him through the night," she says.
He slipped in and out of consciousness.
His legs swelled to twice their normal size because of fluid
buildup as the kidneys stopped functioning. His stomach bloated.
In intensive-care rooms around him, similar battles were being
waged. And lost.
And then, unbelievably, another liver
was found. But the July 19 transplant
surgery
seemed to change little. Patient #10 faded deeper
into a coma, and doctors feared possible brain damage. They
worried whether lingering traces of FIAU would affect the
transplanted organ.
"You felt like the Dutch boy with
his finger in the dike," says surgeon Timothy Pruett,
who leads the transplantation division at the Charlottesville
medical center. "He was very, very sick."
August faded into September. He had brief
fragments of awareness. During one, he asked whether they'd
ever located a liver for him.
"Yes," his wife replied, "and
you've had it for two months."
Lingering
Effects
In the end, seven of the 10 people in
the original protocol group were hospitalized for significant
FIAU toxicity. Five died.
The only other transplant survivor left
the hospital within a matter of weeks; he now lives in the
South and chats every so often, comparing notes, with his
Arlington counterpart.
The drug's toll reverberated through NIH
-- and still sobers scientists there and across the country.
It changed the way many people thought about clinical trials,
made them rethink the question of risk vs. benefit and how
to better reconcile them, Pruett says. Even today, mention
those four letters "and everyone gets a little hushed."
No researcher was affected more than Hoofnagle,
a highly regarded liver specialist who remains a senior investigator
at the National Institute of Diabetes and Digestive and Kidney
Diseases.
In the wake of the recent Hopkins death,
federal officials identified numerous
problems with how that university was supervising
medical research and for four days stopped virtually all of
its trials with human subjects. The repercussions of the FIAU
trial were less harsh.
Inquiries were conducted by the Food and
Drug Administration (FDA), the Institute of Medicine, which
is part of the National Academy of Sciences, and an independent
panel of experts assembled by NIH.
Though the FDA criticized the NIH investigators
and the drug's manufacturer, Eli Lilly & Co., citing violations
of federal reporting regulations, the other two groups exonerated
them and ruled the tragic outcome an unavoidable accident
in which neither negligence nor carelessness played a role.
Not that such conclusions help the public
understand the difficult dimensions of clinical research.
In its final report on the FIAU trails, which was laced with
references to the grief of the families and the "private
and public soul-searching" of scientists, the Institute
of Medicine noted the "erroneous public perception that
new treatments can be developed and tested free of risks only
if enough care is taken."
Michael Gottesman, deputy director for
intramural research at NIH, wishes risk indeed could be eliminated.
But doing so would have other consequences, he says. "We
probably could make incremental [medical] advances, but not
big ones.
"The
big leaps do require the brave to participate."
Patient #10 returned home to Arlington
in late October 1993 -- four months after he had packed that
overnight bag for Bethesda and 80 pounds lighter. He then
spent more months in rehabilitation, charting goals such as
being able to walk to the bathroom independently.
He will remain on Cyclosporine to minimize
the chance of his body rejecting his liver, and every two
months he receives an intravenous injection of immune globulin.
A kidney transplant someday could be in his future because
of the damage to his own.
"They learned a lot from me,"
he says of NIH scientists. "They learned a lot from all
of us."
In the balancing of contributions and
sacrifice, Patient #10 knows the other FIAU families may not
share his sentiments, and above all he does not want to cause
them new pain.
He realizes that his own family might
feel far differently about clinical research were he not alive
today. He remains in a follow-up protocol with Hoofnagle,
and he admits to being more cautious, more questioning, whenever
a new treatment is proposed.
Yet he still believes as he does, strongly,
forthrightly. "You can't go forward without trials. You
can't give [a drug] to cats and dogs, and then give it to
humans and say it worked on cats and dogs. Sometimes trials
don't pan out. And then people are going to get hurt."
Washington
Post July 31, 2001; Page HE01
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