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Traumas create unwitting test subjects

Updated 6/13/2006 11:32 PM ET

By , USA TODAY

As Hilary hung from her seat belt in the overturned wreckage of her

truck - legs broken, colon ruptured and lung bruised - blood oozed from torn

arteries and veins.

Hilary, 27, and her sister, Holly, 25, who was injured less severely in the

crash, waited half an hour for medical help to arrive. By the time an air

ambulance reached them at the crash site, about 45 miles south of Memphis,

it was midday onMarch 15. Hilary's face was pale, her lips were blue, her

faint pulse was fast, and her blood pressure was 55/0. She was in shock.

Because she was close to death, she instantly became eligible for enrollment

in a controversial clinical trial. But because she was in no shape to

consider the risks, the flight nurses did not have to obtain her consent

before giving her an experimental blood substitute.

Within moments, fluid the color of merlot was dripping into her veins.

Hilary, a singer/songwriter and the daughter of country singer Hank

Jr., became one of thousands of people across the nation who, while fighting

for their lives over the past 10 years, unknowingly became test subjects in

a medical trial.

With waived-consent studies becoming more prevalent, critics question

whether the public understands how they work and whether test subjects get

adequate protection.

Although the study that included Hilary has brought criticism, she

believes the infusion of blood substitute helped save her. " I thought I was

going blind, " she says as she recovers in Nashville. " Everything was dark.

My eyes were open but I couldn't see anything. I felt at peace. I kept

wanting to fall asleep, but a truck driver who stopped kept telling me to

wake up and to hang on. "

But another trial, which is reported in today's Journal of the American

Medical Association (JAMA), was halted because a device called the

AutoPulse, which was used to revive cardiac-arrest victims, failed to save

more lives than when rescuers performed cardiopulmonary resuscitation.

According to the study, as many as 10 people in one city may not have been

revived because of their participation. The JAMA study does not identify the

city. But doctors have identified the site as Seattle - which has one of the

highest resuscitation rates in the nation - in discussions at medical

meetings since the AutoPulse trial was halted in March 2005.

Patients in these types of studies - often financed by manufacturers of the

tested product - are treated under a broad federal rule that allows

researchers to test emergency treatments on patients with specific,

life-threatening medical conditions without their explicit consent as long

as they remain under close watch of independent reviewers.

Federal officials and medical researchers say there is no substitute for

this testing of emergency treatments for the leading causes of death: trauma

and cardiac arrest, which claim hundreds of thousands of lives in the USA

each year. To the researchers, studies with negative findings are as

important as successful trials in their search for the best treatments.

Studies have included large, multi-city, randomized trials, which scientists

consider the gold standard for medical research. One study that ended in

October 2003 compared ways to revive patients in cardiac arrest and taught

doctors and city leaders how to deploy automated external defibrillators.

Federal officials say such research is key because emergency treatments are

largely untested. " Many of the treatments that are currently used in

life-threatening circumstances have not been formally studied, " says Sara

Goldkind, a Food and Drug Administration (FDA) bioethicist. " They have not

come to be standard-of-care based upon rigorous scientific data. "

Doctors agree. " The only way to make any sort of significant advance in this

final frontier is to perform these studies with waiver of informed consent, "

says Croce, a Memphis trauma surgeon. " It's clear that multiple

cascades of bad physiologic things happen shortly after injury. Once that

snowball begins to roll down the hill, it's very difficult to stop. To stop

it, you need to intervene early. That is at the scene. "

Critics say the trials are conducted on a slippery ethical slope.

" It has to be done carefully, " says King, a University of North

Carolina ethicist who says corporate sponsors of trials don't always want to

make key study information public. " It is so terribly easy to cut corners

and say this doesn't matter as much and we will just put some notices in the

newspaper. It makes me concerned. "

Two trials in particular - the ongoing blood-substitute trial in which

became involved and the ill-fated AutoPulse study - illustrate

their ability to answer scientific questions and the ethical controversy

that surrounds them.

The PolyHeme trial

About five minutes after flight nurse Cindy began infusing the blood

substitute PolyHeme into ' veins, they were lifting off for the

20-minute helicopter flight to University of Tennessee Health Science Center

in Memphis, where Croce waited with a trauma team.

Ambulances can't carry blood because it must be kept cool and typed to match

each patient. Researchers have sought for decades a substitute that can be

carried by medics in the field.

PolyHeme, which was born from research after the Vietnam War, is made from

chemically modified human hemoglobin by Northfield Laboratories of ton,

Ill.

The study in which was enrolled is the most widespread use yet of

PolyHeme. The trial has raised concern among some ethicists and alarm in

Congress, where Sen. Grassley, R-Iowa, chairman of the Finance

Committee, is conducting an investigation.

Grassley is concerned that people who live in the 19 states where PolyHeme

is being tested have had inadequate notice about the trial. The FDA requires

that community input be sought in the regions around test sites. " It is

outrageous that, for all intents and purposes, the FDA allowed a clinical

trial to proceed, which makes every citizen in the United States a potential

'guinea pig,' without providing a practical, informative warning to the

public, " Grassley wrote in a letter to the FDA in February.

" This study raises significant ethical issues, " says King, who co-wrote an

article in the current edition of The American Journal of Bioethics that

faults the PolyHeme trial for withholding available treatments, namely blood

transfusions, from patients.

In the trial, PolyHeme is appropriately given to patients without their

consent in ambulances, she says, where blood is not available. But some

patients, including , also get the blood substitute for up to 12

hours in the hospital, where blood is available.

King says some patients who die from their injuries therefore will perish

while " being denied an available treatment. " Though she favors the concept

of waived-consent trials, she says PolyHeme could be tested on the

battlefield or during elective surgeries in which " you could get prior

consent. "

Gould, chief executive of Northfield Laboratories, stands behind the

PolyHeme trial. He says it is too complex to be performed on a battlefield

and elective surgery is not the crisis situation best suited for the study

of PolyHeme. Of King's comments, he says, " We have different points of view,

but that is what this is all about. "

Amid the controversy, some cities stopped enrolling patients while the

data-monitoring board reviewed preliminary findings.

The data-monitoring board includes clinicians who specialize in the area

under study and biostatisticians and bioethicists who review study data and

" adverse event " reports. This committee tells the study sponsor when a trial

needs to be modified or stopped. The members of this group have no financial

interest in the outcome.

All of the sites resumed the trial after the board concluded that patients

were safe and that it was safe for the trial to finish.

Results of the study are not expected for months, but and her partner

Cindy believe that they have already seen lives saved by the blood

substitute.

" It's unbelievable, " says. " If Hilary had not received this, I don't

think she would be here today. " Says : " I think she would have

arrested (died) before we got to the hospital. "

EMS officials prefer to act on big trial results because such studies

determine scientifically - using a large number of patients who are randomly

assigned to be tested - whether the treatment works.

" In the old days, manufacturers would come up with a whiz-bang product, and

we'd buy it and try it, " says Poniatowski, operations director for

EVAC Ambulance in Daytona Beach, Fla.

" If it didn't work, we chucked it, " he says. " If it worked, we kept it.

Today, we need to see the data to back those statements up. "

The AutoPulse trial

One trial that was conducted amid swirling accolades and anecdotes of lives

being saved was halted early after a sizable number of test subjects died.

The results of the trial, published today in the Journal of the American

Medical Association, illustrate the key role that independent trial monitors

play in intervening when test subjects need protection.

The device known as the AutoPulse - a portable, battery-operated device that

wraps around an adult's chest and squeezes the ribcage rhythmically to move

blood through the body - began generating awe-inspiring stories of cardiac

arrest survival in 2004. EMS agencies began scooping them up.

" Our medics loved the device and they reported what they felt anecdotally

were amazing saves, " says Marshall Isaacs, director of emergency medical

services for the San Francisco Fire Department. " They said patients pinked

up. "

Emergency medical crews in Richmond, Va., who also report their findings in

today's JAMA, had more promising results when comparing the use of AutoPulse

with previous rescue attempts.

But in the five-city trial that was supposed to enroll 1,837 victims of

cardiac arrest, researchers tested the device head-to-head against manual

chest compressions during CPR by randomly placing patients into one of two

arms of the study. Half of the patients got compressions from the device,

and the other half got manual compressions.

Because the federal rule for waiving consent requires clinical investigators

to consult with the community and instructs the institutional review board

to consider public comments before approving the study, Seattle officials

met with community groups.

The survey of 400 Seattle adults found that 75.3% said it was OK to carry

out the study when consent was not possible; 18.6% objected.

With a majority of those consulted supportive of the trial, researchers

began enrolling patients in Seattle on Sept. 9, 2004. Calgary; Vancouver,

British Columbia; Columbus, Ohio; and Pittsburgh followed that year.

The data-monitoring board halted the trial on March 31, 2005,finding that

the device appeared to be harmful to the patients.

About 6% of patients treated with the AutoPulse survived, while roughly 10%

of patients who were not treated with the device and got traditional, manual

CPR survived.

The FDA says the data-monitoring board provides a safety net.

" Given that people are put into these trials without consent, you owe them a

continuous watch on how they are doing, " says Temple, director of the

FDA's Office of Medical Policy.

And results must be reported, Temple says. " These are studies using a

vulnerable population, " he says. " You owe the world an explanation of what

you were doing and what the results were. "

Within the results published in today's JAMA are the numbers that troubled

the researchers and stopped the study. Of the 65 people who were treated in

Seattle with the AutoPulse, seven were discharged from the hospital alive,

compared with 17 of the 66 who received manual CPR.

" We've thought about that patient population a lot, " says Sayre,

associate professor in the Department of Emergency Medicine at Ohio State

University in Columbus. He hopes that people across the nation learn from

the deaths. " If we had not done this study, then maybe this technology would

be adopted on all patients and that might have hurt more people than it

helped, " he says.

The future

Medical researchers and FDA officials say that they will be looking in

coming months into how these trials of emergency devices and treatments have

been conducted over the past decade to see if improvements are needed.

" Is this a good reg? Is it perfect? Can it be better? Can it be worse? Those

are important policy questions that we feel we can and should address, "

Gould says. " To do research without prospective informed consent defies what

we would all say is good ethical practices, so you have this conundrum. "

That quandary continues.

The National Institutes of Health has set aside $5 million to study both

cardiac arrest and trauma over the next five years in trials using the

waived-consent rule.

Recovering in her mother's home in Nashville, says her music career

is on pause. She was scheduled to be photographed for a pop record album

before the accident, but she is writing songs and longs to return to the

stage.

And she says she is happy that science could learn from her care.

" I think it's a great thing, " says. " God and PolyHeme basically

saved my life. "

Time and data analysis will tell what role PolyHeme played.

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