Despite Undisclosed Deaths / 10 Heart Attacks/ FDA Allows Blood Substitute Exper

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[sSRI-Research] Despite Undisclosed Deaths / 10 Heart

Attacks/ FDA Allows Blood Substitute Experiment With No Conset

 

 

 

Despite Undisclosed Deaths / 10 Heart Attacks/ FDA Allows Blood

Substitute Experiment With No Conset

 

ALLIANCE FOR HUMAN RESEARCH PROTECTION (AHRP)

Promoting Openness, Full Disclosure, and Accountability

www.ahrp.org

 

The Wall Street Journal reports: " The FDA is allowing Northfield

[Laboratories, Inc] to test its blood substitute without the consent

of the trauma patients, who often are unconscious. " Blood substitutes

may be needed on the battlefield. But does that justify testing blood

substitutes in trauma patients in urban communities when life-saving

blood could be tested inasmuch as it has been proven safe and more

effective?

 

The FDA, beyond all comprehension of a possible rationale, approved

Northfield's multi-site trial at 31 medical centers in December, 2003,

under the stewardship of Dr. Mark McClellan-when the agency had

knowledge that the product caused heart attacks in patients in a

prior, unpublished clinical trial whose results have remained concealed:

 

" ten of 81 patients who received the fake blood suffered a heart

attack within seven days, and two of those died. None of the 71

patients in the trial who received real blood were found to have had a

heart attack. "

 

What's more, the FDA remained silent as the company continued to hide

this vital information from physicians conducting the trial, from

patients, and the public, is approaching criminal behavior.

 

Dr. William Hoffman, chief of cardiac-surgery intensive-care, at

Massachusetts General, says " blood substitutes made with hemoglobin as

a starting point..are associated with heart attacks and strokes. "

Human blood is proven safe and effective. Indeed, efforts by (at

least) four companies-Baxter, Biopure, Hemosol, Northfeld-to produce

an artificial blood substitute have ALL demonstrated that there is no

safe substitute for human blood. Artificial products are made with

hemoglobin which binds nitric oxide. This causes basal constriction

seriously raising blood pressure. The blood platelets become sticky

and have been shown to adhere to vascular surfaces, causing blood

vessels to become inflamed and occluded.

 

ALL of the tested blood products have demonstrated the same adverse

effect profile: they caused hypertension crisis, myocardial

infarctions, strokes, and kidney failure. In clinical trials, no

artificial blood product has compared favorably to human blood.

 

Human blood requires refrigeration, which is not possible on the

battlefield. To save soldiers' lives a blood substitute would

potentially be useful. However, no safe blood substitute has been

developed-certainly none whose use can be justified on civilians who

are not far from hospital emergency rooms. Dr. John Hess, who headed

the Army's blood-substitute programs before he shut it down in 1996

" after concluding that all the blood substitutes he evaluated were

toxic. With hemoglobin, the lining of the blood-vessel wall becomes

inflamed. "

Artificial blood experiments on trauma patients violate that first and

foremost condition set forth in FDA's waiver of informed consent Rule.

 

In 1996, the FDA adopted a radical rule granting waiver from informed

consent requirements for trauma patients but only under conditions

specified, the first being:

 

" (1) The human subjects are in a life-threatening situation, available

treatments are unproven or unsatisfactory, and the collection of valid

scientific evidence, which may include evidence obtained through

randomized placebo-controlled investigations, is necessary to

determine the safety and effectiveness of particular interventions. "

 

[see: Protection of Human Subjects: Informed Consent and Waiver of

Informed Consent Requirements in Certain Emergency Research; Final

Rules. Federal Register: 51528-51533. Code of Federal Regulations,

Part 50 section 50.24]

Human blood is available, and its efficacy and safety is proven and

satisfactory.

FDA's waiver of informed consent rule was first applied in 1998, by

Baxter International (competitor to Northfeld) when it conducted a

similar trial to test its blood substitute, HemAssist, without

informed consent. The Baxter trial was stopped when 24 of 52 patients

given the blood substitute died compared to 8 of 46 who had real

blood. This lethal experiment demonstrates that waiver of informed

consent opens the gate to medical disasters.

 

At the same time, Northfeld was conducting its own abdominal aortic

aneurism trial on surgical patients who underwent elective surgery to

repair it-these patients were able to give informed consent. After the

suspension of the Baxter trial, the FDA ordered Northfeld to expand

its trial at 21 medical centers to a voluntary patient base of 600

from 240.

 

In August, 2001, that trial was abruptly suspended without the company

ever disclosing the results-not even to participating trial

investigators.

" Northfield restricted access to the full data " thereby keeping the

participating doctors in the dark about the heart attacks and other

serious adverse events.

 

The Wall Street Journal reports: " These events occurred in 54% of the

PolyHeme patients versus 28% in the control group..Overall, eight

PolyHeme patients died versus four on the conventional therapy. " An

FDA official is quoted stating:

" the adverse-event profile in the aneurysm trial, while significant,

was not a show-stopper. " How many preventable deaths does the FDA

tolerate before it stops the " show? "

 

It is inconceivable how the FDA justifies its approval of the current

PolyHeme trial being conducted on trauma patients in urban centers

across the US -without informed consent: " In lieu of patient consent,

the 31 medical centers testing the product are required to carry out

community-awareness campaigns about the trials. "

 

How do FDA officials explain the agency turning a blind eye to fact

that participating hospitals were misleading the community about the

safety of the substitute blood? " Several hospitals have told

community meetings that previous trials showed PolyHeme to be safe,

failing to mention the 10 heart attacks [associated with PolyHeme] in

their printed materials. "

 

Moreover, the community was not informed that type 0 negative blood

could be used in ambulances-as is done in Israel. If the blood is

proven beneficial in trauma victims, and more lives are saved,

logistical problems can surely be worked out.

 

This experiment demonstrates why FDA's waiver of informed consent Rule

leads to abuse of vulnerable unconscious patients. The experiment

turns the inalienable right of informed consent on its head by

PRESUMING consent unless one is wearing a blue band on one's wrist

when one happens to be in an accident.

 

This PolyHeme experiment increases the risk of death for trauma

patients. It is unconscionable, and should have never been approved

since the FDA had knowledge of the hazardous adverse events from prior

clinical trials-and an existing, safe treatment is available.

 

 

 

How many patients have been subjects of trials testing an artificial

blood product?

How many companies have tested such products?

How many patients who received the artificial blood suffered:

-------- myocardial infarction compared to controls?

-------- stroke compared to controls?

-------- renal failure compared to controls?

What was the survival rate of those receiving the artificial product

compared to those receiving human blood?

 

If the purpose of developing an artificial blood product were to

improve mortality by getting oxygen carrying products to trauma

patients in the ambulance, why not test blood type 0-negative-which is

a universal donor? There is no question that 0-negative blood is

safer than any artificial product and can accomplish the same goals.

 

Surely, we should not be increasing mortality in order to save the

cost of refrigeration in ambulance!

Did the FDA Commissioner approve and sign-off on the PolyHeme

experiment on trauma patients?

If so, the Senate Fifnance Committee may want to hear what the stated

justification was for this devaluation of living human beings.

 

 

 

Contact: Vera Hassner Sharav

212-595-8974

veracare

 

http://online.wsj.com/article/SB114057765651379801.html

THE WALL STREET JOURNAL PAGE ONE

Red Flags

Amid Alarm Bells, A Blood Substitute Keeps Pumping

Ten in Trial Have Heart Attacks, But Data Aren't Published; FDA Allows

a New Study Doctors' Pleas Are Ignored

By THOMAS M. BURTON

February 22, 2006; Page A1

 

Several years ago a clinical trial of a blood substitute called

PolyHeme finished with worrisome results. Ten of 81 patients who

received the fake blood suffered a heart attack within seven days, and

two of those died. None of the 71 patients in the trial who received

real blood were found to have had a heart attack.

 

PolyHeme's maker, Northfield Laboratories Inc., quietly shut down the

trial and didn't publicly disclose the results, which are described in

internal documents viewed by The Wall Street Journal. It decided the

heart attacks might have been due to doctor inexperience in using

PolyHeme, not a problem with the product itself.

 

Now Northfield is in the middle of a new trial. A Food and Drug

Administration official, Jay Epstein, calls the earlier data

" alarming " but not sufficient to stop Northfield from trying out its

product on hundreds of trauma patients.

 

The FDA is allowing Northfield to test its blood substitute without

the consent of the trauma patients, who often are unconscious. In lieu

of patient consent, the 31 medical centers testing the product are

required to carry out community-awareness campaigns about the trials.

Several hospitals have told community meetings that previous trials

showed PolyHeme to be safe, failing to mention the 10 heart attacks in

their printed materials.

 

Some veteran doctors are concerned about the push by Northfield, of

Evanston, Ill., to test its product without publicly disclosing

earlier results. Ronald M. Fairman, chief of vascular surgery at the

Hospital of the University of Pennsylvania, says he repeatedly urged

the company to publish the data but got nowhere. " Even now, it remains

frustrating the multicenter results were not disclosed, " he says.

 

Northfield's chief executive, Steven A. Gould, argues the heart

attacks could well have been caused by doctors pumping too much total

fluid -- PolyHeme plus real blood -- into patients. He says PolyHeme

could help many people, such as those in an ambulance who don't have

access to human blood. " Our experience suggests the risk-benefit

balance is in the patient's favor, " Dr. Gould says.

 

In a statement, Northfield denies it " resisted publication " but says:

" We did not allocate resources to publication. In retrospect,

reporting the full study results earlier would have been better. "

Northfield says any American who doesn't wish to participate in the

current PolyHeme trial should ask the company for a blue plastic

wristband that would alert paramedics. Those who fail to get a

wristband and find themselves in a hospital trauma unit " can withdraw

from the study, without prejudice, at any time, " the company says.

 

Northfield has raised $194 million in stock offerings since going

public on the Nasdaq Stock Market in 1994. Its market value stands at

$334 million on hopes that PolyHeme, its sole product, could be the

first blood substitute approved by the FDA. Results of the new study

are expected this year.

 

Scientists have been hunting for a safe, workable blood substitute for

more than half a century. Unlike donated human blood, artificial blood

may reduce the risk of hepatitis or HIV infection. It eliminates the

need to match blood types of donor and recipient, and has a far longer

shelf life without refrigeration.

 

One use for artificial blood is in the military. Blood needs to be

refrigerated and usually can't be carried into combat. It goes bad in

about 42 days, whereas PolyHeme lasts a year or more. Soldiers who

would otherwise bleed to death on the battlefield might be saved if a

medic could quickly infuse them with an oxygen-carrying blood substitute.

 

But companies seeking this lifesaver have often met with

disappointment. Baxter International Inc. halted a U.S. study of its

blood substitute HemAssist in 1998, because 24 of 52 trauma patients,

or 46%, given HemAssist died compared with only eight of 46, or 17%,

who received standard therapy. Study doctors said the product may have

dangerously raised blood pressure. Shortly before HemAssist failed,

Baxter spent $190 million to buy another company with a blood

substitute. It ultimately abandoned that product, too, after throwing

a total of $500 million into its blood-substitute ventures.

 

Today there are several companies remaining in the blood-substitute

race, but Northfield is the only one known to be in final-stage

clinical trials. Northfield was founded in 1985. Among its founders

was former Navy surgeon Gerald S. Moss, later dean of the University

of Illinois at Chicago College of Medicine. He had worked on a blood

substitute beginning in 1969 under a contract with the Army and Navy.

Later he worked with Dr. Gould, a surgeon, and the two were among

those who started the company.

 

The making of PolyHeme begins with outdated donor blood. A protein

called hemoglobin in red blood cells delivers oxygen throughout the

body. Northfield bursts open red cells in giant metal vats, freeing

the hemoglobin molecules inside.

 

Hemoglobin molecules are known to be dangerous if they aren't held

within red blood cells. The molecules tend to seep into the walls of

blood vessels and cause inflammation. Most relevant to heart attacks,

they can constrict blood vessels and cause clotting. Northfield

chemically links one hemoglobin molecule to another in a process

called polymerization. Dr. Gould says this removes hemoglobin's toxicity.

 

John R. Hess, a University of Maryland research doctor, is skeptical.

He once headed the Army's blood-substitute program but shut it down in

1996 after concluding that all the blood substitutes he evaluated were

toxic. With hemoglobin, Dr. Hess says, " the lining of the blood-vessel

wall becomes inflamed....There's no reason the modification should

change this. "

 

Northfield has voiced optimism for years. In May 1997, a company news

release said, " PolyHeme is in the home stretch with market

introduction planned for sometime during 1999. " The company's

then-chief executive, Richard DeWoskin, said, " We have advanced to the

point that the question of science is now being replaced with the

question of size and scope of the commercial market for our product. "

At the time, Northfield was starting what was to be its pivotal

trial. Patients were randomly assigned to a group receiving PolyHeme

or a control group receiving real blood. This type of study is the

gold standard in medicine. The patients in the trial were undergoing

surgery to repair aneurysms, or ballooned sections, in their aortas.

They gave their consent before participating.

 

After the Baxter product was implicated in deaths in March 1998, the

FDA ordered Northfield's study enrollment target expanded to 600

patients from the original 240. Northfield remained upbeat. An August

1999 news release spoke of PolyHeme's " excellent safety profile. " A

news release in April 2000 said the study was " producing very

important results " but was taking a long time to enroll enough

patients. Then in the second half of 2001, Northfield abruptly shut

down the study, explaining in a Securities and Exchange Commission

filing that it was taking too long to complete.

 

In August 2001, Northfield tried a long-odds maneuver: It asked the

FDA to approve PolyHeme based on earlier research on hospital trauma

patients. In that research, PolyHeme wasn't compared with a control

group receiving standard therapy. Instead, Northfield compared the

results with other hospitals' historical experience with patients who

needed blood but didn't get any. These patients were Jehovah's

Witnesses who declined blood for religious reasons. In November 2001,

the FDA refused to consider the application, citing concern about the

validity of the comparison, according to a Northfield SEC filing.

 

Critical Question

The sudden halt to the big randomized PolyHeme trial left unanswered a

critical question: What were the results? Doctors who had taken part

were curious. In an arrangement that doctors often reject today,

Northfield restricted access to the full data and individual doctors

knew only what happened to their own patients.

 

At the University of Pennsylvania, Dr. Fairman says he and a

colleague, Albert Cheung, repeatedly called Northfield's Dr. Gould.

" We said, 'Let's sit down and write up the data,' " Dr. Fairman

recalls. " He wouldn't do it. " Dr. Cheung proposed a meeting in

Philadelphia of doctors at the 21 hospitals that had taken part in the

study. He says Dr. Gould agreed to the meeting, then canceled it at

the last minute.

 

T.J. Gan, a Duke University anesthesiologist involved in the study,

says he called Northfield three years ago to ask if results had been

published. He says Dr. Gould told him, " Someone's working on it. " Dr.

Gan says, " Regardless of whatever the problem, you publish it and

outline the results. " In its statement, Northfield says company

officials don't recall the specifics of any discussion with Dr. Cheung

about a meeting or the conversation with Dr. Gan. Dr. Gould says he

did inform the FDA of the aneurysm trial's results. The company now

says it plans to make public a medical abstract of the study in April.

 

Besides the heart attacks and deaths in those taking PolyHeme, the

trial suggested the product was linked with other serious adverse

events such as heart rhythm aberrations and pneumonia. These events

occurred in 54% of the PolyHeme patients versus 28% in the control

group, according to Northfield's internal documents. The higher rate

of heart attacks and serious events was considered statistically

significant, meaning there is minimal likelihood they happened by

chance. Overall, eight PolyHeme patients died versus four on

conventional therapy, a difference that wasn't found to be

statistically significant.

 

Such a stark difference in serious adverse events would often be fatal

for a drug or medical device under study. Still, Northfield

persevered. Dr. Gould says the company doesn't believe PolyHeme caused

the heart attacks. Before surgery, patients had their own blood drawn

for possible use during the operation. Dr. Gould says several

hospitals gave patients both PolyHeme and real blood. Together, he

says, the amount of fluid was too much. " It can't be determined, " he

says, whether the heart attacks were due to the " capability and

experience " of doctors " or to the product. "

 

William D. Hoffman, chief of the cardiac-surgery intensive-care unit

at Massachusetts General Hospital in Boston, says blood substitutes

made with hemoglobin as a starting point, a class that includes

PolyHeme, are associated with heart attacks and strokes. " It is

self-serving and potentially misleading to associate harmful effects

with something other than the test drug, " says Dr. Hoffman, who used

to work for another artificial-blood company but left after a dispute

with executives there.

 

The FDA's Dr. Epstein, who is director of the agency's blood-products

office, sides with Dr. Gould, calling Northfield's theory a plausible

one. " Of course it's alarming there were excess deaths in the

treatment group, " he says. " We are highly mindful of the adverse

events. " But, he goes on, " the adverse-event profile in the aneurysm

trial, while significant, was not a show-stopper. " The FDA's review

suggested that " volume overload " rather than " any intrinsic toxicity

of the product " was responsible for the cardiac events, he says.

 

As a result, Northfield was able to embark on a big new trial -- this

time in trauma patients such as victims of shootings or car accidents.

It started signing up trauma centers in December 2003 and as of early

this year about 600 people had taken part. Half get PolyHeme and the

other half get saline solution plus real blood. The study measures the

death rate at 30 days. Northfield's hope is that PolyHeme will be

found equivalent to -- or at least not provably worse than -- the

standard therapy. As of late last year, an independent data monitoring

board hadn't found any statistical differences between the two groups

large enough to warrant halting the study.

 

Dr. Gould says Northfield typically pays hospitals around $10,000 a

patient to participate. Northfield agreed to pay $336,000 to the

University of Texas Health Science Center at Houston and $132,468 to

the University of Kentucky Medical Center, hospital records show. The

hospitals say the money merely covers costs in collecting the data.

" This is not a profit-making endeavor -- it is a scientific one, " says

University of Kentucky surgeon Andrew C. Bernard. Others participating

include the Mayo Clinic, Duke University and Lehigh Valley Hospital in

Allentown, Pa.

 

In the trauma study, patients are in hemorrhagic shock, meaning they

are bleeding so profusely that their blood pressure plummets. The

typical patient can't offer the informed consent that normally is

required for clinical trials. A 1996 FDA rule says it is acceptable to

give trauma patients experimental treatments without their knowledge.

Without the rule, the agency says, trials would be impossible and

society wouldn't benefit from advances in trauma care.

 

Playing Down Risks

In place of individual consent, the FDA has required Northfield and

the hospitals participating in the trauma trial to hold public

meetings at churches, city halls and the like in their communities.

Materials used at the meetings and filed to the FDA often played down

the risks of PolyHeme.

 

The Lehigh Valley Hospital materials for local meetings said, " Past

studies have shown that PolyHeme...has not caused organ damage. "

Materials from the Brooke Army Medical Center near San Antonio for

meetings last July were even more categorical: " In clinical trials to

date, PolyHeme has demonstrated no clinically relevant adverse

effects. Up to now, PolyHeme has not caused any clinically bad problems. "

 

" Aneurysm-surgery patients are vastly different from trauma patients, "

said Col. John Holcomb, a trauma doctor at Brooke. " I know that there

are no safety issues. " A doctor at Lehigh didn't return a phone call

seeking comment.

 

Northfield did tell trauma doctors about the heart attacks in the

earlier study but did so confidentially and with an explanation that

it didn't believe PolyHeme was responsible, according to company

documents and interviews with doctors. The University of Kentucky's

Dr. Bernard says there is a limit on what the public can be told about

the earlier trial results because " everything in the study is

confidential. "

 

Early last year, Keith Berman, a Pasadena, Calif., medical-products

consultant who has studied blood substitutes, urged the FDA to make

the earlier trial's results public. Last year, the agency required

Northfield to mention on its Web site " serious cardiovascular adverse

experiences " with PolyHeme. Five of the 31 hospitals in the trauma

study followed suit, but well after many trauma patients had been treated.

 

Because Northfield needs only about 120 more people to complete its

study, any individual's chance of being enrolled is low. However,

those who are still worried can get the blue plastic wristband from

the company to signal that they refuse to take part.

While Northfield says PolyHeme could be useful in rural ambulances,

battlefields and other settings where real blood is out of reach for

hours, it hasn't conducted a large-scale test focusing solely on that

notion. It says assembling patients for such a trial would be too

difficult and time-consuming. " We all recognize that doing the

[trauma] trial in an urban setting was not ideal, but this was the

only way to get the trial done, " says a Northfield spokeswoman.

 

Write to Thomas M. Burton at tom.burton

 

http://online.wsj.com/article/SB114075393917182277.html

FDA, Northfield Face Inquiry Over Study of Blood Substitute

Chairman of Senate Panel Opens Probe Questioning Methods and Disclosures

By THOMAS M. BURTON

February 24, 2006; Page B4

 

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