AHRP Files Complaint with OHRP Non-Consensual Blood Substitute Experiment

[Guest guest]

SSRI-Research@

Thu, 2 Mar 2006 20:03:37 -0500

[sSRI-Research] AHRP Files Complaint with OHRP Re:

Non-Consensual " Blood Substitute " Experiment on Trauma Patients

 

 

 

AHRP Files Complaint with OHRP Re: Non-Consensual " Blood Substitute "

Experiment on Trauma Patients

 

 

 

 

Mike Leavitt (hhsmail); Bernard Schwetz MD

(BSchwetz); 'mcarome'

Cc: Jay Epstein MD (jay.epstein); Andrew Von

Eschenbach MD (andrew.voneschenbach); Sen Chuck Grassley

 

 

 

 

 

ALLIANCE FOR HUMAN RESEARCH PROTECTION (AHRP)

Promoting Openness, Full Disclosure, and Accountability

www.ahrp.org

 

March 2, 2006

 

Dr. Bernard Schwetz

Office of the Secretary

Department of Health & Human Services

Office of Public Health and Science

Office for Human Research Protections

Rockville, Maryland

 

Dear Dr. Schwetz:

 

One year ago, you received a letter of complaint from Keith Berman,

MPH, MBA regarding the Phase III, open label safety / efficacy

clinical trial of PolyHeme, an investigational " blood substitute "

manufactured by Northfield Laboratories.

 

This controversial, commercial experiment is being conducted without

informed consent in trauma patients who require blood to survive.

PolyHeme is being tested in patients in ambulances and at hospital

emergency facilities where these trauma patients are denied

life-saving real blood.

 

Northfield Laboratories obtained a waiver of consent from the FDA-even

though the experiment does not qualify for a waiver of consent under

FDA's Rule under 21 CFR50.24 which states:

 

" (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. "

 

There is virtually unanimous agreement that human blood is proven

safe, effective, and satisfactory-and hemoglobin solutions are not

equivalent. Furthermore, human blood is available in hospitals.

 

Evidence uncovered by the Wall Street Journal* reveals that the

information provided to communities who were consulted in accordance

with FDA's waiver of consent rule, was false and misleading. Members

of communities that gave their blanket approval for the experiment to

be conducted in hospitals within their community were not informed

about documented evidence of the blood product's potential lethal

hazards for patients.

 

The Wall Street Journal investigative report revealed that results

from the company's earlier clinical trial testing PolyHeme on patients

who did provide consent have remained concealed. That trial was

abruptly suspended in 2001.

 

Federal regulations require that the risks and potential benefits, if

any, must be fully disclosed. Yet, evidence of harm from prior trials

of PolyHeme and other similar artificial blood products is being

concealed from the medical community and from the communities that are

being asked to give blanket surrogate consent. The consent they gave,

therefore is invalid since the information provided was false.

 

Communities were not informed that evidence shows that : " 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. "

See: http://www.ahrp.org/cms/content/view/86/80/

 

AHRP calls upon OHRP to use its authority and take the following actions:

 

1. Immediate suspension of this non-consensual experiment.

2. Immediate analysis of the data obtained so far should be done by an

independent data safety monitoring board to determine whether the

product is safe for human subjects.

 

3. If the results of the independent analysis are positive, Northfield

should be required to re-write the protocol and rewrite appropriate

informed consent documents that fully disclose all the hazards of this

blood substitute--including disclosure of 10 heart attacks and deaths

within 7 days.

 

4. Letters of apology to the community should be sent for having

misled them with false information, while concealing vital safety

information about deaths.

 

Experts in the field agree that: " blood substitutes made with

hemoglobin as a starting point..are associated with heart attacks and

strokes. " ( Dr. William Hoffman, chief of cardiac-surgery

intensive-care, at Massachusetts General).

 

We believe that experimental blood substitutes do not qualify for

informed consent exemption and should, therefore, never be conducted

without informed consent.

 

Sincerely,

 

 

 

Vera Hassner Sharav

President

Alliance for Human Research Protection

212-595-8974

veracare

 

cc: Michael Carome, OHRP

 

 

 

* 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

 

see:http://www.ahrp.org/cms/content/view/86/80/

~~~~~~~~~~~~~~~~~~~~~~~~~

 

Ethicists Blast Study Testing Fake Blood

By LINDSEY TANNER,

Imagine being in a car crash, lying unconscious and bleeding in an

ambulance. With no blood on board, paramedics give you an experimental

substitute, but even at the hospital, you get fake blood for several

hours before doctors try the real thing.

 

Medical ethicists say a study that is doing just that on hundreds of

trauma patients without their consent should be halted.

 

It's a renewed attack on research that began in 2004 after Northfield

Laboratories got federal approval for its study of the blood

substitute Polyheme. Debate was reignited by a Wall Street Journal

story last week that suggested the company tried to hide some crucial

details about another blood substitute study back in 2000. The Journal

reported that 10 heart surgery patients in that Polyheme experiment

had heart attacks, while other patients given real blood did not.

 

The Evanston, Ill.-based company halted that study and hasn't

published the full results, but Northfield Chairman Dr. Steven Gould

says there were no attempts at secrecy. Gould said Tuesday that

Polyheme didn't cause the heart attacks or disproportionately more

deaths. He said the study was stopped, not for safety concerns, but

because enrollment was declining and the company wanted to focus on

trauma research.

 

The current study should never have begun, said Nancy M.P. King, a

University of North Carolina ethicist who co-authored articles for an

ethics journal. She and colleagues wrote that real blood shouldn't be

withheld from people who need it without their consent.

 

" There is a serious ethical flaw in this complicated and novel study, "

says the article to appear next week on the Web site of the American

Journal of Bioethics.

 

Finding a viable blood substitute would revolutionize emergency

medicine and could potentially save millions of lives. The idea is to

create a product that works like human blood but could be carried in

ambulances and given quickly to people of any blood type.

 

Baxter International Inc. halted research on its contender in 1998

when more than 20 patients given the substitute died.

 

Northfield now seeks to lead the race and says Polyheme fits the bill.

It is made by extracting oxygen-carrying hemoglobin from human red

blood cells. Unlike saline fluid, the standard pre-hospital trauma

treatment, Polyheme has some of blood's tissue-nourishing properties,

Northfield says.

 

The company's previous study - from 1998 to 2000 - involved

hospitalized patients with defective heart arteries who consented to

get Polyheme. Northfield's stock sank nearly 28 percent after the Wall

Street Journal reported there were 10 heart attacks among Polyheme

patients. Company stock rebounded later that day and closed up about 2

percent Wednesday, but that's still nearly 13 percent lower than

before the report.

 

In the current study, which began in 2004, trauma victims get Polyheme

or saline fluid on the way to the hospital. Once there, Polyheme

treatment continues for up to 12 hours, while those on saline get

blood transfusions. More than 600 patients at 31 trauma centers in 18

states are enrolled in the study, and preliminary results are expected

later this year.

 

The ethicists say the problem with the study is when the patients

arrive at the hospital. Testing Polyheme against blood should be done

separately in patients who can give consent or who have family members

who can consent, wrote King and University of Hawaii ethicist Ken

Kipnis and Philadelphia anesthesiologist Dr. Robert Nelson. Kipnis

said if the hospital phase can't be eliminated, the whole study should

be suspended.

 

Some hospitalized patients inevitably will die because of their

injuries, but they will have died " while being denied an available

treatment (blood transfusions), " the authors wrote.

 

A separate journal essay by Duke University ethicist Karla FC Holloway

says the study, in mostly urban hospitals, disproportionately exposes

minorities to questionable science.

 

The trauma study was approved under a federal " informed consent "

exemption that applies to emergency research. It requires community

briefings in which residents can opt out - in this case by getting

plastic hospital-style bracelets in case they are injured and unconscious.

 

But King says community briefings have not made it clear that patients

will get experimental treatment and not blood transfusions for several

hours even while in the hospital. Many briefings also did not mention

the previous Polyheme study, and withholding that information was

unethical, the ethicists said.

 

King noted that in January, Northfield sued to keep a weekly San Diego

newspaper from publishing information about the trauma study, arguing

that publication would unfairly reveal trade secrets. " So much about

this trial is secret because the FDA doesn't release information to

the public about products that are being developed by commercial

sponsors, " King said.

 

Gould dismissed concerns about ethics and secrecy and said periodic

reviews by an independent monitor have deemed the trauma study fit to

proceed.

 

A Northfield spokeswoman said a survey of 12 study sites found that

more than 2,000 people had requested " opt out " bracelets, mostly for

religious reasons. Also, 11 of the 600-plus patients dropped out

during the study's hospital phase, she said.

 

Northfield Labs: http://www.northfieldlabs.com

 

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

 

FAIR USE NOTICE: This may contain copyrighted (© ) material the use of

which has not always been specifically authorized by the copyright

owner. Such material is made available for educational purposes, to

advance understanding of human rights, democracy, scientific, moral,

ethical, and social justice issues, etc. It is believed that this

constitutes a 'fair use' of any such copyrighted material as provided

for in Title 17 U.S.C. section 107 of the US Copyright Law. This

material is distributed without profit.