Is it ethical to test people with
experimental treatments without their knowledge or
permission? This is what is in question after the
FDA approved the testing of an artificial blood substitute,
known as PolyHeme.
PolyHeme is a synthetic blood substitute derived
from outdated, donated, human blood. Unlike human
blood though, PolyHeme does not require blood typing
or refrigeration. Another advantage of PolyHeme is
that it can carry oxygen to the tissues, unlike blood
volume expanders like normal saline. Shelf life is
another advantage of the blood substitute. PolyHeme
has a shelf life of 12 months, compared to real blood,
which has a shelf life of about 42 days.
There are some serious safety issues with PolyHeme
though. The first study of PolyHeme was started in
1998 and continued to the year 2000. In this study
consent was obtained from patients as is required
by law. The patients all had aneurysm surgery of the
heart arteries. Ten of the 81 patients receiving the
blood substitute died within a week, while none of
the 71 patients receiving real blood suffered any
heart attacks. This study was not only halted early
because of the deaths, but the company who manufactures
PolyHeme withheld the fact that people died during
the study from the public.
In their most current study, Northfield Laboratories,
the maker of PolyHeme, conducted a second study on
over 700 patients, without their consent. Some patients
receive PolyHeme alone, others received PolyHeme then
saline, and the remainder received saline and blood.
The study was conducted in various cities throughout
the U.S. The FDA approved the testing without consent
based on the 1996 Federal regulation CFR 50.24 waiver
of informed consent.
The study started with a total of 722 patients. A
total of 126 patients were dropped from the study
due to what they called “protocol violations”.
This includes patients that were too young, or they
were excluded for other reasons. Other parameters
that excluded patients included patients who have
sustained unsurvivable injuries, have severe head
injury, are pregnant, have cardiac arrest, or have
objected to the study. Out of the remaining 586 patients,
279 were in the group receiving PolyHeme and 307 patients
were controls. Incidences of death were higher in
each of the groups receiving PolyHeme, compared to
each of the control groups. Although, Northfield Laboratories
claims that the difference in the number of deaths
was not significant.
Northfield Laboratories tried to get FDA approval
based on previous studies of trauma patients. The
other patients they were comparing had not had blood
though. They were trauma patients that had not received
blood because of religious beliefs.
In August of 2006, Northfield Laboratories tried
to get accelerated approval for PolyHeme. The request
was declined by the FDA until further study results
come in. I guess they were in a rush since they signed
a $6.7 million agreement on June 16th, 2006 to purchase
a 106,000 square foot property that they intend to
use to manufacture their product. This is really putting
the cart before the horse since they don’t have
approval for their blood substitute, nor is there
any guarantee of approval.
This brings up the question of how far will Northfield
Laboratories go to get their blood substitute approved
to avoid losing their investment, and the money of
their investors? After all, this has been a costly
venture. Not only have they spent $6.7 million for
the building they intend to manufacture their product
in, but they are also paying the hospitals $10,000
for each patient they test the blood substitute on.
Tack on to that other research and development costs,
manufacturing equipment costs, and other expenses.
Pursuant to CFR 50.24 certain criteria must be met
in order for testing to be performed on patients without
their consent. For example, section (2) (ii) states
“Appropriate animal and other preclinical studies
have been conducted, and the information derived from
those studies and related evidence support the potential
for the intervention to provide a direct benefit to
the individual subjects”. So where are these
previous animal or preclinical studies? The only study
was halted early after a significant increase in deaths
in patients receiving PolyHeme. Section (2) (iii)
states “Risks associated with the investigation
are reasonable in relation to what is known about
the medical condition of the potential class of subjects,
the risks and benefits of standard therapy, if any,
and what is known about the risks and benefits of
the proposed intervention or activity.” Again,
the only clinical study was halted early because of
a disproportionate death rate between those receiving
PolyHeme, and those that did not. This is hardly reasonable,
when standard therapy has been shown to be considerably
safer and effective.
The regulation also requires that they try to gain
consent prior to, or as soon as possible from a legal
representative, such as a relative. From what I have
seen, I don’t think this is being done. For
instance, if a married couple is in an accident, and
only one has sufficient trauma to require blood, are
they obtaining consent from the spouse? It does not
appear that they are. Instead, saline or PolyHeme
were not chosen for the patient until the patient
was on the way to the hospital. And according to news
reports, the decision was based on sealed envelopes
the paramedics opened in route to determine what treatment
the patient would be given. Such a practice would
prohibit the paramedics from explaining the risks
and benefits to the spouse to allow them to make an
informed decision, or give time to obtain consent
even if the spouse was aware of the risks. If no legal
representative can be found, then the company must
provide proof of attempts to contact a legal representative.
Section (7) (ii) states “ Public disclosure
to the communities in which the clinical investigation
will be conducted and from which the subjects will
be drawn, prior to initiation of the clinical investigation,
of plans for the investigation and its risks and expected
benefits”.
The first problem with this is that Northfield Laboratories
did not disclose the adverse effects of their product
found in the 1998 study. In fact they threatened to
sue the group that made the fact public claiming that
the adverse effects, which included death, were part
of their trade secret. I also see a problem with this
regulation by the fact that everyone will not be aware
of the study since not everyone follows, or has access,
to the media. For example, the homeless would not
likely know about the study, and therefore there will
be no disclosure, as is required, to certain groups.
Even though people in these groups may be subjected
to the study. The law does allow life saving measures
in people unable to give consent, such as unconscious
patients. This is called implied consent. For instance,
if a person tries to overdose on drugs to commit suicide
and they refuse treatment, the paramedics cannot touch
the patient. Once they pass out they can claim implied
consent and start treatment. The basis is that the
person, if they were conscious and able to give consent,
would give consent to save their life. Does this apply
to unapproved and untested drugs like PolyHeme though?
I doubt if such an argument would hold up. A person
would probably give consent if they knew, or had reason
to believe, that the drug or treatment had been thoroughly
tested and was an approved treatment. A reasonable
person is not likely going to consent to an unproven,
and potentially dangerous unapproved drug or treatment.
Especially when safer and proven therapies exist.
Northfield Laboratories claims to have followed CFR
50.24 explicitly. I disagree, based on the facts that
they never completed previous trials, their product
has a higher death rate than controls and those receiving
blood, they have not informed the public of their
testing, or the possible dangers of the therapy, and
I don’t see any evidence that they are really
trying to obtain consent as is required by law.
Patients were allowed to opt out of the test in case
they suffered a severe trauma that would leave them
unable to give consent. To do so though they had to
obtain a blue plastic bracelet from the company that
they had to be wearing at the time paramedics arrived.
In order to get the bracelet the person would first
have to be aware of the test. Many people were not
aware that the test was going on until testing had
almost been completed. And as previously pointed out,
people that did not follow the media, or who had no
access to the media, would have still been uninformed
about the testing. The same could apply to those who
do not speak English. Even if the story came on the
TV news, it does not mean they would understand what
the test was about, or how to opt out.
So what are the potential side effects of PolyHeme?
Previous hemoglobin products have all been shown to
cause kidney damage, liver damage, high blood pressure,
and inflammation of the arteries. There is also concern
that allergic reactions may occur. Northfield Laboratories
claims that these adverse effects are not possible,
and their product is safe. Other researchers disagree.
And Northfield Laboratories has not had the greatest
track record of being honest to the public about the
safety record of their product. For instance when
they tried to suppress the fact that 10 patients died
within one week of receiving their product, and no
patients receiving real blood died. And this study
was halted early. Would more deaths have occurred
if the study had continued its full duration? Other
adverse affects reported by the use of PolyHeme were
significant increases in the rate of heart attacks,
arrhythmias, and pneumonia.
Cities listed as participants in the test are : San
Diego, California; Denver, Colorado; Newark, Delaware;
Macon, Georgia; Maywood, Illinois; Indianapolis, Indiana;
Kansas City, Kansas; Lexington, Kentucky; Detroit,
Michigan; Rochester, Minnesota; Durham, North Carolina;
Cleveland, Ohio; Cincinnati, Ohio; Dayton, Ohio; Bethlehem,
Pennsylvania; Hershey, Pennsylvania; Memphis, Tennessee;
Johnson City, Tennessee; Houston, Texas; San Antonio,
Texas; Salt Lake City, Utah; and Morgantown, West
Virginia . The clinics and hospitals listed as participating
were:
UC San Diego Medical Center, San Diego, California
Scripps Mercy, San Diego, California
Denver Health Medical Center, Denver, Colorado
Christiana Hospital, Newark, Delaware
Medical Center of Central Georgia, Macon, Georgia
Loyola University Medical Center, Maywood, Illinois
Wishard Memorial Hospital, Indianapolis, Indiana
Methodist Hospital of Indiana, Indianapolis, Indiana
University of Kansas Medical Center, Kansas City,
Kansas
University of Kentucky Medical Center, Lexington,
Kentucky
Detroit Receiving Hospital, Detroit, Michigan
Sinai Grace Hospital, Detroit, Michigan
The Mayo Clinic, Rochester, Minnesota
Duke University Medical Center, Durham, North Carolina
MetroHealth Medical Center, Cleveland, Ohio
University of Cincinnati Medical Center, Cincinnati,
Ohio
Miami Valley Hospital, Dayton, Ohio
St. Luke’s Regional Resource Trauma Center,
Bethlehem, Pennsylvania
Penn State Milton S. Hershey Medical Center, Hershey,
Pennsylvania
University of Tennessee-Memphis, Memphis, Tennessee
Johnson City Medical Center, Johnson City, Tennessee
University of Texas Health Science Center, San Antonio,
Texas
University of Utah Health Sciences Center, Salt Lake
City, Utah
LDS Hospital, Salt Lake City, Utah
Virginia Commonwealth University Medical Center,
Richmond
West Virginia University/Jon Michael Moore Trauma
Center, Morgantown, West
Virginia
Other hospitals that stopped participating in the
study before it was completed are the Albany Medical
Center, Albany, New York; Lehigh Valley Hospital,
Allentown, Pennsylvania; Brooke Army Medical Center,
Fort Sam, Houston, Texas; Memorial-Hermann Hospital,
Houston, Texas; Sentara Norfolk Hospital, Norfolk,
Virginia; and Inova Fairfax Hospital, Falls Church,
Virginia.