there have been reports in the media (Dalton 2006; Hicks 2006; Burton 2006) and
in journals raising ethical concerns on the use of the blood substitute
PolyHeme in a clinical
trial in trauma patients. The trial has been conducted by Northfield
will recruit over seven hundred subjects at thirty-one hospitals. Federal
regulation, following accepted ethical codes, requires the informed consent of
subjects or their legally-authorized representative. However, regulation
permits waiver of consent in certain minimal-risk experiments. In 1996, under
pressure from trauma researchers, the FDA amended their regulations to allow “emergency research” under an Exception from Informed Consent (EFIC), called
the 21 CFR 50.24 rule. During discussions about the anticipated amendment prior
to 1996, this author opposed the new regulation and stated: “In ten years,
we’ll have had some abuses, and people will start rethinking the rules”
statement in the justification of the EFIC is that the regulation allows “potentially life-saving research to be carried out in an emergency situation”.
The waiver rules have been used infrequently but have enabled researchers to
learn more about treatments for cardiac arrest, severe traumatic injuries, head
injury, and stroke (Sloan et al. 1999; Lewis et al. 2001). It also was key to
approval of a successful life-saving device – the automated defibrillator
(Hallstrom et al. 2004).
required for EFIC research include a life-threatening medical condition for
which current treatments are unproven/unsatisfactory; prior consent is not
feasible; direct benefit to subjects is anticipated; the research’s risks are
minimal, given the patient’s life-threatening circumstances; and, the research
could not be conducted within the “therapeutic window” (when the treatment must
be given) without an EFIC. EFIC research also requires an attempt to obtain
informed consent when feasible; consultation with representatives of the
community where subjects are derived from; prior public disclosure to the
community of the study plan and its potential risks and benefits; post-trial
disclosure of the study’s results and demographics of enrollees to the
community; provision of methods for self-exclusion; and, an independent Data
Monitoring Committee to exercise oversight on the study. Institutional Review
Boards in each research institution make judgments determining which proposed
protocols fulfill these conditions.
ethically-troubling issues associated with these kinds of trials. The most
important ethical concern is the exception from informed consent. How can one
morally justify using another human being in an experimental trial without
their prior consent? It is clearly a repulsive notion to our sense of adherence
to autonomy. However, the justification is that societal interests, under
certain narrow conditions, can take priority over autonomy; this is one of
those situations. Two important issues remain to be evaluated, however. Namely,
a risks and benefit calculation, and whether the subject distribution is fair.
PolyHeme trial, some
of the potential benefits include improved physiologic variables, decreased
blood transfusion exposures, and ultimately decreased morbidity and mortality.
Some of the risks are related to PolyHeme‘s
potential side effects, some of which may be life-threatening. It is important
to evaluate whether, at each stage of the trial, the study design is consistent
with the requirement that PolyHeme is predicted
to benefit subjects more than current treatments.
The PolyHeme Trial
Northfield Laboratories received FDA allowance to commence a protocol
under the EFIC rule to treat subjects in hemorrhagic shock due to traumatic
injuries in the pre-hospital setting. It is a Phase III randomized clinical
trial with two arms. In the control arm, blood volume is replenished with a
current standard-of-care resuscitative fluid having no oxygen carrying
capacity: saline. In the experimental arm, blood volume is replenished with
polymerized hemoglobin-based oxygen carrier obtained from outdated human blood.
The assumption is that PolyHeme will
ameliorate blood volume loss while simulataneously transporting oxygen to
tissues, thereby improving clinical outcomes (Northfield 2003). The
experimental protocol calls for administration of up to six units of PolyHeme for as long as twelve hours from the
initiation of the protocol at the accident site, irrespective of the time of
arrival at the emergency room. Usually, in emergency rooms across the country,
the standard of care is the use of human blood for transfusion, if needed.
ethical concerns have been raised, most importantly that half of the study’s
subjects will continue to receive PolyHeme
after they arrive at the emergency room, in lieu of standard blood transfusions
(Kipnis et al. 2006a, 2006b). This is because the EFIC rule requires that the
current standard of care be “unproven and unsatisfactory”. Where modern blood
banking is available (e.g., trauma centers in the
not considered “unproven and unsatisfactory” despite its limitations. Kipnis
and his colleagues (2006a, 2006b) has
also raised other ethical concerns, including lack of transparency,
interference with IRB deliberation, inadequate disclosure of adverse events,
and the inability of the FDA to intervene once the protocol was approved – the
FDA is locked into an agreement with the sponsor under a Special Protocol
Assessment (SPA) allowed by Public Health Law. Karla Holloway (2006) has raised
the additional concern that such a waiver of consent, without adequate
community consultation, might derail autonomy (or perception thereof) in
populations that historically distrust research institutions.
author’s knowledge, in the PolyHeme trial no
attempt is made to get any kind of informed consent, even an abbreviated
version, at the accident scene, from either the subject or any potential
relative accompanying the subject. The lack of attempt to obtain any form of
informed consent raises an addition ethical concern, since spouses or family
members capable of giving such consent may be available, albeit infrequent. In
rare circumstances, the subject also may be able to give informed consent. An
attempt to obtain informed consent is made after hospital arrival, but PolyHeme administration to the exclusion of
blood transfusions may be continued under the EFIC while these efforts are.
Effective Survival in Shock (RESUS)
(Hemopure) is a polymerized form of bovine hemoglobin, manufactured by the
Biopure Corporation (
U.S. Navy, the Naval Medical Research Center (NMRC) submitted a research
proposal to their IRB for approval to study HBOC-201 as a pre-hospital
resuscitative fluid in trauma subjects with HS, prior to an
In March 2004,
NMRC submitted a pre-IND application and a request for a meeting with the FDA.
The RESUS trial design is generally
similar to the PolyHeme? trial under
the EFIC rule, but has several differences delineated below. Unaware of the
PolyHeme trial design,
RESUS investigators instituted much
stricter ethical requirements. In addition to provision ensuring compliance
with all of the EFIC rules, RESUS
investigators also instituted the several special provisions, including an
abbreviated “pre-enrollment disclosure” (or “right of refusal”) process with a
flash card given to subjects or family members when feasible; exclusion of
subjects with rapid access to standard blood transfusions by using a “blood
transfusions unavailable”-inclusion criterion (based on the urgency of the
subject’s condition); and, allowing initiation of HBOC-201 infusions only in
the pre-hospital setting when blood transfusions are unavailable, with the
proviso that incomplete infusions be completed upon hospital arrival, but
without delaying standard blood transfusions, as indicated.
At a later
date, upon FDA request, the protocol design was improved by adding a brief
informed consent form, including all essential elements of consent, to be used
at the scene when “feasible”. The FDA also questioned whether the inclusion
criteria adequately targeted a population of subjects with severe HS and a
predicted mortality of 34%, as asserted in the protocol. HS was mainly defined
by a low blood pressure (hypotension)-inclusion criterion. After further
analysis of mortality predictions using data in the literature, the National
Trauma Data Base (NTDB), and RESUS
trauma centers, a standard clinical score was added to the inclusion criterion
in order to exclude subjects predicted to do well or to die irrespective of
treatment (very low and high mortality). The change targeted a HS population
with intermediate mortality, one more likely to benefit from improving care
with a new therapeutic agent. Specifically, a Revised Trauma Score in the range
of 1 to 6.5 was added to the inclusion criteria. By making this change, they
found that predicted mortality was much closer to their original estimate (and
target) of 34%.
submitted the pre-IND in early 2004 and followed with an
in a clinical hold by the FDA’s Office of Blood Research and Review (OBRR).
There were several meetings and teleconferences with the FDA, including a Type
A meeting at which Agency objections were discussed. Despite two revisions, and
many responses to clarifications and requests for additional information by the
FDA, the Agency decided to continue the clinical hold and refer the application
to an advisory board.
objections of the FDA were not related to the ethical issues that have recently
surfaced regarding the PolyHeme trial, but
rather on issues related to judgment about the drug’s predicted safety profile
in a pre-hospital trauma trial (FDA 2005, 2006). For example, the FDA objected
to the study’s target population, continuing to disbelieve the predicted death
rate of 34% or believing that the death rate was not high enough. The
however, uses similar trauma centers around the country. To the best of this
author’s knowledge, the
trial’s HS target population is defined only by hypotension without additional
criteria to focus the target population to one with higher mortality. This was
unacceptable to the FDA for the RESUS
trial. Another major objection was the fact that HBOC-201 is a vasoactive
compound; HBOC-201 could raise blood pressure and mislead health care providers
into thinking that subjects are resuscitated better than is actually true. This
could result in secondary adverse effects and potentially affect survivability
of study subjects. Other objections concerned details of study methodology,
with the FDA suggesting that they were not adequate to ensure the safety of
subjects. Similar objections can be made regarding the
Discussion and Concluding Remarks
As someone who
originally objected to the regulations allowing “emergency research” under an
Exception from Informed Consent, this author admires the FDA reviewers’
vigilance in protecting human subjects. However, once the regulation was in place,
it should have been applied fairly and equitably. While we could argue about
the number of lives that could be saved with development of blood substitutes,
there is no doubt that some deaths could be prevented. This is especially true
in combat situations, and should satisfy the direct benefit clause of the EFIC
regulation. As Kipnis and his colleagues have stated, “unlike some critics, we
support the concept of waived consent trials and have contributed to the effort
to improve their design and implementation. We also appreciate the dangers and
limitations of blood and endorse the effort to find safer and easier-to-use
alternatives” (2006b, 20).
It is the
recommendation of the author that the entire file of the RESUS protocol,
and NMRC-FDA correspondence, and minutes of the trial’s advisory board and
meetings with the FDA, immediately be made available to the public. This
transparency would allow for adequate disclosure. An objective reading of the
material would see the rigorous efforts made by the NMRC in providing thorough
oversight to maximize protection of the human subjects; minimization of risks;
an extensive community consultation and disclosure process; detailed disclosure
of potential study risks (including the study product’s safety profile); fair
subject selection; ensuring access to standard care (blood transfusions); an
effort to minimize loss of autonomy (inclusion of processes for signed informed
consent and right of refusal when feasible); and detailed stopping criteria to
be used by the DMC (Freilich 2005). (By September 2006, the FDA’s advisory
committee meeting regarding RESUS trial will have taken place and should result
in nearly all of the those documents becoming available to the public at that
I would like to cite Kipnis et al.’s concluding remark: “Properly conducted,
waived-consent research can augment the capabilities of emergency medicine. It
would be tragic if avoidable failures and conflicts in oversight compromised
the promise of these trials” (2006a, 19). I would add that it also would be
tragic if unfair application of the regulation results in shutting down a
publicly supported trial while lesser trials are allowed to proceed.
Blood-substitute study is criticized by
Trauma trials leave ethicists uneasy. News@Nature
March 26. Published online: 22 March 2006; doi:10.1038/440390b.
October 3, 2005, letter (p. 1-8) addressed to Daniel A. Freilich, MD, CDR, MC,
March 2, 2006, letter (p. 1-11) addressed to Daniel A. Freilich, MD, CDR, MC,
2005. September 6, 2006, letter (p. 1-83) addressed to Alan E. Williams, Food
and Drug Administration/CBER.
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Since 2003, Adil E. Shamoo has served as a paid ethics consultant to the RESUS trial, the Naval Medical Research Center’s (NMRC) proposed clinical trial of Hemopure, a prehospital resuscitative fluid in trauma subjects with hemorrhagic shock. Dr. Shamoo also is a member of the Advisory Board. Dr. Shamoo wrote this article on his own time and on his own volition.
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