BIOETHICAL
LESSONS FROM THE GELSINGER CASE:
THREE MYTHS OF HUMAN EXPERIMENTATION
Jesse Gelsinger had just turned
18 when he volunteered to participate in a gene therapy experiment at the
Institute for Human Gene Therapy at the University of Pennsylvania. When he
appeared for the trial on September 9, 1999, he weighed 130 pounds and had
a normal life expectancy, though he would always suffer from OTC, a genetic
disease affecting the liver's ability to process ammonia. On September 13,
Jesse was strapped down and sedated while a catheter was inserted into his
groin. A doctor then injected 32 trillion particles of an adenovirus into
his liver. Within 4 days, Jesse was in an irreversible coma. The virus had
caused a massive immune response and release of fluids, which swelled his
body by almost 40 pounds. When his parents agreed to a withdrawal of life
support, their son was unrecognizable.
For the moment, put aside the numerous violations of FDA regulations committed
by the Penn research team. Penn and Dr. Wilson have maintained that these
FDA violations did not cause the death of Jesse Gelsinger. While not exactly
accurate, focusing on those mistakes, as the FDA and the media have done,
ignores the root cause of Jesse's death, which must be remedied to avoid further
tragedies. The bioethical decisions made at the inception of the OTC trial
are what killed Jesse Gelsinger, and the blame for those decisions reaches
far beyond the principal investigators.
The first was the decision to permit James Wilson to conduct gene therapy
experiments at Penn while maintaining a majority interest in Genovo, a biotech
company that stood to make millions if the experiments were successful. This
issue was debated at length by Penn's Conflict of Interest Standing Committee
("CISC"),whose job it is to make sure that university research is not burdened
or compromised by conflicts of interest. In the minutes of one such committee
meeting, members asked the critical question: "Since Dr. Wilson's research
will be directed towards a solution in which he has a financial interest in
the outcome, how can Dr. Wilson assure the University that he will not be
conflicted when making decisions that could have an impact on ...the further
development of his intellectual property?" The answer , of course, was he
couldn't. The essence of the experiment was an attempt to prove that Dr. Wilson's
vectors were the appropriate taxicabs for gene transfer. At the same meeting,
the committee asked, "How can Dr. Wilson and the University avoid liability
for any damages if a patient died from any products produced or studied at
the University." Curiously, this prescient question is omitted from the final
minutes of the CISC. The answer to that question was obvious. Hence,
MYTH 1: The purpose of a clinical trial is to benefit medicine and
science at little or no increased risk to the subject.
The truth is every clinical trial is burdened by conflicting interests. Investigators
and their institutions almost always have a financial stake in the experiment.
Investigators can make a million dollars a year doing nothing but clinical
trials. Pharmaceutical companies pay investigators up to $2500 for each subject
recruited. In many trials, like the one in which Jesse Gelsinger died, both
the institution and the investigator stand to profit greatly if the research
is successful and if that success comes before anyone else's. It is too often
a race not against a disease but against other experiments for the riches
a victory may bring.
Investigators have other interests just as dangerous, because these interests
like money divert the investigator's eyes off the patient as an autonomous
being. The need and desire for fame, prestige, respect of their peers, and
the necessity to publish or perish all exert pressure on the investigator
to think of his work first, to bend the rules, and to complete the study at
any and all costs.
But keep in mind, the absence of any self interest- manifested by the belief
in the greater good, the quest for knowledge, the interests of mankind, the
interests of the state-- these too are potential evils. The history of medicine
and science is littered with subjects sacrificed for the greater good: the
Nazi experiments, Unit 731, Tuskeegee, the US Radiation studies, Willowbrook.
These experiments were not poisoned by self-interest. They were poisoned by
the arrogance of men who believed they could make the choice of who would
be martyrs for science or for the greater good. Not surprisingly throughout
history the chosen ones, the subjects, were the prisoner, the mentally infirm,
the Jew, the African American, the poor-- those who the poet called the abandoned
and forsaked.
In any clinical trial, the well being of the subject must be the first priority.
It is the only interest that matters. As the sages advised: a physician must
do no harm; he must never see in the patient anything other than a fellow
creature in pain; he must never do an experiment harmful to the patient even
though advantageous to science or to others.
The second bioethical decision was the approval of the design of the experiment.
Originally, Dr. Wilson and his team designed an experiment on infants born
with OTC, facing almost certain death in the first months of life. The goal
of the study was to see if gene transfer of a healthy OTC gene could allow
these infants to live long enough to be put on the drug regimen designed by
Dr. Batshaw, one of the principal investigators. Without the gene therapy,
the babies would surely die so the benefits to the babies, even though remote,
might outweigh the risks they would die in the experiment. In stepped Arthur
Caplan, Penn's resident bioethicist and consultant to IHGT. That experiment
is unethical, he said, because mothers distraught over the birth of a dying
child could never make an informed decision about whether to allow the infant
to participate in the study. I do not quarrel with that decision. Instead,
Caplan proposed, conduct the experiment on healthy adults with mild forms
of OTC. How is this a more ethical decision? The risks in this study were
great; they were life threatening. The potential benefits to the participants
were nonexistent. Such an experiment violated the Nuremberg Code, the Declaration
of Helsinki, and any conceivable ethical norm governing science and medicine.
Yet this experiment was approved by three different bodies which should have
rejected it as too risky and unethical. First, Penn's IRB approved the study,
presumably without any understanding of the risks to the subjects, the nonexistent
benefits, and the conflicts of interests of not only the principal investigator
but of the University itself. Then it was approved by the Recombinant DNA
Transfer Activities Committee, known as "The RAC," which was composed of the
top scientists in the gene therapy field. A prominent member of the RAC later
admitted that the members should have rejected the study as too risky but
did not because of their own conflicts of interest. Finally, the FDA, the
last gatekeeper, rubber-stamped the RAC's approval of the study, despite its
clear departure from the bioethical rules governing such work. Hence,
MYTH 2: Somebody is watching; the investigator is watched by the IRB,
the IRB by the OHRP, the OHRP by the HHS, the HHS by the FDA, the FDA by Congress.
The truth is no one is watching. There are 2-300,000 trials going on at any
one time involving 7-8,000,000 participants. One major university was conducting
4,000 clinical trials at once; a small southern school 1200. How can an IRB
do what it is supposed to do when some, like the one at the University of
Oklahoma, meet once a month for an hour with dinner to follow. IRBs have certain
critical duties under the law.
First, it is the duty to examine the design of the trials. The IRB must determine
the importance of the knowledge to be gained by the result and the likelihood
of gaining that knowledge by the experiment. The IRB must also make certain
the experiment is based on competent animal studies and generally accepted
scientific principles. The IRB must understand the risk-benefit calculus of
the protocol and determine that the risks have been minimized. This means
that, in a therapeutic trial, a state of clinical equipoise exists between
the experimental treatment and the generally accepted course of treatment.
In a nontherapeutic trial, the standard is minimal risk plus the attendant
risk of the procedures necessary for the collection of data such as blood
tests. For children or incompetents, the standard is nothing more than minimal
risk.
Second, the IRB must evaluate the competence of the investigator. Those performing
human studies should be at the top of their profession. In addition, the IRB
must make certain clinically competent medical personnel are available for
supervision and support.
Third, the IRB must make sure the selection process for subjects is equitable
and just, that it does not take advantage of the minority, the poor, the imprisoned,
the uninsured or the infirm.
Fourth, the IRB must review the informed consent document to determine if
it describes the design and purpose of the trial, the procedures to be performed,
the risks, the benefits, and the alternative treatments available.
Fifth, the IRB must monitor the trial. It must know if the trial falls out
of clinical equipoise; it must make sure adverse events are being reported;
and it must consider changes to the protocol on a prospective basis only.
How can IRBs possibly perform these critical functions given the amount of
trials under their supervision?. They don't do that. They can't do that.
Government agencies are supposed to be doing all the same tasks and monitor
the IRBs. They don't do that. They can't do that. In the 5 years before Jesse
Gelsinger's death there were 39 adverse events reported in gene therapy trials.
Four months after Jesse's death, 700 were reported. In the last 10 years,
there have been 9 deaths reported as adverse events in clinical trials involving
70 to 80 million subjects. One study concluded the number should be at a minimum
20,000. I am not saying 20,000 caused by the experiment. That is not the definition
of an adverse event. Adverse events are any serious health events, expected
or unexpected, occurring during the course of the trial. It is not for the
investigator to determine whether the experiment caused the event before it
is reported. These numbers reveal the obvious: No one knows how safe these
trials really are because no one is watching.
As I said, IRBs are supposed to look at the informed consent document. By
most accounts that is what they spend most of their time on under the assumption
that this document somehow provides their institution a release of liability.
In the Gelsinger case, the informed consent document was misleading, incomplete
and totally lacking in its ability to convey the complex nature of the experiment
to the subjects. It was misleading because it described Gene Therapy as if
it were an established medical procedure and not a speculative theory that
has still not produced a single successful treatment for any disease or affliction.
It was incomplete because it failed to include the fact that monkeys had died
in the same experiment. But, more important, even if these faults had been
corrected, the document could never produce an understanding in the lay reader
of the purpose of the procedure, the substantial risks of the adenovirus injection,
and the limited and speculative benefits to the advancement of medicine. Hence,
MYTH 3: The informed consent document evidences informed consent
The truth is it neither evidences that the subjects are informed or that they
consent. The subjects are not informed because the document is not written
in language they can understand. The subjects are not informed because, when
the document is explained to them by the investigator, the wink of a trusted
eye and the inflection in the voice trained to comfort tell the subjects what
they want and need to hear: they are better off by participating; they are
in good hands; and their interests are what matter. They are not informed
because only the investigators and their fellow scientists understand the
purpose of the experiment, the benefits to the subjects, and the risks of
harm.
It does not evidence consent because it is not the subject's right to consent.
A subject cannot consent to an unethical experiment. Anything more than minimal
risk in a nontherapeutic trial, anything other than clinical equipoise in
a therapeutic trial, is contrary to the ethical norms of Hippocrates, Maimonides,
Nuremberg, and Helsinki. We as a society can not and do not consent to any
experiment on any of us which has a greater risk of harm than the risks of
everyday life. And it is our informed consent that is required.
