The Gelsinger Case
The Gelsinger Case
The Gelsinger Case
10
The Gelsinger Case
Background
The death of Jesse Gelsinger in September 1999 is one of the
defining cases in the recent history of research with humans.
Gelsinger, 18, died during a gene transfer experiment at the
University of Pennsylvania School of Medicine.1 His deaththe
first directly attributed to gene transferraised profound questions about the protection of patients in this high-profile research
field, as well as in other clinical studies. It also raised questions
about adherence to research protocols, the reporting of adverse
events, informed consent, and financial conflicts of interest. It
shook the confidence of the public and the federal government in
the competence and ethics of clinical researchers and the institutions where they work, and led to efforts to improve the protection
of research participants.
Although the terms gene transfer and gene therapy are often
used interchangeably, gene transfer is more precise. Gene transfer
refers to the transfer to a person of recombinant DNA, or the
transfer of DNA or RNA derived from recombinant DNA. The aim
is to modify or manipulate the expression of a gene in the body or
to change the biological properties of cells. Although the promise
of gene transfer is great, progress has been slow. A 1995 review of
the investment in the field by the National Institutes of Health
(NIH) advocated caution: Significant problems remain in all basic
aspects of gene therapy. Major difficulties at the basic level include
shortcomings in all current gene transfer vectors and inadequate
understanding of the biological interaction of these vectors with
the host.2
As of February 2000, several months after Gelsingers death,
more than 4,000 patients had participated in gene transfer studies.
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Of the 372 clinical trials that were registered with the NIH, 89%
were Phase I studies of safety and toxicity.3 For many years, the
public and scientists have been concerned about the potential
environmental and infectious disease risks of recombinant DNA
technology. This is one reason that the federal government has
treated gene transfer studies differently from other clinical research. Extensive data about all trials registered with the NIH are
publicly availablefar more than for most other studies. Investigators who are funded by the NIH or who conduct their work at
institutions that receive NIH support for any type of recombinant
DNA research must comply with specific NIH guidelines. In addition to this, a Recombinant DNA Advisory Committee (RAC)
was established within the NIH in 1974. The RAC is a public
forum for discussion of novel and substantial issues related to gene
transfer trials, including the review of specific protocols. Although
the guidelines and the specific duties of the RAC have changed
over time, it has a critical role in the oversight of this research.4
The Food and Drug Administration (FDA) also regulates clinical
gene transfer trials.
has been viewed as a model for gene transfer directed at the liver.5
The reason is that restoration of the enzyme activity should treat
the disorder, as has been demonstrated by treatment with liver
transplantation.6 Gene transfer for OTC deficiency has been studied in the sparse fur mouse, which is deficient in the enzyme.
Studies in this animal model suggest that the gene defect can be
corrected.1
People with OTC deficiency can develop profound hyperammonemia. Excessive levels of ammonium ion in the brain can
lead to life-threatening encephalopathy, coma, and brain damage.
Complete deficiency usually leads to death during infancy.
Without a liver transplant, only about half of those born with OTC
deficiency will survive to age 5, and many survivors have profound mental impairment. For people with partial enzyme deficiency, a low protein diet supplemented with oral medications
(sodium benzoate and sodium phenylacetate=sodium phenylbutyrate) can be used to minimize the risk of complications or death.
Such treatment eliminates excess urea and precursors of ammonia.
However, adherence to diet and medical therapy is difficult, and
only partially effective.
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Table 10.1
Timeline of Events Leading Up To and Following the Death of Jesse Gelsinger
Date
Event
Date
Event
1992
Apr. 2000
May 2000
Aug. 2000
Sept. 2000
Nov. 2000
Nov. 2000
Sept. 2001
Feb. 2002
1993
1995
1997
1998
June 1999
Apr. 2002
Summer 2002
Apr. 2003
Oct. 2003
Sept. 9, 1999
Sept. 13, 1999
Dec. 1999
Jan. 2000
Feb. 2005
2. The possibility that the adenovirus would provoke an immune response that would damage the liver.
3. The possibility that receiving the vector would prevent the
research participants from receiving it as part of a therapy in
the future. If used again, the vector would likely trigger an
immune response and the body would eliminate it.
The consent document also stated that if a subject developed liver
failure, a liver transplant could be required. Participants were to
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his gene transfer research that made the trial possible. Wilson was
extensively involved in activities such as the preclinical animal
work, the development of the gene transfer vector and its mode of
delivery, the design of the trial, protocol modifications, laboratory
work during the trial, and the analysis of the results.
Jesse Gelsinger
Jesse Gelsinger was diagnosed with partial OTC deficiency when
he was a young child. He was subsequently found to have a unique mutation. Some of his cells had a defective OTC gene with a
large deletion, whereas others had a normal genea condition
known as mosaicism.16 Despite diet and drug therapy, he developed serious hyperammonemia many times, including an episode
of hyperammonemic coma in December 1998 that required treatment with mechanical ventilation. He recovered from this episode
without apparent adverse effects. In 1999, his disease was considered generally controlled.
Gelsinger lived in Tucson, Arizona. He was the 18th subject in
the study and, at age 18, the youngest person enrolled. He had
learned about the trial in 1998 from his physician. His father said
after his death that he was doing this for other people.17 Jesse
Gelsinger set aside his personal life to participate, and took an
unpaid leave from his job.18 According to his father, One night he
even said, The worst that could happen is that I could die and
maybe help doctors figure out a way to save sick babies. Ive never
been more proud of my son than the moment he decided to do
this experiment.17
The doses of the vector in the study ranged from 2 ! 109 to
6 ! 1011 particles=kg of body weight. (The second-highest dose
was 2 ! 1011 particles=kg.) On September 13, 1999, Gelsinger
became the second subject to receive the highest dose of 6 ! 1011
particles=kg; his total dose, based on his weight, was 3.8 ! 1013
particles. In the other study participants, including the first to
receive the highest dose, the adverse effects were transient muscle
aches and fevers and laboratory abnormalities such as thrombocytopenia, anemia, hypophosphatemia, and elevated levels of the
liver enzymes known as transaminases. The adverse events in other
study participants, however, were not life threatening.
About 18 hours following infusion of the adenovirus vector,
Gelsinger developed altered mental status and jaundiceneither of
which had been seen in the first 17 study participants. He subsequently developed the systemic inflammatory response syndrome,
disseminated intravascular coagulation and multiple organ system
failure, and the acute respiratory distress syndrome.1 Gelsinger died
on September 17, 1999, 98 hours following gene transfer.
An autopsy and subsequent studies indicated that his death was
caused by a fulminant immune reaction (with high serum levels of
the cytokines interleukin-6 and interleukin-10) to the adenoviral
vector.1 Substantial amounts of the vector were found not only in
his liver (as expected) but also in his spleen, lymph nodes, and bone
marrow. According to an NIH report on adenoviral safety and
toxicity that was prompted by Gelsingers death, The data suggested that the high dose of Ad [adenoviral] vector, delivered by
infusion directly to the liver, quickly saturated available receptors . . . within that organ and then spilled into the circulatory and
other organ systems including the bone marrow, thus inducing the
systemic immune response.19 The report added, Although the Ad
vector used in the OTC trial was incapable of replicating, the capsid
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Figure 10.1. Jesse Gelsinger, June 22, 1999. Having just been screened
for participation in the Ornithine Transcarbamylase Deficiency clinical
trial, Jesse Gelsinger was ready, just like Rocky Balboa was ready for
battle, to help advance treatments for his disease, says Jesses father, Paul
Gelsinger. Jesse had no real idea of the concealed dangers involved in
what he was about to do, nor of the ethical awareness his death would
bring. Source: Mickie Gelsinger and Paul Gelsinger. Reproduced with
permission.
proteins encoating the vector [the shell of the vector] likely contributed to the participants immune response.
In October 2003, the research team published a report on the
unexpected and tragic consequences of Jesse Gelsingers participation in this trial.1 They concluded that his death pointed to
the limitations of animal studies in predicting human responses,
the steep toxicity curve for replication defective adenovirus vectors, substantial subject-to-subject variation in host responses to
systemically administered vectors, and the need for further study
of the immune response to these vectors.1
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Therapy. He continued as chairman and professor of the Molecular and Cellular Engineering Department. The institute closed in
the summer of 2002.
The University of Pennsylvania also revised its conflict of interest policies. In April 2003, a policy on financial disclosure and
presumptively prohibited conflicts for faculty participating in
clinical trials became effective.37 An earlier version had been used
as an interim policy. The policy prohibited clinical investigators
from maintaining certain significant financial interests such as
service on the board of directors or as an officer of a company or
entity that sponsors a clinical trial, significant equity interest in the
sponsor, or ownership of a proprietary interest in the tested
product. The policy defined significant equity interest as
[A]ny ownership interest, stock options, or other financial
interest whose value cannot be readily determined through
reference to public prices (generally, interests in a nonpublicly traded corporation), or any equity interest in a
publicly traded corporation that exceeds $10,000 (or exceeds
5% ownership) during the time the clinical investigator is
carrying out the study and for 1 year following the completion of the study. Interest in any publicly traded mutual
fund is excluded.
Like policies at many academic medical centers, Penns policy
allowed for exceptions on a case-by-case basis when there are
compelling circumstances. The policy defined compelling circumstances as facts that convince the [Conflict of Interest
Standing Committee] that an investigator should be permitted to
participate in a specific trial in spite of a Significant Financial
Interest. Relevant information includes the nature of the research; the magnitude of the financial interest; the extent to which
the financial interest could be influenced by the research; the
degree of risk to human subjects; and whether the interest is
amenable to management.37
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ble for all aspects of the study. It added, While you assert that
you delegated many aspects of the subject recruitment and subject
management to others, you were the responsible leader of the
investigational team. Indeed, you were present when prospective
subjects cases were discussed, and when protocol modifications
were considered at the OTCD team meetings.45
Following investigations by the Office of Criminal Investigations at the FDA and the Office of Inspector General at the DHHS,
the Department of Justice brought civil charges against the University of Pennsylvania, the Childrens National Medical Center,
Wilson, Batshaw, and Raper. The government alleged that the investigators and their institutions violated the federal False Claims
Act by making false statements and claims in connection with
grant applications and progress reports to the NIH, submissions to
the FDA, information supplied to the IRBs that had oversight over
the research, and by failing to obtain proper informed consent.
In February 2005, the government reached civil settlements
with the investigators and institutions.40 The institutions and investigators did not acknowledge the governments allegations and
maintained that they acted appropriately and within the law at all
times. The investigators did not take responsibility for Gelsingers
death. The University of Pennsylvania agreed to pay a fine of
$517,496 and to increase IRB oversight of clinical research and
training for investigators and clinical coordinators. The settlement
agreement outlined the steps the university had taken to promote
safety in clinical research. For example, between fiscal years 1998
and 2005, the number of full-time employees of the Universitys
Office of Regulatory Affairs, which is responsible for staffing the
IRBs, increased from 5 to 23. In a written statement, the university
said, Out of this tragedy has come a renewed national effort to
protect the safety of those who help to advance new treatments
and cure through clinical research. The Childrens National
Medical Center agreed to pay $514,622 and to increase its IRB
budget and staff.
Wilson continued to work at the University of Pennsylvania.
The agreement terminated the FDAs administrative proceedings
against him. Wilson agreed not to serve as a sponsor of a clinical
trial regulated by the FDA or to participate without restriction in
research with humans until February 2010. (He already had not
been involved with human research participants since January
2000.) Wilson also agreed to meet specified educational, training,
and monitoring requirements related to his research and to lecture
and write an article on the lessons of human research participants
protections learned from the OTC deficiency trial. In a written
statement released by Penn, Wilson said, In the last few years,
I have focused my research on the discovery and design of new
gene-transfer vectors for gene therapy and genetic vaccines.
Reaching this agreement means that I may continue to devote
myself fully and without restriction to my laboratory and that
I may conduct clinical research when it would be appropriate
for scientific advancement. Batshaw and Raper agreed to lesser
restrictions.
Enduring Legacy
More than eight years after Gelsingers death, the case remained
sensitive for the University of Pennsylvania. Despite repeated requests, neither Wilson nor any of the university officials with
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Brennan, litigation may help injured subjects obtain compensation. However, it is also likely to lead IRBs to adopt a more
legalistic, mechanistic approach to ethical review that does not
further the interests of human subjects or scientific progress.50
In response to the Gelsinger case, the American Society of
Gene Therapy revised its conflict of interest policies.51 The Association of American Medical Colleges issued guidelines for
oversight of both individual and institutional financial interests
in human subjects research.52,53 In 2004, after years of consideration, DHHS issued guidance on financial relationships and
interests and human subject protection.54 The department recommended that IRBs, institutions, and investigators consider
whether specific financial relationships create financial interests in
research studies that may adversely affect the rights and welfare of
subjects. Among the questions to be addressed were, What financial relationships and resulting financial interests could cause
potential or actual conflicts of interest? and At what levels
should those potential or actual financial conflicts of interest be
managed or eliminated?54
Despite the various reports and institutional changes following Gelsingers death, it can be argued that nothing has really
changed. Review boards and other oversight mechanisms can do
only so much. As of 2007, Congress had enacted no legislation to
make the system for protecting research participants more efficient
and effective. There had been no new federal regulations. For example, according to David Blumenthal, the guidance from DHHS
about financial relationships is notable for the qualified nature
of its recommendations, which are not backed by any regulatory
authority.55 In addition, improvements in the federal oversight
of research primarily affect federally funded programs. With the
exception of research involving new drugs and medical devices
that is under the jurisdiction of the FDA, there is no requirement
that participants in privately sponsored research receive the same
protection that federal regulations provide.47 The National Bioethics Advisory Commission concluded in 2001 that the difference in protection was ethically indefensible and a fundamental
flaw in the current oversight system.48 This situation remains
unchanged. Although it might seem that that research subjects
should be safer than they were before Gelsingers death, there is no
way to know for sure.
Ethical Issues
The issues raised by the Gelsinger case have a common theme. In
their zeal to help patients with a life-threatening disease, leading
researchers at one of the premier academic medical centers in the
United States lost their focus. They overlooked warning signals
that the experimental intervention was not safe, with tragic, fatal
consequences. The ethical issues relate to the selection of the research subjects, informed consent, adherence to the research protocol, and financial conflicts of interest.
The concerns about the selection of research subjects are
discussed earlier in this chapter. Although adults with mild OTC
deficiency and no mental impairment could provide informed
consent, participation in the trial may have placed them at unnecessary risk. New treatments for OTC deficiency were urgently
needed for patients with severe disease, not mild disease. Both the
enrollment of adults with mild disease or newborns with the lethal
form of the disease can be justified, and both positions can be
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criticized. As a Phase I study of dosage and safety, the Penn experiment was not intended to evaluate the therapeutic effectiveness of gene transfer for OTC deficiency. It is easy to criticize
decisions after a tragedy. There was a rationale for the enrollment
criteria, and many oversight groups approved the protocol.
The case underscores the responsibilities of investigators to
properly obtain informed consent, to clearly disclose all the risks
of research, to adhere to the research protocol, to keep good records, and to communicate promptly and completely with IRBs
and regulatory agencies.13 It also underscores the obligations of
review boards and regulatory agencies to provide effective oversight of research.
There is no evidence that the financial interests of the University of Pennsylvania and Wilson in the success of the research
had any relation to Gelsingers death. Nonetheless, the existence of
their financial interests inherently created uncertainty about their
motives. Even if their motives had nothing to do with making
money and their financial incentives had nothing to do with the
conduct of the study, there was no way that either Penn or Wilson
could effectively respond to the charge that the research was
pursued for financial gain. The informed consent document included a statement about the financial interests of Penn, Wilson,
and Genovo in a successful outcome from the research involved
in this study, although it did not indicate what the financial interests were, or their magnitude.10 It can be argued that although
disclosing this information to subjects was preferable to not disclosing it, the conflicts did not have to exist in the first place. A key
question is whether Penn or Wilson should have been allowed to
have these financial interests at all, or if the clinical trial should have
been conducted by other investigators or at another institution. An
IRB or a conflict of interest committee could require that financial
conflicts be eliminated.
Cooperation between academic medical centers and industry
can advance medical knowledge and speed the development of
new treatments and technologies. Financial relations, however,
complicate this cooperation. Some experts consider a presumption that financial conflicts should be eliminated, not managed, to
be too draconian because it will impede vital research. Others argue that less radical approaches are doomed to fail. According to
Marcia Angell, a former editor-in-chief of the New England Journal
of Medicine,
[O]ur society is now so drenched in market ideology that
any resistance is considered quixotic. But medicine and
clinical research are special, and I believe we have to protect
their timeless values of service and disinterestedness. Patients should not have to wonder whether an investigator is
motivated by financial gain, and the public should not have
to wonder whether medical research can be believed. The
only way to deal with the problem is to eliminate it as much
as possible. 56
Gene transfer is still in its infancy. It continues to hold great
promise, but the risks and benefits are still being discovered. For
example, encouraging results with gene transfer in the treatment
of X-linked severe combined immunodeficiency (X-SCID), a devastating disease of young children, were followed by reports of a
leukemia-like disorder in some of the research participants. One
of these children died in 2004. According to Philip Noguchi of the
FDA, the developments are a reminder that the manipulations
needed to create gene therapy add enormous complexity to con-
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