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Put on Hold
at Gene-Therapy Lab
Four months after the death of
a gene-therapy-study participant at Penn, the U.S. Food and Drug Administration
halted clinical trials at the Institute for Human Gene Therapy, which oversaw
the experiment. Citing numerous serious deficiencies in the oversight
and monitoring procedures of that study designed to test a treatment for
an inherited liver disorderthe agency placed it and seven other investigational
new-drug applications at the IHGT on clinical hold. Several weeks
later, as the Gazette was going to press, the IHGT released a lengthy
response that acknowledged some lapses in protocol but maintained that those
deviations did not lead to the death.
Dr. James M. Wilson,
director of the Institute for Human Gene Therapy.
a January letter, the FDA explained that its two-month inspection had prompted
concerns that subjects enrolled in other studies at the institute would be exposed
to a significant and unreasonable risk. The agency also released a list
of 18 observations from its probe, raising red flags about the labs
adherence to regulations governing informed consent, patient-eligibility, record-keeping
patient, 18-year-old Jesse Gelsinger of Tucson, Ariz., died on Sept. 17 of acute-respiratory-distress
syndrome and multiple-organ failure, four days after he was injected with a
genetically modified cold virus at Penns Medical Center. He had suffered
from ornithose transcarbamylase deficiency (OTCD), which hindered his bodys
ability to process ammonia and had caused him to go into a coma on three occasions.
He had been managing his disease through a restricted diet and large quantities
of medicine. The IHGTheaded by Dr. James M. Wilson, the John Herr Musser
Professor and Chair of Molecular and Cellular Engineeringhad designed
a therapy to deliver a potentially corrective gene to the liver of OTCD patients.
The trial in which Gelsinger participated was to test the drugs safety;
it was halted immediately after he died [Gazetteer, November/December,
January/February]. An FDA spokeswoman said the trials will only be resumed when
the IHGT proves that it can carry them out with the proper amount of oversight.
to the FDA, the studys sponsors:
- Didnt adequately document the process of informed
consent for some of the patients.
- Did not submit to the FDA a
report of the death of two monkeys in a similar study in a timely manner.
The paperwork was filed Oct. 27, 1999, nearly a year after the animal study
- Failed to halt the human study
and immediately notify the FDA after two previous patients developed severe
- Didnt have documentation
for the training of study staff.
- Failed to properly document
the eligibility of all 18 patients when they were admitted into the study.
Eligibility forms were not developed until the fall of 1999, after Gelsingers
- Included Gelsinger in the study
even though the ammonia levels in his blood were too high to meet the eligibility
criteria the day before the drug was administered.
- Admitted Gelsinger to the study
even though the protocol required that the next patient be a female.
to the FDAs action, Dr. Judith Rodin CW66, president of the University,
assembled a committee of six scientists from peer institutions around the country
to review the practices at the IHGT. The committee was to report back to her
in about eight weeks and recommend remedial steps. We intend for our research
programs, particularly those involving human subjects, to meet the highest standards,
Rodin said. Nothing less is acceptable.
February 14, the IHGT issued a 28-page response to the FDAs inspectional
observations. It acknowledged that the FDA has identified important
issues arising out of the OTCD trial, and that the FDAs observations
and insights have been of great value in improving the IHGTs monitoring
efforts. It also vowed to work closely with the FDA to implement new clinical-trial
procedures to improve its monitoring and provide additional patient
safeguards to the fullest extent possible. Saying that it believed from
the very outset that complete candor and cooperation with all relevant governmental
bodies provided the best hope of learning from this tragedythe IHGT
pointed out that it had quickly notified the proper authorities of Gelsingers
worsening condition and death, and immediately and voluntarily halted
the IHGT also asserted that, as deeply regrettable as Jesse Gelsingers
death was, it was simply not foreseeable based on informed medical judgment
and the best scientific information available at the time.
the key points in the IHGTs response were that:
- Gelsinger was properly enrolled and his plasma-ammonia
level did not cause his death, and that neither the FDAs
observations nor its public comments have asserted any such causal link.
The day before the drug was administered, Gelsingers ammonia level had
risen to roughly twice the level recorded at his enrollment in June (from
45ÁM to 91ÁM). However, in consultation with another investigator who
is a recognized OTCD expert, the IHGTs investigator carefully
assessed Gelsingers condition prior to the vector infusion, and concluded
that his plasma-ammonia levels had been transiently elevated and that his
clinical condition was consistent with participation in the study, a conclusion
supported by plasma-ammonia and glutamine measurements taken after infusion.
- Every patient gave informed
consent to participate. In lengthy meetings with patients,
the investigators reviewed the novel and experimental nature of vector
infusion, and made absolutely clear the risks of the trial, including the
possibility of injury and life-threatening liver damage. They also explained
that the study was explicitly a safety study and not a therapeutic trial.
Those points were echoed in the clearly written, multi-page document
that formed the basis of these meetings, and which included the statement
We do not expect you to benefit directly from this study in boldface
- Each patients eligibility
was documented at the time of his or her enrollment in the study,
despite the FDAs observation that a patient-eligibility form was developed
after the study was placed on clinical hold. Regrettably, that observation
has been misinterpreted to suggest that the IHGT attempted to document eligibility
only after the fact, while those documents were actually checklists
used as part of the review undertaken after Gelsingers death, and were
never intended to substitute for contemporaneous documentation of eligibility
- While comprehensive information
about the side effects suffered by two patients was submitted in January 1999,
several months lateand while the IHGT should have discussed them
with the FDA before proceedingthe FDA had already had these
comprehensive reports in its possession for over six months when, in August
1999, it expressly approved the continuation of the trial into the sixth cohort
of patients, which included Gelsinger.
- The sequence of Gelsingers
participation in the trial was appropriate and reflected
the investigators good-faith understanding of the guidelines, as well
as their experienced clinical judgment. At the time of Gelsingers
infusion, none of the three previous male patients had exhibited a significantly
different response to the infusion than the female patients in their respective
cohortsand the FDAs observations do not assert, and
nothing in his medical chart suggests, any causal link between Gelsingers
gender and his death.
- While the IHGT maintained numerous
documented procedures governing clinical processes, they would
have been improved by the adoption of more formal Standard Operating Procedures.
- The deaths of two monkeys occurred
during an unrelated study using different genetic material for the treatment
of a different disease, colorectal cancer. A third monkey infused with the
same generation of the vector used in the OTCD trial exhibited only signs
of mild illness. Furthermore, all three monkeys received dosages approximately
17 times greater than the highest dose administered in the OTCD trial.
If the FDAs allegations
prove to be founded, then the suspension is appropriate, said Dr.
Arthur Caplan, director of Penns Center for Bioethics and the Trustee
Professor of Bioethics in Molecular and Cellular Engineering, before the IHGT
issued its response. But what is really needed, he suggested, is to have
a better system for monitoring human-subjects protection across the boardnot
just for gene therapy.
Satisfying the FDA is not the IHGTs only challenge
at this point. The National Institutes of Health is also investigating the OTCD
trial to determine whether federal patient-safety regulations were violated.
The entire field of gene therapy, as well as the regulatory
process, came under scrutiny at a U.S. Senate hearing in February. Three hours
of testimony presided over by Sen. Bill Frist, R-Tenn., chairman of a subcommittee
on public health, revealed a system in which scientists are slow to report adverse
effects and regulators are too understaffed to pick up on protocol violations.
There is a system-wide problem, said Frist, that we may have
just touched the tip of the iceberg on.
In fact, it was revealed that out of 691 reports submitted
to the NIH regarding serious adverse events in gene-therapy experimentsfrom
abnormal clotting to plummeting blood pressure only 39 were filed on time.
The most emotional message at the hearing came in testimony
from Jesse Gelsingers father, Paul Gelsinger. Although he had been fiercely
supportive of the OTCD researchers at first, he now believes he was misled about
the risks and benefits of the procedure his son underwent and has hired an attorney.
He said that researchers downplayed potential side effects and told him that
another participant in the trial had benefited from the treatment, which turned
out to be false. Gelsinger said, We gave consent, but in no way was it
Gelsinger also criticized the FDA for not doing its part
to sufficiently monitor experiments.
I am all for the continued development of gene therapy,
but it must be better regulated, he said. The concern [of gene therapy]
should not be on getting to the finish line first, he added, but
on making sure no unnecessary risks are taken, no lives filled with potential
and promise are lost forever, no more fathers lose their sons.
Just before the IHGTs operations were put on hold
by the FDA, the University had announced it was forming a committee of 10 faculty
members to review carefully and completely all aspects of Penns
research using human subjects, which received about $213 million in funding
in the 1999 fiscal year. Provost Robert Barchi Gr72 M72 GM73,
who organized that committee, expects it to complete its work near the semesters
end and report to Rodin soon afterward.
Although Jesses death is of paramount concern
to us, the provost explained, the internal review committee would
have been formed in any case. When I first became provost last January, I stated
as one of my goals that a complete review of our research operation was necessary
given the extraordinary rate of increase in our research funding over the last
decade. We need to make certain that our investigators are doing everything
possible to address risks and to protect volunteers in clinical trials.
Noting the recent suspension of research at a number of
other institutions, including Duke University, Caplan said, Human-subjects
protection has gotten lax in all fields, and needs to be tightened
in every institution in all areas around the entire country.
In a Feb. 6 commentary in the Inquirer, Rodin discussed
the steps Penn was taking to ensure that its research would meet the strictest
standards, while explaining that it is impossible to remove all risk from human
Penn is committed to continuing to conduct research,
Rodin wrote. In that light, we will learn from a death while we continue
to mourn it. We will share what we have learned
And we will emerge strengthened
in our ability to translate what we discover in our laboratories into longer,
healthier lives for everyone.
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